CELESTE MIRANDA is a seasoned marketing professional who has gathered significant notoriety in the cannabis industry over the past 6 years. She is a frequent speaker on marketing in the cannabis industry at some of the largest cannabis industry expos and events. Celeste has taken several cannabis start-ups through a very successful launch, gaining unmatched exposure for what are now some of the largest industry brands. She sits on several boards within the cannabis industry including the Cannabis Cultural Association and MC4MS.
CANNABIS
CANNABIS & METABOLISM RELATIONSHIP
JOURNAL OF MEDICINE
Cannabis Research
RETHINKING
CANNABISAND M E TA B O L I S M By Dr. Adam Abodeely MD, MBA, FACS, FASCRS
New research on the endocannabinoid system may help us overcome the obesity epidemic It’s hard to know what to make of the relationship between cannabis and metabolism. On one hand, it’s been well-established that plant-based cannabinoids can make us hungry or put us to sleep, and popular culture has done a great deal to preserve their link to stereotypes of slackers who gorge on junk food, while remaining locked to the couch. On the other hand, I’ve found cannabis users are often highly active, and have a low body mass index (BMI), and there’s little empirical evidence that cannabis leads directly to obesity. In fact, there is ample reason to believe the opposite is true: one study from 2010 compared incidents of diabetes and cannabis use in the United Kingdom, and found that reported diagnoses of diabetes had increased between 2003 and 2006, at the same time that cannabis use in England had declined. In the United States, in states where medical cannabis is still restricted, diabetes remains a growing health problem. Nationwide, the disease affected 30.3 million Americans—nearly a tenth of the population—in 2015. As an advocate of medical cannabis, I feel a special responsibility to explain this paradox. But frankly, it should be important to anyone who cares about the prevalence of metabolic disorders in the United States. According to the Centers for Disease Control (CDC), obesity affects approximately 93.3 million adults each year, and is directly linked with cardiovascular disease, type 2 diabetes, and certain types of cancer. In my experience as a double board certified surgeon, specializing in gastrointestinal ailments, info@cannabisjournalofmedicine.com
I’ve seen how much metabolic problems can affect people’s quality of life, reduce their resistance to disease, and lead to premature death. Obese patients take longer to operate on, are more difficult to anesthetize, and are more exposed to postoperative complications–such as wound infections, pulmonary complications, blood clots, pulmonary embolisms, and death. All of this carries over into a greater burden to the country’s health care system: one study, published in 2009, linked obesity to $147 billion in annual healthcare spending. So long as metabolic disorders pose a significant national crisis, it’s worth asking if or how cannabis might offer us a way out. But not all of the contemporary theories on cannabis and metabolism are compelling: some researchers, for example, have proposed that overeating might compete with cannabis in the brain’s reward pathways, or that sedative effects of cannabis can make people more likely to sleep than eat.[1] Others have noted a correlation between cannabis use and higher levels of physical activity, as well as decreased consumption of alcohol--both of which are key vectors in obesity. This is a somewhat more persuasive theory, but it doesn’t seem to account for the clear link between increased appetite and increased caloric intake associated with cannabis consumption.[2] If we’re going to explain how cannabinoids can make us eat more–without necessarily making us fat—we’ll probably have to look at the role the human endocannabinoid system plays in regulating the way we process food and convert food into energy. • CANNABIS
JOURNAL OF MEDICINE
Dr. Adam Abodeely MD, MBA, FACS, FASCRS is the founder/CEO of ReserveMD™ and is a Board Certified Surgeon specializing in gastrointestinal diseases and cancer. Realizing the benefits of cannabis for patients with such ailments, Dr. Abodeely expanded his medical cannabis practice to include patients with a variety of medical ailments. Being dedicated to patient safety and education, he is an active member in numerous international cannabinoid societies and he serves as Chairman of the Dispensary Review Committee for the Association of Cannabis Specialists. Dr. Abodeely gives presentations to a variety of audiences and provides consultations on various aspects of medical cannabis. Dedicated to advancing the science and education of cannabinoidbased therapies, he has a special interest in formulating products which capture the unique benefits of cannabinoids, terpenes and other natural ingredients to provide optimal synergy and interaction with the human endocannabinoid system. Contact: Adam Abodeely MD, MBA, FACS, FASCRS aabodeely@ reservemdhealth.com (518) 354-1978
