History and Clinical Use of Hops

Introduction of Xanthohumol, the “Miracle Compound"

Prepared for: MD420 Magazine

Prepared by:Jude Espinoza, MD, Medical Director, Board Certified Cardiology & Internal Medicine

March 17, 2019 LONESTAR LIFE SCIENCES

HOPS: A BRIEF HISTORY & SUMMARY

Brief History of Hops in Beer

You probably know that hops are one of the major ingredients in the popular beverage beer. It’s a plant that’s been used to brew the beverage for centuries. However, hops can be used for much more than making an alcoholic liquid. In fact, as you continue to read the following information, you’ll wonder why you didn’t know more about hops before.

Evidence suggests that commercial hop cultivation began in northern Germany during the 12th or 13th century and that the Germans were exporting hopped beer from the 13th century onward. The first evidence of hopped beer being brewed in England is from 1412 and for a time English brewers produced both un-hopped “ale” and hopped “beer.” On April 23, 1516 the Bavarian Reinheitsgebot was put into effect declaring hops one of the three allowable beer ingredi- ents (Yeast hadn’t yet been discovered). In 1710 the English parliament banned the use of non-hop bittering agents, at least in part to prevent brewers from evading the new penny-per-pound hop tax. Thus, hops became the dominant bit- tering agent in beer throughout the western world.

What Are Hops?

Hops (Humulus lupulus) are a perennial plant of the Cannabaceae family that also includes the genus Cannabis (yes, a sister plant to marijuana). In beer, hops provide bitterness to balance the sweetness of malt sugars, as well as flavors, aromas, resins that increase head retention, and antiseptics to retard spoilage. Often referred to as a “vine”, hops are actually a “bine”, using a strong stem and stiff hairs to climb rather than tendrils and suckers to attach. It is the flower of the female hop plant that is used in brewing. Hop flowers or cones resemble pine cones but are composed of thin, green, papery, leaf-like bracts. At the base of these bracts are waxy, yellow lupulin glands that contain alpha acids re- sponsible for bitterness and essential oils that give beer flavor and aroma. The plant has separate male and female bines, but only the female bines develop cones (flowers). If male plants are allowed to pollinate them, the flowers will produce seeds, rendering them useless for brewing. Aside from their use in beer, hops also have medicinal application as a sleep aid. Hop filled pillows were once a common remedy for insomnia since the leaves also have resins that pro- vide a sedative effect.

The top two hops producing countries in the world are the United States (44,324 metric tons) and Germany (39,000 metric tons) as of 2017 hop output data. In the US, the pacific northwest (Washington, Idaho and Oregon) produce more than 90% of all of the hops for American craft and commercial brewers.

Why Are Hops Good For You?

Dried hops can be used for a variety of things. For example, if you’re having problems with inflammation of a joint or other area of the body, you can create a poultice of dried hops. When you apply it directly to the affected area, you’ll LONESTAR LIFE SCIENCES

enjoy soothing relief. In addition, hops can be put in a sachet made of cheesecloth or old nylons and placed under your pillow. This will help you to fall asleep and have sweet dreams if you’re suffering from insomnia.

If you suffer from menstrual cramps that sometimes seem unbearable, hops can also help you to find relief. The plant works to fight muscle spasms that cause the painful cramps. In addition, it can fight spasms in the respiratory system that cause asthma.

This work with muscle spasms extends to the digestive system as well. If you suffer from indigestion or irritable bowel syndrome, hops can bring relief by relaxing the muscles of the digestive system. In addition, hops can be a good treat- ment for increasing your appetite if you’ve lost it due to illness.

Hops can be used in many forms such as infusions, liquid extracts, tinctures, oils, and tablets. You’ll need to do research before taking it to make sure you get the dosage correct. You may also find that hops are an ingredient in teas that are designed to help you sleep at night.

While the hop plant is best known for its role in beer production, the truth is that it’s a handy little plant. It can provide a variety of healthful benefits that make it the perfect solution for some health problems.

As interest in craft beer rises, the phenolic content of beer is being more widely understood, leading to beer emerging as more of a functional beverage. Beer polyphenols derive not only from hops and barley, the primary ingredients of beer, but from various other ingredients added to impart additional flavors. While the phenolic profile of beer is thus extensive and varied, Xanthohumol is a beer-specific polyphenol, being found exclusively in hops. Xanthohumol has been extensively studied for its effects on cancer, inflammation and other diseases. The presence of this and other beer phenols may account for reducing cardiovascular risk and other medical benefits associated with beer consumption. In summary, the xanthohumol and other phenols may contribute to improved health of beer drinkers.

