Saturday, March 18, 2023

Raphael Mechoulam’s 60 years of collaborative cannabis research—and coffee

Listening to the voice of Professor Raphael Mechoulam, with its warmth and humanity, pieces of the puzzle fall into place. The puzzle? The puzzle is how so much progress has been achieved in researching cannabis over the past 60 years, despite the difficulties caused by the way it has been viewed since the mid-twentieth century. It was made illegal around the world, and weighed down by stigma, despite centuries of ubiquity, when cannabis was valued and used medicinally, religiously and recreationally, as well as underpinning trade and agriculture with essential hemp products such as rope and cloth. The twentieth century change in attitude may have been rooted in, at best, intolerance of other cultures, and at worst racism. 

Into this environment in early 1963 stepped, in all innocence, a young scientist who wanted a biologically active plant to research. Raphael Mechoulam knew that the chemical structures of morphine and cocaine were well-known, but cannabis far less-so. CBD had been isolated in the US by Roger Adams and in the UK by Lord Alexander Todd at about the same time in the late 1930s-1940s, but then research had stalled.

The then Dr Mechoulam PhD was interested in the chemical and biological effects of natural products. He approached the administrative head of the Weizmann Institute in Israel at which he was working, and asked for help in acquiring hashish for research purposes from the police. And here begins the chain of good, trusting relationships, many involving cups of coffee, that have enabled the blossoming of research into, and understanding of, cannabis in the ensuing 60 years. On the briefest acquaintance, the senior colleague spoke to the police and vouched for young Mechoulam as a suitable person to take charge of some hashish.

Dr Mechoulam visited the police store of confiscated smuggled material in Tel Aviv. He recounts, “There I drank a cup of coffee with the elderly person in charge, he told me how the police had caught hashish smugglers from the Lebanon, and I told him what we wanted to explore.” A 5kg bag of hashish was entrusted to him, and he returned to the institute on the bus.

Neither he, nor his colleague, nor the police was aware that such an arrangement was illegal.

When it became apparent, a little later, that this was not the text-book approach to embarking on researching an illicit substance, more cups of coffee were drunk: “We had all actually broken the strict laws on illicit substances. The ministry of health was supposed to have approved the research, the police should not have given me such a dangerous substance and I was essentially a criminal. But at the ministry some of the bureaucrats in charge were my ex-colleagues, and after I was severely scolded for breaking the laws, we drank together some more coffee, and I got a properly signed and stamped document.”

A few years later he moved to the Hebrew University in Jerusalem, where he found full support for his work.

The scale of the growth in understanding of this complex plant with its unstable compounds, of how those compounds interact with the human body, and of what that teaches us about the human body itself with the discovery of an endocannabinoid system running alongside the well-known immune system, goes beyond the abilities of a single scientist however brilliant or dedicated. Across the six decades of study, there is a repeating pattern of good human relationships, and cups of coffee, no doubt. What has developed from it is an international, inter-university, inter-disciplinary network of collaborating scientists, each expert in their own field, enabling an exchange of knowledge which opens up possibilities which can then inform more research.

Speaking to the Cannabis Conversation podcast last year, Professor Mechoulam emphasised the shared nature of the achievement: “In this area of natural products, if one wants to have significant results, collaboration is essential. Collaboration is of extreme importance and that is what we have been doing over several decades.”

He explained that while scientists from one discipline can understand what scientists from other disciplines are doing, they don’t know one another’s techniques. Over the years, these international collaborations have opened up the understanding that CBD is anti-epileptic, that it is effective against pain, inflammation and nausea. Collaboration is building up understanding about how other cannabis compounds may interact with CBD to enhance its beneficial effects. Collaboration is revealing how the brain heals itself after damage—and much, much more.

Referred to for many years as the ‘father of cannabis research’, now 92 Professor Mechoulam is called the ‘grandfather’, and he is still actively working. He was listed as an author (with others) on 12 research articles in 2022. So far this year one has been published, determining the involvement of the endocannabinoid system in alcohol addiction. Its findings “suggest that the ECS negatively regulates alcohol consumption and boosting selective endocannabinoids exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.”

He is co-author with Linda A Parker and Erin M Rock of a book published last August by MIT Press, CBD What Does the Science Say? , a “comprehensive review of the scientific literature on the possible benefits of CBD, describing findings from both preclinical and human clinical studies,” according to the publisher.

Professor Mechoulam divides the cannabis research of the past 60 years into four types. Firstly, came the chemistry of the plant cannabinoids. Early in his research he established that CBD was not psychoactive, and with Yehiel Gaoni isolated  Δ9-THC. CBGa acid was discovered, which is apparently the precursor of all the cannabinoids that the plant (or the human body) makes. As Professor Mechoulam puts it, “The chemistry was well-known by the time we finished.”

The second type of research is into endogenous cannabinoids—those made by the body. “They are chemically completely different from the compounds in the plant. We isolated very small amounts in the body, and were lucky to be able to elucidate the structure.” Two were found initially, anandamide or ADA and 2-arachidonoylglycerol or 2-AG, followed by some other ones which seem to be minor.

“They represent the chemical basis of a new biochemical system, very widely used in the body.” According to Professor Mechoulam, anandamide has been cited in 6,000 articles, and 2-AG in 3,000.

The third type of research is into the compounds which are chemically related to the endogenous cannabinoids, and the fourth is into “using the plant cannabinoids as well as the endogenous cannabinoids to prepare compounds which hopefully may become drugs.”

The instability of cannabinoid acids has been addressed, paving the way for medicinal drugs to be developed by industry, as Professor Mechoulam explains. “You see the plant does not synthesise CBD or THC; the plant synthesises their precursor acids. These acids had not been evaluated thoroughly because they are not stable—and a drug has to be stable. Well, we stabilised these acids by making a methyl ester. We found that these methyl esters are valuable compounds.

“We are working with one company on derivatives of these acids. With another company we took cannabidiol and put a fluorine on the molecule, and the compound became more active—namely we could use lower amounts of the material. I hope that they are going ahead with this derivative.

“Derivatives of cannabinoids—hopefully one or two of them will reach the actual drug stage. Making a drug is a complicated matter. It’s not just that it’s a new compound, and has activity, but it shouldn’t do anything else. It should not be toxic of course. These compounds are not toxic, but you never know whether they don’t cause any changes, whether they don’t have any effects which are not desirable. And so it takes a long time and a lot of money to develop a drug.”

There is still so much to understand—things which are indicated but not yet proven. The entourage effect, for instance, whereby some activities of cannabis work better in the presence of other compounds, has yet to be fully understood. Terpenes, which are not active themselves, seem to change the activity of the active compounds. This corresponds with the experience of people using medicinal cannabis who say that total extract is better than purified compounds.

During these sixty years of research, the status of cannabis has been gradually changing in some parts of the world. Legalisation is spreading, medicinal use is being accepted as efficacious—but counterbalancing that is considerable and vocal opposition. In the UK patients are still struggling to get NHS prescriptions for medicinal cannabis, and some police commissioners are getting hot under the collar calling for cannabis to be rescheduled as a class A drug.

Professor Mechoulam is restfully factual and calm as he sets out the knowns and as-yet unknowns of cannabis, the possibilities and the challenges. He explains the chemistry of cannabis in a way which a non-chemist can understand. Listening is a tonic in itself.

Why don’t you take a few minutes, relax, sit back and listen to Professor Mechoulam being interviewed in 2018 by Meir Bialer at the 13th European Congress on Epileptology, or by Anuj Desai on the Cannabis Conversation Podcast in February 2022—with a cup of coffee, of course.

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