Israeli scientist Raphael Mechoulam, who died on March 9 at the age of 92, was the perfect person to discover the main active component of cannabis—THC—in 1964. Small of stature, soft-spoken and plain-speaking, he was insatiably curious, with a little bit of a kindly, mischievous twinkle in his eye at all times.
As illustrated in the film The Scientist, his first experiment with humans and cannabis involved his wife Dalia baking a cake containing THC, and a placebo cake without the special ingredient, which were fed to two groups of the couple's friends. All of the people who had the THC-laced cake were affected, in different ways: some got introspective, some got giggly, some anxious—effects that are familiar today but were then almost unknown.
I remember seeing him at a conference where he spoke very matter-of-factly about taking a sample of the remains of a 14-year-old girl at a Judean cave dating from 1700 BP while on what sounded like a sightseeing tour. The sample contained Δ8-THC that was likely used as an aide to childbirth.* It's now been speculated that anandamide may not only dull the pain of childbirth but help women forget it later.
CBD (cannabidiol) had been isolated by Roger Adams in the 1930s and by Alexander Todd at about the same time, but the structure wasn’t known. A natural products chemist, Mechoulam and his team unraveled the structure of CBD, and isolated THC, along with several other cannabinoids.
At the time, the mechanism of cannabinoid action in the body was not understood. After the cannabis receptor CB1 was discovered in the brain by (female) researcher Allyn Howlett in the 1980s, Mechoulam's team went looking for endogenous (natural in the body) compounds that activate those receptors, because, as he told an interviewer from the International League Against Epilepsy in 2019, "Receptors don’t exist because there’s a plant out there; receptors exist because we, through compounds made in our body, activate them."
When his team identified an endogenous cannabinoid in 1992, they called it anandamide, based on the word “ananda” in Sanskrit, which means “supreme joy.” Author Michael Pollan, who describes the discovery of anandamide in his bestselling book The Botany of Desire, said that Howlett and Mechoulam should be considered for the Nobel prize.
"There are more cannabinoid receptors in the brain than any other receptor known," Mechoulam noted. "The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health," wrote Bradley E. Alger, Ph.D. in his paper Getting High on the Endocannabinoid System. "Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease."
Noticing a historical record of the use of cannabis for epilepsy, Mechoulam spearheaded studies of the use of cannabis for the disease. Along with pediatric oncologist Ava Abrahamov, he also conducted the first study of THC in children, finding that a small amount of THC that caused no psychoactivity but prevented severe vomiting that came with chemotherapy. He laments in the film that children are still suffering rather than benefiting from his research.
Mecholum didn't shy away from the political ramifications of cannabis prohibition and its impedance of research, noting that while the medicinal properties of cannabis have been studied in test tubes and mice, clinical trials in humans are sorely lacking. He tells an amusing story of the NIH refusing him a research grant, saying cannabinoids weren't relevant in the US, until a Senator's son was caught smoking pot and suddenly the US was interested. NIH funded his research for decades, and never interfered with it, he said.
It's said in the film that Mecholum postulated that the hedonic effect of mother's milk could come from its cannabinoids, and that this turned out to be true. I think this refers to the pleasurable effect of breast milk in babies, enabling them to better nourish themselves, but I can't seem to verify it because googling for breast milk and cannabis only turns up studies, like this one funded by Gerber, finding small traces of THC in babies who are breastfed by mothers who use cannabis. Pharmaceutical company Perrigo recently acquired the Gerber infant formula plant in Eau Claire, WI from Nestlé for $170 million.
While maintaining a busy career that saw the publication of over 350 scientific articles under his name, Mechoulam made himself accessible to the cannabis community. He spoke at cannabis conferences, and was interviewed on film, for example in the 2018 Ricki Lake–produced film Weed the People, about the journey parents and their children with cancer are taking with cannabis.
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Professor Heather Bradshaw, whose PhD thesis was on reproductive pain in women, noted in The Scientist that with endocannabinoid studies, "we're actually understanding the mechanism of why women basically have taken cannabis for thousands of years."
I asked Mechoulam around 2016 what he thought of the recently announced news that the US government would be spending $1 million on a literature review of the medicinal uses of cannabis and cannabinoids. "I'd do it for half a million," he quipped with a smile.
"I believe over the next decade to 15 years we will have a lot of cannabinoid drugs, for a variety of diseases and certainly for epilepsy. Probably the epilepsy drugs will be the first," he said in 2019. "As we speak today of corticosteroids, we will probably speak in 10 years about cannabinoids and cannabinoid derivatives."
And we will always speak gratefully of our Father of Cannabinoid Science, Raphael Mechoulam. May his soul forever float in ananda.
*Zias J, Stark H, Sellgman J, Levy R, Werker E, Breuer A, Mechoulam R. Early medical use of cannabis. Nature. 1993 May 20;363(6426):215. doi: 10.1038/363215a0. PMID: 8387642.
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