Researchers identify a molecule capable of inhibiting the cardiovascular effects of THC

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

Currently, only a few countries in the world allow recreational cannabis, apart from Canada, some US states, Mexico and Uruguay. On the other hand, more and more countries, including in Europe, are allowing (or tolerating) its use for medicinal purposes. In fact, tetrahydrocannabinol or THC has the effects of stimulating appetite, relieving pain and calming nausea – properties that are almost vital for people suffering from chronic pain and/or under heavy treatment who consume it to to improve their quality of life.

However, this is not without risk. ” As more states legalize the recreational use of marijuana, users should be aware that it can cause 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 “beneficial” effects it exerts on the central nervous system. The results of their research have just appeared in the journal cell.

A high risk of having a heart attack before the age of 50

As part of their study, Wu and his colleagues analyzed the genetic and medical data of around 500,000 people aged 40 to 69 registered in the British Biobank database – a long-term study initiated in 2006 that aims to identify the respective genetic contributions determine predisposition and environmental exposure to the development of various diseases. Almost 35,000 participants reported smoking cannabis, of which 11,000 used it more than once a month.

The researchers found that these regular smokers were significantly more likely to have a heart attack than other study participants (after adjusting for other factors such as age, gender and body mass index). Specifically, the data showed that regular marijuana smokers were more likely to have a heart attack before the age of 50 than non-users. However, 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 found 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 platelets on the walls of the arteries; Over time, these deposits can reduce or even block blood circulation (this is known as ischemia), cause arterial lesions, or even cause the vessel to rupture. Atherosclerosis can cause serious complications such as a heart attack or stroke.

To confirm their hypothesis, the researchers conducted an experiment using laboratory-cultured endothelial cells (which line the inside of blood vessels): they found that exposure to THC caused inflammation and oxidative stress in these cells. In parallel, the team also ran an experiment on 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 states legalize marijuana use, experts are concerned: I expect that in the coming years we will see an increase in heart attacks and strokes 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 vascular system. This receptor is involved in a variety of physiological processes, including appetite, pain perception, mood, and memory. Too frequent THC exposure, however, leads to overactivation of the CB1 receptor, which can therefore trigger inflammation. Therefore, scientists have long been looking for an antagonistic molecule capable of inhibiting the hyperactivity of this receptor. Unfortunately, the antagonists tested to date are accompanied by undesirable psychiatric disorders, particularly anxiety and mood disorders (because they simultaneously block their effects on the brain).

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

Using machine learning, Wu and his team searched a large molecular database to identify protein structures resembling previously tested antagonists and discovered an ideal candidate: genistein, a molecule found in a range 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 penetrates the brain poorly.

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 stays 99% outside the brain says Chandy. The team now plans to conduct clinical trials to verify and evaluate genistein’s ability to reduce the risk of cardiovascular disease in cannabis users.

Source: T. Wei et al., Cell

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