Researchers have modulated cannabinoid CB1 receptors in addiction treatment in order to affect cravings, the formation of habits, one’s sensitivity to triggers, withdrawal symptoms, and the pleasure one derives from drug use. Now scientists at the National Institute on Alcohol Abuse and Alcoholism have added a new factor to the list: feeling satiated. As the paper published in Cell Metabolism describes, suppressing CB1 activity outside of the central nervous system reduces mice’s desire to drink. Though we used to believe that the brain is the only major hub of neural activity, we now know that the gut acts as a “second brain.” Connecting our diet to our minds, the enteric nervous system links the gut to the brain with 5 times more neural connections than in the whole of a human spine. In the same way that eating satiates hunger, feedback from diet can aggravate or resolve psychological distress. The recent paper delves into detail on one possible mechanism. CB1 receptors exist on cells in the stomach that produce ghrelin, a hunger-inducing hormone. Ghrelin also stimulates a desire to drink, and drinking, in turn, suppresses the release of ghrelin. Activating CB1 receptors contributes to “the munchies” that cannabis enthusiasts know well, but this could also cause a desire to drink. Blocking CB1 with a peripherally restricted antagonist, one that doesn’t get into the brain, significantly reduced mice’s drinking. Practically, there isn’t much evidence that cannabis users drink more. There is reason to believe that chronic cannabis use decreases CB1 activity in fatty tissue, which would have similar effects as a peripherally restricted CB1 inhibitor.
Cannabinoids for Alzheimer's
Cannabinoids have been proposed for numerous neurodegenerative disorders. As a matter of fact, scientists employed by the US government filed a patent in 2001 for Cannabinoids as antioxidants and neuroprotectants, citing their potential for treating Alzheimer’s disease among others. Researchers at the Salk Institute for Biological Studies recently examined isolate cannabinoids and their combination in a preclinical assay of neuroprotection. They checked 11 cannabinoids’ effects on 5 measures of cellular stress that are relevant to Alzheimer’s. Many cannabinoids (CBDV, CBG, Δ8-THC, etc) prevented oxidant-induced cell death. The acid cannabinoids did not show much promise in these models — CBGA was actually cytotoxic at large concentrations, and CBDA and THCA were generally less effective at preventing cellular stress (than their neutral counterparts, CBD and THC). On average, Δ8-THC, Δ9-THC, CBD, CBC, and CBN were potent and effective neuroprotectants in nearly every test. Combining THC with CBN had a synergistic neuroprotective effect. The combination of THC and CBD was additive, but not synergistic.
Driving Under the Influence of Cannabis
Driving under the influence of cannabis (DUIC) is framed as a major risk associated with legalizing cannabis. Studies on cannabis and driving suggest that lighting up before getting behind the wheel increases crash risk between 25-40%. This is equal to the effect of having a single drink one hour before driving. So although policy around DUIC needs to be decided, the danger does not warrant stalling medical or recreational legalization while impairment limits are determined. Doctors at a hospital in Vancouver recently published a prospective study meant to determine how THC in the blood is associated with the likelihood of causing a crash. These are somewhat flawed measures — blood levels of THC aren’t equal to the THC concentration in the brain, and
culpability inflates the supposed risk. But these measures can be a good proxy, in the absence of better data. The doctors found that low levels of THC (less than 5 ng THC/ml in the blood) was not associated with crashes. Higher levels of THC did not lead to a statistically significant effect, but appeared to fall in line with past research showing a slightly increased risk. Scientists are still trying to determine why the danger is not higher. It may be that cannabis replaces recreational alcohol use, so the total number of car crashes decrease. There is also evidence that stoned drivers drive slower and less aggressively, making up for some impairment in their reaction time. The Canadian researchers also tried to discern the effect of combining alcohol and cannabis. This couldn’t be reasonably analyzed in their data, however, the current evidence suggests that this is a quite dangerous combination.
"Changing Demographics of Marijuana Initiation"
The development of legal cannabis is associated with lower teen use and higher adult use. But many scientists, hesitant to give up a lifetime of prohibition, spin their data to emphasize danger. One study from 2017 had shown that attending college is a risk factor for trying cannabis, and suggested that political acceptance of cannabis is promoting use among college students. But this interpretation was taken to task by a scientist at Washington University in St. Louis. The total levels of cannabis use have not changed much since 2000. The increase in college cannabis initiation is matched by a decrease in the number of high school students trying cannabis for the first time. In other words, college may now be a
risk factor for trying marijuana because of a successful public health effort to reduce use among high schoolers. They simply wait a few years longer before trying cannabis for the first time. As the commentary points out,
Given that later initiation is associated with decreased risk for drug-related problems, there may even be a case for cautious optimism.
Exercise Modulates Endocannabinoid Activity
There has been a spate of recent articles on exercise and cannabis. Part of the runner’s high is attributable to endocannabinoid release. In Colorado, cannabis users are more physically active, on average. And in a recent review, Chinese scientists at Shenzhen University describe how the endocannabinoid system may mediate the numerous cognitive effects of exercise. It’s complicated, since activating the endocannabinoid system can augment or reduce cognition, depending on the intensity of activation and the individual’s circumstance. Exercise is an acute stressor. But it’s a healthy stress that engages the body’s homeostatic mechanisms, promoting neurogenesis and other positive adaptations. Regular exercise also improves brain function. The scientists describe specific changes in neurotransmitter pathways that exercise — through the endocannabinoid system — appears to alter. Moderate exercise increases anandamide levels, and this is in turn correlated with elevated mood and greater activity in brain regions that store memory. The authors end with a discussion of the experimental subtleties of probing the relationship between exercise and the endocannabinoid system in humans. A simple and useful experiment would be to test whether or not blocking CB1 receptors prevents some of the benefits of exercise.
