In 2 unpublished interviews, Raphael Mechoulam, PhD, spoke with AJEM about research, education, and what the future holds for cannabis medicine.
Known as the “father of cannabis research,” Raphael Mechoulam, PhD, will go down in history as one of those scientists who should have won the Nobel Prize—but didn’t. During his 60-year career, the prolific researcher isolated and discovered tetrahydrocannabinol (THC), helped identify the main components of the endocannabinoid system (ECS), and most recently created a revolutionary synthetic cannabidiolic acid compound (EPM301). His pioneering spirit and scientific achievements have benefited millions of patients and helped to ignite the burgeoning field of cannabis medicine as we know it today.
The Israeli chemist died on March 9, 2023, at his home in Jerusalem at the age of 92. The news of his passing prompted scores of tributes across the cannabis world and beyond. Dr. Mechoulam leaves behind a legacy of academic excellence, publishing hundreds of research papers and book chapters. The National Institutes of Health (NIH), which rarely funds overseas research, was Dr. Mechoulam’s major source of grant funding for the study of medical cannabis. Less well-known is his reputation as a warm and caring scientist who generously shared credit for research, assembling teams that made some of the most important breakthroughs in cannabinoid and endocannabinoid research.
Path to Cannabis Medicine
Born to a Sephardic Jewish family in Bulgaria that survived the Holocaust, he immigrated to Israel in 1949. The chemistry of natural products fascinated young Rafael. In one of his favorite stories to recount, he obtained 5 kilos of confiscated Lebanese hashish from the Israeli police to analyze its components. Previously, scientists had unsuccessfully tried to identify the active ingredients in cannabis, but unlike soluble alkaloids such as morphine, the slippery cannabinoid lipids proved challenging to elucidate. The hash that he obtained from the police in 1964 allowed Dr. Mechoulam, along with his colleague Yehiel Gaoni, PhD, to isolate and discover the THC compound.1
In 1992, Dr. Mechoulam, with William Devane, PhD, and Lumir Hanus, PhD, discovered and identified a key component of the ECS: anandamide, the first endocannabinoid neurotransmitter ever found.2 They named it after “ananda,” the Sanskrit word for bliss. As Dr. Mechoulam liked to joke, “We wanted to use a Hebrew word for happiness, but we didn’t have any.”
Most recently, Dr. Mechoulam led a team of researchers at EPM, a US-based global biotechnology company that helps to bridge the gap between the pharmaceutical and cannabis industries. In his last significant discovery, at the age of 88, Dr. Mechoulam successfully created a stabilized synthetic CBDa compound called cannabidiolic acid methyl ester or EPM301.3 Acid-based cannabinoids have been notoriously difficult to work with because of their unstable nature, but are far more potent than THC or CBD. Dr. Mechoulam believed this revolutionary discovery had immense potential to treat inflammatory conditions and could be an alternative to steroids and opioids.4
Dr. Mechoulam was not only a brilliant scientist, he was a humble and kind person who cared deeply about his family, friends, and colleagues. He was passionate about advancing knowledge and improving human health through cannabis research. He remains an inspiration to generations of researchers and physician-scientists who follow in his footsteps.
AJEM hopes this tribute will help shine a light on Dr. Mechoulam’s profound contributions to cannabis medicine. In what follows are 2 unpublished interviews.
When Lex Pelger, as a young unknown drug writer, contacted Dr. Mechoulam 10 years ago, Dr. Mechoulam agreed to an in-person interview and spent 2 hours with Pelger because he wanted to share his knowledge. When Meg Block Roloff, MPH, contacted the then 90-year-old Dr. Mechoulam for an interview with AJEM, he happily responded with his preference to conduct the interview over email and promptly answered all her questions.
AJEM will never forget Dr. Mechoulam’s passion for his craft and willingness to share his knowledge. Rest in peace, Dr. Mechoulam. Thank you for all you did.
AJEM: What advice do you have for physicians who want to get involved in cannabis medicine, but never learned about the endocannabinoid system in medical school?
