On behalf of the US Hemp Roundtable:
Diet & the Endocannabinoid System
Cannabis has been a friend to humankind since before the written word, providing fiber for cordage and cloth, seeds for nutrition, and roots, leaves and flowers for ritual and healing. During the Neolithic period, our ancestors discovered uses for every part of cannabis, which was one of the first agricultural crops, perhaps the first, ever to be grown and harvested some 12,000 years ago.
Agriculture, strictly speaking, is not a natural phenomenon. It is an expression of human ingenuity, an invention that has been described as the basis – literally the ground – of modern civilization. “The onset of agriculture was probably one of the most dramatic and important developments in human history,” writes Swiss scientist Jürg Gertsch, who explores the profound consequences of dietary changes brought on by food cultivation in a recent article in the British Journal of Pharmacology, entitled “Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?”
Gertsch’s provocative thesis is that chronic metabolic disorders, currently a worldwide pandemic, are rooted in “a mismatch between ancient genes and high caloric diets” that ensued with the introduction of agriculture. “The multimillion year evolutionary process during which nearly all genetic change reflected the life circumstances of our ancestors [was] suddenly disturbed” when “carbohydrate farming” supplanted the “hunter-gatherer diet rich in animal food,” says Gertsch, who maintains that “the interplay between diet and the endocannabinoid system” is key to understanding today’s obesity/diabetes crisis and its potential remediation.
The endocannabinoid system, an ancient biological signaling network, regulates numerous physiological processes, including intestinal function, glucose metabolism, and the stress response. A dysregulated endocannabinoid system is implicated in metabolic and bowel pathologies and many other diseases. Gertsch discusses the different, yet complementary, roles of the cannabinoid receptors – CB1 and CB2 – pertaining to diet, digestion, and energy metabolism.
Mammalian CB1 receptors are concentrated in the brain and the central nervous system. They are also present in taste buds and the enteric nervous system (the gut-brain axis). Tetrahydrocannabinol (THC), marijuana’s main psychoactive component, boosts appetite and food intake by binding to the CB1 receptor – a phenomenon playfully known as “the munchies.” But CB1 receptors, as Gertsch points out, “can exert paradoxical effects on food intake,” facilitating essential nourishment as well as metabolic imbalance.
CB1 receptor signaling triggers a newborn’s suckling instinct. Mother’s milk is well endowed with arachidonic acid, a basic building block of the brain’s own marijuana-like compounds, anandamide and 2AG. These endogenous cannabinoid compounds bind to the same cell receptors – CB1 and CB2 – that mediate many of the effects of marijuana. Found in eggs, meat, and dairy products, arachidonic acid intake increases endocannabinoid levels in different tissues and is crucial for pre- and post-natal brain development.
Early hominids lived a precarious wilderness existence, requiring significant physical exertion (hunting and gathering) for survival. Famine, microbial infection, traumatic encounters with predators, fight or flight – all were hallmarks of a pre-agriculturist, subsistence lifestyle. Given the metabolic demands of their large brains and strenuous daily activities, our ancestors needed to consume energy-dense, nutrient-rich food.
In addition to heightening one’s sense of smell and stimulating appetite, CB1 receptor signaling “may facilitate survival after excessive physical activity, stress and trauma by restoring homeostasis, suppressing negative memories and reducing anxiety at the level of the central nervous system,” writes Gertsch, who explains that “CB1 receptor activation is associated with increased energy intake and decreased energy expenditure by controlling neural pathways.”
And CB1 taketh away
Combined with rigorous, day-to-day aerobics, the hunter-gatherer diet did not engender obesity, metabolic problems or cardiovascular disease. But the high-fat hunter-gatherer diet, which served our ancestors well, changed significantly with the advent of cultivated food. “Carbohydrate farming incited the most important dietary transition, which is still ongoing to the present day,” says Gertsch. There is a continuum, he maintains, between plant carbohydrate cultivation of yore and today’s over-starched, over-sweetened and over-processed Western diet.
Grain, carbs, sugar, alcohol, high fructose corn syrup: What started as the basis of civilization has spiraled into a mass-marketed refined sugar binge. “Dietary carbohydrates once essential for the cognitive and social development of Paleolithic humans gradually turned into a metabolic stress factor as a function of their glycemic indices,” Gertsch explains. “Epidemiological evidence points toward a pandemic diet-induced glucose toxicity due to excess sugar intake.”
The endocannabinoid system is deeply implicated in this unhealthy worldwide trajectory. Linked to both motivation and reward, CB1 receptor signaling encourages sugar consumption by enhancing neural responses to sweet flavors. It has been shown that chronic CB1 receptor activation in mice causes obesity-related insulin resistance. Aberrant CB1 activity reinforces a metabolically skewed feedback loop: In obese humans, high endocannabinoid levels are found in the liver, pancreas, adipose tissue, and skeletal muscle, where they contribute to insulin resistance, decreased glucose uptake, oxygen depletion, and cardiometabolic distress.