• Hops contain a variety of essential oils as well as various minerals and vitamins that give them their therapeutic benefits. The essential oils found in hops are myrcene, caryophyllene, farnesene and humulene. The oils have sev- eral potent therapeutic properties including anti-inflammatory and antiseptic actions.

• The vitamins found in hops include vitamins C, E, and B6. These nutrients have powerful antioxidant properties which can help protect the body from disease, boost the immune system and slow down the body’s aging process.

• Hops also contain a type of flavonoid compound called xanthohumol which is believed to have anti-inflammatory, antibacterial, antiviral, anti-tumor and anti-clotting properties.

Why Isn’t Xanthohumol More Available?

Straight to the point - there is a hops shortage. If you haven’t noticed the dramatic increase of beer choices in your local grocery or liquor store lately, the craft beer market has exploded over the past eight years and continues to outpace the hops farmers’ ability to keep up with it. In 2012, there were only 2500 breweries nation wide, and in 2016, only four years later, the number of breweries more than doubled to over 5600 - with another 2600 breweries in planning stages for 2017-18. Since American hops plants are temperature sensitive and require tons (literally tons) of water - the Pacific Northwest is the primary source of hops in the US. Since hops are needed to make beer, almost all of the hops pro- duced are sucked up by the brewery market.

The practice of using hops as an agricultural safe product is vanishing in large part because the majority of hops (97%) are used in the brewing industry. 3% of the available global hops supply is used for alternative uses. But less than 1% of all total hops are available for use in the medicinal space. In addition, the overall footprint of all worldwide land available for hops cultivation has significantly declined from its peak in 1988 of 100,000 hectares to less than 50,000 today.

The limitations associated with increased demands from the beer industry along with cultivation limitations have signifi- cantly reduced the availability of hops extracts for healthcare purposes. The good news - that is about to change.

LoneStar Life Sciences Inc has created a new company called LoneStar AgriTech, and as of January 2020, will begin growing the first indoor commercial hops growing facility in Texas for local Texas brewers and for Xanthohumol extrac- tions for healthcare. AgriTech is building its 50,000 square foot indoor greenhouse prototype in south Texas that can grow over 10,000 hops plants per grow cycle, and can have 3 grow cycles per year (over 30,000 plants per acre per year) as compared to only 750 plants per acre per year outdoors. By controlling the indoor temperature, humidity, nutri- tion, water and 18 daily light hours with LED lights, AgriTech will be the most advanced hops growing company in the world. Click here for a video.

Chemical Composition

• Alpha acids: Probably the most important chemical compound within hops are the alpha acids or humulones. Dur- ing wort boiling, the humulones are thermally isomerized into iso-alpha acids or isohumulones, which are respon- sible for the bitter taste of beer.

• Beta acids: Hops contain beta acids or lupulones. These are desirable for their aroma contributions to beer.

• Hops Essential oils: The main components of hops essential oils are terpene hydrocarbons consisting of myrcene, humulene and caryophyllene. Myrcene is responsible for the pungent smell of fresh hops. Humulene and its oxida- tive reaction products may give beer its prominent hop aroma. Together, myrcene, humulene, and caryophyllene represent 80 to 90% of the total hops essential oil.

• Flavonoids: Xanthohumol (xantho is greek for yellow, humor for humulus) is the principal flavonoid in hops and rivals the color of tumeric. The other well-studied prenylflavonoids are 8-prenylnaringenin and isoxanthohumol. Xanthohumol is under basic research for its potential properties, while 8-prenylnaringenin is a potent phytoestro- gen.

• Polyphenols: Plant based micronutrient bioactive compounds with anti-oxidant properties. They play an important role in increasing the ratio of beneficial gut bacteria to help maintain a healthy balance. Polyphenols have also been shown to help prevent and reduce the risk of diabetes, cardiovascular disease, cancer, neurodegenerative and inflammatory diseases. Total polyphenol intake has been shown to decrease “all-cause” mortality by almost 40%.

Clinical Research Supporting Medical Benefits of Hops

The past two decades have witnessed a global explosion in the prevalence of non-communicable, non-infectious chron- ic diseases such as type 2 diabetes, coronary heart disease, autoimmune diseases, and dementia. All of these diseases have been found to be associated with a physiological state of chronic inflammation defined as low-grade inflammation orchestrated by metabolic cells in response to specific immune activating signals, the origin of which is complex but has been found to be related to diet, lifestyle and environmental factors.