CANNABIS
JOURNAL OF MEDICINE
Cannabis Research
PLANT-BASED CANNABINOIDS CAN MAKE US HUNGRY Luckily, a lot of research has already been done this area. One study from 2006 found that stimulating the cannabinoid receptor CB1 stimulated a greater accumulation of lipid droplets in fat cells called adipocytes, and decreased the expression of adiponectin, a protein involved in fat breakdown.[3] Two studies, from 2005 and 2009, found that the endocannabinoid modulator anandamide (AEA) accelerated the process by which adipocytes develop and expand.[4][5] Another study, from 2003, found that the CB1 receptor agonist WIN-55,212 could increase the rate at which mice synthesized fat cells, while yet another study, from 2008, found that activating CB1 receptors increased the rate at which adipocytes were secreted and proliferated.[6][7] These storage-oriented processes are helped along by AEA’s ability to increase glucose uptake into the cells, a process that is mediated by CB1 receptors, according to a study from 2013.[8] Another study, from 2008, indicated that deactivated CB1 receptors expressed by white adipocytes slowed the activity of mitochondria, the cell organelles responsible for converting glucose into energy.[9] None of this is to suggest that there is a direct correlation between endocannabinoid activity and energy storage in the form of fat. To begin with, while there’s some evidence THC reduces the rate of fat breakdown within the visceral organs and under the skin of mice, there has been some variation observed in the parts of the body where fat metabolism was affected, in mice whose CB1 receptor gene was artificially deleted.[9][10] Moreover, a study from 2013, found that AEA can actually attenuate the synthesis of fat when converted into a compound called prostaglandin F2a ethanolamide (PGF2aEA).[12]
Furthermore, there are some signs that CB1 receptor expression is directly regulated by the endocannabinoid receptor peroxisome proliferator-activated receptor d (PPARd), resulting in a “braking” mechanism on the build-up of adipocytes.[13] You can see more of these contradictions in the way the endocannabinoid system participates in digestion and hunger. For example: studies from 2011 and 2013 have indicated that the taste of long chain unsaturated fatty acids stimulates appetite partly by increasing the abundance of endocannabinoid modulators in the gut.[14][15] At the same time, by activating endocannabinoid messengers in the small intestine, fat-containing chyme seems to cause the formation of lipid mediators that promote satiety, according to studies from 2003 and 2008.[16] The developed world’s appetite for cheap, convenient foods have thrown an additional wrench into these mechanisms. We can see this in the way cannabinoids can accelerate the process by which sugar–an abundant ingredient in the Western diet—is converted into fat. But another troublemaker is these foods’ high levels of omega-6 fatty acids—which, in addition to increasing the risk of stroke, heart disease, and other inflammatory or circulatory dysfunctions, have been shown to break down into anandamide and 2-arachidonoylglycerol (2-AG). These endocannabinoid modulators, in turn, bind to CB1 receptors in the brain, further mediating energy uptake and storage into fat tissue, while also stimulating appetite. For a brief period of time, doctors believed they’d found a simple solution to this complicated problem: all they needed to do was find—or develop—a compound that had a high affinity for CB1 receptors, and could thereby block it from being activated by AEA or 2-AG. On the surface of things, this strategy made a lot of sense. Weight loss was linked to a blockage of CB1 receptors in obese mice, for example, while the outright loss of CB1 receptors in mice adipocytes improved the metabolic profile and mitochondrial density of their fat cells. Clearly, there was some direct relationship between the loss of those CB1 receptors and fat metabolism, and rimonabant, a CB1 receptor antagonist, showed some promise as a weight-loss aid.
