Introduction: Dr. Raphael Mechoulam, professor in the Department for Medicinal Chemistry and Natural Products at Hebrew University Hadassah Medical School and School of Pharmacy, Institute for Drug Research, is often referred to as the "Father of Marijuana Research." While at the Weizmann Institute of Science in Rehovot, Mechoulam secured hashish from the head of Israel's investigative branch of the national police for use in his studies, and in 1963 his research group determined the structure of CBD (cannabidiol) and by 1964 had isolated and synthesized THC (tetrahydrocannabinol), the main psychoactive compound of cannabis.
Initially fascinated by his realization that the active component of cannabis remained unknown while the active ingredients of cocaine and opium had been isolated a century before, Raphael Mechoulam's research projects continue to address the chemistry of endogenous cannabinoids and synthesis of novel compounds to be tested as drugs against pain, inflammation, high blood pressure and cancer, with a grant from the US National Institutes of Health. He has collaborated with colleagues in Israel, the US, Canada, Spain, Germany, Brazil, New Zealand, Italy and Japan and consults for a pharmaceutical company.
Anthony Wile: Hello, Dr. Mechoulam. Thank you for speaking with us. A 2012 article about you began, "If some 7,000 Israelis can fill a prescription for marijuana to ease pain and enhance appetite, it's only because half a century ago, Hebrew University Prof. Raphael Mechoulam isolated and synthesized THC, the main psychoactive compound in the cannabis plant." A year before that you had identified the structure of cannabidiol (CBD). What drove you to embark on such an idiosyncratic career? And now that you've been studying this plant for 50 years, what continues to fascinate you about it?
Raphael Mechoulam: I saw nothing 'idiosyncratic' working on a topic which was basically a chemical one (at least at the beginning) but obviously had a social and medical significance. The only problem was that I had to fight academic bureaucrats at the Weizmann Institute until I moved to the more open Hebrew University in Jerusalem.
The work on the plant has now led to the identification of a major physiological system (the endocannabinoid system), which seems to be involved in many human diseases. The plant THC mimics compounds found in the brain, named endocannabinoids (anandamide and 2-AG), which we discovered in 1992 and 1995. These two endogenous brain cannabinoids are of immense importance in the working of our body. Related compounds we found more recently in the brain and in bones have to do with brain protection and even osteoporosis. Never a dull moment.
Anthony Wile: What is the legal status of cannabis in Israel for clinical research and medical purposes as well as individual cultivation and possession for recreational consumption?
Raphael Mechoulam: There are about 18,000 persons who get legal cannabis for their diseases. Permits for medical cannabis have to be approved by the Ministry of Health, which has a special cannabis unit. There are 8 growers who supply the material. There are 10 research groups that investigate the endocannabinoid system. However, possession of cannabis and recreational consumption are illegal and the police open about 10,000 criminal files every year.
Anthony Wile: Do the laws differ on use of the natural plant versus synthetic versions of specific cannabinoids?
Raphael Mechoulam: I believe that they are the same.
Anthony Wile: Have legal issues restricted research into cannabis? How so?
Raphael Mechoulam: I have had no legal problems – but I had to get an official document from the Ministry of Health, which made possible getting hashish (free of charge) from the police.
Clinical investigations are more complicated, as each hospital has to approve any protocol of a clinical trial and in view of the lack of cannabis clinical data on most diseases, getting what is known as 'Helsinki approval' is always difficult.
Anthony Wile: The US National Institute of Health has provided you with funding for research perpetually since the early 1960s when you first provided the institute with THC. However, cannabis remains a Schedule I substance (high potential for abuse; no medical value) in the US, and thus researchers are often unable to get cannabis samples, or cannabis of high quality, for study. Why has NIH funded you?
Raphael Mechoulam: As a few young people in the US were apparently using cannabis in the 1960s (and later), NIH wanted to know all about it. Although NIH does not generally fund foreign researchers, they made an exception in my case. They never interfered with my research and they never asked me (or suggested) to go into any specific direction. As a matter of fact I got a prize from NIDA, the National Institute of Drug Abuse (NIDA) Lifetime Achievement Award, presented by the Director of NIDA, NIH, Bethesda, September 2011.
Anthony Wile: What do you think will be required for the US to deschedule cannabis or otherwise make it legal and more easily accessible for both research and wider prescribing?
Raphael Mechoulam: I assume that the US will gradually make clinical research with cannabis and cannabinoids easier. This has already happened here and in some European countries. I understand that in the US the wind already blows in this direction.
Anthony Wile: Where is most of the research being conducted currently – certain countries, institutions, companies? Is this collaborative or mostly individually? And where is the funding coming from, for the most part?
Raphael Mechoulam: US (mostly preclinical, supported by NIDA), Spain, Italy, Germany, UK (all supported by government sources), Israel and Brazil. My research at present is supported by a donor in Boston (the Kessler Foundation) and by the Brazilian Government (in collaboration with a Brazilian group).
