1 PREFACE

Using medicine to enhance human performance is an art and discipline that has been dominated by two schools of thought; doctors trained to treat disease, and self-styled “gurus” who have very little training in human physiology and pharmacology, if any. Both camps are trying to meet a common demand in the athletic community, “help me get stronger.” While nobody can hold a candle to their work ethic and scholarship, the medical community tends to be too conservative in their approach with the rallying cry of “primere non nocere,” (first do no harm,) cutting them off from providing the best possible results to athletes.

PEDs - Performance The second group is found in the Enhacing Drugs Drugs that help the human body shady corners of the supplement meet or even exceed it’s industry and internet and is echoed in natural athletic potential. gyms all over the world. “Bro science” carelessly spreads a mix of accurate information and dangerous misinformation without any real attempts at academic rigor or due regard for the potential for harm. It is this community that has shaped our collective knowledge of supplements and PEDs.

2 Clearly another approach is needed, and AUGMENTED attempts to bridge that gap by providing quality, rigorously derived information on athletic enhancement without the unnecessary safeguards that are needed to treat sick people.

There is a new academic discipline that is well- suited to the task of applying the tools of medicine to optimize athletic performance called “bioengineering.” Typically bioengineers are tasked with developing powerful new medical techniques for doctors to use in treating disease. But that’s not their only function. Just like an automotive engineer can design both a box truck and a sports car, bioengineers can help treat disease or make a human stronger.

I am a bioengineer. After a roughly ten year career consisting of two terms of service in the Army and a brief stint in law enforcement, I decided to pursue a Master’s in Pharmaceutical Bioengineering at the University of Washington. Afterwards I struggled to find a fulfilling role as a pharmacologist - the snail’s pace of producing scientific evidence while complying with both corporate and FDA regulations

3 proved entirely too frustrating. I had always been the person my military and police colleagues came to for advice on supplementation or staying in shape in spite of a medical condition, and I realized I now had the education needed to create a powerful system for getting in shape.

Life building a family while working full time had taken a toll on my fitness and I wanted a path back to how I looked and felt in my “glory days” as a military officer and street cop. Taking what I already knew, I started reading scientific journal articles and cobbled together a system which I believed could get an out of shape person to automatically build muscle and burn fat with minimal diet and exercise.

Of course, my first test subject had to be myself. Over a period of roughly 18 months I did manage to reduce my body fat by roughly 15% and replace the weight with muscle making no conscientious effort to eat clean. Exercise was occasional at best. Yet it was effective. People began to notice my weight was dropping. I continually had to buy new pants and ultimately had to drill holes in my belt so it would fit properly, until my wife made me buy a new one. People who saw me only sporadically would

4 involuntarily look me over when I walked in the room, surprised at how I had changed in so little time. Those who had been eager to dismiss me when I had been out of shape and in clear poor health started subconsciously paying me more courtesy in our interactions. The contrast was stunning.

One Halloween, watching my little kid trick or treating in the kind of neighborhood I would like to live in, I made the decision to create protocols around the system I had honed and start a business based on them so others could experience what I have. This book is the touchstone for that system and the beginnings of the business I intend to build.

The most challenging aspect of writing this book isn’t the science; that comes very naturally to me. I am a gifted bioengineer and love my field of study. What’s been difficult is communicating complicated biology in a way that’s easy to understand. I’ll admit I haven’t been entirely successful in this regard, which is why I launched an educational website; humanfrontiers.com as well as a facebook group of the same name to help my readers and clients engage with me and each other directly.

5 Some housekeeping notes - it is extremely hard to understand a concept or learn something when you don’t know what the words mean. Italicized: My way of letting When new words or concepts are you know an important concept has been introduced. introduced, they are italicized and Look for a text box for further explained further in a text box. explanation when you see this.

I also haven’t added citations. It’s not that I’m making things up, I’m writing for a novice audience and the busyness of official citations can be cognitively overwhelming. If you want to validate or refute my claims, google or better yet NCBI searches are your friend. My readers are always welcome to challenge or update me. Please, literally I welcome it.

This book is a labor of love and I truly hope you find what you need to achieve the health and fitness level of your dreams. There’s a LOT of information out there, and I hope the knowledge you gain from this book helps you tell the difference between valid claims and what is frankly, bullshit. And if you need help, you know where to find me

6 INTRODUCTION

Biology and chemistry are powerful and complicated sciences. The ability to understand how you work at a chemical level, and knowing how to chemically alter the structure and function of your body to do what you want it takes years of study. The field is constantly expanding making continuing education a must. Biochemistry has a language nearly all its own. While this allows scientists to communicate with one another clearly and concisely, these terms also have the unintended effect of making it difficult for outsiders to do their own research.

Alongside this elegant, complicated science a $40 billion dollar supplement industry has sprung up and with it, a marketing machine that relies heavily on the language of biochemistry for scientific credibility. Sadly, many of the claims made by the supplement industry are misleading if not laughably false. This has resulted in an entire generation of athletes and coaches that have been educated almost entirely by marketing campaigns. Everyone from elite athletes to gym novices have heard locker room conversations that sound like a graduate seminar on

7 what supplements, pharmaceuticals, nutritional strategies, etc. get the best results. Hair splitting, navel gazing speculation over which creatine salt is the most effective or EAAs vs. bovine protein without truly understanding the biological relevance.

Due to some deceptive advertising that presents itself as cutting-edge science, many people have purchased expensive products or committed themselves to programs that ultimately produce poor results. This has harmed the reputation of the industry which is a damn shame. If people seeking to improve their fitness had access to accurate, accessible, and practical information they could use that knowledge to get fantastic results. As an added benefit, it would be very difficult for unscrupulous companies to benefit from misleading marketing.

This book attempts to begin addressing this problem. You will notice something right away; this book doesn’t begin by discussing particular chemicals and how they benefit you. Instead, it tells you exactly how YOUR body grows stronger, then discusses multiple, effective ways to manipulate these biochemical systems in efficient, effective, and usually inexpensive ways to get the exact results

8 you want. We are taking three decades of blended marketing and science that have morphed into common gym lore and throwing it all away. We are replacing it with authentic, cutting edge science from a ‘first principles’ standpoint. We are discarding all old assumptions, ignoring what others have done in the past, examining the best information we have available and creating a new and better way of understanding how to nudge our bodies into getting even stronger than what diet and exercise alone can provide.

The human body, in fact your body right now where you sit, is an incredible network of biochemical reactions all happening in an orchestrated chain that gives rise to life, consciousness, strength, and ultimately you. It is so complicated that tens of thousands of the brightest minds in the world are working in concert to reverse engineer and decipher how it functions at a molecular level. There is so much still unknown, and so much effort being put into discovery, that new advances are made every day and the scientific community is still decades away from a complete picture.

9 That said, science has learned things - important things. We now have a portfolio of work complete enough where we can begin to 'connect the dots' and see how biochemical effects form a living being as the body goes about its daily business. This better understanding of how our biochemistry works allows us to understand disease with higher resolution, making it easier to cure. We have cloned entire animals, conceived babies in test tubes, created crops that are resistant to disease and famine, harnessed genes from organisms in the most extreme habitats on Earth, and even created technology that could feasibly reverse death in limited circumstances.

During this process of discovery and learning, we have also found out a great deal about how the human body tells itself to grow stronger. The key components of physical fitness have been well characterized. But they have not yet been linked together into a fully featured map. This is unfortunate, as your body’s chemistry is Network Effects: A dependent upon what we call network biological process with multiple factors working effects, multiple pathways acting in together to produce a given effect. For example, concert towards a single result. The nutrition, testosterone, and exercise all work together human body’s biochemistry is very to produce muscle growth.

10 similar to how a computer network works; there is input that gets recognized at certain points, which is codified into packets in a computer network or hormones in an organism, that are then distributed throughout the system where other nodes, be they printers, computers, glands, muscles, etc. produce an output. Viewing our own biochemistry through this lens allows us to become hackers of our own network, coaxing our bodies to execute whatever functions we want in ways the original designer never intended.

So how is this hacking accomplished? First by understanding how the system works, and then manipulating it. The primary goal in writing this book is to teach athletes, coaches, and clinicians how to coordinate your nutrition, your workouts, your rest, and even medical drugs to enhance both your health and your athletic abilities. It applies the science of pharmacology to athletic performance, taking a great deal of the guesswork out PEDs/Performance Enhancing Drugs: of supplementation and the legitimate Drugs which increase athletic performance, medical use of performance enhancing also know as ergogenic drugs (PEDs). This book is going to drugs or ergogens. teach you how to 'hack the network' of your biology to produce optimal body composition

11 with minimal effort and expense. You will learn to amplify the signals you want, and silence the ones you want blocked. The result will be greater strength, endurance, resilience, and wellness.

Yes, we will absolutely be discussing the safe use of ‘steroids.’ This book will challenge the ‘bro science’ that is comprised of rumors, anecdotes, bad assumptions and the persistent dumb ideas surrounding steroids and supplements created by 1980’s ‘gurus’. We will also be confronting the histrionics surrounding PEDs that has become doctrine within both the medical and sporting communities. The narrow interests of “spirit of sport” should not deny everyone access to quality of life enhancing drugs.

A secondary goal is to enhance a rational conversation about the potential benefits of PEDs. It is a conversation that is already well underway, and it is not uncommon to find laymen with a surprising understanding of the use of fairly advanced PEDs. On the other hand, this class of drug has been tainted by decades of confusion, propaganda, and misuse. They are powerful and prone to abuse for sure, and in fact have been a factor in tragedies.

12 That tragedy extends from reckless, medically unsupervised misuse. This demonizing lens is the only one society as a whole currently has to view PEDs, and this book will hopefully be the beginning of average people understanding both the benefits and hazards 'steroids' in a more accurate light.

The use of a few, select, very powerful and well characterized nutritional supplements with known mechanisms of action are also discussed in this book. Anything recommended here is first off, agnostic of any brand. They are pure, abundant substances that are fairly inexpensive and can be purchased in bulk. The biological effects they have are almost as well characterized as medical drugs, and they provide immediate, tangible benefits.

You will begin by learning some of the fundamentals of how your body works and gets strong at a biochemical level. This is to help you understand the 'whys' behind the protocols in the book, and will include an executive overview on the practice of medicine and pharmacology to equip you with a mental model of how your body’s chemistry works and methods scientists have developed to 'hack' it.

13 We will then devote several chapters to the key biochemical pathways your body uses to get strong. These were chosen because they’re both effective and easy to manipulate if you understand how they work and what they do.

Several chapters discusses the biology of androgens, and another goes over the basic chemistry of medically available performance enhancing drugs. Rather than producing an exhaustive list, you will only find drugs which are readily available, safe, and well-characterized.

After you’ve built a solid level of knowledge on how these drugs work, we discuss self-monitoring, assays, and how to keep yourself healthy while you enhance your athletic abilities. The following chapter touches on program design.

Ethics are discussed at the end. Not because they’re the least important, but because the brain best remembers the last thing in a series it learned. In some respects the information in this book is dangerous, and to safely and effectively apply the principles detailed here you will need a 'code' to work by.

14 Overall, there are six biochemical systems we are going to focus on that build muscle, burn fat, make you more resistant to injury, and sharpen your thinking. For brevity’s sake we’ll be calling these the six pathways, and there’s a chapter dedicated to describing and teaching you to manipulate each one.

15 CHAPTER 1 - BIOCHEMISTRY

This chapter is going to teach you the basic biology you’ll need to know to understand the theories and protocols in this book. We will also discuss some advanced concepts that are related to the AUGMENTED approach to human enhancement. If you’re already familiar with biology, the author freely admits upfront that what is presented here is incomplete. Biology is an elegant, jingoistic science and always has been. This gets in the way of presenting actionable information. Even in simplified form, the vocabulary used here is likely to confuse you. You are highly encouraged to use the AUGMENTED online community at humanfrontiers.com, which is always available to clarify things.

In modern medicine, the body has traditionally been viewed as a set isolated systems, organs, and chemical functions. This is evident in the way that scholars and physicians define themselves by specialty (for example, cardiology, psychiatry, immunologist, etc.) While this model makes the

16 human body easier to understand, it isn’t representative of how the body actually works. All your cells, tissues, organs, and even some bacteria, are in a constant state of chemical communication and mutual regulation. A massive amount of work in the form of chemical signaling goes into keeping your body in a stable state called “homeostasis” which literally means “staying the same” in latin. Hundreds of thousands of chain reactions are constantly chugging along to keep your body functioning. Understanding how they work, and knowing how to manipulate them to a particular end is the keystone of functional biochemistry, and doing so to make yourself stronger is the focus of this book.

The tools we use to manipulate our own Drugs: Any substance which biochemistry are called ‘drugs.’ Lay culture alters the structure or function of the sees this term as being two things; body. substances which treat disease, or substances used to wack out your brain functioning for recreational purposes. AUGMENTED takes a third approach, using substances to enhance your health rather than repair it. We are not diagnosing or treating an illness. The difference is like a mechanic that fixes broken cars versus one that

17 tunes them to make them faster and more agile. Both kinds of mechanics use the same tools for different purposes.

But what exactly do drugs do? To put it simply, drugs imitate natural biochemicals your body makes to regulate itself, and either power up or block your biochemical functions. Since they’re coming from outside the body, a decent drug also needs a convenient way to enter the bloodstream and also needs to last long enough to have a significant effect, but not so long that the effects are irreversible. Of course there will be more information on this later on, but before the advanced information will make sense there are a few basics that need to be covered.

Biochemicals fall into a few broad categories. We’re going to describe the most common ones and how they work. Understanding this will give you the framework you need to understand how drugs ‘hack’ them. We’ll start with the most basic biochemicals then describe increasingly complex ones, giving you a solid top-down understanding of how the chemistry of your body works.

18 DNA/RNA

DNA is a compact chemical code, not Polymer: A molecule which is a chain of a unlike a computer program, where a cell particular type of smaller molecules. For example; stores information on how to make DNA is a polymer of nucleotides. Proteins are a proteins. DNA is made from four polymer of amino acids. different chemicals called 'nucleotides' strung into a long chain tens of thousands of nucleotides long. The nucleotides are called adenine, guanine, thymine, and cytosine. DNA is a polymer of nucleotides, think of it as a chain. Each nucleotide is a link in the chain

You DNA also has markers that indicate the start and stopping point of a gene, akin to chapters in a book. DNA is permanent, and while it can be 'locked' and 'unlocked,' it usually can’t rewrite itself. DNA is transcribed into RNA so the cell can express the protein it encodes. Instead of directly building proteins itself, DNA creates a smaller, temporary copy of itself called RNA which goes to the part of the cells that builds proteins. The protein builders live right outside the nucleus of the cell and are a sort of biochemical foundry where proteins are forged, with instructions provided as RNA. After the

19 protein is built, RNA breaks down. When DNA is used to create a protein, we call it 'gene expression.'

While we can’t change the content of your DNA, we can keep your cells from 'locking' it by using certain drugs and nutrients. The code of your DNA is unchangeable. But how often it is expressed is undergoing constant change, and we will learn how to hack it in a way that is favorable epigenetics: Changes in to your fitness goals. Changing the type and frequency a gene is expressed, usually which genes are expressed is in response to the person’s called epigenetics, and when environment and nutrition. applied properly it is a powerful biological tool.

THE CENTRAL DOGMA

Before we delve further into advanced biochemistry, you’ll need to understand ‘The Central Dogma.’ This is the how DNA is 'read' by a cell when it is instructed to do its job. The explanation will be left as simple as possible to make it easy to understand.

When a cell is commanded by a biochemical pathway to do something, the cell unpacks a particular string of DNA and makes a chemical

20 mirror-image of it, called RNA. DNA is confined to the nucleus of a cell, but RNA can be chaperoned to the 'factory' of a cell (the super technical term is endoplasmic reticulum or ER,) where it is used to code a string of amino acids into proteins.

It is best to think about it like this. DNA is an architectural library with instructions for building millions of proteins. RNA is a copy of these instructions that are brought to a factory where the protein is built.

PROTEINS/PEPTIDES

Though a widely used word, for our Protein: A large purposes ‘protein’ is not what comes in a molecule made from a string of amino acids jar. When scientists talk about proteins that has a biological they mean a huge molecule that works like function. a tiny machine. Proteins are molecular chains made up of 21 different amino acids, all of which have different chemical properties, all of which can form a structure that performs a useful task, just like a machine. These machines fall into three broad categories; receptors, cytokines, and enzymes. You will learn how and why all three work.

21 A helpful model for understanding how proteins are built and how they interact are the alphabet. Each individual amino acid is like a letter. When amino acids are strung together, they form a protein much like a series of letters forms a word. When words interact with each other, they form a sentence. When proteins interact with each other, they form a biochemical pathway. A series of sentences ultimately forms a book, just like a series of biochemical pathways forms an organism.

Visually, proteins can be expressed in two ways. Smaller proteins are much more sensitive to changes in amino acid sequence (called 'mutations') and are expressed very precisely, as a series of abbreviations. Oxytocin, the 'love hormone' looks like this: is

So, the above is a shorthand for cysteine - tyrosine - isoleucine - glutamine - asparagine - cysteine - proline - leucine - glycine. The two cysteine

22 molecules in the chain are connected by two atoms of sulfur (the S—S in the diagram) to form a disulfide bond. Disulfide bonds are a very common way to attach two very large protein strings together. Oxytocin itself is very small, a 9-mer or nine amino acids strung together.

Larger amino acids would take an entire page to write out this way. They are also far less sensitive to changes in their sequence and are expressed using a ribbon model instead - they literally just draw a picture of it. At right is mTOR complex-1, and it is just a single part of a larger cluster of proteins that act together to measure how many calories you’ve consumed. (mTOR is a very important growth and gene regulation factor that is central to the AUGMENTED system. We will be discussing and learning how to manipulate mTOR in a later chapter.) At this point, you should just understand that proteins can be very large or small, the small ones tend to act as signals and the larger ones can take on machine like functions on a molecular scale.

23 Technically, 'protein' is a blanket term that applies to anything, literally anything, made from a chain of amino acids. For example; sophisticated biological medicines are proteins. So are the contents of your nutritional shake. So is a steak. Also, molecules inside your cells with biochemical functions are proteins. For the sake of this book, a 'protein' means the latter; a large molecule with one of three functions - a factory, a signal, or a switch. Some help create other molecules, others act as a signal between cells, and finally some of them are there to detect a specific type of molecule for a cell. While the term protein applies to any molecule made from a chain of linked amino acids, this book will only address the three major classes of proteins for the sake of clarity. The major classes of biologically active proteins are called enzymes (which create other molecules,) receptors (which detect specific molecules,) and cytokines (which act as a signal between cells,) and respectively.

Enzymes convert one specific type of molecule Enzyme: A protein that into another. You can usually tell a protein is an chemically rearranges enzyme because it ends with the letters 'ase'. another For example, testosterone is converted into molecule. estrogen by an enzyme called aromatase. They

24 behave like tiny chemical factories. Active Site: The part of a protein that attaches to Aromatase has a specific chamber another chemical. The ability to attach or ‘dock’ that fits testosterone perfectly. This depends on the size and shape of the molecule and chamber is called the active site. electromagnetic ‘fit’ too. When testosterone enters the active site of aromatase, it gets converted into estrogen and is spat back out into the bloodstream.

The molecule that interacts with an enzyme to undergo conversion is called a substrate. The molecule the enzyme produces is called the product. In the example above, testosterone is the substrate for aromatase, and estrogen is the product.

Receptors: function as receivers of chemical messages. When they come in contact with a specific molecule, they direct the cell to Receptor: A protein that perform a task by activating DNA. reacts to a specific chemical signal by Receptors are like enzymes in that they sending a message to the DNA of a cell. too have an active site. But when a Ligand: A molecule, receptor comes in contact with the large or small, natural or synthetic, that docks to associated molecule, it relays a an active site, and ether activates it or blocks it. message to the DNA in the nucleus of the cell, which expresses one or several genes as a result. For example, testosterone activates a receptor in a hair follicle cell. The

25 receptor then tells the cell to express Cytokine: A protein that acts as a signal between genes that causes hair to grow. The cells. A cytokine is a kind of ligand. Cytokines more cells that are effected by travel through the bloodstream, drifting testosterone, the faster the hair grows. around until they meet their intended receptor on the surface of another cell, kind of like a message in a Molecules that activate receptors are bottle. called ligands. Ligands can be other proteins like insulin, or small molecules such as testosterone or adrenaline.

Cytokines are protein ligands which deliver a very specific message to a specific tissue with specific effects. They are proteins that act like hormones, traveling from organ to organ through the bloodstream. When used as drugs, they can be incredibly powerful. Unfortunately, they’re also expensive to produce, chemically fragile, and with rare exceptions can’t be taken orally. Large molecule drugs must be injected. As an example, FSH (follicle stimulating hormone,) is secreted by the pituitary gland to activate the secretion of sex hormones from the gonads. Another example would be insulin, which is released in response to digestion and directs the tissues that receive it to start taking in sugar.

26 CELLS

Like anyone who’s taken junior high biology can tell you, your body is made up of cells. These cells are capable of living on their own and specialize into unique types that form a tissue, which forms an organ, which makes up you. Each individual cell has a complete copy of your DNA, which is contained in the nucleus of the cell. Each different type of cell expresses different genes from your DNA. Much of this book contains precise instructions on how to coax your cells into expressing certain genes.

Organisms are a community of cells that have the exact same DNA, and work together as a tightly coordinated team to produce a functional, and hopefully healthy, human being. A team that has such high demands placed upon them has to have a foolproof and precise way for members to communicate, and the tool they use to talk to one another is what we call cell signaling. You are going to learn how to speak directly to your cells.

27 So where do hormones come from? Gland: A small organ Usually from tissue called glands. Glands who’s primary purpose is to secrete hormones are small organs that are switched on by into the bloodstream. certain conditions, and release hormones into the bloodstream in response. Your testicles are glands. So is your hypothalamus. Your pancreas is a huge gland. The master gland, the pituitary, is the smallest. Sometimes tissues have a secondary function as a gland. This is true of your bones, and also fat tissue. Glands are the tools your body uses to send messages between different organs and tissues, allowing them to work together.

SMALL MOLECULES

Before we move on, there’s one more type of molecule that needs to be discussed. Small molecules are also very important in a biochemical pathway. Not all biologically active chemicals are proteins or nucleotides (or carbohydrates or fats.) Small, organic molecules, not made of something chained together, can have biological effects as well. They are a fraction of the size of proteins and can only function as ligands or substrates. Small molecules usually do their work inside the cell and tend to direct the behavior of multiple types of cells

28 at once. Biologically, they fall into two categories: hormones and neurotransmitters.

Chemicals similar to small molecules are usually what you’ll find in drugs that are taken orally. They’re not fragile, fairly inexpensive to manufacture in large quantities, and are very easy to take. Because they interact with so many different kinds of cells, side effects are common. Developing medicines based off small molecules takes years of a guess-and-check process that makes finding drugs that are effective, marketable, and profitable extremely challenging.

Biologically, large and small Pathway: A connected series molecules interact in a chain of chemical reactions your body uses to communicate reaction called a pathway. A with itself that results in a specific output (such as pathway is a multi-step process muscle hypertrophy.) Drugs work by either amplifying or that is similar to the input/output blocking biochemical processes used by computers. pathways. Understanding each step in a biochemical pathway will help you manipulate it to get your desired results. Your body has untold thousands of biochemical pathways, some of which are not very well understood by biochemists. There are, however, a particular few that are of immense

29 interest to athletes; ones that are very well understood and easy to manipulate in multiple ways. You will be learning about these in depth, as well as scientifically validated, effective ways to put them to good use. But, before you can do that there are a few principles you will need to understand first.

THE HPG AXIS AS A MODEL

To help you better understand how biochemical pathways actually work, and because it’s very relevant to the scope of this book, the 'HPG axis' (hypothalamus - pituitary - gonadal) will be used as a teaching model. We will be discussing the production of sex hormones in a male, as it has fewer steps than in females and is easier to understand. Starting from the brain and winding through all the pathways in between, you will understand how testosterone produces everything it does, from bigger muscles, heavy brows, zits, libido, mood elevation, and thicker blood. Any biochemical that causes these changes is called an androgen. The body produces two androgens, testosterone and DHT.