The lipophilic extracts of the common hops (Humulus lupulus) contain compounds that are readily modified to the fami- ly of isohumulones (e.g., iso-alpha acids). The isohumulones have been found to reduce metabolic inflammation and insulin resistance, and positively impact dyslipidemia and obesity. These effects are consistent across studies in multiple cell lines, animal model systems and human intervention trials. Mechanistic work has demonstrated that these isohumu- lones have a unique pleiotropic mechanism of action which is consistent with their demonstrated safety and range of physiological effects. It is suggested from this extensive body of work that specific isohumulones may be important bioactive agents for the application in medical nutrition therapy in the support of diseases associated with chronic in- flammation and insulin resistance. (study link)

Stress & Anxiety: Anybody that enjoys a glass or two of rich, hoppy beer will be familiar with the way that the tension seems to ease from your body. While alcohol may well have something to do with this, hops themselves may also play an important part.

• Hops have been traditionally used for their sedative abilities and may help to ease feelings of anxiety and stress.

• Several studies have demonstrated that hops have sedative effects on the body’s nervous system (study link)

• It is believed to work because it modulates the GABA receptors in the brain. Studies have also shown that hops are more effective as a sedative when used in combination with valerian. (study link)

Improved Sleep: In their leaves, hops contain chemicals that create a sedative effect, which also helps to lessen anxi- ety and induce sleepiness. A 2006 study published in Phytomedicine showed that the effects of hops result in a reduc- tion of locomotor activity as well as body temperature, which encourages sleep and relaxation. There is a growing body of scientific evidence that hops could help people improve their quality of sleep and even help treat sleep con- ditions like insomnia. • Hops have traditionally been used to help with sleep issues and several studies have analyzed its effectiveness as a sleep aid. Several studies have found that hops were effective in promoting sleep in combination with another herb – valerian. (study link)

• A study published in 2012 set out to examine the effects of hops in female nurses chosen because of their stressful jobs and their poor sleep patterns. The study found that the participants who drank non-alcoholic beer containing hops experienced a much-improved quality of sleep compared with the control group. (study link)

Menopause: Studies have found that hops have chemicals that act like estrogen. These chemicals may help relieve some of the symptoms of hormonal changes which occur because of menopause.

• A study done on 100 postmenopausal women found that a vaginal gel using hops as one of the major ingredients reduced dryness in the vagina. It also helped relieve painful intercourse, burning, itching, and vaginal inflamma- tion.

• One study published in 2006 examined the effects of a phytoestrogen extracted from hops (8-prenylnaringenin) on menopausal discomfort.

• The results of the study indicated that a daily intake of hop extract had beneficial effects on many of the discom- forts associated with menopause including hot flashes. (study link)

• Hops also appear to have other estrogenic effects; extracts have been shown to reduce menopausal symptoms, and in one study with 100 postmenopausal women, a vaginal gel containing hops reduced vaginal dryness, painful intercourse, itching, burning and inflammation. However, the study was not designed to distinguish between the effects of hops and other components of the gel, including hyaluronic acid and vitamin E.

Muscle Relaxer: Hops can also be used alone or in combination with valerian to help relax your overly stressed mus- cles, ease stiff joints and prevent spasms and twitching.

• According to experts when these herbs are used in combination, they are even more effective than when used alone.

Anti-Cancer: Xanthohumol’s anti-carcinogenic properties were first described in 1999 when it proved to be very ef- fective at scavenging various free-radicals including super oxides and nitric oxide radicals. XN has been well docu- mented to inhibit new tumor growth and limiting metastasis by inhibiting angiogenesis. Xanthohumol has been shown to inhibit as many as 60 cancers in vitro and the ongoing worldwide studies are looking very promising. XN has been shown to be effective against many different forms of cancer but more conclusive testing is needed for the development of new novel cancer therapies.

• Breast Cancer: In one German study using a culture model of mammary glands isolated from female mice, very low doses of XN mitigated tumor growth by 82% compared to the control group (Hops: Their cultivation, Composi- tion and Usage, M. Biendl, loc 1622 of 1606). Inhibition of new tumor blood vessel growth (angiogenesis) was iden- tified as the most likely reason for its effectiveness. The effect of XN in this study was 100 times more effective than resveratrol. Other studies have shown XN to be 200 times more potent an antioxidant than red wine’s resveratrol, and two times more potent than vitamin C.

