The 1960s was a big decade for cannabis: images of flower power, the summer of love, and Woodstock wouldn’t be complete without a joint hanging from the mouth. But by the early 1960s, scientists knew surprisingly little about the plant. When Raphael Mechoulam, then a young chemist in his 30s at Israel’s Weizmann Institute of Science, was looking for interesting natural products to study, he saw an enticing gap in our knowledge of the hippie weed: the chemical structure of its active ingredients had not worked out.
Mechoulam set to work.
The first hurdle was simply getting some cannabis as it was illegal. “I was lucky,” says Mechoulam in a Personal chronicle of his life’s workpublished this month in the Annual Review of Pharmacology and Toxicology. “The head of administration at my institute knew a policeman…I just went to police headquarters, had a cup of coffee with the policeman in charge of storing illegal drugs, and was handed 5kg of confiscated hashish, believed to have been smuggled from Lebanon.”
By 1964, Mechoulam and his colleagues had determined for the first time the complete structure of delta-9-tetrahydrocannabinol, better known in the world THC (responsible for the psychoactive “high” of marijuana) and cannabidiol, or CBD.
This chemical coup opened the door to cannabis research. Over the decades that followed, researchers including Mechoulam identified more than 140 active compounds called cannabinoids in the cannabis plant and learned how to make many of them in the lab. Mechoulam helped discover that the human body produces its own natural versions of similar chemicals called endocannabinoids, which can affect our mood and even personality. And scientists have now created hundreds of novel synthetic cannabinoids, some of which are more potent than anything found in nature.
Today, researchers are unearthing the vast array of known cannabinoids—old and new, plant or human, natural and synthetic—for possible pharmaceutical applications. But at the same time, synthetic cannabinoids have become a hot trend in recreational drugs, with potentially devastating effects.
For most of the synthetic cannabinoids produced to date, side effects generally outweigh their medicinal uses, says biologist João Pedro Silva of the University of Porto in Portugal, who studies the toxicology of drug abuse and co-authored a 2023 review of the pros and cons of these drugs in the Annual Review of Pharmacology and Toxicology. But, he adds, that doesn’t mean there won’t be better things to come.
The Long Medical History of Cannabis
Cannabis has been used for centuries for everything from suppressing anxiety or pain to stimulating appetite and relieving seizures. In 2018, a cannabis-derived drug — Epidiolex, made up of purified CBD — was approved to control seizures in some patients. Some people with serious medical conditions, including schizophrenia, OCD, Parkinson’s disease and cancer, self-medicate with cannabis in the belief that it will help them, and Mechoulam sees the promise. “There are many papers [these] Diseases and the effects of cannabis (or individual cannabinoids) on them. Most are positive,” he says Interesting Magazine.
That’s not to say that cannabis use comes with zero risk. Silva points to research suggesting that daily cannabis users are at greater risk of developing psychotic disorders depending on the potency of the cannabis; a paper showed a 3.2 to 5 times higher risk. Long-term users can develop cannabinoid hyperemesis syndrome, which is characterized by frequent vomiting. Some public health experts are concerned about driving impairments, and some recreational forms of cannabis contain contaminants such as heavy metals with adverse effects .
Finding medicinal uses for cannabinoids means understanding their pharmacology and weighing their pros and cons.
Mechoulam played a role in the early days of research into the potential clinical uses of cannabis. Based on anecdotal reports going back to ancient times when cannabis helped with seizures, he and his colleagues investigated the effects of THC and CBD on epilepsy. They started in mice and, since CBD showed no toxicity or side effects, progressed to humans. Then in 1980 at the Hebrew University of Jerusalem, Mechoulam jointly published results from a 4.5-month tiny study in patients with epilepsy who were not helped by current medications. The results seemed promising: out of eight people who took CBD, four had almost no seizures throughout the study, and three saw partial improvement. Only one patient was not helped at all.
“We expected these findings to be scaled up by pharmaceutical companies, but nothing happened for over 30 years,” Mechoulam writes in his autobiographical article. It was only in 2018 that the U.S. Food and Drug Administration approved Epidiolex to treat epileptic seizures in people with certain rare and serious medical conditions. “Thousands of patients could have been helped in the four decades since our original publication,” writes Mechoulam.
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