30 3AM on a summer night. You’re lying sound asleep in your bed. The regulating system of your body, a little nubbin near where your brain meets your spinal cord called the 'hypothalamus', takes note of the time and decides you need to release some sex hormones while you sleep. It secrets a tiny amount of a cytokine protein called 'Gonadotropin Releasing Hormone' (GnRH) which travels several millimeters to the master gland of your body, the pituitary gland.

The pituitary gland receives this message and looks in the library of your DNA for instructions on how to make the proteins Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). Up to this point, everything that has occurred has happened entirely inside the brain. But the pituitary gland is special; it is capable of mass-producing hormones, unlike the hypothalamus. It is able to generate so much LH and FSH that it’s noticeable in your bloodstream. Your veins ferry it around your circulatory system and it’s presented to every single cell in your body. All of them ignore the rise in LH and FSH - all except a select few.

31 The few that do take notice of it are located in your gonads, the testicles and ovaries. When the gonads recognize LH and FSH, they too consult the library of your DNA and stitch a specific sequence of amino acids together into an enzyme that could be called a microscopic testosterone factory. The testes produce millions of these tiny proteins. They take a small molecule chemical called DHEA that exists in high concentration in your body and convert it to the sex hormone we all know and love, testosterone. For simplicity’s sake, we’re going to call the enzyme testosterone-ase (the technical term for this enzyme is 17-beta hydroxysteroid dehydrogenase which is not at all easy to remember.)

It is now 3:30 AM. Your testosterone levels are as high as they’re going to be today. The testosterone in your blood starts seeping into the interior of your cells. Once inside each individual molecule of testosterone coursing through your body has several fates it can meet.

It may find a testosterone receptor in any given cell it encounters. Unlike a cytokine or an enzyme, a receptor is a protein machine that detects the presence of a very specific chemical. Testosterone fits very snugly in it’s receptor, and once the receptor is activated by testosterone it commands

32 the cell to do it’s 'testosterone job.' Maybe it’s a skin cell that starts secreting oil on your face and back. Maybe it’s a hair follicle that causes body hair to grow faster. It could be a muscle cell, that responds by adding muscle mass or adding another set of DNA to it’s core.

It could find another enzyme that chemically converts testosterone into a more powerful androgen called 'DHT'. In addition to adding muscle mass, DHT also makes you hairy everywhere but on your head. Male pattern baldness is partially named for this hormone, androgenic alopecia.

Finally, testosterone could also find yet another enzyme. Some enzymes chemically convert testosterone into estrogen. This enzyme, which you’ve already been introduced to, is called aromatase and is especially present in fat cells. The estrogen generated from testosterone goes back into your bloodstream and starts commanding the cells in your body to start doing their estrogen jobs which are just as varied and important as the jobs mandated by testosterone, even for a man.

Ultimately, your hypothalamus realizes that your estrogen levels are steadily rising, and it shuts down production of GnRH, which shuts down LH.

33 Without LH, testosterone production dwindles and ceases.

It is now 5AM, dew settles on the grass outside and you slowly fall into waking consciousness. Adrenaline surging through your body opens your eyes. You lay in bed as the mental fog lifts. The testosterone surge of the last two hours has impacted your libido. You look over at your sweet wife, still sleeping and try to nudge her awake. She answers with a grunt and a sharp elbow to your shoulder. You smile to yourself, roll out of bed and head to the shower to start your day.

All the above described a single biochemical pathway, the HPG axis. It involved every class of protein described above, as well as small molecules. They worked together to keep your hormones both powerful and balanced, resulting in a strong, healthy you. Your body has tens of thousands of such pathways running all at once, and there is a good amount of cross-talk going on between them. There is so much going on that it can’t all be observed at once, yet when they are isolated they no longer work as well as they do in their physiological environment.

34 We are truly emergent, miraculous beings. So much so that understanding our bodies as the sum of individual parts rarely produces an accurate model of how the body works. There can be no tradeoff between accuracy and breadth, the scientific approach needs to be both inclusive and precise. Fortunately, such a system of reasoning is gaining traction, and it is what we will be using moving forward to describe the AUGMENTED system. It is called systems biology, and it is powerful.

35 SYSTEMS BIOLOGY

'The purpose is to confuse and lead into error all but those whom God loves and provides for.' ~ Jabir ibn Hayyan

The human metabolome is several hundred million electrochemical computers working together and giving rise to an ultra complex being. The gap between the body’s ability to function and our ability to understand it is called a miracle by some, or 'emergence' by others. Simply put, emergence means that a system is often more than the sum of its’ parts. Harmonious interaction between complex parts allows each individual piece to work more efficiently. Nowhere is this more true than in biology. Different types of cells work together to form tissues, which in turn work together to form an organism, which work in communities to form a thriving, robust ecosystem.

Reductionism: Breaking a phenomenon down into Scientific research, since Descartes in individual parts and describing them the 1600s up until about the year 2000, individually. This helps build models that can be was focused on reductionism; breaking manipulated mathematically to help down a system into individual parts and predict behaviors.

36 then describing the parts. This kind of scientific thought works very well right up until a civilization creates microchips, at which point reductionism begins to create inefficiencies and lend credence to inaccuracies.

Nowhere is this more apparent than with biology. Biology has very few hard and fast rules that can be universally applied. Using reductionist methods to learn the intricacies of how organisms function is more often than not ineffective. This linear, zero sum method of thinking does not adequately describe the long term outputs the body has to certain stimuli. For example; untold millions were spent by the governments of the world advising to their populations to consume primarily grain based carbohydrates as part of a healthy diet, and only recently has it come to light that this is actually the best way to promote obesity and cardiac disease. Now snake oil salesmen and charlatans are picking through the ruins of this body of information and entire generations of Americans have no idea what to believe.

Enter systems biology. There is a 'new scientific method' coming into play that is made possible by

37 our newfound computational powers. Different systems are linked together and massive amounts of data about their interactions are collected, analyzed, and simplified by computers. At Synergism: Attempting to right, we can see the output of understand how individual components work together several years of the application of using powerful data analytics not available to this new scientific method, called classical scientists. systems biology or synergism.

Systems biology is not confined to a single scientific discipline. Aspects of chemistry, physics, computer science, pharmacology and of course biology come together in a collaborative approach to solving problems, curing disease, and predicting the behavior of ultra-complex networks, networks like the biochemical systems that give rise and life to you. It seeks to understand living things at all their levels and depths, and the models it produces are often multi-scale. We understand how cells relate to tissues, organ systems and complete organisms.

AUGMENTED applies systems biology by understanding which human biochemical pathways result in growth and encouraging them to work together to produce a stronger and healthier you. We view the human body as a network, and the

38 programs we design are polyfaceted and as precise as possible. We also understand that each desired end state, be it increased strength, endurance, explosiveness, or body fat reduction, has multiple inputs.

You will learn how to coordinate your exercise, rest, nutrition, supplementation, and doping strategies to target the strongest factors which encourage your body to realize the full potential of your DNA. Like a bodybuilder understands what lifts produce gains in particular muscle groups, you will know which pathways to focus on to coax your body into being as strong as it can be.

39 MUSCLE AND CONNECTIVE TISSUES…

'In every chain of reasoning, the evidence of the last conclusion can be no greater than that of the weakest link of the chain, whatever may be the strength of the rest.'

~Thomas Reid - Essays on the Intellectual Powers of Man

Enhancing the musculoskeletal system is the cornerstone of athletic performance, and nearly all the pathways we will learn to manipulate in this book in some way relate to this system. First and most obviously, this is where your muscles grow. But there are other, equally important things going on as you gain the ability to run faster, jump higher, react quicker, and perceive more readily. The bones themselves grow at the joints, allowing them to distribute impact better and resist breaking. Cartilage grows with it, for the same reason. Nerves extend more deeply into your muscle tissue, allowing your brain to control them with extreme granularity. The motor cortex of your brain has an impressive amount of control over individual muscle strands, and there is strong evidence this control grows exponentially, particularly with what yogis call 'mindful practice.'

40 Maybe the most mind-blowing feat your Myocytes: Cells that comprise muscle tissue. muscle cells, called myocytes, can Myocytes exhibit biochemical behaviors perform biochemically is called that are distinct from most cells. Your multinucleation. Any high school muscles behave in a very unique way which student who’s taken AP biology can we will learn to harness. sagely explain that muscle cells don’t multiply as do most other cells. What Multinucleation: Rather than dividing, muscle cells or they may not know is that myocytes ‘myocytes’ add multiple nuclei so they can produce proteins usually have more than one nucleus more efficiently. Multinucleation is permanent. The efficiency it which allow them to produce proteins creates will make it much easier to retain your muscle at a faster rate. In particular, they mass for the rest of your life. produce the two proteins necessary for human movement, and they produce a LOT of them, very quickly. They also break them down, usually just as quickly, to produce energy when your ATP and blood sugar has run out. When this muscle protein is created and consumed at equal speeds, this is called 'equilibrium' or 'homeostasis.' If you’re not in equilibrium, you’re either gaining muscle or wasting muscle.

Clearly, the more nuclei a muscle cell has, the faster it can replace these proteins and the more muscle mass you’ll carry at your baseline. When building muscle mass and strength, this should be your goal. Raw size itself, based solely off protein

41 accumulation, can be very transient. Mass gained via multinucleation is far more permanent, and unlike protein accumulation alone is not reversible. Ultimately, multi nucleation will allow the athlete to retain more muscle mass without having to work out nearly as much.

Connective tissue is much more than bio-rope that anchors your muscle to bone. Heavily innervated with sensors that detect strain and pressure, they can override your brain’s commands to contract your muscles and cause you to drop a weight. Connective tissue does not heal quickly, and your muscles are quick to step in and sacrifice themselves to protect it. Choosing an exercise regimen that strengthens rather than depletes your connective tissue is a cornerstone of a quality workout. Strength cannot exist without a healthy foundation. Both your skeleton and the joints that give it mobility need to be cared for. Three factors govern how your skeleton contributes to your athletic performance:

1. The first and most important of the three is the quality of your joints. Padded with cartilage and lubricated with synovial fluid, your joints allow for

42 free movement and protect your bones from the jarring impacts that occur when the human body performs at a high level. The protective tissues in your bones have very little blood flow and do not regenerate readily. Without proper care, they will wear down over time resulting in osteoarthritis that will stop your ability to be active dead in it’s tracks.

Joints themselves are damaged in two ways, each making the other worse. They are breakdown of the tissues themselves, and inflammation. Inflammation is caused in response to any injury to the joint, however slight. When the athlete continues to train in spite of the pain, they move in a way that accommodates the pain they feel rather than what is most efficient and safe, which damages the effected joint in new ways. This causes further inflammation and movement patterns which are even more dysfunctional. Though this cycle is eventually abated with rest, it can become so severe that medical intervention is required. While a discussion of rehabilitative kinestheology is beyond the scope of this book, the work of Doctors Grey Cook and Mark Cheng are highly recommended for the reader who would like to know more.

43 The good news is that regular weight training increases the activity of chrondocytes, the cells that are constantly rebuilding your cartilage. This is assuming the weight training regimen you choose is moderate in the impact on your joints. It is very possible to wear down your connective tissues faster than they can be replaced. Just like with weight training, maintaining healthy joints relies on the hormetic effect; brief and intense and BRIEF bouts of breakdown with substantial rest periods for rebuilding. And of course, there are pharmaceuticals that can enhance this rebuilding effect that we will discuss in a later chapter.

2. The second is the density of your bones themselves. Most people see bones as simple calcium sticks that hold your body upright when actually they’re more like sophisticated piezoelectric glands that happen to provide structure to the other organ systems. If you’d like to learn more about how bones function The Body Electric by Dr. Robert Becker is Hematocrit: The concentration of red blood cells versus plasma highly recommended. in your bloodstream. Higher hematocrit allows you to store more oxygen in your blood and allows the athlete to perform Your body regulates bone density longer without fatigue. just like muscle size and hematocrit. Androgen therapy can increase your hematocrit, raising both your aerobic capacity and your risk of a stroke if it gets too high. 44 Higher bone density prevents them from breaking, essential for the longevity of any athlete or peacekeeper, soldiers, first responders, etc. Like all other factors, exercise assists, as does proper nutrition. Interestingly, a small amount of estrogen is needed to keep bone density at optimal levels. Of course, there are also drugs that can enhance bone density and function and they, like all other things are discussed in later chapters.

3. The final factor is wonderfully simple. The length of your bones, along with their thickness is extremely important. Bones are like the scaffolding of a crane, the muscles are like the motors. The stronger and more stable the scaffolding, the more powerful a motor it can accommodate and the more weight it can lift. Your bone structure is a very important factor in your metabolism, (it alters your mass to surface area ratio,) your athletic performance, and greatly informs what sports you’re likely to be good at. Unlike the other two factors, there is no drug that will make you grow taller or shorter (yet.)

45 Just like your nerves, your muscles and your blood density the structure and function of your skeleton is critical to both your health and athletic output. This is especially true when it comes to avoiding debilitating injuries that can degrade your health long term. Fortunately there are both exercise regimens and pharmaceuticals that can assists with the most important bone factors.

STATE OF THE ART VS. LAY SCIENCE

'General ideas are no proof of the strength, but rather the insufficiency of the human intellect…' ~ Alexis de Tocqueville, Democracy in America

Several concepts which have permeated lay science for decades make a great deal of sense at a glance, but are ultimately incorrect and need to be addressed. While they were the best exercise science could do given the tools available to them at the time they were created, our portfolio of scientific knowledge has advanced significantly and with it we have to abandon old ideas to make room for the new, more accurate ones.

Much of the information masquerading as 'science' is either the result of marketing by the supplement

46 industry or based on long refuted, government sponsored studies that continue to be taught in public curriculum. We will in effect be 'paving over' these embedded myths and help ourselves and those we coach better understand how their bodies get stronger so they can make better decisions with their programming.

One particular assumption that has guided much of nutrition science is the notion that providing the body with excess building blocks for a particular function somehow stimulates the pathways that produce growth. While providing the body with adequate building blocks for the tissues it needs to build is certainly important, without some kind of signal to begin building these nutrients become excess and pass through the body.

AUGMENTED does not remove a concept without replacing it with something superior. Nor does the system claim to have a monopoly on the truth. Rather, we are doing exactly what the scientists who came before us did; using the best tools we have available to decipher the most efficient route to health and fitness. Modern day biology is very fortunate to have more precise tools and more

47 accurate assumptions that those who came before us.

'ANABOLIC' This is an extremely broad word which has generally been used as a synonym for 'muscle gains.' Technically, it means assembling a protein (or any macromolecule,) from smaller units such as amino acids. This term is too broad for our purposes. Technically, gaining body fat is an anabolic function. Rather than focusing on a net gain or loss of macromolecules, we will be looking into the outputs of specific biochemical pathways to produce muscle gains of the utmost quality. We will not be promoting random growth for the random sake of arbitrary growth. AUGMENTED targets and measures the outputs of specific biochemical growth signals.

'CALORIE' The amount of heat energy needed to raise one gram of water one degree kelvin, typically obtained through oxidative reduction of a material (or ‘setting it on fire’ in non-chemist speak.) Substances are literally set on fire in a sealed container with a known quantity and temperature of water, and the change in temperature recorded as the substance is completely consumed. It is a

48 random chemical process that in no way reflects how the body very meticulously and specifically processes the very same materials. The painful fact is that nutrition science stands roughly where surgery was in the 18th century - mildly effective but not completely understood. Nutrition science, at its’ state of the art, needs to abandon several old and incorrect foundational assumptions if it is to advance into a proper arm of biology. Rather than focusing on calories, vitamins, and macronutrients and treating your body’s processes like some kind of un-knowable black box, AUGMENTED describes how particular foods interface with biochemical pathways that are important for maintaining maximum performance.

'CATABOLIC' The literal opposite of anabolic. Every time your body expends any energy for any reason, molecules are broken down and energy is released. Working out is catabolic. Losing body fat is catabolic. Standing there and breathing with you mouth open staring at a TV is catabolic, albeit less so than other activities. Life, in general, is catabolic. Like Tyler Durden said, 'Everything is falling apart.'

Catabolism makes us run faster, jump higher, lift

49 more weights. We are not going to encourage anti- catabolic activities. AUGMENTED embraces controlled doses of catabolism, and the hormetic effects it produces to increase strength and health.

'NATURAL' There is a vein of thought in the health and fitness industry which assumes an extract or substance sourced from nature is somehow immediately superior to synthetically derived equivalents. AUGMENTED rejects this particular assumption and instead evaluates a given object based off the data it produces. A brown, rustic packaging does not confer any kind of quality or utility. We also understand that natural extraction is inefficient, resulting in higher prices and a concomitant, though false, perception of higher value and quality.

'HOLISTIC' A philosophical rejection of reductionism. The intuitive knowledge that the value of a given system is more than the apparent sum of its parts. While this approach is in fact correct, 'holism' fails to offer a superior replacement to reductionism and has given too much latitude to ideas lacking any intellectual value or rigor. It is synonymous with dubious medical information

50 found on the internet. AUGMENTED adds a synergism/systems biology approach on top of a foundation of reductionist observations, allowing us to understand how manipulating an individual part or 'node' of a system effects the entire network. We understand reductionist effects in the context of the larger picture, and understand that a single observation may not be universally applicable.

'THERMODYNAMICS' Calories in, calories out. Thermodynamics began life as a way to design steam train engines. A scientific tool originally intended to describe the expansion of metals at varying temperatures, later misapplied to nutrition science and biology. (There was nothing better available at the time.) While calorie control is a certain method to reduce body mass, compliance has proven incredibly difficult and we now have a better understanding of the pathways which result in body fat consumption and muscle growth. Focusing on pathways; mTOR, AD, and AMPK, and P-PARγ is far more effective than the crude application of calories and thermodynamics to athletic output.

51 WHAT IS A 'METABOLISM' ANYWAYS?

Metabolism, simply stated, is the sum of all biochemical functions in your body. The output of your personal systems biology. It consists of three major factors.

1.Your motion. The amount of energy you expend generating kinetic activity. This includes ongoing functions such as respiration, digestion, your heartbeat, and brain function. It is up-regulated via exercise and heavy labor. The output of exercise is essentially gene expression. Exercise scientists call this 'Excessive Post-Exercise Oxygen Consumption' or EPOC. Biochemists know it is better described as an uptick in gene expression, as we are about to discuss. 2.Your gene expression. Depending on your cell signaling, your body will either adopt a state of rapid gene expression, or slow gene expression. Expressing genes is very energy intensive, and the more that are expressed the less energy will be available for far storage. The most potent signal to up-regulate gene expression is mTOR, discussed in a previous chapter. When people

52 talk about a 'slow' or 'fast' metabolism, it is best interpreted as gene expression. You already know that metabolism isn’t a gene itself, but gene expression. And it is regulated by your biochemical environment. 3.Your body heat. The chemical functions in your body are optimized at 98.6 degrees F, and your cells, especially your brown adipocytes, will go to great pains to keep you there. One of the key factors in maintaining body heat isn’t biochemical, but anatomical. Your ration of surface area to overall mass makes maintaining this critical 98.6F temperature either very easy or very difficult. Paradoxically, obese people retain their body heat far easier than people with low bodyfat percentages, making both obesity and low body fat self-perpetuating states. Simply put, thin people tend to stay that way, (and be cold all the time,) because they readily radiate their body heat while those with high body fat are well-insulated making maintaining their body temperature less calorically expensive.

A given unit of energy, called a 'calorie,' can undergo four fates in a human body. It can be converted into motion, stored as fat, made into organ tissue via

53 gene expression, or converted into heat. When it comes to controlling body composition, our job is to create an environment that is disfavorable to fat storage, and favorable to using fat as a fuel.

Rather than relying on thermodynamics, a systems biology approach would be to first encourage your metabolome to adopt a posture which not only disfavors fat storage, but actually encourages body fat’s use as a fuel source. Caloric restriction can be a useful component for this, but only after the metabolism has been otherwise altered to disfavor fat storage. Premature introduction of caloric restriction results consumption of organ and muscle tissue and can actually encourage fat storage by silencing mTOR on a cellular level.

54 CHAPTER 2 - PHARMACOLOGY

'All is poison and nothing is without poison. Only the dose separates a toxin from a medicine.'

~ Paracelsus, Septem Defensiones

In this chapter, we are going to explore some key aspects of pharmacology. Understanding how a drug effects the body is easy - it says what it does on the box. Understanding how the body effects a drug is much more complicated - and absolutely critical for choosing a precise dose. This chapter is going to be the most difficult, and of course the most important, to understand. You will notice a lot of pictures and graphs. The language used to describe pharmacokinetics/pharmacodynamics (PKDM) is needlessly complicated, but by using illustrations to back up the written descriptions things will be much more clear.

Drugs alter the body, and the body alters drugs. Understanding where, and when and how this happens is extremely important. It's not just the amount of drug that's administered that's important.

55 How long does the drug linger in the bloodstream? For that matter, how long does it linger in the target tissue? What kind of dosing regimen is needed to maintain the delicate balance between an effective dose and an overdose? We're going to be using medicine for what could gently be called 'off label' purposes, and that makes precision very important.

TIMING DOSES

Getting the timing of a course of therapy correct is just as important as selecting the correct drug at the correct dose. The author's great-grandfather, Dr. Hugo Cimino, was a young physician in Africa in the early 1900's when his wife contracted malaria. The microbe that causes malaria bursts out of blood cells at regular intervals and causes the patient to have horrible seizures. As malaria consumes blood cells, the patient slowly develops anemia and weakens until a seizure kills them.

The drug quinine had long been the standard of care for treating this deadly disease. But it never worked predictably. It breaks down in the body incredibly quickly, and unless the malaria microbe was exposed in the open blood it was ineffective.

56 Doctors at the time would flail to administer a dose that was high enough to treat the disease, but no so high as to cause an overdose. People died by the thousands while doctors and nurses watched, nearly helpless.

Dr. Cimino, rational and detached to a fault, started timing the intervals between his wife's seizures. He noticed two sets of malaria causing seizures to occur at two regular intervals. Once he had their timing locked in and could predict seizures reliably, he administered a small dose right before a seizure was about to set in.

These two doses proved effective. She never had another seizure and quickly recovered. Dr. Cimino never reported his technique outside his diary. Nearly 100 years later, Australian physicians published a very similar technique that was met with some fanfare.

Your body works on a schedule, a circadian rhythm. It has scheduled periods of high performance followed by periods of rest and maintenance. Certain tasks occur together, and it is absolutely possible to interrupt the body’s cycle of output and

57 recovery so that neither one works efficiently. For example; diurnal preference, 'morning people' versus 'night people,' is actually a genetic trait that is far more informed by your DNA than your environment. AUGMENTED recommends adopting a schedule for your sleep, supplementation, meals, workouts and work that aligns with what your body naturally prefers.

PHARMACOKINETICS

Pharmacokinetics is a huge word that could be simplified as 'the path a drug takes through the body.' There are four factors that stand out when understanding how a drug works. They are referred to collectively as ADME - absorption, distribution, metabolism, and excretion. ADME answers four important questions about the behavior of a drug:

How does the drug get into the bloodstream? Where does it go once it reaches the bloodstream? Does it undergo any chemical changes inside the body? How does it leave the body? We're going to define each of these principles first, and then discuss practical application:

58 ABSORPTION

As you attend to your personal grooming in the morning, you notice a stiffness in your shoulder. Looks like your old rotator cuff injury is starting to act up. It’s a mild pain, but you don’t want to go through your day with a throbbing arm. You open a drawer, pull out your trusty bottle of store-brand aspirin and pop two in your mouth, washing it down with a swig of water. The tablets go down your throat and reach your stomach, where they dissolve and are pushed into the intestines.

With it’s surprisingly large surface area, the same as that of a football field, the lining of your intestines quickly absorb the dissolved acetylsalicylic acid into your bloodstream….

Absorption is the way that drugs enter the bloodstream. Only a fraction of a drug you take reaches your bloodstream. The rest is broken down long before it gets anywhere near the target tissue. The fraction of a drug that actually manages to get into your blood is called the drug's bioavailability. How the drug is taken, orally, transdermal,

59 intravenously, or via injection, is called the 'route of administration'. The route of administration determines bioavailability, which in turn determines dose. Determining the correct dose of anything, from the amount of sugar in your morning coffee to anesthesia during a delicate surgical procedure, is the cornerstone of pharmacology.

