Head First Copyright © 2017 David Tomen

This book is intended to supplement, not replace, the advice of a trained health professional. If you know or suspect that you have a health problem, you should consult a health professional. The author and publisher specifically disclaim any liability, loss, or risk, personal or otherwise, that is incurred as a consequence, direct or indirectly, of the use and application of any of the contents of this book.

All rights reserved. In accordance with the U.S. Copyright Act of 1976, the scanning, uploading, and electronic sharing of any part of this book without permission of the publisher constitute unlawful piracy and theft of the author’s intellectual property. If you would like to use material from the book (other than for review purposes), prior written permission must be obtained by contacting the publisher at [email protected]. Thank you for your support of the author’s rights.

NootropicsExpert.com 2001 Atlantic Shores Boulevard, Hallandale Beach, FL 33009 First Edition: January 2017

Table of Contents

Introduction 1 Top 7 Brain Hacking Principles 6 There is No “Magic Pill” 6 Dosage and Synergy 7 Start Slow and Low 8 Avoid Tolerance 9 Choosing the Right 11 Stay Safe 12 Evaluating your Nootropic Stack 13 Your Brain is Part of a System 13 How Your Brain Works 15 Brain Architecture 15 Cognitive Architecture 16 Cerebral Cortex 17 The Gatekeepers 17 Neurons & Synapses 18 Cell Membranes 18 Brain Cell Signaling 19 Neurotransmitters 20 Glutamate 21 GABA 21 22 Dopamine 22 Epinephrine & Norepinephrine 23 Serotonin 23 Improve Your Memory with 25 Types of Memory 25 List of Nootropics 28 Acetyl-L- 28 Alpha GPC 33 Alpha- 38 44 Artichoke Extract (Luteolin) 49 Ashwagandha 54 Bacopa Monnieri 60 Cat’s Claw 65 70 Choline Citrate 75 CDP-Choline () 81 Centrophenoxine 86 91 Coenzyme Q10 (CoQ10) 96 102 DHEA 108 DMAE 114 5-HTP 120 Forskolin 127 GABA 133 Ginkgo Biloba 138 143 Gotu Kola 150 Huperzine-A 155 161 169 L-Carnosine 175 L-DOPA 181 186 L- 191 Lion’s Mane 197 L-Theanine 202 208 213 N-Acetyl L-Cysteine 219 N-Acetyl L-Tyrosine 226 NADH 233 239 246 Noopept 252 Oat Straw 259 264 270 Phenylalanine 277 284 (PC) 290 Phosphatidylserine (PS) 295 302 Piperine 308 313 PQQ 320 326 Pterostilbene 332 Resveratrol 339 Rhodiola Rosea 346 SAM-e 353 St. John’s wort 360 Sulbutiamine 369 Tryptophan 375 Turmeric 383 Uridine Monophosphate 391 Vinpocetine 398

Vitamin B1 (Thiamine) 404

Vitamin B3 () 411

Vitamin B5 () 420

Vitamin B6 (Pyridoxine) 427

Vitamin B8 () 434

Vitamin B9 () 441

Vitamin B12 (Cobalamin) 448 Nootropic Stack Recommendations 456 Best Nootropics for Cognition, Thinking and Decision-Making 457 Best Nootropics for Memory 458 Best Nootropics for Depression & Anxiety 460 Best Nootropics for Energy (physical & mental) & Motivation 461 Best Nootropics for Brain Repair and Maintenance 463 How to Create the Best Nootropic Stack 465 The Most Effective Nootropic Stack for You 466 Your First Nootropic Stack 466 Nootropics for Memory 467 Nootropics for Anxiety and Depression 468 Nootropics for Energy and Motivation 470 Nootropics for Brain Repair and Maintenance 471 Conclusion 472 My Nootropic Stack 473 Nootropics Glossary 474 References 493

Introduction

bout 5 years ago, I came home to our 4th floor condo after taking my A dog for her noon walk. Oreo is an 8-pound black Chihuahua with one white paw. Thus her name. We walk 3-times a day. And had done for the last 3 years since she was a puppy. Except this time, I came home for lunch and a couple of minutes later heard a knock at the door. Our neighbor from the 2nd floor had Oreo in her arms. And asked, “Is this your dog”? Somehow, Oreo and I were separated on the elevator coming home. And I hadn’t noticed she was missing when I walked through our door.

Can you Draw a Clock? Losing my dog between the 1st and 4th floor was not a one-time, chance occurrence. I was diagnosed Adult ADD about 10 years ago. Up to then I had no idea why I had a problem with focus all my adult life. I bought and read dozens of self-help books on how to focus. Depression because I couldn’t focus. And lost promotions from yearly management reviews showing I wasn’t “focused”. My doctor prescribed Ritalin and it was like someone turned on the light switch in my brain. Several years after the ADD diagnosis I ended up in the ER. What my wife feared was a heart attack turned out to be hypothyroidism. A non-functioning thyroid came with chronic fatigue syndrome, severe brain fog, memory loss, fibromyalgia, chronic pain, and adrenal fatigue. We endured endless visits to specialists and renowned hospitals including the Cleveland Clinic. Along with episodes of not remembering dates and ap- pointments, a failing business, a crumbling marriage, doctors, endocrinologists, neuroscience specialists and therapists. Two unrelated neurologists tested me for , and early-onset Al- zheimer’s disease. One of the tests was the “Mini-Mental State Exam”. The doctor asked a series of questions designed to test a range of everyday mental skills. The maximum MMSE score is 30 points. A score of 20 to 24 suggests mild 1 David Tomen dementia, 13 to 20 suggests moderate dementia, and less than 12 indicates severe dementia.

I got 30 points on every test which meant I didn’t have dementia.

Mini-cog During the mini-cog, a person is asked to complete two tasks: 1. Remember, and a few minutes later, repeat the names of three common objects. 2. Draw a face of a clock showing all 12 numbers in the right places and a time specified by the examiner.

The results of this brief test can help a physician determine if further evalu- ation is needed.1 I’m a writer, and not an artist. But was able to draw a near perfect clock. So it was becoming increasingly clear that this was not not dementia, or Alzheimer’s. But clearly my brain was not working nearly as well as it should. The medical bills kept stacking up, and the doctors had all but given up. There was nothing wrong with me according to mainstream medicine. But my life was falling apart and I had to make a decision. Either figure this thing out. Or give up and die. I decided there must be a better way.

Nootropics Saved My Life I’m a Virgo. And this means I’m very methodical in my approach to life. There had to be another answer to my cognitive problems. And thus began years of research and experimenting. I had to find out if there was an alternative way to beat severe brain fog, memory loss and depression. Ritalin helped me focus. But was not helping in the memory and thinking department. Years of searching websites, reading stacks of books, and combing through the forums. And little by little, I was able to get my brain working again. With determination and time, it was working better than ever before. With the right combination of supplements and lifestyle changes, I’ been able to turn my life around. My business is more profitable than ever, my relation- ship is better than the day we got married, and my brain is firing on all cylinders. And I continue to tweak and refine every area of my brain and cognition. 2 HEAD FIRST Who This Book is For So if you’re dealing with ADHD. Or are not happy with your life because of brain fog, low energy, moodiness, difficulty sleeping, memory loss or just a general feeling of malaise… this book could be your way back. Nootropics and neuroscience are finally coming of age. Researchers and ordinary neurohackers like us are beginning to understand a lot about the brain. And we’ve found that several things follow from taking care of your head first. Your quality of life is tied to how well your brain functions. If you give your brain what it needs, and slow down brain aging, boost your memory and alertness so you can think faster on your feet, and your brain begins to function the way it was designed or better – everything changes. My life, and the lives of tens of thousands of neurohackers is certainly testa- ment to that! Think about this for a moment. You go to the dentist once a year to see how your teeth are doing. But you don’t think about going to your neurologist once a year to see how your brain is doing. Clearly your brain is more important than your teeth. You can get false teeth. But replacement brains are simply not yet available. One big lesson we have learned is your brain is not going to get better on its own. Researchers at Simon Fraser University in Canada studied 3,305 volunteers aged 16 to 44 years. They concluded that our brains start going south at age 24.2 This means that even if you’re living an optimal lifestyle, eating right, exercis- ing, getting enough sleep, and breathing clean air – your brain health on average starts to decline in your early 20’s. So this book is not just for neurohackers looking to tweak their brain for optimal performance. This book is for you if you want to do better in any area of your life. Including work, athletics, relationships, and spiritual life. Even your body’s overall physical health depends largely on how well your brain works. Take care of your head first and your life gets better.

What is Your Brain Hacking Goal? This is an important question because when it comes to brain health and optimization, your options can be so overwhelming that you’ll put this book down. And never get started. Nootropic supplements can boost alertness, concentration, focus, memory and recall. And can reduce anxiety and depression. Some nootropics have even been proven effective in combating serious neurological diseases like ADHD, ADD, Alzheimer’s, Parkinson’s, Obsessive Compulsive Disorder (OCD), and Major Depressive Disorder. So my advice is to first choose one area of your life that you’d like to improve. Maybe you’d like better memory. Or you’d like a healthier, more effective alterna- 3 David Tomen tive to treating depression than prescription SSRI’s. Maybe anxiety is destroying your quality of life. Nearly every area of your life can be improved with the right nootropic supplement.

How to Use this Book This book is divided into sections that are easy to find and navigate. The first part of the book (Top 7 Brain Hacking Principles) explains how to get started with nootropic supplements. What to expect and how to choose the right supple- ment. General principles that will help keep you safe. And how to evaluate your progress as you try different supplements. The next chapter talks about “How Your Brain Works”. I’ve done my best to keep the neuroscience as simple to understand as possible. While giving you the fundamentals of what’s going on in your brain. And how nootropics affect each area for desired results. The next section is the longest, and provides you with a list of 72 nootropic supplements. Each supplement has an overview of what it is and what it helps in your brain, what goes wrong and why you may need it, how the nootropic feels when you take it, plenty of clinical research to back up what I’m saying, recom- mended dosage and side effects. Including interactions and where you need to be cautious if you’re using any prescription medications. Most of the nootropic supplements I talk about in this book are available at your local vitamin shop or health food store. The can be purchased online from several reputable supplement suppliers. One thing you’ll notice is I don’t talk much about “Smart ” that are commonly referred to in the press as nootropics. However, you may see me refer- ence ADHD stimulants like Adderall or Ritalin. And possibly mention other prescriptions drugs like Modafinil. But experienced neurohackers make a distinction between “Smart Drugs” and nootropics. And that distinction is reflected in this book. I want you to have the best experience possible while optimizing or repairing your brain. And not have to beg your family doctor for a prescription. The section after the long list of individual nootropic supplements in this book provides recommendations for specific brain-hacking goals. I talk about nootropics that have been shown to help specific brain func- tions. This will help you choose between the various supplements you’ve just read about. Brain functions including decision-making and thinking, anxiety and depression, energy and motivation, memory, and antioxidants and repair. The final chapter provides instructions on “How to Build Your Nootropic Stack”. Think of that chapter as a recipe that when assembled, will help you achieve whatever you’re trying to fix or optimize. 4 HEAD FIRST The very end of the book includes a glossary and index. The glossary can be handy to look up words you’re unfamiliar with. And the index of course is a ready reference to the entire book. This book is not meant to be read cover-to-cover like a novel. It’s more like a reference and repair manual for your brain. And the supplements that can help it. I suggest you keep this book handy as you first build your nootropic stack. And refer to it when you hear about something new that you think you’d like to try. Bookmark it, highlight it, write in the margins, circle things – do whatever you need to do to make this book work for you. The next section are my Top 7 Brain Hacking Principles. To get you started in hacking your own brain. And keeping you safe while you’re experimenting. Good luck. And remember. Fix your head first. And most of the other important things in your life will fall into place.

5

Top 7 Brain Hacking Principles

alk into any Vitamin Shoppe, drug store or shop online and you’ll W have thousands of different supplements to choose from. Go to the brain optimization section, and your selection is reduced to a few dozen nootropic supplements. With this smorgasbord of racetams, , herbs, amino acids, and pep- tides within easy reach, you may be tempted to buy a variety of them for your nootropic stack. But I recommend taking a more cautious approach to hacking your brain. Ideally, you should be talking to your health-care provider to make sure these supplements will not interact with any of your prescription medications. However, let’s get real, and consider the state of medicine in many countries including the United States. Your doctor likely has no idea what you’re even talking about. Especially when it comes to natural nootropic supplements. But fear not because we’ve got you covered. In the Chapter “Nootropics List”, each nootropic has a section detailing side effects including interactions with many prescription medications. But don’t rely exclusively on the medication interactions included in this book. Each nootropic could have many more interactions than listed in this book. Please do your own research online for each prescription medication you are taking. And review the contraindications, side effects & drug interactions, warnings and precautions lists for each medication. See how they work in your body and brain. And if there could be any kind of problem combining it with any of the nootropics in your stack.

There is No “Magic Pill”

Bradley Cooper’s character in the blockbuster film Limitless took just one pill called NZT-48. And suddenly had perfect recall, could access the tiniest of snip- pets of past information, and turned them into advanced powers of deduction. His whole brain came alive. Making him seemingly super-human. 6 HEAD FIRST If you are looking for your version of NZT-48 in nootropics, or any supple- ment or prescription drug, it doesn’t exist. It can’t exist. And here’s why. Your brain is arguably the most complex thing in the entire universe. The number of biochemical and bioelectrical processes going on in your brain right now, are mind-blowingly complicated. We have been conditioned by Western medicine in our modern society to choose one pill to fix a health problem. Every disease or health problem has a separate pill. And if the pill you’re prescribed causes depression, you’ll get a prescription for an antidepressant. Of course, the antidepressant doesn’t work. Or makes you sleepy. So you get another pill to keep you awake. And it goes on and on and on… Let’s put a stop to this nonsense right now. And look at how they’ve done it for several thousand years in the Far East. Healers in China and India know that your body and brain need a variety of nutrients in small doses instead of one high dose nutrient or drug. Ancient Chinese medicine, and Ayurveda from India, have known this for millennia. Their formulations include small amounts of several natural ingredients. Eastern doctors learned long ago that many medical conditions respond better to a combination of several active nutrients, instead of just one. Taking a high dose of one nootropic supplement can upset the delicate balance of the complex biochemical interactions in your brain. Western medicine is always looking for that one “magic pill” that alone will cure all ills. One pill to cure Alzheimer’s. Another pill to cure dementia. Yet another pill to cure depression. But your body and brain is far too complicated, with far too many processes going on every instant. One pill is not the answer to everything that can go wrong in your brain. Or that causes disease. With nootropics and brain optimization we must intelligently combine a variety of solutions.

Dosage and Synergy

One of the most critical things to understand in using nootropics is that your stack must work synergistically. Because each supplement has a different mecha- nism of action in your brain and body. And each supplement in your stack should support the other nootropics in your stack. For example, acetylcholine’s function in your brain is needed for encoding new memories, reasoning, concentration, cognition and growth of new neurons (neurogenesis). Once acetylcholine does its job, the enzyme comes in and breaks down acetylcholine. 7 David Tomen You can increase acetylcholine in your brain by adding Alpha GPC, CDP- Choline or Acetyl-L-Carnitine (ALCAR) to your stack. But if you use more than one acetylcholine (ACh) precursor or supplement, you can boost ACh too much. Excess ACh can cause depression, irritability, muscle pain and a host of other problems. Also keep in mind that a nootropic like Huperzine-A inhibits - terase. Which increases ACh levels in your brain. So if you are using Hup-A in your stack, you may want to cut back on your dose of Alpha GPC, CDP-Choline or other choline supplement. Many nootropic supplements either increase ACh or inhibit acetylcholinester- ase. If you take more than one choline supplement, you’ll hit a ceiling and not get a synergistic effect. The same holds true for other neurotransmitters. And many other supple- ments explored in the Nootropics List section of this book.

Start Slow and Low

Every nootropic has an ideal dosage for you. If you take more than your brain needs, you could have a negative reaction. And depending on the supplement, your reaction could include feeling anxious, brain fog, depression, slow thinking, irritability, restlessness, or feeling overly stimulated. This is particularly dangerous when boosting dopamine or serotonin too much. I’ll cover these neurotransmitters in more detail in a few minutes in the section “Stay Safe”. Some nootropics, like most of the B-Vitamins are used by your body and brain. And the excess is excreted in your urine within a few hours. But other nootropics have a cumulative effect. And build up over time. A classic example of this effect is drinking too many cups of coffee. One or two cups give you an energy boost. But 3, 4, or 5 cups can have a cumulative effect and leave you irritable or feeling anxious. Combining a stimulant like with certain nootropics which also have a stimulant effect will produce similar symptoms of anxiety or irritability. And each of our bodies is unique. So you can’t predict how your body and brain will react to a supplement unless you try it. Start with a low dose of any new nootropic you’re adding to your stack. And gradually increase it over the next few days to see how your body reacts. Sometimes you’ll see recommendations of higher doses for certain noot- ropics. Especially on supplement packaging. These dosages are often based on clinical studies. Researchers were using a high dose to elicit a specific response within the time parameters of the trial. If you intend on taking the same nootropic over an extended period, it’s 8 HEAD FIRST very possible that you will need a fraction of the dose used in the trial. You’ll notice this as you read through forum threads. People experience a wide range of responses to different amounts for each nootropic. Our body and brain are unique. And influenced by genetics, the food we eat, what we drink, environmental toxins and a host of other things that affect us. Starting low and slow with any nootropic will minimize side effects. With experience, you’ll soon learn how much of each nootropic produces the best effect for you. You should also be skeptical of dosages listed on product labels. This advice goes for nootropics and even your prescription medications. Supplement compa- nies and doctors don’t know your body as well as you do. Some people are very sensitive to nutrients and medicines where even a very small dose can produce nasty side effects. It’s OK to break pills in half or quarters, or open capsules and only use a small amount until you see how your body reacts. A small dose may be all you need. You’ll often see in nootropics forums the letters YMMV. It stands for “Your Mileage May Vary”. Which means your reaction to a nootropic could be very different to the person standing next to you. I’ll say it one more time. Then leave it alone. For now. Start low and slow.

Avoid Tolerance

With nootropics and many prescription drugs, developing tolerance means that over time your body doesn’t respond to that substance as well as when you first started using it. This doesn’t always mean it suddenly stops working. It just seems to become less effective over time. Not all nootropics are susceptible to tolerance. It’s typically an issue with some of the racetams like Phenylpiracetam. Some people have tolerance issues with Sulbutiamine. And Phenibut users can quickly build up a tolerance when using this nootropic. I talk more specifically about tolerance for supplements in the Nootropics List section of this book. Many prescription meds also come with tolerance problems. Particularly stimulants like Adderall and Ritalin. Even many SSRIs used for depression and anxiety. Tolerance is caused in various ways in your brain and body depending on the substance. For example, many have tolerance issues with Adderall. And I’m going to use Adderall to illustrate how this works in your brain because there is some parallel here to understanding the cause of tolerance with some nootropics. Adderall in your brain alters dopamine concentrations and receptor , as well as calcium ion influx at NMDA receptor sites. Constantly triggering an 9 David Tomen excess influx of calcium ions through NMDA receptors alters synaptic plasticity, neuronal connectivity, and could even cause neuron damage. Over time, changes in NMDA receptor function from excess calcium ions could be part of the cause of tolerance. Now this gets a little complicated so stick with me here. Adderall works by boosting certain proteins (TAAR1) and inhibiting mono- transporter molecules (VMAT2) in your brain. TAAR1 agonism decreases firing of dopamine receptors. And increases pro- tein kinase signaling to the dopamine transporter (DAT). This modification of proteins either stops DAT from functioning. Or affects transport of dopamine to the synapse. And VMAT2 inhibition triggers a release of dopamine from presynaptic vesicles into intracellular fluid. This all results in dopamine depletion in parts of your brain. Leading to tolerance due to low levels of dopamine. To make matters even worse, there’s some evidence that Adderall facilitates the expression of CREB (cAMP response element binding protein) in dopamine terminals. This induces the transcription of various genes which may also cause tolerance in some neurohackers. The bottom-line is concentrations of dopamine, norepinephrine and possibly even serotonin are affected by Adderall. But it depletes dopamine the most. Lead- ing to tolerance. And why Adderall over time doesn’t work as well as it once did. Enough of the neuroscience already. My point is, it is these types of shenani- gans in your brain that can be caused by prescription meds and certain nootropics. Using some of these substances can deplete certain neurotransmitters, and the of neuroreceptors. Nootropics and drugs can alter gene expression in brain cells. They can affect hormone levels and cause oxidative stress in brain cells. Receptors are downregulated and you experience synaptic reorganization. And some neurotransmitter transporters decrease. The result is tolerance. So we need a strategy to counteract this affect. But there’s not one blanket approach to avoiding tolerance because each nootropic or drug works differently in your brain. And even differently for different people. Often, the simplest strategy is cycling the substance you are using. Once you feel you’re not getting the affect you once did, it’s time to stop using that nootropic for a while. Allow your brain to recover before you start using it again. Another strategy is compensating for what’s causing that tolerance in the first place. For Adderall, you could add NDMA antagonists like magnesium, or Huperzine-A to your stack. You could upregulate dopamine by using Inositol which increases dopamine D2 receptor density. Or choline which also increases dopamine receptor densities. And even Sulbutiamine which increases the number of dopamine binding sites. 10 HEAD FIRST Personally, I find that using 1000 mg of DHA in the morning, with 800 mg of Aniracetam and 800 mg of Sulbutiamine along with 800 mg of ALCAR every time I take my dose of Ritalin, prevents tolerance. And an extra dose of these nootropics around 3 pm also prevents the stimu- lant crash that normally comes with using a stimulant like Ritalin. My final advice on tolerance is research each nootropic you are using. Find out exactly how it works in your brain. And if there is a potential for tolerance, find out what you can do to avoid it. Comments in forums can be useful too. But you’ll find that every person in a thread has a different opinion on how to avoid tolerance for a nootropic or prescription med. You must decide for yourself by listening to your body and how it’s reacting. That, combined with your knowledge of a nootropic will provide you with a plan of action to deal with tolerance.

Choosing the Right Nootropic

This entire book is about choosing the right nootropic supplement. But here I want to talk about a couple of examples that could help you build your nootropic stack. In the last section, we explored how using certain nootropics or prescription drugs can affect different parts of your brain. Stimulants like Adderall and Ritalin and their kin can deplete dopamine in your brain. Among other issues which we also covered. To replenish dopamine stores in your brain requires finding out what natural substances can help your brain produce more dopamine. And once you’ve made a list of dopamine-producing options, choose one and try it. One strong word of caution. You may have a list of 6 or 8 difference natural compounds that help your brain produce dopamine. Don’t try using all 6 or 8 at the same time. Because if you boost dopamine too much you’ll experience some nasty side effects. Including irritability, aggression, intense sexual feelings and worst case is psychosis. The same goes for boosting any other neurotransmitter or cognitive function in your brain. Carefully choose and dose the nootropic you choose and see how you react. If it doesn’t produce the effects you want, then try something else. You can also have an unpleasant experience by taking a nootropic at the wrong time of day. For example, if you dose a supplement that acts as a stimulant while indoors and strapped to your desk, you could feel restless and irritable. On the other hand, using the same nootropic with stimulant effects during the weekend could give you the energy to enjoy that mountain hike more. Or a more enjoyable bike ride, or time with your kids. 11 David Tomen So it’s not only important to choose the right nootropic, or nootropic stack, but also that you match the right circumstance, day, time or setting. Many of the nootropics discussed in this book act as stimulants. Includ- ing Tyrosine, St. John’s wort, DHEA, choline, ginseng, gingko, coenzyme Q10, SAMe, DMAE and even high doses of . When combined, their effects can be cumulative and lead to overstimulation or insomnia. It took me several years to settle on exactly what I needed in my personal nootropic stack. And my wife gave me a hard time about the money I was spend- ing on supplements every month. But I no longer get complaints about money spent on supplements. Because the result has been a complete turnaround in my health including the bedroom. My income is higher than it has been a very long time. And it keeps on getting better. Experimenting is your key to success in biohacking and brain optimization. Stick with it and the miracles start to happen.

Stay Safe

Earlier in this chapter I touched on the hazards of messing with neurotransmit- ters in your brain. Let’s take a closer look at things to watch out for when using nootropics. Some supplements can accumulate in brain cells, organs and tissues over time. Meaning the more you take, the more they build up in your body. With those types of nootropics, you need less, not more the longer you use it. I personally find I must re-evaluate my stack from time to time. And reduce dosages if I find I’m becoming over-stimulated, or having other side effects. Most of the nootropics I’ve included in this book have positive effects on your brain and mental health. But high doses of some can have nasty effects which I cover in more detail for each supplement in the Nootropics List section. Let’s look at a couple of examples here. We’ll start with dopamine. Dopamine is associated with feelings of pleasure and reward. This neu- rotransmitter plays a vital role in motivation and reward behavior. Drugs, food, and sex are all capable of boosting dopamine levels in your brain. Increased levels of dopamine can enhance your concentration, improve your mood, and even make you more sociable. But combining N-Acetyl-L-Tyrosine (NALT) with Mucuna Pruriens and L-Theanine, which all increase dopamine levels, and you could have issues. Too much dopamine can result in agitation, anxiety, over-amped cognitive function, hyperactivity, insomnia, and even psychosis. Serotonin plays a role in appetite control, mood, learning and sleep. Low serotonin is widely believed to be the underlying cause of depression. But too 12 HEAD FIRST much serotonin can also cause big problems. And this can happen much more easily than you’d expect. Selective serotonin reuptake inhibitors (SSRIs) like Paxil, Prozac, Zoloft, Celexa, and Lexapro are used by millions to relieve depression by boosting sero- tonin levels. But combining one of these SSRIs with nootropics like tryptophan, or 5-HTP, which also boost serotonin, can lead to excess serotonin levels in your brain. Serotonin Syndrome is a real danger, and one I’ve personally experienced. Excess serotonin can cause agitation, restlessness, diarrhea, nausea, vomit- ing, and rapid changes in blood pressure. When serotonin levels are excessively elevated, your headed for Serotonin Syndrome. And it’s much easier than you’d expect to enter this danger zone. Simply combining 5-HTP with an SSRI and you’re headed for trouble. Serotonin Syndrome symptoms include high fever, irregular heartbeat, sei- zures, loss of consciousness and even death. And I’m not kidding. My doctor’s fiancé died from Serotonin Syndrome. Staying safe when using nootropics means knowing exactly how they work in your brain and body. Learning how two or more nootropics interact. And reviewing the contraindications and warnings for every prescription medication you’re on.

Evaluating your Nootropic Stack

Earlier I mentioned that my personal nootropic stack changes from time to time. I find something I want to try, compare it to my current stack, then decide if I need to eliminate something before adding it. As you gain more experience with neurohacking and nootropics, you’ll likely do the same thing. Testing and evaluating are part of the nootropic experience. And key to success with optimizing your brain. Nootropics can have dramatic benefits touching every part of your life. But just because something is within easy reach on a vitamin store shelf doesn’t mean it’s safe to use. You could be that one person in a thousand who has a bad experience. Does it mean that nootropic should be banned and taken off the market? I don’t believe that’s the answer. Each of us must take personal responsibility for our body and brain. And decide what to use to enhance cognition. Or not to use.

Your Brain is Part of a System

When you take the nootropics presented in this book for optimizing your brain, they not only have an effect on your brain, but on many other organs and tissues. 13 David Tomen Now most nootropics I’ve included in this book have positive effects on both physical and cognitive health. But high dosages of some could cause side effects. In some cases, very severe side effects. You’ll find more on precautions and side effects in the chapter Nootropics List for each individual nootropic. Whenever you’re considering adding some- thing new to your stack, carefully read the review for that nootropic. And keep in mind how it may affect your entire body. Not just your brain. One more thing… ever wondered why you get butterflies in your stomach? Or why an impending decision can cause an attack of intestinal cramps? They happen because your body has two brains. You’re already familiar with the one in your head. But there’s also another vitally important one found in your gut. Like Siamese twins, your two brains are interconnected. When one gets upset, the other does too. Your gut has a powerful influence on all things brain-related. I’ll not go into detail here because this book is about ‘nootropics’. Just realize that all nootropics you take start in your digestive system. Unless you take it sublingually. And can have effects starting in your gut. And all the way up until it crosses your blood-brain barrier. You can learn more about your microbiome and how it affects cognition and mental health by doing an online search. Or going to NootropicsExpert.com and searching for the post “Psychobiotics: The Gut-Brain Connection”. We’ll investigate in detail each of 72 nootropics in detail in the next chapter. I’ve tried most of the supplements discussed in this book. They all work and I have my favorites that I use every day. My dearest wish is that you find your ultimate nootropic stack. And start optimizing your brain today. But first, it helps to understand how your brain works.

14

How Your Brain Works

our brain is the most complex organ in your body. And many specu- Y late the most complex thing in the entire universe. Weighing in at up to 3 pounds (1.36 kg), your brain is the command center for intelligence, interprets what you feel, hear, smell, taste, controls body move- ment and functions, directs your behavior and more. People have been fascinated by the brain since Aristotle in ancient Greece. But until recently the brain was considered too complicated to understand. Times have changed and scientists have learned more about the brain in the last 10 years than in the last several thousand years. The rate of research in neu- robiology and behavioral science has accelerated. As has new research techniques. As a result, we know more about how nootropic supplements work. And can fine-tune our stacks to get the results we want. This chapter will help you understand how your brain works. We’ll touch on how to keep it healthy and optimized. And what happens when the brain is diseased or dysfunctional.

Brain Architecture

Your brain is like a highly skilled team of professionals. Everyone working to- gether, but each with its own unique job function. The macro view divides your brain into three basic teams; forebrain, midbrain and hindbrain. The upper section of your spinal cord, the brain stem and a ball of tissue called the cerebellum (Latin for ‘little brain’) make up the hindbrain. This team controls your body’s vital functions like heart beat and breathing. Your cerebellum also coordinates movement and plays a role in learned movements. Like reaching for a glass when you want a drink. When you play your guitar, or kick a football, you are activating your cerebellum. The very top of your brain stem is called the midbrain. This team controls your reflex actions. And plays a role in controlling eye movement and other voluntary movements. The forebrain is the most highly developed and largest part of your brain. 15 David Tomen This team consists mainly of the cerebrum. And the structures buried beneath the cerebrum including the hippocampus, basal ganglia and olfactory bulb (sense of smell). The cerebrum is the uppermost part of your brain and what you normally associate with the idea of what a brain looks like in pictures. The cerebrum controls your emotions, hearing, vision, personality, all volun- tary actions, and more. This is where intellect and cognition take place, where your memories are stored, imagination and thinking occur, and allows you to plan. The cerebrum is split in two halves or hemispheres. The two cerebral hemi- spheres are connected and communicate with each other via a thick cable of nerve fibers called the corpus callosum. The two hemispheres look alike but each has a unique function. Each in- teracts with the opposite side of your body. When the left side of your brain is damaged, the right side or your body is affected. For example, a stroke in the left hemisphere of your brain can leave your right arm and leg paralyzed.

Cognitive Architecture

Each cerebral hemisphere is divided into ‘lobes’, each specializing in a different function. Let’s start with the two frontal lobes. The two frontal lobes are located directly behind your forehead. Imagining the future, planning a schedule or reasoned arguments are controlled by these two frontal lobes. The frontal lobes act as short-term storage for memory like RAM in your computer. It allows you to keep one idea in mind while other ideas are considered. At the back of each frontal lobe is a motor area which helps control voluntary movement. Like lifting your arm or taking a step. Next door to the motor area is Broca’s area which allows thought to be transformed into words. The parietal lobes are right behind the frontal lobes. And are used for ex- ample when you savor a good meal. This is where smell, taste and texture are processed. The forward section of your parietal lobes (right behind the motor area) are sensory areas. This is where you receive information from the rest of your body about movement, taste, temperature and touch. Arithmetic and reading are also governed by each parietal lobe. Occipital lobes are near the back of your cerebrum. As you look at the words on this page, images from your eyes are processed in the occipital lobes. And linked to information with images stored in your memory. Damage to your oc- cipital lobes can cause blindness. Underneath the parietal and frontal lobes are your temporal lobes. When you listen to music, your brain responds through activity in the temporal lobes. 16 HEAD FIRST An area at the top of each frontal lobe is involved in receiving information from your ears. The underside of each temporal lobe plays a role in forming and retrieving memories. Including those associated with music. Other parts of each temporal lobe help integrate memories and sensations of taste, sound, sight and touch.

Cerebral Cortex

A 2 – 3 mm layer of tissue covering your cerebrum and cerebellum is called the cortex (Latin for ‘bark’). Also referred to as the cerebral cortex, this “gray matter” is where information processing takes place in your brain. The cerebral cortex is ‘gray’ because neurons in this area lack the protective layer that makes most other parts of your brain appear white (“white matter”). The folds you notice in pictures of the brain are there to add surface area to the cortex. Increasing this surface area increases the amount of gray matter and the volume of information you can process.

The Gatekeepers

Deep within your brain is the “inner brain”. Here lie the gatekeepers between your spinal cord and cerebral hemispheres. These team members help determine your emotional state, modify your perceptions and responses depending on that state, and even allow you to initiate movements without thinking about them. Like the lobes in your cerebrum, these team members come in pairs which are duplicated in each half of your brain. The pearl-sized hypothalamus directs several crucial actions. It wakes you up in the morning. And gets the adrenaline flowing when you’re taking an exam or doing a job interview. Your hypothalamus is an important emotional center. Controlling neurotrans- mitters that make you feel angry, exhilarated or unhappy. Thethalamus is near your hypothalamus and a major clearinghouse for infor- mation traveling to and from your spinal cord and cerebrum. A curved set of nerve cells leads from your hypothalamus and thalamus to your hippocampus. This surprisingly tiny hub acts as a memory indexer. Your hippocampus sends memories out to the appropriate part of your cere- brum for long-term storage and retrieves them when needed. Note that the hippocampus, while crucial to long-term memory, it doesn’t store memories. In Alzheimer’s Disease, the hippocampus is one of the first areas of the brain to suffer damage. Disorientation and memory loss are some of the first symptoms in Alzheimer’s. 17 David Tomen Your basal ganglia are clusters of nerve cells surrounding the thalamus. And interconnected with your cerebral cortex, thalamus and brainstem. This area is involved in working memory. Your basal ganglia play a role in decision making, initiating and integrating movements, learning and skill acquisition, procedural learning, reward process- ing, routine behaviors (habits), eye movement, cognition and emotion. Your basal ganglia transfers information that controls the release of dopa- mine. Parkinson’s Disease, which results in rigidity, stiff and shuffling walk and tremors, is a disease of the nerve cells leading to the basal ganglia.3

Neurons & Synapses

Your Central Nervous System and brain are composed of many different types of cells. But the primary functional cell when choosing nootropics for optimizing your brain is a cell called the neuron. The most recent research estimates your brain has an average of 86.1 bil- lion neurons, and 84.6 billion other types of cell including glial cells.4 Glial cells surround and nutritionally support neurons. And may even play a role in brain communication and neuroplasticity. A neuron is a highly specialized cell for processing and transmission of cel- lular signals. Your mood, movements, memories and sensations are the result of neurotransmitters and electrical signals sent and received by neurons. Neurons consist of three parts; the soma (cell body), dendrites and an axon. The soma contains the nucleus which is the control center of the cell. The nucleus is comprised of DNA, mRNA, genes, chromosomes, and proteins. Dendrites are feathery branches extending out from the soma. And act as a type of ‘antenna’ to receive signals sent by neighboring neurons. Each neuron (nerve cell) has a single axon which can vary in length ex- tending out from the cell. Axons act as the cell’s sending unit that allows it to communicate with a neighboring neuron. Each axon can have extensive branches allowing it to communicate with many target cells. The longest axon in your body is the sciatic nerve that extends from the base of your spine down to your toes. The axon terminal contains synapses which are special structures where neurotransmitters are released to communicate with target neurons.

Cell Membranes

Each neuron is encased in a cell membrane which separates the inside of the cell from the outside. This cell membrane acts like a barrier, allowing only necessary 18 HEAD FIRST compounds to enter the cell. And restricts access to undesirable substances like toxins. The cell membrane consists mostly of lipids (fats) which include phospha- tidylcholine (PC), phosphatidylserine (PS), and other lipids. This cell membrane is constantly changing, and is influenced by your diet, stress and your immune system. PC and PS are used as nootropics because manipulation of the composition of the lipids in cell membranes can influence the function of neurons. The cell membrane has two layers. The inner layer facing the inside of the cell. And an outer layer facing the outside. The two most common groups of compounds making up these layers include phospholipids and sterols. Amino acids, fatty acids and phosphorous make up most of the lipids compris- ing phospholipids. Phosphatidylcholine (PC) makes up about 30% of the lipid content in your brain. (PE) makes up about 27% of the lipid content in your brain. And another 10% of your brain lipid content is phosphatidylserine (PS).5 Sterols include which comprise about 20% of the lipid content of your brain. Cholesterol is a precursor from which steroid hormones like DHEA, , estrogen and testosterone are formed. Changing or altering the composition of brain cell membranes can have a profound impact on many aspects of brain function. In many instances, using or DHA, or supplementing with PC or PS can influence cognition, memory and brain health. As much as changing neurotransmitter levels with the use of nootropic supplements.

Brain Cell Signaling

Calcium, chloride, and ions in each brain cell has a different charge. And maintain a voltage gradient across the membrane of that cell. When the voltage changes significantly, an electrochemical pulse called an action potential is generated. This electrical activity can be measured and dis- played as a wave form called Brain Waves. This electrical pulse travels along the cell’s axon. And is transferred across a synapse to a neighboring neuron. The neighboring neuron receives the signal through one of its dendrites. This transfer is known as a synaptic connection. A neuron can form tens of thousands of connections with other neurons. Some estimates report well over 100 trillion synapses.6 Related neurons can form neural networks. And the more signals sent between two neurons, the stronger the connection. With each new experience and each fact that you remember, your brain 19 David Tomen slightly re-wires itself on a physical level. This neuroplasticity leads to long-term potentiation and the development or encoding of long-term memories. Signaling between neurons is not only electrical, but electro-chemical. An axon terminal contains thousands of sacs called vesicles. Each vesicle can contain thousands of neurotransmitter molecules. These neurotransmitters are like chemical messengers which amplify, relay and modulate signals between neurons. When stimulated by an electrical pulse, a neurotransmitter is released. And crosses the synaptic cleft to the neighboring neuron. It then binds to a neurorecep- tor in the dendrite of the receiving (post-synaptic) neuron.

Neurotransmitters

Every emotion or thought you experience is associated with electrochemical nerve impulses. And the release of tiny amounts of neurotransmitters between neurons. Electrochemical nerve impulses and the release of neurotransmitters in cer- tain parts of your brain are happening as you read this sentence. Your eyes sense the shape of letters. And the information is relayed to your cerebral cortex. Your brain interprets these letters and words, and convert them into thoughts. The thought is in turn stored as memory. Your genetic makeup, prior learning experience and memory dictate the nature of these thoughts. Another person reading this same sentence will experience it differently than you because no two people will have the exact same thoughts. Each brain is unique. Everything that you hear, see, smell, taste and touch is processed in your brain with electrochemical messengers. These messengers are neurotransmitters. Dozens of amino acids, , hormones, minerals, peptides and purines act as neurotransmitters. Influencing alertness, cognition, memory, and mood. But investigating all of these neurotransmitters is not necessary for our purposes. Instead, a brief explanation of some of the important neurotransmitters will help you understand how the nootropic supplements discussed in this book affect your cognition. I recommend you use this chapter as a reference. When you find a nootropic you find helpful, refer back to this section to learn more about its chemistry and function in your brain. The two most common neurotransmitters in your brain are glutamate and GABA (Gamma-Aminobutyric Acid). Other crucial neurotransmitters include acetylcholine, dopamine, epinephrine, norepinephrine, melatonin and serotonin. Let’s start with a review of the two most abundant neurotransmitters in your brain; glutamate and Gamma-Aminobutyric Acid (GABA). 20 HEAD FIRST Glutamate Glutamate is the most abundant excitatory neurotransmitter in your brain. Glutamate is stored in synaptic vesicles. And when an electrical impulse is sent down the axon by the neuron, glutamate is released from the presynaptic neuron. At the receiving, or post-synaptic neuron, glutamate binds to glutamate recep- tors like NMDA or AMPA receptors which are then activated. Constant or frequent activation of glutamate receptors strengthens these interconnected synaptic networks. And contributes to the neuroplasticity and long-term potentiation associated with cognitive functions like learning and memory.7 Too much glutamate, or overly-sensitive glutamate receptors can cause cell damage or cell death. And lead to restlessness, irritability, insomnia and even . Scientists have discovered that NMDA receptors in people with Hunting- ton’s Disease are overactivated by glutamate. You get glutamate from foods like meat, poultry, fish, eggs, and dairy products. Glutamate does not easily cross your blood-brain barrier. So, must be transported across by an high-affinity transport system. Glutamate is a precursor for the synthesis of the inhibitory neurotransmitter Gamma-Aminobutyric Acid (GABA). GABA GABA (γ-Aminobutyric acid) is the most abundant inhibitory neurotrans- mitter in your brain. Neurons that produce GABA are known as GABAergic neurons. GABA does not cross the blood-brain barrier. But instead, is synthesized in your brain from the neurotransmitter glutamate using the enzyme glutamate decarboxylase (GAD) and pyridoxal-5-phosphate (Vitamin B6 or P5P) as a cofactor. GABA’s primary role in your brain is to keep glutamate in check. Too much glutamate can cause a . And too much GABA can put in you in coma. An optimized brain has a healthy balance of both GABA and glutamate. GABA helps reduce anxiety, insomnia, nervousness, restlessness and stress. When you take GABA as a supplement it can even increase human growth hormone.8 GABA receptors are stimulated by and which result in relaxation. And a reduction of irritability and stress. Brain disorders like epilepsy, sleep disorders and Parkinson’s disease are affected by GABA. root, American Ginseng, Kava Kava, green, black and oolong tea help increase the effect of GABA on its receptors. The nootropic Phenibut is a deriva- tive of GABA and helps increase GABA levels in your brain. 21 David Tomen Acetylcholine Acetylcholine (ACh) was the very first neurotransmitter to be identified. Dis- covered in 1915 by British physiologist Sir Henry Hallett Dale who later shared the Nobel Prize in Physiology Medicine with Otto Loewi in 1936. Acetylcholine is made from choline and a two-carbon molecule called acetyl. It is synthesized in neurons in your brain and body. ACh binds and activates two classes of receptors; muscarinic and nicotinic. You have two types of nicotinic receptors in your body; muscle-type and neu- ronal-type. The muscle-type receptors are on muscle cells, and are used to activate skeletal muscles and signal a body movement. The neuronal-type receptors have acetylcholine acting as a neuromodulator. Affecting attention, learning and memory. Once it is produced, acetylcholine is stored in cholinergic neurons and released into the synaptic cleft when stimu- lated by an electrical signal. When ACh is released in the synaptic cleft, the enzyme acetylcholinesterase breaks acetylcholine back down into choline and acetyl. Alzheimer’s patients have a shortage of acetylcholine. And one of the ways doctors increase levels of ACh is to inhibit the acetylcholinesterase enzyme with prescription drugs. Leaving more ACh available for cognitive function. Too much acetylcholine can result in continuous stimulation of muscles, glands and your central nervous system. Which can result in fatal convulsions. Nerve agents like gas act as acetylcholinesterase inhibitors and are used in chemical warfare. The Black Widow Spider has a similar effect to Sarin in that it inhibits acetylcholinesterase. The venom causes a massive release of acetylcholine, norepi- nephrine and GABA. Causing cramps, fast pulse, pain and sweating. Nootropic supplements like Alpha GPC and CDP-Choline can boost levels of acetylcholine. Which is particularly important when using racetams like Piracetam which modulates AMPA and NMDA receptors. Piracetam also improves the flow of acetylcholine, and the sensitivity of ACh receptors. Huperzine-A is used a nootropic because it acts as an acetylcholinesterase inhibitor which boosts levels of acetylcholine in your brain. Improving memory, cognition and lucid dreaming. Dopamine Dopamine is an amine synthesized from its precursor L-Dopa in your brain. It belongs to the catecholamine family of neurotransmitters which include epi- nephrine and norepinephrine. Dopamine must be synthesized in dopaminergic neurons in your brain from L-Dopa because it can’t cross the blood-brain barrier on its own. The primary pathway for dopamine synthesis is L-Phenylalanine → L-Tyro- 22 HEAD FIRST sine → L-DOPA → Dopamine. You get the first two amino acids in this pathway from protein-rich foods like eggs, chicken, liver, beer, milk and soybeans. Boosting dopamine levels in your brain leads to better mood, alertness, sex drive and even heightened verbal fluency and creativity. Dopamine in your brain binds to dopamine receptors of which there are 5-types numbered D1 – D5. After dopamine is synthesized in the neuron, it is transported to and stored in vesicles until it is ejected in the synaptic cleft. Upon arrival at the post-synaptic neuron, dopamine binds to and activates dopamine receptors located on dendrites of that neuron. Or presynaptic auto- receptors which are located on the axon of the presynaptic neuron. Once dopamine activates the receptor, it is released back into the synaptic cleft where it’s broken down by the enzyme monoamine oxidase (MAO). Bookmark that last sentence in your brain because many prescription drugs take advantage of that MAO action. Certain drugs block the activity of MAO, and are known as MAO inhibitors (MAOIs). There are two types of MAO inhibitors – type-A and type-B. Both can act as antidepressants, and type-B inhibitors are also used to treat Parkinson’s disease. A decline in dopamine in your brain can lead to learning and memory prob- lems. And worst-case is movement problems like in Parkinson’s patients. Later in this book we’ll explore the nootropics that influence or can boost dopamine levels in your brain. Epinephrine & Norepinephrine The amino acids phenylalanine and tyrosine are converted into dopamine. Dopamine can then be converted into norepinephrine, and then epinephrine. When you take tyrosine as a supplement or get it from food, you can elevate dopamine and norepinephrine levels. Which leads to a boost in alertness and mood. Too much of these neurotransmitters can elevate blood pressure, heart rate, anxiety, irritability and insomnia. Some prescription antidepressants improve mood and boost arousal by increasing levels of epinephrine and norepinephrine. Several enzymes are required to convert phenylalanine all the way through the dopamine pathway to epinephrine. And these enzymes require cofactors like vitamins and other nutrients.

For example, L-Dopa is converted to dopamine with Vitamin B6 as a cofac- tor. Dopamine is converted to norepinephrine with as a cofactor. And norepinephrine requires SAMe to convert to epinephrine. Serotonin Serotonin (5-HT) is a monoamine neurotransmitter. Serotonin is synthesized from 5-Hydroxytryptophan (5-HTP) with Vitamin B6 as a cofactor. And 5-HTP 23 David Tomen comes from the synthesis of Tryptophan which you get from meat, fish, and other protein foods. Once serotonin is synthesized in your brain, your pineal gland can use it to produce melatonin which is used to govern your circadian rhythm and sleep cycles. We have a ton of research to draw on for serotonin because it affects such a vast range of psychological and biological functions. A team at the Cleveland Clinic first discovered serotonin in 1948. Serotonin regulates or is otherwise involved in anxiety, arousal, aggression, mood and cognition. Recall that we referred to dopamine and norepinephrine earlier in this chapter, and their effects on arousal and mood. Serotonin produces similar effects in your brain, but works differently than the catecholamines. However, serotonin receptors modulate the release of several neurotransmit- ters including glutamate, GABA, dopamine, norepinephrine, epinephrine and acetylcholine. Which would account for some of serotonin’s similar effects to that of dopamine and norepinephrine. Where they differ is too much serotonin can cause relaxation, sedation and decreased sex drive. The antidepressant (Prozac®) is a selective serotonin reuptake inhibi- tor (SSRI) and acts to raise serotonin levels in the brain. Maybe even influencing other neurotransmitters in the brain. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of mono- amine neurotransmitters (including serotonin), and increase concentrations of neurotransmitters in the brain. The nootropic5-HTP is an immediate precursor to serotonin, and in some cases, can be used instead of SSRI’s. St. John’s wort can also boost serotonin levels in the brain. And is often used as an antidepressant. When the serotonergic system gets out of whack, it can lead to anxiety, depres- sion, improper social behavior and sexual problems. Other problems with sero- tonin in the brain include insomnia, obesity, eating disorders and even chronic pain. Low serotonin levels can be caused by not getting enough of its precursor tryptophan from food. And for tryptophan to be transported across the blood- brain barrier, it needs a carrier protein. The problem is that carrier protein is also used by other amino acids that need to cross into your brain. Amino acids like phenylalanine and tyrosine which convert in your brain to dopamine and norepinephrine. Imagine this carrier as a very small boat that can only carry one person across the lake at a time. There’s always competition for amino acids to jump on that little boat to get to your brain. So, brain levels of tryptophan are not only determined by levels of trypto- 24 HEAD FIRST phan in your bloodstream. But also by the concentration of competing amino acids trying to get across and into your brain. You can supplement with L-Tryptophan to boost serotonin levels. Or its direct precursor 5-HTP. You can also use the nootropic Cat’s Claw which boosts tryptophan levels which in turn can increase serotonin. Improve Your Memory with Nootropics Looking for an edge to advance your career? How about more confidence and an easier time preparing for and writing that next exam. Preparing that next pre- sentation. Or improving your mood and motivation to help your relationships. Nootropic supplements can help improve: • Alertness • Arousal, libido and sexual enjoyment • Awareness, vision, hearing and sensory perception • Concentration and focus • Creativity and thinking outside the box • Complex problem-solving abilities • Learning and memory • Mood, energy and vitality • Speed of cognition and reaction time • Verbal fluency Research over the last couple of decades has shown that our brain has the remarkable ability to re-wire itself throughout life. Meaning we can not only retain our memories and stabilize our mood. But we now have the knowledge and ability to improve memory and boost mood while taming anxiety. These may sound like lofty promises. But I’m living proof along with thousands of others that improved cognition, better memory and mood, and an overall better quality of life is possible with nootropic supplements. Here I’ll touch on some of what’s happening in your brain. And how noot- ropics can help optimize brain function. Types of Memory Scientists have identified several different types of memory. Including short – and long-term memory and working memory. Let’s look at each type with a short explanation of what they are and how they work in everyday life. Short-Term Memory is also known as primary or active memory. It is characterized as being very brief (i.e. seconds), and is limited to what you can remember and retain for 20 to 30 seconds. 25 David Tomen Your brain can only retain new information to a certain extant (chunk ca- pacity) and only temporarily (temporal capacity). Short-term memory includes things like thinking on your feet, making quick decisions, verbal fluidity, humor, and reaction time. Short-term memory can be improved with certain nootropics. Acetylcholine precursors like Alpha GPC and CDP-Choline, Kava, Rhodiola Rosea, Phosphati- dylserine (PS), and Nicotine have been shown to help alertness, focus, short-term memory and mental clarity. Long-Term Memory describes the type of memory associated with an event or information acquired by your mind long ago. It could be anywhere from a couple of days to a life-time. These memories are often pieced together by the brain with inaccurate or imagined information. This memory storage can come from your perception of an event or thing, conditioning, or any other accurate or faulty input. Long-term memory relies on long-term potentiation (LTP) and the strengthening of connections between neurons and synapses. LTP relies upon brain-derived neurotrophic factor (BDNF). A naturally occurring protein in your brain that is responsible for the growth, maintenance and survival of neurons. When BDNF is released in your brain, new connections form as BDNF attracts dendrites from neurons and connects them to neighboring synapses. As your brain cells fire together, they wire together. These tiny networks in your brain is how long-term memories consolidate and form. Nootropics to boost BDNF include Ashwagandha, Bacopa Monnieri, DHA, Gotu Kola, L-Theanine, Magnesium, N-Acetyl L-Cysteine (NAC), Noopept, Rho- diola Rosea, Pterostilbene, Resveratrol and Turmeric. Nootropics to boost long-term memory include Oat Straw, Nicotine, Nefirace- tam, L-Glutamine, Forskolin, Tryptophan, Vinpocetine, Resveratrol, Pterostilbene, Phosphatidylserine (PS), Phosphatidylcholine (PC), Pramiracetam, Phenylpirace- tam, Piracetam, Picamilon, Oxiracetam, N-Acetyl L-Cysteine (NAC), Noopept, L-Theanine, L-Dopa, Magnesium, Ginseng, Huperzine-A, Lion’s Mane Mushroom, Coluracetam, and Artichoke Extract. Working Memory is distinct from short – and long-term memory. These are memories that are not only remembered, but simultaneously processed. You not only remember information that is important to you. You also remember the purpose of the information, and why you decided to remember it. Working memory uses different parts of your brain compared to short – and long-term memory. Researchers have identified activation in theprefrontal cortex, and other parts of the brain. Calling this model of brain computation FROST (short for FROntal-Striatal-Thalamic).9 Nootropics to boost working memory performance include Gotu Kola, Col- 26 HEAD FIRST uracetam, Creatine, Ginseng, Kava, Nicotine, N-Acetyl L-Tyrosine (NALT), NADH, N-Acetyl L-Cysteine (NAC), Piracetam, Phenylalanine, Phosphatidyl- choline (PC), Phosphatidylserine (PS), Pterostilbene, Turmeric, and Tryptophan. Each form of memory calls on specific pathways in your brain. Select neuroreceptors including AMPA receptors and NDMA receptors are involved in memory. Gene expression in the cellular nucleus. Brain-Derived Neurotrophic Factor (BDNF), long-term potentiation, human nerve growth factor, neurogenesis, and more. The good news is we have control over how our memory works. And many natural nootropics to help boost and maintain the efficiency of these neural networks. Memory and mood are complex subjects and each worthy of a book on their own. But instead of turning this into a book about neuroscience, let’s stay with how you can use nootropics to optimize cognition and mood. The next chapter goes into much more detail on how each nootropic featured in this book works, what it is, where it comes from, available forms, and dosage recommendations. For each nootropic, I also reference several clinical studies that support what neurohackers say about their experience with that nootropic.

27

List of Nootropics

Acetyl-L-Carnitine Acetyl-L-Carnitine may reverse age-related cognitive decline, and improve memory Acetyl-L-Carnitine (ALCAR, ALC or LAC) is a synthesized version of L- Carnitine. Which is a derivative of the amino acids lysine and methionine. L-Carnitine is an amino acid that’s synthesized in your body. You also get it from red meat and dairy. L-Carnitine is considered a “conditionally essential” nutrient because when your body uses it faster than it can produce it, you need supplemental L-Carnitine either from food or a supplement. L-Carnitine is used throughout your body. Here we’re talking about the Acetyl-L-Carnitine form of L-Carnitine because of its affects on brain health and chemistry. L-Carnitine . Acetyl-L-Carnitine: What’s the Difference? L-Carnitine and Acetyl-L-Carnitine are often referred to as Carnitine. But each are structurally different, and each has its advantages. L-Carnitine: Provides energy for the mitochondria of your cells, but is not capable of crossing the blood-brain barrier. Supplemental L-Carnitine is difficult for your body to absorb; only 18% of it reaches your bloodstream. L-Carnitine is favored by athletes and dieters who want Carnitine’s fat- metabolizing benefits. But are not seeking any brain benefits. Acetyl-L-Carnitine: Is easier to absorb and use by your body than L-Carni- tine. One study showed using 2 grams daily for 50 days boosted blood ALCAR levels by 43%.10 ALCAR does everything that L-Carnitine does, but can also cross the blood- brain barrier. In another study, researchers found that ALCAR protects brain cells from oxidative stress, while L-Carnitine does not.11

How does Acetyl-L-Carnitine Work in the Brain? Acetyl-L-Carnitine boosts brain health and function in several ways. But two in particular stand out. 28 HEAD FIRST ALCAR boosts acetylcholine, a neurotransmitter tied to memory and overall brain function. Acetyl-L-Carnitine is a precursor to acetylcholine in the presence of Coenzyme-A. ALCAR donates a “methyl group” to make acetylcholine.12 Alzheimer’s-diseased brains show a 25% to 40% reduction in carnitine acet- yltransferase, a brain enzyme that works with L-Carnitine & Acetyl-L-Carnitine. This brain enzyme decline led researchers to link low ALCAR with low ace- tylcholine, and Alzheimer’s onset. They went on to suggest ALCAR as a viable therapy for brain regeneration.13 ALCAR promotes brain energy by fueling your brain cell’s mitochondria.14 ALCAR works as a shuttle transport for fatty acids through cell membranes. Right to the cell powerplant mitochondria.15 As ALCAR shuttles fatty acids into mitochondria, it provides the fuel that is burned for energy. As ALCAR shuttles fatty acids out of mitochondria, it flushes out toxic byproducts. ALCAR maintains mitochondria in nearly every cell of your body. Your brain consumes at least 20% of your body’s energy. And generates a lot of toxic byproducts. So ALCAR is particularly important for a healthy brain.

How things go bad As we get older, our brain chemistry and energy changes.16 ↓ Nerve growth factor in the brain declines ↓ Acetyl-L-Carnitine levels decline ↓ Acetylcholine levels decline ↓ Mitochondria lose efficiency All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia.

ALCAR to the rescue Research from the Linus Pauling Institute at Oregon State University shows that Acetyl-L-Carnitine will:17 • Restore efficient mitochondrial energy production • Replenish age-related changes to mitochondrial structure • Replenish ALCAR and acetylcholine levels in the brain and body ALCAR has the ability to boost acetylcholine and rejuvenate brain cells (including mitochondria). This has been proven to benefit those with age-related brain diseases like Alzheimer’s and major depression.18

How does Acetyl-L-Carnitine feel? You may not feel ALCAR… unless you’re elderly or have Erectile Dysfunc- 29 David Tomen tion. Within those specific groups, Acetyl-L-Carnitine helps with memory, mood, mental performance and the ability to get and maintain an erection. ALCAR’s brain support and its ability to fuel the mitochondria in your brain cells should boost cognition in all age and gender groups. As a nootropic, ALCAR user reviews report a boost in energy and quick thinking.

The Research In one study, researchers showed that ALCAR may have positive effects for depression and dementia.19 Another study out of Italy; researchers showed that Acetyl-L-Carnitine stimulated the growth of new neurites. More of these minute projections from nerve cell bodies meant increased signaling between cells throughout the central nervous system (brain and spinal cord).20

ALCAR helps with Mild Cognitive Impairment (MCI) A gold-standard double-blind, randomized controlled trial on 1,204 people showed a significant effect on attention, mental performance, memory and higher mental functions.21 In this study ALCAR seemed to ward off further brain deterioration. And could be considered as therapy for brain degeneration.

Acetyl-L-Carnitine slows rate of cognitive decline 130 Alzheimer’s patients were given ALCAR or a placebo daily for a year. They were tested across 14 points of cognitive performance. This research showed a slower decline in cognitive performance with the ALCAR group compared to the placebo group.22

ALCAR effective for Chronic Fatigue Syndrome Acetyl-L-Carnitine has been shown to improve fatigue in patients with chronic fatigue syndrome. In a randomized, double-blind, crossover study; 36 people were treated for 3 months with either (used to treat Chronic Fatigue), or 1 gram of ALCAR twice daily. The results of the study showed that ALCAR was better tolerated and more effective than the pharmaceutical for fatigue.23

Acetyl-L-Carnitine protects from oxidative damage of Ecstasy (MDMA) Research has shown ALCAR to be effective in protecting your mitochon- dria from oxidative stress. And use of MDMA does cause oxidative damage in mitochondria. In this study, male rats were given Acetyl-L-Carnitine before a dose of Ec- 30 HEAD FIRST stasy (MDMA). ALCAR pretreatment “exerts effective neuroprotection against MDMA-induced neurotoxicity at the mitochondrial level”, said the researchers.24 Keep that in mind before your next party.

ALCAR for Erectile Dysfunction In this study, 120 patients were split into 3 groups. Group 1 was given 160 mg of testosterone per day. The 2nd group was given 2 grams of Propionyl-L-Car- nitine plus 2 grams of Acetyl-L-Carnitine per day. And the 3rd group a placebo. Did you know that there’s an International Index of Erectile Function? Turns out the Propionyl-L-Carnitine/Acetyl-L-Carnitine stack was better than testosterone for erectile dysfunction. Without the side effects of an enlarged prostate, better organisms, more sexual desire and improved mood.25

Dosage Notes • Acetyl-L-Carnitine suggested dosage for cognitive benefit is 1 – 4 grams per day. • For improved mood and elimination of chronic fatigue, 1 – 3 grams of ALCAR per day. • For age-related memory concerns, 1 – 2 grams of ALCAR per day.

Side Effects Acetyl-L-Carnitine is produced naturally in your body. So is considered well- tolerated and safe. Side effects are rare but can include nausea, vomiting, increased agitation, weight loss, and restlessness. You can also experience an increase in seizure frequency if you have any kind of seizure disorder.

Available Forms • Acetyl-L-Carnitine: L-Carnitine with an extra acetyl group. This version is more bioavailable and easily crosses the blood-brain barrier. • L-Carnitine: This is the standard form of carnitine found in food. • Lipo-Carn®: A proprietary blend of Alpha-Lipoic Acid and Acetyl-L-Carni- tine. Studies show this combination is a powerful anti-aging duo.Together, these two help combat diabetes, boost energy production, maintain proper cognitive function, protects the body from radiation and chemical toxins, and helps immunity.26 • Propionyl-L-Carnitine: L-Carnitine combined with propionic acid. This form is noted for its antioxidant activity, and is used for heart health ap- plications. Also useful for erectile dysfunction. 31 David Tomen Nootropics Expert Recommendation Acetyl-L-Carnitine 500 – 1,500 mg per day I recommend using Acetyl-L-Carnitine as a nootropic supplement. Your body does synthesize some ALCAR on its own. And from the food you eat. But most Acetyl-L-Carnitine comes from red meat. And unless you eat a lot of great quality grass-fed beef or mutton… ALCAR is especially helpful for those suffering from age-related cognitive decline. Studies show it helps stop or reverse brain degeneration with Alzheimer’s Disease, and depressive disorders. Particularly in the early stages of the disease. I suggest starting with a dose of 500 mg daily. ALCAR is a great compli- ment to a stack including Piracetam. Add a choline source (Alpha GPC or CDP-Choline) typically at a ratio of 1:4. 1 gram of CDP-Choline to 4 grams of Piracetam. Take just enough choline to eliminate a -induced headache. Then add 500 mg of ALCAR. Some have found ALCAR stacked with Coenzyme Q-10 has a profound effect on everything from mood to bipolar disorder. Especially combined with Alpha-Lipoic Acid. Age-related cognitive disorders like Alzheimer’s may want to up the dose to 1,500 mg per day.

32 HEAD FIRST Alpha GPC

Alpha GPC has been shown to reverse age-related cognitive decline, improve memory and learning, and boost athletic workouts Alpha GPC (L-Alpha Glycerylphosphorylcholine, choline alfoscerate) is a choline source derived from soy or sunflower . It is also naturally present in small amounts in your body. You can also get it from eating organ meats, dairy and wheat germ. Choline is considered an essential nutrient because when your body uses it faster than it can produce it, you need supplemental choline either from food or a supplement. You need choline for synthesis of the neurotransmitter acetylcholine. And is part of phosphatidylcholine (PC), used in building cell membranes. In fact, choline is so vital to cognition and nerve function that, without it, we couldn’t move, think, sleep or remember anything. Alpha GPC is used throughout your body. It even helps the production of human growth hormone. Athletes use it for peak performance, and to help build muscle mass. It provides more energy for a workout and quicker recovery.27 Here we’re talking about how Alpha GPC affects your brain health and chemistry. Alpha GPC vs. CDP-Choline vs. Choline Bitartrate: What’s the Difference? Choline is a water-soluble nutrient and its composition is similar to B- vitamins. Alpha GPC, CDP-Choline, Choline Citrate and Choline Bitartrate are all sources of choline. CDP-Choline (cytidine 5′-diphosphocholine): Is only about 18% choline by weight. Your body naturally synthesizes choline into CDP-Choline (Citicoline). It’s then converted to phosphatidylcholine (PC) which assists cell membranes, and helps create acetylcholine. Choline Bitartrate: An economical form of choline, and about 40% choline by weight. So 1 gram of Choline Bitartrate offers 400 mg of actual choline. It does not easily cross the blood-brain barrier. So you won’t experience the same level of nootropic benefit as with Alpha GPC or CDP-Choline. Alpha GPC: About 40% choline by weight and easily crosses the blood-brain barrier. Alpha GPC naturally occurs in your brain as a byproduct of phosphati- dylcholine (PC). When your brain needs more choline, and the choline floating around in your brain is running low, it breaks down PC from cell membranes. And turns it into Alpha GPC. Your body and brain loves it when you use Alpha GPC. Because it doesn’t have to cannibalize its own cells to get more choline. 33 David Tomen How does Alpha GPC Work in the Brain? Alpha GPC boosts brain health and function in several ways. But two in particular stand out. 1. Alpha GPC boosts acetylcholine, a neurotransmitter tied to memory and overall brain function. Alpha GPC is a precursor to acetylcholine. Improving the efficiency of com- munication between neurons in your brain. This increase in neural signaling boosts memory, learning, cognitive processing and mental clarity. In one study, 32 healthy volunteers received either Alpha GPC or a placebo as a pretreatment. Ten days later they were injected with to induce amnesia. The researchers found Alpha GPC was able to prevent the impairment of attention and memory normally caused by scopolamine.28 These researchers showed that memory function in young healthy people could improved. Simply by taking Alpha GPC as a supplement. 2. Alpha GPC directly impacts development of cell membranes in the cerebral cortex. This outer layer of neural tissues or “gray matter” is the information processing center of your brain. It controls intelligence, motor function, organization, personality, planning and touch.29 Published in Clinical Therapeutics, researchers conducted a double-blind, placebo-controlled trial with mild to moderate Alzheimer’s patients. 400 mg capsules were administered 3 – times per day for 180 days. The conclusion of this trial showed consistent improvement in dementia patients given Alpha GPC.30

How things go bad As we get older, our brain chemistry and energy metabolism changes. ↓ Recall, reaction time and mood diminish ↓ Brain cell membranes degenerate ↓ Acetylcholine levels decline31 ↓ Nerve growth factor in the brain declines All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia. But even if you’re not concerned with the effects of aging, Alpha GPC can help.

Alpha GPC to the rescue Research from hundreds of studies have shown that Alpha GPC will: • Improve memory and learning ability32 • Restore the bioavailability of acetylcholine33 • Restore and boost nerve growth factor receptors in the brain34 34 HEAD FIRST • Increase growth hormone in all age groups35 • Boost cognitive performance and memory in Alzheimer’s patients36 Alpha GPC is water-soluble and quickly enters your brain after you take it. Once in your brain, it boosts signal transmission, and protects neurons. Alpha GPC improves your brain function and learning processes by directly increasing synthesis and secretion of acetylcholine. As your body calls for it. This form of choline is not a precursor to phosphatidylcholine (PC), but is a metabolite of PC. This means once PC is metabolized and stripped of its fatty acids – all that remains is Alpha GPC. Instead of scavenging your brain’s own membranes for Alpha GPC, you give it exactly the type of choline its looking for.

How does Alpha GPC feel? If you have trouble getting started in the morning, try coffee and 400 mg of Alpha GPC. Instead of your usual high sugar, high carbohydrate breakfast. Alpha GPC can be a great way to boost your energy. Take it 45 minutes before you work out. Alpha GPC helps with memory, mood, mental performance and energy. Its brain support and ability to fuel the acetylcholine in your brain cells should boost cognition in all age and gender groups.

The Research In one study, researchers showed that Alpha GPC had positive effects for increasing human growth hormone.37

Alpha GPC increases the release of dopamine Another trial demonstrated an increase in the release of dopamine.38 This is particularly significant in showing Alpha GPC can help those suffering from dopamine deficiencies. And alleviating the symptoms of diseases like depressive disorders, and Parkinson’s Disease.

Alpha GPC facilitates learning and memory An ongoing trial demonstrates Alpha GPC improving memory and atten- tion. This research shows Alpha GPC increasing the effectiveness of pairing it with (acetylcholinesterase inhibitor). Far better than using donepezil on its own. And in rats, Alpha GPC boosted learning and memory. It increased brain energy mechanisms and decreased age-related structural changes in the brain.3940

Alpha GPC relieves cognitive impairment in Alzheimer’s Thirteen published clinical trials, involving a total of 4,054 Alzheimer’s patients consistently showed Alpha GPC:41 35 David Tomen • Boosted memory and attention • Promoted recovery in stroke patients • Reversed the symptoms of acute cerebrovascular disease • Is far more effective than using choline or lecithin in treating disease

Dosage Notes Alpha GPC is about 40% choline by weight. So 1,000 mg of Alpha GPC provides approximately 400 mg of choline. • Alpha GPC suggested dosage for cognitive benefit is 400 – 1,200 mg per day. • Athletic training suggested dosage of Alpha GPC is 400 mg first thing in the morning, and another 400 mg dose 15 – 30 minutes before working out. • Clinical treatment of Alzheimer’s Disease, dementia and other cognitive disorders dosage of up to 1,200 mg per day. • For higher dosages, split the daily Alpha GPC total into 2 or 3 doses per day. For example, 1,200 mg would be taken 400 mg at a time.

Side Effects Alpha GPC is produced naturally in your body. So is considered well- tolerated and safe. Side effects are rare but can include fatigue, headaches, nervousness, nausea, diarrhea and gastrointestinal issues. This is often an indication you have too much choline in your body. Because Alpha GPC causes an energy boost in many neurohackers, avoid dosing in the evening. Or you may find difficulty getting to sleep.

Available Forms Because Alpha GPC tends to liquefy at 99-100%, many suppliers offer 50% Alpha GPC powder combined with 50% of a filler like silicon dioxide. Adjust your dosage accordingly. Alpha GPC is made from soy or sunflower lecithin. So if you’re trying to avoid soy in your diet look for Alpha-GPC “no soy”, or labeled as derived from sunflower lecithin.

Nootropics Expert Recommendation

Alpha GPC 400 – 1,200 mg per day I recommend using Alpha GPC as a nootropic supplement. Your body does make some Alpha GPC on its own. And from the food you 36 HEAD FIRST eat. But studies have shown we don’t get an adequate supply of choline from food sources in our modern diet. Alpha GPC is especially helpful for those suffering from age-related cognitive decline. Studies show it helps stop or reverse brain degeneration with Alzheimer’s Disease, and other cognitive disorders. Particularly in the early to mid-stages of the disease. I suggest starting with a dose of 400 mg daily. And Alpha GPC is a great compliment to a stack including any nootropic from the racetam-family. Any- thing that causes an increase in uptake of acetylcholine in your brain. You need to provide your brain with the choline it is demanding. Or it starts cannibalizing your own brain cells for more choline. Signs that your lacking adequate choline are headaches. Use Alpha GPC at a ratio of 1:4. For example, 400 mg of Alpha GPC to 1,600 mg of a racetam like Piracetam. Age-related cognitive disorders like Alzheimer’s may want to up the dose to 1,200 mg per day.

37 David Tomen Alpha-Lipoic Acid Alpha-Lipoic Acid has been shown to boost acetylcholine, improve cognition and memory, and is a powerful antioxidant Alpha-Lipoic Acid (ALA) is a -containing fatty acid naturally found in your body. Lipoic acid is unique among other antioxidants because it is both water – and fat-soluble. You get small amounts of lipoic acid in your diet from spinach and collard greens, broccoli, beef and organ meats. But lipoic acid declines in your body as you age. So you need to supplement with Alpha-Lipoic Acid to achieve the levels your body needs to run optimally. And because Alpha-Lipoic Acid (ALA) is both water – and fat-soluble, it works in all parts of the human cell. The more lipoic acid you have in your system; the more antioxidant benefits you experience. You need alpha-lipoic acid’s antioxidant power. Because it regenerates other antioxidants that were depleted by the ongoing fight with free radicals in your cells. It allows you to use the antioxidants Vitamin C & E, glutathione and CoQ10 already in your body over and over again. In fact, alpha-lipoic acid is so efficient at what it does, it boosts the energy in your cells while reducing inflammation, and getting rid of heavy metals. In your brain, alpha-lipoic acid boosts the production of the neurotransmit- ter acetylcholine. And even increases glucose uptake in brain cells. Providing you with a boost of mental energy. Alpha-Lipoic Acid is used throughout your body. It helps increase insulin sensitivity which reduces the threat of diabetes. And ALA reduces the chances of metabolic syndrome which is associated with cardiovascular disease, diabetes and weight gain.

Alpha-Lipoic Acid vs. S-Lipoic Acid vs. R-Lipoic Acid Lipoic Acid is also known as Alpha-Lipoic Acid, ALA and Thioctic acid. The Alpha-Lipoic Acid you get as a supplement is usually a 50/50 mixture of R- (natural) and S-(unnatural) enantiomers. They are mirror images of each other and called a ‘racemic’ mixture. Most commercially available forms of Alpha-Lipoic Acid include the ‘S- form’, or unnatural form of lipoic acid. Chemically synthesized in 1952, and not found in nature. It is thought that the two enantiomers differ biologically. But much of the research done over the last 30 years has been with the racemic version of Alpha- Lipoic Acid because the R-form was not commercially available. S-Lipoic Acid (the enantiomer not found in nature) may not produce the most essential properties of Lipoic Acid. Including interactions with proteins, enzymes and genes. 38 HEAD FIRST R-Lipoic Acid is the form of lipoic acid occurring naturally in the human body, animals, and plants. This is the only form that functions as a co-factor for mitochondrial enzymes involved in energy production. Be aware that most commercially available forms of Alpha-Lipoic Acid in- clude both S – and R-forms of lipoic acid. Alpha-Lipoic Acid is produced as a mixture because R-Lipoic Acid, when separated from the S-form, is very unstable. And deteriorates very quickly. Making it unusable as a . Very few companies go through the complicated, expensive process required to remove the synthetic S-ALA from R-ALA. So unless the bottle specifically states 100% R-ALA, you’re getting a 50/50 blend. Know that R-ALA may be up to 12 times more effective than S-ALA.

How does Alpha-Lipoic Acid Work in the Brain? Alpha-Lipoic Acid boosts brain health and function in several ways. But two in particular stand out. 1. Alpha-Lipoic Acid boosts acetylcholine, a neurotransmitter tied to memory and overall brain function. ALA increases acetylcholine production by activation of choline acetyltrans- ferase and increases glucose uptake. This process supplies moreAcetyl-CoA for the production of acetylcholine.42 2. Alpha-Lipoic Acid is a promising weapon in the fight against neurodegenera- tive diseases like Alzheimer’s. Oxidative stress plays a key role in cognitive disorders because neurons are highly vulnerable to free radical damage. A recent study showed that lipoic acid may help slow down the progression of Alzheimer’s Disease. An area where no known cure has been produced by the big pharmaceutical companies. In this study, 43 patients with dementia were given 600 mg of Alpha-Lipoic Acid daily for 4 years. Researchers concluded from this study, “alpha-lipoic acid might be a successful ‘neuroprotective’ therapy option for Alzheimer’s disease.”43

How things go bad As we get older, our brain chemistry and metabolism changes. ↓ Acetylcholine levels decline ↓ Oxidative (free radical) damage in neural cells ↓ Heavy metal accumulation in cells All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s, Parkinson’s and dementia. But even if you’re not concerned with the effects of aging, Alpha-Lipoic Acid can help. 39 David Tomen Alpha-Lipoic Acid to the rescue Research from hundreds of studies have shown that Alpha-Lipoic Acid will: • Increase the production of acetylcholine • Improve memory and learning ability • Restore the health of neurons • Boost cognitive performance and memory in Alzheimer’s patients. Alpha-Lipoic Acid is both water – and fat-soluble and quickly crosses the blood-brain barrier after you take it. ALA improves your brain function and learning processes by directly in- creasing the production of acetylcholine. Alpha-Lipoic Acid also helps regenerate depleted antioxidants in your system including Vitamins C and E, glutathione and Coenzyme Q10. By reducing inflammation and heavy metals in your brain, you boost cogni- tive processes and fluid thinking.

How does Alpha-Lipoic Acid feel? You may not feel ALA… unless you’re diabetic or have Alzheimer’s. Within these specific groups, Alpha-Lipoic Acid helps with nerve pain, memory, recall and mental performance. Alpha-Lipoic Acid’s provides brain support because it has the ability to boost acetylcholine. So should boost cognition in all age and gender groups. Your entire body, even your DNA is under endless assault. This assault is caused by everything from poor diet to pollution. And your brain cells are getting hit by free radicals thousands of times per day. This oxidation is damaging your cells. Antioxidants fight back against free radicals. When you supplement with Alpha-Lipoic Acid, not only are you using arguably the most effective free radical scavenger on the planet. You’re regenerating antioxidants like Vitamin C & E, glutathione and CoQ10.44 And they join the fight against free radicals alongside Alpha-Lipoic Acid.

The Research Alpha-Lipoic Acid plays an essential role in mitochondria. The heart of energy-generation in the human cell. Scientists at Emory University School of Medicine found ALA can stimulate telomerase, the enzyme that lengthens telomeres. The effects of many chronic diseases can be traced back to telomere shorten- ing. (Telomeres are the ‘caps’ on the end of each chromosome in your DNA). Any treatment that can restore healthy telomeres has great potential in the fight against chronic disease. In this study scientists showed Alpha-Lipoic Acid boosted the production of 40 HEAD FIRST PGC1-alpha. The telomerase that lengthens telomeres. And they did it in just one day of treatment.45

Alpha-Lipoic Acid reduces wrinkles A topical solution of 5% Alpha-Lipoic Acid was applied to the faces of vol- unteers. This double-blind, placebo-controlled trial showed a reduction in facial lines, almost complete eradication of fine lines, and an overall improvement of skin color and texture in most volunteers.46

Alpha-Lipoic Acid critical for cellular energy Cellular energy is behind every single action that happens in your body. In- cluding your brain. Cellular energy is required for muscle movement, producing new cells, wound healing and thinking. The mitochondria in each of your cells is the source of this energy. This ongoing energy production process is call the Krebs Cycle. Alpha-Lipoic Acid is a cofactor to two key enzymatic reactions within the Krebs Cycle. In the simplest terms, without ALA, cellular energy is not possible. And without cellular energy, well… life is not possible.47

Memory loss reversed with ALA and ALCAR Accumulated oxidative damage to brain cell mitochondria eventually leads to neuronal and cognitive dysfunction. One study on rats showed supplementing with ALCAR and Alpha-Lipoic Acid improved memory. By lowering oxidative damage and improving mito- chondrial function.48

Dosage Notes Taking Alpha-Lipoic Acid with a meal decreases its bioavailability. So I rec- ommend taking ALA on an empty stomach (1 hour before eating). Most Alpha-Lipoic Acid supplements contain a 50/50 mixture of R-LA and S-LA. Supplements claiming to contain only R-LA are often more expensive. And information regarding their purity is not often available. Peak plasma (blood) concentrations of R-LA were found to be 40-50% higher than S-LA. This suggests that R-LA is better absorbed than S-LA.49 • Alpha-Lipoic Acid dosage for cognitive benefit is 2 – 600 mg per day. • ALA dosage for diabetic neuropathy is 800 mg per day divided into two doses. • Alpha-Lipoic Acid dosing for antioxidant benefit is 50 – 100 mg per day.

Side Effects Side effects from using Alpha-Lipoic Acid as a supplement are generally rare. But can include diarrhea, fatigue, insomnia and skin rash. 41 David Tomen Alpha-Lipoic Acid can lower blood sugar levels. So if you have diabetes or low blood sugar, you should take Alpha-Lipoic Acid under the supervision of your doctor. Alpha-Lipoic Acid supplementation can lower levels of thyroid hormone. So get your thyroid labs done when using ALA. And adjust your dosage of both ALA and thyroid meds accordingly.

Alpha-Lipoic Acid can lower levels of Vitamin B1 (Thiamine). This can be dangerous for alcoholics, or in cases of malnutrition. It would be wise to add

Vitamin B1 or Sulbutiamine if you’re taking ALA. The chemical structure of Biotin is similar to that Alpha-Lipoic Acid. And there is some evidence that ALA can compete with Biotin for transport across cell membranes. This may require higher doses of Biotin when you’re using ALA.

Available Forms Most Alpha-Lipoic Acid available as a supplement is a 50/50 combination of R-LA and S-LA. S-LA is the synthetic version of ALA and not found in nature. R-LA and S-LA are combined because R-LA is highly unstable on its own. And degenerates quickly. Studies have shown that 30-40% of an oral dose of Alpha-Lipoic Acid is ab- sorbed. Oral ALA supplements are better absorbed on an empty stomach. Taking ALA with food reduces total plasma (blood) concentrations by about 30%. Thesodium salt version of R-LA may be better absorbed than free lipoic acid, likely because of its higher solubility.50 There is little evidence whether R-LA supplements are more effective than regular Alpha-Lipoic Acid supplements in humans.

Nootropics Expert Recommendation

Alpha-Lipoic Acid 50 – 600 mg per day. I recommend using Alpha-Lipoic Acid as a nootropic supplement. Your body does make some Alpha-Lipoic Acid on its own. And from the food you eat. But the science is clear that supplemental ALA is a potent antioxi- dant. And acetylcholine booster. Alpha-Lipoic Acid can lengthen telomeres which is great for your neurons. And neurogenesis (new neuron creation). ALA also helps regenerate antioxidants already in your system that have been depleted while doing their job. And it helps get rid of free radicals in your cells. So you get a double benefit when using Alpha-Lipoic Acid as an antioxidant. Alpha-Lipoic Acid also helps in the creation of acetylcholine. Which boosts all cognitive functions including memory, recall, focus and concentration. ALA is especially helpful for those suffering with diabetes. Studies show it helps relieve diabetic neuropathy or nerve pain. But care must be taken because 42 HEAD FIRST ALA can lower blood sugar levels. So work with your doctor when using Alpha- Lipoic Acid. I suggest starting with a dose of 400 mg daily. And work your way up to 600 mg per day. Taken in two doses during the day. Alpha-Lipoic Acid is often stacked with B-vitamins.

43 David Tomen Aniracetam Aniracetam has been shown to relieve depression, boost learning & memory, improve verbal fluidity, increase music listening pleasure, and make you more social Aniracetam (1-p-anisoyl-2-pyrrolidinone) is a fat-soluble ampakine noot- ropic in the racetam-class of compounds. AMPA (α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic) refers to one of three glutamate receptors in your brain.51 Theracetam-class of nootropics have a pyrrolidone nucleus at their core. And Aniracetam is a Cholinergic compound, meaning it affects acetylcholine levels in the brain. Aniracetam is up to 10-times more potent than the original racetam, Pirace- tam. It was patented by Swiss-based pharmaceutical company F. Hoffmann-La Roche AG in the 1978. Aniracetam is sold as a prescription drug (Ampamet, Draganon, Memodrin, Referan, Sarpul) in Europe. It is sold as an over-the-counter, unrestricted com- pound in the United States. But not as a dietary supplement. A favorite racetam among the nootropics community. Neurohackers use Aniracetam to boost memory and learning. And to relieve anxiety, depression, stress, and improve sociability.52 One of the original synthetic nootropic compounds, it is known as a cogni- tive enhancer. And is known for its anxiolytic, or anti-anxiety effects. As an ampakine nootropic, Aniracetam helps increase attention span, alertness and boosts memory. Ampakines tend to have a stimulant effect. But do not produce the same stimulant side effects as Ritalin or coffee from prolonged use.

Aniracetam vs. Piracetam: What’s the Difference? Swiss-based pharmaceutical company F. Hoffmann-La Roche AGdeveloped Aniracetam in the late 1970’s as a derivative of Piracetam. Aniracetam is fat-soluble while Piracetam is water-soluble. Fat-soluble mol- ecules cross the blood-brain barrier more easily than water-soluble molecules. Aniracetam works faster in the brain after taking compared to Piracetam be- cause of its superior bioavailability. But its effects don’t last as long as Piracetam. The potency of Aniracetam seems almost counter-intuitive. Because most of an Aniracetam dose is lost in the liver during digestion. Only 0.2% of the original dose is available to the brain.53 Piracetam is nearly 100% bioavailable.54 Both Aniracetam and Piracetam are cognitive enhancers. And both have neu- roprotective qualities. Both racetams are able to improve learning and memory. And both are able to repair brain damage. Aniracetam has additional benefits not shared with Piracetam. Aniracetam can reduce anxiety, depression and fear. And increase sociability.55 This may indicate its effects on dopamine and serotonin receptors in the brain. 44 HEAD FIRST How does Aniracetam Work in the Brain? Aniracetam boosts brain health and function in several ways. But two in particular stand out. 1. Aniracetam modulates AMPA receptors in the brain. The main metabolite of Aniracetam (70-80%) is N-anisoyl-GABA and is responsible for many of its effects. 2-Pyrrolidinone and p-anisilic acid are additional metabolites of the drug (20- 30%), both of which are also active.56 The main function of these metabolites is on the glutamate system in the brain. It desensitizes the glutamate receptors. This causes theneurotransmitter glutamate to become more available in the brain. More glutamate means better cognition and memory. And neural protection and repair due to brain injury. 2. Aniracetam also seems to affect dopamine and serotonin receptors in the brain. Leading to improved mood and sociability. One study published in the European Journal of Pharmacology demonstrat- ed the anti-anxiety effects of Aniracetam. Researchers tracked the brain pathways in mice showing Aniracetam’s mechanism of action.57 Illustrating the effect on dopamine and serotonin.

How things go bad Glutamate is an excitatory relative of GABA. While GABA has a calming effect, glutamate stimulates. Glutamate is the most common neurotransmitter in the central nervous system. But glutamate is actually toxic to neurons. And too much of it in your brain can kill brain cells. Lou Gehrig’s Disease for example, is caused by excess glutamate. But glutamate is a pivotal neurotransmitter in the brain. It links the brain circuits involved in memory, learning and perception. ↑ Too much glutamate can kill neurons ↓ Too little glutamate can cause problems with memory, learning and perception ↓ Acetylcholine levels decline All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Aniracetam can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting acetylcholine and controlling gluta- mate in the brain.

Aniracetam to the rescue Aniracetam modulates AMPA receptors which are involved in how glutamate 45 David Tomen is used in your brain. More of the neurotransmitter glutamate is available. Which means better neural signaling across synapses. Your brain is working optimally despite stress, fatigue and anxiety. There is anecdotal evidence that Aniracetam boosts communication between left and right brain hemispheres. You become more creative. And are prone to making innovative and resourceful decisions. Aniracetam combined with choline boosts the production of the crucial neurotransmitter acetylcholine. Improving memory, recall and focus. Aniracetam is fat-soluble and quickly enters your brain after you take it. Once in your brain, it boosts signal transmission, and protects neurons. Aniracetam boosts acetylcholine so you should add a good choline source. Try Alpha GPC or CDP-Choline with Aniracetam. And give your brain the choline it needs.

How does Aniracetam feel? Nootropics users report: • Aniracetam as a study aid. On its own, Aniracetam seems to increase atten- tion span for many neurohackers. And when combined with caffeine, many report being able to work effortlessly for hours on end. • Increased auditory perception. If you love music, Aniracetam can take you deeper into your listening experience. Minute details like background guitars, and other auditory effects come alive. Every instrument becomes part of the sound stage. • Increased visual acuity. The visual effects of Aniracetam feel like your brain is processing a broader spectrum of what’s in your visual range. Nature and your surroundings look more vibrant and beautiful. • Sociability. Many users report being able to articulate thoughts, and im- proved speaking ability. Language and your vocabulary seem to flow effort- lessly. Thoughts and ideas come with less effort. You should be able to experience the effects of Aniracetam soon after you take it. It’s fat-soluble so it’s digested and enters your cells quickly. And unlike other stimulants, there is no “crash” once Aniracetam leaves your system.

The Research Researchers worked with 276 patients with cognitive disorders. They were given Aniracetam and tested at 3, 6 and 12 months. Improved emotional states and better motor functionality was observed within 3 months. A boost in cognitive performance was observed within 6 months. Findings concluded Aniracetam “is a promising option for patients with 46 HEAD FIRST cognitive deficit” disorders. Improvements held throughout the 12-month study. And there was a favorable effect on emotional stability in patients with dementia.58

Aniracetam as an antidepressant A study published in Psychopharmacology in 2001 showed Aniracetam helped stimulate the release of dopamine. The study reported Aniracetam as ef- fective against depression caused by age-related brain dysfunction.59

Aniracetam improves learning & memory Researchers put rats and mice through six scenarios. From drug-induced memory loss to electric shock avoidance, while administering Aniracetam. The results of all tests conclusively showed Aniracetam improving cognitive function. It didn’t matter what they put these animals through. Learning and memory improved with the use of Aniracetam.60

Aniracetam repairs Fetal Syndrome We’re exposed to toxins everywhere we go. And in everything we do during our day. This toxin exposure wreaks havoc in our body, including our brain. In this study, scientists showed one way to repair damage to synaptic trans- mission in the brain. They exposed pregnant Sprague-Dawley rats to and a saccharin-like sweetener. Pups born to these female rats would normally be extremely cognitively impaired. Just like babies born to alcoholic mothers. In this study, the pups born with fetal alcohol syndrome were treated with Aniracetam 18 and 27 days after birth. Aniracetam completely restored synaptic transmission in their brains. And reversed any cognitive deficits associated with fetal alcohol syndrome.61

Dosage Notes Recommended Aniracetam dosage is 1,500 mg per day. Taken in two 750 mg doses. One Aniracetam dose in the morning, and one in the early afternoon. Aniracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each. Since Aniracetam is a fat-soluble nootropic, you should take it with a meal containing healthy fats. Or with a tablespoon of extra virgin, expeller cold-pressed coconut or olive oil. Or other similar healthy fat to ensure quick absorption.

Side Effects Aniracetam non-toxic. So is considered well-tolerated and safe. Side effects are rare but can include anxiety, fatigue, headaches, nervousness and nausea. Side effects are often a result of unusually high doses of the nootropic. Headaches from using Aniracetam typically happen when you forget to 47 David Tomen combine it with a good choline supplement. Headaches are often a symptom of a choline deficit in your brain.

Available Forms Aniracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each. In Europe and some other countries around the world, Aniracetam is a prescription drug. And sold under the brand names Ampamet, Draganon, Memodrin, Referan, and Sarpul.

Nootropics Expert Recommendation

Aniracetam 1,500 mg per day I recommend using Aniracetam as a nootropic supplement. Your body does not make Aniracetam on its own. So to get its benefits you must take it as a supplement. Aniracetam is especially helpful for those suffering from depression. Studies show it helps stop and reverse the symptoms associated with depression. This nootropic helps boost the activity of dopamine and serotonin in your brain. Personally, I’ve found Aniracetam to be more effective (and safer) than any prescription anti-depressant I’ve ever tried. Aniracetam is also particularly useful to students and executives who want to boost cognition, learning and memory. My experience using Aniracetam shows it helps boost study scores, work flow, learning and memory. Aniracetam also helps improve verbal fluidity and sociability. Words seem to come easily, and vocabulary you didn’t know you had access to come into play. Music sounds richer and fuller, and your listening experience enters a new level of music appreciation. You should use Aniracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Aniracetam to 3,000 mg. if needed.

48 HEAD FIRST Artichoke Extract (Luteolin)

Artichoke Extract (Luteolin) has been shown to boost memory and learning, improve motivation and mood, and stimulate the growth of new neurons in the brain. Artichoke Extract (Luteolin) contains a naturally occurring compound called luteolin. Luteolin is a natural and powerful phosphodiesterase (PDE4) inhibitor. Excess PDE4 in your brain is bad news because it degrades cAMP. Cyclic adenosine monophosphate (cAMP) is a derivative of adenosine triphosphate (ATP). ATP is fuel for mitochondria in each of your cells. cAMP is part of that cellular energy source. As a secondary messenger in neurons, cAMP helps produce proteins for increased neuron growth. Neuron dendrites connect to other neurons through a process called Long-Term Potentiation (LTP). LTP creates an increase in the production of cAMP. Which triggers a bio- chemical cascade of reactions. Which is the basis of learning and memory. When cAMP is degraded, it interferes with efficient brain signaling. And interferes with Long-Term Potentiation. Making it harder to develop memories, and to learn. Artichoke Extract (luteolin) reduces PDE4. When PDE4 is reduced, you not only maintain healthy cAMP cellular energy. Brain signaling is actually amplified.62 When luteolin is combined with another natural herb called Forskolin, you get double duty. Luteolin reduces PDE4 which maintains cellular signal strength. And Forskolin boosts cAMP. Increasing brain signal strength.

Artichoke Extract (Luteolin) vs. Pure Luteolin: What’s the Difference? Luteolin is not bioavailable on its own if taken as a supplement.63 It requires the presence of other naturally occurring bioflavonoids to be metabolized by your body. And to reach the cells in active form. Artichoke Extract contains the compounds -7-rutinoside and nariru- tin, which unlocks Luteolin’s potential to work in your cells.64

How does Artichoke Extract (Luteolin) Work in the Brain? Artichoke Extract (Luteolin) boosts brain health and functions in several ways. But two in particular stand out. 1. Artichoke Extract (luteolin) inhibits PDE4 which boosts cAMP activ- ity in brain cells. cAMP helps stimulate the production of CREB (cAMP response element-binding protein). An increase in CREB enhances Long-Term Potentiation (LTP). LTP is the connection between brain synapses. Strengthening in response to stimulation by neurons on either side. A major component in both learning and memory. 49 David Tomen Memories are stored at a cellular level. And retrieved at a cellular level. This well-travelled pathway is strengthened by boosting cAMP with Artichoke Ex- tract (Luteolin). This improvement in memory was demonstrated by researchers at the Uni- versity of Genoa in Italy. Rats and mice were used in this study. In this case, the PDE4 inhibitor they used was a chemical derivative of . (Rolipram cannot be used in human patients because it causes vomiting). Results of the study showed this derivative enhanced memory function even at low doses. Acting on the same neural pathways as Artichoke Extract in humans.65 2. Artichoke Extract (Luteolin) reduces brain inflammation. Researchers studied the effect of Luteolin on immune system cells in the brain called microglia. Microglia produce cytokines in response to infections and toxins. Over- production of cytokines result in inflammation and the destruction of neurons. In this study, brain cells in mice were pretreated with Luteolin before being exposed to a substance that induced inflammation in brain cells. The same type of inflammation humans experience from daily exposure to toxins. The study showed that Luteolin offered protection against brain inflamma- tion. And its consequences. Including problems with cognition and memory. The research team concluded that Luteolin “may be useful for mitigating neural inflammation”.66

How things go bad Environmental factors, ADHD, illness, stress and aging changes our brain chemistry. ↓ Mood and motivation declines ↓ Memory and recall declines ↓ Long-term memory fades All of these changes are contributing factors to poor quality of life. And as they progress, to neurodegenerative diseases like Alzheimer’s, dementia and Parkinson’s.

Artichoke Extract (Luteolin) to the rescue Research from hundreds of studies, and feedback from neurohackers have shown that Artichoke Extract can: • Improve memory by inhibiting PDE4 in the brain (which boosts cAMP activity) • Boost dopamine levels in the brain • Tame inflammation in the brain 50 HEAD FIRST Artichoke Extract (Luteolin) is water-soluble and quickly enters your brain after you take it. Once in your brain, it inhibits PDE4 which boosts cAMP activity. cAMP is involved in the Long-Term Potentiation process of preserving memories. Artichoke Extract combined with Forskolin is even more effective. Because not only are you helping cAMP activity in the brain, you’re boosting cAMP with Forskolin. Inhibiting PDE4 and boosting cAMP also makes the effect of normal do- pamine production more effective. Boosting processes in this stream of chemical reactions in the brain increases learning and memory.67 Without the side effects of stimulating dopamine production through the use of drugs like Adderall or Ritalin.

How does Artichoke Extract (Luteolin) feel? Many neurohackers report that Artichoke Extract with Forskolin improves mood. It motivates you to want to learn, and to get things done. Some say it works as good as Modafinil. The general consensus is: • Improved mood and motivation • Increased ability to study • Increased ability to retain information • Improved long-term memory

The Research Microglia cells are immune cells in your brain and spinal cord. They produce signaling molecules called cytokines. These cytokines are cell signaling molecules that aid communication between cells in immune responses. When microglial cells are not regulated, they produce excessive levels of cytokines. And inflammatory cytokines kill neurons. Leading to cognitive aging and neurodegenerative diseases like Alzheimer’s. And are responsible for produc- ing symptoms like sleepiness, loss of appetite, memory deficits and depression. Researchers at the University of Illinois at Urbana–Champaign worked with a group of young, and older mice. The mice were fed a control diet, or a luteolin- supplemented diet for 4 weeks. The research team found that luteolin helped regulate microglial cells. And stopped them from producing excess cytokines. This reduced inflammation in the brains of aged mice. And restored memory to levels observed in younger mice.68

Artichoke Extract improves mood Users report that Artichoke Extract boosts mood. Researchers at Kurume University School of Medicine in Japan demonstrated in the lab how this boost in mood occurs. 51 David Tomen When dopamine D1 receptors in the prefrontal cortex of the brain mal- function, psychotic symptoms and other nasty symptoms show up. Including . The study group found that dopamine D1 receptors signal through the cAMP cascade. Which is modulated by PDE4 enzymes. In this study, researchers inhibited PDE4 production in the lab. Showing that an increase in dopamine resulted in influencing cognitive function. Proving the antipsychotic action of suppressing PDE4.69

Artichoke Extract improves memory Researchers at the West Virginia University Health Sciences Center in the USA worked with tame and wild-type mice. Suppressing PDE4 in the mice enhanced memory. And increased the growth of new neurons in the hippocampus of the brains in these mice.70

Dosage Notes For PDE4 suppression: 900 mg Artichoke Extract per day For boosting cAMP: 4 mg Forskolin (Coleus forskohlii) extract per day Note: Check the label of the Forskolin supplement for the amount of actual Forskolin in each capsule. For example, 385 mg of Forskohlii may only be guar- anteed to contain 3.85 – 4 mg of actual Forskolin. Which is what you need. Also note that more Forskolin is not better as it causes a strong fatigue effect at higher doses. For counteracting Forskolin’s effect on Acetylcholinesterase: add 800 mg Acetyl-L-Carnitine (ALCAR) – (200 mg of ALCAR for every 1 mg of Forskolin) per day Many users of this stack report it helpful to supplement with 500 mg Phe- nylalanine, a B-Vitamin Complex and caffeine (coffee or preferably green tea). Note: the above combination of nootropics is known among neurohackers as the CILTEP stack. CILTEP stands for Chemically Induced Long-Term Potentation.

Side Effects Acetylcholinesterase is upregulated by cAMP which makes you sleepy. This means that available Acetylcholine in your brain drops. You can counter- act this with Acetyl-l-Carnitine (ALCAR), which calms the upregulation of Acetylcholinesterase. Artichoke extracts have been documented to lower blood cholesterol in human and animal studies. This means it may potentiate the effects of cholester- ol-lowering and statin drugs. Artichoke Extract affects the liver by stimulating the flow of bile. So if you have liver disease be careful about using this herb. 52 HEAD FIRST Artichoke Extract can also cause gallbladder contractions. So if you have gallbladder disease or gallstones, check with doctor before taking this herb.

Available Forms Two very different forms of artichoke are available. The Globe Artichoke (Cynara cardunculus) which has been cultivated and used since ancient times. And the Jerusalem Artichoke (Helianthus tuberosus) which is from the North- eastern USA. All references to Artichoke Extract in this article is for the Globe Artichoke. Users report that Artichoke Extract (Standardized to 5% Cynarins) of most premium brains are helpful in reducing PDE4.

Nootropics Expert Recommendation

Artichoke Extract (Luteolin) 900 mg per day I recommend using Artichoke Extract as a nootropic supplement. Your body does not make Artichoke Extract (Luteolin) on its own. So you must take it as a standardized supplement. Luteolin on its own as a supplement does not appear to be effective. Luteolin is not bioavailable so your body can’t use it. Luteolin as part of the Artichoke plant is used by your body. Because it contains other that help your body absorb it. Artichoke Extract is especially helpful when combined with Forskolin. It helps boost memory, increases motivation and the desire to learn. And helps improve mood. I suggest dosing Artichoke Extract at 900 mg per day taken in the morn- ing. With 4 mg of Forskolin. Stack this with 800 mg of ALCAR to keep your acetylcholine levels up. I’ve also found that combining this Artichoke Extract stack with caffeine is helpful. The L-Theanine in green tea works with the caffeine boost we need. Without the side effects of coffee. I’ve also found that more in not better with this stack. And taking it early in the day is good for a productive day. The effects last all day. And finally, we are making the effects of normal dopamine function more ef- fective with this stack. It triggers the desirable downstream processes that increase learning and memory. The chemical dynamics of the dopamine system are preserved. And we don’t get the negative side effects of using a stimulant like Adderall or Ritalin. This Artichoke Extract (Luteolin) stack increases mental endurance for en- coding long-term memories.

53 David Tomen Ashwagandha

Ashwagandha has been shown to repair and reverse damage to the brain caused by chronic anxiety and stress Ashwagandha (Withania somnifera) is one of the most powerful herbs in Ayurvedic healing. This ancient herbal remedy has remarkable anti-depressant qualities. And has been shown to be as good as many prescription pharmaceuti- cals in treating depression and anxiety. In Sanskrit, Ashwagandha means “smell of horse”. Meaning this herb im- parts the strength and vigor of a stallion. Ashwagandha is often referred to as “Indian ginseng” because of its rejuve- nating properties. But botanically, Ashwagandha and ginseng are unrelated. Native to India, Pakistan and Sri Lanka. Ashwagandha is now being grown in other regions including the United States. Ashwagandha is in the same family as the tomato. It’s a small woody shrub with oval leaves, and five-petal yellow flowers. The fruit is red and the size of a raisin. The plant is also known as the “Winter Cherry”. Ashwagandha is known as an adaptogen. Which means it helps your body adapt to stress, both mental and physical. The Indian Materia Medica lists Ashwagandha for: • general debility • impotence • general aphrodisiac purposes • brain fatigue • low sperm count • nervous exhaustion • where general vigor must be restored. Ashwagandha extract has been shown to be an effective antioxidant in the brain. Clearing the cellular waste implicated in Alzheimer’s Disease.71 Is also boosts memory and cognition. By reducing stress and increasing acetyl- choline. And regeneration of nerve networks in the brain.

How does Ashwagandha Work in the Brain? Ashwagandha boosts brain health and function in several ways. But two in particular stand out. 1. Ashwagandha enhances GABA receptors and serotonin in the brain. It appears to work on neuron receptors, enabling GABA to connect easier. This inhibits the signals present under a stress response in the brain. Anxiety goes down. 54 HEAD FIRST A study was conducted at The Canadian College of Naturopathic Medicine with 75 volunteers with moderate to severe anxiety. Ashwagandha produced a significant decrease in anxiety levels over the control group.72 2. Ashwagandha improves cognitive and psychomotor performance in a healthy brain. Researchers at Nizam’s Institute of Medical Sciences in Hyderabad, India worked with 20 healthy male volunteers. In this double-blind, placebo-controlled trial participants were given 250 mg capsules of standardized Ashwagandha ex- tract daily for 14 days. Significant improvements in reaction times were reported at the end of the trial. The study suggests that Ashwagandha extract improves cognitive and psychomotor (physical reaction) performance even when you’re in the best of health.73

How things go bad Chronic stress and cortisol can damage your brain. Neuroscientists at the University of California, Berkeley, found that chronic stress triggers long-term changes in brain structure and function.74 Chronic stress changes neural networks. Cortisol creates a domino effect that hard-wires pathways between the hippocampus and amygdala. (The amygdala (lizard brain) is the area responsible for your fight-or-flight response). This hard-wiring caused by stress is not the way the brain was designed. But chronic, ongoing stress tricks the brain into rebuilding circuits and hunkering down for the long haul. This re-wiring appears to be permanent. Unless you intervene with some- thing like Ashwagandha. Chronic stress seems to ‘flip a switch’ in stem cells in the brain. And turns them into a type of cell that prevents connections to the prefrontal cortex. Pre- venting improved learning and memory. And laying down the scaffolding linked toanxiety , depression and PTSD (Post Traumatic Stress Disorder). ↓ Chronic stress unnaturally coats neurons in myelin ↓ Chronic stress reduces the number of neurons ↓ Gray matter decreases and white matter increases. Under conditions of chronic stress and excess cortisol, your brain’s neurons are coated (or sheathed) in myelin. Under healthy conditions this “sheathing” is a protective measure. But this excessive sheathing is likely an evolutionary measure made to reinforce the con- nection between the hippocampus and amygdala. Improving the fight-or-flight response during extended periods of threat or attack. 55 David Tomen In the modern world, chronic stress hijacks your fight-or-flight response system. It backfires in daily life in when you are not typically in physical danger.

Ashwagandha to the rescue Ashwagandha undoes damage to the brain caused by chronic stress. And helps keep it healthy. Ashwagandha improves cognitive function. Glycowithanolides, one of the many compounds found in this herb, reduce cortisol. And overall energy levels are enhanced through optimizing mitochondrial function. It also has GABA-mimicking effects in the brain.Comparable to the effects of prescription benzodiazepines like lorazepam (Ativan). Ashwagandha can also help prevent and repair damage caused by Alzheimer’s, Parkinson’s and Huntington’s disease. Through its antioxidant and inflammation- reducing mechanisms. Ashwagandha even provides protection and regeneration of neurons during opiate and heroin withdrawal. And eases withdrawal symptoms. In Ayurvedic medicine, Rasayana herbs are used to promote a youthful state of physical and mental health. The ancients considered Medhya Rasayana herbs to be working with higher brain function. These are mind-rejuvenating herbs. Of the 8 or 9 most cherished herbal remedies, Ashwagandha is the highest or most prominent of Ayurvedic Rasayana herbs. Acting as an adaptogen, rejuve- nating the nervous system, and boosting the body’s resilience to stress.

How does Ashwagandha feel? Ashwagandha users report: • Ashwagandha as a stress-reliever. If you are experiencing severe fatigue and brain fog, it’s likely stress. Chronic or severe stress can disguise itself in many ways. Including feeling abnormally fatigued. You find that you are not sleeping well. Or don’t feel rested and refreshed when waking up in the morning. Even after taking a sleeping pill. Many report a rapid change in energy and motivation as soon as they take Ashwagandha. Others won’t feel the effects for a couple of weeks before relief sets in. You’ll know Ashwagandha is working when you wake up in the morning feeling refreshed. And eagerly looking forward to starting your day. • Ashwagandha as an anti-anxiety aid. As an anti-anxiety aid users say they feel their self-confidence has been restored. Your speech will feel more fluid and easier, especially in public settings. No more panic attacks. • Ashwagandha as an anti-depressant. Depression, even if it’s not profes- sionally diagnosed, can destroy your life. Ashwagandha users say it is the 56 HEAD FIRST best anti-depressant they’ve ever used. Their energy is restored, motivation is back, and they’re able to focus. Ashwagandha works on many levels in the brain. Cortisol levels are stabi- lized. And the damage to your brain begins to correct itself. Acetylcholine levels rise so you’re able to think clearly again. Neurons get repaired, and cognition and memory return to levels you expe- rienced when you were younger. And GABA receptors are re-activated producing a calming effect.

The Research Researchers at Asha Hospital in Hyderabad, India did a double-blind, ran- domized, placebo-controlled trial with 64 subjects who had a history of chronic stress. The study group took a 300 mg capsule of full-spectrum Ashwagandha root twice a day for 60 days. Follow up calls to participants were done on the 15th, 30th, 45th and 60th day of the trial. Researchers reported serum cortisol levels were substantially reduced. The report concluded “that a high-concentration full-spectrum Ashwa- gandha root extract safely and effectively improves an individual’s resistance towards stress and thereby improves self-assessed quality of life”.75

Ashwagandha as a nootropic One study done in a lab in India subjected laboratory mice to electrocon- vulsive shock treatment. Or were given scopolamine to induce amnesia (memory loss). Both sets of mice were given Ashwagandha extract daily after the shock or chemical treatments. Ashwagandha extract restored their memory and motor skills.76

Ashwagandha as an anti-depressant Scientists did a study on rats to compare Ashwagandha with the popular anti-depressant lorazepam (Ativan). And the tricyclic anti- depressant (Tofranil). Researchers gave the rats either Ashwagandha, lorazepam or imipramine. 30 minutes later they put the rats through a maze, had them interacting socially, and even forced them to swim. They concluded that as a mood stabilizer, Ashwagandha worked on depres- sion and anxiety as well as either of the two anti-depressants.77

Dosage Notes Ayurvedic Pharmacopoeia of India recommends 3 – 6 grams daily of stan- dard ground Ashwagandha powder. • For arthritis: 250 – 500 mg of extract (4-5% withanolides) • For antioxidant protection: 100 – 200 mg of extract (4-5% withanolides) 57 David Tomen • For immunity: 100 – 200 mg of extract (4-5% withanolides) • For relaxation: 250 – 500 mg of extract (4-5% withanolides) • For stress: 250 – 500 mg of extract (4-5% withanolides) • For sexual performance: 250 – 500 mg of extract (4-5% withanolides) For higher does like 500 mg, take 250 mg in the morning and another 250 mg early afternoon.

Side Effects Note: Ashwagandha stimulates your thyroid. So if you are hypothyroid, use Ashwagandha with caution. And check with your endocrinologist to be safe. Ashwagandha is non-toxic at moderate doses. If you are pregnant do not use Ashwagandha as it could cause a miscarriage. This herb is an adaptogen with powerful hormonal effects. Ashwagandha can enhance the effects of sedatives, anti-depressant and anti- anxiety medications including St. John’s Wort. It can also interact and possibly amplify the effects of immune suppressants, blood pressure medication, and drugs used to control blood glucose levels. Ashwagandha can boost the effects of alcohol. And do not use Ashwagandha if you have bleeding issues, or before surgery. Other possible side effects include diarrhea, nausea, abdominal pain, drowsi- ness and slowed pulse.

Available Forms Ashwagandha is available as a powder, capsules, tincture and tea. The root and berry of the plant are used. The ground root of the herb is used as the base of an Ashwagandha supplement. Active ingredients of Ashwagandha include alkaloids, saponins, and witha- nolides. Look for the percentage of active ingredients listed on the bottle or pack- age. Typically, you’ll see something like “standardized to X% of withanolides”. Avoid supplements that list “other ingredients” on the label. And look for Certified Organic to ensure the root used to make your Ashwagandha supple- ment is free of heavy metals, pesticides and herbicides.

Nootropics Expert Recommendation

Ashwagandha Extract 250 – 500 mg per day I recommend using Ashwagandha as a nootropic supplement. Your body does not make Ashwagandha on its own. So to get its benefits you must take it as a supplement. Ashwagandha is especially helpful for those suffering from anxiety and stress. Studies show it helps stop and reverse the devastating effects of stress on your 58 HEAD FIRST brain, and body. This nootropic helps repair the damage to neurons and synapses caused by chronic stress. Ashwagandha is a powerful adaptogen. Which means it helps increase the effect of certain hormones when activity is low. And will block excess stimulation when activity is too high. Ashwagandha as an adaptogen helps balance cortisol in the body caused by chronic stress. Chronically elevated cortisol levels suppress immunity, create fat deposits on the belly, face and neck, reduces libido, causes bone loss, causes insulin resistance, and brain fog. Balancing cortisol levels with Ashwagandha improves your sleep quality, im- munity, stress response, organ function, reduces fatigue, and brain fog. Ashwagandha is also helpful for those suffering from anxiety and panic disor- ders. A study published in Phytomedicine showed the calming effect of this herb was equal to the drug Ativan (lorazepam). Without the side effects. You can safely take up to 750 mg of Ashwagandha extract daily if needed. Most get all the benefit they need with 500 mg. Dosed 250 mg in the morning, and another 250 mg early afternoon.

59 David Tomen Bacopa Monnieri

Bacopa Monnieri has been shown to boost memory and cognition, improve mood, and reduce stress Bacopa Monnieri (Brahmi) is an aquatic herb originally found in the wet- lands and marshy areas of Southeast Asia and India. Bacopa, also known as water hyssop, is often referred to as “Brahmi”. Named after the supreme god Brahma. Ancient Ayurvedic texts talked about Bacopa. It was recommended to devo- tees to help memorize long passages of text. In the West, Bacopa Monnieri is often used to reduce anxiety, depression and stress. But it’s gaining popularity in the nootropic community as a powerful memory and cognition booster. The active compound Bacoside A in Bacopa easily crosses the blood-brain barrier. How does Bacopa Monnieri Work in the Brain? 1. Bacopa Monnieri boosts brain health and function in several ways. But two in particular stand out. Bacopa Monnieri boosts memory. Bacopa’s two active components are bacosides A and B. They improve the signaling of electrical impulses between neurons in your brain. Bacosides also help rebuild damaged neurons. Bacopa Monnieri helps you learn and remember things more easily. In one study, researchers gave 54 volunteers in Portland, Oregon 300 mg of B. Monnieri per day for 12 weeks. After the 12-week study, the people taking Bacopa had: • Better word recall • Better attention • Better memory scores • A great ability to focus while learning • Less anxiety and lower heart rates78

2. Bacopa Monnieri reduces stress. Bacopa has traditionally been used in Ayurveda as a tonic for the nervous system. It helps to reduce anxiety. Research at Banaras Hindu University in India showed Bacopa as effective for anxiety as the benzodiazepine drug lorazepam. One of the side effects of loraz- epam is memory loss. Bacopa Monnieri on the other hand, reduced anxiety while boosting cognition.79

How things go bad Chronic stress and cortisol can damage your brain. Neuroscientists at the 60 HEAD FIRST University of California, Berkeley, found that chronic stress triggers long-term change in brain structure and function.80 Chronic stress damages neural networks. Certain proteins are over-expressed damaging neurons as a result. Toxins invade cells, hijacking their normal, healthy function. And oxidative damage by free radicals harm brain cells if they’re not removed. ↓ Chronic stress reduces memory capacity ↓ Toxins kill brain cells from the inside ↓ Free radicals destroy neurons and synapses Under conditions of chronic stress your brain loses the capacity to transmit signals between neurons efficiently. Memory, cognition, and decision-making all suffer as a result.

Bacopa Monnieri to the rescue Bacopa Monnieri undoes damage to the brain caused by chronic stress. And helps keep it healthy. This is a little complicated, so stay with me here. Your brain is protected by heat-shock protein 70 (Hsp70), cytochrome enzymes EROD and PROD, and superoxide dismutase (SOD). Hsp70 helps proteins in cells retain normal structure so they remain func- tional. EROD (7-ethoxyresorufin-O-deethylase) and PROD (7-pentoxyresorufin-O- dealkylase) are detox enzymes. They protect your brain by converting bad toxins into less harmful compounds. And SOD battles destructive free radicals called superoxides. And converts them into harmless organic compounds.

Bacopa Monnieri Keeps Your Brain Healthy Under Stress When you are under stress, levels of Hsp70 increase in all regions of your brain. But research shows that animals pretreated with Bacopa for 7 days prevent- ed most of this increase in Hsp70. Particularly in areas of the brain responsible for memory. This means that producing less Hsp70 under stress, Bacopa makes your brain less susceptible to stress. Bacopa kept those regions of the brain in a non-stressed state. Even in the presence of stress. Bacopa also has a preemptive action on EROD and PROD. Rats treated with Bacopa, but not under stress, saw an increase in these two enzymes. Sug- gesting that Bacopa helps stockpile these protective enzymes to help you better deal with stress. And when it comes to SOD, researchers said, “Bacopa helps in coping with the combined hypoxic, hypothermic, and immobilization stress, which could lead to an onslaught of free radicals.” So Bacopa helps SOD activity and prepares cells to weather attacks by free radicals.81 Translated, this all means Bacopa helps your brain deal with stress. And helps boost memory. 61 David Tomen How does Bacopa Monnieri feel? The effects of Bacopa are not felt immediately. But seem to build over time. Some users report a pronounced anti-anxiety effect within 2 – 4 days of supple- menting with Bacopa. In one study done in Australia, results were measured at 5 and 12 weeks of taking Bacopa. The results showed improved speed of information processing, and an increase in learning and memory. Maximum reduction in anxiety was realized after 12 weeks of use.82 Some neurohackers say they feel the effects of Bacopa Monnieri sooner than 4 weeks. And the effects seem to keep working even after stopping supplementa- tion. The effects are long-term. Long term users say they consistently feel calmer, can think quicker and have better memory.

The Research

Bacopa Monnieri as a Nootropic This double-blind placebo-controlled investigation was done at Swinburne University in Australia. 107 healthy participants were given 300 mg of Bacopa Monnieri extract for 90 days. After 90 days, the people who took B. Monnieri extract showed significant improvement in spatial memory, memory accuracy and their ability to process visual information.83

Bacopa Monnieri for Stress Reduction Bacopa is likely best known for reducing stress. Recent research at Swinburne University of Technology in Australia confirmed this in the lab. In this double-blind, placebo-controlled cross-over study 17 healthy vol- unteers were given 320 mg or 640 mg of Bacopa extract. The study reported significant mood improvement, and decreased levels of cortisol. This study demonstrated Bacopa’s adaptogenic qualities. Bacopa Monnieri counteracted the effects of stress by regulating hormones involved in the stress response.84

Bacopa Monnieri for Longevity Long-term exposure to aluminum can increase your risk of Alzheimer’s Dis- ease by 60 percent.85 (So check your underarm deodorant label before you read the rest of this section)! Research shows that Bacopa Monnieri can protect you from toxins that are harmful to your brain. Including aluminum. It prevents the buildup of toxins between and inside neurons. And prevents damage to the hippocampus. The area of your brain critical for learning, memory and cognitive power. 62 HEAD FIRST Scientists at Jawaharlal Nehru University in India laced rats’ drinking water with aluminum chloride. The same aluminum that’s toxic to your brain. Some of the rats in this study had the protective power of Bacopa Monnieri going for them. Bacopa Monnieri protected the rat’s brains from oxidative damage from the aluminum. And it worked as well as the Alzheimer’s drug selegiline. Bacopa restored the enzyme superoxide dismutase (SOD) to levels near normal. Indicating Bacopa Monnieri’s anti-aging potential.86

Dosage Notes There is no ‘right’ dosage of Bacopa. Each person’s body is unique. In general, use the lowest dosage that works for you. And Bacopa works better if taken a few days in a row rather than just once. Recommended dosage of Bacopa Monnieri containing 45% bacosides is 200 – 450 mg per day. Recommended dosage of Bacopa Monnieri containing 20% bacosides is 750 mg per day. Higher dosing should be divided equally with your first dose in the morning, and next dose early afternoon. Bacopa is fat-soluble so should be taken with a healthy fat source like or- ganic, cold-pressed virgin olive or coconut oil. Fat helps your body absorb the compounds in Bacopa that bring you benefit. And helps deliver it into your brain cells.

Side Effects Side effects for Bacopa are rare when taken as directed. But can include fatigue and upset stomach.

Available Forms The bioactive component of Bacopa Monnieri is Bacoside A. Which is a mixture of saponins with bacoside A3, bacopaside II, and jujubogenin isomer of bacopasaponin C. Bacopa supplements are available as a powder, capsules and tablets. Check the label for the concentration of Bacosides. A Bacopa extract with a higher Bacoside concentration requires a lower dose.

Nootropics Expert Recommendation

Bacopa Monnieri up to 450 mg per day I recommend using Bacopa Monnieri as a nootropic supplement. Your body does not make Bacopa Monnieri on its own. So you must take it as a supplement. B. Monnieri is especially helpful for those suffering from anxiety and stress. 63 David Tomen Studies show it helps stop and reverse the devastating effects of stress on your brain, and body. This nootropic helps repair damage to neurons and synapses caused by chronic stress. Bacopa is a powerful adaptogen. Which means it helps increase the effect of certain hormones when activity is low. And will block excess stimulation when activity is high. Bacopa Monnieri is also helpful for those suffering from anxiety and panic disorders. A study published in Phytomedicine showed the calming effect of this herb was equal to the drug Ativan (lorazepam). Without the side effects. The ancient Ayurvedic texts knew what we’re only now discovering. That Bacopa is a powerful memory enhancer. Recent studies in Australia and the USA show B. Monnieri helps improve word recall, memory scores, attention and learning. You can safely take up to 450 mg of Bacopa Monnieri extract (45% Baco- sides) daily if needed. Half the dose first thing in the morning. And the other half early afternoon.

64 HEAD FIRST Cat’s Claw

Cat’s Claw has been shown to increase Brain-Derived Neurotrophic Factor, fight in- flammation and free radical damage, repair DNA, alleviate depression, and improve cognition and focus Cat’s Claw (Uncaria tomentosa, Uña de Gato, or Savéntaro) is a South American vine used as a nootropic with potent anti-inflammatory and antioxidant effects that support DNA repair, immune function and normal cell division.87 Cat’s Claw is a large, woody vine that gets its name from the hook-like thorns on the leaf stem resembling the claws of a cat. Cat’s Claw is indigenous to the Amazon rainforest and other tropical areas of South and Central America. Cat’s Claw has been used medicinally by the Aguaruna, Asháninka, Cashibo, Conibo, and Shipibo tribes of Peru for at least 2,000 years. The Asháninka use Cat’s Claw for everything from asthma to urinary tract infections to cancer. I won’t go into the long list of ailments Cat’s Claw is used for here because we’re focusing on the cognitive benefits of this herb. Just rest assured, Cat’s Claw has an amazing track record. Most of the commercially grown Cat’s Claw (Uncaria tomentosa) we get for nootropic use is from Peru. Cat’s Claw is rich in phytochemicals, alkaloids, gly- cosides, tannins, flavonoids, sterol fractions and other compounds. Ignore the marketing hype of “good alkaloids”, “bad alkaloids” and “TAO- Free” for Cat’s Claw. Independent research since the early 1970’s in animals and humans have used everything from freeze-dried ground root and bark to individual extracts of specific Cat’s Claw compounds. Cat’s Claw has been shown to decrease inflammation of arthritis88, prevent DNA damage89, reduce free radical damage90, reduce cancer91, controls pain through serotonin (5-HT2) receptors92, and much more.

How does Cat’s Claw work in the Brain? Cat’s Claw boosts brain health and function in several ways. But two in particular stand out. 1. Cat’s Claw is a neuroprotectant. Cat’s Claw and its extracts have long been used to treat arthritis, asthma, chronic inflammation, immune disorders, pain, wound healing and tumors. Some of the more recent research has focused on the cognitive benefits of Cat’s Claw. And using Cat’s Claw to protect brain function and cognition. One study demonstrated that an extract of Cat’s Claw could enhance DNA repair in the brain.93 Another study showed Cat’s Claw extract boosting Tryp- tophan levels which could have a profound effect on serotonin and mood.94 Dozens of other studies show Cat’s Claw possessing antioxidant properties, anti- 65 David Tomen inflammatory, an immune modulator, anti-tumor, antihypertensive, as well as prevention of stroke.95 2. Cat’s Claw can increase memory and learning. Cat’s Claw extracts can help learning and memory in a healthy as well as a damaged brain. Research shows certain alkaloid extracts of Cat’s Claw can help repair brain cells damaged by stroke or dysfunction of the acetylcholine receptors. The Cat’s Claw alkaloid Rhynchophylline is a NMDA antagonist. 96 Selectively restricting NMDA receptors helps tone down hyperactivity and overstimulation. Providing a calm mind for clear cognition and learning.

How things go bad Chronic stress, anxiety and free radicals (oxidation) damage your brain. This damage can manifest in several ways including memory loss, brain fog, anxiety, depression, and even neurodegenerative diseases like Alzheimer’s and Parkinson’s. ↓ Chronic stress reduces memory ↓ Free radicals kill brain cells ↓ Neuroplasticity declines degrading long-term potentiation97 ↓ Brain – Derived Neurotrophic Factor Declines ↑ NMDA receptors are over-active Under conditions of chronic stress or depression caused by everyday living or chronic pain, your brain loses the capacity to transmit signals between neurons efficiently. Memory, cognition and decision-making all suffer as a result.

Cat’s Claw to the rescue Research from hundreds of studies have shown that Cat’s Claw and its extracts: • Potent antioxidant and anti-inflammatory • Relieves pain through influence on serotonin receptors • Enhances DNA repair • Boosts immune health • Suppresses tumor proliferation • Protects against damage from stroke98 • Improves memory and cognition • Restores the availability of acetylcholine • Improves cerebral circulation • Reduces stress • Helps repair brain cells 66 HEAD FIRST • Eliminates free radicals from within brain cells

How does Cat’s Claw feel? Cat’s Claw is a potent anti-inflammatory and immune booster. Most neuro- hackers report a dramatic decrease in arthritis and joint pain. Cat’s Claw has a reputation for reducing the symptoms of Lyme Disease and Crohn’s Disease. Most who use Cat’s Claw regularly report they don’t get sick as often, experi- ence less pain, and have an easier time getting to sleep and sleeping through the night. Some neurohackers use Cat’s Claw to relieve an over-active mind. Cat’s Claw can calm racing thoughts and make it easier to focus.

The Research

Cat’s Claw Improves Memory Cat’s Claw has been reported to restore memory both in the lab and in user reviews. One method of increasing memory with Cat’s Claw may be through promoting long-term potentiation. Rhynchophylline (Rhy) is an alkaloid isolated from Cat’s Claw that has long been recommended for treatment of diseases in the central nervous system. Researchers in China investigated using Rhy in stroke victims. Rats were injected with Rhynchophylline once daily for 4 consecutive days before surgery, and then one more injection after surgery. The surgery created a stroke in the rats by severing a middle artery in their brain. The team found that Rhynchophylline prevented brain damage from the stroke while increasing BDNF expression.99 Cat’s Claw extract also activated the PI3K/Akt/mTOR signaling pathway which is a necessary component of long- term potentiation.100 Long-term potentiation is the strengthening of synapses between neurons which is one of the major mechanisms in the brain behind learning and memory.

Cat’s Claw Suppresses Cancer Cat’s Claw has traditionally been used by indigenous cultures in South America and other parts of the world to treat cancer. And several studies caught my attention because I came across two Cat’s Claw customer reviews on how the herb helped them survive a dismal diagnosis of brain cancer. Austrian researchers used Cat’s Claw extracts (isopteropodine (A1), ptero- podine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5)) on human leukemia T cells on the lab. Four of the five extracts not only stopped cancer cell growth, but killed the cancer cells outright.101 67 David Tomen Another USA research team found that Cat’s Claw has the ability to regulate immune system cytokines that help your body’s defense against cancer.102 An Italian study investigated using Cat’s Claw extract on breast cancer. The researchers found that Cat’s Claw prevented the growth of 90% of breast cancer cells in the lab.103 A research team in Mexico found that Cat’s Claw extract stopped Wnt- signaling activity in cancer cells.104 The Wnt-signaling pathway is implicated in glioblastoma, the most common and most aggressive cancer that occurs in the brain.

Cat’s Claw Repairs DNA and Boosts Immune System Researchers in Sweden used the C-MED-100 (AC11®) extract of Cat’s Claw in rats and men. Rats were given doses of 0, 5, 10, 20, 40 and 80 mg of the Cat’s Claw extract per kg of body weight for 8 consecutive weeks. White blood cell counts in the 40 and 80 mg treatment groups were significantly elevated over controls. In male volunteers, healthy men were given 5 mg of Cat’s Claw extract per kg of body weight for 6 consecutive weeks. Again white blood cell count was significantly elevated in the male volunteers. The researchers also found that DNA repair got a significant boost by Cat’s Claw extract after whole body irradiation in the rats.105 A 2nd study by the same research group used C-MED-100 extract with 12 healthy men. The volunteers received either 250 mg of the extract, 350 mg of extract or a placebo daily for 8 weeks. Hydrogen peroxide was used to induce DNA damage in the men. Both extracts provided a significant increase in DNA repair compared to the controls who received a placebo.106

Dosage Notes Cat’s Claw is well tolerated by most and considered non-toxic. Cat’s Claw is available in tablets, capsules or as a water or alcohol extract tincture. Ground or freeze-dried Cat’s Claw bark can also be taken as a tea. Cat’s Claw recommended dosage is one 100 mg capsule per day for arthritis. And one 250 or 350 mg capsule per day for cognitive and immune support. Standardized Cat’s Claw vine or root bark extracts usually contain 3% alka- loids and 15% . Don’t mistake Uncaria tomentosa for Uncaria guianensis which is another type of Cat’s Claw from the Amazon basin. U. guianensis has a much lower alka- loid content.

Side Effects Side effects are rare with Cat’s Claw. But may include diarrhea, dizziness or nausea. 68 HEAD FIRST Those with autoimmune diseases, skin grafts, tuberculosis or receiving organ transplants should not use Cat’s Claw because of its effects on the immune system. Cat’s Claw can stimulate the immune system and will counteract any medication you’re using to suppress your immune system. Cat’s Claw is known for lowering blood pressure. So if you have an issue with low blood pressure, or on high blood pressure medication you should not use Cat’s Claw. Cat’s Claw may increase the risk of bleeding so don’t take this herb if you have a bleeding disorder, are on blood thinners, or are planning surgery.

Available Forms Cat’s Claw powdered inner bark of the vine is usually the least expensive form and comes in 1,000 mg capsules. Cat’s Claw standardized extract usually contains 1.5% to 3% oxindole alka- loids and 15% phenols. AC-11® (C-MED-100®) is a patented hot-water extract of Cat’s Claw. It’s standardized to 8% Carboxyl Alkyl Esters. Saventaro® POA Cat’s Claw is a standardized and patented form of Cat’s Claw with 1.3% pentacyclic oxindole alkaloids (POA) (260 mcg) and is purified to be free of tetracyclic oxindole alkaloids (TOA).

Nootropics Expert Recommendation

Cat’s Claw standardized extract up to 250 – 350 mg per day I recommend using Cat’s Claw as a nootropic supplement. Your body does not make Cat’s Claw. So you must take it as a supplement to get its effects. This ancient herb has a long history of safe use as an herbal remedy in many parts of the world. Cat’s Claw (Uncaria tomentosa) is native to South America and the form referred to throughout this section. Cat’s Claw is mostly used as an anti-inflammatory and immune system booster. Cat’s Claw is especially helpful to those dealing with the symptoms of Lyme or Crohn’s Disease. And for those dealing with arthritis, joint pain or Carpel Tunnel Syndrome. AC-11® is often used in nootropic circles for cognitive support. Dosage of AC-11® is 350 mg per day. Cat’s Claw can improve your mood and memory. And protect your brain from free radicals and the toxins you’re exposed to everyday. Cat’s Claw as a nootropic has the potential to keep you mentally sharp for life. You can even out the stress and anxiety of your day by sipping Cat’s Claw tea. Or use a supplement as a cognitive enhancer.

69 David Tomen Choline Bitartrate Choline Bitartrate is known to increase cognition and brain function, improve focus and motivation, and reduce fatigue Choline Bitartrate is choline combined with tartaric acid. Binding choline to tartaric acid increases bioavailability. Choline (2-hydroxy-N,N,N-trimethyl- ethanaminium) is a primary building block for the critical neurotransmitter acetylcholine (ACh). Choline was declared an essential nutrient by the Food and Board of the National Institute of Medicine (USA) in 1998. Choline is considered an essential nutrient because when your body uses it faster than it can produce it, you need supplemental choline either from food or a supplement. Choline is found in foods such as fish, beef steak, liver, chicken liver, eggs, cod, broccoli, peanut butter and milk. You need choline for the production of the neurotransmitter acetylcholine. And to form phosphatidylcholine (PC), used in building cell membranes. Your brain uses acetylcholine to maintain clear communication. In fact, it’s used to maintain communication between all the cells in your body. In fact, choline is so vital to cognition and nerve function that, without it, we couldn’t move, think, sleep or remember anything. When choline is in short supply, your brain goes on a scavenger hunt. And starts to steal choline from nerve cell membranes. In your brain’s attempt to maintain normal acetylcholine signaling, it starts taking cells apart.107 This works in the short term. Your brain uses this technique to keep your memory and other functions running smoothly. But in the long run it takes a toll on your brain at the cellular level.108 This is the primary reason you need to add a choline supplement to your nootropic stack.

Choline Bitartrate vs. CDP-Choline vs. Alpha GPC: What’s the Difference? Choline is a water-soluble nutrient and its composition is similar to B- vitamins. Choline Bitartrate, CDP-Choline, Choline Citrate and Alpha GPC are all sources of choline. Choline Bitartrate: An economical form of choline, and about 40% choline by weight. So 1 gram of Choline Bitartrate offers 400 mg of actual choline. It does not cross the blood-brain barrier as readily as other sources of choline. So you won’t experience the same level of nootropic benefits as with Alpha GPC or CDP-Choline. CDP-Choline (cytidine 5′-diphosphocholine): Is only about 18% choline by weight. Your body naturally synthesizes choline into CDP-Choline (Citicoline). It’s then converted to phosphatidylcholine (PC) which is one of two fatty acids 70 HEAD FIRST that make up the outer layer of cell membranes. And PC provides the choline needed to synthesize acetylcholine (ACh). Alpha GPC: About 40% choline by weight and easily crosses the blood-brain barrier. Alpha GPC naturally occurs in your brain as a byproduct of phosphati- dylcholine (PC). When your brain needs more choline, and the choline floating around in your brain is running low, it breaks down PC from cell membranes. And turns it into Alpha GPC. Your body and brain loves it when you use choline. Because it doesn’t have to cannibalize its own cells to get more choline.

How does Choline Bitartrate Work in the Brain? Choline Bitartrate boosts brain health and function in several ways. But two in particular stand out. 1. Choline Bitartrate boosts acetylcholine, a neurotransmitter tied to memory and overall brain function. Choline Bitartrate is a precursor to acetylcholine. Improving the efficiency of communications between neurons in your brain. This increase in neural signal- ing boosts memory, learning, cognitive processing and mental clarity. A research team in the Netherlands set out to determine if choline bitartrate could affect coordination of movement and visual perception. In this study, they worked with a group of 28 people who took 2 grams of choline bitartrate or a placebo. An hour and 10 minutes after they took the choline or placebo, they had participants try to hit the center of a target. Participants who took the choline were not only far more accurate at hitting the target center than the placebo group. They also did it faster. The researchers concluded there was a “choline-induced bias” towards precision, speed and accuracy. They even measured pupil-size in participants. And determined, “The changes in pupil size suggest that choline uptake alters cholinergic functions in the nervous system.”109 2. Choline Bitartrate Boosts Memory. Researchers and medical professionals have long known about poor memory in people with a choline deficiency. A study at Northwestern University in Chicago tested people with a choline deficiency. They gave them a series of memory tests and found their scores below average. In this study, they then gave one group extra choline, and the others were given a placebo. After 24 weeks, both groups repeated the memory tests. The group who received extra choline showed a dramatic improvement in 71 David Tomen memory. The placebo group performed poorly as expected with scores the same as on the original test.110

How things go bad As we get older, our brain chemistry and energy metabolism changes. This can happen at any age once we enter our adult years. ↓ Brain fog and/or a sense of confusion ↓ Fatigue or lack of energy ↓ Unable to learn new things ↓ Memory loss and poor recall ↓ Feeling distracted or irritable ↓ Poor balance And these changes can happen at any age. Our bodies are influenced by the food we eat (and what we don’t eat!), what we drink, lifestyle habits, and even the air we breathe. Choline Bitartrate can help reverse cognitive decline. It can help you perform better in your work, and at school. By boosting acetylcholine and repairing neural cell membranes.

Choline Bitartrate to the rescue Research from hundreds of studies have shown that choline will: • Eliminate brain fog and confusion • Boost energy • Improve learning • Enhance memory and recall • Help focus and reduce irritability • Improve physical performance • Eliminate fatigue Choline Bitartrate is water-soluble. After it’s digested it will enter your blood- stream and cross the blood-brain barrier. Once in your brain it boosts neural signal transmission, and helps repair neurons. Choline Bitartrate improves your brain function and memory by increasing the production of acetylcholine. And prevents neurons from getting cannibalized when your brain is searching for more choline.

How does Choline Bitartrate feel? After taking Choline Bitartrate you should feel a boost in your ability to think, mood should improve, and your energy level should go up. Choline Bitartrate influences the level of acetylcholine in your brain. This crucial neurotransmitter affects memory, cognition, recall and learning. 72 HEAD FIRST Low levels of choline will leave you with brain fog and an inability to think clearly. You may also experience a drop in mood and some irritability. If you’re using anything from the racetam-family of nootropics and you experience a headache – your brain is likely starved for choline.

The Research

Choline Boosts Cognition The Framingham Heart Study is a long-term, ongoing cardiovascular study on residents in the town of Framingham, Massachusetts. The study began in 1948 with 5,209 adults. And is now on its 3rd generation of participants. This study of Framingham Offspring involved 1,391 dementia-free subjects. Ages ranged from 36 – 83 years. The participants underwent a food-frequency questionnaire, and MRI brain scan. The study was in two parts, from 1991 to 1995, and 1998 to 2001. Study participants were tested for verbal memory, visual memory, verbal learning and executive function. And a MRI-scan measured brain volume. The study concluded that those residents with a higher choline intake was directly related to significantly better cognitive performance.111

Choline Bitartrate Helps with Exercise and Muscle Performance Choline Bitartrate boosts mental energy, focus and concentration. All critical for physical activity and athletic performance. Choline’s effect on your metabolism and neurotransmitters in the brain pro- duce quicker reaction times. And shorten the time needed for mental processing. Choline helps improve your energy levels, mood, and recovery time follow- ing a workout. It is also critical for muscle nerve function, and in preventing fatigue, muscle aches and pain following a workout. When your muscles move, choline is needed to activate the neurotransmitter acetylcholine (ACh). ACh sends signals to muscles, and makes them move.112

Dosage Notes Recommended Choline Bitartrate dosage is 500 mg to 3,000 mg per day. You can use higher doses of Choline Bitartrate because this is a water-soluble version of choline. And a limited amount of this choline source will cross the blood-brain barrier. Other fat-soluble versions of choline such as Alpha GPC and CDP-Choline will more readily cross the blood-brain barrier and make its way into your cells. So lower doses are required.

Side Effects Recommended dosages even for extended periods are considered well-toler- 73 David Tomen ated and safe. While Choline Bitartrate is considered non-toxic, it is possible to experience toxicity with too much choline in your body. If you experience trouble sleeping, headache, diarrhea, low or high blood pressure, nausea, blurred vision or chest pain – you should stop using Choline Bitartrate.

Available Forms Choline Bitartrate is sold in capsule or powder form. Capsules are usually 500 mg each. Many of the nootropic stacks available on the market, and even some brand name vitamins contain Choline Bitartrate in their formula.

Nootropics Expert Recommendation

Choline Bitartrate 500 – 3,000 mg per day I recommend using Choline Bitartrate as a nootropic supplement. Your body does not make Choline Bitartrate on its own. But some versions of choline naturally occur in your body and brain. Choline sources like Alpha GPC and CDP-Choline. You do get some choline from the food you eat. But studies show we don’t get an adequate supply of choline from food sources in our modern diet. Choline Bitartrate is especially helpful for those suffering from age-related cognitive decline. Studies show supplemental choline helps stop or reverse brain degeneration like Alzheimer’s Disease, and other cognitive disorders. Especially in the early to mid-stages of the disease. We suggest starting with a dose of 500 to 1,000 mg daily. Choline Bitartrate is a good compliment to a stack including any nootropics from the racetam-family. Piracetam for example affects your neuroreceptors for acetylcholine. So stack- ing Piracetam and Choline Bitartrate boosts acetylcholine activity even more. If you’re on a tight budget and you need choline, Choline Bitartrate is a great place to start. It is the most affordable version of Choline available. Particularly when purchased in bulk powder form. You just need more of it than other cho- line sources like Alpha GPC or CDP-Choline. Use Choline Bitartrate at a ratio of 6:1. For example, 1,000 mg of Choline Bitartrate with 6,000 mg of Piracetam. If you get a racetam-headache add more choline to your stack.

74 HEAD FIRST Choline Citrate Choline Citrate is known to increase cognition and brain function, improve focus and motivation, and reduce fatigue Choline Citrate is choline combined with citrate which is an ester of citric acid. Binding choline to citrate contributes to the synthesis of acetylcholine (ACh) in your brain. The two precursors required for acetylcholine (ACh) synthesis are Choline (2-hydroxy-N,N,N-trimethyl-ethanaminium) and the enzyme acetyl-Coenzyme A (Acetyl-CoA). Citrate is a citric acid ester which provides a third of the acetyl groups used in the acetylcholine (ACh) synthesis process.113 You can get citric acid from citrus fruit like lemons and limes. And citrate plays another important role in the brain. Citrate is an interme- diate in the Krebs cycle (also known as the TCA cycle or Tricarboxylic Acid cycle, or Citric acid cycle). Citrate synthase catalyzes the condensation of oxaloacetate with acetyl CoA to form citrate. Citrate then acts as the substrate for aconitase and is converted in aconitic acid. This cycle ends with the regeneration of oxaloacetate. This series of chemical reactions is the source of 2/3’s of the energy we get from food. Most of the energy made available by these steps is transferred to form NADH. Which then drives adenosine triphosphate (ATP) synthesis that fuels mitochondria and provides the energy needed for brain cells.114 Now let’s go back to acetylcholine for a minute. Your brain uses acetylcholine to maintain clear communication. In fact, it’s used to maintain communication between all the cells in your body. And you need choline for cognition, memory, sleep and even maintaining your balance, stability and mobility. Your brain needs choline to function. When choline is in short supply, your brain goes on a scavenger hunt. And starts to steal choline from nerve cell membranes. In your brain’s attempt to maintain normal acetylcholine signaling, it starts taking cells apart.115 This works in the short term. Your brain uses this technique to keep your memory and other functions running smoothly. But in the long run it takes a toll on your brain at the cellular level.116 And that’s why you should consider adding choline citrate to your nootropic stack.

Choline Citrate vs. Choline Bitartrate vs. CDP-Choline vs. Alpha GPC: What’s the Difference? Choline is a water-soluble nutrient and its composition is similar to B- vitamins. Choline Citrate, CDP-Choline, Choline Bitartrate and Alpha GPC are all sources of choline. 75 David Tomen Choline Citrate: An economical form of choline combined with citrate, and about 50% choline by weight. So 1 gram of Choline Citrate offers 500 mg of actual choline. Choline Citrate not only provides your brain with choline, but comes with one of the acetyl groups necessary for acetylcholine (ACh) synthesis. Choline Bitartrate: An economical form of choline, and about 40% choline by weight. So 1 gram of Choline Bitartrate offers 400 mg of actual choline. It does not cross the blood-brain barrier as readily as other sources of choline. So you won’t experience the same level of nootropic benefits as with Alpha GPC or CDP-Choline. CDP-Choline (cytidine 5′-diphosphocholine): Is only about 18% choline by weight. Your body naturally synthesizes choline into CDP-Choline (Citicoline). It’s then converted to phosphatidylcholine (PC) which is one of two fatty acids that make up the outer layer of cell membranes. And PC provides the choline needed to synthesize acetylcholine (ACh). Alpha GPC: About 40% choline by weight and easily crosses the blood-brain barrier. Alpha GPC naturally occurs in your brain as a byproduct of phosphati- dylcholine (PC). When your brain needs more choline, and the choline floating around in your brain is running low, it breaks down PC from cell membranes. And turns it into Alpha GPC. Your body and brain loves it when you use choline. Because it doesn’t have to cannibalize its own cells to get more choline.

How does Choline Citrate work in the Brain? Choline Citrate boosts brain health and function in several ways. But two in particular stand out. 1. Choline Citrate boosts acetylcholine (ACh). Acetylcholine is a neurotrans- mitter tied to memory and overall brain function. Choline Citrate is a precursor to acetylcholine. Improving the efficiency of communications between neurons in your brain. This increase in neural signal- ing boosts memory, learning, cognitive processing and mental clarity. But researchers found that circulating choline in the brain decreases with age. This study recruited younger adults between 20 and 40 years, and older adults between 60 and 85 years. After fasting overnight, the subjects received 50 mg of a choline supplement per kilogram of body weight. Labs were drawn to determine choline concentra- tion in the blood. And proton magnetic resonance spectroscopy (1H-MRS) was performed to determine the relative concentration of cytosolic choline-containing compounds in the brain. Both tests were done before, and 3 hours after choline supplementation. Levels of choline in the blood and brain of study subjects were similar before choline supplementation. 76 HEAD FIRST But after choline supplementation, the younger subjects showed a 60% increase of choline in their blood and brain. The older subjects showed only a 16% increase in choline levels. The researchers concluded circulating choline in the brain decreases with age. And given the key role of choline in brain function, this change may be a contributing factor in onset of late life neurodegeneration and dementia.117 So according to this study, older adults should be supplementing with higher doses of a choline supplement like Choline Citrate to maintain cognitive function compared to younger adults. 2. Choline Citrate Boosts Memory. Researchers and medical professionals have long known about poor memory in people with a choline deficiency. A study at Northwestern University in Chicago tested people with a choline deficiency. They gave them a series of memory tests and found their scores below average. In this study, they then gave one group extra choline, and the others were given a placebo. After 24 weeks, both groups repeated the memory tests. The group who received extra choline showed a dramatic improvement in memory. The placebo group performed poorly as expected with scores the same as on the original test.118

How things go bad As we get older, our brain chemistry and energy metabolism changes. But choline deficiency can happen at any age from infancy through to our late adult years. ↓ Brain fog and/or a sense of confusion ↓ Fatigue or lack of energy ↓ Unable to learn new things ↓ Memory loss and poor recall ↓ Feeling distracted or irritable ↓ Poor balance Our bodies are influenced by the food we eat (and what we don’t eat!), what we drink, lifestyle habits, and even the air we breathe. Choline Citrate can help reverse cognitive decline. It can help you perform better in your work, and at school. By boosting acetylcholine and repairing neural cell membranes.