“The generation and excess use of sugars could be seen in analogy to the detrimental impact of the first distilled alcohol on humans. The sudden availability of excess sugars in combination with fats in diet may have led to a collision of genes that evolved to cope with high energy demands due to constant physical activity,” says Gertsch. “Excessive consumption of high-energy palatable food without physical activity contributes to obesity.” Which, in turn, leads to metabolic syndrome, heart disease, and other degenerative conditions.
CB2 to the rescue
CB1 receptors and CB2 cannabinoid receptors play different roles with respect to diet and nutrition. In animal studies, CB2 receptor activation generally causes the opposite effects of CB1. Whereas CB1 receptors promote appetite and food consumption, CB2 receptors tend to inhibit food intake.1
Expressed primarily in immune cells, adipose (fatty) tissue, and the peripheral nervous system, CB2 receptors confer broad anti-inflammatory effects in various disease models. Noting that obesity is a low-grade inflammatory condition, Gertsch discusses the “protective role of CB2 receptors in diet-induced metabolic malignancies.” Preclinical research indicates that CB2 receptor activity can prevent or ameliorate diabetes-associated peripheral neuropathy and pro-inflammatory obesity. CB2 signaling is also protective against brain damage from strokes, concussions, and neurodegenerative ailments.
Gertsch suggests that the contemporary “mismatch between ancient genes and high caloric diets” might be reconciled in part by CB2’s ability to mediate the effects of secondary plant metabolites (terpenes, flavonoids and other polyphenolic compounds) that are found in kitchen spices, leafy greens, and other vegetables. “Dietary secondary metabolites from vegetables and spices are able to enhance the activity of CB2 receptors and may provide adaptive metabolic advantages and counteract inflammation,” Gertsch reports.
Beta-caryophyllene (BCP), for example, is a seemingly ubiquitous aromatic terpene present in many spices (black pepper, cloves, rosemary, etc.) and bitter greens, as well as in numerous cannabis varietals. This versatile plant compound conveys significant health benefits by directly activating the CB2 receptor and via other molecular pathways. BCP has been shown to stimulate insulin production and inhibit tumor growth in human cell lines. Mounting evidence suggests that a steady diet of BCP-rich foods could prevent or mitigate non-alcoholic fatty liver disease through CB2-mediated channels. Eating green leafy vegetables and spices rich in essential oils “may counteract metabolic stress induced by excessive carbohydrate intake,” Gertsch advises.
Healthy fats, healthy people
Several scientific studies have explored the link between the intake of polyunsaturated fatty acids (PUFAs) and the endocannabinoid system. Docosahexaenoic acid (DHA), an omega-3 fatty acid, is the principal long chain PUFA found in the human brain. (Omega oils are considered “essential” fatty acids because they can’t be produced by the body in sufficient amounts and therefore must be ingested.) Dietary DHA and eicosapentaenoic acid (EPA), another long chain PUFA, support neurological function, retinal development, and overall health by up-regulating CB1 receptor gene expression.2 Preclinical research has shown that administering DHA and EPA prevented glucose intolerance and low-grade inflammation of white adipose tissue in obese mice.
The manifold health benefits of omega-3 PUFAs – prominent in oily fish, walnuts, flax and hempseeds, for example – include the prevention of heart disease, dementia, cancer cell proliferation, insulin resistance, and depression. Low levels of DHA and EPA can lead to premature aging, as well as mental illness. Nutritional omega-3 dietary deficiency “abolishes endocannabinoid-mediated neuronal functions” and is associated with neuropsychiatric disease, according to a 2011 report in Nature Neuroscience. Alzheimer’s sufferers and children with attention deficit hyperactivity disorder tend to be deficient in omega-3 fatty acids.
A healthy balance of omega-3 fatty acids and grain-derived omega-6 fatty acids is fundamental for preventing and managing obesity and metabolic syndrome. But a well-balanced ratio of PUFAs is typically lacking in a carb-heavy Western diet that favors greater omega-6 intake at the expense of omega-3. Gertsch suggests that it is possible “to reprogram energy metabolism” by increasing omega-3 and decreasing the amount of omega-6 in one’s diet: “Generally a lower omega-6 to omega-3 ratio is desirable in reducing the risk of many of the chronic diseases of high prevalence in industrial society or societies with high carbohydrate intake.”