The initial amount of drug taken versus Bioavailability: The percentage of a drug that the fraction that reaches the actually reaches the bloodstream. Your digestive bloodstream defines bioavailability, system, gut bacteria, and especially your liver can which is typically expressed as a mangle a drug, chemically neutralizing it. Whatever percentage. For example, aspirin has survives this is bioavailable. a bioavailability of 80%, meaning that if you take a 300mg pill, 240mg shows up in your bloodstream. This is actually very high for a drug taken orally. Many drugs top out at 10% oral bioavailability. So what happens to the rest of the drug substance you take?

Understand that the oral route has many different ways to protect you from any toxins your caveman ancestors might accidentally eat. It is an authentic implementation of what the military calls ‘defense in depth.’ Any drug substance you ingest has to run a gauntlet of defensive mechanisms. In the stomach,

60 everything is broken down by enzymes activated by hydrochloric acid. If this doesn't deactivate the drug, it gets dumped into the intestines where untold billions of hungry bacteria live - bacteria who are amazing at breaking down drugs. (These guys are particularly good at breaking down androgens.)

Assuming a useful amount of drug passes these first two layers of protection, it then has to contend with the liver. Literally everything absorbed by your intestines has to go straight to your First Pass Hepatic liver first. We call this first pass Metabolism: Any substance you ingest goes straight to your liver hepatic metabolism. Your liver's sole for chemical processing. This includes any drugs you take purpose is to host thousands of orally. The chemical reactions in the liver usually neutralize a different kinds of enzymes called CYP portion of the drug. Sometimes though, it activates a drug. 450 enzymes that break down hundreds of thousands of types of chemicals. Finding a chemical that can survive all three layers of protection in a useful concentration is a daunting task, and while taking a drug orally is certainly convenient for the patient, many very useful substances simply aren't capable of entering the bloodstream through the oral route.

Other routes include buccalingual (under the tongue,) intranasal (up the nose) rectal (the grossest

61 and for absorption one of the best,) and it's close cousin intravaginal, and finally the second most convenient and second worst for absorption, transdermal, (a small enough molecule can permeate across the skin at a bioavailability of roughly 10%.)

Of course, any drug can be injected. But even then, the tissue it's injected into has a large effect on bioavailability. Anything injected directly into the bloodstream has a bioavailability of 100%. Some substances are injected into fat or even muscle tissue, forming what's called a deposition or bolus that slowly seeps into the bloodstream over time. Bioavailability for these lingers between 85% - 100% and they are especially helpful because they tend to last a long time.

The math doesn't end once the drug hits the bloodstream. Everyone knows that oil and water don't mix. Different organs can be more oil-friendly, more water-friendly, or a mixture of the two. This effects what organs and tissues the drug winds up after it hits the bloodstream, and brings us to the next facet of ADME...

62 DISTRIBUTION

The aspirin goes through your liver and is converted into it’s active form, salicylic acid. From there it is released into the bloodstream and settles into the collections of intertwined tissues that form your body. Much of it comes to rest in places it’s not needed. But just enough reaches your injured rotator cuff to settle the inflammation around your lingering injury. The biochemical pathway responsible for making injured tissue swell up is blocked. As the swelling subsides, so does your pain…

Once in the bloodstream, the drug doesn't settle evenly in all tissues. It will gravitate toward tissues that have a chemical composition more similar to itself. A fatty drug like a steroid will gravitate towards fatty tissues, while those that readily dissolve in water will linger Partition Coefficient: A way to measure whether a substance in more water-heavy tissues like dissolves better in oil or in water. Usually, a chemical is dropped into a muscle. This degree of water flask containing both oil and water. The flask is then shaken until the versus oil solubility is called chemical is dissolved. The oil and water are then separated to partition coefficient and is determine how much is in each fraction. It is expressed as pKa, and abbreviated as 'pKa.' The higher most drugs have a pKa of around 5. the number the more 'fat like' a

63 drug is. Most drugs have a pKa around 5. Fattier drugs tend to linger in the body for longer, drugs which are more water like are much easier to pee out.

Then there’s volume of distribution or VD. This is a fairly clever way of determining Volume of Distribution: The how much of a drug sticks to the target amount of a drug that remains in the tissue and how much remains flowing bloodstream versus that which sticks to the freely in the bloodstream. It is target receptor. expressed in liters, and based off a blood draw that measures the concentration of the drug in the plasma. The scientist then figures out how many liters of liquid would be required to create the same concentration at the same dose. The more liters required, the more potent the drug, because any amount that is not in the bloodstream must be lingering in the tissue it treats. When VD drops sharply, the body has absorbed all the drug substance it can use.

While VD gives pharmaceutical scientists important clues, it is only a starting point for understanding the quality and effectiveness of a drug. There are more direct methods of measuring how well a drug sticks to its target. While conceptually and mathematically

64 interesting, they require a detailed knowledge of organic chemistry concepts and are beyond the scope of this book. For those who are interested, they are called 'affinity' and 'avidity' and are the output of several molecular dynamics calculations.

METABOLISM

As the aspirin lingers in your body, it begins to break down in several different ways. The liver very quickly broke it down when it first passed through which created salicylic acid. But over time it is altered even more. Atoms of oxygen and sulfur are added. The salicylic acid is combined with other small molecules. As this process moves forward, the anti-inflammatory effects of aspirin slowly begin to fade, and you notice a subtle throbbing in your shoulder coming back around lunchtime.

Metabolism is a broad word, but it the Metabolism: A very broadly context of ADME it means a chemical used word in biology. In pharmacology, metabolizing reaction that stops the action of the a drug means what the body does to stop it from working. drug on the body. Most of the time, the This is usually expressed as a CYP enzyme. For body de-activates a drug substance by example “fluoxitine is metabolized at CYP-2D6” neutralizing it chemically, typically a CYP450 protein adds a molecule of water or a molecule of what is essentially sulphuric

65 acid to the drug which makes the substance more water soluble and therefore easier to pee out. Most of this takes place in the liver. While anything absorbed by the intestines goes straight to the liver, it eventually circulates back through the bloodstream and is metabolized there again. Metabolism also takes place inside cells, and all chemicals in a living environment slowly decay into other substances.

Metabolism doesn’t always inactivate a given drug. In some cases, because we understand the interaction between an enzyme and a substrate so well, the final step in the chemical synthesis of a drug occurs in the Prodrug: A substance that has no drug effect, liver. These are called prodrugs and until it hits the liver. The liver actually are explained in greater detail in a metabolizes it into an later section. For now, just know that active substance. the two concepts are very tightly linked.

Usually, undergoing chemical change deactivates a drug and ends the effect it has on the target tissue. It may linger in the bloodstream, but it can no longer do it's intended job. This happens at different speeds for different drugs. The practical application of knowing how fast a drug metabolizes is finding

66 the length of time between doses. Of course, there's one other way that drugs stop acting on the body. Mercifully, it is by far the simplest concept in ADME...

EXCRETION

Lunch time is over. You brought a protein shake to work with you, which has now coursed through your body and the liquid fraction is pressing against the base of your bladder, nagging you to visit the bathroom. Your urine contains a hodgepodge of chemical waste from your cell’s daily metabolic activities. It also contains what remains of the aspirin you took this morning, most of which has been chemically mangled by your liver until the painkilling effect stopped working. Your shoulder is pounding again, and you go to ask the admin if she happens to have any aspirin or Tylenol in her purse you can have.

For all practical purposes, drugs are excreted from the body in two ways. This is the point where the drug irreversibly leaves the body. Both these methods involve the content of diapers. Renal excretion refers to the action of kidneys. Kidney tissues filter chemicals from the bloodstream into the bladder as the content of urine. Scientifically, this is

67 called Renal excretion. Unscientifically, you pee the substance out. Drugs that are more water soluble tend to leave the body this way. Many drugs that are not water soluble are chemically altered by the liver into water soluble substances so they too can be peed out easily.

The other way for a drug to leave the body is by billary excretion. Bile is a substance that helps the intestines absorb fat. If a drug cannot be excreted in the urine, it typically clings to bile and is excreted during what is colloquially referred to as a ‘deuce.’

Metabolism and excretion both end the action of a drug. This happens at different speeds to different drugs. The speed that a drug becomes Half-Life: The amount of inactive is called the half-life, and the time it takes a dose of a drug to be 50% half life of a drug is important to figuring eliminated from the body. out the time between doses of a drug.

Simply put, half-life is the time it takes for your body to get rid of half the drug you’ve taken. Drugs don’t leave the body at a steady

68 rate. The more of a drug you take, the faster your body gets rid of it. As the concentration of a drug lowers, the body gets rid of it slower. It typically takes the body about four half-lives to get rid of most substances.

For example, let’s say that at 8PM you take 40mg of Benadryl for your allergies. The half-life is four hours:

After ten minutes, the Benadryl hits your bloodstream and you fall asleep.

At 12:00AM, four hours have passed. You now have 20mg in your system.

At 4:00AM, a second half-life has passed, and you only have 10mg left. The concentration has fallen so low you begin to experience allergy symptoms.

At 8:00AM, A third half life has passed. Only 5mg remains in your bloodstream.

By 12PM, no biologically active concentration is left, and your eyes are itching again.

69 The half-life of drugs can vary wildly, anywhere from several minutes to several months. Knowing the half life of a drug allows you to predict how long a single dose will remain active, the 'duration of action' as pharmacologists call it. And the duration of action lets you know your total exposure to the drug’s effects. Even a low dose of a substance can have a large impact on the body if the half-life is long enough.

PRODRUGS

Thanking the admin, you swallow your second dose of aspirin for the day. Just like this morning the drug travels through your intestines and is sent to your liver. And just like it did this morning, the liver cleaves the acetylsalicylic acid into acetic acid, (essentially vinegar,) which leaves the body rapidly, and salicylic acid which travels to the injured site and takes the swelling down. The molecule that heals your pain is not the molecule you originally swallowed, your liver has chemically altered and activated it. Aspirin is a prodrug.

Remember back in the metabolism section, where we discussed how the body chemically neutralizes

70 drugs? Medicinal chemists have found ways to trick the liver into turning a relatively neutral substance into a potent drug. The liver inadvertently winds up 'activating' the drug by performing the final step in the chemical synthesis. The very first drug to work this way is well known - acetylsalicylic acid a.k.a. Aspirin.

Salicylic acid, the active metabolite of Aspirin, is an amazing anti-inflammatory drug that has a grab bag of physiological effects. Unfortunately one of them is to reduce the protective lining in your stomach and give you a nasty ulcer very quickly. Doctors struggled administering it to patients back in the 1800’s. It was a powerful pain reliever, but you ultimately traded one kind of pain for another and it couldn’t be taken long term.

In 1853, a French chemist discovered that by combining a single molecule of vinegar with salicylic acid in a condensation reaction, the effects on the stomach were greatly reduced. What he didn’t know at the time was that the liver simply removed the vinegar molecule from salicylic acid then released it into the bloodstream in its original form. Once aspirin had been absorbed, the liver activated it then

71 sent it through the bloodstream, where it was able to reduce your pain and inflammation, and do much less damage to the stomach.

Another example which you may well be familiar with are testosterone esters and ethers. Testosterone ethanate, testosterone cypionate, testosterone acetate, testosterone mysterate, are all injectables that linger in muscle tissue and slowly release bioidentical testosterone into the bloodstream. They work on essentially the same principle as aspirin, but they slowly convert into the active drugs all by themselves. We will touch on these specific drugs in a later chapter.

OFF-TARGET EFFECTS/'SIDE' EFFECTS

Unfortunately, not all the aspirin does it’s job at your injured rotator cuff. Aspirin blocks cylooxygenase, which is conveniently abbreviated as COX. Blocking COX reduces inflammation throughout the body. But it also reduces the protective lining of your stomach. As your second dose of aspirin kicks in, the lining of your stomach is sharply reduced. And because your stomach is currently digesting the meal you recently ate, you

72 begin to experience some discomfort in your abdomen…

When someone takes a drug, what they are really doing is taking a chemical that targets a specific protein to either activate or block it. But as we saw in the first chapter, a drug can interact with more than one kind of protein. When a drug intended for one protein Off Target Effects: A drug interacting with a protein other interacts with another and causes than the one intended, typically resulting in a side effect. unwanted biological outcomes, these Side Effects: A biological effect outcomes are called off target effects other than the medicinal effect. This can stem from off target or side effects. In the example effects, or from downstream interactions with the intended above, the aspirin is treating your target, or even immune pain. But it’s also causing you indigestion because it’s making your stomach more sensitive. Hopefully the painkilling effects are good enough to where it doesn’t bother you much.

Every drug interacts with some kind of protein in a biochemical process. We call Target: The protein a given drug is designed this protein the target and there are a to interact with. It may interact with other finite amount of them in any body. It is proteins as well, entirely possible to administer so much of creating side effects. a drug that 100% of the target proteins are effected by the drug. We call this a saturation

73 dose. Above a saturation dose, the drug Saturation Dose: The will ONLY increase the side effects. exact amount of a drug needed to Complicating matters, the body often occupy ALL the target proteins in your body. adapts to the long-term presence of a Anything above the saturation dose will drug by down-regulating the pathway it’s only increase the side effects of the drug. intended to enhance. We will, of course, be discussing strategies to minimize this effect in later chapters.

Before you select a drug, a dose, and a dosing interval, you need to understand the four main factors that will affect the client which we just reviewed; ADME. In future chapters, we will be discussing the specific features of androgens at length. It is not straightforward. Any idiot can abuse androgens until they’re bloated with estrogen, clog their arteries, give themselves a scorching case of PMS that manifests as a mood disorder, then drop dead of a heart attack in their 40’s. Many idiots often do. If you are not doing your calculations, if you are using ultrasuperphisiologic (higher than you body can naturally produce,) doses of androgens when what you need to do is back off, if you are shrinking your testicles and acting the hormone- challenged fool in pursuit of a little more size, you may need to consider reworking your regimen.

74 MECHANISM OF ACTION

Mechanism of action is the interaction Agonist: A drug that binds to a protein and between a drug and a protein that makes it work faster. ultimately produces the drug’s effect. Antagonist: A drug that binds to a protein and Although proteins are molecule sized, stops it from working they still behave mechanically. The any further. mechanics of how a protein changes when it binds to a drug is called the mechanism of action (MOA.) Mechanism of Action: The Mechanisms of action fall into two chemical interaction between a ligand/drug and the target broad categories. Drugs that bind to protein that produces a medicinal effect. Generally their protein and stop it from working speaking, the ligand will either stop the protein from working are called antagonists. Think of an (antagonist/inhibitor) or make it work faster (agonist.) antagonist as being the wrong key, but still fitting in the keyhole. As long as it stays there, the actual key can’t get in to unlock the lock which effectively blocks it.

Drugs that bind to their receptor and activate it are called agonists. This is just like putting the correct key in a lock and opening it.

Because biology is complicated, there are several subcategories of each: Suicide inhibitors,

75 competitive antagonists, inverse agonists, etc. When necessary, each will be explained in the chapter that discusses specific substances.

AREA UNDER CURVE (AUC) AND STEADY STATE CONCENTRATION

The chart below shows what happens when a single dose of a drug is taken. You can see that after a dose of a drug, the concentration spikes immediately. The correct dose gets the concentration between the Maximum Therapeutic Concentration (anything above this just increases the side effects) and the Minimum Effective Concentration (anything below this has little effect.) The spread between MTC and MEC is the therapeutic range. The time the drug spends in the body before dropping below the Minimum Effective Concentration is called Duration of Action: the duration of action. The amount of time a dose of a drug’s In the above example with Benadryl, effects lasts. when the duration of action ends your

76 eyes start itching again. AUC is the Area Under the Curve, and represents the total exposure to the drug.

But what happens when you take multiple doses of a drug? If the time between doses is less than the time it takes to eliminate the drug from your bloodstream, the concentration slowly gets higher and higher, because you’re adding more drug faster than the body gets rid of it. One of the quirks in the body metabolizing drugs is that the higher the concentration of a drug gets, the easier it is for the body to get rid of it. Eventually, things balance out and the body is getting rid of the drug about as fast as you’re dosing it. This is called Steady State Concentration or CSS.

Reaching a CSS that is within the therapeutic range is how you determine both the dose of a drug, as well as the time between doses.

77 Now, go back and read that again. If it Fun fact: most steroid users run doesn’t sink in, go back and re-read the concentrations well over MTC. last chapter until it does. Understanding Meatheads… this will keep your dosing regimens safe (under MTC) and effective (over MEC.)

POLYPHARMACY

Poylpharmacy is taking multiple drugs that have the same effect, but work in different ways. Using drugs that work in complimentary ways at different points in a system makes each one even more powerful, sometimes allowing lower doses of each. Pharmacology advocates for using the smallest effective dose of any given substance. Informed use of complimentary drugs keeps dosing at a minimum and creates bigger effects with fewer resources.

The most common example of this approach is the use of multiple antiretrovirals to keep HIV from progressing. To help patients understand what doctors are doing, the medical community calls this a “drug cocktail.” HIV is blocked at three target proteins, requiring any adaptation that occurs to overcome all three at once. This is nearly

78 impossible, preventing HIV from spreading any further and adding decades to a person’s life.

A polypharmacy technique that can readily be employed at home to treat common ailments is to combine doses of acetaminophen and naproxen. (Commonly called Tylenol and Alleve.) They both treat pain, in different ways, and multiply each other’s effects. Mind you, it wouldn’t be effective to combine naproxen with Aspirin or Ibuprofen, as all three of those drugs work in exactly the same way, by blocking COX. However, you could combine any one of those three with CBD for powerful anti- inflammatory effects, because while CBD does reduce inflammation it doesn’t work via the COX pathway. You could even stack a corticosteroid on top of this anti-inflammatory cocktail for even more potent effects.

The opposite of polypharmacy is Stacking: The unfortunate stacking, the practice of taking multiple output of bro science. Taking multiple drugs, and frankly redundant steroids in the usually steroids, that act on the same pathway. hopes of somehow making each more They work together in this case by diminishing each powerful, is at best a waste, at worst other’s effects while foolish. Every last one of them works increasing side effects. primarily at the androgen receptor. This

79 is akin to assuming that if you can get the oven up to 700 degrees your frozen pizza will cook in five seconds. What really happens is you get a pizza that’s frozen in the middle but burned on the outside. Accordingly, stacking results in a burned- out androgen pathway and a hell of a backlash once you cease the drug.

AUGMENTED focuses on pathways that work together with multiple mechanisms of action to produce strong, dense muscles, robust gene expression and a healthy level of bodyfat. The following chapters will discuss specific pathways and detail reliable means for manipulating them.

Our approach targets three primary pathways to accomplish this: mTOR, androgen/AD, and AMPK. Secondary “helper” pathways are P-PARγ, kreb’s cycle, and inflammatory pathways. If you’ve made it through the last few chapters and understood them, well done! You’re now ready for an intelligent conversation about PEDs. We will now look into pathways for muscle growth. The simplest one, mTOR, will be discussed first.

80 CHAPTER 3 mTOR - A POWERFUL PATHWAY FOR GROWTH mTOR is the first biochemical pathway we will learn to manipulate. It is a gatekeeper for almost all biochemical pathways that result in growth. mTOR gauges both how much you’re working out and the quality of your nutrition. It is also very easy to hack, and we will be discussing both strategies to run your mTOR signaling screaming fast as well as the underlying biochemistry. mTOR is not a single protein. It is actually a cluster of three distinct receptors daisy-chained to DNA- activating proteins that live inside every cell in your body. mTOR works as a sort of biological switch. What does this “switch” turn on and off? The answer is some of your most powerful genes for muscle growth and recovery, among other things. What you want to do is build lean muscle, burn fat tissue, all while keeping your metabolism healthy and chugging along. mTOR unlocks and activates genes to do just that. But how?

81 There are three separate factors that activate the three mTOR receptors. Applying each factor amplifies mTOR’s signal to your DNA, directing your cells to express metabolically expensive genes that result in growth in the form of cell proliferation, tissue generation, and the expression of DNA that requires a great deal of calories to maintain. This translates to more fat burned as well as bigger muscles, and of course we want to maximize its effects.

1.mTOR exists primarily to determine how many calories you’ve consumed. It uses leucine as a sort of plumb line to gauge whether or not you’re getting enough food. Fitness competitors in the “cutting” phase often talk about their bodies going into “starvation mode” where fat loss is significantly slowed. This is because mTOR has slowed their metabolism by inhibiting the expression of certain genes, especially in the muscle tissue. Mitochondria are slowed down, muscles burn their protein as fuel as a calorie saving strategy, and the athlete feels sluggish and depressed as brain function is diminished.

2.mTOR also gauges how much exercise you’re getting, what scientists refer to as “oxidative

82 stress.” This is a co-factor in activating mTOR, meaning that while Leucine is the primary stimulus, exercise makes the signal even stronger, in even more cells. Combining exercise with leucine supplementation could be considered a sort of polypharmacy, but on the same pathway which is unusual. Biology will always defy any attempt to find a universal rule or pattern.

3.Finally, insulin stimulates mTOR. This is to ascertain your energy state in the moment. The presence of insulin indicates the presence of blood sugar, and is taken as an immediate indication the athlete is consuming sufficient calories.

COUNTING CALORIES IS COUNTERPRODUCTIVE

Take this information regarding mTOR and contrast it with what has become widespread fitness lore; calories in, calories out. The supposedly ironclad law of thermodynamics demands food intake be reduced significantly, sometimes drastically, in order to create a more favorable body composition. Lately, more sophisticated dietetic approaches have gained traction in the fitness community with macronutrient ratios offering a slightly more granular means of viewing athletic nutrition. Atkins, Paleo,

83 Keto, and any other number of eating strategies have saturated the market with varying degrees of success, the lack of predictability being what is typically expected when a blanket solution is applied to a diverse population.

Additionally, it has not escaped anyone’s notice that as the body sheds adipose tissue it becomes increasingly resistant to doing so. This phenomenon has led to some pretty demented eating regimens to shed those final few percentages of body fat. A lean, shredded appearance is a frustrating target that moves faster the closer you get to it. Additionally, loss of muscle mass is seen as inevitable as the energy deprivation forces the body to feed off it’s own organ tissue. This metabolic slowing is common and breaking through the plateau it causes is viewed as an issue of willpower and discipline, when in fact what we are seeing is a downturn in mTOR signaling.

Thermodynamics, the theory that is the bedrock of current sports nutrition and lends credence to the use of calories as a nutritional metric, was established in the mid-19th century as a way to predict engine efficiency; think steam trains. When it

84 comes to a dead iron girder, thermodynamic theory is perfect and immutable. Applying these principles to something irreducibly elegant, such as the human body, results in agony at best and metabolic disaster at the worst. Rather than applying a strategy based on century old discoveries, basic arithmetic and almost untenable resolve, we should be asking ourselves precisely how and why the human body slows its metabolism.

THE SCIENCE: mTOR is an acronym for ‘mammilian target of rapamycin.’ Rapamycin was an experimental anti fungal agent which showed massive promise for stopping fungal infections dead in their tracks, at least in the lab. It worked by blocking a chemical pathway in yeast that allowed it to grow. However when it was injected into human subjects a problem arose; the patient’s immune system was suppressed and they began losing muscle mass rapidly. Upon further investigation, human beings had nearly the exact same protein with the exact same function as yeast. So when it was used to inhibit the growth of yeast, it inhibited the growth of the person as well. This was a mind-blowing revelation. As scientists

85 dug deeper, they found nearly every living eukaryote had this pathway in some form or another. They very lamely named this protein mTOR, an acronym for “mammalian Target Of Rapamycin.” And now we’re stuck with it.

At around the same time, (the late 1970’s and early 1980’s,) medical scientists were noticing that burn victims who were treated with certain amino acids seemed to recover quickly. The hypothesis was that by providing additional building blocks, the body would be able to rebuild tissue more quickly. This kind of thought had been state of the art for several centuries, but we now understand it to be incorrect. We now know such an approach is like dumping bricks in a vacant lot and expecting them to self- organize into a house. But this time, experimentation almost panned out with a healthy dose of broken clock syndrome.

Several highly flawed studies were commissioned that produced mixed albeit somewhat encouraging results regarding what are called BCAAs. You are already likely familiar with this family of supplements. While the evidence wasn’t strong enough to produce a full medical protocol, the supplement industry was

86 quick to capitalize on the notion that leucine, isoleucine, and valine taken in combination would result in better results in the gym. Several companies rushed products to the market containing branched-chain amino acids or BCAAs, so named because they are amino acids with side chains consisting of hydrocarbon chains that happen to branch out.