Choline Citrate to the rescue Research from hundreds of studies have shown that choline will: • Eliminate brain fog and confusion • Boost energy 77 David Tomen • Improve learning • Enhance memory and recall • Help focus and reduce irritability • Improve physical performance • Eliminate fatigue Choline Citrate is water-soluble. After it’s digested it will enter your blood- stream and cross the blood-brain barrier. Once in your brain it boosts neural signal transmission, and helps repair neurons. Choline Citrate improves your brain function and memory by increasing the production of acetylcholine. And prevents neurons from getting cannibalized when your brain is searching for more choline. And the citric acid part of Choline Citrate is a critical part of the KREBS cycle in our brain cells. Leading to support of brain cell mitochondria. Providing you with mental energy and eliminating fatigue.

How does Choline Citrate feel? After taking Choline Citrate you should feel a boost in your ability to think, mood should improve, and your energy level should go up. Choline Citrate influences the level of acetylcholine in your brain. This crucial neurotransmitter affects memory, cognition, recall and learning. Low levels of choline will leave you with brain fog and an inability to think clearly. You may also experience a drop in mood and some irritability. If you’re using anything from the racetam-family of nootropics and you experience a headache – your brain is likely starved for choline.

The Research

Choline Boosts Cognition The Framingham Heart Study is a long-term, ongoing cardiovascular study on residents in the town of Framingham, Massachusetts. The study began in 1948 with 5,209 adults. And is now on its 3rd generation of participants. This study of Framingham Offspring involved 1,391 dementia-free subjects. Ages ranged from 36 – 83 years. The participants underwent a food-frequency questionnaire, and MRI brain scan. The study was in two parts, from 1991 to 1995, and 1998 to 2001. Study participants were tested for verbal memory, visual memory, verbal learning and executive function. And a MRI-scan measured brain volume. The study concluded that those residents with higher choline intake demon- strated significantly better cognitive performance.119 78 HEAD FIRST Choline Citrate Helps with Exercise and Muscle Performance Choline Citrate boosts mental energy, focus and concentration. All critical for physical activity and athletic performance. Choline’s effect on your metabolism and neurotransmitters in the brain pro- duce quicker reaction times. And shorten the time needed for mental processing. Choline helps improve your energy levels, mood, and recovery time follow- ing a workout. It is also critical for muscle nerve function, and in preventing fatigue, muscle aches and pain following a workout. When your muscles move, choline is needed to activate the neurotransmitter acetylcholine (ACh). ACh sends signals to muscles, and makes them move.120 Researchers found that providing 2 grams of choline prior to exercise pre- vented a fall in choline levels. And raised choline levels above baseline values for up to 2 hours after exercise. The researchers found thatcholine citrate and choline bitartrate were equally effective. One randomized, placebo-controlled study found improve- ments in running times by a significant amount over a 20-mile course when compared to those using a placebo.121

Dosage Notes Recommended Choline Citrate dosage is 500 mg to 3,000 mg per day. You can use higher doses of Choline Citrate because this is a water-soluble version of choline. And a limited amount of this choline source will cross the blood-brain barrier. Studies have found that age has a significant effect on choline uptake into the brain. So older neurohackers are encouraged to use larger doses of Choline Citrate compared to younger neurohackers. Note that other fat-soluble versions of choline such as Alpha GPC and CDP- Choline will more readily cross the blood-brain barrier and make its way into your cells. So lower doses are required.

Side Effects Recommended dosages even for extended periods are considered well- tolerated and safe. While Choline Citrate is considered non-toxic, it is possible to experience toxicity with too much choline in your body. If you experience trouble sleeping, headache, diarrhea, low or high blood pressure, nausea, blurred vision or chest pain – you should stop using Choline Citrate. Or reduce your dose.

Available Forms Choline Citrate is sold in capsule or powder form. Capsules are usually 500 – 650 mg each. Some ready-made nootropic stacks, and even some brand name vitamins contain Choline Citrate in their formula. 79 David Tomen Nootropics Expert Recommendation

Choline Citrate 500 – 3,000 mg per day I recommend using Choline Citrate as a nootropic supplement. Your body does not make Choline Citrate on its own. But some versions of choline naturally occur in your body and brain. Choline sources like Alpha GPC and CDP-Choline. You do get some choline from the food you eat. But studies show we don’t get an adequate supply of choline from food sources in our modern diet. And as we age, our bodies have a difficult time using the choline we get from food. Choline Citrate is especially helpful for those suffering from age-related cognitive decline. Studies show supplemental choline helps stop or reverse brain degeneration like Alzheimer’s Disease, and other cognitive disorders. Especially in the early to mid-stages of the disease. I suggest starting with a dose of 500 to 1,000 mg daily. Choline Citrate is a good compliment to a stack with any nootropics from the racetam-family. Piracetam for example affects your neuroreceptors for acetylcholine. So stacking Piracetam and Choline Citrate boosts acetylcholine activity even more. If you’re on a tight budget and you need choline, Choline Citrate is a great place to start. It is one of the most affordable versions of Choline available. Par- ticularly when purchased in bulk powder form. You just need more of it than other choline sources like Alpha GPC or CDP-Choline. Use Choline Citrate at a ratio of 1:6. For example, 1,000 mg of Choline Citrate with 6,000 mg of Piracetam. If you get a racetam-headache add more choline to your stack.

80 HEAD FIRST CDP-Choline (Citicoline) CDP-Choline is known to increase cognition and brain function, improve focus and motivation, and reduce fatigue CDP-Choline (Cytidine Diphosphate Choline or cytidine 5’-diphospho- choline) is also known as Citicoline. This naturally occurring choline source is present in every cell in your body. CDP-Choline is unique as a choline source. Once it’s digested it separates into cytidine and choline. When it gets to your brain it converts back to CDP-Choline. Choline is considered an essential nutrient because your body uses it faster than it can produce it. So you need to supplement choline either from food or a supplement. You need choline for the production of the neurotransmitter acetylcholine. And to form phosphatidylcholine (PC), used in building cell membranes. In fact, choline is so vital to cognition and nerve function that, without it, we couldn’t move, think, sleep or remember anything. This choline is needed to synthesize the neurotransmitter acetylcholine (ACh). ACh is a primary neurotransmitter released by neurons. This electrical signaling between neurons is involved in memory, learning, cognition and recall. Cytidine is a component of Ribonucleic acid (RNA). This molecule is in- volved in coding, decoding, regulation and the expression of genes. But once it gets into the brain, it converts to uridine. The signaling going on between neurons tends to grab choline molecules from cell membranes when choline is in short supply. This is where uridine steps in. It repairs those same cell membranes. To maintain neuron integrity.

CDP-Choline vs. Alpha GPC vs. Choline Bitartrate: What’s the Difference? Choline is a water-soluble nutrient similar in composition to B-vitamins. CDP-Choline, Alpha GPC, Choline Citrate and Choline Bitartrate are all sources of choline. CDP-Choline (cytidine 5′-diphosphocholine): Is about 18% choline by weight and easily crosses the blood-brain barrier. Your body naturally synthesizes choline into CDP-Choline (Citicoline) in your brain. Taken as a supplement, it’s then converted to cytidine and choline in your gut. Once it crosses the blood-brain barrier it’s converted back to CDP-Choline. The choline then assists cell membranes, and helps create acetylcholine. The added benefit of CDP-Choline is with cytidine. Cytidine can convert into uridine which is critical in the brain. Uridine is needed to synthesize the phosphatidylcholine (PC) in neuron membranes. It helps repair neurons. Choline Bitartrate: An economical form of choline, and about 40% choline by weight. So 1 gram of Choline Bitartrate offers 400 mg of actual choline. It 81 David Tomen does not easily cross the blood-brain barrier. So you won’t experience the same level of nootropic benefits as with Alpha GPC or CDP-Choline. Alpha GPC: About 40% choline by weight and easily crosses the blood-brain barrier. Alpha GPC naturally occurs in your brain as a byproduct of phosphati- dylcholine (PC). When your brain needs more choline, and the choline floating around in your brain is running low, it breaks down PC from cell membranes. And turns it into Alpha GPC. Your body and brain loves it when you use Alpha GPC. Because it doesn’t have to cannibalize its own cells to get more choline.

How does CDP-Choline Work in the Brain? CDP-Choline boosts brain health and function in several ways. But two in par- ticular stand out. 1. CDP-Choline is metabolized in the gut wall and liver to form choline and cytidine. Once choline and cytidine cross the blood-barrier they re-synthesize back into CDP-Choline (Citicoline).122 In the brain choline aids in the synthesis of acetylcholine. And the release of dopamine.123 Acetylcholine is a neurotransmitter associated with memory and learning. 2. CDP-Choline helps repair neural membranes. Choline is a precursor to the neurotransmitter acetylcholine (ACh) in your brain. ACh carries nerve impulses across synapses. And then is broken down by enzymes. ACh is then reassembled for reuse. But this breakdown/reassembly process isn’t foolproof. Some ACh gets lost in the process. So your brain goes looking for more choline to make ACh. If there isn’t enough choline in your blood, it gets it from the phosphatidyl- choline (PC) that makes up the outside of the cell membrane of your neurons. The PC in the cell membrane releases choline to help make acetylcholine. When your neurons lose too much choline, they lose integrity. Nerve im- pulses break down, and cognitive abilities decline.124 Scientists in the lab at MIT showed that this is where uridine steps in. The cytidine in CDP-Choline converts to uridine in your body. And it works as a bridge between choline and neuron membrane synthesis. Uridine is needed to synthesize the PC in neuron membranes. It is first converted to CDP-Choline. Which is then synthesized into new PC. This new PC can then repair damaged neuron membranes. Membranes that were raided to make acetylcholine.125

How things go bad As we get older, our brain chemistry and energy metabolism changes. This can happen at any age once we enter our adult years. 82 HEAD FIRST ↓ Brain cell membranes degenerate ↓ Recall, reaction time and mood diminish ↓ Acetylcholine levels decline126 All of these changes can happen at any age. And our bodies are influenced by the food we eat, what we drink, lifestyle habits, the air we breathe and more. So CDP-Choline can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting acetylcholine and dopamine. And rebuilding neurons in the brain.

CDP-Choline to the rescue Research from hundreds of studies have shown that CDP-Choline will: • Boost cognition127 • Increase brain energy and speed up formation of brain membranes128 • Boost production of acetylcholine129 • Increase blood flow to the brain130 • Offset the harmful effects of stroke131 • Improve memory and learning ability132 • Boost cognitive performance and memory in Alzheimer’s patients133 CDP-Choline is water-soluble and quickly enters your brain after you take it. In fact, studies show it has nearly 100% bioavailability in your body. Take it orally or intravenously and your body absorbs the same amount. Once in your brain it boosts signal transmission, and repairs neurons. CDP- Choline improves your brain function and memory by directly increasing levels of acetylcholine and dopamine. And repairs neurons at the same time.

How does CDP-Choline feel? The most profound indication of the power of this supplement is with those who have suffered a stroke. Stroke survivors report that after continued usage of CDP-Choline, most of the noticeable effects of the stroke are gone. Including muscle paralysis and weakness. Neurohackers report they are better able to concentrate and focus. And experience a significant boost in cognition. You can feel more mentally alert. And you may even ease the fatigue associ- ated with clinical depression by using CDP-Choline. Some use CDP-Choline as an alternative to the stimulants prescribed for ADHD.

The Research In a study at the University of Utah, 75 healthy males were given 250 mg, 83 David Tomen 500 mg of CDP-Choline, or a placebo. Tests were recorded after 28 days of supplementation. The adolescent males receiving 250 or 500 mg of CDP-Choline showed improved attention and psychomotor speed. And reduced impulsivity compared to adolescent males who received placebo. This study indicates CDP-Choline is effective even in younger age groups. And can be particularly helpful to those dealing with ADHD.134

CDP-Choline Enhances Cognition A study published in Food and Nutrition Sciences assessed the potential cog- nitive-enhancing effects of Citicoline (CDP-Choline) in healthy, adult women. This double-blind, randomized, placebo-controlled trial worked with 60 healthy women from 40 – 60 years old. Each volunteer was given a daily dose of 250 mg or 500 mg of Citicoline, or a placebo for 28 days. The women who took either dose of Citicoline for 28 days showed a signifi- cant improvement in cognition. The researchers suggested that Citicoline may improve attentional performance in middle-aged women. And it might eliminate the attention deficits associated with central nervous system disorders (i.e. ADHD).

CDP-Choline Improves Memory Researchers in Japan studied 16 men and women who were given either 500 mg or 2000 mg of Citicoline for 6 weeks. Magnetic resonance spectroscopy (MRS) was used to study the brains of the participants at the end of the study. The research team found ATP in the neurons of those in the study increased by over 14%. And membrane phospholipids were boosted by over 32%. These finding were in specific areas of the brain associated with cognition. And the effect was even more pronounced in the group that received the lower dose of Citicoline. The researchers concluded that Citicoline supplementation could help pre- vent cognitive decline associated with aging. Along with an increase in brain energy reserves and utilization. And an increase in the components needed to synthesize and maintain cell membranes.

Dosage Notes Recommended CDP-Choline dosage is 250 – 500 mg per day. Taken no more than twice per day. Two daily doses would be one CDP-Choline dose in the morning, and one in the early afternoon. If you’re adding CPD-Choline to your stack with a racetam, a typical ratio would be 250 mg of Citicoline to 1 gram of Aniracetam or 4 grams of Piracetam.

Side Effects Recommended dosages even for extended periods are considered well- 84 HEAD FIRST tolerated and safe. While CDP-Choline is considered non-toxic, it is possible to experience toxicity with too much choline in your body. If you experience trouble sleeping, headache, diarrhea, low or high blood pres- sure, nausea, blurred vision or chest pain – you should stop using CDP-Choline.

Available Forms CDP-Choline is sold in capsule and powder form. Capsules are usually 250 – 500 mg each. 500 mg of CDP-Choline in powder form is equivalent to 2-level 1/8 tsp scoops.

Nootropics Expert Recommendation

CDP-Choline 250 – 500 mg per day I recommend using CDP-Choline as a nootropic supplement. CDP-Choline is brain food. And is a natural substance found in every cell in your body. You can get choline from some of the food you eat. But adequate levels of CDP-Choline are only found in organ meats like liver. So to get its benefits you must take it as a supplement. CDP-Choline is vital to maintaining optimal brain health. And has been shown to increase cognitive energy, boost brain function, enhance communica- tion between neurons, and protect neural membranes from free radical damage. I suggest starting with a dose of 250 – 500 mg daily. And CDP-Choline is a great compliment to stack with any nootropic from the racetam-family. Anything that causes an increase in uptake of acetylcholine in your brain. You need to provide your brain with the CDP-Choline it is demanding. Or it starts cannibalizing your own brain cells to make more acetylcholine. Signs that you’re lacking adequate choline are headaches. Use CDP-Choline at a ratio of 1:4. For example, 250 mg of CDP-Choline to 1,000 mg of Aniracetam. Stroke survivors may want to up the dose to 2,000 mg per day.

85 David Tomen Centrophenoxine

Centrophenoxine helps boost cognition & memory and has significant anti-aging benefits preventing and reversing neuronal decay Centrophenoxine (Lucidril® or ) is one of the original noo- tropics. Developed in France in 1959, Centrophenoxine is a combination of DMAE (dimethylethanolamine) and pCPA (parachlorphenoxyacetic acid). DMAE is an amine produced in small amounts in your brain. By prevent- ing the use of choline by other tissues (including synthesis into acetylcholine), DMAE increases choline levels in the bloodstream. pCPA is a synthetic version of auxins (plant growth hormones). Auxins act like natural growth factor in plants. Once digested, Centrophenoxine breaks down into DMAE and pCPA in the liver. This combination was found to make DMAE more bioavailable in the body. And helps DMAE cross the blood-brain barrier more readily. Centrophenoxine can increase your brain energy levels by boosting oxygen flow. It helps flush out dangerous free radicals and cellular waste. And may help improve memory and cognition.

Centrophenoxine vs. DMAE: What’s the Difference? DMAE is used to make Centrophenoxine. DMAE is found in small amounts in your brain. A good food source of DMAE is fish. But there is little evidence that DMAE as a supplement actually crosses the blood-brain barrier. And if it provides the brain enough choline needed to make acetylcholine. Centrophenoxine seems to solve the blood-brain barrier problem. Adding pCPA to DMAE helps DMAE enter your brain. And this combination also seems to be an effective way to boost acetylcholine for some neurohackers. If you’re considering adding DMAE to your stack, Centrophenoxine may be a better alternative.

How does Centrophenoxine Work in the Brain? Centrophenoxine boosts brain health and function in several ways. But two in particular stand out. 1. Centrophenoxine helps improve memory.135 One study shows it does it by boosting acetylcholine (ACh) in your brain by increasing the enzyme acetylcholinesterase.136 Researchers set out to prove this in a clinical trial using lab rats. In this study they compared Centrophenoxine with DMAE. And determined that DMAE was about half as potent as Centrophenoxine in boosting choline and ACh levels.137 86 HEAD FIRST Increased acetylcholine activity helps short-term memory, concentration, and learning. 2. Centrophenoxine takes out the cellular trash. Lipofuscin are more commonly known as age pigments.138 They show up as “age spots” or “liver spots” on aging skin. And they hide in cells throughout your body. Including your brain, liver, kidneys, heart, adrenals and nerve cells. Lipofuscin are the product of oxidation of unsaturated fatty acids. They also contain other cellular heavy metal waste like mercury and aluminum. The buildup of this toxic mess is caused by a breakdown of your normal cellular waste disposal function. Centrophenoxine helps remove lipofuscin from brain cells. And from cells throughout your body. The beneficial effects of Centrophenoxine were observed in several lab stud- ies on older animals. Administration to these animals significantly increased life-span, and it boosted learning ability compared to age-matched controls.139

How Things Go Bad As we get older, our brain chemistry and energy metabolism changes. ↓ Brain cell membranes degenerate from toxic buildup ↓ Memory, recall, reaction time and mood diminish ↓ Acetylcholine levels decline All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging. Including Alzheimer’s and dementia. But even if you’re not concerned with anti-aging, Centrophenoxine may be of some help.

Centrophenoxine to the Rescue Centrophenoxine is one of the oldest and most studied nootropics available today. It was developed in France in 1959. Primarily in the search for something to combat age-related cognitive decline. Centrophenoxine is a combination of pCPA and DMAE. Studies show that DMAE can boost choline levels by inhibiting the use of choline by other tissues. But there’s very little evidence that it can cross the blood-brain barrier. pCPA seems to solve that transport problem. Centrophenoxine is water-soluble and quickly enters your brain after you take it. Once in your brain, it boosts signal transmission, and protects neurons. Centrophenoxine gets to work right away boosting available choline. And it gets busy clearing cells of free radicals and lipofuscin.

How does Centrophenoxine feel? Centrophenoxine offers a gentle brain energy boost when you take it first thing in the morning. You’re able to remember things a little easier. Recall when you need it seems effortless. 87 David Tomen Centrophenoxine works well stacked with Aniracetam, Noopept, and Pi- racetam. It may provide some of the extra acetylcholine racetams demand when you take them. And if you dose half in the morning, and the other half early afternoon, you should feel a brain energy boost throughout your day.

The Research

Centrophenoxine Relieves the Symptoms of ADHD A prescription form of DMAE called Deanol was used in the 1960’s and 70’s to treat learning and behavioral problems in children. What’s now known as ADHD. A 3-month, double-blind, placebo-controlled trial involving 74 children was conducted in 1975. They were split into groups and given 40 mg. of Ritalin or 500 mg of Deanol (DMAE). Positive results from this trial showed DMAE comparable to Ritalin in effectiveness in controlling ADHD.140

Centrophenoxine is Anti-Aging Centrophenoxine is not only an effective cognition booster, it helps reverse the effects of aging in your brain. Much of brain cell membrane is made of phospholipids (fat). And it oxidizes as we age. In other words, free radicals build up. And are not removed from cells efficiently the older we get. Aging brain cells also get clogged up with lipofuscin. Lipofuscin are the product of oxidation of unsaturated fatty acids. They also contain other cellular heavy metal waste like mercury and aluminum. You see lipofuscin show up as ‘age spots’ on older skin. The same thing happens in your brain. Studies have shown that Centrophenoxine helps ‘flush out’ free radicals and lipofuscin from brain cells.141 And used by younger neurohackers, helps this cel- lular waste from building up in the first place.142 Researchers in Hungary conducted a double-blind clinical trial with 50 people suffering from dementia. Average age was 77 years. They gave one group 2 grams of Centrophenoxine for 8 weeks. They found that Centrophenoxine rehydrated ‘intracellular mass’. Proving this compound as a powerful free radical scavenger. It removed free radicals from aging brain cells. And restored them to a healthy state.143 In another study in India, researchers worked with male Wistar rats aged 4, 8, 16 and 24 months. They used these ages because they correlate with human aging from young to elderly. Just like in humans, lipid oxidation and lipofuscin concentration increased with age. The experiment also showed that cellular free radical damage and lipo- fuscin buildup happened at the same time. This buildup of cellular waste contributes to age-related decline in neuronal 88 HEAD FIRST electrical activity (neural signaling). Cognition, memory and learning are all af- fected. The research team found that Centrophenoxine had no effect on younger rat brains. But in the two older age groups they saw a significant decrease in lipid oxidation and lipofuscin concentration. Showing conclusively the anti-aging action of Centrophenoxine.144

Centrophenoxine Improves Memory Centrophenoxine boosts neuronal glucose and oxygen uptake in the brain. And helps the production of RNA and protein. RNA is derived from DNA in the cell nucleus. And enable neurons to form proteins. Which help encode memory and repair damage to brain cells. In one double-blind clinical trial, researchers worked with 50 people suffering from ‘ of medium level’. They gave the group 2 grams of Centrophenoxine, or a placebo for 8 weeks. 48% of the group that received Centrophenoxine showed improvements in memory.145 Another study was made of the effects of Centrophenoxine on the learning and memory of old mice. One group of mice were treated for 3 months and the other group received a placebo. The treated animals showed a significant improvement in memory and learning.146

Dosage Notes Centrophenoxine dosage is typically 500 mg to 1 gram daily. If you’re stacking it with a racetam, split your dose. So a 1-gram dose would be 500 mg first thing in the morning, and the other half early afternoon. Centrophenoxine seems to help increase choline and possibly acetylcholine synthesis in the brain. But keep this in mind; Centrophenoxine and DMAE are related to choline. They are not thesame as choline. Some neurohackers insist it should not replace a regular choline source like Alpha GPC or CDP-Choline. And I agree with this observation. Centrophenoxine can be stacked with a choline source. And yet some neurohackers take Centrophenoxine as a choline source to include in their racetam stack. Or use it as a nootropic on its own. Experiment and see what works best for you. YMMV.

Side Effects Centrophenoxine has been used as a nootropic for nearly 50 years. So it’s safety is well established. It’s non-toxic and should be well tolerated by most neurohackers. Some reported side effects include stomach upset, body odor, drowsiness, confusion, increased blood pressure, moderate depression, and irritability.147 If you deal with epilepsy or bipolar disorder you should avoid Centro- phenoxine entirely. 89 David Tomen Centrophenoxine may boost acetylcholine in some people. So an excess of acetylcholine could cause the above-mentioned side effects. Cycling Centrophenoxine with 5 days using it, and a 2-day break should eliminate any acetylcholine toxicity.

Available Forms Centrophenoxine comes in powder form and capsules. Capsules are typically 250 – 400 mg. Centrophenoxine is water-soluble so it’s not necessary to take it with a fat or oil. You may find it absorbs better or more quickly when taken with food.

Nootropics Expert Recommendation

Centrophenoxine 500 – 1,000 mg per day. I recommend using Centrophenoxine as a nootropic supplement but with some reservation. Your body does not make Centrophenoxine on its own. And it’s not available from food. This nootropic is a combination of DMAE and pCPA, and is only available in supplement form. In some countries Centrophenoxine is prescribed as Lucidril® for treatment of Alzheimer’s or age-related cognitive decline. Studies show Centrophenoxine helps stop or reverse brain degeneration by clearing out free radicals and lipofuscin from brain cells. Making Centrophenox- ine one of the primary anti-aging nootropics. Centrophenoxine may also boost acetylcholine synthesis in your brain for some people. Boosting cognition, memory, recall and learning. But this nootropic is NOT a good source of choline to make aceylcholine for most neurohackers. We have much better options for prescursors to acetylcholine. Including nootropics like Alpha GPC and CDP-Choline. If you are going to try Centrophenoxine, I suggest starting with a dose of 500 mg daily. Possibly more depending on your racetam usage. Age-related cognitive disorders like Alzheimer’s may want to up the dose to 2,000 mg per day.

90 HEAD FIRST Coluracetam Coluracetam has been shown to boost long-term & working memory, relieve depres- sion & anxiety, and enhance color & sound perception Coluracetam (BCI-540, or MKC-231) is a fat-soluble nootropic in the racetam-class of compounds. Coluracetam is much more potent than the original racetam, Piracetam. Coluracetam was patented by Mitsubishi Tanabe Pharma of Japan in 2005. Making it one of the newest racetam-based nootropics. The patent for coluracetam was later sold to BrainCells, Inc. in San Diego, California. BrainCells is a small, privately-held biopharmaceutical company spe- cializing in developing compounds for the treatment of major depressive disorder (MDD), treatment resistant depression (TRD), and Alzheimer’s Disease. Coluracetam is similar in structure to Piracetam. And like all racetam noot- ropics, has a pyrrolidone nucleus at its core. The latest clinical research indicates potential for treating depressive disorders, and retinal and optic nerve damage. Coluracetam is a very strong choline targeting supplement. It boosts your brain’s choline conversion to acetylcholine (ACh) through the high affinity choline uptake (HACU) process. Which increases alertness, attention to detail and memory. 148 Some research, and personal experience shows Coluracetam may affect AMPA receptors.149 Making it a potential ampakine nootropic. Which could ex- plain the stimulant-like effects without the side effects of traditional stimulants. Coluracetam also shows some anxiolytic (anti-anxiety) qualities helping improve mood and quieting anxiety. Neurohackers who have tried Coluracetam say it helps increase attention span, alertness and boosts long-term memory.

Coluracetam vs. Piracetam: What’s the Difference? Piracetam, the original racetam that started the nootropic movement, is a cyclic derivative of GABA. It affects the neurotransmitter acetylcholine (ACh) by helping ACh receptors accept, or be more sensitive to acetylcholine. Coluracetam also boosts acetylcholine in the brain. But through a different mechanism of action. Rather than making the ACh receptors more sensitive to ACh, it actually increases the synthesis of acetylcholine from choline. By affect- ing the high affinity choline uptake (HACU) process.

How does Coluracetam Work in the Brain? Coluracetam boosts brain health and function in several ways. But two in particular stand out. 1. Coluracetam boosts your brain’s choline uptake by targeting and working with the high affinity choline uptake (HACU) process in the brain’s neurons. 91 David Tomen Acetylcholine (ACh) is made up of choline and acetate. These must be avail- able to the neuron terminal at all times. So that ACh can be synthesized whenever it is needed. Free choline circulating in the blood crosses the blood-brain barrier. And is taken up by cholinergic neuron terminals. It gets taken into the neuron by the high affinity choline uptake (HACU) system.150 The synthesis of ACh takes place in the synaptic cleft. The space between neurons as it travels into the neuron. The HACU system is temperature-, energy-, and sodium-dependent. This system is the primary means by which choline needed for the synthesis of ACh is transported into the neuron. And is the rate-limiting step in the production of this critical neurotransmitter.151 When this system breaks down or doesn’t work as efficiently as it was de- signed, you experience problems with memory, learning, and brain fog. Coluracetam affects this process and helps it work more efficiently. In fact, it seems to boost the HACU process. Even in damaged neurons. Increased acetylcholine in neurons helps improve memory, boosts cognition and provides better decision-making capabilities. 2. Coluracetam also seems to improve AMPA potentiation. AMPA receptors are affected by glutamate. Which works in the brain and central nervous system to improve alertness and cognition. Coluracetam works with both AMPA potentiation and choline uptake en- hancement. This combination seems to help improve mood disorders without affecting serotonin levels. Serotonin Reuptake Inhibitors (SSRIs) is the current preferred mainstream medical method for dealing with mood disorders and depression. They come with a list of detrimental side effects. And don’t work for every depressed patient. Researchers reported that Coluracetam was beneficial in treating major clinical depression and anxiety disorder.152 Without affecting serotonin levels in the brain. And without the side effects that go with disrupting serotonin.

How things go bad As we get older, our brain chemistry and energy metabolism changes. ↓ Brain cell membranes degenerate ↓ Recall, reaction time and mood diminish ↓ Conversion of choline to acetylcholine breaks down ↓ Acetylcholine levels decline All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Coluracetam can help mood disorders and age-related cognitive decline. 92 HEAD FIRST But it works as well for the student looking to do better in school. By boosting acetylcholine and controlling glutamate in the brain.

Coluracetam to the rescue Research from a very limited number of studies have shown that Colurace- tam will: • Restore the synthesis of acetylcholine • Restore long-term memory • Improve working memory • Relieve symptoms of severe depression • Treat symptoms of general anxiety • Increase choline uptake even in damaged neurons • Repair retinal and optical nerve damage The benefits from supplementing with Coluracetam seem to be long-lasting. Even after supplementation has stopped.

How does Coluracetam feel? Even with very small doses of Coluracetam you should experience a decrease in anxiety and improved mood. Overall energy levels should go up. Unlike the effect commonly produced by stimulants, Coluracetam offers a more relaxed, calm and free-minded kind of thought-processing. Coluracetam acts quickly to boost long-term and working memory and word-recall. And many nootropic-users report that colors are crisper, or en- hanced. Sound and audio seems to wash through you. Some even report that Coluracetam enhances meditation. There is an ex- tremely pleasant sense of being at peace with the world.

The Research Coluracetam was first discovered the late 1990’s. And because it’s so new, very few clinical trials have been done with humans. Most of the clinical research available to us has been done on animals. BrainCells, Inc., who acquired the patent from the company that first devel- oped Coluracetam, have begun human trials. Here we have two examples of the clinical research done in the last 15 years on animals.

Coluracetam Provides Long-lasting Cognition Improvement Researchers in Japan worked with rats whose memory was chemically im- paired. In this study, rats were dosed with Coluracetam (MKC-231) for 8 days. The team studied the effects on the high affinity choline uptake (HACU) system of the rats after 8-days of repeated Coluracetam treatment. 93 David Tomen They reported an increase ofHACU activity along with a boost in cognition. And concluded that Coluracetam “could induce long-lasting pro-cognitive effects by changing the regulation system”.153

Coluracetam Improves Working Memory A study at Iwate Medical University in Japan was done on mice with working memory deficits. In this study, scientists found that Coluracetam improved work- ing memory at all doses tested. They found it significantly reversed an acetylcholine deficit. And concluded that Coluracetam improved memory deficits by boosting high affinity choline uptake (HACU), and the release of acetylcholine.154

Dosage Notes Recommended Coluracetam dosage is 20 – 80 mg per day. So 20 mg would be taken in two 10 mg doses. One Coluracetam dose in the morning, and one in the early afternoon. Higher doses of Coluracetam are based on clinical trials mostly done on animals. When first adding Coluracetam to your stack, most neurohackers start out with a much smaller dose. And see how you react to it. Coluracetam is typically sold in powder form. Smaller doses are often taken sublingually for faster and better absorption. Since Coluracetam is a fat-soluble nootropic, you should take it with a meal containing healthy fats. Or with a tablespoon of extra virgin, expeller cold-pressed coconut or olive oil. Or other similar healthy fat to ensure quick absorption.

Side Effects Coluracetam non-toxic. So is considered well-tolerated and safe. Many first-time users of Coluracetam report fatigue which is often the result from starting with too high a dose. Remember, Coluracetam works by enhancing choline uptake in your brain. Choline is a precursor to the production of acetylcholine. If not enough choline is available in your system, you’ll feel the side effects. Side effects are rare but can include anxiety, fatigue, headaches, nervousness and nausea. Again, side effects are often a result of unusually high doses of the nootropic. Headaches from using Coluracetam typically happen when you forget to combine it with a good choline supplement. Headaches are often a symptom of a choline deficit in your brain.

Available Forms Coluracetam is usually sold in powder form. A couple of companies offer it in a liquid base making it easier to dose and take sublingually. 94 HEAD FIRST Nootropics Expert Recommendation

Coluracetam 20 – 80 mg per day I recommend using Coluracetam as a nootropic supplement. Your body does not make Coluracetam on its own. So to get its benefits you must take it as a supplement. Coluracetam is unique among racetams because it is a high affinity choline uptake (HACU) enhancer. Coluracetam is especially helpful for restoring long-term memory, boosting cognition and better decision-making. All benefits associated with improved choline uptake into neurons. And the improved synthesis of acetylcholine. Coluracetam also has a strong, albeit brief history of treating major depres- sion. For the healthy neurohacker you’ll get the benefit of a sense of contentment and peace. And as an added bonus, the extra choline activity affects optic nerves. So you may experience enhanced colors and sound. The positive effects of Coluracetam appear to be at least semi-permanent. The benefits continue even after it leaves your system. You should use Coluracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost acetylcholine synthesis, so demands the presence of more choline in your brain. Clinical trials say you can safely boost daily intake of Coluracetam to 200 mg. for major depressive disorder if needed. But I suggest starting with 20 mg per day. And increase your doses only after you see how it works in your system.

95 David Tomen Coenzyme Q10 (CoQ10) Coenzyme Q10 helps fuel ATP for the mitochondria in your brain cells. Boosting energy, cognition, memory and recall Coenzyme Q10 (CoQ10) (2,3-dimethoxy-5-methyl-6-decaprenyl-1,4- benzoquinoneis) a natural antioxidant synthesized by your body. It’s also known as “ubiquinone” because it is ‘ubiquitous’ in the human body. CoQ10 is used by every single cell. Your body uses CoQ10 faster than it can produce it. So you need supple- mental CoQ10 either from food or a supplement. You can get CoQ10 from eating fatty fish, beef, poultry, nuts, seeds and oils. CoQ10 is your cell’s source of energy. It fuels your mitochondria by taking fat and other substances and converting them into usable energy. Brain cells have a higher concentration of mitochondria than most other cells in your body. These mitochondria are like little power plants inside each cell. They even have their own DNA. The source of life and death for neurons lies in mitochondria. Without healthy mitochondria, the natural function of each cell is damaged. And the life of that cell can come to a premature end. Research shows CoQ10 prevents oxidative damage in your brain. Protecting the health of your brain cells.155 CoQ10 is a powerful antioxidant. It protects your cells from free radical damage. Free radicals are oxygen atoms missing electrons. This makes them highly reactive which wreaks havoc in your tissues and DNA. Oxidative damage has been implicated in several neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig (ALS) disease.156 Coenzyme Q10 is used throughout your body. It helps produce energy for your cells, boosts heart health, helps maintain healthy blood pressure and immune system, and reduces the signs of aging. Here we’re talking about how CoQ10 affects your brain health and chemistry.

CoQ10: Ubiquinone vs. Ubiquinol: What’s the Difference? Coenzyme Q10 (CoQ10) is a fat-soluble nutrient produced naturally in your body. The highest concentration of CoQ10 is in organs that require the most energy – including your heart, liver, muscles, kidneys and brain. CoQ10 is in the mitochondria in your cells. This is where cellular energy occurs. It acts as an electron acceptor or donor in the chain of reactions that lead to cellular energy production. When oxidized CoQ10 (ubiquinone) accepts an electron from another molecule in the chain, it becomes Ubiquinol. And when Ubiquinol donates an electron it becomes ubiquinone. This state of equilibrium is necessary and how your body benefits from CoQ10. 96 HEAD FIRST The chemical difference between ubiquinone and Ubiquinol is the Ubiquinol compound contains two hydroxyl groups. This makes it more “hydrophilic”, or easier to dissolve in water. And makes it more bioavailable than ubiquinone.157 In Ubiquinol-form, CoQ10 has the ability to scavenge free radicals in the mitochondria and cell membranes. Sites where free radicals inflict the most damage. Supplement makers have been pushing the Ubiquinol form of CoQ10. They claim it’s the best form because it’s what your body produces naturally. They say it’s absorbed up to 8-times better than other forms of CoQ10. Real world use however, does not always back up the marketing claims. Some people say they feel fatigue when using Ubiquinol. And only energy when using ubiquinone. You’ll have to experiment and find out what works the best for you. Your body can use both. But ubiquinone is far less expensive than Ubiquinol.

How does CoQ10 work in the brain? Coenzyme Q10 boosts brain health in several ways. But two in particular stand out. 1. When you supplement with enough CoQ10, you’re giving your brain cells the fuel it needs to produce adenosine triphosphate (ATP). ATP is the fuel used by the mitochondria in your neurons. Mitochondria are the source of life and death for neurons. They generate your neuron’s energy and control its death. But mitochondria tend to develop defects as we age. As these defects accumulate, mitochondria start to malfunction. This results in a reduction in cellular energy production. And cells die. The result of this dysfunction can be brain fog, cognition problems, poor memory and recall. And ultimately neurodegenerative diseases like Alzheimer’s, Huntington’s, stroke and others.158 Studies show that CoQ10 protects against this cellular damage by raising energy levels. In a study with rats, scientists put CoQ10 in their chow for 10 days before giving them a toxin that caused brain lesions. CoQ10 reduced lesions by 30%. And restored energy production in neurons to nearly normal levels.159 2. CoQ10 preserves brain function, and fights mental illness and migraines. CoQ10 is essential not only in preventing brain deterioration at a structural level, but in maintaining normal function at all ages. Studies are beginning to show some troubling associations between migraine headaches and mental health issues like depression and schizophrenia. Scientists don’t know for sure what causes migraines. But think it may be related to brain energy levels. Studies show that CoQ10 supplementation in chil- 97 David Tomen dren, adolescents and adults had significant decreases in frequency and length of migraines.160 Major depression, bipolar disorder and schizophrenia have long been consid- ered separate health issues. Lately, they are being recognized as having mitochon- drial dysfunction in common. And higher oxidative stress levels.161 Just one of many studies show that depression in older bipolar adults had a significant reduction in symptoms. This was after treatment with 1,200 mg of CoQ10 per day.162

How things go bad As we get older, the chemistry in our brain cells and energy metabolism changes. ↓ Brain cell membranes degenerate ↓ Recall, reaction time and mood diminish ↓ Neurotransmitter levels decline All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia. But even if things haven’t degenerated to such a debilitating level, CoQ10 can help.

CoQ10 to the rescue Research from thousands of studies have shown that Coenzyme Q10 will: • Boost energy levels and stamina • Reduce fatigue • Reduce the possibility of age-related diseases • Lower blood pressure • Lower blood sugar levels • Provide protection and energy to your brain • Boost cerebral blood flow

How does CoQ10 feel? Optimizing your mitochondria is one the most powerful strategies you have to extend your life. Mitochondrial dysfunction is associated with the aging pro- cess, including many age-related diseases. So when taking CoQ10 you should feel better and more energized. Thinking should be clearer. Less fatigue and stamina improved. Some neurohackers report feeling more fatigue while taking Ubiquinol. And actually feel better taking the less optimized form ubiquinone. 98 HEAD FIRST The Research CoQ10 was first isolated from beef hearts at the University of Wisconsin in 1957. Research continued at Merck & Company, Stanford Research Institute, and the University of Texas at Austin. Many studies from around the world have been published since.163

CoQ10 can Improve Learning A study at the University of Texas was conducted to find out if supplement- ing with CoQ10 or could help older mice learn tasks more quickly. The researchers separated groups of older mice. And gave each mouse either CoQ10, Vitamin E, or both antioxidants for 14 weeks. The mice were run through a battery of tests assessing learning, memory and psychomotor function. The study concluded that CoQ10 combined with Vitamin E working in concert boosted performance in all tests.164

CoQ10 Improves Memory Neuron death caused by oxidative stress is implicated in a host of neurode- generative diseases. Including Alzheimer’s, Parkinson’s and stroke. Oxidative stress is an imbalance between the production of free radicals, and the ability of your body to detoxify the harm caused by free radicals. Exposure to toxins in your everyday environment can cause oxidative stress. Researchers at the University of Windsor in Canada demonstrated this effect using human cells in the lab exposed to an herbicide commonly used in North America. Your brain exposed to this toxin causes apoptosis (programmed cell death) and DNA fragmentation. But scientists found that cells pretreated with CoQ10 prevented oxidative stress and neuron damage.165

CoQ10 Reverses Gulf War Illness The profound protective effect of CoQ10 on brain neurons and memory was proven in studies with soldiers who fought in the Persian Gulf War. About one-third of the 700,000 troops deployed during the first Persian Gulf War, have been diagnosed with Gulf War Illness (GWI). Symptoms include fatigue, muscle pain, weakness, and decreased cognitive function. Gulf War Illness was caused by exposure to pesticides, sarin nerve gas, and other toxins during the war. Forty-six United States Gulf War veterans participated in this randomized, double-blind, placebo-controlled study. All had been diagnosed with GWI. The veterans were given CoQ10 in pill form, or a placebo for 3 ½ months. Researchers concluded that 80% of those receiving only 100 mg of CoQ10 during this study saw improvements with headaches, irritability, recall and muscle pain. 99 David Tomen The degree of improvement correlated to the degree in which CoQ10 levels in the blood increased.166

Dosage Notes CoQ10 can help the mitochondria in your brain, and throughout your body, work more cleanly and efficiently. It reduces oxidative stress and damage to mitochondria. Helping to slow the aging process. Dosing CoQ10 depends on what you’re trying to accomplish. Generally dosing for a healthy adult is 30 – 400 mg daily. • As an antioxidant: 60 – 150 mg daily • Muscle control problems: 300 – 3,000 mg daily • Alzheimer’s Disease: 400 mg daily • Heart Attack recovery: 30 – 600 mg daily • To prevent heart disease: 200 mg daily • Chemotherapy side effects: 50 – 90 mg daily • Improve exercise performance: 50 – 300 mg daily • Male infertility and Peyronie’s disease: 30 – 300 mg daily • Diabetic nerve pain: 400 mg daily • Weight loss: 100 mg daily Note: recommended dosing is for as long as you have symptoms. Work with your doctor and get tested for CoQ10 levels in your blood. Once your CoQ10 level are optimized you can scale back to a maintenance dose.

Side Effects The primary “side effect” of using CoQ10 in your nootropic stack is – you’ll feel better. You should have more energy and thinking should be clearer and faster. CoQ10 may reduce the toxic effect of some chemotherapy drugs. And it may enhance the effectiveness of some blood pressure medications. Which can be good or bad depending on your situation. CoQ10 can reduce the efficacy of a blood thinner like Warfarin. It can also lower blood sugar levels. So needs to be monitored if you have diabetes. Caution is advised when using CoQ10 with aspirin. Especially if you have a bleeding disorder. Talk to your doctor if you’re on any medication before you start using CoQ10. A few people who use CoQ10 report rashes, nausea, abdominal pain, dizzi- ness, sensitivity to light, irritability, headache, heartburn or fatigue. 100 HEAD FIRST Some neurohackers say they feel fatigue when using Ubiquinol but not with the less expensive Ubiquinone. Experiment and see what works best for you.

Available Forms There are two types of CoQ10 used in CoQ10 supplements: ubiquinone and Ubiquinol. Some alternative health practitioners advise staying away from ubiquinone because your body has to convert it to Ubiquinol to use it. If you’re under 25 and in good health you can likely get the benefit of CoQ10 with the less expensive ubiquinone. Over 25 and you’re better off with Ubiquinol. Ubiquinol is identical to 95% of the CoQ10 your body is designed to natu- rally produce. Which means your body doesn’t have to convert the CoQ10 to use it. Some in vitro research shows that Ubiquinol is up to 8-times more bioavail- able than other CoQ10 supplements. (“8-times” is likely a bit of an exaggerated marketing claim). CoQ10 comes in liquid and capsule form. Logic says the liquid form is easier to absorb by your body.

Nootropics Expert Recommendation

Coenzyme Q10 200 – 400 mg per pay I recommend using CoQ10 as a nootropic supplement. Your body does make some CoQ10 on its own. And from the food you eat. But studies have shown we don’t get an adequate supply of CoQ10 from food sources in our diet. CoQ10 is especially helpful for those suffering from age-related cognitive decline. Studies show it helps stop or reverse brain degeneration with Alzheimer’s Disease, and other cognitive disorders. In any stage of the disease. I suggest starting with a dose of 200 mg daily. And CoQ10 is a great compli- ment to a stack with any nootropic. You need to provide your brain mitochondria with the fuel they are demand- ing. Or neurons start to break down from the inside. Signs that your lacking adequate CoQ10 is brain fog, slow thinking, headaches and muscle aches. Age-related cognitive disorders that include muscle control problems may want to up the dose to 3,000 mg per day. But for a limited time until CoQ10 blood levels are stabilized. Work with your doctor.

101 David Tomen Creatine Creatine has been shown to boost cognition and prevent mental fatigue Creatine is one of the most effective cognitive enhancers available. This non- is synthesized in your liver, kidneys and pancreas. And used in your brain to re-charge the Adenosine Triphosphate (ATP) that fuels the mitochondria in brain cells. Creatine is stored in your body as creatine phosphate, or phosphocreatine. And is critical for fueling Adenosine Triphosphate (ATP) in the mitochondria of your brain cells. Here’s how it works… ATP is the primary energy molecule used in your cells as energy. ATP is your body’s natural fuel source. ATP is broken down to produce biochemical energy throughout your body. Including in your brain cells. During this biochemical process, ATP loses one of its phosphate molecules. And is changed to adenosine diphosphate (ADP). This is where creatine steps in. Remember, creatine is stored in your body as creatine phosphate. It re-charges ADP by donating a phosphate molecule to ADP. Which produces more ATP that can be used to make more energy. Without creatine to re-charge ATP, your brain’s cells are literally starved for energy.

Creatine Monohydrate vs. Buffered Creatine vs. Creatine Ethyl Ester: What’s the Difference? It’s easy to get confused by the many forms of creatine available. And how to know which one works best in your nootropic stack. Well, let’s get past all the marketing hype, and settle this now. Creatine is one of the most well-researched supplements in the world. Thanks in large part to the sports-nutrition world. Creatine monohydrate is the form used in most of the clinical studies on creatine. It’s the gold standard of creatine. And has been proven over decades of use. Buffered creatine is marketed as being able to outperform creatine mono- hydrate because of its higher pH level. But research does not back up this claim. Researchers in the Exercise and Sport Nutrition Laboratory at Texas A&M University conducted a double-blind study with 36 resistance-trained athletes. They tested creatine monohydrate (Creapure®) against buffered creatine (Kre- Alkalyn®). Following manufacturer’s directions for loading and maintenance phases. And ran the trial for 28-days. The research team concluded there was no evidence that supplementing with a buffered form of creatine resulted in fewer side effects. Or that the buffered form was more efficacious and/or safer than creatine monohydrate.167 102 HEAD FIRST Creatine Ethyl Ester is another form of creatine that is supposed to con- vert back to usable creatine once in your body. It’s marketed as having better absorption than creatine monohydrate. But the research shows it’s actually less effective. Because once in your body, it’s converted into an inactive form called “creatinine”.168 The bottom line is don’t overpay for fancy forms of creatine. No matter how good the marketing hype. Creatine monohydrate is still the least expensive and most effective form of creatine available today.

How does Creatine Work in the Brain? Creatine boosts brain health and function in several ways. But two in par- ticular stand out. 1. Creatine levels linked to optimal memory ability and retention. One study at the University of New Mexico investigated working memory ability. Or the brain’s ability to hold information for future use. Scientists studied children’s brains aged 7 through 12 using magnetic resonance spectroscopy. And measured various brain neurochemicals. The study found that children with the highest levels of creatine in their brain had a better working memory. And concluded, “… we speculate that higher resting creatine levels may allow for greater in-task activation [and] facilitate processing.”169 2. Creatine directly impacts mental fatigue. Another study published in Neuroscience Research examined the effects of supplemental creatine on mental fatigue. 24 healthy adults participated in this double-blind, placebo-controlled study. In this study, the adults who took 8 grams of creatine daily for 5-days showed significantly less mental fatigue while performing math than those who took no creatine.170 The research team said that creatine appeared to help increase oxygen utilization in the brain.

How things go bad ATP and creatine are critical to brain function. If you don’t have adequate creatine to recharge ATP, your brain can’t function at its best. And certain genetic disorders can interrupt brain creatine metabolism. Caus- ing significant neurological defects. Lack of ATP and creatine will affect neuron repair, and the production and transmission of neurotransmitters. If a creatine deficiency is caused by a genetic defect early in life, it can result in developmental delay, mental retardation, speech disabilities and muscle weakness. 103 David Tomen ↓ Cognition, memory, recall, reaction time and mood diminish ↓ Brain cell membranes degenerate ↓ Neurotransmitter levels decline ↓ Mental health, language and fine motor skills decline171 All of these changes in brain energy metabolism are contributing factors to neurodegenerative diseases, including Alzheimer’s, Parkinson’s, ALS, epilepsy, and dementia. But even if you’re not concerned with genetic defects, or the effects of aging, Creatine can help.

Creatine to the rescue Study after study shows that creatine supplementation has a significant impact on working memory and intelligence. Both tasks that require mental speed of processing. Creatine supplementation plays a major role in brain energy capacity. And influencing brain performance. You may find it curious that researchers who study cognition and athletic performance seem to favor using vegetarians and vegans. And giving them cre- atine supplements. They use vegetarians as test subjects because creatine is only found in animal flesh. And vegetarians don’t eat meat. Creatine is not an essential amino acid because we can synthesize it from other amino acids. But amino acids found in plant foods are not synthesized very efficiently. This is the reason why vegetarians have lower creatine levels in their bodies than those of us who eat meat. Our cells run on energy supplied by ATP. We burn ATP energy when using our muscles. But we go through ATP faster when we use our brains. Consider that our brain only makes up about 1 – 3% of our body weight. But the billions of neurons in our brains use 20% of our body’s total ATP-derived energy. ATP energy is used in your brain for neuronal repair. And to produce, pack- age and secrete neurotransmitters. It’s the power behind bioelectrical signals when neurons communicate with each other. During this neuronal activity, ATP loses one of its phosphate molecules. And is changed to ADP. Creatine is needed to recharge ADP by donating a phosphate molecule. So you can use that ATP energy again. This is why every neurohacker should have creatine as part of their nootropic stack.

How does Creatine feel? Once you start supplementing with creatine, you should experience im- proved cognitive function. Thinking will be clearer and faster. 104 HEAD FIRST Mental energy will get a boost. And you won’t feel mentally wasted after an intense mental workout. Reading should be easier and you won’t find yourself re-reading that last sentence or paragraph. Overall, you should feel a boost in both physical and cognitive abilities. And an improvement in your sense of well-being. You’ll feel better!

The Research Creatine was identified way back in 1832. And science has been researching it in every way possible since then. Thousands of studies have been done on physical and brain health. And how they’re related to creatine.

Creatine Boosts Working Memory & Intelligence A research team at the University of Sydney decided to test the effect of creatine supplementation in 45 young adult vegetarians. People who stick to a vegetarian diet are typically deficient in creatine. Because red meat is a main source of this critical nutrient in our diet. In this double-blind, placebo-controlled trial they gave some of the young adults 5 grams of creatine once a day for 6 weeks. Then they tested for intelligence and working memory performance. The researchers found that creatine supplementation had a significant positive effect on both working memory and intelligence. Both methods that they used to test the subjects required speed of processing. The research team concluded brain energy capacity has a profound influence on brain performance. And that brain energy relies on creatine.172

Creatine Increases I.Q & Attention Span Scientists at the University of Sunderland in the U.K. conducted a double- blind, placebo-controlled study. Working with 34 healthy men and women with a mean age of 21 years. None of the participants were vegetarian. One group took 5 grams of creatine daily for 2 weeks. And the other group took a placebo. They were tested before supplementation. And then after 2 weeks of using either creatine or the placebo. The tests consisted of Memory Scanning, Number-Pair Matching, Sustained Attention and Arrow Flankers, followed by an IQ test. These tests were mentally strenuous by any standard. The researchers concluded that those taking creatine tested much better, and showed less mental fatigue than the placebo group. Creatine increased attention span, I.Q, and working memory.173

Creatine Repairs Brain Cells Drugs currently used to treat neurodegenerative diseases like Parkinson’s and 105 David Tomen Alzheimer’s provide temporary relief of symptoms. But do not stop the underly- ing cause of the disease. Scientists are now working on therapies that focus on replacing injured and dead brain cells. And boosting growth factor along with other neurotrophic molecules. These new therapies include developing vaccines. And using compounds like creatine to immunize against these life-threatening diseases.174 One thing scientists know for sure is impaired energy metabolism plays a prominent role in many of these neurological diseases. Recent studies show impaired energy production in the brain causes neuron cell death. Optimal levels of ATP are crucial to maintaining healthy brain cells. And creatine is a critical in maintaining cellular energy levels. Supplementing with creatine has been proven for neuroprotection in a wide range of neurodegenerative diseases. Including Parkinson’s, ALS, Alzheimer’s, stroke and epilepsy.175

Dosage Notes Recommended dosage of creatine for nootropic benefit is 5 grams per day. Studies show that creatine should be consumed with carbohydrates for best absorption.176 The myth that you should not take creatine with caffeine is exactly that – a myth. No reliable study has shown this to be true.

Side Effects Creatine is produced naturally in your body. So is considered well-tolerated and safe. But over-consumption of creatine can be hard on your kidneys and liver. These organs are creatine factories. And too much creatine can overwork them. If you are dealing with liver or kidney problems, talk to your doctor before supple- menting with creatine. Pure creatine is the safest. But many commercially available creatine supple- ments contain contaminants. Check the labels carefully. Review the manufacturer’s website and any other material they offer that attests to their quality standards. Other side effects can include mild diarrhea, gas, upset stomach or stomach cramps, muscle cramps, increased urination, headaches, reduced appetite and water weight gain. Usually when using too much creatine. Or during the “load- ing” phase of creatine supplementation. Because creatine causes an energy boost in many neurohackers, avoid dosing in the evening. Or you may find difficulty getting to sleep.

Available Forms The best dietary source of creatine is found in wild game. Other sources include red meat and certain fish. 106 HEAD FIRST The most common and least expensive form of creatine available as a supple- ment is in powder form. It’s also available in capsules and a liquid. I recommend skipping all the creatine nitrates, ethyl esters, malate, HCL’s and others – and stick with creatine monohydrate in powder form.

Nootropics Expert Recommendation

Creatine 5 grams per day I recommend using Creatine as a nootropic supplement. Your body does make some creatine on its own. And from the food you eat. But if you’re a vegetarian, or don’t get enough quality creatine in your diet every day, you will benefit by adding creatine to your nootropic stack. Creatine is critical for fueling the activity in your neurons needed for cogni- tion, memory, critical thinking, decision-making and more. Creatine is especially helpful if you’re dealing with fatigue. Or putting un- usually high demands on your brain. Resulting in mental fatigue. Studies have shown creatine can help prevent a host of neurodegenerative diseases as well. I suggest a dose of 5 grams daily. It takes a while for creatine to build up in your system. So if you’d like to get the benefits faster, load with 20 grams a day for a week. And then pull back to a maintenance dose of 5 grams daily. And Creatine is a great compliment to a stack including any nootropic from the racetam-family. Anything that causes an increase in uptake of acetylcholine in your brain. And an increase in mental processing. You need to provide your brain with the fuel it demands. And creatine is a proven way to do it.

107 David Tomen DHEA DHEA has been shown to boost cognition, memory, energy levels and motivation. DHEA () is the most abundant natural steroid hormone in your body. It’s sometimes called the “youth hormone”. And is a source of your sex hormones. DHEA is naturally synthesized in your testes, adrenal glands, and brain. It’s a precursor to DHT and testosterone in men, and estrogen in women. And can activate both androgen and estrogen receptors. Besides making DHEA, your adrenal glands also produce cortisol. Which is in direct competition with DHEA for production. When cortisol is high, espe- cially for prolonged periods of time, your adrenal glands wear out. And DHEA production will decline. DHEA can be made in the lab from wild yam and soy. But your body cannot produce DHEA from eating these foods. To boost DHEA you need to take it as a supplement.177

DHEA Declines with Age Your body’s natural production of DHEA varies with age. Low levels are produced before puberty. With peak production in your 20’s. Between ages 25-30 to 75 your DHEA levels will drop by 80%.178 Affecting everything from alertness, memory, recall, and mood to sex drive. Its decline is even implicated in some neurodegenerative diseases. The age-related variation in DHEA production has led scientists to believe that DHEA could be linked to the aging-process itself. Many athletes use DHEA to increase muscle mass, strength and energy. But DHEA use is banned in the U.S. by the National Collegiate Athletic Associa- tion (NCAA). It’s also considered a “banned substance” by the NBA, NFL, and United States Olympic Committee. In Canada, DHEA is considered a ‘drug’ and is only available by prescrip- tion. Which says something about the power of DHEA. It’s technically a steroid, which may be why it’s included in with Performance Enhancing Drugs (PEDs). In 2007, the U.S. Congress tried to re-classify DHEA as an “ drug”. Which means this natural human hormone would have only been avail- able as a prescription drug. Fortunately, this legislation never passed and you can still buy DHEA as an OTC supplement. Here we’re talking about how DHEA affects your brain health and chemistry.

How does DHEA Work in the Brain? DHEA boosts brain health and function in several ways. But two in particu- lar stand out. 1. DHEA boosts working memory. Research has shown that higher DHEA 108 HEAD FIRST levels are directly related to concentration, working memory and executive function (decision-making). A study done in Australia in 2003 and 2004 worked with 295 women aged 21 – 77 years. The researchers set out to investigate whether circulating levels of DHEAS (dehydroepiandrosterone sulfate) contributed to cognitive function. The women in the study went through a comprehensive battery of tests for cognitive function, and DHEAS levels. The researchers concluded that, “Higher endogenous DHEAS levels are independently and favorably associated with executive function, concentration, and working memory.”179 Note: DHEAS is simply DHEA that is produced with the addition of a sul- fate group. Naturally produced in your body, it produces the hormone estrone. DHEAS can be back-converted in the body to DHEA, and both are often simply referred to as DHEA. 2. DHEA enhances mood – naturally. DHEA has been found to improve both mood and energy while alleviating depression. DHEA may be a good natural alternative to traditional antidepressants. A double-blind, randomized, placebo-controlled study was done at the U.S. Na- tional Institutes of Health with 46 men and women. The study subjects had been diagnosed with major or minor depression. The depressed patients went through 6 weeks of DHEA therapy. 90 mg per day for 3 weeks and 450 mg per day for 3 weeks, and 6 weeks of placebo. They were then tested using two different Depression Rating scales, and for sexual function. The study found that DHEA offered a significant improvement in depres- sion symptoms. And major improvements in sexual function. In a very rare admission from the conservative National Institutes of Health, “We find DHEA to be an effective treatment for midlife-onset major and minor depression.”180

How things go bad: As we get older, our brain chemistry and energy metabolism changes. ↓ Concentration, working memory and executive function decline ↓ Neuron receptors degenerate ↓ Adrenals wear out and DHEA levels decline ↓ Appetite regulation, energy and alertness decline All of these age-related changes are influenced by declining DHEA levels. And are contributing factors to neurodegenerative diseases and depression. DHEA levels are an inevitable consequence of aging. And can contribute to the onset of degenerative disease. 109 David Tomen DHEA to the rescue The latest scientific research validates what we know of DHEA’s anti-aging effects. And it’s not just for athletes. DHEA’s neuroprotective benefits are vital to memory and improving mood. DHEA supports cardiovascular health and activates genes that prevent car- diovascular health problems, diabetes and obesity. It boosts quality of life and sexual function. It even improves the appearance of younger-looking skin. DHEA supplementation can enhance cognitive function and memory, and improve decision-making (executive function). It’s even been shown to decrease brain cell death, and promote general cerebral health.181

How does DHEA feel? You should experience a noticeable increase in motivation and drive soon after supplementing with DHEA. Especially if your levels are low. If you are under constant stress, have chronic fatigue, feel weak, depressed or have a low sex drive – find a Naturopathic practitioner. And have your DHEA levels checked. Too many neurohackers suffer unnecessarily from high stress and low DHEA production. Don’t be one of those people.

The Research DHEA is a steroid hormone and has a strong influence on both brain struc- ture and function. Social and physical stress has severe negative effects in your hippocampus. Affecting memory and orientation. DHEA seems to have a neuroprotective role in reducing the toxic effects of glutamate and cortisol elevated by stress. Studies show low DHEA levels in people suffering from major depression. And that if cortisol and DHEA are out of balance it will delay recovery from these diseases. DHEA plays a role in the treatment of depression. Whether its caused by stress or aging. It affects both the cellular structure of the brain and its function.182

DHEA Levels Predict How Long You’ll Live Scientists in Japan set out to determine if DHEA levels could predict longev- ity. The study included 948 men and women aged 21 – 88 years. The researchers measured DHEAS levels at the beginning of the study. And periodically for the next 27 years. DHEAS levels were higher in the men than women as expected. DHEA levels were measured along with blood pressure, and blood sugar. Of the three health measures, DHEAS levels in men were the strongest predictor of longevity. It doesn’t matter what your age, blood pressure or blood sugar levels.183 This 27-year study concluded that DHEAS levels could be a way to predict how long you’ll live. 110 HEAD FIRST DHEA Improves Memory Studies in rodents showed DHEA improved cognition. But there were in- consistent findings in humans tying cognition to DHEA supplementation. So scientists at the University of Newcastle upon Tyne in the U.K. decided to find out for themselves. In this double-blind study, 24 healthy young men were treated with 150 mg per day of DHEA for 7-days. Mood, memory and the stress hormone cortisol were measured. Including scanning their brains to identify brain regions involved in cognition. The study results showed a reduction in evening cortisol concentrations. And improved memory and mood. Recall significantly improved. And the researchers concluded this study was the first to show that DHEA had a beneficial effect on memory in healthy young men.184

DHEA Levels Associated with Mood in Pro Golfers Several studies suggest that DHEAS levels drop following different types of acute stress. Implicating DHEA’s role in coping with stress and recovering from stress. Researchers in Taiwan wanted to find out what happened to DHEA levels during a negative outcome in an athletic competition. In this case, they studied 14 elite golfers participating in a major national golf tournament. The golfers were divided into 2 groups. One group made the cut during the competition. And the other group did not make the cut. DHEAS levels were measured in both groups 1-day before the competition. And then on days 1, 3 and 5 after the players’ final competition. Study results showed that DHEAS levels in players that made the cut during the competition did not change. Those players that failed to make the cut experi- enced a drop in blood concentrations of DHEAS. This study suggests that DHEA plays a role in your coping mechanism during psychologically challenging times. Supplementing with DHEA during times of stress could help alleviate some of the symptoms normally associated with high stress levels.185

Dosage Notes Recommended dosage of DHEA is 25 – 50 mg per day. DHEA is a strong steroid hormone. And low supplemental doses affect gene expression in inhibiting metabolic syndrome. DHEA supplementation boosts bone strength and enhances cognition and memory. DHEA supplementation is not recommended for anyone under 18 years old. And like many nootropics, too much DHEA is NOT a good thing. It can lead to problems. 111 David Tomen Many nootropics users and doctors recommend taking “hormone holidays”. In other words, use DHEA for a month then take a month off. Supplementing with DHEA beyond the normal range may be advisable for short periods of time. Such as restoring a badly depleted adrenal system. But maintaining large doses of DHEA can lead to unpleasant side effects. Note: If you have been diagnosed with a hormone-dependent cancer, you should not supplement with DHEA until your cancer has been cured.

Side Effects Testing for DHEA levels is very important if you’re planning on supplement- ing with this powerful compound. Because if your hormone levels are normal and you start taking DHEA, you could experience side effects like acne, hair loss, tumor formation, heart arrhythmia, and insomnia. At higher than 100 mg doses, DHEA has been linked to side effects. Many experts caution against high-doses of DHEA. Or long-term usage.

Available Forms The most common form of DHEA is in capsule form. Supplement manufac- turers offer capsules ranging from 10 – 100 mg. You can even get DHEA as an ointment, lozenge or cream. Keep in mind that a 25 mg DHEA capsule will not deliver 25 mg of DHEA to your system. It first must pass through your liver where it’s further broken down. Your body is not used to getting hormones through your digestive system. Once swallowed, only 10-15 percent will eventually reach the tissues you are targeting – like your brain. This is why many Naturopathic practitioners suggest using a DHEA cream in- stead. But here again you have a problem. While more DHEA is bioavailable by using DHEA cream on your skin, some argue there’s even a better way to take DHEA. And that’s by applying the cream to the membranes of your vagina if you are a woman. And in your rectum if you are a man. One other option is to take DHEA sublingually. It makes logical sense that if taken under your tongue, DHEA bypasses your liver. And goes directly into your bloodstream. Personally, I use 25 mg of DHEA in capsule form in the morning, and another 25 mg at noon. And have experienced a considerable boost in energy during the day. But cycling one month on, and a one-month off to give my body a “hormonal holiday”.

Nootropics Expert Recommendation

DHEA 25 – 50 mg per day I recommend using DHEA as a nootropic supplement. But with a huge caveat. 112 HEAD FIRST Get your DHEA levels checked before starting supplementation to be on the safe side. Your body does make some DHEA on its own. But DHEA production inevitably declines with age. And possibly even faster depending on the health of your adrenal glands. If you are under constant stress, have chronic fatigue, feel weak, depressed or have a low sex drive – find a Naturopathic practitioner. And have your DHEA levels checked. Too many neurohackers suffer unnecessarily from high stress and low DHEA production. Don’t be one of those people. Maintaining optimal DHEA levels can enhance cognitive function and memory, and improve decision-making (executive function). It’s even been shown to prevent brain cell death, and boost general cerebral health. Start with 25 mg of DHEA per day. And see how you feel. Increase the dose to no more than 50 mg per day. And watch for side effects. And don’t forget to cycle it. Take it for a month and take one month off.

113 David Tomen DMAE

DMAE has been shown to boost alertness, focus, memory, and mental clarity DMAE (Dimethylaminoethanol, Deanol, Deaner) has two methyl groups and is structurally similar to choline. Choline is a direct precursor to acetylcholine (ACh). ACh is a critical neurotransmitter that influences everything from memory to muscle control. And it is the relationship ACh has with DMAE that generates most of the hype around DMAE as a nootropic. But it turns out that DMAE is NOT a precursor to acetylcholine as reported on many nootropic and brain optimization sites. However, many neurohackers report that supplementing with DMAE has worked wonders for their brain. So here we’ll try to clear up some of the confusion and misinformation sur- rounding DMAE as a nootropic supplement. And if adding DMAE to your stack makes sense. DMAE is an amine naturally produced in small amounts in your brain. High levels of DMAE are also found in seafood like anchovies and sardines. Researchers have speculated that DMAE may increase acetylcholine (ACh) levels in the brain by inhibiting choline metabolism in peripheral tissues. By preventing the use of choline by other tissues (including synthesis into acetylcholine), DMAE increases choline levels in the bloodstream.186 Once DMAE crosses the blood-brain barrier, it increases choline levels in the brain. So with higher choline levels present, you would expect elevated levels of acetylcholine (ACh). But research has shown this is not always what happens when DMAE gets to your brain. In one study, DMAE was rapidly taken into the brain. But when it reached synapses – nothing happened. Choline levels rose but did not convert into acetylcholine.187 What’s going on here? First, we must look at how acetylcholine (ACh) is made. ACh is synthesized in a single step reaction catalyzed by the enzyme choline acetyltransferase (ChAT).188 The rate-limiting steps in ACh synthesis are the avail- ability of choline and Acetyl Coenzyme A (Acetyl-CoA). The only other source of acetylcholine (ACh) is synthetization from phosphati- dylcholine (PC) via phosphatidylethanolamine N-methyltransferase (PEMT).189 And this ACh synthesis only happens in cholinergic receptors. So it would appear that DMAE cannot be converted to either choline or ACh. The only way DMAE can increase choline is by inhibiting choline metabolism. And the reason why choline levels rise in the brain when supplementing with DMAE is because the choline does not synthesize into acetylcholine (ACh).190 So why do some neurohackers experience a benefit in increased focus, clearer cognition, and even an antidepressant effect with DMAE? 114 HEAD FIRST It could be that DMAE stimulates cholinergic receptors into taking action.191 And with extra choline floating around because of DMAE, these neuroreceptors may decide to produce some extra ACh.192 DMAE may be useful to those dealing with a choline deficiency in the brain. And studies show that DMAE effectiveness in the brain depends on the health of the cholinergic system in your brain.193 But as neurohackers we have more efficient options available for boosting choline in the brain. Centrophenoxine which is a combination of DMAE and cCPA (parachlorphenoxyacetic acid) seems to boost acetylcholine in the brain much more efficiently than DMAE.

How does DMAE Work in the Brain? DMAE boosts brain health and function in several ways. But two in particu- lar stand out. 1. DMAE is a neuroprotectant. Lipofuscin is a cellular waste product that ac- cumulates in brain cells as we age. It’s the same waste product that causes brown spots on skin. Lipofuscin hides in cells throughout your body includ- ing your brain, eyes, liver, kidneys, heart, adrenals and nerve cells (neurons). Neurohackers often report that supplementing with DMAE produces en- hanced vision. This vision effect may be DMAE’s ability to help remove waste like lipofuscin from cells that affect vision. This lipofuscin removal mechanism of action by DMAE has been shown in animal studies in the lab. Researchers used Centrophenoxine injections on 17-month old female mice. The animals were injected daily for 3 months. The researchers studied changes in pigment layers of the retina of both eyes in the mice. And found there was significant reduction of lipofuscin pigment in the treated animals.194 Centrophenoxine breaks down into DMAE once in your body. And it is the DMAE in this nootropic that provides the lipofuscin scavenger affects. 2. DMAE enhances attention and mood. DMAE has been reported by some neurohackers to improve vigilance, attention, mood and energy while al- leviating depression. A study by German researchers may explain where this feeling of well-being comes from when supplementing with DMAE. This double-blind, placebo-controlled trial used 80 human subjects evenly split between male and female. The study analyzed their brain’s electrical reaction during presentation of five 7-minute video clips followed by a 3-minute pause for each. This procedure was repeated after 6 and 12 weeks of daily intake of DMAE or a placebo. The subjects taking DMAE for 3 months developed significantly less theta and alpha brain waves. 115 David Tomen Decreases in theta and alpha brain waves have been associated with increased vigilance and attention. The subjects using DMAE were also more active and felt better. The researchers concluded that DMAE can induce a state of better feeling of well-being.195

How things go bad As we get older, our brain chemistry and energy metabolism changes. ↓ Concentration, working memory and executive function decline ↓ Cholinergic receptors degenerate ↓ DMAE levels decline ↑ Lipofuscin and free radicals build up in brain cells All of these age-related changes could be influenced by declining DMAE levels. And are contributing factors to neurodegenerative diseases and depression. DMAE levels are an inevitable consequence of aging. And may contribute to the onset of degenerative disease.

DMAE to the rescue DMAE increases choline levels in your brain. This increase in choline and DMAE’s ability to stimulate cholinergic receptors into action may lead to an increase in acetylcholine (ACh) levels. But DMAE does not directly elevate acetylcholine levels in the brain. DMAE is NOT a precursor to acetylcholine.196 Increased ACh levels affect learning and memory. ACh helps the encoding of memories and your ability to concentrate. As neurohackers, we absolutely want to increase acetylcholine levels. Especially if our brain is low on ACh. But DMAE is not the best way to achieve the goal of elevated ACh levels. Research into DMAE is ongoing and there may be some benefits to DMAE supplementation not yet known by the neurohacking or research community.197 DMAE has been used to treat a variety of conditions from cognitive disor- ders including ADHD. DMAE is also used in skin care products to help reduce age spots, fine lines and wrinkles, and even sagging skin.198 Free radicals can cause damage to DNA, upset cellular metabolism, and induce the creation of reactive oxygen species that kill brain cells.199 Some re- search has found that DMAE is a somewhat effective free radical scavenger.200 DMAE has been found to diminish the extent of “cross-linking” of proteins that have been implicated in diseases like Alzheimer’s.201 Researchers think this may be due to DMAE’s effectiveness as a free radical scavenger.202 DMAE is reported to induce lucid dreaming.203

How does DMAE feel? Some neurohackers report that DMAE supplementation causes a noticeable boost in their ability to concentrate. 116 HEAD FIRST DMAE users often report: better memory (especially short-term memory) mentally alert improved focus mental clarity better sleep patterns Dosing more DMAE than recommended has been reported to make you feel edgy and tense. And you may experience muscles spasms, particularly in your shoulders and neck.

The Research

Early DMAE Research A prescription form of DMAE called Deaner or Deanol was in clinical use as far back as the 1960’s and 70’s. Deanol was used for the treatment of learning and behavioral problems associated with shortened attention span. Two clinical trials conducted over 40 years ago proving the efficacy of using DMAE for treating what’s now known as ADHD are below. But in 1983, the FDA in all their wisdom insisted on additional studies to prove the effectiveness of DMAE. And because clinical trials would have been costlier than product sales could support, the company making Deanol and Deaner took them off the market. DMAE is now available as a nootropic supplement. One that your doctor or psychiatrist is unlikely to prescribe to you for treating your ADHD.

DMAE to Treat ADHD One double-blind, placebo-controlled study compared the effects of DMAE supplementation with methylphenidate (Ritalin) for treating ADHD. 74 chil- dren diagnosed with learning problems and hyperactivity were referred to this study. The children received 40 mg of Ritalin, 500 mg of DMAE or a placebo daily for 3 months. Behavior, reaction times and other psychometric tests were done before and after treatment. Both ‘drugs’ proved to be effective according to several tests. The research- ers concluded that DMAE supplementation significantly improved performance in children with learning and behavior disorders.204 Another study conducted by Dr. Carl Pfeiffer of the Brain-Bio center in Princeton, New Jersey with 25 girls and 83 boys found similar results in using DMAE for treating ADHD. In this study, Dr. Pfeiffer found that DMAE enhanced the behavior in 2/3 of the boys and 3/4 of the girls. Attention span was better, irritability and hyper- 117 David Tomen activity were decreased, scholastic ability improved and in some cases even IQ got a boost.205 So if you’re ADHD, and using Ritalin or Adderall and looking for a natural alternative, you may want to try DMAE.

DMAE use in Cosmetics Most of the research on DMAE in the 1950’s and 60’s centered around using this compound for cognitive function and brain health. The most recent research on DMAE is primarily for using the compound in skin cosmetic formulas. DMAE has been shown to increase skin firmness even in young skin. One study with 30 healthy adults aged 36 – 49 applied DMAE gel or a placebo. The results of the study showed that DMAE-treated skin was much firmer.206 Another randomized clinical study used 3% DMAE facial gel applied daily for 16 weeks. The gel was able to reduce forehead lines, wrinkles around the eyes and improving lip shape and fullness. And the effects did not regress even 2-weeks after stopping application. Another open-label extension of the same trial showed that long-term ap- plication of DMAE gel had a good safety profile.207

Dosage Notes Recommended dosage of DMAE is 100 – 200 mg per day. DMAE nootropic supplements are usually sold as DMAE bitartrate. A cap- sule of DMAE bitartrate is only 37% DMAE and the rest is 67% tartaric acid. A 250 mg capsule of DMAE bitartrate yields 92.5 mg of actual DMAE. Take your DMAE dose in the morning before or with breakfast. Dose DMAE a few times a week, but not every day. If you are going to use DMAE, stack it with a good source of choline. Remem- ber that DMAE inhibits choline and metabolism of choline. And you absolutely need choline and acetylcholine for a fully optimized brain. DMAE inhibits phospholipid synthesis. This means you won’t get much help with choline precursors. You need a good source of choline. Without getting into a long explanation of the mechanics – Phosphatidyl- choline (PC) or CDP-Choline and Omega-3’s (DHA) can help offset the damage caused by long-term DMAE use.

Side Effects DMAE is considered non-toxic and safe for short-term or intermittent use. Your body naturally produces some DMAE on its own. You shouldn’t experience any side effects as long as you use DMAE in recom- mended doses. 118 HEAD FIRST Some neurohackers report insomnia, headaches and muscle tension. Usually because the dose was too high. If you have a negative reaction to DMAE stop using DMAE. If you are planning on becoming pregnant do not use DMAE. Clinical stud- ies have shown that DMAE may stunt the growth of the child’s brain.208 If you have epilepsy or bipolar disorder you should avoid using DMAE entirely. See “Dosage Notes” about how to stack DMAE if you’re going to supple- ment with this nootropic.

Available Forms DMAE is available in tablet, capsule, powder, liquid and creams. DMAE tablets and capsules are usually DMAE bitartrate (see “Dosage Notes”) and 150 – 350 mg. Depending on the size of capsule or tablet, do the conversion for pure DMAE, and start slowly with a low dose of 50 mg. And see how you respond.

Nootropics Expert Recommendation

DMAE 100 – 200 mg per day I do NOT recommend using DMAE as a nootropic supplement. But if you must use DMAE, refer to the “Dosage Notes” and “Side Effects” in this chapter. Your body does make some DMAE on its own. But DMAE production inevitably declines with age. Some neurohackers report that using DMAE has a significant effect on con- centration, memory, alertness, focus and mental clarity. But here at Nootropics Expert, I feel there are much more effective and safe ways to improve alertness, concentration, focus, and memory. If you’re going to use DMAE, start with 50 mg of DMAE per day. And see how you feel. Increase the dose no more than 50 mg at a time. And watch for side effects. Don’t forget to cycle it. Take it for a few days and take a couple of days off.

119 David Tomen 5-HTP 5-HTP is known for relieving depression and anxiety, fibromyalgia, insomnia, mi- graines, obesity, and symptoms of Parkinson’s Disease 5-HTP (5-Hydroxytryptophan or oxitriptan) is an amino acid that is naturally produced in your body. 5-HTP is synthesized from the amino acid tryptophan which we get from food. 5-HTP is the immediate precursor of serotonin. And as a nootropic and dietary supplement, 5-HTP is popular with those who advocate its effectiveness in treating depression. Along with a number of other serotonin-related diseases. But using 5-HTP for treating depression and anxiety is not supported by science. The research is contrary to how 5-HTP is viewed by many, including medical doctors. When we dig into the research, we find that 5-HTP may be contraindicated for depression in those whom marketers advocate its use.209 I’m all for boosting neurotransmitter levels and optimizing cognitive perfor- mance here at Nootropics Expert. But now and again I run into a nootropic or dietary supplement that may be popular. But also may be a particularly bad idea. We’re going to get to the bottom of how 5-HTP works in your brain in this chapter. We’ll examine why it’s critical for brain health. And reasons why you may want to find another way to boost serotonin levels in your brain. So again, 5-HTP is an amino acid that’s synthesized from the essential amino acid tryptophan. Tryptophan is hydroxylated by tryptophan hydroxylase to 5-HTP (5-hydroxy- tryptophan), then decarboxylated to serotonin (5-hydroxytryptamine or 5-HT).210

Tryptophan → 5-HTP → serotonin 80-90% of your body’s serotonin is made in your intestines. But serotonin cannot cross the blood-brain barrier. So all the serotonin that your brain needs has to be made within the brain. This is where 5-HTP comes in… 5-HTP crosses the blood-brain barrier more readily than tryptophan. And gets synthesized into serotonin at a faster rate than from tryptophan.211 As a neurotransmitter, serotonin influences directly and indirectly, the ma- jority of brain cells. So if you want to boost serotonin in your brain, some find that supplementing with 5-HTP is better than taking tryptophan. Tryptophan, which your body uses to make 5-HTP, can be found in turkey, chicken, milk, potatoes, pumpkin, sunflower seeds, turnip and collard greens, and seaweed. 5-HTP as a nootropic supplement is a naturally occurring amino acid derived from seed pods of Griffonia simplicifolia, found in West and Central Africa. 5-HTP content in extracts of this plant vary from 2 – 20.83% (from seeds obtained in Ghana).212 120 HEAD FIRST How does 5-HTP Work in the Brain? 5-HTP is a precursor to serotonin. The neurotransmitter serotonin plays a role in sleep, appetite, memory, learning, mood, and sexual function. When tryptophan’s role in converting to 5-HTP for boosting serotonin doesn’t work efficiently, the result is often depression, chronic headache and insomnia. An open-label trial was conducted in Italy to determine the efficacy of using 5-HTP in young subjects with high levels of “romantic stress”. Serotonin has been linked to human romantic attachment. So researchers in this study set out to determine brain levels of Brain-Derived Neurotrophic Factor (BDNF) and serotonin in relation to changes in romantic stress (during the study). 15 healthy subjects (mean age 23.3 years) who had a “romantic breakup” took part. Participants received 60 mg of Griffonia simplicifolia extract contain- ing 12.8 mg 5-HTP daily for 6 weeks. The subjects were evaluated for BDNF and serotonin levels at the beginning of the study, at 3 weeks and then again at the end of the 6-week trial. The scientists observed significant improvements in romantic stress scores from weeks 0 through 3. So far, 5-HTP seems to be working. But no further improvement was seen from weeks 3 through 6. Even though the young people had significantly higher levels of BDNF and serotonin.213

More Involved in Depression and Stress than Serotonin This “romantic breakup” study is a classic illustration of why using 5-HTP alone to treat depression and stress may not work. And if it does work, why it may not work for long. Depression is often more than simple serotonin dysfunction. Depression can also be associated with catecholamine dysfunction, including dopamine and/or norepinephrine. Or a combination of serotonin and catecholamine dysfunction. When you take 5-HTP alone, you are also depleting dopamine, norepi- nephrine, and epinephrine. Synthesis of serotonin from 5-HTP, and dopamine from L-DOPA is catalyzed by the same enzyme, L-aromatic amino acid decarbox- ylase (AAAD). Dopamine and serotonin precursor supplementation must be taken in proper balance. Because when you use only 5-HTP, it dominates dopamine at the AAAD enzyme synthesis level. Blocking dopamine synthesis at the AAAD enzyme through competitive in- hibition will lead to depletion of dopamine and the rest of the catecholamines.214 Going back to our Italian study of young people dealing with “romantic stress”, the subjects stopped responding to 5-HTP in the 2nd half of the study. Likely because their catecholamines became depleted through continuous 5-HTP supplementation. 121 David Tomen Studies have found that when dopamine is depleted enough, 5-HTP will no longer function.215

Catecholamine Dysfunction Affects More Than Just Depression When catecholamine neurotransmitter levels (dopamine and/or norepineph- rine) influence depression, supplementing with 5-HTP alone is not the way to go. Because you may deplete dopamine and norepinephrine, worsening the disease and its underlying cause. But this contraindication is not exclusive to depression. It extends to all other diseases where catecholamine dysfunction has been implicated. Including ADHD216, obesity, anxiety, seasonal affective disorder and Parkinson’s Disease.217

How things go bad Amino acid precursors of serotonin (i.e. 5-HTP) and dopamine (i.e. L- Tyrosine) work together during synthesis, metabolism and transport to the point that they function as one system. When serotonin and dopamine are properly balanced, functions that are regulated only by serotonin, can be regulated by manipulating dopamine levels. And functions regulated only by dopamine in this balanced state can be regulated by manipulating serotonin.218 When you mess with this balance and improperly supplement with serotonin or dopamine precursors, you don’t get the desired effect of using that nootropic. And you increase the possibility of side effects. If you supplement with only one precursor (i.e. 5-HTP to boost serotonin) that dominates the other system (i.e. dopamine synthesis), depletion of the dominated system will occur (i.e. depleted dopamine). And if this effect is pronounced enough, you will not get the benefit you were aiming for when supplementing with the original precursor (i.e. 5-HTP). A powerful example of this effect is in the management of Parkinson’s Disease where the effects of L-DOPA are no longer observed over time due to serotonin depletion.219 Since serotonin and dopamine cannot cross the blood-brain barrier, the number of serotonin and dopamine molecules in the brain is a function of the amount of nutrients (amino acid precursors) that are available to be synthesized into new neurotransmitter molecules. Optimizing brain function with minimal side effects is NOT a function of supplementing until you get sufficiently high amino acid levels. It’s a function of achieving the proper balance between serotonin and dopamine.

5-HTP to the rescue 5-HTP is absolutely critical for synthesis of serotonin in your brain. But supplementing with 5-HTP to boost serotonin does not work well. 122 HEAD FIRST Using 5-HTP to treat depression has had very little success over the last few decades of clinical trials and biohacking. Integrating 5-HTP into your nootropic stack is much more complicated than simply adding some 5-HTP in order to boost serotonin. 5-HTP alone will not work for depression, or any other issue you’re dealing with involving the catecholamines (dopamine, norepinephrine, epinephrine) because of 5-HTP’s tendency to deplete those neurotransmitters. 5-HTP will boost serotonin in your brain.220 But 5-HTP must be carefully stacked with precursors for dopamine and norepinephrine or you risk making the situation worse. You must avoid supplementing with only one of the serotonin or dopamine amino acid precursors. When amino acid precursors are not in balance, you end up with decreased effectiveness of that nootropic, increased side effects, and depletion of the nondominant system.

How does 5-HTP feel? Reactions to supplementing with 5-HTP vary considerably. But the one consistent theme is initial feelings of well-being, better sleep, less need for sleep, improved mood, less social anxiety, lower appetite, improved tolerance for stress and improved cognitive function. And after a couple of weeks of dosing 5-HTP – side effects begin. Serotonin overload results in dopamine and norepinephrine depletion. Side effects include feelings of lethargy, depression, brain fog, stomach pain, and headaches. Worst case scenario is nausea, vomiting and even blacking out. Neurohackers who report consistent success supplementing with 5-HTP stack it with B-Vitamins, a dopamine precursor like NALT, and only use 5-HTP as needed. Those who have a bad experience with 5-HTP from the start often have no idea why they’ve reacted badly. But an educated guess is their depression was catecholamine (dopamine, norepinephrine, epinephrine)-related. And boosting serotonin made their dopamine-related issues worse. Very quickly. One huge word of WARNING: Do NOT take 5-HTP with any antidepres- sant medication. You put yourself in the very real danger of Serotonin Syndrome which can ultimately kill you.

The Research 5-HTP supplements are heavily marketed as a natural remedy for depres- sion. But the science does not support using 5-HTP for depression. We have decades of clinical trials available. And there is no evidence of the efficacy in using 5-HTP for depression. The Department of Public Health at the University of Queensland Medical 123 David Tomen School in Australia did a systematic review of literature dating from 1966 – 2000 for “5-HTP” and “depression”. The researchers found 108 clinical studies of which only 2 studies, one with serotonin (5-HT) and one with L-Tryptophan for a total of 64 patients met sufficient quality criteria to be included. These studies suggest serotonin (5-HT) and L-Tryptophan are better than placebo at alleviating depression. But the researchers noted “the small size of the studies, and the large number of inadmissible, poorly executed studies, cast doubt on the results from potential publication bias, and suggests that they are insufficiently evaluated to assess their effectiveness.”221

5-HTP for Fibromyalgia A double-blind, placebo-controlled trial in Italy studied the efficacy of using 5-HTP in treating fibromyalgia symptoms. 50 patients with primary fibromyalgia syndrome were selected for this study. This 1990 study did not publish the amount of 5-HTP used. But the researchers found a significant improvement in fibromyalgia symptoms with only mild and transient side effects.222

5-HTP for the Treatment of Depression Insufficient activity of the neurotransmitters serotonin and norepinephrine is a central element of the model of depression most widely held by neurobiologists today. In the late 1970’s and 1980’s, numerous studies were performed in which depressed patients were treated with the serotonin precursors L-Tryptophan and 5-Hydroxytryptophan (5-HTP), and the dopamine and norepinephrine precur- sors Tyrosine and L-Phenylalanine. A summary published in the Alternative Medicine Revue looked at the data from all these studies. The author noted that the nature of the studies makes it difficult to draw firm conclusions regarding the efficacy of neurotransmitter precursors for treating depression. While there is evidence that precursor loading could work, particularly for serotonin precursor 5-HTP, more studies of suitable design and size “might lead to more conclusive results”.223 Those studies have not materialized since that report was published 16 years ago.

Dosage Notes Recommended dosage of 5-HTP if you’re going to try it, is 50 mg 1 – 3 times per day. Some studies have used higher doses than my recommended dose, but 5-HTP can be toxic at high doses. For anxiety or depression, 5-HTP is dosed at 150 – 300 mg per day total. 124 HEAD FIRST To relieve post MDMA (Ecstasy) depression, 5-HTP 100 mg on Day 3-7 after MDMA use.224 Successfully supplementing with 5-HTP requires stacking it with a dopamine precursor like L-Tyrosine or L-DOPA along with B-Vitamins (for synthesis), and one of the sulfur-containing amino acids (methionine, cysteine, homocysteine, or ). And you must monitor the effects this stack is having on your body. If you start experiencing side effects of any kind, it’s a good indication that either sero- tonin or dopamine is out of balance.

DO NOT combine 5-HTP with any kind of antidepressant medication. Combining SSRI’s, Tricyclics or MAOI’s with 5-HTP will cause Serotonin Syndrome. An extremely dangerous condition involving severe mental changes, hot flashes, rapidly fluctuating blood pressure and heart rate, and possibly coma. Serotonin Syndrome can kill you. And I’m not kidding here.

Side Effects 5-HTP supplementation can cause heartburn, heart palpitations, headache, stomach pain, nausea, vomiting, diarrhea, drowsiness, sexual problems and muscle issues. 5-HTP can also cause some pretty radical mood changes including agitation, aggressiveness, anxiety, euphoria, poor decision-making, irritability, psychosis, restlessness and insomnia. 5-HTP can make the symptoms of schizophrenia, bipolar disorder and other mental disorders worse. And I can’t emphasize this enough so I’m going to repeat it here in case you missed it…

DO NOT combine 5-HTP with any kind of antidepressant medication. Combining SSRI’s, Tricyclics or MAOI’s with 5-HTP will cause Serotonin Syndrome. An extremely dangerous condition involving severe mental changes, hot flashes, rapidly fluctuating blood pressure and heart rate, and possibly coma. Serotonin Syndrome can kill you. And I’m not kidding.

Available Forms 5-HTP is made from tryptophan in your body. 5-HTP as a nootropic supplement is made from extracts of the African tree Griffonia simplicifolia. 5-HTP supplements are typically in tablet or capsule form. You’ll often find 5-HTP in many ready-made vitamin and herbal formulas.

Nootropics Expert Recommendation

5-HTP 50 mg up to 3-times per day I DO NOT recommend using 5-HTP as a nootropic supplement. 125 David Tomen Your body does synthesize 5-HTP on its own to make serotonin in your brain. You can’t get 5-HTP from food. But you can get L-Tryptophan from food which is synthesized into 5-HTP in your body. 5-HTP may help you if you’re dealing with depression. But you must stack it with a dopamine amino acid precursor, along with B-Vitamins, and a sulfur- containing amino acid. See the “Dosage Notes” in this chapter. IF you are going to try 5-HTP, I suggest starting with a dose of 50 mg daily. You may want to take it in the evening because it could help you sleep. Short-term dosing of 5-HTP of no more than 2 weeks seems to provide the most benefit if you’re going to benefit from this nootropic. Or try using 5-HTP only on an “as needed” basis. For a mood boost, improve social anxiety, and provide a short-term boost in cognition. Unless you are using 5-HTP to alleviate the symptoms after using Extasy (MDMA), 5-HTP supplementation on its own is NOT recommended. Nor is it recommended for long-term use.

126 HEAD FIRST Forskolin

Forskolin has been shown to boost memory and learning, improve motivation and mood, and stimulate cerebral circulation Forskolin (Coleus forskohlii) is the only known nootropic supplement to naturally boost cAMP (Cyclic Adenosine Monophosphate) in your brain. 225 cAMP is important for neural signaling within brain cells. As a secondary messenger in neurons, cAMP produces proteins needed for neuron and synapse growth. This process is calledLong-Term Potentiation (LTP). LTP is the process where synaptic connections get stronger in response to electrical stimulation in the brain. This process happens naturally through life experience. It’s a critical part of synaptic plasticity. And how experience is recorded through learning and memory. Forskolin is a chemical compound extracted from Coleus forskohlii (Plectran- thus barbatus), a perennial plant native to India, Burma and Thailand. Forskohlii has been used for millennia in traditional Ayurvedic medicine to treat heart disease, convulsions, spasms and painful urination.226 Forskolin is used in Western homeopathic medicine to treat allergies, skin conditions, obesity, PMS, irritable bower syndrome, urinary tract infections, bladder infections, cancer, blood clots, male infertility, insomnia and convulsions. Some healthcare providers even use Forskolin intravenously (IV) for heart failure. Researchers and holistic medical practitioners use the extract Forskolin to boost cerebral blood flow, lower blood pressure, treat hypertension, asthma and congestive heart failure. But here, we’re looking at Forskolin as a nootropic. Recall that Forskolin boosts cAMP. cAMP was discovered in 1956 and its production is now known to be the final common pathway for many hormones and transmitter agents. To put this in practical perspective, hormones and neurotransmitters do not enter the cell. Instead, they activate a receptor on the cell membrane that is part of the adenylate cyclase enzyme complex. The production of cAMP in a cell is catalyzed by this complex. The cyclic AMP (cAMP) then activates cAMP dependent protein kinase (PKA), which results in changes in the cell’s function.227 Based on input from the relevant hormone or neurotransmitter. The elevation of cAMP along with PKA is required for long-term potentia- tion (LTP). This increase in neuroplasticity is how long-term memories are formed and encoded in your brain. Researchers have found that increases in cAMP rapidly activates the Brain-Derived Neurotrophic Factor (BDNF) receptor TrkB and induces BDNF- 127 David Tomen dependent long-term potentiation at the Schaffer collateral-CA1 synapse in the hippocampus.228 In simpler terms, Forskolin boosts cAMP levels which affects long-term po- tentiation (LTP). LTP is an integral part of the process in developing and encod- ing long-term memories.

How does Forskolin work in the Brain? Forskolin boosts brain health and function in several ways. But two in par- ticular stand out. 1. Forskolin enhances memory. Forskolin as a nootropic has the unique abil- ity to activate the enzyme adenylate cyclase (AC). The activated AC enzyme then converts to cAMP (Cyclic Adenosine Monophosphate), a secondary mes- senger used for intracellular communication.229 cAMP helps stimulate the production of CREB (cAMP response element- binding protein). An increase in CREB enhances Long-Term Potentiation (LTP). LTP is the connection between brain synapses. Strengthening in response to stimulation by neurons on either side. A major component in both learning and memory. Memories are stored at a cellular level. And retrieved at a cellular level. This well-travelled pathway is strengthened by boosting cAMP with Forskolin.230 2. Forskolin increases cerebral circulation. Coleus forskohlii has tradition- ally been used to treat hypertension (high blood pressure), congestive heart failure and angina (reduced blood flow to the heart). Forskolin is very effective in lowering blood pressure. And scientists believe this ability to boost blood flow is related to Forskolin’s cAMP-elevating ability. Researchers recruited 7 patients with dilated cardiomyopathy (DCM). DCM is a condition in which the heart’s ability to pump blood is decreased due to the left heart ventricle being enlarged and weakened. Forskolin administration dra- matically improved left ventricle function. And increased overall cardiovascular performance.231 Another group of scientists set out to study the effects of Forskolin on cere- bral circulation. In this study, rabbits were anesthetized and measuring devices were attached to blood vessels entering and coming out of the brain. The study found that Forskolin was an effective cerebral vasodilator. Enlarging blood vessels in the brain boosted blood flow. Allowing for more efficient delivery of nutrients and oxygen to brain cells.232

How things go bad Environmental factors like the food we eat, exposure to toxins, polluted air, ADHD, illness, stress and aging changes our brain chemistry. ↓ Mood and motivation declines 128 HEAD FIRST ↓ Memory and recall decline ↓ Long-term memory fades All of these changes are contributing factors to poor quality of life. And as they progress, to neurodegenerative diseases like Alzheimer’s, dementia and Parkinson’s.

Forskolin to the rescue Research from hundreds of studies, and feedback from neurohackers have shown that Forskolin can: • Improve memory by boosting cAMP activity in the brain • Boost catecholamines (dopamine, norepinephrine, and epinephrine) in the brain • Boost cerebral circulation Forskolin is fat-soluble and quickly enters your brain after you take it. Once in your brain, it boosts cAMP activity. cA “MP is involved in the Long-Term Potentiation process of preserving memories. Forskolin combined with Artichoke extract is even more effective. Forskolin effectively boosts cAMP levels but also increases PDE4 in the brain. PDE4 is a cAMP inhibitor and will counteract increases by Forskolin if left unchecked. Inhibiting PDE4 with Artichoke Extract, and boosting cAMP with Forskolin also potentiates dopamine release in the brain. Boosting processes in this stream of chemical reactions in the brain increases learning and memory.233 Without the side effects of stimulating dopamine production through the use of drugs like Adderall or Ritalin.

How does Forskolin feel? Many neurohackers report that Forskolin with Artichoke Extract improves mood. It motivates you to want to learn, and to get things done. Some say it works as good as Modafinil. The general consensus is: • Improved long-term memory • Increased ability to retain information • Increased ability to study • Improved mood and motivation

The Research

Forskolin as a nootropic cAMP responsive element binding protein (CREB) is a protein that modulates the transcription of genes. Increases in cAMP triggers the activation of CREB. 129 David Tomen And this transcription factor is a big part of intracellular signaling. It regulates everything from the production of new sperm cells in men (spermatogenesis), to the circadian rhythms that control your sleep and awake cycles, to memory formation. Forskolin increases cAMP which triggers the activation of CREB. Researchers have found through animal studies that CREB is required for a variety of com- plex forms of memory, including spatial memory and social learning.234

Forskolin reduces anxiety Benzodiazepines (Benzos) like Valium are a class of psychoactive drug used to treat anxiety, insomnia, agitation, muscle spasms, alcohol withdrawal and before medical and dental procedures to keep the patient calm. Benzodiazepines come with a whole host of negative side effects including addiction, cognitive impairment, decreasing effectiveness (tolerance) and nasty withdrawal symptoms. Scientists have been studying non-GABAergic substances that elevate cAMP, and have anti-anxiety activity. So they took a look at Forskolin. In one animal study, researchers compared the effects on anxiety of Forskolin compared to (Valium). And found that Forskolin produced signifi- cant anti-anxiety activity in both stressed and unstressed animals. Diazepam had an anti-anxiety effect on the unstressed animals. But did not work for stressed animals. The researchers noted that the anti-anxiety activity of Forskolin was accompanied by a significant elevation of cAMP levels. There’s cAMP again… The researchers concluded that Forskolin was a better option for treating anxiety. This non-receptor mediated anti-anxiety action through cAMP elevation was preferable to the adverse reactions people get from using receptor-mediated drugs like Benzos.235

Forskolin as a neuroprotectant in chemical warfare If you ever find yourself in a warzone, you may want to have a bottle of Forskolin with you. Acetylcholinesterase (AChE) is the primary in your body. This enzyme catalyzes the breakdown of acetylcholine (ACh) once ACh is used in the synaptic cleft during neurotransmission. This is how it works… During neurotransmission, ACh is released from the first neuron into the synaptic cleft of the 2nd neuron where it binds to ACh receptors. And does its job of passing on the neural signal. Once ACh has done its job, AChE which is also located in that synaptic cleft, steps in and breaks down acetylcholine (ACh) by liberating the choline. The liberated choline is taken up again by another neuron, and ACh is synthesized 130 HEAD FIRST by combining the free recycled choline with Acetyl-CoA through the action of choline acetyltransferase. Chemical warfare agents like Sarin gas, and insecticides like , act to inhibit AChE. Which means they shut down this recycling process needed for acetylcholine production in the brain. Researchers have demonstrated that Forskolin is a very effective AChE pro- moter. Forskolin activates AChE and up-regulates its expression. Using mouse models, the scientists showed that Forskolin boosted AChE expression outside and inside the affected brain cells. They concluded that Forskolin can sufficiently upregulate cellular AChE production and protect cells against chemical warfare agents like Sarin.236 Forskolin works to protect your brain from damage caused by insecticides too. So if your using an insecticide in the house or out in your garden, you may want to protect your brain by dosing with Forskolin first.

Dosage Notes Recommended dosage for Forskolin is 250 mg of Coleus forskohlii at 10%, or 125 mg of Coleus forskohlii at 25%. For boosting cAMP in a CILTEP stack: 4 mg Forskolin extract per day along with 900 mg of Artichoke Extract for PDE4 suppression. NOTE: You will not get the full nootropic benefit of using Forskolin if you dose it on its own. Forskolin has a tendency to boost cAMP and PDE4 levels. And PDE4 suppresses cAMP. Artichoke Extract helps control PDE4. And don’t worry about measuring out an accurate 4 mg for this CILTEP stack. I’ve been using 250 mg of Forskolin (10% ForsLean®) with 900 mg of Artichoke Extract (6%) with great success. For counteracting Forskolin’s effect on Acetylcholinesterase: 800 mg Acetyl-L-Carnitine (ALCAR) – (200 mg of ALCAR for every 1 mg of Forskolin) per day. Many users of this stack report it helpful to supplement with 500 mg Phenyl- alanine, a B-Vitamin Complex and caffeine (coffee or preferably green tea).

Side Effects Forskolin induces CYP3A gene expression in your liver. Which means, like grapefruit juice, Forskolin needs to be used cautiously as it will amplify the effects of other nootropics in your stack. And prescription meds.237 Acetylcholinesterase is upregulated by cAMP which makes you sleepy. This means that available Acetylcholine (ACh) in your brain drops. You can coun- teract this with Acetyl-l-Carnitine (ALCAR), which calms the upregulation of Acetylcholinesterase. The most common side effect with Forskolin is diarrhea because increased cAMP affects the smooth muscle in your gastrointestinal tract. Things move 131 David Tomen through your intestines faster with Forskolin. But this side effect usually happens at much higher than recommended doses of Forskolin. Forskolin reduces blood pressure. So if you’re on high blood pressure meds or have naturally low blood pressure you should avoid using Forskolin.

Available Forms Forskolin is usually marked as “Forskolin” or “Coleus forskohlii” on the bottle. Forskolin typically comes in 125 mg capsules of Coleus Forskohlii (25% Forskolin), or 250 mg capsules of Coleus Forskohlii (10% Forskolin). Look for a Coleus forskohlii or Forskolin supplement with the percentage of Forskolin extract clearly marked on the label. ForsLean® by Sabinsa Corporation is a branded and patented form of Coleus forskohlii that’s been used most often in human trials. So we prefer a supplement that uses ForsLean® as their source of Forskolin. Researchers in India reported that Forskolin concentration can change sig- nificantly depending on where the Coleus forskohlii is grown.238 And why we prefer a standardized version like ForsLean®.

Nootropics Expert Recommendation

Forskolin Extract 125 – 250 mg per day I recommend using Forskolin as a nootropic supplement. Your body does not make Forskolin on its own. So to get its benefits you must take it as a standardized supplement. Forskolin on its own as a supplement for cognition and memory is not very effective because it increases PDE4 (a cAMP reducer) along with boosting cAMP. So the nootropic effects cancel each other out. But Forskolin is especially helpful when combined with Artichoke Extract. It helps boost memory, increases motivation and the desire to learn. And helps improve mood while controlling anxiety. I suggest dosing Forskolin 125 – 250 mg per day with 900 mg of Artichoke Extract taken in the morning. Stack this with at least 800 mg of ALCAR to keep your acetylcholine levels up. I’ve also found that combining this stack with caffeine is helpful. The L- Theanine in green tea comes with the caffeine boost we need. Without the side effects of coffee. And finally, we are making the effects of normaldopamine function more ef- fective with this stack. It triggers the desirable downstream processes that increase learning and memory. The chemical dynamics of the dopamine are preserved. And we don’t get the negative side effects of using a stimulant like Adderall or Ritalin. This Forskolin/Artichoke Extract stack increases mental endurance for encoding long-term memories.

132 HEAD FIRST GABA GABA has a calming effect on brain and body, helps relieve stress and anxiety, and boosts Human Growth Hormone GABA (gamma-aminobutyric acid) is an amino acid and neurotransmitter. GABA is your brain’s primary inhibitory transmitter. Its role is to keep glutamate, the primary excitatory transmitter, from overwhelming you. GABA is synthesized in brain cells from glutamate. It’s estimated that 40% of the synapses in the human brain work with GABA and therefore have GABA receptors. GABA enhances normal sleep cycles, and improves blood pressure. GABA stimulates the pituitary gland to secrete Human Growth Hormone. And helps produce endorphins that make you feel good after a workout or sex. Too much glutamate can cause a seizure, and too much GABA can put you in a coma. A healthy brain maintains a critical balance of GABA and glutamate. GABA acts like a “brake” on neuron circuits during stress. Low GABA levels can result in anxiety, insomnia, poor mood and restlessness. Clinical studies show that boosting GABA with a supplement relieves anxiety, stress, and boosts the production of alpha brain waves.239 If GABA is optimized in your brain you’ll feel focused, relaxed and stress-free. When you normalize GABA levels you’ll experience a reduction in anxiety, insomnia, nervousness, restlessness and stress. Benzodiazepine drugs like Valium and Xanax work by increasing GABA receptor sensitivity.240

How does GABA Work in the Brain? GABA helps brain health and function in several ways. But two in particular stand out. 1. GABA works by preventing neural signaling associated with anxiety from reaching other neurons. It does this by attaching to the receptors that would otherwise excite those neurons. Over-stimulating neurons in certain areas of your brain is what causes anxiety-related symptoms. Researchers in Japan studied the calming effects of GABA with 8 volunteers. They had study subjects cross a suspension bridge as the stressful stimulus. The placebo subjects in this group showed significant drops in blood level markers indicating high stress levels. While the GABA group showed signifi- cantly higher blood levels of these same markers. GABA worked as a natural relaxant and its effects could be seen within 1 hour of taking GABA. The researchers concluded that GABA could enhance im- munity from stress.241 2. GABA also helps decrease Beta brain waves and increase Alpha brain 133 David Tomen waves.242 Beta brain waves are important for attention, alertness, concentra- tion and developing memories. But excess levels of concentration, particu- larly during stress, can lead to anxiety, depression, insomnia and more stress. When you are in an alert state, both Alpha and Beta brain waves can be stimulated. But the type of alertness will determine which brain wave is produced. Alertness during an Alpha wave state is associated with a relaxed state. And a stressed alert state produces a Beta wave. But an excess of Beta brain waves contributes to a variety of nervous disorders including anxiety and stress. As a side note, I’m writing this while listening to binaural music which produces an Alpha state. It allows for a relaxed environment which promotes creativity and productivity.

How things go bad: Low levels of GABA are associated with a variety of health problems. ↑ Anxiety243, panic attacks, stress and insomnia ↑ Muscle spasms, hypertension, convulsion, Tourette’s Syndrome and epilepsy ↑ Dry skin and wrinkles ↑ Poor digestion, bloating, flatulence, and constipation When your neurotransmitters, including GABA, are in balance, you feel motivated, productive and energetic. And you feel calm and relaxed during downtime. When GABA levels are low you feel filled with dread, you’re constantly wor- ried, you have racing thoughts, and you’re frequently late and disorganized.244 Many people in this GABA-slump resort to high carbohydrate foods, and drugs or alcohol to relax.

GABA to the rescue The amino acid L-glutamine is the precursor to GABA production in your body. L-glutamine gets converted to glutamic acid or glutamate. Glutamate is your body’s most abundant excitatory neurotransmitter. Which is responsible for attention span, brain energy, learning ability, memory, and staying awake. An enzyme called glutamate decarboxylase converts glutamate to GABA.

It does it with the help of the active form of Vitamin B6 (Pyridoxal-5-Phosphate (P5P)). The amino acid taurine helps increase the communication and productivity of this enzyme. And zinc helps the release of GABA from its receptors. When this process works efficiently, you feel relaxed with no stress or feelings of anxiety. And you get a more restful night’s sleep.

How does GABA feel? When you balance GABA levels in your brain, you feel relaxed and calm. But 134 HEAD FIRST many neurohackers who try using GABA as a supplement don’t feel the effects. Because the GABA molecule is too large to cross the blood-brain barrier.245 If you do feel the calming effects of GABA within a ½ hour of taking it, it may mean you have a “leaky” blood-brain barrier. Not a good thing.246 Because if GABA can get through, all kinds of nasty stuff can get through too. Including toxins, undigested food particles and anything else in your blood stream that shouldn’t be in your brain. But the good news is, supplementary GABA can also benefit other functions in your body. GABA is found in your adrenal glands, pituitary gland, pancreas and your sex organs.247 GABA is also anti-inflammatory, and has an immune benefit. When all these are running optimally, you’ll feel good. We’ll also cover other ways to boost GABA levels in our brain in the “Avail- able Forms” section of this chapter.

The Research GABA was identified as a neurotransmitter several decades ago. And there has been a lot of research on GABA published since. But most of it is focused on how GABA works. And the drugs and chemicals which affect its action. There is very little research available on using GABA as a supplement. Likely because most scientists believe that GABA taken as a supplement will not cross the blood-brain barrier.

GABA Increases Human Growth Hormone Bodybuilders and athletes use supplementary GABA to help repair and build muscle. And there are several studies supporting the notion that GABA increases Human Growth Hormone. In one study, researchers worked with 19 subjects who were given a single oral dose of 5 grams of GABA. 18 subjects were given a placebo during this trial. 3 hours after the administration of GABA, blood samples were taken. The team reported that “GABA caused a significant elevation of plasma growth hormone levels”.248

GABA helps Reduce Insomnia A Los Angeles study conducted a randomized, double-blind, placebo con- trolled trial with 18 patients with sleep disorders. The patients received either a placebo, or Gabadone (a combination of GABA and 5-hydroxytryptophan). The difference between the two groups of sleep-deprived patients was signifi- cant. The Gabadone group fell asleep faster, stayed asleep longer, and had a better quality of sleep than the placebo group.249

Dosage Notes The recommended daily dosage of GABA is 500 to 1000 mg for a relaxation 135 David Tomen or calming effect. Some neurohackers notice an immediate relaxing effect, while others need to take it for a couple weeks before it starts to kick in. L-Arginine which increases nitric oxide also helps supplementary GABA cross the blood-brain barrier.250 PharmaGABA™ which is a natural form of GABA produced with the help of Lactobacillus hilgardii bacteria is dosed at 50 – 200 mg per day.

Side Effects GABA is considered very safe when taken in normal recommended doses. Bodybuilders who use much higher doses of GABA do report experiencing flushing, tingling, a spike in heart rate and blood pressure, and anxiety.

Available Forms GABA as a supplement is available in tablet, capsule and powder. Scientists have shown that GABA does not readily cross the blood-brain barrier. But many neurohackers report feeling a calming effect when using GABA. PharmaGABA™ is a natural form of GABA made using Lactobacillus hil- gardii bacteria. The same bacteria used to ferment vegetables when making the Korean cabbage dish called kimchi. This form seems to readily cross the blood- brain barrier. Another safe way to change GABA action in the brain is to use any of follow- ing commonly used herbs, vitamins and minerals. Valerian root251, American Ginseng and Kava Kava work by increasing the effect of GABA on its receptors. Extracts of green, black and oolong tea also elicit a GABA effect.252 Magnesium binds to GABA receptor sites and increases its effect.253Taurine protects against glutamate overstimulation. And this inhibitory effect acts as an anxiolytic (anti-anxiety). The neurotransmitter Serotonin enhances GABA. So precursors to Serotonin like tryptophan and 5-HTP can increase GABA action in the brain. The amino acid Theanine in tea provides a calming effect. Theanine inhibits glutamate uptake which would increase GABA levels in the brain.254 And Phenibut, which is a derivative of GABA developed in Russia, also increases levels of GABA in the brain. While some report that Phenibut causes drowsiness and fatigue, it’s a much safer way to boost GABA than with a phar- maceutical like Valium or Xanax.

Nootropics Expert Recommendation

GABA 500 – 1,000 mg per day. I recommend using GABA as a nootropic supplement if you’re feeling anxi- ety or stress. And to calm or keep in check some of the stimulatory effects of some nootropics. 136 HEAD FIRST Your body does make GABA on its own from glutamate in your brain. Most healthy people have an adequate supply of GABA. But if you’re dealing with anxiety or stress and need some extra help in calming things down, GABA can help. While GABA does not readily cross the blood-brain barrier, you have many other options available for regulating or boosting GABA, if GABA as a supple- ment doesn’t work for you. I suggest trying a GABA supplement first at a dose of 500 mg. Or try one of the readily available GABA supplements made by major supplement makers containing PharmaGABA™. Another safe option for regulating GABA levels is to use a vitamin or supple- ment which influences the way GABA works in your brain. Check the “Available Forms” section of this article for details.

137 David Tomen Ginkgo Biloba

Gingko biloba extract has been shown to boost alertness, concentration, focus and memory Ginkgo biloba (Ginkgo or Maidenhair) is one of the oldest species of trees on earth. Scientists consider it a “living fossil” dating back 270 million years.255 It has continued to survive even after major extinction events. Gingko tress can grow to 130 feet (39.6 meters). Some Ginkgo trees in China are thought to be over 2,500 years old. And a 3,000-year-old tree report- edly stands in the Chinese province of Shandong. Four Ginkgo trees survived the atomic explosion in Hiroshima. Only 1,130 meters from the bombs epicenter. Gingko biloba has been used for medicine in China for several millennia. In the oldest Chinese Materia Medica (2800 B.C.), Ginkgo biloba was recom- mended for asthma, swelling of the hands and feet, coughs, vascular disorders, aging and for the brain.256 An extract of Gingko leaves called EGb 761 is standardized to 24% flavone glycosides (flavonoids) and 6% terpenes (ginkgolides and ). This Gingko extract regulates neurotransmitters, protects from brain cell de- generation, increases blood vessel microcirculation (blood flow in the smallest of blood vessels). And has antioxidant activity.257 But there’s more… Ginkgo biloba helps: • Neurotransmitters. Gingko biloba can increase dopamine in the brain. Ginkgo acts as a monoamine oxidase inhibitor (MAOI) which reduces levels of monoamine oxidase (MAO) in the brain. MAO breaks down dopamine.258 One of the benefits of boosting dopamine is to reduce anxiety.259 And to treat ADHD.260 • Cerebral Circulation. Ginkgo biloba increases cerebral blood flow. Im- proving oxygen and glucose availability to neurons for neuronal health. Improving memory, recall, cognition and learning.261 262 • Neuroprotection. Ginkgo Biloba helps boost cerebral blood flow, reduces oxidative stress by eliminating free radicals, and increases nitric oxide which dilates blood vessels.263 As a nootropic, Ginkgo has been shown to be particularly effective in elderly memory loss, slow thinking and reasoning, and tinnitus. One study shows sig- nificant improvement in Parkinson’s and Alzheimer’s patients.264

How does Ginkgo Biloba Work in the Brain? Ginkgo Biloba boosts brain health and function in several ways. But two in particular stand out. 138 HEAD FIRST 1. Cerebral circulation. Ginkgo boosts several brain functions by improving blood circulation in the brain. A study in the Department of Radiology at Johns Hopkins University School of Medicine used MRI’s to measure blood flow in 9 healthy men. MRI’s were done before and after the men took Gingko Biloba Extract 60 mg twice a day for 4 weeks. The study concluded that overall, all regions of the subject’s brains showed a significant change in cerebral blood flow after using Ginkgo.265 2. Cognition and mental performance. Gingko is well known as a memory booster in the nootropics community. Studies have shown Ginkgo helps at- tention, mood and processing speed. One large study at Liberty University in Lynchburg, Virginia was conducted with 262 healthy adults. This 6-week, double-blind, placebo-controlled trial had volunteers taking 180 mg of Ginkgo biloba extract, or a placebo daily for 6 weeks. The subjects were put through several standardized tests. At the end of the 6-week trial, those using Ginkgo showed significant improvement in verbal and visual recall and memory.266

How things go bad As we get older, our brain chemistry and energy metabolism changes. Blood vessels in our brain shrink and get narrower. Preventing the free flow of oxygen- ated blood to neurons. Toxic waste and free radicals accumulate within brain cells. ↓ Memory, recall, reaction time and mood diminish ↓ Critical neurotransmitters decline ↓ Chronic stress reduces memory capacity All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia. But even if you’re not concerned with the effects of aging, Ginkgo biloba can help.

Ginkgo Biloba to the rescue Research from hundreds of studies have shown that Ginkgo biloba will: • Improve memory and cognition267 • Increase reaction time • Restore the availability of dopamine and other neurotransmitters • Improve cerebral blood flow • Reduce stress268 139 David Tomen • Boost mood • Help repair brain cells • Act as an antioxidant to eliminate free radicals

How does Ginkgo Biloba feel? Gingko improves circulation in your body and brain. Thinking, reaction time, energy, and memory should improve. Cold hands and feet are often an indication of poor circulation and Ginkgo could help. Ginkgo has a reputation for helping reduce the symptoms of tinnitus. And it’s also developed a good rep for helping erectile dysfunction (ED) in men. Many neurohackers report it takes several weeks of continued use of Gingko to experience all the benefits this healing herb provides.

The Research Age-related cognitive decline is expected as a normal part of aging in our society. This decline can lead to difficulty performing everyday activities like concentrating on what your loved one is saying. Or remembering to attend a family function you’ve been looking forward to for months. This decline will affect your quality of life and affect your mood. And it’s happening to younger and younger people. But many of us in the nootropics community refuse to accept cognitive decline as “standard”. Note: One important consideration I found in the research on Gingko Biloba. Some of the findings have been contradictory. Some indicating that Gingko does not work. But the overwhelming impression we got from looking at decades of research was that Gingko Biloba takes a while to work. Often it can take many months of supplementation to see results. And extracts work far better than plain, pow- dered, ground Ginkgo.

Ginkgo Biloba Improves Cognition Researchers in Germany set out to study the effects of Ginkgo Biloba in healthy adults. This randomized, double-blind, placebo-controlled trial worked with 66 health volunteers for 4-weeks. One group was given a placebo, and the other group took 240 mg of Ginkgo Biloba extract daily. At the end of the trial, those taking Ginkgo Biloba extract saw significant improvements in their “self-perceived” mental health and quality of life. They performed far better on action and reaction tests. And reported a significant improvement in mood compared to those in the placebo group.269

Ginkgo Biloba Improves Quality of Life Another study with 1,570 men and women in England took either no dietary supplement or 120 mg of Ginkgo Biloba extract daily for 4, 6, or 10 months. 140 HEAD FIRST Participants who took Ginkgo extract experienced improvement in activities of daily living, mood and alertness compared to the control (who took nothing). Activities of daily living included multi-tasking, completing household tasks, concentrating during a conversation, remembering important dates, and giving and following directions. Measures of their mood included ratings of anxiety, depression, energy, drowsiness, sadness and happiness. Alertness factor rated whether they felt alert, clumsy, dizzy, relaxed and tired. Participants in this study who took Ginkgo Biloba extract the longest re- ported the greatest improvement in all ratings measured. 10 continuous months of supplementing with Ginkgo extract was more effective than 4 months. Their life improved even more the longer they took Ginkgo Biloba extract.270

Gingko Biloba Improves Attention and Memory Researchers at the University of Northumbria in the UK set out to deter- mine if a single dose of Gingko would improve attention and memory in healthy volunteers. This placebo-controlled, multi-dose, double-blind trial worked with 20 people. Participants were given either a placebo or single-dose of Gingko Biloba extract of 120, 240 or 360 mg. They were tested for their speed of attention, at- tention accuracy, memory speed and quality of memory. They were tested before the dose or placebo, and again at hours 1, 2.5, 4, and 6 hours. The scientists reported that Ginkgo improved multiple cognitive perfor- mance measures. Most dramatic were with “speed of attention”. And results were better with the highest dose of 360 mg compared to the 240 mg dose. This improvement was noted at the 2.5-hour mark. But was still noticeable 6 hours after supplementing with Gingko. The researchers concluded that Ginkgo dosing can produce “sustained improve- ment in attention in healthy young volunteers”.271

Dosage Notes Recommended dose of Gingko biloba is 40 mg 3-times per day. But daily dosage can range from 120 – 600 mg depending on the disorder being treated. Most Ginkgo biloba products claim that a minimum of 4 weeks is required to achieve a boost in focus, memory and concentration.

Side Effects There is the potential for an increased risk of bleeding when Ginkgo biloba is used concurrently with antiplatelet agents (e.g., aspirin, clopidogrel (Plavix®)), anticoagulants (e.g., warfarin (Coumadin®), enoxaparin (Lovenox®), heparin) or herbs with coumarin constituents (e.g., angelica, anise, capsicum, celery, 141 David Tomen chamomile, clove, danshen, garlic, ginger, horseradish, licorice, onion, papain, red clover). Hypomania has been reported in patients with depression when Ginkgo leaf extract was used in combination with fluoxetine (Prozac®)/buspirone (BuSpar®), St. John’s wort, and melatonin. Ginkgo leaf extract can alter insulin secretion. So patients taking insulin should monitor glucose levels closely. There have also been reports of seizures associated with Ginkgo use with patients using medication used to lower seizure threshold. These drugs include (Diprivan®), mexiletine (Mexitil®), amphotericin B (Fungizone®), , cephalosporins, /cilastatin (Primaxin®), (Well- butrin®), cyclosporine (Neoral®), fentanyl (Sublimaze®), methylphenidate, and theophylline. Ginkgo should be used with caution during pregnancy, due to the potential for increased bleeding risk. Ginkgo should be avoided during breastfeeding, due to a lack of sufficient data.

Available Forms Gingko leaf is produced from green, picked leaves grown on plantations specifically developed for pharmaceutical purposes. Ginkgo biloba extract is available in capsules, tablets, concentrated liquids, sublingual sprays, bars and cola drinks. Standardized products should contain at least 24% flavone glycosides and 6% terpenes (ginkgolides and bilobalides). The products most commonly used in clinical trials are Ginkgo biloba stan- dardized extracts EGb 761 (Tanakan) and LI 1370 (Lichewer Pharma).

Nootropics Expert Recommendation

Ginkgo Biloba extract up to 120 – 240 mg per day I recommend using Ginkgo Biloba as a nootropic supplement. Your body does not make Gingko biloba on its own. So you must take it as a standardized supplement. Gingko biloba that has not been standardized to at least 24% flavone glyco- sides and 6% terpenes does not appear to be effective. So make sure you buy a standardized Ginkgo supplement. Ginkgo increases alertness, focus, concentration and memory even in the young and healthy. Many neurohackers report immediate effects of supplement- ing with Gingko. But others find they need several weeks for the active com- pounds found in Ginkgo to take effect. I suggest dosing up to 240 mg per day split into 3 doses throughout your day. But please refer to the “Side Effects” section of this chapter before you start using Ginkgo. It’s a powerful supplement and could interact with some medications. 142 HEAD FIRST Ginseng

Ginseng is known for calming anxiety, and boosting attention, concentration and memory Ginseng is one of the most popular and well researched herbal medicines in the world. It has been used in North America and Asia for thousands of years. In all, there are 11 species of ginseng. But the name “ginseng” as a nootropic usually refers to either American ginseng (Panax quinquefolius), or Asian gin- seng (Panax ginseng). Panax means “cure-all” in Greek. Researchers in thousands of clinical trials have reported on the efficacy of ginseng for; anti-stress, cognition, memory, anti-wrinkle, flu, digestion, dia- betes, erectile dysfunction, blood circulation, immune deficiency, menopause, anti-oxidant, cancer and much more. Ginseng is rich in various pharmological compounds. Including a series of polyacetylenes, polyphenolic compounds, acidic polysaccharides, and tetracyclic triterpenoid saponins (ginsenosides). Both American and Asian Ginseng contain ginsenosides which researchers believe are the most active ingredient. Here we are investigating ginseng as a nootropic. Ginseng helps: • Mood and Stress. Ginseng helps improve mood and reduce stress. It works as an adaptogen, reducing adrenal fatigue, boosting GABA and providing an anti-stress effect.272 • Neurotransmitters. Ginseng provides neuro-protective effects on the dopaminergic-pathway which can help with ADHD.273 And ginseng is a serotonin and norepinephrine reuptake inhibitor. Working as an antidepres- sant and helping some symptoms of ADHD.274 • Brain Energy. Ginseng acts as an anti-inflammatory by reducing cytokines. And as an anti-oxidant. Boosting ATP production in mitochondria, in part because this antioxidant effect shields mitochondria.275

Overview Ginseng is the most famous medicinal herb in Asia. It must be grown for 5 years before its harvested. The maturity of the plant influences the density of active compounds beneficial to human health. The term “ginseng” comes from the Chinese word ‘rénshēn’ (person + plant root). Because the root shape of ginseng resembles the legs of a human. “Panax” comes from the Greek ‘pan’ (all) and ‘akos’ (cure). In traditional Asian medicine ginseng was used for many different issues affecting human health. An “over-all” cure. 143 David Tomen The four largest producers of ginseng are South Korea, China, Canada and the U.S, with Canada being the largest exporter. The largest consumer of ginseng is South Korea. South Korea also conducts the majority of research on ginseng. With 1,000 scholars who publish at least 100 research papers per year.276 The two primary used for brain function are Asian Ginseng (Panax ginseng), and American ginseng (Panax quinquefolius). Ginsenosides increase protein synthesis and the activity of neurotransmitters in the brain. And ginseng stimulates the formation of blood vessels and improves blood circulation in the brain. Which improves memory and cognitive abilities.277

How does Ginseng Work in the Brain? Ginseng boosts brain health and function in several ways. But two in par- ticular stand out. 1. Ginseng boosts physical and mental energy. Many of us deal with a lack of energy and chronic fatigue nearly every day. In today’s world, and particu- larly in Western society, we’re suffering from mental and physical fatigue. From overworked, stressed students to seniors. But this kind of fatigue is not a natural offshoot of ‘getting older’. Often it’s difficult to pinpoint what exactly is causing this fatigue. And the first thing most of us think of is reaching for an , caffeine, or a prescription stimulant. While these options may work in the short-term, they don’t produce natural energy in your body. This is where ginseng comes in and saves the day. One double-blind, placebo-controlled trial with 30 healthy young adults demonstrated Panax ginseng’s cognitive benefits. The study found that a single dose of 200 mg or 400 mg of ginseng reduced blood glucose levels. And signifi- cantly reduced mental fatigue.278 2. Ginseng improves memory and learning. Most people who use ginseng report feeling more alert. And several trials show Asian ginseng can improve thinking and learning. Some of the research shows Panax ginseng can boost performance on mental arithmetic, concentration, and memory. One example of several that show how ginseng seems to affect memory and learning is by boosting nerve growth factor (NGF) and neurite growth in the brain. This study was done on chicks with the ginsenoside Rb1. The researchers found this ginseng extract significantly potentiated NGF and showed neurite outgrowth. 279

How things go bad Our brain chemistry and energy metabolism are constantly changing. And 144 HEAD FIRST any number of factors from chronic stress to disease and environmental factors can degrade cognitive function. ↓ Memory, recall, reaction time and mood decline ↓ Neurotransmitters and cellular signaling breakdown ↓ Chronic stress reduces memory capacity and overall brain health ↓ Nerve growth factor and neurogenesis decline 1 Free radicals and inflammation damage brain cells 1 Immune system is compromised All of these changes can happen at any age. And are certainly contributing factors to age-related cognitive decline.

Ginseng to the rescue Panax ginseng (Asian) and Panax quinquefolius (American) contain a collection of active compounds called ginsenosides. Thesetriterpenoid saponins (plant chemicals) are unique to the ginseng species of plants. And are steroid-like in nature. Here’s a mind-blowing statistic; well over 100 different ginsenosides exist.280 The major ones are designated Ginsenoside Ro, Rb(1), Rb(2), Rc, etc. All are extracted from the rhizome (root) of the ginseng plant. You’ll notice if you’ve reviewed any of the other nootropics listed on my website NootropicsExpert.com, that I usually include a diagram of the active chemical compound in that nootropic. In this case I’m not including the diagram because each compound extracted from ginsenoside is different. Each ginsenoside has a unique effect in your body and brain. And is often even metabolized differently in your digestive system. Other components of ginseng include: • Polysaccharide ‘Ginsan’ which is an immune system modulator281. Ginsan is likely what helps tame inflammation in the brain. Which helps a host of ce- rebral functions like; neurotransmitters working more effectively, prevents apoptosis (cell death), improves memory, mental energy and more. • Anti-inflammatories or not talked about much in the nootropics com- munity. And I think in the future you’ll be hearing a lot more about how important they are to cognitive health and function. • MicroRNA’s which are gene modulators. Researchers have recently identi- fied up to 73 MicroRNA’s in ginseng.282 These tiny non-coding molecules are capable to regulating the gene expression in the DNA of your brain cells. Which is an extremely complex subject in itself. And have the potential to affect nearly everything that happens in your brain. • Polysaccharides which have anti-cancer effects. Another subject not talked about in nootropic circles. But fundamentally important to brain health.283 145 David Tomen • The amino acids L-Arginine and GABA (gamma-aminobutyric acid), and glutamate.284 The neurotransmitter GABA is naturally produced in your brain and provides anti-anxiety and calming effects. Likely why supple- menting with ginseng has a calming and anti-anxiety effect. Several books could be written on how ginseng affects your brain. Including its appetite-suppressant qualities, ability to boost cognition, reducing fatigue, reducing depression, anxiety, stress, improving memory and learning, as a neuro- protectant, and increasing cerebral blood flow.

How does Ginseng feel? Supplementing with ginseng should boost your energy levels, both physical and mental. Ginseng has stimulant-like qualities and should help if you’re deal- ing with chronic fatigue. But unlike standard stimulants, your boost in energy will come with a more ‘relaxed’ feel. Ginseng can boost mental alertness. And thinking should feel quicker and clearer. Recall and long-term memory should improve. Ginseng also boosts your immune system so you may be able to avoid the flu or a cold. Ginseng is particularly helpful for anyone with a compromised immune system. And if you’re living with, or working around anyone else who is sick.

The Research Much of the research on ginseng comes out of South Korea. And much of this research has been done with Asian ginseng (Panax ginseng). Showing how Panax ginseng improves cognitive function. American ginseng (Panax quinquefolius) has a somewhat different ginsen- oside profile from Panax ginseng. And it too shows promise in benefiting human cognition.

American Ginseng Boosts Working Memory One double-blind, placebo-controlled trial was conducted with 32 healthy young adults. In this trial, researchers used a highly standardized extract of American ginseng (Cereboost™). Cereboost™ is Panax quinquefolius standardized to 10.65% ginsenosides. This trial used doses of 100, 200 and 400 mg of standardized ginseng. And participants’ mood, cognitive function and blood glucose were measured at 1, 3 and 6 hours after taking the ginseng extract. The researchers found that standardized American ginseng provided a sig- nificant improvement in working memory. Reaction time accuracy and ‘calmness’ significantly improved at just the 100 mg dose. And improved with higher doses. The scientists concluded that there was, “robust working memory enhance- 146 HEAD FIRST ment following administration of American ginseng”. And these effects are distinct from that of Asian ginseng. The two ginsengs have different psychopharmacological properties that depend critically on ginsenoside profiles.285 The bottom-line of this study is that the kind of ginseng you use makes all the difference.

Panax Ginseng Protects & Fuels Brain Mitochondria A stroke is caused by insufficient blood flow to that part of the brain where the stroke occurs. Lack of blood flow shuts down the oxygen and nutrient supply to brain cells. And things start to break down in the heart of the cell’s energy center – the mitochondria. This study was done in the Neurology Department at Xijing Hospital in China. Researchers wanted to find out if ginsenoside Rd, one of the major active ingredients in Panax ginseng, could protect the brain from stroke. Rats were given ginsenoside Rd and then subjected to a stroke by reducing blood flow to part of their brain. (Note for gratitude journal – I’m thankful I’m not a lab rat). The scientists found this Panax ginseng extract protected the rat brain from stroke. And it appeared to do it by protecting brain cell mitochondria from dys- function, and apoptosis (cell death).286 Researchers also demonstrated that ginseng activates multiple enzymes in the Krebs cycle. This helps mitochondria extract maximum energy in the form of ATP from glucose fuel.287 Which is one of the reasons why supplementing with Ginseng boosts mental energy.

Ginseng Improves Mental Performance Actoprotector is a new term given to natural compounds that increase mental performance. And enhance your body’s ability to withstand physical loads without increasing oxygen consumption.288 Actoprotectors are a new subclass of adaptogen that increase physical perfor- mance. And some extracts of Panax Ginseng are considered Actoprotectors. The main difference ofActoprotectors and psychostimulants (caffeine, Rit- alin, modafinil, adrafinil, etc.) is that Actoprotectors cause no increase in oxygen consumption or heat production. The result in improved mental and physical performance are similar. But there’s no “crash” in 4 hours like you get from using a stimulant like Ritalin. You don’t experience the same kind of ‘mental load’ when using ginseng.289 Ginseng’s steroid-like phytochemical called ginsenosides are what provide this stimulant-like action in the brain. And an improvement in overall quality of life. One report in 2003 evaluated 9 clinical trials done with humans with 147 David Tomen ginseng doses from 80 – 400 mg. Study duration spanned 2 – 9 months. And nearly every study evaluated demonstrated some improvement in Quality of Life score.290

Dosage Notes Dosage of ginseng depends on the extract used, and quality of the extract. And results seem to be largely dependent on the quantity used.291 To complicate things even more, ginseng dosage depends on the region where its grown, extract strength, and individual needs. The Chinese for example recommend 2 grams daily while in Europe, the suggested range is 100 – 400 mg daily. Many naturopaths recommend cycling ginseng. Use it for 3 to 4 weeks and take a week break. Remember, ginseng has steroid-like active compounds. So taking it for extended periods without a break is not recommended. Ginseng has been and continues to be extensively researched. These doses are based on clinical trial data: • For stress, anxiety or fatigue: 1-gram ginseng daily dosed 500 mg twice per day • For Type 2 diabetes: 200 mg per day • For erectile dysfunction (ED): 900 mg of Panax ginseng 3-times per day The bottom-line is to stay within the dosage recommended by the ginseng supplement manufacturer.

Side Effects Ginseng is a natural supplement and side effects are generally mild. But it can act as a stimulant in some people. Which can cause anxiety and insomnia. Long-term use or higher than recommended doses can cause headache, diz- ziness and stomach upset. If you’re going to use ginseng you should cycle your dosing. Use the recommended dose for 3-4 weeks and take a week off before dosing again. Women may experience menstrual changes when supplementing with ginseng. Ginseng is NOT recommended by the under-18 neurohacker. Or women who are pregnant or breastfeeding. Ginseng may affect blood sugar levels. So if you’re taking drugs for diabetes, check with your doctor first before supplementing with ginseng. Ginseng can interact with: • Blood-thinning medications • Antidepressants • Antipsychotic medications 148 HEAD FIRST • Stimulants including caffeine, Ritalin, Adderall, modafinil, adrafinil, etc. •

Available Forms Ginseng supplements are made from ginseng root and root hairs. It’s avail- able in dried, powdered, capsule and tablet form. Ginseng is also included in some nootropic stacks and other combination supplement formulas. Some with patented ginseng extracts like Cereboost™, GS15-4, and others. Experienced users of ginseng seem to prefer American Ginseng (Panax quin- quefolius) over Asian Ginseng (Panax ginseng). Each is a unique species of ginseng but both have ginsenosides. But American Ginseng is cultivated under stricter conditions avoiding pesti- cides and herbicides. And the colder growing climate encourages higher concen- trations of the active ingredients in ginseng. When buying American ginseng, look for Panax quinquefolius. And when buying Asian ginseng, look for Korean, red or Panax ginseng. And finally, make sure you buy from a reputable supplement maker. Very re- cently GNC, Target, Walgreens and Walmart stores in the U.S. were found to contain either contaminants or little to zero ginseng. Walgreens ginseng brand was found to contain nothing but garlic powder and rice.292

Nootropics Expert Recommendation

Ginseng 100 – 400 mg per day I recommend using Ginseng as a nootropic supplement. Your body does not make Ginseng on its own. So you must take it as a standardized supplement. Ginseng is especially helpful for chronic fatigue. And a great way to provide a natural physical and mental energy boost. Ginseng provides anti-anxiety and calming effects. And can boost mental alertness, memory, recall, and learning. Ginseng is a powerful adaptogen that has been used for thousands of years. The ancient Chinese and other cultures used it for overall health. I suggest starting with a dose of 100 mg daily. You can safely boost it to 4-500 mg per day depending on the brand and extract. But remember that ginseng has steroid-like qualities. So make sure you cycle it. Use it for 3-4 weeks and take a week off. And don’t take it late in the day as it may interfere with sleep. Many neurohackers prefer American over Asian ginseng. It has a slightly different ginsenoside profile. And is grown under stricter conditions ensuring quality and safety. 149 David Tomen Gotu Kola

Gotu kola has been shown to increase memory and cognition, repair and reverse damage to brain cells, and boost acetylcholine Gotu Kola (Centella asiatica) is often called “the student herb” in Bali. Because it sharpens the mind. Gotu kola extract increases dendrite and axon growth in brain cells which helps memory. Native to the wetlands of Asia, the ancient Ayurvedic medical system used gotu kola like a first-aid kit. It was used to treat mental fatigue, anxiety, depres- sion, memory loss, insomnia, fever, syphilis, hepatitis, epilepsy, diarrhea and asthma. Gotu kola even has a link to longevity. The ancients believed that elephants who ate gotu kola leaves lived longer than those that didn’t. In the U.S. and Europe gotu kola is typically used for varicose veins, poor blood circulation in the legs, to treat psoriasis and help heal minor skin wounds. Gotu kola is rich in triterpene saponosides. A study in Japan showed that one of these triterpenoids called asiatic acid was able to stop the growth of cancer cells.293 As a nootropic, gotu kola has been shown to be particularly effective in elderly memory loss, slow thinking and reasoning. One study shows significant improve- ment in Alzheimer’s patients.294 And some of the most exciting new research on gotu kola shows it can spur growth in brain cells. Here we explore all the ways gotu kola can help your brain.

How does Gotu Kola Work in the Brain? Gotu kola boosts brain health and function in several ways. But two in particular stand out. 1. Neural dendrite and axon growth. Gotu kola helps increase the length and branches of neuron dendrites. And boosts axon growth. Dendrites are tree-like branches extending out from neurons in the brain. They receive incoming signals from other neurons. Those signals are transmitted from axons extending out from neighboring neurons. Dendrites and axons can change over time, and in response to environmental cues. Learning something new for example cause dendrites to lengthen. But this natural signaling mechanism in your brain’s neurons degrade over time. And several studies have shown how gotu kola can reverse this damage. Scientists at the Oregon Health & Science University in Portland, Oregon did their research with Sprague-Dawley rats. They put Centella ethaniloc extract, a compound in gotu kola, in the rat’s drinking water. The study concluded that axons grew at a faster rate. And the researchers 150 HEAD FIRST stated that gotu kola extract was useful for accelerating repair of damaged neurons.295 Another study showed rats given gotu kola leaf extract had an increase of 105% in dendrite growth.296 A very recent study conducted at Northwestern University and published in Nature shows how dendrites are critical in memory formation.297 2. Increase in memory and learning. Gotu kola has been revered for thousands of years for boosting memory. We know that gotu kola extract can increase the availability of acetylcholine (ACh) in the brain. It does it by preventing ACh from breaking down. This boost in memory may also benefit from gotu kola’s ability to boost the growth of neuron dendrites and axons. In one randomized, placebo-controlled, double-blind study done in Thai- land, researchers gave 28 people gotu kola extract for 2 months. Daily doses ranged from 250, 500 to 750 mg per day. Cognition in these subjects increased, and they experienced a boost in working memory.298

How things go bad Over the course of your life, your brain will lose 5 – 10% of its weight. It starts in your early 20’s.299 The Framingham Offspring Cohort Study included 1,352 adults who did not have dementia. 7 years after the start of the study they used an MRI to measure participants brain size. And gave them tests to gauge executive function, planning and organizational skills. The researchers found that people with high blood pressure, diabetes, over- weight or smoked had faster brain shrinkage. They showed declines in ability to make decisions, plan, organize and remember details.300 ↓ Memory, cognition, learning and recall decline ↓ Neuronal cell death results in shrinking gray matter ↓ Neuroplasticity declines degrading long-term potentiation301 Your brain will shrink regardless of lifestyle. But you can reduce the speed of this shrinkage by using gotu kola.

Gotu Kola to the rescue Research from hundreds of studies have shown that gotu kola will: • Improve memory and cognition • Restore the availability of acetylcholine • Improve cerebral blood flow • Reduce stress • Help repair brain cells 151 David Tomen • Eliminate free radicals from within brain cells

How does Gotu Kola feel? Gotu kola improves acetylcholine levels in your brain. It increases blood flow and helps reduce oxidative damage and toxins in brain cells. As a result, you may feel a boost in mental activity. Many say that taking Gotu Kola is like “energizing of the brain”. Particularly during a period of high mental demand. Mental blocks or mental fatigue feel like they’re swept away. Others report dreams seem more vivid and intense. And gotu kola seems to have an anxiolytic (anti-anxiety) effect as well.

The Research Ever been on your way to a party with the thought, “I hope I don’t kill too many brain cells”. Science once believed that the adult human brain could not grow new brain cells. We were born with all the brain cells we’ll ever have. Once those cells were gone, they’re gone for good. Not too long ago a study was published in the Journal of Science. It detailed a discovery by scientists of the daily growth of new brain cells in the macaque monkey. And because of this study, we now know your brain can grow new cells. But the reality is, your brain will lose 5 – 10% of its weight. This shrinkage starts right around your 20th birthday. The good news is you can prevent that shrinkage. And you can do it with gotu kola.

Gotu Kola Improves Memory Neurons connect to other neurons at a point called a synapse. Electrical pulses carry chemical messages across this gap. These chemical messengers are neurotransmitters. Each neuron in your brain can form thousands of these links. Dendrites extend out from each neuron to neighboring neurons to receive these messages. Your brain uses these neurons in a type of network. And as one neuron sends signals to another, the synapse between the two gets stronger. The more signals sent between these neurons, the stronger the connec- tion grows. With each new experience, your brain slightly rewires this physical structure. This neuroplasticity determines how your brain is organized. And how memories are formed. Gotu kola extends these neuron dendrites. And helps improve brain neu- roplasticity. A study in animal models demonstrated neurite growth using a compound from gotu kola extract.302 And clearly showed how gotu kola works to boost memory.

Gotu Kola Improves Mood and Cognition Gotu kola has been revered for thousands of years for its ability to enhance 152 HEAD FIRST cognition. So researchers in Thailand worked with 28 people in a placebo- controlled, double-blind trial to put some science behind this reputation. Each participant in this study received an extract of gotu kola at various doses ranging 250, 500, and 750 mg once per day for 2 months. The study showed the higher dose of gotu kola enhanced working memory and mood.303 Researchers in India set out evaluate the nootropic value of gotu kola. Three- month old Swiss albino mice were given doses of gotu kola extract for 15 and 30 days. The researchers found that gotu kola increases acetylcholine activity. And increased dendrites in the mice hippocampus. Showing that gotu kola can pro- mote higher brain function.304

Dosage Notes Recommended dose of gotu kola standardized extract is 50 – 250 mg taken 2 or 3 times daily. Standardized extracts should contain 40% asiaticoside, 29 to 30% asiatic acid, 29 to 30 % madecassic acid, and 1 to 2% madecassoside. In human studies in people with venous insufficiency (poor blood circula- tion in the legs), 90 – 180 mg daily worked well for these patients. As a tincture (1:2 w/v, 30% alcohol): 30 to 60 drops (equivalent to 1.5 to 3 mL, there are 5 mL in a tsp.), 3 times daily.