• XN has also been shown to be cytotoxic (poisonous) to other cancers as well. Xanthohumol has a wide spectrum of chemopreventive activity against neoplastic tumor formation which may ultimately prove to be an effective agent against many forms of cancer. It is believed that hops can help inhibit the growth of cancer cells. A study published in Phytotherapy Research of November 2008 showed this correlation between consumption of hops and inhibition of hepatocellular carcinoma cell lines. Research conducted in the laboratory at Oregon State University has also found that the xanthohumol present in hops may also have applications against various types of cancer.

• So far, they have found it was effective against colon, ovarian and breast cancer cells. There are also indications that the compound may help prevent the development of prostate cancer, liver cancer, skin cancer, brain cancer, lung cancer, thyroid cancer, leukemia and a multitude of other cancers. (link to studies - see Cancer).

• Anti-Angiogenic Effects: Inhibits blood flow to cancer cells (breast cancer example)

• Anti-Carsinogenic Effects: Cancer preventing (breast and ovarian example)

• Chemopreventative Activity: Delays cancer development

Allergies & Asthma: Research conducted in China 2010 showed Xanthohumol and its related compounds were evalu- ated for their effects on modulating the production of interleukin (IL)-12, the most important factor driving T helper 1 immune responses. XN showed the strongest inhibitory effect on IL-12 production in macrophages stimulated by lipopolysaccharide (LPS) or LPS/interferon-gamma. In short, reduction of IL-12 decreases the inflammatory response triggering histamine release and allergy symptoms for skin, ears, eyes, nose and throat.

• Allergic Dermatitis: These compounds have been shown to possess various anti-bacterial, anti-inflammatory, anti- oxidative, anti-angiogenic, anti-melanogenic, anti-osteoporotic and anti-carcinogenic effects. Epidemiological studies on the association between beer drinking and skin disease are limited while direct evidence of beer com- pounds in clinical application is lacking. Potential uses of these substances in dermatology may include treatment of atopic eczema, contact dermatitis, pigmentary disorders, skin infections, skin aging, skin cancers and photopro- tections, which require an optimization of the biostability and topical delivery of these compounds. Xanthohumol (XN) and its related compounds were evaluated for their effects on modulating the production of interleukin (IL)-12, the most important factor driving T helper 1 immune responses. Chronic allergic contact dermatitis, an ex- perimental model for psoriasis, was used to determine the anti-inflammatory effects of XN in vivo. XN might be effective as an anti-inflammatory agent to reduce skin inflammation by inhibiting IL-12 production.

• Asthma & COPD: Xanthohumol has been recorded as reducing IL-6, an inflammatory marker related to chronic lung diseases, by 78-86% in research in mice. IL-6, like other inflammatory cytokines, has been shown to be elevat- ed in different lung diseases, but it was considered a byproduct of ongoing inflammation in the lung. However, recent studies support a dissociation of IL-6 from inflammation in the lung and suggest that this cytokine plays an active role in pathogenesis of asthma and, in all likelihood, COPD. By reducing the inflammatory response of IL-6, the T helper cells triggering the mast cell inflammation is greatly reduced, thus keeping inflamed lung tissue at bay.

Skin Health: We often forget that our skin is the largest organ we have. Skin can also be an external sign of our internal health, so if you are sick, aging, or allergic, our skin shows how we are feeling. Our skin also is the most exposed

• Anti-Bacterial Acne Treatment: Five strains of acne causing bacteria, Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Kocuria rhizophila and, Staphylococcus pyogenes, were selected to use in a controlled study for anti-bacterial properties. Hop extracts xanthohumol and the lupulones showed strong inhibitory activities against all of the strains. Naturally occurring xanthohumol, humulones, and lupulones all showed moderate to strong anticollagenase inhibitory activities.

• Antioxidant capacity was also evaluated with seven different methods based on different reactive oxygen species. Xanthohumol showed the highest activity in total oxygen radical absorbance capacity (anti-oxidant power) as well as singlet oxygen absorbance capacity. So not only does XN kill bacteria, it protects and heals the skin.

• Anti-Aging: In facial products, hops are used as a calming agent. They are high in tannins which can help re- duce inflammation. Plus they promote detoxification and are beneficial as a natural remedy to flush out toxins. That is great news if you are struggling with blemishes. Excessive fluid build-up can become stagnant. Hops have a tonic effect that washes bacteria away. It can even help to fade old acne marks.