And in a boon for the supplement industry, they actually seemed to work. To this day BCAAs are marketed and hundreds of high performing athletes swear by them. But the 'building blocks' hypothesis was ultimately wrong. The fact that BCAAs worked so efficiently was ultimately an example of broken clock syndrome rather than solid bioengineering. As it turns out, one of those three BCAAs actually has a drug like effect, and the other two accomplish relatively very little.

Of the three BCAAs, leucine, and only leucine, activates mTOR with drug-like potency. The human body uses leucine as an indicator of how many calories one has consumed for the purpose of gene regulation. Combined with oxidative stress in the form of exercise along with insulin, your growth and

87 adaptation are kicked into overdrive. Even when operating at a caloric deficit.

That’s right, no more starvation mode. Minimal loss of muscle during caloric restriction. But, how do you put all this into effect? As you can likely imagine at this point, it’s actually not difficult. If you combine all three activating factors at once, your mTOR pathway will skyrocket in activity, unlocking all your growth factors and allow for the expression of very metabolically expensive genes, genes which are typically turned off in starvation mode.

First of all, you will be taking up to five grams of leucine per day in divided doses. The idea is to saturate your cells in leucine to keep mTOR, and with it your metabolism, as active as possible. You also want to make certain that when you do exercise your cells have ample leucine available to maximize it’s effects as a growth factor.

Pro Tip: Regardless of how and when you choose to take To stave off the downturn you leucine, make certain one of your doses occurs experience when you sleep, it’s best to immediately before your workout. This will ensure take a dose right when you wake up, your cells are saturated with leucine as they undergo and another right before going to bed. oxidative stress, kicking The remaining dose should be taken mTOR into overdrive

88 right before exercise. If you don’t exercise in a given day, take a dose between lunch and dinner.

Mercifully, pure leucine powder has a volume of roughly one teaspoon per five grams. It tastes as disgusting as you might expect, and barely dissolves in water. You best bet is to blend it into a smoothie. Yogurt works well as a vehicle, as does encapsulating it. If you do choose to ingest the powder directly, a juice containing citric acid such as orange juice will dissolve leucine powder quickly.

There are of course other ways to Pro Tip: With leucine obtain leucine. Whole milk contains supplementation, you will essentially be able to build nearly an even gram per 250ml, or one muscle and burn fat simultaneously because cup. Beans, particularly black beans, down regulation of mTOR is the primary driver of also have a high concentration of ‘starvation mode.’ leucine in them. No matter what nutrition regimen you follow, supplementing with leucine is strongly recommended as it provides the metabolic effects of a caloric surplus without needing the actual calories.

And what can you expect to experience? That depends on the content of your DNA, both genomic and epigenetic. People who have used this regimen

89 report fairly rapid onset of a variety of effects. Increased energy, decreased cravings for carbs, and increased muscle density seem to occur quickly. Over time, you can expect to see a noticeable reduction in fat, faster recovery from exercise, and of course increased muscle size.

If you are trying to reduce bodyfat, expect your fat loss to accelerate without compromising any muscle tissue you’ve gained. This is leucine’s primary and most powerful effect, and in doing so you have effectively ‘hacked’ your body out of starvation mode and kept your metabolism chugging along at high speed.

Leucine will effect every cell in your system, and some of those cells are not 'you' per se, but gut and skin probiotics. Leucine’s influence on probiotics will change in particular the functioning of your gut, unpredictably but generally favorably. Otherwise, it is a mild but powerful modulator of tissue growth and recovery.

90 CHAPTER 4 - METABOLICS; ENERGY, ATP, AND CREATINE

This chapter will help you understand how your cells create, store, expend, and replenish the energy they use to fuel your movement. You can have the the fastest, most precisely tuned car in the world but if you don’t have gas you’re not going anywhere. This analogy is true for your body as well.

Your cells exclusively use ATP as a fuel source. ATP stands for “adenosine tri-phosphate.” The Adenosine Tri Phosphate: Pictured triphosphate is the part that above, with the triphosphate circled in red. actually stores energy. It takes a huge amount of energy to add that Fun Fact: Adenosine all third and final phosphate to the chain. by itself is what makes you sleepy. Caffeine The adenosine is essentially there to works by blocking the activity of adenosine; it is allow the triphosphate to be an adenosine antagonist. transported around the inside of the cell.

When ATP is burned, that final phosphate is removed and only two phosphates remain. The adenosine stays put. This burnt out molecule is

91 called ADP for “adenosine di-phosphate.” It’s still fairly high energy and gets recycled back into ATP in a process called Kreb’s Cycle. Kreb’s cycle is a complex, multi step process that itself is fueled by sugars, proteins, and fats.

The key to enhancing the energy available to your cells is to accelerate Kreb’s cycle. We are absolutely not going into the details of the individual chemical steps. In the unlikely event that you care very, very much (maybe you’re a second year medical Kreb’s cycle a.k.a. the citric acid cycle. Image downloaded from student,) we’ve included WikiUserPedia, By Narayanese, YassineMrabet, TotoBaggins a diagram at right.

The diagram is only part of a very complicated process of caloric expenditure, and may not be the part you care about the most. For practical purposes, Kreb’s Cycle can be used to accomplish

92 two things: increasing athletic output and reducing body fat.

STRENGTH, POWER, AND CREATINE Creatine is perhaps one of the most successful supplements of all time. It’s fairly easy to use, has mild, if any side effects, and is very affordable. Multiple well designed scientific studies have proven the effectiveness of creatine supplementation time and time again. It works as intended every time it’s used, even in diseased populations or the elderly. There is even strong evidence to suggest it works as a cognition enhancer, which makes absolute sense (the human brain consumes a full third of the calories you burn day to day.)

Are there drawbacks? Of course, but they pale in comparison to the relative benefits. Creatine in solution has a fairy high pH. This can disrupt the delicate chemistry of your gut and cause significant stomach discomfort. It also Hydrophilicity: A chemical that draws draws water to itself, a trait called water to itself. Literally means ‘water hydrophilicity. This is a problem because loving’ in attic Greek. taking creatine can redistribute where water goes in your body and may cause cramps at first, but it’s also a great thing because it

93 also uses hydrophilicity to pull water into your muscles, making them stronger.

Let’s go into detail on how the hydrophilic part of creatine works. When consumed, creatine finds it’s way to the inside of your muscle cells and of course takes a significant amount of water with it. Look at a human muscle chart and you will realize this can be quite a lot of water. This selectively causes your muscles to swell. While this effect was once assumed to be purely cosmetic, changing the volume of a muscle also changes the way the nerves inside the muscle perceive how Ligamentous much weight they’re lifting. These nerves Mechanoreceptors: Nerve endings inside your are called (deep breath,) ligamentous muscles that measure how much weight you’re mechanoreceptors, and one of their many lifting, and shut down a motion if they determine jobs is to shut your muscles down if they you’re lifting too much. think you’re lifting too much as a way of preventing injury. Unless you’re very heavily trained, they likely shut down your lift long before you reach your actual maximum weight. The extra water drawn into the muscle cushions your mechanoreceptors, making them less likely to stop lifting and giving the person the impression they’re much stronger.

94 The real magic with creatine occurs in the Kreb’s cycle, where the extra creatine accelerates the replenishment of ATP. Inside the muscle cell, a molecule of creatine combines with a phosphate molecule, then uses an enzyme to hand the final phosphate onto ATP via the Kreb’s cycle. This allows for faster recovery and a greater work capacity. It also delays the onset of fatigue. All these effects result in better workouts in the gym, as well as better performance on the field.

Creatine also seems to have an additional effect that wasn’t expected by anybody in the scientific community. It has been demonstrated to convincingly, if not conclusively, act as a cognition enhancer. You read that right, creatine can actually make you smarter. (It actually allows you to concentrate hard for longer periods of time.) This honestly makes a great deal of sense. Your brain consumes an immense amount of calories, something on the order of 700 per day. It is an extremely metabolically active organ. That fatigue you feel after a long day at work or a bout of heavy concentration is very real; you have depleted your brain’s reserves of ATP. Creatine conveniently crosses the blood-brain barrier and augments both

95 your ATP reserves there and accelerates ATP replenishment. It makes you both stronger and smarter. What a remarkable substance!

For something so powerful, the side effects are relatively mild and easily overcome. The high pH of creatine, especially creatine monohydrate, can disrupt the function of your stomach causing both discomfort and interfering with absorption. Without getting into things such as waters of crystallization or conjugate bases, just bear in mind that it is best to take creatine with an acidic juice such as orange or grapefruit juice. If your diet prohibits this, you can substitute a small amount of kosher sour salts (which is essentially just citric acid,) to aid your stomach.

The other issue has to do with the volume of distribution of water that changes when you start on creatine. With water uptake into your muscle tissue, you can actually become mildly dehydrated everywhere else and the body needs some time to adjust. If this presents a problem, additional hydration as well as a small amount of potassium supplementation should significantly reduce if not eliminate cramping. Irrespective, over a period of

96 several days your body will adapt (it’s actually your kidneys learning how much water to leave in your blood,) and the cramping issue will eventually self resolve.

MITOCHONDRIA, SUCCINATE AND FAT METABOLISM

ATP is generated in a particular Mitochondrion: The actual place inside a cell where fats location in a cell, an organelle called and carbohydrates are broken down to fuel the production of a mitochondrion. (The plural is ATP. Digest that for a moment, fat metabolism AND mitochondria, not ‘mitochondions.’) cellular energy in the same place!! This system is begging Remember, ATP is the only viable for us to up-regulate it! energy source your cells can use. It is the job of your mitochondria to take carbohydrates and fats, essentially put them on fire, and use the energy released to power their Kreb’s cycle which as we know, generates ATP that is then released to the rest of the cell to fuel metabolic functions.

Mitochondria are a fascinating organelle. They have their own DNA, which is passed exclusively from mother to child. They appear to be an adapted kind of bacteria and could have lived on their own as a very primitive form of life eons ago. Individual mitochondrion can both divide and/or grow in response to changing energy demands. Some cells

97 don’t have any mitochondria, such as your red blood cells. Liver cells can have upwards of 2,000 per cell. Your muscles and brain, obviously, also have high mitochondrial density.

Naturally, athletes are interested in ways to increase mitochondrial density which will in turn replenish their ATP faster and allow for prolonged peak performance. Scientific studies into both sedentary, (read couch potatoes,) and highly conditioned athletes have yielded mixed results. It seems mitochondria adapt very quickly to exercise and lack of exercise, and keeping them dense requires protracted and intense high volume exercise. For athletes who need to stay in peak condition, or rapidly deployable soldiers and/or Author’s note: Want a portable, first responders maintaining peak effective means to wreck yourself quickly while in the field? Look mitochondrial density is important. into kettlebells. I’ve been using them since 2009 and attended a Research data indicates this few instructor courses. They’re a very convenient way to stay in requires multiple bouts of intense fighting shape. exercise, at least four per week.

Just like the exercise facet of promoting mitochondrial density, supplementation for mitochondria is tricky. While several substances are marketed as promoting enhanced mitochondrial

98 function, they’re based on studies that are preliminary at best and tend to have very expensive ingredients such as coenzyme q10.

A recent piece of research that’s pretty convincing and uses a safe, inexpensive substance is succinate. Succinic acid production is one of the steps in the Kreb’s cycle, and evidently too much of it signals mitochondria to start burning fat arbitrarily to produce heat. This effectively raises your metabolism causing them to burn more calories throughout the day.

The concept is relatively simple. When your body is exposed to long periods of cold, it needs a way to warm itself up. The presence of excess succinate is used as a signal to mitochondria to start recklessly burning fat, generating heat for the organism.

Molecules of fat flow from adipocyte to adipocyte, and the thermogenic effect of succinate depletes the fat stores in brown adipocytes (the ones most capable of actually burning fat,) which are then replenished from fat stores elsewhere in the body. So even if the fat-burning effect doesn’t occur in the

99 cells surrounding your abs, it will eventually be replenished from there.

Succinate is a frontier in the science of body composition management, one that may well prove fruitful. Being a new area of scientific inquiry, there is no reliable data available for dosing in human beings. Biologically, it is very safe and is used in medical drugs in fairly high quantities. This is a promising pathway, but one that needs further development before it can be marketed.

Now that we’ve explored some of the more vexing issues in sports biochemistry, we’re going to move on to the next most problematic factors in developing an elite athlete, injury management. How do you maintain a strong training schedule without accumulating injuries? While pharmacology doesn’t have a complete answer, we are going to provide some important information on managing inflammation and keeping your joints supple, precise and free of pain in their function.

100 CHAPTER 5 - INFLAMMATION AND INJURY MANAGEMENT

'Once pain is present, it becomes a driver of muscle tone and tension, compounding the problem with distorted motor control.'

~ Grey Cook, Movement

Everybody knows that training is walking a tightrope between enhancing your health and injuring yourself. If an athlete’s or peacekeeper’s career is going to end early, an accumulation of injuries is nearly always the cause. While this is understood on an intellectual level, the reality is that an injured athlete, with their competitive and aggressive personality, will typically try to push through the injury and work around the pain. Somehow this is looked upon with admiration. Circumventing pain signals has the effect of altering movement patterns and transferring the kinetic burden to other joints and muscles enough to cause them injuries as well. As the athlete continues to fight through the pain, the altered movement pattern literally causes the injury to spread to other joints and often undermines performance to the point where even something as simple as walking or standing hurts, effectively ending the athlete’s career.

101 Great care must be taken to avoid Prehab: Exercises chronic inflammatory injury. First and intended to prevent injuries before they occur, foremost, injury prevention needs to be typically borrowed from rehabilitative physical part of your training regimen. You must therapy. By strengthening the add movements and exercises intended muscles and joints likely to be injured, you prolong not to increase performance outputs, but your athletic career. rather prevent injury. Specialists call these exercises prehab, and it consists of a grab bag of stretching, massage, lifts and joint rotations to keep connective tissue supple and muscles responding appropriately to exercise. Any worthwhile trainer, from the eager kid at a chain gym to coaches for professional sports teams will be aware of at least the basics of this category of programming.

When injuries do occur the workout program needs to switch entirely to a rehab regimen. The original program which caused the injury needs to be altered significantly and at times abandoned completely to avoid making the injury even worse. It should not be resumed until the body is healed and the dysfunctional movement patterns completely reprogrammed to prevent the original pain from re- occurring. Both of these require the aid of a highly

102 skilled clinical practitioner of movement science and are well beyond the scope of this book.

Inflammation: The It’s the biochemical aspect which we as body’s response to injury or infection. Extra blood pharmacologists have the most control, flows to the injured site, resulting in warmth. which is guiding how your body responds Histamines swell the area and give it a red color. to injury at a molecular level. Key to This increases pain, causing loss of function managing the effects of tissue damage is in the effected area and coaxing you into not slowing down your body’s inflammation using it so it can heal. processes. Inflammation is very much a buzzword in the health and wellness community, and there are thousands of scientists dedicated solely to researching specific facets of it. This chapter will discuss means of controlling Prophylaxis: Medicine given as a inflammation as a prophylaxis against preventative measure before injury or sports related injury, meaning treating disease occurs. a potential injury before symptoms start manifesting.

A perfect model to understand inflammation is a zit. It’s a red, warm, swollen lump that is painful to the touch. They occur when a pore first becomes clogged with oil and then gets infected with otherwise helpful bacteria that typically lives peacefully on the surface of your skin. The presence of benign bacteria where they don’t belong

103 is noticed by immune cells, which start spitting out cytokines that cause the surrounding tissue to swell. They also release other cytokines that guide specialized immune cells to come to the site of injury, identify and characterize the invading microorganisms, then deploy antibodies which serve as a marker for destruction by killer T-cells.

This process can occur inside joints and muscle tissue as well. Overtraining or other injuries inflicted to the musculoskeletal system usually manifest as both pain and loss of function, much like a sprained ankle. Your immune system’s responses to injury often inflict further damage on the injured tissues, increasing recovery time even further.

Recognizing problem inflammation is easy. Inflammation presents on the body in four ways; redness, swelling, pain, and heat. Functino laesa: Loss of function in a joint or (Doctors refer to this in Latin as rubor, muscle group due to inflammation. An injury tumor, dolor, and calor, respectively.) It is a which causes weakness as the swelling pinches very primitive immune system which works nearby small nerves. The lack of activity by isolating and then pushing out a accelerates healing. perceived pathogen. When it becomes severe, people will also experience loss of function of a joint or organ known as functino laesa.

104 Loss of function is a killer when it comes to the powerful and precise of movement that defines an elite athlete. You body, ever the adaptive savant, will almost always find a way to work around the pain and loss of function a mildly injured joint incurs. However it does so at the expense of your long-term joint health and acute performance outputs. Simply put, the minor inflammation is like a pebble in your shoe. As your body struggles to work around the pain you start to move imperfectly, shifting the burden of performance to other joints and muscles. Over time, these altered movement patterns become ingrained and are detrimental to the athlete.

Fortunately, this inflammatory response is biochemically guided, and just like with the HPG axis or mTOR we are able to control the chemical signaling to make your body do what we want. In this case, we have methods to decrease inflammation to allow for more correct healing to occur, more quickly. This chapter will address drugs and techniques for managing inflammation and preventing minor tweaks and pulls from becoming long term debilitating movement patterns.

105 Inflammation of muscle and joint tissue causes symptoms that are strongest after long periods of rest, especially first thing in the morning. Inflammatory pain is reduced with exercise and is treated rather easily by over the counter NSAIDs. (If you or a client are experiencing the opposite with pain, most intense in the evening or after exercise with a poor response to NSAIDs, that is indicative of joint damage which is much slower to heal, and you absolutely need to seek out the help of a medical professional.)

Immune cells secrete two categories of Leukotrienes: Small molecule messengers immune cells use chemical signals to communicate with to communicate with one each other. One is a family of small another. Interleukins: Cytokines molecules, the other a category of secreted by immune cells, often in response to cytokines. They have their own leukotrienes, to communicate names, and are called leukotrienes with non-immune cells. and interleukins, respectively.

Interleukins are a subtype of immune-focused cytokines that immune cells use to coordinate their activities. For our purposes, interleukins tell the immune system to either cause swelling, or to stop swelling. The various interleukins are named simply, with ‘IL’ designating the cytokine as an interleukin

106 followed by a number. Human have a total of 36 different interleukins that have a wide variety of biological activities. Their effects run the gamut from recruiting immune cells to an injured site to inducing inflammation, ending inflammation and even command particular immune cells to commit seppuku in a process called apoptosis.

Immune cells also use small molecule signals called leukotrienes, which are Cannabinoids: A family of molecules found in high chemically very much like concentrations in the cannabis plant. They have a range of cannabinoids. Immune cells use effects and applications, from intoxicants to anti- leukotrienes to communicate with one inflammatory to anxiolytics. Some are even classified as another. Because this signaling relies potential chemical weapons. on small molecules, it offers an easily manipulated drug target for managing inflammation.

In particular, suppressing the inflammatory response reduces pain and stops the immune system from damaging injured tissue. This accelerates recovery, allows for more frequent and intense exercise, and helps prevent the development of long term injuries that can be career ending for the athlete. Fortunately there is a litany of cell signaling pathways for immune and inflammation responses, which gives

107 us a great many options when it comes to controlling inflammation and managing post exercise recovery. Two pathways in particular are easy to modulate with safe, long lasting compounds that will protect and preserve your muscles, joints and connective tissues. Read on:

CYCLO OXYGENASE/SALICYLIC ACID

Remember COX from an earlier example in the chapter? You will remember it as the drug target for salicylic acid, which is best delivered orally as the prodrug acetylsalicylic acid, commonly known as Aspirin. A pharmacologist will tell you that salicylic acid has multiple uses and interacts with dozens of biochemical pathways: it reduces pain and inflammation, thins the blood, up-regulates AMPK to help burn fat, and as a negative side effect decreases the protective membranes in the lining of the stomach.

When used in a prophylactic context, salicylic acid and any associated prodrugs will blunt the inflammation response to any injury, large or small, inflicted on the athlete. Salicylic acid also greatly reduces the chances that a latent injury will be

108 aggravated when high performance is most necessary. It will additionally reduce or even eliminate loss of function associated with joint or muscle pain, keeping your athletic output at peak levels when you need it.

Salicylic acid is well tolerated with doses up to an entire gram exhibiting few side effects. One important side effect to note are salicylic acid’s anticoagulant properties. If you start bleeding, you will not stop for a surprisingly long time on higher doses. Salicylic acid and its derivatives are not recommended for sports where the body is routinely impacted, such as martial arts, football, hockey, etc. . CBD/CANNABADIOL AND LEUKOTRIENES

Cannabadiol (CBD) is an orally bioavailable, non- intoxicating analog of THC that is present in cannabis plants. CBD’s chemical cousin THC is a euphoric intoxicant classified by the military as a chemical weapon and currently the subject of a protracted legal and cultural battle. This simple plant is a polarizing focal point for the contrarian, independent nature of American culture and only recently became the a serious subject for scientific

109 research. We do not have a peer reviewed body of data on athletic enhancement to draw from. We do have compelling anecdotes, a well characterized biochemical pathway, in addition to several well respected and demonstrated minimal harms from CBD.

How is it possible that a molecule so structurally similar to THC doesn’t Blood-brain barrier: Cells lining the blood produce a 'high?' Your brain has an cells in the brain that keep out chemicals that additional layer of protection against could disrupt neural function. foreign chemicals that could interfere with its delicate operations called the blood- brain barrier. It is a final layer of defense after the liver; anything your liver chemically alters can’t cross from the bloodstream into the central nervous system. The minor difference between CBD and THC slows CBD from crossing into the brain, while the strong similarities allow CBD to exert effects on the rest of the body; and the effects it exerts are both very unique and powerful.

With CBD unable to access the brain in high concentration, it is confined to the bloodstream where it is free to exert a grab bag of biological effects. One of the more powerful effects is on the

110 immune system. CBD acts as a leukotriene, quickly altering the immune system in favor of less inflammation. Not only does it suppress interleukins responsible for causing inflammation, but also increases interleukins that attenuate the inflammation response. Combine that with a therapeutic index you could drive a truck through and you have an NSAID safer and more powerful than anything in the current pharmacopeia.

CBD has excellent potential for injury management, and especially for treating acute inflammation post exercise and post injury. However, it does come with particular challenges. The oral bioavailability of CBD is comically low, hovering around 6% with buccalingual not faring much better at a paltry 12-20%. The best and most convenient method is using a vaporizer, which renders bioavailability of 40-50%. With a half life of roughly 9 hours, CBD will protect your joints and encourage rapid recovery for a very long time.

CORTICOSTEROIDS

Commonly referred to in sports medicine as ‘steroids,’ corticosteroid injections and pills rely on

111 the anti-inflammatory effects of cortisol to soothe damaged tissue. While they’re the most powerful of the anti inflammatory drugs, they also come with brutal side effects that make long term use undesirable. They are similar in chemical structure to testosterone and other androgens which is why they have the same name in lay speak as anabolic hormones; “steroids.” Their effects are almost completely the opposite over the long term, however.

If testosterone analogues are anabolic, cortisol analogues are catabolic. Their effect is to break down muscle in an emergency to provide quick energy in a fight or flight situation. They are released naturally during periods of stress, and your baseline cortisol levels are an indicator of how much stress you’re experiencing. As a drug, they are taken orally to reduce inflammation or injected directly into a joint to reduce inflammation and restore function to a limb that’s been damaged.

Over time, chronic use of corticosteroids will deplete you. They cause fat to be stored in the cheeks and upper back while catabolizing muscle tissue. Many people experience a sort of trembling stimulatory

112 effect at higher doses. As an injected rescue drug, corticosteroids will preserve limb function despite injury and are spectacular for emergency situations. Because injections are applied directly to the effected tissue, there are far less concerns with weight gain and muscle catabolism.

For the purposes of our system, anti inflammatory drugs are taken prophylactically prior to a training event. A single dose of salicylic acid, preferably taken as aspirin, is used 30 minutes prior to exercise to keep joints soothed despite the impact that comes with training. If an injury occurs, CBD is used in addition to COX inhibitors to promote rapid healing. If a serious injury occurs that could interfere with daily life outside training, see a doctor about getting a cortisol injection as well as physical therapy.

Interestingly, aspirin/salicylic acid has fat- metabolizing properties in addition to being an anti inflammatory drug. These effects are discussed in the next chapter.