There is a lot of collaboration. I have published with friends from all the above countries.
The most advanced cannabis company in the world is in the UK, which has published extensively.
Anthony Wile: We're curious about the path that research is following. You started with identification and analysis of CBD and THC, specific substances, which led to research into potential uses of that substance. Has the path changed so that it begins with a particular ailment and looks for the cannabinoid(s) that could best treat it in order to develop a patentable product?
Raphael Mechoulam: I have published successful clinical trials with CBD in epilepsy (in 1980, which is still essentially the only clinical trial in this area) and recently in graft versus host disease (GVHD); with THC on the side effects in pediatric oncology and in post-trauma. I am not aware of pharma companies (except the UK GW Pharmaceuticals), supporting academic research in this area.
Anthony Wile: Explain the differences between natural cannabis flowers and oils versus synthetic versions of specific cannabinoids. Is one preferable to the other, in certain instances? Are unwanted side effects of synthetic versions a concern?
Raphael Mechoulam: The 'natural cannabis flowers' contain precursors of THC and CBD, which have to be heated or to stay around for some time to convert into THC and CBD. Hence, if consumed without heating (or smoking) they may be inactive. Oils for oral consumption are usually heated, hence they are active, but the effects come on much later than when smoked.
Specific cannabinoids (CBD, for example) are very valuable compounds.
'Synthetic cannabinoids' are compounds different than those in the plant (or the brain) and may be toxic. A person should be crazy to test on himself a compound of this sort.
Anthony Wile: Is it safe (or wise) to prescribe a single cannabinoid, say CBD or CBG or THC, as a stand-alone substance without the other cannabinoids and terpenes that would be found in the whole substance? In other words, how important is the so-called entourage effect?
Raphael Mechoulam: We discovered and named the entourage effect quite a few years ago. But it has never been investigated in a clinical trial. I believe that it is of value. But so is CBD alone.
Anthony Wile: Would you comment on the relatively newer, extremely high-THC/low-CBD strains that seem to be making their way into the hands of recreational users? There are reports of strains with up to 35% THC being consumed now.
Raphael Mechoulam: They are very valuable for the growers. Much less so in the hands of recreational users.
Anthony Wile: In 1992, you, William Devane and Lumir Hanus identified the first endogenous cannabinoid in the human brain, which you named anandamide, the Sanskrit word for "supreme joy" or "bliss," and two years later another endogenous compound, 2-AG. Sixteen years later you had found, "There is almost no physiological system that has been looked into in which endocannabinoids don't play a certain part." Explain briefly the human endocannabinoid system and what this discovery means.
Raphael Mechoulam: Kunos and Pacher of NIH recently wrote:
… modulating endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complications, neurodegenerative[7,8], inflammatory, cardiovascular[10–12], liver[13,14], gastrointestinal, skin diseases, pain[17,18], psychiatric disorders[19,20], cachexia, cancer[21,22], chemotherapy-induced nausea and vomiting, among many others).
[Editor note: This review by Pacher and Kunos, "Modulating the endocannabinoid system in human health and disease – successes and failures," published in The FEBS Journal, can be reviewed here.]
Anthony Wile: Research from the NIH suggests "cannabinoids may be involved in all human diseases." What is the significance of this revelation, if correct?
Raphael Mechoulam: Kunos and Pacher of NIH wrote that, and they may be right.
Anthony Wile: The long history of cannabis as a medicine stretches back thousands of years; for example, there is ample record of its use in ancient China. When did it start to become seriously investigated for use in Western medicine? Has the historical record informed modern research at all?
Raphael Mechoulam: It was never "seriously investigated" in Western medicine. There are very few clinical trials. It was not, and it is not "seriously used" in official Western medicine.
Anthony Wile: What is the status of medicinal cannabis use in Israel now? What are the most common issues it is being used to treat and in what populations? Are such treatments using natural oil extracts or synthetic variations?
Raphael Mechoulam: Pain, gastrointestinal diseases, cancer side effects, pediatric epilepsy, now also PTSD. Only the natural material is approved.
Anthony Wile: You've said that "cannabinoids represent a medicinal treasure trove which waits to be discovered." Indeed, exciting research is being conducted around the world on the potential uses of cannabis in treating a wide variety of ailments and conditions. Tell us about a few of these. What conditions could benefit?
Raphael Mechoulam: Mostly this research is being conducted with animals – very little on humans. There are very few clinical trials. It is promising in neuropathic pain, inflammations, anxiety, schizophrenia (with CBD) and many others (see Pacher and Kunos, above). When CBD becomes a drug the picture may change.
Anthony Wile: Specifically, what is the status of research into cannabis use not just for palliative treatment of the debilitating effects of chemotherapy but in using cannabis oil to actually cure cancer?
