Blocking the CB1 receptor may be useful in medical conditions like metabolic syndrome, but strong inhibitors can have severe side effects. So chemists have attempted to produce new kinds of CB1 modulators, like inhibitors that can’t get into the brain and only affect CB1 receptors in peripheral organs. Many of these ideas have been patented, as scientists at the Research Triangle Institute in North Carolina recently reviewed. They examine national and international patents from the last four years and highlight recent trends in medical research. Broadly speaking, chemical patents are granted for a new class of molecules, a new use for known molecules, or a new route of synthesis. Scientists at University of North Carolina, Greensboro, have patented a class of “beta-arrestin biased” CB1 agonists. Such molecules are thought to weakly activate CB1, but strongly desensitize it by amplifying a homeostatic mechanism. Essentially, this tricks the body into thinking CB1 is overactive, encouraging the internalization of that receptor. Peripherally restricted CB1 antagonists have sparked significant interest, with a handful of new scaffolds patented in recent years. The claims of medical utility usually rely on mouse models of diet-induced obesity and liver disease. Negative allosteric modulators (NAMs) of CB1 are also being patented, particularly chemicals derived from pregnenolone, a cholesterol precursor. These drugs don’t directly activate or inactivate CB1, instead they just change its shape, and this weakens the signals that CB1 sends into the cell. But a NAM for THC’s interaction with CB1 won’t necessarily be a NAM for anandamide, the native ligand at CB1. This substrate-specificity, as it is called, makes developing pharmaceutical NAMs quite difficult. A few antibodies of the CB1 receptor have also been patented, including a NAM. Antibodies typically serve the immune system, but can be used to deliver drugs to specific sites in the body. There are many subtle difficulties in developing antibody-based drugs, and it remains to be seen how successful this avenue will be. Beyond just new chemicals, there are new uses for old chemicals. Patents have been filed for using Rimonabant in the treatment of Parkinson’s disease, spinal injury, and Down syndrome. Hopefully, such endeavors will prove more successful than the disastrous effort to commercialize Rimonabant as a diet pill.
Lower Rates of Cannabis Use After Legalization
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. While 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
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.
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
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
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
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
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
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
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, cannabis 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 cannabinoid research.