• Hops are also great if you have mature skin as it helps to balance moisture levels in the skin. Hops inhibit the elastase enzyme that is responsible for causing cross-linking in collagen. When our collagen is cross-linked, it breaks down, and the signs of aging gradually emerge.

• Hops are beneficial in cleansers, toners, lotions, and creams. Whether you are suffering from problematic skin or just starting to see wrinkles, try adding hops in facial products today!

Hair Health: It certainly sounds a little odd but washing your hair with hop extract or beer can help add shine to your locks and reduce dandruff.

• According to proponents, the antioxidants found in hops can help strengthen the scalp and hair and reduce the amount of hair loss.

• If you would like to give it a try, first rinse your hair with a gentle shampoo then add some liquid hop extract or beer to your scalp and massage it in thoroughly. Leave for a while before rinsing it out and washing your hair as normal. It will make your hair strong as well as increase the thickness. Its potent volatile ingredient mixes with hair follicles and natural oils to protect the hair health.

Anti-Obesity (Weight Loss): A study published in 2012 reported that the flavonoid – xanthohumol – extracted from hops helped reduce body weight and fasting glucose levels in obese rats.

• The researchers also concluded that the results demonstrated the extract may have a beneficial effect on some of the symptoms of metabolic syndrome. (study link)

Diabetes and Metabolic Syndrome: A recent study published in 2017 reported that hop cones (Humulus lupulus) have been used since ancient times as a remedy for many ailments and, as a source of polyphenols and bitter acids, is very effective in the treatment of metabolic syndrome (MS). Hop flavonoids, particularly xanthohumol (XN), are substances with hypoglycemic, antihyperlipidemic, and antiobesity activities. Iso-α-acids (IAA) and matured hop bitter acids (MHBA) improve health by influencing lipid metabolism, glucose tolerance, and body weight. The modulatory effect of IAA and MHBA on lipid metabolism may also be responsible for a loss in body weight. These results suggest promising ap- plications for IAA, MHBA, and XN in humans, particularly in the prevention of diet-induced obesity and diabetes.

• Anti-Diabetic Activity: Decreased insulin requirement

• Anti-Obesity: Reduction of Adipose Fat & LDL

• Improvement of Metabolic Syndrome: Reduction of pre-diabetes

• Heart Health: Another potential benefit of the xanthohumol found in hops is the effect it may have on heart health. A study published in 2012 found that it possessed powerful antiplatelet activity. The researchers concluded it may have a role to play in the prevention and treatment of cardiovascular disease. (study link)

• Dietary XN caused a dose-dependent decrease in body weight gain. Plasma levels of glucose, total triglycerides, total cholesterol, and MCP-1 were significantly decreased in mice on the 60 mg/kg/day treatment regimen. Treat- ment with XN at 60 mg/kg/day resulted in the following:

• Reduced plasma LDL-cholesterol (LDL-C): 80%,

• Reduced Plasma IL-6 (inflammatory marker for pain, arthritis, allergy and asthma): 78%-86%,

• Reduced insulin (sugar hormone) and leptin (hunger hormone) levels by 42%, and 41%, respectively, com- pared to the vehicle control group.

• Reduced Proprotein Convertase Subtilisin Kexin 9 (PCSK-9) levels: 44% lower in the 60 mg/kg dose group compared to the vehicle control group (p ≤ 0.05) which may account for the LDL-C lowering activity of XN.

• Special Note: Injectable anti-cholesterol drugs reducing PCSK-9: PCSK 9 inhibitors are currently the most potent LDL cholesterol lowering agents on the market. Current PCSK 9 receptor blockers including Repatha and Praluent have been shown to reduce LDL cholesterol by only 60% when combined with a statin. These self injectable drugs have been shown to improve cardiovascular outcomes and reduce mortality but their wholesale cost of $14,500 yearly is a major limiting factor. Xanthohumol in comparison, drops PCSK9 by 44% by itself - without the need for any other pharmaceutical drugs! This speaks volumes on the potential of a nutraceutical agent from the hops plant to completely disrupt the cardiovascular market.

• Results of study show that oral administration of XN improves markers of systemic inflammation and metabolic syndrome in diet-induced obese C57BL/6J mice. (study link)

• Hops Antiplatelet Activity (Anti-Clotting) Benefits Cardiovascular Diseases. The Journal of Evidence-based Complementary and Alternative Medicine (May 2012), reported that xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), prevents platelet activation in human platelets. This study demonstrates for the first time that xanthohumol possesses potent antiplatelet activity which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of the thromboxane A(2) formation, thereby leading to inhibition of [Ca(2+)](i) and finally inhibition of platelet aggregation. Therefore, this novel role of xanthohumol may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases.

