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Raphael Mechoulam

The Israeli chemist Raphael Mechoulam, who died last week at 92, should have gotten the Nobel Prize for his role in figuring out how marijuana exerts its effects within the body. ("Elucidating the endocannabinoid system," is how they would have phrased it in Oslo if my should have could have come true.)

When I met Dr. Mechoulam in 1998 I was intensely interested in every aspect of the medical marijuana movement. I had a son with epilepsy that Western Medicine deemed "intractable," and knew of a few studies that attributed anti-seizure effects to compounds in the plant.  The passage of Prop 215 in '96 by California voters had overcome the federal prohibition – a potentially radical shock to Big Pharma, Wall Street, and the whole damn system, I thought. Journalists rely on sources and I had friends in the leadership of the movement – Dennis Peron, Dr. Tod Mikuriya, and District Attorney Terence Hallinan– and among the rank-and-file. My day job as managing editor of Synapse, the internal weekly at UCSF, gave me access to doctors and pharmacologists who could answer technical questions (not all of which were answerable).  The latest findings, I learned from a postdoc named Ian Meng, were reported annually at the International Cannabinoid Research Society symposium. The upcoming ICRS meeting would be held in France in July.  I hoarded my vacation time accordingly. 

Rosie and I flew to Paris in late June. Fumbling to retrieve my high school French, I rented a little car and drove around until we found a hotel room in a district called La Defense. We spent a few days exploring Paris (which Rosie dubbed "civilization"),  then drove through the beautiful countryside to a town on the Mediterranean called La Grande Motte.

The piece that follows is excerpted from a longer account of the ICRS meeting intended for a journal that Tod Mikuriya planned to launch when a few more MDs summoned up the courage to approve cannabis use by their patients. That journal, which he named O'Shaughnessy's, wouldn't come out until 2003. For years he distributed photocopies to patients and colleagues. Reading it now reminds me that before the medical marijuana movement was turned into a stinking pile of capitalism called "The Legal Cannabis Industry," it held out real hope on the political, scientific, and medical fronts. 

The ICRS Meets in La Grande Motte

 In late July, 1998, with no one from the news media showing the slightest interest, some 200 members of the International Cannabinoid Research Society convened in a French town on the Mediterranean called La Grande Motte to share their latest findings. Part of the tab was picked up by Sanofi Recherche, a large pharmaceutical company with headquarters in nearby Montpelier.

The ICRS was organized in 1990 by scientists who had been following each others’ work in the literature and conferring informally for years. The first meeting, held on Crete in 1990, drew 45 participants and was chaired by Rik Musty, a professor of psychology at the University of Vermont. Originally the “C” in ICRS stood for “Cannabis” — the Latin name of the plant known as marijuana when bred for psychoactivity and hemp when bred for fiber — but in 1995, because so few members were actually conducting research with the plant, a vote was taken to change the C-word to “Cannabinoid.”

“Cannabinoid” refers to chemicals from three sources — extracted from the plant, synthesized in the lab, or produced by the body of man, mouse, or lower animal. The body’s own cannabinoids are said to be “endogenous,” and are now being called “endocannabinoids,” just as the body’s own chemicals with morphine-like effects were dubbed “endorphins.”

The first plant cannabinoids were identified in the early 1940s by Roger Adams, a University of Illinois chemist who isolated cannabinol (CBN), cannabidiol (CBD), and a crude form of delta-9-tetrahydrocannabinol (THC). CBD is the predominant compound in cannabis plants that have been bred for fiber, i.e., hemp. THC is the predominant compound in cannabis plants that have been bred for psychoactive potency, i.e., marijuana.

To date more than 60 cannabinoids have been found, most of them chemically inactive when inhaled or ingested into the body. The cannabis plant also contains hundreds of chemical substances that are not unique to it.

In 1964 the precise structure of delta-9 THC was described in a paper by Raphael Mechoulam and Y. Gaoni of the Weissmann Institute of Science in Rehovoth, Israel. This triggered a long search in Mechoulam’s lab and elsewhere for synthetics that would have the therapeutic effects of THC without the psychoactivity. (A drug was determined to be a cannabinoid if it reduced pain, body temperature, spontaneous activity and motor control. The researchers call these four effects “the classic tetrad” of cannabinoid effects. Nowadays cannabinoids are defined by more sophisticated tests.)