Side Effects Side effects are rare with gotu kola. But may include skin allergy and burning sensations if you’re applying it on your skin. Taken internally, side effects could include headache, upset stomach, nausea, dizziness and drowsiness. Gotu kola has been used in some studies that lasted up to one year. But please note that gotu kola has the potential to be harmful to the liver. Some medical authorities caution that it is best not to use gotu kola for more than 6 weeks without talking to your doctor. Asiaticoside, a major part of gotu kola, has also been linked with tumor growth in mice. If you have a history of precancerous or cancerous skin lesions, such as squamous cell, basal cell skin cancer, or melanoma, you should not use gotu kola. And if you have liver disease, or take medications that affect the liver, you should not take gotu kola. Again, check with your doctor if you take any pre- scription medications, or often take over-the-counter pain relievers that could affect your liver.

Available Forms Gotu kola is available in teas, dried leaf in powder form, tinctures, capsules, tablets and ointments. 153 David Tomen Nootropics Expert Recommendation

Gotu Kola extract up to 600 mg per day I recommend using Gotu Kola as a nootropic supplement. Your body does not make gotu kola. So you must take it as a supplement to get its effects. This ancient herb has a long history of safe use as both an herbal remedy, and food throughout much of southeast Asia. Here in the West, gotu kola is mostly used for healing varicose veins and skin conditions. But its overlooked as a nootropic. Gotu kola can improve your mood and memory. And protect your brain from free radicals and the toxins you’re exposed to everyday. Gotu kola as a nootropic has the potential to keep you mentally sharp for life. And if the ancients were right, may even help you live longer. You can even rid your day of stress and anxiety by sipping gotu kola tea. Or use a supplement as a cognitive enhancer. If you’re using gotu kola extract and dosing up to 600 mg per day, split your dose into 200 mg 3-times per day.

154 HEAD FIRST Huperzine-A

Huperzine-A improves cognition, memory, learning, recall, is an antioxidant, helps neuroplasticity, and protects against glutamate-toxicity Huperzine-A (Hup-A) is a water-soluble alkaloid nootropic derived from Chinese Club Moss (Huperzia serrata). This plant is native to southeast Asia. And has been used in traditional medicine for millennia to treat skin conditions, muscle problems and to boost blood circulation. Huperzine-A is a reversible acetylcholinesterase (AChE) inhibitor. Which means it prevents the breakdown down of acetylcholine (ACh). Boosting short- term memory and long-term brain health. Huperzine-A is also a NMDA . This glutamate receptor’s job is to control synaptic plasticity and memory function. Which is a positive thing. But blocking its function can also be effective at times. By preventing damage from too much acetylcholine. And blocking the toxicity from certain nerve agents.305 This combination of boosting acetylcholine and blocking NMDA receptors requires a fine balance. And could explain why it’s beneficial to cycle the use of Huperzine-A. To maintain the delicate balance of neurochemistry in the brain while realizing Huperzine-A’s benefits.

Huperzine-A vs. Huperzia serrata: What’s the Difference? Huperzine-A (Hup-A) is produced in the lab from Huperzia serrata (Chinese Club Moss). Huperzine-A is a standardized compound found in this naturally occurring plant. Note that Huperzine-A and Huperzine serrata are NOT the same supplement. Some nootropic supplement stacks substitute genuine Huperzine-A with Huperzia serrata. All the research I’ve seen uses Huperzine-A in their trials. Not Huperzia serrata. Look for nootropic stacks with genuine Huperzine-A on the label. Or sold as a stand-alone supplement. And avoid stacks or supplements called Huperzine serrata.

How does Huperzine-A Work in the Brain? Huperzine-A boosts brain health and function in several ways. But two in particular stand out. 1. Huperzine-A acts as an acetylcholinesterase (AChE) inhibitor. AChE is an enzyme that breaks down the important neurotransmitter acetylcholine. So Hup-A helps prevent this breakdown. Allowing more acetylcholine to be available which improves memory and learning. Scientists at the Weizmann Institute in Israel uncovered how Huperzine 155 David Tomen A works to block acetylcholinesterase (AChE). They made a 3-D image of the structure of the AChE molecule. And found a deep chasm, called the “active-site gorge”. The scientists found the active-site gorge acts like a guide to funnel acetylcho- line into the interior of the enzyme where it is cut apart prior to recycling. This is how AChE blocks acetylcholine. The study revealed that Huperzine-A has the unique ability to fit into this active-site gorge. Like a key into a lock. And appears to bind more tightly and specifically to AChE than other AChE inhibitors. This ability for Huperzine-A to take acetylcholine’s place within the AChE enzyme is how more acetylcholine is made available in the brain. Professor Joel Sussman said, “It is as if this natural substance were ingeniously designed to fit into the exact spot in AChE where it will do the most good.”306 2. Huperzine-A also plays a neuroprotective role. Researchers discovered that Hup-A prevents glutamate-induced toxicity. Protecting hippocampus and other cerebral neurons from cell death caused by the amino acid glutamate.307 In addition to protecting from glutamate-induced toxicity, Huperzine-A also promotes new dendrite growth in neurons.308

How things go bad As we get older, our brain chemistry and metabolism changes. ↓ Acetylcholine levels decline ↓ Concentration, attention and mental agility decline ↓ Nerve growth factor declines ↓ Free radicals damage brain cell mitochondria All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Huperzine-A can help for age-related cognitive decline, as well as a stu- dent looking to do better in school. By boosting the availability of acetylcholine in your brain.

Huperzine-A to the rescue

Huperzine-A boosts acetylcholine Huperzine-A boosts levels of available acetylcholine in the brain by blocking the effect of the enzyme acetylcholinesterase (AChE). Acetylcholine (ACh) is critical for encoding new memories, reasoning, con- centration, cognition, and neuroplasticity. Not enough ACh can result in diseases like ADHD, Alzheimer’s and other neurodegenerative diseases. Huperzine-A’s benefit as a nootropic can boost short-term mental perfor- mance like attention and memory. And even helping your brain for long-term brain health. 156 HEAD FIRST Huperzine-A is an antioxidant Huperzine-A supports brain cell mitochondria. The main energy centers of each cell. It reduces free radical damage by acting as an antioxidant. Free radicals degrade mitochondria and their function. Studies have shown that Hup-A en- hances the activities of other antioxidant enzymes as well.309

Huperzine-A resists beta-amyloid dysfunction Huperzine-A boosts neuron resistance to beta-amyloid induced dysfunction that could lead to diseases like Alzheimer’s. Beta-amyloid affects ATP levels in mitochondria. Hup-A protects against this damage.310

Huperzine-A prevents glutamate toxicity Huperzine-A protects brain cells from glutamate toxicity. Too much of the neurotransmitter glutamate has been associated with brain cell degeneration. And other cognitive dysfunction and behavior. Hup-A seems to slow down this glutamate toxicity at least partly by acting as a NMDA receptor antagonist.311

Huperzine-A increases nerve growth factor Huperzine-A boosts nerve growth factor (NGF) in the brain. NGF is criti- cal in brain cell development, maintenance and repair. Declines in NGF-levels in the brain are associated with Alzheimer’s and other neurodegenerative diseases. Studies show Hup-A not only prevents this drop of NGF from happening. It actually helps boost the production of NGF.312

How does Huperzine-A feel? Nootropics users report Huperzine-A provides a boost in mental energy. Without the side effects normally associated with a stimulant. Improved cognition and clear thinking are common when using Hup-A. Many report a boost in short-term memory. Recall is better in the long-term. And some with Alzheimer’s report the progression of the disease slows down. Instead of advancing. You should be able to experience the effects of Huperzine-A soon after you take it. It’s water-soluble so it’s digested and enters your cells quickly. One thing to note is; Huperzine-A has a long half-life. In other words, it does not leave your system nearly as quickly as most other nootropics. So many neurohackers restrict their use of Hup-A to a couple of times per week.

The Research Huperzine-A is most known for boosting acetylcholine (ACh) in the brain. Efficient ACh neurotransmission is critical for learning, memory and attention. Reduced levels of ACh are associated with declines in cognition and memory. And are implicated in several neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS and others. 157 David Tomen Huperzine-A supplementation helps even in those with no sign of brain dis- ease. It can enhance attention and memory in most looking to boost cognition.

Huperzine-A Provides Protection in Chemical Warfare If you ever find yourself in a warzone, you may want to stock up on Huperzine-A. Researchers at the Walter Reed Army Institute of Research in Washington D.C. are investigating Huperzine-A’s potential as a pretreatment to protect sol- diers against chemical warfare poisoning. One of the studies conducted at Walter Reed looked at Huperzine-A’s pro- tective potential. Scientists found Hup-A to be twice as effective in protecting against the lethal effects of the nerve agent as the leading drug in that role called . Huperzine-A’s effects lasted for six hours compared to only 90 minutes for the drug.313

Huperzine-A Improves Learning & Memory This study is verification of using Huperzine-A as a nootropic at any age. Researchers in China selected 68 students who complained of bad memory. And their learning performance was getting worse in school. In this double-blind, placebo-controlled trial students were given either 100 mcg of Hup-A or a placebo for 4 weeks. At the conclusion of the trial, researchers found that the students using Hu- perzine-A scored higher on memory testing than those who took the placebo.314

Huperzine-A Improves Cognition Much of the research on Huperzine-A has been done in China. And many of the studies have been with patients suffering from neurodegenerative diseases like Alzheimer’s. One study done in Shanghai worked with 200 patients who met the criteria for having Alzheimer’s Disease. Researchers gave one group of patients 300-500 mcg of Hup-A daily for 8 – 24 weeks. The other group got a placebo. The results of the study showed that Huperzine-A’s effects increased over time. The patients that used Hup-A showed significant improvements in cogni- tion, orientation, attention, memory, mood and behavior.315

Dosage Notes Recommended Huperzine-A dosage is 50 – 200 mcg per day. Hup-A is water-soluble so you don’t need to take it with a meal, or healthy fat like some nootropics. Huperzine-A is typically sold as 50, 100, or 200 mcg tablets or capsules. Several retail nootropic stacks often include Huperzine-A in their formula. So you should not supplement with more Hup-A while using these pre-made stacks. 158 HEAD FIRST Since Huperzine-A has at least a 24-hour half-life most neurohackers prefer cycling. This means using Hup-A every nd2 day or even only twice per week. Huperzine-A is also available as an injection for therapeutic use. Typically used to treat diseases like Alzheimer’s. Or the muscle weakness condition called myasthenia gravis.

Side Effects Huperzine-A can be toxic if used in larger than recommended doses. Or if you already have too much acetylcholine(ACh) in your system. Remember, Hup-A boosts levels of ACh. Side effects with Huperzine-A are rare but can include symptoms similar to choline-overload like fatigue, nausea, vomiting, diarrhea, insomnia, anxiety, diz- ziness, thirst and constipation. Very rarely will Huperzine-A cause cardiac arrhythmia. Symptoms of acute toxicity are similar to those of other cholinergic inhibi- tors. And can include fatigue, muscle tremors, drooling, tears, bronchial mucous and incontinence. Do not use Huperzine-A if you’re dealing with epilepsy. And if you have heart disease, use Hup-A with caution. It can slow heart rate. Huperzine-A may make asthma or emphysema worse. Because it can cause mucous in the lungs. The same goes for those dealing with urinary tract or repro- ductive system blockages. It can cause mucous buildup there as well. An important note for Alzheimer’s patients: Huperzine-A can increase the effects of drugs you may already be taking. Talk to your doctor before trying Hup-A.

Available Forms Huperzine-A is sold in tablet or capsule form. Tablets and capsules are usu- ally 50 – 200 mcg each. Some ready-made nootropic stacks include Huperzine-A in their formula. Huperzia serrata is simply raw, powdered Chinese Club Moss and should be avoided. It’s not standardized so you don’t know how much you’re getting. And it’s NOT the same as Huperzine-A.

Nootropics Expert Recommendation

Huperzine-A 200 mcg per day I recommend using Huperzine-A as a nootropic supplement. Your body does not make Huperzine-A on its own. So to get its benefits you must take it as a supplement. Huperzine-A is especially helpful for those suffering from cognitive dysfunc- tion caused by diseases like Alzheimer’s. 159 David Tomen Huperzine-A is also particularly useful to students and executives who want to boost cognition, learning and memory. Huperzine-A is a fast-acting nootropic that can also help prevent brain de- generation later in life. Huperzine-A does have a long half-life so you may want to cycle it. Either take it every 2nd day, or even twice per week. The benefits are long-lasting and will stay with you.

160 HEAD FIRST Iodine Iodine improves energy levels, cognition, memory and mood Iodine is an essential trace element that combines with the amino acid tyro- sine to form thyroid hormones T4 and T3. Thyroxine (T4) contains four iodine atoms, and triiodothyronine (T3) contains three iodine atoms. Iodine deficiency is recognized as the most common cause of preventable brain damage in the world. Even moderate deficiency results in a loss of at least 10 – 15 IQ points.316 And the reason I’ve added iodine to our list of essential nootropics. Insufficient iodine is not only a problem in developing countries. Studies have found even in Western countries; iodine deficiency has become a critical health problem.317 Your thyroid gland absorbs iodine from your blood supply to make and release thyroid hormones. Your thyroid affects every cell in your body and brain through the hormones T4 and T3.

Within your brain, T4 is converted to T3 by which then affects gene expression controlling metabolism within cells. And activates the catecholamines dopamine, norepinephrine and epinephrine. Malfunctioning thyroid function which is often caused by insufficient iodine results in poor cognition, difficulty learning, problems with recall, depression and anxiety. The most abundant source of Iodine in our diet comes from seafood like kelp, saltwater fish, seal meat, whale meat, oysters, mussels and lobster. Iodine is also found in beans, milk and milk products, eggs, spinach and vegetables grown in or produced from soil rich in iodine. Typically found near coastal areas of the world. The most seriously iodine-deficient parts of the world are mountainous and inland areas. Including much of the agricultural producing areas of Western countries like Australia, Canada, USA and Europe. Nearly all of your body’s functions in nearly every tissue rely on thyroid hormones. Their actions and influence are so wide ranging that you cannot live without them. Thyroid hormones affect brain development, heart rate, lung function, blood function, bone growth, steroid hormone production, including the breakdown of sugar, fat and protein. And even some immune processes. Iodine is even involved in how the other nootropics in your stack are utilized by cells in your brain. The bottom-line is Iodine could be one of the most important additions to any nootropic stack.

How does Iodine work in the Brain? Iodine boosts brain health and function in several ways. But two in particular stand out. 161 David Tomen 1. Iodine is critical for neurotransmitters. Iodine is required for the produc-

tion of thyroid hormones T4 and T3. Thyroid hormone receptors in the brain help regulate the production and use of all important neurotransmitters.

Not enough iodine results in too little T3 and T4 in your body. Symptoms of inadequate thyroid hormones (hypothyroidism) include insomnia, fatigue, dif- ficulty concentrating, depression, dry skin and hair, cold sensitivity, frequent and heavy periods for woman, and joint and muscle pain. 2. Iodine is required for a healthy immune system. Iodine is antibacterial, antiparasitic, antiviral and has anticancer properties. Your thyroid is the main storage site for iodine. But this is also concentrated in your glandular system including your salivary and sweat glands. Ovaries, breasts, pancreas, cerebral spinal fluid, skin, stomach, prostate and your brain all contain high concentrations of iodine. Iodine is a powerful method for removing heavy metals and halides like fluoride, chlorine and bromine from your system. These chemicals compete for the same thyroid receptors in cells used by thyroid hormones. So remov- ing these toxins will help thyroid hormones do their job of gene expression and metabolism.

How things go bad

Iodine is needed by the thyroid to produce the thyroid hormones T4 and

T3. Part of the endocrine system, the thyroid secretes hormones that enter your circulatory system. And are transported throughout your body. Every cell has receptor sites for thyroid hormones. Neurotransmitters are used by neurons to communicate with one another. The presynaptic neuron releases a neurotransmitter which then binds to a recep- tor on the postsynaptic cell. Here we’re going to explore how neurotransmitters relate to the endocrine system and thyroid health. And what can go wrong. Thyroid hormones are involved in the gene expression needed for neurotrans- mitter release.318 Low levels of iodine result in low levels of thyroid hormones which result in low neurotransmitter levels.

Iodine and Serotonin

Several studies have shown that low T3 results in reduced levels of serotonin in the brain. If you don’t respond to SSRI’s for depression it could be due to a thyroid hormone imbalance.319 The result is depression.

Iodine and GABA In animals and humans there is a direct link between thyroid levels and GABA. Thyroid hormones affect enzymes responsible for synthesis and degrada- 162 HEAD FIRST tion of GABA, levels of glutamate and GABA, GABA release and reuptake, and GABA(A) receptor expression and function.320 GABA is your brain’s natural Valium. GABA can help turn off stress after you get upset. Or even prevent a stress response in the first place. Low iodine results in low levels of thyroid hormones affecting GABA. Which can lead to depression or anxiety.

Iodine and Dopamine Thyroid hormones play a role in dopamine release in the brain.321 One study showed that an imbalance between thyroid hormones and dopamine could be responsible for restless leg syndrome.322

Iodine and Acetylcholine Thyrotrophic-releasing hormone (TRH) increases acetylcholine (ACh) syn- thesis.323 One study showed that those with hypothyroidism had significantly decreased acetylcholine in the hippocampus. And that administration of T4 nor- malized ACh levels.324 Insufficient iodine can result in hypothyroidism. And negatively affect ACh synthesis in the brain. Affecting cognition, memory, learning, recall and mood. Not enough iodine in your diet negatively affects neurotransmitters in your brain. And can result in depression, brain fog, anxiety, learning and memory problems, and ultimately lead to neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Iodine to the rescue Most neurohackers associate Iodine with the thyroid because Iodine is needed to produce thyroid hormones T4 and T3. But Iodine is also concentrated in your salivary glands, stomach, breasts, ovaries, eyes and in your brain. Deficiency in Iodine in any tissue will cause problems in that area of your body. And weaken your immune system. Symptoms of low Iodine show up as brain fog, skin problems, fibroids, fibromyalgia, and chronic fatigue. Iodine can kill bacteria, fungal infections, and viruses. Iodine will remove fluoride, chlorine and bromine.325 And helps your body detox heavy metals like mercury and cadmium that other detox methods can’t remove. Iodine helps prevent and even reverse breast cancer. And helps prevent mental retardation in young children. Your brain needs sufficient Iodine for cognition through several mechanisms of action. This essential element is involved in gene expression that controls the synthesis of neurotransmitters in your brain. And how they work. Iodine helps remove fluoride throughout your body including your brain. Studies show that fluoride can damage your brain, reduce intelligence, and impair 163 David Tomen memory. Fluoride has even been associated with dementia according to a study by The National Academies of Science, Engineering and Medicine.326 One recent study showed that water fluoridation in England is linked to higher rates of underactive thyroid.327 One of the simplest things you can do to boost cognition and your thyroid is to stop using fluoridated water and tooth- paste. And start supplementing with Iodine to remove the fluoride toxicity and boost thyroid health. Iodine Deficiency Disorders are considered one of the biggest worldwide public health problems today. Studies around the world show none of us are immune from Iodine deficiency. Estimates range from 10 – 90% of the world population don’t get sufficient Iodine depending on where you live.328 Adding Iodine to your stack if you are deficient is one of the easiest and least expensive ways to prevent and even cure a host of health problems. Including boosting cognition and memory.

How does Iodine feel? Many neurohackers report an increased level of focus, energy, memory, and cognitive ability when supplementing with Iodine. You should also experience improved quality of sleep. And have an overall improvement in mood. Others report a profound difference in energy levels, they are more alert, and fatigue in the afternoon disappears. A few even report a significant improvement in tinnitus.

The Research One of the most common reasons we use nootropics is to boost memory and mental energy. Memory loss drastically reduces quality of life. And simple brain fog makes it difficult to accomplish the simplest of tasks. Research has shown that Iodine is involved in memory, learning and cogni- tion on several levels. And supplementing with Iodine is one of the most fundamental things you can do to boost cognition.

Iodine raises the world’s IQ The world’s greatest concentration of iodine deficient countries in the 1990’s was the former Soviet republics of Central Asia. Worldwide, about 2 billion people or a 3rd of the world population get too little iodine. Studies show that iodine deficiency is the leading preventable cause of mental disorders. Even moderate deficiency lowers intelligence by 10 – 15 IQ points. The most visible and severe effects manifest as goiters, dwarfism and cretin- ism. Ever hear someone use the derogatory term “cretin” to describe someone with low intelligence? Cretin describes a child born and raised with severe mental disabilities, small 164 HEAD FIRST stature and weakness all due to not enough Iodine in the mother’s diet when she was pregnant. In Japan, people get Iodine from seafood, seaweed, vegetables grown in Iodine-rich soil or animals that eat grass grown in that soil. But even in wealthy nations like the USA and the UK, people still need to supplement. Usually by using iodized salt. Or adding it to their stack as a supplement. According to Dr. Gerald Burrow, a former dean of Yale’s medical school, “For 5 cents per person per year, you can make the whole population smarter than before”. Simply by adding iodine to the salt supply. Back in the old Soviet republic, Kazakh children were stunted compared to same-age Russian children. A survey of 5,000 households in 1996 found that 10 percent of children were stunted. And iodine deficiency identified as the main culprit. In Kazakhstan, Turkmenistan, Tajikistan, Uzbekistan, and Kyrgyzstan cam- paigns were run promoting iodized salt. Salt companies were persuaded to add iodine to salt before putting it in stores. In Kazakhstan in 1999, only 29% of households were using iodized salt. Now, 94% of households are. And in 2007, the United Nations certified the country officially free of iodine deficiency disorders. In raising the world’s IQ, the secret’s in the salt.329

Iodine deficiency and ADHD A 10-year study conducted in Italy investigated children born to 16 women from an iodine-deficient area (Area A) and 11 control women in an iodine-sufficient area (Area B). ADHD was diagnosed in 11 of the 16 children born in Area A but none in Area B. Total IQ score was nearly 20-points lower in Area A children compared to Area B. The researchers noted that the prevalence of ADHD in children born in Area A could only be compared to similar children with a resistance to thyroid hormones. And that iodine-deficiency was the likely cause of ADHD due to a critical re- 330 duction in intracellular thyroid hormone T3 available to the developing brain. Dosage Notes Recommended Iodine dosage is very difficult because everyone needs dif- ferent amounts based on your body’s ability to use the Iodine. And the level of exposure you have to daily toxins like fluoride, chlorine, and other halides. If you are dealing with a severe health problem, then your dosages would need to be higher that someone trying to maintain good health. Maintenance and for optimal cognition – Natural health practitioners once thought that 25 mg per day was good for maintenance. But recent infor- 165 David Tomen mation on the exposure we have daily to toxic load from bromines, fluorides and chlorine bombarding our system may require higher doses. Natural health doctors are now recommending a minimum of 50 mg per day. Cancer – Cancer is a result of mutated cells. Iodine is critical for the P53 gene which prevents damaged cells from dividing.331 Iodine and selenium helps P53 do its job of eliminating abnormal cells. Cancer patients have used 50 – 300 mg of Iodine per day successfully. Supporting supplements to take with Iodine include: • Selenium – 200 – 400 mcg per day. Selenium is required for the production

of T3. And assists in detox. • Vitamin C – 2,000 – 5,000 mg per day helps support thyroid symporters which transport thyroid hormones through the body including across the blood-brain barrier. And assists in detox. • Magnesium – 400 mg per day. (See my chapter on Magnesium as a nootropic). Iodine is fat-soluble and should be taken with food particularly if you have a sensitive stomach. The supporting supplements can be taken at the same time as your Iodine dose. Iodine should be taken early in the day because it can increase energy levels so much you could have problems sleeping.

Side Effects Most forms of Iodine can cause diarrhea and bloating. Particularly at higher doses. Those with a sensitive stomach could experience stomach pain and is the reason I suggest taking Iodine with food. It is also possible to overdose on Iodine. So please start at a lower dose and see how your body reacts. Symptoms of Iodine overdose include abdominal pain, delirium, fever, vomiting and shortness of breath. Iodine is a powerful method for removing toxins and heavy metals from your body which can also produce unpleasant effects. If you experience flu-like symptoms when starting Iodine its very likely you’re feeling the effects of toxins being flushed out of your cells and your body. For more on Iodine toxicity you can browse this extremely poorly formatted, very long post on the Toxicology Data Network.

Available Forms Iodine is sold in many forms but the main thing to look for; does the prod- uct contain both Iodine and Iodide. Your body needs both forms. Breasts look for Iodine and the thyroid needs Iodide. Contrary to some sources; your body cannot convert supplemental Iodine to Iodide. Also important is to find a product that provides milligram (Mg) doses vs. 166 HEAD FIRST microgram (Mcg) amounts. Mcg doses will offer very little health benefit. And are much more expensive compared to Lugol’s.

Recommended forms • Lugol’s liquid – Iodine/Potassium Iodide – 2% and 5% solutions. 2% solu- tion is 2.5 mg/drop and 5% solution is 6.25 mg/drop • Iodoral – Lugol’s formula in pill form – Iodine/Potassium Iodide – 12.5 mg and 50 mg • Biotics Research Iodizyme – 12.5 mg per tablet of Iodine/Iodide • Tri-Iodine by Vitaminlife – 12.5 mg per tablet of Iodine/Iodide

Other forms not recommended “Nascent Iodine” which is iodine in its atomic state and is a very low dose. Not enough to detox heavy metals, fluoride, bromine and chloride. Or to satu- rate tissues. Iosol which is Iodine only, and the micro doses have the same issues as Na- scent Iodine Prolamine which has 3 mg of Iodine and 20 mg of Calcium which is too low to detox the body and saturate tissues Pure Encapsulations, Solaray, Source Naturals, Progressive Labs and NOW all offer mcg doses of Iodide only Kelp because of low Iodine status, not being able to determine levels of Iodine and possibly toxic due to arsenic and halides

Nootropics Expert Recommendation

Iodine 25 – 50 mg per day I recommend using Iodine as a nootropic supplement. Your body does not make Iodine on its own. So to get its benefits it needs to come from your diet. Or you must take it as a supplement. Iodine is especially helpful for those dealing with brain fog, poor cognition and memory, low energy levels and a sluggish thyroid. Iodine is also particularly useful to help rid your body of the daily toxins we’re exposed to every day including heavy metals, fluoride, chloride, bromine and other halides. While most forms of Iodine are helpful for overall health, keep in mind it’s the thyroid hormones T4 and T3 which influence cognitive health. Thyroid hormones are produced from tyrosine and Iodine. And the produc- tion of T3 from T4 requires selenium which should be a part of your stack when using Iodine. 167 David Tomen I recommend an Iodine supplement which contains both Iodine and Potas- sium Iodide to boost cognition. Iodine is a fast-acting nootropic that can also help prevent brain degenera- tion later in life.

168 HEAD FIRST Kava Kava is known for its anti-anxiety and calming effects, improving cognition & memory, and reducing irritability and depression Kava (Piper methysticum) is a small shrub native to the South Pacific islands including Vanuatu, Fiji, Hawaii, and others. And has been safely used by islanders for 3,000 years. Piper methysticum (Piper is Latin for ‘pepper’. And methysticum is derived from the Greek for ‘intoxicating’). In Polynesia and Micronesia, Kava has been traditionally used as a ceremo- nial drink. Kava is best known for elevating contentment, mood, well-being and a sense of relaxation. Several clinical studies have found kava to be effective in treating symptoms of anxiety. Other studies have shown kava to help improve sleep quality. As a nootropic, kava is used primarily to lower anxiety with a potency rival- ling some anti-anxiety prescription drugs. Kava helps: • Neurotransmitters. Kava affects brain levels of GABA receptors. GABA is the ‘calming’ neurotransmitter. And an increase in receptor sites for GABA accounts for Kava’s anti-anxiety properties.332 • Neuroprotection. Kava provides protective effects against strokes. Two of Kava’s compounds, dihydromethysticin and methysticin are similar in potency to which is used to treat Alzheimer’s Disease.333 • Cognition. Kava improves reaction time and cognitive function. Kava- lactones in Kava interact with ion channels in the brain. Influencing neu- rotransmitter function.334 Kava continues to have a central place in everyday life in the islands where its grown. 335 It’s used as a ceremonial beverage in Fiji where it’s commonly given to the Head of State.336 Kava root contains a collection of 6 bioactive compounds called kavalactones (kavapyrones); including kawain, dihydrokavain, methysticin, dihydromethysti- cin, yangonin, and desmethoxyyangonin. Kava also contains small amounts of other alkaloids, flavonoids and glutathione. The presence of glutathione seems to reduce the toxicity of some other kava- lactones. Standardized extracts are important in deciding on what Kava supple- ment to buy to ensure reliability and safety.337 The main compounds in Kava readily cross the blood-brain barrier. And reaches your brain in about 45 minutes after taking the supplement.338

How does Kava work in the Brain? Kava boosts brain health and function in several ways. But two in particular stand out. 169 David Tomen 1. Kava boosts cognition. Kava relaxes the muscles and mind, but it doesn’t affect cognition the way other antidepressants and anti-anxiety drugs do. After a review of 10 clinical studies of Kava, scientists at Australia’s Brain Sciences Institute at Melbourne University found Kava did not negatively affect cognition. In fact, some studies on Kava show it “significantly improved visual attention and working memory processes”. The research team stated that Kava’s “enhanced cognition may be attributed to the ability of Kava to inhibit re-uptake of noradrenaline in the pre-frontal cortex”.339 2. Kava relieves anxiety. Several clinical studies have shown that Kava relieves anxiety. California’s Global Neuroscience Initiative Foundation took a look at 24 studies of Kava and other herbal medicines for anxiety. And there was substantial evidence that Kava relieved not only anxiety, but also restlessness and insomnia. They even looked at animal studies that showed Kava has anxiolytic effects “but not sedative or mental impairing” effects “which are typical side effects caused by benzodiazepines”.340

How things go bad Chronic stress, anxiety, loss of neuroreceptors and neurotransmitters can damage your brain. And one of the ways this manifests is memory loss. It comes as no surprise that people with memory loss experience higher rates of anxiety and depression. As verified in one Australian research study.341 ↓ Chronic stress reduces memory capacity ↓ Bioavailability of neurotransmitters decline ↓ Number of neuroreceptors decline ↑ Increase in anxiety destroys quality of life Under conditions of chronic stress your brain loses the capacity to transmit signals between neurons efficiently. Memory, cognition, and decision-making all suffer as a result.

Kava to the rescue Kava has a long and proven record of medicinal therapeutic value. Much of the clinical evidence supports the use of Kava in treatment of anxiety. Unlike benzodiazepines, Kava does not have similar sedative and mental impairing effects. And Kava seems to provide this calming effect by increasing the number of GABA-a receptors.342 Kava extracts have also been seen to bind to GABA, dopamine, serotonin and opioid receptors as well.343 This implies that more of each neurotransmitter is available to the brain since their associated receptors are blocked or inhibited by Kava. Kava extracts have also shown antidepressant effects. Some of the trials dem- 170 HEAD FIRST onstrating this effect on depression also noted that Kava raised no safety concerns at the doses and duration studied. Unlike some well-known pharmaceutical antidepressants. Kava has also been shown to boost cognition and attention. In one study researchers stated that Kava’s “enhanced cognition may be attributed to the ability of kava to inhibit re-uptake of noradrenaline in the pre-frontal cortex…” And finally, Kava also prevents and may even treat several types of cancer. Research shows for example that one of the components of Kava, Flavokawain B reduces prostate tumor growth and inhibits cancer.344 And that’s just one of many examples of how different components of Kava can fight cancer in the lung, bladder and other organs.

How does Kava feel? This can be a little complicated so stay with me. Any particular preparation of Kava will contain up to 18 different kavalactones. Each will have some type of psychoactive effect in your brain. And to complicate things even more, there are several distinct strains of Kava grown in Hawaii and the South Pacific today. All with their own unique profiles of kavalactones and as a result, their own subtle differences in effect. In general, supplementing with Kava (Piper methysticum) can make you feel relaxed, enhancing calmness and lowering anxiety while promoting sociability. Higher doses can generate feelings of gentle euphoria, with greater sedation and mild motor impairment. Many neurohackers say that at lower doses, Kava’s effects are a little like those generated by alcohol and certain kinds of anti-anxiety medications. Some users say it works as well as popping a Xanax. You should experience an increase in focus along with a sense of calm. And even though Kava works well as a sleep aid, taking it during the day shouldn’t make you drowsy.

The Research Kava has a lot of clinical research to back up its reputation as a nootropic. Research studies have been noted throughout this chapter. Here are two more…

Kava as an anti-anxiety therapy A study at the University of Melbourne, revealed that Kava could be an alter- native treatment for those suffering from Generalized Anxiety Disorder (GAD). In this 6-week placebo-controlled, double-blind trial, 75 patients with clini- cally diagnosed GAD were given Kava or a placebo. Participants were given Kava extract tablets twice per day for a total dose of 120 mg kavalactones for the first 3 weeks. In cases of non-response, the dose was increased to a double-dose twice per day for the 2nd three weeks of the trial. 171 David Tomen γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Kava was well-tolerated. And results showed no significant differences in liver function. One interesting observation during this study was that subjects who had genetic differences in GABA transporters modified their response to Kava. This last observation is just another clue on why some people respond to some nootropics different than others. And why we often say that, “Your Mileage May Vary” when using a nootropic. At the conclusion of this trial, 26% of the Kava group were considered in remission for their anxiety symptoms compared to the placebo group. Overall, all participants who received Kava, showed a significant reduction in anxiety levels. And one additional finding of this study was that Kava increased the female participants sex drive.345

Kava enhances cognitive performance Researchers conducted a double-blind, placebo-controlled trial with healthy volunteers. The purpose of the trial was to investigate the effects of Kava on emotions and cognitive performance. One group was given a single dose of Kava extract (300 mg). And that single dose led to an increase in “cheerfulness”, improved accuracy and speed in task performance, increased visual attention and a boost in short-term memory. The research team compared the effects of Kava to conventional benzodi- azepine-type anxiolytics which tend to impair cognitive performance. The team concluded Kava is a potent anxiolytic agent which can boost cognitive function.346

Dosage Notes Kava extracts are made with a variety of different strengths, and from differ- ent source plant material. So it’s difficult to recommend exact dosages. Fortunately, Kava is relatively forgiving as far as dose is concerned. So taking 2-3 times the recommended dose of an extract should cause no issues. Some neurohackers claim that extracts are just not strong enough. And the only way to get the full effect of Kava is to use ground Kava root which can be found at some natural food stores. Make sure it smells fresh (it should have a relatively strong smell). Fresh powder is used to make a cold tea by making a cold water extraction. Fresh powder is soaked in cold water for 15-20 minutes or more, stirring or shaking occasionally. You can then strain out the powder if you like. If you want to go the capsule route, look for a Kava extract called “WS1490”. For anxiety and other cognitive issues use 300 mg of this extract daily. Preferably 172 HEAD FIRST split into three 100 mg doses. One dose in the morning, one early afternoon and the last in the evening. You can also choose a Kava extract supplement with 250 mg total kavalac- tones. You can use this multiple times throughout the day. If you use only a single dose, take it just prior to sleep.

Side Effects Kava has a long and proven track record of medicinal therapeutic value. But if you start doing research on Kava, you’ll see reports of possible liver toxicity. Let’s address this right now. Most research shows there is little to no evidence to support this notion of liver damage when using Kava. For example, one large review out of the University of Melbourne included 24 clinical studies. One of the researchers stated, “Of the 435 clinical trial participants taking Kava supplements in our review, some at high doses, no liver issues were reported. Therefore, the current review supports the conclusion that liver toxicity is indeed a rare side effect.”347 For most of the history of the Kava industry, it’s been harvested and prepared by native, Pacific Islanders. Roots are stored in bulk after harvest. And could develop mold or acquire other contaminants. Increasingly, many Kava suppliers harvest and process their Kava using in- ternational manufacturing standards such as ISO, GMP and others. And because of the restrictions by first world countries (esp. the European Union) on the importation of raw ingredients, these protocols are now stricter. So when selecting a Kava product, make sure the manufacturer is adhering to good manufacturing practices. Long-term heavy and consistent consumption of Kava could cause a scaly skin rash called dermopathy. This is reversible when Kava use stops. And finally, Kava should not be mixed with prescription drugs. Don’t use Kava if you’re pregnant or breastfeeding. Kava use may make you unable to drive (similar to alcohol). Don’t use Kava if you have liver problems. And avoid com- bining Kava with Xanax, clonazepam, lorazepam, , and Ambien.

Available Forms In the South Pacific, whole Kava root are chewed for their medicinal value. Kava is also available in liquid form, as tinctures, and standardized extracts as capsules or tablets.

Nootropics Expert Recommendation

Kava extract 250 – 500 mg per day I recommend using Kava as a nootropic supplement. 173 David Tomen Your body does not make Kava on its own. So you must take it as a supplement. Kava is especially helpful for those suffering from anxiety and stress. Studies show it helps stop and reverse the devastating effects of anxiety and stress in your brain, and body. Kava also has a reputation for lifting mood. And doesn’t have the same side effects as prescription antidepressants. And unlike pharmaceuticals like benzodiazepines, Kava boosts cognition and short-term memory. The usual serving of prepared Kava in the South Pacific is 2-4 fluid ounces. Depending on how its prepared, a bilo (coconut half shell) can contain anywhere from 150 – 500 mg of kavalactones. And native islanders often consume several bilos in a Kava drinking session. Although the local Kava Committee has issued an advisory upper limit of 300 mg of kavalactones per day, many Pacific islanders consume far more, with- out any ill effects.

174 HEAD FIRST L-Carnosine

L-Carnosine improves cognition, memory, energy levels, prevents brain cell death, and is anti-aging L-Carnosine (β-alanyl-L-histidine) is a dipeptide of the amino acids beta- alanine and histidine. Carnosine is found throughout your body. The highest concentrations are in high energy demand areas such as your brain, heart and muscles. (Don’t mistake l-carnosine for l-carnitine). L-Carnosine is known as the ‘longevity molecule’. But don’t let that put you off if you’re not concerned about anti-aging. Carnosine levels decrease with age – starting at age 10! And decrease by 63% by the time you reach 70 years.348 It removes heavy metals which accumulate in, and damage brain cells caus- ing diseases like Alzheimer’s.349 And it prevents cross-linking of proteins which cause the neurofibrillary tangles found in Alzheimer’s.350 L-Carnosine is one of the most powerful antioxidants known. It’s a heavy- metal scavenger. It’s a super auto-regulator. And it stands alone when it comes to preventing and reversing advanced glycation end products (AGEs) or cross- linking. And it’s highly concentrated in your brain. Your brain uses l-carnosine to repair tissue and clear away toxins. And increase the energy output of your mitochondria. It suppresses excess immune responses when your immune system is in hyper mode. And it stimulates the immune response if you have a weakened immune system. L-Carnosine even seems to have the ability to normalize brain waves. L-Carnosine fights mitochondrial dysfunction by relieving oxidative stress caused by accumulation of free radicals in cells.351 This not only works in your brain cells. L-Carnosine is used by athletes to achieve better results. Its buffering nature contributes to the acid-base balance in muscles. Researchers have found l-carnosine restores neurotransmitter receptors. Receptors that were damaged from stroke or glutamate toxicity.352 And l-carnosine reduces damage to telomeres. These caps on the end of DNA strands shorten with each cell replication. This natural, ongoing process is used for example in long-term potentiation needed to form memories. L- carnosine slows the rate of shortening of telomeres.353 Some l-carnosine is naturally produced in your body by the enzyme carnosine synthetase. And you can get l-carnosine from food – primarily from red meat and poultry. But a typical meal provides only about 250 mg of carnosine. It’s then quickly degraded in your body by the carnosinase enzyme. This means carnosine from food doesn’t last long enough in your body to provide much benefit. And if you’re a vegetarian, you won’t be getting much carnosine other than what’s naturally produced in your body. 175 David Tomen Supplementing with at least 1,000 mg of l-carnosine per day overwhelms that carnosinase enzyme. Allowing you to maintain consistent blood levels of this vital nutrient.

How does L-Carnosine Work in the Brain? L-Carnosine boosts brain health and function in several ways. But two in particular stand out. 1. L-Carnosine is critical for brain health. L-Carnosine’s antioxidant, neuro- protective, chelating, and anti-glycation activity not only maintains optimal brain health. This dipeptide can be used to prevent and treat neurodegenera- tive diseases, diabetes, diseases of the sense organs (i.e. eyes) and cancer.354 L-Carnosine has been shown to reduce oxidative and glycemic stress.355 And it reduces inflammation. L-carnosine reduces the accumulation of b-amyloid plaque which plays a role in cognitive dysfunction and Alzheimer’s. And it helps remove heavy metals that cross the blood-brain barrier and accumulate in brain cells.356 2. L-Carnosine is required for healthy mitochondria. In your brain, you can have thousands of mitochondria in each cell. And they pump out energy in the form of ATP (adenosine triphosphate). 20% of your body’s total ATP is located in your brain. Glycation during this energy production reduces the functionality and effi- ciency of mitochondria. This is turn can cause apoptosis (cell death).357 Glycation happens when proteins or DNA bond chemically to sugar molecules. These sugar molecules go on to form advanced glycation end products (AGEs). These AGEs are implicated in Alzheimer’s, skin wrinkles, hardened arteries, and reducing the function of most major organs. Including your brain. A study in the Netherland was done to examine the association between AGEs and cognitive function. This population-based study also included 215 people with type 2 diabetes. Researchers tested for global cognitive functioning, information process- ing speed, verbal memory (immediate and delayed word recall), and response inhibition. The study found there was a direct correlation with markers measured for AGEs and decreased cognitive performance. And the associations were no different between healthy people and those with diabetes.358 Another study out of the University of California determined that l-carnosine was able to prevent AGEs.359 Free electrons are a byproduct of this energy production. These electrons convert oxygen to a highly reactive form capable of damaging brain cells. And wreaking havoc with DNA in the long-term. 176 HEAD FIRST If left unchecked, it leads to neurodegenerative disease like memory loss, cognition dysfunction, and eventually diseases like Alzheimer’s.

How things go bad As we get older, our brain chemistry and metabolism changes. ↓ ATP levels decline in mitochondria ↓ Cognition, learning, memory and recall decline ↓ AGEs damage brain cells ↓ Free radicals damage brain cell mitochondria All of these changes can happen at any age. And can start at age 10 or earlier (in the case of autism). So l-carnosine supplementation can help for age-related cognitive decline, as well as anyone who wants to boost cognition, learning, recall and memory.

L-Carnosine to the rescue There is a proven high correlation between human lifespan and l-carnosine levels. L-carnosine is highly concentrated in your muscles and brain. And is directly involved in a number of life-extending activities. L-Carnosine helps prevent the buildup of advanced glycation end products (AGEs) that damage mitochondria. And eventually end in premature cell death. It is a heavy metal chelator and works by removing heavy metal accumula- tion in brain cells. L-carnosine is an anti-oxidant and pH buffer in muscle cells preventing lactic acid buildup.

How does L-Carnosine feel? When you supplement with l-carnosine you’ll notice younger looking skin. And you’ll have more energy. You should experience a boost in cognition and decision-making capability. Thinking could be more fluid and your motivation may see a boost. These changes are reported by neurohackers in their 20’s and 30’s as well as the more senior user. But most of the talk and research on l-carnosine is on its anti-aging and longevity benefits. So what if I told you it also helps fight the flu? It turns out that the influenza virus raises nitric oxide (NO) and oxygen free radicals such as superoxide anion (O₂⁻). When NO and O2 – interact, they form peroxynitrite, the pathogen that causes pneumonia. The excess amount of toxicity and oxygen radicals generated overwhelms your immune system. A study in the American Journal of Therapeutics reports that l-carnitine can put a stop to this overwhelm. And help you avoid or get rid of the flu or cold. And eating chicken soup to make you feel better when your sick is not an ‘old wife’s tale’ after all. Chicken soup is rich in l-carnosine.360 177 David Tomen The Research

L-Carnosine improves cognition Animal and human studies suggest NMDA antagonists worsen executive func- tion. This dysfunction is often caused by glutamate toxicity. And if this persists, you end up with diseases like schizophrenia. This double-blind, placebo-controlled study worked with 75 adults with schizophrenia. They were stable in their symptoms at the time of the study. Subjects were randomly selected to receive 2 grams of l-carnosine per day for 3 months. Executive dysfunction, memory, attention and motor speed were assessed at the beginning, and at 4 and 12 weeks. The l-carnosine group performed much better in executive function tests. And were better at strategy with fewer errors than the placebo group.361

L-Carnosine improves autism symptoms in children L-Carnosine enhances frontal lobe function in your brain. And acts as a neuroprotectant. It also works with GABA for an anticonvulsive effect. This double-blind study worked with 31 children with autism for 8 weeks. They were given 800 mg of l-carnosine per day. The scientists then used several autism rating scales to measure results. After 8 weeks of l-carnosine use, the children showed significant improve- ment in behavior, sociability, communication and vocabulary. The researchers concluded that l-carnosine enhanced neurologic function.362

L-Carnosine is anti-aging In 1965, Dr. Leonard Hayflick found that human cells have a limited capac- ity to divide. After which they become ‘senescent’. This is now known as the “Hayflick Limit”. Hayflick discovered that your cells go through 3 phases. First is rapid cell division called ‘mitosis’. The 2nd is where mitosis slows. And the 3rd stage is ‘se- nescence’ where the cell stops dividing entirely. They remain alive for a while and then do a particularly disturbing thing. They commit suicide. This programmed cell death is called ‘apoptosis’. This cell life cycle occurs throughout your body and its trillions of cells. Including in your brain. But what if there was some way to slow down this programmed cell death? Turns out there is. And it’s called L-Carnosine. Researchers at Sydney Laboratory in Australia found that l-carnosine extend- ed cell life. They put cultured aged human cells in a petri dish with carnosine. The cells reverted back to juvenile cells. When they put those same newly rejuvenated cells in a culture that had no 178 HEAD FIRST carnosine, they reverted back to their old self again. Put them back in carnosine and they got young again.363 This experiment has been done again and again in labs around the world. Establishing l-carnosine as the best anti-aging thing since Ponce de Leon was searching for the Fountain of Youth right here in Florida (where I’m writing this chapter). David Guetta thinks that Miami is “the sexiest city in the world”. Could be that everybody in Miami is using l-carnosine.

Dosage Notes Recommended L-Carnosine dosage in 1,000 mg per day. To keep a consistent level of l-carnosine in your body, split your dose into two 500 mg doses. One in the morning and one later in the afternoon. One important note on l-carnosine. When you supplement with l-carnosine it binds to aldehydes. Preventing them from making proteins. The byproduct is lipofuscin. This age pigment is not dangerous. But shows up as brown spots on your brain, skin and other organs. As lipofuscin builds up over time, and this process is accelerated when using l-carnosine, it can interfere with proper organ and cellular functions. This is why we recommend stacking l-carnosine with DMAE and acetyl- L-carnitine (ALCAR). DMAE is a naturally occurring nutrient that boosts available choline. And ALCAR boosts mitochondria energy while acting as a neuroprotectant. Both DMAE and ALCAR help flush lipofuscin from your brain and body. So stack your daily dose of 1,000 mg of l-carnosine with DMAE and ALCAR at their recommended doses. L-Carnosine is water-soluble so you don’t need to take it with a meal, or healthy fat like some nootropics.

Side Effects Carnosine is considered extremely non-toxic and safe. High doses can cause insomnia. And l-carnosine can cause a stimulant effect. So take your nd2 dose before evening.

Available Forms L-Carnosine comes in powder, capsule, tablet and liquid form. Most major supplement manufacturers offer 500 mg tablets or capsules. But make sure you read the labels and get l-carnosine in its natural form. Some manufacturers will try to fool you by calling their synthetic carnosine natural sounding names like “nature-identical”. But lab created l-carnosine is not the real thing and not nearly as bioavailable. 179 David Tomen Nootropics Expert Recommendation

L-Carnosine 1,000 mg per day I recommend using L-Carnosine as a nootropic supplement. Your body does make some L-Carnosine on its own from the amino acids beta-alanine and histidine. And you can get small quantities from red meat and poultry. But it’s easily and quickly broken down by the enzyme carnosine synthetase. So to get its benefits, and enough to overwhelm the carnosine synthetase enzyme, you must take it as a supplement. L-Carnosine is especially helpful for repairing brain cells at the mitochon- drial level. It removes heavy metals, works as a very powerful antioxidant, and gets rid of AGEs. Advanced glycation end products (AGEs) kill brain cells. Foods that are high in AGEs include roasted, fried, sautéed and barbecued meats, nuts and tofu. Those fries you had for lunch? Brain cell death. Your natural production of l-carnosine starts to drop at age 10. So anyone will benefit from supplementing with this anti-aging nutrient. L-Carnosine helps control blood glucose levels, prevent Alzheimer’s, wound healing, protects from the side effects of chemo therapy, alcohol-induced liver damage, combatting heart disease, and eye health by protecting or repairing cataracts. L-Carnosine is also particularly useful if you’re dealing with autism or Al- zheimer’s. For autism, dose up to 800 mg per day. For Alzheimer’s, dose at least 1,000 mg per day.

180 HEAD FIRST L-DOPA

L-DOPA (Mucuna Pruriens) is known for improving brain health, is an antioxidant and heavy metal chelator, improves memory & cognition, lowers symptoms of depres- sion, and boosts libido L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine) is an amino acid syn- thesized in your brain by the amino acid l-tyrosine. L-DOPA is a necessary precursor to the neurotransmitter dopamine. Called a catecholamine, dopamine is then synthesized into the other catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). And for a dopamine boost, neurohackers use Mucuna Pruriens, which contains high levels of L-DOPA.364 This legume, native to the tropical regions of India, Africa and the West Indies, and also known as velvet bean, has been used in Ayurveda medicine since 1500 B.C. The ancients used Mucuna Pruriens to treat things like snakebite, intestinal problems, sexual issues, and a melancholy mood. Raising levels of the neurotransmitter dopamine in your brain helps regulate mood and cognition.365 Dopamine and norepinephrine are essential for memory, cognition, and a positive mood. A lack of either of these neurotransmitters can lead to a lower mood state, loss of memory, brain fog, poor energy, and more. And if left un- checked will eventually result in neurodegenerative diseases like Parkinson’s.

Mucuna Pruriens vs. L-DOPA: What’s the Difference? Mucuna Pruriens is an extract of the velvet bean plant that grows 3 – 18 meters in height. L-DOPA (levodopa) is generally synthetic and made in the lab. The natural version of L-DOPA from Mucuna Pruriens is generally well- tolerated by most people. And the compounds in the plant are bio-identical to those chemicals naturally made in your body. Not so with synthetic L-DOPA. Synthetic L-DOPA is metabolized into dopamine in your body by an enzyme called aromatic L-amino acid decarboxylase (AADC). And the majority of synthetic L-DOPA will be converted peripherally (not in the central nervous system and brain). This can cause problems. So when used therapeutically, as in treating Parkinson’s Disease, L-DOPA is administered in combination with an inhibitor of peripheral AADC. Drugs like carbidopa (or other AACD inhibitors) ensure most of the L-DOPA is preserved for conversion to dopamine in the brain. And not the rest of your body. This is critical for nootropic users to keep in mind. Chronic, or prolonged use of synthetic L-DOPA can lead to things like dyskinesia. This is a movement dis- order where neurological discoordination results in uncontrollable, involuntary movements.366 181 David Tomen We’re not telling you this to dissuade you from using L-DOPA. Stick with an extract of Mucuna Pruriens and you should be fine.

How does L-DOPA Work in the Brain? L-DOPA boosts brain health and function in several ways. But two in par- ticular stand out. 1. L-DOPA improves memory. It’s metabolized into dopamine in your body by an enzyme called aromatic L-amino acid decarboxylase (AADC). This in- creases dopamine levels in your brain. Researchers at the University of Münster in Germany conducted a study with 40 healthy people. In this randomized double-blind study, they gave one group 100 mg of levodopa daily for 5 days. The other group took a placebo. 90 minutes later on each day, subjects were given a memory test based on vocabulary. The study found that levodopa significantly enhanced the speed, overall success, and long-term retention of novel words.367 2. L-DOPA promotes brain health. Research suggests Mucuna Pruriens protects your brain by regulating cognitive and neural functions. And even encouraging neural activity. Researchers in India showed that Mucuna Pruriens is a potent antioxidant. They performed assays to evaluate the enzymatic and nonenzymatic antioxidants in extracts. They found high levels of flavonoids, alkaloids, tannic acids, gallic acids, quercetin equivalents, and sitosterol equivalents.368 All of these compounds scavenge for free radicals in your brain. Free radicals are formed during normal brain activity, like the synthesis of ATP that fuels your mitochondria. Your brain is equipped to eliminate some of these free radicals on its own. But especially in today’s environment in which we live, your brain is overwhelmed. Free radicals cause inflammation which damage, and can kill brain cells. Affect- ing memory, learning, recall, cognition and mood. Mucuna Pruriens has been proven to be a very effective brain inflammation fighter. It even has the ability to chelate heavy metals like mercury and lead in brain cells. And it’s antibacterial.369 Mucuna Pruriens helps your brain make naturally occurring neuronal pig- ments called neuromelanins. They’re similar to the melanin found in your skin. And they’re often found in regions of your brain where dopamine is active. The synthesis of neuromelanins in the various regions of your brain is an important protective process. The melanic component is generated through the removal of reactive/toxic quinones that would otherwise cause neurotoxicity. This melanic component promoted by Mucuna Pruriens is what chelates and accumulates toxic, heavy metals like mercury and lead.370 182 HEAD FIRST How things go bad As we get older, our brain chemistry and energy metabolism changes. ↓ Dopaminergic neurons are damaged or die ↓ Dopamine levels decline ↓ Stress levels increase ↓ Long-term memory and mood decline All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Parkinson’s Disease.

L-DOPA to the rescue Mucuna Pruriens extract contains high levels of L-DOPA, the precursor to the crucial neurotransmitter dopamine. Dopamine is further synthesized into the neurotransmitters epinephrine (adrenaline) and norepinephrine (noradrenaline). Dopamine plays a critical role in learning and absorbing new information. Increasing brain levels of dopamine helps regulate mood and boost cognition. Research also suggests that Mucuna Pruriens provides antioxidants that defend against oxidative damage caused by free radicals.371

How does L-DOPA feel? Neurohackers report that using Mucuna Pruriens helps in multi-tasking, improving motivation, more focus, less stress, and a sense of calm. You could find your energy levels increase, less brain fog, and a boost in overall mood. A more positive outlook on life. And an increase in libido.

The Research

Mucuna Pruriens helps reduce stress A study was conducted to assess the role of Mucuna Pruriens in infertile men. It was done at King George’s Medical University in Lucknow, India. The study included 60 men who were undergoing infertility screening. And no surprise here; were found to be suffering from stress. The control group in this study were 60 age-matched men who had initiated at least one pregnancy. The infertile men were given 5 grams of Mucuna Pruriens seed powder per day for 3 months. Semen samples were collected at the begin- ning of the study. And after 3 months of treatment. The researchers found that treatment with Mucuna Pruriens significantly decreased stress levels. And increased sperm count to the same level as the fertile control group of men. They “concluded that M. pruriens not only reactivates the anti-oxidant defense system of infertile men but it also helps in the management of stress and improves semen quality.”372 183 David Tomen L-DOPA improves learning This study in Germany was done with 40 healthy subjects. They were given 100 mg of L-DOPA or a placebo for 5 days in a randomized, double-blind trial. Subjects were trained on artificial vocabulary using a high-frequency, repeti- tive approach. This was done 90 minutes after L-DOPA administration on each day of the trial. The researchers found that L-DOPA significantly enhanced the speed, over- all success, and long-term retention of the words.373

L-DOPA as an anti-depressant Increasing dopamine in your brain also boosts your mood and libido. This study was done in India with mice. Researchers used the well-known Forced Swimming Test (FST), Tail Suspension Test (TST), and Chronic Unpredictable Mild Stress (CUMS) test. The mice were fed Mucuna Pruriens seed extract, and then evaluated while performing, well… what mice do in the lab. The research team found that Mucuna Pruriens seed extract has significant antidepressant qualities. Which would simply verify what we already know in humans.374 Using Mucuna Pruriens extract is a great anti-depressant.

Dosage Notes L-DOPA (Mucuna Pruriens 98% extract) suggested dosage for cognitive benefits is 250 – 500 mg per day. I recommend that you cycle the use of L-DOPA (Mucuna Pruriens). And use it only 4 or 5 days a week. This will help avoid tolerances and dependencies (which are common with any dopamine agonist).

Side Effects L-DOPA is produced naturally in your body. So is considered well-tolerated and safe. And L-DOPA from Mucuna Pruriens extract is particularly well toler- ated by most people. Research shows that the natural form of L-DOPA from Mucuna Pru- riens compared to synthetic versions of L-DOPA provides similar results. But without the common side effects of nausea, vomiting, and involuntary muscle movement.375 But be very careful when working with dopamine. Too much and you can experience symptoms like hair loss, auditory or visual hallucinations, psychosis, Dyskenesia and more. Of course, if you begin to experience any of these side effects, stop supple- menting with L-DOPA (Mucuna Pruriens) immediately. Like any natural supplement, it’s always better to find an organic source. 184 HEAD FIRST Available Forms Mucuna Pruriens is typically available in powder, capsule or tablet form. Some are pure, dried Mucuna Pruriens powder. Several manufacturers offer Mucuna Pruriens extracts ranging from 15% – 98% L-DOPA. Or they tell you how many mg of L-DOPA is in each capsule or tablet. A few manufacturers call it “Velvet Bean Extract” with the percentage of L-DOPA in each capsule or tablet. It’s the same as Mucuna Pruriens. Try to find “organic” or “certified organic” if you can. And for Nootropic use, avoid synthetic L-DOPA which is typically used to treat Parkinson’s Disease.

Nootropics Expert Recommendation

L-DOPA (Mucuna Pruriens) 250 – 500 mg per day I recommend using L-DOPA as a nootropic supplement. Your body does synthesize some L-DOPA on its own. And converts it into the essential neurotransmitters dopamine, epinephrine, and norepinephrine. But as you get older, dopamine receptors die. Or your body doesn’t convert the necessary amino acids well enough to supply the neurotransmitters you need for an optimized brain. L-DOPA is helpful to boost energy levels, clear brain fog, improve mood and libido. L-DOPA is especially helpful for those suffering from neurodegenerative dis- eases like Parkinson’s. And the natural form of L-DOPA from Mucuna Pruriens often offers better results with fewer side effects than prescription drugs. I suggest starting with a dose of 100 – 250 mg daily for nootropic use. L-DOPA should be cycled. Use it for 4 or 5 days and take a break. Tolerance is often a problem when working with dopamine. As is dependence or addiction.

185 David Tomen Lemon Balm

Lemon Balm is known for its anti-anxiety and calming effects, improving focus, memory and cognition, and reducing irritability and depression Lemon Balm (Melissa officinalis)is an herb that’s native the Mediterranean region. And now found in gardens throughout Europe and North America. Lemon balm has a long history as a treatment for stress, anxiety, thyroid issues, indigestion, infections, viruses and inflammation. Related to the mint family of herbs, lemon balm has a subtle lemon scent. And its small white flowers attract bees. Hence the botanical name ‘Melissa’, which is Greek for honey bee. The first recorded medical use of lemon balm dates back to Dioscorides, the ancient Greek physician, who used the herb for its anti-bacterial and soothing properties. The famous Swiss Renaissance physician, Paracelsus, called it the “elixir of life”. In the 16th century, English botanist John Gerard, gave it to his students to “quicken the senses”. This appears to be the first recorded use of the herb for brain and cognitive health. The most recent research shows lemon balm has remarkable healing and regenerative effects on your brain. It stimulates memory, and supports the health of your brain’s white matter. Lemon balm’s two primary compounds that affect brain health are eugenol and .376 Eugenol is an antioxidant 5-times more potent than alpha-tocopherol found in Vitamin E. So lemon balm acts to boost your body’s natural healing processes by eliminating free radicals that damage brain cells. And lemon balm helps increase levels of your body’s most powerful built-in antioxidants, dismutase and glutathione peroxidase.377 Rosmarinic acid promotes an anti-depressant effect in your brain by down- regulating mitogen-activated protein kinase phosphatase-1 (Mkp-1). And it upregu- lates brain-derived neurotrophic factor (BDNF), along with boosting dopamine synthesis.378

How does Lemon Balm work in the Brain? Lemon Balm boosts brain health and function in several ways. But two in particular stand out. 1. Lemon Balm boosts memory. Lemon balm increases the activity of the neurotransmitter acetylcholine (ACh) in your brain. When your brain sends signals, it uses acetylcholine to keep the signals moving. But once used, your brain removes acetylcholine with an enzyme called acetylcholinesterase (AChE).379 186 HEAD FIRST But if you have too much AChE, as is the case with Alzheimer’s patients, it restricts brain signaling. One way to prevent this signal failure is to prevent the breakdown of acetylcholine. The compound rosmarinic acid in lemon balm encourages blood flow, which helps to keep brain cells from dying.380 And it inhibits the formation of AChE. The result is that your brain is stimulated, memories continue to form, and brain fog is eliminated. 2. Lemon Balm reduces stress. One-way lemon balm does this is to promote GABA, a glutamate inhibitor in your brain. Glutamate excites brain cells to act. While this excitation is necessary, too much glutamate results in cell death. Lemon balm promotes a better balance in glutamate levels, and helps new cell growth.381 The result is a boost in memory and reduction in stress. Largely due to eugenol, one of the components of lemon balm.

How things go bad Chronic stress, anxiety, poor blood flow and free radicals (oxidation) can damage your brain. And one of the ways this manifests is memory loss. It comes as no surprise that people with memory loss experience higher rates of anxiety and depression. As verified in one Australian research study.382 ↓ Chronic stress reduces memory capacity ↓ Toxins kill brain cells from the inside ↓ Free radicals destroy neurons and synapses ↓ Acetylcholine (ACh) levels decline ↓ Brain-derived neurotrophic factor (BDNF) declines Under conditions of chronic stress your brain loses the capacity to transmit signals between neurons efficiently. Memory, cognition, and decision-making all suffer as a result.

Lemon Balm to the rescue Lemon Balm undoes damage to the brain caused by chronic stress and oxida- tive damage. It boosts GABA levels and keeps toxic glutamate overload in check. Lemon balm inhibits the enzyme AChE that breaks down acetylcholine (ACh) levels in your brain. Boosting ACh improves memory, recall and cognition. Rosmarinic acid in lemon balm works as an antidepressant. And boosts brain-derived neurotrophic factor (BDNF) which promotes the growth, matu- ration and maintenance of brain cells. And the eugenol in lemon balm is a very powerful antioxidant. Eliminating oxidative damage in brain cells by neutralizing free radicals. And boosting your brain’s own antioxidants to provide even more protection. 187 David Tomen How does Lemon Balm feel? The effects of supplementing with Lemon Balm (Melissa officinalis) can provide an anti-anxiety effect within minutes of taking it. Some users say it works as well as popping a Xanax. You should experience an increase in focus along with a sense of calm. And even though lemon balm works well as a sleep aid, taking it during the day shouldn’t make you drowsy. Users report lemon balm effective in taming racing thoughts that come with Obsessive Compulsive Disorder (OCD). Some even use lemon balm as an effec- tive way to control irritable bowel syndrome.

The Research Research continues in medicinal plants and herbs that have been used for millennia to treat cognition and memory problems. One study conducted at the University of Newcastle upon Tyne in the UK, found Melissa officinalis to be one of the strongest in its effects on acetylcholine receptors. And being an effective aid for memory.383

Lemon Balm as a Nootropic Lemon Balm has been shown to improve problem-solving and memory in both human and animal models. And age seems to make no difference. All groups using lemon balm showed better recall and problem-solving. Some recent studies with Alzheimer’s patients have shown improvement when using lemon balm. In one study done in China, researchers gave Sprague Dawley rats eugenol. One of the active compounds found in lemon balm, eugenol is a potent antioxidant. In this case it helped test subjects get their memory back.384 Another study noted that lemon balm inhibits acetylcholinesterase (AChE). This enzyme breaks down the critical neurotransmitteracetylcholine (ACh). ACh is crucial to creating memories and cognition. Lemon balm was shown to boost and support mood and memory.385

Lemon Balm for Stress Reduction A double-blind, placebo-controlled experiment was conducted in the UK with 18 healthy volunteers. The subjects received two separate single doses of standardized lemon balm extract (300 mg and 600 mg), or a placebo, on separate days. Followed by a 7-day washout period. Mood was assessed before dosing, and 1-hour after dosing with lemon balm extract. The study subjects did a 20-minute version of the Defined Intensity Stressor Simulation (DISS) battery of tests. The results showed that a 600 mg dose of lemon balm eliminated the nega- 188 HEAD FIRST tive mood effects of doing the DISS tests. They reported an increase in calmness and reduced alertness. The researchers also reported a significant increase in mathematical process- ing, with no reduction in accuracy. This was after taking the lower 300 mg dose. The nootropic benefits of lemon balm, according to this test, was a boost in cognition, and had a calming effect.386

Dosage Notes Lemon balm has a long history of use in treating a host of ailments. Including memory and cognition, gas, bloating, earache, vomiting, headache, toothache and insomnia. For nootropic use, Melissa officinalis (lemon balm) comes in tea and cap- sule form. For the most potent dosage, find lemon balm extract in capsules. The suggested dose by most naturopaths and alternative health doctors is 300 mg of lemon balm extract 2-3 times per day. Dosage of lemon balm leaf as a tea is 1 – 2 grams per cup of tea. You can use lemon balm in the morning to address daytime anxiety. And towards evening to support relaxation and sleep.

Side Effects Lemon balm is considered non-toxic and very safe for most users. Most neurohackers won’t experience any side effects. Note: Lemon balm may have an “antithyrotropic effect”. So if you’re hypo- thyroid, and on thyroid medication, you may want to avoid using lemon balm. And use caution when combining lemon balm with; anti-anxiety meds, anti- histamines, muscle relaxers, anti-seizure drugs or tranquilizers.

Available Forms For nootropic use, lemon balm supplements are available as loose-leaf tea, tinctures, and capsules. Most neurohackers use lemon balm capsules which come as ground leaves, or an extract. The lowest active dose is 300 mg of standard lemon balm. Supplementing above this dose seems to offer dose-dependent benefits. In other words, you’ll get more benefit by taking higher doses. (i.e. 300 mg lemon balm 2-times per day).

Nootropics Expert Recommendation

Lemon Balm extract 300 – 600 mg per day I recommend using Lemon Balm as a nootropic supplement. Your body does not make Lemon Balm on its own. So you must take it as a supplement. Lemon Balm is especially helpful for those suffering from anxiety and stress. Studies show it helps stop and reverse the devastating effects of anxiety and stress 189 David Tomen on your brain, and body. This nootropic helps repair damage to brain cells caused by chronic stress and anxiety. Lemon balm is reported to work well for those dealing with Obsessive Com- pulsive Disorder (OCD). Taming racing thoughts, and helpful in dealing with stressful situations. Lemon balm is also helpful for those suffering from Alzheimer’s. It has been shown to help reduce agitation and improve symptoms of mild to moderate Alzheimer’s disease. It may also be of benefit in relieving some symptoms of ADHD. You can safely take up to 900 mg of Lemon Balm (Melissa officinalis) extract daily if needed. One dose first thing in the morning. One dose early afternoon. And the last dose in the evening. And for memory, lemon balm is great to stack with CDP Choline and Acetyl L-carnitine.

190 HEAD FIRST L-Glutamine

L-glutamine can help improve alertness, concentration, focus, memory and mood, boost Human Growth Hormone and reduce anxiety L-glutamine is a conditionally essential amino acid and main precursor for the production of the neurotransmitters glutamate and GABA (γ-aminobutyric acid) in your brain. L-glutamine supplementation is mostly talked about in athletic and body building circles for its effect on human growth hormone and muscle recovery after a workout. But L-glutamine is largely ignored by the nootropics community. L-glutamine is so critically important to the optimized brain that by reading this chapter, you’ll understand why it may be an important addition to your nootropic stack. As an ‘excitatory’ neurotransmitter, glutamate is released from pre-synaptic cells and then binds to post-synaptic cells inducing activation. Too much gluta- mate and neurons become overactive causing a toxic environment that is harmful to neurons. And to cognition. To keep this process in check, glutamate is also a precursor to the ‘inhibitory’ neurotransmitter GABA. GABA works by preventing neural signaling in over-ex- cited neurons caused by glutamate that could result in anxiety and depression.387 The balance of glutamine and glutamate has been identified in an array of brain conditions (i.e. mental illness, tumor, neurodegeneration) as well as in normal brain function.388 The precursor relationship between glutamine and glutamate/GABA is often referred to in scientific and research circles as the Gln/Gly(GABA) cycle.389 Glu- tamine is naturally synthesized from glutamate and ammonia in brain cells called astrocytes in a reaction catalyzed by glutamine synthetase (GS). Newly synthesized glutamine is transferred to neurons and hydrolyzed by phosphate-activated glutaminase (PAG) to then produce glutamate. A portion of which may be decarboxylated to GABA or transaminated to Aspartate. Glutamate, the excitatory neurotransmitter and GABA, the calming neu- rotransmitter rely on this cycle to maintain homeostasis within your brain. Glu- tamine also modulates the synthesis of Nitric Oxide by controlling the supply of its precursor arginine. When this cycle gets out of whack, things start to break down. The results can be particularly nasty. And result in conditions like epilepsy, or hepatic en- cephalopathy which effects behavior, mood, speech, sleep and the way you move. L-glutamine becomes a “conditionally” essential amino acid when your body can’t produce enough on its own. And you need to replenish L-glutamine levels either through supplementation or food.390 191 David Tomen L-glutamine can be found in foods such as beef, pork, fish, eggs, milk and dairy products, wheat, cabbage, beets, beans, spinach and parsley.

How does L-glutamine work in the Brain? L-glutamine helps brain health and function in several ways. But two in particular stand out. 1. L-glutamine is critical for an optimized brain. L-glutamine is a precursor to the neurotransmitter glutamate in your brain. The balance of glutamine and glutamate is crucial to an optimized and healthy brain. The normal cycling of glutamine and glutamate takes a huge amount of energy in the brain. Research has estimated that the Gln/Gly(GABA) cycle ac- counts for more than 80% of cerebral glucose consumption.391 So when you’re using nootropics like Resveratrol or PQQ to boost mental energy, much of that energy is going towards maintaining this Gln/Gly(GABA) cycle. A disruption of this cycle results in all kinds of problems including Reye’s Syndrome, epilepsy, bipolar disorder, schizophrenia, anxiety, depression, and alcohol addiction.392 One Korean study measured Glutamate and Glutamine concentrations in the prefrontal cortex of mice infused with an astrocyte toxin. And they used other inhibitors to disrupt the Glu/Gln cycle. Glutamate and glutamine levels decreased on the 5th day in the mice. The animals experienced immobility and a decreased preference for sucrose (sugar). A sure indication in mice of depression. Direct infusion of L-glutamine completely reversed all the impairments that were originally induced in the animals. And the researchers concluded that neuronal deficiency of L-glutamine causes depression.393 2. L-glutamine also helps prevent brain aging. Researchers have long been on the hunt to determine what causes the human brain to age. Recently, mitochondrial dysfunction has been implicated in the loss of brain function in neurodegenerative diseases and aging.394 Leading to an abnormal increase in the excitatory neurotransmitter glutamate. A study at the New York University School of Medicine used 28 patients with mild traumatic brain injury and 22 matched controls. Gray and white matter in their brains was measured using MRI’s. The study found that one year after traumatic brain injury there was signifi- cant global brain atrophy. Much larger than in the control subjects. The team noted the amount of brain damage from just one concussion. And that this type of injury was not exclusive to a severe blow to the head. Even mild injury could cause brain damage.395 Most of the damage was associated with a disrupted Glu/Gln cycle and an abnormal increase in glutamate levels.396 192 HEAD FIRST How things go bad Low levels of L-glutamine are associated with a variety of health problems. ↓ Cellular energy drops and immune system weakens ↓ Short – and long-term memory declines ↓ Anxiety, insomnia and lack of concentration ↑ Muscle spasms, hypertension, convulsion, Tourette’s Syndrome and epilepsy ↑ Ammonia levels rise in brain cells397 ↓Poor digestion, bloating, flatulence, and constipation When your neurotransmitters, including L-glutamine and glutamate are in balance, you feel motivated, productive and energetic. And you feel calm and relaxed during downtime. When L-glutamine levels are low you feel filled with dread, you’re constantly worried, you have racing thoughts, and you’re frequently late and disorganized. Many people in this L-glutamine – slump resort to high carbohydrate foods, and drugs or alcohol to relax.

L-glutamine to the rescue The amino acid L-glutamine is the precursor to L-glutamate production in your body. L-glutamate gets converted to GABA. Glutamate is your body’s most abundant excitatory neurotransmitter. Which is responsible for attention span, brain energy, learning ability, memory, and staying awake. An enzyme called glutamate decarboxylase converts glutamate to GABA.

It does it with the help of the active form of Vitamin B6 (Pyridoxal-5-Phosphate (P5P)). The amino acid taurine helps increase the communication and productivity of this enzyme. And zinc helps the release of GABA from its receptors. When this Gln/Gly(GABA) cycle works efficiently, you feel relaxed with no stress or feelings of anxiety. Detoxification of your liver results in a more restful night’s sleep. Focus, concentration, memory and mood all improve.

How does L-glutamine feel? During times of chronic, long-term stress caused by physical exertion or illness, glutamine levels in your body can drop by 50% or more.398 Supplementing with L-glutamine can improve your quality of life, increase energy levels, reduce muscle aches, improve digestion and gut health, improve quality of sleep, and reduce pain and fatigue. When you balance L-glutamine levels in your brain, you feel relaxed and calm. Cravings for sugar and alcohol will decline. L-glutamine will help in recovery from workouts and improve performance. You may find it easier to lose weight. 193 David Tomen Many neurohackers use L-glutamine to help heal Leaky Gut Syndrome and reduce the symptoms of Crohn’s and Celiac Disease. As a nootropic, L-glutamine can help improve alertness, concentration, focus, memory and mood.

The Research L-glutamine was identified as a neurotransmitter several decades ago. And there has been a lot of research on L-glutamine published since. But most of it is focused on strength training and maintaining muscle mass in athletes. And for people healing from surgery or recovering from illness. But L-glutamine can be a powerful nootropic as well. Here are a couple of studies looking at L-glutamine for brain health.

L-glutamine Increases Human Growth Hormone Bodybuilders and athletes use supplementary L-glutamine to help repair and build muscle. And there are several studies supporting the notion that L- glutamine increases Human Growth Hormone. In one study, researchers worked with 9 healthy subjects and gave them 2 grams of L-glutamine in a cola drink. Blood samples were taken before drinking the cola-spiked drink, then again at 30 mins., 60 and 90 mins. The researchers found that both blood L-glutamine and human growth hor- mone levels were significantly higher than before taking L-glutamine. The team concluded that “a surprisingly small oral L-glutamine load was capable of elevating growth hormone”.399 Human growth hormone and Brain-Derived Neurotrophic Factor (BDNF) are intricately linked. BDNF is involved in Long-Term Potentiation and the encoding of long-term memories.

L-glutamine Improves Cerebral Performance Lack of concentration and poor memory can be improved by supplementing with L-glutamine and Vitamin B3 (niacin). Some of the glutamine in your blood is transformed into glutamic acid in your brain. Glutamic acid functions first as fuel, but it also gets rid of excess ammonia by binding to this cellular toxin and converting it into glutamine. A study in the Netherlands conducted a randomized, double-blind, placebo controlled trial with 42 healthy men and woman aged 40 – 76 years. Subjects received a 5-gram stack containing glycine, L-glutamine and niacin twice daily for 3 weeks. The L-glutamine stack increased Human Growth Hormone a whopping 70% compared to placebo. But surprisingly it wasn’t the growth hormone that improved memory and vigor. It was insulin-like growth factor-I that improved 194 HEAD FIRST memory and vigor. Attributed to the L-Glutamine stack the subjects took for 3 weeks.400

Dosage Notes Most people don’t get enough L-glutamine from food alone. And why adding L-glutamine to your nootropic stack can boost your immune system, improve your ability to fight infection and diseases, and boost cognition. The recommended daily dosage of L-glutamine is 2 to 5 grams per day. Serious power athletes often dose up to 10 grams of L-glutamine per day.

Side Effects L-glutamine is considered very safe when taken in normal recommended doses. Rarely do people report side effects like nausea, vomiting, flatulence, ab- dominal pain, constipation, dry mouth, hemorrhoids, dizziness, depression, skin rashes, insomnia and increased sweating. Remember, the balance between L-glutamine and glutamate (Gln/Gly(GABA) cycle) is critical for optimal health. Some recent research has shown that L-glutamine can stimulate tumor growth. So if you are dealing with any form of cancer you should not use L-glutamine. If you are dealing with cirrhosis of the liver, you should avoid L-glutamine. If you have severe liver disease that includes difficulty thinking or confusion (hepatic encephalopathy), don’t use L-glutamine. If you are allergic or sensitive to Monosodium glutamate (MSG), you may be sensitive to L-glutamine because your body converts it to glutamate. And if you have a severe mental disorder including mania or frequently have seizures you may want to avoid L-glutamine.

Available Forms L-glutamine as a supplement is available in tablets, capsules and powder. The most commonly available form of L-glutamine as a nootropic supple- ment is called “free form” glutamine. Trans-Alanyl or Alanyl-L-glutamine is an amino acid attached to another amino acid which aids in digestion of this supplement. If you are using it to boost athletic performance and speed recovery, both forms of L-glutamine are best taken right before or after a workout. Using it with small meals before or after your workout session can help support your metabolism and weight loss goals. And will assist in muscle building, recovery and maintenance.

Nootropics Expert Recommendation

L-glutamine 2 – 5 grams per day. I recommend using L-glutamine as a nootropic supplement if you’re dealing 195 David Tomen with anxiety or stress. And to calm or keep in check some of the stimulatory ef- fects of some nootropics. Your body does make L-glutamine on its own from glutamate in your brain. But most people do not maintain an adequate supply of L-glutamine in their system. And if you’re dealing with illness, recovery from surgery, strenuous physical activity like working out, Leaky Gut Syndrome, Crohn’s or Celiac Disease, and need some help in recovery, L-glutamine can help. L-glutamine also helps to curb the desire for sugar, carbs and alcohol. I suggest first trying a L-glutamine supplement at a dose of 500 mg. And see how you react. You can safely dose up to 20 grams of L-glutamine per day. But most neurohackers find much lower doses effective for boosting cognition, mood and memory.

196 HEAD FIRST Lion’s Mane

Lion’s Mane Mushroom is known for stimulating Nerve Growth Factor, improving cognition and memory, and relieving depression Lion’s Mane (Hericium erinaceus) is a medicinal mushroom proven to ben- efit the brain, nerves and immune system. Unlike other mushrooms sporting a cap and stem, Lion’s Mane has long, flowing, white tendrils. Resembling a Lion’s Mane. Other names includeMon - key’s Head, Bearded Tooth, Pom Pom Blanc, Hedgehog Mushroom and Satyr’s Beard. This parasitic fungus grows hanging off logs and trees. And is native to North American, Europe and Southeast Asia. In Japan, it’s called yamabushitake or “those who sleep in mountains”. Referring to the Shugendo sect of hermit monks and their long, flowing robes. Known for its powerful effects as a “brain tonic”, Lion’s Mane is said to have been used as a tea for thousands of years by Buddhist monks. To enhance brain power, and heighten their ability to focus during meditation. As a nootropic, Lion’s Mane has been shown to be particularly effective in stimulating Nerve Growth Factor (NGF) in the brain. NGF is produced in the hippocampus throughout life. Modulating cholin- ergic receptors and neuroplasticity.401 And is essential for learning. Nerve Growth Factor are special proteins that function to regenerate neurons. Lion’s Mane contains two unique classes of NGF’s – hericenones and erinacines which easily cross the blood-brain barrier. Lion’s Mane, like other medicinal mushrooms, contain high amounts of the antioxidant beta-glucoxylan and four other polysaccharides and polypeptides. Having a significant impact on enhancing your immune system. And decreasing tumor growth. Lion’s Mane has also been studied in reducing amyloid plaques. These clumps of beta-amyloid proteins block signals between neurons. And are implicated in Alzheimer’s and other neurodegenerative diseases. Lions’ Mane is also used to treat Lyme’s Disease, and digestive tract issues. Here we’re talking about Lion’s Mane Mushroom and its effects on brain health and chemistry.

How does Lion’s Mane Work in the Brain? Lion’s Mane boosts brain health and function in several ways. But two in particular stand out. 1. Lion’s Mane Mushroom stimulates the synthesis of Nerve Growth Factor (NGF). NGF is a protein that plays a major role in the maintenance, survival and regeneration of neurons. NGF is required by your brain to keep neurons strong and healthy. When 197 David Tomen various neurological disorders occur, your brain is unable to produce its own internal source of NGF. In a study done in Kuala Lumpur in 2013, scientists showed that Lion’s Mane extract induced NGF synthesis and promoted neurite outgrowth.402 2. Lion’s Mane is effective in reducing anxiety and depression. Some even call it the “smart mushroom” for its ability to improve cognition, memory and work as an anti-depressant. A study by researchers in Japan worked with 30 women. The female subjects had been complaining about menopause, depression, sleep quality and other issues. The women randomly received Lion’s Mane-laced cookies or a placebo for 4 weeks. The researchers found that Lion’s Mane “has the possibility to reduce depression and anxiety, and these results suggest a different mechanism from NGF-enhancing action of H. erinaceus”. 403

How things go bad Science once believed that the brain could not grow new brain cells. That once our brain developed during childhood, and we reached adulthood, we had all the brain cells we’d ever have. Now we know that neurons can regenerate. But that doesn’t mean they will regenerate. A number of health issues can contribute to neurodegeneration. ↓ Decrease in Nerve Growth Factor = Decrease in Long-Term Potentiation affecting long-term memory404 ↓ Brain cells die and are not replaced ↓ Neuroplasticity declines resulting in poor memory ↓ Neurotransmitters decline resulting in anxiety, poor mood and depression All of these age-related changes are contributing factors to neurodegenerative diseases like Alzheimer’s, Parkinson’s and others. And anxiety, depression and mood disorders affect quality of life.

Lion’s Mane to the rescue At least a dozen peer-reviewed studies have been published on Lion’s Mane benefits to brain health since 1991. Dr. Kawagishi of Japan was first to identify the Nerve Growth Factor properties of Lion’s Mane Mushroom.405 In one double-blind, placebo-controlled trial, researchers in Japan worked with 50 – 80 year men and women. All suffered from mild cognitive impairment. The trial subjects received four 250 mg tablets containing 96% of Yama- bushitake (Lion’s Mane) dry powder three times a day for 16 weeks. The men and women were tested at 4, 8, 12 and 16 weeks. At each of the testing periods, the subjects who had used Lion’s Mane showed a significant improvement in cognitive scores. And their scores were increasing 198 HEAD FIRST while on Lion’s Mane supplementation. But 4 weeks after stopping Lion’s mane supplementation, their cognitive scores decreased significantly. The researchers concluded that Lion’s Mane Mushroom is effective in im- proving mild cognitive impairment.406

How does Lion’s Mane feel? You may not experience the effects of supplementing with Lion’s Mane Mushroom immediately. But many users report with continued use of Lion’s Mane, a boost in mood and mental energy. Some report it increases depth perception. And an improvement in sense of smell. Others testify to improved decision-making, the ability to solve problems and learning. Likely due to Lion’s Mane ability to improve neuroplasticity. The overall consensus is Lion’s Mane Mushroom’s ability to lessen anxiety, reduce depression, and improve concentration.

The Research Lion’s Mane Mushroom has been used as a food and since ancient times in East Asia. And it has been reported in scientific research that Lion’s Mane promotes Nerve Growth Factor both in the petri dish as well as in animal and human test subjects.

Lion’s Mane Prevents Cognitive Dysfunction In this study, researchers examined the effects of Lion’s Mane on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Amyloid β(25- 35) peptide is implicated in diseases like Alzheimer’s. Mice were injected with the peptide on days 7 and 14 of the trial. And they were fed a diet containing Lion’s Mane over 23-days of the experiment. The results showed that Lion’s Mane prevented short-term and visual recognition memory induced by amyloid β(25-35) peptide. They concluded that Lion’s Mane Mushroom “may be useful in the preven- tion of cognitive dysfunction”.407

Lion’s Mane Induces Nerve Growth Factor In this trial, mice were fed Lion’s Mane 5% freeze-dried powdered extract for 7 days. Researchers found an increase in the level of Nerve Growth Factor (NGF) in the hippocampus of the mice. Concluding that Lion’s Mane “contains active compounds that stimulate NGF synthesis”.408

Lion’s Mane Repairs Nerves This study done with rats, Lion’s Mane extract was able to promote neuron regrowth after injury. Rats with gluteal nerve damage were able to walk again after consuming water containing Lion’s Mane extract. 199 David Tomen The researchers concluded that Lion’s Mane regenerates damaged nerve cells. In this case, the reversal was so profound, the rats went from being totally disabled to walking again.410

Dosage Notes Dosing of Lion’s Mane Mushroom depends on the strength of the extract. It’s available in capsule or powder form. For Lion’s Mane 10:1 extract (30% polysaccharide), daily dosage is 500 – 1,000 mg taken 1 to 3 times per day. Other retail extract dosages of Lion’s Mane ranges from 300 mg to 3000 mg dosed 1 – 3 times per day. Check the label and see what the manufacturer recommends. And when first using the supplement, start with the lowest dose and see how your body reacts.

Side Effects Lion’s Mane Mushroom is non-toxic and considered very safe. So there are very few side effects reported. Some neurohackers report itchy skin from higher doses. Likely attributable to a boost in Nerve Growth Factor. Lion’s Mane has been tested in animals showing no side effects or toxicity even up to 5 grams per kilogram.

Available Forms Lion’s Mane Mushroom (Hericium erinaceus) as a supplement is usually offered as an extract. In powdered form, or in a capsule. Supplement makers of nootropic stacks sometime include Lion’s Mane as well. For example, MindLab Pro includes 500 mg of the full fruit extract in their formula. Each formula will be different depending on synergy with the stack, and type of extract used. When choosing a Lion’s Mane supplement, there’s debate over the best form of extraction to achieve the mushroom’s full medicinal benefit. Some say your best option is a hot water extraction. Another says alcohol extraction. Another claims both are necessary. But when it comes to mushrooms, saying that one is “more potent” than another is just too simplified to be true. This is as much an art as it is science. Look at the manufacturer’s literature and marketing material. And read the reviews on shopping sites as well as forums. And find out what works best for you. Types of Lion’s Mane available: • Plain Lion’s Mane: Pure, powdered mushroom. Often freeze-dried, and the cheapest form available. Can be added to water, juice or smoothies. • Lion’s Mane Extracts: A more potent form of mushroom. Often presented 200 HEAD FIRST as 14:1 or 10:1 extracts (14 pounds or 10 pounds reduced to 1 pound of extract). • Standardized Lion’s Mane: Processed to provide exact levels of active ingredients. You can get Lion’s Mane standardized to 30% and 50% polysaccharides (the active hericenones and erinacines are metabolites of polysaccharides). • Lion’s Mane tea: Since this is a popular mushroom in the kitchen, the taste is acceptable. But it’s hard to get a handle on how much actual active ingredient you’re getting. • Amycenone®/PLM-Fraction: This “branded” product is standardized to Hericenones 0.5%, Amyloban 6%. It seems to target a lesser-known Lion’s Mane active ingredient–Amyloban–which is positioned as a mushroom compound that fights beta-amyloid proteins. Originating in Japan, it is extremely expensive, and may be found in a supplement called Amyloban®3399. And if you decide to pick your own, before consuming any wild mushroom, make sure that it is accurately identified. Mushroom poisoning is a real problem if you pick the wrong one. For a full list of Mycology societies that may be able to help you, go to the North American Mycological Association website (www.namyco.org).

Nootropics Expert Recommendation

Lion’s Mane 300 to 3,000 mg per day I recommend using Lion’s Mane as a nootropic supplement. Your body does not make Lion’s Mane on its own. So you need to take it as a supplement. Lion’s Mane is especially helpful for regenerating brain cells. It prevents neurodegenerative diseases like Alzheimer’s and Parkinson’s. And it boosts long-term potentiation for memory and mental sharpness. By stimulating Nerve Growth Factor. Lion’s Mane also helps boost mood, tame anxiety and relieve depression. For a better quality of life. I suggest starting with a dose of 500 mg daily. The best human study used 750 mg per day. But another researcher found lower concentrations may stimu- late NGF better than higher concentrations.411 Start at 500 mg per day and see how it works for you. If you don’t experience a benefit, boost Lion’s Mane in small increments of 250 mg per day until you notice an improvement. Lion’s Mane is a great compliment to a nootropic stack including Anirace- tam, Alpha GPC and Omega-3’s for an immediate cognitive boost. 201 David Tomen L-Theanine L-Theanine is known for boosting alpha and theta brain waves, anti-anxiety, boost- ing cognition, improving memory, and better quality sleep L-Theanine (r-glutamylethylamide) is a non-dietary amino acid found in tea. And especially high levels in green tea (camellia sinensis). L-Theanine was first isolated from green tea in Japan by Sakato in 1949. As an analogue of glutamate and glutamine, it’s hydrolyzed in your intestine and liver into l-glutamate and ethylamine. And easily crosses your blood-brain barrier. L-Theanine is one of the very few nootropics known to modulate brain waves. It affects alpha brain waves which are associated with relaxation. Provid- ing an alert calmness, L-Theanine helps in promoting super-learning, flow states and joy. L-Theanine boosts the neurotransmitters serotonin, dopamine and GABA in your brain. As well as increasing Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF).412 L-Theanine is known for helping to relieve stress, improve cognition, boost mood and cognitive function.

How does L-Theanine Work in the Brain? L-Theanine boosts brain health and function in several ways. But two in particular stand out. 1. L-Theanine reduces physical and mental stress. L – Theanine helps in- crease alpha brain waves which are associated with mental relaxation and concentration. One study in South Korea worked with 20 healthy male volunteers aged 18 – 30 years. One group was given L-Theanine tablets, and the other group a placebo daily for 7 days. Brain waves were measured 40 minutes after administration of the tablets. The researchers analyzed alpha wave power values. And concluded that L-The- anine tablets promoted the release of alpha brain waves related to mental relaxation and concentration.413 In May 2016, researchers at Simon Fraser University in Canada developed a technology to clinically measure brain wave patterns. With this technology, we’re now able to detect cognitive dysfunction before it happens. Imagine the implications of this new technology when applied to the nootropics world.414 2. L-Theanine increases neurotransmitters. Research shows that L-Theanine increases dopamine, serotonin, and GABA in your brain.415 And it reduces the excitatory neurotransmitter glutamate which is associated with stress, tension and agitation.416 202 HEAD FIRST A study done in Japan worked with 12 people who underwent 4 separate trials. One in which they took L-Theanine at the start of the experiment. One in which they took it half-way through. And two control trials in which they took either a placebo or nothing. The results showed that L-Theanine resulted in a reduction in heart rate and s-IgA associated with acute stress. The researchers concluded that L-Theanine could cause anti-stress effects via the inhibition of cortical neuron excitation.417

How things go bad: As we get older, our brain chemistry and energy metabolism changes. ↓ Neurotransmitter levels decline ↓ Glutamate levels increase ↓ Stress levels increase ↓ Long-term memory and mood decline ↓ Quality of sleep declines All of these changes can happen at any age once we reach adulthood. And are contributing factors to the neurodegenerative diseases of aging, and quality of life.

L-Theanine to the rescue L-Theanine energizes without draining, calms without putting you to sleep, and motivates without causing a jagged edge. Tea (as a source of L-Theanine) can have as much caffeine as some coffees. And yet doesn’t exert the same “speedy” effect. And the reason is the ingredient L-Theanine. You can actually see L-Theanine’s effect in your brain using an EEG. Brain waves are smoothed out rather than flattened out.418 So your body is relaxed, your mind is calmed, but you don’t get sleepy. And L-Theanine, once it crosses the blood-brain barrier, raises levels of serotonin and dopamine.419 L-Theanine even improves your quality of sleep. Researchers in Japan gave volunteers 200 mg of L-Theanine daily and recorded their sleep patterns. Sleep quality, recovery from exhaustion, and feeling refreshed were all enhanced by L-Theanine.420 And L-Theanine puts you in a better mood. Once it crosses your blood-brain barrier, L-Theanine changes levels of amino acids affecting serotonin, dopamine, and GABA. Having a modulating effect on mood.421

How does L-Theanine feel? Your unique neurochemistry including neurotransmitters, brain waves, brain structure and even regional brain activity will influence your response to L-Theanine. Most neurohackers report a calming effect within 30 – 45 minutes of taking 203 David Tomen L-Theanine. Cognition gets a boost, and energy levels rise without the jitteriness caused by stimulants like caffeine. Some report L-Theanine has stopped their anxiety and panic attacks. Just don’t combine it with anti-anxiety meds like Xanax. Most report an overall improvement in the sense of well-being and quality of life. And nearly all remark on better quality sleep.

The Research

Green Tea reduces incidence of stroke Research has found that if L-Theanine is present in the body at the time stroke occurs, brain damage will be significantly reduced. In this monster study done in China, researchers selected 14,212 subjects from 12 provinces. Ages ranged from 35 – 60 years old. The study looked at tea drinking status, dose and type of teas. This study concluded there was a 40% decreased risk of stroke in those who drank green, black or jasmine teas.422

L-Theanine improves memory In this double-blind, placebo-controlled study, the effect of L-Theanine on memory and attention was investigated. 91 subjects with mild cognitive impairment were enrolled in this study. One group received 1,680 mg of L-Theanine daily for 16 weeks. And the control group received a placebo. The study concluded that L-Theanine increased brain Theta waves associated with cognitive alertness and creativity. And there were improvements in memory. The results of this study suggested thatL-Theanine has potential as an intervention for cognitive improvement.423 And that is an understatement by any stretch. People spend years meditating. With the goal of reaching consistent access to brain wave states like Theta. In this trial, they did it with a dose of L-Theanine. The same type of dose you could get with a few cups of quality green tea.

L-Theanine reduces stress Considerable research has been dedicated to L-Theanine and its benefits to stress reduction in both animal and human studies. And we have ample documen- tation that corticosterone and stress exert negative effects on memory.424 Corticosteroids which are secreted after stress, have a profound impact on long- term potentiation and memory formation.425 In this animal study, rats were fed water containing L-Theanine for 3 weeks and put through some stress inducing exercise. The researchers found that corti- costerone levels were lower in the rats who used L-Theanine compared to those who had none. 204 HEAD FIRST In fact, stress had no effect on the animals who were fed L-Theanine. Memory was not affected. The researchers concluded that L-Theanine modified corticoste- rone secretion. And L-Theanine is a strong preventive measure in preventing memory loss otherwise induced by stress.426

Dosage Notes Recommended dosage of L-Theanine is 200 – 400 mg once or twice per day. With a maximum of 1,200 mg per day according to the Cleveland Clinic.427 L-Theanine is water soluble so you can take it with water. Labels on quality green tea often only display the amount of green tea leaf available in each bag in milligrams (mg). But not it’s L-Theanine content. Green tea that’s steeped correctly will offer 1-2% L-Theanine per cup. So 1,500 mg of green tea leaf would be about 30 mg. of L-Theanine (at 2%). We often say that YMMV, and this is especially applicable to L-Theanine. Find out what works best for you. Start at a lower dose like 100 mg. And work your way up until you achieve the effects you’re looking for.

Side Effects L-Theanine is a naturally occurring amino acid found in plants like tea or one species of mushroom. So it’s considered non-toxic and very safe. Theanine seems to decrease blood pressure. So if you’re on meds for high blood pressure, use L-Theanine with caution. Your blood pressure could go too low.

Available Forms L-Theanine is available in green, black and white teas. Green tea contains the most L-Theanine. A great side benefit for neurohackers is green tea also contains caffeine. A cup of good quality green tea has less caffeine than a cup of coffee. About 10 mg less.

L-Theanine + Caffeine stack One study done at Unilever in the UK looked at the combined effects of L-Theanine and caffeine on cognitive performance and mood. They compared 50 mg of caffeine with and without 100 mg of L-Theanine. The research team had 27 volunteers participate. And based measurements on word recognition, rapid visual information processing, critical flicker fusion threshold, attention switching and mood. Performance was measured at the beginning, and again 60 minutes and 90 minutes after consumption. Separated by a 7-day washout period. Caffeine improved alertness at 60 mins. And accuracy on attention-switching at 90 mins. The L-Theanine and caffeine combination improved both speed and accuracy, and reduced susceptibility to distracting information on the memory task. 205 David Tomen The research team concluded that, “L-Theanine and caffeine in combination are beneficial for improving performance on cognitively demanding tasks”.428 And for an added bonus, L-Theanine takes the jittery-edge off of caffeine consumption.

L-Theanine from green tea Extracting the optimal amount of L-Theanine from green tea is both art and science. Researchers at the University of Newcastle in Australia set out to determine optimal conditions for water extraction of L-Theanine from green tea. They examined 4 different extraction methods. And learned that temperature, extrac- tion time, ration of water-to-tea and tea particle size had significant impacts on extraction yield of L-Theanine from green tea. They concluded, “The optimal conditions for extracting theanine from green tea using water were found to be extraction at 80 °C for 30 min with a water-to-tea ratio of 20:1 mL/g and a tea particle size of 0.5-1 mm.” 429 So to get the most nootropic value when using green tea as your L-Theanine source – follow the directions. Just sayin’…

L-Theanine Supplements L-Theanine is available in capsule or tablet form from several supplement manufacturers. Japanese company Taiyo is the oldest and most established company in the green tea supplement industry. Taiyo developed and patented a method for L-Theanine extraction from green tea called ‘Suntheanine®’. Suntheanine is included as the L-Theanine source from several large supple- ment makers including Mind Lab Pro. And if it has Suntheanine on the label, you are assured that the amount of L-Theanine listed is the actual amount in each capsule. Research has shown that some supplement makers using their own extrac- tion method for L-Theanine, contain more than just the “L” form of Theanine. Turns out if it’s not done exactly right, you end up with a “D” form of Theanine. D-Theanine may have a very different action in your body than L-Theanine. We’re not saying it’s dangerous. You just may not get all the benefit of pure L-Theanine. So read the labels and reviews by people who have tried the product. With a little experimentation you’ll find a L-Theanine supplement that works for you.

Nootropics Expert Recommendation

L-Theanine 250 – 500 mg per day I recommend using L-Theanine as a nootropic supplement. Your body cannot make L-Theanine on its own. It’s a non-dietary amino acid only available from tea (and one little-known mushroom). 206 HEAD FIRST L-Theanine affects Alpha and Theta brain waves. This alone will help calm your mind, reduce stress, and help you stay alert. You’ll get even more cognitive benefit by stacking L-Theanine with caffeine. L-Theanine helps boosts the neurotransmitters dopamine, serotonin, and GABA. Improving alertness and attention. And boosting cognition and memory. And it reduces the excitatory neurotransmitter glutamate which is associated with stress, tension and agitation. L-Theanine helps to prevent strokes, and even reduces the damaging effects if you’ve had a stroke. And L-Theanine has been shown to improve sleep quality. I suggest starting with a dose of 100 – 250 mg of L-Theanine daily for noot- ropic use. Using either a quality supplement, or high quality green tea.

207 David Tomen Magnesium

Magnesium improves cognition, memory, learning, recall, reduces brain fog, is an antioxidant, helps neuroplasticity, and protects against glutamate-toxicity Magnesium is the 4th most abundant mineral in your body. And critical for optimal cognitive health. It is a cofactor in more than 300 enzymatic reactions in your body. 430 But many of us in Western society are living with a magnesium deficiency. And most are unaware of this deficiency. Magnesium in our diet comes from foods like green leafy vegetables, beans, nuts, seeds, whole grains, poultry, beef, and salmon. Tap, mineral and bottled water also used to be good sources of magnesium. But varies by brand, source and if the magnesium has been filtered out during processing. Magnesium assists in converting energy supplied by food to a useable form to produce adenosine triphosphate (ATP). The primary fuel source for your mitochondria. Magnesium is also needed for the synthesis of RNA and DNA.431 In your brain, magnesium regulates the activity in neuron ion channels. These channels are like tiny electrical switches. Governing the flow of neurotransmitters within neurons. Magnesium also regulates brain synaptic plasticity. Which is critical for learning and memory. Magnesium is critical to all of your body’s electrical and electrochemical activities. It’s involved in muscle contractions, heart rhythm, nerve function and brain cell activity. Low blood magnesium levels show up as seizures, hypertension, stroke, mi- graines, and ADHD. It can also result in insulin resistance and type II diabetes. Magnesium is an essential part of neuroplasticity. Brain plasticity is the ability of your neurons to make cell-to-cell connections to form and regulate learning and memory. With aging, or insufficient magnesium in our diet, we lose brain plasticity which results in a loss of cognitive function.432 This is why a young person, with an active, flexible brain easily catches new ideas. And simply thinks faster than a person whose brain has lost plasticity and is more fixed in their patterns. Magnesium is even involved in how the other nootropics in your stack are utilized by cells in your brain. The bottom-line is magnesium could be one of the most important additions to any nootropic stack.

How does Magnesium Work in the Brain? Magnesium boosts brain health and function in several ways. But two in particular stand out. 1. Magnesium is critical for neuroplasticity. Your brain is capable of forming 208 HEAD FIRST new connections between neurons. When you take in new information, a signal is sent across the synaptic space between neurons. The ability of your brain to form these new connections is referred to as neuroplasticity. This neuroplasticity is how learning and memories are formed. When these signaling pathways break down, memories fade. And you start to forget simple things like people’s names or phone numbers. A simple example of how this works is reading this article. As you read this, your brain is forming and reforming new neural connections. When things aren’t optimal, you find yourself reading and re-reading sentences. Magnesium is critical for maintaining this neuroplasticity. And your abil- ity to learn and form memories. Magnesium ions control the ion channels, or electrical switches for this signaling.433 The more signals that these ion channels transmit, the stronger the connec- tions between neurons. And the stronger the formation of the resulting memory. Many studies demonstrate the detrimental impact of insufficient magnesium on optimal cognitive function.434 2. Magnesium is required for ATP synthesis. ATP (adenosine triphosphate) is the main energy source for the mitochondria in brain cells. 20% of your body’s total ATP is located in your brain. For ATP to be biologically active, it must be bound to a magnesium ion (Mg- ATP). 435 About two thirds of your brain’s energy budget is used to help neurons send signals to neighboring neurons. The remaining third is used for housekeep- ing, or cellular maintenance. Wei Chen, a radiologist at the University of Minnesota Medical School was co-author of a study on the brain’s use of ATP. The team used magnetic resonance spectroscopy (MRS) to measure the brain’s energy production during shifts in activity. Their study on lab rats noted that when the rats were knocked out, they produced 50% fewer ATP molecules than when mildly anesthetized. Chen noted that the ATP produced when the brain is inactive goes to cell maintenance.436 This housekeeping is important for keeping the brain tissue alive. The other two thirds are needed for other cellular processes including re- charging neurons so they can fire. And create the electrical signals needed for neuron communication. Required for learning, memory, recall and cognition. Without magnesium, your brain cannot produce ATP, and all brain function breaks down.

How things go bad As we get older, our brain chemistry and metabolism changes. ↓ ATP levels decline in mitochondria 209 David Tomen ↓ Cognition, learning, memory and recall decline ↓ Brain cell plasticity declines ↓ Free radicals damage brain cell mitochondria All of these changes can happen at any age. And can be a result of not getting an adequate supply of magnesium. So magnesium supplementation can help for age-related cognitive decline, as well as anyone who wants to boost cognition, learning, recall and memory.

Magnesium to the rescue Magnesium plays a critical role in supporting neuroplasticity which is fun- damental for a youthful, flexible brain. A brain that is optimized to support cognition, learning and memory. Raising brain magnesium levels has been proven to restore neuroplasticity and improve cognitive function.437 Magnesium deficiency has been associated with Alzheimer’s Disease. Scien- tists have found that treatment with magnesium-L-threonate decreases β-amyloid deposits in the brain. And is able to rebuild signaling pathways in neurons help- ing to restore memory.438 And magnesium is required for ATP synthesis in brain cells. Providing the mental energy needed for cognition, memory, recall and learning.439

How does Magnesium feel? Most neurohackers report an increased level of focus, energy, memory, and cognitive ability when supplementing with magnesium. You should also experience an improved quality of sleep. And have an overall improvement in mood.

The Research One of most common reasons we use nootropics is to boost memory and mental energy. Memory loss drastically reduces quality of life. And simple brain fog makes it difficult to accomplish the simplest of tasks. Research has shown that magnesium is involved in memory, learning and cognition on several levels. And supplementing with magnesium is one of the most fundamental things you can do to boost cognition.

Magnesium improves long-term memory Synapses in the hippocampus and other areas of the brain strengthen the more they’re used. Even brief repetitive activity results in a substantial increase in synaptic strength. The results can last for several hours. Or even weeks afterwards. This is called ‘long-term potentiation’.440 Several studies have been conducted on magnesium supplementation and its effects on memory in the last 20 years. With positive results. This study on aged and young rats found that adding magnesium to their food improved learning.441 210 HEAD FIRST Magnesium relieves depression Researchers have found magnesium works in the hippocampus to suppress the release of the stress hormone ACTH (adrenocorticotrophic hormone). This is the hormone that tells your adrenal glands to release more cortisol and adrenaline. Too much cortisol eventually damages the hippocampus in the brain. This causes a negative feedback loop which results in even more stress. Which is toxic to the brain and your entire body. And one of the causes of chronic depression. A study was done with 5,708 people aged 46-49 and 70-74 years old in Norway. The aim of the study was to examine the association between magne- sium intake and depression and anxiety. The researchers concluded that low magnesium intake is related to depres- sion. And they stated, “These findings may have public health and treatment implications.”442 Another study done with 12 subjects found that magnesium supplementa- tion improved sleep and lowered the stress hormone cortisol. Concluding that mag- nesium has “possible efficacy… as a mood stabilizer”.443

Magnesium may relieve symptoms of ADHD Magnesium in the treatment of ADHD is becoming more mainstream. And there is a growing body of research that supports the idea that one of the factors causing ADHD is a lack of magnesium. A study in Poland showed that 95% of the children examined with ADD or ADHD were magnesium deficient.444

Dosage Notes Recommended magnesium dosage in most common forms is 400 mg per day. But the problem is most magnesium supplements don’t work well as a nootropic. Because they don’t cross the blood-brain barrier. Research begun at MIT by Dr. Inna Slutsky came up with a new magnesium supplement called Magnesium-L-threonate (MgT). This new magnesium com- pound easily crosses the blood-brain barrier.445 This form of magnesium was patented and now produced by MagteinTM Science. Several supplement companies sell magnesium with this branded form. Recommended dose of Magnesium-L-threonate is 1 gram per day. Magnesium is water-soluble so you don’t need to take it with a meal, or a healthy fat like you do with some nootropics.

Side Effects Most forms of magnesium can cause diarrhea and bloating. Magnesium- l-threonate contains less elemental magnesium per dose and should not cause gastrointestinal upset. 211 David Tomen Available Forms Magnesium is sold as magnesium aspartate, citrate, lactate, chloride and magnesium L-threonate. Depending on the type of magnesium; it comes in capsules, chewable tablets, powder, extended release tablets, or in a liquid solution. A more bioavailable form of magnesium is now available. Magnesium-l- threonate (MgT) is patented and is called MagteinTM. Magnesium-l-threonate easily crosses the blood-brain barrier. And is recom- mended if you’re adding magnesium to your stack.

Nootropics Expert Recommendation

Magnesium-L-threonate 1 gram per day I recommend using Magnesium-L-threonate as a nootropic supplement. Your body does not make Magnesium on its own. So to get its benefits it needs to come from your diet. Or you must take it as a supplement. Magnesium is especially helpful for boosting memory, learning, recall, mood and cognition. Magnesium is also particularly useful to help alleviate some of the symptoms of ADHD. And to help restore memory caused by neurodegenerative disease like Alzheimer’s. While most forms of magnesium are helpful for overall health, most are not very helpful for cognitive health. I recommend Magnesium-L-threonate (MgT). MgT has been proven in the lab to easily cross the blood-brain barrier. And to boost cognition. Magnesium-L-threonate is a fast-acting nootropic that can also help prevent brain degeneration later in life.

212 HEAD FIRST Melatonin

Melatonin is known for helping insomnia, is a powerful antioxidant and anti- inflammatory, protects against neurodegenerative diseases, stroke and brain trauma Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced in your pineal gland. Melatonin is often referred to as the “sleep hormone”. As your body’s central clock, melatonin tells your body, brain and organs when to be active and when to take a break and rest. Your pineal gland is a pea-sized organ located in the center of your brain and shaped like a tiny pine cone (hence its name). Your pineal gland is filled with cells that respond to light and darkness. Many Eastern traditions refer to the pineal gland as the “third eye” for this reason. Your pineal gland acts as your body’s central clock through its secretion of melatonin. Telling your brain, body and organs when it’s time to be active and when it’s time to rest. This is the reason why melatonin is referred to as the “sleep hormone”. Melatonin and the neurotransmitter serotonin are both derived from the amino acid L-tryptophan. First L-tryptophan is hydroxylated by the enzyme tryptophan hydroxylase. The intermediate is decarboxylated by PLP and 5-hydroxy- L-tryptophan (5-HTP) to produce serotonin (5-HT or 5-hydroxytryptamine). Serotonin acts as a neurotransmitter on its own. But is also converted into N-acetyl-serotonin by the enzymes serotonin N-acetyl transferase and Acetyl-CoA. Hydroxyindole O-methyl transferase and SAMe convert N-acetyl-serotonin into melatonin through methylation of the hydroxyl group.446 This process is first fueled by the tryptophan you get from foods like turkey, chicken, tuna, oats, bananas, peanuts and chocolate. Or from a L-tryptophan supplement. You can also supplement with 5-HTP to produce serotonin which will create melatonin. Or supplement with SAMe to produce melatonin. Or you can take a melatonin supplement on its own and bypass this entire process. Besides acting as your body’s biological clock, melatonin is also a potent free- radical scavenger. And a wide-spectrum antioxidant. The beauty of melatonin as an antioxidant is its ability to easily cross the blood-brain barrier. Age-related decline in melatonin levels is a primary contributing factor to several neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS, Hun- tington’s Disease, stroke and brain trauma.447 Adding melatonin to your nootropic stack gives you a head-start in protect- ing yourself against Alzheimer’s and Parkinson’s Disease, decreases your chance of stroke, and helps reverse the brain damage caused by stroke or brain injury. The bonus is a good night’s sleep and feeling refreshed the next day. With your brain firing on all cylinders. 213 David Tomen How does Melatonin work in the Brain? Melatonin helps brain health and function in several ways. But two in par- ticular stand out. 1. Melatonin promotes quality sleep. Your pineal gland acts as your body’s central clock by secreting melatonin. This action tells your brain and other organs when it’s time to be active, and when it’s time to rest. Melatonin helps regulate other hormones and maintains your body’s circadian rhythm.448 Your pineal gland responds to darkness by producing melatonin. Blood levels of melatonin are low during the day, with peak levels occurring from 2 – 4 AM.449 One study at Duke University Hospital surveyed clinical trials from 1948 – 2009. Researchers found that children with ADHD using melatonin doses of 3 – 6 mg showed improvement in how fast the kids went to sleep. And significantly better quality of sleep.450 Another extensive survey of clinical trials was conducted by the U.S. Depart- ment of Health and Human Services on melatonin use for sleep disorders. The overall conclusion of this research showed melatonin effective in improv- ing quality of sleep and how fast a person went to sleep. This study included those who did not suffer with insomnia, those who did, and others who had messed up circadian rhythm patterns due to shift work and jet lag.451 2. Melatonin prevents neurodegenerative disease. Melatonin improves longevity by increasing the longevity gene called SIRT1. This gene plays an important role in maintaining metabolism and neuroplasticity.452 Melatonin is a powerful antioxidant protecting your brain from free radicals and oxidative damage. It stimulates gene expression of intracellular antioxidant systems. And melatonin helps relieve the free radical damage that occurs after traumatic brain injury or stroke.453 Research has found that melatonin levels and Alzheimer’s Disease are closely linked. Greatly reduced melatonin levels have been found in Alzheimer’s patients.454 High levels of melatonin are maintained throughout your youth and middle age. But as you age and melatonin levels drop, you are at greater risk for brain damage both now and in the future. Your chances of having a stroke greatly increase as melatonin levels decline.455

How things go bad Low Melatonin levels are associated with a variety of health problems. Much more than just insomnia. ↑ Insomnia, restlessness and poor sleep quality (sundowning) ↓ Circadian rhythm goes out of sync 214 HEAD FIRST ↑ Agitation and activity increases later in the day (sundowning) ↓ Benzodiazepines like Valium® and Xanax® suppress melatonin levels456 ↑ Stroke risk increases Melatonin deficiency is one of the earliest indicators of Alzheimer’s Dis- ease.457 Abnormal oxidation and inflammatory protein accumulation can lead to Parkinson’s Disease. And is associated with low levels of melatonin in the brain. Low levels of melatonin lead to increased free radical production and risk of stroke goes up. Oxidative damage to brain cells is a leading culprit in traumatic brain injury.

Melatonin to the rescue Melatonin is both a neurotransmitter and hormone. This ‘neurohormone’ is produced in your pineal gland from the neurotransmitter serotonin with the assistance of SAMe and other enzymes. Melatonin is the mechanism used by your pineal gland to function as your body’s biological “clock”. And is in charge of the “circadian rhythm” that tells your system when to be active, and when to rest. As a nootropic supplement and sleep aid, melatonin exerts its effects by acting as a ‘phase re-setter’ rather than as a hypnotic-type drug. Supplementing with inexpensive melatonin helps restore your body’s natural antioxidant protection. Guarding against age-related changes in your brain. Melatonin protects cholinergic neurons from the amyloid and tau protein buildups related to Alzheimer’s Disease. Melatonin offers potent antioxidant protection for your brain. Supplement- ing with melatonin helps protect your brain against neurodegenerative disease, reduces stroke risk and guards against brain trauma.

How does Melatonin feel? I use melatonin every night to help me sleep. I open and empty 3 mg of a Now Foods 5 mg melatonin capsule in about 4 oz. of tart cherry juice. And take it 90 minutes before bedtime. Sleep comes on within 5 minutes of hitting the pillow. And I sleep through the night. But melatonin as a sleep aid has mixed reviews among neurohackers. And for good reason. Melatonin is a hormone that your body naturally produces from serotonin. Too much melatonin is not good. Some find that supplementing with melatonin works well, and others find it disrupts sleep patterns. If you are perfectly healthy and do not deal with insomnia on a regular basis, you don’t need to supplement with melatonin. Everyone’s body chemistry is unique. Some find that a ½ mg of melatonin works well. And others require 5 mg. Experimentation is key with this hormone. Some have found that melatonin helps regulate disrupted circadian rhythms caused by jet lag or night shift work. 215 David Tomen The Research

Melatonin Lowers Cholesterol Melatonin levels decrease as we age, and the possibility of heart disease increases. And studies in the last 10 years show that melatonin and your cardio- vascular system are linked. Patients with cardiovascular disease have decreased melatonin levels. Studies also show that people with heart disease have high levels of LDL- cholesterol. Research has found that supplemental melatonin decreases choles- terol by 38%. And reduces LDL accumulation by 42%. One study demonstrated that just 1 mg of melatonin reduced blood pres- sure within 90 minutes of supplementation. Melatonin reduces blood pressure through its antioxidant properties, by decreasing norepinephrine and epineph- rine, and relaxing the smooth muscle of the heart aorta wall.458

Melatonin Helps Reduce Insomnia Studies show that sleep disorders affect 50 – 70 million Americans, or about 20% of the population. A sleep disorder exists whenever a lower quality of sleep results in impaired functioning, or excessive sleepiness. Insomnia is the most common sleep disorder affecting 6 – 12% of the adult population. A double-blind placebo-controlled study in France worked with 244 adults with primary insomnia. Patients received prolonged-release melatonin nightly for up to 12 months of the trial, followed by a 2-week withdrawal period. Outcome was measured based on the patient’s sleep diary, adverse events, vital signs and lab tests recorded at each visit. The study concluded that pro- longed-release melatonin was helpful in relieving insomnia during the trial. And patients did not experience any adverse events or withdrawal symptoms when they stopped using melatonin.459

Melatonin Relieves Mild Cognitive Impairment Mild cognitive impairment (MCI) is often the final step before dementia. Approximately 12% of MCI patients convert to Alzheimer’s Disease or other dementia disorders every year. Researchers in Argentina took a look at the first and final assessment of 50 MCI patients, 25 of whom had received a daily dose of 3-9 mg of melatonin at bedtime for 9 – 18 months. Patients who took melatonin showed significantly better performance in the mini Mental State examination and the cognitive test used to assess Alzheimer’s. The team conducted several other tests and found better performance in every test but one. The researchers concluded that melatonin can be a useful drug for treating mild cognitive impairment.460 216 HEAD FIRST Melatonin Replaces Benzos for Sleep Many people use benzodiazepines for sleep. Drugs like Xanax®, Valium® and Ativan® all have nasty side effects. And studies going back 25 years show benzos depress natural melatonin levels.461 This is a problem because drugs taken for sleep are depleting the very hor- mone your body uses for sleep. To make matters worse, regular benzodiazepine use is now recognized as putting you at greater risk for dementia.462 This study done in Argentine had subjects use fast release melatonin 3 – 9 mg daily for 3 years just before bedtime. And it significantly improved cognitive and emotional performance. Including the daily sleep-awake cycles of patients. A follow up study was done with 91 MCI patients. 61 patients received 3 – 24 mg of fast release melatonin at bedtime for 15 to 60 months. Patients given melatonin showed significantly better cognitive performance and every other parameter tested. Depression scores in the patients also decreased. And showed an improve- ment in quality of sleep and wakefulness. Before the study began, 62.8% of the patients were using benzodiazepines to help them sleep. At the conclusion of the study only 9.8% were using benzos to help them sleep along with melatonin.463 My recommendation is if you are using one of these drugs for sleep, it would be wise to start using melatonin instead. And start weaning yourself off the benzos.

Dosage Notes Unlike all the other nootropics we talk about on Nootropics Expert, and in this book, there is no recommended dosage for melatonin supplementation. Everyone has different responses to its effects. Lower doses like ½ mg of melatonin work well for some who are especially sensitive. And higher doses can cause anxiety and irritability. The best approach is to start with very low doses of melatonin (i.e. ½ mg) and see how your body reacts. The right dose should produce a restful night’s sleep with no irritability or fatigue the next day. For jet lag: ½ – 5 mg of melatonin an hour before bedtime at your final destination.

Side Effects Melatonin is considered very safe when taken in normal recommended low doses. Some may experience nightmares or vivid dreams when supplementing with melatonin. Melatonin can cause drowsiness if taken during the day. And if you experi- 217 David Tomen ence a “sleep hangover” the next day, you took too much melatonin the night before. Other side effects include abdominal cramps, dizziness, headache, irritabil- ity, decreased libido, breast enlargement in men and reduced sperm count. Melatonin can interfere with fertility if you’re trying to get pregnant. Do not use melatonin while you’re pregnant. Melatonin can worsen symptoms of depression. So if you’re dealing with depression, or are using antidepressant medications you should avoid melatonin. Remember that melatonin is a hormone. So if you have hormone-related issues you must be careful about using melatonin. Melatonin may increase the risk of bleeding and should be avoided if you’re taking anticoagulant medications. Or are anticipating surgery. Melatonin can interfere with steroids and immunosuppressant medications and cause them to lose their effectiveness.

Available Forms Melatonin is available in capsules, tablets and liquid. Capsules and tablets usually range from 1 – 5 mg.

Nootropics Expert Recommendation

Melatonin 1 – 3 mg per day. I recommend using melatonin as a nootropic supplement. Your body does make melatonin on its own from serotonin in your brain. Most healthy people have an adequate supply of melatonin. But if you’re dealing with insomnia and need some extra help in getting to sleep and staying asleep, melatonin can help. Melatonin easily crosses the blood-brain barrier, and takes effect in about 90 minutes. Avoid taking melatonin immediately before bed because you may have trouble falling asleep. Melatonin is especially helpful to those dealing with jet lag or shift work that has you working nights. Disrupted natural circadian rhythms can be normalized by supplementing with melatonin. I suggest first trying a melatonin supplement at a dose of ½ – 1 mg taken 90 minutes before bedtime. And see how you feel. If you readily fall and stay asleep until morning you know you’ve got the dose right. Then adjust your dose up or down depending on how you react. Most people don’t need more than 3 – 5 mg per night.

218 HEAD FIRST N-Acetyl L-Cysteine

N-Acetyl L-Cysteine (NAC) is a powerful anti-oxidant, can boost mood, lower anxi- ety, improve memory, and reduce compulsive behavior N-Acetyl L-Cysteine (NAC or N-acetylcysteine) is the N-acetyl derivative of the naturally occurring amino acid L-cysteine. And works primarily by helping restore the body’s natural antioxidant glutathione (γ-glutamylcysteinylglycine; GSH). As the most abundant antioxidant in your body, GSH is responsible for maintaining oxidative balance in each of your cells. Taking glutathione as a nootropic supplement does not adequately restore GSH levels in your brain because it can’t cross the blood-brain barrier. This vastly underrated nootropic, NAC easily penetrates the blood-brain barrier and raises glutathione levels in your brain.464 NAC has been used to treat acetaminophen poisoning for decades.465 Every year there are 56,000 ER visits from Tylenol overdose, resulting in at least 100 deaths.466 NAC provides the glutathione your liver needs to fight off the metabo- lite NAPQI in Tylenol that does severe liver damage. As a nootropic, NAC helps prevent glutamate toxicity, boosts dopamine, and reduces inflammation, oxidative and free radical damage. L-Cysteine is naturally produced in your body using the amino acid methio- nine. You can also get L-Cysteine from eating ricotta and cottage cheese, yogurt, pork, chicken, turkey, duck, wheat germ, granola and oat flakes. But acute stress, illness, or a poor diet can deplete L-Cysteine levels in your body and brain. The quickest and most efficient way to boost levels of L-Cysteine is to supplement with N-Acetyl L-Cysteine (NAC). NAC regulates the amount of glutamate in your brain. Glutamate is a neurotransmitter that is responsible for sending signals between neurons in the brain. This plays an important role in learning and forming memories. But too much glutamate can be toxic to brain cells. NAC regulates the amount of glutamate and keeps it at safe, healthy levels. NAC influences the amount of dopamine available in your brain. It works to keep dopamine receptors healthy and able to transmit and receive dopamine. These neurotransmitters are crucial for cognitive energy and drive, motor control, feelings of pleasure, and focus. NAC is a precursor to the powerful anti-oxidant glutathione (GSH). GSH is a potent anti-inflammatory, anti-oxidant and free radical scavenger. Your brain is especially vulnerable to inflammation, free radical and oxida- tive damage. If left unchecked, inflammation, oxidation and free radicals can negatively affect cognition, long-term potentiation, memory and mood. As a nootropic, NAC can boost glutathione and dopamine levels in your brain. 219 David Tomen NAC is also used by medical professionals to treat serious cognitive disorders like schizophrenia, bipolar disorder, severe depression and anxiety.

How does N-Acetyl L-Cysteine work in the Brain? N-Acetyl L-Cysteine boosts brain health and function in several ways. But two in particular stand out. 1. N-Acetyl L-Cysteine reduces oxidative stress. Oxidative stress results in free radical damage in brain cells. Leading to neurodegeneration and ultimately Alzheimer’s, Parkinson’s and other age-related neuronal disorders. Proteins and DNA are injured, inflammation, tissue damage and cellular apoptosis (cell death) are the result. And neurohackers are not immune to oxidative stress no matter what your age. Keep this in mind the next time you reach for a Diet Coke. Consumption of the artificial sweetener aspartame induces cortical inflammation and oxidative stress. Researchers did a study with 30 adult male Wistar rats randomly divided into 3 groups. The control group received distilled water. The second group was given aspartame. And the third group was given aspartame and NAC. Oral administration was done in the morning daily for 90 days. The study found that NAC boosted Brain-Derived Neurotrophic Factor

(BDNF) levels, blocked the COX-2 and PGE2 inflammatory enzymes, and re- duced the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) inflammatory cytokines in the rat cerebral cortex. They also found that NAC replenished glutathione levels. The researchers concluded that NAC prevented neurotoxicity and improved neurological function, suppressed brain inflammation, and oxidative stress response.467 2. N-Acetyl L-Cysteine relieves depression. Major depressive disorder is one of the most common psychiatric disorders. It’s a burden on the individual, family and the community. And the pharmaceutical companies are making literally billions on selling various anti-depressants. Not treating the cause, producing a host of side effects, and in most cases just ‘dumbing down’ the symptoms. But the pipeline for new anti-depressant drug discovery is at a near stand- still for treating problems like schizophrenia, bipolar disorder, depression and common forms of autism. The good news is that neuroscience continues to work on the problem. And have shown that many of these disorders share inflammation and oxidative stress as part of their disease physiology. Neuroscientists also discovered that associated pathways causing these diseas- es include a reduction in proteins that stimulate neuron growth (neurotrophins), increased apoptosis (cell death), and reduced energy generation in mitochondria. 220 HEAD FIRST It turns out that NAC seems to have multiple effects on all these pathways. NAC reduces the core symptoms of schizophrenia, reduces depression, and reduces cravings for a number of addictions including cocaine, cannabis and .468

How things go bad As we get older or suffer from chronic illness, our brain and body chemistry and energy metabolism changes. ↓ Oxidative stress in brain cells increase ↓ Free radicals damage neurons ↓ Dopamine receptors stop working ↓ Glutamate toxicity causes cell damage and apoptosis ↓ Brain-Derived Neurotrophic Factor (BDNF) declines ↓ Mitochondria energy declines All of these changes are often attributed to chronic illness, lifestyle choices, and aging. Unchecked, they could lead to neurodegenerative diseases like Parkinson’s, Alzheimer’s, major depression, schizophrenia, OCD, addictions, autism, and a drop in quality of life.

N-Acetyl L-Cysteine to the rescue N-Acetyl L-Cysteine (NAC) is a slightly modified version of the sulfur-con- taining amino acid L-Cysteine. When taken as a supplement, NAC replenishes intracellular levels of the natural antioxidant glutathione (GSH). Restoring your cells’ ability to fight damage from reactive oxygen species (ROS). Conventional medicine has used NAC for decades as an inhaled mucous thinner to treat symptoms of cystic fibrosis. NAC is given intravenously (IV) or orally as a treatment for acute acetaminophen poisoning. NAC quickly restores glutathione levels, averting permanent disability or death. The nootropics community has recently discovered NAC as a way to suppress inflammation in the brain. NAC prevents oxidative stress on brain cells, eliminates free radicals, restores Brain-Derived Neurotrophic Factor (BDNF), rejuvenates do- pamine receptors, and improves overall cognitive function. NAC can help boost cognition, Long-Term Potentiation for long-term memory formation, short-term and working memory, improve your mood and quell anxiety.

How does N-Acetyl L-Cysteine feel? Neurohackers report that supplementing with NAC could be the best noo- tropic they’ve ever used for their brain and overall health. Comments include: • Thinking is clearer (less brain fog) • Memory improves 221 David Tomen • Concentration and attention improves • Less anxiety • Less depression • Less irritable • Mood improves (like a ‘clean high’) • Symptoms caused by ADHD meds disappear • Obsessive Compulsive behavior decreases • Sleep quality improves • Energy levels increase • Weight maintenance is easier • Less flu and colds • Skin looks better • Feel younger • Hangovers are less severe

The Research

N-Acetyl L-Cysteine increases dopamine Treatments for Parkinson’s Disease are limited to replacing dopamine in the brain. As well as some medications designed to slow down the disease. In 2016, researchers at Thomas Jefferson University showed the oxidative stress in the brain could play a critical role in the progression of Parkinson’s. And this stress lowers levels of glutathione, a compound produced in the brain to counteract oxidative stress. Studies show that N-Acetyl L-Cysteine (NAC) helps reduce oxidative damage to neurons by helping restore the levels of the antioxidant glutathione. In this study, Parkinson’s patients were placed into two groups. The first group received 50 mg/kg NAC intravenously (IV) once per week. And 600 mg of NAC as a supplement twice a day on non-IV days. The second control group received only their standard Parkinson’s treatment. Patients were evaluated at the beginning of the study and again 3 months later. The evaluation consisted of the Unified Parkinson’s Disease Rating Scale (UPDRS), and a SPECT brain scan which measures the amount of dopamine transporter in the brain. Compared to controls, the patients receiving NAC had significant improve- ments in their scores. One of the study authors said, “We have not previously seen an intervention for Parkinson’s disease have this kind of effect on the brain”. This 222 HEAD FIRST study demonstrated for the first time the direct effect of NAC on the brain’s dopamine system. NAC has the unique ability to enable dopamine neurons to recover their function.469

N-Acetyl L-Cysteine repairs Traumatic Brain Injury Traumatic brain injury (TBI) is a major public health issue affecting 1.7 mil- lion Americans each year.470 TBI can be caused by sports injuries, work accidents, car and motorcycle accidents, falls, and your wife hitting you over the head with a frying pan. Many survivors end up with long-term or even permanent neurocognitive dysfunction. Affecting cognition, motor function (movement) and personality. These disabilities are estimated to cost $9.2 billion in lifetime medical costs and $51.2 billion in productivity losses.471 A major cause of TBI comes from blast exposure on the battlefield. Symptoms are similar to other causes of TBI; dizziness, hearing loss, headache, memory loss, sleep issues, and neurocognitive dysfunction. In a brain subjected to TBI there is glutamate toxicity, free-radical injury to brain cells, electrolyte imbalances, mitochondrial dysfunction, inflammation, apoptosis (cell death) and stroke.472473 This double blind, placebo-controlled study was conducted with 81 active duty service members at a forward deployed field hospital in Iraq. All service members in this study were exposed to significant ordinance blast and met the criteria for TBI. Service members were randomly assigned to receive either a placebo or N- Acetyl L-Cysteine (NAC) for 7 days. The resolution after 7 days of all the TBI symptoms listed above was the main outcome measure of this study. The researchers concluded that NAC was a safe pharmaceutical countermea- sure of blast-induced TBI. And that further work on long term outcomes and the potential use of NAC in civilian TBI is warranted.474

N-Acetyl L-Cysteine helps alleviate depression Both depression and bipolar disorder are complicated by glutathione deple- tion. The researchers in this double-blind, multicenter, placebo-controlled study worked with 75 subjects with bipolar disorder. Subjects received 1 gram of NAC twice daily for 24 weeks. NAC treatment caused a significant improvement with depression with those using NAC. The researchers concluded, “NAC appears a safe and effective augmentation strategy for depressive symptoms”. In this case with people suffering from bipolar disorder.475

Dosage Notes N-Acetyl L-Cysteine (NAC) suggested dosage for cognitive benefit is 600 mg 3-times per day. 223 David Tomen Clinical studies have found that doses up to 2,000 mg per day are safe and effective. And one German study showed the safety of 2,800 mg per day for 3 months in patients with cystic fibrosis.476 NAC has also proven effective against seasonal influenza and flu-like illnesses. One large study of older adults in Italy took 600 mg of NAC twice daily for 6 months. Only 25% of those adults who used NAC experienced flu-like episodes compared to 79% in the placebo group.477

Side Effects N-Acetyl L-Cysteine (NAC) is the N-acetyl form of the naturally occurring amino acid L-Cysteine. NAC is considered non-toxic and very safe. NAC is a slightly modified version of the sulfur-containing amino acid L- Cysteine. So NAC in powder form can have an unpleasant smell. Very rarely can NAC cause nausea, vomiting, diarrhea or constipation. Even more rare are rashes, fever, headache, drowsiness, low blood pressure and liver problems. Side effects can be a result of very high doses of NAC. And if you have a genetic condition called Cystinuria do not use NAC. This rare condition causes stones to form in the kidneys, ureter and bladder from cysteine. NAC is the N-Acetyl form of Cysteine.

Available Forms N-Acetyl L-Cysteine is available in powder, tablet and capsule form. NAC capsules and tablets are usually 600 mg. Some supplement makers add other compounds to their formula. So ensure you read labels carefully. And stick with manufacturers who follow Good Manu- facturing Practices (GMP). And are GMP-Certified.

Nootropics Expert Recommendation

N-Acetyl L-Cysteine (NAC) 600 mg, 3-times per day I highly recommend using N-Acetyl L-Cysteine (NAC) as a nootropic supplement. Your body does synthesize some L-Cysteine from methionine. And you can get L-Cysteine from foods such as dairy, poultry, pork, and some grains and nuts. But most of us don’t get enough N-Acetyl L-Cysteine from our diet. So supple- mentation will help. And N-Acetyl L-Cysteine is a highly bioavailable form of L-Cysteine. So you should feel its effects faster. NAC is helpful for most neurohackers to improve mood, memory, cognition, and concentration. And NAC helps alleviate brain fog, anxiety, and irritability. NAC is especially helpful to those dealing with Obsessive Compulsive Dis- 224 HEAD FIRST order (OCD). And stacked with ADHD meds, NAC helps alleviate some of the negative side effects associated with stimulants. You can safely use up to 1,800 mg of NAC per day. The usual dose for cogni- tive improvement is 600 mg dosed 3 times throughout your day.

225 David Tomen N-Acetyl L-Tyrosine N-Acetyl L-Tyrosine (NALT) enhances working memory, executive function, creative flow states, stress reduction, better mood, anti-anxiety and lessens symptoms of ADHD N-Acetyl L-Tyrosine (NALT or NAT) is a highly bio-available form of the amino acid L-Tyrosine. Your brain uses the enzyme tyrosine hydroxylase to convert L-Tyrosine into L-DOPA. Decarboxylation of L-DOPA results in synthesis of the neurotransmitter dopamine.478 “Tyrosine” is derived from the Greek word tyros, meaning cheese. It was first discovered by German chemist Justus von Liebig in 1846 in the protein casein from cheese. Tyrosine is considered a non-essential amino acid because it can be synthesized in your body from phenylalanine. Which is found in many high-protein foods such as poultry, fish, dairy, nuts, soy products, lima beans, avocados and bananas. Once converted into dopamine, the enzyme dopamine-beta-hydroxylase converts it into the neurotransmitters norepinephrine (noradrenaline) and epi- nephrine (adrenaline). This triad of neurotransmitters are collectively referred to as “catecholamines”. N-Acetyl L-Tyrosine can be a highly effective nootropic for boosting cogni- tive function. And is particularly helpful in maintaining cognitive performance when you’re under practically any kind of stress. Particularly for musicians play- ing live music like I did for many years. NALT helps maintain optimal cognitive performance during music played above 90 dB’s. N-Acetyl L-Tyrosine works in synergy with stimulants like methylpheni- date (i.e. Ritalin).479 Drugs like Ritalin work by blocking the reuptake of the neurotransmitters dopamine, and norepinephrine. And if there’s not enough dopamine available to do the job, Ritalin doesn’t work very well. NALT potenti- ates increases in extracellular dopamine.

NALT also stimulates the production of thyroid hormones T3 (triiodothyro- nine) and T4 (thyroxine) which are crucial in maintaining both overall physical and cognitive health. NALT can boost libido, memory, focus, concentration, mood, offers anti- depressant effects, and improves executive function in those with ADHD. NALT enhances working memory and executive function in the prefron- tal cortex. It helps with creative flow states, is fuel for inspiration, cognitive flex- ibility, and the kind of “convergent thinking” you do in multiple choice exams.

N-Acetyl L-Tyrosine (NALT) vs. L-Tyrosine: What’s the Difference? N-Acetyl L-Tyrosine (NALT) is the amino acid L-Tyrosine with an acetyl group added. When you take NALT as a supplement, it breaks down in your kidneys back into L-Tyrosine. So in theory, the two supplements offer the same benefits. 226 HEAD FIRST There is some debate in the nootropics community on which is more effec- tive; NALT or plain L-Tyrosine. NALT is a more soluble form of L-Tyrosine so it should be more bioavailable to your body. However, some studies report that in some cases, a sizeable percentage of supplemental NALT is excreted in urine before it’s converted into L-Tyrosine.480 On a personal note, I haven’t had any issues using NALT as a source of L-Tyrosine. It gives me a dopamine and adrenal boost you’d expect from supple- menting with a dopamine precursor. When dealing with ADHD/ADD it’s particularly effective when stacked with ALCAR (Acetyl-L-Carnitine). ALCAR easily crosses the blood-brain barrier for boosting acetylcholine levels. And seems to positively influence se- rotonin levels. And NALT provides my brain with the dopamine it needs to mitigate symptoms of ADHD/ADD. But in the interests of full transparency, I stack this with 20 mg of Rit- alin twice a day. Clearly, my brain doesn’t have the capacity to produce enough dopamine on its own. And needs the boost that comes from supplementing with NALT. So like all nootropics, your mileage may vary. Always take into account how each nootropic works synergistically with others in your stack. And how they work with any meds you need to take. This is as much art as it is science. And experimentation is key for optimal cognition, and a ‘Limitless’ mindset.

How does N-Acetyl L-Tyrosine work in the Brain? N-Acetyl L-Tyrosine boosts brain health and function in several ways. But two in particular stand out. 1. N-Acetyl L-Tyrosine improves memory and cognition under acute stress. Acute stress is defined as short-term stressors that can affect cognition. Ex- amples are extreme heat or cold. Things like cold showers, extreme sports, car accidents, relationship problems, intense movies, business deals gone awry, exams and war zones. In one study done at the University of Bedfordshire in the UK, the effect of L-Tyrosine on cognitive performance was measured before an exercise task. Researchers recruited 8 soccer players. And had them complete a 90-minute soccer simulation performance test in an environmental chamber set at 77 de- grees Fahrenheit. The soccer players were given either L-Tyrosine before exercise or a placebo. Cognitive performance was measured before the exercise task. Then again at “half-time”, following half time, and following the entire simulation. The cognitive performance task assessed dual-task and vigilance. The out- 227 David Tomen come revealed that cognitive vigilance and reaction time among soccer players significantly improved following administration of L-Tyrosine. Results showed that in warm-weather conditions, L-Tyrosine could enhance cognitive function and prevent cognitive impairment during exposure to exercise-heat stress.481 2. N-Acetyl L-Tyrosine boosts neurotransmitters. NALT turns into L-Tyro- sine once taken as a supplement. It then converts into the neurotransmitter dopamine. Dopamine is used to control movement in your body, is funda- mental to memory, attention and problem solving. The unused dopamine can then convert into the neurotransmitters norepi- nephrine (noradrenaline) and epinephrine (adrenaline). Norepinephrine is important for attentiveness, emotions, sleeping, dreaming and learning. Epinephrine drives your ‘flight-or-flight’ response. It’s what prompts your reaction to dangerous circumstances, emergency situations, or in stressful situa- tions or environments. In one study done in the Netherlands, researchers determined if L-Tyrosine could boost cognitive resources associated with cognitive control. They performed tests designed to measure “working memory” using the N-Back Test. Study participants were asked to engage in a “1-back” condition of easy difficulty and then a 2-back condition of tougher difficulty. Those that used L-Tyrosine demonstrated superior performance in the 2-back test, but not the 1-back test. The study authors suggested that L-Tyrosine provides greater cognitive en- hancement when cognitive demand increases. The bottom-line; supplementation of L-Tyrosine may help you increase your IQ score due to maximizing catecholamine reserves.482

How things go bad As we get older, our brain and body chemistry and energy metabolism changes. ↓ Dopaminergic neurons are damaged or die ↓ Neurotransmitter levels decline ↓ Thyroid hormones decline ↑ Stress levels increase ↓ Working memory and mood decline All of these changes are often attributed to aging. But could be a result of dietary and lifestyle choices. Unchecked, they could lead to neurodegenerative diseases like Parkinson’s, a drop in quality of life and depression.

N-Acetyl L-Tyrosine to the rescue N-Acetyl L-Tyrosine (NALT) can boost levels of the neurotransmitters dopa- 228 HEAD FIRST mine, norepinephrine and epinephrine. And can help a sluggish thyroid produce more T4 and T3. NALT can help boost cognition especially in stressful situations. It helps improve decision making, ‘flow state’ and creativity, cognitive flexibility, and working memory. NALT converts into L-Tyrosine which then converts into L-DOPA to pro- duce dopamine. L-DOPA is also used to make melanin in your body. This con- version process helps in the removal of neurotoxic quinones. And chelates heavy metals like mercury and lead which can accumulate in and damage neurons. The dopamine that is not used by your brain is available to produce norepi- nephrine (noradrenaline) which is important for attentiveness, emotions, sleeping, dreaming and learning. NALT can be an effective nootropic when stacked with ADHD/ADD meds like Ritalin or Adderall. It helps supply extracellular dopamine needed to im- prove the effectiveness of stimulants used to boost the uptake of dopamine in your brain.

How does N-Acetyl L-Tyrosine feel? Keep in mind that NALT is a precursor to catecholamines. So if you’re not ‘low’ on dopamine, norepinephrine or epinephrine – you may not ‘feel’ anything. Many neurohackers report a lift in mood, better focus, concentration, in- creased energy, and an overall sense of well-being. NALT can help readjust your motivation levels. It can help lower anxiety levels, especially social anxiety. Supplementing with N-Acetyl L-Tyrosine can help bring your blood pres- sure down if it’s elevated from a stressful situation or environment. Take it before the stressful event if you can. NALT helps buffer the effects of stimulants like caffeine or amphetamines. It helps potentiate and prolong the effects of Ritalin or Adderall, and reduces the crash. If you’re into athletics or do manual work, you’ll find that supplementing with NALT before a workout or construction job will leave you feeling great afterwards. It helps mitigate many of the effects of acute stress caused by short- term stressors. And NALT helps your body to produce melanin, so you may find it easier to get a tan while at the beach.

The Research

N-Acetyl L-Tyrosine to treat ADHD Several studies have investigated using L-Tyrosine for the treatment of ADHD. One informal study published in the 1980’s determined that L-Tyrosine 229 David Tomen resulted in short-term relief from ADHD symptoms. But subjects eventually reached tolerance and a diminished effect. This is important for neurohackers to keep in mind. It seems that NALT on its own can benefit some more than others. Regardless if your treating ADHD, or are perfectly cognitively healthy. I’ve seen more than one report of nootropic users experiencing tolerance after just a week of supplementing with NALT. But most peer-reviewed, published studies show positive results. One study published in Neuropsychiatric Disease and Treatment in 2011 looked at using amino acid precursors for the treatment of ADHD. Including L-Tyrosine for dopamine, and 5-HTP for serotonin. The study used 85 young people aged 4 – 18 years old, all with a clinical diagnosis of ADHD. They were treated for an initial period of 8 – 10 weeks. Urinary samples to determine serotonin and dopamine levels were collected within the first 4 weeks. If they didn’t reach adequate levels, subjects were moved to higher dosing levels 2 and then 3 until they got relief from symptoms. Researchers found that the dopamine and serotonin precursors yielded similar results to Strattera and Ritalin. And “the amino acid protocol may be equal in efficacy to potent, pharmaceutical ADHD medications”.483

L-Tyrosine reduces blood pressure under stress This study is particularly interesting for its nootropic application. It’s com- monly understood that blood pressure rises when we’re under stress. The source of stress doesn’t really matter. Stress up = blood pressure up. A study in Amsterdam showed that L-Tyrosine administration decreased blood pressure about 15 minutes after ingestion. This study involved assessing task performance following acute stress. Acute stress is usually short-term and can be caused by driving, fighting, athletics, martial arts training, war, combat training, Crossfit, cold showers, loud music, intense movies, loud noises, business deals, relationships, school, exams and more. The point is, this study is applicable to every one of us. The study found that L- Tyrosine reduced diastolic blood pressure within 15 minutes of taking the supplement. And blood pressure normalized within 1 hour. This study tells us that L-Tyrosine (and NALT) may promote a decrease in blood pressure caused by stress. And could be used to mitigate the effects of stressful situations if taken prior to the stressful event.484

N-Acetyl L-Tyrosine promotes cognitive flexibility Cognitive flexibility applies to those who can adjust their thinking quickly to adapt to novel situations and stimuli. A high degree of cognitive flexibility is 230 HEAD FIRST associated with increased fluid intelligence, superior reading and comprehension, and a healthier brain. Recent research (2015) supports the idea that L-Tyrosine (and NALT) pro- motes cognitive flexibility. In this trial, researchers recruited 22 adults. And setup a double-blind, placebo-controlled study. All subjects were assigned a task switching procedure to measure their flexibility. The results showed that receiving L-Tyrosine supplements increased cognitive flexibility compared to the placebo group. The researchers determined that “L-Tyrosine can facilitate cognitive flexibility by repleting cognitive resources”.485 The team observed that increased cognitive flexibility was likely due to a boost in dopamine concentrations. They noted that L-Tyrosine enhanced usage of vari- ous cognitive resources. And one way to increase your cognitive flexibility would be to start supplementing with N-Acetyl L-Tyrosine. It stands to reason that people who are close-minded, set it their ways, are resistant to change and can’t cope with unexpected stimuli or situations have “cognitive rigidity”. And it’s likely due to suboptimal dopamine levels.