• Thrombosis (anti-clotting): XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. The study also demonstrated that XN induces Sirt1 expres- sion and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of ex- tracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet acti- vation in a DC-SIGN-dependent manner.

• Summary: XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible thera- peutic implications.

Liver Health: Funny thing how a beer additive can reduce the inflammation and fibrosis of an alcoholic liver, but it CAN! Not only that, Hepatitis C virus is a major cause of chronic liver disease worldwide. Xanthohumol, a prenylated flavonoid from hops, has various biological activities including an antiviral effect. In conclusion, xanthohumol displays anti-hepatitis C virus activity in a cell culture system and may be potentially used as an alternative or complementary treatment against the hepatitis C virus.

• Anti-Hepatitis C Viral: Potentially used as an alternative or complementary treatment against the hepatitis C virus.

• Anti-Fibrogenic Activity: Inhibits liver inflammation & fibrosis (liver disease) • Inhibition of HSC Activation: Fatty Liver & Cancer Cells

Brain Health: Recent research carried out in China suggests that xanthohumol – a compound found in hops may help protect the brain’s cells from oxidative stress.

• According to the researchers, this type of oxidative stress can lead to degenerative disorders such as Parkinson’s and Alzheimer’s disease.

• The researchers at Lanzhou university concluded that xanthohumol may protect the brain from damage and re- duce the risk of various brain disorders. Results demonstrate that Xn is a novel small-molecule activator of Nrf2 in neuronal cells and suggest that Xn might be a potential candidate for the prevention of neurodegenerative disor- ders. (study link) Antioxidant and neuroprotective studies show that the anti-inflammatory capacity of Xanthohumol can very very helpful in protecting and repairing damaged brain cells.

• Alzheimer Dementia (AD): “revealed that XN modulated 51 proteins that involve oxidative stress, ER stress, pro- teasomal function, chaperone, cytoskeleton, ATPase and Metabolism. In vitro findings suggest that XN is a promis- ing candidate for AD therapy that merits prompt evaluation for efficacy and safety in animal models of AD. The ability of XN to modulate multiple proteins, pathways and functions to effect reduction of AD-like pathology ex- pressed by N2a/APP cells might have advantages in treating this complex neurodegenerative disease. The result showed xanthohumol treatment modulated the inflammation and apoptosis of aged brains, exerting a protective effect on damage induced by aging.

• Stroke: A study was performed on rats to simulate a stroke by MCAO (middle cerebral artery occlusion) induced cerebral ischemia. Treatment with xanthohumol (0.2 and 0.4 mg/kg; intraperitoneally) 10 min before MCAO dose- dependently attenuated focal cerebral ischemia and improved neurobehavioral deficits in cerebral ischemic rats. Xanthohumol treatment produced a marked reduction in infarct size compared to that in control rats. In conclusion, this study demonstrates for the first time that in addition to its originally being considered an agent preventing tumor growth, xanthohumol possesses potent neuroprotective activity. This activity is mediated, at least in part, by inhibition of inflammatory responses (i.e., HIF-1α, iNOS expression, and free radical formation), apoptosis (i.e., TNF-α, active caspase-3), and platelet activation, resulting in a reduction of infarct volume and improvement in neurobehavior in rats with cerebral ischemia. Therefore, this novel role of xanthohumol may represent high thera- peutic potential for treatment or prevention of ischemia-reperfusion injury-related disorders.

Autoimmune Booster for Overall Health: In September of 2009, Molecular Nutrition and Food Research published a study that reported the anti-inflammatory properties of hops. This mean hops may help treat arthritis, gout, digestive issues, muscle pain, and other issues related to inflammation. Rarely are you able to find a plant, like hops, to be so powerful in so many ways.

• Anti-Microbial Activity: Anti-Bacterial & Anti-Fungal

• Anti-Viral Activity: Broad spectrum virus killer (against HIV) • Anti-Inflammatory Activity: Reduction of Inflammation

• Anti-Oxidative Activity: Reduction of Free Radical Oxidation

• ROS Scavenging Properties: Potent Anti-Oxidant

What Does All of This Research Mean?

