The entourage effect was a term first used to describe the various endocannabinoids that work together. Recent research emphasizes how two of these chemicals (OEA and PEA) exert subtle anti-inflammatory and antidepressant effects through a receptor called PPAR-alpha. PPAR-alpha regulates gene expression. Many plant cannabinoids - including CBD and THCA - activate the related protein, PPAR-gamma. OEA and PEA are chemically very similar to anandamide and all three are primarily broken down by the same enzyme, FAAH. The medical effects of FAAH inhibitors are probably due, in large part, to the elevation of these endogenous entourage chemicals.
Cannabis for Weight Loss
In spite of the munchies, using THC-rich cannabis is associated with lower weight and a smaller risk for Type II diabetes. This is well substantiated by human epidemiology and research. But it naively seems to contradict quite a bit of preclinical research on the role of the endocannabinoid system in metabolism, which has shown that activating the CB1 receptor promotes weight gain and reduces insulin sensitivity. Researchers at Indiana University suggest one explanation in a new paper, based on the fact that the modern western diet incorporates much fewer omega-3 fatty acids than omega-6. Omega-6 fatty acids are precursors to endocannabinoids, and so the imbalance in the Western diet may lead to overactivity at CB1 in metabolic tissues. Heavy or long-term cannabis use could desensitize the CB1 receptor, offsetting the effect of the elevated levels of endocannabinoids from diet. This is a plausible explanation, although other reasons have been proposed as well. According to the scientists, “Once patients become aware that the side effects of medical Cannabis may include weight loss and reduced risk of obesity-associated medical conditions, [the] shift toward medical Cannabis is likely to accelerate. Available data suggests that this will save many lives, not only from reduced rates of obesity-related chronic illness, but also from reduced deaths from pharmaceutical overdose” [emphasis added]. That’s certainly food for thought.
CB2 Protects Against Fibrosis
Smoking cigarettes is well known to cause lung damage, but this is not only due to smoke. Nicotine in whatever form – even nicotine replacement therapies like a patch – causes lung inflammation and fibrosis by activating acetylcholine receptors. Polish scientists recently examined how the endocannabinoid system fits into the picture. Activating the CB2 receptor ameliorated nicotine-induced fibrosis, while blocking the receptor exacerbated the problem. Fibrosis involves the accumulation of a protein called collagen between cells. This ultimately impairs the absorption of oxygen in the lungs. CB2 activation slowed the differentiation or migration of a major collagen-releasing immune cell (the myofibroblast) to the lungs. This is one of many studies indicating that CB2 agonists – in some cases – will reduce fibrosis. The endocannabinoid system is bidirectional, however. Sometimes cannabinoids can worsen fibrosis, particularly CB1 agonists in the kidneys and liver.
Pesticides and Cannabis
A new article from the California Department of Pesticide Regulations (CDPR) warns of the dangers of cannabis because it may be contaminated with organophosphate pesticides (e.g. chlorpyrifos, glyphosate). The CDPR walks through what could happen if a pregnant woman uses chlorpyrifos-contaminated cannabis. Pesticide toxicity is important concern, but this is a bit ironic coming from the CDPR, which has consistently failed to provide sensible limits for pesticides on cannabis.
For years there has been a federal halt on the approval of neonicotinoids for new uses because of their devastating environmental impact on pollinators like bees (see here). Yet the CDPR allows two such neonicotinoids - acetamiprid and imidacloprid - to be used on cannabis. (The Xerces Society has detailed major issues with imidacloprid regulations in California.) Project CBD has repeatedly submitted comments to California’s Bureau of Cannabis Control in regard to these facts, but to no avail.
Much funding has been devoted to studying drug use and risky sexual practices. While this is a serious issue that should be addressed, such research has been misused to stigmatize marginalized groups. It is used to justify greater enforcement of racist drug laws in communities of color by insinuating that poor black women are misusing their autonomy, and hence need to be forced into rehabilitation programs for their own good. But even the premise may be wrong among cannabis users. Researchers in Los Angeles have recently shown that, among homosexual men, cannabis users are safer about sex and have dramatically lower rates of STIs compared with people not using illicit drugs or using other illegal drugs.