A 2014 paper by Japanese scientists reported that the ratio of dietary omega-6 to omega-3 fatty acids influences how CB1 cannabinoid receptors regulate fear memory. The upshot is that altering the omega-6/omega-3 ratio in one’s diet could improve treatment regimens for anxiety and PTSD, as well as for metabolic disorders. Human beings have evolved in such a way as to have “an advanced capacity to digest and metabolize higher fat diets,” says Gertsch, who concludes that a “low-carb, high fat diet should be the most effective measure against obesity” – with the caveat that a high fat diet must be combined with regular physical exercise, much like in the hunter-gatherer days before agriculture.
Given what scientists know about how the endocannabinoid system functions, there is a strong basis for adopting a high fat, low carb diet with lots of fresh vegetables and spices, both as a general health practice and a remedy for many maladies.
Martin A. Lee is the director of Project CBD and the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.
Copyright, Project CBD. May not be reprinted without permission.
1 THC binds directly to the CB2 receptor and activates it, but not as potently as THC binds to CB1, the “psychoactive” receptor.
2 When metabolized, fatty acids yield large quantities of mitochondria-mediated ATP, the main energy source for most cellular functions. Fatty acids are important components of phospholipids that form the phospholipid bilayers out of which all the membranes of cells and the membranes of organelles within cells, such as mitochondria and the nucleus, are created. In addition to modulating cannabinoid receptor activity, diet affects cell membrane fluidity and permeability, which, in turn, impacts the ability of fatty acid binding proteins to transport endogenous cannabinoids and plant cannabinoids through the cell's membrane and into the cell’s interior, where they activate nuclear and mitochondrial receptors.
- Gertsch J. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?. Br J Pharmacol. 2016 Nov 27;PubMed PMID: 27891602.
- Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. PubMed PMID: 18574142; PubMed Central PMCID: PMC2449371.
- Gertsch J. Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action?. Commun Integr Biol. 2008;1(1):26-8. PubMed PMID: 19704783; PubMed Central PMCID: PMC2633791.
- Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, et al. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Mar;14(3):345-50. PubMed PMID: 21278728.
- Notarnicola M, Tutino V, De Nunzio V, Dituri F, Caruso MG, et al. Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Tumor Growth in Transgenic ApcMin/+ Mice, Correlating with CB1 Receptor Up-Regulation. Int J Mol Sci. 2017 Feb 24;18(3)PubMed PMID: 28245562.
- Rashid MA, Katakura M, Kharebava G, Kevala K, Kim HY. N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J Neurochem. 2013 Jun;125(6):869-84. PubMed PMID: 23570577; NIHMSID: NIHMS465637; PubMed Central PMCID: PMC3775276.
- Wood JT, Williams JS, Pandarinathan L, Janero DR, Lammi-Keefe CJ, et al. Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma. J Lipid Res. 2010 Jun;51(6):1416-23. PubMed PMID: 20071693; PubMed Central PMCID: PMC3035504.
- Yamada D, Takeo J, Koppensteiner P, Wada K, Sekiguchi M. Modulation of fear memory by dietary polyunsaturated fatty acids via cannabinoid receptors. Neuropsychopharmacology. 2014 Jul;39(8):1852-60. PubMed PMID: 24518289; PubMed Central PMCID: PMC4059893.
Photo Credits: BBC.com, Lena Guirguis, Health Staff, Brit & Co
VXL Distributors prides itself in providing the highest quality of the CBD on the market.
All of our manufacturers/partners import the CBD from the E.U., the letter attached to this link will provide a clear path to the legalities of our Industry and shine some light on the D.E.A announcement from 12/14/16.
Cannabidiol oil, also known as CBD oil, reduces the frequency and severity of seizures in children and adults with severe, intractable epilepsy, according to findings presented by researchers from the University of Alabama at Birmingham at the American Epilepsy Society 70th Annual Meeting.
UAB researchers presented eleven abstracts, or research findings, at the meeting. A key finding was that CBD provided a significant reduction in frequency of seizures for a majority of the patients in the study, and that approximately two-thirds of patients saw a greater than 50 percent reduction in severity.
"It is encouraging that both frequency and severity of seizures appear to improve in the majority of patients in our study, patients who have limited treatment options," said Jerzy P. Szaflarski, M.D., Ph.D., professor in the Department of Neurology and director of the UAB Epilepsy Center. "Our research adds to the evidence that CBD may reduce frequency of seizures, but we also found that it appears to decrease the severity of seizures, which is a new finding."
The results were based on an open-label study of 81 patients — 42 children and 39 adults — who experienced four or more seizures per month. UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April 2015. The studies, an adult study at UAB and a pediatric study at Children's of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly's Law.
After one month of beginning CBD therapy, 68 percent of the patients had experienced a greater than 25 percent reduction in seizure frequency; 58 percent had a greater than 50 percent reduction; 36 percent had a greater than 75 percent reduction and 9 percent were seizure-free. Those results were maintained at three and six months.