In 1974 Eli Lilly produced a synthetic THC which has been marketed in England and elsewhere as Nabilone. In the mid-1980s Pfizer produced a synthetic cannabinoid suitable for research. Pfizer’s synthetic, CP-55940, proved to be highly psychoactive and couldn’t be marketed as a medicine. But unlike THC, which exerts a weak, fleeting effect, CP-55940 would bind long enough to reveal where in the body it acted.

Receptors in the Brain

The existence of cannabinoid receptors in the brain — proteins on the outside of certain cells to which cannabinoids bind, inducing a squaredance of molecular events within the cells — was established in 1988 by Alynn Howlett and William Devane at St. Louis University. The researchers were astonished to find that these receptors, now known as CB1 receptors, are at least 20 times more prevalent in the brain than opioid receptors.

CB1 receptors are concentrated in the cerebellum and the basal ganglia (regions responsible for motor control, which may explain why marijuana reportedly eases muscle spasticity); in the hippocampus (storage of short-term memory); and in the limbic system (emotional control). Cannabinoids acting through the CB1 receptors seem to play a role in the processes of reward, cognition, and pain perception, as well as motor control.

In 1992 a second cannabinoid receptor was found in cells of the immune system in “peripheral” areas of the body. The discovery of this second receptor type — called the CB2 receptor, or the “peripheral receptor — strongly implied that effective non-psychoactive drugs involving the immune system could be developed.

Also in ’92, Mechoulam and Devane, working together at Hebrew University, identified an endogenous cannabinoid, a relatively simple molecule called arachidonyl ethanolamine, or AEA, which they named “anandamide” after the Sanskrit word for “bliss.” Devane reportedly came up with the name after Mechoulam said he “couldn’t think of a single happy word in Hebrew.”

A second endogenous agonist, 2-arachidonyl glycerol (2-AG), has been found in the brain at concentrations 170 times greater than anandimide.

The endocannabinoids are said to be weak agonists. (An agonist is a drug that binds to and activates a receptor.) They have a slightly weaker affinity for the CB1 receptor than THC, which itself is a low-efficacy partial agonist. This makes the endocannabinoids hard to study and helps explain the preference for stronger, longer-lasting synthetics as receptor probes in the research labs.


Researchers now have 10 different synthetic cannabinoids at their disposal. WIN 55212-2, an aminoalkylindole developed by Sterling Winthrop in the 1980s, is considerably stronger than THC. (Sterling Winthrop is now owned by Sanofi, which in turn has merged with Synthelabo.) Mechoulam’s lab at Hebrew University has created several synthetic agonists.

In addition to the synthetic agonists that bind to and activate the cannabinoid receptors, researchers have been employing two antagonist drugs from Sanofi — one that blocks the CB-1 receptor and one that blocks the CB-2 receptor. Antagonists enable researchers to see what the body does when it is deprived of cannabinoid activation. The effectiveness of a new antagonist from Pfizer was discussed in a paper at the 1998 ICRS meeting. Sanofi has an antagonist drug in clinical trials in Europe. It is being tested as an antipsychotic, but other effects — on appetite, memory, etc. – will be assessed.

Sanofi also has several promising agonist drugs in the pipeline, according to researcher Francis Barth. The company has decided to position itself at the forefront of cannabinoid research because the therapeutic potential outweighs the political constraints. As Barth put it in a recent review paper, “Potential therapeutic applications range from the well-described analgesia, anti-emesis, appetite stimulation and antiglaucoma properties to the less documented antirheumatic, antipyretic and bronchodilatory effects.” What drug company can ignore such a range of applications?

