Quick Hits

Welcome to Project CBD Quick Hits, where we collect some of the most interesting and informative tidbits of research into cannabis over the past week.

Lower Rates of Cannabis Use After Legalization

Posted: April 10, 2019

A new study suggests that marijuana use among working 12th graders has increased since legalization in Colorado, and therefore interventions to reduce youth use are necessary. But working 12th graders were the only subgroup whose cannabis use increased since legalization. Everyone else — working 8th and 10th graders and all unemployed survey participants — used cannabis at a lower rate. The study’s data actually illustrate that legalization reduces youth use of cannabis, but the authors emphasized the 12th grade data and ignored the key take-away. It is important to study different populations, like working teens, but fearful conclusions about cannabis needs to be put in context, not aggrandized. The authors misleadingly conclude that states legalizing marijuana may consider implementing interventions to support healthy behaviors among working youth. They seem to overlook that legalizing cannabis achieves this goal.

The Gateway to Opiates

Posted: April 10, 2019

The gateway theory of addiction is a slippery slope fallacy. It argues that when people are introduced to mild drugs like cannabis, they later escalate to dangerous drugs like amphetamines and opioids. In the era of reefer madness, this was an excuse to demonize cannabis by associating it with lethal drugs. Although the theory is wrong, there are a few real aspects of addiction it captures. Opioids are devastating in part because of tolerance and sensitization. When the body is exposed to opioids, it tones down endogenous opiate activity however it can. After a few weeks of consistent use — be it medical morphine or fentanyl on the street — the body is nearly resistant to painkilling and pleasure from the initial dose of opioids, and one goes into withdrawal in their absence. Tolerance occurs, to some degree, with all drugs. Sensitization is an overlooked and subtle process in which occasional use of an opioid potentiates the rewarding feelings they confer, contributing to their highly addictive nature. Even worse, some non-opiate drugs cause opioid tolerance and sensitization. Researchers at Virginia Commonwealth University provide evidence that cannabis does not do this, again undermining the gateway theory. The synthetic cannabinoid used in their rat model of addiction did not cause opioid sensitization. But amphetamine (like Adderall) and maintenance opiates including methadone and buprenorphine did cause sensitization to future opioid addiction. If there’s a gateway, it appears to be early opioid prescriptions, not cannabis.

CB1 Kinetics

Posted: April 9, 2019

When a receptor is overactive — because of a drug or disease — the body attempts to normalize activity by internalizing the receptor, hiding it from molecules at the cell surface. Internalization is a key homeostatic mechanism. But a receptor’s degree of activation doesn’t perfectly parallel the subsequent internalization. Some ligands are «biased,» preferring activation over desensitization, or vice versa. Research from scientists at the University of Otago in New Zealand recently studied the bias of cannabinoids, including THC, anandamide, and 2-AG, at the CB1 receptor. 2-AG was about four times more potent than anandamide and 13 times more potent than THC in its ability to push CB1 inside the cell. The paper presents two models for studying internalization. The first is a set of experiments that determines the average time that CB1 spends on the surface of the cell, where it can be activated easily. The second is a more complicated theoretical model that interprets kinetics, the dynamic binding and release of a ligand and receptor. Kinetic models can also account for the availability of internal messengers and other aspects of cellular function. Though theory can appear esoteric, understanding such models helps when researchers are designing experiments or new pharmaceuticals. This study shows that measuring a compound’s affinity for CB1 should be done at multiple time points, otherwise the rate of internalization will confound the results. In other words, comparing the potency of cannabinoids at the same time will lead to artifacts in the data, since CB1 will internalize at a different rate in each experiment. From the perspective of drug design, these results suggest that THC is less likely to cause tolerance than drugs that block endocannabinoid degradation or transport. This is speculative, but in alignment current preclinical research.

