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Raphael Mechoulam

The New Science of Cannabinoid-Based Medicine:

An Interview with Dr. Raphael Mechoulam

By David Jay Brown

Raphael Mechoulam, Ph.D., is the Lionel Jacobson Professor of Medicinal Chemistry at the Hebrew University of Jerusalem, where he has been working on cannabinoid chemistry (a term he coined) for over forty years. Throughout this time Dr. Mechoulam and colleagues have made some of the most important contributions to the field of cannabinoid research. His lab was the first to identify and synthesize delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. This discovery in 1964 (with Dr. Yehiel Gaoni) opened the door to a whole new field of medical research that began exploring, not only the therapeutic potential of THC (marketed as Marinol in America), but other natural and synthetic cannabinoids as well, and offered exciting new insights into how the brain functions.

Dr. Mechoulam, along with pharmacologist Dr. Habib Edery and colleagues, went on to isolate and elucidate the structures of most members of the cannabinoid group of compounds in the cannabis plant. Twenty-eight years after discovering THC, in 1992, Dr. Mechoulam, along with Dr. William Devane and and Dr. Lumir Hanus, identified the brain’s first endogenous cannabinoid (or endocannabinoid)-the brain’s natural version of THC-which they called “anandamide,” from the Sanskrit word “ananda,” which means “eternal bliss” or “supreme joy.” 

It turns out that the brain actually has a whole family of cannabinoid neurotransmitters and receptors. Just as the active compound in opium (morphine) led to the discovery of the endorphin (endogenous morphine) system in the brain, the active compound in cannabis (THC) led to the discovery of the brain’s endocannabinoid system. Later Dr. Mechoulam and colleagues identified the THC metabolites and, more recently, along with Dr. Lumir Hanus and Dr. Shimon Ben-Shabat, he discovered a second endocannabinoid known as 2-arachidonylglycerol (2-AG). These findings have profoundly advanced our understanding of cannabinoid systems.  

Endocannabinoids function as neuroprotective agents, they are part of the brain’s reward system, and they help with the reduction of pain. Vigorous exercise stimulates the release of anandamide, and the sense of euphoric well-being that comes with a healthy workout-what jogging enthusiasts refer to as a “runner’s high”-is due to elevated levels of endocannabinoids. The endocannabinoid system in the brain is also believed to help mediate emotions, consolidate memory, and coordinate movement. In fact, cannabinoid receptors are found in higher concentrations than any other receptor in the brain, and the endocannabinoid system acts essentially in just about every physiological system that people have looked into. 

While the political  controversy over medical marijuana continues in America, pharmaceutical companies-such as G.W. Pharmaceuticals in the United Kingdom and Sanofi-Aventis in France-are busy researching and developing a wealth of new medications based on compounds found in the cannabis plant. Controlled studies have revealed therapeutic utility of cannabinoids in the treatment of multiple sclerosis and other spasticity ailments, asthma, rheumatoid arthritis, cancer chemotherapy side-effects, glaucoma, AIDS wasting syndrome, and seizure disorders such as epilepsy. Analgesic action and tumor retardation have also been shown.

But even more exciting is the wave of new drugs that are currently being developed from cannabinoid analogs-both agonists and antagonists, meaning drugs that both activate and deactivate cannabinoid receptors in the brain. From new types of pain killers and neuroprotective agents for head trauma and stroke victims, to appetite stimulants and appetite suppressants. Most recently, one of the synthetic compounds (HU-211) from Dr. Mechoulam’s lab  has completed phase 2 clinical trials against head trauma with evidence of a neuroprotective effect. The pace of cannabinoid research has certainly been accelerating over the past few years, and Dr. Mechoulam-who has been at the forefront of this research since the beginning-thinks these new drugs are just the tip of the iceberg.

Dr. Mechoulam is recognized as one of the world’s experts on cannabinoid-based medicine. In addition to his groundbreaking discoveries, he has written hundreds of scientific papers on his cannabinoid research, and he is the author of the book Cannabinoids as Therapeutic Agents, an early review of the research in this area. Dr. Mechoulam has received numerous honors and awards for his outstanding contributions to the field, and he was the president of the International Cannabinoid Research Society. Dr. Mechoulam is a member of the Israel Academy of Sciences, and among the numerous prizes that he has received for his work, is the highest national scientific prize in Israel-the Israel Prize. 

I interviewed Dr. Mechoulam on December 21, 2004. Raphael is mentally energetic, kind, and generous. We spoke about how he came to discover THC and anandamide, the role that endocannabinoids play in the brain, natural ways to increase the brain’s production of anandamide, and the vast array of new cannabinoid-based drugs that are being developed.

David: What originally inspired your interest in cannabinoid chemistry?

Raphael: That was many years ago. I had completed my Ph.D. and I was back from the Rockefeller Institute (now Rockefeller University) in New York. I was a pure organic chemist at that time, and I was interested mainly in natural products-hopefully natural products with physiological activity. Now, surprisingly, I found that from a chemical point of view cannabis was quite an unknown product. While morphine had been isolated from opium almost 150 years before that, the active compound in cannabis was actually unknown. People had never isolated it a pure form. That was a something that I realized after really reading the literature quite carefully. Of course the structure and synthesis were unknown. So I thought it was a good idea to look at cannabis because, essentially, nobody was working on cannabis at that time. So I started working on it. We got the material, surprisingly, from the police. I got five kilograms of hashish to work on, and that was the start of the story. I thought it would be over in a couple of months, and it has been going on and on and on forever.

David: What initially motivated your search to identify the primary psychoactive component of cannabis, and could you briefly summarize how you came to discover THC?

Raphael: We were looking for natural compounds with biological activity and these were obviously compounds with important biological activity. But until we had identified the compounds, elucidated their structures, and synthesized them, it was quite impossible to do any biological work with them. There were stories about what these compounds were supposed to do. There was quite a lot of work from people in France during the previous century, and, of course, a lot of historical literature, but this is not science. Even in those days this was not something that could be accepted as scientific evidence, and we obviously needed a strong basis for physiological work. So the work we did at that time was in collaboration with biologists because, obviously, you cannot isolate an active compound without having something to test your fractions. You separate the materials by various chemical means , and you have to test those fractions that are active. 

Now, active in those days meant that we had to give them to some kind of animal. There were no in vitro tests (no tests that we could do in the test tube) at the time-so we gave the fractions to monkeys. Then we chose those fractions that caused sedation in monkeys. The monkeys fell asleep when we gave them rather high doses. So we could fractionate the materials in this manner and, ultimately, we ended up with THC in its pure form for the first time. Then we elucidated the structure so we could work on the biology of this compound.

You see, most scientists will work in one field, such as chemistry, pharmacology, or physiology, and I think they’re making a mistake, because there is no such thing as one field of science. Normally, everything is connected. Nature doesn’t realize the differences between chemistry, biology, physics, physiology, or whatever. We create different fields of science because we are incapable of grasping all these things together. So my idea was to start with chemistry because that area was unknown and one could not advance further. But, after identifying the chemical structure of the active compound, one could go into the other fields, which I did over the next few decades.

David: How did you come to discover the brain’s first endogenous cannabinoid, and why did you name it “anandamide?”

Raphael: After we had identified THC, we also had to identify the rest of the materials in cannabis. Surprisingly, it is a terrible mixture, and that was one of the reasons why it had never been isolated. The technical means for identifying THC were not available in the nineteenth century, or early twentieth century, up until the ‘50s, really. So once we had THC and some of the

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