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info@cannabisjournalofmedicine.com
CANNABIS
PLANT-BASED CANNABINOIDS CAN PUT US ON SLEEP In one study, human subjects treated with rimonabant lost weight by a rate of four to six kilograms, over a period of six to twelve months, compared to subjects who received a placebo. These results were seen alongside improvements in diabetic symptoms–including insulin sensitivity–and reductions in fat cell proliferation.[17] As a result, rimonabant was briefly applied in Europe as a treatment for obesity. The downsides were considerable, however: over time, the drug was also associated with severe psychiatric effects, including anxiety and depression, and due to these concerns, it was only available commercially for a few years before being taken off the market. Meanwhile, there is still some interest in CB1 receptor antagonists that cannot overstep the blood-brain barrier, and therefore only function peripherally. The results have been mixed: in 2010, researchers developed a CB1 antagonist called AM6545, which had none of the emotional or behavioral effects mediated by rimonabant, and which reduced body fat levels in obese mice. The compound also seemed to improve glucose tolerance, reduced insulin levels in the blood, and increased the proliferation of adiponectin, but it remains unclear where its impact on metabolism really took place. At present, the strongest candidate for these reactions is within the liver–which is responsible for the breakdown of glucose and fats—in part because a specific genetic removal of the CB1 receptors from mice seemed to protect them from glucose intolerance, and from fat accumulation within the liver.[18] Further research into what these compounds can do has been limited, and so the search for an approach to obesity through the help of cannabis continues.
info@cannabisjournalofmedicine.com
This is motivated by the abundance of clear evidence for plant-based cannabinoids’ ability to lower BMI. One 2018 review article looked at all the available investigations into cannabis use and adiposity; after removing studies that only took place over a few days (making it would be difficult to distinguish fluctuations in water weight from genuine changes in body composition), and taking out studies in which the subjects had been diagnosed with AIDS, cancer, or other serious illnesses (for which cannabis was meant to stimulate appetite and increase caloric intake), the authors took a closer look at a pool of nine studies. All of these correlated reductions in BMI with cannabis use, and in all but one of these was the correlation statistically significant. There are some reasonable explanations for why the evidence should be so compelling. To begin with, the high level of omega-6 fatty acids in the Western diet— especially in processed foods made with refined grains and hydrogenated vegetable oils—almost certainly results in elevated levels of AEA and 2-AG. This is because omega-6 fatty acids are the precursors for the production of AEA and 2-AG. Therefore more omega-6 fatty acids results in the increased production of our natural endocannabinoids. Levels of AEA and 2-AG which are too elevated may cause over-activation of CB1 receptors, setting off appetite signals in the brain, enhancing the tastes and smells of foods, rapidly increasing the rate at which glucose is transferred into the cells, and accelerating the degree to which fat cells develop and proliferate around the body. It’s worth keeping in mind that all of these changes are linked to metabolic dysfunction associated with obesity and type-2 diabetes, while these symptoms are typically reversed when CB1 receptors are activated less.
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CANNABIS USERS ARE OFTEN HIGHLY ACTIVE The underlying logic is that plant-based cannabinoids–such as THC–have the potential to correct the imbalance in AEA and 2-AG levels that are the consequence of a diet high in omega-6 fatty acids. Some of this could be seen among frequent cannabis users, for whom the CB1 receptor is down-regulated during chronic use and for several weeks after abstaining from cannabis use, according to a study from 2016.[19] This downregulation of the CB1 receptor will help offset the increased activation of the receptor despite the elevated levels of circulating AEA and 2-AG. Another, strongly supported theory is that moderate cannabis use reduces symptoms related to metabolism—including diabetes, chronic insulin resistance, and Alzheimer’s.[20] All of these conditions are marked by an abundance of inflammatory markers, which plant-based cannabinoids such as THC and CBD have been shown to slow down and attenuate. The most interesting theory, however, has to do with what happens when people adjust their diet to include higher levels of omega-3 fatty acids. These can be found in green vegetables, certain varieties of eggs, oceanic fish, and seaweed, and have been correlated with some improvements in inflammatory or cardiovascular dysfunctions. More importantly, omega-3 fatty acids and omega-6 fatty acids are broken down by the same enzymes—including elognase and _-6-desaturase, both of which are produced in finite quantities. By “competing” with omega-6 fatty acids for these enzymes, omega-3 fatty acids effectively slow down the synthesis of compounds that activate CB1 receptors, including AEA and 2-AG.[21] With this in mind, it’s possible that people who take daily omega-3 fatty acid supplements–while also consuming moderate amounts of cannabis–can reduce the activation and proliferation of CB1 receptors in their fat tissue, leading to far greater improvements in BMI and other cardiometabolic risk factors than diet alone.