CB1, Gene Expression, and Obesity

Posted: April 8, 2019

A synthetic cannabinoid pharmaceutical called Rimonabant was briefly approved in Europe as an anti-obesity drug. Rimonabant inhibits the CB1 receptor, reducing its activity below normal levels and blocking other compounds, like THC or anandamide, from activating it. It was taken off the market in 2008 for causing suicidal thoughts, among other psychiatric problems, which occurred when this pharmaceutical shut down cannabinoid activity in parts of the brain. Rimonabant is still a common tool for researchers studying the effect of CB1 inhibition, particularly in regard to obesity. A new study from scientists at the University of South Carolina described how CB1 inhibition by Rimonabant leads to changes in gene regulation, and a subsequent anti-obesity effect. The drug alters the level of immune-regulating microRNAs, which interfere with the ability of cells to make proteins from DNA, the universal genetic code. This mutes the effects of certain inflammatory genes, skewing immune cells to an anti-inflammatory state.

Big Bellies: Pregnancy & Obesity

Posted: April 3, 2019

A mother’s diet while she’s pregnant is known to affect the child’s eventual food preferences. A new animal study from scientists in the U.S. and Brazil examines how a high-fat diet during pregnancy influences the offspring’s predisposition to obesity and related complications later in life, and this appears to be mediated by changes in the endocannabinoid system. The researchers showed that the biochemical response to a high fat diet depends on whether the offspring was male or female. Male rats displayed many more dysregulated metabolic pathways compared to females. This discrepancy between sexes, with male rats being more sensitive to alterations in endocannabinoid function, is consistently seen in preclinical work. Despite the more apparent effect in males, both sexes had biomarkers suggesting a predisposition to future metabolic disorders. It’s important to be aware of the potential social consequences of this sort of research. A fetus will be affected by most medical and lifestyle choices, including antidepressant use, which seems to double the risk of autism. But women should not be consigned to producing and raising children. Considering the highly restricted access to abortion in the Americas, along with the lack of medical coverage for contraception in the US, there is a danger in publishing research which can be used to blame mothers for potential harms they could cause to a fetus. This has been particularly problematic with the prosecution of women addicted to drugs.

Singing Praises of the ECS

Posted: April 3, 2019

The endocannabinoid system forms part of what makes us feel pleasure — from the runner’s high, eating good food, and according to new research singing. Saoirse O’Sullivan’s group at University of Nottingham (UK) examined the effects of singing and dancing on endocannabinoid levels. Singing (in a group of people who like to sing) increased fatty acid ethanolamide concentrations by 30-50% in the blood — more than is typically associated with exercise. The authors suggest that some of the mental health benefits of singing may be due to the rise in anandamide, PEA, and OEA levels. Previous research has found that song birds utilize their endocannabinoid system when learning music.

ABHD6, an Exceptional Enzyme

Posted: April 3, 2019

2-AG is the most abundant endocannabinoid. It is derived from the lipid membrane that separates a cell from its environment — a cell will cut 2-AG out of its membrane, allowing the molecule to drift to neighboring cells. Upon meeting those neighbors, it slips into their membrane, where it binds to cannabinoid receptors and communicates a message. Those neighboring cells don’t send 2-AG back after the message is received, but instead cut up 2-AG to terminate the signal. An enzyme called ABHD6 is gaining recognition as an important regulator of 2-AG levels. Nephi Stella and other researchers at the University of Washington recently reviewed its role in endocannabinoid signaling. Although ABHD6 is not the major 2-AG-metabolizing enzyme, it is active in the immune system and certain brain cells. In neurons, it sits on the side producing 2-AG, helping to ensure that the cannabinoid sends information in the right direction. ABHD6 mediates the synaptic plasticity caused by cannabinoids, wherein the brain weakens connections that are no longer used. ABHD6 may do this by regulating the movement of key neurotransmitter receptors. Besides metabolizing cannabinoids, it can also attach to non-cannabinoid receptors and pull them inside the cell. There’s still a lot unknown about ABHD6; it is targeted by the Epstein-Barr virus (causing Mono) and is dysregulated in Lupus, cancer, and other diseases. Future research on ABHD6 is worth looking out for.