“They all have their toes in the water,” says Lesley Iverson, a British scientist sent to the ICRS conference as an observer by the House of Lords. Glaxo Wellcome, Roche, and Bayer A.G. were all represented by men and women in their twenties and early thirties who are designing and testing cannabinoid drugs. Merck Frosst has developed two potent agonists, which were described at the meeting as being selective for the CB-2 receptor. Eli Lilly's synthetic THC drug, Nabilone, is on the market in Switzerland, England, Ireland and Canada to combat nausea, although it is less efficacious than smoked marijuana and failed US FDA toxicity tests. Companies that for years saw nothing but potential competition in cannabis now see a source of marketable synthetics. One young scientist from Bayer said he’d been given career advice by the head of drug development as he left for the conference: “If it ends in oid, you must avoid.” But he seemed more amused than threatened.

“The Field is Moving Away from the Plant”

The town to which Sanofi had invited the cannabinoid researchers, La Grande Motte, was built in the ’60s on a sandy marsh reclaimed from the mosquitoes in an attempt to increase tourism in the Languedoc region. The architect, Jean Balladur, was in his pyramid period, and the downtown skyline consists of 8- to 10-story hotels that slope away from the observer as they rise. Balladur is quoted in the “Office de Tourisme” brochure saying “La Grande Motte will enter the 21st century young and new, rising out of the sand like a problem-free child.” The buildings already showed more signs of deterioration than the centuries-old ones we’d been admiring en route, but we had a problem-free time there, saw the only flamingoes in Europe gulping shrimp in the lagoons, and heard a hot blues trio at a sidewalk cafe around midnight. LGM draws a lively crowd of French families whose four-week vacations are subsidized by their employers and government. “A little bit of socialism goes a long way,” Rosie observed.

The ICRS members were staying at the Hotel Mercure, a U-shaped 10-story building near the beach. The meeting was a long block away at the “Palais des Congres,” an auditorium that, from afar, looks like a giant oil can laid on its side. Rosie said, "The French don't do moderne as well they do ancien.

The schedule called for 70 papers to be presented over the course of three days. Speakers had a total of 15 minutes to describe their research and answer questions. They were supposed to talk for 10 and leave five for questions. All relied on slides to help tell their stories — the standard scientific-meeting format. The details of another 63 studies were described on posters tacked to partitions in a large room where coffee was served during the breaks. A few hours were set aside for sessions at which the authors stood by their posters and answered questions.

ICRS members are university-connected scientists and/or working for pharmaceutical companies. Many are funded by the National Institute on Drug Abuse, a U.S. government agency whose stated interest for years has been to prove the harmfulness of marijuana. Some of the brilliant young researchers we met in La Grande Motte said, sincerely, that taking NIDA money doesn’t influence their objectivity — they’re conducting basic scientific research that will explain the body’s endogenous cannabinoid system and lead to useful synthetic drugs. Nevertheless, the net effect of virtually all the funding going to people who are trying to develop synthetics or “elucidate the basic mechanism” is to deflect research away from the plant itself.

A postdoc rationalized his choice thus: “If you care about cost-effective treatment for individuals, then you would be in favor of the classic natural cannabinoids. However, if you care about drugs that optimally treat the various conditions, then you start looking at receptor distribution and maximizing activity and things like that.” All but a very few of the ICRS members in La Grande Motte fell into the latter category. “The field is moving away from the plant,” is how Dale Deutsch, a biochemist who edits the ICRS Newsletter, summed up the trend.

The first two days of the meeting were devoted mainly to reports from pharmacologists and biochemists on the processes by which cannabinoids are made, exert their effects, and get broken down. The focus was on the molecular level. For example, Romelda Omeir, a graduate student in Deutsch’s lab at SUNY Stony Brook, reported on her study of how anandamide gets broken down. The enzyme that does the dismantling had been identified in ’93. [An enzyme is a large protein molecule consisting of hundreds of amino acids that catalyzes a biochemical reaction.] Omeir used a technique called mutagenesis analysis — altering the amino acids one by one until the enzyme ceases to work. After much painstaking benchwork she found the “active site” — Serine 241 — the amino acid that actually snips anandamide, making it dysfunctional. Someone else in Deutsch’s lab is studying the part of the enzyme that holds anandamide in place while Serine 241 is snipping it.

And so it went (mostly over our heads). Razdan described an effort to make the anandamide molecule less susceptible to chemical breakdown by replacing the amide bond with urea or carbamate derivatives... Meschler and Howlett described a new antagonist for the CB-1 receptor, manufactured by Pfizer, called CP-272871... Piomelli of the Neurosciences Institute in San Diego (funded by Novartis) has determined how the production of the endogenous cannabinoid 2-AG in neurons is controlled by NMDA receptors.