The more we learn about phytobiotics (plant based medicine), the more we become amazed that Hippocrates, the fa- ther of medicine (460 BC - 370 BC), had it right the entire time - “Let thy food be thy medicine and medicine be thy food!” In fact, the Hippocratic Oath to “do no harm” we take when becoming doctors may actually mean something again. Modern medicine has become a prescription writing culture where there is a pill for every ill, to a point where prescription drugs have now become the number one accidental killer in the United States (passing car accidents back in 2008).

In the 1930’s, medical cannabis was the second most prescribed drug of choice in the US for a multitude of ailments. Before it was prohibited in 1933, the outcome of using cannabis was more important than the science needed to explain it. Bottom line - all doctors knew sim- ply that “it worked”. Now with the return of medical cannabis, and with the scientific evidence to back up as to how it works (see endocannabinoid system), more doctors are beginning to revert back to the past of using medicinal plant based products as potential alternatives to either enhance or replace current synthetic drug ther- apies from FDA approved drugs.

Plant based materials like Xanthohumol and cannabis show incredible promise for the future of medicine and continue to gain momentum in patient acceptance. Patients and doctors are becoming increasingly frustrated at the limitations and restrictions given to them from corporations (pharma and insurance companies) in control of the purse strings of American healthcare. The threat of natural alternatives to big pharma is becoming more obvious every passing day, and during the ever growing American opioid epidemic (caused by prescription medications), there is no better reason for patients to look at pharmaceutical companies as money hungry monsters rather than companies looking out for their clients’ health. The oath we take to do no harm can finally mean something again. Doctors (and their patients) want choices, and they want natural alternatives to synthetic drugs.

So here is a really important question… If revolutionary plant based products, like cannabis and hops, are showing such a huge potential capacity of providing a safer, non-toxic, less expensive natural option for better health as more of a nutritional “food supplement”, what could the potential overall impact from such a line of products be to American Healthcare?

1. Reduction of Pharmaceutical Prescriptions: If xanthohumol and cannabis can have crossover affects for relieving or helping multiple conditions, then imagine the cost savings for patients taking multiple prescriptions for multiple medical conditions. Take a look at Figure 1 below.

Category Qualifying Medical Conditions of xanthohumol and cannabinoids Xantho Cannabis

Alzheimers, Parkinson’s, Multiple Sclerosis, Epilepsy, Tourette’s, Concussion, Neurological YES YES Migraines, Stroke, CTE (concussion brain disorder)

Psychological Stress, ADD/ADHD, PTSD, PMS, Depression, Bipolar, Anxiety YES YES

Gastrointestinal Anorexia, Gastro disorders, Nausea, Crohn’s, Apetite Loss, Type 2 Diabetes YES YES

Lupus, Allergies & Asthma, HIV/AIDS, Cancer, Psoriasis, Hashimoto’s, Type 1 Autoimmune YES YES Diabetes, Rheumatoid Arthritis, Celiac, Irritable Bowel Syndrome, Thyroid

Cramps, Migraines, Insomnia, Spinal Injury, Fibromyalgia, muscle spasms, Pain/Sleep YES YES Inflammation, Arthritis, Pain, Post-Surgical, Dental

Anti-platelet, anti-cholesterol, congestive heart failure, PCSK9 inhibitor, anti- Cardiac YES YES inflammatory

Glaucoma, Fatigue, Hypertension, Muscular Dystrophy, Obesity, Bone growth/ Other YES YES repair, Osteoporosis, Wound Healing

This would mean an immediate reduction in the number of prescriptions written for these types of medical conditions. Imagine the cost savings in Medicare and Medicaid alone - not even counting commercial insurance cost reduction. This would also mean an immediate reduction in adverse side effects of multiple medications.

One striking chart shows why pharma companies are fighting legal marijuana (see right). There's a body of research showing that painkiller abuse and overdose are lower in states with medical marijuana laws. These studies have generally as- sumed that when medical marijuana is available, pain patients are increasingly choosing pot over powerful and deadly prescription narcotics. But that's always been just an assumption…until now.

Now a new study, released in the journal Health Affairs, validates these findings by providing clear evidence of a missing link in the causal chain running from medical marijuana to falling overdoses. They found that, in the 17 states with a medical-marijuana law in place by 2013, prescriptions for painkillers and other classes of drugs fell sharply compared with states that did not have a medical-marijuana law. The drops were quite significant: In medical-marijuana states, the average doctor prescribed 265 fewer doses of antidepressants each year, 486 fewer doses of seizure medication, 541 fewer anti-nausea doses and 562 fewer doses of anti-anxiety medication. By estimating the cost savings to Medicare from the decreased prescribing, the researchers found that about $165 million was saved in the 17 medical marijuana states in 2013. The estimated annual Medicare prescription savings would be nearly half a billion dollars if all 50 states were to implement similar programs.