Cannabis & Weight Loss

Posted: April 3, 2019

Increasing consideration of the public health impact of cannabis legalization has led to a closer look at its impact on obesity. Cannabis is associated with weight loss and decreased opioid use, in spite of the munchies and the gateway theory of addiction. Weight loss and the consequent savings on health care for obesity-related complications need to be considered in economic and political analyses of cannabis legalization. The importance of these factors is bolstered by a new longitudinal study from researchers at Michigan State University, who analyze data from roughly 40,000 people over three years. Any amount of cannabis use was associated with lower BMI, but persistent users had the greatest decrease in BMI. Longitudinal studies, which track how individuals change over time, are more able to draw conclusions about cause and effect than other kinds of surveys. There are limitations, however. For example, cannabis users are more likely to smoke tobacco, which is known to reduce appetite and lower weight. As well, “use” was defined as any cannabis exposure in the past 12 months, but did not take into account the frequency and duration of use. Such considerations limit more detailed conclusions, although the study adds to the growing consensus that cannabis use leads to weight loss.

Cannabis Use Protects the Gut in Schizophrenia

Posted: April 3, 2019

An essential connection between the gut and mind is now recognized by Western medicine. Diseases like schizophrenia and Parkinson’s are closely related to digestive disorders and metabolic dysregulation. Researchers in Copenhagen probed this connection by analyzing medical records from over 20,000 people with schizophrenia. In people with schizophrenia, cannabisinfo-icon use disorder is associated with decreased risk of disorders of gut–brain interaction and inflammatory bowel disease [IBD], and possibly also other serious disorders of the digestive organs, according to the scientists. Cannabis-using schizophrenics were 30% less likely to have IBD and 10% less likely to have severe digestive disorders, but no beneficial effect was found in healthy individuals. Many antipsychotics cause metabolic dysregulation and increase weight, probably in part by disrupting endocannabinoid signaling. The authors suggest that cannabis may correct this in schizophrenics, but not healthy individuals. This study considered people with a DSM V diagnosis of cannabis use disorder. A study published just two days earlier defined cannabis use as any use in the past year. The lack of a consensus on what constitutes use leads to many contradictions in cannabinoidinfo-icon research.

New Cannabinoid-Drug Interactions

Posted: March 27, 2019

The interactions between plant cannabinoids and a drug-metabolizing enzyme called carboxylesterase 1 (CES1) was recently published in Drug Metabolism and Distribution. Researchers at the Universities of Michigan and Florida showed that THC, CBD, and cannabinol (CBN) all inhibit CES1. CES1 is important for activating or inactivating drugs that regulate blood pressure, as well as the ADD drug Ritalin. The concentrations at which the cannabinoids inhibit CES1 are large, but the interaction with high-dose CBD could be problematic. Large doses of CBD (hundreds or thousands of miligrams) are sometimes necessary, especially when CBD is used as an isolate. According to this study, THC and CBN are more potent inhibitors of CES1 than CBD, but they are used at much lower doses. Thus it is unlikely that THC or CBN will cause problematic interactions with CES1, though THC could conceivably inhibit CES1 at the peak of a high in heavy cannabis users. THC’s metabolites were also assayed, but they did not strongly affect CES1. Finally, there was some evidence that taking THC or CBN half an hour before the other drugs led to a greater interaction than taking both at the same time, but this didn’t seem to be the case with CBD. (This could be an artifact of the experimental method, or could suggest the mechanism of inhibition.) There’s a significant question that the researchers didn’t answer: What about chronic cannabis consumption? Often times the body adapts to the drugs it encounters; if CBD is inhibiting the CES1 enzyme, the liver may produce more of the enzyme to maintain balance. Currently there is no data to answer this question. The potential for cannabinoid-drug interactions shouldn’t be used to dredge up fears about cannabis, but it highlights another class of drugs that should be monitored when taking large doses of CBD.