RM: Physicians must learn new advances all the time. My father, a physician, never learned about antibiotics at his medical school but had to read and learn extensively about them in his later years. I doubt whether medical schools teach cannabis medicine at present, but they will have to do so within the next decade.
AJEM: As you look back on your career, what accomplishments are you most proud of?
RM: The discovery of the endogenous cannabinoids anandamide and 2-AG.5,6
AJEM: Did you always want to be a chemist?
RM: When I was 18 in Bulgaria, I thought we’d be leaving that communist country. But for some strange reason—governments are always crazy—they said medical students couldn’t leave. So, I changed my MD plans and started in chemical engineering. And then we left. I started chemistry for reasons that had little to do with what I wanted to do.
We came to Israel [in 1949], and I wanted to continue my studies—but no chemistry department. I had to wait a year for their chemistry program to start. I finished my master’s in biochemistry in 1952 [at Hebrew University]. I took my PhD at Weizmann [Institute of Science] and continued in natural products at Rockefeller Institute in New York City, always working on the chemistry of these compounds. I wanted to work between chemistry and biology.
I asked for a grant from the NIH [US National Institutes of Health] in the early 1960s to study cannabis, and although they were pretty generous at the time, they said no. They said it’s not an American problem because nobody uses it here—just in Mexico—so call us when you have something relevant. Then a year later, they called me and asked, “Can you come over?” It turns out that somebody important [a US senator] called the NIH and said that their son was smoking pot. They asked, “Is he ruining his brain?” And the NIH realized that they didn’t know.
They had never given a grant for marijuana before, but now it’s getting used in America, so they gave me kilos of THC—the world’s supply—and I took it back to Israel. Then the NIH started spending a huge amount of [money on] research on THC, but not in humans.
The NIH is special; nothing else like it in the world—the main funders of biomedical research, excellent scientists, and excellent administrators. I’ve known most of the heads of the NIH. Good scientists, not politicians. The NIH is the biggest institution by far for biomedical research. So, when they wanted to investigate cannabis, they decided to do it in a serious way. But they can’t change the laws. They couldn’t perform clinical research for cannabis in the US.
By the way, I think they’re doing a fantastic job. But I’m not objective. They’ve been my major funder for 45 years. I always had to apply and put in grant proposals and get them evaluated—but once they gave me the grant, they never came around to interfere. Their system is that if a fellow has a grant and doesn’t do serious work, they won’t give him a second one.
People became interested in the cannabinoid field and began flocking around. From a small group of scientists, it’s now a pretty large field, especially once anandamide and the receptors were discovered.
Dr. Allyn Howlett [PhD] is an excellent scientist. She discovered the very first receptor. We invited her student Bill Devane because if a receptor exists, it’s not because some plant contains the compound. It’s because we have something endogenous. So obviously, there are chemicals we produce that do something with these receptors. [William Devane’s] PhD was discovering the receptor, so he knew everything about that. My group is chemical, so we needed someone who knew how to work with the receptor. That’s how we found anandamide.5
AJEM: What’s it like not to see anandamide being tested in humans?
RM: Anandamide is an endocompound. My brain makes it. Your brain makes it. Essentially, it’s a protective compound, although it does all kinds of things. The reason that it has never been tested in humans is for silly reasons.
When insulin was discovered, it was in use 6 months later. Anandamide was discovered almost 25 years ago—but has never been tested clinically. To the best of my knowledge, it’s nontoxic. My papers have been referenced 3000 or 4000 times [now 72k+ citations]. There are 10,000 papers total—and still, it’s not tested. Medicine is harder now than it was before. A scientist is terrified. If they don’t have all the regulatory requirements, they go to prison. And if something happens to a patient, then it’s really terrible. Everybody brings their lawyers.
We found that 2-AG [the second discovered endocannabinoid neurotransmitter] works against brain trauma in mice, and a few of the other endocannabinoids work as well. When the body has endogenous diseases like bacteria and viruses from the outside world, the immune system works against them. But not everything is based on attacks from proteins. Things like brain trauma and kidney disease are not treated by the immune system. So how would our body not have defenses against these other diseases?