113 CHAPTER 6 - BODY COMPOSITION, INSULIN, AND AMPK

A low body fat percentage is the icing on the cake for those pursuing a serious health and fitness regimen. Fat cells, as you might expect, are about the laziest cells in your body. Called adipocytes, they do very little as far as gene expression goes. Their job is simply to store and release fat in the form of triglycerides on command. By now, you should Adipocyte: Cells that store fat and also have understand that tapping into these glandular functions, sending chemical signals biological signals is the key to controlling throughout the body. their function.

Adipocytes come in three varieties, two of which we care about. The two important ones are white adipocytes, who’s function is to store energy, and brown adipocytes who produce heat and keep your body at a comfortable 98.6º so you can efficiently carry out your metabolic functions. The third variety

114 lives inside your bone marrow and seems to contribute to bone health, though they haven’t been the subject of intensive study.

White adipocytes only expand when their capacity for storing fat is maxed out. They are also, as previously mentioned, responsible for creating estrogen from testosterone as well as hunger signaling. The nucleus of the cell is squished off to the side like an afterthought, and they can be as large as 2mm in diameter which is huge for an individual cell. Adipocytes are stimulated to aggressively store fat when exposed to insulin, which we will discuss at length later in this chapter.

Brown adipocytes get their distinct color from their high mitochondrial density. Rather than storing fat, their job is to burn it to produce heat. Tissues composed of brown adipocytes is called 'brown adipose tissue' which is abbreviated as BAT. Burning off BAT is notoriously difficult, particularly if your only tool is exercise. We will, of course, be discussing how to manipulate their chemical signaling.

115 The transport, storage, and metabolism of fat is a complicated, multi step chain that has to be maximized at every opportunity to prevent storage of fat while maximizing its use as a fuel. Careful attention must be made both to factors which encourage fat use and stop the storage of fats. This book details the two most accessible, AMP-K and insulin signaling. Because body fat levels are tightly related to energy use, hundreds of pathways exert an influence.

Body fat as a fuel is analogous to diesel oil. With more than twice the energy per gram of carbohydrates and proteins and nearly infinite storage capacity, fat depots are there to keep you alive. It is slow as fuels go, yet under the right conditions is actually your body’s preferred source of calories as it goes about its mundane daily activities. The others (carbohydrates and protein catabolism,) are typically only used when energy demand is high such as when you exercise.

Relying solely on reducing calories to encourage fat metabolism is a savage practice that, as the epidemiology data shows, is ineffective at controlling weight loss within a population. You need to

116 convince you body it’s okay to use your fat for fuel, and we will be taking a multi-pronged approach to achieve this. Diet and exercise certainly being factors, we are going to further explore the 'whys' behind how and why specific regimens work. For the experienced coach or athlete, some of this is going to look very familiar.

INSULIN

Insulin is a buzzword in the fitness and nutrition fields these days, and for good reason It is powerfully, and recklessly, anabolic. Part of this means insulin does in fact assist in building muscle, and back in the 90’s, somebody read a paragraph in a medical textbook that said insulin was “anabolic” and made it the subject of a bodybuilding magazine article. Then several bodybuilders self-induced hypoglycemia by injecting insulin after a workout only to wake up on the floor with a doctor who happened to be nearby at the time pouring sugar packets into their mouths.

Insulin will exert effects on muscle tissue regardless of injecting it or not. Using artificial insulin is insane and these days, far too expensive. Your pancreas

117 can produce it in near unlimited quantities. Unfortunately, not only does insulin also encourage fat storage, but when insulin is high burning fat is next to impossible. These facts lead to familiar advice - avoid simple sugars with the exception of 90 minutes following a bout of intense training. Simple sugars and even some of the simpler carbohydrates have a higher glycemic index, meaning that more insulin is secreted per unit mass of carbohydrate. This has the effect of lowering blood sugar which, like a crackhead, makes you immediately crave more simple carbs for a rapid uptick in blood sugar.

The author’s knowledge of nutrition science being scant (it appears nutrition science is about as granular as surgery was in the 1800’s) the only advice AUGMENTED can render is to avoid simple carbs and particularly fructose in an effort to allow fat to be used as fuel. This will also cause a lower fraction of calories consumed to be stored as fat, upending the idea that there is a direct correlation between calories and body fat. The relationship between the two is not nearly as tight as nutrition science would have you believe. If you want to lower

118 your body fat, and you should, your first step is to control your insulin.

APIDOCYTES AND AROMATASE

Fat tissue, in addition to storing energy and making you look fat, also functions as a gland and has some say in how your hormones function. Excess body fat does an excellent job of jamming your cell signaling in multiple ways. It reduces your sensitivity to your own insulin, forcing your body to pump out more per gram of sugar consumed, making you even fatter. It also lowers your surface area in ratio to your overall body mass, basically giving your body a layer of insulation which makes you less efficient at shedding body heat and lowering your BMR. Finally, it converts more of your free testosterone into estrogen, short circuiting your HPG axis, lowering your testosterone, and ultimately making you fatter.

If you or your client has a significant amount of body fat, testosterone levels will naturally be suppressed by the HPG axis’ feedback mechanisms. It will be necessary to use aromatase inhibitors to allow for higher levels of endogenous testosterone, let alone preserving any supplementary hormones provided

119 via HRT. Otherwise, the heightened estrogen will blunt testosterone levels and potentially result in hypogonadism that may well take weeks if not months to undo.

AMP-K AND SALICYLIC ACID

The biochemical pathways that guide the use of fat as a fuel are very complicated, which makes them very susceptible to being manipulated. A molecule of fat has to first be stored in adipocytes, then be released on demand, transported into the inside of a cell, chaperoned to the mitochondria and then Author’s Note: This diagram is here to show you exactly how complicated AMPK is and display the depth of its oxidized to produce ATP. reach in your body. Notice it works closely with mTOR. Image downloaded from: Experimental & Molecular Mechanically, body fat is Medicine (2016) 48, e245; doi:10.1038/emm.2016.81 nearly literally 'burned' by your mitochondria and is ultimately converted into carbon dioxide and water. Since heavy breathing doesn’t rapidly reduce body fat, we have to assume

120 that there are several steps between a fat molecule being stored in an adipocyte to it being burned in your mitochondria.

The most direct and easily activated step on this long journey is AMP-K (AMP activated protein kinase.) AMPK is a key part of the biochemical pathway that burns fat. It essentially notices burnt- out molecules of ATP (ADP and AMP) then demands more body fat from the cells and encourages the mitochondria to use fat as a fuel. Needless to say, this is something you absolutely want to encourage. As it turns out, encouraging it is as simple as popping a few aspirin. The experiments confirming this were performed on rats, which is entirely okay. AMPK is what biologists call ‘highly conserved,’ meaning nearly all living things have it with very little alteration. If it works on a rat it will very likely work on you as well.

Salicylic acid directly activates AMPK and ramps up its activity over 100 fold. Remember in an earlier chapter we explained that aspirin is a prodrug? It ultimately produces salicylic acid making it a nearly ideal fat burner.

121 Current experimental regimens use doses of salicylic acid which hover close to toxic concentrations. Anecdotally, ECA stacks (ephedrine, caffeine, aspirin, a solid piece of polypharmacy,) were extremely effective prior to the FDA’s ban on ephedra. These products contained doses of salicylic acid which were more consistent with traditional therapeutic doses. Based on this historical data, 2000-4000mg per day is likely to make a significant contribution to fat reduction and is fairly well tolerated. Some medically approved regimens for treatment of rheumatic disease use up to 6000mg/day, so we can assume the lower amount is safe.

Caveats? Any clinician will tell you that Aspirin makes it difficult for blood to clot.

Body fat control is a complex issue, and it can be challenging to pinpoint a regimen that burns it as fast as the client will almost definitely want. Insulin management via nutrition discipline and enhancing AMPK signaling via salicylic acid are two relatively easy methods to accelerate fat expenditure. Coaches are encouraged to experiment with a variety of credible protocols regarding diet and

122 exercise to optimize their client’s results. Bear in mind that the adipose tissue is in itself a source of cell signaling, and as body composition changes cell signaling is altered with it. Frequent assessments and alterations to protocols as needed are strongly encouraged.

AUGMENTED further advises that caloric restriction be applied as a last resort and enhanced with heavy leucine supplementation to avoid metabolic downturn. Coaches are further admonished to take ease of client compliance into heavy consideration during protocol creation, as in the author’s experience this is the primary driver of success and failure.

123 CHAPTER 7 - AUGMENTING THE CENTRAL NERVOUS SYSTEM

Unlike other chapters in this book, we won’t be discussing a single pathway in this chapter but instead an entire organ. The brain is ultra sophisticated and unlike biochemical pathways, works so fast and with such a degree of precision that makes it impossible to meaningfully observe in real time in a living organism. If ever there was a situation where the content is overwhelmingly complex, studying the human brain is certainly it. So true to our philosophy, rather than trying to describe the content of how the brain works we are going to look at it in context and monitor the outputs.

Your brain has a direct and powerful impact on your physical prowess. The better your brain works, the better you work. It impacts your decision making, your judgement, the precision and power of your movement, and the fidelity of your hormone signaling. The brain has several different sub- organs, such as the temporal lobe or motor cortex, that govern different functions. It works by

124 Neural Pathway: A combining both biochemical pathways system in the brain that uses a combination of which we already understand, and nerve circuits and chemical signals to create neural pathways which are more like a biological effect. a wired circuit. Your brain has more Hebbian Theory: The potential neural pathways than there more a neural pathway is used, the stronger the are atoms in the universe. The brain is signal it creates and the easier it is to use. This is self-reinforcing, meaning the more a the biological basis of what we call ‘habits.’ neural pathway is used, the stronger Hebbian theory is succinctly described as the signal it sends in a phenomenon ‘nerves that fire together called Hebbian theory. wire together.’

Manipulating the neural and biochemical pathways in your brain is essentially just learning. But once you understand how and why the brain learns, it’s much easier to coax it into habitually executing the behaviors you want to develop. The more you repeat a behavior the easier it becomes for your brain to execute, nearly everyone understands this on an instinctual level. What they may not know is that there are pharmaceutical ways to accelerate this phenomenon. Additionally, there are roles that the brain plays in movement that are not well known to most people, roles that we will learn to augment in multiple ways.

125 NEURONS

Neurons are the name for cells that make up nerve tissue. Your brain is in essence a densely packed, coherently organized bundle of nerves that extend into your body via your spinal cord. They behave like small computers, batteries, and wires at the same time, transmitting signal through your body at about the speed of sound. A chain of neurons is called a nerve, and is best thought of as a wire that quickly transmits a signal from one specific location to another in your body.

Most of your body is focused on homeostasis, keeping everything as consistent as possible. Your nerve cells do the opposite; their purpose is to change and adapt with your environment, quickly. They are where your intellect and judgement begin. Nerve cells are capable of altering themselves to suit your environment, and they can do so extremely efficiently. If you think this sounds like a feature we can readily direct and exploit, you’re absolutely right. We’re about to discover the depth of your nerve cell’s reach, and how to make them do what we want.

126 INNERVATION, STRENGTH, AND POWER

Legends abound in the popular culture of otherwise completely unconditioned people displaying momentary superhuman strength. Grandmothers whose grandchildren became trapped under cars lifted the car, rescuing their child. Inmates in mental institutions bending the bars on their holding cells or snapping handcuffs. Drug users fighting multiple police officers with relentless intensity, driving their metabolic demand so high that their lungs could not replenish their oxygen supply and they died, essentially suffocating at a cellular level in the open air.

These people did not have big muscles, yet they performed incredible feats of strength. How is this possible?

There is a direct connection between the quality of your brain function and your strength and athletic skill. As it turns out, contracting a muscle under normal conditions recruits very few muscle cells. Our ability to move a given weight is largely dependent not on the size of the muscle as previously

127 assumed, but more so on our ability to recruit muscle cells in a coordinated manner. Muscle tissue is capable of contractions much greater than what is asked of them in day to day life, and even in the gym. To become truly strong, muscular hypertrophy alone is not enough. You need to train Innervation: Growth of in such a way that encourages both nerve axons into tissue, typically innervation and enhances the quality of muscle, that allows the brain to control it your motor cortex. better.

Innervation is the growth of new nerves Motor Cortex: The area of the brain that is into the muscle tissue that allows the responsible for movement. It requires brain to get a stronger contraction out just as much, if not more, training than of a muscle. Every single muscle fiber your muscles. is activated by a motor nerve, and there are training methods that make these nerves send stronger and more powerful impulses to the muscle. There are also pharmaceuticals that work on the CNS which also increase this impulse, but they are heavily controlled, dangerous, addictive, and not worth discussing in detail. The StrongFirst organization has developed training regimens that are highly effective in developing innervation based strength, and the book Power to the People! by Pavel Tsatsouline (who is also chairman of

128 StrongFirst,) is a concise and very actionable read on the subject.

NEUROSTEROIDS

There are several steroids which directly impact the function of your brain. We have already discussed androgens and estrogens, and both have an impact on your mood and energy levels. These are classified as drugs and are available by prescription only.

Strangely, two hormone precursors are available at your local vitamin shop and they have powerful and complementary neurological effects. Neurosteroids have subtle effects that manifest over the long term, protecting the nerves you have and encouraging your nerve cells to form stronger connections which is key to developing new skills.

Dehydroepiandrostenedione (DHEA): A neurosteroid with a ridiculously long name and a mercifully short acronym. DHEA is a sex hormone precursor that metabolizes into androstenedione and from there, into testosterone or estrogen. In addition

129 to being a feedstock for sex hormones, it has measurable neurological effects.

Rather than acting as a direct stimulant, DHEA sensitizes the brain GABA pathway: The circuits in your brain that use to its own, natural, stimulatory effects. Gamma-amino butyric acid as a chemical signal. The DHEA inhibits the GABA pathway, GABA pathway generally acts as a means of soothing the which is the system your brain uses to brain at a cellular level. Valium based drugs and soothe itself. This results in slightly alcohol are two drug substances that activate it. stronger neurochemical signals which ultimately accelerate motor skill acquisition, learning, and habit formation.

DHEA is very inexpensive, costing roughly $1 USD per gram when purchased in bulk. A good daily dose is roughly 50mg, taken at breakfast. Do not expect rapid effects. DHEA will subtly increase the brain’s ability to adapt and form habits. These habits will be a direct result of your interaction with your environment and are agnostic of whether or not they are productive. The old programmer axiom ‘garbage in garbage out’ definitely applies here. If you choose to use DHEA to accelerate learning, make certain you are very conscientious about your behavior and reactions throughout your day, because every input you give to your brain will be amplified.

130 Pregnenolone: Pregnenolone is the immediate precursor to DHEA, and has nearly the opposite effects on your neurology as DHEA. It sensitizes your brain to GABA ultimately producing a soothing effect. This substance essentially reverses the effects of DHEA. Pregnenolone is most useful for enhancing the effects of sleep. Not only will it allow for better rest quality, but as your HPG axis activates in your sleep, pregnenolone will metabolize into testosterone.

OTHER SUPPLEMENTS: Safe and effective substances for improving brain function are not limited to steroids. There are a few supplements that are so effective and benign that they need to be discussed. As with the neurosteroids mentions above, these can be bought for very little money at your neighborhood supplement store and they are highly unlikely to produce any unwanted effects.

Ginko Biloba: Ginko Biloba increases blood flow throughout the brain, improving both cognition and memory. Providing more oxygen and nutrients to the nerve cells allows them to fire and recharge

131 more rapidly, essentially overclocking your brain. Users of ginkgo report a rapid onset, with focus and memory improving in less than 20 minutes. Unlike prescription cognitive enhancers such as amphetamine, ginkgo renders a mental edge without a high. 120 mg, two times per day, taken with a meal, will produce optimal results.

Theanine/Caffeine: This is a wonderful, synergistic combination. Caffeine of course provides stimulation, alertness, and the ability to focus. Theanine enhances the focus effect while drastically reducing some of the jittery side effects of caffeine. The two together produce a cognitive edge without the negative effects that come with prescription stimulants. A 1:2 ratio of caffeine and theanine, respectively, in the morning can work wonders for your productivity. Recommended dose is 100mg of caffeine and 200mg of theanine.

5-hydroxy tryptophan (5-HTP): 5-HTP is a direct chemical precursor to serotonin and makes it easy for your brain to produce this antidepressant neurotransmitter. The effects are mild, but can make a huge difference in your productivity, particularly if

132 you occasionally struggle with a lack of motivation or energy.

GABA: Actual GABA, the soothing inhibitory neurotransmitter, is shockingly orally bioavailable. FDA has granted it GRAS (generally recognized as safe) status and it is sold as a supplement. It is inexpensive and effective for enhancing sleep and in some limited cases reducing anxiety. For some, particularly those suffering from PTSD, it immensely enhances quality of life. Dose should be between 200-500mg/day at bedtime.

FURTHER READING:

The author is far from a subject matter expert on neurology and the information presented here should be considered to be a starting point for enhancing your brain function. This chapter has borrowed heavily from the work of Doctor Daniel Amen, M.D., who has authored several excellent books which are very readable despite the complexity of the subject being discussed. You are strongly encouraged to peruse his work, as it will

133 open entirely new frontiers for enhancing your productivity and living your best possible life.

134 CHAPTER - 8 AD, THE ANDROGEN PATHWAY

“Buckle up baby, the androgen chapter is gonna be a monster and understanding it is important for designing your own programs.”

~ Jordan G. Cimino, M.Sci, author of AUGMENTED

Before we can understand how synthetic versions of testosterone work, we need to know how the original molecule functions in the body. Your endocrine system is a very delicate and highly tuned pathway, and if you're imprecise with it, it will absolutely rebel. While complicated, it doesn’t take a genius to understand the mechanics of how it works. That said, to understand what is discussed in this chapter you will need a firm grasp on the principles of pharmacology discussed earlier.

Pharmacophore: The basic At right (and on the cover of this chemical structure needed for a molecule to interact with a book,) is the steroid pharmacophore. ligand. Words such as ‘steroid’ or ‘tryptamine’ refer to chemical It is the template from which all structures associated with a particular biochemical pathway. steroids, from testosterone to Scientists experiment with chemically modified hydrocortisone to estrogen, comes pharmacophores to see if they have medicinal activity.

135 from. Different functional group or moieties Moiety: A named chemical feature, (MOY-et-eez) attached at specific places at such as an alcohol or a ketone, that is the pharmacophore give the steroid its’ part of the structure function. of a larger molecule.

There are three key features a steroid HAS to have if it's going to function as an anabolic drug:

1. A steroid skeleton. This has four carbon rings, three hexagons, one pentagon. The rings are named A through D. This gives the steroid consistent shape and the right dimensions to fit into its intended receptors. The carbon atoms in steroid skeleton are assigned numbers. Chemists use this to describe what additional moieties go where. The additional atoms are also given Greek letters 'alpha' means the atoms are facing away from us, 'beta' means they're Chirality: Molecules can be left or right handed, much like your left and right facing towards us. It seems like a hands. They are composed of the same elements, in the same subtle distinction, but when it configurations, just mirror images of each other, like your hands. Flipping a comes to steroid function this molecule to it’s mirror image can drastically change biological effects. matters in a big way. We call this ‘Chiral’ means ‘hand’ in ancient Greek. chirality and it's one of the more difficult concepts for chemistry students to grasp.

136 2. A ketone group at carbon #3. There are a few exceptions to this which we will address. A 'ketone' is an atom of oxygen double bonded to an atom of carbon. The carbon atom cannot be at the end of a chain.

3. A beta (not alpha) hydroxyl group at carbon #17. Hydroxyl is a carbon atom bonded to an oxygen atom bonded to a hydrogen atom. In the diagram it will look like an 'OH'. You'll notice in the 3D model, the hydroxyl (a.k.a alcohol,) it's facing towards us. If the hydroxyl is on the other side, the steroid will not bond to the receptor. It is that picky.

Once a steroid has these features, it can activate the androgen receptor. Author’s note: This is a testosterone molecule. The double bonded oxygen atom at carbon #3 is a ketone. The single bonded oxygen at carbon #17 is an alcohol, and There are other features that there’s a double bond between carbons 4-5. a synthetic steroid can have which allow it to do other things. For example, notice the single carbon atom sticking up between rings A and B? That's carbon 19. It doesn't do much as far as activating the

137 androgen receptor goes. However, aromatase, the enzyme that manufactures estrogen from testosterone, needs that carbon. It essentially burns carbon Estrogen: Notice the extreme similarity to 19, and the testosterone. Carbon 19 has been burned rearrangement of away changing the configuration of the A-ring. electrons in the steroid skeleton quickly converts testosterone (and androstenedione) into an estrogen. So if a steroid has a ketone at carbon 3, a double bond at carbon 4, and a carbon 19 (and nothing else in the A ring) the body can turn it into estrogen. If it doesn't have all these features, aromatase can't make estrogen out of it.

It is important to reiterate that aromatase exists in high ratios in fat tissue.

Good to know, right?

In the early days of bodybuilding, steroids were uncontrolled and sold mail-order in the back of superman comics along with decoder rings and X- Ray vision glasses. The gym lore in the day divided

138 steroids into two large classes; 'cutting' steroids (for losing weight and gaining definition,) and 'bulking' steroids (for gaining strength and mass.)

What drives these both these effects is simply, estrogen. Any aromatize-able steroid will have a small fraction (roughly 0.3%,) converted to estrogen. Don’t let this seemingly small number fool you. Estrogen is potent at microgram, not milligram doses. Once it reaches a dose where the androgen receptors are fully occupied and the concentration is above MTC, ALL the testosterone gets converted to estrogen. This is one of the reasons why dose management is extremely important, as is constantly monitoring your hormone levels. Interestingly enough, estrogen does have some performance enhancing effects.

Among other things, estrogen causes you to retain water. This water collects directly under the skin and in the joints. The water that collects under the skin gives the appearance of greater size. The water that collects in the joints cushions the cartilage and connective tissue, blunting the baroreceptors, pain, and blocking neurofeedback that tells you a given weight is too heavy, lending the appearance of

139 greater strength and allowing for more intense workouts.

The extra estrogen will also likely make you emotional, crush anything that resembles libido, shrink your testicles, and makes Gynecomastia: Excess development you very prone to injury as your body is no of breast tissue in a male, colloquially longer able to gauge whether a given called ‘bitch tits.’ In many cases can only weight is safe for your tendons. Your be treated with SHBG levels skyrocket and absorb a surgery. significant portion of your androgens. It will also cause other unwanted effects; gynecomastia for sure, psychological instability, fat deposits in the gluteus and triceps, and maybe even a widening of the hips. Controlling estrogen while using steroid-based PEDs is the keystone of safe, effective use.

Historically, the notion of post-cycle therapy (PCT) was intended to help an Post-Cycle Therapy (PCT): A regimen of anti estrogens and athlete who had foolishly abused gonadotropins intended to repair an athlete’s HPG axis steroids reboot his endocrine system after several weeks of ultra- high doses of androgens. and get it functioning with some AUGMENTED categorically rejects this abusive approach semblance of normality. These are the to use of PEDs. same people who would 'stack' multiple, redundant drugs in the hopes it would

140 exert some kind of synergistic effect. In truth, it just skyrocketed the side effects creating a tangle of biological missteps that could take months to unravel.

Rather than attempting to fix a hormonal feedback mess that took months to make, this book advocates a more granular approach which combines regular hormone level monitoring and prophylactic antiestrogens or aromatase inhibitors to stave off unwanted side effects before they occur. The procedure for balancing your hormones throughout the cycle will be detailed in later chapters, as will the drugs involved.

Getting itself turned into estrogen isn't the only stupid trick testosterone is capable of. It also can be converted into a more potent androgen, DHT. DHT is essentially the same as regular testosterone, but the double-bond at carbon four is replaced by two hydrogen atoms. Though this seems like a minor modification, DHT is five times more powerful an androgen than testosterone. The conversion occurs mostly inside skin and hair follicle cells, and this narrow volume of distribution results in some unwanted effects.

141 And what might these unwanted effects be? Androgens that interact with skin cells cause your face and brow and back to excrete extra oil. This extra oil clogs your pores, resulting in acne. As if this weren't attractive enough, DHT also beautifies your hair by making it fall out, male pattern baldness style. The medical term for this baldness directly indicts DHT as a cause; androgenic alopecia.

Paradoxically, DHT causes you to grow extra hair from your neck down to your ankles. Over time, excess testosterone will cause your heart to grow to the size of your head, and will also impart an equally freaky big penis that is prone to erectile dysfunction. All the while the excess estrogen causes you to develop female secondary characteristics.