Dosage Notes N-Acetyl L-Tyrosine (NALT) suggested dosage for cognitive benefit is 350 – 500 mg twice per day. You may find your body responds to smaller doses. Or even more if your stacking it with stimulants like ADHD meds. Listen to your body and see how you react.

Side Effects NALT quickly turns into the non-essential amino acid L-Tyrosine once you take it. So is considered non-toxic and very safe. Most neurohackers don’t have any negative side effects. At higher doses there are reports of stomach issues and migraines. Migraine problems usually happen to those who already suffer from migraines. This may be an indication that your neurotransmitter levels are already optimal and you don’t need to supplement with NALT. NALT can increase your thyroid hormones. So if you’re hyperthyroid you shouldn’t use NALT. And if you’re taking MAO inhibitors (MAOI’s) like selegiline, Azilect, Mar- plan or Nardil you should not use NALT. MAOI’s work in your brain and effect neurotransmitters. So using NALT in combination with MAOI’s could throw off the delicate balance of neurotransmitters needed for optimal brain health and cognition. 231 David Tomen Available Forms N-Acetyl L-Tyrosine is available in powder, capsule and tablet form. Cap- sules and tablets are usually 300 – 500 mg. Some pre-made nootropic stacks and workout stacks also include NALT as part of their formula. Ensure you read labels carefully, and stick with manufacturers who follow Good Manufacturing Practices (GMP). And are GMP-Certified.

Nootropics Expert Recommendation

N-Acetyl L-Tyrosine (NALT) 350 – 500 mg twice per day I recommend using N-Acetyl L-Tyrosine (NALT) as a nootropic supplement. Your body does synthesize some L-Tyrosine from phenylalanine which comes from high-protein foods like chicken, fish, almonds, avocados and bananas. But most of us don’t get enough L-Tyrosine from our diet. So supplemen- tation will help. And N-Acetyl L-Tyrosine is a highly bioavailable form of L- Tyrosine. So you should feel its effects faster. NALT is helpful for most neurohackers to combat stress and sleep depriva- tion. It’ll boost dopamine, norepinephrine and epinephrine levels. It’s particularly helpful if you take NALT prior to a stressful situation, work- out or physically demanding job. NALT is especially helpful to those dealing with ADHD/ADD. It’s a great compliment to stack with stimulant meds like Ritalin or Adderall. NALT will provide the dopamine your brain needs. It will help smooth out and prolong the effects of stimulant meds. And help prevent the associated crash when they wear off. A good stack for ADHD is using your usual med dose with NALT 500 mg and ALCAR 500 mg. You can safely use up to 1,500 mg per day when stacking with ADHD meds. But dosed throughout your day.

232 HEAD FIRST NADH

NADH is known for increased alertness, clarity, focus, memory, enhanced mood and energy, and is a potent antioxidant and free radical scavenger NADH ( Adenine Dinucleotide + Hydrogen, or coenzyme

1) is the active coenzyme form of Vitamin B3 (niacin). Discovered early in the 1900’s, it’s also known as Coenzyme 1. Every cell in your body contains NADH. NADH is the primary carrier of electrons in the transfer of food from your diet into energy. This energy is stored as adenosine triphosphate (ATP). ATP provides the fuel for mitochondria in each of your cells. Not enough NADH leads to ATP depletion, which can eventually lead to cell death.486 Studies have shown that supplementing with NADH improves cognitive function, enhances cellular energy, increases endurance, switches ‘off’ aging genes, and extends life span. You get small amounts of NADH by eating meat, poultry and fish. Vegeta- bles have very low concentrations of NADH. So vegetarians are typically low in NADH. And since NADH is very unstable, much of it is lost through cooking. When you supplement with NADH, cerebral electrical activity increases in areas of your brain used for attention, cognition, focus, memory, concentration, and decision making.

How does NADH work in the brain? NADH boosts brain health in several ways. But two in particular stand out. 1. NADH increases the production ATP. NADH carries the electrons needed for the synthesis of ATP. Your brain cell mitochondria depend on this fuel (ATP) to function and stay healthy. By providing the means for ATP synthesis, NADH is involved in cognition, focus, concentration, memory, and processing speed.487 And NADH plays an important role in mediating brain aging and tissue damage. Even decreasing the damage done by strokes.488 In one double-blind, placebo-controlled study researchers did a 3-month trial with Chronic Fatigue Syndrome patients. 86 patients were chosen to receive either 20 mg of NADH daily or a placebo for the first 2-months. Mean age of the participants was 47 years. The study measured the intensity of fatigue, functional performance, mood state, functional impact of fatigue, quality of life, sleep quality, and exercise ca- pacity. Each was measured prior to the study. And then at 30, 60 and 90 days of treatment. The study found that oral administration ofNADH resulted in decreased anxiety and maximum heart rate.489 233 David Tomen 2. NADH increases neurotransmitters. NADH is directly involved in the production of the critical neurotransmitters dopamine and norepinephrine. Dopamine is usually made inside the neurons that use it. The amino acid tyrosine is first converted to L-DOPA through the enzyme tyrosine hydroxylase. L-DOPA is then converted to dopamine. Research shows that tyrosine hydroxylase is the rate-limiting controller of dopamine synthesis. This is seen in Parkinson’s patients where tyrosine hydroxylase is much lower than in healthy people. To complicate things even more, we need to understand what makes tyrosine hydroxylase work. The coenzyme that activates tyrosine hydroxylase is tetrahydro- biopterin (H4BP). And it’s NADH that activates this enzyme, and helps produce H4BP. Researchers in Austria conducted an open label trial with 885 Parkinson’s patients. The study was conducted to try a therapy that might increase the brain’s own dopamine production instead of directly giving the patents L-DOPA. In this study, 415 patients received intravenous (IV) NADH and 470 pa- tients got an oral dose of NADH. Both groups showed overall good response to treatment including improvements in motor function, walking, pushing, posture and speech. They also experienced improvements in cognition and mood. The researchers found increased dopamine metabolites in the urine of the patients. Indicating that NADH induced an increase in dopamine production. Most of the Parkinson’s patients were able to reduce and even eliminate their other Parkinson medications.490

How things go bad As we get older, NADH levels decline. And no amount of healthy eating or exercise can stop this decline. ↓ Dopamine and norepinephrine levels decline ↓ Intra-cellular genome communications break down ↓ Energy levels decline All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and Parkinson’s. But even if things haven’t degenerated to such a debilitating level, NADH can help. In fact, it’s required for dopamine synthesis.

NADH to the rescue Research has shown that people with low NADH levels are far more vulner- able to addiction, disease and other chronic conditions. Low NADH levels can happen at any age. Even at birth. In our Western society, NADH is lost in cooking and food processing. And 234 HEAD FIRST what little remains is broken down by stomach acid and degraded before it’s absorbed in your digestive tract. When you take NADH as a supplement, your cells think oxygen levels are normal and start working as if they were younger, undamaged cells. Research from hundreds of studies have shown that NADH will: • Boost energy levels and stamina • Reduce fatigue • Reduce the possibility of age-related diseases • Lower blood pressure • Provide protection and energy to your brain • Boost cerebral blood flow

How does NADH feel? Using NADH as a nootropic can boost ATP synthesis in your brain. And increase the production of the neurotransmitters dopamine, norepinephrine and serotonin. You should experience a boost in mental and physical energy levels, a better mood, improved cognition and alertness. NADH even helps relieve symptoms related to jet lag. And has been shown to alleviate the symptoms of Chronic Fatigue Syndrome including less brain fog, improved mood and energy, and better cognition. And neurohackers report more endurance during workouts and running.

The Research

NADH helps reduce Jet Lag Current remedies for jet lag don’t work very well. Chronic commuters have resorted to melatonin, stimulants, sedatives and phototherapy. And all have pro- duced dismal results in recovering from jet lag. NASA investigated the efficacy of using NADH as a countermeasure for jet lag. NADH increases cellular production of ATP and facilitates dopamine synthesis. So the thinking was NADH could counteract the effects of jet lag on cognitive function and sleepiness. 35 healthy frequent travelers were recruited in this double-blind, placebo- controlled study. Testing was conducted on the West Coast before subjects flew overnight to the East Coast. Subjects were given either 20 mg of sublingual NADH, or a placebo. All underwent testing to assess cognitive function, mood, and sleepiness in the morning and afternoon the day after the red-eye flight. Jet lag resulted in sleepiness for half the participants, and a third of them ex- 235 David Tomen perienced deterioration of cognitive function. The morning following the flight, subjects experienced lapses of attention, disruptions to working memory, divided attention and visual perceptual speed. Those who received NADH performed significantly better on cognitive and motor tests, showed better performance on other measures, and reported less sleepiness than those who took a placebo. NASA concluded that, “Stabilized NADH significantly reduced jet lag-induced disruptions of cognitive functioning, was easily administered, and was found to have no adverse side effects”.491

NADH regenerates stem cells in the brain Researcher Hongbo Zhang wanted to understand how the regeneration pro- cess deteriorated with age. So he teamed up with colleagues from ETH Zurich, the University of Zurich and universities in Canada and Brazil. Under normal conditions, stem cells react to signals sent by your body, and regenerate damaged organs by producing new specific cells. Fatigue in stem cells is one of the main causes of poor regeneration. Resulting in degeneration in tissues, organs and the brain. The research team set out to revitalize stem cells in the muscles of elderly mice. They gave nicotinamide riboside to 2-year-old mice (which is considered “old” for a mouse). Nicotinamide riboside is a precursor to NADH. The results showed muscular regeneration was much better in mice that received nicotinamide riboside. They lived longer than the mice that didn’t get it. Parallel studies have revealed a comparable effect on stem cells of the brain and skin. This work on the aging process has potential for treating diseases that can affect, and be fatal even in young people, with illnesses like muscular dystrophy. No negative side effects were observed in any of the studies following use of nicotinamide riboside, or stabilized NADH. It appears to boost the functioning of all cells. Including cells that have been damaged.492

NADH decreases anxiety Studies show that NADH may be low in those suffering chronic fatigue syn- drome (CFS). So researchers in Spain set out to evaluate the efficacy of supple- menting NADH in those with CFS. The research team recruited 86 CFS patients with a mean age of 47 years to take part in a 3-month double-blind, placebo-controlled trial. The patients were given 20 mg of NADH or a placebo for 2 months. The team found that those using NADH experienced a significant decrease in anxiety symptoms. And maximum heart rate dropped.493

NADH reduces symptoms of Chronic Fatigue Chronic Fatigue Syndrome (CFS) has baffled researchers and the medical 236 HEAD FIRST community for years. Its cause is unknown, and it’s associated with a myriad of symptoms. But the main common denominator in all Chronic Fatigue cases is severe fatigue. And no therapeutic regimen has proven effective for this condition. In this study, 31 patients fulfilling the criteria for CFS were selected to participate. They were given NADH or other nutritional supplements for 24 months. The 12 patients who received NADH had a dramatic and statistically significant reduction of chronic fatigue symptoms.494

Dosage Notes

NADH is a coenzyme, antioxidant form of Vitamin B3 (niacin). It’s a natu- rally occurring enzyme found in all living cells. And necessary for cellular ATP synthesis and energy production. NADH is available in tablet form as 5, 10 and 20 mg tablets. It’s faster-acting if you can find sublingual tablets. If you’re looking to boost dopamine, stack your NADH with N-Acetyl L- Tyrosine (NALT). Because NADH converts tyrosine to dopamine.

Side Effects Your body naturally produces NADH. So it’s non-toxic and very well toler- ated. NADH should not produce side effects.

Available Forms NADH is highly unstable and for it to remain effective needs to be in a stabilized form. Most neurohackers recommend the patented, stabilized form of NADH that’s made by a German company called ENADA. A couple of major supple- ment manufacturers license the ENADA brand of NADH. Check the label.

Nootropics Expert Recommendation

NADH 10 mg per pay I recommend using NADH as a nootropic supplement. Your body does make some NADH on its own. And from eating meat, poul- try and fish. But studies have shown we don’t get an adequate supply of NADH from food sources because most of it is lost in cooking. NADH is particularly helpful for vegetarians because very little NADH is available from vegetables. NADH is especially helpful for those suffering Chronic Fatigue Syndrome. I suggest starting with a dose of 10 mg daily. And NADH is a great compli- ment to a stack with any nootropic. Do your best to find a stabilized form of NADH like the patented ENAND. 237 David Tomen For a more effective dopamine boost, stack your NADH with NALT. NADH converts tyrosine to dopamine. You need to provide your brain mitochondria with the ATP fuel it is de- manding. Or neurons start to break down from the inside. Signs that your lack- ing adequate NADH is brain fog, slow thinking, fatigue and low endurance. Some clinics in the USA and other countries are using NADH therapy as a treatment for addiction, anxiety, depression, chronic stress and post-traumatic stress disorder (PTSD). Intravenous (IV) NADH has been used effectively since the 1960’s for de- toxing patients from alcohol, opiates, tranquilizers and stimulants.495

238 HEAD FIRST Nefiracetam Nefiracetam has been shown to reduce apathy, improve cognition, learning, and long- term memory, reduce anxiety, depression and stress, boost nerve growth factor, and is neuroprotective Nefiracetam (DM-9384, N-(2, 6-dimethylphenyl)-2-(2-oxopyrrolidine- 1-yl)-acetamide) is in the racetam-family of nootropic compounds. It is a fat- soluble nootropic. Nefiracetam was developed by Daiichi Seiyaku in the 1990’s as a treatment for cerebrovascular disorders. In 1999, Nefiracetam was in phase II clinical trials in the USA for treatment of cognition problems as a consequence of stroke, and Alzheimer’s type dementia.496 It is similar in structure to Piracetam with a phenyl group and two methyl groups added to the amine of Piracetam. Nefiracetam, like all racetam nootropics, has a pyrrolidone nucleus at its core. The structure of Nefiracetam is similar to Aniracetam. And Nefiracetam is a cholinergic compound, meaning it affects acetylcho- line levels in the brain. Nefiracetam is used as a prescription drug in Japan. And as a supplement in the United States. One of the most recent synthetic nootropic compounds, it is known as a cognitive enhancer. And is known for its anxiolytic, or anti-anxiety effects. Nefiracetam is considered to be much more potent than Piracetam. As a nootropic, it helps increase attention span, alertness, cognition, learning and boosts memory.

Nefiracetam vs. Piracetam: What’s the Difference? Japan-based pharmaceutical company Daiichi Seiyaku developed Nefirace- tam in the late 1990’s as a derivative of Piracetam. Nefiracetam is fat-soluble while Piracetam is water-soluble. Fat-soluble molecules cross the blood-brain barrier more easily than water-soluble molecules. Both Nefiracetam and Piracetam are cognitive enhancers. And both have neu- roprotective qualities. Both racetams are able to improve learning and memory. And both are able to prevent brain damage. Nefiracetam has additional benefits not shared with Piracetam. Nefiracetam can reduce anxiety and depression. And exhibits several other memory enhanc- ing qualities over Piracetam. Nefiracetam increases the amount of time calcium channels in neurons remain open. Tied to protein kinase A (PKA) and the Gi alpha subunit (Gi/o pro- tein), signaling is enhanced in the neuroreceptor independent of the synapse. This calcium channel pathway is critical for long-term potentiation (LTP) and the formation of long-term memories.497 239 David Tomen Nefiracetam also potentiates protein kinase C alpha (PKCα) which is involved in long-term potentiation (LTP).498 PKCα is dependent on glutamate signaling. And Nefiracetam activates Ca2+/calmodulin-dependent protein kinase II (CaMKII) which is critical in memory formation. Again dependent on glutamate signaling.499 Finally, Nefiracetam potentiates acetylcholine receptors in the hippocampus which encourages glutamate release and LPT. Piracetam does not share this memory enhancing quality.500 The bottom-line is Nefiracetam seems to be a much more potent memory en- hancer that the original nootropic Piracetam.

How does Nefiracetam work in the Brain? Nefiracetam boosts brain health and function in several ways. But two in particular stand out. 1. Nefiracetam enhances memory. In several studies and clinical trials, re- searchers have noted Nefiracetam’s anti-amnesia effects. And they’ve arrived at this observation by noting Nefiracetam interacting with individual acetyl- choline receptors in the brain. One study conducted at the Albert Einstein Healthcare Network in Philadel- phia worked with older rabbits. Researchers use a technique called the “nictitat- ing membrane (NM)/eyeblink response” in rabbits which is used in the lab to study age-related memory disorders. In this case, the team used Nefiracetam to study its effect on retention and relearning. The scientists administered 5, 10 or 15 mg/kg of Nefiracetam to 34 “retired” rabbits over 15 days. And then tested retention and relearning 1, 5 and 12-weeks post-training. The researchers found that the effect of Nefiracetam on the ability of older rabbits to relearn was apparent up to 5 weeks after using Nefiracetam. In other words, Nefiracetam had a significant effect on memory long after the rabbits stopped using it. The researchers concluded that Nefiracetam likely has an even greater effect on memory the longer you use it.501 This testing model is dependent on cholinergic (acetylcholine) firing in the brain.502 2. Nefiracetam alleviates depression. Nefiracetam enhances signaling of

GABA on GABAa receptors when GABA is too low. And has a suppressive effect when GABA is too high.503 Leading to stabilized mood and sociability. No mood swings! Nefiracetam also provides an antidepressant effect by activating the enzyme Ca2+/calmodulin-dependent protein kinase II (CaMKII). Scientists in Japan 240 HEAD FIRST worked with mice with depressive-like behaviors. The mice were given 1 mg/ kg per day of Nefiracetam. And noticed antidepressant effects within a day of supplementation.504 Note that this antidepressant effect takes a completely different approach to controlling depression compared to SSRI’s. Prescription antidepressants like SSRI’s mess with serotonin levels in your brain to control depression. And unlike Nefiracetam, come with a host of side effects. Also note that the CaMKII enzyme is associated with a boost in long-term memory formation.

How things go bad Glutamate is an excitatory relative of GABA. While GABA has a calming effect,glutamate stimulates. Glutamate is the most common neurotransmitter in the central nervous system. Glutamate can be toxic to neurons. And too much of it in your brain can kill brain cells. Lou Gehrig’s Disease for example, is caused by excess glutamate. But glutamate is a pivotal neurotransmitter in the brain. It links the brain circuits involved in memory, learning and perception. ↑ Too much glutamate can kill neurons ↑ Too much GABA can cause brain damage ↓ Too little GABA can cause depression ↓ Too little glutamate can cause problems with memory, learning and perception ↓ Acetylcholine levels decline All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Nefiracetam can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting acetylcholine and controlling gluta- mate and GABA in the brain.

Nefiracetam to the rescue Nefiracetam modulates GABA (gamma aminobutyric acid) in your brain. GABA is the primary inhibitory neurotransmitter in the brain. Its role is to keep glutamate, the primary excitatory neurotransmitter from overwhelming your brain. And causing damage. When GABA levels are too low, you experience anxiety, insomnia, poor mood and restlessness. Left unchecked it can lead to neurodegenerative disease and a very poor quality of life. But when GABA is too high, you have a toxic environment in your brain. Causing damage to neurons and other areas of your brain. Nefiracetam modulates GABA levels, keeping them steady for a healthy brain. And improved long-term memory. 241 David Tomen Nefiracetam contributes to learning by enhancing long-term potentiation (LTP). Enhancing NMDA-dependent LTP at low concentrations and AMPA dependent LTP at higher concentrations.505 Nefiracetam combined with choline boosts the production of the crucial neurotransmitter acetylcholine. Improving memory, recall and focus. Nefiracetam is fat-soluble and quickly enters your brain after you take it. Once in your brain, it boosts signal transmission, and protects neurons. Nefiracetam boosts acetylcholine so you should add a good choline source. Tr y Alpha GPC or CDP-Choline with Nefiracetam. And give your brain the choline it needs.

How does Nefiracetam feel? Several studies have noted that short-term or one-time use of Nefiracetam doesn’t do much. Supplementing Nefiracetam every day for 7 days or more is needed to experience the full benefit of this nootropic. Nootropics users report: • Nefiracetam as a study aid. Nefiracetam provides calm focus, recall and cognition for many neurohackers. It improves attention span, motivation, and alleviates apathy and mental fatigue. • Increased visual acuity. The visual effects of Nefiracetam feel like your brain is processing a broader spectrum of what’s in your visual range. Nature and your surroundings look more vibrant and beautiful. • Mood. Many users report a calm focus and being able to articulate thoughts, and improved speaking ability. Language and your vocabulary seem to flow effortlessly. Thoughts and ideas come with less effort. Some experienced users of Aniracetam say they prefer Nefiracetam. You may recall that the chemical structure of Nefiracetam is very similar to Aniracetam. And the clinical studies support its superior ability to affect memory. You should be able to experience the full effects of Nefiracetam within 7 days of starting to supplement with it. It’s fat-soluble so it’s digested and enters your cells quickly.

The Research Nefiracetam was developed by a company in Japan in the late 1990’s. As a result, the majority of the published research available in the Western directories was conducted in Japan. And most of it on rats and mice. Clinical trials for Nefiracetam have been conducted in China and the USA for use in treating Alzheimer’s Disease. So far, no large pharmaceutical company in the USA has formulated a prescription drug version of Nefiracetam to my knowledge. 242 HEAD FIRST Nefiracetam as an Antidepressant Researchers at The University of Iowa in the USA conducted a double-blind, placebo-controlled trial with 159 stroke patients with major depression. Patients received 600 mg or 900 mg of Nefiracetam or a placebo within 10 days to 3 months after their stroke. The trial ran for 12 weeks with patients evaluated at 4, 9 and 12 weeks of the trial. The study concluded that Nefiracetam produced a significant improvement in the most severely depressed patients.506

Nefiracetam Improves Learning & Memory Much of the research on Nefiracetam has been done with learning and memory in mind. One study conducted in Ireland used Nefiracetam with rats. Scopolamine, a memory inhibitor, was given to the rats while they were in training. Scopolamine is used to purposely inhibit memory. When the researchers gave the memory- deprived rats Nefiracetam, task recall improved and significantly improved memory deficits.507 Another Irish study with rats showed 40-days of Nefiracetam supplementa- tion induced Nerve Growth Factor and neurogenesis. Proving that Nefiracetam could facilitate long-term memory consolidation.508

Nefiracetam Reduces Apathy Supplementing with Nefiracetam is reported by many neurohackers to boost motivation and a “get it done” attitude. Which is the opposite of ‘apathy’. Stroke patients who suffer depression commonly experience apathy. Re- searchers at The University of Iowa conducted a study with 137 stroke patients with major depression. 70 of which also met published diagnostic criteria for apathy. The patients were assigned a placebo, or 600 mg or 900 mg of Nefiracetam per day for 4 weeks. Patients who used 900 mg of Nefiracetam had a significantly greater improvement in Apathy Scale scores compared to the other two groups. Conclusion: Nefiracetam reduces apathy.

Dosage Notes Recommended Nefiracetam dosage is 100 mg to 900 mg per day. Taken in divided doses. One Nefiracetam dose in the morning, and one in the early afternoon. Nefiracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 400 – 600 mg each. Since Nefiracetam is a fat-soluble nootropic, you should take it with a meal containing healthy fats. Or with a tablespoon of extra virgin, expeller cold-pressed coconut or olive oil. Or other similar healthy fat to ensure quick absorption. 243 David Tomen Nefiracetam also boosts acetylcholine (ACh) activity in your brain. To avoid a “racetam headache” make sure to stack Nefiracetam with a good choline source like CDP-Choline or Alpha GPC. Note that most studies suggest, and many neurohackers report that it will take at least 7 days of daily dosing of Nefiracetam to experience the full benefit of this nootropic.

Side Effects Nefiracetam non-toxic. So is considered well-tolerated and safe. Side effects are rare but can include anxiety, fatigue, headaches, nervousness and nausea. Side effects are often a result of unusually high doses of the nootropic. Headaches from using Nefiracetam typically happen when you forget to combine it with a good choline supplement. Headaches are often a symptom of a choline deficit in your brain. Nearly all of the toxicity studies on Nefiracetam have been done on animals. And prolonged usage of this nootropic have shown no toxic effects at recom- mended doses. One study with male Beagle dogs reported a reduction in testicular testoster- one after a single treatment of Nefiracetam. But before you write this nootropic off, note that the dose was a ridiculous 180 or 300 mg/kg dose.509 That’s the equivalent of 16 or 27 grams of Nefiracetam for a 200 lb. male human. And dogs happen to metabolize Nefiracetam differently than humans and primates. The metabolite M-18 in dogs seems to be the culprit. And is not found in humans or monkeys.510 I’m not going to belabor this point. But to say that Nefiracetam is safe and non-toxic if used at recommended doses. As long as you’re not a Beagle. Just don’t give it to your dog!

Available Forms Nefiracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 400 – 600 mg each.

Nootropics Expert Recommendation

Nefiracetam 100 – 900 mg per day I recommend using Nefiracetam as a nootropic supplement. Your body does not make Nefiracetam on its own. So to get its benefits you must take it as a supplement. Nefiracetam is especially helpful for those suffering from apathy, loss of mo- tivation and memory loss. Studies show it helps stop and reverse the symptoms associated with apathy. And this nootropic helps boost the activity of GABA, glutamate and ace- 244 HEAD FIRST tylcholine in your brain. All involved in long-term potentiation and formation of long-term memory. Nefiracetam is also particularly useful to students and executives who want to boost cognition, learning and especially long-term memory. Neurohackers with experience using Nefiracetam show it helps boost study scores, work flow, learning and memory. You should use Nefiracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Nefiracetam to 1,200 mg if needed. All daily dosing of Nefiracetam should be in divided doses if above 200 mg per day. One dose in the morning and another early afternoon.

245 David Tomen Nicotine

Nicotine has been shown to improve concentration, focus, mental clarity, motivation, memory, and reduce mood swings and anxiety Nicotine (3-(1-Methyl-2-pyrrolidinyl) pyridine) is an alkaloid found in tobacco leaves. But nicotine is also present in very small amounts in plants from the Solanaceae or nightshade family including potatoes, tomatoes and eggplant.511 Nicotine has been used by humans for its psychoactive (nootropic) proper- ties for thousands of years. But it is only in the last several decades that nicotine’s mechanism of action in the brain has been revealed. Nicotine works primarily by upregulating nicotinic acetylcholine receptors (nAChR) in the brain. Stimulating and regulating the release of a host of neu- rotransmitters including serotonin, dopamine and norepinephrine. Increasing neural signaling of neurotransmitters and boosting alertness, cognition and memory. Studies have shown however that this upregulation of nAChR is dose de- pendent. And too much nicotine desensitizes these receptors.512 So low doses of nicotine are key in using nicotine as a nootropic for cognitive benefit. Since we’re investigating nicotine as a nootropic here, it’s important to point out that I am not encouraging smoking. Smoking tobacco has been shown to increase cognition. But the harmful effects of tobacco have been proven extensively.513 Including this study that showed life-time smokers have less gray matter in the prefrontal cortex compared to non-smokers. Affecting the brain’s reward, impulse control and decision-making circuits.514 New drugs derived from nicotine and research on nicotinic acetylcholine re- ceptors are in clinical trials for Alzheimer’s, ADHD, anger management, anxiety, depression, schizophrenia, Tourette Syndrome and wound healing.515 As a nootropic, we’re talking about using a nicotine lozenge or gum for cog- nitive enhancement. Again, I’m NOT talking about smoking tobacco. Smoking is the cause of 5 – 6 million deaths per year. Affecting 18 different organs in your body. But it’s not the nicotine in tobacco that kills. The biggest issue with using nicotine as a nootropic is that it can be addic- tive. But it’s not the nicotine that causes cancer. Nicotine however could be a “tumor promoter” (if you already have tumors in your body). Nicotine binds specifically to the nicotinic (nAChR) in your brain. And it deregulates essential processes like regulation of cell proliferation, apoptosis (programmed cell death), migration, invasion, angiogenesis, inflamma- tion and cell-mediated immunity of stem cells, adult tissues and cancer cells.516 As a nootropic, nicotine works in smalls doses (i.e. 1-2 mg) used occasionally 246 HEAD FIRST when you need that cognitive boost. If you have cancer or a tendency to tumor growth you should avoid using nicotine as a nootropic.

How does Nicotine work in the Brain? Nicotine boosts brain health and function in several ways. But two in par- ticular stand out. 1. Nicotine boosts memory. Nicotine binds to presynaptic nicotinic acetyl- choline receptors in the brain. And boosts the release of acetylcholine (ACh), dopamine, serotonin, and glutamate.517 Neurotransmitters known to be involved in cognitive processes. Problems with cholinergic signaling has been implicated in neurologic dis- orders including schizophrenia, ADHD and addiction. And much of the study of nicotine’s effects on cognition has been done looking for treatments for these disorders.518 The National Institute of Drug Abuse conducted a meta-analysis of 41 double-blind, placebo-controlled studies between 1994 and 2008. The analysis found significant positive effects of nicotine on fine motor performance, alertness, attention and accuracy, response time, short-term and working memory.519 2. Nicotine improves attention. Attention deficits are often associated with those dealing with ADHD. The inability to focus can cause all kinds of problems both in relationships, and on the job. Nicotine has been shown to improve attentiveness in smokers. And helps alleviate attention deficits in Alzheimer’s Disease, schizophrenics and adults with ADHD. A double-blind study conducted at Duke University Medical Center used nicotine patches to see if it would improve attentiveness in non-smoking adults without attention deficits. Subjects received 7 mg of nicotine per day using a transdermal patch for a 4 ½ hour morning session. Nicotine significantly decreased the number of omission errors during test- ing. And in this study, decreased the variance in “hit reaction time” which is used a measure of attentiveness. The study showed that nicotine reduced attention deficit, and even im- proved attentiveness in normal adult non-smokers.520

How things go bad As we get older, our brain chemistry and energy metabolism changes.521 ↓ Acetylcholine signaling in the brain declines ↓ Dopamine, norepinephrine, epinephrine and serotonin levels decline ↓ Alertness, attention and memory declines ↑ Anxiety, depression and stress increases 247 David Tomen All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia.

Nicotine to the rescue Nicotine boosts levels of dopamine, epinephrine (adrenaline), norepineph- rine and serotonin. And stimulates the growth of new blood vessels. Even increas- ing the number of red blood cells. Nicotine rapidly crosses the blood-brain barrier. Within 20 seconds of putting a nicotine lozenge under your tongue. It has the fastest action of any nootropic we review on Nootropics Expert, and in this book. Alpha brain waves increase with nicotine which provides a relaxed state as- sociated with super-learning, flow states and joy.522 Nicotine stimulates electrical and neurotransmitter activity throughout your brain. Helping alertness, mood, motivation, selective attention, sustained attention, and decreases distraction.523 Nicotine helps pre-attentional processing which is your ability to detect information. It brings you down when you’re up. And it brings you up when you’re down. And it helps you cope with stress and anxiety. And nicotine improves short-, long-, and working memory processes.524

How does Nicotine feel? Neurohackers report nicotine improves mental clarity and motivation. Mood swings are minimized and less anxiety. Concentration and focus significantly get a boost with nicotine as a nootropic. All forms of memory get a boost with nicotine. Short and long-term memory. And working memory. Nicotine induces long-term potentiation in the hippocampus which is the basis for the neuroplasticity that helps encode long- term memory.525 The key with nicotine is to use low doses. And only use it occasionally. Too much nicotine desensitizes the alpha-7 nicotinic acetylcholine receptor. So toler- ance is an issue. But your receptors recover fairly quickly if you give them a break for a day.

The Research Much of the research conducted with nicotine was done with cigarette smok- ers. The studies were to determine the effects of abstinence (quitting smoking) on cognition. Or funded by tobacco companies out to prove smoking was good for you (i.e. improved cognition). So keep an open mind when reviewing these studies. My intent is certainly not to encourage smoking. But to show the effects of nicotine regardless of the delivery system to the human brain. 248 HEAD FIRST Nicotine boosts IQ Researchers in New Zealand conducted a trial with 10 women and 6 men ranging in age from 18 – 32 years. All participants were smokers and were in- structed not to smoke during the 2-hour period prior to the experiment. Each subject completed the even and odd numbers of the Raven’s Advanced Progressive Matrices (APM) test in two sessions. APM is a test to measure intel- ligence (IQ). In each of 2 experimental sessions, subjects were given 20 minutes to com- plete the assigned half of the APM. Before beginning the test, subjects took 6 puffs of a medium (0.8 mg) cigarette every 20 seconds. After 10 minutes, subjects were prompted to take 2 additional puffs. Results of the experiment showed that APM scores were significantly higher in the smoking session compared to the non-smoking session. Suggesting that nicotine acts to enhance intelligence.526 Another study at the University of Colorado may explain part of this boost in IQ. Nicotine was found to increase the efficiency of neural communication between areas of the brain involved in cognition. And even the rest of the brain.527

Nicotine improves typing speed Researchers conducted 5 experiments to study the effects of using 2 mg of nicotine on keyboard typing speed. In study after study nicotine produced a reliably consistent increase in typing speed.528 Nicotine will also improve and increase the speed of your handwriting. Sci- entists in Germany noted that nicotine has consistently been shown to improve psychomotor performance. So they recruited 38 smokers and 38 non-smokers to participate in a study. Both groups received gum containing 0, 2 or 4 mg of nicotine. And their handwriting performance was assessed after they chewed the nicotine gum. Sub- jects were asked to perform a simple writing task. Movement time, velocity and acceleration of handwriting movements were measured. Nicotine reduced movement times, increased writing velocity and more fluid handwriting movements were observed. The results suggested that nicotine can enhance psychomotor performance to a significant degree in a real-lie motor task.529

Nicotine boosts memory Nicotine has been shown to improve short-term and working memory in several studies. In this study conducted in the UK, researchers recruited 60 smokers and 60 non-smokers in a double-blind procedure. Half of the subjects chewed nicotine gum and the other half chewed a pla- cebo prior to performing a memory task. Results showed that nicotine significantly improves short-term memory.530 249 David Tomen Nicotine for the treatment of ADHD Several studies have shown the benefits of nicotine in treating the symptoms of ADHD. Focusing and memory break down in those of us with ADHD and ADD. And treatment with Ritalin, Adderall or other stimulants often corrects this inattentiveness and memory impairment. But it does nothing for the ac- companying depression and anxiety. And this is the reason why many Adult ADHD sufferers smoke. This study showed that using a nicotine patch not only helped decrease anxiety and depres- sion symptoms of ADHD. It also helped smokers stop using tobacco products while taking care of their ADHD symptoms.531 In this study, nicotine was compared to the effects Ritalin and or a placebo had in treating ADHD. Nicotine improved performance and reduced errors. It decreased depression, and decreased overall severity of ADHD symptoms.532 Another double-blind, placebo-controlled trial worked with 6 smokers and 11 nonsmokers with Adult ADHD. Nicotine decreased ADHD symptoms, increased vigor, and improved reaction time.533

Dosage Notes Nicotine as a nootropic is dosed at 1 – 2 mg on an as needed basis. Nicotine gum typically comes in 2 – 4 mg. You can cut a 4 mg piece of gum in half for a 2 mg dose. Gum releases the nicotine dose over the course of 20 – 30 minutes. The problem with nicotine gum is aspartame along with other unhealthy sweeteners. Nicotine patches come in varying strengths and usually contain more nico- tine than gum or lozenges. Neurohackers (contrary to package warnings) cut the patch to size depending on the dose they want to use. My preferred method is nicotine lozenges. The mini-lozenges are best because they’re not full of toxic chemicals like the larger lozenges. The 2 mg mini-lozenge cut in half provides a nice cognitive boost in 10 – 20 minutes.

Side Effects Nicotine is addictive primarily because it boosts levels of dopamine in your brain.534 Not nearly as addictive as smoking tobacco but addictive nonetheless. Nicotine can cause increased heart rate, dizziness, cough, sneezing, sinus problems, upset stomach, constipation, and headaches. Nicotine does not “cause” cancer. But may be a tumor promoter. So if you had or currently have cancer you should avoid nicotine. If you are dealing with a gut infection of H pylori bacteria, you should not use nicotine until you get this problem under control. 250 HEAD FIRST Available Forms Nicotine as a nootropic comes in gum, inhalers, lozenges, and transdermal patches. See “Dosage Notes” for specific dosing instructions. Mini-lozenges are the safest and best form for nootropic use. Nicotine spray is a newer option you may want to try. You get a 1 mg dose for each spray under your tongue (sublingually). Great for a quick cognitive boost and burst of energy. There’s about 100 sprays in each container. Of course there is also smoking and chewing tobacco for your nicotine dose which I DO NOT recommend. Vaping is another option. But it can come with a host of potential issues if you’re not familiar with vaping. The safest option is rebuildable coils using stainless steel wire and organic cotton with vegetable glycerin as your nicotine base. And keeping the temperature and wattage low.

Nootropics Expert Recommendation

Nicotine 1 – 2 mg per dose I recommend using Nicotine as a nootropic supplement. Your body does not make nicotine on its own. So if you are going to supple- ment with nicotine, you must take it as a supplement. Nicotine is helpful for those dealing with short-, long – and working memory problems, low energy, depression or anxiety. Nicotine is especially helpful for dealing with the symptoms of Adult ADD or ADHD. Nicotine can help relieve most of the symptoms of ADHD. And is a good compliment to your existing ADHD meds. While nicotine is a powerful cognitive enhancer, it is also addictive and can lead to tolerance and withdrawal symptoms in some people. So caution is advised. And if you’re prone to addiction please stay away from nicotine. As neurohackers, we have great acetylcholine agonists available to us if you don’t want to experiment with nicotine. Most of the racetams will boost acetyl- choline use in the brain. I suggest starting with a dose of ½ – 1 mg of nicotine in mini-lozenge or spray form. Nicotine will compliment nearly everything in your current noot- ropic stack. There is no benefit to dosing more than 2 mg of nicotine for cognitive benefit. And too avoid addiction and tolerance I suggest only using nicotine occasionally.

251 David Tomen Noopept Noopept is known for boosting cognition, memory, learning, perception, logical think- ing and mood Noopept (n-phenylacetyl-l-prolylglycine ethyl ester or GVS-111) is often included in the racetam-family of nootropic compounds. But is not a true “race- tam” because it does not have a 2-oxo-pyrrolidine nucleus. Noopept was developed in Russia where it is called Ноопепт or GVS-111. Russian-based pharmaceutical company JSC LEKKO Pharmaceuticals synthe- sized Noopept in 1996 based off the endogenous neuropeptide cycloprolylglycine (CPG). Researchers in Moscow found Noopept similar to piracetam in not only it’s nootropic effect, but also anxiolytic activity.535 Noopept is a water-soluble ampakine nootropic. AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic) refers to one of three glutamate recep- tors in your brain.536 Noopept could also be considered a Cholinergic compound because it af- fects acetylcholine levels in the brain. Noopept does not appear in blood samples when taken as a supplement. Instead it elevates concentrations of cycloprolylglycine (CPG) in the brain. CPG is a dipeptide consisting of proline and glycine which acts as a modulator of acetylcholine transmission and AMPA receptor function.537 One of the newer synthetic nootropic compounds, Noopept is known as a cognitive enhancer. And is known for its anxiolytic, or anti-anxiety effects. Noopept is considered to be up to 1000-times more potent than Piracetam. As an ampakine nootropic, it helps increase attention span, alertness and boosts all three levels of memory; memory formation, retention and recall. Ampakines tend to have a stimulant effect. But do not produce the same stimulant side effects as Ritalin or coffee from prolonged use.

Noopept vs. Piracetam: What’s the Difference? Russian-based pharmaceutical company JSC LEKKO Pharmaceuticals devel- oped Noopept in the late 1990’s as a peptide analogue of the original nootropic Piracetam.538 Noopept and Piracetam are both water-soluble. And both Noopept and Piracetam are cognitive enhancers. Both have neuroprotective and anxiolytic (anti- anxiety) qualities.539 Both racetams are able to improve learning and memory. And both are able to repair brain damage. But Noopept has additional benefits not shared with Piracetam. First, the ef- fective dose of Noopept compared to Piracetam is 1,000-times lower. A typical dose of Noopept is 10 – 30 mg while Piracetam is often dosed up to 3 or 4,000 mg. Second, Piracetam facilitates only the early stages of the memory process. On 252 HEAD FIRST the other hand, Noopept influences memory consolidation AND retrieval steps as well. So Noopept helps you develop the memory, retain the memory, and then recall what you have stored in memory.540 Noopept also has additional selective anxiolytic (anti-anxiety) action. Researchers believe this is due in part to Noopept’s antioxidant effect, anti- inflammatory action, and the ability to prevent the neurotoxic effect of too much calcium and glutamate.

How does Noopept work in the Brain? Noopept boosts brain health and function in several ways. But two in par- ticular stand out. 1. Noopept modulates AMPA and NMDA receptors and acetylcholine (ACh) transmission. Noopept boosts the level of cycloprolylglycine (CPG) in the brain. CPG is a dipeptide consisting of proline and glycine which acts as a modulator of acetylcholine transmission, and AMPA and NMDA receptor function. When brain cells are starved of oxygen, glutamate which is your brain’s pri- mary excitatory neurotransmitter, does not work efficiently with neuroreceptors. The result can be a toxic buildup of glutamate within brain cells. Causing neuron damage and ultimately, neuron death. Noopept modulates neuroreceptor function keeping glutamate transmission at normal levels. Protecting neurons and other brain cells from glutamate damage. Noopept has also been shown to modulate acetylcholine flow in your brain. Restoring the harmony of glutamate and acetylcholine function not only protects your brain from damage. It can boost cognition, memory, learning, recall, mood and relieve anxiety. 2. Noopept increases Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and mRNA. NGF and BDNF are directly related to neu- roplasticity. This ability to repair and even grow new brain cells can have profound implications. Particularly with someone with neurodegenerative brain damage like Parkinson’s or Alzheimer’s. And even affecting Long-Term Potentiation needed for long-term memory development. mRNA affects the expression of genes and intracellular communication in brain cells. This ongoing brain signaling and gene expression within brain cells is required for healthy cognition. One study conducted in Moscow showed long-term use of Noopept boosted NGF, BDNF and mRNA. The animal subjects in this study showedno sign of tolerance. And long-term use of Noopept even potentiated the neurotrophic effect.541

How things go bad Glutamate is an excitatory relative of GABA. While GABA has a calming 253 David Tomen effect, glutamate stimulates. Glutamate is the most common neurotransmitter in the central nervous system. But glutamate can be toxic to neurons. And too much of it in your brain can kill brain cells. Lou Gehrig’s Disease for example, is caused by excess glutamate. But glutamate is a pivotal neurotransmitter in the brain. It links the brain circuits involved in memory, learning and perception. ↑ Too much glutamate can kill neurons ↓ Too little glutamate can cause problems with memory, learning and perception ↓ Acetylcholine levels decline ↓ Nerve Growth Factor declines ↓ Brain-Derived Neurotrophic Factor declines All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Noopept can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting NGF, BDNF and acetylcholine, and controlling glutamate in the brain.

Noopept to the rescue Noopept modulates AMPA and NDMA receptors. AMPA receptors are as- sociated with how glutamate and calcium is used in your brain. With Noopept, it’s more of a neuroprotective role. Similar to the AMPA receptor, the NMDA receptor is also associated with glutamate and calcium use in your brain. They work together to modulate how neurons use glutamate. Noopept modulates levels of glutamate within and between neurons. It prevents glutamate toxicity, and influences Long-Term Potentiation (LTP). LTP is associated with neuroplasticity that allows long-term memories to form. There is clinical evidence that Noopept boosts communication and neuron signaling. By boosting Alpha and Beta brain wave activity. You become calmer and more creative. It’s easier to go into a flow state. And you are prone to making innovative and resourceful decisions. Noopept produces an anxiolytic (anti-anxiety) effect. It stimulates dopamine receptors (D2 and D3) and acetylcholine nicotinic receptors. And Noopept also seems to modulate some serotonin receptors. All contributing to a better mood and less anxiety. Noopept has been shown in the lab to boost Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). NGF and BDNF are both involved in neuroplasticity, and the repair and replacement of damaged brain cells. Result- ing in overall better brain health, memory and cognition.542 Noopept is water-soluble and quickly enters your brain after you take it. Once in your brain, it boosts signal transmission, and protects neurons. 254 HEAD FIRST How does Noopept feel? Nootropics users report: • Noopept as a study aid. On its own, Noopept increases focus and attention for many neurohackers. Mental arithmetic and grasping difficult concepts is easier. • Increased verbal fluidity. Your conversation skills could increase with Noo- pept. Vocabulary comes easier. Being able to focus contributes to a more balanced dialogue. Neurohackers report being more outgoing, friendly and less self-conscious. • Improved mood. With Noopept you may find yourself better able to deal with stressful situations and work issues that normally get you down. Once you get past the first few weeks of unpleasant memories related to PTSD you may find overwhelming emotions will subside. You could feel detached in a pleasant way from painful memories. • Music appreciation. Many users report increased pleasure when listening to music while using Noopept. For some it takes music to a different plane. Distinguishing between instruments in sound tracks is easier. As a whole, music sounds better. • Long-term memory. Noopept affects NGF and BDNF which affects long- term potentiation. Some neurohackers report memories long forgotten suddenly spring up. Which could be good or bad I suppose depending on the memory. But reports say memories are clear. And if they’re unpleasant there is an emotional detachment shielding from unpleasant feelings. You should be able to experience the effects of Noopept soon after you take it. It’s water-soluble and enters your cells quickly especially if you take it sublingually. A word of caution however; don’t go over the recommended 10 – 30 mg per day dose! You will not experience any added benefit, and could bring on unwanted side effects. There is some debate on the water-solubility of Noopept. It’s not truly fat- soluble but it certainly doesn’t hurt to use a quality “good fat” when taking your Noopept dose.

The Research

Noopept increases Nerve Growth Factor & BDNF A study published by the Russian Academy of Medical Sciences in Moscow shows that Noopept stimulates Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). In this study, researchers studied the effect of single and long-term treatment 255 David Tomen (28 days) of Noopept. They found that one-time treatment boosted mRNA in the cerebral cortex of rats. mRNA is a molecule in brain cells that carries codes from DNA where they specify the amino acid sequence of proteins. And long-term treatment of Noopept increased Brain-Derived Neuro- trophic Factor (BDNF). The researchers speculated that this sequence of events in the brain plays a role in the restoration of neurons. Improving neurotrophin synthesis in the hippocampus boosts cognitive function. Particularly consolidation and delayed memory retrieval. The research team concluded that Noopept “holds much promise to prevent the development of Alzheimer’s disease in patients with mild cognitive impairment”.543

Noopept boosts Brain Waves Researchers in Moscow studied the effects of injecting Noopept in rats to see how it would affect brain waves. The team found that Noopept increased Alpha and Beta brain wave activity throughout the brain. You experience Alpha waves as you become more relaxed. Alpha waves are associated with super-learning, flow state and joy. Beta waves are associated with concentration, alertness and cognition. The researchers observed thatNMDA receptors were involved with a single injection of Noopept. While AMPA receptors were activated after longer-term use of Noopept.544 NMDA receptors are associated with Long-Term Potentiation (long-term memory) and neuroplasticity. AMPA receptors are associated with increased brain signaling activity. Boosting cognition and memory.

Noopept improves memory Noopept is known within the nootropic community for enhancing memory. And dozens of studies support this claim of better memory when using Noopept. One study done at the Russian Academy of Medical Sciences in Moscow experimented with Noopept on rats. The animals were trained in passive avoid- ance response. The animal’s ability to both form a memory and retain a memory was im- paired. But once the rats received a dose of Noopept, they were able to retain a memory and retrieve that memory later. In other words, Noopept normalized learning capacity in animals with damage done to their cerebral cortex. And promoted training ability in rats with a hereditary learning deficit. The researchers noted that “Noopept improves all three stages of memory”. And was most pronounced in those with impaired memory function.545 Another study, again done with rats noted that Noopept stimulated learning after just a single administration. And repeated administration actually increased 256 HEAD FIRST the number of successful learners among the animals who failed the initial training.546

Dosage Notes Recommended Noopept dosage is 10 – 30 mg per day. Noopept is very bioavailable and easily crosses the blood-brain barrier.547 Noopept is sold in tablet, capsule and powder form. Tablets and capsules are usually 10 mg each. Noopept is primarily water-soluble nootropic, but won’t easily dissolve in water or juice. So it may help if you take it with a meal containing healthy fats. Or with a tablespoon of extra virgin, expeller cold-pressed coconut or olive oil. Or other similar healthy fat to ensure quick absorption. For even quicker absorption you can use Noopept sublingually. Let the tablet or powder dissolve under your tongue so it can go straight into your blood- stream, and into your brain. Bypassing your digestive system completely.

Side Effects Noopept is a synthetic nootropic and consider non-toxic. So is considered well-tolerated and safe. As long as you stay within the recommended dosage. Side effects are rare but can include fatigue, headaches, insomnia or stomach upset. Side effects are often a result of unusually high doses of the nootropic. Headaches from using Noopept typically happen when you forget to com- bine it with a good choline supplement. Headaches are often a symptom of a choline deficit in your brain.

Available Forms Noopept is sold in tablet, capsule and powder form. Tablets and capsules are usually 10 mg each. In Russia and some other Eastern European countries, Noopept is a prescrip- tion drug.

Nootropics Expert Recommendation

Noopept 10 – 30 mg per day I recommend using Noopept as a nootropic supplement. Your body does not make Noopept on its own. So to get its benefits you must take it as a supplement. Noopept is especially helpful for those looking to boost cognition, memory and recall. This nootropic helps boost the activity of acetylcholine in your brain. It modulates glutamate receptors which normalizes optimal neurotransmitter function. And increases Nerve Growth Factor (NGF) and Brain-Derived Neuro- trophic Factor (BDNF) which helps the neuroplasticity needed for Long-Term Potentiation. 257 David Tomen Noopept is also particularly useful to students and executives who want to boost cognition, learning and memory. My experience using Noopept shows it helps boost study scores, work flow, learning and memory. Noopept also helps improve verbal fluidity and sociability. Words seem to come easily, and vocabulary you didn’t know you had access to come into play. Music sounds richer and fuller, and your listening experience enters a new level of music appreciation. You should use Noopept with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You should not exceed doses of more than 30 mg per day. Start with 10 mg and see how you respond.

258 HEAD FIRST Oat Straw

Oat Straw has been shown to relieve stress and anxiety, increase energy, boost cogni- tion, and improve libido Oat Straw (avena sativa) is green oat grass. The tops of the oat plant in the milky stage before mature oat plants form a head. Avena sativa, or the common oat plant is a popular cereal grain that has been used by humans as nutrition for at least 3,000 years. Oats are grown in temperate climates world-wide as food for humans and livestock. And as an ingredient used in cosmetics. The oat plant is descended from avena sterilis, a wild oat that originated in the ‘Fertile Crescent’ that spanned from Israel to western Iran to Europe. It was domesticated about 3,000 years ago in Europe. Tea brewed from oats has traditionally been used as a sedative. And as an herbal treatment for insomnia and nervous disorders. In 1987, the German Commission E declared oat straw be used as a “nervine herb”. The Commission determined that oat straw extract was an effective herbal remedy for anxiety and stress (i.e. nerves).548 The nootropic benefits of Oat Straw were first revealed in the Middle Ages in Europe. In was recommended for boosting mental health, and as a restorative to the nervous system.549 Saint Hildegard of Bingen, a nun and herbalist born in 1098 in what is now present-day Germany, considered oats to be a favorite ‘happiness’ herb.550 Avenanthramides (bioactive compounds unique in oats) have been shown to enhance nitric oxide (NO) production in human smooth muscle cells.551 And have anti-inflammatory, anti-proliferative, and anti-itching activity. Protecting against heart disease, colon cancer and skin irritation.552 Oat straw extract inhibits phosphodiesterase type 4 (PDE4). PDE4 is a compo- nent of signaling pathways involved in the mediation of antidepressant activity.553 Oat straw has a reputation in men’s health as a sexual performance enhancer. More recent studies have shown oat straw can improve cognitive performance as well. PDE4 inhibitors can prolong the effects of cAMP in the brain which can improve long-term memory, wakefulness, is neuroprotective, works as an anti- inflammatory and antidepressant. Oat straw extract inhibits monoamine oxidase B (MOA-B) which increases dopamine levels in the brain. Helping brain disorders like ADHD and Parkin- son’s Disease.554 Oat straw extract suppresses inflammatory cytokines by inhibiting nuclear factor κB (NF-κB) activation555 Cytokines are implicated in a number of brain disorders including major depression, schizophrenia and Alzheimer’s Disease.556 259 David Tomen How does Oat Straw work in the Brain? Oat Straw boosts brain health and function in several ways. But two in particular stand out. 1. Oat Straw boosts cerebral circulation. Oat straw extract increases blood flow to and within the brain through several mechanisms of action. Oat straw contains the amino acid arginine which synthesizes to create nitric oxide (NO). NO dilates blood vessels allowing more blood to flow. Avenanthramides (bioactive compounds unique in oats) have been shown to enhance nitric oxide (NO) production in human smooth muscle cells. And the suppression of inflammatory cytokines in combination with increased nitric oxide increases blood flow. A study with 37 healthy older adults (60+ years) participated in a 24-week randomized, double-blind, placebo-controlled trial. Participants received 1500 mg per day of oat straw extract or a placebo. The study showed that cerebral vascular responsiveness increased by 42%. This indicates that the middle cerebral artery was able to dilate in response to stress.557 And more blood flow to the brain increases oxygen and nutrient delivery to brain cells. 2. Oat Straw increases Alpha Brain Waves. You experience alpha brain wave patterns as you become more relaxed. And is associated with super-learning, flow states and joy. German researchers conducted a double-blind, randomized, placebo-con- trolled crossover study using 1,250 or 2,500 mg of oat straw extract compared to placebo. An EEG was used to measure brain wave frequencies in this trial. The researchers noted that oat straw extract affected brain wave patterns in an area of the brain associated with cognition. The subjects performed better in arithmetic with fewer errors.558

How things go bad Ever noticed how older people seem more frail? They suffer from cognitive dysfunction and an overall decline in well-being. Research show these conditions are associated with a drop in dopamine levels as we age.559 ↓ Dopamine levels decrease ↑ Monoamine oxidase B (MOA-B) increases ↓ Mood, cognition and bodily function decline Dopamine levels begin to decline by 13% per decade after age 45.560 Cogni- tion, mood and sexual function all suffer as a result. And gradually progress into diseases such as Alzheimer’s and Parkinson’s. 260 HEAD FIRST Oat Straw to the rescue Researchers have found that this age-related decrease in dopamine is caused by an enzyme called monoamine oxidase-B (MAO-B). In our youth, MAO-B regulates the exact amount of dopamine we need in our brain. But as we age, MAO-B levels get out of hand and increase too much.561 As MOA-B levels rise, dopamine levels fall. Research has shown that inhibition of MOA-B preserves brain function by protecting dopamine. And extends cognition, sexual function and life span.562 Oat Straw extract has been found to inhibit MOA-B, and enhance dopamine that normally declines with age.563 Oat straw extract can: • Work as an antidepressant • Help you cope with stress • Reduce anxiety • Control inflammation • Relieve skin irritation • Increase libido and sexual performance

How does Oat Straw feel? Most neurohackers report that supplementing with oat straw extract in- creases energy levels and libido. Others report more mental clarity, less anxiety, and an overall sense of well-being. Men say it increases libido and morning wood.

The Research

Oat Straw Improves Memory An Australian study was conducted with a group of elderly people. Some showed signs of mild cognitive impairment while others showed no impairment. Researchers wanted to measure cognitive performance after taking oat straw extract. Subjects were randomly assigned to receive a single dose of oat straw extract once a week. The study used 0 mg, 1,600 mg or 2,400 mg of oat straw extract. This was a “crossover” trial which means each subject was rotated through all 3 doses. So each participant functioned as a “control” during the trial. Researchers used the Stroop Color-Word Test which measures memory, execu- tive function, catching errors, appropriate responses and attention. In this study, those who did not use oat straw extract had an average of 261 David Tomen 3.39 errors on the test. Those receiving 1,600 mg made only 1.2 errors (a 65% improvement). The subjects who reported no cognitive impairment did even better with an average of 0.55 errors compared to placebo who averaged 2.13 errors (a 74% improvement). The 2,400 mg subjects performed about as well as those taking a placebo. The 2,400 mg dose of oat straw extract is significant because it shows that suppressing MAO-B too much will not improve cognition.564

Oat Straw for Improved Cognition A study using oat straw extract (Neuravena®) assessed the effects of a single dose with healthy adults aged 40 – 65 years with self-declared memory decline. Participants received a single dose of 800 or 1,600 mg of oat straw extract. Cognitive function was assessed measuring attention, spatial-working-episodic memory and executive function before dosing. Testing was done 1, 2.5, 4 and 6 hours after dosing. The results showed that 800 mg of oat straw extract increased speed of performance. Participants experienced improved performance of delayed word recall in terms of errors. And executive function in terms of decreased thinking time and overall completion time. The researchers concluded that acute (one-time) dosage of oat straw extract produced optimal effects on cognition at or below 800 mg. Once again showing that when inhibiting MOA-B, too much inhibiting does more harm than good.565 Oat straw extract enhances attention and concentration without the side effects of insomnia, nervousness, or anxiety.

Dosage Notes Oat straw extract recommended dosage: • Oat straw powder in a capsule is 350 mg up to 3-times daily • Oat straw tincture ½ to 1 teaspoon up to 3-times daily • Oat straw tea up to 3 cups per day Most clinical studies showed the most effective dose to be between 800 – 1,600 mg per day. You should not exceed the recommended dosage because studies show that inhibiting MOA-B in excess will not provide the benefits normally associated with oat straw supplementation.

Side Effects Oat straw is natural, non-toxic and considered very safe. Exceeding recommended doses however can inhibit MOA-B too much and you will not get the cognitive benefit you’re looking for with oat straw. 262 HEAD FIRST Available Forms Oat straw is available as powdered leaves and stems in capsule form, oat straw extract standardized 10:1 or 20:1, and alcohol extract tinctures. Neuravena® (EFLA®955) is a patented oat straw extract made by Frutarom Health and licensed to some supplement manufacturers.

Nootropics Expert Recommendation

Oat Straw extract 800 – 1,600 mg per day I recommend using Oat Straw as a nootropic supplement. Your body does not make Oat Straw on its own. So you must take it as a supplement. Oat Straw is especially helpful for those dealing with dopamine decline due to aging. As we age and particularly past age 40, MOA-B is produced in excess in our brains which causes dopamine to decline. Declining dopamine levels affect cognition, sexual function, mood and lon- gevity. Oat straw extract is a natural inhibitor of MOA-B and will help restore dopamine to youthful levels. Oat Straw is also helpful for those suffering from Parkinson’s or Alzheimer’s disease. Increased MOA-B, loss of dopamine receptors, and declining dopamine levels all contribute to neurodegenerative disease. Studies have found that using oat straw extract early in the diagnosis of disease can help alleviate symptoms of these diseases. You can safely take up to 1,600 mg of Oat Straw extract daily if needed. Half the dose first thing in the morning. And the other half early afternoon. Oat straw extract acts as a stimulant so avoid taking it too late in the day or it may affect sleep. Do not exceed recommended doses (more than 1,600 mg) of oat straw ex- tract. You’ll suppress MOA-B too much which can mess with dopamine levels in your brain.

263 David Tomen Oxiracetam

Oxiracetam has been shown to improve short and long-term memory, boost concentra- tion and focus, improve cognition and increase cognitive energy Oxiracetam (4-Hydroxy-2-oxopyrrolidine-N-acetamide or ISF-2522) is a water-soluble Ampakine nootropic in the racetam-class of compounds. Oxirace- tam is considerably more potent than the original racetam, Piracetam.566 Oxiracetam was the 3rd racetam nootropic developed in the 1970’s. It is chemically derived from Piracetam (2-oxo-1-pyrrolidinoacetamide) where the main difference is the addition of a hydroxyl group. Oxiracetam, similar to other racetam nootropics, has a pyrrolidone nucleus at its core. Oxiracetam modulates AMPA-sensitive glutamate receptors, and in- creases neurotransmitter release.567 AMPA (α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic) refers to one of three glutamate receptors in your brain.568 A favorite racetam among the nootropics community. Neurohackers use Oxiracetam to boost memory and learning, support brain health and for its mild stimulant properties. Oxiracetam helps: • Brain Optimization: Oxiracetam significantly improves cognition and memory, sensory perception and reflexes. Focus and concentration get a boost. And recall is easier. • Neurotransmitters: Oxiracetam enhances choline-acetyltransferase (ChAT) in your brain.569 ChAT is the enzyme responsible for acetylcholine (ACh) synthesis. ACh is the neurotransmitter critical for encoding new memories, reasoning, concentration, cognition and neuroplasticity. • Brain Energy: Oxiracetam modulates AMPA-receptors in your brain. Ampak- ines provide a stimulant-effect by influencing glutamate receptors. Without any of the side effects associated with stimulants.570 Oxiracetam also seems to boost ATP synthesis in brain cells.571 Oxiracetam is sold as an over-the-counter, unrestricted compound in much of the world including the United States. Oxiracetam is considered to be more potent than Piracetam. As an ampa- kine nootropic, it helps increase attention span, alertness and boosts memory. Including the ability to form long-term memories even if taken after the initial memory formation.572 Ampakines tend to have a stimulant effect. But do not produce the same stimulant side effects as Ritalin or coffee from prolonged use.

Oxiracetam vs. Piracetam: What’s the Difference? Oxiracetam was developed in the 1977 as a derivative of Piracetam. 264 HEAD FIRST Oxiracetam and Piracetam are both water-soluble. The half-life and noot- ropic benefits are similar. The potency of Oxiracetam seems to be about 5-times that of Piracetam. So it’ll take less to get the same nootropic effect. Both Oxiracetam and Piracetam are cognitive enhancers. And both have neu- roprotective qualities. Both racetams are able to improve learning and memory. And both are able to repair brain damage. Oxiracetam has additional benefits not shared with Piracetam. Oxiracetam provides more of a stimulatory effect than Piracetam. Some even compare it to Modafinil. Many prefer Oxiracetam over Piracetam. But if you’re a first-time user of Oxiracetam, start with a lower dose and see how you react to it. And make sure you stack it with a good choline source to avoid the racetam-headache and ir- ritability sometimes associated with racetams.

How does Oxiracetam Work in the Brain? Oxiracetam boosts brain health and function in several ways. But two in particular stand out. 1. Oxiracetam boosts memory and cognition. Oxiracetam modulates AMPA receptors in the brain. These receptors work like control channels, overseeing and regulating synaptic transmission. Oxiracetam also increases the density of binding sites for neurotransmitters on AMPA receptors.573 The result of these actions is a stimulant-effect without any of the negative side effects associated with stimulants. And there is clinical evidence that this stimulant action has an effect on memory and cognition. One double-blind, placebo controlled trial was done with 65 patients di- agnosed with primary degenerative dementia. Patients were given 800 mg of Oxiracetam twice daily for 12 weeks, or a placebo. Subjects were tested before the trial, and after 6 and 12 weeks of treatment. The researchers found a significant difference in favor of Oxiracetam based on a ‘quality of life scale’, and several neurological tests for memory.574 Oxiracetam also seems to prevent an imbalance of acetylcholine activity when NMDA receptors are malfunctioning.575 AMPA and NMDA receptors work to- gether for the flow of glutamate necessary for learning and memory processes. Including Long-Term Potentiation that is associated with neuroplasticity that allows long-term memories to form. 2. Oxiracetam boosts the availability of acetylcholine (ACh) in the brain. Leading to improved short-term and long-term memory. And eliminating ‘brain fog’. Oxiracetam does this by boosting the sensitivity of ACh receptors. Oxiracetam enhances protein kinase C (PKC) which affects M1 acetylcholine 265 David Tomen receptors. Oxiracetam even demonstrates the ability to repair these receptors when damaged.576 More ACh results in better memory and learning.

How things go bad Glutamate is an excitatory relative of GABA. While GABA has a calming effect, glutamate stimulates. Glutamate is the most common neurotransmitter in the central nervous system. Glutamate is a pivotal neurotransmitter in the brain. It links the brain cir- cuits involved in memory, learning and perception. ↓ Too little glutamate can cause problems with memory, learning and perception ↓ AMPA and NMDA receptors wear out or die ↓ Acetylcholine levels decline ↓ Cholinergic neurons wear or die out All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Oxiracetam can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting acetylcholine and controlling gluta- mate in the brain.

Oxiracetam to the rescue Clinical studies have looked at using Oxiracetam to treat Alzheimer’s, ADHD, dementia, concussions and other brain disorders. Many of these trials demonstrated Oxiracetam’s ability to improve learning, spatial learning perfor- mance, memory, recall and quality of life scores. Oxiracetam works similar to other racetams by targeting the neurotransmit- ters acetylcholine (ACh) and glutamate. ACh has a significant impact on memory formation and recall. And glutamate plays a role in memory formation, motiva- tion and attention. Oxiracetam encourages the use of acetylcholine in your brain. So when using Oxiracetam you must ensure you have adequate choline levels available to make acetylcholine. Most neurohackers stack Oxiracetam with a choline supplement like Alpha GPC or CDP-Choline. Oxiracetam is used to boost short and long-term memory, eliminate brain fog, improve attention and focus, and the ability to learn.

How does Oxiracetam feel? Nootropics users report that Oxiracetam clears brain fog, improves focus and motivation. Especially when learning new material or working through a tedious task. You could see a significant improvement in recall. Reading is easier giving 266 HEAD FIRST you the ability to get through more pages faster and retain the information for later. And some report an improvement in mood which could be the result of more acetylcholine available for use in the brain. Oxiracetam does have a stimulant-effect so try not to take it too late in the day as it may interfere with a good night’s sleep. You should be able to experience the effects of Oxiracetam soon after you take it. It’s water-soluble so it’s digested and enters your cells quickly. And unlike other stimulants, there is no “crash” once Oxiracetam leaves your system.

The Research Researchers worked with 96 patients diagnosed with dementia for 12 months. Patients were treated with 1600 mg per day of Oxiracetam or a placebo. And were assessed at 2, 6 and 12 months of the trial. The patients treated with Oxiracetam showed a significant improvement in reaction time and cognition. The placebo group experienced a worsening of conditions. The study authors concluded that Oxiracetam favorably acts on the symptoms of dementia. And can improve information processing, reaction times and attention.577

Oxiracetam helps Traumatic Brain Injury Traumatic brain injury (TBI) is a major public health issue affecting 1.7 mil- lion Americans each year.578 TBI can be caused by sports injuries, work accidents, car and motorcycle accidents, falls, and your wife hitting you over the head with a frying pan. Many survivors end up with long-term or even permanent neurocognitive dysfunction. Affecting cognition, motor function (movement) and personality. These disabilities are estimated to cost $9.2 billion in lifetime medical costs and $51.2 billion in productivity losses.579 In a brain subjected to TBI there is glutamate toxicity, free-radical injury to brain cells, electrolyte imbalances, mitochondrial dysfunction, inflammation, apoptosis (cell death) and stroke.580 In one study done with 30 Wistar rats, researchers looked at the role Oxi- racetam could have on TBI. The animals were randomly divided into 3 groups. Rats in the treatment group were given 100 mg/kg of Oxiracetam for 21 days. Neurologic impairment scores were measured on days 1, 4, 7, 14 and 21. The researchers found the treatment group has significantly less brain im- pairment after 7, 14 and 21 days. And concluded that Oxiracetam shows promise in decreasing neural injury caused by TBI. Increasing learning ability, memory and space cognition.581

Oxiracetam Improves Cognition and Memory Researchers worked with 43 patients to evaluate the effects of Oxiracetam on 267 David Tomen ‘organic brain syndrome’ (OBS). OBS is brain dysfunction that is not attribut- able to a specific disease like Alzheimer’s or dementia. This double-blind, placebo-controlled study had one group of patients taking 800 mg of Oxiracetam twice a day for 8 weeks, and the other group took a placebo. In OBS patients with mild to moderate cognitive impairment, Oxiracetam improved cognition, logic and attention. The placebo group experienced no change in cognitive impairment.582 Another study with memory impaired rats showed that Oxiracetam restored acetylcholine receptors. Restoring learning and memory as a result.583

Dosage Notes Recommended Oxiracetam dosage is 750 – 1,500 mg per day. Divided in two equal doses. One Oxiracetam dose in the morning, and one in the early afternoon. Oxiracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each. Since Oxiracetam boosts the efficiency of acetylcholine in your brain, you should stack it with a good choline source like Alpha GPC or CDP Choline.

Side Effects Oxiracetam non-toxic. So is considered well-tolerated and safe. Side effects are rare but can include anxiety, fatigue, headaches, nervousness and nausea. Side effects are often a result of unusually high doses of the nootropic. Headaches from using Oxiracetam typically happen when you forget to combine it with a good choline supplement. Headaches are often a symptom of a choline deficit in your brain.

Available Forms Oxiracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each.

Nootropics Expert Recommendation

Oxiracetam 750 – 1,500 mg per day I recommend using Oxiracetam as a nootropic supplement. Your body does not make Oxiracetam on its own. So to get its benefits you must take it as a supplement. Oxiracetam is especially helpful for those suffering from lack of energy, brain fog and the inability to focus. Oxiracetam influences AMPA and NMDA recep- tors in your brain. Improving the efficiency of the neurotransmitter glutamate. This excitatory brain chemical is responsible for sending signals between neuron in the brain. And plays a critical role in learning and forming memories. 268 HEAD FIRST Oxiracetam is also particularly useful to students and executives who want to boost cognition, learning and memory. It boosts the efficiency of the neu- rotransmitter acetylcholine (ACh) in your brain. ACh is critical for encoding new memories, reasoning, concentration, cognition and growth of new synapses (neuroplasticity). Oxiracetam also helps improve verbal fluidity and sociability. Words seem to come easily, and vocabulary you didn’t know you had access to come into play. You should use Oxiracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Oxiracetam to 2,800 mg if needed.

269 David Tomen Phenibut

Phenibut has a calming effect on brain and body, helps relieve stress and anxiety, and boosts Human Growth Hormone Phenibut (β-Phenyl-GABA, β-phenyl-γ-aminobutyric acid, Noofen, Citrocard) is an analogue of the inhibitory neurotransmitter GABA. The ad- dition of a phenyl ring allows Phenibut to cross the blood-brain barrier (BBB). Neurohackers prefer Phenibut when the goal is to raise GABA levels in the brain because GABA as a supplement cannot cross the BBB. Clinical studies show that boosting GABA with a supplement like Phenibut relieves anxiety, stress, and boosts the production of alpha brain waves.584 If GABA is optimized in your brain you’ll feel focused, relaxed and stress-free. Phenibut helps: • Balance mood. Phenibut has an inhibitory effect on overly stimulated neurons because it raises GABA levels in your brain. Low GABA levels lead to anxiety, depression and insomnia. GABA helps restore that balance. Promoting a more positive mood which improves focus and relaxation.585 • Boost Human Growth Hormone. Bodybuilders and athletes use Phenibut before resistance training. Studies show by raising GABA levels, you can boost blood levels of Human Growth Hormone.586 Promoting greater re- covery support and lean muscle growth. • Neurotransmitters. Phenibut stimulates dopamine receptors, and antago- nizes beta-phenethylamine (PEA).587 Dopamine aids in memory formation, attention, focus, and cognition. PEA increases the action of dopamine, nor- epinephrine, acetylcholine and serotonin. It’s partly behind the overstimu- lation that causes irritability, restlessness, and agitation that could be caused by too much dopamine and norepinephrine. Phenibut can counteract this affect giving you a cognition boost without the negatives.588 GABA (gamma-aminobutyric acid) is the major inhibitory or relaxing neu- rotransmitter in your brain.589 GABA’s primary role is to keep the major excitatory neurotransmitter glutamate in check. GABA is naturally synthesized in your brain from glutamate. It’s estimated that 40% of the synapses in the human brain work with GABA and therefore have GABA receptors. So when using Phenibut to boost GABA, you enhance normal sleep cycles, and improve blood pressure. GABA even stimulates the pituitary gland to secrete Human Growth Hormone. And helps produce endorphins that make you feel good after a workout or sex. Soon after Phenibut was discovered in St. Petersburg, Russia, it was being prescribed by doctors to lower stress and anxiety, treat PTSD and insomnia. 270 HEAD FIRST Phenibut was included in the medical kit for Russian astronauts on the Soyuz-19 and Salyut-4 missions as a ‘tranquilizer’.590 Phenibut is one of the only tranquilizers that lowers stress levels without negatively affecting performance. As a nootropic, when you use Phenibut to normalize GABA levels you’ll experience a reduction in anxiety, insomnia, nervousness, restlessness and stress. Phenibut can be a more natural, safer alternative to Benzodiazepine drugs like Valium and Xanax. These pharmaceuticals work by increasing GABA recep- tor sensitivity.591

How does Phenibut Work in the Brain? Phenibut helps brain health and function in several ways. But two in par- ticular stand out. 1. Phenibut boosts GABA in the brain. Phenibut is a derivative of GABA. And easily crosses the blood-brain barrier. GABA on its own cannot cross this barrier unless paired with a dedicated carrier.592 GABA works by preventing neural signaling associated with anxiety from reaching other neurons. It does this by attaching to the receptors that would otherwise excite those neurons. Over-stimulating neurons in certain areas of your brain is what causes anxiety-related symptoms. The majority of studies on Phenibut have been conducted in Russia. And most studies have been done with animals. In this study using rabbits, scientists looked at anxiety behaviors and how they were effected by Phenibut. They exposed the rabbits to emotional stimuli causing anxiety in the animals. Anxiety caused the rabbits to ‘freeze’ and exhibit defensive reactions. Behaviors very similar to what happens in humans when they’re under stress. When the rabbits were administered Phenibut, the anxiety-caused reactions of defensiveness and passive reactions (freezing) decreased to normal behavior.593 2. GABA changes brain waves. Using Phenibut as a nootropic helps increase GABA levels in your brain. And we know that GABA helps decrease Beta brain waves and increase Alpha brain waves.594 Beta brain waves are important for attention, alertness, concentration and developing memories. But excess levels of concentration, particularly during stress, can lead to anxiety, depression, insomnia and more stress. When you are in an alert state, both Alpha and Beta brain waves can be stimulated. But the type of alertness will determine which brain wave is produced. Alertness during an Alpha wave state is associated with a relaxed state. And a stressed alert state produces a Beta wave. But an excess of Beta brain waves contributes to a variety of nervous disorders including anxiety and stress. Most of the clinical studies available done with humans use GABA supple- mentation rather than Phenibut. But the outcome of using GABA could be 271 David Tomen applied to using Phenibut to increase GABA levels in the brain. Phenibut crosses the blood-brain barrier more effectively than GABA. In this study, researchers investigated using GABA on relaxation and immu- nity during stress in humans. They evaluated the effect on 13 subjects of GABA intake on brain waves. An electroencephalogram (EEG) was used to measure brain waves after subjects took water only, GABA or L-Theanine. 60 minutes after administration, the study showed that GABA significantly increased Alpha waves and decreased Beta waves compared to water or L-Theanine. The researchers concluded that raising brain levels of GABA induced relax- ation and diminished anxiety.595 And you raise brain levels of GABA effectively when supplementing with Phenibut.

How things go bad Low levels of GABA are associated with a variety of health problems. ↑ Anxiety596, panic attacks, stress and insomnia ↑ Muscle spasms, hypertension, convulsion, Tourette’s Syndrome and epilepsy ↑ Dry skin and wrinkles ↑ Poor digestion, bloating, flatulence, and constipation When your neurotransmitters, including GABA, are in balance, you feel motivated, productive and energetic. And you feel calm and relaxed during downtime. When GABA levels are low you feel filled with dread, you’re constantly wor- ried, you have racing thoughts, and you’re frequently late and disorganized.597 Many people in this GABA-slump resort to high carbohydrate foods, and drugs or alcohol to relax.

Phenibut to the rescue Phenibut is an analogue of GABA. The addition of a phenyl ring allows Phenibut to cross the blood-brain barrier much more easily than GABA taken as a supplement. We need adequate GABA levels in our brain because it’s an inhibitory neu- rotransmitter. When we raise GABA levels by supplementing with Phenibut, we help keep glutamate in check. Glutamate is your body’s most abundant excitatory neurotransmitter. Which is responsible for attention span, brain energy, learning ability, memory, and staying awake. So GABA is calming and glutamate is stimulating. And they must be in bal- ance with each other for optimal cognitive health. An imbalance of these two neurotransmitters can cause fibromyalgia, chronic fatigue syndrome, poor memory and cognition, anxiety and depression. 272 HEAD FIRST But when these two neurotransmitters work together efficiently, you feel re- laxed with no stress or feelings of anxiety. And you get a more restful night’s sleep. Adding Phenibut to your nootropic stack can help bring GABA and gluta- mate back into balance.

How does Phenibut feel? When you balance GABA levels in your brain, you feel relaxed and calm. But many neurohackers who try using GABA as a supplement don’t feel the effects. Because the GABA molecule is too large to cross the blood-brain barrier.598 Note: If you do feel the calming effects of supplementing with GABA within a ½ hour of taking it, it may mean you have a “leaky” blood-brain barrier. Not a good thing.599 Because if GABA can get through, all kinds of nasty stuff can get through too. Including toxins, undigested food particles and anything else in your blood stream that shouldn’t be in your brain. But here were talking about increasing our GABA levels using Phenibut. Neurohackers report that adding Phenibut to their stack relieves anxiety, there is less stress and they feel more relaxed. In fact, some say it’s the best anti-anxiety ‘medication’ they’ve ever used. Including some well know pharmaceuticals (i.e. Clonazepam, Diazepam, Alpra- zolam) used to treat anxiety. With none of the nasty side effects that come with prescription meds. Social functions could get some help with Phenibut. You could feel less inhibited, speak freely and feel more confident. Others report that Phenibut boosts sex drive, and for men it helps control ejaculation. And it helps for a better night’s sleep. Athletes report that Phenibut goes well with a workout. Because Phenibut has been shown to boost Human Growth Hormone. You’ll be able to work out with less fatigue, energy levels will go up, muscles won’t be as sore and recovery could be faster. Phenibut takes 2 – 4 hours before you begin to feel its effects. A strong word of caution: do not increase the dose or take additional Phenibut if you think things are not happening fast enough! Wait at least 24 hours before taking another dose.

The Research GABA was identified as a neurotransmitter several decades ago. And there had been a lot of research on GABA published since. But most of it is focused on how GABA works. And the drugs and chemicals which affect its action. There is very little research available on using GABA as a supplement. Likely because most scientists believe that GABA taken as a supplement will not cross the blood-brain barrier. And there is even less research available on using Phenibut. Particularly in 273 David Tomen humans. Most of the clinical trials have been done in Russia and were done with animals. Here we talk about how GABA can affect your cognition and overall health. This research supports the idea that using Phenibut to raise GABA levels can have a profound effect on your quality of life.

GABA Increases Human Growth Hormone Bodybuilders and athletes use Phenibut or even GABA to help repair and build muscle. And there are several studies supporting the notion that GABA increases Human Growth Hormone. In one study, researchers worked with 19 subjects who were given a single oral dose of 5 grams of GABA. 18 subjects were given a placebo during this trial. 3 hours after the administration of GABA, blood samples were taken. The team reported that “GABA caused a significant elevation of plasma growth hormone levels”.600

GABA helps Reduce Insomnia A Los Angeles study conducted a randomized, double-blind, placebo con- trolled trial with 18 patients with sleep disorders. The patients received either a placebo, or Gabadone (a combination of GABA and 5-hydroxytryptophan). The difference between the two groups of sleep-deprived patients was signifi- cant. The Gabadone group fell asleep faster, stayed asleep longer, and had a better quality of sleep than the placebo group.601 Neurohackers consistently report a similar effect on sleep quality when using Phenibut.

Dosage Notes The recommended daily starting dosage of Phenibut is 200 – 300 mg for a relaxation or calming effect. Give it 2 – 4 hours before it starts to kick in. More experienced Phenibut users go with 1 – 1 ½ grams per dose. And up to 3-times per week. Since you can quickly build up a tolerance to Phenibut dosing less often is preferred. Many advise keeping Phenibut use to once or twice per week with almost no side effects and no hangover the next day. Phenibut can be very addictive for some people and the withdrawal from continuous use is particularly nasty. So if you’re going to try Phenibut make sure you follow dosage recommendations.

Side Effects Phenibut is considered safe when taken in normal recommended doses. Bodybuilders who use much higher doses of Phenibut do report experienc- ing flushing, tingling, a spike in heart rate and blood pressure, and anxiety. 274 HEAD FIRST You can build up tolerance to Phenibut quickly. And if you have an addictive personality you should avoid using Phenibut. Most neurohackers suggest cycling Phenibut. Using recommended doses for 4 or 5 days and taking a few days off. Others suggest only using Phenibut once per week. You’ll have to find out what works for you if you decide to try Phenibut. And expect to have a rough ride at first. Too much and the withdrawal can be nasty. You are strongly advised not to combine Phenibut with alcohol. And abso- lutely DO NOT combine Phenibut with benzodiazepines.

Available Forms Phenibut as a supplement is available in tablet, capsule and powder. Scien- tists have shown that Phenibut easily crosses the blood-brain barrier. Phenibut is an analogue of GABA developed in Russia, and it increases levels of GABA in your brain. While some report that Phenibut causes drowsiness and fatigue, it’s a much safer way to boost GABA than with a pharmaceutical like Valium or Xanax.

Nootropics Expert Recommendation

Phenibut 200 – 300 mg per day. I recommend using Phenibut (with caution) as a nootropic supplement if you’re feeling anxiety or stress. And to calm or keep in check the stimulatory ef- fects of some nootropics. Your body does make GABA on its own from glutamate in your brain. Most healthy people have an adequate supply of GABA. But if you’re dealing with anxiety or stress and need some extra help in calming things down, Phenibut can help. Phenibut is particularly helpful if you’re dealing with Post Traumatic Stress Disorder (PTSD). I’ve seen reports by combat veterans who say that Phenibut worked far better than any prescription anti-anxiety med. I suggest trying a Phenibut supplement first at a dose of 200 – 300 mg. Phenibut can be a powerful method of boosting GABA levels in your brain. But it also has addictive potential especially if you’re prone to addiction. Phenibut takes 2 – 4 hours to take effect in your body. Do not yield to temptation and take more just because you’re not feeling anything. Sometimes the beneficial effects of Phenibut are not felt until the next day. Cycle your use of Phenibut to avoid tolerance and side effects. Your sweet spot could be every 2nd or 3rd day. Or even just once a week. Find out what works best for you. The ‘hangover’ from abusing Phenibut is particularly nasty. You should be 275 David Tomen able to avoid these side effects by keeping doses low. And limiting the days you use Phenibut. You can safely work your way up to 1,500 mg of Phenibut per day on the day that you dose. Some athletes go as high as 3,000 mg. But for nootropic use, a higher dose is not necessary or recommended.

276 HEAD FIRST Phenylalanine Phenylalanine enhances working memory, executive function, creative flow states, stress reduction, better mood, anti-anxiety and lessens symptoms of ADHD Phenylalanine is a highly bio-available essential amino acid. Your body naturally converts L-Phenylalanine into the amino acid L-Tyrosine which is then converted into L-DOPA. Decarboxylation of L-DOPA results in synthesis of the neurotransmitter dopamine.602 Once converted into dopamine, the enzyme dopamine-beta-hydroxylase con- verts dopamine into the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). This triad of neurotransmitters are collectively referred to as “catecholamines”. Phenylalanine is naturally found in protein-rich foods like soybeans, cheese, nuts, seeds, beef, lamb, chicken, pork, fish, eggs, dairy, beans, and whole grains. The artificial sweetener aspartame also contains Phenylalanine. As a nootropic supplement, you may find several different forms ofPhe - nylalanine available. L-Phenylalanine is the natural form found in proteins. D-Phenylalanine is a mirror image of L-Phenylalanine that is made in the lab. And DL-Phenylalanine is a combination of the two forms.603 L-Phenylalanine can be a highly effective nootropic for boosting cognitive function because it boosts norepinephrine and dopamine production. Resulting in increased attention, motivation and working memory. D-Phenylalanine (but not L-Phenylalanine) has been used to treat chronic pain although the clinical research in this area is sparse.

L-Phenylalanine also stimulates the production of thyroid hormones T3 (tri- iodothyronine) and T4 (thyroxine) which are crucial in maintaining both overall physical and cognitive health. L-Phenylalanine is an essential amino acid that you get from food or a supple- ment. The enzyme phenylalanine hydroxylase converts Phenylalanine in your liver into the amino acid L-Tyrosine.604 Many neurohackers prefer L-Phenylalanine over other catecholamine precur- sors because it supports neurotransmitter production without directly increasing neurotransmitter levels. This last part is key because indiscriminately increasing neurotransmitters across the board can lead to imbalances and tolerance. Which can defeat the purpose of taking the nootropic in the first place. For example, not enough epinephrine can decrease cognition. And too much norepinephrine can decrease attention, processing speed and executive function.605

L-Phenylalanine vs. D-Phenylalanine: What’s the Difference? L-Phenylalanine is an essential amino acid which means you must get it from 277 David Tomen food. Or as a supplement. Your body cannot synthesize Phenylalanine on its own. L-Phenylalanine (LPA) is converted into the amino acid L-Tyrosine in your liver. Once L-Tyrosine crosses the blood-brain barrier, it is converted into L-DOPA. Which is further converted into the neurotransmitters dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline). D-Phenylalanine (DPA) is a synthetic version of, and mirror image of L- Phenylalanine created in the lab. DPA has a different mechanism of action in the body than LPA. D-Phenylalanine (DPA) slows the action of the enzymes carboxypeptidase A or endorphinase and enkephalinase. These enzymes degrade endorphins. Slowing down these enzymes that reduce endorphins can help reduce pain.606 DL-Phenylalanine is a 50/50 combination of L-Phenylalanine and D- Phenylalanine. By combining the two in theory you get the best of both an antidepressant and pain reducer.

How does L-Phenylalanine work in the Brain? L-Phenylalanine boosts brain health and function in several ways. But two in particular stand out. 1. L – Phenylalanine decreases depression. L-Phenylalanine is converted into L-Tyrosine which in turn is converted into L-DOPA in the brain. L-DOPA is then used to make the feel good neurotransmitter dopamine. So depres- sion could be the result of not getting enough of the first amino acid (L- Phenylalanine) in the chain of events needed to produce dopamine. In one study done in Germany, 20 depressed patients received from 75-200 mg per day of DL-Phenylalanine for 20 days. At the end of the trial 12 of the depressed patients could be discharged without any further treatment. 4 of the patients had a moderate decrease in depressive symptoms. And 4 patients showed no response.607 2. L-Phenylalanine boosts neurotransmitters. L-Phenylalanine turns into L-Tyrosine once taken as a supplement. It then converts into the neurotrans- mitter dopamine. Dopamine is used to control movement in your body, is fundamental to memory, attention and problem solving. The unused dopamine can then convert into the neurotransmitters norepi- nephrine (noradrenaline) and epinephrine (adrenaline). Norepinephrine is important for attentiveness, emotions, sleeping, dreaming and learning. Epinephrine drives your ‘flight-or-flight’ response. It’s what prompts your reaction to dangerous circumstances, emergency situations, or in stressful situa- tions or environments. 278 HEAD FIRST This balance in neurotransmitters is critical to the fully optimized, healthy brain. And why some neurohackers choose L-Phenylalanine to allow the body to make the neurotransmitters it needs. Instead of causing an imbalance by boost- ing one neurotransmitter over another. A study in Venezuela investigated ADHD and autism, and the implications of amino acids on these neuropsychiatric disorders. 40 subjects affected by autism and 11 with ADHD along with 41 healthy subjects were included in this study. The researchers found that those with ADHD had decreasing Phenylalanine and increasing glycine which disrupted their inhibitory neurotransmission system. Not enough phenylalanine and increasing lysine was present in those with autism.608 Another study at Ohio State University looked at amino acids in 28 ADHD patients. And found all subjects with ADHD had significantly lower levels of the amino acids phenylalanine, tyrosine, tryptophan, histidine, and isoleucine. The researchers concluded each subject had a general deficit in amino acid transport, absorption or both.609

How things go bad As we get older, our brain and body chemistry and energy metabolism changes. ↓ Dopaminergic neurons are damaged or die ↓ Neurotransmitter levels decline ↓ Thyroid hormones decline ↑ Stress levels increase ↓ Working memory and mood decline All of these changes are often attributed to aging. But could be a result of dietary and lifestyle choices. Unchecked, they could lead to neurodegenerative diseases like Parkinson’s, a drop in quality of life and depression.

L-Phenylalanine to the rescue L-Phenylalanine can boost levels of the neurotransmitters dopamine, nor- epinephrine and epinephrine. And can help a sluggish thyroid produce more T4 and T3. L-Phenylalanine can help boost cognition especially in stressful situations. It helps improve decision making, ‘flow state’ and creativity, cognitive flexibility, and working memory. L-Phenylalanine converts into L-Tyrosine which then converts into L-DOPA to produce dopamine. L-DOPA is also used to make melanin in your body. This conversion process helps in the removal of neurotoxic quinones. And chelates heavy metals like mercury and lead which can accumulate in and damage neurons. The dopamine that is not used by your brain is available to produce norepi- 279 David Tomen nephrine (noradrenaline) which is important for attentiveness, emotions, sleeping, dreaming and learning. L-Phenylalanine may be an effective nootropic when stacked with ADHD/ ADD meds like Ritalin or Adderall. It helps supply extracellular dopamine needed to improve the effectiveness of stimulants used to boost the uptake of dopamine in your brain.

How does L-Phenylalanine feel? Keep in mind that L-Phenylalanine is a precursor to catecholamines. So if you’re not ‘low’ on dopamine, norepinephrine or epinephrine – you may not ‘feel’ anything. Many neurohackers report a lift in mood, better focus, concentration, increased energy, and an overall sense of well-being. L-Phenylalanine can help readjust your motivation levels. It can help lower anxiety levels, especially social anxiety. Supplementing with L-Phenylalanine can help bring your blood pressure down if its elevated from a stressful situation or environment. Take it before the stressful event if you can. L-Phenylalanine helps buffer the effects of stimulants like caffeine or am- phetamines. It helps potentiate and prolong the effects of Ritalin or Adderall, and reduces the crash. If you’re into athletics or do manual work, you’ll find that supplementing with L-Phenylalanine before a workout or construction job can leave you feeling great afterwards. It may help mitigate many of the effects of acute stress caused by short-term stressors. And L-Phenylalanine helps your body produce L-Tyrosine which helps to produce melanin, so you may find it easier to get a tan while at the beach.

The Research

Phenylalanine as an Antidepressant Several studies have investigated using Phenylalanine for the treatment of depression. One study published in the journal Arzneimittel-Forschung looked at using DL-Phenylalanine in a small group of patients who failed to respond to popular antidepressants like MAOIs. In this study, researchers worked with 23 patients diagnosed with depression and who had not responded to standard antidepressants. They were given 50 or 100 mg of Phenylalanine daily for 15 days. The researchers found that Phenyl- alanine completely improved mood in 17 of the patients. Within 13 days of the 15-day trial.610 Another study in the Journal of Neural Transmission studied DL-Phenylala- 280 HEAD FIRST nine use with 20 depressed patients. The subjects were given 75 – 200 mg/day of DL-phenylalanine for 20 days. The study found that 8 patients completely recovered from depression. And another 4 experienced a significant improvement in mood. Another 4 patients saw mild to moderate improvements, and another 4 did not respond to treatment. This study shows that Phenylalanine has considerable antidepressant properties. And is effective for the majority of people suffering from depression.611

Phenylalanine for ADHD Phenylalanine for ADHD seems at first glance as a natural solution for ADHD symptoms. It’s a precursor to the neurotransmitter dopamine which is targeted with stimulants like Ritalin and Adderall. But the very limited clinical evidence tell a different story for practical use. In this double-blind crossover study, 19 patients with ADD were given DL- phenylalanine or a placebo for 2 weeks. 13 of the ADD patients experienced a significant improvement in ADD symptoms compared to the placebo. And patients saw an improvement in mood. But the patients who did respond to DL-Phenylalanine lost all positive ben- efits within 3 months. And it’s interesting that a later study with ADHD patients using L-phenylalanine (not DL-Phenylalanine) produced no clinical benefit.612 Another study from 1987 treated 11 hyperactive boys for 2 weeks with D-Phenylalanine. There was no significant improvement or deterioration in behavior.613 There is a modern school of thought that there are several different types of ADD and ADHD. And the symptoms are caused by malfunctions in different parts of the brain depending on the ‘type’ of ADHD. The bottom line is some dealing with ADHD may benefit from supplement- ing with Phenylalanine. And that DL-Phenylalanine may be the best option. Try it and see if it works for you.

Dosage Notes L-Phenylalanine suggested dosage for cognitive benefit is 500 mg up to 3-times per day. You may find your body responds to smaller doses. Or even more if your stacking it with stimulants like ADHD meds. Listen to your body and see how you react. Since L-Phenylalanine is an amino acid, for best absorption and so it’s not competing with other amino acids, take it at least an hour before food. L- Phenylalanine works best on an empty stomach.

And take L-Phenylalanine with Vitamin B6 and Vitamin C to further maxi- mize absorption. And give your body what it needs to produce the neurotrans- mitters dopamine, norepinephrine and epinephrine. 281 David Tomen L-Phenylalanine is also needed along with L-Tyrosine to synthesize the CoQ10 needed to fuel your brain’s mitochondria.

Side Effects L-Phenylalanine quickly turns into the non-essential amino acid L-Tyrosine once you take it. So is considered non-toxic and very safe. Most neurohackers don’t have any negative side effects. Important Caution: People with phenylketonuria (PKU), and women who are breastfeeding or pregnant, should not take phenylalanine supplements. Aspartame, found in artificial sweeteners such as NutraSweet, is a source of phe- nylalanine. People with PKU should not use aspartame. If you are pregnant, ask your doctor about using this artificial sweetener.614 At higher doses there are reports of stomach issues and migraines. Experts say that L-Phenylalanine is toxic in doses above 5000 mg. And higher doses will not give you any added benefit. If you try recommended doses of L-Phenylalanine and do not feel any ben- efit, then this nootropic may not be right for you. You could try L-Tyrosine or NALT instead. L-Phenylalanine can increase your thyroid hormones. So if you’re hyperthy- roid you shouldn’t use L-Phenylalanine. And if you’re taking MAO inhibitors (MAOI’s) like selegiline, Azilect, Mar- plan or Nardil you should not use L-Phenylalanine. MAOI’s work in your brain and affect neurotransmitters. So using L-Phenylalanine in combination with MAOI’s could throw off the delicate balance of neurotransmitters needed for optimal brain health and cognition. And taking L-Phenylalanine with MAOI’s could cause a severe drop in blood pressure which could lead to a heart attack or stroke.

Available Forms L-Phenylalanine is available in powder, capsule and tablet form. Capsules and tablets are usually 500 mg. Phenylalanine is also available as D-Phenylalanine and the 50/50 combined form of DL-Phenylalanine. You may find one form works better for you than another. Ensure you read labels carefully, and stick with manufacturers who follow Good Manufacturing Practices (GMP). And are GMP-Certified.

Nootropics Expert Recommendation

L-Phenylalanine 500 mg up to 3-times per day I recommend using L-Phenylalanine as a nootropic supplement. Your body does synthesize some L-Tyrosine from phenylalanine which comes from high-protein foods like chicken, fish, almonds, avocados and bananas. 282 HEAD FIRST But most of us don’t get enough L-Phenylalanine from our diet. So supple- mentation will help. And L-Phenylalanine is a highly bioavailable, natural form of this amino acid. So you should feel its effects faster. L-Phenylalanine is helpful for most neurohackers to combat stress and sleep deprivation. It’ll boost dopamine, norepinephrine and epinephrine levels. It’s particularly helpful if you take L-Phenylalanine prior to a stressful situa- tion, workout or physically demanding job. L-Phenylalanine could be helpful to those dealing with ADHD/ADD. It’s a great compliment to stack with stimulant meds like Ritalin or Adderall. L- Phenylalanine will provide the dopamine your brain needs. It will help smooth out and prolong the effects of stimulant meds. And help prevent the associated crash when they wear off. You can safely use up to 1,500 mg per day when stacking with ADHD meds. But dosed throughout your day.

283 David Tomen Phenylpiracetam

Phenylpiracetam has been shown to boost alertness, cognition, clarity, focus, learning and memory, provides a stimulant-effect, and reduces symptoms of depression and anxiety Phenylpiracetam ((R,S)-2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamide, Phenotropil, Fenotropil, Carphedon, Fonturacetam ) is a water-soluble noot- ropic in the racetam-class of compounds. Phenylpiracetam was created by adding a phenyl group to the original noo- tropic Piracetam. Russian chemists synthesized Phenylpiracetam in 1983 to boost the physical and mental performance of astronauts during space flight. It’s currently used by Russian cosmonauts on the International Space Station.615 Phenylpiracetam combats physical and mental fatigue. It enhances memory, mood and focus. It facilitates learning and retention, reduces brain fog, increases alertness and boosts physical stamina and tolerance to cold. It turns out that Phenylpiracetam is very effective in boosting athletic per- formance. It provides significant stimulatory effects and helps you resist cold. Leading to a ban by the World Anti-Doping Agency from use by athletes in the Olympics and other professional sports.616 Russian cyclist Anton Reshetnikov was suspended in 2007 for 2 years from the International Cycling Union for using Carphedon.617 One year earlier (2006), Russian Olympic athlete Olga Pyleleva lost her silver metal for using Carphedon.618 Carphedon is a brand name for Phenylpiracetam. Adding a phenyl group to Pi- racetam boosts the bioavailability of Phenylpiracetam. It easily crosses the blood- brain barrier and is considered 20 to 60-times more potent than Piracetam.619 Neurohackers report that Phenylpiracetam enhances alertness, focus, memory, and learning. It reduces brain fog. And it provides physical stamina and cold tolerance while combating physical and mental fatigue. Phenylpiracetam helps: • Prevent Anxiety & Fear: Phenylpiracetam helps reduce symptoms of anxi- ety and fear. Unlike popular prescription anti-anxiety and anti-depressant drugs, Phenylpiracetam has no sedative action or other adverse side effects associated with these medications.620 • Neuroreceptors: Phenylpiracetam increases the density of acetylcholine (ACh), NMDA, GABA and dopamine receptors in the brain.621622More re- ceptors mean more binding sites for neurotransmitters that affect memory formation, cognition, sleep and mood. • Cerebral Circulation: Phenylpiracetam increases blood flow in the brain. 284 HEAD FIRST As a derivative of Piracetam, this nootropic has the same mechanism of action when it comes to blood flow. It suppresses the constriction of blood vessels allowing the freer flow of blood. More oxygen and nutrients get to brain cells boosting alertness, cognition, focus and mood.623 Phenylpiracetam is also an effective treatment for epilepsy. This debilitating condition is caused by sudden surges of electrical activity in the brain. This tem- porary disturbance in messaging systems between brain cells can cause a seizure. Normal brain function gets halted or mixed up. This is where Phenylpiracetam comes in. Phenylpiracetam has been shown in clinical studies to affect Alpha and Beta brain waves.624 Scientists haven’t quite figured out why it works, but Phenylpi- racetam has an ‘anti-convulsive’ action in the brain. They did conclude after one clinical trial, “Phenotropil reduced the frequency of seizures and improved cognitive function in the absence of epileptiform EEG abnormalities.”625 Phenylpiracetam is sold as a prescription drug in Russia and several Eastern European countries. In the United States, Phenylpiracetam is sold as an unregu- lated OTC research compound.

How does Phenylpiracetam work in the Brain? Phenylpiracetam boosts brain health and function in several ways. But two in particular stand out. 1. Phenylpiracetam as a stimulant. Phenylpiracetam increases the density of neuroreceptors. Studies have shown it increases the density of acetylcholine (ACh), dopamine, GABA, and NMDA receptors. This translates into more receptors for each of these important neurotransmitters to bind with and boost their effectiveness. The increase in density of neuroreceptors likely accounts for Phenylpirace- tam’s stimulant-like properties. Similar to Ritalin or Adderall, this nootropic increases the effectiveness of dopamine in your brain. Increasing alertness, decision-making capability, and cognition. But unlike stimulants like Ritalin and Adderall, Phenylpiracetam does not come with any stimulant-like side effects. You should not experience any fatigue, rapid heartbeat, decreased appetite or irritability. Rather you’ll feel increased stamina, have more physical endurance and get smarter. Just don’t try using Phenylpiracetam if you’re planning on being an Olympic athlete. It was banned several years ago because it’s too effective to be used in professional sports. We don’t want an unfair advantage now, do we? 2. Phenylpiracetam decreases anxiety and depression. For similar reasons to how Phenylpiracetam works as a stimulant, it can also tame symptoms of 285 David Tomen anxiety and depression. It increases the density of receptors for acetylcholine (ACh), GABA and NMDA receptors.626 This increase in receptor sites for GABA, choline and glutamate affects levels of the calming neurotransmitters GABA and serotonin in your brain. Phenylpi- racetam floods your brain with the neurochemicals you need to chill out.627

How things go bad As we get older, our brain chemistry and metabolism changes. And it seems these changes are affecting younger and younger people. ↓ Recall, reaction time and learning capacity declines ↓ Neurotransmitter levels decline ↓ Density of ACh, dopamine, GABA and NMDA receptors decline ↓ Acetylcholine levels decline ↓ Cerebral blood flow declines ↓ Stamina and endurance decline All of these changes are contributing factors to age-related cognitive decline. Early signs of these effects can be seen in poor decision-making, difficulty learn- ing, and even recalling simple things like an important appointment. But even if you’re not concerned with the signs of aging, Phenylpiracetam can help.

Phenylpiracetam to the rescue Phenylpiracetam is highly bioavailable when used as a nootropic. Once digested it quickly gets absorbed and crosses the blood-brain barrier. Phenylpiracetam modulates neuroreceptors. It’s been shown to increase the density of receptors for GABA, NMDA, dopamine and acetylcholine. More neuroreceptors result in more of each neurotransmitter being able to bind to neurons. And affect alertness, cognition, memory, recall and mood. Phenylpiracetam has a positive effect on physical performance by increasing endurance, and reducing physical and mental fatigue. In fact, these effects are so potent that Phenylpiracetam has been banned from professional sports by the World Anti-Doping Agency. Phenylpiracetam has been shown to act as a stimulant. But unlike pharma- ceutical drugs, it does not affect your cardiovascular or respiratory system. And does not have the side effects of jitteriness, restlessness or irritability like regular stimulants. Phenylpiracetam is also noted for increasing your threshold to tolerance for cold.

How does Phenylpiracetam feel? Many neurohackers say Phenylpiracetam is the strongest nootropic they’ve 286 HEAD FIRST ever experienced. It’s highly bioavailable and you experience the effects within 30 minutes of taking it. Phenylpiracetam increases concentration, motivation, memory, physical endurance, and tolerance to cold. Learning is quicker and stress is reduced. Learning and processing information becomes easier with Phenylpiracetam. You’re not re-reading sentences and paragraphs trying to understand them. Short and long-term memory improves. Motor skills improve so you’re typing faster and more accurately. Those dealing with depression report a decrease in depressive symptoms. More confidence helps in social situations and conversations are easier. Productivity rises and you assume a “get it done’ mentality. Procrastination is a thing of the past. Phenylpiracetam is a popular pre-workout supplement. It increases your endurance and reduces both physical and mental fatigue. And if you’re one of the unfortunate ones who live in a cold climate you’ll find that your tolerance for cold is better.

The Research Phenylpiracetam was developed in Russia in 1983. And the majority of research done with this nootropic has been conducted in Russia. Published in Russian medical journals in Russian. So we have limited clinical trial data to draw on. And like many nootropics we rely on nootropic user reviews. The following is two samples of clinical trials I was able to find that have been translated into English. And published in Western medical databases.

Phenylpiracetam Improves Cognition A study done by Russian researchers investigated the effects of Phenylpirace- tam on cognition. 99 adults aged 40 – 60 suffering from cognition deficits due to surgery or brain trauma were enrolled in this study. Volunteers were given 200 mg of Phenylpiracetam daily for 30 days. The researchers found that those using the nootropic showed a significant improve- ment in motor coordination, higher brain function, memory, attention and counting. And a reduction in both anxiety and depression.628

Phenylpiracetam Boosts Cerebral Circulation Researchers in Moscow recruited 400 patients suffering from ischemic stroke. This is the most common type of stroke where blood vessels carrying blood to the brain are blocked by a blood clot. Half of the group received 400 mg of Phenylpiracetam daily for a year. The control group got a placebo. The research team found that the group who received Phenylpiracetam expe- 287 David Tomen rienced a significant restoration in cognitive function, and resumed daily activities. Far better than the control group who took a placebo.629

Dosage Notes Recommended Phenylpiracetam dosage is 100 mg twice per day. One Phenylpiracetam dose in the morning, and one in the early afternoon. Don’t use Phenylpiracetam later in the day because its stimulant effect can cause insomnia. You can develop a tolerance to Phenylpiracetam, so consider taking it only on days when you need the extra focus. Or try cycling it one week on and one week off.

Side Effects Phenylpiracetam is non-toxic. So is considered well-tolerated and safe. As with many of the racetams, Phenylpiracetam can cause headaches because it boosts the use of acetylcholine in your brain. Choline supplements like Alpha GPC or CDP-Choline can help you avoid this side effect. Tolerance is a problem with Phenylpiracetam and builds rather quickly. Used to often, it will soon lose its effects. So try using Phenylpiracetam only when you need extra cognitive power, or before a workout. Or try cycling it one week on and one week off to avoid tolerance. Many neurohackers find that stacking Phenylpiracetam with a choline supplement boosts the effect even more with improved memory and cognition. And this is supported in several research studies.

Available Forms Phenylpiracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 100 mg each.

Nootropics Expert Recommendation

Phenylpiracetam 100 mg 2-times per day I recommend using Phenylpiracetam as a nootropic supplement. Your body does not make Phenylpiracetam on its own. So to get its benefits you must take it as a supplement. Phenylpiracetam is especially helpful for those suffering from ADHD or brain fog. This nootropic has a stimulant-like effect similar to that of pharmaceu- tical stimulants. But without the side effects of increased heart rate, irritability and restlessness. Phenylpiracetam can boost athletic performance. It has been shown to im- prove physical performance, increase stamina and endurance. And even provides cold-weather resistance. Phenylpiracetam is also particularly useful to students and executives who 288 HEAD FIRST want to boost alertness, cognition, clarity, focus, learning and memory. This noot- ropic also has anti-depressant and anti-anxiety benefits. Studies have shown that Phenylpiracetam can be effective in relieving the frequency of epileptic seizures in those dealing with epilepsy. It even compli- ments some epilepsy medications. You should use Phenylpiracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost the effectiveness of neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Phenylpiracetam to 400 mg. But be aware that tolerance to the effects of this nootropic build quickly. So I recom- mend using Phenylpiracetam only on days when you need the extra cognitive power. Or cycle the use of this nootropic one week on, and one week off.

289 David Tomen Phosphatidylcholine (PC)

Phosphatidylcholine (PC) is known to repair brain cells and neural connections, boost acetylcholine, and improve alertness, cognition, focus, memory and mood Phosphatidylcholine (PC, or Ptd-Cho) is one of two fatty acids that make up the outer layer of the membrane covering each of the 70 trillion cells in your body. Phosphatidylcholine is also converted in your body through a process called hydrolysis to make up the fatty acids AA, oleic, linoleic, linolenic, and DHA. These fatty acids contribute to the signaling within and between brain cells for long-term potentiation (LTP). LTP is behind the formation of long-term memories. The synthesis of the neurotransmitter acetylcholine (ACh) is largely dependent on the choline provided by Phosphatidylcholine. ACh is critical for cognition, learning and memory. Your brain cells are each encased in a membrane. This bi-lipid layer of two fatty acid tails face each other. The outer layer of each cell contains mostly the phospholipids phosphatidylcholine (PC) and sphingomyelin, while the inner layer contains predominantly phosphatidylserine, phosphatidylinositol, and phosphatidylethanolamine. The outer layer of each cell membrane is highly permeable. But the inner layer is much less permeable. These two fatty acid tails are in a constant state of movement, vibrating at millions of times a second. This continual vibration could be considered the ‘backbone of life’. And is the basis of everything that happens in your brain. The amount and type of long-chain fatty acids in your diet affects the com- position of these cell membranes. The structure and function of your cells depend on the ideal balance of fats including cholesterol, oleic, palmitic and stearic fatty acids. And essential fatty acids like Omega 3. Without this proper balance, cell membrane function is compromised. When you don’t have enough phosphatidylcholine, brain cell membranes lose integrity and eventually die. Some phosphatidylcholine is naturally synthesized in your body. We also get PC from some of our food including beef, oysters, eggs and some vegetables. As a nootropic supplement, Phosphatidylcholine is derived from lecithin found in soybeans and sunflower seeds. Note that lecithin and phosphatidylcholine are NOT the same thing. Plain leci- thin is not an efficient source of phosphatidylcholine or choline. As a nootropic, look for as pure of a source of phosphatidylcholine (PC) as you can afford. And you can be sure that our modern diet does not provide the ideal balance 290 HEAD FIRST of fatty acids (phospholipids) to maintain brain cell integrity. It’s why we experi- ence brain fog, memory loss, slow thinking and poor decision making. Some progressive health care researchers and practitioners have found that supplementing with phosphatidylcholine (PC) can lessen the symptoms of dis- eases like MS, diabetes, immune system problems, asthma, and neurodegenera- tive diseases like Alzheimer’s.

How does Phosphatidylcholine Work in the Brain? Phosphatidylcholine boosts brain health and function in several ways. But two in particular stand out. 1. Phosphatidylcholine is needed for long-term memory. The hydrolysis of Phosphatidylcholine (by a process called phospholipase A2-catalyzed hydrolysis) is used to make the free fatty acids AA, oleic, linoleic, linolenic and DHA. These free fatty acids facilitate synaptic transmission by targeting nicotinic ACh receptors using protein kinase C (PKC). This messenger system is needed for long-term potentiation (LTP). Researchers have determined that these fatty acids are critical for learning and memory.630 2. Phosphatidylcholine helps repair neurons. Cholinergic neurons are unique among cells because they serve two functions. PC is a major component of brain cell membranes. And serves as a storage pool for the choline needed as a precursor for acetylcholine (ACh) synthesis. Researchers demonstrated how this works. They incubated human cholin- ergic cells in the lab. And followed the metabolic link between membrane com- position and turnover, and ACh synthesis. And proved that ACh is synthesized from choline derived from the degradation of Phosphatidylcholine. If there is not enough choline available to maintain brain cell membrane integrity, and to synthesize the neurotransmitter acetylcholine, brain cell func- tion breaks down. You experience brain fog, poor memory and decision making. And ultimately leading to neurodegenerative diseases like Alzheimer’s, and other motor neuron disorders.631

How things go bad As we get older, our brain chemistry and energy metabolism changes. This can happen at any age once we enter our adult years. ↓ Brain cell membranes degenerate ↓ Recall, reaction time and mood diminish ↓ Acetylcholine levels decline All of these changes can happen at any age. Our bodies are influenced by the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Phosphatidylcholine can help for age-related cognitive decline, as well as a student looking to do better in school. 291 David Tomen Phosphatidylcholine to the rescue Phosphatidylcholine (PC) has been around as long as humans have walked this planet. PC is a critical component of the top layer of the membrane sur- rounding each one of the cells in your body. And yet some are talking about Phosphatidylcholine as the “New Wonder Drug”. How could this be? Turns out that PC is a fatty acid. As are many of the fats we consume in our modern diet. Long-chain fatty acids affect the composition of our cell membranes. When we eat bad fats our cell membrane fluidity is affected, ion channels disrupted, hormones, regulation of neuroreceptors, signaling and other signaling chemicals are affected. Incorrect amounts or types of long chain fatty acids can lead to a cascade of serious health and cognition problems. The easiest and simplest way to correct many of these cognition problems is to supplement with Phosphatidylcholine as a nootropic. You’ll feel better as cells are repaired. Digestion issues could be eliminated or minimized. And brain fog, cognition and memory problems could become a non-issue.

How does Phosphatidylcholine feel? If you eat a perfectly healthy diet and are in optimal physical and mental health, using Phosphatidylcholine may not do anything for you. But if you’re like most in the Western world relying on fast food, processed food and other unhealthy lifestyle habits, then PC may help. Neurohackers report that supplementing with Phosphatidylcholine lifts brain fog, improves working memory and boosts alertness. Others say it helps them prevent anxiety and panic attacks. Mental clarity is improved, and energy levels rise. Ray Kurzweil, the famous inventor and futurist, gets phosphatidylcholine intravenously once a week at his health clinic. His theory is that this will rejuve- nate all his body’s tissues.632

The Research A double-blind study in California with 80 college students investigated the effect of Phosphatidylcholine on memory. The students received a placebo or either 10 or 25 grams of Phosphatidylcholine (PC). 25 grams of PC was esti- mated to supply about 3.75 grams of choline. Memory was tested at 60 and 90 minutes after taking PC. The researchers recorded a significant improvement in memory after 90 minutes, and only a slight improvement after 60 minutes. This 1993 study was the first to test the relationship between a single dose of Phosphatidylcholine on memory in healthy human subjects.633 292 HEAD FIRST Phosphatidylcholine Prevents Brain Cell Death Streptococcus pneumonia is the most common cause of bacterial meningitis. And is the most common cause of death from pneumonia. If it doesn’t kill you, it can cause paralysis, mental retardation and learning disorders. In humans, it’s your hippocampus neurons that are the first to die as a result of meningitis. Cell death is officially called “apoptosis”. But I’m using cell death to drive a point home. Phosphatidylcholine (PC) is an essential component of your cell membranes. And a deficiency of PC, either from chemicals or bad nutrition leads to cell death. And the first to go are your hippocampal neurons. The same neurons used for learning and memory. Researchers in Tennessee found that a variety of brain cells die after you get pneumonia. Because it interferes with Phosphatidylcholine synthesis. And apoptosis inhibitors can’t even stop this cell death from happening. The research team determined that the only way to prevent cell death from pneumonia infection was supplementing with Phosphatidylcholine. Even after the infection set in. The researchers concluded that supplementing withPhosphatidylcholine was the best way to prevent what they called an “apoptotic cascade”. And the best thera- peutic intervention.634

Phosphatidylcholine Improves Memory Studies on the effect of Phosphatidylcholine on memory are limited. So researchers in Japan decided to remedy this lack of data by testing PC in mice with dementia. They administered PC to mice with dementia and to normal mice. And compared differences in memory, choline and acetylcholine concentration, and choline acetyltransferase (ChAT) activity. ChAT is the enzyme responsible for the synthesis of acetylcholine in the brain. The researchers found that giving phosphatidylcholine for 45 days to mice with dementia improved memory. And generally increased brain choline and acetylcholine concentrations to or above the levels of the normal control mice. The research team concluded that phosphatidylcholine increases brain acetyl- choline concentration and improves memory.635

Dosage Notes Recommended Phosphatidylcholine dosage is 1,200 mg to 5 grams per day. And divide your total daily dose into 2 or 3 equal doses and dosed throughout the day. To enhance bioavailability and boost absorption, take PC 30 minutes before a meal. Do not take Phosphatidylcholine with acetylcholinesterase (AChE) inhibitors 293 David Tomen since this combination may excessively increase acetylcholine (ACh) levels and potentially cause cholinergic side effects. AChE inhibitors include donepezil (Aricept), (Cognex), (Exelon) and Huperzine-A.

Side Effects Phosphatidylcholine is naturally produced in your body and is considered well tolerated and safe. PC is not toxic. Some may experience sweating, stomach upset and diarrhea. Particularly if you’re already high in choline.

Available Forms Phosphatidylcholine is sold in tablet, capsule, liquid and powder form. Capsules can run from 420 – 1,300 mg each. 500 mg of Phosphatidylcholine in powder form is equivalent to 2-level 1/8 tsp scoops. Phosphatidylcholine is sometimes used interchangeably with “lecithin,” although the two are different. Choline is a component of phosphatidylcholine, and is also a component of lecithin. Although closely related, these terms are not the same.

Nootropics Expert Recommendation

Phosphatidylcholine 1,200 mg to 5 grams per day I recommend using Phosphatidylcholine as a nootropic supplement. Phosphatidylcholine helps build and repair cell membranes. And is found in every one of the 70 trillion cells in your body. You can get Phosphatidylcholine from some of the food you eat. But Phosphatidylcholine is only found in foods like beef, eggs, oysters and some vegetables. PC levels decline as you age and you are unlikely to get nearly enough through diet. So to get its benefits you must take it as a nootropic supplement. Phosphatidylcholine is vital to maintaining optimal brain health. And has been shown to increase cognitive energy, boost brain function, enhance communication between neurons, and protect neural membranes from free radical damage. I suggest starting with a dose of at least 1,200 mg daily. And Phosphati- dylcholine is a great compliment to a stack including any nootropic from the racetam-family. Anything that causes an increase in uptake of acetylcholine in your brain. You need to provide your brain with the choline it is demanding. Or it starts cannibalizing your own brain cells to make more acetylcholine. Signs that you’re lacking adequate choline are headaches. Use Phosphatidylcholine at a ratio of 1:4. For example, 250 mg of Phospha- tidylcholine to 1,000 mg of Aniracetam. If you have liver damage like cirrhosis, you may want to increase the dose up to 4.6 grams per day for liver repair.

294 HEAD FIRST Phosphatidylserine (PS)

Phosphatidylserine (PS) is known to improve alertness, attention, cognition, memory, recall and mood, lower anxiety, and help you lose weight Phosphatidylserine (PS) is a phospholipid component of brain cell mem- branes. The membrane is the outer casing surrounding each cell. PS plays a vital role in cell-to-cell signaling in the brain. And is needed to maintain the fluidity of all cell membranes. Phosphatidylcholine (PC) is the most abundant phospholipid in the brain. Followed by a slightly lesser amount of Phosphatidylserine (PS). PC is in the outer layer of brain cell membranes, and PS is part of the inner layer. Both are critical to maintaining optimal cognitive health. PS is synthesized from PC in the brain by exchanging the base head group with a serine. Phosphatidylserine (PS) supports the formation and sending of neural sig- naling within neurons. And across synaptic junctions that link one neuron with another. This cellular communication contributes to how we form memories. Phosphatidylserine (PS) also helps produce nerve growth factor (NGF) that ensures healthy neurogenesis. And PS even assists in building mitochondria which are the energy source in every one of your brain cells. When your brain cell membranes are healthy, they are malleable, fluid and flexible. But by the time we reach our 20’s, phospholipids including Phosphati- dylserine (PS) start declining. This outer casing starts to harden. And attention, concentration, memory, mood and learning begin to suffer.636 The good news is you can prevent this cellular damage from happening. The amount and type of long-chain fatty acids in your diet affects the composition of these cell membranes. The structure and function of your cells depend on the ideal balance of fats including cholesterol, oleic, palmitic and stearic fatty acids. And essential fatty acids like Omega 3. Without this proper balance, cell membrane function is compromised. But our typical modern diet does not provide the ideal balance of fatty acids (phospholipids) to maintain brain cell health. It’s why we experience brain fog, memory loss, slow thinking and poor decision making. You naturally get Phosphatidylserine (PS) from foods like cow brains, pig spleen and chicken hearts. So there must be some merit to the saying, “Eat brains and get smarter”. Unfortunately, not many of us include organ meat as part of our daily meal plan. So the best way to maintain healthy levels of Phosphatidylserine (PS) in your brain is taking PS as a nootropic supplement. PS was originally made from bovine (cow) brains. But with the mad cow 295 David Tomen disease scare, PS supplements are now made from extracts of soy or sunflower lecithin. Phosphatidylserine (PS) is arguably one of the most effective and important noot- ropics we have available today. PS keeps our brain cells healthy. And has a reputa- tion for improving alertness, attention, cognition, memory, recall and mood.

How does Phosphatidylserine work in the Brain? Phosphatidylserine boosts brain health and function in several ways. But two in particular stand out. 1. Phosphatidylserine is needed for memory. PS stimulates the brain chemi- cals that boost neural signaling for quick, clear thinking. In fact, Phosphati- dylserine is one of the most effective memory boosters known. PS has been shown that it can slow, halt and even reverse the progression of age-related cognitive decline. One study with 149 patients meeting the criteria for age-associated memory impairment were given 100 mg of Phosphatidylserine or a placebo for 12 weeks. The patients who received PS showed improved performance on tests related to learning and the memory tasks of daily life. The study concluded thatPS was a promising candidate for treating memory loss later in life.637 2. Phosphatidylserine helps repair neurons. PS works in concert with DHA (Omega-3) to protect brain cells from damage. And boost neuronal survival. You brain is made up largely of DHA fat. The kind of fat you get from supplementing with Omega-3’s. And a decrease in DHA content in the brain results in cognitive impairment. Studies show that Alzheimer’s Disease is associ- ated with lower Omega-3 fatty acid intake. Researchers in Canada looked at samples provided by the Memory and Aging Project. And found a significant difference in plasma fatty acid profiles of those with Alzheimer’s, mild cognitive impairment and those with perfectly healthy brains. The team found that DHA in Phosphatidylserine in both disease categories was 12-14% lower than those of healthy brains. They concluded that Alzheimer’s Disease is associated with lower DHA and Phosphatidylserine.638 Trials and clinical studies like these provide plenty of motivation to supple- ment with Phosphatidylserine and DHA. It will help you ward off neurodegen- erative disease. DHA and PS for an optimized brain.

How things go bad As we get older, our brain chemistry and energy metabolism changes. This can happen at any age once we enter our adult years. ↓ Brain cell membranes lose fluidity ↓ Neurotransmitter signaling declines 296 HEAD FIRST ↓ Recall, reaction time and mood diminish ↓ Memory declines All of these changes can happen at any age. And starts as early as our 20’s. Our cell membranes are influenced by the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Phosphatidylserine (PS) can help for age-related cognitive decline, as well as a student looking to do better in school.

Phosphatidylserine to the rescue Phosphatidylserine (PS) makes up about 15% of the total phospholipid pool in your brain. PS is located mainly in the internal layer of your brain cell membranes. PS is involved in governing membrane fluidity, and the regulation of all activity going on in that brain cell. PS interacts with cellular proteins, modulates the activity of neuroreceptors, enzymes, ion channels and signaling molecules. Supplementing with Phosphatidylserine improves brain function that tends to decline with age. Healthy brain cell membranes support neuroplasticity so neurons can form the connections needed to convert new experiences into memories. Phosphatidylserine helps lower cortisol and ACTH levels during intense exercise.639 PS is even effective in relieving stress. And putting you in a better mood during exams.640 Many clinical trials with PS have shown improvements in working – and long-term memory, recall, logic and even speech. Attention span increases while using PS. And motivation, socialization and initiative all increased when using Phosphatidylserine as a nootropic.

How does Phosphatidylserine feel? Neurohackers report that using Phosphatidylserine (PS) as a nootropic: • Boosts energy levels • Improves alertness • Less brain fog • Better memory • Logical thinking improves • Concentration is better • Clarity of thought • Weight loss • Easier to remember names, phone numbers, tasks, etc. • Mood improves 297 David Tomen • Anti-anxiety • Lowers cortisol • Relieves insomnia • Vivid dreams There are reports that PS helps with Tourette’s Syndrome. Phosphatidylserine (PS) a great compliment to ADHD meds. PS helps tame the symptoms of ADHD. And doesn’t interfere with popular stimulants like Ritalin and Adderall. You may even be able to cut back on the ADHD meds once Phosphatidylserine builds up in your system.

The Research

Phosphatidylserine Reduces Beta Brain Waves Beta brain waves have the most rapid pattern of all the brain waves produced in your brain. Beta waves are associated with concentration, arousal, alertness and cognition. But it would be unpleasant to be in a constant state of arousal. This study in Germany gave 16 healthy subjects Phosphatidylserine (PS) for 42 days. The team tested brain wave patterns before supplementation. And again in 42 days. The main finding in this study was that chronic Phosphatidylserine supple- mentation significantly decreases Beta brain waves. And the results showed that the PS group were connected to a more relaxed state compared to the controls.641

Phosphatidylserine Reduces Stress Studies have shown that Phosphatidylserine blunts the release of cortisol in response to exercise stress. And PS improves mood. In this study, researchers at the University of Wales Swansea gave young adults 300 mg of Phosphatidylserine each day for a month. The study resulted in these young adults feeling less stressed after doing a stressful arithmetic task. And they were in a better mood. The researchers con- cluded that PS supplementation improves mood and reduces stress even in healthy, young people.642

Phosphatidylserine Improves Cognition in Athletes Phosphatidylserine is found in the cell membranes of most animals and plants. PS has been shown to reduce stress and increase performance in runners, cyclists and golfers. This double-blind, placebo-controlled study was conducted to study the ef- fects of PS on cognitive function, mood and endocrine response before and after intense exercise. 18 lower body, resistance-trained male college athletes took Phosphatidylser- 298 HEAD FIRST ine for 14 days, or a placebo. Following 14 days of supplementation, participants performed an acute bout of lower body resistance training. Mood and cognitive function were measured before, 5 minutes after and 60 minutes after exercise. And blood samples were drawn prior to, 5, 15, 25, 40 and 60 minutes after exercise. Blood was tested for cortisol and testosterone. The researchers found that PS significantly increased cognitive function prior to exercise. And PS prevented both mood and hormones from being negatively affected prior to and following resistance exercise.643

Phosphatidylserine Reduces Symptoms of ADHD Researchers in Japan conducted a randomized, double-blind, placebo con- trolled trial with 36 children aged 4 – 14 years. The kids were diagnosed with ADHD but had not received any conventional ADHD treatment prior to the trial. The children received 200 mg of PS or a placebo daily for 2 months. The team recorded the children’s ADHD symptoms, short-term and working memory, and mental performance. The team found that Phosphatidylserine significantly improved ADHD symp- toms and short-term memory. ADHD symptoms that were reduced included inattention, short-term memory, and impulsivity. The placebo group saw no improvement during the trial.644 Another study with 200 ADHD children looked at the effects of Phosphati- dylserine combined with Omega 3’s for 30-weeks. The key finding of this trial was a significant reduction in the restlessness/impulsive scale and an improvement in emotions. The researchers concluded that Phosphatidylserine with Omega 3 may reduce ADHD symptoms in children with ADHD. And it was especially effective in a subgroup of hyperactive-impulsive, emotionally and behaviorally-dysregulated ADHD children.645 The bottom line is that if you have Adult ADD like I do, or you have chil- dren with ADHD or ADD, consider 200 mg of Phosphatidylserine for a couple of months before going with Adderall or Ritalin. And add in some Omega 3’s for good measure. Or find a ready-made nootropic stack like Mind Lab Pro™ that already has 100 mg of Phosphatidylserine in their formula. No side effects and you just might get rid of the ADHD symptoms that are plaguing you.

Phosphatidylserine Improves Memory Several studies have shown that using Phosphatidylserine as a nootropic to boost memory works well both for age-related cognitive decline as well as more serious diseases like Alzheimer’s and dementia. A double-blind, placebo controlled trial in Tel Aviv worked with 18 healthy 299 David Tomen elderly volunteers with age related cognitive decline. The volunteers took 100 mg of Phosphatidylserine 3-times per day for 12 weeks. They were evaluated at the start of the trial, at 6 weeks of treatment and at the end of the trial. All but two of the volunteers showed significant improvement in memory from using Phosphatidylserine (PS). Memory and cognition improved in the first 6 weeks of PS use. And continued to get better until the end of the 12-week trial.646 Another trial with 51 Alzheimer’s patients using 100 mg of Phosphatidylser- ine for 12 weeks showed that PS may be a promising candidate for the early stages of Alzheimer’s Disease.647

Dosage Notes Recommended Phosphatidylserine (PS) dosage is 100 mg 3-times per day. If you’re concerned about Genetically Modified Organisms (GMO) like I am, make sure you find Phosphatidylserine (PS) that is non-GMO. Because most PS is derived from the lecithin of soybeans. And oddly enough a manufacturer may use both GMO and non-GMO. And not have it marked on the packaging. I’m aware of at least one supplement maker who offers non-GMO PS in their 120-count bottles. But their 60-count bottles are made with GMO soybean lecithin. Do your research. Even better is find Phosphatidylserine (PS) that is made from non-GMO sunflower lecithin. Especially if you’re allergic or react to soy.

Side Effects Phosphatidylserine (PS) is naturally produced in your body and is considered well tolerated and safe. PS is non-toxic. Some may experience insomnia or stomach upset at higher than recom- mended doses. Medications for Alzheimer’s may interact with Phosphatidylserine because these drugs are often Acetylcholinesterase (AChE) inhibitors. An AChE inhibitor will increase the amount of acetylcholine (ACh) in your brain. And since PS in- creases ACh, you may end up with too much acetylcholine.

Available Forms Phosphatidylserine is sold in tablet or capsule form. Capsules can run from 100 to 300 mg each. Plain PS was originally sourced from cow brains. But since the mad cow disease scare, most PS supplements are now made from soybean lecithin. Enzymotec makes a unique form of Phosphatidylserine called Sharp PS®. It is made from vegetable sources that are not soy-based, and is non-GMO. Sev- eral supplement makers offer this branded form of PS which they license from Enzymotec. 300 HEAD FIRST Mind Lab Pro™ offers a nootropic stack that includes 100 mg of Sharp PS® that is derived from non-GMO sunflower lecithin. CHEMI Nutra makes a branded form of PS made from soy lecithin called SerinAid®. A few supplement makers license this brand of PS for use in their PS products.

Nootropics Expert Recommendation

Phosphatidylserine 100 mg 3-times per day I recommend using Phosphatidylserine (PS) as a nootropic supplement. Phosphatidylserine (PS) is arguably one of the most effective and important noot- ropics we have available today. PS keeps our brain cells healthy. And has a reputa- tion for improving alertness, attention, cognition, memory, recall and mood. PS helps lower cortisol which can help with insomnia. And provide you with a stress-free workout in the gym or on the court. Phosphatidylserine (PS) clears brain fog, boosts energy levels, helps alertness, and provides clarity to your thought process. You can get Phosphatidylserine from food. But the highest concentrations of PS are found in organ meats like cow brains and pig spleen. PS levels decline as you age starting in your 20’s. And you are unlikely to get nearly enough through diet. So to get its benefits you should take it as a nootropic supplement. I suggest starting with a dose of PS at 100 mg 3-times per day. Dosing should not exceed 500 mg per day. And there is little benefit to overdoing it with Phos- phatidylserine (PS).

301 David Tomen Picamilon

Picamilon is known for having a strong anti-anxiety effect while boosting concentra- tion, focus, memory and motivation, and lowering blood pressure Picamilon (nicotinyl-y-aminobutyric acid, or N-nicotinoyl-GABA) is a derivative of the inhibitory neurotransmitter GABA and nicotinic acid (niacin or Vitamin B3). Russian scientists conducted a lot of research into GABA and cognitive health in the 1960’s and 70’s. The nootropics community has benefited from this research. It was the Belgians who started the development of the racetam-family of nootropics. And not too long afterwards, Russian scientists continued the research on GABA-derived compounds and gave us Phenibut and Picamilon. GABA’s role is to keep glutamate, the primary excitatory transmitter, from overwhelming your brain. Too much glutamate can cause a seizure, and too little GABA can put you in a coma. A healthy brain maintains a critical balance of GABA and glutamate. GABA acts like a “brake” on neuron circuits during stress. Low GABA levels can result in anxiety, insomnia, poor mood and restlessness. Clinical studies show that boosting GABA with a supplement like Picamilon relieves anxiety, stress, and boosts the production of alpha brain waves.648 If GABA is optimized in your brain you’ll feel focused, relaxed and stress-free. But the big challenge for cognitive health is trying to boost GABA levels in the brain. GABA cannot cross the blood-brain barrier on its own. It needs help to carry it across this barrier.

Including Vitamin B3 (niacin) in the Picamilon formula helps GABA to cross the blood-brain barrier. And the reason why some neurohackers prefer Picamilon when the goal is to raise GABA levels in the brain. Picamilon is unique among GABA boosters because it can boost cerebral circulation as well.649 It increases cerebrovascular activity better than Piracetam and Vinpocetine. It’s even better at boosting blood flow than prescription vasodi- lating agents like , papaverine, and xanthinol niacinate. So when using Picamilon to boost GABA, you enhance cerebral circulation, and lower blood pressure. GABA even stimulates the pituitary gland to secrete Human Growth Hormone. And helps produce endorphins that make you feel good after a workout or sex. As a nootropic, when you use Picamilon to normalize GABA levels you’ll improve blood flow to and within your brain. And you’ll experience a reduction in anxiety, insomnia, nervousness, restlessness and stress. Picamilon exhibits the properties of a tranquilizer with a stimulating compo- nent. But unlike tranquilizer drugs, Picamilon does not induce muscle relaxation, drowsiness or lethargy. 302 HEAD FIRST How does Phenibut Work in the Brain? Phenibut helps brain health and function in several ways. But two in par- ticular stand out. 1. Picamilon boosts cognition. Picamilon is a derivative of GABA and niacin. And easily crosses the blood-brain barrier. GABA on its own cannot cross this barrier unless paired with a dedicated carrier.650 When niacin is bonded to GABA the molecule easily enters the brain. Once in the brain, Picamilon separates back into niacin and GABA. GABA works by preventing neural signaling associated with anxiety from reaching other neurons. It does this by attaching to the receptors that would otherwise excite those neurons. Over-stimulating neurons in certain areas of your brain is what causes anxiety-related symptoms. Studies have shown this unique combination of niacin and GABA affect the regulation of neurotransmitters in the brain. Picamilon was shown in one study on Parkinson’s disease to normalize serotonin and dopamine content, and dopamine uptake in the brain.651 2. Picamilon improves cerebral blood flow. Picamilon is more effective than Piracetam and Vinpocetine in improving blood flow to cerebral vessels in the brain. It easily crosses the blood-brain barrier to protect neurons against the effects of diminished oxygen flow. Improving cognitive function. Picamilon separates into niacin and GABA once it crosses the blood-brain barrier. Niacin acts as a vasodilator relaxing blood vessels and allowing the freer flow of blood in the brain. Picamilon is often prescribed in Russia for treatment of migraine headaches. A study published in Nutrition Journal reviewed clinical trials from 1990 – 2004 looking at studies using niacin to treat migraines, and other tension-type headaches. The conclusion from this review showed niacin’s effectiveness for its vasodila- tory properties in increasing cerebral blood flow. And its ability to improve mito- chondrial energy metabolism.652 The result is fewer migraines and less headaches when using a nootropic containing niacin.

How things go bad Low levels of GABA and poor cerebral circulation are associated with a variety of health problems. ↑ Anxiety653, panic attacks, stress and insomnia ↑ Muscle spasms, hypertension, convulsion, Tourette’s Syndrome and epilepsy ↓ Neurotransmitters decline ↓ ATP energy levels decline starving mitochondria in brain cells 303 David Tomen When your neurotransmitters, including GABA, are in balance, you feel motivated, productive and energetic. And you feel calm and relaxed during downtime. When GABA levels are low you feel filled with dread, you’re constantly wor- ried, you have racing thoughts, and you’re frequently late and disorganized.654 Many people in this GABA-slump resort to high carbohydrate foods, and drugs or alcohol to relax.

Picamilon to the rescue

Picamilon is an analogue of GABA and nicotinic acid (Vitamin B3 or niacin). The addition of niacin allows GABA to cross the blood-brain barrier (BBB). We need adequate GABA levels in our brain because it’s an inhibitory neu- rotransmitter. When we raise GABA levels by supplementing with Picamilon, we help keep glutamate in check. Glutamate is your body’s most abundant excitatory neurotransmitter. Which is responsible for attention span, brain energy, learning ability, memory, and staying awake. So GABA is calming and glutamate is stimulating. And they must be in bal- ance with each other for optimal cognitive health. An imbalance of these two neurotransmitters can cause fibromyalgia, chronic fatigue syndrome, poor memory and cognition, anxiety and depression. But when these two neurotransmitters work together efficiently, you feel re- laxed with no stress or feelings of anxiety. And you get a more restful night’s sleep. The addition of nicotinic acid in the Picamilon formula helps improve cogni- tion even more. One study with 96 healthy volunteers was done to determine the effects on memory with nicotinic acid. The study found that nicotinic acid (niacin) enhanced cell metabolism and oxygen supply in the brain. Resulting in an improvement in short-term and long- term memory.655 Adding Picamilon to your nootropic stack can help bring GABA and gluta- mate back into balance.

How does Picamilon feel? When you balance GABA levels in your brain, you feel relaxed and calm. But many neurohackers who try using GABA as a supplement don’t feel the effects. Because the GABA molecule is too large to cross the blood-brain barrier.656 Note: If you do feel the calming effects of supplementing with GABA within a ½ hour of taking it, it may mean you have a “leaky” blood-brain barrier. Not a good thing.657 Because if GABA can get through, all kinds of nasty stuff can get through too. Including toxins, undigested food particles and anything else in your blood stream that shouldn’t be in your brain. But here were talking about increasing our GABA levels using Picamilon. 304 HEAD FIRST Neurohackers report that adding Picamilon to their stack relieves anxiety “better than Xanax”. There is less stress and they feel more relaxed. Picamilon also offers a stimulant effect providing mental clarity, dreams can be vivid, and it’s not sedating like Phenibut. Social functions could get some help with Picamilon. You could feel less inhibited, speak freely and feel more confident. Picamilon generates a calm focus without making you drowsy. Some neurohackers maintain that the ‘magic’ with Picamilon is in the nicotinic acid. And I’d have to agree with this observation. It’s what provides the stimulant-effect and gives you an energized type of calmness. The cognitive benefits of niacin are considerably understated in the noot- ropics community. Just check out the research and studies in my NADH chapter for more on the magic of niacin.

The Research Nearly all the research with Picamilon has taken place in Russia. It’s pub- lished in Russian journals in Russian. Most of these trials are not indexed in international or US medical databases. I won’t get into the politics of this type of behavior here in this book on nootropics and brain optimization. I’m here to educate and collate information for you on nootropics to help cognitive health. The sources I have been able to find shows Picamilon extensively studied in animals and humans. And has been shown to act like a tranquilizer without the sedative effects of muscle relaxation, drowsiness or lethargy. The studies show Picamilon decreases anxiety, fear, irritability and symptoms of emotional stress. It inhibits aggression, and restores physical working capacity after stressful work. Picamilon has been proven to prevent forgetfulness, enhance memory, recall and improve mood. It decreases headaches, dizziness and tinnitus. It increases mental and motor activity in patients with anxiety and depression. Picamilon has been shown to prevent or suppress diabetic neuropathy658, and alleviate the effects of alcohol withdrawal. It helps glaucoma, retinal and optic nerve damage659. And helps those with neurologically-based urinary problems. Here we talk about how Picamilon, nicotinic acid and GABA can affect your cognition and overall health. This research supports the idea of using Picamilon to raise GABA and niacin levels. And the cognitive benefits can have a profound effect on your quality of life.

Picamilon increases dopamine uptake Reports by neurohackers repeatedly show that Picamilon provides a ‘calm focus’ without making you drowsy. And this study, done in the Ukraine gives us a clue on how this works. 305 David Tomen This study was done with Parkinson’s patients. It’s well know that serotonin and dopamine content and dopamine uptake by neurons in Parkinson’s Disease is decreased. This research found that Picamilon normalized dopamine uptake in Parkin- sonism. And that Picamilon is “involved in the regulation of brain neurotransmis- sion under experimental parkinsonism and can be useful in treatment of Parkinson’s disease”.660

Picamilon boosts brain cell mitochondria function We know from our research on nootropics that NADH boosts ATP energy production that helps power brain cell mitochondria. And this “energizing” effect that’s often spoken of when using Picamilon comes at least in part from its niacin component. This study done on one-month old rats looked at trauma of the brain. The researchers studied oxidative damage done on brain mitochondria 1, 4, 7 days and 4 weeks after the trauma. The young rats were given several different nootropics to see the effect on the rat’s mitochondria. And they concluded that Picamilon had a protective effect on the function of brain mitochondria during the trauma.661 Picamilon increases blood supply, oxygen saturation and blood circulation in the brain.662 This boost in blood flow663 brings the nutrients and oxygen need to fuel ATP that power brain cell mitochondria.

Dosage Notes The recommended daily starting dosage of Picamilon for anxiety is 50 mg 2 or 3 times per day. If you’re looking for a stimulatory effect you can safely increase your dose to 100 mg 2 or 3 times daily.

Side Effects Picamilon is considered safe when taken in normal recommended doses. Picamilon has not been shown in clinical trials to produce any allergic or toxic effects. The only side effects noted were headache, dizziness and nausea. And nearly always when taken above recommended doses. At higher doses Picamilon can lower blood pressure. So if you are already on blood lowering medication, or have an issue with low blood pressure, you should not use Picamilon.

Available Forms Picamilon as a nootropic supplement is available in powder, tablet and cap- sule form. But very few major supplement retailers sell the tablet or capsule form of Picamilon. If you choose the buy bulk Picamilon powder from a vendor, make sure you ask for a genuine Certificate of Analysis to verify its authenticity. 306 HEAD FIRST Nootropics Expert Recommendation

Picamilon 50 – 100 mg 2 or 3 times per day. I recommend using Picamilon as a nootropic supplement if you’re feeling anxiety or stress. And to calm or keep in check the stimulatory effects of some nootropics. Your body does make GABA on its own from glutamate in your brain. Most healthy people have an adequate supply of GABA. But if you’re dealing with anxiety or stress and need some extra help in calming things down, Picamilon can help. Picamilon is particularly helpful if you’re dealing with anxiety. Some neu- rohackers report that Picamilon is as effective in dealing with anxiety as many prescription anti-anxiety meds. Picamilon exhibits the properties of a tranquilizer with a stimulating compo- nent. But unlike tranquilizer drugs, Picamilon does not induce muscle relaxation, drowsiness or lethargy. In addition to its calming effects, Picamilon may help improve your memory, recall and concentration. There is no reported added benefit to doses higher than those recommended. In fact, the reverse appears to be true. Lower recommended doses have more of a calming and cognitive effect for most people.