With the endocannabinoid system … CB1 causes the changes we know—the marijuana effects. CB2 just sits there doing nothing when you’re healthy—it does a few things—but not too many. But when there is body damage of some sort, all of a sudden, it starts working. We collected data on CB2 for the heart, atherosclerosis, stroke, liver, and autoimmune disorders. Now we know it does much more—psychiatric conditions—inflammations. Here we have a parallel system that works together with the immune system.
AJEM: What are your thoughts on endocannabinoid deficiency syndrome and autoimmune disorders?
RM: We showed 10 years ago that cannabinoids work against rheumatoid arthritis.7 So we tried it on diabetes type 1, which is also an autoimmune disorder—and it worked very well.8 But we never went ahead to try it in humans because we never had the money to test it.
You see, cannabinoids were not used for many years for various reasons. US physicians didn’t want to have the label that they’re cannabis physicians, which was wrong in the sense that there are no “cannabis physicians.” If a doc gives opiates [correctly], it’s fine—but when they produce a line of people going out of the door, that’s not medicine. Many physicians [feared] being labeled in that way.
A few years ago, parents figured out that CBD helped—but it was in the literature 35 years ago. We published that CBD is excellent in [the treatment of] epilepsy with 15 patients in a double-blind study.9 For the half who got 200 mg a day for a couple of months, out of those 7 or 8 patients, 4 had no convulsions at all. All of them responded, but 1. That was 35 years ago, and how many clinical trials? Zero. [Of course, now the use of CBD for epilepsy is one of the hottest areas of clinical cannabinoid research.]
Suddenly, the neurologists are saying, “Ah—we should do that.” And they say, “Yes, there was a paper published 35 years ago. It was a small one.” Of course, it was a small one! Half a kilo of CBD was a big investment for me. A pharma company can spend a couple of million for 10 kilos of CBD. But I’m an academic. Under the present conditions, it’s almost impossible for an academic to develop a new drug. Maybe it could have been done 100 years ago—but now the [regulations] are so strict that you need a half billion [dollars] to develop a drug.
AJEM: Which of the cannabinoids do you think are the most exciting?
RM: Most of the CB2 specific agonists [molecules that bind and activate only the CB2 receptor].
THC is not a good drug. It does too many things in the body. It’s a drug, but no one has broken into the pharmacy to steal dronabinol [a synthetic form of THC]. People would do that for heroin or morphine, but not THC, for the simple reason that no one uses THC. They’ll use marijuana. However, THC is excellent for PTSD [post-traumatic stress disorder]. Give 5 mg once a day, and they’re in much better shape. One of the problems with PTSD is that they don’t sleep well. They have nightmares that frighten them—but there’s a small paper that shows it worked.10
CBD is something else. There’s evidence for different things like bone marrow transplants, anxiety, Crohn’s disease, or epilepsy. I remember a mother of an epileptic child who came to me when the cannabis bottle was finished. But with the next bottle, the attacks came back. It turned out that the one that worked had a lot of CBD, but the next one didn’t.
CBD has also been proven to be helpful for schizophrenia.11 [Researchers] gave up to 800 mg of CBD to [people with schizophrenia] for a couple of months and compared it with one of the well-known drugs. They found that both caused very positive effects but with a minor difference. The typical anti-schizophrenia drug had unpleasant side effects; many patients refused to use it. CBD is an anti-schizophrenic compound.
AJEM: What about cannabinoids and epigenetics [the turning on and off of genes]?
RM: The only group to do work on this is the outstanding scientist [Mauro Maccarrone, PhD, MSc]. He has a large group of very good scientists. He just published a new paper a few days ago.12 He found that CBD acts on the enzymes that puts a methyl group on DNA [to deactivate it].