Collectively, the effects of androgens Virilization: are grouped together in a single word, Hormonally induced male characteristics. virilization. It is an effect that makes This includes a broadened brow and you gravitate towards having more shoulders, deepened voice, body hair, and male features. Most people are denser muscles. surprised to learn that every single human fetus is anatomically female, with testosterone exposure during pregnancy causing the

142 fetus’ anatomy to shift from female to male. In genetically male fetuses with mutant versions of the androgen receptor, male sex characteristics never develop and they are born anatomically female despite the presence of a Y chromosome.

And what, exactly, does virilization entail? Everything that happened to you at about 12. More body hair, higher muscle density. A broadening of the brow, jaw, and shoulders. A deeper voice. Sharply increased libido. Higher mental alertness and an improved ability to read other’s emotional states. Paradoxically, it also causes more selfish behavior along with a decreased sensitivity to risk. When these Hirutism: Unwanted, hormonally induced male effects occur in a woman, it is not characteristics in a female. Particularly facial hair and a called virilization but hirsutism and deepening of the voice. Generally considered a is regarded as a harmful side effect. negative side effect.

One final factor worth mentioning in the pharmacology of steroids is the proverbial onion in the ointment, sex hormone binding globulin or SHBG. This is a protein circulating in your blood with active sites that cling to androgens and estrogens, then does nothing with them. It is intended to be a regulator of hormone levels. Sex

143 hormones bound to SHBG are essentially de-activated, and SHBG can be thought of as a kind of flypaper for steroids. When measuring overall testosterone Sex Hormone Binding Globulin: levels, 'free' testosterone is the Seen above as a ribbon model bound with a single molecule of important factor, meaning that which testosterone, center left. SHBG can hold up to eight molecules of is unbound to SHBG. At right, we sex hormones, irrespective of can see a ribbon model of SHBG type. with a molecule of testosterone bound to it in green center left.

So what determines your levels of SHBG? Two factors, thyroid hormones and estrogen levels, seem to exert a strong influence on the concentration of SHBG in your blood. The more estrogen, the higher the SHBG. You will learn to take control of your estrogen levels in a dedicated section to aromatase inhibition.

The Androgen pathway is manipulated by what are colloquially called ‘anabolic steroids.’ Many of these drugs are prodrugs for natural sex hormones. The rest are chemically close but are modified to slightly alter their effects. Some are more powerful than

144 natural testosterone. Several are poisonous to the liver.

From the 1930’s on, chemists were very focused on making minor alterations to testosterone’s structure in the hope of creating a drug that would yield the muscle building results of androgens without the virilizing effects such as facial hair, oily skin, and a broadened jaw. A standard was established where the weight ratio of the prostate gland to a specific muscle (levator scapulae, a small muscle in the neck,) was used after extensive androgen therapy to determine the anabolism versus androgenicity of the steroid. Scientists called this the anabolic to androgenic ratio, or A:A for short. Testosterone was assigned a 1:1 ratio as a baseline. By way of comparison, oxandrolone came in at 10:1 and stanazolol an impressive 30:1. Certain SARMs, which we’ll cover in a later chapter, have ratios as high as 90:1.

145 CHAPTER 9 - THE PHARMACOLOGY OF ANABOLIC STEROIDS 'Pharmacology is benefited by the prepared mind. You need to know what you are looking for.'

Siddhartha Mukherjee - The Emperor of All Maladies

As the title implies, this chapter will go into detail on the pharmacology of several PEDs. This is not intended to be an exhaustive list. There are hundreds of varieties of anabolic steroids that have been synthesized all over the world. The steroids here were chosen based on a few factors, primarily their availability through proper medical channels. Because FDA requirements for marketing a drug in the USA are so stringent, we can confidently say they are both safe and effective.

Literal thousands of anabolic compounds exist, but very few have approved Indication: The disease state a drug is approved indications in the US or EU. Those to treat. For example, testosterone cypionate which did not stand up to the high is approved to treat primary hypogonadism standards set forth by the regulatory in males. bodies of these nations aren’t worth including, as they are less effective and

146 more dangerous. Those which are included are distributed in their respective nations via established channels for pharmaceuticals, ICH (International Counsel of manufactured to high standards of purity Harmonization) A transnational organization and potency, and have had their biological that standardizes effects exhaustively characterized per ICH pharmacology worldwide. guidelines.

With black or grey market steroids, you have absolutely no idea what you are actually taking. It could be what you think you paid for. It could be grapeseed oil with DHEA in it, a cheap androgen precursor that is very difficult to distinguish from an active androgen (aside from the fact it won’t increase your muscle mass.) It could be just grapeseed oil in a glass vial. On the flip side, it could be several orders of magnitude more potent than what the label states which practically ensures an overdose. This is why part of the AUGMENTED ethos is to obtain androgens from a proper pharmacy with a legitimate prescription.

During what is called the golden age of steroid research, the aim of medicinal chemists was to create a chemical cousin of testosterone that had all of the benefits and none of the drawbacks. The

147 overall aim was to produce a steroid that increased muscle mass without any virilizing effects such as increased body/facial hair or male pattern baldness. Researchers were especially interested in substances that increased muscle mass, and in their efforts created thousands of testosterone analogues. It is the very best of these analogues and their various effects that this chapter will address.

Not a single one was perfect, but they Structure-Activity made several important discoveries that Relationship (SAR): How the chemical structure of a drug shed light on how the chemical effects the biological effects it produces. SAR depends on structure of an androgen influenced the a drug having the correct shape along with the correct biological effects it created. We call the electrochemical charge to relationship between chemical structure interact with a receptor. and physiological outcome Structure Activity Relationship, or SAR. Understanding SAR as it relates to steroids will help you predict the effects of any given androgen based on chemical structure alone.

This chapter is the one you will continually refer back to. It contains historical, anecdotal, and pharmacological information on the best performance enhancing steroids available. We’re going to start our with the most common steroids,

148 with well characterized effects based off decades of use. Then we’ll move on to some of the more exotic ones. It should be assumed that if a steroid is not listed here it is to be avoided.

The drugs are described using a format that is similar to the package insert required for all drugs distributed in the US. We first discuss the indication, followed by medical dosing, potential side effects, and a brief discussion of the biology followed by anecdotal notes on each will follow.

TESTOSTERONE:

By far the most common steroidal PED is testosterone. Your body literally makes it naturally. It is medically available in many forms, and a doctor can prescribe it for several different disease states. It is extremely easy and inexpensive to manufacture at industrial scale. This section will detail several different drugs that get testosterone into your bloodstream. While they have several different names, in the end they all raise the level of testosterone in your bloodstream. It is very important to understand they pharmacokinetics of

149 the testosterone you’re running to achieve a worthwhile CSS.

Like most steroid hormones, testosterone has a grab bag of biological effects. To demonstrate the wide variety of effects testosterone has in your body, consider this. All embryos start out anatomically female. Male fetuses are exposed to a super-dose of testosterone in the womb, which literally converts them from female to male. A second round of testosterone at about two years of age virilizes the brain. The third, which occurs at the onset of puberty, results in secondary sex characteristics. A broadening of the brow and shoulders, increased body hair, deepening of the voice, and greater muscle density all present with this third round of hormone spikes.

Testosterone continues to make its’ presence felt throughout adulthood. People with high testosterone naturally carry more muscles mass, have higher bone densities, report higher libido, and tend to have a preference for high-risk professions. They also carry their adipose (body fat,) differently, with less fat deposited in the face and more gravitating towards the lower abdomen.

150 Unfortunately, testosterone itself has next to zero oral bioavailability. The probiotics in your gut are very fond of eating it for you, well before it hits your bloodstream. If that weren’t enough, the small fraction that does get absorbed intact by the intestines gets decimated by your liver in first pass hepatic metabolism. The only two viable routes of administration for raw testosterone are injections and transdermal gels. Gels have a relatively low bioavailability, hovering at around 10%. Injections offer 100% bioavailability but run the risk of infection and heavy hormone fluctuation that can dysregulate your endocrine system over time. Shots of pure testosterone last 4-8 hours before wearing off completely, and then there you are.

TESTOSTERONE: ESTERS AND ETHERS

Testosterone ethers and esters (ending with ethanate, acetate, cypionate, and others,) are inactive prodrugs when first injected. They’re referred to as esters and ethers, based on the kind of chemical bond that keeps it inactive during storage. Doctors tend to prefer esters and ethers because they require weekly visits, resulting in more

151 office visit fees and allowing for better Deposition: An monitoring of the patients progress. Their injection into the muscle tissue that job is to sit in what’s called a deposition lingers for a long period of time, slowly of oil in your fat tissue, where it’s slowly releasing a drug substance into the broken down into active testosterone bloodstream. which then seeps into your bloodstream. The rate at which these injections turn into active testosterone is the half life. The shorter the half life, the faster it breaks down into testosterone and the more frequently you’ll need to inject. For testosterone cypionate, this sits at roughly eight days.

Biologically, this treatment is a Author’s Note: I personally take 100mg of testosterone cypionate per little offbeat. The release of week. I am known for having near interminable patience but even this testosterone is tied to your low dose of androgens makes it hard to control my emotions the day I get circadian rhythms, and the my injections. Please monitor yourself and believe others when constant feed of hormones into they say you’re acting differently. your bloodstream throws everything a little out of sync. Testosterone is released while you’re in your deepest sleep, while your body is undergoing a myriad of growth and repair tasks. It is relatively low during the day. Compromising this, running high test during your waking hours may contribute to the reported irritability and aggression known as 'roid

152 rage. It may also result in a higher fraction ‘Roid Rage: Street term for extreme of the testosterone being converted into irritability caused by excess use of estrogens, which in turn likely contributes anabolic steroids. to ‘roid rage.

Naturally, testosterone runs in bursts and your levels are highest in the early morning hours. Constantly bathing your muscle cells in androgens isn’t necessary to keep them running at peak levels. Like we discussed earlier, once a cell receives the testosterone signal it starts making changes to how it expresses your DNA right away, and these changes can take hours or even days to come to completion. Any excess will contribute to unwanted effects, many of which are purely psychological.

The other current standard of care for administering testosterone is Androgel. Androgel is, essentially, (literally,) hand sanitizer with testosterone dissolved into it. It contains ethyl alcohol, used to dissolve the testosterone, isopropyl mysterate which both makes the solution a gel and helps your skin absorb the active ingredient, and of course testosterone.

While this treatment is easily performed at home, it does have drawbacks. First of all, bioavailability

153 lingers at around 10% which is fairly low. You have to remember to dose daily which can be a challenge for some people. Finally, there is a danger of contact dosing with women or children, which over time can effect their hormones as well.

There are also benefits, however. It is possible to emulate your body’s own circadian release of testosterone by applying Androgel at bedtime, allowing you to run normal levels of testosterone during the day and minimizing the side effects. In order to maximize the transdermal absorption and minimize the risk of transferring active androgens to women or children, it is best to apply Androgel in your underarms or between your upper thighs behind your testicles. Bear in mind the latter option may burn as the alcohol evaporates. There is a product on the market, Axiron by Eli-Lily, that is intended to be applied to the underarm.

METHYLTESTOSTERONE

As we discussed earlier, your gut bacteria loves to eat the alcohol group off carbon 17 on just about any steroid you take orally. One of the very first successful attempts involved chemically protecting

154 the alcohol by adding a short carbon chain called an 'alkyl group' to protect the alcohol group. This had two effects; it kept the gut bacteria from eating the steroid, and unfortunately made it liver toxic as well. Many steroids have this chemical feature, and are known collectively as 17-alpha-alkylated steroids. The 'alpha' means that the carbon chain is facing away from us, and the alcohol is facing towards us.

Biologically, it’s effects are almost indistinguishable from testosterone except for a slightly longer half life. The combination of liver toxicity without any real added benefit makes this a steroid to avoid. Unless you have an iron liver and are seriously averse to needles or gels, there are more effective, cheaper, safer options. (Reality check; you do NOT have an iron liver and should not be frightened of periodic injections.)

STANAZOLOL (WINSTROL)

INDICATION: Stanazolol Stanazolol: Notice the unique, five ring chemical began life with multiple structure along with the lack of a double bond in the A ring. indications; to treat wasting

155 states and as a growth promoter for people with dwarfism. It has had all medical indications supplanted by superior drugs making it somewhat difficult to obtain via pharmacy channels, and it is no longer marketed in the United States. This substance can still be prescribed off-label and may be available at compounding pharmacies. It is included here because it is so common, albeit increasingly difficult to obtain.

DOSING: Stanazolol is available in 2mg tablets, though the recommended dose for individuals wanting to add long term muscle mass seems to be 25mg daily, or 50mg every other day. It can also be injected into fatty tissues where it will slowly enter the bloodstream.

SIDE EFFECTS: Stanazolol is 17-a alkylated, making it somewhat liver toxic in the oral route. It is not recommended for pregnant or lactating women as it readily crosses the placental barrier and can cause deformities. It can also be passed to the infant via breast milk, is orally bioavailable, and will have a detrimental effect on an infant’s development.

156 SUMMARY: Known colloquially as 'winny,' stanazolol is fairly unique. It is one of the few steroidal PEDs that contains nitrogen. The added nitrogen gives it some unique properties, making it more water-like. It also allows it to form a microcrystalline suspension in water, and is also fairly water soluble. This unique chemical structure makes it fairly resistant to metabolism.

Biologically, it has potency for the androgen receptor that rivals DHT. Not only does it almost completely ignore SHBG, but it can actually lower SHBG levels making it a great choice should find your ratio of free to bound testosterone to be too low. It also has a half-life of nearly 24 hours making once a day dosing feasible and increasing it’s potency further. The molecular structure of stanazolol makes conversion into estrogen via aromatase literally impossible.

As far as synthetic steroids go stanazolol is fairy close to perfect. It is potent at low doses, has little downstream effects on the HPG axis, (in fact it improves on some key metrics of sex hormone health,) and is legally available via a prescription. However, it does confound the results of the

157 androgen assays we will be using to determine the results of the supplementation regimens. It certainly has a place in the AUGMENTED system, but not as a primary androgen. It is recommended stanazolol be employed ONLY when an unfavorable ratio of free to bound testosterone is found, and then only at low doses to lower levels of SHBG.

OXANDROLONE (ANAVAR)

INDICATIONS: Anavar is used to treat a variety of conditions. From pain caused by osteoporosis to post-surgical recovery to counteracting the effects of corticosteroids, oxandrolone is a nearly ideal synthetic androgen. It is one of the few remaining androgens available in the United States via pharmacy channels.

DOSING: 2.5mg daily with escalating doses up to 40mg have been noted to be effective in creating decent lean body mass.

SIDE EFFECTS: Typical of androgens, Anavar virilizes any tissues it comes in contact with. For

158 women in particular, this means facial hair, acne, and a widening of the jaw and brow.

SUMMARY: Anavar is particularly safe and relatively side effect free as far as androgens go. It is incapable of aromatization and surprisingly non liver toxic for an orally bioavailable steroid. If it is possible to obtain off label it can lower your SHBG and with it the amount of testosterone you need to take to get free testosterone within the desired range.

METANDIENONE (DIANABOL)

INDICATIONS: Metadienone was originally intended as a synthetic hormone replacement therapy for the treatment of hypogonadism. It has been largely replaced by bioidentical testosterone and is no longer commercially available in the United States. It is available OTC in Mexico and in Asia.

DOSING: Experimental doses consisted of 100mg/ day. Results of this experiment can be reviewed at DOI: 10.1042/cs0600457 - Effects of methandienone

159 on the performance and body composition of men undergoing athletic training.

SIDE EFFECTS: Heavily estrogenic and liver toxic, it is strongly recommended this particular drug be avoided. Metadienone has a minor affinity for the estrogen receptor, but with estrogen running a ratio of 100/0.03 in terms of potency, this leads to serious side effects. Expect bloating, emotional instability, growth of breast tissue and even lactation with higher doses of this drug.

SUMMARY: Metadienone has been included here to warn readers away from it. However, it is a common anabolic steroid that needs to be discussed. While it is touted as a 'bulking' drug, the truth is that most of the weight gained will be water under the skin due to strong estrogenic properties. This water retention cushions the joints, allowing for heavier lifting, but both the strength and size gains disappear almost immediately when the drug is discontinued. The estrogenic effects of metadienone, such as a widening of the hips and development of breast tissue are rather more permanent. There are also reports of higher than average psychological effects with this drug.

160 Because better options exist with fewer side effects, dianabol/metadieneone is a substance to avoid.

NANDROLONE (DECA-DURABOLIN)

INDICATIONS: Nandrolone is still used for AIDS patients to prevent wasting and burn victims as a means of preserving muscle tissue during healing. Interestingly, it is also formulated as eye drops to reduce recovery time after eye surgery.

DOSING: Medical prescriptions for nandrolone are typically cautious, consisting of roughly 100-200mg/ week. Historical gym doses approach several times this amount, 350-700 mg per week. This is well above saturation dose and will only worsen any side effects.

SIDE EFFECTS: The side effect profile of nandrolone is typical with a few exceptions. It also functions as progestogen, meaning it’s more likely than other steroids to cause hypogonadism. The higher the dose, the more impact these side effects will have.

161 SUMMARY: Nandrolone is both medially available and, at appropriate doses is very effective as a muscle building agent. It is also well-tolerated. Because it lacks carbon-19, it cannot be converted into an estrogen. While it does have some progestogen activity that results in shrunken testicles, this is unlikely to happen with appropriate medical doses.

Low doses of nandrolone ethers, (50mg/week) especially nandrolone phenylpropionate, (NPP) have recently been used in tandem with testosterone ethers for HRT. The mild water retention does an excellent job of protecting joints and giving cartilage the space to slowly regenerate.

162 CHAPTER 10 ANTIESTROGENS AND GONADOTROPINS

The intent of this chapter is to teach you how to keep levels of LH and FSH at healthy levels despite using androgenic PEDs, as well as avoiding estrogenic side effects. There are two ways this can be accomplished. The first and preferred method is via the use of anti estrogens, specifically aromatase inhibitors to keep the HPG axis chugging along. (We do not want to block your estrogen receptors. Even ultra-macho stud he men need their estrogen to be at the right levels.) The second involves using an expensive, injectable cytokine, Human Chorionic Gonadotropin (hCG) which kickstarts the endocrine system.

AROMATASE INHIBITORS AND ESTROGEN ANTAGONISTS Antiestrogens are central to the AUGMENTED approach to human enhancement. To find out why, let’s have another discussion about the HPG axis. In addition to all the other jobs it has, estrogen serves as a benchmark for how much testosterone

163 your body needs to produce, and HRT can often raise estrogen artificially. There is a class of anti-estrogen drugs called Aromatase Inhibitors: Aromatase is an enzyme aromatase inhibitors that keep estrogen that converts testosterone or androstenedione into levels low, even when you’re on HRT. estrogens. Aromatase inhibitors block the 'Bro science' has traditionally had production of estrogen. athletes administer aromatase inhibitors after six to eight weeks of startlingly high dose steroid injections.

The thing is, there is absolutely no reason to put off anti estrogen therapy until after your 'cycle' is done. Further, with reasonable doses it just isn’t necessary to cycle off androgens at all. Just like flying a large jet, even and steady administration of PEDs alongside aromatase inhibitors will result in continual long term gains and health benefits. The challenge is to augment your testosterone without your body shutting down natural production.

Your body doesn’t just pull estrogen out of thin air and dump it into your bloodstream. It has to make it from something else, something chemically similar, a substrate. And that substrate is testosterone. Naturally, the higher your circulating testosterone the higher your levels of estrogen, and our job becomes

164 one of evening out estrogen to keep it at a healthy level and prevent the grab bag of side effects it creates. Rather than repairing the HPG axis after overloading it for several months, AUGMENTED advocates an approach of ongoing monitoring and maintenance.

Just like with androgens, there is a library of drugs available to inhibit estrogen production. Those which are detailed below are available through pharmaceutical channels. Obtaining a prescription from a medical doctor may be difficult, as most of them are indicated to treat breast and ovarian cancers. Doctors of Naturopathic medicine may be more willing to do so.

The more mild aromatase inhibitors are referred to as 'maintenance drugs' in the AUGMENTED system. They prevent several of the side effects stemming from the high estrogen that comes with having higher than natural levels of testosterone. They need to be taken at such

Estrogen antagonists are referred to as 'rescue drugs', because while they don’t stop the production of estrogen, they make the brain blind to it’s

165 presence and effectively reboot the HPG axis if it gets damaged by excess hormones. Hypogonadism and gynoclomastia are the two primary indicators of a damaged HPG axis. Should any of these symptoms develop it is best to use a rescue protocol as well as discontinue and review your androgen protocol.

AROMATASE INHIBITORS

For some people, adding supplemental testosterone causes an unacceptable surge of estrogen along with it - the body just converts it into estrogen too fast. This results in mood swings and left untreated can lead to growth of breast tissue and even encourage certain cancers. Armoatase inhibitors protect the natural function and balance of your hormones while taking androgens. They work by blocking the enzyme that converts androgens to estrogens. Like carbohydrates, your body needs estrogen. Also like carohydrates, an excess will cause you to bloat up and gain undesirable weight.

So to keep your estrogen levels in a healthy range, we employ aromatase inhibitors DURING, not after, androgen therapy. This will abate some of the side

166 effects that can be attributed to estrogen, prevent any hypogonadism, better regulate your mood, as well as curtail the development of breast tissue. Obtaining these drugs via a legitimate prescription may prove to be difficult. Perhaps mercifully, an affordable and reasonably effective supplement exists that exhibits acceptable inhibition at aromatase. Information on this supplement is included in this section.

EXEMESTANE

INIDICATIONS: Exemestane is used in the treatment of estrogen receptor dependent (ER positive,) breast cancer. It is a suicide inhibitor, meaning it works by chemically welding itself into the enzyme it inhibits, permanently deactivating it. As such it is almost too powerful for our purposes.

DOSING: 25mg/day is the preferred dosing. Single doses of up to 800mg have been tested with no adverse effects. It is important to note that nearly a

167 gram of ANY biologically active substance is a hell of a lot, and when it comes to balancing your hormone profile more is absolutely not better.

SIDE EFFECTS: This is one of the more interesting anti estrogens in that the side effects are very similar to those of anabolic steroids. Exemestane can in fact stimulate effects comparable to that of a weak androgen, inducing acne and increased muscle mass.

SUMMARY: Exemestane has a unique biological mechanism of action. Most inhibitors simply stick to an enzyme better than the natural substrate does and prevent it from operating. Exemestane is a 'suicide inhibitor,' meaning it chemically alters both itself and aromatase chemically, bonding to the active site covalently and essentially destroying the aromatase. As such, the dosing is very low and the effects last a very long time.

WHITE BUTTON MUSHROOMS/CONJUGATED LINEOLIC ACID

No prescription, no problem. White button

168 mushrooms have been shown to block the activity of aromatase in a dose-dependent manner. Scientists in a well-cited and reviewed study chopped up 200 pounds of white button mushrooms, boiled them, then took the water and shook it with a solvent. After separating the individual chemicals on a column they determined that several of the chemicals inhibited estrogen biosynthesis, most notably conjugated lineolic acid or CLA. (PMID: 17178902)

Inclusion of a plant-based remedy is out of character for this book. But this particular one has a well studied, well characterized mechanism of action. It has both minimal cost and minimal risk and may well provide an effective stopgap for those unable to obtain pharmaceutical grade aromatase inhibitors. The apparent active ingredient, CLA, is also available in purified form at retail. CLA can be sourced from a variety of different plants. None is particularly better than the other, so going with the least expensive option is the best choice.

CLA/white button mushrooms are relatively weak as far as estrogen inhibitors go, and that’s exactly what AUGMENTED calls for. We need just enough an

169 effect to prevent feedback inhibition of the HPG axis, we absolutely do not want to cease estrogen production entirely. Remember, estrogen is responsible for bone density and other critical biochemical pathways in the long term.

It is also interesting to note that CLA has multiple, beneficial biological effects. By interacting with a pathway in fat cells call p-PARγ (gamma) CLA accelerates fat metabolism and helps reduce fatty tissue, especially around the abdominal area.

ANASTROZOLE (ARIMIDEX)

INDICATIONS: Anastrozole is typically used after five years of tamoxifen therapy for ER-positive breast cancer. It is also given as a prophylactic (preventative) therapy for women at high risk for developing ER positive cancers of any kind.