307 David Tomen Piperine

Piperine has been shown to amplify the effects of nootropics, decrease anxiety, improve mood and boost memory Piperine is an alkaloid extracted from Black Pepper (Piper Nigrum). And used to increase the bioavailability and metabolism of nootropic supplements and drugs. Black Pepper (Piper Nigrum) is a flowering vine native to south India. Its dried fruit is used world-wide as a spice and seasoning. Piperine was discovered in 1819 by Hans Christian Ørsted who isolated it from Piper Nigrum. This is the same Danish chemist who figured out that electric currents create magnetic fields.664 Piperine’s effects are similar to grapefruit juice and St. John’s wort. Piperine makes nootropics and pharmaceuticals more bioavailable by inhibiting the drug transporter P-glycoprotein, and inhibiting the major drug-metabolizing enzyme CYP3A4 primarily in your liver.665 This action amplifies the effect of nootropics by preventing elimination in your liver and urine. And allowing increased absorption for use by your body and brain. But piperine does more than just boost the action of your nootropic stack. It acts as a nootropic as well. In this chapter we investigate how Piperine can help optimize your brain. Research has found Piperine can protect against oxidative damage by inhib- iting free radicals and reactive oxygen species. Piperine protects against oxidative stress. And has been found to have anti-mutagenic and anti-tumor capabilities.666

How does Piperine work in the Brain? Piperine boosts brain health and function in several ways. But two in par- ticular stand out. 1. Piperine is an anti-depressant. Piperine is a monoamine oxidase (MAO) in- hibitor (MAOI). Piperine inhibits both MAO-A and MAO-B. Research has found that Piperine is as effective as the popular pharmaceutical antidepressant Prozac® (fluoxetine).667 Piperine has a profound effect on serotonin in the brain. Piperine has been shown in the lab to provide a substantial increase in serotonin (5-HT) in both the hippocampus and frontal cortex.668 And this is where it gets very interesting. Scientists found that combining Pip- erine with Resveratrol provided significant antidepressant action. But this stack also offered relief from oxidative stress, inflammation and provided neuroprotection.669 Resveratrol on its own is a good antidepressant. And Piperine also provides antidepressant action as a MAO Inhibitor and serotonin booster. When combined, 308 HEAD FIRST Piperine also boosts the bioavailability of Resveratrol. This combination is a potent natural antidepressant. Without the side effects that come with prescription MAOI’s and SSRI’s. 2. Piperine boosts bioavailability. Piperine inhibits the drug transporter P- glycoprotein, and the major drug-metabolizing enzyme CYP3A4. This can have profound implications on how well and how much of each nootropic in your stack actually gets to your brain. Your liver protects you by attaching a glucuronide molecule to nootropics (and drugs) which sends a signal for them to be excreted in your urine. This process prevents excessive levels of nootropic supplements (and drugs) in your body. But it can also work against your brain optimization goals. A great example is curcumin, the bioactive compound found in turmeric. You will not experience the medicinal properties of curcumin when taken on its own. Curcumin has very poor bioavailability when taken as a supplement because of its rapid metabolism in your liver and intestinal wall. Researchers in India gave mice 2 grams/kilogram of curcumin and tested blood levels over 4 hours. Very small amounts of curcumin were detected in blood in the first 2 hours. The scientists then administered the same amount of curcumin combined with 20 mg/k of Piperine. Blood levels of curcumin were detected sooner with Piperine added. And stayed in the blood longer. Bioavailability of curcumin in mice increased by 154% when combined with Piperine. The researchers then tried the experiment with humans. A 2-gram dose of curcumin on its own was not detectable in blood samples. But curcumin com- bined with Piperine in humans made a profound difference. 2-grams of curcumin combined with 20 mg of Piperine in humans showed up in blood samples within 15 minutes. And Piperine increased the bioavail- ability of curcumin by 2000%.670

How things go bad The job of our liver is to clear our body of unwanted compounds and toxins. And excrete them as waste through our urine. But some of the nootropics and especially prescription drugs are seen as “foreign matter” by our liver. The noot- ropics are eliminated as ‘waste’ even if our intention was to benefit our body and brain. To make matters even worse, add aging to the mix. And then our brain chemistry and energy metabolism changes. ↓ Serotonin, dopamine and norepinephrine levels decline ↓ Recall, reaction time and mood diminish ↓ Toxins, oxidation and free radicals damage neurons ↓ Brain cell membranes degenerate 309 David Tomen ↓ Bioavailability of nootropics and supplements decline All of these changes can happen at any age. And some are contributing factors to the neurodegenerative diseases of aging, including Alzheimer’s and dementia. This is where Piperine can help.

Piperine to the rescue Research from hundreds of studies have shown that Piperine will: • Boost the bioavailability of nootropics • Increase the effectiveness of nootropics • Work as an antidepressant • Relieve oxidative stress • Prevent inflammation • Provide neuroprotection • Protect against tumors and cancers

How does Piperine feel? Piperine on its own has antidepressant capabilities. So you may feel your mood improve. If you are using curcumin or turmeric for its anti-inflammatory benefit, you’ll likely find that these supplements will be much more effective in relieving pain by adding Piperine. You should notice a substantial benefit in the effectiveness of most nootropics and prescriptions meds when stacked with Piperine. Some neurohackers report a reduction in anxiety (that can be caused by some supplements) by taking it with Piperine. If you are dealing with arthritis you may find pain levels will decrease by using Piperine. This nootropic is a potent anti-inflammatory even on its own. You may be able to reduce the amount of some nootropics and medica- tions by stacking them with Piperine. Because the effectiveness of most of these supplements and meds will get a boost by combining them with Piperine.

The Research

Piperine Potentiates the Effects of Curcumin Stress in everyday life puts every one of us in danger of developing some type of cognitive disorder. And curcumin is a proven therapy to help protect us from this assault on our cognition and brain health. To help illustrate what happens in our brain when under stress, scientists subjected male Laca mice to stress-induced cognitive impairment for 28 days. Chronic stress impaired memory, locomotor activity, elevated toxins like 310 HEAD FIRST nitrate, decreased the master antioxidant glutathione, damaged mitochondria enzyme function, reduced acetylcholine levels, and increased stress cortisol levels. Researchers then treated the mice with either 200 or 400 mg/k per day of curcumin. All of the damage caused by stress was reversed to a certain extent. Then the team added 20 mg/k of Piperine to a reduced daily curcumin (100 or 200 mg/k) supplement. The results clearly demonstrated that Piperine en- hanced the bioavailability of the curcumin. And greatly potentiated the effects against stress-induced cognitive impairment.671

Piperine as an Antidepressant Researchers injected mice with 60 mg/k of Piperine. An hour after the injec- tion, the team measured serotonin, dopamine and norepinephrine levels. Sero- tonin levels were significantly higher in the cerebral cortex of the mice. Dopamine levels were markedly higher in the hippocampus, midbrain and cerebellum. And norepinephrine levels were lower in every part of the brain.672 Scientists in Korea analyzed Piperine (ethanol extract) for its monoamine oxidase (MAO) inhibitor capabilities. Piperine showed an inhibitory effect against MAO-A and MAO-B. The team found that Piperine exhibited the same type of antidepressant effect in the brain as the popular prescription drug Prozac® (fluoxetine). The researchers concluded that Piperine possesses potent anti-depressant properties. And Piperine is a promising pharmacotherapeutic candidate as an antidepressant agent.673

Piperine Protects Against Alzheimer’s A study conducted in Thailand looked at Piperine’s effect on memory and neurodegeneration in an animal model of Alzheimer’s Disease. Adult male Wistar rats were given Piperine at doses ranging from 5, 10 and 20 mg/k of body weight for 2 weeks before and 1 week after artificially induced Alzheimer’s-like conditions in the rat’s brain. The results showed that Piperine at all dosage ranges significantly improved memory impairment and neurodegeneration in the hippocampus. The scientists speculated the mechanism of action for Piperine to produce these effects could be a decrease in lipid peroxidation and the acetylcholinesterase enzyme. (This enzyme degrades acetylcholine synthesis in the brain). Piperine also demonstrated a neurotrophic effect in the hippocampus.674

Dosage Notes The recommended dosage of Piperine to enhance bioavailability of nootropic supplements is 5 – 20 mg per day. Many nootropic stacks and some supplement formulas (i.e. curcumin, tur- meric and resveratrol) come pre-stacked with the appropriate dose of Piperine. 311 David Tomen Side Effects Piperine is an extract of Black Pepper and considered non-toxic and safe to use at recommended doses. Piperine potentiates the effect of nearly all nootropic supplements and prescription medications. So be very aware that boosting the effects of certain supplements or drugs could produce unwanted consequences. Be cautious of using Piperine in addition to Piperine that may already be in one or more of your supplements. Too much Piperine will not only amplify most of the supplements and drugs you’re taking. But could also negate the effects of some.

Available Forms BioPerine® is a patented form of Piperine made by Sabinsa Corporation. And licensed to other supplement manufacturers to include in their formulas, or as a standalone product. It’s the only source I’m aware of who have clinical studies to back up their claims of safety and efficacy. You can also get Piperine by grinding black peppercorns on your food. The problem is there is no way to measure how much Piperine you’re actually using.

Nootropics Expert Recommendation

Piperine up to 20 mg per day I recommend using Piperine as a nootropic supplement. Your body does not make Piperine on its own. So you must take it as a supplement. Piperine is especially helpful for boosting the bioavailability of other noot- ropics in your stack. Beware that Piperine also amplifies the potency of other supplements and meds you are taking. Boosting the effect of certain SSRI’s and some other meds could be extremely dangerous. Piperine is also an effective antidepressant, and can help lower stress and anxiety. Piperine is a potent anti-inflammatory and could help reduce pain if you are dealing with arthritis. Or other conditions caused by excess inflammation in your body. Piperine is a powerful neuroprotectant and makes a great addition to any nootropic stack.

312 HEAD FIRST Piracetam

Piracetam has been shown to increase cerebral circulation, improve creativity and verbal fluency, boost memory, learning and recall and improve mood Piracetam (2-oxo-1-pyrrolidine-acetamide, Nootropil) was the first in the racetam-family of nootropic compounds. It is a water-soluble ampakine noot- ropic. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic) refers to one of three glutamate receptors in your brain.675 Developed by a fellow of famous Russian physiologist Ivan Pavlov, Dr. Corneliu Giurgea first synthesized Piracetam at Belgian-based pharmaceutical company UCB Pharma in the 1964. Piracetam is considered the first true noot- ropic ever developed. As a cyclic derivative of GABA, Piracetam was first intended to be a calming type of drug for motion sickness. But in spite of its connection with GABA, Piracetam didn’t show the behavior usually associated with this calming neu- rotransmitter. And cannot directly affect GABA receptors.676 Instead, Dr. Giurgea discovered that Piracetam was able to boost cognition even in healthy people. The company launched this new ‘drug’ as ‘Nootropil’ in Europe in the early 1970’s. The success of Nootropil soon allowed UCB Pharma to expand its operations which led to many new pharmaceutical drugs. Dr. Giurgea coined the term “nootropic” to describe this class of cognition- optimizing compounds.677 Nootropic was derived from the Greek words for “mind” (noos) and “towards” (tropein). Piracetam is sold as a prescription drug (Nootropil and Lucetam) in Europe. In South America, Piracetam is sold under the names Noostan (Argentina), Breinox (Venezuela and Ecuador), and Nootropil (Mexico). Piracetam is also branded as Lucetam, Oikamid, Smart, Geratam, Biotropil, Neurobasal, Stimulan and Nocetan in countries around the world. In the United States, Piracetam is sold as an OTC supplement as Piracetam and Nootropil. Dozens of racetam derivatives have since been developed based on the origi- nal Piracetam. All synthetic compounds, racetams share a pyrrolidone nucleus. Piracetam is a cyclic derivative of GABA. But oddly enough, it doesn’t affect GABA receptors in the brain. Instead, Piracetam was found to modulate AMPA and NMDA receptors and improve the function of the neurotransmitter acetylcho- line (ACh). AMPA and NMDA receptors along with acetylcholine are associated with learning and memory.678 And when Piracetam is stacked with a choline supple- ment its effects are even more pronounced. Researchers have shown in hundreds of clinical studies that Piracetam significantly improves learning and memory. Piracetam also increases cerebral blood flow. Blood delivers oxygen and glu- 313 David Tomen cose needed for cellular metabolism, and helps carry away cellular waste. Critical for the highly optimized brain. If you’re going to start experimenting with racetams, my recommendation is to start with Piracetam. Because it works, it’s safe and it’s cheaper than all the other nootropics in the racetam-family. Piracetam helps: • Inflammation: Piracetam is a potent analgesic (anti-pain). This analgesic effect is related to inhibition of inflammatory markers including IL-1β. And the prevention of reduced glutathione, ferric reducing ability and free radical scavenging ability.679 • Neurotransmitters: Piracetam potentiates the flow of, and increases the effect of acetylcholine (ACh) in the brain.680 And studies have shown it significantly improves learning and memory.681 • Cerebral Blood Flow: Piracetam increases blood flow in the brain.682 Better blood flow delivers more oxygen and nutrients to neurons improving cogni- tion, memory and focus.

How does Piracetam work in the Brain? Piracetam boosts brain health and function in several ways. But two in par- ticular stand out. 1. Piracetam modulates AMPA and NMDA receptors in the brain. And improves the flow of acetylcholine (ACh) and sensitivity and density of ACh receptors.683 This German study conducted with lab mice showed Piracetam elevated NMDA receptor density. And normalized the way those receptors worked with L-Glutamate similar to that of a healthy brain. Deficits at the level of NMDA receptors could be one of the mechanisms of action underlying age-related cognitive decline. And the researchers concluded that Piracetam showed cognition-enhancing properties.684 This effect on NMDA receptor sites is directly related to our interest in using Piracetam for Long-Term Potentiation and the support of long-term memory formation. Neuroplasticity is dependent on activation of NMDA receptors.685 And this neuroplasticity is at the heart of memory formation. Reviews of Piracetam used by neurohackers frequently report the return of long-lost memories. Further proof of the efficacy in using Piracetam to support learning and memory. 2. Piracetam increases cerebral blood flow. Several studies have shown how Piracetam positively influences brain blood flow. Cerebral blood flow is criti- 314 HEAD FIRST cal for the highly optimized brain. Blood delivers oxygen and glucose needed for cellular metabolism, and helps carry away cellular waste.686 Strokes can be caused by an interruption in cerebral blood flow. Starving parts of the brain of oxygen and glucose. This double-blind, placebo-controlled study was done with 24 stroke patients. One group received 2,400 mg of Pirace- tam twice daily, and the other a placebo. Before treatment, both groups were comparable in performance during language tasks. The study found that Piracetam improved recovery of various language functions. And this effect was attributed to increased blood circulation to areas of the brain related to language. The placebo group showed very little improvement in areas of language.687

How things go bad As we get older, our brain chemistry and metabolism changes. And it seems these changes are affecting younger and younger people. ↓ Recall, reaction time and learning capacity declines ↓ ATP energy levels decline ↓ Density of AMPA and NMDA receptors decline ↓ Acetylcholine levels decline ↓ Cerebral blood flow declines All of these changes are contributing factors to age-related cognitive decline. Early signs of these effects can be seen in poor decision-making, difficulty learn- ing, and even recalling simple things like an important appointment. But even if you’re not concerned with the signs of aging, Piracetam can help.

Piracetam to the rescue Piracetam helps increase blood flow in the brain, improves oxygen levels, enhances glucose use in brain cells, maintains brain cell mitochondria and ATP synthesis. Piracetam is also a potent modulator of AMPA-sensitive glutamate recep- tors in neurons. It increases the density of specific binding sites for AMPA in neuronal synapses.688 Glutamate is the primary excitatory neurotransmitter in your brain. This glutamate activity by Piracetam affects alertness, focus, attention, memory and learning. And one of the reasons why neurohackers consistently report that Pi- racetam improves mental performance and memory. Piracetam increases high-affinity choline uptake (HACU) which is the process that occurs in cholinergic nerve endings and facilitates acetylcholine (ACh) forma- tion. Boosting ACh with Piracetam produces a powerful effect on learning and memory.689 315 David Tomen Piracetam also boosts choline receptor density in the frontal cortex. The area of your brain used for working memory and decision-making.690 ATP energy is critical to your brain’s survival. Brain cells must produce all of their own ATP from glucose and oxygen. This brain energy carbohydrate metabolism depends on cerebral blood flow, oxygen uptake and glucose. Piracetam enhances this glucose utilization, and increases ATP synthesis needed to power brain cell mitochondria.691 And Piracetam has analgesic (anti-pain) benefits. This anti-pain action is linked to Piracetam’s anti-inflammatory properties.692 Inflammation can cause pain, and studies have shown Piracetam can have profound effect on pain. Piracetam boosts acetylcholine so you should add a good choline source. Try Alpha GPC or CDP-Choline with Piracetam. And give your brain the choline it needs.

How does Piracetam feel? Most neurohackers report a noticeable benefit from Piracetam after about 2 weeks. Consider that Piracetam is modulating your brain’s chemistry. And this change is unlikely to occur immediately. Your brain needs some time to adjust to the new change in acetylcholine (ACh) levels and how it uses it. Increased cerebral blood flow takes a while to bring up levels of oxygen and nutrients. And for your neuronal cells to respond. Your mileage may vary depending on your own neuro-chemical makeup. Many suggest starting with an ‘attack dose’ for the first 3-days. A 3,000 mg ‘attack dose’ of Piracetam for example to start with theoretically gets more of the supplement into your system right away. So it takes less time to build up before you start feeling the effects. From there, step down to a maintenance dose and vary the quantity until you find your own sweet spot. Once you begin to notice the effects of Piracetam you’re likely to feel a mood boost, less social anxiety, heightened creativity, improved verbal fluency and better memory. Piracetam does boost your brain’s use of acetylcholine. So you will likely find that adding a good choline source (Alpha GPC or CDP-Choline) to your Piracetam stack helps improve the effectiveness of this nootropic. And help avoid a ‘racetam-headache’.

The Research We have plenty of evidence that Piracetam improves memory in animals and people who are suffering from many types of cognitive impairment. Keep in mind that most of the scientific research available for nootropics is done for sick people trying to get well. The return on investment for research at institutions and universities comes 316 HEAD FIRST from treating diseases. And not from helping ordinary biohackers like us trying to get a competitive advantage at work or in school. We can however extrapolate the findings from these studies and learn if and how something like Piracetam can help our memory and cognition. Once-in- awhile someone does take the time to conduct such a study on healthy people. Like this one done with normal, healthy volunteers. Researchers gave this healthy group of participants four 400 mg capsules of Piracetam 3-times per day (4,800 mg total) for 14 days. No effects on memory were observed after 7 days during this experiment. But after 14 days verbal learn- ing had significantly increased.693

Piracetam Improves Cognition Researchers in Belgium (where Piracetam originated) conducted an analysis of 19 double-blind, placebo-controlled studies done with patients suffering demen- tia or cognitive impairment and who took Piracetam. The results of this meta-analysis demonstrated the difference between people who used Piracetam or used a placebo. The end result of this analysis provided compelling evidence for the usefulness of Piracetam in a diverse group of people with cognitive impairment.694 Several studies and user reviews have shown that Piracetam dosage makes a difference. And unlike some other nootropics where you start at a lower dose and work your way up, with Piracetam I recommend you start at a higher dose. This study in Germany with 78 elderly patients showed that there was a significant difference in cognition improvement while dosing Piracetam at 1,600 mg 3-times per day (4,800 mg total). There was no difference in cognition with patients who received 800 mg 3-times per day.695

Piracetam Enhances ATP Production Piracetam is used around the world to treat cognitive impairment in aging, brain injuries, dementia and Alzheimer’s Disease. Several studies show that Piracetam enhances ATP production, mitochondrial membranes and neurite out- growth in neurons. In this study, scientists investigated the effects of Piracetam on mitochondrial function. Human brain cells were treated with Piracetam under normal condi- tions and under conditions imitating aging and damage by ROS (reactive oxygen species). And with cells representing early-stage Alzheimer’s Disease. The cells representing Alzheimer’s conditions showed impaired mitochon- drial function under baseline conditions. Piracetam was able to restore this impairment in cells and shift mitochondrial function back to normal. The researchers showed that Piracetam is able to repair mitochondria in those with mild Alzheimer’s and return cell function back to normal.696 317 David Tomen Dosage Notes Recommended Piracetam dosage is 1,600 mg 3-times per day. One Pirace- tam dose in the morning, and one in the early afternoon, and one later in the afternoon. You will likely want to start with an ‘attack dose’ when you’re first starting out with Piracetam. Refer to the “How does Piracetam feel?” section of this chapter for more on ‘attack doses’. Dosing Piracetam varies widely between neurohackers. Experimenting and finding the dose where you experience the most benefit is key. You may find a lower dose works well for you. Or you may find you need to increase your dose even more. Dosing Piracetam is directly related to your own unique neurochemistry.

Side Effects Piracetam is non-toxic. So is considered well-tolerated and safe. As with many of the racetams, Piracetam can cause headaches because it boosts the use of acetylcholine in your brain. Choline supplements like Alpha GPC or CDP-Choline can help you avoid this side effect. Many neurohackers find that stacking Piracetam with a choline supplement boosts the effect with improved memory and cognition. And this is supported in several research studies.697

Available Forms Piracetam is sold in tablet, capsule and powder form. Tablets and capsules are usually 800 mg each. In Europe, Asia, South America and some other countries around the world, Piracetam is a prescription drug. And sold under many different brand names (including Nootropil). Refer to the Introduction of this chapter for some of these brand names.

Nootropics Expert Recommendation

Piracetam 1,600 mg 3-times per day I recommend using Piracetam as a nootropic supplement. Your body does not make Piracetam on its own. So to get its benefits you must take it as a supplement. If you’re going to start experimenting with racetams, my recommendation is to start with Piracetam. Because it works, it’s safe and it’s cheaper than all the other nootropics in the racetam-family. Piracetam is especially helpful for those suffering from most types of age- related cognitive decline. Piracetam is also particularly useful to students and executives who want to boost cognition, learning and memory. 318 HEAD FIRST You should use Piracetam with a good choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Piracetam to 9,600 mg. if needed. Studies have shown that Piracetam is completely non-toxic even at high doses. You may find however that a lower dose than my recommended amount works better for you.

319 David Tomen PQQ

PQQ helps create new mitochondria in brain cells, is a very potent antioxidant, stimulates Nerve Growth Factor, and boosts energy, cognition, memory and learning PQQ (pyrroloquinoline quinone or methoxatin) is a very potent antioxi- dant and plays a significant role in cognition and memory. PQQ is the first nutrient discovered that promotes thegrowth of new mito- chondria (mitochondriogenesis) in your cells. Brain cells have a higher concentra- tion of these little cellular power plants than most other cells in your body.698 You can have anywhere from two to several thousand mitochondria in each brain cell. They even have their own DNA. When you increase the number of mitochondria, you have more cellular energy to power through your day. PQQ was only discovered recently. But it’s been around for a very long time. So don’t roll your eyes when some New Ager claims that we’re made of stardust. PQQ was discovered aboard NASA’s spaceship “STARDUST” in interstellar dust particles.699 PQQ was first recognized as an enzyme cofactor in bacteria by Norwegian biochemist Jens Hauge in 1964.700 It wasn’t until 2003 that Japanese brain re- searcher Tadafumi Kato found that PQQ also occurs in rodents and other mam- mals, including humans. As an enzyme cofactor, PQQ is critical to the life of your brain cells. And some would say it’s even critical to life itself. “Cofactors” are molecules that act as a helper for enzymes that need assistance to work properly. Recent studies verify the unique ability of PQQ to stimulate the creation of new mitochondria.701 And to improve the function of your existing mitochon- dria. But why would you want to hack your mitochondria? It is an understatement to overstate the dramatic impact this has not only in your brain. But in your entire body. Mitochondria’s role is to convert the food we eat into energy that powers cells to perform at peak function. This process ofmitochondriogenesis stops and reverses brain cell death, and brain degeneration. PQQ is the only nutrient that can do this. And more energy in your brain cells means quicker thinking, better memory, amped-up alertness, less mental fatigue and more. PQQ stimulates the growth of new neurons through the promotion of nerve growth factor (NGF) in brain cells. Resulting in improved memory, cognition and learning.702 PQQ is also a potent antioxidant mopping up free radicals that would oth- erwise damage brain cells. PQQ is used in every cell in your body. And is particularly useful in brain cells. It’s about a close you can get to a vitamin without ‘officially’ being declared a vitamin. 320 HEAD FIRST You get PQQ from some of the food you eat including beans, celery, cocoa, fermented foods (i.e. tempeh, natto), kiwi, papaya, parsley, potatoes, spinach and wine. Babies get it from breast milk.

How does PQQ work in the brain? PQQ boosts brain health in several ways. But two in particular stand out. 1. PQQ promotes the growth of new mitochondria. This is the only known nutrient that can perform this function. Mitochondria are the source of life and death for neurons. They generate your neuron’s energy and control its death. But mitochondria tend to develop defects as we age. As these defects accumulate, mitochondria start to malfunction. This results in a reduction in cellular energy production. And cells die. The result of this dysfunction can be brain fog, cognition problems, poor memory and recall. And ultimately neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington’s, stroke and others. Studies show that PQQ protects against this cellular damage by repairing and helping to create new mitochondria. Studies with mice and rats, and eliminating PQQ from their diet have shown reduced mitochondria. To demonstrate how this process works, scientists added PQQ to mouse cells in the lab. And they showed that PQQ activated the cAMP response element- binding protein (CREB), and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). This pathway is known to regulate mitochon- drial biogenesis.703 2. PQQ helps grow new neurons. This unique nutrient promotes the produc- tion of nerve growth factor (NGF). Assisting in brain cell repair, maintenance, and regeneration. Including many of the cells that are crucial for cognition, memory and learning. NGF is especially important for maintaining neuroplasticity. This process is how brain cells form connections to communicate with each other. And is how we learn new stuff and then record it to memory. By stimulating the production of NGF, PQQ has been found to protect memory and cognition in both animals and humans. In one study, scientists demonstrated PQQ’s ability to promote the healing of injured nerves. The team used 90 healthy White Wistar rats, and divided them into 3 groups. The rats had injured (purposely) sciatic nerves. And were treated with Vitamin E, PQQ or combination of both. The scientists found that 12 weeks after surgery and the introduction of PQQ to the wound, the nerves grew back! They concluded that the combination of Vitamin E with PQQ promoted nerve regeneration.704 321 David Tomen Another way that PQQ influences new neuron development is by protecting neuron stem and progenitor cells from glutamate toxicity (oxidative damage). This allows neurons to survive and potentially form new brain cells.705

How things go bad As we get older, the chemistry in our brain cells and energy metabolism changes. ↓ Neurons degenerate ↓ Recall, reaction time, memory, and mood diminish ↓ Neurotransmitter levels decline All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging, including Alzheimer’s and dementia. But even if things haven’t degenerated to such a debilitating level, PQQ can help.

PQQ to the rescue Research from hundreds of studies have shown that PQQ will: • Boost energy levels and stamina • Reduce fatigue • Improve sleep • Reduce the possibility of age-related diseases • Improve cognition, memory, learning and recall • Repair damage caused by strokes • Protects against Alzheimer’s and Parkinson’s • Lowers LDL (bad) cholesterol706 PQQ is an extremely powerful antioxidant. For example, PQQ is able to carry out 20,000 catalytic conversions, compared only 4 for Vitamin C.707 The studies in Parkinson’s Disease prevention and PQQ are particularly interesting. And applicable to neurohackers of any age. We are exposed to pesticides in most of the fruit and vegetables we pick up at the supermarket. And who knows what kind of brain damage we subject ourselves to every day just from the food we eat. In the lab, animals (rats and mice) have a pesticide injected directly into their brain to induce Parkinson’s-like symptoms. In one study, PQQ not only showed a protective effect against pesticide caused brain damage. It actually preserved brain mitochondria near control levels. 708 The message here is buy organic food, or supplement with PQQ. And you may be able to avoid getting Parkinson’s Disease later in life. (I do both just to be on the safe side 12). 322 HEAD FIRST How does PQQ feel? Mitochondria biogenesis means that your body is creating new mitochondria. PQQ increases the number of mitochondria in your brain cells. And throughout your body where energy demands are high. Increasing your body’s mitochondria is one of the anti-aging ‘holy grails’. Boosting these tiny cellular energy power plants can prevent further damage. It can add overall energy to daily life. And maybe even slow down the aging process. Neurohackers report dramatic improvements in mental and physical energy when adding PQQ to their nootropic stack. And I recommend adding CoQ10 for the synergistic effect. PQQ has a cumulative effect and benefits should continue to improve over continued usage. For some the effects are immediate. For others it could take 2 or 3 months of dosing PQQ every day or every 2nd day. PQQ is particularly effective if you’ve suffered mitochondrial damage from using statins. Memory improves and you’ll be able to think things through more easily. Alertness gets a boost. And better vision and less eyestrain if you’re working on a computer, or staring at a screen all day. Blood pressure readings could normalize. And you’ll feel refreshed and well- rested when waking up. If you are dealing with Fibromyalgia you may get some benefit from PQQ with alleviating your chronic pain.

The Research

PQQ Improves Mood This study in Japan investigate the effectiveness of supplemental PQQ on stress, fatigue, quality of life and sleep. 17 adult male and female subjects took 20 mg of PQQ daily for 8 weeks. Changes in stress, fatigue, quality of life measures and sleep were evaluated. The study showed that vigor, fatigue, tension-anxiety, depression, anger-hostility and confusion improved following administration of PQQ. Measures for quality of life, appetite, sleep, obsession and pain also improved significantly. The volunteers also showed significant improvement in sleepiness at awakening, sleep onset and maintenance, and sleep duration. The researchers concluded that supplementing withPQQ improved sleep quality and duration, mood improved due to less fatigue, and appetite, pain and ob- session all showed improvement. And that PQQ is a “useful dietary supplement”.709

PQQ Improves Cognition PQQ is effective on its own in improving brain function. But when it is combined with CoQ10 the results are even more astounding. This synergy was 323 David Tomen first observed in animal studies. And was further demonstrated in a double-blind, placebo-controlled trial in Japan. 71 middle-aged and elderly volunteers age 40 – 70 were supplemented with 20 mg per day of PQQ. The result was an improvement on tests of higher cogni- tive function compared to placebo. Then the research team gave the volunteers 20 mg of PQQ along with 300 mg of CoQ10. And the results in improved cognitive function were even more dramatic. PQQ and CoQ10 are both involved in mitochondrial function. So these results did not come as a big surprise.710

PQQ Boosts Memory Many older adults experience problems with memory and other cognitive functions. And these issues seem to be happening to younger and younger people. As neurohackers, we always ask the question, “Are these declines inevitable?” And to that we say a profound, “No”! In this Japanese double-blind, placebo-controlled trial 65 adults aged 50 – 70 years with forgetfulness were recruited. The volunteers were given 20 mg of PQQ and 100 mg of CoQ10 per day for 24 weeks. The research team found that PQQ taken either alone, or in combination with CoQ10 has the potential to prevent, or even reverse, the decline in cognitive function caused by aging and oxidative stress. The team concluded “PQQ was found to improve not only immediate memory, but also other higher brain functions such as spatial awareness. The effects of PQQ were enhanced when the substance was used with CoQ10.”711

Dosage Notes You get PQQ from some of the food you eat including beans, celery, cocoa, fermented foods (i.e. tempeh, natto), kiwi, papaya, parsley, potatoes, spinach and wine. Babies get it from breast milk. Estimated daily intake of PQQ is 100 – 400 mcg. But it’s unlikely you’re get- ting enough PQQ from diet alone. And supplementation of this mitochondria generator could help. Clinical studies with humans and animals tell us that 20 mg of PQQ daily is needed to experience cognitive benefit.

Side Effects The primary “side effect” of using PQQ in your nootropic stack is – you’ll feel better. You should have more energy and thinking should be clearer and faster. PQQ is non-toxic and supplementation is well-tolerated by most people.

Available Forms PQQ comes in table or capsule form 10 mg, 20 mg and 30 mg. But you need to be aware of different forms of PQQ on the marketplace. 324 HEAD FIRST There is only 1 form available that is produced naturally. And that is BioPQQ® by Mitsubishi Gas Chemical Company of Japan. This company makes PQQ through bacterial fermentation. BioPQQ is licensed to several supplement makers. Other forms are produced through a chemical synthesis, involving the use of fairly toxic compounds, and have unresolved safety issues.

Nootropics Expert Recommendation

PQQ 10 – 20 mg per pay I recommend using PQQ as a nootropic supplement. Your body does not make PQQ on its own. You can get some PQQ from the food you eat. But studies have shown we may not get an adequate supply of PQQ from food sources in our diet. PQQ helps create mitochondria in your brain cells. When cellular energy gets a boost, you can experience better and faster thinking, learning is easier, recall is faster, and you’ll be more resistant to fatigue. PQQ is especially helpful for those suffering from age-related cognitive de- cline. Studies show it helps stop or reverse brain degeneration with Alzheimer’s and Parkinson’s Disease. Especially in the early stages of the disease. I suggest starting with a dose of 10 – 20 mg daily. And PQQ is a great compliment to a stack including any nootropic. It works particularly well when combined with CoQ10. You need to provide your brain cells with fresh mitochondria and supply neurons with the fuel it is demanding. Or neurons start to break down from the inside. Signs that your lacking adequate PQQ is brain fog, slow thinking, headaches and muscle aches. Age-related cognitive disorders that include muscle control problems may want to up the dose to 30 mg per day. But for a limited time until PQQ blood levels are stabilized. Work with your doctor.

325 David Tomen Pramiracetam

Pramiracetam has been shown to boost overall cognition, focus, working – and long- term memory, and learning Pramiracetam (N-[2-[di(propan-2-yl) amino] ethyl]-2-(2-oxopyrrolidin- 1-yl) acetamide, CI-879, Pramistar, Neupramir, Remen) is a fat-soluble noot- ropic in the racetam-class of compounds. Pramiracetam was first synthesized by scientists at Parke-Davis in the late 1970’s. It was first tested with Alzheimer’s patients. Seeing mixed results, the company tried it with major depressive disorder. And licensed Pramiracetam as an orphan drug to Menarini who continued research on using it for dementia. In 1991, the company licensed Pramiracetam to Cambridge Neuroscience Inc. (CNI).712 The nootropic was then tested for restoring cognitive function after stroke or traumatic brain injury. Researchers found that Pramiracetam was up to 30-times more potent than the original Piracetam. In Europe this nootropic is prescribed for the treatment of dyslexia, ADHD, dementia and other memory problems. Brand names for prescription Pramiracetam include Pramistar, Neupramir and Remen. Pramiracetam has gained a reputation in the nootropics community for optimizing cognition. It’s a favorite with students and executives for boosting cognition, focus, memory, and recall. Pramiracetam helps: • High Affinity Choline Uptake (HACU): Pramiracetam has been shown to significantly increase HACU in the hippocampus. This action boosts acetylcholine (ACh) use which accounts at least in part for Pramiracetam’s ability to enhance cognition and memory.713 • Neurotransmitters: Pramiracetam has a profound effect on the synthesis of the neurotransmitter acetylcholine (ACh).714 ACh is critical for encoding new memories, concentration, cognition and neuroplasticity. • Cerebral Blood Flow: Pramiracetam increases nitric oxide (NO) activity in your brain.715 NO acts as a vascular dilator which means it relaxes blood vessels allowing for the freer flow of blood. Increased blood flow delivers more oxygen and nutrients to brain cells promoting better learning and memory. Pramiracetam was developed by Parke-Davis in the late 1970’s from Pi- racetam by substituting the amide group with a dipropan-2-ylaminoethyl group. Parke-Davis was once America’s largest and oldest drug maker. It has since been acquired by Pfizer as part of their acquisition of Warner-Lambert in 2000. Parke-Davis has an interesting history and were pioneers in many areas in- 326 HEAD FIRST cluding drugs that affect cognition. Even conducting some research with peyote in the early 1900’s.716 Pramiracetam as a nootropic is legal, and sold in many parts of the world as the prescription drug Pramistar, Neupramir, or Remen. In the United States, Pramiracetam is sold as an OTC ‘research compound’, and readily available to the nootropics community. Pramiracetam shares a unique quality with Coluracetam in the racetam-class of nootropics. Its primary method of action is boosting high affinity choline uptake (HACU) in the hippocampus. It helps increase acetylcholine synthesis and function which helps overall cognition, improved memory and recall, learn- ing, and focus. Pramiracetam has been shown in the lab to not directly influence GABA, dopamine, norepinephrine, or serotonin in the brain.717 So don’t look to Pramirace- tam to correct mood and anxiety issues. Pramiracetam does increase nitric oxide activity in your brain. Helping to increase cerebral circulation which improves the efficiency of brain cells needed for motor function, learning and visual function.

How does Pramiracetam work in the Brain? Pramiracetam boosts brain health and function in several ways. But two in particular stand out. 1. Pramiracetam improves memory. Several animal and human studies show that Pramiracetam has a significant impact on memory. In this animal study researchers administered Pramiracetam to rats in a one- trial test. This is significant because it proves that Pramiracetam works right out of the gate. It doesn’t take multiple doses, or a couple of weeks to build up in your system. It works on the first day you use it. The scientists found that rats had a significant improvement in retention by using Pramiracetam. And the effect lasted for 24 hours.718 2. Pramiracetam increases high-affinity choline uptake (HACU). Studies have shown that Pramiracetam boosts HACU in the hippocampus. The increase in acetylcholine (ACh) makes more of this neurotransmitter avail- able to neurons for cognitive processing. Increasing attention, mental clarity, memory and verbal skills.719 High affinity choline uptake (HACU) is the uptake of choline in synapses needed for acetylcholine (ACh) synthesis. This is a critical link in the chain of events needed for your brain to make ACh.720 Studies with Pramiracetam and other racetam nootropics like Coluracetam show that boosting HACU increases memory. And even restores memory function in parts of the brain that have been damaged.721 327 David Tomen How things go bad As we get older, our brain chemistry and metabolism changes. And it seems these changes are affecting younger and younger people. ↓ Recall, reaction time and learning capacity declines ↓ Acetylcholine receptors decline ↓ Acetylcholine levels decline ↓ Cerebral blood flow declines ↓ Nitric Oxide levels decline All of these changes are contributing factors to age-related cognitive decline. Early signs of these effects can be seen in poor decision-making, difficulty learn- ing, and even recalling simple things like an important appointment. But even if you’re not concerned with the signs of aging, Pramiracetam can help.

Pramiracetam to the rescue Pramiracetam helps boost acetylcholine (ACh) synthesis and use in your brain, and increases cerebral circulation. As a nootropic, Pramiracetam easily crosses the blood-brain barrier.722 And since it is fat-soluble, it must be taken with a healthy fat to ensure absorption. Pramiracetam increases the amount and efficiency of acetylcholine by influ- encing the high affinity choline uptake (HACU) system in your brain. This increase in ACh can have a profound effect on overall cognition and memory. With Pramiracetam, you’ll find it easier to focus and learning ability will improve. This increase in ACh in your hippocampus helps with logic and under- standing complex mathematical and technical subjects if that’s your thing. Increased neuroplasticity from more acetylcholine and improved cerebral circulation affects long-term potentiation.723 So you may find it easier to recall long-forgotten memories.

How does Pramiracetam feel? Many neurohackers report that taking Pramiracetam quickly gets your brain firing on all cylinders. There is an intense increase in focus and possibly even a boost in confidence. But once you get accustomed to this laser-like focus, the novelty wears off and you become used to being able to focus at will. Pramiracetam is reported to be great for intense, long study sessions. Or when you face logical, attention-based tasks where you need sharp focus. Like when you’re doing a presentation before the Board, or a group of VC’s. This nootropic makes burning through tedious, arduous tasks that require a level of sustained focus easier, and that would otherwise seem difficult. Others report improved recall ability, fluidity of thought, and ease of verbal communication and numerical calculations. 328 HEAD FIRST The Research

Pramiracetam Normalizes Brain Waves Researchers working with old Fisher-344 rats found that the aged rats had a consistently different EEG profile from young rats. They found slow brain waves were present in both the frontal cerebral cortex and hippocampus. Theta brain wave activity was missing altogether but was dominant in the brains of young rats. Theta brain waves are associated with creativity, integrative experiences and relief from trauma. Theta waves are commonly experienced by meditators. An “ah-ha moment” is a burst of Theta waves in your brain. This research team found that Pramiracetam normalized brain wave activity in the old rats. And even more interesting was that its older sibling Piracetam did not produce this effect on brain waves. And that tolerance to Piracetam was a problem. While it hasn’t been proven in the lab, this study shows that Pramirace- tam would be of benefit to the older generation looking to improve cognitive function.724

Pramiracetam Improves Memory Researchers in Italy investigated Pramiracetam effects on memory, and memory training by a therapist. Types of memory measured were objective memory and metamemory performance. Metamemory is both the inner-knowledge of one’s own memories combined with the processes for formulating new memories with no inner-knowledge. 35 healthy volunteers were chosen with an average age of 64.8 years. 10 subjects received memory training only, 8 received Pramiracetam, 10 received both memory training and Pramiracetam, and the control group received nothing. Results of the study showed that those receiving both memory training and Pramiracetam experienced a significant improvement in memory. Followed by the Pramiracetam group. The memory training-only group and control group scored the lowest. The research team concluded that Pramiracetam significantly improves memory. And the addition of memory training to Pramiracetam has an even more profound effect of both types of memory measured.725

Pramiracetam Enhances Cognition This double-blind placebo-controlled study worked with young males who suffered cognition problems due to brain injuries. The men had problems with memory and recall. One group received 400 mg of Pramiracetam daily for 18 months. And the 329 David Tomen other group a placebo. Memory was measured during the trial and for 1-month after Pramiracetam was discontinued. The researchers found that Pramiracetam produced a significant improvement in cognition, memory and recall.726

Dosage Notes Recommended Pramiracetam dosage is 250 – 400 mg up to 3-times per day. One Pramiracetam dose in the morning, and one in the early afternoon, and if you’re doing a 3rd dose do it later in the afternoon. Pramiracetam is fat-soluble so for best results take it with a quality fat like extra virgin, cold-pressed unrefined coconut oil, MCT oil or olive oil. If you don’t take Pramiracetam with supplemental fat, don’t expect much of an improvement in cognition. Pramiracetam is one of two racetams (the other is Coluracetam) that have a profound effect on high affinity choline uptake (HACU). This means it will help your brain make more acetylcholine (ACh) and boost the use of ACh. Acetylcholine is synthesized from the available choline in your brain. Which means for best results you should stack Pramiracetam with supplemental choline. We recommend a good quality choline source like Alpha GPC or CDP-Choline. Pramiracetam tastes particularly nasty. So you may want to get capsules or tablets rather than powder (unless you’re making your own capsules). DO NOT try to take Pramiracetam sublingually because it will literally burn the lining of your mouth.

Side Effects Pramiracetam is non-toxic. So is considered well-tolerated and safe. As with many of the racetams, Pramiracetam can cause headaches because it boosts the use of acetylcholine in your brain. Choline supplements like Alpha GPC or CDP-Choline can help you avoid this side effect. Many neurohackers also find that stacking Pramiracetam with a choline supplement boosts the effect with improved memory and cognition. And this is supported in several research studies. Some users report that Pramiracetam blunts their emotions. Decisions when it comes to life and work issues are logic-based rather than emotional. This can be good or bad depending on the situation of course. You could call it “emotional objectivity”.

Available Forms Pramiracetam is sold in tablet, capsule and powder form. Tablets and cap- sules are usually 250 or 300 mg each. In Europe, Pramiracetam is a prescription drug under brand names Pramis- tar, Neupramir, or Remen. 330 HEAD FIRST Nootropics Expert Recommendation

Pramiracetam 250 – 400 mg up to 3-times per day I recommend using Pramiracetam as a nootropic supplement. Your body does not make Pramiracetam on its own. So to get its benefits you must take it as a supplement. Pramiracetam is especially helpful for those suffering from age-related cogni- tive decline. Its boosts high affinity choline uptake (HACU) which means more acetylcholine (ACh) is available in your brain. Providing a significant improve- ment in cognition and memory. Pramiracetam is also particularly useful to students and executives who want to boost cognition, focus, learning and memory. Pramiracetam is fat-soluble so stack it with a good quality fat like coconut oil, olive oil or MCT oil. You should use Pramiracetam with a choline supplement like Alpha GPC or CDP-Choline. It helps boost neural acetylcholine, so demands the presence of more choline in your brain. You can safely boost daily intake of Pramiracetam to 1500 mg if needed. But most find that lower doses are more effective.

331 David Tomen Pterostilbene

Pterostilbene is a very potent antioxidant, stimulates Brain-Derived Neurotrophic Factor, promotes neuroplasticity, is anti-anxiety, boosts dopamine, and helps cogni- tion, learning and memory Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene, PTE) is a naturally derived polyphenol antioxidant found in blueberries, grapes, and in the bark of the Indian Kino Tree. Pterostilbene, a naturally occurring dimethylether analog of resveratrol, is a phytoalexin that, like resveratrol, is made by plants to fight infection, insect infestation, heat and ultraviolet exposure.727 Pterostilbene and resveratrol are both ‘stilbene’ polyphenols. But Pterostilbene is much more bioavailable than resveratrol. It rapidly crosses the blood-brain bar- rier, and stays in your body much longer than resveratrol (half-life of 105 mins. vs. 12 mins.).728 Pterostilbene shows 80% bioavailability while resveratrol only has 20% bioavailability.729 Pterostilbene is gaining a reputation in the nootropics community for con- trolling brain inflammation, boosting dopamine, helping reverse cognitive decline and fighting brain cell aging. Pterostilbene helps: • Neuroplasticity. Pterostilbene increases hippocampus neurogenesis, boosts insulin-like growth factor-1 (IGF-1), and modulates the receptor kinase path- way that is central in the learning and memory process. Increasing neuro- plasticity in the hippocampus improves learning and memory functions.730 • Neuroprotectant. Pterostilbene is a potent antioxidant and anti-inflamma- tory. It reduces reactive oxygen species (ROS), and increases the antioxidant glutathione and superoxide dismutase (SOD).731 Crucial to overall brain health, maintaining signaling pathways and leading to improved learning and memory. • Brain-Derived Neurotrophic Factor (BDNF). Pterostilbene has been shown in clinical trials to elevate BDNF in the hippocampus. Improving learning and memory.732 Pterostilbene and resveratrol are both ‘stilbene’ polyphenols. And both boost cognition, learning and memory. But Pterostilbene works differently than Resve- ratrol. And is not a replacement for Resveratrol. Here’s why… Resveratrol has been getting a lot of press lately because of its ability to boost learning, memory and cognitive power. But Pterostilbene is much more bioavailable 332 HEAD FIRST than resveratrol. And may be the preferred polyphenol to add to your nootropic stack. Pterostilbene stands out because of its structural differences from Resveratrol. Pterostilbene has two methoxy groups and one hydroxyl group. Resveratrol has three hydroxyl groups. This combination in Pterostilbene improves lipophilicity which means it can dissolve in fats, oil and lipids. Lipids are what makes up the shell or membrane encasing each one of your cells. So Pterostilbene can more easily cross through your cell walls. In fact, several published studies refer to Pterostilbene as having much better bio-activity than Resveratrol. You can easily add Pterostilbene to your diet. It’s found in blueberries, cran- berries, sparkleberries, lingonberries, grapes, and in the bark of the Indian Kino Tree. But to get the therapeutic benefits of Pterostilbene, a preferred way of getting this potent antioxidant is to take it as a supplement. Pterostilbene has been shown to prevent the loss of the neurotransmitter dopamine from memory centers in your brain. Supplementing with PTE raises its levels in your hippocampus which is where memory is processed. Pterostilbene also has the effect of caloric restriction on cells which pro- foundly effects gene expression. This tricks your body into improving memory because it’s thinking there is food scarcity. And it provides an adaptive response. The polyphenol Pterostilbene increases neuroreceptor sensitivity which im- proves neuronal signaling. And PTE promotes the formation of new synaptic con- nections which boosts neuroplasticity. Improving long-term potentiation resulting in formation of long-term memories.

How does Pterostilbene work in the brain? Pterostilbene boosts brain health in several ways. But two in particular stand out. 1. Pterostilbene mimics caloric restriction. Restricting calories by fasting has been implicated in increased synaptic plasticity resulting in improved learn- ing. Scientists determined that this enhancement in synaptic plasticity was caused by increased brain cell signaling. The signaling increase is mediated by CREB (cAMP response element binding protein).733 CREB has a proven role in neuronal plasticity and long-term memory forma- tion in the brain. And has been shown to be critical in the formation of spatial memory.734 In several studies, Pterostilbene has been shown to modulate gene expres- sion. PTE up-regulates those genes that stimulate apoptosis (programmed cell 333 David Tomen death). And down-regulate those genes that allow cancer cells for example, to invade and metastasize.735 And this gene modulation is linked to increases in CREB and Brain-Derived Neurotrophic Factor (BDNF). An increase in BDNF helps long-term potentiation needed for the development of long-term memory. In this study, researchers supplemented aging animals with blueberry ex- tract for 12 weeks. This extract contained PTE. Spatial working memory tasks emerged within 3 weeks of supplementation. And persisted for the remainder of the testing period. This memory enhancement correlated with the activation of CREB. And increases in brain-derived neurotrophic factor (BDNF) in the hippocampus. In fact, PTE was implicated in the entire chain of the ERK-CREB-BDNF signaling pathway that boosts memory.736 2. Pterostilbene boosts dopamine. But it increases dopamine in kind of a ‘back door’ approach. We have plenty of research showing that neurodegen- eration is caused by oxidative stress. And that anti-oxidants can stop and even reverse damage to neurons. Potentially leading to an increase in the release of important neurotransmitters like dopamine. PTE is a potent antioxidant. One study done a Tufts University in Boston investigated stilbene com- pounds like PTE and their effect on reversing the effects of aging. The researchers used 344 Fisher rats and gave them either a low (0.004%) or a high (0.016%) concentration of Pterostilbene. Results from this study showed that PTE was effective in reversing cogni- tive deficits. And Pterostilbene increased dopamine release. A boost in working memory correlated with Pterostilbene levels in the hippocampus.737

How things go bad As we get older, the chemistry in our brain cells and energy metabolism changes. ↓ Neurons and synapses degenerate ↓ Recall, reaction time, memory, and mood diminish ↑ Anxiety levels increase ↓ Neurotransmitter levels decline ↓ Oxidation damages brain cells All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging including Alzheimer’s, Parkinson’s and dementia. But even if things haven’t degenerated to such a debilitating level, PTE can help.

Pterostilbene to the rescue Pterostilbene helps improve memory and provides neuroprotection through different mechanisms of action than most other nootropics in a typical stack. 334 HEAD FIRST PTE works primarily through gene expression. Easily passing through cell walls, PTE modulates genes that influence other proteins, mitochondria and even cell DNA. We talk a lot about apoptosis (programmed cell death) as a negative event in nootropic circles. But the reality is that apoptosis is an integral part of a healthy brain. Pterostilbene stimulates apoptosis to make way for healthy new cells to be born (neurogenesis). And helps down-regulate invaders like cancer cells. Prevent- ing them from invading healthy brain tissue and metastasizing.738 Some supplement makers are mistakenly marketing their Pterostilbene as an “upgraded-version” of Resveratrol. But the research shows Pterostilbene and Resveratrol work together to boost cognitive health. Resveratrol works at the beginning of the cascade of neurochemical events that activates genes leading to cognitive benefits. And Pterostilbene provides its gene expression effects in the downstream portion of this molecular cascade. Pterostilbene has a kind of ‘reverse effect’ on boosting dopamine. Rather than directly increasing dopamine levels like some nootropics, PTE prevents the loss of dopamine in brain memory centers. This is not nearly as strange as it sounds. Because this mechanism of action is similar to how Ritalin works as a stimulant. By preventing the uptake of do- pamine by neuroreceptors, Ritalin keeps more dopamine available for increased alertness, cognition and memory formation. PTE prevents brain injury from lack of blood flow and could have profound applications in the recovery from stroke. This effect could be beneficial even in healthy brains who suffer from brain fog due to poor cerebral circulation. Pterostilbene provides well-documented antioxidant activity.739 Affecting neuroreceptor sensitivity for improved neural signaling. PTE even promotes new synaptic connections between neurons. Improving neuroplasticity leading to better learning and memory.740

How does Pterostilbene feel? Neurohackers report that supplementing with Pterostilbene boosts energy levels, provides clearer thinking and improved mood. Taken before an anxiety-producing event, PTE takes the edge off with no sedation. Aging baby boomers report feeling younger after using Pterostilbene. They feel more alert, less joint and lower back pain, more energy, less anxiety, and better focus.

The Research We have hundreds of studies talking about the benefits of Resveratrol. But mostly animal studies for Pterostilbene. So just bear in mind that life is not a clinical study. 335 David Tomen Take what you can from this article on PTE, and read user reviews on some of the major sites. Then add Pterostilbene to your stack and see if it makes a difference in your life. If you notice a difference, please bookmark this chapter, and tell your friends about it. And help a brother (or sister) out.

Pterostilbene Reduces Anxiety A study at the University of Mississippi investigated using Pterostilbene for anxiety disorders. Using mice, the team administered PTE in 1 – 10 mg/kg doses. Measuring the effects of each dose for its anxiolytic effect. To measure this mood effect, the team evaluated decreases in extracellular regulated kinase 1 and extracellular regulated kinase 2 in the mice. These signaling pathways are involved in mood modulation in both animals and humans.741 The research team found that no anxiolytic (anti-anxiety) activity was found at higher doses of Pterostilbene. But at lower doses of PTE (1 and 2 mg/kg), there was significant anti-anxiety activity in the brain. And unlike standard anti- anxiety drugs, there was no impairment of motor movement. In other words, there were no negative physical effects of using PTE for anxiety issues. The team concluded that, “These results suggest that Pterostilbene has the poten- tial for therapeutic drug development for anxiety disorders.”742

Pterostilbene Improves Cognition Recent studies have shown that Pterostilbene and Resveratrol protect against age-related diseases like Alzheimer’s. So this study looked at comparing the two ‘stilbenes’ to find out which was more effective in improving cognitive deficits, and Alzheimer’s pathology. The pathology of Alzheimer’s can be broken down into; cellular stress, in- flammation and other pathology markers known to be altered in the disease. Researchers at Case Western Reserve University in Cleveland, Ohio looked at the mechanism of action behind each of these pathology markers. They used SAMP8 mice which are bred to model age-related Alzheimer’s. Two months of a Pterostilbene diet (but not Resveratrol) improved radial arm water maze function in these mice compared to controls who were fed a standard mouse diet. This is where it gets good. Markers of cellular stress, inflammation, and Alzheimer’s pathology were all positively modulated by Pterostilbene. The team concluded that “diet-achievable doses of Pterostilbene is a potent modulator of cognition and cellular stress”. Much better than Resveratrol. The research team said that this success in improving cognition with Pteros- tilbene was due to its ability to increase peroxisome proliferator-activated receptor alpha (NR1C1) expression. This particular receptor is encoded by the pPARA gene. And as you may recall 336 HEAD FIRST from earlier in this chapter, Pterostilbene’s big claim to fame is ‘gene expression’ and modulation. The team also noted that PTE works better than Resveratrol because of its increased ability to cross the blood-brain barrier. And superior bioavailability.743 Pterostilbene is one of the only nootropics that improves cognition directly by modifying genes (gene expression).

Pterostilbene Protects Neurons Blueberries have been reported to provide long-term neuroprotective effects. But researchers in China wanted to dig deeper to determine what in blueberries provided this benefit. Was it Pterostilbene? The research team dosed mice with 2.5 – 80 mg/kg of PTE for 3 days. Then induced a middle cerebral artery occlusion for 90 minutes. In other words, they gave the mice a stroke. The team gave the mice another dose of PTE immediately after the stroke, at 1 hour and at 3 hours. The team found the most therapeutic window for neuroprotection was 1 hour after the stroke dosed at 10 mg/kg. Pterostilbene improved motor function, eliminated blood flow disruption, increased neuron survival and reduced cell apoptosis (cell death). The team con- cluded that you could protect the brain from stroke using Pterostilbene. And this neuroprotective effect of Pterostilbene was associated with preventing oxidative stress and neuron death.744

Dosage Notes Pterostilbene is found in small quantities in some plant foods. A cup of blueberries for example, contains only about 20 mcg of Pterostilbene. But even in small amounts, Pterostilbene is believed to provide some of the benefits talked about in this chapter. Based on all of the published animal studies, the recommended daily dose of Pterostilbene is 50 mg for cognitive benefit.

Side Effects The primary “side effect” of using Pterostilbene in your nootropic stack is – you’ll feel better. You should have more energy and thinking should be clearer and faster. And Pterostilbene provides an anti-anxiety effect. Pterostilbene is non-toxic and supplementation is well-tolerated by most people. One randomized, double-blind placebo-controlled trial conducted at the University of Mississippi School of Pharmacy did an analysis of safety in humans. 80 subjects were divided into four equal groups. Each group received either; 125 mg of Pterostilbene twice daily, the 2nd group 50 mg twice daily, the 3rd 337 David Tomen group 50 mg plus 100 mg of grape extract twice daily, and the 4th group a match- ing placebo twice daily. The trial ran for 6-8 weeks. The researchers concluded that “Pterostilbene is generally safe for use in humans up to 250 mg per day”.745 But the benefits from Pterostilbene follow a bell-curve. With little or no benefit at lower doses, optimal benefits around 50 mg per day, and no benefit again at much higher doses. Like other nootropics, more of Pterostilbene is not necessarily better.

Available Forms Pterostilbene comes in tablet or capsule form and is available by several well- known supplement makers. Some pre-made nootropic stacks like Mind Lab Pro include PTE in their formula. pTeroPure® is a branded form of Pterostilbene derived from blueberries. And marketed as yielding 99.9% purity. You can also get Pterostilbene from blueberries. But you’d have to eat a lot of berries to get your quota of 50 mg per day. Blueberry extract supplements contain Pterostilbene. But do not typically indicate exactly how much is in the extract.

Nootropics Expert Recommendation

Pterostilbene 50 mg per pay I recommend using Pterostilbene as a nootropic supplement. Your body does not make Pterostilbene on its own. You can get some Pterostil- bene from blueberries and a few other fruits. But studies have shown we may not get an adequate supply of Pterostilbene from food sources in our diet. Especially if you don’t eat a lot of fruit every day. Pterostilbene has been used in Ayurvedic medicine for thousands of years as a “blood tonic”. Pterostilbene helps protect neurons, and boosts other antioxidants that shield your brain cells from oxidative stress. Protecting brain cells in memory centers of the brain helps boost dopamine. Resulting in better alertness, learning and memory. The boost in memory and learning also comes from Pterostilbene’s ability to promote neuroplasticity. And PTE helps maintain cerebral circulation by protecting brain blood vessels from lack of oxygen, and oxidative stress. Pterostilbene is especially helpful for those dealing with anxiety. PTE pro- vides an anxiolytic effect without the sedation you’d normally get from using anti-anxiety drugs. I suggest starting with a dose of at least 10 mg daily. And Pterostilbene is a great compliment to a stack including any nootropic. It works particularly well when combined with Resveratrol.

338 HEAD FIRST Resveratrol

Resveratrol is a potent antioxidant, boosts BDNF, increases cerebral circulation, im- proves energy and memory, and potentially promotes longevity Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a polyphenol stilbenoid and phytoalexin that certain plants produce in response to stress, such as injury or fungal infection. Resveratrol is a naturally occurring compound found most famously in red wine. Some speculate that the Resveratrol found in red wine accounts for the “French Paradox”. And how the French can dine on baguettes, cheese, paté and pastries. While avoiding putting on weight and living longer. Recent research may soon lead the nootropics community to classifying Res- veratrol as an Ampakine nootropic. With some rather profound neuroprotective effects in the brain. Resveratrol is gaining a reputation among neurohackers for controlling brain inflammation, boosting dopamine, helping reverse cognitive decline and fighting brain cell aging. Resveratrol helps Brain-Derived Neurotrophic Factor (BDNF). Higher levels of BDNF are associated with increased intelligence, mood, productivity and memory. And decreased risks of neurodegenerative diseases like Alzheimer’s and Parkinson’s. Resveratrol increases BDNF in your hippocampus. Resveratrol is a neuroprotectant. Resveratrol protects your brain by boosting the production of the enzyme heme oxygenase which protects against oxidative stress.747 Resveratrol shields mitochondria from injury during interruptions in blood flow such as a stroke.748 And Resveratrol prevents the release of toxic glu- tamate during a stroke.749 It even protected the brain when administered 6 hours after a stroke.750 Resveratrol improves cerebral circulation. Resveratrol increases blood flow in your brain. Improving your brain’s blood flow increases oxygen and nutrient levels. Providing your brain with the fuel it needs for optimized cognition. Initial research on Resveratrol led researchers to believe that the compound works by mimicking calorie restriction and decreasing chronic inflammation. As soon as word got out about the first clinical studies at Harvard Medical School, red wine and Resveratrol were soon christened the new “Fountain of Youth”. But Dr. David Sinclair who led the Harvard study says, “You would need to drink a hundred to a thousand glasses of red wine to equal the doses that improve health in mice.”751 However, more research has revealed some rather profound benefits to adding Resveratrol to your nootropic stack. 339 David Tomen Several human studies show that Resveratrol can increase cerebral circula- tion, protect against heart disease, and increase insulin sensitivity in diabetics. Even more studies in animals have shown that Resveratrol can reduce de- pression, treat addictions, protect against memory loss, is anti-anxiety, reduces plaques in Alzheimer’s disease, improves learning, memory and mood, protects the brain from stroke and shields from hearing loss. Resveratrol is found in red wine, blueberries, cranberries, raspberries, bilber- ries, grapes, peanuts, pistachios, cocoa and dark chocolate.752 Here we’re going to dig into how Resveratrol helps your brain. Some of this is going to get a little geeky, so stay with me here…

How does Resveratrol work in the brain? Resveratrol boosts brain health in several ways. But two in particular stand out. 1. Resveratrol improves memory. Resveratrol is an inhibitor of enzyme PDE4 (Phosphodiesterase-4). PDE4 inhibitors have been shown to be memory en- hancers.753 Studies demonstrate that when you inhibit PDE4, you raise levels of cAMP in the brain.754 cAMP-dependent pathways in the brain activate AMPK (AMP-activated protein kinase).755 This effect of activating AMPK has a number of implications. First, this would make Resveratrol an Ampakine nootropic similar to some of the racetams. Second, studies show that AMPK is activated by increases in the cellular AMP/ATP ratio. This helps preserve cellular energy. And would account for at least some of Resveratrol’s neuroprotective properties.756 This same study at the Washington University School of Medicine in St. Louis, Missouri demonstrated that Resveratrol combined with the nootropic ALCAR increased neurite growth which would have a profound effect on boost- ing memory. And Resveratrol also stimulated mitochondrial biogenesis. The researchers concluded, “These findings suggest that neuronal activation of AMPK by Resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.” 2. Resveratrol boosts BDNF. Brain-Derived Neurotrophic Factor (BDNF) has been called “Miracle-Gro for the brain” by Harvard Neuropsychiatrist John Ratey. When BDNF is released, nerve cells connect to other cells or their synapses. As brain cells “fire together”, they “wire together”. And this is how new neural networks are formed and consolidated to create memory. Researchers in Iran administered Resveratrol to rats for 30-days. The team was looking at the effects of Resveratrol on the abundance of mRNA encoding Brain-Derived Neurotrophic Factor in the hippocampus. The team measured levels of BDNF in the rat brains and found that Resvera- 340 HEAD FIRST trol elevated the level of BDNF in the hippocampus of these rats. And concluded that the neuroprotective effects of Resveratrol are due to its ability to boost BDNF mRNA.757

How things go bad As we get older, the chemistry in our brain cells and energy metabolism changes. ↓ Neurons and synapses degenerate ↓ Recall, reaction time, memory, and mood diminish ↓ Cerebral circulation decreases ↓ Neurotransmitter levels decline ↓ Oxidation damages brain cells All of these age-related changes are contributing factors to the neurodegen- erative diseases of aging including Alzheimer’s, Parkinson’s and dementia. But even if things haven’t degenerated to such a debilitating level, Resveratrol can help.

Resveratrol to the rescue Resveratrol is an antioxidant polyphenol which are present in foods like red wine, green tea, apples, berries, pomegranates and dark chocolate. Polyphenols are among the most effective natural ways to combat aging. And to prevent the health issues that often lead to cardiovascular and neurodegenera- tive disease. Resveratrol helps prevent free radical damage to brain cells. Oxidative damage to brain cell membranes causes deterioration. And eventually leads to premature cell death (apoptosis). Resveratrol has the unique ability to modulate cell apoptosis. And promotes cell death only in instances where your brain would be healthier with fresh, new cells. Resveratrol promotes neurogenesis. Resveratrol inhibits the PDE4 enzyme that raises levels of cAMP in your brain. Much like Luteolin (Artichoke Extract) in the CILTEP stack. cAMP- dependent pathways in the brain activate AMPK which in turn energize brain cells, and boost memory. Resveratrol helps boost cerebral circulation, and Brain-Derived Neurotrophic Factor (BDNF). BDNF helps new neural networks to form which is the basis for memory formation.

How does Resveratrol feel? Research shows that Resveratrol can: • Improve memory by inhibiting PDE4 in the brain (which boosts cAMP activity) • Tame inflammation in the brain 341 David Tomen • Boost cerebral blood flow for more oxygen and nutrients to fuel brain cells • Increase BDNF helping new neural networks to form for memory consolidation • Neuroprotective qualities that prevent damage to brain cells Resveratrol quickly enters your brain after you take it. Once in your brain, it inhibits PDE4 which boosts cAMP activity. cAMP is involved in the Long-Term Potentiation process of preserving memories. Inhibiting PDE4 and boosting cAMP also makes the effect of normal do- pamine production more effective. Boosting processes in this stream of chemical reactions in the brain increases learning and memory. Without the side effects of stimulating dopamine production through the use of drugs like Adderall or Ritalin. Neurohackers report the effects of Resveratrol can be subtle. But you don’t want to take it later in the afternoon or it could affect your sleep. You may experience improved mood and motivation, increased ability to study, increased ability to retain information and improved long-term memory.

The Research As a young neurohacker, you may not be concerned about the horrors of a disease like Alzheimer’s. Yet several clinical studies make the case for using Resveratrol to boost your memory. And to avoid ever having to be concerned about this debilitating disease. 84,767 Americans die every year from Alzheimer’s disease. And more than 230,000 suffer from dementia severe enough to require nursing home care.758 The Alzheimer’s Association estimates that more than 5 million Americans are living with this disease. And you have a 1 in 3 chance of developing Alzheimer’s or another dementia in your lifetime.759 Now that I have your attention, let’s look at some clinical studies on using Resveratrol to prevent Alzheimer’s and dementia.

Resveratrol Protects Against Alzheimer’s Some of Resveratrol’s neuroprotective ability comes from its ability to in- terfere with the cascade of events arising from an accumulation of abnormal proteins called amyloid-beta. Amyloid-beta causes oxidative stress and inflammation that damages brain cells. Especially in memory centers in the brain. Hence the reason why Alzheimer’s causes such profound memory loss. A study conducted at the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease in New York looked at the cascade of events leading up to Amyloid-beta accumulation that causes much of the problem with Alzheimer’s. The research team demonstrated how Resveratrol activates several metabolic 342 HEAD FIRST sensors, including AMPK (AMP-activated protein kinase). AMPK signaling con- trols Amyloid-beta metabolism. So Resveratrol activates AMPK which reduces levels of Amyloid-beta deposits in the cerebral cortex.760 Another study in Italy showed how Resveratrol prevents β-amyloid aggrega- tion by scavenging oxygen free radicals, and inducing protective enzymes such as heme oxygenase. Again preventing the build-up of deposits causing Alzheimer’s.761 More recent studies show that Resveratrol can prevent Amyloid-beta proteins from clumping together into small collections of individual molecules called oligomers. This action alone has a profound effect on preventing Amyloid-beta damage and preventing Alzheimer’s.762 And one more study, again about Resveratrol’s ability to activate AMPK and reduce Amyloid-beta build-up, shows that Resveratrol crosses the blood-brain barrier. And stays in the brain to do its magic. Verifying that using Resveratrol as a nootropic is an effective cognitive enhancer.763

Resveratrol Improves Memory The research team at the Max Planck Institute for Human Cognitive and Brain Sciences investigated the effect of Resveratrol on brain function and memory in healthy overweight older adults. 23 people, aged 50 – 75, took 200 mg of Resveratrol daily for 26 weeks. The control group of 23 subjects took a placebo. Memory tasks, neuroimaging, microstructure and functional connectivity of the hippocampus were measured before and after the trial. The study found that Resveratrol had a significant impact on subject’s ability to remember words. Subjects had a significant increase in functional connectivity in the hippocampus. And there was a decline in glycated hemoglobin (HbA1c), which indicates improved blood sugar control. The researchers concluded that Resveratrol can enhance memory along better hippocampus function.764

Resveratrol Improves Cerebral Circulation A study conducted at Northumbria University at Newcastle upon Tyne in the UK assessed the effects of Resveratrol on cognition and cerebral blood flow in healthy adults. In this double-blind, placebo-controlled study, 22 healthy adults received a placebo and 2 doses (250 and 500 mg) of trans-Resveratrol in counterbalanced order on separate days. The subjects performed a selection of cognitive tasks that activate the frontal cortex 45-minutes after taking Resveratrol. Near-infrared spectroscopy assessed frontal cortex changes in oxygenated and deoxygenated hemoglobin in order to evaluate blood flow and hemodynamics during the 36 minutes of task performance. The research team found that Resveratrol increased cerebral circulation. And 343 David Tomen this effect was entirely dependent on the size of the dose of Resveratrol. Blood flow was determined by measuring total hemoglobin concentrations. The researchers concluded that Resveratrol can increase cerebral blood flow even with a single dose of the supplement.765

Dosage Notes Resveratrol is found in small quantities in red wine, and some plant foods. Red wine contains about 1.5 – 3 mg of Resveratrol per liter of wine. So if you do the math, comparable amounts of Resveratrol from red wine for a 150 lb. person means 750 – 1,500 bottles of red wine a day. Resveratrol has a considerably shorter half-life than its cousin Pterostilbene. And is easily absorbed but has poor bioavailability once digested.766 It’s half-life is 1 – 3 hours, and 2 – 5 hours following repeated dosing.767 Micronized Resveratrol, which has a much smaller particulate size, has been shown to have a 3.6-fold increase in bioavailability compared to standard Resveratrol.768 And many of the clinical studies done in animals suggest a human equivalent of 1 – 2 grams for a 150 – 200 lb. person. Many supplement makers offer much smaller quantities in capsules or tablets. (I do not advise taking such high doses of Resveratrol). But even in small amounts, Resveratrol is believed to provide some of the benefits talked about in this chapter. Based on all of the published studies, the recommended daily dose of Res- veratrol is 20 mg for heart health, insulin sensitivity and longevity. For cognitive benefit, and increasing cerebral blood flow, recommended dose is 250 – 500 mg of Resveratrol. It’s better to dose on the lower end of recommended doses of Resveratrol. And see how your body reacts.

Side Effects Resveratrol is non-toxic and supplementation is well-tolerated by most people. We do not have many human studies on Resveratrol and must rely on user reviews. Resveratrol has mild estrogenic activity in the body. So if you’re estrogen is low you should avoid supplementing with Resveratrol. This is a potentially serious side effect. And short of getting your labs done, it may show up as joint pain or arthritis-like symptoms. Some neurohackers report having trouble sleeping, or staying asleep. Particu- larly if taken in the afternoon or evening. If you are dealing with a blood disorder which causes bleeding you should avoid Resveratrol. If you are taking aspirin, warfarin or clopidogrel you should not use Resveratrol. 344 HEAD FIRST Long term side effects reported by some neurohackers include diarrhea, dis- colored urine, dizziness, insomnia, jitters, joint pain, stomach pain and tendinitis.

Available Forms Resveratrol comes in tablet, capsule or powder form and is available by sev- eral well-known supplement makers. Most Resveratrol supplements are made from Japanese Knotweed. And some from grape skin extract. The bioactive form used in clinical studies and found in supplements is ‘Trans-Resveratrol’. ‘Cis-Resveratrol’ is a cis isomer and still bioactive but has a very different chemical structure. Purity of Resveratrol is extremely important. Most Resveratrol is made from Japanese Knotweed. A poor quality extract can contain high amounts of Emodin which can act as a laxative and cause stomach cramps. High purity Resveratrol extract (99%+) from Japanese Knotweed contains insignificant amounts of Emodin. And should cause far fewer side effects. Your safest bet when choosing a Resveratrol supplement is an extract from grapes or red wine which contain no impurities.

Nootropics Expert Recommendation

Resveratrol 20 – 250 mg per pay I recommend using Resveratrol as a nootropic supplement. Your body does not make Resveratrol on its own. You can get some Resvera- trol from red wine and a few other fruits. But studies have shown we may not get an adequate supply of Resveratrol from food sources in our diet. Especially if you don’t eat a lot of fruit containing Resveratrol every day. Or don’t drink red wine. I recommend choosing a Resveratrol supplement that is either 99% pure from Japanese Knotweed. Or a pure extract from grapes or red wine. Resveratrol is unique among antioxidants because it easily crosses the blood- brain barrier. And helps protect your brain from free radical damage. Resveratrol helps improve memory by influencing the cAMP-dependent pathways in your brain that activate AMPK. And Resveratrol boosts cerebral blood flow which increases the amount of oxygen and nutrients your brain cells need for optimized cognition. Resveratrol is especially helpful for those concerned about developing Al- zheimer’s or dementia. Because it helps prevent the accumulation of abnormal proteins like amyloid-beta. I suggest starting with a dose of at least 20 mg daily. And Resveratrol is a great compliment to a stack including any nootropic. One study showed Resveratrol worked synergistically with ALCAR to boost memory. And Resveratrol works particularly well when combined with Pterostilbene.

345 David Tomen Rhodiola Rosea

Rhodiola Rosea is known for improving alertness, energy, memory and mood, is anti- anxiety and anti-depressant, reduces fatigue, and boosts cognition and concentration Rhodiola Rosea L. (Golden Root, Roseroot) has been used for several thou- sand years in traditional medicine. It grows in primarily dry sandy ground at high altitudes in the arctic areas of Europe and Asia. The plant is 12 – 30 high and produces yellow blossoms. The Greek physi- cian, Dioscorides, first recorded the medicinal applications of ‘rodia riza’ in 77 C.E. in De Materia Medica.769 In Russia, Rhodiola Rosea is widely used as a remedy for fatigue, poor concen- tration, and decreased memory. It’s also believed to make workers more productive. The Journal of the American Botanical Council reported on 180 studies done on Rhodiola Rosea since 1960. The bulk of the research shows how this herb works in treating physical endurance, fatigue, depression, impotence, infec- tions, fertility, cold and flu, tuberculosis, cancer, and anxiety.770 German researchers describe the benefits of Rhodiola Rosea for pain, head- ache, scurvy, hemorrhoids, as a stimulant, and as an anti-inflammatory.771 This ancient remedy has remarkable stress-relieving and anti-anxiety proper- ties. And stands shoulder to shoulder with some of the most potent drugs used to treat depression and anxiety. This ancient herbaladaptogen has remarkable anti-depressant and anti- anxiety qualities. And has been shown to be as good as many prescription phar- maceuticals in treating depression and anxiety. In total, Rhodiola Rosea contains 140 compounds in the roots and rhizome. The critical components include rosavin, rosarian, and rosin, collectively known as rosavins. Certain chemicals must be present for Rhodiola Rosea to work. And these include rosavin, rosarin, rosin, salidroside, and tyrosol. The first 3 of these com- pounds are found only in Rhodiola Rosea. It takes a synergistic combination of these chemicals for this herb to be effective. To ensure the supplement you choose works and contains pure Rhodiola Rosea, it needs to be standardized to contain at least 3% rosavins and 1% salidro- side. This is the ratio found in the natural root. (See more about selecting the right Rhodiola Rosea supplement in “Available Forms” later in this chapter). Studies on organs, tissues, cells and enzymes show that Rhodiola Rosea ex- tracts exhibit adaptogenic effects that are neuroprotective, cardio protective, anti- fatigue, anti-depressive, anxiolytic, nootropic, and has life-extension qualities.772 Rhodiola Rosea is known as an adaptogen. Which means it helps your body adapt to stress, both mental and physical. 346 HEAD FIRST How does Rhodiola Rosea work in the Brain? Rhodiola Rosea boosts brain health and function in several ways. But two in particular stand out. 1. Rhodiola Rosea enhances mood. Reports from the nootropics community, and data from clinical trials show that Rhodiola Rosea encourages a balanced mood. One double-blind, placebo-controlled trial worked with male and female subjects aged 18 – 70 years. All were diagnosed with mild to moderate depression. One group received two 340 mg tablets of Rhodiola Rosea extract (SHR-5) daily. A second group received double the dose of the first group per day. And the third group received a placebo daily. The efficacy of SHR-5 extract for depression complaints was assessed on the first day. And again on day 42 of the trial. The research team reported that Groups A and B saw significant improvements in depression, insomnia, emo- tions and overall quality of life. The team concluded that Rhodiola Rosea extract has potent anti-depres- sant qualities in those with mild to moderate depression. When administered in doses of either 340 or 680 mg per day over 6-weeks.773 2. Rhodiola Rosea improves mental performance under stress. Mental fatigue can cause brain fog, and make it hard to focus. It can affect your performance at school, and on the job. Rhodiola Rosea stimulates your nervous system to fight fatigue that stifles mental clarity. And studies show it even saves injured neurons. And encourages the growth and development of brain cells. One animal study in China explored the effects of Rhodiola Rosea on the number of neurons in the hippocampus of rats with depression induced by chronic stress. This study has a direct correlation on how Rhodiola Rosea works in the human brain. And its value as a nootropic. In this study, 50 rats were divided into 5 groups: normal control, untreated, negative control, positive control and Rhodiola Rosea-treated groups. The research team found that the number of neurons in the hippocampus in the Rhodiola Rosea-treated group were increased and recovered to normal level. The study concluded that Rhodiola Rosea promotes the proliferation and dif- ferentiation of neural stem cells in the hippocampus. And may play a role in saving injured neurons of the hippocampus.774

How things go bad Chronic stress and cortisol can damage your brain. Neuroscientists at the University of California, Berkeley, found that chronic stress triggers long-term changes in brain structure and function.775 347 David Tomen Chronic stress changes neural networks. Cortisol creates a domino effect that hard-wires pathways between the hippocampus and amygdala. (The amygdala (lizard brain) is the area responsible for your fight-or-flight response). This hard-wiring caused by stress is not the way the brain was designed. But chronic, ongoing stress tricks the brain into rebuilding circuits and hunkering down for the long haul. This re-wiring appears to be permanent. Unless you intervene with some- thing like Rhodiola Rosea. Chronic stress seems to ‘flip a switch’ in stem cells in the brain. And turns them into a type of cell that prevents connections to the prefrontal cortex. Pre- venting improved learning and memory. And laying down the scaffolding linked toanxiety , depression and PTSD (Post Traumatic Stress Disorder). ↓ Chronic stress reduces levels of serotonin and norepinephrine ↓ Chronic stress reduces the number of neurons ↑ Anxiety and depression increases ↓ Chronic stress induces brain fog and memory loss Under conditions of chronic stress and excess cortisol you experience mental and physical fatigue.

Rhodiola Rosea to the rescue Rhodiola Rosea undoes damage to your brain caused by chronic stress. It helps keep it healthy. And even improves your body and brain’s response to stress. Rhodiola Rosea relieves stress by balancing your body’s stress-response system. And helps your body return to a relaxed state by influencing key brain chemicals like serotonin, norepinephrine and beta-endorphins (opioid neuropeptides).776 Rhodiola Rosea can also help prevent and repair damage caused by C-reactive protein and free radicals. Rhodiola Rosea even provides protection and regeneration of neurons during periods of stress. It helps in the synthesis and re-synthesis of ATP. The main fuel source for the mitochondria in your cells. Any kind of fatigue you experience – regardless of source – Rhodiola Rosea is like your “magic bullet”. Mood, energy, stamina and concentration can all increase with a dose of this herb. Many neurohackers even report improved libido and sexual performance when using Rhodiola Rosea. If you get an effective dose of real standardized Rhodiola Rosea extract, you should experience an effect.

How does Rhodiola Rosea feel? The time required to begin feeling the effects of Rhodiola Rosea depends 348 HEAD FIRST on your genetics, mental and physical condition, environment, behavior and lifestyle. Some neurohackers report feeling its effects in just a few days. While others require as much as 3 weeks. Clinical studies show that most people experience the full benefits of Rhodiola Rosea in 30 – 40 days. If you don’t notice a change within 40 days, Rhodiola Rosea may not be effective for you. Many report that Rhodiola Rosea provides a pronounced anti-anxiety effect. Depression lifts and overall quality of life improves. Rhodiola Rosea should give you an energy lift. It could improve your mood, focus, level of concentration and alertness.

The Research Rhodiola Rosea has a reputation in the nootropic community for its energiz- ing and anti-fatigue qualities. One double-blind, placebo-controlled trial was carried out with 161 cadets aged from 19 – 21 years. The intent was to measure the effect of a single dose of Rhodiola Rosea extract (SHR-5) on capacity for mental work against a back- ground of fatigue and stress. An additional objective was to try two different doses of the extract. The other dose being 50% higher. So the cadets were given either 2 or 3 capsules of Rhodiola Rosea extract. The study showed a “pronounced anti-fatigue effect” in the cadets. With no significant differences between the two dosage groups. But there was a “possible trend in favor of the lower dose” in the cognitive tests.777

Rhodiola Rosea as a nootropic The aim of this study was to investigate the effect of repeated low-dose treat- ment of Rhodiola Rosea extract (SHR-5) on mental performance with fatigued physicians. The researchers recruited a group of 56 healthy, young physicians working night duty at the Armenian State Medical University. Tests involved overall level of mental fatigue, associative thinking, short-term memory, calculation, ability of concentration, and speed of audio-visual perception. Tests were done before and after night duty during 3 periods of 2 weeks each. The young doctors received Rhodiola Rosea extract tablets or a placebo for the first 2 weeks. Followed by a 2 week ‘washout’ period. And finishing with another 2 weeks of Rhodiola Rosea extract tablets or a placebo. The research team found a statistically significant improvement in cognitive tests during the first 2 weeks. No side effects were reported. Andthe young doctors had a reduction in general fatigue under stressful conditions.778 349 David Tomen Rhodiola Rosea as an anti-depressant One study published in Phytomedicine was run as a “proof of concept” trial to evaluate the efficacy of using Rhodiola Rosea compared to the anti-depressant ‘sertraline’ for major depressive disorder. Sertraline (Zoloft®) is a pharmaceutical SSRI used to treat depression, anxiety, panic attacks, and obsessive-compulsive disorder (OCD). And it comes with a host of side effects including fatigue, diarrhea, anorexia, convulsions, confusion, decreased libido, and ejaculation failure. This trial recruited 57 people diagnosed with depression. They were given standardized Rhodiola Rosea extract, sertraline, or a placebo for 12 weeks. 3 different depression scoring tests were used during the trial. The researchers concluded that Rhodiola Rosea produced less antidepressant effect than sertraline, but it also resulted in “significantly fewer adverse events and was better tolerated.” The research team concluded that even though Rhodiola offered slightly less anti-depressant benefits, it possessed “a more favorable risk to benefit ratio for those with mild to moderate depression”.779

Dosage Notes Recommended dose of Rhodiola Rosea is 150 – 200 mg per day. Look for an extract that is standardized to contain rosavins and salidrosides in a 3:1 ratio. This mimics the ratio of these compounds that naturally occur in Rhodiola Rosea root. No additional benefit seems to come from taking more than 1,000 mg per day.

Side Effects Rhodiola Rosea is a natural adaptogen and herb that has been used success- fully for thousands of years. It’s considered non-toxic and safe. And very few side effects have been reported. Considerably higher than recommended doses could result in dry mouth, nausea, upset stomach, headache, insomnia and weight loss. Since Rhodiola Rosea acts as a Monoamine Oxidase Inhibitor (MAOI), you should not use it if you’re taking MAOI meds. MAOI’s are a type of anti-depres- sant drug used to treat bipolar disorder, panic disorder, social anxiety disorder and PTSD. MAOI meds influence serotonin levels in the brain. So taking MAOI’s in combination with Rhodiola Rosea has the potential to cause serotonin syndrome.

Available Forms Rhodiola Rosea is available as a powder, capsules, tablets and tea. 350 HEAD FIRST Active ingredients of Rhodiola Rosea include rosavins and salidrosides. Make sure you look for the percentage of active ingredients listed on the bottle or package. Ideally you’re looking for a 3:1 ratio of rosavins and salidrosides. This mimics the ratio of these compounds naturally occurring in the Rhodiola Rosea root. Now this is where it gets tricky. And probably the reason why some forum threads and user reviews report no effect from using Rhodiola Rosea. In the late 1980’s, demand for Rhodiola Rosea-based phytomedicines dra- matically increased. The wild-grown, raw material was over-harvested, resulting in a steady decline in the quality and effectiveness of Rhodiola Rosea. Studies revealed that other species of genus Rhodiola were being substituted for Rhodiola Rosea. While some of these mixed batches were highly variable in quality, others had no pharmacological or nootropic effect.780 So do your best to find out where the supplement maker gets their raw Rhodiola Rosea. Hostile environments like Siberia seem to produce higher qual- ity Rhodiola Rosea. The active ingredients for most nootropic benefit include; Rosavin, Rosari- din, Rosarin, Rosin, Salidroside, and Tyrosol. The first 3 are collectively referred to as “rosavins”. And the other big one is “salidroside” which has several iterations. Avoid supplements that list “other ingredients” on the label. And look for Certified Organic to ensure the root used to make your Rhodiola Rosea supple- ment is free of heavy metals, pesticides and herbicides.

Nootropics Expert Recommendation

Rhodiola Rosea Extract 150 – 200 mg per day I recommend using Rhodiola Rosea as a nootropic supplement. Your body does not make Rhodiola Rosea on its own. So to get its benefits you must take it as a supplement. Rhodiola Rosea is especially helpful for those suffering from anxiety and stress. Studies show it helps stop and reverse the devastating effects of stress in your brain, and body. This nootropic helps repair the damage to neurons caused by chronic stress. Rhodiola Rosea is a powerful adaptogen. Which means it helps increase the effect of certain hormones when activity is low. And will block excess stimulation when activity is too high. Rhodiola Rosea as an adaptogen helps balance norepinephrine in the body caused by chronic stress. It also boosts serotonin and the feel-good opioid chemi- cal beta-endorphins. Using Rhodiola Rosea can help eliminate brain fog, increase concentration during brutal periods like exams or business presentations, boost energy by in- creasing the ATP fueling your mitochondria, and protect your brain cells from free radical damage. 351 David Tomen Rhodiola Rosea helps alleviate mental and physical fatigue, improves stress response, and provides better quality of sleep. It can even help out your sex life. Rhodiola Rosea is especially helpful for those suffering from anxiety and panic disorders. Studies have shown the calming effect of this herb was equal to some popular antidepressant and anti-anxiety drugs. Without the side effects. You can safely take up to 600 mg of Rhodiola Rosea extract daily if needed. Most get all the benefit they need with 150 – 200 mg. Half of the dose in the morning, and another early afternoon. And make sure your getting genuine Rhodiola Rosea extract with a 3:1 ratio of rosavins and salidrosides. Read the user reviews and labels.

352 HEAD FIRST SAM-e SAM-e has been shown to relieve depression, anxiety, brain fog, and pain including arthritic and fibromyalgia pain, improve memory, mood and sociability, and support liver health SAM-e (S-Adenosyl Methionine, Ademethionine, Adomet) is the naturally- occurring amino acid methionine bound to an ATP molecule. And is found in nearly every cell in your body. SAM-e helps produce and breakdown the neurotransmitters acetylcholine, dopamine, serotonin, norepinephrine and melatonin in your brain. SAM-e maintains cell membranes and plays a role in a healthy immune system. Studies show that SAM-e is very effective in treating depression without the side effects of prescription antidepressants. And while pharmaceutical antidepres- sants can take from 6 to 8 weeks to begin working, SAM-e can work much faster. The latest research shows that SAM-e can be anti-anxiety, reduces pain in- cluding in fibromyalgia, and can improve learning, memory and mood. SAM-e is made from methionine and ATP (adenosine triphosphate) during a cycle that recycles the amino acid homocysteine. This cycle requires Vitamin 6B and B12 and folate (B9) to work properly. SAM-e is a precursor to the crucial antioxidant glutathione which is used in your brain and liver. When glutathione levels drop in your body, liver damage from oxidative stress begins within seconds of exposure to alcohol or toxins. SAM-e is a methyl donor that contributes to several essential processes in your brain. As a methyl donor, SAM-e is involved in the production and recycling of hormones, cytokines, and the neurotransmitters acetylcholine, dopamine, norepinephrine, and serotonin. This methyl donor process is call ‘methylation’, and contributes to gene expres- sion. Affecting how your cells work and communicate including your cell DNA. SAM-e modifies important molecules in cell membranes that control com- munications within and between brain cells. SAM-e boosts the number of mus- carinic receptors in certain parts of your brain which are critical to this cellular communications network. SAM-e is used to treat depression, anxiety, osteoarthritis pain, fibromyalgia, and liver disease. SAM-e is sold as an OTC supplement in the United States and Canada. And as a prescription drug in several European Union countries, and Russia. SAM-e is marketed under the brand names Adomet, Gumbaral, Samyr, Heptral, Agotan, Donamet, Isimet and Admethionine.

How does SAM-e Work in the Brain? SAM-e boosts brain health and function in several ways. But two in particu- lar stand out. 353 David Tomen 1. SAM-e helps alleviate depression. SAME-e is one of the main building blocks your brain needs to produce the neurotransmitters acetylcholine, dopamine, serotonin, norepinephrine and melatonin. By raising the levels of dopamine in your brain, SAM-e helps enhance memory, motivation and learning. Researchers at the West Los Angeles VA Medical Center studied the antide- pressant effect of oral SAM-e in a randomized, double-blind, placebo-controlled trial for 15 patients with major depression. The researchers found that SAM-e is a safe, effective antidepressant with few side effects and a rapid onset of action. And may be useful for those who cannot tolerate prescription tricyclic antidepressants.781 2. SAM-e directly influences neuronal signaling. SAM-e increases the number of muscarinic receptors in the hippocampus. We have two kinds of acetylcho- line (ACh) receptors in our brain. 1) Nicotinic receptors and 2) Muscarinic receptors. Most of the nootropics we investigate here in Head First influence nicotinic receptors and ACh. Muscarinic receptors have a very different mechanism of action. They are part of a large family of G-protein-coupled receptors (GPCRs) which are used as an intracellular secondary messenger system. Your brain has a very complex system of control to regulate different pro- cesses going on in different cells at different times. For this to work, there must be a sophisticated means of communication between cells. GPCRs and their G proteins provide this intercellular communication. And form one of the most important signaling systems in your brain. They are in- volved in nearly every aspect of your physiology and behavior. G proteins work by binding neurotransmitters, hormones, growth factors, cytokines, odorants and photons at the cell surface to the GPCR, and activate that receptor. Everything you see, hear, smell, or taste goes through this signaling process. And SAM-e increases the number of these muscarinic receptors in parts of your brain, including your hippocampus. In one study, aged rats were given SAM-e for 30 days. Supplementation with SAM-e restored the number of mus- carinic receptors to levels found in the same areas in young animals.782 Supplementing with SAM-e to increase muscarinic receptors in your brain can boost neuroplasticity and increase learning, memory, mood and even smell and vision.

How things go bad You have healthy levels of SAM-e throughout your body when you’re young. But as you age, your body makes less of it. This is why young people bounce back 354 HEAD FIRST from difficult experiences more easily. They’ve got higher levels of dopamine and a higher pain threshold than adults. SAM-e is a major methyl donor in your body. It is involved in the biosynthe- sis of hormones, neurotransmitters, proteins and phospholipids.783 SAM-e participates in a sequence of events involving folic acid (folate) and

Vitamin B12. Folate converts to 5-MTHF (5-methyltetrahydrofolate) which converts freely circulating homocysteine back into the amino acid Methionine

(using Vitamin B12). L-Methionine then binds to an Adenosine group from ATP to create SAM-e. SAM-e is then able to donate methyl groups (called methylation) to a variety of reactions including the production and breakdown of the neurotransmitters dopamine, serotonin, norepinephrine and melatonin in your brain. This methylation process degrades SAM-e into S-Adenosylhomocysteine. Which is then fed back into this cycle from the beginning. This process is referred to as a ‘one-carbon cycle’.

If you don’t have enough folate or Vitamin B12 available, this SAM-e meth- ylation process breaks down. And the result can be depression, brain fog, poor recall and memory, and pain.

This lack of folate and Vitamin B12 can affect you regardless of age. This is a big enough problem that the Canadian government mandated folate fortification of all flour, and some corn and rice products to address this issue in 1998.784

Low levels of SAM-e, folic acid, Vitamin B6 and B12 can lead to all kinds of problems. And genetic defects that don’t allow the use of these important vitamins can result in the same symptoms. ↓ Cognition, memory, recall, and mood diminish

↓ Folic acid, Vitamin B6 & B12 absorption declines ↑ Homocysteine levels rise ↑ Pain levels rise ↓ Mental health, language and fine motor skills decline All of these changes in brain energy metabolism are contributing factors to neurodegenerative diseases, including Alzheimer’s, Parkinson’s, ALS, epilepsy, and dementia. But even if you’re not concerned with genetic defects, a lack of B-Vitamins, or the effects of aging, SAM-e can help.

SAM-e to the rescue Stress-related disorders like anxiety, major depression and PTSD are some of the most debilitating illnesses known to man. And if you’re reading this, and dealing with any of these, supplementing with SAM-e may help. To cope with stress requires changes in the expression of “immediate-early 355 David Tomen genes” in your hippocampus. The same area of your brain you use forlearning and memory. Stressful events result in epigenetic (gene) modifications within ‘immediate- early genes’ in your hippocampus neurons. DNA methylation acts to suppress the expression of these genes. This is where SAM-e comes in… SAM-e is a methyl donor for the enzyme that methylates your DNA. When SAM-e levels are high enough, a stressful event will not result in DNA de-methylation. Instead, a stressful event enhances DNA methylation of ‘immediate-early genes’. Which suppress their expression and allows you to adapt in a healthy way to this stressful situation.785 SAM-e is a powerful antidepressant. In 2005, researchers combed through the databases of Medline, Psychinfo, AMED, and Cochrane Controlled Trials Reg- ister. And collated the findings of randomized, controlled trials studying SAM-e for depression through to September 2001. The team concluded after analyzing all the clinical evidence that SAM-e was effective in treating major depression in adults.786 SAM-e is also a potent pain-killer. A recent study looked at 56 people with arthritis in their knees. One group took the COX-2 inhibitor Celebrex while the other took SAM-e for 16 weeks. Researchers found that SAM-e was as effective as Celebrex at eliminating pain. And without the potential side effects of heart attack or stroke that can be caused by using Celebrex.787 Another study on the effect of SAM-e with 17 fibromyalgia patients con- firmed a close relationship between primary fibromyalgia and psychologic prob- lems including depression. SAM-e treatment improved the depressive state of these patients. And SAM-e was found to be an effective and safe therapy in the management of fibromyalgia.788

How does SAM-e feel? For some, supplementing with SAM-e can be life-changing. SAM-e can have a profound effect on emotions, depression, and feelings of anxiety. You may experience improved concentration, energy, alertness, and feelings of well-being. Even vision can become clearer. Once you start supplementing with SAM-e, you should experience at the very least, a general sense of well-being. SAM-e works particularly well for those who deal with depression or anxiety. Neurohackers report that they no longer have panic attacks. And the feeling of doom is gone. 356 HEAD FIRST Adding SAM-e to your nootropic stack can improve sociability, and not feel- ing overwhelmed by life. Brain fog lifts and thinking is clearer and faster. Others say that the “dark cloud has lifted”, and all the negativity and stress is gone. Things that normally would irritate are just brushed off, and you move on.

One big word of caution: SAM-e needs Vitamins B6 & B12 and folate to work. Or SAM-e will elevate your homocysteine levels. High homocysteine can cause heart attacks. You’ll notice reference to B-Vitamins several times in this chapter on SAM-e.

It is that important. Use Vitamin B6 & B12 and folate every day that you supple- ment with SAM-e. Or use a B-Complex formula that contains folate (B9). The Research

SAM-e Lifts Mood We have made significant progress in the last 100 years in diagnosing and treating depression. And yet, 10’s of millions still suffer from depression. In 2014, an estimated 15.7 million adults in the United States had at least one major depressive episode in the previous year.789 In the United States, one in ten Americans are using antidepressants.790 I don’t have statistics from other countries but I suspect many have similar prob- lems. Unfortunately, antidepressants only work 30 – 50% of the time. And come with a host of side effects. One reason that many people continue to suffer from depression is that most doctors are not aware of the link between homocysteine and depression. If you’re dealing with depression and have had little success with antidepres- sants, you may have something as simple (and as serious) as a folate deficiency.

Or low levels of Vitamin B12. Studies show a link between folate deficiency and impaired metabolism of serotonin, dopamine, and norepinephrine. One study looked at 46 patients with severe depression. 24 of these patients had raised levels of homocysteine. And significantly lower levels of folate, SAM-e, and other metabolites. The researchers concluded that looking at total homocysteine levels could be a measure of depression. Caused by folate deficiency, impaired methylation (SAM-e), and neurotransmitter metabolism (SAM-e). And a potential benefit to simply using vitamin replacement to treat severe depression.791 Or supplementing with SAM-e to treat depressive symptoms.

SAM-e to Treat Adult ADHD Ritalin and Adderall are thought to be the most effective treatment in children and adults with ADHD. These stimulants work by potentiating both dopamine and norepinephrine at the synaptic cleft. But stimulant meds for ADHD come with side effects. 357 David Tomen SAM-e acts as a methyl donor and is involved in many metabolic pathways. It has both adrenergic and dopamine receptor agonist activity. A research team at the University of California used SAM-e with subjects diagnosed with Adult ADHD in a 9-week double-blind, placebo-controlled trial. The research team found that 75% of the patients had a significant improve- ment in ADHD symptoms while using SAM-e. And the 25% who did not respond to SAM-e, did not respond to Ritalin either.792

SAM-e Treats Depression Scientists at the US Department of Health and Human Services conducted an analysis of 102 individual studies in 25 databases on SAM-e and depression in 2002. The report distilled data gleaned from published studies conducted around the world up to 2002. This comprehensive report is called, ““S-Adenosyl-L-Methionine for Treat- ment of Depression, Osteoarthritis, and Liver Disease.” The researchers found that SAM-e is just as effective as standard antidepressant drugs at treating depression. The agency concluded, “Treatment with SAM-e was equivalent to standard therapy for depression”.793

Dosage Notes Recommended dosage of SAM-e for nootropic benefit is 400 mg per day. SAM-e for depression: 400 – 1600 mg daily in divided doses SAM-e for bone and joint health: 200 – 1200 mg daily in divided doses SAM-e for liver problems: 1600 mg daily in divided doses Some research and many user reports suggest that once positive effects are achieved, SAM-e doses can be reduced. Some report benefit with as little as 100 mg of SAM-e daily. Studies show that SAM-e should be consumed with B-Vitamins. When SAM-e donates its methyl group, it breaks down into homocysteine. Elevated homocysteine levels are associated with increased heart disease, birth defects and depression. In order to prevent homocysteine accumulating, sufficient levels of B-Vitamins must be present to convert homocysteine into the potent antioxidant glutathione. Take SAM-e on an empty stomach and an hour before eating any food. SAM-e is best digested in your intestines and not your stomach. Not letting SAM-e settle into your digestive tract could cause stomach upset.

Side Effects SAM-e is produced naturally in your body. So is considered well-tolerated and safe. If you have bipolar disorder, you could develop mania when supplementing with SAM-e. So check with your doctor before using SAM-e. 358 HEAD FIRST If you’re on antidepressant medication, you should check with your doctor before supplementing with SAM-e. High doses of SAM-e can cause gas, upset stomach, diarrhea, constipation, dry mouth, headache, dizziness, anxiety or skin rashes. SAM-e may also trigger an allergic reaction in some people.

Available Forms SAM-e is available in 200 and 400 mg tablets. For optimal effects with SAM-e, stable, enteric-coated tablets are recom- mended. SAM-e should be taken on an empty stomach, either one hour before or two hours after meals. SAM-e is highly unstable so check expiration dates. And you should get tablets that are packed in sealed, gel-packs for freshness. Avoid SAM-e in powder form as you’ll likely be unsatisfied with the results.

Nootropics Expert Recommendation

SAM-e 400 mg per day I recommend using SAM-e as a nootropic supplement. Your body does make some SAM-e on its own. But SAM-e levels decrease as we age. And you cannot get SAM-e from food. SAM-e is critical for the methylation process needed for making important neurotransmitters including acetylcholine, dopamine, serotonin, norepinephrine and melatonin. SAM-e is also involved in the cycle which produces the critical antioxidant glutathione. And it’s involved in maintaining brain cell membrane integrity and fluidity. SAM-e increases muscarinic receptors in your hippocampus which boosts the activity of acetylcholine and other critical neurotransmitters in your brain. Lead- ing to improved learning, memory and mood. SAM-e is especially helpful if you’re dealing with depression. Or having dif- ficulty coping with any kind of stress. I suggest a dose of 400 mg daily. It may take a while for SAM-e to build up in your system. So be patient. Once you’re achieving the affects you want from SAM-e, you can eventually try scaling back your dose to 100 or 200 mg.

359 David Tomen St. John’s wort

St. John’s wort has been shown to relieve depression as well as some prescription antidepressants St. John’s wort () is regarded as a wildflower, herb and weed. As a nootropic, St. John’s wort is considered a powerful antidepressant. St. John’s wort is native to Europe. But can be found growing wild through- out Asia, Africa, North and South America and Australia. Greek physicians Galen and Dioscorides prescribed St. John’s wort as a di- uretic, for healing wounds and treating menstrual disorders. In the Middle Ages, it was used as a talisman for warding off evil spirits. St. John’s wort is best harvested on St. John’s Day (June 24) when the herb is in peak bloom. Legend has it that if you placed a sprig of the herb under your pillow on St. John’s Eve, St. John himself may appear in a dream, and bless you for another year. (Not sure if this applies when you put a bottle of St. John’s wort extract under your pillow, but worth a try). 12 St. John’s wort first crossed the radar of modern herbalists and naturopaths in 1997. A study published in the British Medical Journal entitled, “St John’s wort for depression—an overview and meta-analysis of randomised clinical trials” pushed it to superstar herbal antidepressant status. This meta-analysis of 23 previously published studies on St. John’s wort was drawn from foreign medical journals. The analysis showed that overall, St. John’s wort was significantly superior to placebo. And was as effective as pharmaceutical antidepressants.794 The British Medical Journal published another study in 2005 showing that St. John’s wort was equally effective in treating depression and better tolerated than the widely prescribed antidepressant (Paxil).795 The two major active constituents of St. John’s wort are hypericin (a naph- todianthrone) and hyperforin (a phloroglucinol). The plant contains a total of seven groups of medicinally active compounds.796 Researchers have extensively documented St. John’s wort as having antide- pressant, antiviral, antioxidant, anti-cancer, and antibacterial effects.797 The most recent clinical studies show that hyperforin is the constituent in St. John’s wort that has the most antidepressant action. If you’ve had limited success using St. John’s wort for depression and anxiety, your choice of supplement may be the problem. Go to “Dosage Notes” in this chapter to learn what extracts work best.

How does St. John’s wort Work in the Brain? St. John’s wort boosts brain health and function in several ways. But two in particular stand out. 360 HEAD FIRST 1. St. John’s wort reduces depression. Hyperforin is the major antidepressive constituent of St. John’s wort. Hyperforin inhibits the uptake of serotonin, dopamine and norepinephrine in the brain.798 By making more of each of these neurotransmitters available in the brain, mood is elevated and depres- sive symptoms decline. Clinical trials also demonstrate that the level of antidepressant effect of St. John’s wort extract is entirely dependent on the concentration of hyperforin.799 A study in Berlin compared the efficacy of using St. John’s wort extract (WS 5570) to paroxetine (Paxil) in treating moderate to severe depression. In this multicenter, randomized, double-blind study, 130 patients who received 900 mg or 1800 mg per day of St. John’s wort, or 40 mg of paroxetine were included. The study showed that St. John’s wort and paroxetine were equally effective in preventing relapse in continuation of treatment after recovery from moderate to severe depression. And that St. John’s wort was an important alternative treat- ment option for long-term prevention of depression.800 2. St. John’s wort reduces stress. St. John’s wort is licensed in Germany to treat anxiety, depression and sleep disorders. But scientists and researchers are still working on what in this plant provides the anxiolytic effects. The anti-anxiety effects of St. John’s wort have been attributed to the binding affinity of at least 10 different extracts of the herb. Including naphthodianthrones like hypericin, flavonoids, xanthones, and bioflavonoids for adenosine triphosphate

(ATP). GABAA, GABAB and glutamine receptors, as well as the inhibition of monoamine Oxidase-A and – B activity. And synaptic uptake of serotonin, do- pamine and norepinephrine.801 All we know for sure at this point is that St. John’s wort works to help allevi- ate some forms of anxiety. One German study ran a multicenter, randomized, placebo controlled, 6-week trial comparing the efficacy of St. John’s wort extract LI 160 (600 mg/day), and placebo in 151 out-patients suffering from anxiety. The data from the trial shows thatSt. John’s wort extract (LI 160) has superior effectiveness in controlling anxiety symptoms. And tolerability of the extract was excellent.802

How things go bad Depression can be experienced at any age. Imbalances in neurotransmitters including serotonin, dopamine, and norepinephrine can affect everything from cognition to mood. ↓ Memory, recall, reaction time and mood diminish ↓ Neuroreceptors decline ↓ Neurotransmitters levels decline 361 David Tomen ↓ Anxiety, panic attacks, stress and insomnia rise ↓ Neuroplasticity declines degrading long-term potentiation Under conditions of depression and chronic stress your brain loses the ca- pacity to transmit signals between neurons efficiently. Memory, cognition, and decision-making all suffer as a result.

St. John’s wort to the rescue St. John’s wort inhibits synaptic uptake in your brain of serotonin, dopamine, and norepinephrine with approximately equal affinity. Research shows that St. John’s wort also has an affinity foradenosine (ATP), GABA and glutamate receptors. And in the lab, scientists discovered it downregu- lates beta-adrenergic receptors and upregulates serotonin receptors.803 Adrenergic receptors are a class of G protein receptors that are targets of the catecholamines like norepinephrine and epinephrine (adrenaline). This upregula- tion and downregulation of neurotransmitter concentrations are in areas of the brain implicated in depression. And finally, neuroendocrine studies show that St. John’s wort is involved in the regulation of genes that control HPA-axis function. Also contributing to the antidepressant action of this herb.804 Much of the therapeutic activity is attributable to St. John’s wort active phy- tochemical ingredients hypericin, hyperforin and several flavonoids.805 This novel mechanism of action is unlike any other single pharmaceutical antidepressant or nootropic. And underlies St. John’s wort’s profound effect on depression. St. John’s wort also has strong antibacterial806 and antiviral807 properties. And St. John’s wort inhibits tumor cell growth.808 Research shows that St. John’s wort extracts decrease oxidative stress and prevent neurotoxicity, and inflammation. And may be an effective treatment for oxidative stress-related neurodegenerative disorders like Parkinson’s and Alzheimer’s.809 St. John’s wort shows promise as an anti-inflammatory.810 Thousands of years of clinical use shows St. John’s wort works as a wound-healing agent. And St. John’s wort even helps reduce the effects of opium dependence by reducing withdrawal symptoms.811 Handy if you’re coming off of opiates.

How does St. John’s wort feel? If you have had problems with using SSRI prescription antidepressants, St. John’s wort extract may be a good option for you. St. John’s wort does not produce the same side effects as pharmaceutical antidepressants. Sex drive is not affected. No withdrawal symptoms when you stop taking St. John’s wort. 362 HEAD FIRST Users of St. John’s wort extract say it often works sooner than expected, and gets better over time. St. John’s wort extract helps provide better focus, and fewer Obsessive-Com- pulsive Disorder (OCD) symptoms. Users report an end to procrastination, less irritation, and better mood. St. John’s wort extract takes the edge off situations that would normally stress you. Feelings of anxiety are less or non-existent. Women going through menopause report feeling more emotionally stable when using St. John’s wort extract. Mood swings are no longer an issue. If you deal with PTSD you may find that St. John’s wort extract will put a stop to the rage. And long-term depression could be a distant memory. If you are sure your depression is caused by a serotonin imbalance, you should feel the mood-lifting effects of St. John’s wort. But neuroscience is a complicated subject. And everyone’s body and wiring are different. St. John’s wort does not work for all types of depression or anxiety. If your depression is caused by a hormone imbalance, a depleted microbi- ome, an issue with dopamine levels or other neuroreceptor issue, you may not experience the benefit of St. John’s wort. And please, please do not combine St. John’s wort with prescription antide- pressants! Serotonin Syndrome is real and could kill you. Literally.

The Research

The Politics of Treatment for Depression Most clinical studies using St. John’s wort for depression have been con- ducted in Europe. And were targeted in cases of mild to moderate depression. And then came a study done at Vanderbilt University in the US in 2001 which made headline news and created a ton of controversy. This study discred- ited the herb’s use in treating patients with major depression. I’m including this study to draw your attention to why we cannot always rely on “clinical studies” to study a nootropic’s efficacy in brain optimization. And why the nootropics community often resorts to personal experience, and the reviews of other neurohackers. This double-blind, placebo-controlled trial worked with 200 adult outpa- tients (mean age 42.4 years) who were diagnosed with major depression. Patients were randomly assigned to receive 900 mg per day of St. John’s wort extract or a placebo for 4 weeks. And if they did not respond, the dose was raised to 1,200 mg per day (or a placebo) for another 8 weeks. The researchers concluded that there was no significant change in patient depression scores. And that St. John’s wort was no better than placebo for treating major depression. 363 David Tomen Their conclusion was, “St. John’s wort was not effective for treatment of major depression”.812 I bring this study up for one reason: the study was funded by Pfizer, the phar- maceutical manufacture of Zoloft. The leading synthetic antidepressant medication. In 2015, the FDA in the US pushed Pfizer Inc. to modify the safety warning for Zoloft. Linking Zoloft to causing heart defects in newborns. This in response to hundreds of lawsuits by women who say they weren’t adequately warned that Zoloft could cause defects in their newborns. Zoloft sales for Pfizer made the company $3.3 billion in 2005.813 It seems to me that having a major pharmaceutical company funding the study of an herb that is in direct competition to one of their main profit-centers is a direct conflict of interest. And there was no way Pfizer was going to have a clinical trial show that St. John’s wort was as good as, or better than Zoloft. It’s also interesting that sales of St. John’s wort annual USA sales reached a peak of $315 million in 1998. But had declined to about $60 million by 2006.814 Bad press strongly affected the sales of this natural antidepressant. And yet the sales of pharmaceutical antidepressants continue to rise.

St. John’s wort as a Treatment for Mild-to-Moderate Depression A study at St. John’s Episcopal Hospital in New York compared St. John’s wort to the SSRI sertraline (Zoloft) in the treatment of depression. In this double-blind, randomized study, 30 outpatients (mean age 45.5 years) with mild to moderate depression received 600 mg per day of standardized St. John’s wort extract or 50 mg per day of sertraline for 1 week. This was followed by 900 mg per day of St. John’s wort extract or 75 mg per day of sertraline for another 6 weeks. The severity of depression symptoms was significantly reduced in both treat- ment groups. Clinical response was noted in 47% of patients receiving St. John’s wort. And 40% in patients receiving sertraline. The researchers concluded thatSt. John’s wort extract was at least as effective as sertraline in the treatment of mild to moderate depression.815

St. John’s wort for Major Depression I include this study done in 2008 for using St. John’s wort as treatment for major depression as a response to the questionable study sponsored by Pfizer in 2001. This study done in Munich, Germany investigated whether extracts of St. John’s wort are more effective than placebo in treating major depression. And as effective with fewer side effects than standard antidepressant drugs. This study was a review of 29 trials including a total of 5,489 patients. It included 18 comparisons with placebo and 17 comparisons with synthetic “stan- 364 HEAD FIRST dard antidepressants”. The standard antidepressants included tricyclic and SSRI antidepressants. The author’s conclusions reported that the available evidence suggests that St. John’s wort extracts were superior to placebo in patients with major depression. St. John’s wort extracts were similarly effective as standard antidepressants. And St. John’s wort extracts had fewer side effects than standard antidepressants.816

St. John’s wort helps Obsessive-Compulsive Disorder A study done at the Dean Foundation for Health Research and Education analyzed 12 patients who had been diagnosed with OCD. Patients received 450 mg of St. John’s wort twice daily for 12 weeks. The study included weekly evaluations using three different Obsessive- Compulsive scales. And a monthly evaluation with the Hamilton Rating Scale for Depression. Changes in obsessive compulsive behavior occurred within one week of supplementing with St. John’s wort. And changes continued to improve over the course of the 12-week trial. 5 of the 12 patients were rated “much” or “very much” improved, 6 patients were rated “minimally” improved, and 1 person had no change in symptoms. The researchers concluded that St. John’s wort could be an effective treat- ment for Obsessive-Compulsive Disorder (OCD).817

Dosage Notes St. John’s wort is available from local health food and vitamin stores and online. St. John’s wort comes in capsule, tablet and powder form. It’s also avail- able as tinctures, teas and oil-based lotions. Most St. John’s wort supplements are standardized to contain 3% hypericin. But the most recent clinical studies show that hyperforin is the constituent in St. John’s wort that has the most antidepressant action. Researchers say that the benefits of St. John’s wort are only applicable to standardized extracts such as LI 160, WS 5570/2, and ZE 117.818 Check the labels and look for: • Perika® which is WS 5570 extract • Kira® which is LI 160 extract • New Chapter SC27 who produce their own extract There are reports and some clinical data which suggest that the photosensitivity caused by hypericin can cause cataracts and blindness. All the more reason to play it safe, and go with a high quality St. John’s wort extract containing hyperforin.819 Recommended doses for St. John’s wort extract: • St. John’s wort for anxiety: 900 mg twice daily 365 David Tomen • St. John’s wort for mild to moderate depression: 300 mg 3-times daily • St. John’s wort for severe depression: 900 – 1800 mg daily • St. John’s wort for OCD: 450 – 1800 mg daily for 12 weeks • St. John’s wort for PMS: 300 – 900 mg daily for 2 menstrual cycles • St. John’s wort for irritable bowel syndrome: 450 mg twice daily for 12 weeks • St. John’s wort for nerve pain: three 900 mcg hypericin tablets for 2 treat- ment periods of 5 weeks each

Side Effects Side effects with St. John’s wort are generally mild and can include stomach upset, hives, skin rashes, fatigue, restlessness, headache, dry mouth, dizziness and confusion. St. John’s wort can interfere with getting pregnant, or make infertility worse. It can make ADHD symptoms worse. Particularly if you’re taking Ritalin. St. John’s wort may increase the risk of psychosis in those with schizophrenia, and may contribute to dementia in those with Alzheimer’s. St. John’s wort can interact with medications used during surgery. So if you’re anticipating surgery avoid St. John’s wort. Do not take St. John’s wort if you have bipolar disorder. Some St. John’s wort extracts can make your skin and eyes overly sensitive to sunlight. You should avoid sunlamps, tanning booths and tanning beds while using a St. John’s wort product containing hypericin. There is some clinical data showing that St. John’s wort products that contain hypericin may cause blindness.820

St. John’s wort and Serotonin Syndrome Cytochrome P450 3A4 (CYP3A4) is a liver enzyme whose job is to oxidize small, foreign organic molecules and toxins so they can be removed from your body. Some substances, including St. John’s wort and grapefruit juice, affect the enzyme CYP3A4. And can amplify or weaken the action of those drugs and nootropics.821 St. John’s wort interacts with tricyclic, SSRI and MAOI antidepressants. Taking St. John’s wort with these medications increases their action, and could lead to serotonin syndrome which can be deadly. Do not take St. John’s wort with antidepressants including: • Tricyclic: (Elavil), (Pamelor), imipramine (Tofranil) 366 HEAD FIRST • SSRI: Citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft) • MAOI’s: (Phenelzine (Nardil), tranylcypromine (Parnate) St. John’s wort can reduce levels of antihistamines in your body. It can in- crease the risk of bleeding when combined with Plavix and birth control pills. Do not use St. John’s wort with Warfarin as it can reduce its effectiveness. Drugs that suppress the immune system can lose their effectiveness with St. John’s wort. It should not be used with drugs that treat HIV and AIDS. St. John’s wort can increase the sedative effect of barbiturates, benzodiaz- epines (Valium), and triptans that treat migraines. St. John’s wort also interacts with antifungal drugs, statins, calcium channel blockers, and any other medication that is broken down by the liver. Which covers a lot of drugs and nootropics. Serotonin Syndrome is not to be messed with. An overload of serotonin in your brain can make you very sick. And can ultimately kill you. I’m not kidding here. If you suspect anything could cause problems if it’s increased or decreased in your system, do not use St. John’s wort. If your goal is to treat depression and mood issues, you have many other safer options available to you.

Available Forms St. John’ wort is available in tablet, capsule and powder form. Most are standardized to contain 0.3% hypericin. But the most recent clinical studies show that hyperforin is the constituent in St. John’s wort that has the most antidepres- sant action. Researchers say that the benefits of St. John’s wort are only applicable to standardized extracts such as LI 160, WS 5570/2, and ZE 117.822 Check the labels and look for a product containing: • Perika® which is WS 5570 extract • Kira® which is LI 160 extract • New Chapter SC27 who produce their own extract St. John’s wort is also available in tinctures, teas and oil-based skin lotions.

Nootropics Expert Recommendation

St. John’s wort extract up to 900 – 1,800 mg per day I recommend using St. John’s wort extract as a nootropic supplement. But with the strongest warning I’ve issued for any nootropic mentioned in this book. Do not combine St. John’s wort with prescription antidepressants because the combination puts you in serious danger of Serotonin Syndrome. St. John’s wort may also nullify or amplify the effects of other drugs includ- 367 David Tomen ing nootropics in your stack. This is caused by the suppression or induction of certain enzymes in your liver. Check the “Side Effects” portion of this chapter. And do your research before using St. John’s wort if you are taking any other medication or nootropic. Your body does not make St. John’s wort on its own. So to experience its antidepressant effects, you must take it as a supplement. St. John’s wort is especially helpful for those suffering from depression, anxi- ety and stress. Studies show it may help stop and reverse the devastating effects of stress on your brain, and body. St. John’s wort stacks well with SAM-e. You can safely take up to 1,800 mg of St. John’s wort daily if needed. Half the dose first thing in the morning. And the other half early afternoon. St. John’s wort can cause insomnia. So avoid taking it too late in the day.

368 HEAD FIRST Sulbutiamine

Sulbutiamine has been shown to boost motivation, improve focus, enhance memory and alleviate depression Sulbutiamine (isobutyryl thiamine disulfide) is a synthetic derivative of

Vitamin B1 (thiamine). Thiamine was the firstB Vitamin to be discovered by researchers. That’s why it’s called B1.

Sulbutiamine is simply two vitamin B1 molecules joined together. This chemical bond helps thiamine more easily cross the blood-brain barrier. Japanese scientists first synthesized Sulbutiamine in an attempt to quell a health crisis within the Japanese population. After WWII, the Japanese diet largely consisted of rice. This left them deficient in several key nutrients includ- ing thiamine. Insufficient thiamine led to a central nervous system disorder called Beriberi. But supplementing with thiamine alone didn’t help. Because of its poor bioavail- ability. And a lot of thiamine was needed to cure Beriberi symptoms. Sulbutiamine is far more bioavailable than standard thiamine. It is fat-solu- ble (thiamine is water-soluble) which helps it more easily cross the blood-brain barrier. The discovery of Sulbutiamine cured the Japanese population of a life- threatening disease. And it has since been tested and used throughout the world with much success. Throughout this chapter I’ll refer to Sulbutiamine interchangeably with thiamine. Sulbutiamine is the stronger of the two so it’s affects are amplified compared to standard thiamine. Thiamine is a coenzyme used by your body to metabolize food for energy. And to maintain proper heart, nerve and brain function. Thiamine also helps digest and extract energy from food. It turns nutri- ents into adenosine triphosphate (ATP). ATP is the fuel used by your cell’s mitochondria. And thiamine helps convert carbohydrates into glucose. The energy your body uses for your brain and nervous system. One more thing about this miracle B-vitamin. Thiamine contributes to the development of myelin sheaths which wrap around the axons of neurons to protect them from damage. Your body does not produce thiamine on its own. So you must get it from food including beef, brewer’s yeast, legumes (beans, lentils), milk, nuts, oats, oranges, pork, rice, seeds, wheat, whole-grain cereals, and yeast. But thiamine has poor bioavailability. By synthesizing thiamine and produc- ing Sulbutiamine you end up with a fat-soluble compound that is easily digested. And readily crosses the blood-brain barrier. 369 David Tomen Sulbutiamine vs. Thiamine: What’s the Difference?

Sulbutiamine is a synthetic version of Vitamin B1 (Thiamine). It is two 1B molecules chemically bonded together. Thiamine is water-soluble and does not easily cross the blood-brain bar- rier. Sulbutiamine is a fat-soluble compound that easily crosses the blood-brain barrier. Sulbutiamine functions in the body just like thiamine. But because it’s more bioavailable, it’s more effective than thiamine.

How does Sulbutiamine Work in the Brain? Sulbutiamine boosts brain health and function in several ways. But two in particular stand out. 1. Sulbutiamine is a fat-soluble molecule that crosses the blood-brain barrier more readily than thiamine. Once in your brain, it increases levels of thia- mine pyrophosphate (TPP). Thiamine pyrophosphate (TPP) is directly involved in thecitric acid cycle (KREBS) in the brain. This cycle breaks fatty acids, amino acids and monosaccharides into smaller molecules that produce adenosine triphosphate (ATP) energy for your mito- chondria. And provide the building blocks of the molecules needed to produce brain cells. A deficiency of TPP can eventually show up as Wernicke encephalopathy and Korsakoff syndrome. In our society this syndrome is typically caused by chronic alcoholism. But it can also occur after obesity (bariatric) surgery, Crohn’s disease, anorexia and if you’re on kidney dialysis. Symptoms of Wernicke-Korsakoff syndrome include confusion, inability to form memories, loss of memories and muscle coordination, confabulation (making up stories) and vision changes. And can ultimately (and very rapidly) lead to coma and death.823 Less severe cases of thiamine deficiency include fatigue, weight loss, irritabil- ity and confusion. 2. Sulbutiamine also contributes to the production of the enzyme PDH which is essential in making the neurotransmitter acetylcholine. And for the syn- thesis of myelin, which forms a sheath around the axons of neurons. Ensuring these neurons can conduct signals.824 The citric acid cycle and enzyme α–KGDH play a role in maintaining opti- mal levels of the neurotransmitters glutamate, and gamma–aminobutyric acid (GABA). When thiamine levels decrease, the activity of these enzymes are reduced.825 370 HEAD FIRST How things go bad We depend on our diet for thiamine. Very little thiamine is stored in your body. And depletion can occur within 14 days. Thiamine deficiency can be caused by alcoholism, Alzheimer’s Disease, anemia, athletes who reduce food intake, cancer, clogged arteries, Crohn’s dis- ease, diabetes, diarrhea and kidney disease. And even a poor diet. ↓ Low thiamine levels can slow creation of ATP ↓ Low thiamine levels can cause problems with memory, learning, recall and perception ↓ Acetylcholine levels decline All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more. So Sulbutiamine can help age-related cognitive decline, as well as a student looking to do better in school. By boosting acetylcholine, dopamine and GABA in the brain. And increased brain energy by fueling cell mitochondria with ATP. And building myelin sheaths that protect our neurons.

Sulbutiamine to the rescue Sulbutiamine is directly involved in the citric acid cycle that provides adenos- ine triphosphate (ATP) energy for your mitochondria. Sulbutiamine also plays a role in maintaining optimal levels of the neu- rotransmitters glutamate, and gamma–aminobutyric acid (GABA). And contrib- utes to the production of the enzyme PDH which is essential in making the neurotransmitter acetylcholine. Sulbutiamine will boost cognition, memory and decision-making. And has very effective anxiolytic (anti-depressant) qualities.

How does Sulbutiamine feel? Sulbutiamine is a fat-soluble form of thiamine which crosses the blood-brain barrier. It has been shown to improve glutamatergic, cholinergic, and dopaminer- gic neurological transmissions. It may also increase the density of D1 dopamine receptors.826 Nootropics users report: • Sulbutiamine as a study aid. On its own, Sulbutiamine seems to increase attention span for many neurohackers. And when combined with caffeine or any one of the racetams, many report being able to work effortlessly for hours on end. Study and work seems less stressful. • Boost motivation. Sulbutiamine boosts motivation and many report gives them the drive they need for study or work. • Increased focus. Sulbutiamine helps provide laser-like focus at work and 371 David Tomen school. Some report even with the most tedious of tasks. While staying in a very good mood. • Sociability. Many users report being able to articulate thoughts, and im- proved speaking ability. Language and your vocabulary seem to flow effort- lessly. Thoughts and ideas come with less effort. • Improved mood. Personally, I’ve found Sulbutiamine to be more effective than any prescription anti-depressant I’ve ever tried. And without the side effects. You should be able to experience the effects of Sulbutiamine soon after you take it.

The Research

Sulbutiamine Improves Mood A study at the University of Wales Swansea in the UK worked with 120 young adult females. Study participants took either a placebo or 50 mg thiamine for 2 months. Mood, memory and reaction times were monitored before and after taking the tablets. The results indicate that after 2 months of thiamine supplementation, the young females: • Were more clearheaded • Felt more composed and energetic • Reaction times improved • Improved mood.827

Sulbutiamine for Chronic Fatigue If you deal with chronic fatigue, Sulbutiamine may be a better option than another cup of coffee. Or a stimulant. Researchers at the Hospital Saint-Antoine in Paris studied 326 patients. All suffering from chronic fatigue. Patients were given 400 mg or 600 mg of Sulbu- tiamine daily. Or a placebo in this double-blind, parallel-group study. Patients were tested on the 7th and 28th days of the trial. Those that used 600 mg of Sulbutiamine had less fatigue.828

Sulbutiamine Improves Memory Poor memory is associated with low levels of choline activity in the brain. Choline is a precursor to the neurotransmitter acetylcholine (ACh). ACh trans- mission between neurons helps in memory formation. Scientists decided to find out if Sulbutiamine could help boost choline uptake. They gave a group of mice Sulbutiamine for 10 days, and then tested 372 HEAD FIRST their memory. The findings suggested Sulbutiamine improved memory forma- tion. And it was due to an increase in choline activity in the brain.829 Another study in France involved giving Sulbutiamine or a saline solution to rats for 9 weeks. The results of this study concluded Sulbutiamine provided better working and episodic memory.830

Sulbutiamine Improves Athletic Performance Many neurohackers use Sulbutiamine for a boost in physical energy. And it’s created some controversy in professional sports. The Moscow Anti-Doping Center analyzed 16,000 blood samples in a Rus- sian lab in 2009. They were looking for anabolic steroids in athletes. They found that 100 samples contained Sulbutiamine. These samples were collected in-competition. Indicating that Sulbutiamine was intentionally admin- istered for its “ergogenic and mild stimulating properties”.831

Sulbutiamine Improves Erectile Dysfunction One small study was conducted with 20 patients suffering from psychogenic erectile dysfunction. This type of ED is defined as the inability to achieve or maintain an erection because of psychologic factors. The men were given a prescription form of Sulbutiamine ‘Enerion’ for 30- days. 16 of the men showed significant improvement based on the international index of erectile function (IIEF). 3 of 6 men with arterial disorders in their penis showed that Sulbutiamine corrected the problem. The study concluded that erectile dysfunction can be effectively treated with Sulbutiamine.832

Dosage Notes Recommended Sulbutiamine dosage is 400 mg to 1,000 mg per day. Higher doses should be split with one dose in the morning, and the other early afternoon. Some neurohackers warn about dosing Sulbutiamine too late in the day. It’s mild ‘stimulant’ qualities could interfere with sleep. If you’re just starting out with Sulbutiamine, I suggest starting with a low dose and see how your body reacts. Tolerance can be a problem with Sulbutiamine. So when taking it for ex- tended periods, you may find it beneficial to cycle on and off the supplement. For example, take Sulbutiamine for 5 days, and take 2 days off before your next dose. Sulbutiamine powder tastes nasty. So you’d be advised to take it in capsule form. You can save on the cost of Sulbutiamine by making your own capsules. And Sulbutiamine is fat-soluble so take it with a tablespoon of extra virgin, cold-pressed coconut or olive oil for better absorption.

Side Effects Sulbutiamine non-toxic. So is considered well-tolerated and safe. 373 David Tomen Side effects are rare but can include skin rashes and eczema-like outbreaks and higher doses. Sulbutiamine can also create mood swings. Particularly if you’re bipolar or are taking bipolar medication. If you take Sulbutiamine late in the day you may find it interferes with sleep. Some find it has mild stimulant effects. There are some reports that Sulbutiamine can be addictive. If you have addiction-like tendencies, you may want to be cautious about using this supple- ment. It does affect dopamine levels in the brain.

Available Forms Sulbutiamine is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each. It’s sold as a prescription medication in some countries under the brand names Arcalion, Enerion, Bisibuthiamine, and Youvitan.

Nootropics Expert Recommendation

Sulbutiamine 1,500 mg per day I recommend using Sulbutiamine as a nootropic supplement. Your body does not make Sulbutiamine on its own. So to get its benefits you must take it as a supplement. Sulbutiamine is especially helpful for those suffering from depression. Expe- rience shows it helps stop and reverse the symptoms associated with depression. Likely because this nootropic helps boost the activity of dopamine, serotonin, GABA and glutamate in the brain. Personally, I’ve found Sulbutiamine to be more effective (and safer) than any prescription anti-depressant I’ve ever tried. Sulbutiamine is also particularly helpful to students and executives who want to boost cognition, learning and memory. Sulbutiamine can produce a noticeable increase in mental clarity. And give you a significant energy boost physically and mentally. You’ll feel more awake and alert. Without the side effects you’d get from stimulants like caffeine. Sulbutiamine also stacks very well with racetams like Piracetam and Aniracetam

374 HEAD FIRST Tryptophan

Tryptophan has been shown to help alleviate anxiety, depression, ADHD, SAD, OCD, PMS, memory loss, and pain Tryptophan is an essential amino acid and precursor to serotonin, melatonin and niacin (Vitamin B3) in your body. The enzyme Tryptophan hydroxylase converts Tryptophan into 5-HTP (5-hydroxytryptophan). The decarboxylation of 5-HTP to serotonin is dependent on the presence of

Vitamin B6, and pyridoxal 5’-phosphate (P5P). The further conversion of serotonin into melatonin requires the presence of SAM-e (S-Adenosyl-L-methionine). Serotonin is often referred to as the “happiness molecule”. Low serotonin levels can result in pain, insomnia, depression, seasonal affective disorder, and chronic fatigue. For your body to manufacture serotonin, it needs an adequate supply of the natural amino acid Tryptophan. As a nootropic supplement, Tryptophan is used for anxiety, ADHD, depression, insomnia, memory loss, pain, and eating disorders.833 Tryptophan is found in abundance in oats, bananas, dried prunes, milk, tuna, cheese, bread, chicken, turkey, peanuts and chocolate. Eating food containing Tryptophan will increase levels of this amino acid in your body. But not necessarily boost serotonin levels in your brain. Here’s why… Tryptophan is one of 8 essential amino acids and has the lowest concentration in the body of all the amino acids. Tryptophan requires and competes for active transport to the brain. And competes for the same receptors as the other amino acids. Research has also found that serotonin levels are enhanced by carbohydrates in your meals because insulin release accelerates the serum removal of some of the amino acids that Tryptophan is competing with. And if your meal has a higher percentage of proteins, it also slows serotonin elevation in your brain.834 Since Tryptophan from food has issues working its way to your brain to make serotonin, why not skip that step and supplement with 5-HTP instead? Tryptophan and 5-HTP both penetrate the blood-brain barrier. And 5-HTP is the intermediate step in serotonin synthesis. See my chapter on 5-HTP for more on why supplementing with 5-HTP instead of Tryptophan is not such a good idea. A lack of bioavailable Tryptophan in your body can have a big impact on your life. Low levels of Tryptophan and serotonin imbalances in the brain are 375 David Tomen associated with ADHD. Studies have found that children with ADHD have 50% lower than average levels of Tryptophan.835 Low levels of Tryptophan can result in short – and long-term memory loss. Supplementing with Tryptophan has been found to improve memory in healthy adults.

How does Tryptophan work in the Brain? Tryptophan boosts brain health and function in several ways. But two in particular stand out. 1. Tryptophan boosts memory. Tryptophan’s main nootropic mechanism of action is as a precursor to the neurotransmitter serotonin. Other neurotrans- mitters such as melatonin, dopamine, norepinephrine and beta-endorphin increase following Tryptophan supplementation.836 Research shows that Tryptophan and serotonin play a significant role in memory. Enhanced brain serotonin has been shown to improve cognitive per- formance in animals and humans. And decreasing levels of serotonin through Tryptophan depletion impairs cognition. A study done in Pakistan assessed memory in rats following Tryptophan administration. The rats received Tryptophan doses of 50 and 100 mg/kg of body weight for 6 weeks. The study showed significant improvement in memory of rats following both doses of Tryptophan.837 2. Tryptophan enhances mood. As a precursor to serotonin, Tryptophan can have a significant effect on mood. Supplementing with Tryptophan has been found to increase not only serotonin, but growth hormone and prolactin as well. Researchers infused 11 healthy male subjects with doses of 5, 7.5 and 10 grams of Tryptophan. And then monitored their hormonal and behavioral responses. Tryptophan produced significant effects on mental and physical sedation but did not increase levels of tranquilization. Tryptophan provided a calming effect without knocking these guys out even at high doses.838

How things go bad As we get older, our brain chemistry and energy metabolism changes. ↓ Tryptophan levels decline ↓ Tryptophan hydroxylase levels decline ↑ Stress, insulin resistance and age increase

↓ Magnesium and Vitamin B6 levels decline ↓ Neurotransmitter levels decline ↓ Concentration, working memory and executive function decline ↓ Appetite regulation, energy and alertness decline 376 HEAD FIRST All of these changes can happen at an age. And are influenced by declining Tryptophan levels. Very little dietary Tryptophan is available for protein and serotonin synthesis. And for many people this can be a problem. Anxiety, depression, ADHD, memory loss, binge eating and a host of other mental and physical issues have been correlated with low Tryptophan levels.

Tryptophan to the rescue Just living in our modern society seems to leave us irritable, stressed-out, and anxious. Worst case is problems sleeping, depression, aggressive behavior, reduced motivation, pain and even suicidal thinking. And all have been traced to not enough serotonin in our brain.839 Serotonin, the happiness molecule relies on an adequate supply of Trypto- phan for synthesis. Researchers now recognize that the role serotonin plays in psychiatric and behavior disturbances comes from Tryptophan depletion.840 Tryptophan hydroxylase is the rate-limiting enzyme needed for serotonin production. And is involved in the conversion of Tryptophan to 5-HTP (5-Hy- droxytryptophan) needed to make serotonin. This enzyme (Tryptophan hydroxylase) can be inhibited by stress, insulin resistance, magnesium or Vitamin B6 deficiency, or increasing age. Tryptophan and 5-HTP can penetrate the blood-brain barrier. But Trypto- phan requires active transport and competes for the same receptors with other amino acids including tyrosine, phenylalanine, valine, leucine, and isoleucine.841 To complicate things even more, serotonin levels are enhanced by carbohy- drates in our diet because insulin release accelerates serum removal of the amino acids competing for Tryptophan transport. And high levels of protein in our diet slows increase in serotonin.842 So now you know why it’s helpful to add supplemental L-Tryptophan to your nootropic stack.

How does Tryptophan feel? Many try L-Tryptophan the first time to cure insomnia or as an alternative to prescription sleep meds. Dosing L-Tryptophan in the evening will typically ensure you’ll feel great the next day. You should have more energy for working out. Anxiety levels should decrease. Happiness levels should rise. Tryptophan could help with memory. Music will sound better. Feelings of self-esteem will improve. Some neurohackers report being able to taper off prescription antidepressant meds by supplementing with L-Tryptophan.

The Research 5-HTP and Tryptophan are natural alternatives for the treatment of depres- sion. And often used as alternatives to prescription antidepressant treatments be- cause they don’t come with the side effects associated with antidepressant drugs. 377 David Tomen But as neurohackers we don’t have a lot of research to help us decide if supplementing with Tryptophan makes sense. (If we base our decisions on clini- cal trials). Much of the research looks at finding out if low levels of Tryptophan are associ- ated with depression and poor cognition. But there is very little clinical evidence that supplementing with Tryptophan will help reverse low Tryptophan levels. And if adding this nootropic to our stack will boost mood and cognition. Researchers at the University of Queensland in Australia decided to comb through the research to find out if clinical trials supported the natural health claims of using 5-HTP and/or Tryptophan for depression. The team located 108 trials of which only 2 studies involving a total of 64 people had sufficient data to qualify. The team concluded that the very limited data showed 5-HTP and Tryptophan better that placebo for alleviating depression. But that larger and more studies were needed before their widespread use could be recommended.843

Low Tryptophan = Depression and Poor Cognition 20 patients in remission or partial remission from depression were studied in a double-blind, crossover design trial. Tryptophan was artificially depleted in these patients so scientists could look at the effects on cognition and mood. The research team found what we see in real life. Lower levels of Tryptophan had a negative effect on mood, their ability to process positive information, and attention.844

Tryptophan Helps Manage Depression Serotonin has been recognized as the neurotransmitter that is key to manag- ing depression for the last 30 years. Most of the prescription drug therapies for depression work by raising serotonin levels at the relevant synapses. We also know that Tryptophan is the immediate precursor to serotonin in the brain. So researchers, using a “what came first, the chicken or the egg” ap- proach, decided to find out if low serotonin levels or low Tryptophan levels were to blame for depression symptoms. Researchers in China analyzed levels of Tyrosine, Tryptophan and serotonin in patients with major depressive disorder. And found that all three were decreased in depressed patients. (Note that Tyrosine is a precursor to dopamine in the brain).845 The Center for Addiction and Health in Toronto conducted a randomized, double-blind, placebo-controlled trial with 30 depressed individuals. Treatment was fluoxetine (Prozac®) 20 mg per day, 2-4 grams of Tryptophan per day or a placebo for 8 weeks. Mood was assessed using the Hamilton Depression Rating Scale and the Beck Depression Index during the trial. During the 1st week there was a signifi- cant decrease in depression in those who used fluoxetine or Tryptophan. 378 HEAD FIRST At 4 weeks the research team recorded a disruption in sleep patterns for those using fluoxetine or a placebo. But not the Tryptophan group. The team concluded that combining 20 mg of fluoxetine with 2 g of Tryp- tophan was a safe protocol for treating depression. Patients experienced a rapid decrease in depressive symptoms. And the combination had a protective effect on sleep patterns.846 DO NOT TRY THIS AT HOME. The trials combining Tryptophan with SSRI’s, SNRI’s and MAOI’s are all done under professional supervision. But remember, Tryptophan is a precursor to serotonin. And antidepressant meds also boost serotonin in the brain. When combined, serotonin levels are boosted even more. Herein lies the problem. If you increase serotonin too much, you put your- self in real danger of Serotonin Syndrome. Which can lead to all kinds of nasty side effects. Including death.847 DO NOT combine Tryptophan with antidepressant meds unless you are doing so under the careful supervision of a doctor. It is much too dangerous attempting this on your own.

Tryptophan Boosts Exercise Performance Ever wondered why you cut a workout session short even though physical fatigue wasn’t an issue? Researchers found it could be due to low Tryptophan levels. And its effects on serotonin in your brain. 20 healthy young men aged 21 years used a cycle ergometer at about 50% of their physical capacity for 10 minutes followed by maximum intensity exercise for another 30 minutes. This sequence was repeated 3-times, and after the th4 series, each participant continued at the highest speed they could sustain for 20 minutes. This protocol was performed twice: once with and once without Trypto- phan. Researchers found peak power output during the last 20 minutes were higher on trials performed with Tryptophan than those who performed on a placebo.848 Another trial in Spain recruited 12 healthy sportsmen who ran on a treadmill until exhaustion. Once while supplementing with Tryptophan and once with a placebo. Total exercise time, perceived exertion rate, maximum heart rate, peak oxygen consumption, pulse recovery rate, and excess post-exercise oxygen consumption were determined during the two trials. Total exercise time was nearly 50% greater after receiving Tryptophan than after receiving a placebo. Perceived exertion rate was lower when using Tryptophan. The researchers concluded that the longer exercise time could be due to increased pain tolerance as a result of Tryptophan supplementation.849 379 David Tomen Tryptophan Relieves Symptoms of Seasonal Affective Disorder Seasonal Affective Disorder (SAD) is a form of depression experienced by many during the winter months. Symptoms include difficulty waking, decreased energy, weight gain, carbohydrate craving, difficulty concentrating, decreased libido, withdrawal, anxiety, depression and irritability. The first order of treatment is often light therapy. But many do not respond to light therapy typically because of a mutation in the melanopsin gene and the associated signaling pathway between the retina and the pineal gland.850 The pineal gland in your brain is your source of melatonin which influences sleep cycles. Melatonin is synthesized from serotonin which is synthesized from Tryptophan.851 So if light therapy doesn’t work, possibly supplementing with Tryptophan to stimulate production of serotonin and melatonin could be effective. Researchers at the University of British Columbia in Vancouver, Canada set out to find if Tryptophan could help those with Seasonal Affective Disorder (SAD) where light therapy failed. Patients were treated for 2 weeks using light therapy. Those who did not respond to light therapy were treated with 1 g Tryptophan 3-times per day for 2 weeks while continuing light therapy. The addition of Tryptophan resulted in a significant reduction in depression. 64% of the patients in this study showed very good clinical responses to the combined treatment with minimal side effects.852

Dosage Notes Recommended dosage of Tryptophan is 500 – 1,000 mg per day for cogni- tive benefit. The University of Michigan Health Department recommends much higher doses for: • Lowering appetite and cravings: .5 – 2 grams per day • Depression or Anxiety: 2 – 6 grams per day (with medical supervision) • Chronic pain or migraines: 2 – 4 grams per day in divided doses • Sleep disorders or insomnia: 1 – 2 grams at bedtime853 Tryptophan is a precursor to the neurotransmitter serotonin in the brain. Tryptophan hydroxylase is the rate-limiting enzyme needed for serotonin produc- tion. And requires magnesium and Vitamin B6 to synthesize serotonin.

Tryptophan is also a precursor to the synthesis of Vitamin B3 (niacin). So if you don’t have enough niacin in your body, supplementing with L-Tryptophan will not efficiently produce serotonin because it’s being used to produce niacin.

Which also depletes stores of the vitamin cofactors B1, B2 and B6. 380 HEAD FIRST So supplement L-Tryptophan with a B-Vitamin complex that includes Vita- mins B3 and B6, and magnesium. Note that some of the clinical trials used in this post use much higher doses of Tryptophan. Which is not recommended and usually not necessary. Too much Tryptophan will make you sleepy. And could produce excess levels of 5-HTP and serotonin which can lead to Serotonin Syndrome.

Side Effects Tryptophan is a normal part of your diet and considered non-toxic and safe at recommended doses. But in the unlikely event that you already have adequate levels of Tryptophan in your body, supplementing with more could cause problems. As can dosing more that the recommended amount. Tryptophan could cause stomach upset, loss of appetite, nausea, heartburn, drowsiness, headaches, dry mouth and sexual problems. Start at the lowest dose to see how your body reacts. When first starting with L-Tryptophan take your dose in the evening to avoid possible drowsiness issues. Caution: Low to moderate doses of Tryptophan (30 mg per pound of body weight), or about 4.5 grams for the average 165 lb. adult is considered safe and free of side effects. However, most don’t need to dose at nearly these levels. DO NOT use L-Tryptophan if you are taking antidepressant medications including SSRI’s. Because these drugs delay normal degradation of serotonin in brain synapses leaving more serotonin circulating in your brain. Too much Tryptophan in combination with these drugs can produce Sero- tonin Syndrome which can lead to delirium, involuntary muscle contractions, high fever, and coma. And worse case and a very real scenario is death.854

Available Forms L-Tryptophan is available in tablet and capsule form usually 500 – 1,000 mg. You also get Tryptophan in foods you eat including chocolate, oats, bananas, dried dates, milk, cottage cheese, meat, fish, turkey, and peanuts. Approximately 300 mg of Tryptophan is available in three ounces of turkey, lamb, beef, tuna, or peanuts. Fortunately, relative to other amino acids, small amounts are needed for a therapeutic effect. But there are all kinds of reasons why your body may not be making good use of the Tryptophan you’re getting from food. See “Tryptophan to the rescue” for more on why it may be a good idea for you add Tryptophan to your stack.

Nootropics Expert Recommendation

Tryptophan 500 – 1,000 mg per day I recommend using Tryptophan as a nootropic supplement. Your body does get some Tryptophan from the food you eat. But this amino 381 David Tomen acid is competing with other amino acids for transport to your brain. It’s compet- ing for the same receptors. And carbohydrates vs. proteins in your meals can affect Tryptophan’s ability to synthesize serotonin in your brain. Supplementing with L-Tryptophan will make more of this amino acid avail- able to synthesize serotonin and melatonin. L-Tryptophan is especially helpful for those with low serotonin levels. Boost- ing this crucial neurotransmitter can help alleviate insomnia, pain, depression and anxiety. Adding L-Tryptophan to your nootropic stack can also boost the neurotrans- mitters dopamine, norepinephrine and melatonin. Improving sleep, cognition, memory, mood and decision-making. Start with 500 mg of L-Tryptophan per day and take it in the evening. See how your body reacts and how you feel the next day. Increase the dose to no more than 2 grams per day as needed. And watch for side effects.