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All of this warrants a great deal more investigation and research which is continuing to emerge and hopefully cannabis will provide another weapon against the obesity epidemic. Though the overall potential for cannabis in addressing metabolic disorders is not quite clear, there are some very encouraging signs, and I am convinced that cannabis treatments hold a great deal of promise in helping patients better manage problems related to irregular blood sugar, pancreatic cell dysfunction, insulin sensitivity, and obesity. In the future, there is ample reason to believe that cannabis can have a positive role in treating these ailments. info@cannabisjournalofmedicine.com
CANNABIS
CANNABIS USERS HAVE A LOW BODY MASS INDEX REFERENCES 1. Warren M, Frost-Pineda K, Gold M. Body mass index and marijuana use. J Addict Dis. 2005; 24:95–100. 2. Sabia JJ, Swigert J, Young T. The effect of medical marijuana laws on body weight. Health Econ. 2017;26:6–34. 3. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006; 91:3171–3180.
13. Furuya DT, Poletto AC, Freitas HS, et al. Inhibition of cannabinoid CB1 receptor upregulates Slc2a4 expression via nuclear factor-kappaB and sterol regulatory element-binding protein-1 in adipocytes. J Mol Endocrinol. 2012;49:97–106. 14. DiPatrizio NV, Joslin A, Jung KM, Piomelli D. Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. FASEB J. 2013;27(6):2513–2520. 15. Schwartz GJ, et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008;8(4):281–288.
4. Bouaboula M, Hilairet S, Marchand J, et al. Anandamide induced PPAR-gamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol. 2005;517:174–181.
16. Gaetani S, Oveisi F, Piomelli D. Modulation of meal pattern in the rat by the anorexic lipid mediator oleoylethanolamide. Neuropsychopharmacology. 2003;28(7):1311–1316.
5. Karaliota S, Siafaka-Kapadai A, Gontinou C, et al. Anandamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation. Obesity (Silver Spring). 2009;17:1830–1838.
17. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370(9600):1706–1713
6. Bellocchio L, Cervino C, Vicennati V, et al. Cannabinoid type 1 receptor: another arrow in the adipocytes’ bow. J Neuroendocrinol. 2008;20 Suppl 1:130–138
18. Tam J, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120(8):2953–2966.
7. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423–431
19. D’Souza DC, Cortes-Briones JA, Ranganathan M, et al. Rapid changes in cannabinoid 1 receptor availability in cannabis-dependent male subjects after abstinence from cannabis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:60–67
8. Silvestri C, Martella A, Poloso NJ, et al. Anandamide-derived prostamide F2alpha negatively regulates adipogenesis. J Biol Chem. 2013;288:23307–23321.
20. Eubanks LM, Rogers CJ, Beuscher AE, et al. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol Pharm. 2006;3:773–777
9. Tedesco L, Valerio A, Cervino C, et al. Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes. Diabetes. 2008;57:2028–2036.
21. Kim J, Li Y, Watkins BA. Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity. Prostaglandins Other Lipid Mediat. 2013;104–105:32–41.
10. Kola B, Hubina E, Tucci SA, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280:25196–25201.
22. Clark, Thomas M.; Jones, Jessica M.; Hall, Alexis G.; Tabner, Sara A.; Kmiec, Rebecca L.; Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis and Cannabinoid Research. 2018;259-271:3.1
11. You T, Disanzo BL, Wang X, et al. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise. Lipids Health Dis. 2011;10:194. 12. Matsusue K, Peters JM, Gonzalez FJ. PPARbeta/delta potentiates PPARgamma-stimulated adipocyte differentiation. FASEB J. 2004;18:1477–1479.