DOSING: Anastrozole’s power is seen in the dosing levels, 500 mcg/week is enough to exert therapeutic effects.

170 SIDE EFFECTS: The side effects of anastrozole are what you might expect from something so powerful. It causes symptoms consistent with menopause, including insomnia, hot flashes and osteoporosis.

SUMMARY: Anastrozole is a powerful aromatase inhibitor. This makes the fact that a prescription is difficult to obtain acceptable, as using it for our maintenance protocol would be difficult. If you are in fact positive for BCRA, whether male or female, obtaining a prophylactic prescription may be possible. Particularly if you’re already on HRT of some sort.

TAMOXIFEN/NOLVADEX

INDICATIONS: Tamoxifen, (also known as Nolvadex and Taxol,) is used to treat multiple conditions. ER-positive breast cancer for sure, but it is also used as a male infertility treatment as blocking the estrogen receptors encourages the release of gonadotropins.

171 DOSING: 20mg/day is used for breast cancer patients and nearly completely blocks the activity of estrogen. It may in fact be too powerful for our purposes. AUGMENTED recommends beginning with half this dose, 10mg/day, and titrating upwards should side effects begin to occur.

SIDE EFFECTS: Nolvadex is a SERM, (Selective Estrogen Receptor Modulator, meaning it acts as an agonist at some estrogen receptors and an antagonist at others,) and accordingly the side effects can sometimes be counterintuitive. It is also a prodrug, meaning that if a person has variant genes or expression of CYP2D6 the effects will change wildly. Understanding and predicting the effects of nolvadex on an individual is possible using solely the knowledge presented in this book, but compared to other, equally effective options it is relatively unpredictable. Unexpected and beneficial side effects, such as increased bone density and a more favorable blood lipid profile are possible alongside negative cognitive side effects and possible blood clots.

SUMMARY: Tamoxifen/Nolvadex is a fascinating compound that frankly, needs further development.

172 Two of the major metabolites it produces are currently under investigation for several disease states, though these are not included in this edition because they are not yet readily available. If you do not respond typically to most drugs then it is suggested you avoid this particular antiestrogen. It is also very important to note that nolvadex is not an aromatase inhibitor and is not suitable for HPG axis maintenance during HRT. Along with rHCG, tamoxifen/nolvadex is best suited as a 'rescue' drug should you manage to damage your HPG axis.

CLOMID/CLOMIPHENE

INDICATIONS: Clomid is indicated to induce ovulation in women by 'kickstarting' the cytokines in the HPG axis. Like taxol, it is an ER antagonist rather than an aromatase inhibitor.

DOSING: Typical doses are 50mg daily for seven days during the luteal phase of the menstrual cycle to induce fertility. The dosing scheme as an HPG rescue would be similar.

173 SIDE EFFECTS: Side effect profile is consistent with the symptoms of menopause. Hot flashes, pelvic pain, and reversible enlargement of the gonads, both testicles and ovaries. Vision side effects such as cataracts and double vision have also been reported.

SUMMARY: Clomid is rather direct in it’s effects on the estrogen receptors in the brain and hypothalamus. Similar to tamoxifen, it does not inhibit the production of estrogen and therefore is useful primarily as a rescue drug.

174 CHAPTER 11 - PEPTIDES AND BIOLOGICS

Biologics is a word used to describe Biologics: An injectable, protein pharmaceuticals that are made of large based drug. Highly potent with very specific proteins rather than small molecules. effects, and typically far fewer side effects. These are also called ‘Peptides.’ Small Chemically fragile and expensive to both molecules almost always have a variety produce and store. of biological effects owing to their ability to bond to several different proteins. By way of contrast, biologics are extremely specific as ligands are almost never exhibit off target effects. This makes them incredibly reliable; they interact with a single point in a single chemical pathway very consistently. Small molecules tend to be manufactured by a synthetic chemical route, whereas biologics are manufactured using processes involving living microbes.

Just how big is the difference in size? We’re familiar with the structure of testosterone and steroids, who have a molecular weight of around 300 daltons. By way of comparison, erythropoietin has a molecular weight of 37,000 daltons. Biologics are so large, and so sophisticated that they tend to behave like

175 nano machines. This structure/function relationship is so fragile that not only must biologics be injected without exception, but they have to be stored under very specific conditions or they will unravel and break down. In spite of their chemical delicacy, they are incredibly powerful can be made to interact with just about any biochemical pathway.

Each of the biologics in this chapter will require extra description so the reader can assess their utility in their own program. They are also likely to be very difficult to obtain, and expensive as well.

ERYTHROPOIETEN (EPOGEN)

Erythropoieten/Epogen/EPO is a cytokine manufactured by Amgen that increases the amount of red blood cells in the circulatory system. The increased red blood cell density allows your blood to hold more oxygen, causing endurance to skyrocket. Natural EPO is secreted by the kidneys when they sense the oxygen saturation of your blood is too low. The EPO travels from the kidneys to the bone marrow, where it stimulates the production of new red blood cells.

176 EPO raises a key measure of blood quality, the hematocrit. Hematocrit is the concentration of red blood cells relative to plasma and white blood cells. It is also called 'blood density.' Raising hematocrit will drastically increase endurance by raising the amount of oxygen your blood can store. It will delay the onset of fatigue, muscle pain, and decrease recovery time.

Raising hematocrit can be accomplished naturally by several different means. 'Blood doping,' as its’ called, sharply increases athletic performance while lowering recovery time. The body is stimulated to release EPO by lowering the oxygen concentration in the blood. Hematocrit is raised slowly, and constant stimulation is needed to maintain blood density at high levels.

The most common blood doping practice is 'blood spinning.' The athlete donates a pint of blood, which is centrifuged and stored for later. The blood loss resulting from the donation lowers blood oxygen content, which in turn releases a steady stream of EPO. Over a period of weeks, the athlete’s red blood cell concentration returns to normal and the donated blood is reintroduced. This

177 creates a rapid increase in hematocrit that raises the athlete’s oxygen capacity almost instantly.

At high altitudes, the body compensates for decreased oxygen density by raising hematocrit. Altitude training has been used for decades by athletes seeking to gain an edge. Experiments have been conducted using special depressurized homes that ultimately mimicked the effects of altitude training in collegiate athletes.

Interval training also raises hematocrit. Intense bouts of exercise deprive the blood of oxygen, with the low oxygen levels stimulating the release of natural EPO. But with both altitude and interval training, the uptick in hematocrit is hard-won and very reversible.

Ultimately, high hematocrit is a key aspect of physical fitness. High hematocrit increases the oxygen capacity of your blood, where it matters the most. It allows aerobic activity to continue for much longer than it normally can, with the blood taking and retaining more oxygen with each breath you take.

178 RECOMBINANT HUMAN GROWTH HORMONE/ SOMATROPIN/HGH

Human growth hormone is the apex of cytokines. It will cause your entire body to regenerate. Your muscles yes, but also your skin, bones, and some organ tissues as well. Unlike most biologics, rHGH has multiple biological effects.

The most interesting effect as it applies to the AUGMENTED system is the effect it has on muscle tissue. It causes muscle growth independent of mTOR or androgens, potentially adding a third pathway to hypertrophy. Anecdotal reports among athletes who have used it illicitly state HGH causes explosive muscle gains.

But that’s not where the benefits end. HGH also increases bone density which is critical for injury prevention. In children, it can cause them to grow taller as adults because of increased cartilage production in growth plates at the femur and humorous bones. Additionally, it can restore cartilage in joints as well when co-injected with hyaluronic acid (which we discuss in the next section.)

179 The drawbacks? There are a few. HGH causes your bones to continue to grow at any age. These include the bones in your face, which may alter your appearance slightly. When the jawbone expands after all your teeth have grown in, the teeth will drift apart in the mandible and you will have little control over how they drift apart without the assistance of an orthodontist. You may well end up with a gap between your two front teeth you didn’t have before.

Also, HGH cause ALL your organs to grow, not just your bones and muscles. This includes the liver, pancreas, and intestines. As the intenstines grow, the push the abdominal wall forward resulting in a pot-belly appearance that persists despite the athlete’s body fat percentage. This is why several champion-level bodybuilders have protruding guts despite having extremely low body fat.

Finally, the expense needs to be addressed. HGH from a legitimate clinic runs from $1000-$5000 per month making it inaccessible to most. Black market sources are extremely unreliable, especially given the storage requirements for injectable HGH.

180 HYALURONIC ACID (SYNVISC ONE)

Synvisc is a stunningly simple piece of biotechnology. It is, in lay terms, a pharmaceutical grade Jell-O injection for your knees. It is indicated to treat osteoarthritis in the knees when NSAIDS (aspirin and naproxen,) fail to control the pain. It cushions the knee joint which both preserves cartilage and reduces pain. The injections last roughly six months.

Hyluronic acid in a chain, called a 'polymer,' is what creates the bulk of cartilage tissue. This doesn’t necessarily result in regeneration of connective tissue, though regeneration is certainly a possibility particularly when combined with rHGH. Synvisc, used before osteoarthritis begins to show symptoms, can preserve your knee function for years.

Synvisc is indicated for the treatment of osteoarthritis pain that does not respond to aspirin or Tylenol. To obtain it, patient would need to present in the clinic twice. The first time the chief complaint would be of knee pain that comes and goes. The doctor will recommend a combination of

181 Tylenol and naproxen. When the patient returns and says the two over the counter drugs don’t work, the doctor will be able to prescribe Synvisc.

DENOSUMAB (PROLIA)

Prolia will increase the density of your bones, allowing them to grow faster and making them less susceptible to breaking. It is indicated for treating osteoporosis as well as some forms of bone cancer. It is an antibody which is chemically identical to those naturally produced by the human body, which effectively hides it from the immune system. This allows it to linger in the blood for weeks or even months at therapeutic levels and injections are required on a similar timeline.

Your body has a particular kind of cell, called an osteoclast, which breaks down bone tissue to replenish blood calcium. These cells are activated by a cytokine called RANKL which is released by several different tissues to 'request' more calcium. For example, mammary tissue in lactating mothers will release RANKL when it needs more calcium to produce milk. This same phenomenon also occurs

182 in steroids abusers who develop gynecomastia for the same reason. (Yes, it is very possible for a runaway HPG feedback loop to develop high enough prolactin levels for a male to produce breastmilk. The author has personally witnessed it, unfortunately.) This makes RANKL modulated loss of bone density a concern for this population.

Prolia is an antibody which is chemically identical to those a human makes, allowing it to last in the system for months. Antibodies have two parts, one that is 'sticky' to a specific protein, (the variable region) the other a signal for immune cells to absorb and destroy the protein (the constant region.) Antibodies are both a ligand and a cytokine. Natural antibodies stick to a specific protein on a virus or bacteria, but it also works for just the protein itself. Sticking to the protein inactivates it, and eventually an immune cell arrives and destroys it.

Compared to the bulging, ripped muscles and low body fat other substances discussed in this book can produce, higher bone density and stronger joints may seem much less glamorous. But when looked at through a long-term lens, stronger bones

183 and joints may be the best thing you can do for yourself. Sprains, strains, breaks, and degenerated cartilage have ruined the careers of thousands of talented athletes sometimes before they had any real chance to flourish.

Prolia is not in high demand as a PED and may be difficult to obtain. It is indicated for post- menopausal women who are at high risk for fractures after a bone scan reveals osteoporosis. Obtaining this drug for an athlete or peacekeeper will require an open minded doctor willing to prescribe it off-label as a prophylactic. It is extremely important that the body be provided sufficient vitamin D as well as calcium during Prolia therapy as the body will be unable to provide itself with calcium should it need to.

HUMAN CHORIONIC GONADOTROPIN (HCG)

INDICATIONS: hCG is used, sometimes on a single-dose basis, to restore testicular function. It is a complex cytokine that must be injected - in no way is it orally bioavailable. It is marketed by Merck under the brand name Pregnyl.

184 DOSING: This is a fairly complicated issue, and it is best to discuss this with a physician who can reconstitute the powder into an injectable at the correct pH and tonicity at the appropriate dose and volume. The discipline of chemistry that allows someone to do this correctly is called 'stoichiometry' and is a math-intensive process. Please leave this to professionals. Rest assured that should you get hypogonadism, the use of hCG is very much indicated and a physician may well prescribe it to you should you need it.

SIDE EFFECTS: Continued use will produce side effects consistent with a 'overheating' HPG axis, both androgenic and estrogenic. This is a potent rescue drug, and only a single dose should be required to 'reboot' your endocrine system.

SUMMARY: hCG is the ultimate rescue drug. It is a relatively large cytokine that can have rapid, dramatic effects at the right dose. The application and reconstitution of this drug is beyond the scope of this book - doing it even slightly wrong could destroy the drug substance or worse, harm the user. 'Home kits' for hCG are available online and absolutely not recommended without advanced

185 training in biochemistry. Purity of the substance would normally be an issue but you can actually confirm the presence of hCG with a simple pregnancy test.

The persistent fad, the 'hCG Diet,' does need to be addressed. It is absolutely, categorically useless as as weight loss aid. The science behind it is a fusion of alchemy, snake oil, and new agey lies. In the author’s opinion, the hCG diet is a boiling crock of monkey excrement being heated by a dumpster fire. Nor is there such a thing as an orally bioavailable herbal compound or supplement that 'naturally' increases serum levels of hCG.

BPC-157

BPC-157 is a peptide that is naturally present in your gut tissue. It encourages the growth of new blood vessels in a process called angiogenesis. People have began experimenting with it fairly broadly to treat everything from bowel discomfort to healing damaged muscles and connective tissues.

The daily dose is roughly 250-1000mcg (micrograms guys, not milligrams.) The only viable route of

186 administration is subcutaneous injection. Nasal sprays or anything claiming to be orally bioavailable are complete bunk.

BPC-157 is a very fragile molecule. It’s sensitive to mechanical shock, so much so that it has to be reconstituted very carefully. It doesn’t last long even in cold temperatures once reconstituted and must be used soon after it has water added. It’s even photosensitive - direct light accelerates decomposition so it has to be stored in a dark place.

There isn’t much reliable data on human use. Most of the data out there comes from animal studies or individual anecdotes. Some people have experienced miraculous healing. However there is strong evidence that it helps grow new blood vessels faster, and healing properties are a natural downstream effect.

MELANOTAN-2/PT-141

These two peptides are virtually identical and have some very bizarre biological effects, ones that you wouldn’t think go together. They also have an

187 interesting kind of scientific drama surrounding their development.

Melanotan-2 began life as a sort of “sunless tanning agent.” It works directly on skin tissue to produce more melanin which darkens the skin without the damaging effects of UV light. But during animal testing, one of the scientists noticed the rats were mating at a higher than normal rate. This guy then proceeded to smuggle a small sample out of the lab to his personal home, where he gave himself an injection to see what would happen. One can only imagine what this guy’s personal life is like.

As it goes, he made a significant error in his math and gave himself twice the intended dose. What followed was a painful eight-hour erection as well as nausea and vomiting. He retuned to the lab the following day with bold new ideas for applications for melanotan-2.

Melanotan-2 and PT-141 differ in a single atom and have no remarkable difference in function. The two entities exist because of some scientific and legal trickery involving a research license between two companies that resulted in a lawsuit and significant cash settlement. PT-141 is now licensed as an injection to treat low female libido and called “Vyleesi.”

188 It causes spikes in blood pressure and increases libido sporadically. Some people respond to it powerfully, others notice next to no effects.

Neither have specific performance enhancing effects, other than darkening your skin and improving libido. These substances tend to be marketed alongside other performance enhancing peptides and so deserved an entry in this chapter.

189 CHAPTER 12 - SARMS AND INDS

SARMs are experimental chemicals that usually don’t have a steroid structure, but very selectively perform the anabolic effects of testosterone in skeletal muscle only. They tend to have an A:A ratio nearly an order of magnitude higher than steroid based androgens at a shocking 90:1. They actually block natural testosterone in some tissues, and could hypothetically reverse male pattern baldness, clear acne and undo prostatic hypertrophy. In many ways, they are the realization of the “holy grail” of steroid chemistry.

Commercially available SARMs are sold as research chemicals. There are several performance enhancing research chemicals available that are called SARMs for marketing purposes, but don’t actually work with the androgen pathway. We’ll include them in this section anyways as the fitness community has come to understand them as SARMs.

190 Some of the research chemicals described in this chapter are actively undergoing clinical trials and will be scheduled into prescription-only categories if they’re approved. Others are “orphaned,” having failed their clinical trials or fallen off-patent. There is, as of this writing, draft federal legislation to ban some of them.

Substances in the “orphan" category are almost entirely unregulated with a solid body of publicly available data to describe their effects. Of course, the marketing and “broscience" behind them has spread an enormous amount of disinformation and we will be directly discussing each of the most popular substances in the following sections.

Two of these substances come especially recommended, owing to their confirmed safety profile and ability to compliment HRT very well. In particular, Ligandrol and RAD-140 enhance the action of androgens in muscle tissue while keeping other tissues safe and for this, they are discussed first. Both SARMs have passed basic human safety testing and have been scientifically demonstrated to dramatically increase muscle mass with few side effects.

191 Others SARMs are called out for being dangerous for a variety of reasons. The marketing surrounding them is dubious and little actual safety data exists for them, save for credible danger of cancer or other serious side effects. This information is provided to prevent the reader from being deceived by unethical marketing practices.

The way these compounds are named needs to be discussed, because it can be somewhat confusing. When scientists create new drugs, they do so by the hundreds of thousands, then test them in a lab, then with animal models, then on healthy humans, and finally on actual patients. The letters at the beginning of the drug tell you what pharmaceutical company is researching the drug. So “RAD” is from Radiant Pharmaceutics, “AMG” is from Amgen, “MK” is Merck, etc. Sometimes they will have two because one pharmaceutical company bought the rights from another, as is the case with Ligandrol Author’s Note: While doing (LGD-4033 became VK-5211 when journal article research for this chapter I downloaded several Ligand Pharmaceutics licensed articles for LGD-3033 instead of LGD-4033. Both drug Ligandrol to Viking Therapeutics. candidates happened to be SARMs, which is unusual. Making matters worse, there is a SARM Turns out LGD-3033 wasn’t that got shelved called LGD-3033 nearly as good as Ligandrol.

192 which only adds to the confusion.)

RAD-140

RAD-140 (Testolone,) is a SARM currently in clinical trials to treat breast cancer with initial results expected in late 2020. There has been a single case Chemical Structure of RAD-140 report of liver injury published in Notice the lack of a steroid skeleton. It turns out the most powerful the medical literature involving a “steroids,” aren’t steroids. 49 year old male with the presence of RAD140 confirmed with extensive chemical testing. The doctors were unable to draw any definitive conclusions regarding the cause of the patient’s issues, making only a post-hoc connection between the two.

Animal based experiments seem to indicate that RAD-140 is safer than bioidentical testosterone when given as hormone replacement therapy, which makes a great deal of sense. RAD-140 enhances skeletal muscle more effectively than natural testosterone and also has neuroprotective effects that can slow the aging process in the brain.

193 RAD-140 compliments testosterone therapy quite well because it partially blocks the activity of testosterone at the prostate which can prevent non- cancerous swelling of the prostate called “benign prostatic hypertrophy” or BPH. BPH can make it difficult to urinate while making you feel as though you have to pee all the time.

Finally, there are some literature references to neuroprotective effects, which are not at all unheard of for androgens.

RAD-140, with a half life of 24-36 hours is best dosed daily between 10-30mg/day. Any more won’t produce further muscle building effects. RAD-140 pairs well with HRT but is redundant when combined with other SARMs.

LIGANDROL

VK5211 also known as LGD-4033 (Ligandrol) like RAD-140, is an investigational SARM currently being developed to combat muscle wasting syndromes and osteoporosis. Ligandrol’s very unique chemical Currently undergoing phase 2 clinical structure (for an androgen.)

194 trials to help elderly hip fracture patients recover more completely, it has been demonstrated under tightly controlled studies to measurably increase muscle mass in as little as three weeks.

With a half life of 24-36 hours, ligandrol can exert it’s powerful anabolic effects at very small doses. Published experiments used escalating doses at 0.1mg, 0.3mg, and 1mg over a period of 21 days. Average gain in lean muscle was 1.21 kg at 1mg/ day, roughly 2.5 pounds.

Ligandrol appears to increase muscle gains in a dose-dependent manner up to about 5mg/day, after which gains start to drop off sharply. There are also published studies as well as anecdotal reports stating that ligandrol enhances libido in both men and women.

Ligandrol has other beneficial effects as well. It lowers SHBG and triglycerides which could improve cardiac function. Additionally, it can increase bone density which makes the athlete less prone to injury. Like RAD-140, it makes an excellent compliment to HRT. For those seeking to naturally maximize their testosterone Ligandrol is not recommended as it

195 causes a powerful yet reversible drop in testosterone levels at doses of 1mg/day or more, though testosterone returns to normal in roughly one week after discontinuation.

Overall, Ligandrol is the best studied, safest, and most potent of all the SARMs. It stands a decent chance of passing phase 3 clinical trials and being scheduled by the FDA as a pharmaceutical. Given the safety and efficacy data Ligandrol comes strongly recommended, especially for women, people over 35, and those on HRT. Younger people should use Ligandrol for no more than a month at a time, and exceeding 5mg/day is discouraged to minimize lowering of natural testosterone.

YK-11

This substance is not recommended. Notice the steroidal structure and lack of carbon-19, which gives it enormous potential for side effects. There is also some frightening structure with oxygen Chemical structure of YK-11, the only atoms stemming from carbon-17 steroidal SARM currently being evaluated.

196 which is obviously unstable. Most of the work with YK-11 has been done in a lab only.

Marketing efforts describing YK-11 as a myostatin inhibitor come from a single study performed on cultured cells that briefly mentions changes in mRNA expression to a family of proteins, TGF-β . Whether this applies to myostatin itself, and whether that effect works in humans, is completely unknown and frankly is unlikely owing to the steroidal structure of YK-11.

Speaking of steroidal structures, YK-11 most closely resembles the natural hormone progesterone, at right. Progesterone is best described as a “pregnancy” hormone and YK-11’s structure-activity relationship in light of the similarity is unstudied and unknown. The lack of carbon-19 as well as the enone moiety in the A ring (which could cause estrogenic activity,) Progesterone (above) side by side with raises serious concerns about YK-11 (below.) Notice the structural similarities between both molecules. This YK-11s viability as a safe muscle is an engraved invitation for side effects. building agent.

197 It does produce gains. So do other, safer, better studied SARMs. It has also been reported to cause mood instability which comes as no surprise at all, given the similarity to both estrogen and progesterone. Unless and until YK-11 is better characterized and revealed to be both powerful and safe, it is best to avoid this SARM.

GW-510516/ CARDARINE

Cardarine or “Endurobol” isn’t a SARM and doesn’t work with the AR pathway. Cardarine’s chemical structure. Instead, it increases endurance by interacting with the p-PARy pathway It was developed in the 1990’s by GlaxoSmithKline as a treatment for obesity. It never reached clinical trials, as lab animals dosed at a human level of roughly 300mg/day developed cancer in multiple tissues. There is no data for human use as a result.

It needs to be said, however, that Cardarine is effective at 10-20 mg per day for a 100kg person. It is extremely effective in bolstering endurance and

198 reducing body fat. As a P-PARy agonist, it could be considered a more potent form of CLA.

As far as performance enhancement goes, this is a kind of “holy grail” with a turd of sorts in it. The benefits are immense, but the resulting side effects could be described as “ultra-cancer.” These effects most likely come from Cardarine’s ability to modify existing cancer cells to be more powerful and spread more quickly, allowing the cancerous cells to “outrun” the immune system’s ability to combat it. Owing to this potentially dangerous effect, Cardarine is not recommended, especially given CLA’s function.

MK-677/IBUTAMORIN

MK-677 was first synthesized and studied in the mid 90’s as a treatment for several growth disorders involving the IGF-1/GH axis, essentially as a means to increase growth hormone without constant injections.

199 MK-677 Works fairly indirectly by mimicking the the “hunger hormone” ghrelin, which in turn causes the liver to release a growth hormone called “insulin like growth factor -1” or simply IGF-1. It is an effective mass builder that compliments androgen or SARM therapy very well. While the drug substance itself has a half-life of roughly four hours (at least in beagles,) each dose seems to increase circulating levels of natural IGF-1 for 24 hours.