L-Tryptophan requires adequate levels of Vitamin B3, B6 and magnesium for serotonin synthesis. So add a good B-Complex vitamin and magnesium to your stack when using L-Tryptophan.

382 HEAD FIRST Turmeric

Turmeric has been shown to increase Brain-Derived Neurotrophic Factor, fight depres- sion, improve cognition, focus and libido, and protect the brain from inflammation Turmeric (Curcuma longa) is one of the most powerful natural remedies in Ayurvedic and Chinese medicine. This ancient herbal remedy has been used for at least 6,000 years.855 It is one of the most studied herbs in Ayurvedic, Siddha, Unani and Chinese healing. Turmeric has remarkable nootropic properties. And stands far above many modern medicines used to treat neurodegenerative diseases like depression, Al- zheimer’s and stroke. Turmeric is a perennial shrub native to southern Asia. It is a member of the ginger family (Zingiberaceae). And the Chinese name, jianghuang, literally means “yellow ginger.” Most of the turmeric we get is grown in India. But turmeric is also cultivated in China, Taiwan, Japan, Myanmar (Burma), Indonesia and throughout Africa. The major constituent of turmeric is curcumin (diferuloylmethane), which constitutes up to 90% of total curcuminoid content, with desmethoxycurcumin and bisdemethoxycurcumin comprising the remainder. Turmeric is used extensively in several countries as part of their system of national medicine. Turmeric is listed in the official Ayurvedic Pharmacopoeia of India. In the Pharmacopoeia of the People’s Republic of China. In the Japanese Herbal Medicines Codex. In Germany, turmeric is listed in the Drug Codex, approved in the Commis- sion E monographs, and in the form of tea in the official German Standard License monographs. Curcumin and turmeric have been extensively researched for their anti- tumor, antioxidant, anti-inflammatory and analgesic (pain-relieving) properties. In fact, a search of the U.S. PubMed database for research on turmeric returns 5,334 clinical trials on animals and humans.856 And yet the National Center for Complementary and Integrative Health which is part of the same U.S. National Institutes of Health has this to say about turmeric: “There is little reliable evidence to support the use of turmeric for any health condition because few clinical trials have been conducted.”857 That statement by an official medical resource in the USA tells you something about the American health care system. And its view of alternative medicines. And why books like “Head First” and websites like Nootropics Expert are so important for our nootropics community. So we can make our own decisions on how to boost our cognitive health. Turmeric, also known as “Indian Saffron”, has been used for thousands of years in traditional South Asian cuisine, and is the basic ingredient in curry. 383 David Tomen One recent study with 1,010 elderly Asian subjects found that those who ate curry “often” or “very often” had significantly higher cognitive performance.858 Turmeric has potent antidepressant qualities. And has been found to be more potent than the antidepressant Prozac. Researchers think Turmeric works by reducing the stress hormone cortisol while increasing levels of the neurotrans- mitter serotonin. Turmeric’s main active component curcumin provides protection against Alzheimer’s, major depression, epilepsy, and other neurodegenerative disorders. Scientists believe that much of this protective action comes from curcumin’s anti-inflammatory and antioxidant properties. Curcumin modulates neurotransmitter levels in your brain. And on a mo- lecular level is a potent inhibitor of reactive astrocyte expression which prevents apoptosis (cell death) in your brain.859

How does Turmeric Work in the Brain? Turmeric boosts brain health and function in several ways. But two in par- ticular stand out. 1. Turmeric enhances neuroplasticity. Brain-Derived Neurotrophic Factor (BDNF) is a growth hormone responsible for the creation of new neurons (neurogenesis) in your brain. Higher levels of BDNF can increase mood, intelligence, memory and productivity. And can reduce risks for neurode- generative diseases like Alzheimer’s and Parkinson’s. Using turmeric or its active compound curcumin can boost your intelligence and memory. And can elevate your mood especially if you’re prone to depression. Several studies have shown that turmeric or its active component curcumin significantly boosts BDNF.860 Researchers found that curcumin activated extracellular signal-regulated ki- nases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Administration of curcumin to mice in this study increased the number of newly generated cells in the hippocampus. Showing that curcumin enhances hippocampus neurogenesis. And that curcumin activity in the brain enhances neuroplasticity and repair of brain cells.861 Another study using the turmeric volatile oil Ar-turmerone showed this com- pound also supported regeneration of brain cells. Scientists discovered that when neural stem cells were bathed in Ar-turmerone, up to 80% more stem cells grew into neurons or other cells. Scientists then injected this turmeric extract into a part of rat’s brains where these cells are located. And witnessed a similar increase in growth of stem cells into neurons.862 2. Turmeric boosts dopamine and serotonin levels in the brain. These are 384 HEAD FIRST the ‘feel good’ neurotransmitters in your brain. Turmeric and its active com- pound curcumin has been studied, and used effectively as an anti-depressant for centuries. Researchers in India set out to establish how curcumin worked in the brain to provide this antidepressant action. In this study they investigated both curcumin and its ability to boost mood as well as the effect of Piperine as a bioavailability enhancer. The scientists found that curcumin increased serotonin and dopamine levels in the brain. And inhibited monoamine oxidase enzymes (both MAO-A and MAO-B) just like popular prescription antidepressant MAOI’s. Curcumin even enhanced the effectiveness of popular SSRI antidepressants Prozac, Effexor, and Zyban. The team found no increase in norepinephrine when using curcumin to boost neurotransmitters. Avoiding the irritability and other symptoms of an over- amped fight-or-flight response. And the scientists found that stacking curcumin with Piperine significantly boosted bioavailability. They concluded that curcumin combined with Piperine was a “potent natural antidepressant approach to managing depression”.863

How things go bad Chronic stress, anxiety and free radicals (oxidation) damage your brain. This damage can manifest in several ways including memory loss, brain fog, anxiety, depression, and even neurodegenerative diseases like Alzheimer’s and Parkinson’s. ↓ Chronic stress reduces memory ↓ Toxins kill brain cells ↓ Free radicals destroy neurons and synapses ↓ Serotonin and dopamine decline ↓ Brain-Derived Neurotrophic Factor declines Under conditions of chronic stress or depression your brain loses the capacity to transmit signals between neurons efficiently. Memory, cognition and decision- making all suffer as a result.

Turmeric to the rescue A member of the ginger family of herbs, turmeric is the seasoning that gives curry powder its yellow color. It’s long been known for its anti-inflammatory and antioxidant properties. And is actively studied today for applications as a nootropic. Turmeric or anyone of its several active compounds including curcumin and Ar-turmerone undoes damage to your brain caused by depression or chronic stress. Turmeric and curcumin boost neuron regrowth (neurogenesis), increases den- 385 David Tomen drites, repairs DNA, reduces inflammation, counters free radical damage, and boosts neurotransmitters. Turmeric inhibits monoamine oxidase enzymes (both MAO-A and MAO-B) just like popular prescription antidepressant SSRI’s and MAOI’s. Research shows that curcumin or turmeric can boost the effects of some popular antidepressants. Boosting the ‘feel-good’ neurotransmitters serotonin and dopamine can al- leviate depression, improve mood, boost alertness, cognition, decision-making, memory and even libido. Curcumin, the most active component of turmeric, activates genes to pro- duce a huge array of antioxidants that serve to protect your mitochondria. Curcumin also improves glucose metabolism, which is great for maintaining a healthy balance of gut bacteria. This critical microbiome in your gut directly influences how well your brain functions.

How does Turmeric feel? Curcumin is the main active component of turmeric. So most of the positive reviews and studies have been conducted using curcumin. Curcumin is known to possess antimicrobial, anti-inflammatory, anti- hypertensive, anti-hyperlipidemic, anti-tumor, anti-cancer, anti-phlogistic, anti- diabetic, anti-psoriasis, anti-thrombotic, anti-hepatotoxic and a host of other useful properties. If you are in perfect physical and mental health you may not feel the effects of supplementing with turmeric or curcumin. Turmeric’s neuroprotective quali- ties may not be felt if your brain is in perfect working order. But the effects of long-term supplementation will help you ward off diseases like Alzheimer’s and Parkinson’s. The most frequent comment from supplementing with turmeric comes from those dealing with chronic pain. Turmeric relieves the pain of osteoarthritis and fibromyalgia. Chronic pain usually results in insomnia or poor sleep quality, loss of memory, depression, and other stress-related symptoms. Adding curcumin or turmeric to your nootropic stack can help relieve chronic pain. You’ll sleep better and feel more alert the next day. Supplementing with turmeric or curcumin improves attention, work- ing memory, and mood. And is reported to relieve the symptoms of migraine headaches.

The Research

Eat Your Curry Curcumin, from the curry spice turmeric, has been shown to have antioxi- dant and anti-inflammatory properties. And can reduce beta-amyloid plaques that 386 HEAD FIRST are associated with Alzheimer’s Disease. But scientists were not satisfied with the evidence of turmeric’s benefits in real life. So in 2003, a research team in Singapore recruited 1,010 non-demented elderly Asian people aged 60 – 93 years. The authors of the study compared Mini-Mental State Examination (MMSE) scores for three categories and regular curry consumption. The scientist found that those who consumed curry “occasionally” and “often or very often” had much higher MMSE scores than those who “never or rarely” consumed curry. The study authors reported that regular curry consumption was evidence of better cognitive performance. The bottom-line 1 eat your curry.864

Turmeric as an anti-depressant A study conducted in India looked at the efficacy and safety of using curcumin, one of the active ingredients found in turmeric, for treating major depression. 60 patients diagnosed with major depressive disorder were chosen to receive either 20 mg of fluoxetine (Prozac), 1000 mg of curcumin, or a combination of both daily for 6 weeks. The study found that the best response (77.8%) was with the group of patients treated with a combination of curcumin and Prozac. The Prozac-only group experienced a 64.7% improvement in depression symptoms. And the curcumin-only group came in at 62.5%. The researchers concluded that curcumin could be used as an effective and safe treatment for patients with major depression.865

Curcumin Reduces Stress Turmeric has long been used in traditional Chinese medicine to manage stress and depression-related disorders. Scientists had already figured out tur- meric’s antidepressant effects in animal and human studies. So they imagined that curcumin may also alleviate stress caused by HPA (hypothalamic-pituitary- adrenal) dysfunction. For this study the scientists used rats. They subjected the animals to stress for 20 days by putting them through several tasks known to stress a rat. Putting rats through this unfortunate (for the rats) series of events produced the kind of symptoms you would see in humans subjected to ongoing, chronic stress. The rats had abnormal adrenal gland weight, increased thickness in the ad- renal cortex, elevated cortisol levels, and reduced glucocorticoid receptor (GR) mRNA expression. These changes were reversed by giving the rats curcumin in their food. The research team also found that chronic stress down-regulated BDNF levels, and reduced the ratio of cAMP to CREB levels in the hippocampus and frontal cortex 387 David Tomen of the rats. Giving the rats curcumin blocked all these stress-induced physical responses in their brains. The scientists concluded that these results provided compelling evidence that the behavioral effects of curcumin in chronically stressed animals, and by extension humans, could be related to the modulating effects of curcumin on the HPA axis and neurotrophin expressions.866

Dosage Notes You cannot get the immediate therapeutic and nootropic benefits of turmeric by simply eating more curry. Or adding turmeric to your food. Turmeric root contains only about 3% curcumin. The most convenient way to start experiencing the benefits of turmeric is to get a high quality, 100% organic turmeric extract that contains at least 95% curcuminoids. But curcumin and turmeric on their own are poorly absorbed by your gut. You must boost the bioavailability and absorption of this potent nootropic. And the most efficient way to boost bioavailability is to combine turmeric or curcumin with Piperine. One study showed combining curcumin with 20 mg of Piperine increased bioavailability by 2000%!867 Turmeric is fat-soluble so you must take it with a high quality fat for maxi- mum absorption. You can use organic, cold-pressed coconut or olive oil. Standardized turmeric or curcumin extract (95% curcuminoids) 750 mg 3-times per day. Turmeric liquid extract (1:1) 30 – 90 drops per day. Tincture (1:2) 15 – 30 drops 4-times per day. Dried turmeric root powder 2.5 – 4 grams per day.

Side Effects Turmeric is natural and considered non-toxic and safe when taken at recom- mended doses. Taking large amounts of turmeric for extended periods can cause stomach upset, and possibly ulcers. If you have gallstones or obstruction to your bile passages you should not supplement with turmeric. Turmeric may lower blood sugar levels which could be a problem for diabetics. Pregnant and breastfeeding women should not supplement with turmeric. And because turmeric can act as a blood thinner, stop supplementing with turmeric 2 weeks before surgery. Turmeric can also strengthen the effects of blood thinning medications.

Available Forms Turmeric is available as a powder, tablets, capsules, tincture and tea. And 388 HEAD FIRST is preferred over curcumin if you’re using it for inflammatory conditions like arthritis, tendonitis, or an autoimmune condition. Curcumin is a natural chemical found in, and extracted from turmeric. Sev- eral companies have developed their own version of this powerful nootropic. Sabinsa’s Curcumin C3 Complex® boasts the most clinical studies of any of the patented forms of curcumin. This curcumin product is standardized to95% Curcuminoids. Sabinsa also produces the standardized Piperine extract called BioPerine®. And supplement makers who feature Curcumin C3 Complex® from Sabinsa also typically include BioPerine® in their formula. BCM95® by DolCas Biotech is a standardized extract of turmeric containing curcumin-essential oil complex of 86% curcuminoids and 7-9% essential oils. As far as I can tell this is the only extract that includes turmeric volatile oils which is important to cognitive health. Recall from earlier in this article that turmeric volatile oil Ar-turmerone supported regeneration of brain cells Longvida® is a standardized curcumin extract that the company claims is at least 67-285 times more bioavailable than standard 95% curcumin. But does not contain any of the volatile oils found in natural turmeric. One study showed that this extract increases synapses in mice.868 Another study in humans showed Longvida® significantly improved attention, working memory, and mood com- pared to placebo.869 Meriva® is another patented form of curcumin combined with soy lecithin. The two compounds are a 1:2 ratio with microcrystalline cellulose added. The company claims that the addition of soy lecithin improves bioavailability of curcumin. Total curcumin in each capsule is 20%. Much higher doses of this curcumin extract are needed for optimizing cognition. And is primarily targeted at bone, joint, eye and skin health. Active ingredients of Turmeric include curcuminoids and volatile oils. Look for the percentage of active ingredients listed on the bottle or package. Your best option is choosing a standardized extract of at least 95% curcuminoids. Unless the supplement contains a patented compound from the companies listed above, you can assume that the extract has been processed using toxic sol- vents to extract curcumin from turmeric (not good). And avoid supplements that list “other ingredients” on the label. Look for Certified Organic to ensure the root used to make your Turmeric supplement is free of heavy metals, pesticides and herbicides.

Nootropics Expert Recommendation

Turmeric Extract (95% curcuminoids) 750 mg 3-times per day I recommend using Turmeric or Curcumin as a nootropic supplement. Your body does not make Turmeric on its own. So to get its benefits you must take it as a supplement. 389 David Tomen Turmeric is the anti-Alzheimer’s spice. Studies show that in parts of India where curries are eaten most often, Alzheimer’s disease is extremely rare. Turmeric is especially helpful for those suffering from depression or chronic pain. Turmeric has a combination of curcuminoids, volatile oils and proteins that make it anti-bacterial, anti-cancer, anti-inflammatory, and anti-septic. Some neurohackers maintain that turmeric or curcumin is the best nootropic. You can increase the bioavailability of turmeric by combining it with Piperine (black pepper extract) and a healthy fat like olive or coconut oil. You can safely take up to 3,000 mg of Turmeric extract daily if needed. Most get all the benefit they need with 750 mg. Dosed 3-times per day.

390 HEAD FIRST Uridine Monophosphate

Uridine Monophosphate has been shown to increase neuron and synapse density, do- pamine and acetylcholine release, boost learning and memory, and decrease depression Uridine Monophosphate (UMP or 5′-uridylic acid) is a pyrimidine nucleo- side found in all living organisms ranging from humans to bacteria. Uridine is one of 4 repeating units that make up RNA (Ribonucleic Acid). RNA and DNA (deoxyribonucleic acid) are the main information carrying mol- ecules in each of your cells. Uridine is so important to brain development, that it is included in human baby formulas.870 RNA works as a messenger molecule, carrying the blueprint provided by DNA to tiny cellular factories called ribosomes. Ribosomes are in charge of pro- tein synthesis and use the blueprint sent over from DNA by RNA to produce the right protein for the job required. Uridine is essential for optimized cognition and memory throughout your life. When taken as a nootropic supplement, Uridine Monophosphate easily crosses the blood-brain barrier.871 UMP has much better bioavailability than dietary sources of uridine. CDP-Choline levels are increased once uridine reaches your brain. CDP- Choline is required for the synthesis of phosphatidylcholine (PC). PC in turn is a precursor of the essential neurotransmitter acetylcholine (ACh). Increased levels of PC and acetylcholine improves cognitive function. Uridine is also a major building block for the synthesis of neurons and syn- apses. And uridine enhances the growth of dendrites, which are projections from neurons that facilitate connections with other neurons.872 The bottom line is that without uridine to make up RNA, DNA couldn’t get the info out for proteins to be synthesized. And life as we know it would cease to exist. Our bodies create some uridine. And we get uridine from the RNA of foods we eat including beets, beer, broccoli, fish, mushrooms, oats, parsley, sugar cane, tomatoes, and brewer’s yeast. Beer provides some of the highest uridine content of all the foods tested. The problem is most of the uridine we get from food never makes it from our digestive system to our brain. So we need to supplement with uridine monophos- phate (UMP) to experience the benefits of uridine. Uridine does much more than merely act as a building block of RNA. Uri- dine acts in the formation of neurotransmitters, and the creation of new synapses. Adding uridine monophosphate to your nootropic stack can help improve alertness, focus, memory, learning ability and mood. Researchers have found that Uridine Monophosphate alone can improve 391 David Tomen memory. But stacking UMP with DHA (Omega-3) and choline works in synergy, increasing the number of synapses. Resulting in improved cognition.873

How does Uridine Monophosphate Work in the Brain? Uridine Monophosphate boosts brain health and function in several ways. But two in particular stand out. 1. Uridine improves memory. Uridine helps boost learning and memory in several ways. Uridine helps the growth of new synapses in your brain, increases signaling between neurons, and assists in the formation of acetylcholine (ACh). Memory is largely dependent on neuroplasticity which is associated with the ability to learn and form memories. This process of turning experiences into memories relies on the growth of new neurons (neurogenesis), new synapses (syn- aptogenesis), dendrite formation, and network reorganization. New neurons (neurogenesis) are encased in a phospholipid layer made up partly of phosphatidylcholine (PC). PC is made from CDP-Choline which is produced with the help of uridine.874 Supplementing with uridine gives your brain the ability to create more phospholipids by providing an abundance of CDP-Choline. Resulting in new and stronger neurons. Uridine is a precursor to the formation of CDP-Choline which is a precursor to the formation phosphatidylcholine (PC). PC separates into choline and sphin- gomyelin in your brain. Choline is then available to form acetylcholine (ACh). Optimal ACh levels is crucial for cognitive performance.875 Uridine also helps increase synapse formation (synaptogenesis) by enhancing neurite growth. Uridine signals this outgrowth by activating the P2Y2 receptor which controls neuron differentiation and synaptic protein synthesis.876 2. Uridine impacts mood. Uridine stimulates the release of the ‘feel-good’ neurotransmitter dopamine in your brain. Phospholipids like phosphatidylcholine (PC) are required for cellular growth and repair, and specifically for synaptic function. PC synthesis is controlled by levels of its precursor CDP-Choline which is produced from cytidine triphosphate (CTP) and phosphocholine. Researchers found that supplementing with uridine monophosphate boosted levels of CDP-Choline. By promoting the synthesis of uridine triphosphate (UTP), which was partly converted to CTP. Uridine also enhanced neurite outgrowth with the help of nerve growth factor (NGF). The research team found thatdopamine release correlated with neurite outgrowth influenced by UMP.877 Increased levels of dopamine has a significant affect on mood, learning and attention. 392 HEAD FIRST How things go bad Uridine levels decline as we age. And if you were not breast-fed as a baby, you started life at a deficit. Breast milk provides the uridine required for optimal brain growth. ↓ Cognition, memory, recall, reaction time and mood diminish ↓ Brain cell membranes degenerate ↓ Neurotransmitter levels decline ↓ Neurons and synapses decline All of these changes in brain energy metabolism are contributing factors to neurodegenerative diseases, including Alzheimer’s, Parkinson’s, ALS, epilepsy, and dementia. But even if you’re not concerned with age-related cognitive decline, or the effects of aging, Uridine Monophosphate can help.

Uridine Monophosphate to the rescue Uridine plays a critical role in the pyrimidine metabolism in your brain.878 In the simplest terms, uridine monophosphate promotes neuron and synapse growth and DNA repair.879 Benefits reported by neurohackers include; uplifting and stabilizing mood, reducing stress and OCD symptoms, a reduction in anxiety, and modulating and normalizing dopamine release. Adding uridine monophosphate to your nootropic stack helps: • Reduce general cognitive decline • Increase free phosphatidylcholine (PC) • Increase acetylcholine in your brain • Increase receptor (neurogenesis), and synapse (synaptogenesis) densities • Improve cellular phospholipid membrane health • Boost learning and memory

How does Uridine Monophosphate feel? Neurohackers report the effects ofuridine monophosphate (UMP) supple- mentation is most pronounced when stacked with DHA or Omega-3’s. UMP elevates mood and relieves depression. Feelings of “well-being’ are enhanced. And verbal fluidity, memory and focus are all noticed at doses as low as 150 mg of UMP. Those dealing with ADHD report that uridine monophosphate increases cognition without causing anxiety or mood changes. This is backed up by science that shows uridine reduces the side effects associated with medication that effects dopamine and GABA neurotransmission.880 Others report that uridine monophosphate helps bring clarity of thought, 393 David Tomen resolving problems is faster and easier, math is easier, and making decisions from a clear emotional state simplifies life. The common thread through most reviews on uridine monophosphate is greater success when stacking UMP with a choline like Alpha GPC and Omega-3’s. This synergy is backed up by multiple clinical trials.

The Research We have plenty of research on uridine monophosphate. But most of the stud- ies and trials have been done using animals. Likely because uridine is naturally found in every cell of the human body. It’s a key element in a chain of four molecules that make up the RNA chain. And since uridine is a natural element, it cannot be patented. So very little money can be made by the large pharmaceutical companies since UMP can’t be sold as a “drug”. The clinical evidence that we do have for uridine monophosphate strongly suggests that it is a powerful and useful nootropic.

Uridine Monophosphate Boosts Intelligence Consumption of certain nutrients can influence brain function even if you’re not trying to “fix a problem”. We know that supplemental DHA (Omega-3) can improve cognition in humans. DHA makes up 60% of your brain and is most prominent in the phospholipid membrane of each of your brain cells. Adding DHA to your nootropic stack has also been shown to increase the density of dendritic spines in the hippocampus which enhances synaptic transmission.882 Researchers have found that supplemental Uridine Monophosphate (UMP) also promotes synthesis of synaptic phosphatides. But scientists found that taking DHA with UMP has an even greater effect on synthesis of synaptic phosphatides. Greater than taking each nootropic on its own. Scientists also found that combining DHA with UMP and choline amplifies increases in dendritic density in the hippocampus. In one very detailed study with gerbils, researchers found that the combina- tion of DHA, UMP and choline significantly increased learning and memory in the young animals.883 Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal said of this study, “Now that we know how to make gerbils smarter, it’s not too far a stretch to hope that people’s intelligence can also be improved. Quite frankly, this can’t happen soon enough, as every environmentalist, advocate of evolution and war opponent will attest.” The synergy of these three nootropics (DHA, UMP and choline) in boosting learning and memory are powerful motivation for any neurohacker to add these supplements to their stack. 394 HEAD FIRST Uridine Monophosphate Fights Depression Research has confirmed the antidepressant effects of omega-3 fatty acids. Associate Professor of Psychiatry William A. Carlezon Jr. of Harvard also found that uridine, a compound found in sugar beets and molasses, has similar effects. And when both Omega-3 and uridine were used in combination, there were found to be effective at lower doses of each. Professor Carlezon speculated that the antidepressant effects of Omega-3 and uridine were caused by affecting fats in the brain. Making membranes more resilient eased the flow of neurotransmitters. An imbalance of neurotransmitters is thought to be a cause of depression. To test this theory, the Professor and his colleagues put rats through a 15- minute swim test during which the animals eventually stopped trying to climb out of the water tank and became largely immobile. Just enough to keep their heads above water. After the test, the rats were dried off with a towel, placed in a warm enclosure for 30 minutes and then returned to their cages. The next day, rats were retested for 5 minutes each. And the rats that hadn’t received enough omega-3’s or uridine became motionless much more quickly. The researchers equate the onset of immobility in rats to depression in humans. The animals that received either Omega-3 or uridine, or lower doses of both, continued to swim around. Professor Carlezon said of the study, “They seem to be protected from the ability of stress to cause depression”. Adding Omega-3’s or uridine monophosphate to your stack can help you avoid depression. For an even more pronounced antidepressant effect, combine Omega-3’s with uridine monophosphate, but at lower doses of each.884

Uridine Monophosphate May Help Prevent Alzheimer’s Alzheimer’s researchers agree that cognitive decline seen in Alzheimer’s patients is caused by loss of brain synapses. Researchers at MIT had a theory that restoring some of these synapses could provide an effective treatment for Alzheimer’s. An MIT team reported in Brain Research that rodents given a cocktail of DHA (Omega-3), uridine and choline showed a greatly increased concentration of dendritic spines. These dendritic spines receive messages in postsynaptic neurons. The head of the research team Professor Richard Wurtman said of the study that synapse regeneration had occurred. To Alzheimer’s researchers, this synapse regeneration was very unusual and came as a surprise. In this study, some of the rats received all three compounds (Omega-3, uridine and choline), and some received only one. The improvements in synapse growth and cognitive ability were greatest in the rats given all three.885 395 David Tomen Other research ongoing for at least the last 10 years shows that early treat- ment using “diet” could significantly slow the progression of Alzheimer’s disease. I would argue that most neurohackers supplementing with Omega-3’s, uridine monophosphate and choline could avoid Alzheimer’s altogether. Published in the Journal of Nutritional Biochemistry, a study from the Uni- versity of Eastern Finland and conducted throughout Europe proved you could reduce dementia risk. And reduce amyloid accumulation in Alzheimer’s mouse models. The results of this study showed that even slight changes in the composition of the diet may, under a sufficiently long period of time and at an early stage of the disease, lead to significant changes in brain metabolism and improved memory performance.886 The supplements used in this study included uridine-monophosphate, phos- pholipids, B-vitamins, and antioxidants. This combination has been put into a new supplement called “Souvenaid” which is undergoing clinical trials in Europe and the United States.

Dosage Notes Recommended dosage of Uridine Monophosphate (UMP) for nootropic ben- efit is 150 – 250 mg per day twice per day. I recommend taking UMP with a good that includes the B- Vitamin group and a broad range of trace minerals including magnesium. For best results stack UMP with Omega-3’s that include at least 700 mg of DHA and 300 mg of EPA. Introduce a good choline source after a couple of weeks of supplementing with uridine monophosphate. Start with 50 mg of Alpha GPC or CDP Choline. And increase your dose depending on response to 300 mg. If you find that choline supplementation increases depression, stop using choline and try using ALCAR as an alternative. Everyone’s body chemistry is different. To find the optimal dose of uridine monophosphate for you will take patience and some experimentation. Too little UMP and you won’t see any benefit for a long time. Too much uridine and you’ll feel emotionally dull and/or overly focused.

Side Effects Uridine is produced naturally in your body. So is considered well-tolerated and safe. Taking uridine monophosphate with food may help avoid any side effects. Neurohackers report only minor side effects like a decrease in emotions (feeling like a robot). But this has only been noted at very high doses of uridine monophosphate. If you do not respond well to B-Vitamins or SAM-e, you may not enjoy the benefits of UMP. To learn more about the methylation-factor involved in this 396 HEAD FIRST reaction for some people, you can read about methylation here (http://www. enzymestuff.com/methylation.htm).

Available Forms Uridine Monophosphate (UMP) is available in capsule and powder form. UMP is water soluble and can be taken sublingually. Sublingual doses are reported to be up to 7 – 10-times the equivalent dose compared to taking UMP orally. Triacetyluridine (TAU) comes in capsules, and is fat soluble. TAU is up to 4 – 7-times stronger when taken orally compared to UMP. Neurohackers report that UMP is more effective, and a better value that TAU.

Nootropics Expert Recommendation

Uridine Monophosphate 150 – 250 mg twice per day I recommend using Uridine Monophosphate (UMP) as a nootropic supplement. Your body does make some uridine on its own. And you get uridine from the food you eat. But research has shown that your body does not retain enough of a usable form of uridine for cognitive benefit. Uridine Monophosphate is critical for the formation of RNA (ribonucleic acid). The main messenger molecule needed to transfer DNA’s blueprints for protein synthesis. Uridine is a precursor in the synthesis of CDP Choline. Which is a precursor to the synthesis of phosphatidylcholine (PC). PC is required for the synthesis of acetylcholine (ACh). Uridine enhances the release of the feel-good neurotransmitter dopamine. And uridine enhances the growth of neurons and synapses. Uridine Monophosphate is especially helpful if you’re dealing with stress or depression. I suggest a dose of 150 – 250 mg of UMP twice daily. It takes a while to feel the effects of uridine monophosphate. But you can amplify the effects of UMP by stacking it with 300 mg of Alpha GPC or CDP Choline and 700-1,000 mg of DHA (Omega-3). Do not push it by taking much more than the recommended dose of UMP. You may experience unwanted side effects.

397 David Tomen Vinpocetine

Vinpocetine is known for increasing cerebral circulation, taming inflammation and oxidative stress, and boosting alertness, cognition, concentration, memory and mood Vinpocetine (periwinkle extract, ethyl apovincaminate, Cavinton, Bravinton, Ceractin, Intelectol) is a semi-synthetic derivative of vincamine, an alkaloid derived from the lesser periwinkle plant (Vinca Minor L.). A flowering plant native to central and southern Europe and Turkey, Vinca Minor is also grown as ground cover in the United States. Vinpocetine was first isolated from the periwinkle plant in 1975 by chem- ist Csaba Szántay. Hungarian pharmaceutical company Gedeon Richter began manufacturing Vinpocetine in 1978. Vinpocetine continues to be one of the company’s top selling drugs world-wide.887 Vinpocetine is used as a prescription drug in Japan, Europe, Mexico and Russia for the treatment of cognitive and cerebrovascular disorders. In the USA and Canada, Vinpocetine is sold as an OTC dietary supplement. Other uses include using Vinpocetine for the prevention of motion sick- ness, menopause symptoms, chronic fatigue syndrome, seizure disorders, hearing and eye disorders, and even as a topical application to increase female sexual response.888 Since it was first released in 1978, Vinpocetine has earned a well-deserved reputation with the nootropics community for optimizing cognitive health. Primarily by boosting cerebral blood flow. But to understand how and why Vinpocetine boosts cognition and protects your brain, we need to dive in to how blood flows in your brain. An optimized adult brain gets about 1/7th of your heart’s output of blood every minute. Your brain needs this blood flow for a constant supply of glucose, oxygen and other nutrients to keep it functioning properly. Unlike other organs and muscles in your body, your brain cannot stand an interruption in this steady flow of blood. Two carotid arteries in the sides of your neck send blood to the front and top of your brain. Arteries in your vertebrae (spine) join with your carotid arteries at the base of your brain to form the Circle of Willis.889 The Circle of Willis is critical because it is the only area of your body where all four major blood vessels join. Allowing blood to be sent to areas where it is needed. Even if one of the major blood vessels becomes blocked. We’ll take a look at “How things go bad” later in this chapter. The good news is that Vinpocetine can have a profound effect on maintaining and repairing your brain’s blood vessels, cerebral blood flowing through theCircle of Willis, and to individual brain cells. 398 HEAD FIRST Vinpocetine not only helps increase cerebral blood flow, it also works as a powerful antioxidant and anti-inflammatory in your brain. And Vinpocetine inhibits the enzyme PDE1 which can increase cAMP and cGMP levels. These cyclic nucleotides in turn activate a series of kinases that phosphorylate the transcription factors cAMP response element binding protein (CREB) and serum response factor (SRF), leading to the expression of plasticity- related genes.890 Boosting neuroplasticity enhances cognition and memory.

How does Vinpocetine work in the Brain? Vinpocetine boosts brain health and function in several ways. But two in particular stand out. 1. Vinpocetine boosts cerebral circulation. Your brain only accounts for about 2% of your bodyweight, but it consumes about 20% of the oxygen and nutrients circulating in your blood.891 This is why strong, healthy cere- bral blood flow is so critical to your brain health and cognitive performance. Vinpocetine inhibits an enzyme called PDE1 (phosphodiesterase type 1) while reducing calcium levels in brain cells. When both of these are elevated, the smooth muscle in blood vessels contract, narrowing the diameter of blood vessels. And restricting blood flow to that area of the brain. You may be familiar with PDE5 inhibitors like Viagra® which work to dilate blood vessels and maintain healthy blood flow to your penis. Vinpocetine has a similar mechanism of action in your brain. In two separate clinical studies, chronic ischemic post-stroke patients were treated with either a single infusion, or daily infusion of Vinpocetine for 2 weeks. Vinpocetine increased cerebral glucose uptake and glucose metabolism in both the stroke region of the patient’s brains as well as the intact brain tissue. Patients in the 2-week long treatment also showed increased cerebral blood flow especially in the thalamus, basal ganglia and visual cortex regions of the brain.892 2. Vinpocetine is an anti-inflammatory. Vinpocetine prevents the upregu- lation of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) by TNFα (tumor necrosis factor alpha). This sounds a little complicated, but has serious implications in the develop- ment of Parkinson’s and Alzheimer’s Disease. Here’s how it works… NFκB is a protein complex that controls transcription of DNA, cytokine pro- duction (signaling protein) and cell survival. TNFα is a signaling protein (cytokine) involved in inflammation produced by neurons. Vinpocetine inhibits this action. Vinpocetine also reduces the TNFα-induced expression of the mRNA of pro-inflammatory molecules such as interleukin-1β, monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). 399 David Tomen Researchers have found that Vinpocetine prevents this inflammatory response at the cellular nucleus level. And this mechanism of action is independent of Vinpo- cetine’s action on PDE1. This is a very big deal because TNFα contributes to the neuronal cell death found in Parkinson’s Disease. And there is growing evidence that the accumula- tion of amyloid-β protein leads to an up-regulation of interleukins and TNFα that contributes to neurodegeneration leading to Alzheimer’s Disease. Scientists are now working on trying to determine if Vinpocetine can reduce inflammation in the brain. And help protect the brain from developing Parkin- son’s or Alzheimer’s.893

How things go bad Poor cerebral blood flow, inflammation and free radicals (oxidation) can damage your brain. And one of the ways this manifests is memory loss. Left unchecked, it can develop into serious neurodegenerative diseases like Alzheimer’s and Par- kinson’s Disease. ↓ Cognitive function declines ↓ Inflammation kills brain cells from the inside ↓ Free radicals destroy neurons and synapses ↑ Anxiety, depression and moodiness increase ↓ Concentration and memory declines Poor cerebral circulation causes a domino effect in the brain affecting many critical processes. Memory, cognition, and decision-making all suffer as a result.

Vinpocetine to the rescue Vinpocetine is one of the most researched nootropics on the planet. It was introduced to clinical practice in Hungary in 1978 for the treatment of cerebro- vascular (brain blood flow) disorders and related symptoms. Since then Vinpocetine has become a “reference compound” in pharma- cological research of cognitive deficits caused by hypoxia (oxygen deficiency), ischemia (inadequate blood supply) and research into cyclic nucleotides (cAMP and cGMP). Vinpocetine’s mechanism of action in the brain includes: • Increasing brain blood circulation and oxygen utilization • Increased tolerance for hypoxia and ischemia • Anticonvulsant activity • Inhibiting the PDE1 enzyme • Increasing the pliability of red blood cells • Inhibiting the aggregation of platelets (blood clots)894 Hundreds of studies in animals and humans have shown Vinpocetine can 400 HEAD FIRST repair and reverse the effects of damage caused by strokes. Vinpocetine can prevent the inflammation and damage by free radicals that can lead to neurode- generative diseases like Parkinson’s and Alzheimer’s. Vinpocetine can improve glucose and oxygen supply to critical brain cells through increased blood flow. Improving cognition, concentration, mental agil- ity, anxiety, depression and memory.

How does Vinpocetine feel? You should be able to feel the effects of Vinpocetine within an hour of taking it. Neurohackers report that Vinpocetine reduces brain fog and mental fatigue. Most experience improved focus, memory and even an improved sense of well-being. Vinpocetine’s effect on short-, working – and long-term memory can be profound. Remembering names, numbers and life events becomes easier. At work or in school, Vinpocetine can assist in learning and helping your brain commit it to memory. You should feel a significant difference in your abil- ity to focus at work. Like any nootropic, Vinpocetine is not going to turn back the clock 30 or 40 years. But it will help to keep your brain functioning more smoothly.

The Research

Vinpocetine Improves Memory 12 healthy female volunteers were treated with 40 mg Vinpocetine 3-times per day, or a placebo, for 2 days in this randomized double-blind crossover study. On day 3 of the study, and one hour following morning dosage of Vinpo- cetine, the women completed a battery of psychological tests. The study found that those who used Vinpocetine had a significant improvement in memory when compared to placebo.895

Vinpocetine Repairs Long-Term Potentiation If you have been having problems with long-term memory lately, this study is for you. Researchers produced a “medial septal lesion” on rats in the lab. The medial nuclei are an area of the brain composed of medium-size neurons. These neurons receive signals from different areas of your brain including your hippocampus. A lesion cuts off communication with an important memory-formation area of your brain. The effect of a lesion in this study was on hippocampus function and the long-term potentiation pathway. The scientists found that damage in this area of the brain negatively affects long-term potentiation. The rats were then given either physostigmine, pirace- tam, Vinpocetine or Hydergine one hour after the lesion. And once-a-day for 6 days after the operation. 401 David Tomen The study found that all of the drugs used in this study produced complete restoration of long-term potentiation. And shows that Vinpocetine is one of the most effective and least expensive ways to restore long-term potentiation and long-term memory formation.896

Vinpocetine Enhances Cognitive Performance A placebo-controlled, randomized double-blind trial was conducted at the University of Surrey with 203 dementia patients using Vinpocetine. Patients received either 10 mg of Vinpocetine 3-times per day, 20 mg of Vinpocetine 3-times per day or a placebo 3-times per day for 16 weeks. The patients were assessed on cognitive performance and measure of quality of life, including depression. Both Vinpocetine groups experienced a signifi- cantly improved cognitive performance score compared to placebo. The study concluded thatVinpocetine was useful in the management of patients with symptoms of dementia. And there was no statistical difference in cognitive scores with 10 mg or 20 mg of Vinpocetine.897

Dosage Notes Vinpocetine has a reputation among neurohackers and in clinical trials for safety at recommended doses. The recommended dosage for Vinpocetine is 10 mg taken 3-times per day with food. Vinpocetine seems to be more effective when taken with a meal or high quality fat like coconut or olive oil. You can safely dose up to 60 mg of Vinpocetine per day total. But clinical trials and user experience nearly always report that higher doses provide no added benefit.

Side Effects Vinpocetine is well-tolerated and safe for use by most people. But if you’re particularly sensitive to supplements and drugs, try a starting dose of 5 mg of Vinpocetine and see how your body reacts. If you’re dealing with low blood pressure you should avoid using Vinpocetine. This nootropic affects blood flow not only in your brain, but through your entire system. If you take Vinpocetine and feel light-headed or dizzy it could be a sign your blood pressure is low. Vinpocetine affects clotting factors in your blood. And may decrease red blood cell platelet aggregation. So if you are using blood thinners or high doses of aspirin you should avoid Vinpocetine. Stop taking Vinpocetine at least 2 weeks before surgery because of its effect on blood thinning and flow.

Available Forms Vinpocetine usually comes in 5, 10 or 20 mg tablets. 402 HEAD FIRST Vinpocetine is available as an OTC supplement in the United States and Canada. Many countries around the world require a prescription to purchase Vinpocetine. Some of the better pre-made nootropic stacks like Mind Lab Pro include Vinpocetine in their formula.

Nootropics Expert Recommendation

Vinpocetine 10 mg 3-times per day I recommend using Vinpocetine as a nootropic supplement. Your body does not make Vinpocetine on its own. So you must take it as a supplement. Vinpocetine easily crosses the blood-brain barrier and is available within an hour of taking it. Vinpocetine works more effectively if taken with food. Vinpocetine is especially helpful for those suffering from brain fog and memory loss. Vinpocetine helps increase cerebral blood flow bringing more oxygen and nutrients to brain cells. Vinpocetine is helpful for those dealing with stroke recovery. This nootropic helps restore blood flow to damaged areas of the brain affected by stroke. And helps prevent damage caused by the increase in free radicals typically released during stroke recovery. Vinpocetine is also helpful for those suffering from Alzheimer’s. It has been shown to boost blood flow to areas of the brain affected by amyloid-β protein ag- gregation. Vinpocetine helps tame inflammation associated with the disease. And studies are now underway to determine if Vinpocetine can prevent Alzheimer’s from taking hold in the first place. You can safely take up to 60 mg of Vinpocetine daily if needed. One dose first thing in the morning. One dose early afternoon. And the last dose in the evening. And for memory, Vinpocetine is great to stack with most of the racetams. Neurohackers report good success stacking Vinpocetine with Gotu Kola.

403 David Tomen

Vitamin B1 (Thiamine)

Vitamin B1 is known as an effective mosquito repellant, boosts motivation, improves focus, enhances memory, alleviates chronic pain, depression and anxiety

Vitamin B1 (Thiamine)is the first B Vitamin to be discovered by research- ers. “Thio-vitamine” refers to its sulfur-containing content. It’s called B1 because it was the first of the B complex vitamins to be identified. It was Kanehiro Takaki, surgeon general of the Japanese navy back in 1884 that figured something was amiss. Sailors were dying on his ships from a disease called Beriberi. And Takaki surmised it had something to do with sailors eating only white rice. It wasn’t until 1897 that Christiaan Eijkman, a military doctor in the Dutch East Indies figured out that the bran removed from white rice was causing prob- lems. Something was missing in the diet. In 1911, Polish biochemist Casimir Funk isolated what he called a “vita- mine” from rice bran. Dutch chemists went on to isolate and crystallize the active agent in 1926. US chemist Robert Williams determined the structure of Vitamin 898 B1. And synthesized it in 1936. In Japan, it was found that insufficient thiamine led to a central nervous system disorder called Beriberi. But supplementing with thiamine alone didn’t help because of its poor bioavailability. A lot of thiamine was needed to cure Beriberi symptoms.

So Japanese scientists created a derivative of Vitamin B1 called Sulbutiamine in an attempt to quell the health crisis within the Japanese population. Sulbutiamine is far more bioavailable than standard thiamine. It is fat-solu- ble (thiamine is water-soluble) which helps it more easily cross the blood-brain barrier. Advanced neurohackers add Sulbutiamine to their stack instead of standard

Vitamin B1 (thiamine) because it’s better absorbed and used by your brain than B1. Thiamine is a coenzyme used by your body to metabolize food for energy. And to maintain proper heart, nerve and brain function. Thiamine also helps digest and extract energy from food. It turns nutri- ents into adenosine triphosphate (ATP). ATP is the fuel used by your cell’s mitochondria. And thiamine helps convert carbohydrates into glucose. The energy your body uses for your brain and nervous system. One more thing about this miracle B-vitamin. Thiamine contributes to the development of myelin sheaths which wrap around neurons to protect them from damage. Your body does not produce thiamine on its own. So you must get it from 404 HEAD FIRST food including beef, brewer’s yeast, legumes (beans, lentils), milk, nuts, oats, oranges, pork, rice, seeds, wheat, whole-grain cereals, and yeast.

Thiamine vs. Sulbutiamine: What’s the Difference?

Sulbutiamine is a synthetic version of Vitamin B1 (Thiamine). It is two B1 molecules chemically bonded together. Thiamine is water-soluble and does not easily cross the blood-brain barrier. Sulbutiamine is a fat-soluble compound that easily crosses the blood-brain barrier. Sulbutiamine functions in the body just like thiamine. But because it’s more bioavailable it’s more effective than thiamine.

How does Vitamin B1 (Thiamine) work in the Brain?

Vitamin B1 (Thiamine) boosts brain health and function in several ways. But two in particular stand out. 1. Thiamine increases levels of thiamine pyrophosphate (TPP). TPP is directly involved in the citric acid (KREB) cycle in the brain. This cycle breaks fatty acids, amino acids and monosaccharides into smaller molecules that produce adenosine triphosphate (ATP) energy for your mito- chondria. And provide the building blocks of the molecules needed to produce brain cells. A deficiency of TPP can eventually show up as Wernicke encephalopathy and Korsakoff syndrome. In our society this syndrome is typically caused by chronic alcoholism. But it can also occur after obesity (bariatric) surgery, Crohn’s disease, anorexia, diabetes, and if you’re on kidney dialysis. Symptoms of Wernicke-Korsakoff syndrome include confusion, inability to form memories, loss of memories and muscle coordination, confabulation (making up stories) and vision changes. And can ultimately (and very rapidly) lead to coma and death.899 Less severe cases of thiamine deficiency include fatigue, weight loss, irritabil- ity and confusion. 2. Thiamine also contributes to the production of the enzyme PDH which is essential for making the neurotransmitter acetylcholine. And for the synthe- sis of myelin, which forms a sheath around the axons of neurons. Ensuring these neurons can conduct signals.900 The citric acid (KREB) cycle and enzyme α–KGDH play a role in maintain- ing optimal levels of the neurotransmitters glutamate, and gamma–aminobutyric acid (GABA). When thiamine levels decrease, the activity of these enzymes are reduced.901

How things go bad We depend on our diet for thiamine. Very little thiamine is stored in your body. And depletion can occur within 14 days. 405 David Tomen Thiamine deficiency can be caused by alcoholism, Alzheimer’s Disease, anemia, athletes who reduce food intake, cancer, clogged arteries, Crohn’s disease, diabe- tes, diarrhea, gastric bypass surgery and kidney disease. And even a poor diet. Several foods are also considered “anti-thiamine factors” (ATF) and contrib- ute to the risk of thiamine deficiency in otherwise healthy people. Certain plants contain ATF, which react with thiamine to form an oxidized, inactive product. Consuming large amounts of tea and coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, have been associated with thiamine depletion in humans.902 ATF include mycotoxins (molds) that break thiamine down in the blood. If you eat certain raw, fresh-water fish, raw shellfish and ferns you are at a greater risk of thiamine deficiency.903 Thiamine is also inactivated by cooking food. Thiamine is a cofactor of several enzymes including transketolase, pyruvate de- hydrogenase, and alpha-ketoglutarate dehydrogenase. Thiamine deficiency decreases cerebral glucose utilization which results in mitochondrial damage. Scientists have seen through the electron microscope; disintegrating mito- chondria, chromatin clumping, and swelling of degenerating neurons. Yikes! ↓ Low thiamine levels can slow creation of ATP ↓ Energy levels drop ↓ Low thiamine levels can cause problems with memory, learning, recall and perception ↓ Acetylcholine levels decline ↓ Blood pressure drops, reflexes decline, and calf muscles get tender ↓ Heart muscles enlarge ↓ Severe thiamine deficiency can result in psychosis Thiamine supplementation can help nearly every active adult, as well as a student looking to do better in school. By boosting acetylcholine, glutamate and GABA in the brain. Providing increased brain energy by fueling cell mitochon- dria with ATP. And building myelin sheaths that protect our neurons.

Vitamin B1 (Thiamine) to the rescue Thiamine occurs in your body as free thiamine and as various phosphorylated forms: thiamine monophosphate (TMP), thiamine triphosphate (TTP), and thia- mine pyrophosphate (TPP), which is also known as thiamine diphosphate. The synthesis of TPP from free thiamine requires magnesium, adenosine triphosphate (ATP), and the enzyme thiamine pyrophosphokinase. TPP is required for the metabolism of carbohydrates and branched-chain amino acids. Thiamine is directly involved in thecitric acid (KREB) cycle that provides adenosine triphosphate (ATP) energy for your mitochondria. Thiamine also plays a role in maintaining optimal levels of the neurotrans- mitters glutamate, and gamma–aminobutyric acid (GABA). And contributes to 406 HEAD FIRST the production of the enzyme pyruvate dehydrogenase (PDH) which is essential in making the neurotransmitter acetylcholine. Thiamine will boost cognition, memory and decision-making. And provides very effective anxiolytic (anti-depressant) qualities.

How does Vitamin B1 (Thiamine) feel? Thiamine is water-soluble, and has been shown to improveglutamate , and γ-aminobutyric acid (GABA) neurological transmissions.904 If you are perfectly healthy and don’t have a thiamine deficiency, you’ll likely not feel anything after supplementing with thiamine. But I’ve come across study after study, and reports on forums, where lab tests showed thiamine and thiamine pyrophosphate within range. And yet people were dealing with “mild thiamine deficiency”. The problem is “mild thiamine deficiency” can turn your world upside down. If you are hypothyroid or dealing with Hashimoto’s there is a very good chance you would benefit from thiamine supplementation. Same with diabetes, fibromyalgia and inflammatory bowel disease. Neurohackers report that supplementing with thiamine is an effective mos- quito repellent. Many report thiamine supplementation boosts attention, energy, and mo- tivation. A reduction in brain fog and increased mental clarity with less anxiety. Those dealing with fibromyalgia and nerve pain report a significant decrease in pain levels.

The Research

Most of the research conducted on Vitamin B1 (Thiamine) has been with people dealing with fatigue or pain associated with fibromyalgia, thyroid disease and other debilitating conditions. And most have very few participants. But the results in every trial I’ve reviewed are profound.

Vitamin B1 (Thiamine) Improves Symptoms of Fibromyalgia If you’ve ever had to deal with fibromyalgia, you are familiar with the hell of living with chronic pain, fatigue, insomnia and more. Some studies suggest that many of the symptoms of fibromyalgia could be re- lated to mild thiamine deficiency due to a dysfunction of the active transport of thiamine from blood to the mitochondria. One very small study conducted in Italy recruited 3 female patients with fibromyalgia. Levels of thiamine and thiamine pyrophosphate in the blood were measured. The patients then received from 600 mg to 1800 mg of thiamine per day. And the results were astounding: • Patient 1: 71.3% reduction in fatigue; 80% reduction in pain • Patient 2: 37% reduction in fatigue; 50% reduction in pain 407 David Tomen • Patient 3: 60.7% reduction in fatigue; 60% reduction in pain One patient reported improvement at 600 mg of thiamine. Doses for the other 2 patients were increased by 300 mg every 3 days. And experienced improvement in their symptoms at a dose of 1500 mg. None of the patients experienced side effects.905

Vitamin B1 (Thiamine) for Chronic Fatigue If you deal with chronic fatigue, Thiamine may be a better option than another cup of coffee. Or a stimulant. Researchers in Italy noted that previous studies on fatigue and related dis- orders like inflammatory bowel disease improved after therapy with high-dose thiamine. The team chose 3 stroke patients who also experienced fatigue. Severity of fatigue was assessed using the Fatigue Severity Scale. Note that lab tests showed free thiamine and thiamine pyrophosphate levels were within the healthy reference range in all the patients. High-dose thiamine therapy was started. And resulted in a significant de- crease in fatigue. The researchers concluded that post-stroke fatigue and related disorders could be a manifestation of mild thiamine deficiency. Likely due to dysfunc- tion of intracellular transport of thiamine, or other enzyme abnormalities.906

Vitamin B1 (Thiamine) and Hashimoto’s Thyroiditis Researchers in Italy hypothesized that the chronic fatigue accompanying in- flammatory and autoimmune diseases is a clinical manifestation of mild thiamine deficiency. Hashimoto’s thyroiditis is both an autoimmune disease and cause of hypo- thyroidism. In this study, 3 Hashimoto’s patients complaining of chronic fatigue were recruited. All 3 patients received 600 mg of thiamine per day, or 100 mg of thiamine intravenously (IV) once every 4 days. Thiamine treatment led to partial or complete remission of fatigue within a few hours or days.907

Dosage Notes

The recommended dosage of Vitamin B1 (Thiamine) according to the Ameri- can FDA is 1.2 mg per day. Pregnant and breastfeeding women is a whopping 1.4 mg per day. Many neurohackers would laugh at these recommendations. “Mild thiamine deficiency” affects a significant segment of the population in any country. Most clinical studies use thiamine doses from 300 up to 1800 mg per day. The bottom-line is thiamine dosing is completely up to you. No side effects are reported even at higher doses. 408 HEAD FIRST The Mayo Clinic recommends: • Menstrual cramps – 100 mg per day

• Epilepsy – 50 mg per day

• Alcoholic liver disease and withdrawal – 100 mg injections of thiamine hydrochloride

• Coma or hypothermia – 100 mg injections

• Thiamine deficiency due to nutrition – 100 mg injections

• Wernicke-Korsakoff Syndrome – 5 – 200 mg injections908 Some natural health clinics offer (expensive) thiamine therapy intravenously (IV) and doses are usually 25 – 50 mg per session.

Side Effects

Vitamin B1 (Thiamine) is non-toxic. So is considered well-tolerated and safe. Side effects are rare but very high doses can include stomach upset. If you are taking Digoxin, diuretics or Dilantin you should consult your doctor before supplementing with thiamine.

Available Forms

Thiamine hydrochloride (HCl): Most Vitamin B1 (Thiamine) supplements available from online retailers and vitamin shops come as Thiamine hydrochlo- ride (HCl). And come in 50 – 500 mg tablets. Benfotiamine (S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine. This fat-soluble form of thiamine is much more bioavail- able than HCI. Benfotiamine typically comes in 150 – 250 mg capsules. Dosage is up to 900 mg per day. Tetrahydrofurfuryl disulfide (TTFD) (Fursultiamine): TTFD is a disul- fide derivative of thiamine developed in Japan for treating Beriberi. It’s a synthetic form of thiamine naturally occurring in garlic.909 TTFD is a form of thiamine that is water-soluble, and much more difficult to find in vitamin shops. Brand names include Lipothiamine, Allithiamane, Adventan, Alinamin-F, Benlipoid, Bevitol Lipophil, Judolor. TTFD comes in 50 mg capsules. And the primary side effect is you smell like garlic after taking it.

Sulbutiamine: Sulbutiamine is my preferred form of Vitamin B1 (Thiamine) for cognitive enhancement. Sulbutiamine is sold in tablet, capsule and powder form. Tablets and capsules are usually 750 mg each. Sulbutiamine is a synthetic version of thiamine (two thiamine molecules bound together). It’s sold as a prescription medication in some countries under the brand names Arcalion, Enerion, Bisibuthiamine, and Youvitan. 409 David Tomen Nootropics Expert Recommendation

Vitamin B1 (thiamine) 50 – 100 mg per day

I recommend using Vitamin B1 (Thiamine) as a nootropic supplement. Your body does not make thiamine on its own. So to get its benefits you must get it from food, or take it as a supplement.

Vitamin B1 is especially helpful for those suffering from low energy levels, anxiety, depression, and chronic pain. Experience shows thiamine helps stop and reverse the symptoms associated with fatigue. Likely because this nootropic helps boost the activity of acetylcho- line, GABA and glutamate in the brain. Thiamine is also a very effectivemosquito repellant. I live in SE Florida where we’re currently under a Zika scare. But I do not experience problems with mos- quitoes. Likely because of adequate thiamine levels in my body. Personally, I’ve found Sulbutiamine to be much better for cognition than standard thiamine. And more effective (and safer) than any prescription anti- depressant I’ve ever tried. Sulbutiamine is also particularly helpful to students and executives who want to boost cognition, learning and memory.

Vitamin B1 can produce a noticeable increase in mental clarity. And give you a significant energy boost physically and mentally. You’ll feel more awake and alert. Without the side effects you’d get from stimulants like caffeine.

Vitamin B1 is a must have addition for any nootropic stack. If you are using any of the racetams like Piracetam and Aniracetam you may want to consider adding Sulbutiamine as well.

410 HEAD FIRST

Vitamin B3 (Niacin)

Vitamin B3 is known for increased alertness, clarity, focus, memory, enhanced mood and energy, is a potent antioxidant and free radical scavenger, lowers LDL-cholesterol, increases HDL-cholesterol and lowers triglycerides

Vitamin B3 (Niacin, nicotinic acid, 3-pyridine-carboxylic acid) is one of eight B-Vitamins. Niacin is a precursor to the coenzymes nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). NAD is needed to catabolize fats, carbohydrates, proteins and alcohol. And NAD is involved in cell signaling and DNA repair. Niacin is found in, and critical for the health of every cell in your body. NADH is the reduced form of NAD (Nicotinamide Adenine Dinucleotide), making it the “active” form which can donate electrons. NADH is the primary carrier of electrons from glucose and lactate for ad- enosine triphosphate (ATP) synthesis. ATP is the fuel source for mitochondria. The power supply in each of your brain cells. So you need niacin to produce NADH to transfer the energy from the food you eat into a type of energy your body can use. Not enough NADH leads to ATP depletion, which can eventually lead to cell death.910 Studies have shown that supplementing with niacin improves cognitive func- tion, enhances cellular energy, boosts cerebral circulation, increases endurance, switches ‘off’ aging genes, and extends life span. Niacin naturally occurs in foods like eggs, fish, meat, milk, peanuts, mush- rooms, green vegetables, and yeast. Your body also naturally synthesizes niacin from the amino acid tryptophan you get from food. This synthesis requires Vitamin B6, riboflavin and an enzyme containing . But only about 2% of dietary tryptophan is converted to niacin. Not nearly enough that your body requires which is why supplementation is needed. Niacin supplementation has been used to treat addiction, ADHD, arthritis, Alzheimer’s Disease, depression, memory loss and schizophrenia. And for detox- ing nearly every foreign substance that can find its way into your fat cells. The Russian-designed nootropic Picamilon is a combination of niacin and GABA. And is used to improve memory, concentration, focus, relieve anxiety and lower blood pressure. As a nootropic, niacin helps boost cognition, memory and neuroplasticity.

How does Niacin work in the brain? Niacin boosts brain health in several ways. But two in particular stand out. 1. Niacin increases cellular energy. Niacin is the precursor to NAD. NAD 411 David Tomen acts as an electron carrier, meaning it can accept and donate electrons to various enzymes involved in energy metabolism. NAD is transformed into NADH. NADH then donates its electron to the electron transport chain where a number of ATP molecules are formed. Using niacin as a supplement increases the available NAD molecules that can take part in energy metabolism. And increasing the amount of energy in each cell.911 By providing the means for ATP synthesis, niacin is involved in cognition, focus, concentration, memory, and processing speed. And niacin plays an im- portant role in mediating brain aging and tissue damage. Even decreasing the damage done by strokes. Researchers at Massachusetts General Hospital in Boston studied the neuro- protective effects of CoQ10 and niacin in mouse models of Parkinson’s Disease (PD). Impaired energy metabolism has been associated with some symptoms of PD. Researchers administered MPTP which is poison to neurons. It disrupts the energy metabolism of neurons that release dopamine. The affected dopamine cells are also unable to release as much glutamate which results in decreased dopamine in people with PD. The combination of CoQ10 and niacin protected against both mild and moderate dopamine depletion. The researchers concluded thatCoQ10 and niacin improve mitochondrial energy production.912 2. Niacin increases Brain Derived Neurotrophic Factor (BDNF). BDNF has been termed “Miracle-Gro for the brain”. Higher levels of BDNF have been associated with increased intelligence, mood, productivity and memory. Researchers at Henry Ford Hospital in Detroit tested the hypothesis that niacin could increase synaptic plasticity and axon growth in stroke patients. Male Wistar rats were purposely given a stroke and then treated with ex- tended release niacin (Niaspan) for 14 days. Niacin increased synaptic plasticity and axon growth as a result of restored BDNF.913 Another study published in the Journal of Clinical Endocrinology and Me- tabolism showed that niacin stimulated growth hormone.914

How things go bad Niacin deficiency is considered rare by government health agencies, particu- larly in the West. But even mild niacin deficiency can have a negative impact on your health and cognition. Mild niacin deficiency can be caused by digestive problems that decreases the amount of Vitamin B3 (niacin) or tryptophan that your body absorbs. If you are gluten intolerant you’re at a higher risk of being niacin deficient. 412 HEAD FIRST If you have Irritable Bowel Syndrome (IBS) or Crohn’s Disease you have an increased chance of niacin deficiency. Excessive alcohol consumption, birth control pills, anorexia, and those on a vegan diet can be deficient in niacin. ↓ Energy levels decline ↑ Fatigue increases ↓ Anxiety, hyperactivity, depression, headaches and hallucinations ↓ Metabolism declines ↑ Insomnia increases ↑ Irritability increases Some experts believe a lack of niacin and other B-Vitamins is at least partially responsible for the large increase in mental health disorders and violent crimes in recent decades.915 All of these niacin deficiency-related changes are contributing factors to the neurodegenerative diseases of aging, age-related cognitive decline, including Alzheimer’s and schizophrenia. But even if things haven’t degenerated to such a debilitating level, niacin can help.

Niacin to the rescue Research has shown that people with low niacin levels are far more vulner- able to addiction, depression, heart disease, schizophrenia, and other chronic conditions. Low niacin levels can happen at any age. Even at birth. Niacin can improve cholesterol levels. Supplementing with niacin has been shown to help those who are at increased risk for heart attacks, stroke and other forms of heart disease. Niacin can help reduce hardening of the arteries (atherosclerosis) and assist in avoiding heart disease. And niacin helps reduce inflammation. Niacin plays a role in diabetes treatment because it helps balance blood sugar levels. Niacin helps to reduce skin inflammation, flare ups, irritation, redness and for treating severe cases of acne. Niacin can help protect against Alzheimer’s and dementia.916 Niacin supple- mentation is also associated with decreased risk for age-related cognitive decline, memory loss, migraines, depression, motion sickness, insomnia and even alcohol dependence. Niacin is also used for treating and to help prevent schizophrenia. Studies show that niacin supplementation lowers the risk or severity of ADHD. Niacin is an effective treatment for erectile dysfunction (ED) because it acts as a vasodilator that helps improve blood flow to the penis. 413 David Tomen How does Niacin feel? Niacin supplementation can help relieve depression and anxiety. Circulation should improve and you’ll feel like you have more energy. People taking statins to control cholesterol report severe side effects. But when adding niacin to their supplement stack, most experience a reduction in blood pressure. And some have stopped taking statins as a result. Those dealing with Obsessive Compulsive Disorder (OCD) report combining niacin with St. John’s wort reduced OCD symptoms. And was better than using the SSRI Prozac®, or the benzodiazepine Ativan® (lorazepam). Taken before bedtime some neurohackers report a reduction in insomnia. Lower back pain and hip pain may be reduced with niacin supplementation. Niacin can help reduce severe acne and other skin inflammation problems.

The Research

Niacin helps Reduce Bad Cholesterol Therapeutic doses of niacin have been shown to reduce serum cholesterol. Niacin significantly increases HDL-cholesterol (good cholesterol), decreases LPL- cholesterol (bad cholesterol) and triglycerides. Changes in blood lipid profile considered to be protective of your heart. Low levels of HDL-cholesterol are one of the major risk factors for coronary heart disease. And an increase in HDL levels is associated with a reduction of that risk. The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of niacin in 8,241 men aged 30 to 64 years old. All men had experienced some type of heart problem. Compared to placebo, patients who took 3 grams of niacin daily experienced an average 10% reduction in total blood cholesterol, a 26% decrease in triglycer- ides, a 27% decrease in recurrent heart attacks, and a 26% decrease in stroke.917

Niacin for Detox If you are dealing with chronic health issues, chances are good you could benefit from a detoxification program. Even if you’re feeling perfectly ‘healthy’ you could likely use a good detox. Simply living in our modern society exposes us to thousands of chemicals that have the potential to get into our bodies from the food we eat, air we breathe, water we drink and things we touch. One study done in Portland, Oregon investigated the effects of a 7-day detox program on well-being in 25 disease-free, healthy participants. The 7-day detox produced a statistically significant (47%) reduction in the Metabolic Screening Questionnaire scores. And a 23% increase in liver detox capacity.918 Even healthy people feel better after detox. 414 HEAD FIRST In 1977, L. Ron Hubbard developed his “Sweat Program” to facilitate detox. The program includes niacin, sauna and a supplement regimen to restore critical vitamins and minerals to the newly detoxed body. This niacin detox program has been used to treat Gulf War Syndrome, the fire fighters and first responders to the 9/11 attacks in New York919, and is used by hundreds of naturopaths. Niacin affects adipocytes which causes an increase in free fatty acid (FFA) release from adipose tissue (body fat). Release of free fatty acids releases fat-stored toxins for excretion from the body. Niacin also causes prostaglandin D2 release which dilates small blood vessels in the skin. The same reaction responsible for the “niacin flush”. This dilation increases the movement of xenobiotics (foreign chemicals) for excretion through sweating (which is where the sauna comes into the detox program). Niacin is also a precursor to NADH which regenerates the master antioxidant glutathione. Niacin reduces inflammation by decreasing reactive oxygen species and inflammatory cytokines.

Niacin helps treat Depression Niacin is especially helpful if you are taking antidepressants. Drugs to treat depression have an anti-inflammatory effect, including inhibition of the rate- limiting enzyme of the kynurenine pathway. This metabolic pathway is involved in the production of NAD and NADH. The inhibition of this pathway increases serotonin as more tryptophan be- comes available for serotonin synthesis. More serotonin helps decrease depression. But this also leaves less tryptophan available for niacin synthesis. Which causes depression and basically cancels out the benefits of using antidepressants.920 So if you’re on SSRI’s you may want to add niacin to your stack.

Niacin for the Treatment of Erectile Dysfunction Dyslipidemia is the name of the condition involving high LDL-cholesterol (bad), high triglycerides (bad), and low HDL-cholesterol (bad). Dyslipidemia is closely related to erectile dysfunction (ED). Researchers in Hong Kong ran a placebo-controlled trial with 160 male patients with ED and dyslipidemia. Half the men with ED received 1500 mg of niacin, and the other half received a placebo daily for 12 weeks. The main outcome of the study was a significant improvement in erectile function. And the researchers concluded that “niacin alone can improve erectile function in men suffering from moderate to severe ED”.921

Dosage Notes Niacin is naturally produced in your body from tryptophan. And you get niacin from eating certain foods including beef, chicken, tuna, sunflower seeds, 415 David Tomen salmon, green peas, turkey, and mushrooms. So niacin is considered non-toxic and safe. Note that higher doses of niacin are usually divided into evenly split doses 2 – 4 times per day. So 2 gram of niacin daily would be 500 mg 4-times per day. • Prevention of heart disease: niacin 4 grams per day • Lowering bad cholesterol and boosting good cholesterol: niacin 4 grams per day • To slow the progression of newly diagnosed type 1 diabetes: Niacinamide 25 mg/kg of body weight daily

• Preventing or treating Vitamin B3 (niacin) deficiency: 50 – 100 mg per day • To treat pellagra (severe niacin deficiency): 300 – 500 mg daily • For treating osteoarthritis: Niacinamide 3 grams per day • For reduced risk of cataracts: 44 mg of niacin per day • Preventing Alzheimer’s Disease: 100 mg per day. Note that there is no reli- able evidence that niacin can prevent Alzheimer’s although there is plenty of evidence that Alzheimer’s patients consistently show low niacin levels. • Treating erectile dysfunction (ED): 500 mg 3-times per day • Treating schizophrenia: 3 grams of niacin and 3 grams of ascorbic acid (Vitamin C) daily922

Side Effects Standard niacin (nicotinic acid) is naturally produced in your body. And considered non-toxic. Niacin can lower blood pressure so if you are on blood pressure lowering medication be cautious about supplementing with niacin. Niacin may decrease the effectiveness of diabetes medication because long- term use of niacin can increase blood sugar. So you may need to increase your diabetes meds. Statins are notorious for causing muscle wasting. And when combined with niacin it may increase this muscle wasting problem. You may want to cut back on your statins as you increase your niacin dose. Many stop taking statins altogether when using niacin. Niacin (nicotinic acid) and sustained-release niacin causes “flushing” in many people. Here we address how to reduce or eliminate the side effect of niacin flushing.

Preventing Niacin Flushing Regular immediate-release niacin (nicotinic acid) causes “flushing” in many people. And they avoid supplementing with niacin as a result. 416 HEAD FIRST Standard niacin flushing results from activation of the niacin receptor G protein-coupled receptor 109A (GPR109A) in skin Langerhans cells. This leads to the production of prostaglandins, including prostaglandin D2 (PGD2) and prosta- glandin E2 (PGE2), which act on receptors in the capillaries (small blood vessels in your skin).923 This flushing sensation comes from blood vessel dilation and manifests itself as redness, warmth of the skin and tingling or itching. It happens rapidly and lasts for about 1 hour. This flushing sensation is NOT an allergic reaction. And only feels uncom- fortable. Here are some strategies to avoid niacin flushing. First, “slow-release” niacin may prevent flushing. But is NOT the answer because it will not provide the LDL-cholesterol (bad) lowering benefits. And can be toxic to your liver when used long-term.924 Inositol hexanicotinate is commonly referred to as no-flush niacin or flush- free niacin and is preferred by many neurohackers. Even though I’ve seen a couple of clinical studies claiming this version of niacin has no effect on lipid profiles when it comes to cholesterol925, user reviews consistently report the opposite. They do not experience flushing with Inositol hexanicotinate even at high doses, and their cholesterol and triglyceride levels all benefited and came within a healthy range. A newer version of “extended-release” niacin called Niaspan® does not pro- duce the flushing effect. And has been shown to have the same effects on good cholesterol and triglycerides as instant-release niacin.926 Niaspan® is prescription- only and is now available as a prescription generic at lower cost. One effective way to reduce flushing with instant-release niacin and extended- release niacin is to take a 325 mg aspirin tablet 30 minutes prior to taking your niacin.927 You can also try splitting your dose of niacin into smaller doses taken throughout the day. Flushing will be reduced if not completely eliminated. And long-term niacin users note that flushing goes away after about a week of long- term niacin use.

Available Forms

Vitamin B3 (Niacin) is not stored in your body and must be ingested daily from food or as a supplement. Niacin as a supplement comes in several forms: • Niacin (nicotinic acid, (pyridine-3-carboxylic acid) or ‘free-form’ nico- tinic acid even at large doses of 3 or 4 grams are nearly completely absorbed by adults. This version causes ‘flushing’ above 50 mg which can be avoided. Refer to the “Side Effect” section of this article on niacin. Doses above 1500 mg per day can be toxic to your liver. 417 David Tomen • Niacinamide (nicotinic acid amide) has a similar profile to that of free form niacin. But unlike free-form niacin does not produce a flushing effect. Doses above 3 grams per day can be toxic to your liver. • Slow-release niacin is nicotinic acid using an ion exchange or wax matrix developed to slowly release niacin to avoid the flushing effect. Liver toxicity has been shown in doses above 500 mg of extended-release niacin. • Inositol hexanicotinate (IH) is an “extended-release niacin” sold as “Flush Free Niacin” and has 6 molecules of niacin covalently bonded to one molecule of inositol. The IH version of niacin does not produce a flush- ing effect. Studies show that an average of 70% of the dose you take gets absorbed by your body. Studies show that the benefits to lowering bad cholesterol with the IH form of niacin are not nearly as effective as free-from niacin.928 But user reviews are the opposite of these clinical findings. No toxicity is associated with high doses of IH. Slo-Niacin®, is sold over the counter. Niaspan® is an extended-release niacin formula sold as a prescription drug. Note: Both slow-release niacin and extended-release niacin (inositol hexanicotinate) are marketed and labeled as “Flush-Free Niacin”. But they are not the same and you should avoid slow-release niacin. Slow-release niacin causes liver toxicity at relatively low doses and does not provide the lipid balancing effects like free-form niacin and extended-release niacin.

Nootropics Expert Recommendation

Vitamin B3 (Niacin) 1000 mg 3-times per pay I recommend using Niacin as a nootropic supplement. Your body does make some Niacin on its own. And you can get it by eating meat, poultry and fish. But studies have shown we don’t get an adequate supply of Niacin from food sources. Niacin is particularly helpful for vegetarians because very little Niacin is available from vegetables. Niacin is especially helpful for those suffering Chronic Fatigue Syndrome and ADHD. I suggest starting with a dose of 500 mg daily. And Niacin is a great compli- ment to a stack including any nootropic. Do your best to use either free-form niacin if you can tolerate the flush. Or even better, use an extended-release ver- sion of niacin that has no flush and no associated toxicity. You need to provide your brain mitochondria with the ATP fuel it is de- manding. Or neurons start to break down from the inside. Signs that you’re lacking adequate Niacin is brain fog, slow thinking, fatigue and low endurance. 418 HEAD FIRST Some clinics in the USA and other countries are using Niacin therapy as a treatment for addiction, anxiety, depression, chronic stress and even schizophrenia. I recommend starting with a low dose of Niacin until you build a tolerance to avoid the niacin “flush”. Increase your dose every few days until you get to the dose you find gives you the most cognitive benefit.

419 David Tomen

Vitamin B5 (Pantothenic Acid)

Vitamin B5 is known to enhance alertness, cognition, energy, hearing, vision, elevate mood, lower anxiety and normalize healthy cholesterol levels

Vitamin B5 (Pantothenic Acid) is one of 8 water-soluble B-vitamins that are absolutely vital to the highly optimized brain. And is essential to all forms of life.

Vitamin B5 is found in every cell in your body including your brain. The name Pantothenic is derived from the Greek word pantothen, meaning “from everywhere”. Reflecting the idea that small amounts ofpantothenic acid can be found in nearly every food. Foods rich in pantothenic acid include animal organs (liver and kidney), fish, shellfish, milk products, eggs, avocados, legumes, mushrooms, and sweet potatoes. Avocados contain the highest amount of pantothenic acid among com- monly consumed foods, with one avocado containing about 2 mg. Pantothenic Acid is a precursor in the biosynthesis of Coenzyme-A (CoA). CoA is an essential enzyme in a variety of chemical reactions that sustain life. CoA as Acetyl-CoA is required for generating energy from fat, carbohydrates and proteins. This energy in the form of glucose is the fuel source for each cell. Acetyl-CoA is also involved in the citric acid cycle (KREBs), in the synthesis of essential fats, cholesterol, steroid hormones, vitamins A and D, and the neu- rotransmitters acetylcholine (ACh) and serotonin. Coenzyme A derivatives are also required for the synthesis of melatonin which controls your circadian rhythm and sleep/awake cycle. And for the me- tabolism of drugs and toxins in your liver.

Vitamin B5 is essential for the synthesis of acetylcholine (ACh). Adequate levels of ACh can boost focus, memory, learning, and reduce brain fog.

Vitamin B5 is critical for converting nutrients from food into energy, bal- ancing blood sugar, reducing LDL-(bad) cholesterol, lowering blood pressure, preventing nerve damage and pain, and preventing heart failure.

Vitamin B5 plays a part in the synthesis and metabolism of proteins, carbohy- drates and fats. Turning them into energy that your brain uses to fire neurotrans- mitters in your brain.

Vitamin B5 is required for the manufacture of red blood cells, and the stress and sex hormones produced in your adrenal glands.

As a nootropic, Vitamin B5 is crucial for converting the choline in your nootropic stack into acetylcholine (ACh). Without adequate levels of B5 you will not experience the benefits of using precursors to ACh like Alpha GPC and CDP-Choline.

How does Vitamin B5 (Pantothenic Acid) work in the Brain?

Vitamin B5 (Pantothenic Acid) boosts brain health and function in several ways. But two in particular stand out. 420 HEAD FIRST 1. Vitamin B5 increases energy. Pantothenic acid is an essential coenzyme in-

volved in mitochondrial aerobic respiration. Vitamin B5’s role in the citric acid cycle (KREBs) and electron transport chain helps convert nutrients from food into energy which is used to make adenosine triphosphate (ATP). ATP is the fuel source within each of your cells. Pantothenic acid takes part in the synthesis of Acetyl-CoA which is at the heart of the KREBs cycle. Acetyl-CoA in your brain is also involved in the synthesis of cholesterol, amino acids, phospholipids, and fatty acids. CoA is also involved in the synthesis of the neurotransmitters acetylcholine and serotonin, and steroid hormones. User reviews of those supplementing with pantothenic acid claim to having more energy. This boost in energy comes from this long series of events stemming from pantothenic acid.929

2. Vitamin B5 helps reduces stress. Pantothenic acid is often referred to as the “anti-stress vitamin”. Your adrenal glands use CoA (made partly from pan- tothenic acid) along with cholesterol and Vitamin C to manufacture cortisol and epinephrine. When cortisol levels are low, your ability to cope and respond to stress is compromised. And if your cortisol levels are abnormally high (a common prob- lem), your body’s reserve of pantethine (the active form of pantothenic acid) needs to be replenished in order to sustain good adrenal function.930

Vitamin B5 has a reputation for reducing stress, anxiety and depression. How things go bad Chronic stress, anxiety and lower acetylcholine levels can damage your brain. This damage can manifest in several ways including memory loss, brain fog, anxiety, depression, and even neurodegenerative diseases like Alzheimer’s and Parkinson’s. ↓ Acetylcholine synthesis declines ↓ Concentration, memory, learning, and recall decline ↑ LDL-cholesterol (bad) and triglycerides increase ↓ HDL-cholesterol (good) levels decline ↓ Wound healing takes longer ↓ Energy levels decline ↑ Numbness, tingling, burning sensations, shooting pain in the feet increase

Vitamin B5 supplementation can help increase acetylcholine, epinephrine and serotonin levels in your brain. And help modulate cortisol levels produced in your adrenal glands. Helping you to cope with stress and lessen depression.

Vitamin B5 (Pantothenic Acid) to the rescue

When you take Vitamin B5 as a supplement, it is converted to pantethine. Pantethine is a more stable disulfide (double bonded) form of pantothenic acid. 421 David Tomen It is this active form of pantothenic acid that is converted into the enzyme Coenzyme-A (CoA). CoA plays a critical role in the metabolism and breakdown of the three essential micronutrients: proteins, carbohydrates and fats. CoA is a cofactor in more than 70 enzymatic pathways including: • Amino acid catabolism • Acetylcholine synthesis • Carbohydrate metabolism • Fatty acid oxidation • Heme synthesis • Pyruvate degradation • Phase II detox acetylation CoA is also involved in the initial steps of cholesterol synthesis and all the downstream metabolites of cholesterol including steroid, and bile acids. CoA helps break down the carbon skeleton of amino acids which are metabo- lized to pyruvate and enter the KREBs cycle. This cycle is crucial to ATP synthesis which fuels your mitochondria. CoA directs acetyl groups to form ubiquinone (CoQ10), squalene and cholesterol. You also need CoA for the transport of long chain fatty acids into mitochondria where fats are converted into energy. The bottom-line is CoA is behind the production of hemoglobin, bile, sex and adrenal hormones (steroids), cholesterol and the neurotransmitters acetyl- choline and serotonin in your brain.

How does Vitamin B5 (Pantothenic Acid) feel?

Vitamin B5 is water-soluble, and has been shown to improve mood, energy and cognition. Neurohackers who supplement with pantothenic acid report being wonder- fully optimistic, energetic and mentally sharp.

People report Vitamin B5 helps them focus better, they feel a profound in- crease in energy and concentration improves. Many people dealing with acne find their skin looks great. Acne is cleared within a few days to a few weeks of supplementing with pantothenic acid.

Men and women find that supplementing with Vitamin B5 helps prevent hair loss. And if taken early enough may even help avoid hair turning prema- turely gray. Some neurohackers report that pantothenic acid helps improve vision and hearing. 422 HEAD FIRST The Research

Vitamin B5 (Pantothenic Acid) reduces Acne 100 people of Chinese descent (45 males and 55 females) aged 10 – 30 years with severe acne were treated with high-dose pantothenic acid. A total of 10 grams per day were given in 4 divided doses. Participants were also asked to apply a cream to affected areas 4 – 6 times per day. The cream contained 20% pantothenic acid. Their face became noticeably less oily within 3 days of starting therapy. Within 2 weeks, facial pore size became smaller and acne lesions began to heal. And the rate of new acne eruptions had slowed. By 8 weeks, acne was usually controlled. Most acne lesions were gone and new eruptions occurred only occasionally. The participants with severe acne required 6 months of treatment to control acne. The author of the study noted that in some of the severe cases, daily doses of 15 – 20 grams of pantothenic acid would produce a faster response. 35 patients were monitored for 18 months; the maintenance dose needed to control acne ranged from 1 – 5 grams per day of pantothenic acid.931

Vitamin B5 (Pantethine) to decrease LDL-Cholesterol User reviews consistently show success with lowering LDL-cholesterol and triglycerides, and raising HDL-cholesterol by supplementing with Vitamin B5 (Pantethine). The National University of Health Sciences in Illinois conducted an evalua- tion of clinical trials from 1966 to 2002 for studies using the pantethine version of Vitamin B5 to improve cholesterol. 28 clinical trials with a pooled population of 646 ‘hyperlipidemic’ subjects were evaluated. Mean age of participants were 52.8 years. Average study length was 12.7 weeks with an average dosage of 900 mg per day of pantethine. The mean decrease of LDL-cholesterol (bad cholesterol) was 10 – 20%. The mean decrease of triglycerides was 14 – 33%. And the mean increase of HDL- cholesterol (good cholesterol) was 4 – 11%. The researchers concluded that “pantothenic acid was an effective therapeutic option in treating patient populations with total serum cholesterol levels greater than 200 mg/dL, and/or serum triacylglycerol levels greater than 150 mg/dL.” The team noted that the full benefit of pantethine may not be attained until at least 4 months from beginning supplementation. And that pantethine is a well-tolerated therapeutic agent that deserves much more attention than it has recently received.932

Vitamin B5 (Pantothenic Acid) increases Longevity

Vitamin B5 is believed to extend life span. But research in humans for obvi- 423 David Tomen ous reasons has been difficult. Humans live longer than most mammals. And tracking human subjects for life would be prohibitively expensive. So animal research is the next best thing. A team in Austin gave 33 young male and female mice 300 μg of calcium pantothenate daily in drinking water. Forty-one control mice did not receive the vitamin supplement. The mean life span for mice who received calcium pantothenate was 653.1 days. And for the control mice life span was 549.8 days. The mice using Vitamin 933 B5 lived 19% longer. has long been used as a longevity supplement. And some of the science backs this up. Pantothenic acid is the primary anti-aging factor isolated from royal jelly. The combination of pyridoxine, biotin and sodium yeast nucleate extended the lifespan of the common fruit fly. And the addition of pantothenic acid further increased life span.934

Seems that supplementing with pantothenic acid (Vitamin B5) will help you live longer.

Dosage Notes If you are using an acetylcholine (ACh) precursor like Alpha GPC or CDP

Choline in your nootropic stack, you should be using Vitamin B5. Because B5 is needed to make Coenzyme-A (CoA). CoA and choline are needed to synthesize acetylcholine.

The recommended dosage of Vitamin B5 (Pantothenic Acid) is a one-to-two ratio with a choline supplement. For example, 250 mg of Vitamin B5 with 500 mg of CDP Choline.

If you don’t get enough Vitamin B5, you may not notice significant improve- ments when supplementing with your preferred choline source. If you’ve added choline to your racetam stack and still get a “choline headache” it’s likely because you don’t have adequate Vitamin B5 in your system. Pantothenic Acid or Pantethine is generally well tolerated in doses up to 1,200 mg/day. Some neurohackers report doses above 1,000 mg can induce gastrointes- tinal side effects like nausea or heartburn. Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for additional pantothenic acid. Use of Pantothenic Acid in combination with cholesterol-lowering drugs

(statins) or with Vitamin B3 (niacin or nicotinic acid) may produce additive ef- fects on blood lipids. So be careful because you could lower LDL-cholesterol to unhealthy levels.

Side Effects

Vitamin B5 (Pantothenic Acid) is non-toxic. So is considered well-tolerated and safe. 424 HEAD FIRST Side effects are rare but very high doses can include stomach upset, nausea or diarrhea. If you are taking the antibiotic tetracycline, you should avoid using extra

Vitamin B5 because it could negate the effects of tetracycline. If you are on cholinesterase inhibitors used for treating Alzheimer’s, you should not be using Vitamin B5. Available Forms

When choosing a Vitamin B5 supplement, your basic choice is between Pantethine or Pantothenic Acid. Pantethine is by far the more active choice when it comes to producing CoA. And this is backed up by many clinical trials. Researchers have pointed out that Pantethine creates twice as much CoA compared to Pantothenic Acid. However, Pantothenic acid does have its benefits. It enhances adrenal func- tion and modulates inflammation. If you can, find a supplement that combines both.

Vitamin B5 supplement labels will show pantothenic acid as “Calcium” or “sodium D-pantothenate” which is used for treating stress, migraines and allergies. Pantethine is mainly recommended for lowering blood cholesterol levels. And pantethine is better for stacking with a choline supplement because it creates more CoA than other forms of pantothenic acid.

Pantothenol (panthenol) is a stable alcohol analog of Vitamin B5 (panto- thenic acid), which can be rapidly converted to pantothenic acid by humans.

Nootropics Expert Recommendation

Vitamin B5 (Pantothenic Acid) up to 1,000 mg per day

I recommend using Vitamin B5 as a nootropic supplement.

Your body does not make Vitamin B5 on its own. So to get its benefits you must get it from food, or take it as a supplement.

Vitamin B5 is especially helpful for those suffering from low energy levels, anxiety, depression, and chronic pain.

Experience shows Vitamin B5 helps stop and reverse the symptoms associated with high cholesterol levels. B5 will lower ‘bad’ LDL-cholesterol and triglycerides as well as raise ‘good’ HDL-cholesterol.

Vitamin B5 is also particularly helpful to students and executives who want to boost cognition, learning and memory. Because it raises acetylcholine levels in your brain.

Vitamin B5 can produce a noticeable increase in mental clarity. And give you a significant energy boost physically and mentally. You’ll feel more awake and alert. Without the side effects you’d get from stimulants like caffeine. 425 David Tomen

Vitamin B5 is a must have addition for any nootropic stack. If you are using any of the racetams like Piracetam and Aniracetam and are using a choline supplement to raise acetylcholine levels, you absolutely need extra pantothenic acid.

The recommended dosage of Vitamin B5 (Pantothenic Acid) is a one-to-two ratio with a choline supplement. For example, 250 mg of Vitamin B5 with 500 mg of CDP Choline.

426 HEAD FIRST

Vitamin B6 (Pyridoxine)

Vitamin B6 is known to enhance alertness, cognition, energy, elevate mood, lower anxiety and normalize homocysteine levels

Vitamin B6 (Pyridoxine, Pyridoxal, Pyridoxamine) is one of 8 water- soluble B-vitamins that are absolutely vital to the highly optimized brain. And is essential to all forms of life.

Vitamin B6 is found in every cell in your body and brain. Vitamin B6 is a necessary cofactor in the folate cycle. Vitamin B6 a required coenzyme for the synthesis of dopamine, epinephrine, GABA, melatonin, norepinephrine, and serotonin.935

As a nootropic, Vitamin B6 is crucial for the synthesis of these neurotransmit- ters. Even mild deficiency results in down-regulation of GABA and serotonin synthesis. Leading to poor sleep, behavior, cardiovascular function, and the loss of hypothalamus-pituitary control of hormone secretion.936

Vitamin B6 was first isolated in the 1930’s. The “6” in Vitamin6 B refers to six common forms, namely pyridoxal, pyridoxine (pyridoxol), pyridoxamine, and their phosphorylated forms. Pyridoxal phosphate (pyridoxal 5’-phosphate, P-5-P, PLP), the active form of Vitamin B6 is said to be the most versatile organic cofactor in biology. More than 140 distinct enzyme activities in your body and brain depend on PLP.937 The biochemical reactions in your body by PLP-dependent enzymes include the making of hemoglobin, amino acid synthesis and fatty acid metabolism. PLP also functions as a coenzyme that catalyzes the release of glucose from stored glycogen. Turning it into the type of energy your brain cells can use for fuel. Pyridoxal phosphate helps control inflammation in your brain. Low levels of PLP are associated with severe inflammation in the brain.938 Leading to neuro- degenerative diseases like Alzheimer’s and Parkinson’s. And contributes to heart disease, arthritis, inflammatory bowel disease and diabetes.

Vitamin B6 has a direct effect on your immune system, gene transcription and expression. And is involved in glucose regulation.

Vitamin B6 protects your blood-brain barrier by regulating homocysteine levels. Excess homocysteine can damage blood vessel linings and neurons, result- ing in cognitive decline. B6 also helps form myelin, the fatty sheath that sur- rounds and protects neurons.

Foods rich in Vitamin B6 include bananas, beef, chickpeas, pistachios, pork, potatoes, and turkey. Even mild Vitamin B6 deficiency can deplete neurotransmitters which leads 427 David Tomen to cognitive decline. Resulting in brain fog, anxiety, depression and overall poor mental performance.

How does Vitamin B6 (Pyridoxine) work in the Brain?

Vitamin B6 (Pyridoxine) boosts brain health and function in several ways. But two in particular stand out.

1. Vitamin B6 is a cofactor in neurotransmitter synthesis. Vitamin B6 and its role in amino acid metabolism makes it a critical component for the synthe- sis of all major neurotransmitters including dopamine, GABA, melatonin, norepinephrine and serotonin.

The synthesis of these neurotransmitters is entirely dependent on 6B levels in your brain. Even mild deficiency results in less GABA and serotonin synthesis. Resulting in poor sleep patterns, irritability, anxiety, depression, panic attacks and stress. Low dopamine and norepinephrine levels due to lack of Vitamin B6 leads to depression and loss of memory. B-Vitamins play a crucial role in optimized cognition. And should be part of every nootropic stack. Unfortunately, there is very little talk in nootropic circles of these vitamins. A review of vitamin intakes in Germany, the UK, the Netherlands and the USA was conducted to compare vitamin intake to national recommendations. And the study found intake was below recommendations of even the most criti- cal of vitamins. Including B-Vitamins. The authors of the study noted that this gap exists in vitamin intake and na- tional recommendations for a significant portion of the population. Even though diverse foods were available.939

2. Vitamin B6 helps reduce inflammation. B6 along with Vitamin B12 and folate help control homocysteine. High levels of homocysteine have been implicated in inflammation leading to damage of blood vessels. Causing heart and neurodegenerative disease. But homocysteine is not the bad guy when it’s in balance. We need this amino acid for the synthesis of cysteine which is a precursor to the master anti- oxidant glutathione. It’s when homocysteine gets out of control that causes problems in our brain and our cardiovascular system. One of the issues with aging is brain shrinkage. Gray matter shrinkage in key areas of the brain have been identified in Alzheimer’s Disease. Professor David Smith at Oxford University in England conducted a study with 156 elderly patients (age 70+) who were suffering mild memory loss and 428 HEAD FIRST higher than average levels of homocysteine. High levels of homocysteine are typi- cally the result of deficiencies in Vitamins B6, B12 and folic acid.

For 2 years, the elderly patients received 20 mg of Vitamin B6, 0.5 mg of

Vitamin B12 and 0.8 mg of folic acid (folate). The findings of this study were dramatic. Those who took only placebo experienced brain atrophy of 5.6% over those 2 years. Brain shrinkage in those who took the B-Vitamins had only 0.6% brain shrinkage. This study showed a 7-fold difference in gray matter shrinkage in just 2 years.

Vitamin B6 along with B12 and folic acid helped protect brain density. And specifically in the areas of the brain vulnerable to Alzheimer’s.940

How things go bad

Vitamin B6 deficiency is a lot more common than you’d expect in our modern society. B6 from diet alone, especially for vegetarians and the aged is not adequate to supply what our body and brain needs. ↓ Concentration, memory, learning, and recall decline ↑ Anxiety, confusion, irritability, and depression increase ↑ Homocysteine and inflammation increases ↓ Energy levels decline

Vitamin B6 is critical for nerve function. And a deficiency can result in psychiatric disorders, seizures, migraines, chronic pain and mood disorders like depression.

Vitamin B6 (Pyridoxine) to the rescue

Vitamin B6 is involved in the regulation of cognition function and mood.

B6 is a cofactor in the neurotransmitters directly related to alertness, anxiety, attention, concentration, memory and mood.941 When you add Phenylalanine to your stack to boost the neurotransmitters dopamine, epinephrine, norepinephrine and melatonin, it will not work without

Vitamin B6. B6 is a critical cofactor in the synthesis of these neurotransmitters. The same holds true for any nootropic you use with the intention of boost- ing any of the major neurotransmitters in your brain. Vitamin B6 is absolutely required if you want them to do their job.

You need Vitamin B6 to help control inflammation in your brain. B6 suppresses the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).942

Vitamin B6 is essential for controlling elevated homocysteine levels which can damage blood vessels crucial for optimal cerebral circulation. A 2008 review of research in the previous 10 years covering a total of 77 studies and 34,000 subjects demonstrated the relationship between cognitive deficits and 943 dementia and the status of folate, or vitamins B12, or B6 and homocysteine levels.

Vitamin B6 is a coenzyme involved in the synthesis of Heme, an iron-con- 429 David Tomen taining component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout your body and brain.

Vitamin B6 concentrations in your brain are about 100-times higher than levels in your blood. B6 is critical to the highly optimized brain.

How does Vitamin B6 (Pyridoxine) feel?

Vitamin B6 is water-soluble, and has been shown to improve energy and mood.

Both men and women report a boost in libido when supplementing with B6.

Women report that Vitamin B6 helps control mood swings resulting from PMS.

Neurohackers report that Vitamin B6 helps sleep and creates vivid dreams. Many prefer it over melatonin for sleep. Those suffering with carpal tunnel syndrome have consistently found relief in symptoms by using Vitamin B6. Many find B6 useful for tendonitis and other joint pain.

Some report that supplementing with Vitamin B6 helps prevent sunburn.

And a few have found relief from tinnitus by using B6.

Those dealing with ADHD have found that using Vitamin B6 has helped reduce the reliance on ADHD meds. Likely because B6 is a cofactor in the syn- thesis of dopamine and norepinephrine.

The Research

Vitamin B6 (Pyridoxine) promotes vivid dreams

Read the reviews of those supplementing with Vitamin B6 and you’ll come across several reports of improved sleep and vivid dreams. And we have science to back this up. 12 college students participated in a double-blind, placebo-controlled trial to examine the various claims that Vitamin B6 increase dream vividness, and the ability to recall dreams.

The students were given 100 or 250 mg of Vitamin B6 or a placebo prior to bedtime for 5 consecutive days. Morning reports indicated a significant difference in ‘dream-salience scores’. This is a composite score measuring dream vividness, bizarreness, emotionality and color.

The study suggests that Vitamin 6B may act by increasing arousal during rapid eye movement (REM) sleep. The researchers hypothesized it had some- thing to do with the conversion of tryptophan to serotonin.944

Vitamin B6 (Pyridoxine) may prevent Parkinson’s Disease

A study out of the Netherlands suggests that Vitamin B6 could cut the risk of Parkinson’s Disease in half. Researchers in Rotterdam recruited 5,289 people over the age of 55 and assessed their dietary intake using food questionnaires. This study looked into 430 HEAD FIRST reports that increased levels of the amino acid homocysteine might promote Parkinson’s Disease.

Numerous studies have reported that higher intakes of folate, Vitamin B12 and Vitamin B6 decrease blood homocysteine levels and could offer protection from Parkinson’s.

It has also been proposed that Vitamin B6 could provide antioxidant effects. And could reduce the risk factor for Parkinson’s by a mechanism that is not related to homocysteine. After 9.7 years of follow-up, 72 new cases of Parkinson’s Disease had been di- agnosed. The average Vitamin B6 intake was 1.63 mg per day, average B12 intake was 5.3 mcg per day, and average folate intake was 218.7 mcg per day. No significant reductions in the risk of Parkinson’s were found for folate or Vi- tamin B12. But when the researchers limited their calculations to the 66% of participants who were smokers, they found that the protective effects of high

Vitamin B6 intake appeared limited to this group. The researchers noted that several studies indicate the protective effects of nicotine on brain cells, and reduced the risk of Parkinson’s. Which suggests that

Vitamin B6 plus nicotine provides mutually reinforcing beneficial effects.

Since folate and Vitamin B12 showed no relationship to reduced Parkinson’s, the researchers concluded it was not homocysteine that was behind the newly diagnosed patients.

The study authors said that the apparent benefits of6 B , “may point towards an alternative mechanism… because several lines of evidence suggest neuropro- tective properties of Vitamin B6 through antioxidant capacities”. Oxidative stress has been shown to be prominent in Parkinson’s Disease, and higher Vitamin B6 intake may reduce Parkinson’s risk through its antioxidant effects.945

Vitamin B6 (Pyridoxine) to beat Panic Attacks Reduced serotonin levels are known as one of the causes of panic attacks and hyperventilation attacks. Serotonin is synthesized from tryptophan. And for the synthesis of serotonin, you need Vitamin B6 and iron. The clarify how this works, researchers at Atago Hospital in Japan checked the blood levels (vitamins B2, B6, and B12 and iron) of patients who came into the ER with a panic attack or hyperventilation attack. The team measured parameters in 21 patients compared to 20 healthy volunteers. The study found that both Vitamin 6B and iron levels were signifi- cantly lower in the panic and hyperventilation attack people than in the healthy volunteers.

There was no significant difference in Vitamin B2 or B12. The study con- 431 David Tomen cluded that low blood concentrations of Vitamin B6 and iron are involved in panic and hyperventilation attacks.946

Dosage Notes Recommended dosage of pyridoxal 5’-phosphate (P-5-P) form of Vitamin

B6 is up to 100 mg per day. P-5-P is the only ‘active’ form of B6 available and preferred for nootropic usage. (see “Side Effects” for toxicity with Vitamin 6B ). The enzyme L-dopa decarboxylase depends on P-5-P to convert L-DOPA into dopamine. And is involved in the final stages of serotonin synthesis.947 An analysis of data collected in the USA in 2003-2004 indicated that Vita- 948 min B6 intake from food averaged about 1.9 mg per day. The problem is some forms of Vitamin B6 from plants (pyridoxine glucoside) are not very bioavailable. In most cases, and certainly that of neurohackers using nootropics to boost neurotransmitters or improve mood, Vitamin B6 from diet alone is not enough. The study mentioned above shows that even those supplementing with 2 mg per day of Vitamin B6 or less had blood levels of B6 much too low.

Vitamin B6 is water-soluble and you excrete it in urine, so supplementation daily is critical. Women taking birth control pills, or who are menstruating are usually low in Vitamin B6. Those following a strict vegetarian diet are also typically deficient in B6. Drugs like L-DOPA, anti-tuberculosis medications, metal chelators, meth- ylxanthines to treat respiratory conditions, and long-term use of NSAIDs, anti- convulsants, and phenobarbital all inhibit Vitamin B6 metabolism. If you are using any of these drugs you are likely low in B6.

You can safely dose up to 100 mg per day of Vitamin B6 with no toxic effects. Side Effects

Vitamin B6 (Pyridoxine) is non-toxic at recommended doses. So is considered well-tolerated and safe. Side effects are rare but very high single doses can include stomach upset, nausea or diarrhea. Pyridoxine neuropathy is a form of nerve damage caused by high doses of

Vitamin B6 when taken for extended periods. Symptoms are loss of coordination, extreme skin sensitivity, bone pain, muscle weakness, and numbness.

Pyridoxine neuropathy has been reported in doses of Vitamin B6 of 200 mg to 5 grams per day for extended periods. When dosing was stopped, symptoms usually disappeared.949 950 This nerve damage has been identified as the destruction of axons and neurons which is reversible at lower levels of toxicity. And irreversible at higher levels of 951 952 Vitamin B6 toxicity. 432 HEAD FIRST Available Forms

Vitamin B6 from food and supplements comes in the form of Pyridoxine, Pyridoxal, and Pyridoxamine.

These forms of B6 are considered ‘inactive’, but are converted in your liver and intestines into the active form of Vitamin B6 called pyridoxal 5’-phosphate (P-5-P). For nootropic use, look for a P-5-P supplement or a B-Complex formula that uses P-5-P.

Nootropics Expert Recommendation

Vitamin B6 as pyridoxal 5’-phosphate (P-5-P) up to 100 mg per day

I recommend using Vitamin B6 as a nootropic supplement.

Your body does not make Vitamin B6 on its own. So to get its benefits you must get it from food, or take it as a supplement.

Vitamin B6 is especially helpful for those suffering from low energy levels, anxiety, depression, and chronic pain.

Experience shows Vitamin B6 helps stop and reverse the symptoms associated with high homocysteine levels. B6 in combination with folic acid and Vitamin

B12 will lower high homocysteine implicated in heart disease and Alzheimer’s.

Vitamin B6 is also particularly helpful to students and executives who want to boost cognition, learning, memory and mood. Because it raises dopamine, GABA, norepinephrine, epinephrine and serotonin levels in your brain.

Vitamin B6 can help those dealing with ADHD because it helps synthesize dopamine and serotonin in your brain. ADHD symptoms should decline and you may be able to cut back on your ADHD meds.

Vitamin B6 is a must have addition for any nootropic stack. If you are using any nootropics to raise dopamine, GABA or serotonin levels, you absolutely need extra Vitamin B6.

433 David Tomen

Vitamin B8 (Inositol)

Vitamin B8 is known to decrease anxiety, depression, panic attacks, mood swings, Obsessive-Compulsive Disorder and alleviate the symptoms causing bulimia

Vitamin B8 (Inositol, cyclohexanehexol) is a sugar alcohol and isomer of glucose. As a nootropic, inositol is involved in brain cell signaling, and is a com- ponent of cell membranes.

Vitamin B8 is no longer considered a ‘true’ B-Vitamin because your body can make inositol on its own. A “true vitamin” is either essential for life and/or cannot be made by the human body. So inositol no longer qualifies. Inositol is used in your brain as a “secondary messenger”. It facilitates com- munication between brain cells. All of your major neurotransmitters need inositol to relay messages. Inositol is also a component making up the phospholipid ‘shell’ encasing each brain cell. Once again, inositol acts as a messenger of sorts by assisting in the transport of amino acids, proteins and neurotransmitters across and into the brain cell. Inositol is a ‘group’ of 9 molecules called ‘stereoisomers’. Myo-inositol is the most abundant stereoisomer, making up 90-95% of the total free inositol in your body.

As a nootropic, Vitamin B8 (Inositol) can be used to treat panic attacks and anxiety, depression, Obsessive Compulsive Disorder (OCD), bulimia, depression in bipolar disorder and mood swings. Myo-inositol is involved in cell-signaling. In the simplest terms, myo-inositol hears from the first neuron that it’s about to fire over a neurotransmitter. And passes that information on to the receiving neuron. Not enough inositol and the neurotransmitter can’t do its job. Inositol is one busy molecule in your body: • Myo-inositol affects mRNA which regulates cell volume.953 • Phosphatidylinositol signaling pathways control signals inside and outside of brain cells.954 • Inositol plays a role in DNA repair955 • Inositol affects long-term potentiation956 • Myo-inositol is a component of cell membranes • Myo-inositol regulates cell metabolism • Myo-inositol regulates cell energy consumption

How does Vitamin B8 (Inositol) work in the Brain?

Vitamin B8 (Inositol) boosts brain health and function in several ways. But two in particular stand out. 434 HEAD FIRST

1. Inositol influences neuroplasticity and neurotransmitters. Transcranial Direct Current Stimulation (tDCS) has been used to treat depression, Parkin- son’s Disease, stroke and pain. But the maximum effect of tDCS in the brain was not until several minutes after treatment. Which indicates the effects of tDCS is not by direct neurotransmitter action like you would expect for example if you were using a nootropic.957 Researchers concluded the effect of tDCS was best explained by the activation of a ‘secondary messenger system’, and modulation of brain cell membrane proteins. Neurotransmitters, neuromodulators and hormones have been shown to exert their action via an intracellular (inside the cell) secondary messenger system in which the activated neuroreceptor stimulates the turnover of inositol phospholipids.958 Clinical studies have found that low levels of inositol are present in patients with anorexia, brain disorders and depression.959 And abnormal levels of myo- inositol in middle-aged adults can signal the initial stages of cognitive decline such as Alzheimer’s and dementia.960 2. Inositol helps reduce anxiety and depression. Long-term potentiation needed for encoding long-term memories, and long-term depression, rely on neural signal transmission and synaptic plasticity. And both are strongly influenced by the myo-inositol and phosphoinositide pathway.961 A meta-analysis and systematic review of clinical studies were evaluated comparing inositol for depression and anxiety disorders. The researchers concluded that inositol was beneficial for treating depression and anxiety.962

How things go bad Inositol is an important component of brain cell membranes. And is critical as a secondary messenger for both intra – and extra-cellular signaling. Low inositol levels have been found in those with major depressive disorder, Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Science does not yet know if low inositol is a result of, or contributes to these diseases. ↓ Inositol levels decline ↓ Serotonin and dopamine receptor density declines ↓ Anxiety and depression get worse ↓ Concentration, cognition and memory decline ↑ LDL-cholesterol (bad) and triglycerides increase ↓ HDL-cholesterol (good) levels decline ↑ Inflammation and oxidative stress damage neurons

Vitamin B8 supplementation can help increase the density of serotonin and dopamine receptors in your brain. And improve neurotransmitter signaling. Helping you to cope with stress, lessen depression and improve memory. 435 David Tomen

Vitamin B8 (Inositol) to the rescue Myo-inositol enhances serotonin neuroreceptor sensitivity.963 And several studies have proposed a SSRI-like role for myo-inositol. Researchers believe inositol works as a SSRI because it is a secondary messenger of serotonin. In other words, inositol gets a message from the 1st neuron that says it wants to send over a serotonin molecule. Inositol picks up that message and lets the receiving neuroreceptor know there’s an incoming serotonin molecule. Serotonin signaling is fixed and depression goes away.964 In some regions of your brain, serotonin acts more like a “neuromodulator” rather than a “classic” neurotransmitter. And can affect glutamate and GABA as well.965 As a secondary messenger, inositol is an integral part of neuroplasticity and neurotransmitter signaling. Affecting anxiety, alertness, concentration, cognition, depression and all forms of memory. A large percentage of patients do not respond to SSRI’s when used to treat depression or anxiety. The problem could be depression not related to serotonin or GABA deficiency (they could have a dopamine problem instead). But if it is serotonin-related depression and there is no response to SSRI’s, inositol may help. Myo-inositol helps relay the messages sent and received by serotonin receptors. Another problem with SSRI’s like lithium is Serotonin Syndrome. Too much serotonin can be released in the brain which can be toxic and deadly. Or the SSRI can deplete stores of inositol which raises serotonin levels too high. Once again, inositol comes to the rescue. Researchers found that myo- inositol + lithium alleviated Serotonin Syndrome.966 Myo-inositol regulates blood sodium levels which helps in the maintenance of healthy myelin sheaths that protect neurons. Myo-inositol protects your brain from a leaky blood-brain barrier that if left unchecked, would allow toxins produced in your liver to enter your brain.967 Inositol can relieve anxiety and Obsessive-Compulsive Disorder (OCD). Myo- inositol can reduce panic attacks. And inositol can reduce mood swings. Studies show that inositol is as effective as SSRI’s in treating the symptoms of bulimia and binge eating.968 Inositol can protect against lung cancer caused by smoking.969 Myo-inositol increases sperm concentration, total sperm count, decreases fol- licle stimulating hormone and luteinizing hormone in infertile males.970 Myo-inositol can help lower LDL-cholesterol (bad-cholesterol), C-reactive protein and blood glucose levels while increasing HDL-cholesterol (good cholesterol).971 Inositol reduces inflammation. Phosphatidylinositol reduces pro-inflammatory 436 HEAD FIRST cytokines.972 And D-chiro-inositol decreases the mRNA expression and secretion of tumor necrosis factor-α, interleukin 6 (IL-6).973 D-chiro-inositol has anti-aging properties and can extend lifespan.974 The bottom-line is inositol is a potent pseudo-vitamin and can be a great com- pliment to any nootropic stack.

How does Vitamin B8 (Inositol) feel? Inositol makes it easier to fall asleep. Unlike other sleep-inducing nootropics or sleep meds, it doesn’t “knock you out”. Falling asleep is just effortless. Inositol increases serotonin and dopamine receptor densities. So damage that you may have done to dopamine receptors are repaired (particularly an issue with ADHD stimulant meds). And serotonin is simply more effective. Anxiety decreases, motivation goes up and depression goes away. Inositol is great for social occasions because anxiety levels decrease. In fact, inositol outperformed fluoxetine (Prozac®) at reducing panic attacks and can become effective in just a few days. With no side effects. Some neurohackers feel that supplementing with inositol is the best anti- depressant they’ve every used. The real beauty of inositol is you can safely com- bine it with the current antidepressant (i.e. SSRI) medication you currently take. Your antidepressant meds may work better! Inositol is a proven remedy for treating the symptoms of Obsessive-Compulsive Disorder (OCD). You should feel a noticeable reduction in negative thoughts. Some things just won’t bother you as much. And won’t dominate your thoughts so easily. And inositol is an effective method of taming panic attacks.

The Research

Inositol to Treat Panic Attacks Estimates are that only about 70% of patients respond to standard drug treatments for panic disorder. And many often discontinue the drugs because of negative side effects. Israeli researchers decided to compare inositol with the SSRI fluvoxamine (Luvox®) for panic disorder. In this double-blind, controlled, random-order cross- over study 20 patients completed 1 month of 18 grams per day of inositol and 1 month of 150 mg per day of fluvoxamine. In the first month, inositol reduced the number of panic attacks per week by 4 compared to only 2.4 for fluvoxamine. Nausea and fatigue were noted with those using Luvox® but not with inositol. The natural compoundinositol was more effective than a SSRI for treating panic disorder.975 437 David Tomen

Vitamin B8 (Inositol) for Depression A study published in the American Journal of Psychiatry noted that levels of inositol in depressed patients were lower than normal. In this trial, the authors administered 12 grams per day of inositol or a placebo to depressed patients for 4 weeks. The overall improvement in depression scores was significantly greater than placebo by week 4. And no side effects were noted. The researchers commented that “this is the first time a precursor strategy for a secondary messenger rather a neurotransmitter” was used in treating depression. The authors concluded that “inositol had a significant antidepressant effect”.976 Another study tried using inositol to treat Premenstrual Dysphoric Disorder (PMDD). PMDD is a particularly nasty form of PMS. It’s a condition in which a woman has severe depression, irritability and tension before menstruation. Scientists don’t really know what causes PMDD except it has something to do with serotonin. Serotonin is the “calming neurotransmitter”. When it fails for any reason you get depressed, irritable, obsessive, negative and worried. In this 2-phase clinical trial, PMDD patients were given myo-inositol in powder form, or a soft-gel capsule equivalent to 2 grams of myo-inositol. The results showed a significant improvement on 3 different scales of mea- suring depression. Inositol significantly improved PMDD and associated depression, irritability and tension.977

Vitamin B8 (Inositol) for OCD Inositol is good for treating Obsessive-Compulsive Disorder (OCD). OCD is a type of anxiety characterized by unwanted, recurring thoughts and behaviors. One double-blind, controlled crossover trial treated 13 OCD patients with 18 grams per day of inositol for 6 weeks. The OCD patients had significantly lower scores on the Yale-Brown Obses- sive Compulsive Scale when taking inositol than when taking placebo. The authors concluded that “inositol is effective in depression, panic, and obsessive-compulsive disorder, a spectrum of disorders responsive to selective serotonin reuptake inhibitors (SSRI’s)”.978

Dosage Notes Recommended dosage for inositol is up to 3 grams per day. Typically split into 3-doses of 1 gram each. One in the morning, one at noon, and your final dose before bedtime. Clinically effective dosage for depression and anxiety is up to 12 grams per day. Split your dose into 3-times per day. 4 grams in the morning, 4 grams at noon and 4 grams prior to bedtime. Clinically effective dosage for OCD is up to 18 grams per day. Split into 3 equal doses of 6 grams each. 438 HEAD FIRST The clinical dosages mentioned here are the ones used in clinical trials. Most people experienced relief of symptoms within 3 months. Some people showed improvements within a week or sooner. Important note: It may not be necessary for you to go as high as 12 or 18 grams per day. Inositol could be just as effective for you in much smaller doses. Most neurohackers notice benefits when taking 3 – 4 grams per day or less.

Side Effects

Vitamin B8 (Inositol) is non-toxic. So is considered well-tolerated and safe. Higher doses like those used in clinical trials could result in flatulence, stomach upset, nausea, diarrhea, increased mood swings for bipolar or psychosis patients. If you’ve been diagnosed with bipolar or bipolar-spectrum disorder, please consult a pharmacist or your doctor before using inositol. Studies have shown and neurohackers verify that inositol supplementation may reduce testosterone levels and libido. Most of the Low-T reports were by woman but I’ve heard a few men reporting Low-T and libido from inositol as well.

Available Forms Inositol is available in capsules, softgels, and in powder form. Inositol powder is the least expensive way to supplement with this nootropic. Inositol is basically a sugar so it tastes sweet. Not as sweet as sugar but it tastes good on its own. Or mixed in your favorite beverage. Lecithin is comprised of both inositol and choline. So lecithin as a supplement will provide you with inositol. Inositol is often supplied by supplement manufacturers as “inositol + cho- line”. The thinking behind this combined supplement is that inositol compli- ments the effects of choline. When inositol and choline are used together, they are supposed to improve nerve function and help you metabolize cholesterol. But high doses of choline can leave you depressed and sleepy. So if you want to add inositol to your nootropic stack, I suggest you avoid the combination and go with straight inositol.

Nootropics Expert Recommendation

Vitamin B8 (Inositol) up to 3 grams per day

I recommend using Vitamin B8 (Inositol) as a nootropic supplement.

Your body does make Vitamin B8 on its own. And you get it from food. So it is unlikely that you are inositol deficient. But if you want to try inositol for its anti-anxiety and antidepressant benefits, you must take it as a supplement. Inositol is especially helpful for those suffering from anxiety, depression, panic attacks, or OCD. 439 David Tomen Experience shows Inositol helps stop and reverse the symptoms associated with high cholesterol levels. B8 will lower ‘bad’ LDL-cholesterol as well as raise ‘good’ HDL-cholesterol.

Vitamin B8 is also particularly helpful to quell anxiety caused by social situations.

Vitamin B8 can help you get a good night’s sleep. Many find it more effec- tive than sleep meds and other nootropics used for sleep. You’ll awaken feeling refreshed and calm. Ready to start your day.

The recommended dosage of Vitamin 8B (Inositol) is up to 3 grams per day. But start at a gram or less, and work your way up depending on how you feel. Clinical doses of 12 or 18 gram are usually not needed for most people.

440 HEAD FIRST

Vitamin B9 (Folate)

Vitamin B9 is known to improve mood, energy, initiative, alertness, concentration, psychomotor speed, and social activity

Vitamin B9 (Folate, folic acid, 5-methylenetetrahydrofolate) is water- soluble, and one of 8 B-Vitamins. Folate functions as a coenzyme in single-carbon transfers in the synthesis of DNA and RNA. And converts homocysteine to methionine which is used in the synthesis of S-Adenosyl-methionine (SAMe).979 As a nootropic, folate is also involved in gene expression, amino acid synthe- sis, myelin synthesis, and is required for the synthesis of the neurotransmitters dopamine, epinephrine, norepinephrine and serotonin. Many neurohackers, including doctors and other health professionals con- fuse folate with folic acid. They are NOT the same. In this chapter, we’ll explore the differences between folate and folic acid. And how Vitamin B9 (folate) is critical for the fully optimized brain. Folate is used in red blood cell production, helps break down and use pro- teins, and just about every other process in your body. Folate deficiency is found in at least a third of those suffering from depres- sion. Folate touches nearly everything happening in your brain. And the reason why we’re investigating it here. Folate should be part of your nootropic stack. Green leafy vegetables, or ‘foliage’ are rich sources of folate. And how ‘folate’ got its name. You can also get folate from citrus fruit juice, legumes, fortified foods and liver. When you eat vegetables containing folate, or eat flour-enriched with folic acid, an enzyme called MTHFR (5,10-methylenetetrahydrofolate reductase) con- verts folic acid and food folate into 5-methylenetetrahydrofolate (methyl-folate or 5-MTHF). Folate is a general term for a group of various tetrahydrofolate (THF) deriva- tives naturally found in food. Folic acid refers to an oxidized synthetic compound used in dietary supplements and food fortification. THF can enter the main and natural folate metabolic cycle which starts out in the mucosa of your small intestine. Synthetic folic acid on the other hand undergoes initial reduction and methylation in your liver, where conversion to the THF form requires the enzyme dihydrofolate reductase. One of the problems with choosing the unnatural folic acid version is if there is low activity of the dihydrofolate reductase enzyme, combined with high intake of folic acid, you end up with unnatural levels of unmetabolized folic acid enter- ing your circulation. Several studies have reported the presence of this unmetabolized folic acid 441 David Tomen in blood following consumption of folic acid supplements, or folic acid-fortified food.980 We have growing evidence in Western society that we generally test for excess levels of unnatural folic acid. Due mainly to eating processed foods and folic acid-enriched flour. And still suffer from a folate deficiency. High doses of synthetic folic acid may increase your risk of cancer, immune system damage and other health problems.981

Problems with MTHFR Another major problem affecting folate deficiency is problems with the MTHFR gene. Remember that this enzyme called MTHFR (5,10-methylene- tetrahydrofolate reductase) is needed to convert folic acid and food folate into 5-methylenetetrahydrofolate. There are two common variants in this gene that affects the functioning of MTHFR. They are called C677T and A1298C. Both variants are genetically inherited. And depending on their presence in your system, can reduce the ef- fectiveness of MTHFR from 30 – 70%. Another cause for folate deficiency. Estimates of the prevalence of these mutations in our general population are up to 60%. Some doctors report that nearly every patient in their practice have one or both MTHFR mutations.982 And we have clinical evidence of the association between both MTHFR mutations in depression, bipolar disorder, and schizophrenia.983 Folate is one busy molecule in your body: • Donates a methyl group to homocysteine to make SAMe. The methyl donor SAMe is involved in the formation of phospholipids, glutathione, myelin, coenzyme Q10, carnitine and creatine in your brain • Synthesizes the enzyme cofactor biopterin (BH4) which is critical for the synthesis of major neurotransmitters including dopamine, epinephrine, norepinephrine and serotonin • Synthesizes DNA and tRNA • Recycles and reduces the inflammatory amino acid homocysteine • Builds red and white blood cells and platelets.

How does Vitamin B9 (Folate) work in the Brain?

Vitamin B9 (Folate) boosts brain health and function in several ways. But two in particular stand out. 1. Folate influences neuroplasticity and neurotransmitters. Folate is re- quired for the synthesis of the neurotransmitters dopamine, epinephrine, and serotonin. 442 HEAD FIRST The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L- methylfolate), participates in re-methylation of the amino acid homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming the above-mentioned neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neu- rotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. Studies have shown that those being treated for depression with SSRI antide- pressants, and not responding to these drugs, can get a much better response by taking folate with their antidepressants.984 2. Folate helps reduce depression. Folate is involved in one-carbon metabolism in the brain. This folate cycle is responsible for the synthesis of methyl groups, which are utilized by SAMe in several methylation reactions involving nu- cleoproteins, proteins, phospholipids, neurotransmitters and monoamines.

Deficiency of both folate and Vitamin B12 will impair methylation processes. Causing the accumulation of homocysteine. Low concentrations of folate in your blood, red blood cells and cerebrospinal fluid are associated with depression and dementia. Research shows that cognitive function is related to methylation processes in your brain.985 This depression hypothesis is supported by the similar effect of SAMe on monoamine metabolism, which is also implicated in depression.986 The lowest concentrations of folate and SAMe in cerebrospinal fluid are found in dementia, including Alzheimer’s Disease.987

How things go bad

Methyl-folate (5-MTHF) works with Vitamins B2, B6 and B12 as well as cofac- tors like magnesium in this methylation cycle in every cell in your body and brain. The metabolic process called methylation occurs when one molecule pro- vides a methyl group, which is a carbon atom linked to three hydrogen atoms, to another molecule. And makes things like creatine, carnitine, CoQ10, phospha- tidylcholine (PC), melatonin and a bunch of other crucial neurotransmitters and substances in your body. Methylation is involved in cognition, repairing DNA, turning genes on and off, fighting infections and inflammation, getting rid of toxins and much, much more. Problems with methylation (which can be caused by not enough folate) can contribute to addictions, Alzheimer’s, anxiety, ADD and ADHD, bipolar and manic depression, chronic fatigue syndrome, dementia, diabetes, fibromyalgia, schizophrenia, and hypothyroidism. Methylation is not only involved in the synthesis of neurotransmitters, but breaking them down as well. This critical step, when broken, causes a buildup of 443 David Tomen neurotransmitters that can lead to seizures, insomnia, panic attacks, fits of rage, and more. Much more. A deficiency of methyl-folate (5-MTHF) in your body caused by problems with this methylation pathway leads to a deficiency of glutathione, your major antioxidant. This can take shape as fibromyalgia, chronic fatigue, increased immune activation, chemical sensitivities and even diseases like ALS, MS, and Parkinson’s. Not enough folate and you can experience: ↓ Mitochondrial dysfunction988 ↓ Depression, mood and social function decline ↓ Cognitive function declines ↓ Concentration, cognition and memory decline ↑ Risk of Alzheimer’s and dementia increase ↑ Risk of anemia increases ↑ Irritability, forgetfulness, and mental sluggishness increase

Vitamin B9 supplementation can help increase the density of serotonin and dopamine neurotransmitters in your brain. And improve neurotransmitter sig- naling. Helping you to cope with stress, lessen depression and improve memory.

Vitamin B9 (Folate) to the rescue Depression affects about a quarter of the US population who will have at least one depressive episode in their lifetime. (My apologies to our readers from other countries. I only have statistics for the USA). But world-wide, folate deficiency is found in at least a third of those suffering from depression. And research shows that folate levels even in the “normal range” might be inadequate for methyl donation and neurotransmitter synthesis. By adding folate, or methyl-folate to your nootropic stack, you’re adding a necessary ingredient for the synthesis of the neurotransmitters dopamine, epi- nephrine, norepinephrine and serotonin. The active metabolite of folate (5-MTHF, L-methyl-folate) participates in the re-methylation of the amino acid homocysteine creating methionine. SAMe, the downstream metabolite of methionine, is involved in several methyl donor reactions, including forming most of your major neurotransmitters. Methyl-folate also seems to save the day by stepping in, and substituting for tetrahydrobiopterin (BH4), an essential cofactor in neurotransmitter synthesis (when BH4 is low). The bottom-line: folate helps boost alertness, attention, cognition, memory, and mood. And helps alleviate brain fog, anxiety and depression.

How does Vitamin B9 (Folate) feel? Up to 60% of us do not produce enough of the enzyme needed to break down the synthetic folic acid found in supplements and fortified foods like 444 HEAD FIRST breakfast cereal and bread. And the simple presence of this impostor in our diet is likely contributing to many of our modern diseases. Neurohackers report that dosing with methyl-folate: • Boosts alertness and energy levels • Relief from chronic pain • Tolerance for heat increases • Sociability increases • Relief from depression, fatigue and paranoia • Fewer headaches • Mental clarity increases • Much happier, calmer, more energetic • Gingivitis and gum inflammation decreases

The Research

Folate as an Antidepressant Many who use antidepressants experience little to no relief in depressive symptoms. And researchers set out to find out why antidepressant meds were not working. Dr. Jerome Sarris of the University of Melbourne decided to do a meta- analysis of clinical trials using ‘nutrients’ along with antidepressants in PubMed, CINAHL, Cochrane Library, and Web of Science up to 2015. The research team found that Omega-3’s combined with antidepressants boosted the success of using these meds for depression. The team also found strong evidence for methyl folate, Vitamin D, and SAMe. The research showed that using folic acid or inositol provided no benefit. The team concluded there was strong evidence for using methyl folate, Omega-3, Vitamin D and SAMe with antidepressants to reduce depression.989 Another study in Milan compared using methyl-folate with the antidepres- sant Trazadone. 96 patients with dementia received either 50 mg of methyl-folate per day, or 100 mg of Trazadone. After 4 weeks of treatment, depression scores for the methyl-folate patients decreased more than for the Trazadone patients.990

Folate Reduces Risk for Dementia Folate deficiency is associated with a tripling in the risk of developing de- mentia among elderly people. Researchers tracked 518 people over the age of 65 for 2 years for dementia development. The study found that the onset of dementia was much more likely in those whose folate levels fell over 2 years.991 445 David Tomen Another study published in the British Medical Journal looked at the neuro- logical status of 24 folate-deficient patients compared with a control group of 21 normal folate-level patients. The study showed a significant increase in organic brain syndrome in the fo- late-deficient group.992 Organic brain syndrome is a general term used to describe decreased mental function caused by something other than psychiatric illness.

Vitamin B9 (Folic Acid) Improves Memory A study published in the Journal of the American Medical Association evalu- ated nutritional status and cognitive function in 260 men and women older than 60 years. The study showed there was a significant relation between impaired abstract thinking ability and memory, and lower folate levels and intake.993 In another open study of 38 folate deficient subjects with depression, leth- argy, and memory impairment, 50 mg of folinic acid per week for 120 days significantly improved visuomotor performance, visuospatial memory, logical reasoning, associative memory, and activities for daily living.994

Dosage Notes

Recommended dosage for Vitamin B9 (Folate) is 500 mcg.

If you decide to add folate to your nootropic stack, start with B12 in the form of methylcobalamin. And then introduce your dose of methyl-folate and cofactors such as Vitamin B2, Vitamin B3, Vitamin B6, trimethyl glycine, and Vitamin C If you have an adverse reaction to methyl-folate (agitation, increased anxiety, headache), you can take Vitamin B3 (nicotinic acid or niacinamide) in 50 mg dosages every 30 minutes until you experience relief.

Note that Vitamin B3 (niacin) requires SAMe for its metabolism. And can contribute to a drop in methylation if you’re low in SAMe. It is also a cofactor for the enzyme COMT that breaks down norepinephrine, epinephrine, and estrogen, which are all potentially elevated if you are experiencing anxiety.

Side Effects

Vitamin B9 (Folate) is non-toxic. So is considered well-tolerated and safe.

But note that higher doses of Vitamin B9 like those used in clinical trials nearly always use synthetic folic acid. If you are deficient in Vitamin 12B , and many people are, can manifest as anemia. And is undisguisable from folate deficiency.

Large doses of folate could correct anemia. Without correcting the underlying B12 deficiency. And leave you at risk for irreversible brain damage. This is why the US Institute of Medicine advises that all adults limit their intake of folic acid supplements to 1 mg daily. Note that it is unlikely that you’ll encounter this problem by using folate or 446 HEAD FIRST methyl-folate instead of folic acid. But we don’t have the science yet to back this claim up. High concentrations of unmetabolized folic acid in your blood, especially if you’re low in Vitamin B12, could result in a compromised immune system. And problems with cognition. Other side effects of usingfolic acid, particularly in high doses include stomach problems, insomnia, skin reactions, confusion, loss of appetite, nausea and seizures. Many medications interfere with folic acid absorption including antibiotics, Dilantin, Daraprim, chemo meds, antacids, proton pump inhibitors, anti-seizure medications, NSAIDS (ibuprofen and naproxen), Azulfidine, and Methotrexate.

Available Forms

Vitamin B9 (Folate) is available in capsules, softgels, and in powder form. Studies have shown that the active form of folate, methyl-folate, which is more easily absorbed, and easily crosses the blood-brain barrier, may be effective in the prevention and treatment of depression and dementia.995 Look for a folate supplement that says “L-methylfolate”, “5-methyltetrahy- drofolate” or “5-MTHF” on the label. Even better, with the word Quatrefolic® or Metafolin® which are branded forms of folate ensuring their purity and effectiveness. Avoid any product, including , which list “folic acid” on the label.

Nootropics Expert Recommendation

Vitamin B9 (Folate) up to 500 mcg

I recommend using Vitamin B9 (Folate) as a nootropic supplement.

Your body does not make Vitamin B9 on its own. So you must get folate from food or a supplement.

Vitamin B9 (Folate) is especially helpful for those suffering from anxiety, depression, panic attacks, or OCD. Folate can help improve energy levels, reduce insomnia, and help increase energy levels.

Experience shows Vitamin B9 helps stop and reverse the symptoms associ- ated with high homocysteine levels.

Vitamin B9 is also particularly helpful to quell anxiety caused by social situations.

Vitamin B9 can help you get a good night’s sleep. You may find it as effective as sleep meds and other nootropics used for sleep. You’ll awaken feeling refreshed and calm. Ready to start your day.

The recommended dosage of Vitamin 9B (Folate) is up to 1,000 mcg per day. Start low at 500 mcg and see how your body reacts. Please refer to Dosage Notes in this chapter for adding the other B-Vitamins to your stack for an optimal methylation cycle. Your neurotransmitters are count- ing on it. 447 David Tomen

Vitamin B12 (Cobalamin)

Vitamin B12 is known to enhance alertness, cognition, energy, vision, elevate mood, lower anxiety and pain, and relieve insomnia

Vitamin B12 (Cobalamin) is one of 8 water-soluble B-vitamins that are absolutely vital to the highly optimized brain. And is essential to every cell in your body including your brain.

Vitamin B12 is essential for the synthesis of DNA, RNA and neurotransmit- ters, the maintenance of myelin sheaths protecting neurons, and red blood cell formation.

Deficiency in B12 results in myelopathy (spinal cord disease), neuropathy (nerve disease), sensory disturbances, imbalance when walking, weakness, and psychiat- ric problems ranging from cognitive and behavioral problems to dementia.

Vitamin B12 as a nootropic can improve alertness, energy levels, boost at- tention span, concentration, intelligence and memory. B12 supplementation can help relieve stress, depression, insomnia and help balance your mood.

Vitamin B12 has the coolest and most complex chemical structure of any nootropic we explore in Head First. Vitamin B12 is called “Cobalamin” because it contains the rare earth element .996

Vitamin B12 is absorbed in your intestines from food or a supplement using a process called intrinsic factor. The vitamin is then transferred totranscobalamin

II (TC-II/B12) which acts as a transporter. Through a very complex process which I’m not going to try to explain here,

B12 is converted into the active forms coenzyme 5’-deoxyadenosyl and methylco- 997 balamin (MeB12).

Foods rich in Vitamin B12 include fish, shellfish, meat (especially liver), poul- 998 try, eggs, milk and milk products. The two best sources by far of B12 are clams and liver.

You cannot get adequate amounts of Vitamin B12 from plants. Vegetarians and vegans are especially in danger of B12 deficiency. Regardless of what food and supplement manufacturers say.

Plant foods contain analogs of B12 which are similar to, but not the same as,

Vitamin B12. They bind to 12B receptors and block your intake of true B12.

Trying to get your Vitamin B12 from yeast products like Red Star Nutritional Yeast or Marmite is also problematic. These products do not naturally contain

B12 but are fortified with it.

And Vitamin B12 is light sensitive. If stored in open bins or clear plastic bags or jars, B12 vaporizes and disappears.

Meat and animal products are your best source of natural Vitamin B12. But once again, relying solely on food for adequate B12 is difficult because it is de- stroyed during cooking.999 448 HEAD FIRST

You are much safer using a good Vitamin B12 supplement for your nootropic stack. See “Available Forms” later in this chapter for more.

How does Vitamin B12 (Cobalamin) work in the Brain?

Vitamin B12 (Cobalamin) boosts brain health and function in several ways. But two in particular stand out.

1. Vitamin B12 increases cognition. Vitamin B12 is a precursor in the biosyn- thesis of all major neurotransmitters in your brain including acetylcholine, dopamine, GABA, norepinephrine and serotonin.

Vitamin B12 is an integral part of the one-carbon cycle involved in the synthesis of methionine. This amino acid, methionine donates the methyl group required for methylation to occur. This biochemical process helps synthesize neurotransmitters, myelin (the sheath that protects neurons), and keeps homocysteine levels in check. Elevated levels of homocysteine have been associated with several neurodegenerative dis- eases including Alzheimer’s and Parkinson’s Disease.

Even mild Vitamin B12 deficiency has been associated with accelerated cognitive decline. Researchers at Tufts University examined data from 549 men and women enrolled in the Framingham Heart Study. They focused on scores on the Mini-Mental State Examination (MMSE), which is a short list of questions and tasks used to screen for dementia. The subjects were divided into 5 groups, based on their vitamin B12 blood levels. MMSE scores declined by 0.24 points per year over the 8-year follow-up period. Cognitive decline was faster in the bottom 2 groups that had the lowest levels of Vitamin B12.

The researchers concluded that “having plasma (blood) Vitamin 12B levels from 187 to 256.8 pmol/L… predicts especially rapid cognitive decline”.1000

2. Vitamin B12 helps reduce depression. Vitamin B12 is a precursor in the biosynthesis of GABA and serotonin. GABA is an amino acid and neurotrans- mitter produced by glutamate in your brain. This inhibitory neurotransmitter prevents other ‘excitatory’ neurotransmitters from being released. Resulting in an anti-anxiety and calming effect. Serotonin is a neurotransmitter made from the amino acid tryptophan. This inhibitory neurotransmitter governs the stimulatory neurotransmitter dopamine from overwhelming your brain. Adequate serotonin levels make you feel confi- dent, easy-going, flexible, happy and positive. One case study out of India reviewed the case of a 57-year-old woman who was given months of anti-psychotic and antidepressant medications. Including 2 rounds of electro-shock therapy before anyone thought to check her Vitamin

B12 levels. 449 David Tomen This woman’s symptoms included anxiety, constipation, movement abnor- malities, perceptual disturbances (hearing her name called), lethargy, tearfulness and finally catatonia. She remained depressed, suicidal and lethargic despite her treatment.

Within 2 months of identifying her Vitamin B12 deficiency and subsequent treatment, this woman reverted to her baseline 14 years before. And remained stable with no additional treatment.1001

How things go bad

Vitamin B12 deficiency usually causes neurological and psychiatric issues in adults aged 40 – 90. B12 deficiency rarely affects younger people. But can be a problem if the mother is deficient during pregnancy.

A B12 deficiency can manifest as disease of the spinal cord (myelopathy), dis- ease of the nerves (neuropathy), sensory disturbances, gait abnormalities, weak- ness, cognitive and behavioral disturbances and dementia. ↓ Neuron myelin sheath is damaged ↓ Neurons degenerate ↓ Weakness, vision problems, cognition issues, abnormal reflexes ↓ Bladder and erectile dysfunction ↓ Tingling sensation, pain and numbness ↓ Delusions, hallucinations, memory decline, depression and dementia ↓ Brain shrinkage ↓ Impaired DNA synthesis and replication

Vitamin B12 deficiency can often be caused by Pernicious anemia which is an autoimmune disease that affects the mucous membrane layer of the stomach. This can be a result of destruction of parietal cells, lack of hydrochloric acid, or a failure to produce intrinsic factor. Parietal cells are required to create intrinsic factor to supply your body with adequate Vitamin B12. When these cells are damaged, intrinsic factor is not pro- duced. And B12 cannot be absorbed for use by your body and brain. Parietal cell death can be caused by excess alcohol consumption, ulcerative gastritis, H. pylori infection, gastric bypass surgery and even age.

Intrinsic factor is required for Vitamin B12 absorption from food or supple- ments. If left untreated you experience B12 deficiency even if you’re getting B12 from food or supplements.

If you or your doctor suspect Vitamin B12 deficiency and do a blood test, the labs may show B12 levels within the bell curve. But it doesn’t reflect how much 12B is actually in your cells. Pernicious anemia is sometimes passed down through families. This is most common in those of Scandinavian or northern European descent. Grave’s Dis- ease, and Addison’s Disease. Type-1 diabetes can also cause pernicious anemia. 450 HEAD FIRST Review the symptoms of deficiency listed here. Do your research. And if you suspect you may be deficient in Vitamin 12B , tell your doctor and take action now. If your doctor tells you it’s not a problem, please find another doctor!

Vitamin B12 (Cobalamin) to the rescue

When you take Vitamin B12 (Cobalamin) as a nootropic supplement, it is transported across your intestinal wall by the carrier protein intrinsic factor. It is then degraded, freeing cobalamin to be attached to transcobalamin II for trans- port to cells in your body.1002

Vitamin B12 is a co-factor in the one-carbon cycle that is required for the synthesis of DNA, RNA, neurotransmitters (acetylcholine, dopamine, GABA, norepinephrine and serotonin), and the myelin sheath that protects each of the neurons in your brain. This one-carbon pathway is involved in the synthesis of the amino acid methionine. This amino acid donates methyl groups for the methylation of DNA, RNA, neurotransmitters and myelin. Methionine is synthesized from the amino acid homocysteine. Preventing high levels of this amino acid to accumulate will prevent problems throughout your body including neurodegenerative disease. Cobalamin is also required for the conversion of methylmelonyl CoA into succinyl Coenzyme-A for the myelin sheath that protects your neurons. Problems with this conversion degrades myelin. Causing problems with your central ner- vous system and damaging axons on the neurons in your brain.

Vitamin B12 can: • Reduce the severity and frequency of asthma attacks and allergies • Reverse early signs of Alzheimer’s Disease if caught in time • Lift your mood by boosting the “happy molecule” serotonin in your brain • Reduce the side effects of Metformin in diabetes patients • Provide optimal concentration, focus and memory • Reduce the risk of macular degeneration and prevent blindness • Maintain healthy hair, skin and nails • Remove homocysteine and protect your heart • Raise sperm counts and improve sperm mobility in men • Prevent neuron damage if you lack intrinsic factor • Reduce some of the symptoms of schizophrenia • Help prevent osteoporosis and build strong bones

The key message here is to maintain optimal Vitamin B12 levels in your body 451 David Tomen and brain. Don’t be duped by marketers selling Vitamin B12 energy drinks boast- ing more energy. Or a magic pill to boost memory, or aid in weight loss. If you have a specific health problem like pernicious anemia or are deficient in this vitamin, then B12 can help. If you maintain optimal levels of Vitamin B12 in your system, supplementing will not increase your energy levels.

Vitamin B12 is a key brain vitamin that plays an important role in a healthy nervous system and optimally functioning brain. Low levels of B12 can definitely lead to poor memory and cognition.

How does Vitamin B12 (Cobalamin) feel?

Neurohackers who supplement with Vitamin B12 report a reduction in brain fog and better sleep. People on statins for cholesterol and metformin for diabetes report a dra- matic decrease in pain. Neurohackers report better focus and mood, colors seem brighter and more intense, energy levels improve, and an overall improved sense of well-being.

If you are Vitamin B12 deficient you may feel a big boost in energy. And feelings of deep exhaustion can disappear within a few days.

The Research

Much of the research in Vitamin B12 and B12 deficiency are presented as individual ‘case reports’ on one person. One report in French was about a woman with no history of psychiatric prob- lems. But upon admission she was uncooperative, disoriented, had memory and attention problems, a sleep disorder and she looked older than her real age. This woman was depressed, had a guilt complex, devalued herself, and her movements and speech were very slow. A lab test revealed she had a problem with intrinsic factor.

Her therapy was Vitamin B12 replacement using hydroxycobalamin 1,000 mg per day for 10 days. Her mental state improved dramatically within a few days.1003 Another case report was of a middle-aged man with Obsessive-Compulsive Disorder (OCD). He was given methylcobalamin therapy and symptoms of OCD dramatically improved.1004

Vitamin B12 and Folate Prevent Alzheimer’s

A study in Stockholm explored the association of low Vitamin B12 and folate levels with the occurrence of Alzheimer’s Disease. A population based study sampled 370 non-demented people aged 75 years or older and who had not been treated with B12 and folate. This group was followed for 3 years to detect the incidence of Alzheimer’s.

The researchers compared low levels of B12 and folate with people who had normal levels of the two vitamins. 452 HEAD FIRST

Subjects who had low levels of Vitamin B12 or folate had twice the risk of developing Alzheimer’s. And this association was even stronger in subjects with good baseline cognition.

The study concluded that Vitamin 12B and folate may be involved in the de- velopment of Alzheimer’s Disease. And that monitoring blood B12 and folate con- centration in the elderly may be relevant for the prevention of Alzheimer’s Disease.1005

Vitamin B12 (Cobalamin) to Treat Depression Research shows that people with major depression often have low blood levels of folate and Vitamin B12. Low folate levels are also linked to poor response to antidepressants. And treatment with folic acid and/or Vitamin B12 has been shown to improve response to antidepressants.

Folate and Vitamin B12 are involved in one-carbon metabolism in which SAM-e is formed. SAM-e donates methyl groups that are crucial for neurological function. Increased homocysteine is a functional marker of both folate and Vitamin

B12 deficiency. Increased homocysteine levels are found in depressed patients. One study out of Norway showed increased blood levels of homocysteine were associated with increased risk of depression (but not anxiety). The researchers concluded that doses of both folic acid (800 mcg daily) and Vitamin B12 (1 mg daily) should be tried to improve treatment outcomes for depression.1006

Dosage Notes

Vitamin B12 is water-soluble, and considered non-toxic in recommended doses. A varied diet including meat, seafood and milk products should provide enough Vitamin B12 to prevent deficiency. But vegetarians and vegans cannot get enough B12 from food and should supplement. Typical recommended dosage for nootropic benefit and optimal brain health is 100 mcg or 1 mg of Vitamin B12 per day.

Neurohackers older than 40 and those who have a problem with Vitamin B12 absorption should use 100 – 400 mcg or 1-4 mg of B12 per day.

If you test Vitamin B12 deficient, recommended dosage is 2,000 mcg daily for a week, then 1,000 mcg doses of B12 once per week for a month. Thereafter, your maintenance dose is 1,000 mcg monthly.1007

Side Effects

Vitamin B12 (Cobalamin) is non-toxic. So is considered well-tolerated and safe.

Doses as high as 2 mg of Vitamin B12 daily by mouth or 1 mg monthly by injection have been shown to produce no significant side effects. 453 David Tomen

When high doses of Vitamin B12 are given orally, only a small percentage can be absorbed which likely explains the low toxicity levels. Proton pump inhibitors and other drugs used to treat acid reflux is known to prevent absorption of Vitamin B12. So you may need to take B12 sublingually. Antibiotics, drugs to treat gout and metformin to treat diabetes all decrease

Vitamin B12 levels or B12 absorption. If you use any of these drugs you should have your levels checked and possibly supplement with Vitamin B12. used as an anesthetic and recreational drug oxidizes and inactivates

Vitamin B12. So you should likely get tested and possibly supplement with B12. Available Forms

Vitamin B12 is available as tablets, capsules, liquid drops, sublingual tablets, sprays and lozenges. The sublingual tablets, sprays and lozenges are marketed as more absorbable or bioavailable. Some clinical studies do not support this claim but user experi- ence shows otherwise. Logic tells us that a lozenge or spray absorbed under your tongue gets into your bloodstream and across the blood-brain barrier more readily than something you swallow and need to digest.

Low quality Vitamin B12 supplements, and B12 found in multivitamins or

B-Complex formulas, is usually cyanocobalamin. This form of B12 is not well ab- sorbed, and produces a small amount of cyanide in your body (cyanocobalamin).

Higher quality Vitamin B12 comes as methylcobalamin or adenosylcobala- min which are the forms of B12 naturally occurring in your body.

Methylcobalamin is your better choice if you are deficient in B12, or have the MTHFR genetic defect which reduces your ability to methylate this vitamin. Adenosylcobalamin works better for some who want to avoid the cyanide that comes in cyanocobalamin, and who can’t tolerate methylcobalamin.

Hydroxycobalamin is another high quality form of Vitamin B12 that con- verts to methylcobalamin in your body.

If you test Vitamin B12 deficient, your doctor may encourage you to get

Vitamin B12 shots. Especially if you have pernicious anemia, nerve damage or chronic digestive problems like Crohn’s Disease or ulcerative colitis.

But research has found that taking oral B12 supplements is as effective as 1008 B12 shots. And user reviews support this finding.

Note that Vitamin B12 needs to be balanced with Vitamin B6 and Folate (folic acid) for best results if using as a nootropic supplement.

Nootropics Expert Recommendation

Vitamin B12 (Cobalamin) 1 mg per day

I recommend using Vitamin B12 as a nootropic supplement. 454 HEAD FIRST

Your body does not make Vitamin B12 on its own. So to get its benefits you must get it from food, or take it as a supplement.

I recommend staying away from cheap cyanocobalamin B12 supplements. Go with Methylcobalamin, Adenosylcobalamin, or Hydroxycobalamin.