I think it’s quite simple. DNA produces everything in our body using a long list of reactions. That’s the factory that produces proteins and enzymes to make materials. But sometimes it may work overtime or not too well. Somebody has to regulate it, and it seems like the ECS is part of that regulatory system of DNA. To what extent it’s a major regulator, we don’t know enough yet. I believe that the reason CBD has so many effects is because of its epigenetic effects. Maccarrone proved this in 1 or 2 cases. And anandamide does the same thing.
AJEM: Is this new research a nice reason to get to meetings?
RM: I try to not go to too many meetings because—for God’s sake—I’m 85 years old. I try to relax a little bit, although not that successfully.
AJEM: What about cannabinoids and cancer?
RM: For anticancer, there are very good papers on animals. Lots of mechanisms—but for clinical trials, there are zero. We have the planning and the paperwork for trials, but we don’t have enough money. A good friend of mine did a study on high levels of CBD for protection against the side effects of cancer treatments on bone marrow. He had excellent results, but when he tried to publish it, his paper was not accepted because the sample size was too small—only 40 patients. But he was giving high levels of CBD and seeing excellent results. The journals are used to publishing clinical trials with lots of patients—while the academics don’t get that many.
AJEM: What about your theory of FAAH for personality?
[FAAH (fatty acid amide hydrolase) is the enzyme that degrades anandamide and functions as a regulator of anandamide levels as well as a tool of homeostasis]
RM: Until quite recently, we knew almost nothing about the chemistry of personality. You have 50 people in the audience, you have 50 different personalities. People say it’s genetics, fine—but what does that mean? It means that you have some different chemistry. We have, in our brains, 200 to 300 compounds that are similar to anandamide. Fatty acids bound to amino acids. And since there are so many of both, they can form all kinds of combinations. PEA [palmitoylethanolamide] has been known about for ages and does all kinds of interesting things. Oleamide—we looked at it—comes from olive oil. It’s believed that people in the Mediterranean region have less of some diseases like osteoporosis. Women in the Mediterranean region have 50% less osteoporosis than women in the north. The reason for this was thought to be olive oil, which probably means oleic acid.
We tested oleic acid, and it didn’t do anything different, so we guessed maybe it’s a metabolite [breakdown product]. We synthesized 2 or 3 of the metabolites and looked for them in the brain and the body. Oleoyl serine, at low concentrations, is a fantastic osteoporosis drug. Drugs that old people like me take, they stop osteoporosis in the body. Instead, this compound actually starts building the bone back. That’s why apparently olive oil is good for osteoporosis—it’s metabolized into oleoyl serine and help. All women after [age] 55 have osteoporosis because of hormones. But it is always different and varies from small to very serious. This may be because of endogenous oleoyl serine. We tried it in mice. We took the ovaries out of them and after 40 days, they started developing osteoporosis. Oleoyl serine brought the bone growth back.13 [There are 200] compounds of this type in your brain and they do all kinds of things—but we still haven’t found any company interested in developing these compounds into a drug.
AJEM: What was it like to be working with a plant that has so much stigma?
RM: We were lucky in many respects. It would have been impossible in the US to do what I did here. Israel has a bunch of groups doing good work. There’s great work at Haifa on psychology. The Ministry of Health has medical committees that must decide on every case. Even if somebody is not allowed, they can reapply to a special committee that will decide.
In the beginning, it was just marijuana—medical cannabis. Now depending on the disease, we have different ratios of cannabinoids. Because cannabis was illegal for so long, people don’t know the differences between the varieties or that the terpenes affect the actions of the other cannabinoids.
AJEM: How must the traditional research and pharmaceutical model change so investigators can accurately evaluate cannabis compounds?
RM: Research should be done on the pure natural products as well as on defined mixtures of the natural products with other cannabis plant constituents.
AJEM: What research studies are you closely following and what gaps in cannabis medicine do you hope will be filled in the next 5 to 10 years?
RM: The biochemical and clinical effects of CBD, CBG [cannabigerol], and the endocannabinoids. We have few modern clinical trials with CBD and CBG. I hope to see such investigations. We have no human trials with anandamide and 2-AG. Unbelievable!