The Grand Old Man

There was no reference to a promising new medication — no mention of the word “patients” — until Raphael Mechoulam read a paper describing “A Novel Group of Stable, Non-Hydrolysable Endocannabinoid Analogs.” The grand old man of the field, now in his mid-60s, talks and gestures with a charming Israeli lilt; for some reason he reminded me of Crumb's Mr. Natural.

Mechoulam reported that he and his co-workers, by adding an ether group to 2-AG, had created a variant that is more than three times as strong (in mice tested for the classic tetrad of effects) and lasts longer (40 minutes compared to six). They had named it HU — for Hebrew University — 310. “HU-310 causes a reduction of blood pressure which is considerably more potent than that observed with anandamide or 2-AG,” Mechoulam said like a throwaway line.

I caught up with him during a break and asked if I had heard right. Yes, he said, “We might have a very useful medicine here... But this is still preliminary. We’re much further along with HU-211, which we know exerts a strong antioxidant effect and we hope will prevent strokes and lower blood pressure. It also has potent anti-pain effects in chronic pain,” Mechoulam said. “But it doesn’t bind to the receptor. How does it act?” He shrugged. “We’re missing something. My impression is that it’s either a third cannabinoid receptor or there is some specific membrane effect.”

A Shakespearean Confrontation

On the third and final day of the ICRS meeting, an elderly gentleman, who had only just arrived, angrily informed the softspoken professor Tibor Wenger — as Wenger finished reporting that anandamide stimulates release of the pituitary hormones via a yet-unknown CB receptor that is not activated by THC — that Wenger’s research was “based on totally false premises.” A buzz of recognition went through the audience: this was the famous Gabriel Nahas, an anesthesiologist now at NYU who had spent most of his career trying to prove and publicize the health hazards of marijuana. “Nancy Reagan’s favorite scientist,” whispered Dr. John McPartland to his wife. “Every time something comes out about why marijuana works, Nahas is there to refute it.”

Nahas had been scheduled to give a paper on the unsuitability of THC as an adjunct to anesthesia. But he said, when he got to the lectern, that he had more important findings to share. Having just spent three months reviewing the literature, he had come to inform his colleagues that their recent discoveries were all wrong, right down to their nomenclature. “THC does not interact directly with neurotransmitters or neuromodulators,” he explained, “but acts directly on cell membranes in the manner of an anesthetic to alter their response.” He said that THC “deregulates” the signals that are constantly being regulated by arachidonyl ethanolamine. (Nahas hates the name “anandamide.” He says, “Bliss has nothing to do with it!”)

Mechoulam rose to restate the evidence for cannabinoids functioning as neurotransmitters. “It is not just a membrane effect,” he said. “There is an interplay of effects on the receptor and membrane.” This drew a brief outburst of applause. Nahas repeated that the evidence was all in the literature and cited studies done in the 1970s. As Mechoulam was asking “What receptor is it that you illustrate in your slide there?” the chair of the session, UCLA pulmonologist Donald Tashkin said that “in the interests of time,” the discussion should be continued elsewhere.

During the break Mechoulam found Nahas seated by himself at a coffee table in a cafeteria where the posters were displayed. Mechoulam pulled up a chair and told his colleague, “The field moves on. We’re old men coming to the end of our careers, these young people will soon know much more than we even suspect...” Far from treating him as a political enemy, Mechoulam seemed to be responding to the anguish Nahas had shown on stage, trying to soothe him. “A real therapist,” I thought. But Nahas would have none of it. He whipped out a notebook and started illustrating his points for Mechoulam, punching the pad emphatically with his pencil, insisting that THC operates through a “direct effect on cell membranes that deregulates cell function!”

Outside the conference hall we ran into Mechoulam. I got a smile from both of them when I said, "I have to have a picture of the two of you, because he discovered THC in 1964 and she discovered THC in 1964!"

One Comment

  1. jonah raskin March 20, 2023

    Thanks. Good Piece!

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