Vitamin B12 is especially helpful for those dealing with brain fog, fatigue, nerve pain, sleep and memory problems.

Vitamin B12 supplementation is critical for anyone over 40 years old because of absorption issues with B12 from food.

Vitamin B12 is also particularly helpful if you are using proton pump in- hibitors for acid reflux, have Type-1 diabetes, or show positive for dementia or Alzheimer’s.

The recommended dosage for Vitamin B12 deficiency is 2,000 mcg daily for a week, then 1,000 mcg doses of B12 once per week for a month. Then your maintenance dose is 1,000 mcg monthly.

Remember that Vitamin B12 needs to be balanced with Vitamin B6 and Folate (folic acid) for best results if using as a nootropic supplement.

455

Nootropic Stack Recommendations

n this book we have looked at dozens of nootropic supplements. Here I we’re going to take it a step further and look at some recommendations. Most neurohackers find that to reach their brain hacking goals, it takes a combination of supplements working together. We call this a “nootropic stack”. And all it means is 2 or more supplements working together, in synergy, to fix something in the brain. Or boost something. When it comes to boosting cognitive performance – you can choose to improve memory, focus, stamina, neuroprotection, creativity, and mood. And I realize this sounds like an overall, general type of neurohacking. But I’ve found that “fixing” or repairing a problem with your brain falls under the category of “boosting cognitive performance”. Everything else tends to fall into place. But one of the first things I want you to understand is “one-size-fits-all” doesn’t apply when it comes to nootropic supplements. There isn’t one “magic pill” no matter what the television commercials say. Each of us has a brain that is unique to us. Our brain ‘wiring’ is influenced by genetics, food, water, environmental toxins, lifestyle, and a thousand other things. This uniqueness was verified by researchers at Carnegie Mellon University who used a diffusion MRI to map the brain’s structural connections in 699 brains. They found that each person’s connections are so unique they could identify a person based on this brain “fingerprint” with near perfect accuracy.1009 So when recommending certain nootropics to help brain function, please understand that these are just ‘suggestions’. This is certainly not medical advice. And caution is strongly advised when using any of these supplements. If possible, work with a naturopathic health professional who understands natural supplements. How they interact with certain health conditions. And many prescription drugs. Always start with the lowest dose possible to see how your body reacts. Understand that combining two or more nootropics could mean reducing the dosage of each. Successfully using nootropic supplements to boost, and repair your brain 456 HEAD FIRST means a lot of trial and error to find out which nootropics in this book are appropriate for you. For each of these recommendations, I encourage you to refer to the previous chapter which covers each nootropic in much more detail. And includes dosage notes, side effects, drug interactions, and available forms.

Best Nootropics for Cognition, Thinking and Decision-Making

Ever gone to the supermarket to get a box of Cheerios? And it wasn’t until you got to the supermarket, you realized that there were 20 difference kinds of Cheerios. You saw original Cheerios. There were honey-nut Cheerios, apple- cinnamon, multigrain, banana nut, and then of course all the generic varieties of Cheerios. And then you find yourself spending a half hour in the cereal aisle of the supermarket. Trying to choose between boxes of Cheerios. Do you think this could be a problem? Cognition is the mental action or process you go through when hunting down the ideal box of Cheerios. And understanding it through thought, experi- ence and your physical senses. Cognition includes thinking, knowing based on experience, short-, work- ing-, and long-term memory, decision-making and problem solving. Whoever thought selecting a box of Cheerios could be so complicated? There’s a lot going on in your brain making the ideal selection, and will likely take more than one nootropic. You can start with: • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory and learning. • Lion’s Mane Mushroom. Lion’s Mane increases Brain Nerve Growth Factor or neurogenesis. Improving attention, focus, thinking, depression, anxiety, and helps repair damaged neurons. • N-Acetyl L-Tyrosine (NALT). NALT is a bio-available form of L- Tyrosine which is a precursor to dopamine in your brain. More dopamine helps improve alertness, focus, working memory and executive function (decision-making). • Rhodiola Rosea. Rhodiola boosts mood by influencing serotonin and norepinephrine levels in your brain. Rhodiola is known for improving alert- ness, energy, memory, mood, is anti-anxiety and anti-depressant, reduces fatigue, and boosts cognition and concentration.

• Vitamin B6. B6 is a required coenzyme for the synthesis of most major 457 David Tomen neurotransmitters in your brain. And helps enhance alertness, cognition, energy, memory and mood. Your brain cannot make these critical neu-

rotransmitters without Vitamin B6.

• Vitamin B9 (folate). Folate is required for the synthesis of nearly all major neurotransmitters in your brain. Folate is known to improve mood, energy, initiative, alertness, concentration, psychomotor speed, and social activity

• Vitamin B12. B12 is essential for the synthesis of DNA, RNA and neurotrans- mitters in your brain. B12 enhances alertness, cognition, memory, decision- making and mood. Your brain cannot make these critical neurotransmitters

without Vitamin B12. You’ll find me recommending B-Vitamins often in these stacks. Because without B-Vitamins, you’re brain simply won’t work. Many neurohackers, myself included, found it wasn’t until we added critical B-Vitamins to our nootropic stack that took our cognition to the next level. For each nootropic in this stack, please refer to the previous section of this book where each supplement is listed. There you’ll find dosage recommenda- tions, side effects, drug contraindications and more.

Best Nootropics for Memory

Let’s go back to the cereal aisle in the supermarket for a minute. Your search for the perfect box of Cheerios relies on your memory. The type of Cheerios you bought before. Warnings from the Environmental Working Group about GMO’s. Your kid’s favorite Cheerios. How to read the labels. Remembering the shopping list before you left home. There’s a lot going on in your brain just to buy a box of Cheerios. And it uses several different types of memory. Short-term memory is also known as primary or active memory. And is limited to what you remember for 20 to 30 seconds. At this point we’re comparing the different kinds of Cheerios sitting on the supermarket shelf. Long-term memory is the type of memory associated with an event or infor- mation you acquired long ago. This is a complicated form of memory influenced by your perception of an event or thing, conditioning or any other input. And is encoded using long-term potentiation and strengthening neurons and synapses. Long-term memory comes in when you remember that your family hated the type of Cheerios you brought home 3 weeks ago. And made you vow to never buy them again. Working memory is distinct from short-, and long-term memory. These are memories that are not only remembered, but simultaneously processed with 458 HEAD FIRST information that is important to you. You remember the purpose of the informa- tion, and why you decided to remember it. Working memory comes in when your reading Cheerios box labels. And recall that you should avoid GMO’s. And why GMO’s are bad for you. Added sugar is bad for you too. Each type of memory can be assisted by different nootropics. Because neu- rotransmitters, cerebral blood flow, long-term potentiation, hormones and more all come into play for memory. Just to buy a box of Cheerios. • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory and learning. • DHA (Omega 3). DHA makes up a large portion of your brain’s gray matter. This fatty acid helps form cell membranes, neurons and synapses which are needed to form and encode memories. • Huperzine-A. Hup-A helps promote memory by increasing acetylcholine (ACh) levels. Boosting ACh with Huperzine-A means you need to make sure there’s enough material available to make ACh in your brain. And we do that by using Alpha CPC or CDP-Choline. • L-Theanine. Found naturally in green tea and available as a nootropic supplement, L-Theanine helps boost dopamine and serotonin. Improving anxiety, focus, learning, and mood. This prevents you from melting down in the cereal aisle in the hunt for the perfect Cheerios selection. • Noopept. Noopept stimulates dopamine, and nicotinic (ACh) and se- rotonin receptors in your brain. Boosting cognition, memory, retention, logical thinking, improving your reflexes and mood. Here we’re taking our Cheerios hunt to the next level. • Phosphatidylserine (PS). PS is vital for brain health. Highly concentrated in cell membranes, PS helps in the release, storage and activity of neu- rotransmitters and receptors. Boosting cognition, focus, memory and recall. • Piracetam. The original nootropic, Piracetam influences AMPA and NMDA receptors in your brain. Affecting learning and memory. Make sure you boost your choline source when using Piracetam. By increasing your dosage of Alpha GPC or CDP-Choline. Boosting all types of memory with this nootropic stack means you’ve re- membered to grab the grocery list before you left home. You realize your family likes only one type of Cheerios. You recall where it is on the shelf once you get to the supermarket. And within a couple of weeks, your 30 – minute Cheerios hunt has been whittled down to 30-seconds. Life is good. Just a reminder to check dosage recommendations, side effects, drug interac- 459 David Tomen tions and more in the chapter before this where each nootropic is discussed in much more detail.

Best Nootropics for Depression & Anxiety

Do you remember what it used to be like to be in a ‘good mood’ all of the time? Making the trip to the supermarket to pick up the family’s Cheerios was fun. Simply marveling at the marketing ingenuity behind 20 different kinds of Cheerios made you laugh. There was no anxiety behind choosing the right box of Cheerios. And no depression behind the ridiculous increase in Cheerios prices from two years ago. But anxiety and depression are something most of us have had to deal with at one time of another. For me, being ADD and hypothyroid was like a double whammy. And it took a while to dig out of the hole I was in. Anxiety and depression are often ‘grouped’ together both in nootropic circles as well as in the psychiatric/medical world. But they are two distinctly different conditions. Even though the cause of anxiety and depression may overlap. All kinds of conditions can contribute to anxiety and depression. Neu- rotransmitter levels that are out of balance can cause severe depression. Illness and stress can cause anxiety and depression. Poor cerebral blood flow, a lack of Brain-Derived Neurotrophic Factor (BDNF), mental fatigue from lack of cellular energy, Alzheimer’s, Parkinson’s, stroke and more can all cause anxiety and depression. Here are a few nootropics that can help lift your mood, and quell the anxiety. But realize this is by no means an exhaustive list. These are what I’ve found work for me. They may work for you too. And if your depression or anxiety is severe, please, please seek professional help while you’re exploring your nootropic options. • Aniracetam. This member of the racetam-family of nootropics, Anirace- tam is very well known for helping anxiety and depression. And one of my favorites. Aniracetam activates D2 and D3 dopamine receptors in your brain. Improving anxiety, cognition, learning, memory and mood. I have used Aniracetam every day for the last few years. And can’t imagine doing without it. • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory, mood and learning. And the choline is needed when using any racetam (like Aniracetam). • Ashwagandha. Used for thousands of years in Ayurvedic medicine, Ashwa- gandha helps relieve stress, fatigue, restores energy and concentration, and normalizes blood sugar. 460 HEAD FIRST • Bacopa Monnieri. Bacopa is believed by some to be the best nootropic available today. This adaptogen helps prevent chemical and physical stress instead of suppressing them like many modern antidepressants. • Lemon Balm. This plant from the mint family, Lemon Balm inhibits the GABA transaminase enzyme. Which in turn helps maintain adequate levels of GABA in your brain. Resulting in a calming effect and relieving anxiety and depression. • Rhodiola Rosea. Rhodiola increases AMPK which helps decrease depres- sion and stress-related mood swings, reduces fatigue, stimulates energy and alertness and boots cognition.

• Sulbutiamine. Synthesized in the lab from Vitamin B1 (thiamine), Sulbu- tiamine is another favorite of mine because it boosts memory, motivation and is a heck of an antidepressant. I can’t imagine going a day without my 2-doses of Sulbutiamine.

• Vitamin B6. B6 is a required coenzyme for the synthesis of most major neurotransmitters in your brain. And helps enhance alertness, cognition, energy, memory and mood.

• Vitamin B12. B12 is essential for the synthesis of DNA, RNA and neu-

rotransmitters in your brain. B12 enhances alertness, cognition, memory, decision-making and mood. Note that you don’t need every nootropic listed here to alleviate your anxiety and depression. In fact, using everything on this list could do more harm than good unless you dramatically reduced your dosage of each. For example, if you decide to try Bacopa and Rhodiola, start with a dosage of 150 mg daily of Bacopa and only 50 mg per day of Rhodiola. And avoid using Lemon Balm and Ashwagandha. Experiment, and find your favorites. Each supplement is readily available at your local vitamin shop or online. Go for purity and organic if possible. The only nootropics in this stack I’d suggest you use no matter what else you choose are Alpha GPC or CDP-Choline and the B-Vitamins. Make shopping for Cheerios fun again.

Best Nootropics for Energy (physical & mental) & Motivation

If you’ve ever felt mentally drained after writing an exam, an intense study session, a misunderstanding with your partner, or working out a business prob- lem ▬ nootropics can help. 461 David Tomen Energy and motivation kinda’ go hand-in-hand in my book. When I’m energized, it usually translates into motivation to get things done. When energy stores are depleted in my brain and body, I’m burned out and nothing much is going to happen. Mental fatigue has a variety of causes. Depleted neurotransmitters can cause fatigue as well as a host of other issues. A lack of Adenosine Triphosphate (ATP) which is the energy source for brain cells is another cause of mental fatigue. And leads to neurodegenerative disease. Hormones that are out of balance can cause fatigue. And poor cerebral blood flow which provides oxygen and nutrients to brain cells can result in fatigue. The amount of available mental energy has a direct influence on cognitive and mental performance. Let’s look at the nootropics that can fix mental fatigue and boost motivation. • Acetyl L-Carnitine (ALCAR). ALCAR boosts acetylcholine (ACh) and transports fatty acids through cell membranes into mitochondria for use as brain cell fuel. One of my favorite nootropics, ALCAR increases memory, mental alertness, fluid thought and is a powerful antioxidant. If you decide to try ALCAR, you may be able to avoid using other choline precursors such as Alpha GPC or CDP-Choline. • Coluracetam. One of the newer racetams, Coluracetam works as a choline uptake enhancer. And improves AMPA potentiation. The net result is a boost in energy levels. Unlike prescription stimulants, Coluracetam offers a more relaxed, calm and free-minded kind of thought-processing. • CoQ10 & Ubiquinol. CoQ10 is essential for producing Adenosine Triphos- phate (ATP) that fuels the mitochondria in brain cells. Improving athletic performance, works as an antioxidant, and battles fatigue and depression. Ubiquinol should be part of every nootropic stack. Particularly if you’re over 40. • Creatine. Creatine acts as fuel for cells. Including your brain cells. And provides ‘energy on demand’ when you need it. Creatine is a favorite of nootropic users because of the fuel demanded by brain cells when using racetams. After crossing your blood-brain barrier, creatine binds to phos- phate. Creatine phosphate in turn fuels energy consumption by your brain. • NADH. NADH is a coenzyme used in the formation of Adenosine Triphos- phate (ATP), the energy source for mitochondria in your brain cells. NADH boosts alertness, mental performance, energy and memory. • Noopept. This peptide-derived nootropic related to the racetam family, Noopept increases Brain-Derived Neurotrophic Factor (BDNF), and stimu- 462 HEAD FIRST lates dopamine, nicotinic (ACh) and serotonin receptors. Boosting energy, cognition, memory, logical thinking, and improves reflexes and mood. • Phenylpiracetam. A Russian derivative of Piracetam, Phenylpiracetam improves concentration, memory, motivation, mental energy and offers a stimulant effect. • Rhodiola Rosea. Rhodiola increases AMPK which triggers the use of stored energy from fats in your brain cells. Boosting alertness, energy and cognition while decreasing depression and stress-related mood swings. • Pramiracetam. A derivative of and more potent than Piracetam, Prami- racetam stimulates choline uptake in your brain. Boosting energy levels, providing focused stimulation for better mental drive and motivation. If you choose Noopept or one of the racetams, make sure to add a good choline source like Alpha GPC or CDP-Choline. Check the full description in the previous chapter for dosage instructions. CoQ10 (Ubiquinol) and NADH can be added to every nootropic stack. And once again, choose your favorite from this list. You only want one of the racetams for this stack. A good choline source. And possibly Rhodiola. Experiment and find out what works best for you to raise your energy and motivation levels.

Best Nootropics for Brain Repair and Maintenance

According to the American Center for Disease Control (CDC) an estimated 1.7 million in the US suffer from Traumatic Brain Injury every year. 1010 And that’s just for the USA. This is clearly a world-wide problem for the human race. Brain injury covers a lot of territory and includes concussion, Post Stroke Syndrome, sports and athletic injuries, damage from pharmaceuticals, environ- mental toxins, bad food and water, polluted air and more. The mechanics of injury can affect cerebral blood flow, torn tissue, damage to neurons, altered brain waves and neurotransmitters, free radical and oxidative damage and more. Now the “official” line from the FDA and other governmental authorities in the USA and many countries world-wide, nootropic supplements and other ‘natural’ substances cannot repair brain injury. While this is certainly not medical advice, and you should absolutely seek pro- fessional medical help for brain injury, neurohackers have found relief on their own experimenting with nootropics. Here’s a small sample of what we’ve found useful. • CDP-Choline. CDP-Choline provides your brain with choline which aids in 463 David Tomen the synthesis of acetylcholine (ACh). And cytidine in CDP-Choline converts to uridine which is important for neural membrane synthesis. • DHA (Omega 3). DHA makes up a large portion of your brain’s gray matter. This fatty acid helps form cell membranes, neurons and synapses which are needed to form and encode memories. • Phosphatidylcholine (PC). PC is a phospholipid which helps build and repair brain cell membranes. • PQQ. The enzyme cofactor PQQ facilitates the growth of new mitochon- dria in your brain cells. Boosting the production of nerve growth factors in cells that support creation of new neurons. And reduces inflammation and oxidative stress. • Pramiracetam. This derivative ofPiracetam , Pramiracetam increases ace- tylcholine receptors in your brain. By stimulating choline uptake in your brain, this nootropic boosts energy levels and improves cognition and motor coordination. • Pterostilbene. Found in cranberries, blueberries and grapes, Pterostilbene is a potent antioxidant, stimulates Brain-Derived Neurotrophic Factor (BDNF), and promotes neuroplasticity. By reducing oxidative stress, Pterostilbene not only helps repair your brain, but also helps prevent heart attacks and stroke. • Resveratrol. This polyphenol antioxidant found in the skin of grapes, Resveratrol improves blood flow and reduces inflammation. Improving cell survival and neurogenesis in the hippocampus, resulting in better memory and learning. • Turmeric. Turmeric is unique in its ability to reduce inflammation common to Parkinson’s, Alzheimer’s and brain tumors. Now there’s a temptation to throw everything into this nootropic stack if you’re having real problems with brain damage. But once again caution is advised. Work with a professional neurologist while you’re experimenting, and exploring your nootropic options. All the nootropics on this list are safe to use within recommended doses. But each of us has unique brain and body chemistry. And each of us will react differently to everything on this list. These are general guidelines on what we’ve found to work with brain repair. And maintaining a healthy brain. Start with low doses of three or four from the list. See how your body and brain reacts. And continue to experiment. Try new nootropics until you find your ideal stack.

464

How to Create the Best Nootropic Stack

f you’ve spent any time on my website NootropicsExpert.com, or have I experimented with nootropics before, you have a good idea how certain noo- tropic supplements can benefit your brain. But if you’re just getting started with nootropics, the choices can seem over- whelming. Where do you start? Allow me a minute or two to share my story. How I discovered nootropics. And how I ended up with the nootropic stack I’m using now. About ten years ago my wife introduced me to her psychiatrist. My career and relationship were on rocky ground and she was desperate. So was I. What happened next was nothing short of a miracle to my mind. Within 10 minutes this very wise and knowledgeable man diagnosed me as Adult ADD. This of course was news to me. But what happened as a result of that first meeting was a complete life change. This doctor prescribed Ritalin. From the first day it was like someone had flipped the switch. And turned the lights on in my brain. For the first time in my adult life I could focus. My thinking became clearer. This complete transformation lasted for about 7 years. But Ritalin wasn’t as effective for ADD symptoms as it was in the beginning. I had been diagnosed as hypothyroid a couple of years prior. The brain fog and fatigue were taking its toll on my career and marriage again. We tried switch- ing to Adderall and it didn’t work. By then I’d learned enough about how my brain worked. Had a good idea what was wrong. And decided to go the “natural” route with nootropics. I discovered a pre-formulated nootropic stack that helped me avoid going back on stimulants. My life started to turn around and continued to get better as I experimented with other nootropics. I continue to use that pre-formulated nootropic stack (which I’ll tell you about in a minute). My current daily nootropic stack is constantly evolving the more I learn. 465 David Tomen The Most Effective Nootropic Stack for You

So what’s your story? What are you trying to do with nootropics? If you are a university student, an entrepreneur, a business executive, a stay- at-home mom or dad, or a senior – what are you trying to improve? It could be just one thing you want to work on. Like improving your memory. Maybe you have a difficult time focusing like I did. Or you find learning new material, a skill or language an insurmountable problem. You could have an issue with anxiety, or bouts of depression. Procrastination could leave you feeling like a failure because of a lack of motivation. For many of us, it’s more than just one problem we’re trying to fix. In my case, the combination of ADD and hypothyroidism caused problems with anxi- ety, cognition, focus, memory, and depression. That’s a lot to deal with and a lot to fix.1011 1012 The good news is it’s entirely possible with the right combination of noot- ropics to address each of these issues. My life is a good example of what’s possible with the right nootropic stack. I’m deeply grateful for doing extremely well in my career. My marriage is better than I ever dreamed possible. And my future looks amazing. But where do you start? If you’re trying to fix one thing, like memory or de- pression, it narrows the list of nootropics down to something more manageable. But to be perfectly honest with you, one nootropic that works for me, may not work as well for you. Each of us have unique brain “wiring”. Our chemical makeup is different. And is affected by foods we eat, where we live, the air we breathe, the genes we inherited from our parents, and more. So experimentation is key. Pick your top choice of something you’d like to improve. Once you find something that works reasonably well, go to the next thing on your list. With time, effort and diligent experimenting you’ll find the perfect noot- ropic stack for you.

Your First Nootropic Stack

My recommendation is to create your own nootropic stack when starting out. Tailor your stack to each issue your trying to solve. It’ll likely be more expen- sive because you need to get each individual nootropic or supplement. The advantages at first outweigh the cost in my opinion. When you find something that works, you then need to figure out how much of that nootropic works best with your brain and body. If you try something and it doesn’t work as well as expected, or what you were promised in the marketing hype, or what you read on the forums – pitch it. 466 HEAD FIRST And try something else. Flexibility and experimentation is key when you’re getting started with noot- ropics. A pre-formulated stack doesn’t allow that flexibility. Keep that option in reserve until you nail down what works best for you. Then look for a nootropic stack that fills all your requirements. Let’s briefly look at some of your options for major issues to get you started. This is by no means an exhaustive list but a way to point you in the right direction. Use the search function on Nootropics Expert to find every nootropic that works for memory, or depression, or anxiety, or whatever it is you need to fix.

Nootropics for Cognition, Thinking and Decision-Making Cognition is the mental action or process you go through when learning something new and understanding it through thought, experience and your physical senses.1013 Cognition includes thinking, knowing, short-, working-, and long-term memory, decision-making and problem solving. That’s a tall order to cover and will likely take more than one nootropic. You can start with: • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory and learning. • Lion’s Mane Mushroom. Lion’s Mane increases Brain Nerve Growth Factor or neurogenesis. Improving attention, focus, thinking, depression, anxiety, and helps repair damaged neurons. • N-Acetyl L-Tyrosine (NALT). NALT is a bio-available form of L- Tyrosine which is a precursor to dopamine in your brain. More dopamine helps improve alertness, focus, working memory and executive function (decision-making).

• Vitamin B6. B6 is a required coenzyme for the synthesis of most major neurotransmitters in your brain. And helps enhance alertness, cognition, energy, memory and mood.

• Vitamin B12. B12 is essential for the synthesis of DNA, RNA and neu- rotransmitters in your brain. B12 enhances alertness, cognition, memory, decision-making and mood.

Nootropics for Memory We use several different types of memory every day. Short-term memory is also known as primary or active memory. And is limited to what you remember for 20 to 30 seconds. Long-term memory is the type of memory associated with an event or infor- mation you acquired long ago. This is a complicated form of memory influenced 467 David Tomen by your perception of an event or thing, conditioning or any other input. And is encoded using long-term potentiation and strengthening neurons and synapses. Working memory is distinct from short-, and long-term memory. These are memories that are not only remembered, but simultaneously processed with information that is important to you. You remember the purpose of the informa- tion, and why you decided to remember it.1014 Each type of memory can be assisted by different nootropics. Because neu- rotransmitters, cerebral blood flow, long-term potentiation, hormones and more all come into play for memory. • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory and learning. • DHA (Omega 3). DHA makes up a large portion of your brain’s gray matter. This fatty acid helps form cell membranes, neurons and synapses which are needed to form and encode memories. • Huperzine-A. Hup-A helps promote memory by increasing acetylcholine levels. • L-Theanine. Found naturally in green tea and available as a nootropic supplement, L-Theanine helps boost dopamine and serotonin. Improving anxiety, focus, learning, and mood. • Noopept. Noopept stimulates dopamine, nicotinic and serotonin receptors in your brain. Boosting cognition, memory, retention, logical thinking, improving your reflexes and mood. • Phosphatidylserine (PS). PS is vital for brain health. Highly concentrated in cell membranes, PS helps in the release, storage and activity of neu- rotransmitters and receptors. Boosting cognition, focus, memory and recall. • Piracetam. The original nootropic, Piracetam influences AMPA and NMDA receptors in your brain. Affecting learning and memory.

Nootropics for Anxiety and Depression Do you remember what it used to be like to be in a ‘good mood’ all of the time? Anxiety and depression are something most of us have had to deal with at one time of another. For me, being ADD and hypothyroid was like a double whammy. And it took a while to dig out of the hole I was in. Anxiety1015 and depression1016 are often ‘grouped’ together both in nootropic circles as well as in the psychiatric/medical world. But they are two distinctly dif- ferent conditions. Even though the cause of anxiety and depression may overlap. All kinds of conditions can contribute to anxiety and depression. Neu- 468 HEAD FIRST rotransmitter levels that are out of balance can cause severe depression. Illness and stress can cause anxiety and depression. Poor cerebral blood flow, a lack of Brain-Derived Neurotrophic Factor (BDNF), mental fatigue from lack of cellular energy, Alzheimer’s, Parkinson’s, stroke and more can all cause anxiety and depression.’ Here are a few nootropics that can help. This is by no means an exhaustive list. And if your depression or anxiety is severe, please, please seek professional help while you’re exploring your nootropic options. • Aniracetam. This member of the racetam-family of nootropics, Aniracetam is very well known for helping anxiety and depression. And one of my fa- vorites. Aniracetam activates D2 and D3 dopamine receptors in your brain. Improving anxiety, cognition, learning, memory and mood. • Alpha GPC or CDP-Choline. Both nootropics help boost acetylcholine (ACh) in your brain. ACh is associated with memory and learning. And the choline is needed when stacked with any racetam. • Ashwagandha. Used for thousands of years in Ayurvedic medicine, Ashwa- gandha helps relieve stress, fatigue, restores energy and concentration, and normalizes blood sugar. • Bacopa Monnieri. Bacopa is believed by some to be the best nootropic available today. This adaptogen helps prevent chemical and physical stress instead of suppressing them like many modern antidepressants. • Lemon Balm. This plant from the mint family, Lemon Balm inhibits the GABA transaminase enzyme. Which in turn helps maintain adequate levels of GABA in your brain. Resulting in a calming effect and relieving anxiety and depression. • Rhodiola Rosea. Rhodiola increases AMPK which helps decrease depres- sion and stress-related mood swings, reduces fatigue, stimulates energy and alertness and boots cognition.

• Sulbutiamine. Synthesized in the lab from Vitamin B1 (thiamine), Sulbu- tiamine is another favorite of mine because it boosts memory, motivation and is a heck of an antidepressant.

• Vitamin B6. B6 is a required coenzyme for the synthesis of most major neurotransmitters in your brain. And helps enhance alertness, cognition, energy, memory and mood.

• Vitamin B12. B12 is essential for the synthesis of DNA, RNA and neu- rotransmitters in your brain. B12 enhances alertness, cognition, memory, decision-making and mood. 469 David Tomen Nootropics for Energy and Motivation If you’ve ever felt mentally drained after writing an exam, an intense study session, a misunderstanding with your partner, or working out a business prob- lem ▬ nootropics can help. Energy and motivation kinda’ go hand-in-hand in my book. When I’m energized, it usually translates into motivation to get things done. When energy stores are depleted in my brain and body, I’m burned out and nothing much is going to happen. Mental fatigue has a variety of causes. Depleted neurotransmitters can cause fatigue as well as a host of other issues. A lack of Adenosine Triphosphate (ATP) which is the energy source for brain cells is another cause of mental fatigue. And leads to neurodegenerative disease. Hormones that are out of balance can cause fatigue. And poor cerebral blood flow which provides oxygen and nutrients to brain cells can result in fatigue. The amount of available mental energy has a direct influence on cognitive and mental performance. Let’s look at the nootropics that can fix mental fatigue and boost motivation. • Acetyl L-Carnitine (ALCAR). ALCAR boosts acetylcholine (ACh) and transports fatty acids through cell membranes into mitochondria for use as brain cell fuel. One of my favorite nootropics, ALCAR increases memory, mental alertness, fluid thought and is a powerful antioxidant. • Coluracetam. One of the newer racetams, Coluracetam works as a choline uptake enhancer. And improves AMPA potentiation. The net result is a boost in energy levels. Unlike prescription stimulants, Coluracetam offers a more relaxed, calm and free-minded kind of thought-processing. • CoQ10 & Ubiquinol. CoQ10 is essential for producing Adenosine Triphos- phate (ATP) that fuels the mitochondria in brain cells. Improving athletic performance, works as an antioxidant, and battles fatigue and depression. • Creatine. Creatine acts as fuel for your brain cells. And provides ‘energy on demand’ when you need it. • NADH. NADH is a coenzyme used in the formation of ATP, the energy source for mitochondria in your brain cells. NADH boosts alertness, mental performance, energy and memory. • Noopept. This peptide-derived nootropic related to the racetam family, Noopept increases BDNF, and stimulates dopamine, nicotinic and serotonin receptors. Boosting energy, cognition, memory, logical thinking, and im- proves reflexes and mood. • Phenylpiracetam. A Russian derivative of Piracetam, Phenylpiracetam 470 HEAD FIRST improves concentration, memory, motivation, mental energy and offers a stimulant effect. • Rhodiola Rosea. Rhodiola increases AMPK which triggers the use of stored energy from fats in your brain cells. Boosting alertness, energy and cognition while decreasing depression and stress-related mood swings. • Pramiracetam. A derivative of and more potent than Piracetam, Prami- racetam stimulates choline uptake in your brain. Boosting energy levels, providing focused stimulation for better mental drive and motivation.

Nootropics for Brain Repair and Maintenance According to the American Center for Disease Control (CDC) an estimated 1.7 million in the US suffer from Traumatic Brain Injury every year.1017 And that’s just for the USA. This is clearly a world-wide problem for the human race. Brain injury covers a lot of territory and includes concussion, Post Stroke Syndrome, sports and athletic injuries, damage from pharmaceuticals, environ- mental toxins, bad food and water, polluted air and more. The mechanics of injury can affect cerebral blood flow, torn tissue, damage to neurons, altered brain waves and neurotransmitters, free radical and oxidative damage and more. Now the “official” line from the FDA and other governmental authorities in the USA and many countries world-wide, nootropic supplements and other ‘natural’ substances cannot repair brain injury. While this is certainly not medical advice, and you should absolutely seek professional medical help for brain injury, neurohackers have found relief on their own experimenting with nootropics. Here’s a small sample of what we’ve found useful: • CDP-Choline. CDP-Choline provides your brain with choline which aids in the synthesis of acetylcholine (ACh). And cytidine in CDP-Choline con- verts to uridine which is important for neural membrane synthesis. • DHA (Omega 3). DHA makes up a large portion of your brain’s gray matter. This fatty acid helps form cell membranes, neurons and synapses which are needed to form and encode memories. • Phosphatidylcholine (PC). PC is a phospholipid which helps build and repair brain cell membranes. • PQQ. The enzyme cofactor PQQ facilitates the growth of new mitochon- dria in your brain cells. Boosting the production of nerve growth factors in cells that support creation of new neurons. And reduces inflammation and oxidative stress. 471 David Tomen • Pramiracetam. This derivative of Piracetam, Pramiracetam increases ace- tylcholine receptors in your brain. By stimulating choline uptake in your brain, this nootropic boosts energy levels and improves cognition and motor coordination. • Pterostilbene. Found in cranberries, blueberries and grapes, Pterostilbene is a potent antioxidant, stimulates Brain-Derived Neurotrophic Factor (BDNF), and promotes neuroplasticity. By reducing oxidative stress, Pterostilbene helps prevent heart attacks and stroke. • Resveratrol. This polyphenol antioxidant found in the skin of grapes, Resveratrol improves blood flow and reduces inflammation. Improving cell survival and neurogenesis in the hippocampus, resulting in better memory and learning. • Turmeric. Turmeric is unique in its ability to reduce inflammation common to Parkinson’s, Alzheimer’s and brain tumors.

Conclusion

There are many ways to address each issue you’re dealing with when it comes to optimizing brain health and function. If you’re a nootropic veteran I’m sure you’ll find holes in my recommenda- tions. Each section is most definitely not a conclusive list of nootropics for a single condition. I encourage you to visit, and use the “Search” function on my website Noo- tropicsExpert.com. Enter the issue you’re dealing with and you’ll get a list of articles with suggestions for your nootropic stack. There are a ton of ‘nootropics’ websites out there. And the last truly authori- tative books written on the subject were published 15 and 20 years ago. So it can get very confusing and overwhelming. Especially if you’re just starting out with nootropics and brain optimization. My intention with Noo- tropicsExpert.com, and for this book, was to collate as much good information in one place as I could find. To make it easier for anyone at any level of expertise. But one strong word of caution when experimenting with new nootropic supplements. For example, by no means should you include everything listed under “memory” in your stack. One or two options from each section can help you toward your ideal nootropic stack. Many nootropics work synergistically and together can make a more power- ful solution than a nootropic on its own. When combining several nootropics in a stack you’ll want to back off to the lowest recommended dose of each to start. 472 HEAD FIRST My Nootropic Stack

Early in this chapter I promised to reveal the pre-formulated stack that I used to replace prescription stimulants for Adult ADD. After experimenting with many of the well-known stacks, I settled on Mind- Lab Pro. MindLab Pro contains therapeutic dosages of 11 top quality natural noo- tropics I’ve included in this book. I’ve found it less expensive to use this stack than buying each nootropic on its own. All I’ve had to add is coconut oil, DHA, Aniracetam and Sulbutiamine. If you have questions about building your perfect nootropic stack, I encour- age you to post a question in the comments section on the relevant article or review at NootropicsExpert.com. I or another experienced neurohacker in our community will help you out.

473

Nootropics Glossary

Acetylcholine Acetylcholine (ACh) is the acetic ester of choline, and is a neurotransmitter. ACh is found throughout your body. But in nootropics we typically refer to ace- tylcholine function in the Central Nervous System and specifically the brain.1018 Some nootropics upon entering your brain separate into compounds that can make acetylcholine. Others may increase the uptake of acetylcholine in the brain. Acetylcholine’s function in the brain is critical for encoding new memo- ries, reasoning, concentration, cognition, and growth of new synapses (neuro- plasticity). Lack of acetylcholine can result in diseases like ADD, ADHD and Alzheimer’s.

Adaptogen Adaptogens are a class of herbs that help the body adapt to stress, and exert a normalizing effect in your body. As a nootropic, adaptogens can help strengthen mental fortitude, and can help maintain active, energized thinking in response to the brain-dulling effects of prolonged stress. Adaptogens are valued for their ability to boost endurance and physical per- formance. Examples of adaptogens popular in the nootropic community include Rhodiola and Ashwagandha.

Adenosine Triphosphate (ATP) Adenosine Triphosphate (ATP) is the “energy currency of life”. ATP is a coenzyme that is synthesized in the energy factories called mitochondria within each of your brain cells. Adequate levels of ATP are crucial for peak brain performance. As we age, blood flow to the brain decreases and ATP production declines. If your brain cells don’t have an adequate supply of ATP, they die.

Advanced Glycation End Products (AGEs) AGEs form in your body when proteins or fats combine with sugars (glyca- 474 HEAD FIRST tion). This can harm the normal function of cells, making them more susceptible to damage and premature aging. Your body can naturally rid itself of harmful AGEs, but it doesn’t eliminate them effectively when too many are ingested through food. The accumulation of AGEs has been linked to aging, chronic illness, and cardiovascular, liver and Alzheimer’s disease.

Age-Related Cognitive Decline Studies have shown the aging brain undergoes a loss of grey and white matter volumes in the brain.1019 This has become one of the biggest health threats of this century. And it’s primarily because we’re living longer. It manifests as brain fog, memory problems, verbal communication declines, cognition slows down, and eventually could develop into dementia or Alzheimer’s Disease. Many nootropics help prevent and often reverse the effects of Age-Related Cognitive Decline.

Agonist An agonist is a chemical substance in your body that is capable of activating a neuroreceptor to induce a full or partial response.

Alkaloid An alkaloid is typically of plant origin. It contains nitrogen which gives an alkaline (pH value greater than 7.0) reaction when mixed with a solution such as water. Many alkaloids cause pharmacological effects in humans. Alkaloid substance names generally end in “-ine”. Examples are caffeine, morphine, quinine and nicotine.

Amino Acids Amino acids are used in every cell of your body and are used to form proteins. Amino acids give cells their structure, transport and store nutrients, and influence the function of arteries, glands, organs and tendons. They repair tissue and remove waste from cells. Scientists have discovered about 50 amino acids. Only 20 are used to make proteins in your body. Of those 20, 9 are defined as essential. Meaning your body needs to get them from sources outside the body like food. The other 11 can be synthesized within your body. Essential Amino Acids: Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, and Valine. Nonessential Amino Acids: Alanine, Arginine, Asparagine, Aspartate, Cyste- ine, Glutamate, Glutamine, Glycine, Proline, Serine and Tyrosine. 475 David Tomen Amyloid Plaques & Neurofibrillary Tangles Amyloid Plaques are accumulations of protein fragments that have clumped together in the space between brain neurons. This prevents normal brain func- tion. And is strongly indicated in the formation of Alzheimer’s Disease. Neurofibrillary Tangles are found within brain cells. In microtubules neces- sary for interaction with brain cells. When these microtubules collapse, twisted fibers of these proteins are called Neurofibrillary Tangles. And are also strongly indicated in the formation of dementia and Alzheimer’s Disease.

Ampakines Ampakines are nootropics that modulate AMPA receptors in your brain. These receptors work like control channels, overseeing and regulating synaptic transmissions. Ampakines seem to adjust neuroreceptors in order to allow them to work as needed rather forcing them. The result of this action is a stimulant-like effect without any of the negative side effects associated with stimulants (i.e. nervous- ness, insomnia). Many racetams could be considered Ampakines.

AMPA Receptors The AMPA receptor is paired with an ion channel so that when glutamate binds to this receptor, the channel lets sodium ions enter that neuron. This sodium causes the dendrite of that neuron to become locally depolarized. Once this depolarization reaches a critical threshold, it triggers an action so this nerve impulse is transmitted to the next neuron.

Antagonist An antagonist is a chemical substance in your body which counteracts or blocks the effects of another substance. For example, an antagonist at a neurore- ceptor blocks or lowers the activity of that receptor.

Anxiolytics Anxiolytics are anti-anxiety natural nootropic supplements, or prescription drugs used to prevent anxiety.

Apoptosis Apoptosis is ‘programmed cell death’ in your body and brain. If cells are no longer needed, they commit suicide. In a healthy adult human, billions of cells die in various parts of your body every hour for different reasons. But mainly to main- tain homeostasis within that organ or body tissue. When apoptosis is disrupted, disease happens. Cancer is a classic example of cell proliferation gone awry. 476 HEAD FIRST Attention Deficit Disorder ADD is officially called Attention-Deficit/Hyperactivity Disorder, or AD/ HD (American Psychiatric Association, 1994). This disease is divided into three subtypes; inattentiveness, impulsivity, and hyperactivity. Scientific evidence suggests that the disorder is genetically transmitted in many cases. And results from a chemical imbalance or deficiency in certain neurotransmitters.1020 ADD is characterized by a person’s inability to complete tasks and process information at normal rates. The abnormal function of the neurotransmitter dopamine is usually implicated in this disease.

Attention Deficit/Hyperactivity Disorder See Attention Deficit Disorder.

Axons Each neuron in your brain can have thousands of dendrites, but only one axon. The neuron uses its axon to transmit an action potential (electrochemical signal) down the length of the axon. With the intent of finding neighboring neuron’s dendrites to communicate with.

Ayurveda Ayurveda is the traditional Hindu system of medicine practiced for thou- sands of years in India. It is based on the ideal balance of bodily systems and uses diet, herbal treatments and yoga.

Benzodiazepines Benzodiazepines are a class of psychoactive drugs used to treat anxiety, insomnia, panic attacks, and other conditions. Benzodiazepines work by enhancing the effect of the neurotransmitter GABA which is responsible for governing the activity of neurons related to stress and anxiety. Well known benzodiazepines include Valium, Klonopin and Xanax.

Bioavailability Bioavailability is the proportion of the nootropic or other substance that once it enters your body’s circulation, is able to have an effect. And is not just eliminated as waste.

Blood-brain Barrier Theblood-brain barrier is made up of a layer of endothelial cells that when functioning properly, allows precise control over the substances that enter or leave the brain. The blood-brain barrier’s main function is to protect the brain from things 477 David Tomen that may injure it. In the world of nootropics, we’re interested in substances and compounds that easily cross the blood-brain barrier. Or what needs to be added to help it cross.

Brain-Derived Neurotrophic Factor (BDNF) Neurotrophic factors are a family of proteins that are responsible for the growth and survival of nerve cells. In the brain they’re called brain-derived neurotrophic factor and the brain nerve cells are called neurons. In the brain, BDNF is released by either a nerve cell or a support cell, such as an astrocyte, and then binds to a receptor on a nearby nerve cell. This binding results in the production of a signal which can be transported to the nucleus of the receiving nerve cell. There, it prompts the increased production of proteins associated with nerve cell survival and function.1021

Brain waves The brain is an electrochemical organ. Researchers speculate that a fully functioning brain can generate as much as 10 watts of electrical power. So brain waves are an electrical impulse in the brain.1022 Brain waves occur when neurons send signals between each other. There are several different types of brain waves. But the main ones are Beta, Alpha, Theta, and Delta. Beta waves are the most rapid pattern. And are associated with concentra- tion, arousal, alertness and cognition. You experience Alpha waves as you become more relaxed. The brain waves slow into an Alpha wave pattern. Associated with super-learning, flow states and joy. Still slower brain wave patterns are Theta waves. Often experienced by medi- tators. When you’re dreaming at night, you’re making Theta waves. Theta waves are associated with creativity, “integrative experiences” and relief from trauma. An “ah-ha moment” is a burst of Theta waves in your brain. The slowest of all brain wave patterns are Delta Waves. They are generally associated with dreamless sleep. Very advanced meditators are able to remain alert in this deep, trance-like state. Delta waves are associated with leadership, persuasion, achievement and Oneness.

Catecholamines Catecholamines are amines derived from the amino acid tyrosine. In noot- ropics we focus mostly on dopamine, epinephrine (adrenaline), and norepinephrine which act as hormones or neurotransmitters.

Central Nervous System Thecentral nervous system is the entire accumulation of nerves in the brain and spinal cord. 478 HEAD FIRST This nerve “highway” uses neurons to send and receive information through- out your body. And is protected by cerebrospinal fluid (CFS).

Cerebral The word “cerebral” gets its meaning from cerebrum, which is Latin for brain.

Cerebral Circulation Cerebral Circulation refers to the way blood flows, or circulates, in the brain. Cerebral circulation is your brain’s source for the healthy exchange of oxygen and nutrients needed to function properly.

Chronic Fatigue Syndrome (CFS) Chronic Fatigue Syndrome (CFS) is a disorder that causes extreme ongoing fatigue. Not the kind of fatigue that goes away after you rest. Symptoms last for 6 months or more. And is characterized by a general feel- ing of being unwell, muscle pain, memory problems, pain in multiple joints, headaches and sleep problems. CFS is often treated medically with stimulants like Adderall.

Circadian Rhythm Circadian rhythm is your 24-hour built-in body clock. It can be affected by external cues like light and temperature. Circadian rhythms are critical in determining your sleeping and eating pat- terns. Patterns in brain wave activity, hormone production and other biological processes in your body are linked to this daily cycle.

Cognition Cognition is the mental action or process of acquiring knowledge and understanding through thought, experience and the senses. Cognition includes thinking, knowing, memory, decision-making and problem solving.

Concentration Concentration is defined as the action or power of focusing your attention or mental effort. Without distractions or interference. Certain nootropics can help to bolster your enthusiasm, skill and commit- ment towards your desired goal.

Coenzyme A coenzyme is an organic molecule (nonprotein) that binds with a protein to form an active enzyme. By themselves, coenzymes cannot catalyze a reaction, but can help enzymes to. Vitamins B1, B2 and B6 can serve as coenzymes. Cortex In your brain, the cortex is the outer layer of gray matter covering the cere- 479 David Tomen bral hemispheres. It is understood to be the area of higher mental functions such as cognition, intellect, and volition. Cyclic Adenosine Monophosphate (cAMP) Cyclic Adenosine Monophosphate (cAMP) is a derivative of adenosine triphosphate (ATP) and is used for intracellular signaling. In the brain, cAMP affects the function of higher-order thinking in the prefrontal cortex. It is thought to play an important role in the formation of memories. In theory, by boosting cAMP, you can increase memory function and optimize overall brain performance.

Cycling Tolerance is a problem with some nootropics. Consistent non-stop use can cause their effectiveness to diminish over time. It is also possible for some nootropic users to develop a psychological depen- dence (addiction) to compounds from prolonged use. Even though there is no physical addiction or withdrawal symptoms. One way to circumvent or avoid tolerance or dependence is to “cycle” the use of certain nootropics. Find out what the tolerance characteristics (if any) are for each of the nootropics you are using. And develop a schedule to stop their use for a short period of time. For example, you could use Huperzine-A for 5 days at the recommended dose and take a break for 2 days.

DNA (deoxyribonucleic acid) DNA is located in each of your cell’s nucleus (cellular DNA). A small amount of DNA is also found in the mitochondria within each cell (called mitochondrial DNA or mtDNA). And is stored as code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is kind of like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell. 480 HEAD FIRST Demethylation Demethylation is the removal of a methyl group from a molecule.

Dendrites Dendrites are like branches projecting out of neurons that act like an an- tenna. Dendrites receive electrical signals sent by the synapses of neighboring neuron axons. You can have as many as 15,000 dendrites projecting from a single neuron. When you experience incoming stimuli from your senses, neuron activity in- creases. And dendritic spines change size, shape and conduction leading to long- term potentiation (LTP). This change in dendritic spines (neuroplasticity) and long-term potentiation plays a fundamental role in learning and memory.

Dopamine Dopamine is a neurotransmitter that serves as a chemical signal or messen- ger between neurons (brain nerves). When it’s released from the first neuron, it travels into the space (synapse) between the two neurons. And bumps up against receptors on the second neuron. Dopamine has five receptor types it interacts with. But is mostly associated with “feel good” or reward behavior life sex, drugs and rock and roll. Dopamine also aids in memory formation, learning and retention, attention and focus, cognition, and sleep. Insufficient levels of dopamine are associated with anxiety, Attention Deficit Disorder (ADD) and Parkinson’s Disease.

Downregulation Downregulation is a process in your brain where the amount of activity in a particular neuron receptor decreases. This typically happens in response to abnormally high activity in response to one particular drug or nootropic. In other words, too much of one nootropic all at once. Or for an extended period of time.

Encoding Before information can be stored as memories, it first needs to be encoded. Encoding is the conversion of information into a form the brain can use. There are 3 types of encoding: 1. Acoustic encoding is when you use sound to record information. 2. Visual encoding is when a person uses mental images to remember something. 3. Semantic encoding is when you remember the actual meaning or signifi- cance of information. Semantic encoding is the most important part of long term memory encoding. 481 David Tomen Epinephrine Epinephrine is also called adrenaline. Epinephrine is typically released in response to acute stress (fight or flight response). This hormone is secreted mainly by the adrenal glands. In the medulla region of the adrenals, the amino acid tyrosine is transformed into norepinephrine. Through a complex process involving an enzyme and cells in the adrenal medulla, norepinephrine is turned into epinephrine. Epinephrine increases cardiac output and raises glucose levels in the blood. In the brain, surges of epinephrine can negatively affect memory. Epinephrine plays an important role in regulating arousal, reward and sensitivity to our environment.1023

Executive Function Executive function is a set of mental skills including working memory, mental flexibility and self-control that help you get things done. These skills are controlled in the frontal lobe of your brain. They help you pay attention, manage time, switch focus, plan and organize, remember details, and avoid saying the wrong thing. When executive function isn’t working well, your behavior is less controlled. Executive function is often related to ADHD.

Fat Soluble There are two varieties of supplements; water soluble and fat soluble. Water soluble supplements like any of the B Vitamins and Vitamin C dis- solve in water. And excess amounts are excreted through your kidneys if you have excess amounts in your system. Fat soluble supplements including vitamins A, D, E, K and most of the racetams dissolve in fat. And are stored in fat in your body (your brain is 60% fat). For fat soluble nootropics to be more effective they need to be taken with some type of fat. Examples are a tablespoon of coconut or extra virgin olive oil. Unlike water soluble supplements which go directly into your bloodstream, fat-soluble nootropics are absorbed through your intestinal wall and into your lymph system. Once in your lymph system, the nootropics are sent to your bloodstream where they are available for use by your brain.

Focus Focus is the act of directing your total attention towards a specific task. Suc- cessful focus is achieved with a singular presence of mind when completing a task. Conversely, multi-tasking is not focus. Focus is simply the act of undergoing only one task.

Free Radicals Free radicals, reactive oxygen species and reactive nitrogen species are gen- 482 HEAD FIRST erated by your body by various natural systems, exposure to different natural chemical conditions or pathological states. A balance between free radicals and antioxidants to counteract them is necessary for healthy cell function. Free radicals cause problems for lipids, proteins and DNA and can trigger a number of human diseases. Antioxidants can assist in coping with this oxidative stress.

Glial Cells Glial cells or glia are distinct from neurons (nerve cells). Types of glial cells include astrocytes, ependymal cells, microglia, Schwann cells, and oligodendrocytes. And make up the white matter in your brain which accounts for about 90% of your brain cells. Astrocytes help provide nutrients to neurons. And oligodendrocytes help produce the myelin sheath coating protecting the axons protruding from neurons.

Glutamate Glutamate is a neurotransmitter that is responsible for sending signals be- tween neurons in the brain. This plays an important role in learning and forming memories.

Gray Matter Gray matter in the brain is packed with billions of neurons. Because there are so many of them it’s tempting to think of neurons as very tiny. In reality, some neurons have axons (nerve fibers) that are very long. When many axons are grouped together, they appear as white matter. White matter is a collection of long, insulated axons which are the outgoing branches of neurons that connect various parts of the brain together. The white color comes from myelin, which is the lipid, insulating material wrapped around those long axons.

Hippocampus The hippocampus is a small region of your brain associated with long-term memory and spatial navigation. In disease such as Alzheimer’s, the hippocampus is one of the first areas of the brain to become damaged. This leads to memory loss and disorientation.

Histamine Histamine is a type of biogenic amine neurotransmitter that is responsible for behavior like wakefulness and arousal. It also plays an important part in motiva- tion and reward-oriented behavior. Histamine is essential in the acquisition and storage of short and long-term memory. When histamine signaling goes wrong in the brain it can lead to addic- tive behavior and degenerative diseases like Parkinson’s and multiple sclerosis.1024 483 David Tomen Ion Channel An Ion Channel is a cell structure which lets ions enter or leave. Ion chan- nels are sometimes associated with neuroreceptors which open or close a channel depending on the presence of a neurotransmitter.

Krebs Cycle Krebs Cycle is also known as the “citric acid cycle”, or tricarboxylic acid (TCA) cycle. This cycle is at the center of cellular respiration in your brain. And through- out the cells in your body. The Krebs cycle is a series of chemical reactions used to release stored energy through the oxidation of acetyl-CoA (which is derived from carbohydrates, fats and proteins). It releases this energy in the form of adenosine triphosphate (ATP). This metabolic pathway is derived from citric acid (tricarboxylic acid) that is consumed and regenerated by this sequence of events to complete the cycle. This cycle consumes acetate (acetyl-CoA) and water, and reduces NAD+ to NADH. Which produces carbon dioxide as a waste byproduct. The NADH generated by the Krebs cycle is fed into the oxidative phosphory- lation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients needed as chemical energy to form ATP. The primary source of fuel for your brain cell’s mitochondria. You can maintain and boost the health of your cellular Krebs cycle by using the nootropics Alpha-Lipoic Acid, Choline Citrate, Ginseng, Magnesium,

NADH and Vitamin B5 (Pantothenic Acid). Long-Term Memory Long-Term Memory describes the type of memory associated with an event or information acquired by the mind long ago. These memories are often pieced together by the brain with inaccurate or imagined information. This inaccurate memory storage can come from your perception of an event or thing, conditioning, or any other faulty input. Healthy, psychologically sound individuals have access to an impressive information storage system to draw from. On the other hand, unhealthy and psychologically messed-up people can also access this storage system. Both groups can boost access to this long-term memory with the use of certain Nootropics.

Long-Term Potentiation Long-Term Potentiation is the term used to describe a strengthening of synapses needed to create long-term memory. “Neurons that fire together, wire together”. Transcription factors such as cAMP responsive element binding protein (CREB), once a phosphate group is added, leads to gene expression. Which 484 HEAD FIRST leads to changes in expression of proteins needed for producing and maintaining changes in synaptic strength. And long-term memory.

Mild Cognitive Impairment (MCI) Mild Cognitive Impairment is characterized by cognitive impairment out- side of the expected decline caused by aging. Unchecked, MCI can eventually lead to dementia. Those suffering mild cognitive impairment begin to notice difficulty with memory and cognition. Amyloid Plaques & Neurofibrillary Tangles, poor blood flow, and strokes all con- tribute to MCI. There is no known single cause of mild cognitive impairment. MCI is likely caused by a combination of factors. And is often prevented or reversed through the use of nootropics.

MAOI Monoamine Oxidase Inhibitor (MAOI) is a substance which inhibits naturally occurring enzymes in your brain. This inhibition helps increase levels of neurotransmitters like serotonin and dopamine. Be cautious about using nootropics that boost neurotransmitters like sero- tonin or dopamine combined with MAOI’s. Too much serotonin or dopamine can cause serious problems in the brain including “serotonin syndrome”.

Mitochondria Mitochondria are organelles within each of your cells responsible for metabolizing or breaking down carbohydrates and fatty acids used to generate cellular energy. This cellular energy is in the form of a chemical molecule called adenosine triphosphate (ATP) which is generated within the mitochondria.

Myelin Myelin sheaths are a combination of proteins and phospholipids that form an insulating-like sheath around axons in your brain. And are what give your brain’s white matter its white color. Myelin helps insulate and protect axons much like electrical tape wrapped around a bunch of wires. Myelin also assists optimal action potential (electrical signaling) through the axon. Insufficient or damaged myelin is linked to neurodegeneration and diseases such as Multiple Sclerosis. SAM-e, Vitamin B1 (Thiamine), Vitamin B6, Vitamin

B9 (folate), and Vitamin B12 are critical for normal myelin formation. Naturopath A Naturopath is a health care practitioner who uses natural systems of heal- ing including the use of supplements instead of prescription drugs. 485 David Tomen NDMA Receptors Similar to the AMPA receptor, the NMDA receptor is also paired with an ion channel. But this channel lets calcium ions rather than sodium ions into the neuron. When this cell is at resting potential, the calcium channel is blocked by mag- nesium ions (Mg2+), so that even if glutamate binds to the receptor, calcium cannot enter that neuron. For these magnesium ions to leave that channel, the neuron’s dendrites must be depolarized. This happens through the sustained action of the AMPA receptors. Once the magnesium leaves the NDMA receptors, large numbers of calcium ions enter that cell. This sets off several biochemical reactions that make this synapse more efficient for an extended period of time. This is called Long-Term Potentiation, and is associated with the plasticity that allows long-term memories to form.

Nerve Growth Factor Nerve Growth Factor (NGF) is a group of small biomolecules (neurotrophic factors) and small protein-like molecules (neuropeptides) involved in the regula- tion of growth, maintenance, neurogenesis and survival of neurons.

Neurons Neurons are nerve cells in your brain. They function as conduits of informa- tion from one neuron to another neuron. This signaling between neurons are actually chemically-produced electrical signals. As the human brain ages, the production of new neurons begins to slow. Old neurons begin to die. And age-related disease begins to set in. Neurogenesis, or the birth of new neurons can be initiated with the use of certain nootropics.

Neurogenesis Neurogenesis is defined as the birth and growth of new neurons. The science on neurogenesis is fairly new but this much we know – neurogenesis plays a major role in learning, memory formation and recall.

Neuroplasticity Neuroplasticity is the ability of your brain to change structure. This includes the internal structure of neurons, and an increase in the number synapses be- tween neurons. Some evidence indicates that short-term memory depends on electrical and chemical events in the neurons rather than changes in structure. Long-term memory may be dependent on changes in brain structure including neurogen- esis, and increases in synapses between neurons. 486 HEAD FIRST Neuroreceptor A neurotransmitter receptor, or neuroreceptor are typically proteins on the surface of cells that recognize and bind to specific neurotransmitters. Neuroreceptors allow cells to communicate with one another through chemical signaling. Once bound, the receptor can change shape, and cause a cascade of chemical events within the cell. These events can alter which genes are turned on or off and can make the cell more or less likely to release its own neurotransmitters. Each type of neurotransmitter can have multiple receptors each with a differ- ent role to play in the brain.

Neurotransmitter A Neurotransmitter is a broad term that refers to chemicals that act as com- municators of information. Thus relaying signals in the brain to other parts of the brain. And throughout the body. To be considered a neurotransmitter, a molecule must; • be produced inside a neuron, found in the neuron’s terminal button, and released into the synaptic gap upon the arrival of an action potential. • produce an effect on the postsynaptic neuron. • after it has transmitted its signal to this neuron, it must be deactivated rapidly. • have the same effect on the postsynaptic neuron when applied experimen- tally as it does when secreted by a presynaptic neuron.1025 Examples of neurotransmitters are acetylcholine, dopamine, GABA, gluta- mate, norepinephrine and serotonin.

Nootropic A nootropic is a substance capable of enhancing brain or mental function. Nootropics can help you boost memory, learning and overall brain function. The term “nootropic” is relatively new. Romanian psychologist and chemist Dr. Corneliu Giurgea synthesized Piracetam in 1963. And coined the term “nootropic” in 1972.1026 It is derived from the Greek nous (“mind”) and trepein (to bend). Dr. Giurgea described a nootropic as having the characteristics of enhanc- ing learning and memory. It should protect the brain while increasing natural cognitive processes. And should not be toxic, nor stimulate or depress the brain.

Nootropic Stack A nootropic stack refers to combining two or more nootropics to achieve a desired effect. 487 David Tomen Noradrenaline Noradrenaline is another name for norepinephrine.

Norepinephrine Norepinephrine is a stress hormone. It affects parts of the brain where atten- tion and responding actions are controlled. Along with epinephrine, norepinephrine underlies the fight-or-flight re- sponse. It increases heart rate, triggering the release of glucose from energy stores. And increases blood flow to skeletal muscle. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase. It is released from the adrenal medulla into the blood as a hormone. It is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out by binding to adrenergic receptors.1027

OTC OTC = Over-the-counter means substances like supplements which are available in online or brick & mortar stores without a prescription.

Oxidative Stress Oxidative Stress often results from an imbalance between the production of free radical reactive oxygen species, and the antioxidants required to counteract them. Because your brain is the most energy-intensive organ in your body, it also hosts high free radical activity. If left unchecked, these free radicals can damage and even destroy neurons. This oxidative stress is linked to a host of neurodegenerative diseases including Alzheimer’s and Parkinson’s Disease. Several nootropics have been shown to combat oxidative stress including Acetyl-L-Carnitine (ALCAR), Alpha-Lipoic Acid, Coenzyme Q10, Ginkgo biloba, Gotu kola, L-Carnosine, N-Acetyl L-Cysteine (NAC), Piperine, PQQ, Pterostilbene, Resveratrol, Rhodiola Rosea, St. John’s wort, and Vinpocetine.

Peptide A peptide is a compound consisting of two or more amino acids linked in a chain. All humans have peptides in their body. You could consider peptides one of the building blocks of life. When a peptide chain gets especially long, it turns into a protein. The amino acid chain of peptides is called a covalent bond. A covalent bond occurs when atoms share electrons. This particular covalent bond is known as a peptide bond or amide bond. It forms when the carboxyl group of one amino acid attaches to another. Some peptides regulate hormones, while others can have an antibiotic function. 488 HEAD FIRST pH pH is a measure of acidity or alkalinity of a substance.

Phospholipids Phospholipids are a combination of lipids (fats) and . Phospha- tidylcholine (PC) and phosphatidylserine (PS) are the two most important phospholipids in the cells of your body. Your body cannot function normally without them. Phospholipids are also critical for optimal brain health. They assist brain cells in communicating. And influence how well neuroreceptors function. Phospholipids are found in many foods. But are in higher concentrations in soy, eggs and the brain tissue of animals. Taking supplemental phosphatidylcholine (PC) and phosphatidylserine (PS) can lead to improved memory and learning.

Potentiation Potentiation is the influence of a lesser active drug or substance on the effects realized from a drug already in your system.

Precursor A precursor is a compound that participates in a chemical reaction that pro- duces another compound. In your body and brain, the term “precursor” refers to a chemical compound preceding another in a metabolic pathway.

Psychosis Psychosis is a person’s loss of ability to distinguish reality as perceived by others. It’s often seen as hallucinations, delusions and disturbances of thought and mood.

Racetams Racetams all stem from the original “nootropic” called piracetam. Both pi- racetam and nootropic were named by the inventor of piracetam, the Romanian psychologist and chemist Dr. Corneliu Giurgea. The most common racetams are Aniracetam, Piracetam, Pramiracetam, and Oxiracetam. They all share a 2-pyrrolidone nucleus made up of oxygen, nitrogen, and hydrogen. Racetams are known for boosting energy, focus, learning, memory and mood. Racetams can also help increase neuroplasticity, making it easier to learn, absorb and memorize new concepts.

Recall Recall is one of the three major components of memory. The others are en- coding and storage. Think of the human brain like an organic computer. Recall 489 David Tomen is the process of retrieving a memory that has been encoded and stored in the brain’s supercomputer. Receptor A receptor is a structure on or inside a cell which receives a chemical signal.

Reuptake Reuptake is the process by which used neurotransmitters are taken back into cells to be recycled or destroyed.

Serotonin Serotonin is a neurotransmitter made from the amino acid tryptophan. The human body cannot make tryptophan so you must get it from the food you eat. Tryptophan is most abundant in meat and fowl. Once you eat food containing tryptophan, your digestion grabs the proteins in your gut. Which is transported by your blood to your brain. And then con- verted to serotonin. Serotonin is an inhibitory neurotransmitter which means it governs excessive stimulating hormones like dopamine from firing in the brain. Serotonin is pres- ent throughout the entire brain, from bottom to top. When you have adequate serotonin levels in your brain and it’s working properly, you’ll be confident, easy-going, flexible, happy, and positive. Serotonin deficiency can result in you becoming depressed, irritable, obses- sive, negative and worried.

Serotonin Syndrome Serotonin Syndrome symptoms usually occur within several hours of taking a new drug or nootropic. Or increasing the dose of the drug or nootropic you’re already using. Symptoms can include agitation, confusion, rapid heart rate, dilated pupils, loss of muscle coordination, muscle rigidity, heavy sweating, diarrhea, headache, and shivering. Severe serotonin syndrome can be life-threatening. Signs include high fever, seizures, irregular heartbeat and unconsciousness. Caution is strongly advised when using any nootropic that boosts serotonin uptake in your brain. Especially when combining them with any drug or noot- ropic that is already boosting serotonin.

Short-term Memory Short-term Memory is also known as primary or active memory. It is charac- terized as being very brief (i.e. seconds), and is limited to what you can remember and retain for 20 to 30 seconds. The human brain can only retain new information to a certain extant (chunk capacity) and only temporarily (temporal capacity). 490 HEAD FIRST Short-term memory can be boosted using certain nootropics.

Stimulant A stimulant is any substance that increases activity in the central nervous system. Stimulants can cause wakefulness, alertness, and often feelings of well- being. An overdose of stimulants can cause anxiety, jitteriness, and insomnia. Examples of stimulants include the prescription drugs Adderall and Ritalin.

Sublingual Sublingual refers to taking a nootropic or other supplement by placing it under your tongue. Dissolving a substance under your tongue allows for better bioavailability because it’s absorbed directly into your bloodstream through the tissues in your mouth.

Synapses Synapses are the empty spaces between neurons (brain nerve cells). When neurons fire, they send electrical signals across the synaptic cleft to the neuron next door. Healthy brain activity is dependent on the proper function of synaptic ac- tivity. Obstructions like Amyloid Plaques can block synapses and cause serious problems with many brain functions including cognition, learning and memory.

Tolerance In pharmacology, tolerance describes the decrease or loss of effectiveness or response to a drug or nootropic. Typically, due to recent or prolonged exposure to that substance. Tolerance also includes the need for increasing doses of a drug or nootropic over time to maintain the same effect. Cycling is often used by nootropic users to counteract tolerance. An example of cycling is using a nootropic for 5 days, taking a 2-day break from using the nootropic and resuming use for another 5 days.

Upregulation Upregulation is a process in which the number or activity of receptors in- creases, typically in response to abnormally low activity.

White Matter See definition of Gray Matter to get an understanding of brain White Matter.

Uptake Uptake is the absorption by your body, and in the case of nootropics, by your brain, of a substance like a nootropic. 491 David Tomen Working Memory Working memory is distinct from short and long-term memory. These are memories that are not only remembered, but simultaneously processed. You not only remember information that is important to you, you also remember the purpose of the information, and why you decided to remember it.

YMMV YMMV = Your Mileage May Vary is a term commonly used in the noo- tropic community. Meaning people experience reactions to certain nootropics very differently. Always remember that when someone describes their experience with a nootropic, you are unlikely to have the exact same experience.

492

References

1 “Tests for Alzheimer’s Disease and Dementia” Alzheimer’s Association alz.org Retrieved February 15, 2016. (source)

2 Thompson J.J., Blair M.R., Henrey A.J. “Over the Hill at 24: Persistent Age-Related Cognitive- Motor Decline in Reaction Times in an Ecologically Valid Video Game Task Begins in Early Adult- hood” PLOS One April 9, 2014 (source)

3 Stocco A., Lebiere C., Anderson J.R. “Conditional Routing of Information to the Cortex: A Model of the Basal Ganglia’s Role in Cognitive Coordination” Psychology Review 2010 Apr; 117(2): 541–574. (source)

4 Azevedo F.A., Carvalho L.R., Grinberg L.T., Farfel J.M., Ferretti R.E., Leite R.E., Jacob Filho W., Lent R., Herculano-Houzel S. “Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain.” Journal of Comparative Neurology. 2009 Apr 10;513(5):532-41 (source)

5 Suzuki H., Park S.J., Tamura M., Ando S. “Effect of the long-term feeding of dietary lipids on the learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in adult mice: a comparison of sardine oil diet with palm oil diet.” Mechanisms of Ageing and Development. 1998 Mar 16;101(1-2):119-28. (source)

6 “New imaging method developed at Stanford reveals stunning details of brain connections” Stanford Medicine November 17, 2010 (source)

7 McEntee W.J., Crook T.H. “Glutamate: its role in learning, memory, and the aging brain.” Psychopharmacology (Berlin). 1993;111(4):391-401. (source)

8 Powers M.E., Yarrow J.F., McCoy S.C., Borst S.E. “Growth hormone isoform responses to GABA ingestion at rest and after exercise.” Medicine and Science in Sports and Exercise. 2008 Jan;40(1):104-10. (source)

9 Ashby F.G., Ell S.W., Valentin V.V., Casale M.B. “FROST: a distributed neurocomputational model of working memory maintenance.” Journal of Cognitive Neuroscience. 2005 Nov;17(11):1728- 43. (source)

10 Rebouche C.J. “Kinetics, , and regulation of L-carnitine and acetyl-L-carnitine metabolism.” Annals of the New York Academy of Sciences 2004 Nov;1033:30-41. (source)

11 Liu J., Head E., Kuratsune H., Cotman C.W., Ames B.N. “Comparison of the effects of L-car- nitine and acetyl-L-carnitine on carnitine levels, ambulatory activity, and oxidative stress biomarkers in the brain of old rats.” Annals of the New York Academy of Sciences 2004 Nov;1033:117-31. (source) 493 David Tomen 12 White H.L., Scates P.W. “Acetyl-L-carnitine as a precursor of acetylcholine.” Neurochemical Research 1990 Jun;15(6):597-601. (source)

13 Kalaria R.N., Harik S.I. “Carnitine acetyltransferase activity in the human brain and its mi- crovessels is decreased in Alzheimer's disease.” Annals of Neurology 1992 Oct;32(4):583-6. (source)

14 Berg J.M., Tymoczko J.L., Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. (source)

15 Berg J.M., Tymoczko J.L., Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. (source)

16 Costell M., O'Connor J.E., Grisolía S. “Age-dependent decrease of carnitine content in muscle of mice and humans.” Biochemical and Biophysical Research Communications 1989 Jun 30;161(3):1135-43. (source)

17 Gomez L.A., Heath S.D., Hagen T.M. “Acetyl-L-carnitine supplementation reverses the age- related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the L-carnitine content in the rat heart” Mechanics of Aging Development 2012 Feb-Mar; 133(0): 99–106. (source)

18 Pettegrew J.W., Levine J., McClure R.J. “Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depres- sion.” Molecular Psychiatry 2000 Nov;5(6):616-32. (source)

19 Ferrari F., Gorini A., Villa R.F. “Functional proteomics of synaptic plasma membrane ATP-ases of rat hippocampus: effect of l- and relationships with Dementia and Depression pathophysiology.” European Journal of Pharmacology 2015 Jun 5;756:67-74. (source)

20 Taglialatela G., Navarra D., Olivi A., Ramacci M.T., Werrbach-Perez K., Perez-Polo J.R., Angelucci L. “Neurite outgrowth in PC12 cells stimulated by acetyl-L-carnitine arginine amide.” Neurochemical Research 1995 Jan;20(1):1-9. (source)

21 Montgomery S.A., Thal L.J., Amrein R. “Meta-analysis of double blind randomized controlled clini- cal trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease” International Clinical Psychopharmacology 2003 Mar;18(2):61-71. (source)

22 Spagnoli A. et. Al. “Long-term acetyl-L-carnitine treatment in Alzheimer's disease.” Neurology. 1991 Nov;41(11):1726-32. (source)

23 Tomassini V., Pozzilli C., Onesti E., Pasqualetti P., Marinelli F., Pisani A., Fieschi C. “Com- parison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomized, double-blind, crossover trial.” Journal of Neurological Sci- ence 2004 Mar 15;218(1-2):103-8. (source)

24 Alves E. et. Al “Acetyl-l-carnitine provides effective in vivo neuroprotection over 3,4-methylene- dioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain” Cellular Neuroscience Volume 158, Issue 2, 23 January 2009, Pages 514–523 (source)

25 Cavallini G., Caracciolo S., Vitali G., Modenini F., Biagiotti G. “Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging.” Urology 2004 Apr;63(4):641-6. (source)

26 Liu J., Head E., Gharib A.M., Yuan W., Ingersoll R.T., Hagen T.M., Cotman C.W., Ames B.N. “Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxida- 494 HEAD FIRST tion: partial reversal by feeding acetyl-L-carnitine and/or R-alpha – lipoic acid.” Proceeding of the National Academy of Sciences of the United States of America 2002 Feb 19;99(4):2356-61. (source)

27 Ziegenfuss T., Landis J. Hofheins J. “Acute supplementation with alpha-glycerylphosphorylcho- line augments growth hormone response to, and peak force production during, resistance exercise” Journal of the International Society of Sports Nutrition 20085(Suppl 1):P15 (source)

28 Canal N., Franceschi M., Alberoni M., Castiglioni C., De Moliner P., Longoni A. “Effect of L-alpha-glyceryl- on amnesia caused by scopolamine.” International Journal of Clinical Pharmacology, Therapy, Toxicology. 1991 Mar;29(3):103-7. (source)

29 Kidd P.M. “Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management.” Alternative Medicine Review 2005 Dec;10(4):268-93. (source)

30 De Jesus Moreno Moreno M. “Cognitive improvement in mild to moderate Alzheimer's de- mentia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double- blind, randomized, placebo-controlled trial.” Clinical Therapeutics 2003 Jan;25(1):178-93. (source)

31 Cohen B.M., Renshaw P.F., Stoll A.L., Wurtman R.J., Yurgelun-Todd D., Babb S.M. “De- creased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.” JAMA 1995 Sep 20;274(11):902-7. (source)

32 Drago F., Mauceri F., Nardo L., Valerio C., Lauria N., Rampello L., Guidi G. “Behavioral effects of L-alpha-glycerylphosphorylcholine: influence on cognitive mechanisms in the rat.” Phar- macology, Biochemistry and Behavior 1992 Feb;41(2):445-8. (source)

33 Bronzetti E., Felici L., Amenta F. “Effect of ipsilateral lesioning of the nucleus basalis magno- cellularis and of L-alpha-glyceryl phosphorylcholine treatment on choline acetyltransferase and acetylcholinesterase in the rat fronto-parietal cortex.” Neuroscience Letters 1993 Dec 24;164(1- 2):47-50 (source)

34 Vega J.A., Cavallotti C., del Valle M.E., Mancini M., Amenta F. “Nerve growth factor receptor immunoreactivity in the cerebellar cortex of aged rats: effect of choline alfoscerate treatment.” Mechanisms of Ageing and Development 1993 Jun;69(1-2):119-27. (source)

35 Ceda G.P., Ceresini G., Denti L., Marzani G., Piovani E., Banchini A., Tarditi E., Valenti G. “alpha-Glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects.” Hormone and Metabolic Research 1992 Mar;24(3):119-21 (source)

36 Parnetti L., Abate G., Bartorelli L., Cucinotta D., Cuzzupoli M., Maggioni M., Villardita C., Senin U. “Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer's type.” Drugs Aging 1993 Mar-Apr;3(2):159-64 (source)

37 Ceda G.P., Ceresini G., Denti L., Magnani D., Marchini L, Valenti G., Hoffman A.R. “Ef- fects of cytidine 5'-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects.” Acta Endocrinologica (Copenha- gen).1991;124(5):516-20. (source)

38 Trabucchi M., Govoni S., Battaini F. “Changes in the interaction between CNS cholinergic and dopaminergic neurons induced by L-alpha-glycerylphosphorylcholine, a cholinomimetic drug.” Farmaco Sci. 1986 Apr;41(4):325-34. (source) 495 David Tomen 39 Traini E., Bramanti V., Amenta F. “Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline – containing phospholipid with a still interesting profile as cognition enhancing agent.” Current Alzheimer’s Research 2013 Dec;10(10):1070-9. (source)

40 Florio T., Bajetto A., Thellung S., Arena S., Corsaro A., Bonavia R., Merlino M., Schettini G. “Prolonged treatment with α-glycerylphosphorylethanolamine facilitates the acquisition of an active avoidance behavior and selectively increases neuronal signal transduction in rats” Aging Clinical and Experimental Research October 1999, Volume 11, Issue 5, pp 335-342 (source)

41 Parnetti L., Amenta F., Gallai V. “Choline alphoscerate in cognitive decline and in acute cere- brovascular disease: an analysis of published clinical data.” Mechanisms of Ageing and Development 2001 Nov;122(16):2041-55. (source)

42 Ahmed H.H. “Modulatory effects of vitamin E, acetyl-L-carnitine and α-lipoic acid on new potential biomarkers for Alzheimer's disease in rat model.” Experimental Toxicologic Pathology 2012 Sep;64(6):549-56. (source)

43 Hager K., Kenklies M., McAfoose J., Engel J., Munch G. “Alpha-lipoic acid as a new treatment option for Alzheimer’s disease—a 48 months follow-up analysis.” Journal of Neural Transmission. Supplementum. 2007;72:189-93. (source)

44 Biewenga G.P., Haenen G.R., Bast A. “The pharmacology of the antioxidant lipoic acid.” Gen- eral Pharmacology 1997 Sep;29(3):315-31. (source)

45 Shiqin Xiong, Nikolay Patrushev, Farshad Forouzandeh, Lula Hilenski, R. Wayne Alexander. PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases. Cell Reports, 2015; DOI: 10.1016/j.celrep.2015.07.047

46 Sherif S., Bendas E.R., Badawy S. “The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle.” European Journal of Pharmaceutics and Biopharmaceutics 2014 Feb;86(2):251-9. (source)

47 Berg J.M., Tymoczko J.L., Stryer L. “The Citric Acid Cycle Oxidizes Two-Carbon Units”Bio - chemistry. 5th Edition WH Freeman, New York; 2002 (source)

48 Liu J., Head E., Gharib A.M., Yuan W., Ingersoll R.T., Hagen T.M., Cotman C.W., Ames B.N. “Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha – lipoic acid.” Proceeding of the Na- tional Academy of Sciences of the United States of America 2002 Feb 19;99(4):2356-61. (source)

49 Hermann R., Mungo J., Cnota P.J., Ziegler D. “Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms” Clinical Pharmacology 2014; 6: 195–204. (source)

50 Carlson D.A., Smith A.R., Fischer S.J., Young K.L., Packer L. “The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects.” Alternative Medicine Review 2007 Dec;12(4):343-51. (source)

51 Purves D., Augustine G.J., Fitzpatrick D., et al., editors. “Glutamate Receptors” Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. (source)

52 Malykh A.G., Sadaie M.R. “Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.” Drugs. 2010 Feb 12;70(3):287-312. (source) 496 HEAD FIRST 53 Roncan G. “Human Pharmacokinetics of Aniracetam” Springer – Drug Investigation June 1993, Volume 5, Supplement 1, pp 68-72 (source)

54 Gouliaev A.H., Senning A., “Piracetam and other structurally related nootropics” Brain Re- search Reviews 19 (1994) 180-222 (source)

55 Nakamura K. “Aniracetam: Its Novel Therapeutic Potential in Cerebral Dysfunctional Disor- ders Based on Recent Pharmacological Discoveries” CNS Drug Reviews 2002 Neva Press, Branford, Connecticut Vol. 8, No. 1, pp. 70–89 (source)

56 Testa B., Mayer J.M. (1 August 2003). Hydrolysis in Drug and Prodrug Metabolism. John Wiley & Sons. pp. 109–. ISBN 978-3-906390-25-3.

57 Nakamura K., Kurasawa M. “Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.” European Journal of Pharmacology 2001 May 18;420(1):33-43. (source)

58 Koliaki C.C., Messini C., Tsolaki M. “Clinical Efficacy of Aniracetam, Either as Monotherapy or Combined with Cholinesterase Inhibitors, in Patients with Cognitive Impairment: A Comparative Open Study” CNS Neuroscience & Therapeutics Volume 18, Issue 4, pages 302–312, April 2012 (source)

59 Nakamura K, Tanaka Y. "Antidepressant-like effects of aniracetam in aged rats and its mode of action." Psychopharmacology (Berlin). 2001 Nov;158(2):205-12. (source)

60 Cumin R., Bandle E.F., Gamzu E., Haefely W.E. “Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents.” Psychopharmacology (Berlin) 1982;78(2):104-11. (source)

61 Wijayawardhane .1, Shonesy B.C., Vaglenova J., Vaithianathan T., Carpenter M., Breese C.R., Dityatev A., Suppiramaniam V. “Postnatal aniracetam treatment improves prenatal ethanol in- duced attenuation of AMPA receptor-mediated synaptic transmission.” Neurobiology of Disease 2007 Jun;26(3):696-706. (source)

62 Barad M., Bourtchouladze R., Winder D.G., Golan H., Kandel E. “Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory” Proceedings of the National Academy of Sciences USA 1998 Dec 8; 95(25): 15020–15025. (source)

63 Shimoi K. et. Al “Intestinal absorption of luteolin and luteolin 7-O-β-glucoside in rats and humans” FEBS letters Volume 438, Issue 3, 6 November 1998, Pages 220–224 (source)

64 Wang M., Simon J.E., Aviles I.F., He K., Zheng Q.Y., Tadmor Y. “Analysis of antioxidative phe- nolic compounds in artichoke (Cynara scolymus L.).” Journal of Agricultural and Food Chemistry 2003 Jan 29;51(3):601-8. (source)

65 Brun o. et. Al. “GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.” British Journal of Pharmacology 2011 Dec;164(8):2054-63. (source)

66 Jang S., Kelley K.W., Johnson R.W. “Luteolin reduces IL-6 production in microglia by inhibit- ing JNK phosphorylation and activation of AP-1.” Proceeding of the National Academy of Sciences USA 2008 May 27;105(21):7534-9. (source)

67 Almeida L.E., Murray P.D., Zielke H.R., Roby C.D., Kingsbury T.J., Krueger B.K. “Autocrine ac- tivation of neuronal NMDA receptors by aspartate mediates dopamine – and cAMP-induced CREB- dependent gene transcription.” Journal of Neuroscience 2009 Oct 7;29(40):12702-10. (source) 497 David Tomen 68 Jang S., Dilger R.N., Johnson R.W. “Luteolin inhibits microglia and alters hippocampal-depen- dent spatial working memory in aged mice.” The Journal of Nutrition 2010 Oct;140(10):1892-8. (source)

69 Kuroiwa M. et. Al “Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/ DARPP-32 signaling cascade in frontal cortex.” Psychopharmacology 2012 Feb;219(4):1065-79. (source)

70 Li Y.F., Cheng Y.F., Huang Y., Conti M., Wilson S.P., O'Donnell J.M., Zhang H.T. “Phos- phodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.” Journal of Neuroscience 2011 Jan 5;31(1):172-83. (source)

71 Kurapati K.R. , Atluri V.S., Samikkannu T., “Nair M. Ashwagandha (Withania somnifera) Re- verses β-Amyloid1-42 Induced Toxicity in Human Neuronal Cells: Implications in HIV-Associated Neurocognitive Disorders” PLOS One journals.plos.org October 16, 2013 (source)

72 Cooley K., Szczurko O., Perri D., Mills E.J., Bernhardt B., Zhou Q., Seely D. “Naturo- pathic care for anxiety: a randomized controlled trial ISRCTN78958974.” PLoS One. 2009 Aug 31;4(8):e6628. (source)

73 Pingali U., Pilli R., Fatima N. “Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants” Pharmacognosy Res. 2014 Jan-Mar; 6(1): 12–18. (source)

74 “New evidence that chronic stress predisposes brain to mental illness” University of California, Berkeley Feb. 11, 2014, Retrieved Mar. 24, 2016 (source)

75 Chandrasekhar K., Kapoor J., Anishetty S. “A prospective, randomized double-blind, placebo- controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwa- gandha root in reducing stress and anxiety in adults.” Indian Journal of Psychological Medicine 2012 Jul;34(3):255-62. (source)

76 Dhuley J.N. “Nootropic-like effect of ashwagandha (Withania somnifera L.) in mice.”Phyto - therapy Research 2001 Sep;15(6):524-8. (source)

77 Bhattacharya S.K., Bhattacharya A., Sairam K., “Ghosal S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study.” Phytomedicine 2000 Dec;7(6):463- 9. (source)

78 Calabrese N.D., Gregory W.L., Leo M., Kraemer D., Bone K., Oken B. “Effects of a Standard- ized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial” Journal of Alternative and Complimentary Medicine 2008 Jul; 14(6): 707–713. (source)

79 Bhattacharya S.K., Ghosal S. “Anxiolytic activity of a standardized extract of Bacopa monniera: an experimental study.” Phytomedicine. 1998 Apr;5(2):77-82 (source)

80 “New evidence that chronic stress predisposes brain to mental illness” University of California, Berkeley Feb. 11, 2014, Retrieved Mar. 24, 2016 (source)

81 Chowdhuri D.K., Parmar D., Kakkar P., Shukla R., Seth P.K., Srimal R.C. “Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain.” Phytotherapy Research 2002 Nov;16(7):639-45. (source) 498 HEAD FIRST 82 Stough C., Lloyd J., Clarke J., Downey L.A., Hutchison C.W., Rodgers T., Nathan P.J. “The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects.” Psychopharmacology 2001 Aug;156(4):481-4. (source)

83 Stough C., Downey L.A., Lloyd J., Silber B., Redman S., Hutchison C., Wesnes K., Nathan P.J. “Examining the nootropic effects of a special extract of Bacopa monniera on human cogni- tive functioning: 90 day double-blind placebo-controlled randomized trial.” Phytotherapy Research 2008 Dec;22(12):1629-34 (source)

84 Benson S., Downey L.A., Stough C., Wetherell M., Zangara A., Scholey A. “An acute, double- blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.” Phytotherapy Research 2014 Apr;28(4):551-9. (source)

85 Jansson E.T. “Aluminum exposure and Alzheimer's disease.” Journal of Alzheimer’s Disease 2001 Dec;3(6):541-549. (source)

86 Jyoti A., Sharma D. “Neuroprotective role of Bacopa monniera extract against aluminium- induced oxidative stress in the hippocampus of rat brain.” Neurotoxicity 2006 Jul;27(4):451-7. (source)

87 Williams J.E. “Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on Una de Gato and Sangre de Grado.” Alternative Medicine Revue. 2001 Dec;6(6):567-79. (source)

88 Hardin S.R. “Cat's claw: an Amazonian vine decreases inflammation in osteoarthritis.” Comple- mentary Therapies in Clinical Practice. 2007 Feb;13(1):25-8. (source)

89 Akesson C., Lindgren H., Pero R.W., Leanderson T., Ivars F. “Quinic acid is a biologically active component of the Uncaria tomentosa extract C-Med 100.” International Immunopharmacology. 2005 Jan;5(1):219-29. (source)

90 Shi Z., Lu Z., Zhao Y., Wang Y., Zhao-Wilson X., Guan P., Duan X., Chang Y.Z., Zhao B. “Neuroprotective effects of aqueous extracts of Uncaria tomentosa: Insights from 6-OHDA induced cell damage and transgenic Caenorhabditis elegans model.” Neurochemistry International. 2013 Jun;62(7):940-7. (source)

91 Rizzi R., Re F., Bianchi A., De Feo V., de Simone F., Bianchi L., Stivala L.A. “Mutagenic and antimutagenic activities of Uncaria tomentosa and its extracts.” Journal of Ethnopharmacology. 1993 Jan;38(1):63-77. (source)

92 Jürgensen S., Dalbó S., Angers P., Santos A.R., Ribeiro-do-Valle R.M. “Involvement of 5-HT2 receptors in the antinociceptive effect of Uncaria tomentosa.”Pharmacology, Biochemistry and Behavior. 2005 Jul;81(3):466-77. (source)

93 Sheng Y., Li L., Holmgren K., Pero R.W. “DNA repair enhancement of aqueous extracts of Uncaria tomentosa in a human volunteer study.” Phytomedicine. 2001 Jul;8(4):275-82. (source)

94 Pero R.W., Lund H. “Dietary quinic acid supplied as the nutritional supplement AIO + AC-11® leads to induction of micromolar levels of nicotinamide and tryptophan in the urine.” Phytotherapy Research. 2011 Jun;25(6):851-7 (source)

95 Aguilar J.L., Rojas P., Marcelo A., Plaza A., Bauer R., Reininger E., Klaas C.A., Merfort I. “Anti-inflammatory activity of two different extracts of Uncaria tomentosa (Rubiaceae).” Journal of Ethnopharmacology. 2002 Jul;81(2):271-6. (source) 499 David Tomen 96 Mohamed A.F., Matsumoto K., Tabata K., Takayama H., Kitajima M., Watanabe H. “Effects of Uncaria tomentosa total alkaloid and its components on experimental amnesia in mice: elucidation using the passive avoidance test.” Journal of Pharmacy and Pharmacology. 2000 Dec;52(12):1553- 61. (source)

97 Barnes C.A. “Long-term potentiation and the ageing brain.” Philosophical Transactions of the Royal Society of London Series B Biological Sciences. 2003 Apr 29;358(1432):765-72. (source)

98 Kang T.H., Murakami Y., Takayama H., Kitajima M., Aimi N., Watanabe H., Matsumoto K. “Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuro- nal damage in the hippocampus: putative neurotransmitter receptors involved in their action.” Life Sciences. 2004 Dec 3;76(3):331-43. (source)

99 Huang H., Zhong R., Xia Z., Song J., Feng L. “ Neuroprotective effects of rhynchophylline against ischemic brain injury via regulation of the Akt/mTOR and TLRs signaling pathways.” Molecules. 2014 Jul 30;19(8):11196-210. (source)

100 Sui L., Wang J., Li B.M. “Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex.” Learning and Memory. 2008 Oct 2;15(10):762-76 (source)

101 Bacher N., Tiefenthaler M., Sturm S., Stuppner H., Ausserlechner M.J., Kofler R., Konwalinka G. “Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.” British Journal of Haematology. 2006 Mar;132(5):615-22. (source)

102 Spelman K., Burns J., Nichols D., Winters N., Ottersberg S., Tenborg M. “Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.” Alternative Medicine Revue. 2006 Jun;11(2):128-50. (source)

103 Riva L., Coradini D., Di Fronzo G., De Feo V., De Tommasi N., De Simone F., Pizza C. “The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line.” Anticancer Research. 2001 Jul-Aug;21(4A):2457-61. (source)

104 Gurrola-Díaz C.M., García-López P.M., Gulewicz K., Pilarski R., Dihlmann S. “Inhibitory mechanisms of two Uncaria tomentosa extracts affecting the Wnt-signaling pathway.”Phytomedi - cine. 2011 Jun 15;18(8-9):683-90. (source)

105 Sheng Y., Bryngelsson C., Pero R.W. “Enhanced DNA repair, immune function and reduced toxicity of C-MED-100, a novel aqueous extract from Uncaria tomentosa.” Journal of Ethnophar- macology. 2000 Feb;69(2):115-26. (source)

106 Sheng Y., Li L., Holmgren K., Pero R.W. “DNA repair enhancement of aqueous extracts of Uncaria tomentosa in a human volunteer study.” Phytomedicine. 2001 Jul;8(4):275-82. (source)

107 Ulus I.H., Wurtman R.J., Mauron C., Blusztajn J.K. “Choline increases acetylcholine release and protects against the stimulation-induced decrease in phosphatide levels within membranes of rat corpus striatum.” Brain Research 1989 Apr 10;484(1-2):217-27. (source)

108 Wurtman R.J. “Choline metabolism as a basis for the selective vulnerability of cholinergic neurons.” Trends in Neuroscience 1992 Apr;15(4):117-22. (source)

109 Naber M., Hommel B., Colzato L.S. “Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study.” Scientific Reports 2015 Aug 14;5:13188. (source) 500 HEAD FIRST 110 Buchman A.L., Sohel M., Brown M., Jenden D.J., Ahn C., Roch M., Brawley T.L. “Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study.” Journal of Parenteral and Enteral Nutrition. 2001 Jan-Feb;25(1):30-5. (source)

111 Poly C., Massaro J.M., Seshadri S., Wolf P.A., Cho E., Krall E., Jacques P.F., Au R. “The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort.” The American Journal of Clinical Nutrition 2011 Dec;94(6):1584-91 (source)

112 Sanders L.M., Zeisel S.H. Choline – Dietary Requirements and Role in Brain Development Nutrition Today 2007; 42(4): 181–186. (source)

113 TUČEK S. “Acetylcoenzyme A and the Synthesis of Acetylcholine in Neurones: Review of Recent Progress” General Physiology and Biophysiology. (1983), 2, 313—324 (source)

114 Ebenhöh O., Heinrich R. “Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems.” Bulletin of Math- ematical Biology. 2001 Jan;63(1):21-55. (source)

115 Ulus I.H., Wurtman R.J., Mauron C., Blusztajn J.K. “Choline increases acetylcholine release and protects against the stimulation-induced decrease in phosphatide levels within membranes of rat corpus striatum.” Brain Research 1989 Apr 10;484(1-2):217-27. (source)

116 Wurtman R.J. “Choline metabolism as a basis for the selective vulnerability of cholinergic neurons.” Trends in Neuroscience 1992 Apr;15(4):117-22. (source)

117 Cohen B.M., Renshaw P.F., Stoll A.L., Wurtman R.J., Yurgelun-Todd D., Babb S.M. “De- creased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.” JAMA. 1995 Sep 20;274(11):902-7. (source)

118 Buchman A.L., Sohel M., Brown M., Jenden D.J., Ahn C., Roch M., Brawley T.L. “Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study.” Journal of Parenteral and Enteral Nutrition. 2001 Jan-Feb;25(1):30-5. (source)

119 Poly C., Massaro J.M., Seshadri S., Wolf P.A., Cho E., Krall E., Jacques P.F., Au R. “The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort.” The American Journal of Clinical Nutrition 2011 Dec;94(6):1584-91 (source)

120 Sanders L.M., Zeisel S.H. Choline – Dietary Requirements and Role in Brain Development Nutrition Today 2007; 42(4): 181–186. (source)

121 Conlay L.A., Wurtman R.J., Blusztajn K., Coviella I.L., Maher T.J., Evoniuk G.E. “Decreased plasma choline concentrations in marathon runners.” New England Journal of Medicine. 1986 Oct 2;315(14):892. (source)

122 Rao A.M., Hatcher J.F., Dempsey R.J. “CDP-choline: neuroprotection in transient forebrain ischemia of gerbils.” Journal of Neuroscience Research 1999 Dec 1;58(5):697-705. (source)

123 Adibhatla R.M., Hatcher J.F., Dempsey R.J. “Citicoline: neuroprotective mechanisms in cerebral ischemia.” Journal of Neurochemistry 2002 Jan;80(1):12-23 (source)

124 Wurtman R.J. “Choline metabolism as a basis for the selective vulnerability of cholinergic neurons.” Trends in Neuroscience 1992 Apr;15(4):117-22. (source) 501 David Tomen 125 Wang L., Pooler A.M., Albrecht M.A., Wurtman R.J. “Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats.” Journal of Molecular Neuroscience 2005;27(1):137-45. (source)

126 Cohen B.M., Renshaw P.F., Stoll A.L., Wurtman R.J., Yurgelun-Todd D., Babb S.M. “De- creased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.” JAMA 1995 Sep 20;274(11):902-7. (source)

127 De Bruin N.M.W.J., Kiliaan A.J., De Wilde M.C., Broersen L.M. “Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats” Neurobiol- ogy of Learning and Memory Volume 80, Issue 1, July 2003, Pages 63–79 (source)

128 Hurtado O. et. Al “Neuroprotection afforded by prior citicoline administration in experimen- tal brain ischemia: effects on glutamate transport.” Neurobiology of Disease 2005 Mar;18(2):336- 45. (source)

129 Adibhatla R.M., Hatcher J.F., Dempsey R.J. “Citicoline: neuroprotective mechanisms in cerebral ischemia.” Journal of Neurochemistry 2002 Jan;80(1):12-23. (source)

130 Watanabe S., Kono S., Nakashima Y., Mitsunobu K., Otsuki S. “Effects of various cerebral metabolic activators on glucose metabolism of brain.” Folia Psychiatr Neurol Jpn. 1975;29(1):67- 76. (source)

131 Clark W.M. “Efficacy of citicoline as an acute stroke treatment.” Expert Opinion on Pharmaco- therapy. 2009 Apr;10(5):839-46. (source)

132 De Bruin N.M., Kiliaan A.J., De Wilde M.C., Broersen L.M. “Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats.” Neurobiology of Learning and Memory. 2003 Jul;80(1):63-79. (source)

133 Silveri M.M. et. Al. “ Citicoline enhances frontal lobe bioenergetics as measured by phospho- rus magnetic resonance spectroscopy.” NMR in Biomedicine 2008 Nov;21(10):1066-75. (source)

134 McGlade E., Agoston A.M., DiMuzio J., Kizaki M., Nakazaki E., Kamiya T., Yurgelun-Todd D. “The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males.” Journal of Attention Disorders 2015 Jul 15. pii: 1087054715593633. (source)

135 Marcer D., Hopkins S.M. “The differential effects of meclofenoxate on memory loss in the elderly.” Age and Ageing. 1977 May;6(2):123-31. (source)

136 Sharma D., Singh R. “Centrophenoxine activates acetylcholinesterase activity in hippocampus of aged rats.” Indian Journal of Experimental Biology. 1995 May;33(5):365-8. (source)

137 Wood P.L., Péloquin A. “Increases in choline levels in rat brain elicited by meclofenoxate.” Neuropharmacology 1982 Apr;21(4):349-54. (source)

138 Katz M.L., Robison W.G. Jr. “What is lipofuscin? Defining characteristics and differentiation from other autofluorescent lysosomal storage bodies.” Archives of Gerontology and Geriatrics. 2002 May-Jun;34(3):169-84. (source)

139 Nandy K., Bourne G.H. “Effect of centrophenoxine on the lipofuscin pigments in the neu- rones of senile guinea-pigs.” Nature. 1966 Apr 16;210(5033):313-4. (source)

140 Lewis J.A., Young R. “Deanol and methylphenidate in minimal brain dysfunction.” Clinical Pharmacology and Therapeutics. 1975 May;17(5):534-40. (source) 502 HEAD FIRST 141 Roy D., Pathak D.N., Singh R. “Effect of centrophenoxine on the antioxidative enzymes in various regions of the aging rat brain.” Experimental Gerontology. 1983;18(3):185-97. (source)

142 Ludwig-Festl M., Gräter B., Bayreuther K. “[Increase in cell metabolism in normal, diploid human glial cells in stationary cell cultures induced by meclofenoxate].” Arzneimittel-forschung. 1983;33(4):495-501. (source)

143 Fülöp T. Jr., Wórum .I, Csongor J., Leövey A., Szabó T., Pék G., Zs – Nagy I. “Effects of centrophenoxine on body composition and some biochemical parameters of demented elderly people as revealed in a double-blind clinical trial.” Archives of Gerontology and Geriatrics. 1990 May-Jun;10(3):239-51. (source)

144 Sharma D., Maurya A.K., Singh R. “Age-related decline in multiple unit action potentials of CA3 region of rat hippocampus: correlation with lipid peroxidation and lipofuscin concentration and the effect of centrophenoxine.” Neurobiology of Aging. 1993 Jul-Aug;14(4):319-30. (source)

145 Pék G., Fülöp T., Zs-Nagy I. “Gerontopsychological studies using NAI (‘Nürnberger Alters- Inventar’) on patients with organic psychosyndrome (DSM III, Category 1) treated with centro- phenoxine in a double blind, comparative, randomized clinical trial.” Archives of Gerontology and Geriatrics. 1989 Jul;9(1):17-30. (source)

146 Nandy K. “Centrophenoxine: effects on aging mammalian brain.” Journal of the American Geriatrics Society. 1978 Feb;26(2):74-81. (source)

147 Casey D.E. “Mood alterations during deanol therapy.” Psychopharmacology (Berlin). 1979 Apr 11;62(2):187-91. (source)

148 Takashina K., Bessho T., Mori R., Eguchi J., Saito K. “MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats.” Journal of Neural Trans- mission (Vienna). 2008 Jul;115(7):1027-35. (source)

149 Akaike A., Maeda T., Kaneko S., Tamura Y. “Protective effect of MKC-231, a novel high affinity choline uptake enhancer, on glutamate cytotoxicity in cultured cortical neurons.” Japanese Journal of Pharmacology. 1998 Feb;76(2):219-22. (source)

150 Ray B., Bailey J.A., Simon J.R., Lahiri D.K. “High-affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in neuronal cultures for mechanistic and drug discovery studies.” Current Protocols in Neuroscience. 2012 Jul;Chapter 7:Unit 7.23. (source)

151 “Uptake of Choline, a Precursor of Acetylcholine” Williams College williams.edu Retrieved May 3, 2016 (source)

152 Brauser D. “Neurogenesis-Stimulating Compounds Show Promise in the Treatment of Major Depression” Medscape Medical News September 21, 2009 (source)

153 Bessho T., Takashina K., Eguchi J., Komatsu T., Saito K. “MKC-231, a choline-uptake en- hancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats.” Journal of Neural Transmission (Vienna). 2008 Jul;115(7):1019-25. (source)

154 Murai S., Saito H., Abe E., Masuda Y., Odashima J., Itoh T. “MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine in- duced by ethylcholine aziridinium ion in mice.” Journal of Neural Transmission General Section. 1994;98(1):1-13. (source) 503 David Tomen 155 Wadsworth T.L., Bishop J.A., Pappu A.S., Woltjer R.L., Quinn JF. “Evaluation of coen- zyme Q as an antioxidant strategy for Alzheimer's disease.” Journal of Alzheimer’s Disease. 2008 Jun;14(2):225-34. (source)

156 Kidd P.M. “Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management.” Alternative Medicine Review 2005 Dec;10(4):268-93. (source)

157 Failla M.L., Chitchumroonchokchai C., Aoki F. “Increased bioavailability of ubiquinol com- pared to that of ubiquinone is due to more efficient micellarization during digestion and greater GSH-dependent uptake and basolateral secretion by Caco-2 cells.” Journal of Agricultural Food Chemistry 2014 Jul 23;62(29):7174-82 (source)

158 Spindler M., Beal M.F., Henchcliffe C. “Coenzyme Q10 effects in neurodegenerative disease” Neuropsychiatry Disease Treatment 2009; 5: 597–610. (source)

159 Beal M.F., Henshaw D.R., Jenkins B.G., Rosen B.R., Schulz J.B. “Coenzyme Q10 and nico- tinamide block striatal lesions produced by the mitochondrial toxin malonate.” Annals of Neurology 1994 Dec;36(6):882-8. (source)

160 Hershey A.D., Powers S.W., Vockell A.L., Lecates S.L., Ellinor P.L., Segers A., Burdine D., Manning P., Kabbouche M.A. “Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine.” Headache 2007 Jan;47(1):73-80. (source)

161 Maes M., Galecki P., Chang Y.S., Berk M. “ A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.” Progress in Neuropsychopharmacology and Biological Psychiatry. 2011 Apr 29;35(3):676-92. (source)

162 Forester B.P., Zuo C.S., Ravichandran C., Harper D.G., Du F., Kim S., Cohen B.M., Renshaw P.F. “Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression.” Journal of Geriatric Psychiatry and Neurology. 2012 Mar;25(1):43-50. (source)

163 Saini R. “Coenzyme Q10: The essential nutrient” Journal of Pharmacy and Bioallied Sciences. 2011 Jul-Sep; 3(3): 466–467. (source)

164 McDonald S.R., Sohal R.S., Forster M.J. “Concurrent administration of coenzyme Q10 and alpha-tocopherol improves learning in aged mice.” Free Radical Biology and Medicine. 2005 Mar 15;38(6):729-36. (source)

165 McCarthy S., Somayajulu M., Sikorska M., Borowy-Borowski H., Pandey S. “Paraquat in- duces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10.” Toxicology and Applied Pharmacology. 2004 Nov 15;201(1):21-31. (source)

166 Golomb B.A., Allison M., Koperski S., Koslik H.J., Devaraj S., Ritchie J.B. “Coenzyme Q10 benefits symptoms in Gulf War veterans: results of a randomized double-blind study.” Neural Computation. 2014 Nov;26(11):2594-651. (source)

167 Jagim A.R. et. Al. “A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate.” Journal of the International Society of Sports Nutrition. 2012 Sep 13;9(1):43. (source)

168 Giese M.W., Lecher C.S. “Non-enzymatic cyclization of creatine ethyl ester to creatinine.” Biochemical and Biophysical Research Communications. 2009 Oct 16;388(2):252-5. (source) 504 HEAD FIRST 169 Yeo R.A., Hill D., Campbell R., Vigil J., Brooks W.M. “Developmental instability and work- ing memory ability in children: a magnetic resonance spectroscopy investigation.” Developmental Neuropsychology. 2000;17(2):143-59. (source)

170 Watanabe A., Kato N., Kato T. “Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.” Neuroscience Research. 2002 Apr;42(4):279-85. (source)

171 Wyss M., Schulze A. “Health implications of creatine: can oral creatine supplementation pro- tect against neurological and atherosclerotic disease?” Neuroscience. 2002;112(2):243-60 (source)

172 Rae C., Digney A.L., McEwan S.R., Bates T.C. “Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.” Proceedings: Biological Sciences/The Royal Society. 2003 Oct 22;270(1529):2147-50. (source)

173 Ling J., Kritikos M., Tiplady B. “Cognitive effects of creatine ethyl ester supplementation.” Behavioral Pharmacology. 2009 Dec;20(8):673-9. (source) (full study)

174 Esposito E., Cuzzocrea S. “New therapeutic strategy for Parkinson's and Alzheimer's disease.” Current Medical Chemistry. 2010;17(25):2764-74. (source)

175 Klein A.M., Ferrante R.J. “The neuroprotective role of creatine.” Sub-cellular Biochemistry. 2007;46:205-43. (source)

176 Green A.L., Simpson E.J., Littlewood J.J., Macdonald I.A., Greenhaff P.L. “Carbohydrate ingestion augments creatine retention during creatine feeding in humans.” Acta Physiologica Scan- dinavica. 1996 Oct;158(2):195-202. (source)

177 DHEA U.S. National Library of Medicine – Medline Plus (source)

178 Weiss, E., Villareal D.T., Fontana L., Han D., Holloszy J.O. “Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans” Aging (Albany NY). 2011 May; 3(5): 533–542. (source)

179 Davis S.R., Shah S.M., McKenzie D.P., Kulkarni J., Davison S.L., Bell R.J. “Dehydroepian- drosterone sulfate levels are associated with more favorable cognitive function in women.” Journal of Clinical Endocrinology and Metabolism. 2008 Mar;93(3):801-8. (source)

180 Schmidt P.J., Daly R.C., Bloch M., Smith M.J., Danaceau M.A., St Clair L.S., Murphy J.H., Haq N., Rubinow D.R. “Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression.” Archives of General Psychiatry. 2005 Feb;62(2):154-62. (source)

181 Lazaridis I., et. Al. “ Dehydroepiandrosterone Interacts with Nerve Growth Factor (NGF) Receptors, Preventing Neuronal Apoptosis” PLoS Biology. 2011 Apr; 9(4): e1001051. (source)

182 Herbert J. “, brain damage, and mental illness” Experimental Gerontology Volume 33, Issues 7–8, November–December 1998, Pages 713–727 (source)

183 Enomoto M., Adachi H., Fukami A., Furuki K., Satoh A., Otsuka M., Kumagae S., Nanjo Y., Shigetoh Y., Imaizumi T. “Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study).” Journal of Amercian Geriatrics Society. 2008 Jun;56(6):994-8. (source)

184 Alhaj H.A., Massey A.E., McAllister-Williams R.H. “Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study.” Psychopharmacology (Berl). 2006 Nov;188(4):541-51. (source) 505 David Tomen 185 Wang H.T., Chen SM, Lee S.D., Hsu M.C., Chen K.N., Liou Y.F., Kuo C.H. “The role of DHEA-S in the mood adjustment against negative competition outcome in golfers.” Journal of Sports Science. 2009 Feb 1;27(3):291-7 (source)

186 Haubrich D.R., Gerber N.H., Pflueger A.B. “Deanol affects choline metabolism in peripheral tissues of mice.” Journal of Neurochemistry. 1981 Aug;37(2):476-82. (source)

187 Jope R.S., Jenden D.J. “Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis.” Journal of Pharmacology and Experimental Therapeutics. 1979 Dec;211(3):472-9. (source)

188 Zeisel S.H. “Choline: Critical Role During Fetal Development and Dietary Requirements in Adults” Annual Review of Nutrition. 2006; 26: 229–250. (source)

189 Waymiare J.C. “Chapter 11: Acetylcholine Neurotransmission” The UT Medical School at Houston (source)

190 Millington W.R., McCall A.L., Wurtman R.J. “Deanol acetamidobenzoate inhibits the blood- brain barrier transport of choline.” Annals of Neurology. 1978 Oct;4(4):302-6. (source)

191 Kostopoulos G.K., Phillis J.W. “The effects of dimethylaminoethanol (deanol) on cerebral cortical neurons.” Psychopharmacology Communications. 1975;1(3):339-47. (source)

192 Haubrich D.R., Gerber N.H., Pflueger A.B. “Deanol affects choline metabolism in peripheral tissues of mice.” Journal of Neurochemistry. 1981 Aug;37(2):476-82. (source)

193 Russell R.W., Jenden D.J. “Behavioral effects of deanol, of hemicholinium and of their interac- tion.” Pharmacology, Biochemistry and Behavior. 1981 Aug;15(2):285-8. (source)

194 Dylewski D.P., Nandy S., Nandy K. “Effects of centrophenoxine on lipofuscin in the retinal pigment epithelium of old mice.” Neurobiology of Aging. 1983 Spring;4(1):89-95. (source)

195 Dimpfel W., Wedekind W., Keplinger I. “Efficacy of dimethylaminoethanol (DMAE) contain- ing vitamin-mineral drug combination on EEG patterns in the presence of different emotional states.” European Journal of Medical Research. 2003 May 30;8(5):183-91. (source)

196 Zahniser N.R., Chou D., Hanin I. “Is 2-dimethylaminoethanol (deanol) indeed a precursor of brain acetylcholine? A gas chromatographic evaluation.” Journal of Pharmacology and Experimental Therapy. 1977 Mar;200(3):545-59. (source)

197 Lewis J.A., Lewis B.S. “Deanol in minimal brain dysfunction.” Diseases of the Nervous System. 1977 Dec;38(12 Pt 2):21-4. (source)

198 Grossman R. “The role of dimethylaminoethanol in cosmetic dermatology.” American Journal of Clinical Dermatology. 2005;6(1):39-47. (source)

199 Siesjö B.K., Agardh C.D., Bengtsson F. “Free radicals and brain damage.” Cerebrovascular and Brain Metabolism Reviews. 1989 Fall;1(3):165-211. (source)

200 Malanga G., Aguiar M.B., Martinez H.D., Puntarulo S. “New insights on dimethylamino- ethanol (DMAE) features as a free radical scavenger.” Drug Metabolism Letters. 2012 Mar;6(1):54- 9. (source)

201 Nagy I., Nagy K. “On the role of cross-linking of cellular proteins in aging.” Mechanisms of Ageing and Development. 1980 Sep-Oct;14(1-2):245-51. (source) 506 HEAD FIRST 202 Nagy I., Floyd R.A. “Electron spin resonance spectroscopic demonstration of the hydroxyl free radical scavenger properties of dimethylaminoethanol in spin trapping experiments confirming the molecular basis for the biological effects of centrophenoxine.” Archives of Gerontology and Geriatrics. 1984 Dec;3(4):297-310 (source)

203 Sergio W. “Use of DMAE (2-dimethylaminoethanol) in the induction of lucid dreams.” Medi- cal Hypotheses. 1988 Aug;26(4):255-7. (source)

204 Lewis J.A, Young R. “Deanol and methylphenidate in minimal brain dysfunction.” Clinical Pharmacology and Therapeutics. 1975 May;17(5):534-40. (source)

205 PFEIFFER C.C., JENNEY E.H., GALLAGHER W., SMITH R.P., BEVAN W. Jr., KILLAM K.F., KILLAM E.K., BLACKMORE W. “Stimulant effect of 2-dimethylaminoethanol; possible precursor of brain acetylcholine.” Science. 1957 Sep 27;126(3274):610-1. (source)

206 Uhoda I., Faska N., Robert C., Cauwenbergh G., Piérard G.E. “Split face study on the cutane- ous tensile effect of 2-dimethylaminoethanol (deanol) gel.” Skin Research and Technology. 2002 Aug;8(3):164-7. (source)

207 Grossman R. “The role of dimethylaminoethanol in cosmetic dermatology.” American Journal of Clinical Dermatology. 2005;6(1):39-47. (source)

208 Fisher M.C., Zeisel S.H., Mar M.H., Sadler T.W. “Inhibitors of choline uptake and me- tabolism cause developmental abnormalities in neurulating mouse embryos.” Teratology. 2001 Aug;64(2):114-22. (source)

209 Hinz M., Stein A., Uncini T. “5-HTP efficacy and contraindications.” Neuropsychiatric Disease and Treatment. 2012;8:323-8. (source)

210 Turner E.H., Loftis J.M., Blackwell A.D. “Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan.” Pharmacology and Therapeutics. 2006 Mar;109(3):325- 38. (source)

211 Birdsall T.C. “5-Hydroxytryptophan: a clinically-effective serotonin precursor.” Alternative Medicine Revue. 1998 Aug;3(4):271-80. (source)

212 Lemaire P.A., Adosraku R.K. “An HPLC method for the direct assay of the serotonin pre- cursor, 5-hydroxytrophan, in seeds of Griffonia simplicifolia.” Phytochemical Analysis. 2002 Nov- Dec;13(6):333-7. (source)

213 Emanuele E., Bertona M., Minoretti P., Geroldi D. “An open-label trial of L-5-hydroxytryp- tophan in subjects with romantic stress.” Neuro Endocrinology Letters. 2010;31(5):663-6. (source)

214 Hinz M., Stein A., Uncini T. “APRESS: apical regulatory super system, serotonin, and dopa- mine interaction.” Neuropsychiatric Disease and Treatment. 2011;7:457-63. (source)

215 Hinz M., Stein A., Uncini T. “Relative nutritional deficiencies associated with centrally acting monoamines.” International Journal of General Medicine. 2012;5:413-30 (source)

216 van Praag H.M. “n search of the mode of action of antidepressants. 5-HTP/tyrosine mixtures in depressions.” Neuropharmacology. 1983 Mar;22(3 Spec No):433-40. (source)

217 Hinz M., Stein A., Uncini T. “5-HTP efficacy and contraindications” Neuropsychiatric Disease and Treatment. 2012; 8: 323–328. (source) 507 David Tomen 218 Hinz M., Stein A., Uncini T. “APRESS: apical regulatory super system, serotonin, and dopa- mine interaction.” Neuropsychiatric Disease and Treatment. 2011;7:457-63. (source)

219 Hinz M., Stein A., Uncini T. “Amino acid management of Parkinson’s disease: a case study” International Journal of General Medicine. 2011; 4: 165–174. (source)

220 Birdsall T.C. “5-Hydroxytryptophan: a clinically-effective serotonin precursor.” Alternative Medicine Revue. 1998 Aug;3(4):271-80. (source)

221 Shaw K., Turner J., Del Mar C. “Are tryptophan and 5-hydroxytryptophan effective treat- ments for depression? A meta-analysis.” Australia and New Zealand Journal of Psychiatry. 2002 Aug;36(4):488-91. (source)

222 Caruso I., Sarzi Puttini P., Cazzola M., Azzolini V. “Double-blind study of 5-hydroxytrypto- phan versus placebo in the treatment of primary fibromyalgia syndrome.” Journal of International Medical Research. 1990 May-Jun;18(3):201-9. (source)

223 Meyers S. “Use of neurotransmitter precursors for treatment of depression.” Alternative Medi- cine Revue. 2000 Feb;5(1):64-71. (source)

224 Wang X., Baumann M.H., Dersch C.M., Rothman R.B. “Restoration of 3,4-methylenedioxy- methamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan.” Neuroscience. 2007 Aug 10;148(1):212-20. (source)

225 Seamon K.B., Daly J.W. “Forskolin: a unique diterpene activator of cyclic AMP-generating systems.” Journal of Cyclic Nucleotide Research. 1981;7(4):201-24. (source)

226 Dubrey M.P., Srimal R.C., Nityanand S., Dhawan B.N. “Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii” Journal of Ethnopharmacology Volume 3, Issue 1, January 1981, Pages 1-13 (source)

227 Ding X., Staudinger J.L. “Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway.” Journal of Pharmacology and Experimental Therapy. 2005 Feb;312(2):849-56. Epub 2004 Sep 30. (source)

228 Patterson S.L., Pittenger C., Morozov A., Martin K.C., Scanlin H., Drake C., Kandel E.R. “Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase.” Neuron. 2001 Oct 11;32(1):123-40. (source)

229 Huang Y.Y., Li X.C., Kandel E.R. “cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase.” Cell. 1994 Oct 7;79(1):69-79. (source)

230 Cooke S.F., Bliss T.V.P. “Plasticity in the human central nervous system” Journal of Neurology May 2006 (source)

231 Kramer W., Thormann J., Kindler M., Schlepper M. “Effects of forskolin on left ventricular function in dilated cardiomyopathy.” Arzneimittelforschung. 1987 Mar;37(3):364-7. (source)

232 Wysham D.G., Brotherton A.F., Heistad D.D. “Effects of forskolin on cerebral blood flow: implications for a role of adenylate cyclase.” Stroke. 1986 Nov-Dec;17(6):1299-303. (source)

233 Almeida L.E., Murray P.D., Zielke H.R., Roby C.D., Kingsbury T.J., Krueger B.K. “Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine – and cAMP-induced CREB-dependent gene transcription.” Journal of Neuroscience 2009 Oct 7;29(40):12702-10. (source) 508 HEAD FIRST 234 Silva A.J., Kogan J.H., Frankland P.W., Kida S. “CREB and memory.” Annual Review of Neuroscience. 1998;21:127-48 (source)

235 Malik R., Gilhotra N. “A NOVEL NON–RECEPTOR AND NON – GABAERGIC ANTI- ANXIETY-LIKE ACTIVITY OF FORSKOLIN: SYNERGY WITH DIAZEPAM” International Journal of Pharmacy and Pharmaceutical Sciences Vol. 7, Issue 2. 2015 (source)

236 Curtin B.F., Pal N., Gordon R.K., Nambiar M.P. “Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against exposure in neuro 2A cells.” Molecular and Cellular Biochemistry. 2006 Oct;290(1-2):23-32 (source)

237 Ding X., Staudinger J.L. “Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway.” International Journal of Pharma- cology and Experimental Therapy. 2005 Feb;312(2):849-56. Epub 2004 Sep 30. (source)

238 Tamboli E.T., Singh M., Kamal Y.T., Garg M., Parveen R., Mujeeb M., Ahmad S. “Meta- bolic diversity in Coleus forskohlii Briq. of Indian subcontinent.” Natural Product Research. 2013;27(19):1737-42 (source)

239 Nemeroff C.B. “The role of GABA in the pathophysiology and treatment of anxiety disorders.” Psychopharmacology Bulletin. 2003;37(4):133-46. (source)

240 “HOW DRUGS AFFECT NEUROTRANSMITTERS” McGill University Canada (source)

241 Abdou A.M., Higashiguchi S., Horie K., Kim M., Hatta H, Yokogoshi H. “Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.” Biofactors. 2006;26(3):201-8. (source)

242 Abdou A.M., Higashiguchi S., Horie K., Kim M., Hatta H, Yokogoshi H. “Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.” Biofactors. 2006;26(3):201-8. (source)

243 Enna S.J. “Role of gamma-aminobutyric acid in anxiety.” Psychopathology. 1984;17 Suppl 1:15-24. (source)

244 Struzyńska L., Sulkowski G. “Relationships between glutamine, glutamate, and GABA in nerve endings under Pb-toxicity conditions.” Journal of Inorganic Biochemistry. 2004 Jun;98(6):951-8. (source)

245 Kuriyama K., Sze P.Y. “Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals” Neuropharmacology Volume 10, Issue 1, January 1971, Pages 103–108 (source)

246 Montagne A., et. Al. “Blood-brain barrier breakdown in the aging human hippocampus.” Neuron 2015 Jan 21;85(2):296-302 (source)

247 Watanabe M., Maemura K., Kanbara K., Tamayama T., Hayasaki H. “GABA and GABA receptors in the central nervous system and other organs.” International Revue of Cytology. 2002;213:1-47. (source)

248 Cavagnini F., Invitti C., Pinto M., Maraschini C., Di Landro A., Dubini A., Marelli A. “Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man.” Acta Endocrinologica (Copenhagen). 1980 Feb;93(2):149-54. (source). 509 David Tomen 249 Shell W., Bullias D., Charuvastra E., May LA., Silver D.S. “A randomized, placebo-controlled trial of an amino acid preparation on timing and quality of sleep.” American Journal of Therapeutics. 2010 Mar-Apr;17(2):133-9. (source)

250 Shyamaladevi N., Jayakumar A.R., Sujatha R., Paul V., Subramanian E.H. “Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier.” Brain Research Bulletin. 2002 Jan 15;57(2):231-6. (source)

251 Yuan C.S., Mehendale S., Xiao Y., Aung H.H., Xie J.T., Ang-Lee M.K. “The gamma-amino- butyric acidergic effects of valerian and on rat brainstem neuronal activity.” Anesthesia and Analgesia. 2004 Feb;98(2):353-8 (source)

252 Hossain S.J., Hamamoto K., Aoshima H., Hara Y. “Effects of tea components on the response of GABA(A) receptors expressed in Xenopus Oocytes.” Journal of Agriculture and Food Chemistry. 2002 Jul 3;50(14):3954-60. (source)

253 Möykkynen T., Uusi-Oukari M., Heikkilä J., Lovinger D.M., Lüddens H., Korpi E.R. “ Mag- nesium potentiation of the function of native and recombinant GABA(A) receptors.” Neuroreport. 2001 Jul 20;12(10):2175-9. (source)

254 Sugiyama T., Sadzuka Y. “Theanine and glutamate transporter inhibitors enhance the an- titumor efficacy of chemotherapeutic agents.”Biochim Biophys Acta. 2003 Dec 5;1653(2):47-59. (source)

255 The IUCN Red List of Threatened Species. iucnredlist.org Retrieved April 25, 2016 (source)

256 Popa A. “Ginkgo Biloba and Memory” Pharmacotherapy Update – Cleveland Clinic Vol. V, No. V September/October 2002 (source)

257 EGb 761: ginkgo biloba extract, Ginkor. Drugs in R. & D. 2003;4(3):188-93. (source)

258 Wu W.R., Zhu X.Z. “Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminer- gic toxicity in C57 mice.” Life Sciences. 1999;65(2):157-64. (source)

259 Woelk H., Arnoldt K.H., Kieser M., Hoerr R. “Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double- blind, placebo-controlled trial.” Journal of Psychiatric Research. 2007 Sep;41(6):472-80. (source)

260 Uebel-von Sandersleben H., Rothenberger A., Albrecht B., Rothenberger L.G., Klement S., Bock N. “Ginkgo biloba extract EGb 761® in children with ADHD.” Z Kinder Jugendpsychiatr Psychother. 2014 Sep;42(5):337-47. (source)

261 Mashayekh A., Pham D.L., Yousem D.M., Dizon M., Barker P.B., Lin DD. “Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study.” Neu- roradiology. 2011 Mar;53(3):185-91. (source)

262 Blecharz-Klin K., Piechal A., Joniec I., Pyrzanowska J., Widy-Tyszkiewicz E. “Pharmacological and biochemical effects of Ginkgo biloba extract on learning, memory consolidation and motor activity in old rats.” Acta Neurobiologiae Experimentalis (Wars). 2009;69(2):217-31. (source)

263 Ahlemeyer B., Krieglstein J. “Neuroprotective effects of Ginkgo biloba extract.” Cellular & Molecular Life Sciences. 2003 Sep;60(9):1779-92. (source) 510 HEAD FIRST 264 Kanowski S., Herrmann W.M., Stephan K., Wierich W., Hörr R. “Proof of efficacy of the ginkgo biloba…” Pharmacopsychiatry. 1996 Mar;29(2):47-56. (source)

265 Mashayekh A., Pham D.L., Yousem D.M., Dizon M., Barker P.B., Lin DD. “Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study.” Neu- roradiology. 2011 Mar;53(3):185-91. (source)

266 Mix J.A., Crews W.D. Jr. “A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings.” Human Psychopharmacology. 2002 Aug;17(6):267-77. (source)

267 Popa A. “Ginkgo Biloba and Memory” Pharmacotherapy Update – Cleveland Clinic Vol. V, No. V September/October 2002 (source)

268 Jezova D., Duncko R., Lassanova M., Kriska M., Moncek F. “Reduction of rise in blood pres- sure and cortisol release during stress by Ginkgo biloba extract (EGb 761) in healthy volunteers.” Journal of Physiology & Pharmacology. 2002 Sep;53(3):337-48. (source)

269 Cieza A., Maier P., Pöppel E. “Effects of Ginkgo biloba on mental functioning in healthy volunteers.” Archives of Medical Research. 2003 Sep-Oct;34(5):373-81. (source)

270 Trick L., Boyle J., Hindmarch I. “The effects of Ginkgo biloba extract (LI 1370) supplementa- tion and discontinuation on activities of daily living and mood in free living older volunteers.” Phytotherapy Research. 2004 Jul;18(7):531-7. (source)

271 Kennedy D.O., Scholey A.B., Wesnes KA. “The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers.” Psychopharmacology (Berlin). 2000 Sep;151(4):416-23. (source)

272 Filaretov A.A., Bogdanova T.S., Podvigina T.T., Bodganov A.I. “Role of pituitary-adreno- cortical system in body adaptation abilities.” Experimental and Clinical Endocrinology. 1988 Dec;92(2):129-36. (source)

273 Radad K., Gille G., Moldzio R., Saito H., Rausch W.D. “Ginsenosides Rb1 and Rg1 ef- fects on mesencephalic dopaminergic cells stressed with glutamate.” Brain Research. 2004 Sep 17;1021(1):41-53. (source)

274 Niederhofer H. “Panax ginseng may improve some symptoms of attention-deficit hyperactiv- ity disorder.” Journal of Dietary Supplements. 2009;6(1):22-7. (source)

275 Li X.T., Chen R., Jin L.M., Chen H.Y. “Regulation on energy metabolism and protec- tion on mitochondria of Panax ginseng polysaccharide.” American Journal of Chinese Medicine. 2009;37(6):1139-52. (source)

276 Baeg I.H., So S.H. “The world ginseng market and the ginseng (Korea)” Journal of Ginseng Research 2013 Mar; 37(1): 1–7. (source)

277 Choi K.T. “Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer.” Acta Pharmacologica Sinica. 2008 Sep;29(9):1109-18. (source)

278 Reay J.L., Kennedy D.O., Scholey A.B. “Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity.” Journal of Psychopharmacology. 2005 Jul;19(4):357-65. (source)

279 Nishiyama N., Cho S.I., Kitagawa I., Saito H. “Malonylginsenoside Rb1 potentiates nerve 511 David Tomen growth factor (NGF)-induced neurite outgrowth of cultured chick embryonic dorsal root ganglia.” Biological and Pharmaceutical Bulletin. 1994 Apr;17(4):509-13. (source)

280 Jia L., Zhao Y. “Current evaluation of the millennium phytomedicine—ginseng (I): etymol- ogy, pharmacognosy, phytochemistry, market and regulations.” Current Medicinal Chemistry. 2009;16(19):2475-84. (source)

281 Ahn J.Y., Choi I.S., Shim J.Y., Yun E.K., Yun Y.S., Jeong G, Song J.Y. “The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll-like receptor-mediated inflam- matory signals.” European Journal of Immunology. 2006 Jan;36(1):37-45. (source)

282 Wu B., Wang M., Ma Y., Yuan L., Lu S. “High-throughput sequencing and characterization of the small RNA transcriptome reveal features of novel and conserved microRNAs in Panax ginseng.” PLoS One. 2012;7(9):e44385 (source)

283 Li C., Cai J., Geng J., Li Y., Wang Z., Li R. “Purification, characterization and anticancer activity of a polysaccharide from Panax ginseng.” International Journal of Biological Macromolecules. 2012 Dec;51(5):968-73. (source)

284 Kuo Y.H., Ikegami F., Lambein F. “Neuroactive and other free amino acids in seed and young plants of Panax ginseng.” Phytochemistry. 2003 Apr;62(7):1087-91. (source)

285 Scholey A., Ossoukhova A., Owen L., Ibarra A., Pipingas A., He K., Roller M., Stough C. “Effects of American ginseng (Panax quinquefolius) on neurocognitive function: an acute, ran- domised, double-blind, placebo-controlled, crossover study.” Psychopharmacology (Berlin). 2010 Oct;212(3):345-56. (source)

286 Ye R., Zhang X., Kong X., Han J., Yang Q., Zhang Y., Chen Y., Li P., Liu J., Shi M., Xiong L., Zhao G. “Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia.” Neuroscience. 2011 Mar 31;178:169-80 (sourcel)

287 Wang J.R., Zhou H., Yi X.Q., Jiang Z.H., Liu L. “Total ginsenosides of Radix Ginseng modu- lates tricarboxylic acid cycle protein expression to enhance cardiac energy metabolism in ischemic rat heart tissues.” Molecules. 2012 Oct 29;17(11):12746-57. (source)

288 Oliynyk S., Oh S. “The pharmacology of actoprotectors: practical application for improvement of mental and physical performance.” Biomolecules and Therapeutics (Seoul). 2012 Sep;20(5):446- 56 (source)

289 Olinyk S., Oh S., “Actoprotective effect of ginseng: improving mental and physical perfor- mance” Journal of Ginseng Research 2013 Apr; 37(2): 144–166. (source)

290 Coleman C.I., Hebert J.H., Reddy P. “The effects of Panax ginseng on quality of life.” Journal of Clinical and Pharmaceutical Therapy. 2003 Feb;28(1):5-15. (source)

291 Kennedy D.O., Scholey A.B., Wesnes K.A. “Dose dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers.” Nutritional Neuroscience. 2001;4(4):295-310. (source)

292 O’Connor A. “New York Attorney General Targets Supplements at Major Retailers” The New York Times February 3, 2015. well.blogs.nytimes.com (source) Retrieved May 18, 2016

293 Wang L., Xu J., Zhao C., Zhao L., Feng B. “Antiproliferative, cell-cycle dysregulation effects of novel asiatic acid derivatives on human non-small cell lung cancer cells.” 512 HEAD FIRST 294 Orhan G., orhan I., Sener B. “Recent Developments in Natural and Synthetic Drug Research forAlzheimer’s Disease” Letter in Drug Design & Discovery 2006 (source)

295 Soumyanath A., Zhong Y.P., Gold S.A., Yu X., Koop D.R., Bourdette D., Gold B.G. “Cen- tella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro.” Journal of Pharmacy & Pharmacology. 2005 Sep;57(9):1221-9. (source)

296 Gadahad M.R., Rao M., Rao G. “Enhancement of hippocampal CA3 neuronal dendritic arborization by Centella asiatica (Linn) fresh leaf extract treatment in adult rats.” Journal of the Chinese Medical Association. 2008 Jan;71(1):6-13. (source)

297 Sheffield M.E.J., Dombeck D.A. “Calcium transient prevalence across the dendritic arbour predicts place field properties” Nature 517, 200–204 (08 January 2015) (source)

298 Wattanathorn J. et. Al. “Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica.” Journal of Ethnopharmacology. 2008 Mar 5;116(2):325-32. (source)

299 Peters R. “Ageing and the brain” Postgrad Medical Journal 2006 Feb; 82(964): 84–88. (source)

300 Seshadri S., Wolf P.A., Beiser A., Elias M.F., Au R., Kase C.S., D'Agostino R.B., DeCarli C. “Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study.” Neurology. 2004 Nov 9;63(9):1591-9. (source)

301 Barnes C.A. “Long-term potentiation and the ageing brain.” Philosophical Transactions of the Royal Society of London Series B Biological Sciences. 2003 Apr 29;358(1432):765-72. (source)

302 Wanakhachornkrai O., Pongrakhananon V., Chunhacha P., Wanasuntronwong A., Vattanajun A., Tantisira B., Chanvorachote P., Tantisira M.H. “Neuritogenic effect of standardized extract of Centella asiatica ECa233 on human neuroblastoma cells.” BMC Complementary and Alternative Medicine. 2013 Aug 4;13:204. (source)

303 Wattanathorn J., Mator L., Muchimapura S., Tongun T., Pasuriwong O., Piyawatkul N., Yimtae K., Sripanidkulchai B., Singkhoraard J. “Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica.” Journal of Ethnophar- macology. 2008 Mar 5;116(2):325-32. (source)

304 Rao S.B., Chetana M., Uma Devi P. “Centella asiatica treatment during postnatal period enhances learning and memory in mice.” Physiology and Behavior. 2005 Nov 15;86(4):449-57. (source)

305 Coleman B.R., Ratcliffe R.H., Oguntayo S.A., Shi X., Doctor B.P., Gordon R.K., Nambiar M.P. “[+]- treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats.” Chemico-Biological Interactions. 2008 Sep 25;175(1-3):387-95. (source)

306 Raves M.L., Harel M., Pang Y.P., Silman I., Kozikowski A.P., Sussman J.L. “Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A.” Nature Structural Biology. 1997 Jan;4(1):57-63. (source)

307 Gordon R.K., Nigam S.V., Weitz J.A., Dave J.R., Doctor B.P., Ved H.S. “The NMDA receptor ion channel: a site for binding of Huperzine A.” Journal of Applied Toxicology. 2001 Dec;21 Suppl 1:S47-51. (source)

308 Shen J.N., Wang D.S., Wang R. “The protection of acetylcholinesterase inhibitor on 513 David Tomen β-amyloid-induced injury of neurite outgrowth via regulating axon guidance related genes expres- sion in neuronal cells” International Journal of Clinical and Experimental Pathology. 2012; 5(9): 900–913. (source)

309 Xiao X.Q., Wang R., Han Y.F., Tang X.C. “Protective effects of huperzine A on beta-amy- loid(25-35) induced oxidative injury in rat pheochromocytoma cells.” Neuroscience Letters. 2000 Jun 9;286(3):155-8. (source)

310 Gao X., Tang X.C. “Huperzine A attenuates mitochondrial dysfunction in beta-amyloid- treated PC12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism.” Journal of Neuroscience Research. 2006 May 1;83(6):1048-57. (source)

311 Hynd M.R., Scott H.L., Dodd P.R. “Glutamate-mediated excitotoxicity and neurodegenera- tion in Alzheimer's disease.” Neurochemistry International. 2004 Oct;45(5):583-95. (source)

312 Tang L.L., Wang R., Tang X.C. “Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells.” Acta Pharmacologica Sinica. 2005 Jun;26(6):673-8. (source)

313 Saxena A., Qian N., Kovach I.M., Kozikowski A.P., Pang Y.P., Vellom D.C., Radić Z., Quinn D., Taylor P., Doctor B.P. “Identification of amino acid residues involved in the binding of Huper- zine A to .” Protein Science. 1994 Oct;3(10):1770-8. (source)

314 Sun Q., et. Al. “Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students” Acta Pharmacologica Sinica 1999; (7):601—603(source)

315 Wang B.S., Wang H., Wei Z.H., Song Y.Y., Zhang L., Chen H.Z. “Efficacy and safety of natu- ral acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis.” Journal of Neural Transmission (Vienna). 2009 Apr;116(4):457-65. (source)

316 Delange F. “Iodine deficiency as a cause of brain damage.” Postgrad Medical Journal. 2001 Apr;77(906):217-20. (source)

317 Hoption Cann S.A. “Hypothesis: dietary iodine intake in the etiology of cardiovascular dis- ease.” Journal of the American College of Nutrition. 2006 Feb;25(1):1-11. (source)

318 Vara H., Martínez B., Santos A., Colino A. “Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus.” Neuroscience. 2002;110(1):19-28. (source)

319 Duval F., Mokrani M.C., Bailey P., Correa H., Diep T.S., Crocq M.A., Macher J.P. “Thyroid axis activity and serotonin function in major depressive episode.” Psychoneuroendocrinology. 1999 Oct;24(7):695-712. (source)

320 Wiens S.C., Trudeau V.L. “Thyroid hormone and gamma-aminobutyric acid (GABA) interac- tions in neuroendocrine systems.” Comparative Biochemistry and Physiology. Part A Molecular and Integrative Physiology. 2006 Jul;144(3):332-44 (source)

321 Peterson A.L., Gilman T.L., Banks M.L., Sprague J.E. “Hypothyroidism alters striatal do- pamine release mediated by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).” Synapse. 2006 Apr;59(5):317-9. (source)

322 Pereira J.C., Pradella-Hallinan M., Pessoa H. “Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypoth- esis” Clinics (Sao Paulo). 2010 May; 65(5): 548–554. (source) 514 HEAD FIRST 323 Annerbo S., Lokk J. “A Clinical Review of the Association of Thyroid Stimulating Hormone and Cognitive Impairment” ISRN Endocrinology. 2013; 2013: 856017. (source)

324 Wang N., Cai Y., Wang F., Zeng X., Jia X., Tao F., Zhu D. “Effects of thyroxin and donepezil on hippocampal acetylcholine content and syntaxin-1 and munc-18 expression in adult rats with hypothyroidism.” Experimental and Therapeutic Medicine. 2014 Mar;7(3):529-536. (source)

325 Vobecký M., Babický A., Lener J., Svandová E. “Interaction of bromine with iodine in the rat thyroid gland at enhanced intake.” Biology Trace Element Research. 1996 Sep;54(3):207- 12. (source)

326 “Fluoride in Drinking Water: A Scientific Review of EPA's Standards (2006)” The National Academies Press Page 205 (source)

327 Peckman S., Lowery D., Spencer S. “Are fluoride levels in drinking water associated with hypothyroidism prevalence in England?” Journal of Epidemiology and Community Health 24 Febru- ary 2015 (source)

328 Kapil U. “Health Consequences of Iodine Deficiency” Sultan Qaboos University Medical Jour- nal. 2007 Dec; 7(3): 267–272. (source)

329 McNeil D. G. “In Raising the World’s I.Q., the Secret’s in the Salt” The New York Times nytimes.com Dec. 16, 2006 Retrieved on September 4, 2016 (source)

330 Vermiglio F., Lo Presti V.P., Moleti M., Sidoti M., Tortorella G., Scaffidi G., Castagna M.G., Mattina F., Violi M.A., Crisà A., Artemisia A., Trimarchi F. “Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries.” Journal of Clinical Endocrinology and Metabo- lism. 2004 Dec;89(12):6054-60. (source)

331 “Enzyme's Cancer-promoting Activities Linked To Inactivation Of 'Genome Guardian'” Baylor College of Medicine October 16, 2007 (source)

332 Jussofie A., Schmiz A., Hiemke C. “Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.” Psychopharmacology (Berlin). 1994 Dec;116(4):469-74. (source)

333 Backhauss C., Krieglstein J. “Extract of kava (Piper methysticum) and its methysticin constitu- ents protect brain tissue against ischemic damage in rodents.” European Journal of Pharmacology. 1992 May 14;215(2-3):265-9. (source)

334 Cairney S., Maruff P., Clough A.R. “The neurobehavioural effects of kava.” Australian and New Zealand Journal of Psychiatry. 2002 Oct;36(5):657-62. (source)

335 Singh Y.N. “Kava: an overview.” Journal of Ethnopharmacology. 1992 Aug;37(1):13-45. (source)

336 Schelosky L., Raffauf C., Jendroska K., Poewe W. “Kava and dopamine antagonism.” Journal of Neurology, Neurosurgery & Psychiatry 1995 May; 58(5): 639–640. (source)

337 Olsen L.R., Grillo M.P., Skonberg C. “Constituents in kava extracts potentially involved in hepatotoxicity: a review.” Chemical Research in Toxicology. 2011 Jul 18;24(7):992-1002. (source)

338 Keledjian J., Duffield P.H., Jamieson D.D., Lidgard R.O., Duffield A.M. “Uptake into mouse brain of four compounds present in the psychoactive beverage kava.” Journal of Pharmaceutical Sciences. 1988 Dec;77(12):1003-6. (source) 515 David Tomen 339 LaPorte E., Sarris J., Stough C., Scholey A. “Neurocognitive effects of kava (Piper methysti- cum): a systematic review.” Human Psychopharmacology. 2011 Mar;26(2):102-11. (source)

340 Lakhan S.E., Vieira K.F. “Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review” Nutrition Journal 20109:42 DOI: 10.1186/1475-2891-9-42 (source)

341 Sohrabi H.R., Bates K.A., Rodrigues M., Taddei K., Martins G., Laws S.M., Lautenschlager N.T., Dhaliwal S.S., Foster J.K., Martins R.N. “The relationship between memory complaints, perceived quality of life and mental health in apolipoprotein Eepsilon4 carriers and non-carriers.” Journal of Alzheimer’s Disease. 2009;17(1):69-79. (source)

342 Jussofie A., Schmiz A., Hiemke C. “Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.” Psychopharmacology (Berlin). 1994 Dec;116(4):469-74. (source)

343 Dinh L.D., Simmen U., Bueter K.B., Bueter B., Lundstrom K., Schaffner W. “Interac- tion of various Piper methysticum cultivars with CNS receptors in vitro.” Planta Medica. 2001 Jun;67(4):306-11. (source)

344 Tang Y., Li X., Liu Z., Simoneau A.R., Xie J., Zi X. “Flavokawain B, a kava chalcone, induces apoptosis via up-regulation of death-receptor 5 and Bim expression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth.” International Journal on Cancer. 2010 Oct 15;127(8):1758-68. (source)

345 Sarris J., Stough C., Bousman C.A., Wahid Z.T., Murray G., Teschke R., Savage K.M., Dowell A., Ng C., Schweitzer I. “Kava in the treatment of generalized anxiety disorder: a double- blind, randomized, placebo-controlled study.” Journal of Clinical Psychopharmacology. 2013 Oct;33(5):643-8. (source)

346 Thompson R., Ruch W., Hasenöhrl R.U. “Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava). Human Psychopharmacology. 2004 Jun;19(4):243-50. (source)

347 Teschke R., Sarris J., Schweitzer I., “Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited” British Journal of Clinical Pharmacology. 2012 Feb; 73(2): 170–174. (source)

348 Stuerenburg H.J., Kunze K. “Concentrations of free carnosine (a putative membrane-protec- tive antioxidant) in human muscle biopsies and rat muscles.” Archives of Gerontology and Geriatrics. 1999 Sep-Oct;29(2):107-13. (source)

349 Hipkiss A.R. “Could carnosine or related structures suppress Alzheimer's disease?” Journal of Alzheimer’s Disease. 2007 May;11(2):229-40. (source)

350 Wang A.M., Ma C., Xie Z.H., Shen F. “Use of carnosine as a natural anti-senescence drug for human beings.” Biochemistry. 2000 Jul;65(7):869-71. (source)

351 Nagai K., Niijima A., Yamano T., Otani H., Okumra N., Tsuruoka N., Nakai M., Kiso Y. “Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves.” Experimental and Biological Medicine (Maywood). 2003 Nov;228(10):1138-45. (source)

352 Khama-Murad A.Kh., Mokrushin A.A., Pavlinova L.I. “Neuroprotective properties of l- carnosine in the brain slices exposed to autoblood in the hemorrhagic stroke model in vitro.” Regulatory Peptides. 2011 Feb 25;167(1):65-9 (source) 516 HEAD FIRST 353 Shao L., Li Q.H., Tan Z. “L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.” Biochemical and Biophysical Research Communications. 2004 Nov 12;324(2):931-6. (source)

354 Budzeń S., Rymaszewska J. “The biological role of carnosine and its possible applications in medicine.” Advances in Clinical and Experimental Medicine. 2013 Sep-Oct;22(5):739-44. (source)

355 Kohen R., Yamamoto Y., Cundy K.C., Ames B.N.. "Antioxidant activity of carnosine, ho- mocarnosine, and anserine present in muscle and brain." Proceedings of the National Academy of Sciences USA Vol. 85, pp. 3175-3179, May 1988. (source)

356 Brown C.E., Antholine W.E. “Chelation chemistry of carnosine. Evidence that mixed com- plexes may occur in vivo” The Journal of Physical Chemistry 1979, 83 (26), pp 3314–3319 (source)

357 Alikhani Z., Alikhani M., Boyd C.M., Nagao K., Trackman P.C., Graves D.T. “Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apop- tosis through cytoplasmic and mitochondrial pathways.” Journal of Biological Chemistry. 2005 Apr 1;280(13):12087-95. (source)

358 Spauwen P.J. et. Al. “Associations of advanced glycation end-products with cognitive func- tions in individuals with and without type 2 diabetes: the maastricht study.” Journal of Clinical Endocrinology and Metabolism. 2015 Mar;100(3):951-60. (source)

359 Pepper E.D., Farrell M.J., Nord G., Finkel S.E. “Antiglycation effects of carnosine and other compounds on the long-term survival of Escherichia coli.” Applied and Environmental Microbiol- ogy. 2010 Dec;76(24):7925-30. (source)

360 Babizhayev M.A., Deyev A.I. “Management of the virulent influenza virus infection by oral formulation of nonhydrolized carnosine and isopeptide of carnosine attenuating proinflammatory cytokine-induced nitric oxide production.” American Journal of Therapeutics. 2012 Jan;19(1):e25-47 (source)

