Research into cannabis and its wide variety of components by Prof. Raphael Mechoulam was ignored for decades.
By JUDY SIEGEL-ITZKOVICHPROF. RAPHAEL MECHOULAM(photo credit: JUDY SIEGEL-ITZKOVICH)Half a century ago, the Weizmann Institute of Science in Rehovot and the National Institutes of Health in the US said they “weren’t interested” in Prof. Raphael Mechoulam’s research on the active ingredients in cannabis. Unwilling to further pursue organic chemistry research, they were rather shortsighted.“There wasn’t a single lab in the USA that worked on cannabis. When I asked the NIH for a grant, they said: ‘Sorry, we can’t give it to you. This isn’t an American problem,” he recalled. Later, the NIH reconsidered and provided him with research money for 45 years. There is currently huge pressure throughout the US for medical cannabis to be made available to relevant patients. Even recreational use of the drug has been approved in the states of Colorado and Washington, and campaigns to legalize marijuana for non-medical use are being proposed in other states.Today, medical marijuana – smoked, baked into cookies, infused into oils and produced in other forms – is sought worldwide to ease the suffering of patients with cancer, AIDS, multiple sclerosis, Parkinson’s disease, Tourette’s syndrome, Crohn’s disease and others. There are currently over 14,000 authorized Israeli users, and in four years, the figure is expected to triple. But only now are clinical trials on the positive and negative effects of cannabis constituents and derivatives being launched.The 83-year-old Mechoulam sits in his Jerusalem office at the Hebrew University Institute for Drug Research on the Hadassah Medical Organization campus in Ein Kerem.Although he has long passed retirement age, he is welcome to continue his research on campus financed by grants from Israel and abroad.IN A Jerusalem Post interview in his office and lab, Mechoulam recalled that his father, Dr. Moreno Mechoulam, was a pediatrician, director of the Jewish Hospital in Sofia, Bulgaria, where Raphael was born in 1930, and president of the local Zionist organization, Maccabi. His mother was a housewife and woman of leisure.But the idyll ended when anti-Semitic laws were enforced by the Nazis, and his father was sent to a concentration camp, which he survived. After the Communist takeover of pro-German Bulgaria in 1944, Mechoulam studied chemical engineering, which he disliked. When his family wanted to leave the country, he was not sure if medical students would receive permission to leave, so he studied chemistry instead. The family immigrated to Israel the year after the establishment of the independent Jewish state.He went into the academic program of the Israel Defense Forces and did research on insecticides. He finished his doctoral degree in chemistry in the 1950s and traveled to New York for a postdoctoral fellowship at the (then) Rockefeller Institute. Returning to Israel, he lived in Tel Aviv with his wife Dalia, a teacher, and traveled to Rehovot every day. Raphael and Dalia, to whom he has been married for some 55 years, have three children – son Roy, a mathematics professor; daughter Hadas, a pediatric ophthalmologist; and daughter Dafna, a pediatric neurologist – and seven grandchildren."MORPHINE WAS isolated from opium and then cocaine from coca leaves in the 19th century, but the active cannabis ingredient wasn’t known until our work and hence it was also not known how cannabis worked,” Mechoulam said. A year after he encountered apathy to his research into cannabis both in Israel and in the US, “the chief pharmacologist of the US National Institute for Mental Health came to see me. He said that one US senator wanted to know how marijuana affects the brain, because his son was using it.”Among his important foreign contacts is Dr. Nora Volkow, a Mexican-born Jewish researcher in the field of addictions who happens to be the granddaughter of Leon Trotsky, the Russian Marxist revolutionary, Soviet politician and founder of the Red Army. She is now director of the US National Institute on Drug Abuse.
