Researchers identify a molecule that can inhibit the cardiovascular effects of THC

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The legalization of cannabis use, whether for medical or recreational purposes, is a long-standing debate in France. But it’s not without reason: researchers at Stanford University have shown that the main psychoactive component of cannabis, THC, leads to inflammation of endothelial cells and the development of atherosclerosis. People who regularly use marijuana have an increased risk of developing cardiovascular disease. Scientists have nevertheless found a molecule capable of eliminating these unwanted side effects.

Currently, few countries in the world allow cannabis for recreational use, with the exception of Canada, some US states, Mexico and Uruguay. On the other hand, more and more countries, including in Europe, allow (or tolerate) its use for medical purposes. Indeed, Tetrahydrocannabinol or THC has the effect of stimulating appetite, reducing pain and calming nausea – properties almost essential for those suffering from chronic pain and/or under heavy treatment, who consume it for their quality of improve life.

However, this is not without risk. † As more states legalize the recreational use of marijuana, users should be aware that it can have cardiovascular side effects. said Joseph Wu, professor of cardiovascular medicine and radiology, and director of the Stanford Cardiovascular Institute. However, he and his team have identified a molecule that could limit these unwanted cardiovascular effects without depriving THC of the “positive” effects it causes on the central nervous system. The results of their research have just appeared in the journal Cell

A high risk of heart attack before age 50

As part of their study, Wu and colleagues analyzed the genetic and medical data of approximately 500,000 people aged 40 to 69, registered in the UK Biobank database – a long-term study started in 2006 that aims to measure the respective contributions of genetic predisposition and exposure of the environment to the development of various diseases. Nearly 35,000 participants reported smoking cannabis, 11,000 of whom used it more than once a month.

The researchers noted that these regular smokers were significantly more likely to have a heart attack than other study participants (taking into account other factors such as age, gender, and body mass index). In particular, the data showed that regular marijuana smokers were more likely than non-users to have a heart attack before age 50. However, a premature infarction increases the risk of heart failure, arrhythmia and subsequent infarction.

After analyzing the blood of volunteers who were asked to smoke a marijuana cigarette, the team also noted that levels of inflammatory molecules increased significantly over the following three hours. Inflammation of blood vessels is one of the hallmarks of atherosclerosis, a disease characterized by the progressive deposition of fatty plaques on the walls of arteries; in the long run, these deposits can reduce or even block blood circulation (this is called ischemia), cause arterial lesions, or even lead to rupture of the vessel. Serious complications can arise from atherosclerosis, such as a heart attack or stroke.

To confirm their hypothesis, the researchers performed an experiment on endothelial cells (which line the insides of blood vessels) grown in the lab: they found that exposure to THC caused inflammation and oxidative stress in these cells. At the same time, the team also conducted an experiment with mice fed a high-fat diet (to raise their cholesterol levels). Some of them were injected with THC in an amount equivalent to smoking one marijuana cigarette a day: they developed much larger atherosclerotic plaques than the control mice.

Protecting medicinal cannabis users

As more US states legalize marijuana use, experts are concerned: I expect to see an increase in heart attacks and strokes in the coming years said Mark Chandy, a Stanford Cardiovascular Institute researcher and co-author of the study.

THC binds to a cannabinoid receptor called CB1, which is primarily expressed by cells in the brain, but also in the heart and circulatory system. This receptor is involved in a variety of physiological processes, including appetite, pain sensation, mood and memory. But too frequent exposure to THC leads to overactivation of the CB1 receptor, which can cause inflammation. As a result, scientists have long been looking for an antagonist molecule that can inhibit the hyperactivity of this receptor. Unfortunately, the antagonists tested so far have been associated with unwanted psychiatric disorders, especially anxiety and mood disorders (because they simultaneously block the effect on the brain).

Genistein inhibits the effects of THC on the vascular system, but helps to maintain its beneficial effects on the brain (improvement of mood, reduction of pain, etc.). © T. Wei et al.

Using machine learning, Wu and his team searched a large molecular database to identify protein structures similar to previously tested antagonists, and discovered an ideal candidate: genistein, a molecule found in a number of plants, such as soybeans, beans or lupins. Genistein is known for its antioxidant properties and for its protective effect against vascular inflammation. It turns out that this molecule binds well to the CB1 receptor, but does not penetrate well into the brain.

When administered to THC-treated mice and added to THC-treated endothelial cell cultures, genistein had the desired effect: cardiovascular effects were eliminated, while analgesic or sedative effects were preserved. † Genistein is therefore potentially a safer drug than previous CB1 antagonists. It is already used as a dietary supplement and 99% of it remains outside the brain says Chandy. The team now plans to conduct clinical trials to verify and evaluate genistein’s ability to reduce cardiovascular disease risk in cannabis users.

Source: T. Wei et al., Cell

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