To assess seizure severity, researchers led by Jenifer DeWolfe, M.D., associate professor of neurology, used the Chalfont Seizure Severity Scale, a questionnaire given prior to therapy and re-administered at intervals throughout treatment. Fifty-seven patients were followed for three months: 67 percent experienced a more than 50 percent decrease in seizure severity, while 33 percent did not. Of 47 patients followed for six months, 64 percent had a greater than 50 percent decrease in seizure severity and 36 percent did not.
"These are encouraging results, but it is important to note that each patient may respond differently to CBD, and the dose for optimal seizures control varies," said Martina Bebin, M.D., professor of neurology and co-primary investigator of the CBD studies. "There appears to be an optimal CBD dose range where the patient achieves maximum benefit. If outside this CBD dosing range, the seizure frequency may not improve and may even increase. More research is needed, including determining why and how CBD helps some people with epilepsy but not others."
Among the other UAB abstracts presented at the AES meetings:
- CBD oil was associated with an improvement in mood, an effect independent of the extent of seizure reduction. Lead author Pongkiat Kankirawatana, M.D., professor of pediatrics, says CBD oil may have overall positive effects on mood, which should be further investigated in patients with epilepsy and other chronic conditions in controlled studies.
- A study led by Szaflarski and Bebin found that the optimum dose in both children and adults was between 20 and 25 mg/kg/day.
- Jane Allendorfer, M.D., assistant professor of neurology, found that CBD, in a selected group of patients with epilepsy who experienced overall improved seizure control, has the potential for positive cognitive effects that are associated with corresponding fMRI signal changes.
- One abstract reports on an interaction between warfarin, a drug used as an anticoagulant, and CBD. This underscores the importance of monitoring appropriate laboratory work in patients receiving CBD oil along with other medications, according to study lead Brannon Vines, M.D., a clinical neurophysiology fellow.
- Significant drug interactions were identified between CBD and commonly-used medications for epilepsy, including clobazam, rufinamide, topiramiate, zonisamide and eslicarbazepine. This study, led by neurology fellow Tyler Gaston, M.D., emphasizes the importance of monitoring anti-epilepsy drug levels during treatment with CBD.
- Electrical discharges measured by EEG decreased significantly after initiation and maintenance of CBD, particularly in pediatric patients, according to a study led by Leslie Grayson, M.D., a neurology fellow.
- Using fMRI imaging, Amber Gregory, a graduate student in psychology, showed that persons with epilepsy showed gains in working memory that were associated with a shift in neural recruitment as examined with functional MRI.
- An abstract aimed at examining associations between social determinants of health, such as age, gender and socioeconomic factors against health status, quality of life and mood states showed that higher age and low income were associated with lower health ratings among epilepsy patients, according to study led Magdalena Szaflarski, Ph.D., assistant professor of sociology.
The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.
The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants.
Source: Here, University of Alabama at Birmingham
Patient Survey: Cannabis in the Treatment of Age-Related Pain
Pain affects one’s mood, memory, relationships, and overall quality of life. Chronic pain can cause frustration, depression, anger, social isolation, anxiety, poor sleep, and other health risks. Fifty percent of older adults who live on their own and 75-85 percent of the elderly in care facilities reportedly suffer from chronic pain.
This survey—a collaboration between Care By Design and Project CBD—sought to answer several questions: How satisfied are patients with cannabis as an analgesic? How does medical marijuana compare to other pain management approaches, in particular, opiates? How do the most common pain management therapies compare in terms of their impact on quality of life?
Eight hundred people, most between 50 to 70 years old, responded to the survey. Over 80 percent reported that they were suffering from chronic pain; close to half reported suffering from acute pain.
A significant decrease in opiate usage among elderly patients on cannabis therapy was the study’s most notable finding. Over half of respondents reported that they had used both cannabis and opiates for pain management. Of this subgroup, 91 percent said they used fewer or no opiates after beginning cannabis therapy. Sixty-three percent said that they went off opiates altogether.
Other Key Findings:
- A striking number of patients (around half) reported that opiates had a negative impact on overall wellbeing, and resulted in worsening mood, energy, functional ability and sleep.
- Cannabis was the only therapeutic approach for which there were no reports of worsening pain. In contrast, surgery, exercise, and nerve blockers benefited some but resulted in increased pain in a significant minority of survey participants.
- There were no significant differences in outcomes for patients using plant-derived high THC products compared to whole plant CBD-rich products; both types of cannabis were found to be highly effective in managing pain.
- The most common method of cannabis administration was vaporization, which is generally a safe mode of administration—barring additives and thinning agents that can be found in low quality vaping products.
According to this patient survey, cannabis therapy appears to be an effective pain management tool with few negative side effects. Patient-reported outcomes of cannabis’ efficacy together with its low side effect profile suggest that it should be considered as a first-line treatment for pain and/or as an adjunct treatment to opiates rather than as a medication of last resort.