361 Chengappa K.N. et. Al. “A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia.” Schizophrenia Research. 2012 Dec;142(1- 3):145-52. (source)

362 Chez M.G., Buchanan C.P., Aimonovitch M.C., Becker M., Schaefer K., Black C., Komen J. “Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders.” Journal of Child Neurology. 2002 Nov;17(11):833-7. (source)

363 McFarland G.A., Holliday R. “Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts.” Experimental Gerontology. 1999 Jan;34(1):35- 45. (source)

364 Prakash D., Niranjan A., Tewari S.K. “Some nutritional properties of the seeds of three Mucuna species.” International Journal of Food Sciences and Nutrition. 2001 Jan;52(1):79-82. (source)

365 Amsten A., Wang M., Paspalas C. “Neuromodulation of Thought: Flexibilities and Vulner- abilities in Prefrontal Cortical Network Synapses” Neuron Volume 76, Issue 1, p223–239, 4 October 2012 (source)

366 Jenner P. “Molecular mechanisms of L-DOPA-induced dyskinesia.” Nature Reviews Neurosci- ence. 2008 Sep;9(9):665-77 (source)

367 Knecht S., Breitenstein C., Bushuven S., Wailke S., Kamping S., Flöel A., Zwitserlood P., 517 David Tomen Ringelstein E.B. “Levodopa: faster and better word learning in normal humans.” Annals of Neurol- ogy. 2004 Jul;56(1):20-6. (source)

368 Uma S., Gurumoorthi P. “Dietary antioxidant activities in different germplasms of Mucuna.” Journal of Medicinal Food. 2013 Jul;16(7):618-24 (source)

369 Bala V., Debnath A., Shill A., Bose U. “Anti-Inflammatory, Diuretic and Antibacterial Activi- ties of Aerial Parts of Mucuna pruriens Linn.” International Journal of Pharmacology 2011 | Volume: 7 | Issue: 4 | Page No.: 498-503 (source)

370 Zecca L., et. Al. “New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals” Proceedings of the National Academy of Sciences USA 2008 Nov 11; 105(45) (source)

371 Yadav S.K., Prakash J., Chouhan S., Singh S.P. “Mucuna pruriens seed extract reduces oxida- tive stress in nigrostriatal tissue and improves neurobehavioral activity in paraquat-induced Parkin- sonian mouse model.” Neurochemistry International. 2013 Jun;62(8):1039-47 (source)

372 Shukla K.K., Mahdi A.A., Ahmad M.K., Jaiswar S.P., Shankwar S.N., Tiwari S.C. “Mucuna pruriens Reduces Stress and Improves the Quality of Semen in Infertile Men.” Evidence Based Complement and Alternative Medicine. 2010 Mar;7(1):137-44 (source)

373 Knecht S., Breitenstein C., Bushuven S., Wailke S., Kamping S., Flöel A., Zwitserlood P., Ringelstein E.B. “Levodopa: faster and better word learning in normal humans.” Annals of Neurol- ogy. 2004 Jul;56(1):20-6. (source)

374 Rana D.G., Galani V.J. “Dopamine mediated antidepressant effect of Mucuna pruriens seeds in various experimental models of depression.” Ayu. 2014 Jan;35(1):90-7. (source)

375 Tharakan B., Dhanasekaran M., Mize-Berge J., Manyam B.V. “Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage.” Phytotherapy Research. 2007 Dec;21(12):1124-6. (source)

376 “Melissa officinalis” TimTec Nature Inspired Research Products naturalcompounds.org Retrieved May 29, 2016 (source)

377 Zeraatpishe A., Oryan S., Bagheri M.H., Pilevarian A.A., Malekirad A.A., Baeeri M., Abdol- lahi M. “Effects of Melissa officinalis L. on oxidative status and DNA damage in subjects exposed to long-term low-dose ionizing radiation.” Toxicology and Industrial Health. 2011 Apr;27(3):205- 12. (source)

378 Kondo S., Omri A.E., Han J., Isoda H. “Antidepressant-like effects of rosmarinic acid through mitogen-activated protein kinase phosphatase-1 and brain-derived neurotrophic factor modula- tion” Journal of Functional Foods Volume 14, April 2015, Pages 758–766 (source)

379 Kennedy D.O., Wake G., Savelev S., Tildesley N.T., Perry E.K., Wesnes K.A., Scholey A.B. “Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties.” Neuropsychopharmacology. 2003 Oct;28(10):1871-81. (source)

380 Luan H., Kan Z., Xu Y., Lv C., Jiang W. “Rosmarinic acid protects against experimental diabetes with cerebral ischemia: relation to inflammation response.” Journal of Neuroinflammation. 2013 Feb 17;10:28. (source)

381 Yoo D.Y., Choi J.H., Kim W., Yoo K.Y., Lee C.H., Yoon Y.S., Won M.H., Hwang I.K. “Effects 518 HEAD FIRST of Melissa officinalis L. (lemon balm) extract on neurogenesis associated with serum corticosterone and GABA in the mouse dentate gyrus.” Neurochemistry Research. 2011 Feb;36(2):250-7. (source)

382 Sohrabi H.R., Bates K.A., Rodrigues M., Taddei K., Martins G., Laws S.M., Lautenschlager N.T., Dhaliwal S.S., Foster J.K., Martins R.N. “The relationship between memory complaints, perceived quality of life and mental health in apolipoprotein Eepsilon4 carriers and non-carriers.” Journal of Alzheimer’s Disease. 2009;17(1):69-79. (source)

383 Wake G., Court J., Pickering A., Lewis R., Wilkins R., Perry E. “CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory.” Journal of Ethnopharmacology. 2000 Feb;69(2):105-14. (source)

384 Liu Z., Niu W., Yang X., Wang Y. “Effects of combined acupuncture and eugenol on learning- memory ability and antioxidation system of hippocampus in Alzheimer disease rats via olfactory system stimulation.” Journal of Traditional Chinese Medicine. 2013 Jun;33(3):399-402. (source)

385 Obulesu M., Rao D.M. “ Effect of plant extracts on Alzheimer's disease: An insight into therapeutic avenues.” Journal of Neurosciences in Rural Practice. 2011 Jan;2(1):56-61. (source)

386 Kennedy D.O., Little W., Scholey A.B. “Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm).” Psychosomatic Medicine. 2004 Jul- Aug;66(4):607-13. (source)

387 Petroff O.A. “GABA and glutamate in the human brain.” Neuroscientist. 2002 Dec;8(6):562- 73. (source)

388 Ramadan S., Lin A., Stanwell P. “Glutamate and Glutamine: A Review of In Vivo MRS in the Human Brain” NMR Biomed. 2013 Dec; 26(12): 10.1002/nbm.3045. (source)

389 Albrecht J., Sidoryk-Węgrzynowicz M., Zielińska M., Aschner M. “Roles of glutamine in neurotransmission.” Neuron Glia Biology. 2010 Nov;6(4):263-76 (source)

390 Tapiero H., Mathé G., Couvreur P., Tew K.D. Glutamine and glutamate. Biomédecine and Pharmacotherapy. 2002 Nov;56(9):446-57. (source)

391 Sibson N.R., Dhankhar A., Mason G.F., Rothman D.L., Behar K.L., Shulman R.G. “Stoichio- metric coupling of brain glucose metabolism and glutamatergic neuronal activity.” Proceedings of the National Academy of Sciences U S A. 1998 Jan 6;95(1):316-21. (source)

392 De Witte P. “Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol.” Addiction and Behavior. 2004 Sep;29(7):1325-39. (source)

393 Lee Y., Son H., Kim G., Kim S., Lee D.H., Roh G.S., Kang S.S., Cho G.J., Choi W.S., Kim H.J. “Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice.” Journal of Psychiatry and Neuroscience. 2013 May;38(3):183-91. (source)

394 Lin M.T., Beal M.F. “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.” Nature. 2006 Oct 19;443(7113):787-95. (source)

395 Zhou Y., Kierans A., Kenul D., Ge Y., Rath J., Reaume J., Grossman R.I., Lui Y.W. “Mild trau- matic brain injury: longitudinal regional brain volume changes.” Radiology. 2013 Jun;267(3):880- 90. (source)

396 Boumezbeur F., Mason G.F., de Graaf R.A., Behar K.L., Cline G.W., Shulman G.I., Roth- man D.L., Petersen K.F. “Altered brain mitochondrial metabolism in healthy aging as assessed by 519 David Tomen in vivo magnetic resonance spectroscopy.” Journal of Cerebral Blood Flow and Metabolism. 2010 Jan;30(1):211-21 (source)

397 Suárez I., Bodega G., Fernández B. “Glutamine synthetase in brain: effect of ammonia.” Neurochemistry International. 2002 Aug-Sep;41(2-3):123-42. (source)

398 Mittendorfer B., Volpi E., Wolfe R.R. “Whole body and skeletal muscle glutamine metabo- lism in healthy subjects” American Journal of Physiology, Endocrinology and Metabolism. 2001 Feb; 280(2): E323–E333. (source)

399 Welbourne T.C. “Increased plasma bicarbonate and growth hormone after an oral glutamine load.” American Journal of Clinical Nutrition. 1995 May;61(5):1058-61. (source)

400 Arwert L.I., Deijen J.B., Drent M.L. “Effects of an oral mixture containing glycine, glutamine and niacin on memory, GH and IGF-I secretion in middle-aged and elderly subjects.” Nutritional Neuroscience. 2003 Oct;6(5):269-75. (source)

401 Conner J.M. et. Al. “NGF Is Essential for Hippocampal Plasticity and Learning” The Journal of Neuroscience 2 September 2009, 29(35): 10883-10889 (source)

402 Lai P.L., Naidu M., Sabaratnam V., Wong K.H., David R.P., Kuppusamy U.R., Abdullah N., Malek S.N. “Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia.” International Journal of Medicinal Mushrooms. 2013;15(6):539-54. (source)

403 Nagano M., Shimizu K., Kondo R., Hayashi C., Sato D., Kitagawa K., Ohnuki K. “Reduc- tion of depression and anxiety by 4 weeks Hericium erinaceus intake.” Biomedical Research. 2010 Aug;31(4):231-7. (source)

404 Kelly A., Conroy S., Lynch M.A. “Evidence that nerve growth factor plays a role in long- term potentiation in the rat dentate gyrus.” Neuropharmacology. 1998 Apr-May;37(4-5):561-70. (source)

405 Kawagishi H., et. Al. “Erinacines A, B and C, strong stimulators of nerve growth factor (NGF)-synthesis, from the mycelia of Hericium erinaceum” Tetrahedron Letters Volume 35, Issue 10, 7 March 1994, Pages 1569–1572 (source)

406 Mori K., Inatomi S., Ouchi K., Azumi Y., Tuchida T. “Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo- controlled clinical trial.” Phytotherapy Research. 2009 Mar;23(3):367-72. (source)

407 Mori K., Obara Y., Moriya T., Inatomi S., Nakahata N. “Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice.” Biomedical Research. 2011 Feb;32(1):67-72. (source)

408 Mori K., et. Al. “Nerve Growth Factor-Inducing Activity of Hericium erinaceus in 1321N1

409 Human Astrocytoma Cells” Biology Pharmaceutical Bulletin September 2008 31(9) 1727— 1732 (2008) (source)

410 Wong K.H., Naidu M., David P., Abdulla M.A., Abdullah N., Kuppusamy U.R., Sabaratnam V. “Peripheral Nerve Regeneration Following Crush Injury to Rat Peroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.: Fr) Pers. (Aphyllophoromycetideae).” Evidence-Based Complementary and Alternative Medicine. 2011;2011:580752. (source) 520 HEAD FIRST 411 Sabaratnam V., Kah-Hui W., Naidu M., David P.R. “Neuronal Health – Can Culinary and Medicinal Mushrooms Help?” Journal of Traditional and Complimentary Medicine 2013 Jan-Mar; 3(1): 62–68. (source)

412 Yamada T., Terashima T., Wada K., Ueda S., Ito M., Okubo T., Juneja L.R., Yokogoshi H. “Theanine, r-glutamylethylamide, increases neurotransmission concentrations and neurotrophin mRNA levels in the brain during lactation.” Life Sciences. 2007 Sep 29;81(16):1247-55. (source)

413 Song C.H., Jung J.H., Oh J.S., Kim K.S. “Effects of Theanine on the Release of Brain Alpha Wave in Adult Males.” Korean Journal of Nutrition 2003 Nov;36(9):918-923. (source)

414 Hajira S. G. et. Et. “Developing Brain Vital Signs: Initial Framework for Monitoring Brain Function Changes Over Time.” Frontiers in Neuroscience. 2016 May 12;10:211 (source)

415 Nathan P.J., Lu K., Gray M., Oliver C. “The neuropharmacology of L-theanine(N-ethyl-L- glutamine): a possible neuroprotective and cognitive enhancing agent.” Journal of Herbal Pharma- cotherapy. 2006;6(2):21-30. (source)

416 Lu M., Gray, Oliver C. “The Neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine)” Journal of Herbal Pharmacotherapy Volume 6, Issue 2, 2006 (source)

417 Kimura K., Ozeki M., Juneja L.R., Ohira H. “L-Theanine reduces psychological and physi- ological stress responses.” Biological Psychology. 2007 Jan;74(1):39-45. (source)

418 Kakuda T., Nozawa A., Unno T., Okamura N., Okai O. “Inhibiting effects of theanine on caf- feine stimulation evaluated by EEG in the rat.” Biosci Biotechnol Biochem. 2000 Feb;64(2):287- 93. (source)

419 Yokogoshi H., Kobayashi M., Mochizuki M., Terashima T. “Effect of theanine, r-glutamyle- thylamide, on brain monoamines and striatal dopamine release in conscious rats.” Neurochemistry Research. 1998 May;23(5):667-73. (source)

420 Kobayashi K., Nagato Y., Nobuyuki, Sugimoto S. “Effects of L-Theanine on the Release of .ALPHA.-Brain Waves in Human Volunteers.” Nippon Nogeikagaku Kaishi 72(2):153-157 · De- cember 1997 (source)

421 US Patent Application 20040171624; Japanese Patent Application 2001-253740 (source)

422 Chen Z., Li Y., Zhao L.C., Zhou B.F., Yang J., Wang Z.W., Guo M., Wu Y.F. “[A study on the association between tea consumption and stroke]. – in Chinese Zhonghua Liu Xing Bing Xue Za Zhi. 2004 Aug;25(8):666-70. (source)

423 Park S.K., Jung I.C., Lee W.K., Lee Y.S., Park H.K., Go H.J., Kim K., Lim N.K., Hong J.T., Ly S.Y., Rho S.S. “A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study.” Journal of Medicinal Food. 2011 Apr;14(4):334-43. (source)

424 Garcia R. “Stress, hippocampal plasticity, and spatial learning.” Synapse. 2001 Jun 1;40(3):180- 3. (source)

425 Joëls M., Karst H., DeRijk R., de Kloet E.R. “The coming out of the brain mineralocorticoid receptor.” Trends in Neuroscience. 2008 Jan;31(1):1-7. (source)

426 Tamano H., Fukura K., Suzuki M., Sakamoto K., Yokogoshi H., Takeda A. “Preventive effect 521 David Tomen of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.” Brain Research Bulletin. 2013 Jun;95:1-6. (source)

427 “L-Theanine Supplement Review” Cleveland Clinic Wellness clevelandclinicwellness.com Re- trieved June 3, 2016 (source)

428 Owen G.N., Parnell H., De Bruin E.A., Rycroft J.A. “The combined effects of L-theanine and caffeine on cognitive performance and mood.” Nutritional Neuroscience. 2008 Aug;11(4):193-8. (source)

429 Vuong Q.V., Stathopoulos C.E., Golding J.B., Nguyen M.H., Roach P.D. “Optimum condi- tions for the water extraction of L-theanine from green tea.” Journal of Seperation Science. 2011 Sep;34(18):2468-74. (source)

430 Rude R.K., Singer F.R., Gruber H.E. “Skeletal and hormonal effects of magnesium deficiency.” Journal of American College of Nutrition. 2009 Apr;28(2):131-41. (source)

431 Grober U., Schmidt J., Kisters K. “Magnesium in Prevention and Therapy” Nutrients. 2015 Sep; 7(9): 8199–8226. (source)

432 Wang D., Jacobs S.A., Tsien J.Z. “Targeting the NMDA receptor subunit NR2B for treat- ing or preventing age-related memory decline.” Expert Opinion on Therapeutic Targets. 2014 Oct;18(10):1121-30. (source)

433 Palacios-Prado N., Chapuis S., Panjkovich A., Fregeac J., Nagy J.I., Bukauskas F.F. “Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by con- nexin36.” Nature Communications. 2014 Aug 19;5:4667. (source)

434 Xu Z.P., Li L., Bao J., Wang Z.H., Zeng J., Liu E.J., Li X.G., Huang R.X., Gao D., Li M.Z “Magnesium Protects Cognitive Functions and Synaptic Plasticity in Streptozotocin-Induced Sporadic Alzheimer’s Model” PLOS One September 30, 2014 (source)

435 Garfinkel L., Garfinkel D. “Magnesium regulation of the glycolytic pathway and the enzymes involved.” Magnesium. 1985;4(2-3):60-72. (source)

436 Swaminathan N. “Why Does the Brain Need So Much Power?” Scientific American April 29, 2008 Retrieved May 21, 2016 (source)

437 Wang D., Jacobs S.A., Tsien J.Z. “Targeting the NMDA receptor subunit NR2B for treat- ing or preventing age-related memory decline.” Expert Opinion on Therapeutic Targets. 2014 Oct;18(10):1121-30. (source)

438 Yu X1, Guan P.P., Guo J.W., Wang Y., Cao L.L., Xu G.B., Konstantopoulos K., Wang Z.Y., Wang P. “By suppressing the expression of anterior pharynx-defective-1α and – 1β and inhibiting the aggregation of β-amyloid protein, magnesium ions inhibit the cognitive decline of amyloid pre- cursor protein/presenilin 1 transgenic mice.” FASEB Journal. 2015 Dec;29(12):5044-58. (source)

439 Saylor P., Wang C., Hirai T.J., Adams J.A. “A second magnesium ion is critical for ATP bind- ing in the kinase domain of the oncoprotein v-Fps.” Biochemistry. 1998 Sep 8;37(36):12624-30. (source)

440 Madison D.V. “Mechanisms underlying long-term potentiation of synaptic transmission” Annual Review of Neuroscience 1991. 14:379-97 (source)

441 Landfield P.W., Morgan G.A. “Chronically elevating plasma Mg2+ improves hippocampal 522 HEAD FIRST frequency potentiation and reversal learning in aged and young rats.” Brain Research. 1984 Nov 19;322(1):167-71. (source)

442 Jacka F.N. et. Al. “ Association between magnesium intake and depression and anxiety in community-dwelling adults: the Hordaland Health Study” Australian and New Zealand Journal of Psychiatry Volume 43, Issue 1, 2009 (source)

443 Held K., Antonijevic I.A., Künzel H., Uhr M., Wetter T.C., Golly I.C., Steiger A., Murck H. “Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans.” Pharmacopsychiatry. 2002 Jul;35(4):135-43. (source)

444 Kozielec T., Starobrat-Hermelin B. “Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD).” Magnesium Research [1997, 10(2):143-148] (source)

445 Slutsky I., et. Al. “Enhancement of Learning and Memory by Elevating Brain Magnesium” Neuron Volume 65, Issue 2, p165–177, 28 January 2010 (source)

446 “Pathway: serotonin and melatonin biosynthesis” MetaCyc metacyc.org (source)

447 Pandi-Perumal S.R., BaHammam A.S., Brown G.M., Spence D.W., Bharti V.K., Kaur C., Hardeland R., Cardinali D.P. “Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.” Neurotoxicity Research. 2013 Apr;23(3):267-300. (source)

448 Altun A., Ugur-Altun B. “Melatonin: therapeutic and clinical utilization.” International Jour- nal of Clinical Practice. 2007 May;61(5):835-45 (source)

449 Lee C.O. “Complementary and alternative medicines patients are talking about: melatonin.” Clinical Journal of Oncology Nursing. 2006 Feb;10(1):105-7. (source)

450 Bendz L.M., Scates A.C. “Melatonin treatment for insomnia in pediatric patients with atten- tion-deficit/hyperactivity disorder.” Annals of Pharmacotherapy. 2010 Jan;44(1):185-91 (source)

451 “Melatonin for Treatment of Sleep Disorders” U.S. Department of Health and Human Services (source)

452 Chang H.M., Wu UI., Lan C.T. “Melatonin preserves longevity protein (sirtuin 1) expression in the hippocampus of total sleep-deprived rats.” Journal of Pineal Research. 2009 Oct;47(3):211- 20. (source)

453 Chen H.Y., Hung Y.C., Chen T.Y., Huang S.Y., Wang Y.H., Lee W.T., Wu T.S., Lee E.J. “Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats.” Journal of Pineal Research. 2009 Oct;47(3):260-70. (source)

454 Cardinali D.P., Furio A.M., Brusco L.I. “Clinical Aspects of Melatonin Intervention in Al- zheimer’s Disease Progression” Current Neuropharmacology. 2010 Sep; 8(3): 218–227. (source)

455 Kitkhuandee A., Sawanyawisuth K., Johns N.P., Kanpittaya J., Johns J. “Pineal calcification is associated with symptomatic cerebral infarction.” Journal of Stroke and Cerebrovascular Diseases. 2014 Feb;23(2):249-53 (source)

456 McIntyre I.M., Burrows G.D., Norman T.R. “Suppression of plasma melatonin by a single dose of the benzodiazepine alprazolam in humans.” Biological Psychiatry. 1988 May;24(1):108-12. (source) 523 David Tomen 457 Cardinali D.P., Furio A.M., Brusco L.I. “Clinical Aspects of Melatonin Intervention in Al- zheimer’s Disease Progression” Current Neuropharmacology 2010 Sep; 8(3): 218–227. (source)

458 Sewerynek E. “Melatonin and the cardiovascular system.” Neuro Endocrinology Letters. 2002 Apr;23 Suppl 1:79-83. (source)

459 Lemoine P., Garfinkel D., Laudon M., Nir T., Zisapel N. “Prolonged-release melatonin for insomnia – an open-label long-term study of efficacy, safety, and withdrawal.” Therapeutics and Clinical Risk Management. 2011;7:301-11. (source)

460 Furio A.M., Brusco L.I., Cardinali D.P. “Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study.” Journal of Pineal Research. 2007 Nov;43(4):404-9. (source)

461 McIntyre I.M., Burrows G.D., Norman T.R. “Suppression of plasma melatonin by a single dose of the benzodiazepine alprazolam in humans.” Biological Psychiatry. 1988 May;24(1):108-12. (source)

462 Gallacher J., Elwood P., Pickering J., Bayer A., Fish M., Ben-Shlomo Y. “Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS).” Journal of Epidemiology and Community Health. 2012 Oct;66(10):869-73 (source)

463 Cardinali D.P., Vigo D.E., Olivar N., Vidal M.F., Furio A.M., Brusco L.I. “Therapeutic appli- cation of melatonin in mild cognitive impairment.” American Journal of Neurodegenerative Disease. 2012;1(3):280-91 (source)

464 Neuwelt E.A., Pagel M.A., Hasler B.P., Deloughery T.G., Muldoon L.L. “Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxic- ity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model.” Cancer Research. 2001 Nov 1;61(21):7868-74 (source)

465 Scalley R.D., Conner C.S. “Acetaminophen poisoning: a case report of the use of acetylcyste- ine.” American Journal of Hospital Pharmacy. 1978 Aug;35(8):964-7. (source)

466 Neergaard L. "Most Popular painkiller is lead cause of acute liver failure" National AIDS Treatment Advocacy Project natap.org Dec. 25, 2005 retrieved June 17, 2016 (source)

467 Saleh A.A.S. “Anti-neuroinflammatory and antioxidant effects of N-acetyl cysteine in long- term consumption of artificial sweetener aspartame in the rat cerebral cortex” The Journal of Basic & Applied Zoology Volume 72, October 2015, Pages 73–80 (source)

468 European College of Neuropsychopharmacology (ECNP). "Amino acid offers potential therapeu- tic alternative in psychiatric disorders." Science Newsline Medicine sciencenewsline.com October 7, 2013 Retrieved June 18, 2016 (source)

469 Monti D.A., Zabrecky G., Kremens D., Lian T.W., Wintering N.A., Cai J., Wei X., Bazzan A.J., Zhong L., Bowen B., Intenzo C.M., Iacovitti L., Newberg A.B. “N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data.” PLOS ONE, 2016; 11 (6): e0157602 (source)

470 Faul M, Xu L, Wald MM, Coronado VG (2010) “Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006”. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. (source) 524 HEAD FIRST 471 Rutland-Brown W., Langlois J.A., Thomas K.E., Xi Y.L. “Incidence of traumatic brain injury in the United States, 2003.” Journal of Head Trauma Rehabilitation. 2006 Nov – Dec;21(6):544-8. (source)

472 Yi J.H., Hazell A.S. “Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury.” Neurochemistry International. 2006 Apr;48(5):394-403 (source)

473 Farkas O., Povlishock J.T. “Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage.” Progress in Brain Research. 2007;161:43-59. (source)

474 Hoffer M.E., Balaban C., Slade M.D., Tsao J.W., Hoffer B. “Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study.” PLoS One. 2013;8(1):e54163. (source)

475 Berk M., Copolov D.L., Dean O., Lu K., Jeavons S, Schapkaitz I., Anderson-Hunt M., Bush A.I. “N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial.” Biological Psychiatry. 2008 Sep 15;64(6):468-75 (source)

476 Dauletbaev N., Fischer P., Aulbach B., Gross J., Kusche W., Thyroff-Friesinger U., Wagner T.O., Bargon J. “A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis.” European Journal of Medical Research. 2009 Aug 12;14(8):352-8. (source)

477 De Flora S., Grassi C., Carati L. “Attenuation of influenza-like symptomatology and im- provement of cell-mediated immunity with long-term N-acetyl cysteine treatment”. The European Respiratory Journal. 1997 Jul;10(7):1535-41. (source)

478 Slominski A., Zmijewski M., Pawelek J. “L-tyrosine and L-DOPA as hormone-like regulators of melanocytes functions” Pigment Cell Melanoma Research. 2012 Jan; 25(1): 14–27. (source)

479 Woods S.K., Meyer J.S. “Exogenous tyrosine potentiates the methylphenidate-induced in- crease in extracellular dopamine in the nucleus accumbens: a microdialysis study.” Brain Research. 1991 Sep 27;560(1-2):97-105. (source)

480 Magnusson I., Ekman L., Wångdahl M., Wahren J. “N-acetyl-L-tyrosine and N-acetyl-L- cysteine as tyrosine and cysteine precursors during intravenous infusion in humans.” Metabolism. 1989 Oct;38(10):957-61. (source)

481 Coull N.A., Watkins S.L., Aldous J.W., Warren L.K., Chrismas B.C., Dascombe B., Mauger A.R., Abt G., Taylor L. “Effect of tyrosine ingestion on cognitive and physical performance utilis- ing an intermittent soccer performance test (iSPT) in a warm environment.” European Journal of Applied Physiology. 2015 Feb;115(2):373-86. (source)

482 Colzato L.S., Jongkees B.J., Sellaro R., Hommel B. “Working memory reloaded: tyrosine repletes updating in the N-back task.”Frontiers in Behavioral Neuroscience. 2013 Dec 16;7:200. (source)

483 Hinz M., Stein A., Neff R., Weinberg R., Uncini T. “Treatment of attention deficit hyper- activity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation”Neuropsychiatric Disease and Treatment. 2011; 7: 31–38. (source)

484 Deijen J.B., Orlebeke J.F. “Effect of tyrosine on cognitive function and blood pressure under stress.” Brain Research Bulletin. 1994;33(3):319-23. (source)

485 Steenbergen L., Sellaro R., Hommel B., Colzato L.S. “Tyrosine promotes cognitive flexibility: 525 David Tomen evidence from proactive vs. reactive control during task switching performance.” Neuropsychologia. 2015 Mar;69:50-5 (source)

486 Mills J.C., Nelson D., Erecińska M., Pittman R.N. “Metabolic and energetic changes during apoptosis in neural cells.” Journal of Neurochemistry. 1995 Oct;65(4):1721-30. (source)

487 Ying W. “NAD+ and NADH in brain functions, brain diseases and brain aging.” Frontiers in Bioscience. 2007 Jan 1;12:1863-88. (source)

488 Ying W. “NAD+ and NADH in ischemic brain injury.” Frontiers in Bioscience 2008 Jan 1;13:1141-51. (source)

489 Alegre J., Rosés J.M., Javierre C., Ruiz-Baqués A., Segundo M.J., de Sevilla T.F. “[Nicotin- amide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome]. In Spanish Revista Clinica Espinola. 2010 Jun;210(6):284-8 (source)

490 Birkmayer J.G., Vrecko C., Volc D., Birkmayer W. “Nicotinamide adenine dinucleotide (NADH)—a new therapeutic approach to Parkinson's disease. Comparison of oral and parenteral application.” Acta Neurologica Scandinavia Suppl. 1993;146:32-5. (source)

491 Kay G.G., Viirre E., Clark J. “Stabilized NADH as a Countermeasure for Jet Lag” NASA Johnson Space Center nasa.gov (source)

492 Zhang H., Ryu D., Wu Y., Gariani K., Wang X., Luan P., D’amico D., Ropelle E.R., Lutolf M.P., Aebersold R., Schoonjans K., Menzies K.J., Auwerx J. “NAD repletion improves mitochon- drial and stem cell function and enhances lifespan in mice”. Science, 2016 DOI: 10.1126/science. aaf2693 (source)

493 Alegre J., Rosés J.M., Javierre C., Ruiz-Baqués A., Segundo M.J., de Sevilla T.F. “[Nicotin- amide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome].” In Spanish Revista Clinica Espanola. 2010 Jun;210(6):284-8. (source)

494 Santaella M.L., Font I., Disdier O.M. “Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome.” Puerto Rico Health Sciences Journal. 2004 Jun;23(2):89-93. (source)

495 Morales R.A. “Brain Restoration: ‘Too Good To Be True’ for Addiction and Disease?” The Fix thefix.com March 30, 2014 retrieved June 13, 2016 (source)

496 Crespi F. “Nefiracetam. Daiichi Seiyaku.” Current Opinion in Investigational Drugs. 2002 May;3(5):788-93. (source)

497 Malenka R.C., Kauer J.A., Perkel D.J., Nicoll R.A. “The impact of postsynaptic calcium on synaptic transmission — its role in long-term potentiation” Trends in Neurosciences Volume 12, Issue 11, p444–450, 1989 (source)

498 Kim H., Han S.H., Quan H.Y., Jung Y.J., An J., Kang P., Park J.B., Yoon B.J., Seol G.H., Min S.S. “Bryostatin-1 promotes long-term potentiation via activation of PKCα and PKCε in the hippocampus.” Neuroscience. 2012 Dec 13;226:348-55. (source)

499 Moriguchi S., Han F., Shioda N., Yamamoto Y., Nakajima T., Nakagawasai O., Tadano T., Yeh JZ, Narahashi T., Fukunaga K. “Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.” Journal of Neurochemistry. 2009 Jul;110(1):170-81 (source) 526 HEAD FIRST 500 Nishizaki T., Matsuoka T., Nomura T., Kondoh T., Watabe S., Shiotani T., Yoshii M. “Pre- synaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long- lasting facilitation of hippocampal neurotransmission.” Alzheimer’s Disease and Associated Disorders. 2000;14 Suppl 1:S82-94. (source)

501 Woodruff-Pak D.S., Green J.T., Pak J.T., Shiotani T., Watabe S., Tanaka M. “The long- term effects of nefiracetam on learning in older rabbits.” Behavioral Brain Research. 2002 Oct 17;136(1):299-308. (source)

502 Fontán-Lozano A., Troncoso J., Múnera A., Carrión A.M., Delgado-García J.M. “Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning.” Learning and Memory. 2005 Nov-Dec;12(6):557-63. (source)

503 Huang C.S., Ma J.Y., Marszalec W., Narahashi T. “Effects of the nootropic drug nefiracetam on the GABAA receptor-channel complex in dorsal root ganglion neurons.” Neuropharmacology. 1996;35(9-10):1251-61. (source)

504 Han F., Nakano T., Yamamoto Y., Shioda N., Lu Y.M., Fukunaga K. “Improvement of depres- sive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbecto- mized mice.” Brain Research. 2009 Apr 10;1265:205-14 (source)

505 Moriguchi S., Han F., Shioda N., Yamamoto Y., Nakajima T., Nakagawasai O., Tadano T., Yeh J.Z., Narahashi T., Fukunaga K. “Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.” Journal of Neurochemistry. 2009 Jul;110(1):170-81 (source)

506 Robinson R.G., Jorge R.E., Clarence-Smith K. “Double-blind randomized treatment of post- stroke depression using nefiracetam.”Journal of Neuropsychiatry and Clinical Neurosciences. 2008 Spring;20(2):178-84. (source)

507 Doyle E., Regan C.M., Shiotani T. “Nefiracetam (DM-9384) preserves hippocampal neural cell adhesion molecule-mediated memory consolidation processes during scopolamine disruption of passive avoidance training in the rat.” Journal of Neurochemistry. 1993 Jul;61(1):266-72. (source)

508 Odumeru O., Murphy K.J., O'Connell A.W., Regan C.M., Shiotani T. “Influence of nefirace- tam on NGF-induced neuritogenesis and neural cell adhesion molecule polysialic acid expression: in vivo and in vitro comparisons.” Behavioral Brain Research. 1997 Feb;83(1-2):173-8. (source)

509 Shimomura K., Shimada M., Hagiwara M., Harada S., Kato M., Furuhama K. “Testicular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancer.” Reproductive Toxicology. 2004 May;18(3):423-30. (source)

510 Goto K., Ishii Y., Jindo T., Furuhama K. “Effect of nefiracetam, a neurotransmission en- hancer, on primary uroepithelial cells of the canine urinary bladder.” Toxicological Sciences. 2003 Mar;72(1):164-70. (source)

511 “The Nicotine Content of Common Vegetables” The New England Journal of Medicine 1993; 329:437August 5, 1993 (source)

512 Gentry C.L., Lukas R.J. “Regulation of nicotinic acetylcholine receptor numbers and func- tion by chronic nicotine exposure.” Current Drug Targets: CNS and Neurological Disorders. 2002 Aug;1(4):359-85. (source)

513 Wu W.K.K., Cho C.H. “The Pharmacological Actions of Nicotine on the Gastrointestinal Tract” Journal of Pharmacological Sciences 94, 348 – 358 (2004) (source) 527 David Tomen 514 Kühn S., Schubert F., Gallinat J. “Reduced thickness of medial orbitofrontal cortex in smok- ers.” Biological Psychiatry. 2010 Dec 1;68(11):1061-5. (source)

515 Graham M. “Researchers light up for Nicotine, the wonder drug” Wired Magazine June 20, 2007 wired.com (source)

516 Cardinale A., Nastrucci C., Cesario A., Russo P. “Nicotine: specific role in angiogenesis, prolif- eration and apoptosis.” Critical Reviews in Toxicology. 2012 Jan;42(1):68-89 (source)

517 Di Matteo V., Pierucci M., Di Giovanni G., Benigno A., Esposito E. “The neurobiological bases for the pharmacotherapy of nicotine addiction.” Current Pharmaceutical Design. 2007;13(12):1269- 84. (source)

518 Mansvelder H.D., van Aerde K.I., Couey J.J., Brussaard A.B. “Nicotinic modulation of neuronal networks: from receptors to cognition.” Psychopharmacology (Berlin). 2006 Mar;184(3- 4):292-305. (source)

519 Heishman S.J., Kleykamp B.A., Singleton E.G. “Meta-analysis of the acute effects of nicotine and smoking on human performance.” Psychopharmacology (Berlin). 2010 Jul;210(4):453-69. (source)

520 Levin E.D., Conners C.K., Silva D., Hinton S.C., Meck W.H., March J., Rose J.E. “Transder- mal nicotine effects on attention.” Psychopharmacology (Berlin). 1998 Nov;140(2):135-41. (source)

521 Costell M., O'Connor J.E., Grisolía S. “Age-dependent decrease of carnitine content in muscle of mice and humans.” Biochemical and Biophysical Research Communications 1989 Jun 30;161(3):1135-43. (source)

522 Domino E.F., Ni L., Thompson M., Zhang H., Shikata H., Fukai H., Sakaki T., Ohya I. “To- bacco smoking produces widespread dominant brain wave alpha frequency increases.” International Journal of Psychophysiology. 2009 Dec;74(3):192-8 (source)

523 Lawrence N.S., Ross T.J., Stein E.A. “Cognitive mechanisms of nicotine on visual attention.” Neuron. 2002 Oct 24;36(3):539-48. (source)

524 Heishman S.J., Kleykamp B.A., Singleton E.G. “Meta-analysis of the acute effects of nicotine and smoking on human performance” Psychopharmacology (Berlin). 2010 Jul; 210(4): 453–469. (source)

525 Fujii S., Ji Z., Morita N., Sumikawa K. “Acute and chronic nicotine exposure differentially facilitate the induction of LTP.” Brain Research. 1999 Oct 30;846(1):137-43. (source)

526 Stough C., Mangan G., Bates T., Pellett O. “Smoking and Raven IQ.” Psychopharmacology (Berl). 1994 Nov;116(3):382-4. (source)

527 Wylie K.P., Rojas D.C., Tanabe J., Martin L.F., Tregellas J.R. “Nicotine increases brain func- tional network efficiency” NeuroImage 63 (2012) 73–80 (source)

528 West R.J., Jarvis M.J. “Effects of nicotine on finger tapping rate in non-smokers.” Pharmacol- ogy, Biochemistry and Behavior. 1986 Oct;25(4):727-31. (source)

529 Tucha O., Lange K.W. “Effects of nicotine chewing gum on a real-life motor task: a kinematic analysis of handwriting movements in smokers and non-smokers.” Psychopharmacology (Berlin). 2004 Apr;173(1-2):49-56 (source) 528 HEAD FIRST 530 Phillips S., Fox P. “An investigation into the effects of nicotine gum on short-term memory.” Psychopharmacology (Berlin). 1998 Dec;140(4):429-33. (source)

531 Cocores J.A. “Transdermal Nicotine in Adult ADHD With Depression and Anxiety” The Primary Care Companion 2008; 10(3): 253–254. (source)

532 Levin E.D., Conners C.K., Silva D., Canu W., March J. “Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder.” Experimental and Clinical Psychopharmacology. 2001 Feb;9(1):83-90. (source)

533 Levin E.D., Conners C.K., Sparrow E., Hinton S.C., Erhardt D., Meck W.H., Rose J.E., March J. “Nicotine effects on adults with attention-deficit/hyperactivity disorder.” Psychopharma- cology (Berlin). 1996 Jan;123(1):55-63. (source)

534 Jasinska A.J., Zorick T., Brody A.L., Stein E.A. “Dual role of nicotine in addiction and cog- nition: a review of neuroimaging studies in humans.” Neuropharmacology. 2014 Sep;84:111-22. (source)

535 Gudasheva T.A., Konstantinopol'skii M.A., Ostrovskaya R.U., Seredenin S.B. “Anxiolytic activity of endogenous nootropic dipeptide cycloprolylglycine in elevated plus-maze test.” Bulletin of Experimental Biology and Medicine. 2001 May;131(5):464-6. (source)

536 Purves D., Augustine G.J., Fitzpatrick D., et al., editors. “Glutamate Receptors” Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. (source)

537 Gudasheva T.A. et. Al. “The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.” European Journal of Drug Metabolism and Pharmacokinetics. 1997 Jul-Sep;22(3):245-52. (source)

538 Ostrovskaya R.U., Mirsoev T.K., Romanova G.A., Gudasheva T.A., Kravchenko E.V., Trofimov C.C., Voronina T.A., Seredenin S.B. “Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration.” Bulletin of Experimental Biology and Medicine. 2001 Oct;132(4):959-62. (source)

539 Gudasheva T.A., Konstantinopol'skii M.A., Ostrovskaya R.U., Seredenin S.B. “Anxiolytic activity of endogenous nootropic dipeptide cycloprolylglycine in elevated plus-maze test.” Bulletin of Experimental Biology and Medicine. 2001 May;131(5):464-6. (source)

540 Ostrovskaia R.U., Gudasheva T.A., Voronina T.A., Seredenin S.B. “[The original novel nootropic and neuroprotective agent noopept].” in Russian Eksp Klin Farmakol. 2002 Sep- Oct;65(5):66-72. (source)

541 Ostrovskaya R.U., Gudasheva T.A., Zaplina A.P., Vahitova J.V., Salimgareeva M.H., Jamidanov R.S., Seredenin S.B. “Noopept stimulates the expression of NGF and BDNF in rat hippocampus.” Bulletin of Experimental Biology and Medicine. 2008 Sep;146(3):334-7. (source)

542 Ostrovskaia R.U., Vakhitova Iu.V., Salimgareeva M.Kh., Iamidanov R.S., Sadovnikov S.V., Kapitsa I.G., Seredenin S.B. “[On the mechanism of noopept action: decrease in activity of stress- induced kinases and increase in expression of neutrophines].” in Russian Eksp Klin Farmakol. 2010 Dec;73(12):2-5. (source)

543 Ostrovskaya R.U., Gudasheva T.A., Zaplina A.P., Vahitova J.V., Salimgareeva M.H., Jamidanov R.S., Seredenin S.B. “Noopept stimulates the expression of NGF and BDNF in rat hippocampus.” Bulletin of Experimental Biology and Medicine. 2008 Sep;146(3):334-7. (source) 529 David Tomen 544 Vorobyov V., Kaptsov V., Kovalev G., Sengpiel F. “Effects of nootropics on the EEG in con- scious rats and their modification by glutamatergic inhibitors.” Brain Research Bulletin. 2011 May 30;85(3-4):123-32. (source)

545 Romanova G.A., Shakova F.M., Gudasheva T.A., Ostrovskaya R.U. “Impairment of learning and memory after photothrombosis of the prefrontal cortex in rat brain: effects of Noopept.” Bulletin of Experimental Biology and Medicine. 2002 Dec;134(6):528-30. (source)

546 Ostrovskaya R.U., Mirsoev T.K., Romanova G.A., Gudasheva T.A., Kravchenko E.V., Trofimov C.C., Voronina T.A., Seredenin S.B. “Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration.” Bulletin of Experimental Biology and Medicine. 2001 Oct;132(4):959-62. (source)

547 Boiko S.S., Ostrovskaya R.U., Zherdev V.P., Korotkov S.A., Gudasheva T.A., Voronina T.A., Seredenin S.B. “Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration.” Bulletin of Experimental Biology and Medicine. 2000 Apr;129(4):359-61. (source)

548 “Avenae herba (oat herb)” Commission E Herbal Monograph 15.10.1987. #193. (source)

549 Moccetti T., Wullschleger C., Schmidt A., Aydogan C., Kreuter M.H. “Bioactivity-based development of a wild green oat (Avena sativa L.) extract in support of mental health disorders” Zeitschrift für Phytotherapie 2006; 27 – P24 (source)

550 Campbell-Atkinson F. Hildegard of Bingen 1098-1179 "The Sybil of the Rhine." European Journal of Herbal Medicine. 2004;6(3):28-38. (source)

551 Nie L., Wise M.L., Peterson D.M., Meydani M. “Avenanthramide, a polyphenol from oats, inhibits vascular smooth muscle cell proliferation and enhances nitric oxide production.” Athero- sclerosis. 2006 Jun;186(2):260-6 (source)

552 Meydani M. “Potential health benefits of avenanthramides of oats.” Nutrition Revues. 2009 Dec;67(12):731-5 (source)

553 Dlaboga D., Hajjhussein H., O’Donnell J.M. “Regulation of phosphodiesterase-4 (PDE4) expression in mouse brain by repeated antidepressant treatment: Comparison with rolipram” Brain Research Volume 1096, Issue 1, 22 June 2006, Pages 104–112 (source)

554 Moccetti T., Wullschleger C., Schmidt A., Aydogan C., Kreuter M.H. “Bioactivity-based development of a wild green oat (Avena sativa L.) extract in support of mental health disorders” Zeitschrift für Phytotherapie 2006; 27 – P24 (source)

555 Guo W., Wise M.L., Collins F.W., Meydani M. “Avenanthramides, polyphenols from oats, inhibit IL-1beta-induced NF-kappaB activation in endothelial cells.” Free Radical Biology and Medicine. 2008 Feb 1;44(3):415-29. (source)

556 Kronfol Z., Remick D.G. “Cytokines and the brain: implications for clinical psychiatry.” American Journal of Psychiatry 2000 May;157(5):683-94. (source)

557 Wong R.H., Howe P.R., Coates A.M., Buckley J.D., Berry N.M. “Chronic consumption of a wild green oat extract (Neuravena) improves brachial flow-mediated dilatation and cerebrovascular responsiveness in older adults.” Journal of Hypertension. 2013 Jan;31(1):192-200 (source)

558 Dimpfel W., Storni C., Verbruggen M. “Ingested oat herb extract (Avena sativa) changes EEG 530 HEAD FIRST spectral frequencies in healthy subjects.” Journal of Alternative and Complementary Medicine. 2011 May;17(5):427-34. (source)

559 Arnsten A.F., Cai J.X., Steere J.C., Goldman-Rakic P.S. “Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor perfor- mance in monkeys.” Journal of Neuroscience. 1995 May;15(5 Pt 1):3429-39. (source)

560 Knoll J. “Deprenyl (selegiline): the history of its development and pharmacological action.” Acta Neurologica Scandinavia: Supplements. 1983;95:57-80. (source)

561 Mazzio E., Deiab S., Park K., Soliman K.F. “High throughput screening to identify natural human monoamine oxidase B inhibitors.” Phytotherapy Research. 2013 Jun;27(6):818-28 (source)

562 Knoll J., Dallo J., Yen T.T. “Striatal dopamine, sexual activity and lifespan. Longevity of rats treated with (-) deprenyl.” Life Sciences. 1989;45(6):525-31. (source)

563 Wong R.H.X. et. Al “ Chronic Effects of a Wild Green Oat Extract Supplementation on Cog- nitive Performance in Older Adults: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial” Nutrients. 2012 May; 4(5): 331–342. (source)

564 Berry N.M., Robinson M.J., Bryan J., Buckley J.D., Murphy K.J., Howe P.R. “Acute effects of an Avena sativa herb extract on responses to the Stroop Color-Word test.” Journal of Alternative and Complementary Medicine. 2011 Jul;17(7):635-7. (source)

565 Kennedy D.O., Jackson P.A., Forster J., Khan J., Grothe T., Moccetti T., Haskell-Ramsey C.F. “Acute effects of a wild green-oat (Avena sativa) extract on cognitive function in middle-aged adults: A double-blind, placebo-controlled, within-subjects trial” Nutritional Neuroscience 30 Nov 2015 pages 1 – 17 (source)

566 Banfi S., Fonio W., Allievi E., Pinza M., Dorigotti L. “Cyclic GABA-GABOB analogues. IV. Activity on learning and memory.” Farmaco Sci. 1984 Jan;39(1):16-22. (source)

567 Marchi M., Besana E., Raiteri M. “Oxiracetam increases the release of endogenous gluta- mate from depolarized rat hippocampal slices.” The European Journal of Pharmacology. 1990 Aug 28;185(2-3):247-9. (source)

568 Purves D., Augustine G.J., Fitzpatrick D., et al., editors. “Glutamate Receptors” Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. (source)

569 Mochizuki D., Sugiyama S., Shinoda Y. “[Biochemical studies of oxiracetam (CT-848) on cholinergic neurons].” in Japanese Nihon Yakurigaku Zasshi. 1992 Jan;99(1):27-35. (source)

570 Copani A., Genazzani A.A., Aleppo G., Casabona G., Canonico P.L., Scapagnini U., Ni- coletti F. “Nootropic drugs positively modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro- pionic acid-sensitive glutamate receptors in neuronal cultures.” Journal of Neurochemistry. 1992 Apr;58(4):1199-204. (source)

571 Gabryel B., Trzeciak H.I., Pudełko A., Cieślik P. “Influence of piracetam and oxiracetam on the content of high-energy phosphates and morphometry of astrocytes in vitro.” Polish Journal of Pharmacology. 1999 Nov-Dec;51(6):485-95. (source)

572 Mondadori C., Möbius H.J., Borkowski J. “The GABAB receptor antagonist CGP 36,742 and the nootropic oxiracetam facilitate the formation of long-term memory.” Behavioral Brain Research. 1996 May;77(1-2):223-5. (source) 531 David Tomen 573 Nicoletti F., Casabona G., Genazzani A.A., Copani A., Aleppo G., Canonico P.L., Scapagnini U. “Excitatory amino acids and neuronal plasticity: modulation of AMPA receptors as a novel substrate for the action of nootropic drugs.” Functional Neurology. 1992 Sep-Oct;7(5):413-22. (source)

574 Bottini G., Vallar G., Cappa S., Monza G.C., Scarpini E., Baron P., Cheldi A., Scarlato G. “Oxiracetam in dementia: a double-blind, placebo-controlled study.” Acta Neurologica Scandinavia. 1992 Sep;86(3):237-41. (source)

575 Belfiore P., Ponzio F., Biagetti R., Berettera C., Magnani M., Pozzi O. “Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7.” Neuro- science Letters. 1992 Aug 31;143(1-2):127-30. (sourcewhomever )

576 Fordyce D.E., Clark V.J., Paylor R., Wehner J.M. “Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice.” Brain Research. 1995 Feb 20;672(1-2):170-6. (source)

577 Rozzini R., Zanetti O., Bianchetti A. “Treatment of cognitive impairment secondary to degen- erative dementia. Effectiveness of oxiracetam therapy.” Acta Neurol (Napoli). 1993 Feb;15(1):44- 52. (source)

578 Faul M, Xu L, Wald MM, Coronado VG (2010) “Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006”. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. (source)

579 Rutland-Brown W., Langlois J.A., Thomas K.E., Xi Y.L. “Incidence of traumatic brain injury in the United States, 2003.” Journal of Head Trauma Rehabilitation. 2006 Nov – Dec;21(6):544-8. (source)

580 Yi J.H., Hazell A.S. “Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury.” Neurochemistry International. 2006 Apr;48(5):394-403 (source)

581 Li J.W., Yang D.J., Chen X.Y., Liang H.Q. “[Protective effect of oxiracetam on traumatic brain injury in rats]. in Chinese Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2013 Jul;29(4):298-300. (source)

582 Moglia A., Sinforiani E., Zandrini C., Gualtieri S., Corsico R., Arrigo A. “Activity of oxiracetam in patients with organic brain syndrome: a neuropsychological study.” Clinical Neuropharmacology. 1986;9 Suppl 3:S73-8. (source)

583 Magnani M., Pozzi O., Biagetti R., Banfi S., Dorigotti L. “Oxiracetam antagonizes the disruptive effects of scopolamine on memory in the radial maze.” Psychopharmacology (Berl). 1992;106(2):175-8. (source)

584 Nemeroff C.B. “The role of GABA in the pathophysiology and treatment of anxiety disor- ders.” Psychopharmacology Bulletin. 2003;37(4):133-46. (source)

585 Lapin I. “Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug.” CNS Drug Revues. 2001 Winter;7(4):471-81. (source)

586 Cavagnini F., Benetti G., Invitti C., Ramella G., Pinto M., Lazza M., Dubini A., Marelli A., Müller E.E. “Effect of gamma-aminobutyric acid on growth hormone and prolactin secretion in man: influence of pimozide and domperidone.” Journal of Clinical Endocrinology and Metabolism. 1980 Oct;51(4):789-92. (source) 532 HEAD FIRST 587 Lapin I. “Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug.” CNS Drug Revues. 2001 Winter;7(4):471-81. (source)

588 Anden N.E., Wachtel H. “Biochemical Effects of (β-Parachlorophenyl-GABA) on the Dopamine and the Noradrenaline in the Rat Brain” Acta Pharmacologica et Toxicologica Volume 40, Issue 2, pages 310–320, February 1977 (source)

589 Petroff O.A. “GABA and glutamate in the human brain.” Neuroscientist 2002 Dec;8(6):562- 73. (source)

590 Neumyvakin I.P., Krupina T.N., Polevoĭ L.G., Semeĭkina L.A. “[Principles for making up pharmaceutical kits to supply cosmonauts with drug packs].” in Russian Kosm Biol Aviakosm Med. 1978 May-Jun;12(3):27-31. (source)

591 “HOW DRUGS AFFECT NEUROTRANSMITTERS” McGill University Canada (source)

592 Kuriyama K., Sze P.Y. “Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals” Neuropharmacology Volume 10, Issue 1, January 1971, Pages 103–108 (source)

593 Ziablitseva E.A., Pavlova I.V. “[Effect of GABA receptor agonist phenibut on behavior and respiration of rabbits in the negative emotional situation].” Zh Vyssh Nerv Deiat Im I P Pavlova. 2007 Jul-Aug;57(4):479-88. (source)

594 Abdou A.M., Higashiguchi S., Horie K., Kim M., Hatta H, Yokogoshi H. “Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.” Biofactors. 2006;26(3):201-8. (source)

595 Abdou A.M., Higashiguchi S., Horie K., Kim M., Hatta H, Yokogoshi H. “Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.” Biofactors. 2006;26(3):201-8. (source)

596 Enna S.J. “Role of gamma-aminobutyric acid in anxiety.”Psychopathology. 1984;17 Suppl 1:15- 24. (source)

597 Struzyńska L., Sulkowski G. “Relationships between glutamine, glutamate, and GABA in nerve endings under Pb-toxicity conditions.”Journal of Inorganic Biochemistry. 2004 Jun;98(6):951- 8. (source)

598 Kuriyama K., Sze P.Y. “Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals” Neuropharmacology Volume 10, Issue 1, January 1971, Pages 103–108 (source)

599 Montagne A., et. Al. “Blood-brain barrier breakdown in the aging human hippocam- pus.” Neuron 2015 Jan 21;85(2):296-302 (source)

600 Cavagnini F., Invitti C., Pinto M., Maraschini C., Di Landro A., Dubini A., Marelli A. “Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man.” Acta Endocrinologica (Copenhagen). 1980 Feb;93(2):149-54. (source).

601 Shell W., Bullias D., Charuvastra E., May LA., Silver D.S. “A randomized, placebo-controlled trial of an amino acid preparation on timing and quality of sleep.” American Journal of Therapeutics. 2010 Mar-Apr;17(2):133-9. (source) 533 David Tomen 602 Slominski A., Zmijewski M., Pawelek J. “L-tyrosine and L-DOPA as hormone-like regulators of melanocytes functions” Pigment Cell Melanoma Research. 2012 Jan; 25(1): 14–27. (source)

603 “Phenylalanine” University of Maryland Medical Center umm.edu/health (source)

604 Meisburger S.P., Taylor A.B., Khan C.A., Zhang S., Fitzpatrick P.F., Ando N. “Domain Movements upon Activation of Phenylalanine Hydroxylase Characterized by Crystallography and Chromatography-Coupled Small-Angle X-ray Scattering.” Journal of the American Chemical Society. 2016 May 25;138(20):6506-16. (source)

605 Tavernier G. et. Al. “Norepinephrine Induces Lipolysis in β1/β2/β3-Adrenoceptor Knockout Mice” Molecular Pharmacology September 2005 vol. 68 no. 3 793-799 (source)

606 Walsh N.E., Ramamurthy S., Schoenfeld L., Hoffman J. “Analgesic effectiveness of D- phenylalanine in chronic pain patients.” Archives of Physical Medicine and Rehabilitation. 1986 Jul;67(7):436-9. (source)

607 Beckmann H., Ludolph E. in German “[DL-phenylalanine as an antidepressant. Open study (author's transl)].” Arzneimittelforschung. 1978;28(8):1283-4. (source)

608 Zavala M., Castejón H.V., Ortega P.A., Castejón O.J., Marcano de Hidalgo A., Montiel N. in Spanish “[Imbalance of plasma amino acids in patients with autism and subjects with attention deficit/hyperactivity disorder].” Revista de Neurologica. 2001 Sep 1-15;33(5):401-8. (source)

609 Bornstein R.A., Baker G.B., Carroll A., King G., Wong J.T., Douglass A.B. “Plasma amino acids in attention deficit disorder.” Psychiatry Research. 1990 Sep;33(3):301-6. (source)

610 Fischer E., Heller B., Nachon M., Spatz H. “Therapy of depression by phenylalanine. Prelimi- nary note.” Arzneimittelforschung. 1975 Jan;25(1):132. (source)

611 Beckmann H., Strauss M.A., Ludolph E. “Dl-phenylalanine in depressed patients: an open study.” Journal of Neural Transmission. 1977;41(2-3):123-34. (source)

612 Wood D.R., Reimherr F.W., Wender P.H. “Treatment of attention deficit disorder with DL- phenylalanine.” Psychiatry Research. 1985 Sep;16(1):21-6. (source)

613 Zametkin A.J., Karoum F., Rapoport J.L. “Treatment of hyperactive children with D-phenyl- alanine.” American Journal of Psychiatry. 1987 Jun;144(6):792-4. (source)

614 “Phenylalanine” University of Maryland Medical Center umm.edu Retrieved July 7, 2016 (source)

615 Zvejniece L. et. Al. “Investigation into Stereoselective Pharmacological Activity of Phenotro- pil” Basic & Clinical Pharmacology & Toxicology Volume 109, Issue 5, pages 407–412, November 2011 (source)

616 Prohibited Lists January 2016 World Anti-Doping Guide (source)

617 “Two Russian U23 riders positive” Cycling News cyclingnews.com Oct. 18, 2007 retrieved June 30, 2016 (source)

618 Piper E. “Pyleva says she took drugs by mistake” redOrbit redorbit.com Feb. 17, 2006 Re- trieved June 30, 2016 (source) 534 HEAD FIRST 619 Malykh A.G., Sadaie M.R. “Piracetam and Piracetam-Like Drugs” Drugs February 2010, Volume 70, Issue 3, pp 287-312 (source)

620 Akhapkina V.I., Akhapkin R.V. in Russian “[Identification and evaluation of the neuroleptic activity of phenotropil].” Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(7):42-6. (source)

621 Firstova Y.Y., Abaimov D.A., Kapitsa I.G., Voronina T.A., Kovalev G.I. “The effects of scopol- amine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task” Neurochemical Journal June 2011, Volume 5, Issue 2, pp 115-125 (source)

622 Zvejniece L. et. Al. “Investigation into Stereoselective Pharmacological Activity of Phenotro- pil” Basic & Clinical Pharmacology & Toxicology Volume 109, Issue 5, pages 407–412, November 2011 (source)

623 Mirzoian R.S., Gan'shina T.S. in Russian “[Mechanism of the cerebrovascular effect of pirace- tam].” Biull Eksp Biol Med. 1985 Jan;99(1):64-6. (source)

624 Gower A.J., Noyer M., Verloes R., Gobert J., Wülfert E. “ucb L059, a novel anti-convulsant drug: pharmacological profile in animals.”European Journal of Pharmacology. 1992 Nov 10;222(2- 3):193-203. (source)

625 Grebeniuk O.V., Zhukova N.G., Alifirova V.M. in Russian “[The efficacy of add-on treatment with phenotropil in adult patients with locally-induced epilepsy.]” Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(11 Vypusk 2. V pomoshch' prakticheskomu vrachu):27-31. (source)

626 Firstova Y.Y., Abaimov D.A., Kapitsa G., Voronina T.A., Kovalev G.I. “The effects of scopol- amine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task” Neurochemical Journal June 2011, Volume 5, Issue 2, pp 115-125 (source)

627 Samotrueva M.A., Tyurenkov I.N., Teplyi D.L., Serezhnikova T.K., Khlebtsova E.B. “Psycho- immunomodulatory effect of phenotropil in animals with immune stress.” Bulletin of Experimental Biology and Medicine. 2011 May;151(1):51-4. (source)

628 Savchenko A.Iu., Zakharova N.S., Stepanov I.N. in Russian “[The phenotropil treatment of the consequences of brain organic lesions].” Zh Nevrol Psikhiatr Im S S Korsakova. 2005;105(12):22-6. (source)

629 Koval'chuk V.V., Skoromets A.A., Koval'chuk I.V., Stoianova E.G., Vysotskaia M.L., Me- likhova E.V., Il'iaĭnen E.V. in Russian “[Efficacy of phenotropil in the rehabilitation of stroke patients].” Zh Nevrol Psikhiatr Im S S Korsakova. 2010;110(12 Pt 2):38-40. (source)

630 Nagat T., Yaguchi T., Nishizaki T. “DL – and PO- as a promising learn- ing and memory enhancer” Lipids Health Dis. 2011;10:25. (source)

631 Blusztajn J.K., Liscovitch M., Richardson U.I. “Synthesis of acetylcholine from choline de- rived from phosphatidylcholine in a human neuronal cell line.” Proceedings of the National Academy of Sciences U S A. 1987 Aug;84(15):5474-7. (source)

632 Wolf G. “Futurist Ray Kurzweil Pulls Out All the Stops (and Pills) to Live to Witness the Singularity” Wired Magazine wired.com March 24, 2008 retrieved July 11, 2016 (source)

633 Ladd S.L., Sommer S.A., LaBerge S., Toscano W. “ Effect of phosphatidylcholine on explicit memory.” Clinical Neuropharmacology. 1993 Dec;16(6):540-9. (source) 535 David Tomen 634 Zweigner J., Jackowski S., Smith S.H., Van Der Merwe M., Weber J.R., Tuomanen E.I. “Bacterial inhibition of phosphatidylcholine synthesis triggers apoptosis in the brain.” Journal of Experimental Medicine. 2004 Jul 5;200(1):99-106. (source)

635 Chung S.Y., Moriyama T., Uezu E., Uezu K., Hirata R., Yohena N., Masuda Y., Kokubu T., Yamamoto S. “Administration of phosphatidylcholine increases brain acetylcholine concentration and improves memory in mice with dementia.” The Journal of Nutrition. 1995 Jun;125(6):1484-9. (source)

636 Kosicek M., Hecimovic S. “Phospholipids and Alzheimer’s Disease: Alterations, Mechanisms and Potential Biomarkers” International Journal of Molecular Science. 2013 Jan; 14(1): 1310–1322. (source)

637 Crook T.H., Tinklenberg J., Yesavage J., Petrie W., Nunzi M.G., Massari D.C. “Effects of phosphatidylserine in age-associated memory impairment.” Neurology. 1991 May;41(5):644-9. (source)

638 Cunnane S.C., Schneider J.A., Tangney C., Tremblay-Mercier J., Fortier M., Bennett D.A., Morris M.C. “Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease.” Journal of Alzheimer’s Disease. 2012;29(3):691-7. (source)

639 Monteleone P., Beinat L., Tanzillo C., Maj M., Kemali D. “Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans.” Neuroendocrinology. 1990 Sep;52(3):243-8. (source)

640 Benton D., Donohoe R.T., Sillance B., Nabb S. “The influence of phosphatidylserine supple- mentation on mood and heart rate when faced with an acute stressor.” Nutritional Neuroscience. 2001;4(3):169-78. (source)

641 Baumeister J., Barthel T., Geiss K.R., Weiss M. “Influence of phosphatidylserine on cog- nitive performance and cortical activity after induced stress.” Nutritional Neuroscience. 2008 Jun;11(3):103-10. (source)

642 Benton D., Donohoe R.T., Sillance B., Nabb S. “The influence of phosphatidylserine supple- mentation on mood and heart rate when faced with an acute stressor.” Nutritional Neuroscience. 2001;4(3):169-78. (source)

643 Parker A.G., Gordon J., Thornton A., Byars A., Lubker J., Bartlett M., Byrd M., Oliver J., Simbo S., Rasmussen C., Greenwood M., Kreider R.B. “The effects of IQPLUS Focus on cogni- tive function, mood and endocrine response before and following acute exercise.” Journal of the International Society of Sports Nutrition. 2011 Oct 21;8:16 (source)

644 Hirayama S., Terasawa K., Rabeler R., Hirayama T., Inoue T., Tatsumi Y., Purpura M., Jäger R. “The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled clinical trial.” Journal of Human Nutrition and Dietetics. 2014 Apr;27 Suppl 2:284-91. (source)

645 Manor I., Magen A., Keidar D., Rosen S., Tasker H., Cohen T., Richter Y., Zaaroor-Regev D., Manor Y., Weizman A. “The effect of phosphatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled trial, followed by an open-label extension.” European Psychiatry. 2012 Jul;27(5):335-42. (source)

646 Schreiber S., Kampf-Sherf O., Gorfine M., Kelly D., Oppenheim Y., Lerer B. “An open trial 536 HEAD FIRST of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.” Israeli Journal of Psychiatry and Related Sciences. 2000;37(4):302-7. (source)

647 Crook T., Petrie W., Wells C., Massari D.C. “Effects of phosphatidylserine in Alzheimer's disease.” Psychopharmacology Bulletin. 1992;28(1):61-6. (source)

648 Nemeroff C.B. “The role of GABA in the pathophysiology and treatment of anxiety disor- ders.” Psychopharmacology Bulletin. 2003;37(4):133-46. (source)

649 Mirzoyan R.S., Gan'shina T.S., Kosoi M.Y., Aleksandrin V.V., Aleksandrov P.N. “Effect of picamilon on the cerebral cortical blood supply and microcirculation in the pial arteriolar system” Bulletin of Experimental Biology and Medicine May 1989, Volume 107, Issue 5, pp 668-670 (source)

650 Kuriyama K., Sze P.Y. “Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals” Neuropharmacology Volume 10, Issue 1, January 1971, Pages 103–108 (source)

651 Kuchmerovs'ka T.M., Donchenko H.V., Fomenko H.I., Chichkovs'ka H.V., Pakirbaieva L.V., Klymenko A.N. “[Correction by nicotinamide and nicotinoyl-GABA of dopamine metabolism in rat brain in experimental Parkinson's disease].” in Ukrainian Ukr Biokhim Zh (1999). 2001 Nov-Dec;73(6):108-12. (source)

652 Prousky R., Seely D. “The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature” Nutrition Journal 2005 (source)

653 Enna S.J. “Role of gamma-aminobutyric acid in anxiety.” Psychopathology. 1984;17 Suppl 1:15-24. (source)

654 Struzyńska L., Sulkowski G. “Relationships between glutamine, glutamate, and GABA in nerve endings under Pb-toxicity conditions.” Journal of Inorganic Biochemistry. 2004 Jun;98(6):951-8. (source)

655 Loriaux S.M., Deijen J.B., Orlebeke J.F., De Swart J.H. “The effects of nicotinic acid and xanthinol nicotinate on human memory in different categories of age. A double blind study.” Psychopharmacology (Berl). 1985;87(4):390-5. (source)

656 Kuriyama K., Sze P.Y. “Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals” Neuropharmacology Volume 10, Issue 1, January 1971, Pages 103–108 (source)

657 Montagne A., et. Al. “Blood-brain barrier breakdown in the aging human hippocam- pus.” Neuron 2015 Jan 21;85(2):296-302 (source)

658 Kuchmerovskaia T.M., Parkhomets P.K., Donchenko G.V., Obrosova I.G., Klimenko A.P., Kuchmerovskiĭ N.A., Pakirbaeva L.V., Efimov A.S. in Russian “[Correction of diabetic neuropathies using aldose reductase inhibitors and pikamilon].” Vopr Med Khim. 1998 Nov-Dec;44(6):559-64. (source)

659 Basinskiĭ S.N., Krasnogorskaia V.N., Lenis Iu.A. in Russian “[Pathogenetic treatment of central chorioretinal dystrophies with pikamilon].” Vestn Oftalmol. 2001 Mar-Apr;117(2):42-4. (source)

660 Kuchmerovs'ka T.M., Donchenko H.V., Fomenko H.I., Chichkovs'ka H.V., Pakirbaieva L.V., Klymenko A.N. in Ukrainian “[Correction by nicotinamide and nicotinoyl-GABA of dopamine metabolism in rat brain in experimental Parkinson's disease].” Ukr Biokhim Zh (1999). 2001 Nov- Dec;73(6):108-12. (source) 537 David Tomen 661 Novikov V.E., Kovaleva L.A. in Russian “[The effect of nootropic agents on brain mitochon- drial function in the dynamics of craniocerebral trauma from the age aspect].” Eksp Klin Farmakol. 1998 Mar-Apr;61(2):65-8. (source)

662 Sapegin I.D., Beketov A.I. in Russian “[The effect of pikamilon and fenibut on the blood supply of the brain at rest and under gravitational exposures].” Eksp Klin Farmakol. 1993 Jan- Feb;56(1):28-31. (source)

663 Mirzoian R.S., Gan'shina T.S. in Russian “[The new cerebrovascular preparation pikamilon].” Farmakol Toksikol. 1989 Jan-Feb;52(1):23-6. (source)

664 Oersted, "Über das Piperin, ein neues Pflanzenalkaloid" [On piperine, a new plant alkaloid], (Schweigger's) Journal für Chemie und Physik, vol. 29, no. 1, pages 80-82 (1820). (source)

665 Bhardwaj R.K., Glaeser H., Becquemont L., Klotz U., Gupta S.K., Fromm M.F. “Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4.” Journal of Pharmacology and Experimental Therapeutics. 2002 Aug;302(2):645-50. (source)

666 Srinivasan K. “Black pepper and its pungent principle-piperine: a review of diverse physiologi- cal effects.” Critical Revues of Food Science and Nutrition. 2007;47(8):735-48. (source)

667 Lee S.A., Hong S.S., Han X.H., Hwang J.S., Oh G.J., Lee K.S., Lee M.K., Hwang B.Y., Ro J.S. “Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity.” Chemical and Pharmaceutical Bulletin (Tokyo). 2005 Jul;53(7):832-5. (source)

668 Mao Q.Q., Xian Y.F., Ip S.P., Che C.T. “Involvement of serotonergic system in the antidepres- sant-like effect of piperine.” Progress in Neuro-psychopharmacology and Biological Psychiatry. 2011 Jun 1;35(4):1144-7 (source)

669 Huang W., Chen Z., Wang Q., Lin M., Wu S., Yan Q., Wu F., Yu X., Xie X., Li G., Xu Y., Pan J. “Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of system.” Metabolic Brain Disease. 2013 Dec;28(4):585-95. (source)

670 Shoba G., Joy D., Joseph T., Majeed M., Rajendran R., Srinivas P.S. “Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.” Planta Medica. 1998 May;64(4):353-6. (source)

671 Rinwa P., Kumar A. “Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice.” Brain Research. 2012 Dec 7;1488:38-50 (source)

672 Mori A., Kabuto H., Pei Y.Q. “Effects of piperine on convulsions and on brain serotonin and catecholamine levels in E1 mice.” Neurochemistry Research. 1985 Sep;10(9):1269-75. (source)

673 Lee S.A., Hong S.S., Han X.H., Hwang J.S., Oh G.J., Lee K.S., Lee M.K., Hwang B.Y., Ro J.S. “Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity.” Chemical and Pharmaceutical Bulletin (Tokyo). 2005 Jul;53(7):832-5. (source)

674 Chonpathompikunlert P., Wattanathorn J., Muchimapura S. “Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease.” Food and Chemical Toxicology. 2010 Mar;48(3):798-802 (source) 538 HEAD FIRST 675 Purves D., Augustine G.J., Fitzpatrick D., et al., editors. “Glutamate Receptors” Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. (source)

676 Genton P., Van Vleymen B. “Piracetam and : close structural similarities but different pharmacological and clinical profiles.” Epileptic Disorders. 2000 Jun;2(2):99-105. (source)

677 Shorvon S. “Pyrrolidone derivatives.” Lancet. 2001 Dec 1;358(9296):1885-92. (source)

678 Ahmed A.H., Oswald R.E. “Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.” Journal of Medicinal Chemistry. 2010 Mar 11;53(5):2197-203. (source)

679 Navarro S.A., Serafim K.G., Mizokami S.S., Hohmann M.S., Casagrande R., Verri W.A. Jr. “Analgesic activity of piracetam: effect on cytokine production and oxidative stress.” Pharmacology, Biochemistry and Behavior. 2013 Apr;105:183-92. (source)

680 Bering B., Müller W.E. “Interaction of piracetam with several neurotransmitter receptors in the central nervous system. Relative specificity for 3H-glutamate sites.” Arzneimittelforschung. 1985;35(9):1350-2. (source)

681 Genton P., Van Vleymen B. “Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles.” Epileptic Disorders. 2000 Jun;2(2):99-105. (source)

682 Malykh A.G., Sadaie M.R. “Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.” Drugs. 2010 Feb 12;70(3):287-312. (source)

683 Stoll L., Schubert T., Müller W.E. “Age-related deficits of central muscarinic cholinergic recep- tor function in the mouse: partial restoration by chronic piracetam treatment.” Neurobiology of Aging. 1992 Jan-Feb;13(1):39-44. (source)

684 Cohen S.A., Müller W.E. “Effects of piracetam on N-methyl-D-aspartate receptor properties in the aged mouse brain.” Pharmacology. 1993 Oct;47(4):217-22. (source)

685 Williams J.M., Guévremont D., Kennard J.T., Mason-Parker S.E., Tate W.P., Abraham W.C. “Long-term regulation of N-methyl-D-aspartate receptor subunits and associated synaptic proteins following hippocampal synaptic plasticity.” Neuroscience. 2003;118(4):1003-13. (source)

686 Kojiro I., Secher N.H. “Cerebral blood flow and metabolism during exercise” Progress in Neurobiology Volume 61, Issue 4, July 2000, Pages 397–414 (source)

687 Kessler J., Thiel A., Karbe H., Heiss W.D. “Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients.” Stroke. 2000 Sep;31(9):2112-6. (source)

688 Copani A., Genazzani A.A., Aleppo G., Casabona G., Canonico P.L., Scapagnini U., Ni- coletti F. “Nootropic drugs positively modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro- pionic acid-sensitive glutamate receptors in neuronal cultures.” Journal of Neurochemistry. 1992 Apr;58(4):1199-204. (source)

689 Pepeu G., Spignoli G. “Nootropic drugs and brain cholinergic mechanisms.” Progress in Neuro- psychopharmacology and Biological Psychiatry. 1989;13 Suppl:S77-88. (source)

690 Pilch H., Müller W.E. “Piracetam elevates muscarinic cholinergic receptor density in the fron- tal cortex of aged but not of young mice.” Psychopharmacology (Berl). 1988;94(1):74-8. (source) 539 David Tomen 691 Grau M., Montero J.L., Balasch J. “Effect of Piracetam on electrocorticogram and local cere- bral glucose utilization in the rat.” General Pharmacology. 1987;18(2):205-11. (source)

692 Navarro S.A., Serafim K.G., Mizokami S.S., Hohmann M.S., Casagrande R., Verri W.A. Jr. “Analgesic activity of piracetam: effect on cytokine production and oxidative stress.” Pharmacology, Biochemistry and Behavior. 2013 Apr;105:183-92. (source)

693 Dimond S.J., Brouwers E.M. “Increase in the power of human memory in normal man through the use of drugs.” Psychopharmacology (Berl). 1976 Sep 29;49(3):307-9. (source)

694 Waegemans T., Wilsher C.R., Danniau A., Ferris S.H., Kurz A., Winblad B. “Clinical efficacy of piracetam in cognitive impairment: a meta-analysis.” Dementia and Geriatric Cognitive Disorders. 2002;13(4):217-24. (source)

695 Kretschmar J.H., Kretschmar C.H. “[On the dose-effect relationship in the therapy with piracetam (author's transl)].” in German Arzneimittelforschung. 1976;26(6):1158-9. (source)

696 Stockburger C., Kurz C., Koch K.A., Eckert S.H., Leuner K., Müller W.E. “Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam.” Biochemical Social Transactions. 2013 Oct;41(5):1331-4. (source)

697 Platel A., Jalfre M., Pawelec C., Roux S., Porsolt R.D. “Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes.” Pharmacology, Biochemistry and Behavior. 1984 Aug;21(2):209-12. (source)

698 Rucker R., Chowanadisai W., Nakano M. “Potential physiological importance of pyrrolo- quinoline quinone.” Alternative Medicine Revue. 2009 Sep;14(3):268-77. (source)

699 Krueger F.R., Werther W., Kissel J., Schmid E.R. “Assignment of quinone derivatives as the main compound class composing 'interstellar' grains based on both polarity ions detected by the 'Cometary and Interstellar Dust Analyser' (CIDA) onboard the spacecraft STARDUST.” Rapid Communications in Mass Spectrometry. 2004;18(1):103-11. (source)

700 HAUGE J.G. “GLUCOSE DEHYDROGENASE OF BACTERIUM ANITRATUM: AN ENZYME WITH A NOVEL PROSTHETIC GROUP.” Journal of Biological Chemistry. 1964 Nov;239:3630-9. (source)

701 Kuo Y.T., Shih P.H., Kao S.H., Yeh G.C., Lee H.M. “Pyrroloquinoline Quinone Resists Denervation-Induced Skeletal Muscle Atrophy by Activating PGC-1α and Integrating Mitochon- drial Electron Transport Chain Complexes.” PLoS One. 2015 Dec 8;10(12):e0143600. (source)

702 Terry A.V. Jr., Kutiyanawalla A., Pillai A. “Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats.” Physiology and Behavior. 2011 Feb 1;102(2):149-57. (source)

703 Chowanadisai W., Bauerly K.A., Tchaparian E., Wong A., Cortopassi G.A., Rucker R.B. “Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element- binding protein phosphorylation and increased PGC-1alpha expression.” Journal of Biological Chemistry. 2010 Jan 1;285(1):142-52 (source)

704 Azizi A., Azizi S., Heshmatian B., Amini K. “Improvement of functional recovery of transected peripheral nerve by means of chitosan grafts filled with vitamin E, pyrroloquinoline quinone and their combination.” International Journal of Surgery. 2014;12(5):76-82. (source)

705 Guan S., Xu J., Guo Y., Ge D., Liu T., Ma X., Cui Z. “Pyrroloquinoline quinone against 540 HEAD FIRST glutamate-induced neurotoxicity in cultured neural stem and progenitor cells.” International Jour- nal of Developmental Neuroscience. 2015 May;42:37-45. (source)

706 Nakano M., Kawasaki Y., Suzuki N., Takara T. “Effects of Pyrroloquinoline Quinone Disodi- um Salt Intake on the Serum Cholesterol Levels of Healthy Japanese Adults.” Journal of Nutritional Science and Vitaminology (Tokyo). 2015;61(3):233-40 (source)

707 Paz M.A., Martin P., Flückiger R., Mah J., Gallop P.M. “The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ derivatives, and isomers and the specificity of inhibitors”. Anals of Biochemistry. 1996 Jul 1; 238(2):145-9. 1 (source)

708 Qin J., Wu M., Yu S1, Gao X., Zhang J., Dong X., Ji J., Zhang Y., Zhou L., Zhang Q., Ding F. “Pyrroloquinoline quinone-conferred neuroprotection in rotenone models of Parkinson's disease.” Toxicology Letters. 2015 Nov 4;238(3):70-82 (source)

709 Nakano M., Yamamoto T., Okamura H., Tsuda A., Kowatari Y., “Effects of Oral Supplemen- tation with Pyrroloquinoline Quinone on Stress, Fatigue, and Sleep” Functional Foods in Health and Disease 2012, 2(8):307-324 (source)

710 Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. “Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons.” Food Style. 2009;13(7):50-53. (Source)

711 Nakano M., Kawasaki Y., Suzuki N., Takara Y. ““PQQ was found to improve not only im- mediate memory, but also other higher brain functions such as spatial awareness. The effects of PQQ were enhanced when the substance was used with CoQ10.” Journal of Nutritional Science and Vitaminology 61, 233-240, 2015 (source)

712 “CAMBRIDGE NEUROSCIENCE DEVELOPING WARNER-LAMBERT's PRAMI- RACETAM” Pharma Intelligence (source)

713 Pugsley T.A., Shih Y.H. “Some neurochemical properties of pramiracetam (CI-879), a new cognition-enhancing agent” Drug Development Research Volume 3, Issue 5, pages 407–420, 1983 (source)

714 Brust P. “Reversal of scopolamine-induced alterations of choline transport across the blood- brain barrier by the nootropics piracetam and pramiracetam.” Arzneimittelforschung. 1989 Oct;39(10):1220-2. (source)

715 Corasaniti M.T., Paoletti A.M., Palma E., Granato T., Navarra M., Nisticò G. “Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat.” Functional Neurology. 1995 May-Jun;10(3):151-5. (source)

716 Sutin, Lawrence (2000). Do What Thou Wilt: a life of Aleister Crowley. Macmillan. p. 253. ISBN 978-0312252434.

717 Pavlík A., Benesová O., Dlohozková N. “Effects of nootropic drugs on brain cholinergic and dopaminergic transmission.” Activitas Nervosa Superior (Praha). 1987 Mar;29(1):62-5. (source)

718 Ennaceur A., Cavoy A., Costa J.D., Delacour J. “A new one-trial test for neurobiological studies of memory in rats. II: Effects of piracetam and pramiracetam” Behavioural Brain Research Volume 33, Issue 2, 1 June 1989, Pages 197–207 (source)

719 Shih Y.H., Pugsley T.A. “The effects of various cognition-enhancing drugs on in vitro rat 541 David Tomen hippocampal synaptosomal sodium dependent high affinity choline uptake.” Life Sciences. 1985 Jun 3;36(22):2145-52. (source)

720 Simon J.R., Atweh S., Kuhar M.J. “Sodium-dependent high affinity choline uptake: a regula- tory step in the synthesis of acetylcholine.” Journal of Neurochemistry. 1976 May;26(5):909-22. (source)

721 Murai S., Saito H., Abe E., Masuda Y., Odashima J., Itoh T. “MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice.” Journal of Neural Transmission 1994;98(1):1-13. (source)

722 Auteri A., Blardi P., Celasco G., Segre G., Urso R. “Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.” International Journal of Clinical Pharmacological Research. 1992;12(3):129-32. (source)

723 Malen P.L., Chapman P.F. “Nitric Oxide Facilitates Long-Term Potentiation, But Not Long- Term Depression” The Journal of Neuroscience, 1 April 1997, 17(7): 2645-2651; (source)

724 Poschel B.P., Ho P.M., Ninteman F.W. “Arousal deficit shown in aged rat's quantitative EEG and ameliorative action of pramiracetam compared to piracetam.” Experientia. 1985 Nov 15;41(11):1433-5. (source)

725 De Vreese L.P., Neri M., Boiardi R., Ferrari P., Belloi L., Salvioli G. “Memory training and drug therapy act differently on memory and metamemory functioning: evidence from a pilot study.” Archives of Gerontology and Geriatrics. 1996;22 Suppl 1:9-22. (source)

726 McLean A. Jr., Cardenas D.D., Burgess D., Gamzu E. “Placebo-controlled study of pramirace- tam in young males with memory and cognitive problems resulting from head injury and anoxia.” Brain Injury. 1991 Oct-Dec;5(4):375-80. (source)

727 Kuć J., Rush J.S. “Phytoalexins” Archives of Biochemistry and Biophysics. 1985 Feb 1;236(2):455- 72. (source)

728 Asensi M., Medina I., Ortega A., Carretero J., Baño M.C., Obrador E., Estrela J.M. “Inhibi- tion of cancer growth by resveratrol is related to its low bioavailability.” Free Radical Biology and Medicine. 2002 Aug 1;33(3):387-98. (source)

729 Kapetanovic I.M., Muzzio M., Huang Z., Thompson T.N., McCormick D.L. “Pharmaco- kinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats.” Cancer Chemotherapy and Pharmacology. 2011 Sep;68(3):593-601. (source)

730 Casadesus G., Shukitt-Hale B., Stellwagen H.M., Zhu X., Lee H.G., Smith M.A., Joseph J.A. “Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supple- mentation in aged rats.” Nutritional Neuroscience. 2004 Oct-Dec;7(5-6):309-16 (source)

731 Wang B., Liu H., Yue L., Li X., Zhao L., Yang X., Wang X., Yang Y., Qu Y. “Neuroprotec- tive effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway.” Brain Research. 2016 Jul 15;1643:70-9 (source)

732 Rendeiro C., Vauzour D., Kean R.J., Butler L.T., Rattray M., Spencer J.P., Williams C.M. “Blueberry supplementation induces spatial memory improvements and region-specific regula- tion of hippocampal BDNF mRNA expression in young rats.” Psychopharmacology (Berlin). 2012 Oct;223(3):319-30 (source)

733 Estrada N.M., Isokawa M. “Metabolic Demand Stimulates CREB Signaling in the Limbic 542 HEAD FIRST Cortex: Implication for the Induction of Hippocampal Synaptic Plasticity by Intrinsic Stimulus for Survival.” Frontiers in Systems Neuroscience. 2009 Jun 9;3:5 (source)

734 Silva A.J., Kogan J.H., Frankland P.W., Kida S. “CREB AND MEMORY” Annual Review of Neuroscience Vol. 21: 127-148 (source)

735 Ferrer P., Asensi M., Priego S., Benlloch M., Mena S., Ortega A., Obrador E., Esteve J.M, Estrela J.M. “Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and ac- tivation of cell death in metastatic B16 melanoma.” Journal of Biological Chemistry. 2007 Feb 2;282(5):2880-90 (source)

736 Williams C.M., El Mohsen M.A., Vauzour D., Rendeiro C., Butler L.T., Ellis J.A., Whiteman M., Spencer J.P. “Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels.” Free Radical Biology and Medicine. 2008 Aug 1;45(3):295-305. (source)

737 Joseph J.A., Fisher D.R., Cheng V., Rimando A.M., Shukitt-Hale B. “Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging.” Journal of Agriculture and Food Chemistry. 2008 Nov 26;56(22):10544-51. (source)

738 Pan M.H., Chang Y.H., Badmaev V., Nagabhushanam K., Ho C.T. “Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells.” Journal of Agriculture and Food Chemistry. 2007 Sep 19;55(19):7777-85 (source)

739 Prior R.L., Gu L, Wu X., Jacob R.A., Sotoudeh G., Kader A.A., Cook R.A. “Plasma anti- oxidant capacity changes following a meal as a measure of the ability of a food to alter in vivo antioxidant status.” Journal of the American College of Nutrition. 2007 Apr;26(2):170-81. (source)

740 Casadesus G., Shukitt-Hale B., Stellwagen H.M., Zhu X., Lee H.G., Smith M.A., Joseph J.A. “Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supple- mentation in aged rats.” Nutritional Neuroscience. 2004 Oct-Dec;7(5-6):309-16. (source)

741 Einat H., et. Al. “The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation” The Journal of Neuroscience, August 13, 2003 • 23(19):7311–7316 • 7311 (source)

742 Al Rahim M., Rimando A.M., Silistreli K., El-Alfy A.T. “Anxiolytic action of pterostilbene: involvement of hippocampal ERK phosphorylation.” Planta Medica. 2013 Jun;79(9):723-30. (source)

743 Chang J., Rimando A., Pallas M., Camins A., Porquet D., Reeves J., Shukitt-Hale B., Smith M.A., Joseph J.A., Casadesus G. “Low-dose pterostilbene, but not resveratrol, is a potent neu- romodulator in aging and Alzheimer's disease.” Neurobiology Aging. 2012 Sep;33(9):2062-71. (source)

744 Zhou Y., Zhang X.M., Ma A., Zhang Y.L., Chen Y.Y., Zhou H., Li W.J., Jin X. “Orally administrated pterostilbene attenuates acute cerebral ischemia-reperfusion injury in a dose – and time-dependent manner in mice.” Pharmacology, Biochemistry and Behavior. 2015 Aug;135:199- 209 (source)

745 Riche D.M., McEwen C.L., Riche K.D., Sherman J.J., Wofford M.R., Deschamp D., Gris- wold M. “Analysis of Safety from a Human Clinical Trial with Pterostilbene” Journal of Toxicology

746 Volume 2013 (2013), Article ID 463595 (source) 543 David Tomen 747 Sakata Y., Zhuang H., Kwansa H., Koehler R.C., Doré S. “Resveratrol protects against experi- mental stroke: putative neuroprotective role of heme oxygenase 1.” Experimental Neurology. 2010 Jul;224(1):325-9. (source)

748 Agrawal M., Kumar V., Kashyap M.P., Khanna V.K., Randhawa G.S., Pant A.B. “Ischemic insult induced apoptotic changes in PC12 cells: protection by trans resveratrol.” European Journal of Pharmacology. 2011 Sep;666(1-3):5-11 (source)

749 Li C., Yan Z., Yang J., Chen H., Li H., Jiang Y., Zhang Z. “Neuroprotective effects of resvera- trol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodula- tor in rats.” Neurochemistry International. 2010 Feb;56(3):495-500. (source)

750 Shin J.A., Lee H., Lim Y.K., Koh Y., Choi J.H., Park E.M. “Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke.” Journal of Neuroimmunology. 2010 Oct 8;227(1-2):93-100 (source)

751 Godman H. “Diet rich in resveratrol offers no health boost” Harvard Medical School Harvard. edu Retrieved July 22, 2016 (source)

752 Hurst W.J., Glinski J.A., Miller K.B., Apgar J., Davey M.H., Stuart D.A. “Survey of the trans-resveratrol and trans-piceid content of cocoa-containing and chocolate products.” Journal of Agricultural Food and Chemistry. 2008 Sep 24;56(18):8374-8. (source)

753 Li Y.F., Cheng Y.F., Huang Y., Conti M., Wilson S.P., O'Donnell J.M., Zhang H.T. “Phos- phodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.” Journal of Neuroscience. 2011 Jan 5;31(1):172-83 (source)

754 Park S.J., Ahmad F., Philp A., Baar K., Williams T., Luo H., Ke H., Rehmann H., Taussig R., Brown A.L., Kim M.K., Beaven M.A., Burgin A.B., Manganiello V., Chung J.H. “Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.” Cell. 2012 Feb 3;148(3):421-33. (source)

755 Chung J.H. “Metabolic benefits of inhibiting cAMP-PDEs with resveratrol” Adipocyte. 2012 Oct 1; 1(4): 256–258. (source)

756 Dasgupta B., Milbrandt J. “Resveratrol stimulates AMP kinase activity in neurons.” Proceed- ings of the National Academy of Sciences U S A. 2007 Apr 24;104(17):7217-22. (source)

757 Rahvar M., Nikseresht M., Shafiee S.M., Naghibalhossaini F., Rasti M., Panjehshahin M.R., Owji A.A. “Effect of oral resveratrol on the BDNF gene expression in the hippocampus of the rat brain.” Neurochemistry Research. 2011 May;36(5):761-5. (source)

758 “Alzheimer’s Disease” Centers for Disease Control and Prevention cdc.gov Retrieved July 21, 2016 (source)

759 “2016 ALZHEIMER'S DISEASE FACTS AND FIGURES” Alzheimer’s Association alz.org Retrieved July 21, 2016 (source)

760 Vingtdeux V., Giliberto L., Zhao H., Chandakkar P., Wu Q., Simon J.E., Janle E.M., Lobo J., Ferruzzi M.G., Davies P., Marambaud P. “AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.” Journal of Biological Chemistry. 2010 Mar 19;285(12):9100-13. (source) 544 HEAD FIRST 761 Granzotto A., Zatta P. “Resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties against Aβ and Aβ-metal complexes toxicity.” PLoS One. 2011;6(6):e21565. (source)

762 Ladiwala A.R., Lin J.C., Bale S.S., Marcelino-Cruz A.M., Bhattacharya M., Dordick J.S., Tessier P.M. “Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers.” Journal of Biological Chemistry. 2010 Jul 30;285(31):24228-37 (source)

763 Vingtdeux V., Giliberto L., Zhao H., Chandakkar P., Wu Q., Simon J.E., Janle E.M., Lobo J., Ferruzzi M.G., Davies P., Marambaud P. “AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.” Journal of Biological Chemistry. 2010 Mar 19;285(12):9100-13. (source)

764 Witte A.V., Kerti L., Margulies D.S., Flöel A. “Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults.” Journal of Neuroscience. 2014 Jun 4;34(23):7862-70. (source)

765 Kennedy D.O., Wightman E.L., Reay J.L., Lietz G., Okello E.J., Wilde A., Haskell C.F. “Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation.” American Journal of Clinical Nutrition. 2010 Jun;91(6):1590-7. (source)

766 Walle T., Hsieh F., DeLegge M.H., Oatis J.E. Jr., Walle U.K. “High absorption but very low bioavailability of oral resveratrol in humans.” Drug Metabolism and Disposition. 2004 Dec;32(12):1377-82. (source)

767 Almeida L., Vaz-da-Silva M., Falcão A., Soares E., Costa R., Loureiro A.I., Fernandes-Lopes C., Rocha J.F., Nunes T., Wright L., Soares-da-Silva P. “Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers.” Molecular Nutrition and Food Research. 2009 May;53 Suppl 1:S7-15. (source)

768 Howells L.M., Berry D.P., Elliott P.J., Jacobson E.W., Hoffmann E., Hegarty B., Brown K., Steward W.P., Gescher A.J. “Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics.” Cancer Prevention Research (Philadelphia). 2011 Sep;4(9):1419-25 (source)

769 Brown R.P., Gerbarg P.L., Ramazanov Z. “Rhodiola rosea: A Phytomedicinal Overview” The Journal of the American Botanical Council Issue: 56 Page: 40-52 herbalgram.org (source)

770 Brown R.P., Gerbarg P.L., Ramazanov Z. “Rhodiola rosea: A Phytomedicinal Overview” The Journal of the American Botanical Council Issue: 56 Page: 40-52 herbalgram.org (source)

771 Panossian A., Wikman, Wagner H. “Plant adaptogens III.* Earlier and more recent aspects and concepts on their mode of action” Phytomedicine, Vol. 6(4), pp. 287–300 (source)

772 Panossian A., Wikman G., Sarris J. “Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy.” Phytomedicine. 2010 Jun;17(7):481-93. (source)

773 Darbinyan V., Aslanyan G., Amroyan E., Gabrielyan E., Malmström C., Panossian A. “Clini- cal trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression.” Nordic Journal of Psychiatry. 2007;61(5):343-8. (source)

774 Qin Y.J., Zeng Y.S., Zhou C.C., Li Y., Zhong Z.Q. “[Effects of Rhodiola rosea on level of 5-hydroxytryptamine, cell proliferation and differentiation, and number of neuron in cerebral hip- pocampus of rats with depression induced by chronic mild stress].” in Chinese Zhongguo Zhong Yao Za Zhi. 2008 Dec;33(23):2842-6. (source) 545 David Tomen 775 “New evidence that chronic stress predisposes brain to mental illness” University of California, Berkeley Feb. 11, 2014, Retrieved Mar. 24, 2016 (source)

776 Lishmanov Iu.B., Trifonova Zh.V., Tsibin A.N., Maslova L.V., Dement'eva L.A. “[Plasma beta-endorphin and stress hormones in stress and adaptation].” – in Russian Biull Eksp Biol Med. 1987 Apr;103(4):422-4. (source)

777 Shevtsov V.A., Zholus B.I., Shervarly V.I., Vol'skij V.B., Korovin Y.P., Khristich M.P., Ro- slyakova N.A., Wikman G. “A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work.” Phytomedicine. 2003 Mar;10(2- 3):95-105. (source)

778 Darbinyan V., Kteyan A., Panossian A., Gabrielian E., Wikman G., Wagner H. “Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.” Phytomedicine. 2000 Oct;7(5):365-71. (source)

779 Mao J.J., Xie S.X., Zee J., Soeller I., Li QS., Rockwell K., Amsterdam J.D. “Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial.” Phytomedi- cine. 2015 Mar 15;22(3):394-9. (source)

780 Booker A., Jalil B., Frommenwiler D., Reich E., Zhai L., Kulic Z., Heinrich M. “The authen- ticity and quality of Rhodiola rosea products.” Phytomedicine. 2016 Jun 15;23(7):754-62 (source)

781 Kagan B.L., Sultzer D.L., Rosenlicht N., Gerner R.H. “Oral S-adenosylmethionine in depres- sion: a randomized, double-blind, placebo-controlled trial.” American Journal of Psychiatry. 1990 May;147(5):591-5. (source)

782 Muccioli G., Scordamaglia A., Bertacco S., Di Carlo R. “Effect of S-adenosyl-L-methionine on brain muscarinic receptors of aged rats.” European Journal of Pharmacology. 1992 Nov 2;227(3):293-9. (source)

783 Park L.K., Friso S., Choi S.W. “Nutritional influences on epigenetics and age-related disease.” Proceedings of the Nutrition Society. 2012 Feb;71(1):75-83. (source)

784 Ray J.G., Cole D.E., Boss S.C. “An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise?” Clinical Biochemistry. 2000 Jul;33(5):337-43. (source)

785 Saunderson E.A., Spiers H., Mifsud K.R., Gutierrez-Mecinas M., Trollope A.F., Shaikh A., Mill J., Reul J.M. “Stress-induced gene expression and behavior are controlled by DNA methyla- tion and methyl donor availability in the dentate gyrus.” Proceedings of the National Academy of Sciences U S A. 2016 Apr 26;113(17):4830-5 (source)

786 Williams A.L., Girard C., Jui D., Sabina A., Katz D.L. “S-adenosylmethionine (SAMe) as treatment for depression: a systematic review.” Clinical and Investigative Medicine. 2005 Jun;28(3):132-9. (source)

787 Najm W.I., Reinsch S., Hoehler F., Tobis J.S., Harvey P.W. “S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial.” BMC Musculoskeletal Disorders. 2004 Feb 26;5:6. (source)

788 Tavoni A., Vitali C., Bombardieri S., Pasero G. “Evaluation of S-adenosylmethionine in primary fibromyalgia.” A double-blind crossover study. American Journal of Medicine. 1987 Nov 20;83(5A):107-10. (source) 546 HEAD FIRST 789 “Major Depression Among Adults” National Institute of Mental Health nimh.nih.org Retrieved July 25, 2016 (source)

790 Rabin R.C. “A Glut of Antidepressants” The New York Times blog blogs.nytimes.com Retrieved July 25, 2016 (source)

791 Bottiglieri T., Laundy M., Crellin R., Toone B.K., Carney M.W., Reynolds E.H. “Homo- cysteine, folate, methylation, and monoamine metabolism in depression.” Journal of Neurology, Neurosurgery and Psychiatry. 2000 Aug;69(2):228-32. (source)

792 Shekim W.O., Antun F., Hanna G.L., McCracken J.T., Hess E.B. “S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: preliminary results from an open trial.” Psychopharmacology Bulletin. 1990;26(2):249-53. (source)

793 “S-Adenosyl-L-Methionine (SAMe) for Depression, Osteoarthritis, and Liver Disease” US Department for Health and Human Services archive.ahrq.gov Retrieved July 25, 2016 (source)

794 Linde K., Ramirez G., Mulrow C.D., Pauls A., Weidenhammer W., Melchart D. “St John's wort for depression—an overview and meta-analysis of randomised clinical trials.” British Medical Journal 1996 Aug 3;313(7052):253-8. (source)

795 Szegedi A, Kohnen R, Dienel A, Kieser M, "Acute Treatment of Moderate to Severe Depression with Hypericum Extract WS(R) 5570 (St. John's Wort): Randomized, Controlled, Double-Blind, Non-Inferiority Trial versus Peroxetine", British Medical Journal 2005, BMJ Online First Retrieved July 29, 2016 (source)

796 Nahrstedt A., Butterweck V. “Biologically active and other chemical constituents of the herb of Hypericum perforatum L.” Pharmacopsychiatry. 1997 Sep;30 Suppl 2:129-34. (source)

797 Barnes J., Anderson L.A., Phillipson J.D. “St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties.” Journal of Pharmacy and Pharmacology. 2001 May;53(5):583-600. (source)

798 Müller W.E., Singer A., Wonnemann M. “Hyperforin—antidepressant activity by a novel mechanism of action.” Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S98-102. (source)

799 Laakmann G., Schüle C., Baghai T., Kieser M. “St. John's wort in mild to moderate depres- sion: the relevance of hyperforin for the clinical efficacy.” Pharmacopsychiatry. 1998 Jun;31 Suppl 1:54-9. (source)

800 Anghelescu I.G., Kohnen R., Szegedi A., Klement S., Kieser M. “Comparison of Hypericum extract WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moder- ate to severe depression: results from a randomized multicenter study.” Pharmacopsychiatry. 2006 Nov;39(6):213-9. (source)

801 Butterweck V. “Mechanism of action of St John's wort in depression: what is known?” CNS Drugs. 2003;17(8):539-62. (source)

802 Volz H.P., Murck H., Kasper S., Möller H.J. “St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial.” Psychopharmacology (Berlin). 2002 Nov;164(3):294- 300 (source)

803 Klemow K.M., Bartlow A., Crawford J., Kocher N., Shah J., Ritsick M. “Chapter 11Medical Attributes of St. John’s Wort (Hypericum perforatum)” Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. (source) 547 David Tomen 804 Butterweck V., Hegger M., Winterhoff H. “Flavonoids of St. John's Wort reduce HPA axis function in the rat.” Planta Medica. 2004 Oct;70(10):1008-11. (source)

805 Butterweck V. “Mechanism of action of St John's wort in depression: what is known?” CNS Drugs. 2003;17(8):539-62. (source)

806 Schempp C.M., Pelz K., Wittmer A., Schöpf E., Simon J.C. “Antibacterial activity of hyperfo- rin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria.” Lancet. 1999 Jun 19;353(9170):2129. (source)

807 Tang J., Colacino J.M., Larsen S.H., Spitzer W. “Virucidal activity of hypericin against en- veloped and non-enveloped DNA and RNA viruses.” Antiviral Research. 1990 Jun;13(6):313-25. (source)

808 Schempp C.M., Kirkin V., Simon-Haarhaus B., Kersten A., Kiss J., Termeer C.C., Gilb B., Kaufmann T., Borner C., Sleeman JP, Simon J.C. “Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis.” Oncogene. 2002 Feb 14;21(8):1242-50. (source)

809 Zou Y.P., Lu Y.H., Wei D.Z. “Protective effects of a -rich extract of Hypericum perforatum L. against hydrogen peroxide-induced apoptosis in PC12 cells.” Phytotherapy Research. 2010 Jan;24 Suppl 1:S6-S10. (source)

810 Tedeschi E., Menegazzi M., Margotto D., Suzuki H., Förstermann U., Kleinert H. “Anti- inflammatory actions of St. John's wort: inhibition of human inducible nitric-oxide synthase ex- pression by down-regulating signal transducer and activator of transcription-1alpha (STAT-1alpha) activation.” Journal of Pharmacology and Experimental Therapy. 2003 Oct;307(1):254-61 (source)

811 Feily A., Abbasi N. “The inhibitory effect of Hypericum perforatum extract on morphine withdrawal syndrome in rat and comparison with clonidine.” Phytotherapy Research. 2009 Nov;23(11):1549-52 (source)

812 Shelton R.C., et. Al. “Effectiveness of St John's wort in major depression: a randomized con- trolled trial.” JAMA. 2001 Apr 18;285(15):1978-86. (source)

813 Feeley J., Koons C. “Pfizer Weighing FDA Request to Change Zoloft's Warnings” Bloomberg News Bloomberg.com Retrieved July 28, 2016 (source)

814 Tilburt J.C., Emanuel E.J., Miller F.G. “Does the evidence make a difference in consumer behavior? Sales of supplements before and after publication of negative research results.” Journal of General Internal Medicine. 2008 Sep;23(9):1495-8. (source)

815 Brenner R., Azbel V., Madhusoodanan S., Pawlowska M. “Comparison of an extract of hy- pericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study.” Clinical Therapy. 2000 Apr;22(4):411-9. (source)

816 Linde K., Berner M.M., Kriston L. “St John's wort for major depression.” Cochrane Database of Systematic Revues. 2008 Oct 8;(4):CD000448 (source)

817 Taylor L.H., Kobak K.A. “An open-label trial of St. John's Wort (Hypericum perforatum) in obsessive-compulsive disorder.” Journal of Clinical Psychiatry. 2000 Aug;61(8):575-8. (source)

818 Klemow K.M., Bartlow A., Crawford J., Kocher N., Shah J., Ritsick M. “Chapter 11Medical Attributes of St. John’s Wort (Hypericum perforatum)” Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. (source) 548 HEAD FIRST 819 Wielgus A.R., et. Al. “Phototoxicity in Human Retinal Pigment Epithelial Cells Promoted by Hypericin, a Component of St. John’s Wort” Photochemical Photobiology. 2007; 83(3): 706–713. (source)

820 Booth J.N. 3rd., McGwin G. “The association between self-reported cataracts and St. John's Wort.” Current Eye Research. 2009 Oct;34(10):863-6. (source)

821 Wenk M., Todesco L., Krähenbühl S. “Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females.” British Journal of Clinical Pharmacology. 2004 Apr;57(4):495-9. (source)

822 Klemow K.M., Bartlow A., Crawford J., Kocher N., Shah J., Ritsick M. “Chapter 11Medical Attributes of St. John’s Wort (Hypericum perforatum)” Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. (source)

823 Wernicke-Korsakoff syndrome. Medline Plus Medical Encyclopedia nlm.nih.gov/medlineplus Retrieved April 7, 2016 (source)

824 Martin P.R., Singleton C.K., Hiller-Sturmhofel S. “The Role of Thiamine Deficiency in Al- coholic Brain Disease” National Institute on Alcohol Abuse and Alcoholism nih.gov Retrieved April 7, 2016 (source)

825 Singleton C.K., Martin P.R. “Molecular mechanisms of thiamine utilization.” Current Molecu- lar Medicine 2001 May;1(2):197-207. (source)

826 Ollat H., Laurent B., Bakchine S., Michel B.F., Touchon J., Dubois B. “[Effects of the associa- tion of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease]”. L’Encephale 2007 Mar-Apr;33(2):211-5.

827 Benton D., Griffiths R., Haller J. “Thiamine supplementation mood and cognitive function- ing.” Psychopharmacology 1997 Jan;129(1):66-71. (source)

828 Tiev K.P., Cabane J., Imbert J.C. “[Treatment of chronic postinfectious fatigue: randomized double-blind study of two doses of sulbutiamine (400-600 mg/day) versus placebo].” La Revue de Medicine Interne 1999 Oct;20(10):912-8. (source)

829 Micheau J., Durkin T.P., Destrade C., Rolland Y, Jaffard R. “Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation.” Pharmacology, Biochemistry and Behavior 1985 Aug;23(2):195-8. (source)

830 Bizot J.C., Herpin A., Pothion S., Pirot S., Trovero F., Ollat H. “Chronic treatment with sulbutiamine improves memory in an object recognition task and reduces some amnesic effects of in a spatial delayed-non-match-to-sample task.” Progress in Neuro-psychopharmacology & Biology Psychiatry. 2005 Jul;29(6):928-35. (source)

831 Sobolevsky T., Rodchenkov G. “Sulbutiamine in sports.” Drug Testing and Analysis 2010 Nov- Dec;2(11-12):643-6. (source)

832 Dmitriev D.G., Gamidov S.I., Permiakova O.V. “[Clinical efficacy of the drug enerion in the treatment of patients with psychogenic (functional) erectile dysfunction].” Urology 2005 Jan- Feb;(1):32-5. (source)

833 Sidransky H. Tryptophan: Biochemical and Health Implications. CRC Press; Boca Raton, FL: 2002. 549 David Tomen 834 Lieberman H.R., Caballero B., Finer N. “The composition of lunch determines afternoon plasma tryptophan ratios in humans.” Journal of Neural Transmission. 1986;65(3-4):211-7. (source)

835 Johansson J., et. Al “Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study” Behavior and Brain Function. 2011; 7: 40. (source)

836 den Boer J.A., Westenberg H.G. “Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder.” Psychiatry Research. 1990 Mar;31(3):267- 78. (source)

837 Khaliq S., Haider S., Ahmed S.P., Perveen T., Haleem D.J. “Relationship of brain tryptophan and serotonin in improving cognitive performance in rats.” Pakistan Journal of Pharmaceutical Sciences. 2006 Jan;19(1):11-5. (source)

838 Winokur A., Lindberg N.D., Lucki I., Phillips J., Amsterdam J.D. “Hormonal and behavioral effects associated with intravenous L-tryptophan administration.” Psychopharmacology (Berlin). 1986;88(2):213-9. (source)

839 Sandyk R. “L-tryptophan in neuropsychiatric disorders: a review.” International Journal of Neuroscience. 1992 Nov-Dec;67(1-4):127-44. (source)

840 Bell C., Abrams J., Nutt D. “Tryptophan depletion and its implications for psychiatry.” British Journal of Psychiatry. 2001 May;178:399-405. (source)

841 Caballero B., Finer N., Wurtman R.J. “Plasma amino acids and insulin levels in obesity: response to carbohydrate intake and tryptophan supplements.” Metabolism. 1988 Jul;37(7):672-6. (source)

842 Lieberman H.R., Caballero B., Finer N. “The composition of lunch determines afternoon plasma tryptophan ratios in humans.” Journal of Neural Transmission. 1986;65(3-4):211-7. (source)

843 Shaw K., Turner J., Del Mar C. “Tryptophan and 5-hydroxytryptophan for depression.” Cochrane Database of Systematic Revues. 2002;(1):CD003198. (source)

844 Booij L., Van der Does A.J., Haffmans P.M., Riedel W.J., Fekkes D, Blom M.J. “The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients.” Journal of Psychopharmacology. 2005 May;19(3):267-75. (source)

845 Sa M., Ying L., Tang A.G., Xiao L.D., Ren Y.P. “Simultaneous determination of tyrosine, tryptophan and 5-hydroxytryptamine in serum of MDD patients by high performance liquid chromatography with fluorescence detection.” International Journal of Clinical Chemistry. 2012 Jun 14;413(11-12):973-7. (source)

846 Levitan R.D., Shen J.H., Jindal R., Driver H.S., Kennedy S.H., Shapiro C.M. “Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.”Journal of Psychiatry and Neurosci- ence. 2000 Sep;25(4):337-46. (source)

847 Fernstrom J.D. “Effects and side effects associated with the non-nutritional use of tryptophan by humans.” Journal of Nutrition. 2012 Dec;142(12):2236S-2244S (source)

848 Javierre C., Segura R., Ventura J.L., Suárez A., Rosés J.M. “L-tryptophan supplementation can decrease fatigue perception during an aerobic exercise with supramaximal intercalated anaerobic 550 HEAD FIRST bouts in young healthy men.” International Journal of Neuroscience. 2010 May;120(5):319-27. (source)

849 Segura R., Ventura J.L. “Effect of L-tryptophan supplementation on exercise performance.” International Journal of Sports Medicine. 1988 Oct;9(5):301-5. (source)

850 Roecklein K., Wong P., Ernecoff N., Miller M., Donofry S., Kamarck M., Wood-Vasey W.M., Franzen P. “The post illumination pupil response is reduced in seasonal affective disorder.” Psychia- try Research. 2013 Nov 30;210(1):150-8. (source)

851 McGrath R.E., Buckwald B., Resnick E.V. “The effect of L-tryptophan on seasonal affective disorder.” Journal of Clinical Psychiatry. 1990 Apr;51(4):162-3. (source)

852 Lam R.W., Levitan R.D., Tam E.M., Yatham L.N., Lamoureux S., Zis A.P. “L-tryptophan augmentation of light therapy in patients with seasonal affective disorder.”Canadian Journal of Psychiatry. 1997 Apr;42(3):303-6. (source)

853 “L-Tryptophan” University of Michigan Health System (source)

854 Fernstrom J.D. “Effects and side effects associated with the non-nutritional use of tryptophan by humans.” Journal of Nutrition. 2012 Dec;142(12):2236S-2244S (source)

855 Ravindran P.N., Babu K.N., Sivaraman K. “Turmeric: The Genus Curcuma”; CRC Press Pg 5 March 1, 2007 ISBN 9780849370342 (source)

856 “Tumeric” US National Library of Medicine ncbi.nlm.hih.gov Retrieved August 4, 2016 (source)

857 “Turmeric” National Center for Complementary and Integrative Health nih.gov (source)

858 Ng T.P., Chiam P.C., Lee T., Chua H.C., Lim L., Kua E.H. “Curry consumption and cognitive function in the elderly.” American Journal of Epidemiology. 2006 Nov 1;164(9):898-906. (source)

859 Kulkarni S.K., Dhir A. “An Overview of Curcumin in Neurological Disorders” Indian Journal of Pharmaceutical Sciences. 2010 Mar-Apr; 72(2): 149–154. (source)

860 Wang R., Li Y.B., Li Y.H., Xu Y., Wu H.L., Li X.J. “Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB.” Brain Research. 2008 May 19;1210:84-91. (source)

861 Kim S.J., Son T.G., Park H.R., Park M., Kim M.S., Kim H.S., Chung H.Y., Mattson M.P., Lee J. “Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus.” Journal of Biological Chemistry. 2008 May 23;283(21):14497-505. (source)

862 Hucklenbroich J. et. Al. “Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo” Stem Cell Research & Therapy 2014 5:100 (source)

863 Kulkarni S.K., Bhutani M.K., Bishnoi M. “Antidepressant activity of curcumin: involvement of serotonin and dopamine system.” Psychopharmacology (Berlin). 2008 Dec;201(3):435-42. (source)

864 Ng T.P., Chiam P.C., Lee T., Chua H.C., Lim L., Kua E.H. “Curry consumption and cognitive function in the elderly.” American Journal of Epidemiology. 2006 Nov 1;164(9):898-906. (source)

865 Sanmukhani J., Satodia V., Trivedi J., Patel T., Tiwari D., Panchal B., Goel A., Tripathi C.B. 551 David Tomen “Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial.” Phytotherapy Research. 2014 Apr;28(4):579-85. (source)

866 Xu Y., Ku B., Tie L., Yao H., Jiang W., Ma X., Li X. “Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB.” Brain Re- search. 2006 Nov 29;1122(1):56-64. Epub 2006 Oct 3. (source)

867 Shoba G., Joy D., Joseph T., Majeed M., Rajendran R., Srinivas P.S. “Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.” Planta Medica. 1998 May;64(4):353-6. (source)

868 Ma Q.L., Zuo X., Yang F., Ubeda O.J., Gant D.J., Alaverdyan M., Teng E., Hu S., Chen P.P., Maiti P., Teter B., Cole G.M., Frautschy S.A. “Curcumin suppresses soluble tau dimers and cor- rects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice.” Journal of Biological Chemistry. 2013 Feb 8;288(6):4056-65 (source)

869 Cox K.H., Pipingas A., Scholey A.B. “Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population.” Journal of Psychopharmacology. 2015 May;29(5):642-51. (source)

870 MacKinnon R.C., Simpson R.A., Maclennan C. “In vivo and in vitro techniques used in the study of RNA synthesis in the brains of rats and mice at various ages from birth to senility.” Journal of Anatomy 1969 Mar; 104(Pt 2): 351–360. (source)

871 Cansev M. “Uridine and cytidine in the brain: their transport and utilization.” Brain Research Revues. 2006 Sep;52(2):389-97. (source)

872 Pooler A.M., Guez D.H., Benedictus R., Wurtman R.J. “Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected].” Neuroscience. 2005;134(1):207-14. (source)

873 Sakamoto T., Cansev M., Wurtman R.J. “Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus.” Brain Research. 2007 Nov 28;1182:50-9. (source)

874 Cansev M., Watkins C.J., van der Beek E.M., Wurtman R.J. “Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils.” Brain Research. 2005 Oct 5;1058(1-2):101- 8 (source)

875 Wang L., Albrecht M.A., Wurtman R.J. “Dietary supplementation with uridine-5'-mono- phosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat.” Brain Research. 2007 Feb 16;1133(1):42-8. (source)

876 Wurtman R.J., Cansev M., Sakamoto T., Ulus I.H. “Use of phosphatide precursors to promote synaptogenesis.” Annual Review of Nutrition. 2009;29:59-87. (source)

877 Wang L., Pooler A.M., Albrecht M.A., Wurtman R.J. “Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats.” Journal of Molecular Neuroscience. 2005;27(1):137-45. (source)

878 Moffatt B.A., Ashihara H. “Purine and Pyrimidine Nucleotide Synthesis and Metabolism” Arabidopsis Book. 2002; 1: e0018. (source)

879 Dobolyi A., Juhasz G., Kovacs Z., Kardos J. “Uridine Function in the Central Nervous System” Current Topics in Medicinal Chemistry, 2011, 11, 1058-1067 (source) 552 HEAD FIRST 880 Myers C.S., Fisher H., Wagner G.C. “Uridine reduces rotation induced by l-Dopa and meth- amphetamine in 6-OHDA-treated rats” Pharmacology Biochemistry and Behavior

881 Volume 52, Issue 4, December 1995, Pages 749–753 (source)

882 Sakamoto T., Cansev M., Wurtman R.J. “Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus.” Brain Research. 2007 Nov 28;1182:50-9 (source)

883 Holguin S., Martinez J., Chow C., Wurtman R. “Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils” The FASEB Journal. 2008 Nov; 22(11): 3938–3946. (source)

884 Powell A. “Rx for depression: 'Mangia, mangia!' Harvard Gazette Archives new.harvard.edu March 03, 2005 Retrieved August 9, 2016 (source)

885 Trafton A. “'Cocktail' of compounds improves brain function in rodents” MIT News news. mit.edu November 26, 2007 retrieved August 9, 2016 (source)

886 Koivisto H. et. Al. “Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition.” Journal of Nutritional Biochemistry. 2014 Feb;25(2):157-69. (source)

887 Gedeon Richter Ltd. Annual Report 2015 (source)

888 “Vinpocetine” US National Toxicology Program [CAS No. 42971-09-5] September 2013 (source)

889 Tubbs R.S. “Circle of Willis Anatomy” Medscape June 03, 2013 (source)

890 Beavo J.A. “Cyclic nucleotide phosphodiesterases: functional implications of multiple iso- forms.” Physiological Revues. 1995 Oct;75(4):725-48. (source)

891 Kalaria R.N. “Vascular Basis for Brain Degeneration: Faltering Controls and Risk Factors for Dementia” Nutrition Reveiws. 2010 Dec; 68(Suppl 2): S74–S87. (source)

892 Vas A., Gulyás B., Szabó Z., Bönöczk P., Csiba L., Kiss B., Kárpáti E., Pánczél G., Nagy Z. “Clinical and non-clinical investigations using positron emission tomography, near infrared spec- troscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences.” Journal of the Neurological Sciences. 2002 Nov 15;203-204:259-62. (source)

893 Medina A. “Vinpocetine as a potent antiinflammatory agent” Proceedings of the National Academy of Sciences U S A. 2010 Jun 1; 107(22): 9921–9922. (source)

894 Kiss B., Kárpáti E. in Hungarian “[Mechanism of action of vinpocetine].” Acta Pharmaceutica Hungary. 1996 Sep;66(5):213-24. (source)

895 Subhan Z., Hindmarch I. “Psychopharmacological effects of vinpocetine in normal healthy volunteers.” European Journal of Clinical Pharmacology. 1985;28(5):567-71. (source)

896 Molnár P., Gaál L., Horváth C. “The impairment of long-term potentiation in rats with medial septal lesion and its restoration by cognition enhancers.” Neurobiology (Budapest). 1994;2(3):255- 66. (source)

897 Hindmarch I., Fuchs H.H., Erzigkeit H. “Efficacy and tolerance of vinpocetine in ambulant 553 David Tomen patients suffering from mild to moderate organic psychosyndromes.” International Clinical Psycho- pharmacology. 1991 Spring;6(1):31-43. (source)

898 Williams R.R., Cline J.K. “Synthesis of Vitamin B1” Journal of the American Chemical Society 1936, 58 (8), pp 1504–1505 (source)

899 Wernicke-Korsakoff syndrome. Medline Plus Medical Encyclopedia nlm.nih.gov/medlineplus Retrieved April 7, 2016 (source)

900 Martin P.R., Singleton C.K., Hiller-Sturmhofel S. “The Role of Thiamine Deficiency in Al- coholic Brain Disease” National Institute on Alcohol Abuse and Alcoholism nih.gov Retrieved April 7, 2016 (source)

901 Singleton C.K., Martin P.R. “Molecular mechanisms of thiamine utilization.” Current Molecu- lar Medicine 2001 May;1(2):197-207. (source)

902 Wilcox C.S. “Do diuretics cause thiamine deficiency?”Journal of Laboratory and Clinical Medicine. 1999 Sep;134(3):192-3. (source)

903 Vimokesant S.L., Hilker D.M., Nakornchai S., Rungruangsak K., Dhanamitta S. “Effects of betel nut and fermented fish on the thiamin status of northeastern Thais.”American Journal of Clinical Nutrition. 1975 Dec;28(12):1458-63. (source)

904 Hutson S.M., Sweatt A.J., Lanoue K.F. “Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes.” Journal of Nutrition. 2005 Jun;135(6 Suppl):1557S-64S. (source)

905 Costantini A., Pala M.I., Tundo S., Matteucci P. “High-dose thiamine improves the symptoms of fibromyalgia.” BMJ Case Reports. 2013 May 20;2013 (source)

906 Costantini A., Pala M.I., Catalano M.L., Notarangelo C., Careddu P. “High-dose thiamine improves fatigue after stroke: a report of three cases.” Journal of Alternative and Complementary Medicine. 2014 Sep;20(9):683-5. (source)

907 Costantini A., Pala M.I. “Thiamine and Hashimoto's thyroiditis: a report of three cases.” Journal of Alternative and Complementary Medicine. 2014 Mar;20(3):208-11. (source)

908 “Thiamine (Vitamin B1)” Mayo Clinic mayoclinic.org Retrieved September 23, 2016 (source)

909 Lonsdale D. “Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent.” Medical Science Monitor. 2004 Sep;10(9):RA199-203. (source)

910 Mills J.C., Nelson D., Erecińska M., Pittman R.N. “Metabolic and energetic changes during apoptosis in neural cells.” Journal of Neurochemistry. 1995 Oct;65(4):1721-30. (source)

911 Liou S. “Nicotinamide” Stanford University standford.edu Retrieved September 25, 2016 (source)

912 Schulz J.B., Henshaw D.R., Matthews R.T., Beal M.F. “Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity.” Experimental Neurology. 1995 Apr;132(2):279-83. (source)

913 Cui X., Chopp M., Zacharek A., Roberts C., Buller B., Ion M., Chen J. “Niacin treatment of stroke increases synaptic plasticity and axon growth in rats.” Stroke. 2010 Sep;41(9):2044-9 (source) 554 HEAD FIRST 914 Quabbe H.J., Luyckx A.S., L'age M., Schwarz C. “Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189).” Journal of Clinical Endocrinology and Metabolism. 1983 Aug;57(2):410-4. (source)

915 Onusic S. “Violent Behavior: A Solution in Plain Sight” The Weston Price Foundation April 22, 2013 (source)

916 Morris M.C., Evans D.A., Bienias J.L., Scherr P.A., Tangney C.C., Hebert L.E., Bennett D.A., Wilson R.S., Aggarwal N. “Dietary niacin and the risk of incident Alzheimer's disease and of cog- nitive decline.” Journal of Neurology, Neurosurgery and Psychiatry. 2004 Aug;75(8):1093-9. (source)

917 Canner P.L., Berge K.G., Wenger N.K., Stamler J., Friedman L., Prineas R.J., Friedewald W. “Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.”Journal of American College of Cardiology. 1986 Dec;8(6):1245-55. (source)

918 MacIntosh A., Ball K. “The effects of a short program of detoxification in disease-free individu- als.” Alternative Therapies in Health and Medicine. 2000 Jul;6(4):70-6. (source)

919 Cecchini M, Root D, Rachunow J, Gelb P. “Chemical Exposures at the World Trade Center Use of the Hubbard Sauna Detoxification Regimen to Improve the Health Status of New York City Rescue Workers Exposed to Toxicants.” Townsend Letter. April 2006;263:58-65. (source)

920 Viljoen M., Swanepoel A., Bipath P. “Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake.” Medical Hypotheses. 2015 Mar;84(3):178-82 (source)

921 Ng C.F., Lee C.P., Ho A.L., Lee V.W. “Effect of niacin on erectile function in men suffer- ing erectile dysfunction and dyslipidemia.” Journal of Sexual Medicine. 2011 Oct;8(10):2883-93 (source)

922 Hoffer L.J. “Vitamin Therapy in Schizophrenia” Israeli Journal of Psychiatry and Related Sci- ences Vol 45 No. 1 (2008) 3–10 (source)

923 Kamanna V.S., Ganji S.H., Kashyap M.L. “The mechanism and mitigation of niacin-induced flushing” International Journal of Clinical Practice. 2009 Sep; 63(9): 1369–1377. (source)

924 McKenney J.M., Proctor J.D., Harris S., Chinchili V.M. “A comparison of the efficacy and toxic effects of sustained – vs immediate-release niacin in hypercholesterolemic patients.” JAMA. 1994 Mar 2;271(9):672-7. (source)

925 Norris R.B. “"Flush-free niacin": dietary supplement may be "benefit-free". Preventive Cardiol- ogy. 2006 Winter;9(1):64-5. (source)

926 Knopp R.H., Alagona P., Davidson M., Goldberg A.C., Kafonek S.D., Kashyap M., Sprecher D., Superko H.R., Jenkins S., Marcovina S. “Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.” Metabo- lism. 1998 Sep;47(9):1097-104. (source)

927 Jungnickel P.W., Maloley P.A., Vander Tuin E.L., Peddicord T.E., Campbell J.R. “Effect of two aspirin pretreatment regimens on niacin-induced cutaneous reactions.” Journal of General Internal Medicine. 1997 Oct;12(10):591-6. (source)

928 “Niacin: Nicotinic Acid, Nicotinamide, and Inositol Hexanicotinate” Vitamin and Mineral Safety 3rd Edition. Council for Responsible Nutrition (source) 555 David Tomen 929 Rucker R.B., Bauerly K. “Pantothenic acid”. In: Zempleni J., Suttie J.W., Gregory J.F. III, Stover P.J., editors. Handbook of Vitamins. 5th ed. CRC Press; Boca Raton, FL, USA: 2013

930 Tahiliani A.G., Beinlich C.J. “Pantothenic acid in health and disease.” Vitamins and Hormones. 1991;46:165-228. (source)

931 Leung L.H. “Pantothenic acid deficiency as the pathogenesis of acne vulgaris.” Medical Hy- potheses. 1995 Jun;44(6):490-2. (source)

932 McRae M.P. “Treatment of hyperlipoproteinemia with pantethine: A review and analysis of efficacy and tolerability” Nutrition Research April 2005 Volume 25, Issue 4, Pages 319–333 (source)

933 Pelton R.B., Williams R.J. “Effect of Pantothenic Acid on the Longevity of Mice”Experimental Biology and Medicine 2016 (source)

934 Honda Y. et. Al. “Lifespan-Extending Effects of Royal Jelly and Its Related Substances on the Nematode Caenorhabditis elegans” PLoS One 2011; 6(8): e23527. (source)

935 Clayton P.T. “B6-responsive disorders: a model of vitamin dependency.” Journal of Inherited Metabolic Disease. 2006 Apr-Jun;29(2-3):317-26. (source)

936 Kennedy D.O. “B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review” Nutrients. 2016 Feb; 8(2): 68. (source)

937 Percudani R., Peracchi A. “A genomic overview of pyridoxal-phosphate-dependent enzymes” EMBP reports 2003 Sep; 4(9): 850–854. (source)

938 Sakakeeny L., Roubenoff R., Obin M., Fontes J.D., Benjamin E.J., Bujanover Y., Jacques P.F., Selhub J. “Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflam- mation in a population of U.S. adults.” Journal of Nutrition. 2012 Jul;142(7):1280-5. (source)

939 Troesch B., Hoeft B., McBurney M., Eggersdorfer M., Weber P. “Dietary surveys indicate vitamin intakes below recommendations are common in representative Western countries.” British Journal of Nutrition. 2012 Aug;108(4):692-8 (source)

940 Douaud G., Refsum H., de Jager C.A., Jacoby R., Nichols T.E., Smith S.M., Smith A.D. “Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment” Proceedings of the National Academy of Sciences USA vol. 110 no. 23 (source)

941 Malouf R., Grimley Evans J. “The effect of vitamin B6 on cognition.” Cochrane Database System Revue. 2003;(4):CD004393. (source)

942 Huang S.C., Wei J.C.C., Wu D.J., Huang Y.C. “Vitamin B6 supplementation improves pro-inflammatory responses in patients with rheumatoid arthritis” European Journal of Clinical Nutrition (2010) 64, 1007–1013 (source)

943 Smith A.D. “The worldwide challenge of the dementias: a role for B vitamins and homocyste- ine?” Food Nutrition Bulletin. 2008 Jun;29(2 Suppl):S143-72. (source)

944 Ebben M., Lequerica A., Spielman A. “Effects of pyridoxine on dreaming: a preliminary study.” Perceptual and Motor Skills. 2002 Feb;94(1):135-40. (source)

945 De Lau L.M.L., Koudstaal P.J., Witteman J.C.M., Hofman A., Breteler M.M.B. “Dietary folate, vitamin B12, and vitamin B6 and the risk of Parkinson disease” Neurology July 25, 2006 vol. 67 no. 2 315-318 (source) 556 HEAD FIRST 946 Mikawa Y., Mizobuchi S., Egi M., Morita K. “Low serum concentrations of vitamin B6 and iron are related to panic attack and hyperventilation attack.” Acta Medica Okayama. 2013;67(2):99- 104. (source)

947 Allen G.F., Neergheen V., Oppenheim M., Fitzgerald J.C., Footitt E., Hyland K., Clayton P.T., Land J.M., Heales S.J. “Pyridoxal 5'-phosphate deficiency causes a loss of aromatic L-amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic L-amino acid decarboxylase and vitamin B(6) deficiency states.” Journal of Neurochemistry. 2010 Jul;114(1):87- 96 (source)

948 Morris M.S., Picciano M.F., Jacques P.F., Selhub J. “Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004.” American Journal of Clinical Nutrition. 2008 May;87(5):1446-54. (source)

949 Parry G.J., Bredesen D.E. “Sensory neuropathy with low-dose pyridoxine.” Neurology. 1985 Oct;35(10):1466-8. (source)

950 Dalton K., Dalton M.J. “Characteristics of pyridoxine overdose neuropathy syndrome.” Acta Neurologica Scandinavia. 1987 Jul;76(1):8-11. (source)

951 Xu Y., Sladky J.T., Brown M.J. “Dose-dependent expression of neuronopathy after experimen- tal pyridoxine intoxication.” Neurology. 1989 Aug;39(8):1077-83. (source)

952 Perry T.A., Weerasuriya A., Mouton P.R., Holloway H.W., Greig N.H. “Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.” Experimental Neurology. 2004 Nov;190(1):133-44. (source)

953 Wiese T.J., Dunlap J.A., Conner C.E., Grzybowski J.A., Lowe W.L. Jr., Yorek M.A. “Osmotic regulation of Na-myo-inositol cotransporter mRNA level and activity in endothelial and neural cells.” American Journal of Physiology. 1996 Apr;270(4 Pt 1):C990-7. (source)

954 Majerus P.W., Ross T.S., Cunningham T.W., Caldwell K.K., Jefferson A.B., Bansal V.S. “Recent insights in phosphatidylinositol signaling.” Cell. 1990 Nov 2;63(3):459-65. (source)

955 Fisher S.K., Novak J.E., Agranoff B.W. “Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance.” Journal of Neurochemistry. 2002 Aug;82(4):736-54. (source)

956 Nishiyama M., Hong K., Mikoshiba K., Poo M.M., Kato K. “Calcium stores regulate the polarity and input specificity of synaptic modification.” Nature. 2000 Nov 30;408(6812):584-8. (source)

957 Siegel G., Agranoff B., Albers R., Molinoff P. Basic neurochemistry. New York: Raven Press; 1994.

958 Gamper N., Shapiro M.S. “Regulation of ion transport proteins by membrane phosphoinositi- des.” Nature Reviews: Neuroscience. 2007 Dec;8(12):921-34. (source)

959 Rango M., Cogiamanian F., Marceglia S., Barberis B. “Myoinositol content in the human brain is modified by transcranial direct current stimulation in a matter of minutes: A 1H-MRS study” Magnetic Resonance in Medicine Volume 60, Issue 4 October 2008 Pages 782–789 (source)

960 Eagen D.E., et. Al. “Elevated Serum C-Reactive Protein Relates to Increased Cerebral Myoino- sitol Levels in Middle-Aged Adults” Cardiovascular Psychiatry and Neurology. 2012; 2012: 120540. (source) 557 David Tomen 961 Nishiyama M., Hong K., Mikoshiba K., Poo M.M., Kato K. “Calcium stores regulate the polarity and input specificity of synaptic modification.” Nature. 2000 Nov 30;408(6812):584-8. (source)

962 Mukai T., Kishi T., Matsuda Y., Iwata N. “A meta-analysis of inositol for depression and anxiety disorders.” Human Psychopharmacology. 2014 Jan;29(1):55-63 (source)

963 Rahman S., Neuman R.S. “Myo-inositol reduces serotonin (5-HT2) receptor induced ho- mologous and heterologous desensitization.” Brain Research. 1993 Dec 24;631(2):349-51. (source)

964 Gianfranco C., Vittorio U., Silvia B., Francesco D. “Myo-inositol in the treatment of premen- strual dysphoric disorder.” Human Psychopharmacology. 2011 Oct;26(7):526-30. (source)

965 Ciranna L. “Serotonin as a Modulator of Glutamate – and GABA-Mediated Neurotransmis- sion: Implications in Physiological Functions and in Pathology” Current Neuropharmacology. 2006 Apr; 4(2): 101–114. (source)

966 Kofman O., Levin U. “Myo-inositol attenuates the enhancement of the serotonin syndrome by lithium.” Psychopharmacology (Berlin). 1995 Mar;118(2):213-8. (source)

967 Herman-Sucharska I., Grzybek M., Grochowska A., Karcz P., Urbanik A. article in Polish “[Myoinositol trends in HMRS brain spectrum of patients with hepatic encephalopathy].” Przegl Lek. 2010;67(4):247-50. (source)

968 Gelber D., Levine J., Belmaker R.H. “Effect of inositol on bulimia nervosa and binge eating.” International Journal of Eating Disorders. 2001 Apr;29(3):345-8. (source)

969 Han W., et. Al. “The Chemopreventive Agent Myoinositol Inhibits Akt and Extracellular Signal-Regulated Kinase in Bronchial Lesions from Heavy Smokers” Cancer Prevention Research US National Library of Medicine 2013 Jul 18 (source)

970 Calogero A.E., et. Al. “Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo- controlled study” Andrology Volume 3, Issue 3 May 2015 Pages 491–495 (source)

971 Maeba R., Hara H., Ishikawa H., Hayashi S., Yoshimura N., Kusano J., Takeoka Y., Yasuda D., Okazaki T., Kinoshita M., Teramoto T. “Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome.” Journal of Nutritional Science and Vitaminology (Tokyo). 2008 Jun;54(3):196-202. (source)

972 Inafuku M., Nagao K., Inafuku A., Yanagita T., Taira N., Toda T., Oku H. “Dietary phos- phatidylinositol protects C57BL/6 mice from concanavalin A-induced liver injury by modulating immune cell functions.” Molecular Nutrition and Food Research. 2013 Sep;57(9):1671-9 (source)

973 Fortis-Barrera Á., Alarcón-Aguilar F.J., Banderas-Dorantes T., Díaz-Flores M., Román-Ramos R., Cruz M., García-Macedo R. “Cucurbita ficifolia Bouché (Cucurbitaceae) and D-chiro-inositol modulate the redox state and inflammation in 3T3-L1 adipocytes.” Journal of Pharmacy and Phar- macology. 2013 Oct;65(10):1563-76 (source)

974 Hada B., Yoo M.R., Seong K.M., Jin Y.W., Myeong H.K., Min K.J. “D-chiro-inositol and pinitol extend the life span of Drosophila melanogaster.” Journal of Gerontology. Series A, Biological Sciences and Medical Sciences. 2013 Mar;68(3):226-34. (source)

975 Palatnik A., Frolov K., Fux M., Benjamin J. “Double-blind, controlled, crossover trial of inosi- 558 HEAD FIRST tol versus fluvoxamine for the treatment of panic disorder.” Journal of Clinical Psychopharmacology. 2001 Jun;21(3):335-9. (source)

976 Levine J., Barak Y., Gonzalves M., Szor H., Elizur A., Kofman O., Belmaker R.H. “Double- blind, controlled trial of inositol treatment of depression.” American Journal of Psychiatry. 1995 May;152(5):792-4. (source)

977 Carlomagno G., Unfer F., Buffo S., D’Ambrosio F. “Myo-inositol in the treatment of premen- strual dysphoric disorder” Human Psychopharmacology Volume 26, Issue 7 October 2011 Pages 526–530 (source)

978 Fux M., Levine J., Aviv A., Belmaker R.H. “Inositol treatment of obsessive-compulsive disor- der.” American Journal of Psychiatry. 1996 Sep;153(9):1219-21. (source)

979 Selhub J. “Folate, vitamin B12 and vitamin B6 and one carbon metabolism.” Journal of Nutri- tion, Health and Aging. 2002;6(1):39-42. (source)

980 Powers H.J. “Folic acid under scrutiny.” British Journal of Nutrition 2007 Oct;98(4):665-6 (source)

981 Troen A.M. et. Al. “Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women” The Journal of Nutrition January 2006 vol. 136 no. 1 189-194 (source)

982 Miller A.L. “The Methylation, Neurotransmitter, and Antioxidant Connections Between Folate and Depression” Alternative Medicine Review Volume 13, Number 3 2008 (source)

983 Gilbody S., Lewis S., Lightfoot T. “Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review.” American Journal of Epidemiology. 2007 Jan 1;165(1):1-13 (source)

984 Miller A.L. “The methylation, neurotransmitter, and antioxidant connections between folate and depression.” Alternative Medicine Review. 2008 Sep;13(3):216-26. (source)

985 Reynolds E.H., Carney M.W., Toone B.K. “Methylation and mood.” Lancet. 1984 Jul 28;2(8396):196-8. (source)

986 Bottiglieri T., Crellin R., Reynolds E.H. ‘Folate and neuropsychiatry’. In: Bailey LB, editor. Folate in health and disease. New York: Marcel Dekker; 1995. pp. 435–462

987 Bottiglieri T., Godfrey P., Flynn T., Carney M.W., Toone B.K., Reynolds E.H. “Cerebro- spinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with par- enteral and oral S-adenosylmethionine.” Journal of Neurology and Neurosurgery Psychiatry. 1990 Dec;53(12):1096-8. (source)

988 Nikkanen J., et. Al. “Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism” Cell Metabolism Volume 23, Issue 4, p635–648 (source)

989 Sarris J., Murphy J., Mischoulon D. Papakostas G.I., Fava M., Berk M. Ng C.H. “Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses” The American Journal of Psychiatry Volume 173, Issue 6, June 01, 2016, pp. 575-587 (source)

990 Passeri M., Cucinotta D., Abate G., Senin U., Ventura A., Stramba Badiale M., Diana R., La Greca P., Le Grazie C. “Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with 559 David Tomen depression: results of a double-blind multicenter study.” Aging (Milano). 1993 Feb;5(1):63-71. (source)

991 “Folate Deficiency Associated With Tripling Of Dementia Risk, Study Shows” Science Daily February 5, 2008 retrieved November 15, 2016 (source)

992 Reynolds E.H., Rothfeld P., Pincus J.H. “Neurological disease associated with folate defi- ciency.” British Medical Journal. 1973 May 19;2(5863):398-400 (source)

993 Goodwin J.S., Goodwin J.M., Garry P.J. “Association between nutritional status and cognitive functioning in a healthy elderly population.” JAMA. 1983 Jun 3;249(21):2917-21. (source)

994 Rapin J.R., Le Poncin M., Grebyl J. “Blood folate deficiencies and cognitive functions in aging.” Trends in Biomedical and Gerontology. 1988;1:221–223.

995 Mischoulon D., Raab M.F. “The role of folate in depression and dementia.” Journal of Clinical Psychiatry. 2007;68 Suppl 10:28-33. (source)

996 Yamada K. “Cobalt: Its Role in Health and Disease” Interrelations between Essential Metal Ions and Human Diseases Volume 13 of the series Metal Ions in Life Sciences pp 295-320 (source)

997 Seetharam B. “Receptor-mediated endocytosis of cobalamin (vitamin B12).” Annual Review of Nutrition. 1999;19:173-95. (source)

998 “Vitamin B12 Dietary Supplement Fact Sheet” National Institutes of Health (source)

999 “Vegan Sources: is B12 Vegan?” VeganHealth.org retrieved October 9, 2016 (source)

1000 Morris M.S., Selhub J., Jacques P.F. “Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study.” Journal of the American Geriatric Society. 2012 Aug;60(8):1457-64 (source)

1001 Berry N., Sagar R., Tripathi B.M. “Catatonia and other psychiatric symptoms with vitamin B12 deficiency”Acta Psychiatrica Scandinavica Volume 108, Issue 2 August 2003 Pages 156–159 (source)

1002 Wuerges J., Garau G., Geremia S., Fedosov S.N., Petersen T.E., Randaccio L. “Structural basis for mammalian vitamin B12 transport by transcobalamin.” Proceedings of the National Acad- emy of Sciences U S A. 2006 Mar 21;103(12):4386-91 (source)

1003 Durand C., Mary S., Brazo P., Dollfus S. article in French “[Psychiatric manifestations of vitamin B12 deficiency: a case report]. L’ Encephale. 2003 Nov-Dec;29(6):560-5. (source)

1004 Sharma V., Biswas D. “Cobalamin deficiency presenting as obsessive compulsive disorder: case report.” General Hospital Psychiatry. 2012 Sep-Oct;34(5):578.e7-8. (source)

1005 Wang H.X. et. Al “Vitamin B12 and folate in relation to the development of Alzheimer’s disease” Neurology May 8, 2001 vol. 56 no. 9 1188-1194 (source)

1006 Coppen A., Bolander-Gouaille C. “Treatment of depression: time to consider folic acid and vitamin B12.” Journal of Psychopharmacology. 2005 Jan;19(1):59-65. (source)

1007 Butler C., et. Al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials” Family Practice (2006) 23 (3): 279-285. (source)

1008 Butler C., et. Al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 560 HEAD FIRST deficiency: a systematic review of randomized controlled trials” Family Practice (2006) 23 (3): 279-285. (source)

1009 Yeh F.C., Vettel J.M., Poczos B., Grafton S.T., Erickson K.I., Tseng W.I., Verstynen T.D. “Quantifying Differences and Similarities in Whole-Brain White Matter Architecture Using Local Connectome Fingerprints” PLOS Computational Biology November 15, 2016 (source)

1010 “Get the Stats on Traumatic Brain Injury in the United States” U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES – Centers for Disease Control and Prevention (source)

1011 “Attention deficit hyperactivity disorder” Medline Plus U.S. National Library of Medicine (source)

1012 Mayo Clinic Staff “Hypothyrodism” Mayo Clinic mayoclinic.org (source)

1013 “Cognition” Frontiers in Psychology journal.frontiersin.org (source)

1014 Cowan N. “What are the differences between long-term, short-term, and working memory?” Progress in Brain Research 2008; 169: 323–338. (source)

1015 “Anxiety Disorders” National Institute of Health nimh.nih.gov (source)

1016 “Depression” National Institute of Health nimh.nih.gov (source)

1017 “Get the Stats on Traumatic Brain Injury in the United States” U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES – Centers for Disease Control and Prevention (source)

1018 Yawmire J.C. “Chapter 11: Acetylcholine Neurotransmission” The University of Texas Health Sciences Center of Houston neuroscience.uth.tmc.edu Retrieved March 3, 2016 (source)

1019 Samson R.D, Barnes C.A. “Impact of aging brain circuits on cognition.” The European Journal of Neuroscience 2013 Jun;37(12):1903-15. (source)

1020 Attention Deficit Disorder add-adhd.org Retrieved on March 3, 2016. (source)

1021 Liou S. “Brain-derived neurotrophic factor (BDNF)” Stanford University 26 June, 2010 Retrieved March 3, 2016 (source)

1022 “What is the function of the various brainwaves?” Scientific American 22 December, 1997 (source)

1023 Meffor I.N. “Epinephrine in mammalian brain.” Progress in Neuro-psychopharmacology & Biological Psychiatry. 1988;12(4):365-88. (source)

1024 Passani M.B., Panula P., Lin J.S. “Histamine in the brain” Frontiers in Systems Neuroscience 2014; 8: 64. (source)

1025 “Synapse – The Brain” McGill University Retrieved on March 4, 2016 (source)

1026 Giurgea C. “Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology” Actualités Pharmacologiques (Paris). 1972;25:115-56.

1027 “Norepinephrine” Rice University Retrieved March 4, 2016 (source)

561