The following chart is an example of how XN and Cannabis can be detrimental to the profits of the top 50 medications in the United States. This is the true reason why pharmaceutical companies are trying all they can to suppress the emer- gence of phytobiotic medications. It’s all about the dollars, not patients.

CBD or Product Category Common Medical Conditions 2015 Sales Xantho (billions) THC

Rheumatoid Arthritis, Psoriasis, Crohn’s, Humira Autoimmune $8.3 YES YES Colitis

Abilify Psychological Depression, Bipolar, Autism, Brain function $8.0 YES YES

Sovaldi Autoimmune Hepatitis C $6.9 YES YES

Crestor Autoimmune Lipid control for Heart Disease $5.9 YES YES

Enbrel Autoimmune Rheumatoid Arthritis, Psoriasis $5.9 YES YES

Harvoni Autoimmune Hepatitis C $5.3 YES YES

Acid Reflux, GERD, esophagitis, heartburn, Nexium Gastrointestinal $5.3 YES YES Gut Health

Advair Autoimmune Asthma $4.7 YES YES

Lantus Autoimmune Type 1 and Type 2 Diabetes $4.7 YES YES

Rheumatoid Arthritis, Crohn’s, Psoriasis, Remicade Autoimmune $4.6 YES YES Colitis

Tot al Market Value of Top 10 Medications: $59.6

Tot al Market Value of Top 50 Medications: $189 2. Reduction of overall cost of chronic conditions: Chronic Conditions are the leading cause of death and disability in the United States. Here are just some basic chunks of information regarding the cost of chronic disease in the US.

*41% of healthcare spending attributed to 12% of Americans. U.S. adults with five or more chronic conditions spend 14 times more on health services on average than those with no chronic conditions, according to a new RAND Health re- port prepared for the Partnership to Fight Chronic Disease.

*133 million Americans (45% of the population) have at least one chronic disease.

*Chronic diseases are responsible for 7 out of every 10 deaths in the U.S., killing more than 1.7 million Americans every year.

*Chronic diseases can be disabling and reduce a person’s quality of life, especially if left undiagnosed or untreated.

*Many Chronic Conditions are caused and triggered by obesity and poor diet.

If Xanthohumol and cannabis have the ability, and more importantly the opportunity, to reduce the impact of chronic conditions such as pain, cancer, heart disease and stroke, not to mention reduce the overall cost of the American Opioid Epidemic, imagine the over reduction of health care costs across the board - which includes the cost of pharmaceutical drugs.

The following chart “Chronic Diseases” shows the “X” where Xanthohumol (XN), Cannabidiol (CBD), and THC (the psy- choactive component of cannabis) shows research where these natural compounds can be affective against such dis- eases. Please pay particular attention to the 2016 cost to the American Healthcare System. Chronic pain costs more than cancer, heart disease and diabetes combined.

Healthcare Chronic Diseases Fatality Data XN CBD THC Cost 2016

10% moderate pain, 11% severe pain, 33% joint pain, 25% arthritis, Chronic Pain $635 Billion X X X and 12% for functional disability

Heart Disease $317 Billion An adult dies every 40 seconds in the us X X X

Tobacco Smoking $300 Billion About 500,000 Americans die from Lung Cancer each year X X X

Alcohol Related $249 Billion Kills 88,000 X X X

Diabetes $245 Billion 7th leading cause of death X X X

Alzheimers $223 Billion 5th leading cause of death in US X X X

Cancer $171 Billion Kills 600,000/yr. Will be leading cause of death by 2040 X X X Healthcare Chronic Diseases Fatality Data XN CBD THC Cost 2016

Obesity $147 Billion More than 30% adults, 17% of kids in US are clinically obese X X X

Arthritis $128 Billion Affects 23% (54M) adults, estimated to be 78M by 2040 X X X

Asthma $56 Billion 1 in 12 Americans (25M), increases every year X X

Stroke $33 Billion Causes 130,000 deaths per year X X X

Opioid Epidemic $78.5 Billion 116 people die from opioids every day (42,249 record deaths, 2016) X X X

1 in every 5 veterans. 1 in 3 women are sexually abused. PTSD $2 Billion X X X 10% of women, 4% of men suffer from PTSD/Depression/Suicidal

Americans suffering from depression have high rates of chronic Depression $44 Billion X X disease