Raphael Mechoulam: There are many reports on the treatment of various cancers in mice; unfortunately, well-designed human trials have not been done. It is unbelievable that neither government agencies nor private foundations have gone ahead or encouraged clinical trials – but this is a fact! There are no real published clinical trials with cannabinoids against any cancer!
Anthony Wile: At the 2004 Cannabis Therapeutics Conference you presented on the role of cannabinoids as anti-inflammatories, a possible treatment for PTSD and as a neuroprotectant for brain injury. Now, ten years later, have those potentials been substantially investigated, and is the research to date providing the kind of answers you'd hoped for?
Raphael Mechoulam: We just published a small clinical trial on PTSD. There have been no well-designed human trials for brain injury but observations seems to confirm our prediction.
Anthony Wile: You pointed out at one point that much work remains to be done before medical marijuana can be available to people of all ages in quantified doses: "We don't know exact amounts and how to use it, so we cannot give it to everybody." Are we closer to knowing that? What about letting people self-medicate with the plant itself? Is that generally a bad idea?
Raphael Mechoulam: We are not much closer, but many of our 18,000 patients seem to be learning to self-medicate. However, such medication is a major problem for many individuals. Most physicians are also still in the dark.
Anthony Wile: Turning to marijuana's social arena, like any drug, we believe that personal responsibility is essential to managing one's consumption and knowledgeable use of a product, marijuana being no different that caffeine, alcohol, sugar, tobacco, pharmaceuticals, etc. How do you feel about marijuana being used as a recreational substance, by people of legal age, as compared to these other substances?
Raphael Mechoulam: This is a social decision not a medical one. Our society says 'yes' to tobacco (although millions die of it) or high alcohol drinks (although millions die of it or become addicts) or high-stakes gambling (although it may ruin families). When our society says 'yes' to recreational cannabis it will join the above, irrespective of anything.
Anthony Wile: Are you encouraged by legalization of medical cannabis around the world? Do you expect more countries to shift in that direction? Will other drugs be legalized as well?
Raphael Mechoulam: Medical cannabis should be legal, but well regulated (as are almost all medicinal agents).
Anthony Wile: Here at High Alert, we think there is a great opportunity to build businesses around cannabis. What do you think? From a research perspective, what cannabis products would be of specific value to the medical area?
Raphael Mechoulam: Cannabidiol, cannabidiol derivatives and specific CB2 agonists.
Anthony Wile: Any concluding thoughts, or other topics or publications you'd like to mention?
Raphael Mechoulam: Last year Dr. Parker and I published (in the Annual Review of Psychology) the following:
If subtle chemical disparity is one of the causes for the variability in personality—an area in psychology that is yet to be fully understood—we may have to look for a large catalog of compounds in the brain with distinct CNS effects. Is it possible that the above-described large cluster of chemically related anandamide-type compounds in the brain is related to the chemistry of the human personality and the individual temperamental differences? It is tempting to assume that the huge possible variability of the levels and ratios of substances in such a cluster of compounds may allow an infinite number of individual differences, the raw substance which of course is sculpted by experience. The known variants of CB1 and FAAH genes … may also play a role in these differences. If this intellectual speculation is shown to have some factual basis, it may lead to major advances in molecular psychology.
Anthony Wile: Thank you for making the time to speak to us and for your many decades of persistence and courage.
References for Dr. Mechoulam's first three papers:
R. Mechoulam and Y. Shvo. The structure of cannabidiol. Tetrahedron, 19, 2073-2078 (1963).
Y. Gaoni and R. Mechoulam. The structure and synthesis of cannabigerol, a new hashish constituent. Proc. Chem. Soc., 82 (1964).
Y. Gaoni and R. Mechoulam. Isolation, structure and partial synthesis of an active constituent of hashish. J. Amer. Chem. Soc., 86, 1646-1647 (1964).
Dr. Raphael Mechoulam has pioneered research into cannabis and this interview shows us once more that the health benefits of the plant are as yet not well understood. He even points out his astonishment that there has not been more research regarding the health effects of cannabis.
It is useful to read interviews with pioneers such as Dr. Mechoulam because it reminds us of the abysmal state of non-pharma research in the US and the West generally. The West's medical model is commonly held up as a successful healthcare paradigm but it is based on a mechanical idea of "fixing" the body instead of bringing it back into balance. Ancient medical models stressed bringing the body back into balance using, among other healing technniques, natural plants.
Among these was cannabis, with its proven health benefits. By pioneering the study of the health effects of cannabis in the modern era, researchers like Dr. Mechoulam are helping Westerners rediscover a lost heritage of natural healing.
As this heritage is better understood, cannabis and hemp will be in ever greater demand; both patients and entrepreneurs will benefit accordingly. Prohibition will surely be seen as an unfortunate detour on the way to a healthier future.
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