The global pharmaceutical firms have not been enthusiastic about financing basic and applied research into medical cannabis because it has existed for millennia and thus can’t be patented, he explained, adding that nevertheless the potential medical benefits are significant – but must be proven in clinical trials.“I looked for interesting subjects at Weizmann. I was surprised that so little was known in my field,” he said.So innocent that he didn’t realize he could have applied to the Health Ministry to get cannabis samples for research, Mechoulam contacted the director of the investigative branch of the Israel Police, who was a friend of a Weizmann colleague and was himself unaware of bureaucratic restrictions. The police officer gave him five kilos of hashish that had been smuggled in from Lebanon.“I remember taking the hashish home on the bus. It had a very strong smell, and my fellow passengers wondered what it was that I was carrying.”In decades of working with marijuana, the HU scientist declares that – unlike some American presidents – he never smoked it or otherwise used it.“But our team did experiment with it after we isolated the THC [tetrahydrocannabinol, the primary psychoactive component of cannabis]. Five people, including my wife, got 10 milligrams of THC in the form of oil dripped on a cake, and five others got a placebo. Everybody was affected differently. She dreamed a bit, and she hasn’t touched marijuana since. Another person didn’t feel high, but he couldn’t stop talking... another had an anxiety attack.”His excellent relationship with law enforcement continued, and Mechoulam has been getting hashish – which also comes from cannabis, but is processed differently than marijuana – for decades.He coined a new term, “cannabinoids” (referring to the active constituents of cannabis) – which became a whole new field of research with implications not only in the treatment of pain, lack of appetite and nausea but in virtually every other field of medicine.In 1963, working with Dr. Yechiel Gaoni and Dr. Habib Edery, Mechoulam was the first to isolate THC as the most important active ingredient in hashish.“We tested the compound on rhesus monkeys, and it made all of them fall asleep; nothing else affected them that way. The team also elucidated THC’s structure and synthesized it. We published our findings in the Journal of the American Chemical Society the following year.”But when he felt he wasn’t getting anywhere at Weizmann, he turned down other offers, including one from the Technion-Israel Institute of Technology in Haifa, and moved to the School of Pharmacy in Jerusalem.There his group discovered in the 1990s the endocannabinoids anandamide, produced by the brain, and 2-arachidonoyl glycerol (2-AG), produced by peripheral organs.Endocannabinoids are a group of neuromodulatory lipids (fats), and their receptors in the brain are involved in a variety of physiological processes including pain-sensation, appetite, mood and memory; they mediate the psychoactive effects of marijuana.Regulating endocannabinoids may have therapeutic potential in almost all human disorders including cardiovascular, metabolic, inflammatory, liver, skin, gastrointestinal, psychiatric, oncological, pain and neurodegenerative diseases.He also identified cannabidiol (CBD), one of about five dozen active cannabinoids in cannabis. This natural chemical, which often constitutes about two-fifths of extracts of the marijuana plant, does not cause “highs” but is useful in oil form for treating numerous diseases, particularly those involving inflammations. CBD also reduced sugar levels in diabetes-prone mice and reduced the effects of cardiac ischemia (inadequate blood supply to the heart).“We did some clinical trials years ago. For example, together with pediatric oncologist Dr. Aya Abramov at Shaare Zedek Medical Center, we gave THC under the tongue to children undergoing very difficult treatment that made them nauseous and caused vomiting. All of the kids had positive results. In a total of 450 treatments, there wasn’t a single case with nausea and vomiting. But nobody followed up on it.”Today, there are synthetic drugs for it, said former HU rector Mechoulam, who has received numerous prestigious awards including the Israel Prize in exact sciences (2000), Rothschild Prize in chemical sciences and physical sciences (2012), EMET Prize in chemistry (2012), Hebrew University Medical Faculty Prize for excellence in research (2010) and numerous foreign awards, and who in 1994 was elected to the Israel Academy of Sciences and Humanities.“Thirty-five years ago, we did a clinical study on epilepsy with CBD in Brazil. The results there too were excellent, and there were no side effects, but no other researchers followed it up. Studies by our and other groups showed that CBD helped schizophrenia patients, but again, nobody was interested. Hospital Helsinki committees [charged with giving approval for suitable medical experimentation on humans] don’t always approve use of medical cannabis,” said the HU researcher.“Together with clinicians at the Geha Psychiatric Hospital we are trying to get a permit to evaluate CBD on patients with anxiety and suicidal tendencies, but we haven’t received one yet. There are hundreds of published articles on cannabinoids and cancer, but not one well-established clinical trial. It’s a vicious cycle; researchers don’t give the compounds to patients because there are no serious clinical trials, and clinical trials are not conducted in the US because there is no approval for giving the drugs.”Mechoulam said he “wouldn’t give medical cannabis for everything. Israel is going in the right direction by giving approval gradually for different diseases. It’s impossible to know if people who say they’re in terrible pain [actually are] because it’s subjective and can’t be measured. I presume there is some abuse. Driving is a problem, because it can cause confusion and slow reactions, but legal users generally avoid driving.”He stresses that approval of recreational cannabis is a social issue and not a medical one. Personally he does not support the approval of recreational cannabis in Israel.And he also regards alcoholism, gambling and smoking tobacco as “very dangerous.”He predicted that in another decade, the approved use of medical cannabis for all kinds of conditions will be central, as medications will be prepared that work like THC but without the active ingredient that causes a “high” effect on patients.Mechoulam has not confined his interest only to cannabis. He has done research on levona, the Hebrew word for frankincense or Boswellia sacra, which was used as incense in the Holy Temple in Jerusalem. The Hebrew University chemist, together with his then PhD student Arieh Moussaieff, showed that a major ingredient of Middle Eastern incense lowers anxiety and has an antidepressant- like effect on mice.“The Talmud mentions Boswellia resin as a potion put in wine to ‘benumb the senses’ so that [those] condemned to death would not worry... It [their findings] provides a biological basis for deeply rooted cultural and religious traditions.”Thus, Mechoulam’s research gives new meaning to the term “High Priest.”