It is not without side effects. MK-677 can produce extreme fatigue that is immediately reversible when the IND is discontinued. Because the brain is sensitive to ghrelin and MK-677 can cross the blood- brain barrier, there is the potential for unknown psychological or behavioral side effects as well.

MK-677 is a useful as a bulking drug and may have anti-aging properties as well. Beware the side effects and use only as a final addition to your regimen, and never add anything else at the same time as MK-677 to keep the source of any new side effects clear.

200 NOTES ON PROGRAMMING AND HRT WITH SARMS

The key benefit of SARMs, and particularly of RAD-140 and LGD-4033, is the ability to activate the androgen receptor in skeletal muscle with a minimal side effect profile. Contrast this with steroid based androgens which mimic testosterone more directly and accordingly effect every cell in the body.

While combining multiple steroids or running high levels of testosterone is a dubious practice, SARMs combined with HRT are an excellent way to augment your strength while maintaining healthy endocrine function. Because these substances are experimental, designing optimal protocols will be somewhat difficult. However, the ability to exceed physiological androgen levels to enhance strength with minimal side effects. Generally speaking, you’ll want to be on an HRT program that optimizes your testosterone levels, then add SARMs to enhance muscle mass. More details on this in the programming chapter.

201 CHAPTER 13 - SELF MONITORING AND ASSAYS 'More is not better, less is not better; the precise amount required is best.'

Mike Mentzer ~ Heavy Duty

We do not guess and we do not assume when it comes to our health and wellness. This chapter is going to teach you how to recognize signs that your testosterone is too high, and ways to objectively measure the effects your HRT is having on your body.

'Normal' Testosterone levels are between 250-1100 nanograms per deciliter (expressed as ng/dL.) With an average sitting roughly around 650ng/dL. Our goal is to keep it in the upper ranges of normal over a long period of time. We keep free testosterone (that not bound by SHBG,) as high as possible with hormone replacement therapy, and confirm testosterone is in a powerful yet safe range with testosterone testing kits.

The HPG axis is highly adaptive and sensitive. You can experience serious fluctuations in hormone levels which can push you into unwanted side effects or an ineffective concentration for muscle

202 building and repair. You can’t expect to need the same dose from month to month or even week to week. This makes it important to keep a close eye on your androgen levels, to recognize signs of too high or too low a dose, and know how to select a new dose if necessary.

Hormone panels have generally been performed using blood draws. This is a mildly invasive procedure which requires a clinic visit and honestly provides much more information than we need for this program. The two metrics we care about, assuming you are completely healthy, are your testosterone and estrogen levels. Measuring these alone probably doesn’t warrant a diagnostic blood draw, and they need to be monitored fairly closely making repeat blood draws cost prohibitive.

Spit assays are a new development in measuring testosterone levels. They currently enjoy an unhealthy level of skepticism in the medical community, as clinicians are usually reluctant to adopt anything without a tidal wave of overwhelmingly positive data. For our purposes, they provide a convenient, reasonably accurate, and perhaps most importantly an affordable means to

203 monitor testosterone levels with a good degree of granularity. High resolution data is important to decision making for optimizing hormone levels and other key markers of health, and also helps keep side effects to a minimum.

Spit assays are medically accepted as a means to measure cortisol levels, which like testosterone is a steroid molecule. Based on our current understanding of steroid chemistry, if spit assays are valid for one steroid they should be sufficient for others as well. This, combined with the fact that AUGMENTED is not intended to treat disease states, spit assays are adequate for our purposes.

So under what circumstances should you take a hormone test? There are two bright lines you need to pay very close attention to during HRT:

1. You’re seeing diminished benefits from your HRT. For example, your libido is low and you’re starting to feel depressed. Your testicles are for some reason smaller. This includes family or friends mentioning such symptoms. If this occurs during HRT, it could mean your body has slowed down testosterone production in response to the

204 synthetic hormones. If you take the test for these reasons and your result comes back lower than your baseline testosterone levels, please go see a doctor for help.

2.You’re enjoying your HRT too much. People are noticing you’re too aggressive, too emotional, and they’re saying something. You find yourself angered too easily. You’re a jerk and you don’t care. Your testicles are shrinking for some reason but you don’t have time for that. Order a test and if it comes back above 1,100 ng/dL consult your doctor then titrate your dose down until the side effects go away.

3.You’re starting to exhibit physical signs of overdose. You have acne on your face and back like it’s junior high all over again. Your nipples are tender. You’re having to get up to pee several times through the course of the night due to a swollen prostate. These are physical signs of testosterone that is too high and it will be necessary to adjust your testosterone levels whether

205 The goal is to keep testosterone levels at the high end of normal. The American Medical Association has defined 'normal' testosterone based on a broad population survey of healthy adult males with a BMI below 30 and no history of hormone related pathology. As you can see above, the low versus high end of normal is over a fourfold difference. You could drive a Mac truck between 250-1100ng/dL (some schools also claim 300-900ng/dL as a standard.) There is absolutely a substantial difference in the quality of life at either end of the spectrum, and if your doctor tells you that low or Author’s note: Your mileage may vary. With 100mg of testosterone cypionate per week, my even median levels of free testosterone hovers around 500ng/dL. My muscles have grown significantly at this level testosterone are 'normal' it and I feel like I’m 20. While free testosterone provides an objective measurement, how you may be worthwhile to find feel at a given level is also worth considering. At my current dose I’m getting all the benefits and another doctor. almost none of the side effects. You should find yourself a ‘sweet spot’ like that, too. Exceeding the threshold of 1100ng/dL puts you at increased risk for side effects with little increase in benefits. Remember the notion of a 'saturation dose' mentioned in an earlier chapter? Physiologically, exceeding the high end of normal has a minimal effect on your muscle’s ability to grow. It does, however, drastically effect any side effects androgens are likely to produce, such as

206 acne, mood swings, cardiovascular damage, fluid retention, diminished testicle size, and estrogen- related side effects.

When reading the results of a testosterone assay, bear in mind that total vs. free testosterone is very important. SHBG carries testosterone and other sex hormones, preventing them from exerting their intended effects. Strictly speaking, we only care about the free testosterone detected in the assay. Total testosterone is not a useful measurement for our purposes.

VIRILIZATION:

Spit assays and blood draws are good for monitoring your testosterone levels from day to day or week to week. There are also ways to determine how much testosterone you’ve been exposed to over the course of your lifetime, and also monitor how your HRT is effecting you over the long term. Androgens have a pronounced effect on multiple organs and tissues, and your skeletal system is no exception. Over time, heightened levels of androgens will effect the way your skeleton grows and with it, your

207 appearance. Recall what happens to young men when they hit puberty. The jaw and brow are both broadened, along with the shoulders. Facial and body hair develops, and ironically the hair on top of the head recedes. Expect this process to continue should you pursue the HRT portion of the AUGMENTED system.

(On a side note, the anti fungal miconazol nitrate can inhibit the action of testosterone where applied to the surface of the skin, topically. Additionally the nitrates increase blood flow. Both actions could theoretically re-grow hair on the scalp by themselves, and using both at the same time would be similar to employing both Propecia and Rogaine at once. The most commonly available OTC cream containing miconazol nitrate is Monostat 7. Do with this information what you will, there is compelling anecdotal evidence that miconazole nitrate applied directly to the scalp makes hair grow faster and thicker.)

The following point needs to be labored; Long term use of androgens of any kind, testosterone and testosterone analogs, will change your facial appearance and enlarge your vocal cords deepening

208 your voice. These effects are irreversible without serious plastic surgery. Some of you may consider this to be a good thing. Others, such as competitive fitness models, may have an enormous problem with it.

Women using androgen therapy to enhance sports performance need to be aware of how supplemental testosterone can effect their reproductive health. One of testosterone’s effects is to increase the thickness of the uterine lining during ovulation, which works directly against most hormonal birth control regimens, especially those with progestogens or levonorgestrel. Androgens will increase menstrual flow noticeably and may result in worse PMS symptoms. There is also an excellent chance it will nullify the effects of hormone based birth control including both pills and implants leading to unwanted pregnancy. This is particularly likely given testosterone’s impact on libido and lowering of risk aversion. Women are strongly advised to consult in depth with an HRT specialist well versed in reproductive health.

Another easy way to self monitor is via the psychological effects that testosterone wields. Most

209 steroid users are chasing testosterone’s psychological effects in addition to their muscle building tendencies. While not directly involved in neurotransmission, testosterone does have a massive antidepressant effect. In fact it makes you the opposite of depressed; confident, assertive to the point of aggression, and tireless in pursuing your goals. The flip side is it will make you confident when you’re dead wrong, assertive in situations that require tact, and can cause you to pursue goals that aren’t in your best interest. Not only that, but the testosterone will convince your brain you are correct in doing so. Anabolic steroids can be mind bending at high doses, and this is a large part of why chronic low dosing, rather than burst and taper protocols, are advocated in the AUGMENTED system.

Steroid hormones are powerful. While they can have a positive impact on your athletic output and quality of life, there are some hazards you will want to avoid. If you choose to operate in the blind with your dosing it is just a matter of time until you start incurring negative side effects, and they may have a significant impact on your long term health. Monitoring both your physical and mental state are important to protecting your well being while you

210 carefully coax your body into the best shape possible. We also understand that self-monitoring can be very subjective, so we periodically check androgen levels, either via spit or blood tests. Doing this insures you can stay on HRT almost indefinitely and continue to enjoy the benefits of enhanced health and wellness.

211 CHAPTER 14 - PROGRAMMING; PUTTING ALL THE PIECES TOGETHER

You have just absorbed and digested over 20,000 words worth of advanced systems biology and ergogenic pharmacology. Or you have just skipped ahead to this section. Either way, good job. Either way, the question remains how all this information translates into an actionable, coherent program. AUGMENTED is not an exercise program, but rather a supplementation and pharmaceutical protocol. While it does not advocate for one workout regimen over another, AUGMENTED will accelerate the results you get from your program.

We do not confuse pursuing an inefficient system for hard work. We do not double down on a system or program that is not yielding results. There is no virtue in wasting time and effort in lieu of exploring a potentially more efficient route to fitness goals. AUGMENTED is a simple system. We are putting our bodies in what a computer programmer would call a 'recursive loop,' and the question and the

212 answer are both within your body. The system is not 'data driven,' as variance between individuals is significant enough to render a body of aggregate data nearly useless. Simply put, we need to figure out what works for you yourself, rather than averaging what worked for scores of people who are not you.

TIER 1 - BASIC SUPPLEMENTATION

Consider this the “foundation” for your supplementation regimen. It is the bare minimum in the AUGMENTED system and consists of the safest, most affordable, evidence supported and highly effective supplements. It will coax your body into building and maintaining muscle mass while gently controlling body composition with minimal effort. The initial supplementation regimen is as follows:

LEUCINE - 3500mg DAILY: This is taken in two evenly divided doses of 1750mg. It ramps up mTOR which maximizes gene expression even in a caloric deficit. The first dose is taken immediately when you wake up in the morning along with your breakfast. The second dose is taken right before you go to bed at night.

213 Remember that the cornerstone of the program, the mTOR pathway, needs oxidative stress AND insulin AND leucine to fully activate. We can think of this as correlating to exercise, nutrition, and supplementation, respectively. In many cases, supplementing with leucine alone can replace a protein shake. In powder form, leucine dissolves nicely in acidic juices - orange juice in particular. That combined with the swift insulin kick from the sugar in the juice will give your mTOR pathway a solid lift with commensurate fat loss, muscle gain, and enhanced immune function.

CONJUGATED LINEOLIC ACID (CLA) 1000mg DAILY: This is taken in a single dose right before bed. It’s purpose is to partially inhibit estrogen production, forcing the body to ramp up testosterone in response. Because testosterone is produced during deep sleep, CLA is dosed to sync up with maximum testosterone concentration. Lipids like CLA tend to have a very long half life, and the concentration will stay high enough throughout the night to have the intended effects.

214 Additionally, CLA will ramp up the P-PARγ pathway which encourages adipocytes to release fat so it can be metabolized in the muscle tissue.

(Optional) SALICYLIC ACID: 3000mg DAILY: If body fat reduction is a concern, add any form of salicylic acid (acetylsalcylic acid, salsalate, or salicylic acid itself,) to your regimen. Monitor yourself very carefully for ulcers or any kind of stomach pain and if it begins, reduce or eliminate salicylic acid. Take it in evenly divided doses throughout the day.

CREATINE 5 grams DAILY: Creatine has multiple benefits. It provides extra energy to your skeletal muscle, accelerates recovery between sets, and even delays the onset of mental fatigue in high concentration situations. It also adds a good amount of size to your muscles to enhance that athletic aesthetic that’s one of the many rewards of fitness.

The type of creatine (monohydrate, hydrochloride, etc.) isn’t especially important. Buy the cheapest stuff you can and don’t get pulled in to paying twice

215 the price for over engineered creatine that charges a 60% premium for 1% better effects.

The Tier 1 regimen works - both well and slowly. The key to being successful with it is tremendous consistency. Finding the easiest possible means of preparing and taking these supplements is key to obtaining the outcome you’re seeking.

As you monitor your progress towards your goals, you will see initial rapid progress that begins to taper off over time. As the plateau begins to manifest, your next step will be hormone optimization, a step which will require the assistance of an HRT medical professional.

TIER 2: ANDROGEN AUGMENTATION

By adding testosterone supplementation, we are gingerly crossing the line into the medical field. At the outset, you will need the assistance of a medical professional who will help you safely find a dose of androgens and aromatase inhibitors which will balance your testosterone and estrogen.

216 Testosterone injections can produce several unwanted side effects, some of which are silently harmful in the long term. Make sure you’re getting regular blood tests, at least every six months but preferably every three.

The output of an androgen supplementation program should be testosterone concentrations of 800-900 ng/dl, or something very close. Higher concentrations yield minimal advantage while putting your health at serious risk. Dial in both your supplementation and testosterone doses until you hit this level, then continue to monitor it as your body will adapt and you will experience some drift that will necessitate adjusting your doses.

After your first six months, giving your body time to adjust to everything you’re doing to it, you will need to collect metrics again. Hormone levels, weight, body fat, and athletic output will need to be re- evaluated to make certain your program is assisting you in achieving your goals. The needle should be moving on your body and athletic metrics as well.

217 If your testosterone is outside the range of 800-900 ng/dL and there are no medical red flags, ask your doctor adjust your testosterone dose accordingly.

At first, as with all new programs, you will notice surprisingly quick changes to all your metrics. As time goes on, maybe over the course of a year to 18 months, you will notice a plateau where your metrics level out in spite of your program. This is the upper level of your body’s ability to perform without incurring physical or biochemical injury, and you would be wise to respect these limitations and not push yourself beyond it. Rest assured that following this program doesn’t just change the way your metabolism works in the moment; it actually alters your gene expression permanently and you will never, ever be able to go back to your baseline.

It is very likely that your physician will offer either a transdermal gel or testosterone cypionate injections. These are the standards of care and work quite well. Between the two, the testosterone cypionate is safer and more effective. With a half-life of eight days, once a week injections are preferred to reach a steady-state concentration. The initial dosing will be 100mg/week, though using 140mg as a first-time

218 ‘booster’ dose is acceptable. This period lasts eight weeks and is put in place to make certain there are no unexpected negative reactions to the hormone replacement therapy. Assuming a 100kg male, this should raise testosterone levels by roughly 300ng/ dL.

After twelve weeks, a second blood draw is performed. We want to see how the HPG axis has responded to the testosterone regimen. In addition to serum testosterone levels, we also assay for SHBG, GnRH, and estrogens. Estrogens within normal ranges are acceptable. If estrogen is outside the normal range (it will typically be too high,) make certain GnRH is within normal range and introduce an aromatase inhibitor. Many options are available, but anastrozole is preferable due to low cost and excellent safety profile. Other options (like exemestane,) may be too powerful for long term use.

From this point forward, the biosurveillance regimen is performed every 12 weeks. Maintaining a testosterone concentration within 700-900 ng/dL should be the goal. In addition to determining

219 androgen levels, your quarterly blood draw should also check for the following:

Gonadotropin Releasing Hormone (GnRH): This is the chemical signal from the pituitary to the gonads which results in the release of testosterone. Expect these levels to decline as you progress with hormone replacement therapy. When GnRH levels decline, your testicles will naturally atrophy (e.g. shrink,) as their services are no longer needed. This understandably bothers some men. Should your testicles begin to shrink, consider adding GnRH to your regimen.

Sex Hormone Binding Globulin (SHBG): SHBG should be within 16.5-55.9 nano moles per liter. Recall that SHBG essentially stores sex hormones and is an indirect way of lowering the concentration of androgens by preventing them from reaching their target tissues. If levels begin to approach the high end, it will blunt the effects of your testosterone therapy. A small daily dose of stanazolol can be prescribed off label to reduce SHBG and restore effectiveness to your regimen. You may also find reducing your estrogen is helpful if it’s on the higher end of normal.

220 Estrogen: Estrogen should be between 7.6 to 42.6 picograms per milliliter. Make no mistake, male or female your body needs estrogen to function properly. Testosterone therapy will naturally raise your estrogen levels via aromatase as more androgens are available as a substrate. If you find your estrogen is approaching the upper limit, first attempt to regain control by raising your dose of CLA. Should that not work, move on to anastrozole and then exemestane. Another option is to back off androgens for a period, or work at losing body fat if you’re carrying a significant amount.

Hematocrit: This is a critical marker of health. As we mentioned in an earlier chapter, this is the percentage of your blood that is made of red blood cells. If it is too high, moving blood through your fine capillaries becomes difficult for your heart and you are likely to develop a condition called “veinous thrombosis” that is detrimental to your performance.

While one would naively assume that a higher hematocrit is better, this isn’t the case. Heavily oxygenated blood that can’t readily reach your cells is practically useless. The same amount of red

221 blood cells with an appropriate ratio of plasma (the non red blood cell fraction of your blood,) allows all that extra oxygen to efficiently reach your cells.

Your hematocrit needs to be between 37.5% to 51% of your blood, by volume. Any higher and you’re placing stress on your heart. Should you exceed the 51% threshold, ramp up your cardio training to increase your blood plasma. If this doesn’t work, you will need to donate blood or back off on your androgen supplementation.

This chapter will close with the following, you need to closely monitor your hormone levels while undergoing the AUGMENTED program. Balancing your HPG axis at a high-performing level is a moving target, and your body will attempt to adapt in a way that thwarts your intentions.

We do not operate in the blind. We do not guess. We protect our health while coaxing the body into being the best it can be.

Ultimately, your androgen/HRT regimen is in control of your doctor. Metabolic endocrinology is a highly complex medical science that can result in

222 significant harm if approached improperly. Once your hormones are properly balanced (a great benchmark for those on HRT is having your estrogen within normal range,) we can begin the third tier.

TIER 3: SARMS AND INDS

Once the basics and HRT have been addressed, we can start enhancing the AD and other pathways using highly specific SARMs which can safely deliver the effects of heavy androgen use with reduced danger. HRT mimics “natural” sex hormone function - which you need to stay healthy. By stacking SARMs on top of it you get the best of both worlds, and since SARMs only down regulate naturally produced testosterone we don’t have to worry about side effects.

The suggestions for SARMs are simple, either:

5mg Ligandrol/day (preferred) or

30mg RAD-140/day.

223 Using any more than this places you on a level of diminishing returns, risks side effects, and is wasteful. If you absolutely must, adding MK-677 (15mg/day) is an option but this is beginning to push your body out of balance and will cause odd complications that will essentially result in you aging faster in some respects.

You now have a complete set of tools, with solid instructions, that will make physical strength come much easier to you. Being strong and in shape will not change who you are, it will just make you more of what you’ve always been.

My sincere hope is that being stronger, thinking more clearly, and recovering faster allows you to compromise your morals less, overcome life’s obstacles with grace and presence of mind, and enable you to manifest your greatest intentions much easier.

The next and final chapter is intended to give you more perspective into how your role in the world will change once you’re augmented. Read on - please.

224 CHAPTER 15 - ETHICS

YOUR STRENGTH

'Strength is provided, not to subjugate, not to demean, not to harm, but as a means of expressing & protecting love.'

~ Dr. Mark Cheng

Whatever and whomever you are, this book was written to help make you stronger. We are blessed to live in one of the safest, technologically advanced, and prosperous eras in human history. Strength has gone from being a necessity for survival to a novelty and then a luxury. Those who seek to be strong are often viewed as trying to cover up for other shortcomings in their lives, which is unfortunate. In most cases, strength correlates tightly with physical health, intelligence and longevity. Being strong allows you to be of greater service to your community, especially when things are at their worst. It is a means of self development with strong dividends.

225 However, this is not what people have noticed. In our culture strength is synonymous with bullying attitudes, low intelligence, and emotional insecurity. In many instances, this reputation is well earned and it should be no surprise that most people in the athletic community can readily identify “that guy” in their immediate presence.

When viewed through this cultural lens, performance enhancing drugs which accelerate your muscular development and in some cases extend it beyond natural physiological limitations are viewed as a negative. Most laymen can readily recite the side effects of anabolic steroid use; ‘roid rage, acne, testicular atrophy. They have no idea the health, quality of life and longevity these drugs can produce if used responsibly and with medical oversight.

We admonish our readers to carry their strength humbly, modestly, and in service to their communities. Physical strength, athletic prowess, and frankly attractiveness does not define you and does not complete you. It can begin you, it can give you the confidence to be productive in service to others. But it is not and can not be an end unto

226 itself. If this book has helped you, please also carry these words with you.

YOUR INTELLECT:

'…give me the strength to surrender my strength to thine will with love.'

~ Rabindranath Tagori, Gitanjali

I have tried desperately to avoid using the personal pronoun ‘I’ while writing this book. This is not a book about me, it is a book about you. Writing it has taken me over a year and it is dawning on me as I type out these final paragraphs that my readers are, in effect, my students. I am a teacher by profession and thrive on connecting with the people I educate. I wish you well and hope I have empowered you, immensely, to be the person you dream of being. As we part ways for now, I leave you with this;

Think in specifics, not generalities. The minute you stop observing phenomenon directly, you slowly start applying past observations to current conditions that may not be congruent. Over time, you will begin to apply old solutions to new problems and won’t be able to understand why they’re not working. This is a cognitive flaw that will slowly render you irrelevant.

227 Never stop learning, never stop observing. Be open to new ideas, no matter how much expertise you develop.

Only long term gains are gains. We live in a culture that has a built-in expectation of instant gratification. But that which is gained quickly can be lost just as quickly. That which is patiently developed can also be lost quickly, but it will be of much higher quality and much more durable.

The information in this book is designed to literally change the way your body expresses your DNA. But even with the dramatic epigenetic shift, gains will come with some hard work, consistency, and time. Work the program. Give yourself ample time to achieve your goals, physical or otherwise, and allow them time to develop properly.

A system is more than the sum of its parts: See how the components of your program work together. From leucine and insulin and exercise working together to activate mTOR, the neural enhancement that allows you to design and execute your workout regime, everything works together.

228 Anticipate and mitigate downstream effects: As you design your program, consider potential dangers well in advance and have a plan for mitigating them if and when they occur. It’s natural to have grand visions of what will go right, but you should also consider what can go wrong and put plans into place for them before they become problematic. It’s a cliche thing to say but a stitch in time saves nine.

Be willing to be wrong: Being shown that you’re wrong about something is an amazingly powerful thing. It gets you closer to the truth and makes your belief system more congruent with reality. It can also rattling to the ego, which is why so many people find themselves resistant to changing their minds, even when presented with sufficient evidence that they’re wrong. Consider the evidence and allow it to shape your opinion. Intellectual stubbornness is the hallmark of a dull mind.

229 WHERE WE GO FROM HERE

“Poor is the student who does not surpass his teacher” ~ Aristotle

AUGMENTED is imperfect. It is far from perfect. It is my hope that this book sparks a robust community that is scientifically literate and passionate about health, wellness, and athletic performance.

As of this writing, there are plans in the works for partnerships that will produce a thriving community for the development and sharing of knowledge regarding the AUGMENTED system. You are strongly encouraged to participate, both to share your knowledge as well as develop your own. It is fairly stereotypical to say fitness is a journey, not a destination. But let’s be honest, it is both, and for those who choose to tread this road there are perks along the way. Let’s continue this journey together.

Thank you so much for reading.

~ Jordan G. Cimino, M. Sci.

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