info@cannabisjournalofmedicine.com
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Cannabis Research
INTRODUCING A NEW, NON-OPIOID PAIN SOLUTION:
RAPIDCBDTM By Larry Banegas, Kumeyaay.com
The report “World Analgesics Market - Opportunities and Forecasts, 2015-2022” projects that the world analgesics market would reach $26.4 billion by 20221. Pain sufferers have long regarded plant botanicals as a source of healing; there are more than 100 plants known to have pain relieving properties2. Consumers have sought retail brands of topical pain relief with menthol as an active ingredient3. There is a “new” botanical that consumers need to be aware of for pain relief: cannabidiol. In a study published by the National Institutes of Health4, it is stated that, “The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and 'breakthrough’ pain.” The study also states, “Chronic pain relief can be best achieved through the transdermal route.” Today, the United States faces a health epidemic: prescription opioid addiction. To address this problem, manufacturers are producing a new topical combination of CBD with menthol. These non-habit forming ingredients are a welcome solution for consumers who do not wish to pursue prescription opioid pain medications or are looking for an alternative to prescription pain medicine. The irony is that CBD is anything but “new”. CBD is a naturally occurring component of the hemp plant. Hemp is from the cannabis genus and cannabis for medicinal use dates back to the ancient Chinese emperor, Shen-Nung (c.2700 B.C.). Having compiled the medical encyclopedia called, Pen Ts'ao,5 Shen-Nung is regarded as the Father of Chinese Medicine. Cannabis or “Ma”was used by the Chinese to treat weaknesses (menstruation), gout, rheumatism, malaria, beri-beri, constipation, and absentmindedness. During the second century A.D., the Chinese surgeon, Hua T'o, began to use cannabis as an anesthesia. CBD is activated in the body through CB2 receptors located in the skin. CB2 receptors play a role in antinociception, or the relief of pain.6 Menthol is a known active ingredient with cooling properties. Working similar to ice, menthol binds with temperature-sensitive receptors in the skin and is thought to modulate pain signals within the body’s natural pain relieving systems. CBD, known to be hydrophobic and lipophilic, does not dissolve or emulsify readily in water, but will dissolve in fat. Bioavailability of CBD depends on the way that the cannabinoid is delivered into the human body. Today, science has enabled CBD to be water soluble as well as time-release. The new topical pain cream, RapidCBD™, delivers a powerful combination of micro-encapsulated time-released CBD called Cebidiol™. In Cebidiol™, consumers will benefit from menthol plus eight additional homeopathic ingredients including lavender and rosemary essential oils to relieve pain. The RapidCBD™ Cooling Pain Cream is ideal after strenuous activity and has been proven to be as effective and work as fast as an FDA approved OTC topical pain relief solution. The immediate availability of RapidCBD™ is welcome news for consumers who are seeking a non-opioid solution for muscle aches, strains and joint pain. 1 -http://www.prnewswire.com/news-releases/analgesics-market-is-expected-to-reach-264-billion-globally-by-2022-575688921.html 2 -http://www.motherearthliving.com/health-and-wellness/the-best-herbs-for-pain-relief.aspx 3 -http://health.usnews.com/health-products/top-rec-topical-analgesics-arthritis-joint-pain-135 4 -http://www.ncbi.nlm.nih.gov/pubmed/20545522 5 -https://www.psychologytoday.com/blog/the-teenage-mind/201105/history-cannabis-in-ancient-china 6 -https://en.wikipedia.org/wiki/Cannabinoid_receptor
loidosI Isodiol S.A. Rue du Mole 1 c / o Athemis Gestion SA 2000 Neuchatel / Switzerland www.isodiol.com • 1(855) 979-6751
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Micro-encapsulated, time released. Temporarily resolves muscle and joint pain associated with back pain, neck pain, arthritis, muscle strain, bruises and sprains.
DESCRIPTION Enjoy an instant and continual cooling, soothing and pain relief experience with RapidCBD™ Cooling Pain Cream. We combine micro-encapsulated, time-released Cebidiol™ with stimulating menthol and 8 homeopathic ingredients, along with lavender and rosemary essential oil to relieve aches and pains. This gel cream is ideal for use after strenuous activity and has been proven to be effective and work fast as a topical pain relief solution.
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Isodiol S.A. Rue du Mole 1 c / o Athemis Gestion SA 2000 Neuchatel / Switzerland www.isodiol.com • 1(855) 979-6751
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