CBD vs. Methamphetamine
Little needs to be said about the devastating impact methamphetamine abuse can have. It is a highly addictive substance whose use can lead to transient psychotic behavior and long-term cognitive problems. As part of an Iranian researcher’s PhD thesis, two scientists demonstrate that CBD can reduce the likelihood of methamphetamine relapse, even while one deals with stresses like sleep deprivation. This is particularly important because drug withdrawal often causes temporary insomnia, yet many of the medications that induce sleep are highly addictive. The researchers injected CBD directly into rats’ brain and measured the conditioned place preference for meth - a common preclinical predictor of addiction and relapse - under different experimental conditions. The implications for humans are, of course, speculative as of now.
CBD and Autism
In his first article of the new year, Raphael Mechoulam and other Israeli scientists look at the “real life experiences of medical cannabis treatment in autism.” Published in Nature, the study found that just under a third of patients report significant improvements and over half report moderate improvements while using CBD-rich oil derived from cannabis (30% CBD, 1-2% THC). The improvements include decreased aggression and agitation, fewer seizures, and better sleep, appetite and ability to concentrate. Around 10-20% of patients stopped taking various medications (mostly antipsychotic and antiepileptic drugs) within 6 months of starting cannabis treatment. One quarter of people experienced some negative side effects like sedation or restlessness, but none were severe. And about one in 5 stopped treatment because it wasn’t effective. Even though there remains a lot to be discovered about how and why CBD can improve the lives of people with autism, it is clear that cannabis can be used safely by this population and should be studied further.
Across political boundaries, a group of scientists from Russia, China, and the USA crystallized the CB2 cannabinoid receptor. This is a major achievement that will deepen our understanding of how CB2 works at a chemical level, even though X-rays of the crystal don’t provide a perfect representation of CB2 as it exists in the body. Many of these scientists were also involved in crystallizing the other main cannabinoid receptor, CB1, in 2016. These developments are also a major help to those trying to design new drugs targeting cannabinoid receptors. To get a better sense of what “understanding” the chemical structure of the CB2 entails, see these articles on A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor and Structure-kinetic relationship studies of cannabinoid CB2 receptor agonists reveal substituent-specific lipophilic effects on residence time.
Concussions and Alcoholism
Traumatic brain injury (TBI) leads to numerous problems, including alcoholism and suicide. New findings indicate that endocannabinoids aid TBI recovery: When researchers boosted 2-AG levels shortly after injury, rats displayed less anxiety and less interest in alcohol. This is significant since alcoholism is a serious comorbidity of brain injury. The researchers link the protective effect of 2-AG to changes in glutamate transmission in the central amygdala, the part of the brain that processes traumatic and fearful memories. Other preclinical research has demonstrated that endocannabinoids can play a protective role after traumatic brain injuries, like concussion, by ameliorating glutamatergic toxicity.
Self-Medicating for Endometriosis
Endometriosis is a poorly-understood condition causing severe chronic pain and alterations in a woman’s menstrual cycle. As an understudied disease, treatment is limited. Scientists surveyed over 400 Australian women to see what actions they took to treat their pelvic pain. Cannabis, heat, CBD oil, and dietary changes were rated most effective by women, in that order. Unfortunately, more women used alcohol than cannabis to manage symptoms; self-medicating with alcohol promotes chronic inflammation and led to worsening pain and fatigue in over half of such women. This underscores the importance of not treating cannabis like alcohol in the ongoing saga of legalization. (Note: endometriosis is diagnosed with an invasive surgical procedure, and so many women who likely have endometriosis go undiagnosed. The group that responded to this survey had a confirmed diagnosis.)