Marijuana use and heart attack risk have been correlated in a large human study in the United States. Also, Stanford University scientists and international collaborators found that a molecule in soybeans may counteract these effects, reports the research published in Cell.
People who use marijuana have an increased risk of heart disease and heart attack, according to a large study led by researchers at Stanford Medicine and including scientists from National Taiwan University, University of Copenhagen, Academia Sinica, the University of Colorado School of Medicine and the University of California, San Francisco.
The study also showed that the psychoactive component of the drug, known as THC, causes inflammation in endothelial cells that line the interior of blood vessels, as well as atherosclerosis in laboratory mice, wrote Krista Conger for Stanford Medicine on 29 April 2022.
The inflammation and atherosclerosis can be blocked by a small molecule called genistein that occurs naturally in soy and fava beans, the researchers found. Because genistein has limited brain penetration, it doesn’t inhibit THC’s ability to stimulate appetite, dull pain and tamp down nausea — characteristics vital to medicinal marijuana users.
“As more states legalise the recreational use of marijuana, users need to be aware that it could have cardiovascular side effects,” said Dr Joseph Wu, professor of cardiovascular medicine and of radiology, and the director of the Stanford Cardiovascular Institute.
“But genistein works quite well to mitigate marijuana-induced damage of the endothelial vessels without blocking the effects marijuana has on the central nervous system, and it could be a way for medical marijuana users to protect themselves from a cardiovascular standpoint.”
In part because THC, or tetrahydrocannabinol, is a controlled substance in the United States and therefore strictly regulated in medical research, the investigators cautioned that the long-term health effects of regular use remain largely unclear.
“Marijuana has a significantly adverse effect on the cardiovascular system,” said instructor of medicine Dr Mark Chandy. “As more states legalise marijuana use, I expect we will begin to see a rise in heart attacks and strokes in the coming years. Our studies of human cells and mice clearly outline how THC exposure initiates a damaging molecular cascade in the blood vessels. It’s not a benign drug.”
Wu, who holds the Simon H Stertzer, MD, Professorship, is the senior author of the study, which was published online on 29 April in Cell. Chandy shares lead authorship with former postdoctoral scholar Dr Tzu-Tang Wei and instructor Dr Masataka Nishiga.
THC and inflammation
The researchers analysed the genetic and medical data of about 500,000 people ages 40 to 69. The data was from the UK Biobank. Nearly 35,000 participants reported smoking cannabis; of those, about 11,000 smoked more than once a month.
The more-than-monthly smokers were significantly more likely than others in the study to have a heart attack after controlling for other factors including age, body mass index and sex.
The researchers found that frequent marijuana smokers were also more likely than non-users to have their first heart attack before the age of 50 – an unusual medical event called a premature heart attack that increases a person’s lifelong risk of subsequent heart attack, heart failure and life-threatening arrhythmias that can cause sudden death.
Inflammation of the blood vessels is a primary hallmark of atherosclerosis – the thickening of the vessel wall due to the build-up of plaques made up of fats, cholesterol and other substances – which can lead to heart attack.
The researchers found that the levels of inflammatory molecules in the blood of volunteers who smoked a marijuana cigarette increased significantly over the subsequent three hours. They further showed that THC promotes inflammation and hallmarks of atherosclerosis in human endothelial cells grown in the laboratory.
Finally, laboratory mice bred to have high cholesterol levels and fed a high-fat diet developed significantly larger atherosclerosis plaques when injected with THC at levels comparable to smoking one marijuana cigarette per day than did control animals.
THC binds to a receptor called CB1 on cells in the human brain, heart and vasculature system. The receptor recognises naturally occurring cannabinoids, or endocannabinoids, which regulate mood, pain perception, immune function and metabolism.
But frequent marijuana use causes inappropriate activation of CB1, which can cause inflammation and atherosclerosis, and it is associated with obesity, cancer and diabetes.
Researchers have been trying to develop molecules called antagonists to block CB1’s function in conditions in which the receptor is overactive, like obesity, but until now the use of the antagonists has been thwarted by psychiatric side effects including mood disorders and anxiety arising from their activity in the brain.
Search for CB1 antagonists
The researchers used machine-learning techniques to screen a large database of protein structures and identify molecules structurally similar to previously identified CB1 antagonists that could block THC’s inflammatory and atherosclerotic properties without causing psychiatric side effects.
They found that genistein, a naturally occurring molecule in soybeans, binds to CB1 but has poor brain penetration. When they added the genistein molecule to THC-treated human endothelial cells or gave it to the THC-injected mice with high cholesterol, they found genistein blocked the drug’s deleterious effects and did not block the psychoactive effects of THC on the brain.
“We didn’t see any blocking of the normal painkilling or sedating effects of THC in the mice that contribute to marijuana’s potentially useful medicinal properties,” Chandy said. “So genistein is potentially a safer drug than previous CB1 antagonists. It is already used as a nutritional supplement, and 99% of it stays outside the brain, so it shouldn’t cause these particular adverse side effects.”
The researchers hope to conduct clinical trials to learn whether genistein can reduce the risk of cardiovascular disease in marijuana users. They’d also like to extend their studies to include CBD – another cannabinoid in marijuana that does not have the psychoactive effects of THC.
“There’s a growing public perception that marijuana is harmless or even beneficial,” Wu said, comparing the legalisation of marijuana use to vaping, which was first marketed as a safe way to stop smoking but has since been shown to cause lung damage and lead to increased tobacco use.
“Marijuana clearly has important medicinal uses, but recreational users should think carefully about excessive use.”
The research was supported by the Stanford Cardiovascular Institute, the American Heart Association, the Steven M Gootter Foundation, the Taiwan Ministry of Science and Technology, the Royal College of Physicians and Surgeons, the Leducq Foundation, and the Tobacco-Related Disease Research Program.
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation
Tzu-Tang Wei, Mark Chandy, Masataka Nishiga, Angela Zhang, Kaavya Krishna Kumar, Dilip Thomas, Amit Manhas, Siyeon Rhee, Johanne Marie Justesen, Ian Y Chen, Hung-Ta Wo, Saereh Khanamiri, Johnson Y Yang, Frederick J. Seidl, Noah Z Burns, Chun Liu, Nazish Sayed, Jiun-Jie Shie, Chih-Fan Yeh, Kai-Chien Yang, Edward Lau, Kara L Lynch, Manuel Rivas, Brian K Kobilka and Joseph C Wu.
Author affiliations: Stanford University, National Taiwan University, University of Copenhagen, Academia Sinica, University of Colorado School of Medicine and UC-San Francisco.
Published online in Cell on 29 April 2022.
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD.
A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist.
Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC.
In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.
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