AJEM: What do you think the future will hold for cannabis medicine?
RM: I assume that we shall have both cannabis extracts (as we have today) and specific cannabinoids—be they natural products or synthetic cannabinoids used as medical agents.
AJEM: What are you studying in your latest research?
RM: Synthetic CBD-like cannabinoids, which are better (more potent) than CBD.14 [I am also studying] endogenous anandamide-like compounds with significant biological activity (mostly protective) in various fields [including]: reactivating antibiotic activity against antibiotic resistant microbes,15 action against addiction and withdrawal symptoms,16 and bone formation.17
AJEM: What is your secret to good health and longevity?
RM: Presumably my genes.
Dr. Mechoulam, a Professor of Medicinal Chemistry at the Hebrew University of Jerusalem since 1966, mentored many students and collaborators. He received numerous awards and honors for his scientific contributions, including the Israel Prize, the EMET Prize, the Harvey Prize, the NIDA Discovery Award, and several honorary doctorates. He was also a founding member of the International Association for Cannabinoid Medicines and the International Cannabinoid Research Society.
For more on Dr. Mechoulam, please watch an excellent documentary called The Scientist and read his reflections on his scientific journey, which he shared at the age of 91, in the Annual Review of Pharmacology and Toxicology.
- Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646-1647. doi:10.1021/ja01062a046
- Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. 1992;258:1946-1949. doi:10.1126/science.1470919
- Cision PR Newswire. EPM introduces groundbreaking cannabinoid acid technology and new commercial licensing platform at CannMed 2019 conference. Accessed July 22, 2023. https://www.prnewswire.com/news-releases/epm-introduces-groundbreaking-cannabinoid-acid-technology-and-new-commercial-licensing-platform-at-cannmed-2019-conference-300922924.html
- The Jerusalem Post. Father of cannabis research plans a new revolution nearly 60 years later. Acessed July 10, 2023. https://www.jpost.com
- Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-1949. doi:10.1126/science.1470919
- Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83-90. doi:10.1016/0006-2952(95)00109-d
- Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000;97(17):9561-9566. doi:10.1073/pnas.160105897
- Weiss L, Zeira M, Reich S, et al. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 2006;39(2):143-151. doi: 10.1080/08916930500356674
- Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175-185. doi:10.1159/000137430
- Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A. Preliminary, open-label, pilot study of add-on oral Δ9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig. 2014;34(8):587-591. doi:10.1007/s40261-014-0212-3
- Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94. doi:10.1038/tp.2012.15
- Ribeiro A, Pontis S, Mengatto L, et al. A potent systemically active n-acylethanolamine acid amidase inhibitor that suppresses inflammation and human macrophage activation. ACS Chem Biol. 2015;10:1838-1846. doi:10.1021/acschembio.5b00114
- Smoum R, Bar A, Tan B, et al. Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass. Proc Natl Acad Sci U S A. 2010;107(41):17710-17715. doi:10.1073/pnas.091247910
- Kogan NM, Peters M, Mechoulam R. Cannabinoid quinones— a review and novel observations. Molecules. 2021;26(6):1761. doi.org/10.3390/molocules26061761
- Feldman M, Smoum R, Mechoulam R, Steinberg D. Antimicrobial potential of endocannabinoid and endocannabinoid-like compounds against methicillin-resistant Staphylococcus aureus. Sci Rep. 2018;8(1):17696. doi:10.1038/s41598-018-35793-7
- Donvito G, Piscitelli F, Muldoon P, et al. N-oleoyl-glycine reduces nicotine reward and withdrawal in mice. Neuropharmacology. 2019;148:320-331. doi:10.1016/j.neuropharm.2018.03.020
- Baraghithy S, Smoum R, Attar-Namdar M, Mechoulam R, Bab I, Tam J. HU-671, a novel oleoyl serine derivative, exhibits enhanced efficacy in reversing ovariectomy-induced osteoporosis and bone marrow adiposity. Molecules. 2019;24(20):3719. doi:10.3390/molecules24203719