Racial Disparities in Cannabis Arrests
The push to criminalize cannabis has always revolved around race. As legalization movements gain momentum, it is important to pay back a debt owed to those who were most harmed by the drug war. That includes expunging drug crimes and reinvesting industry profits in the minority communities targeted by police throughout the drug war. Yet in Washington state, legalization is struggling to address even the basic issue of drug arrests: racial disparities have increased since legalization. Public health experts in Oregon and Washington recently published a paper on the rate of arrests for cannabis possession in WA. The total number of arrests have gone down for everyone — which is a major improvement. But African Americans are arrested for (legally) possessing cannabis at a 5x higher rate than Whites. Before legalization, the disparity was half as large, implying that Washington law enforcement have doubled down on race-based policing, even as society moves away from the catastrophe of criminalizing drug use.
CBD and Opiate Addiction
Much research demonstrates that cannabis promotes the safety and efficacy of opioids. A 2009 paper demonstrated that CBD suppresses the cues or triggers associated with heroin. By interacting with memory systems in the brain, CBD helps relieve compulsions to use opioids. Researchers led by Yasmin Hurd at Mount Sinai have published many papers on these topics, the most recent being a clinical trial of CBD for reducing relapse to heroin. Acute ingestion of high doses of pure CBD (400-800 mg) dramatically reduced participants’ response to heroin triggers while simultaneously ameliorating anxiety. The benefits appeared to extend even further — after dosing for three days, the participants experienced relief for up to a week, similar to what has been seen in preclinical work. The study was carefully designed as a double-blind placebo-controlled trial, which is typical for testing drugs in humans, but has been difficult to achieve because of the schedule 1 status of cannabis.
FABP1 and THC metabolism
The endocannabinoid system is collection of proteins and oily lipids that orchestrate the body’s regulation of homeostasis. Most of the body is water, however, so cannabinoids usually reside on the boundary of cells. Transport molecules, like albumin, carry fats through the bloodstream. Within an individual cell, other molecules called fatty acid binding proteins (FABPs) carry cannabinoids to their destination. The destination could be CB1 receptors on the mitochondria or metabolic enzymes embedded in the cell’s manufacturing hub, the endoplasmic reticulum. A new paper from scientists at Stonybrook University examined the importance of FABPs in the breakdown of THC in the liver. THC normally activates CB1 and CB2 cannabinoid receptors on the cell surface, but it needs to be brought inside the cell to be metabolized. When the gene encoding FABP1 is deleted from rats, the rate of THC metabolism is dramatically slowed. The rats“ brains were exposed to about five fold more THC, in total. The maximal concentration of THC“s psychoactive metabolite, 11-OH-THC, was also diminished in the absence of FABP1. Acute doses of THC became more potent as a result. This could be one of the mechanisms by which CBD and THC interact — CBD competes with THC to be picked up by FABP1, consequently inhibiting THC’s breakdown.
Pharmaceuticals for Cannabis Addiction?
Many drugs have been proposed as
treatment for cannabis addiction, from pure THC or CBD-rich cannabis, to Ambien. These studies often employ participants who are not trying to quit, and overlook the harms associated with the replacement medication. (Replacing one joint a day by a 240 mg THC capsule was considered a success in one study.) A new paper by researchers at Harvard and Yale sought to assess the potential of a pharmaceutical used in Alzheimer’s treatment, galantamine. They hoped that galantamine would reduce cognitive impairment, which is sometimes seen in heavy cannabis users, though these participants smoked an average of 2 joints a day. (Cognitive effects, when they occurs, are not permanent. They appears to fade after 2-4 weeks of quitting cannabis.) And, indeed, the abstract makes it seem as if this goal was achieved: they conclude by highlighting the “feasibility of the administration of galantamine for individuals with [cannabis use disorder],” and recommending that future studies
investigate the potential of galantamine to improve cognitive deficits associated with [cannabis use disorder]. But their results did not find any beneficial effect of galantamine. Although this is reported elsewhere in the paper, it is a startling and deceptive omission from the conclusion. The lack of any discernible benefit should be clearly and obviously reported, since this was the primary question of the study, even if the authors had hoped for a different result.
CBD Extract for Ulcerative Colitis
CBD has shown promise in a number of gastrointestinal disorders, particularly autoimmune problems like Crohn’s. But a recent clinical trial of CBD may put a damper on hopes for treating ulcerative colitis. The study, run by British doctors and supported by GW pharmaceuticals, sought to test the potential of a CBD-rich extract. CBD did not appear to cause a remission of ulcerative colitis, which was the primary aim of the study. Each capsule contained 50 mg CBD and «an appreciable amount of THC,» which is an unfortunately vague description. Patients were instructed to take four capsules per day at first, and increase up to ten capsules (500 mg CBD), split across two doses each day. But many patients took less, stopping at about 300 mg CBD per day. There appeared to be a beneficial effect of CBD on ulcerative colitis symptoms among the patients who used the full dose, but post-hoc analyses like these are more likely to be false positive results. Quality-of-life measures also improved with CBD treatment. The data were not strikingly positive, but different experimental designs may prove more effective. The study was designed with the expectation that CBD causes remission in 50% of ulcerative colitis cases. It may be that CBD can be helpful but is not as powerful a medication as the authors had hoped. Or, since patients didn’t take the full dose, formulating the extract as an under-the-tongue tincture may be more appropriate. The use of a CBD-rich extract, rather than an isolate, is promising, but a chemical profile of the extract should have been provided with the article for the sake of reproducibility. And finally, the CBD extract was safe in this group of patients. The placebo group reported more side effects, presumably due to the ongoing disease.