Dr. Raphael Mechoulam (1930–2023), an Israeli professor and pioneer in cannabis research, also known as the “father of cannabinoid research,” died on March 9, 2023, at the age of 92. He was born in Sofia, Bulgaria, to Jewish parents. His family later moved to Israel, where he began studying chemistry. When Mechoulam began researching cannabis in the 1960s, it was considered a dangerous psychoactive drug with no medical benefits. However, he studied it throughout his academic life and became a leading expert and advocate for the use of cannabis in medicine. In this memoir, I summarize his contributions to pharmacological and medical science, including his groundbreaking discovery of endocannabinoids, which contributed to our understanding of the endocannabinoid system (ECS), and his isolation of THC (tetrahydrocannabinol) and CBD (cannabidiol) from plant sources.

Isolation of psychoactive cannabinoid

Mechoulam was inspired to research cannabis after studying history and closely observing the mechanisms of action of other medicinal plants. Morphine was isolated from opium poppies in the early 19th century, and cocaine from coca leaves in the mid-19th century. But by the turn of the 20th century, only one compound had been extracted from cannabis: cannabinol, a non-psychoactive metabolite of THC. In the mid-20th century, most of the chemistry and pharmacology of cannabis was still unknown, although the first recorded use of cannabis as a medicine was around 2700 BC in China. The Chinese also called it "the medicine that takes away the mind" and it was used mainly to relieve pain, gastrointestinal disorders, insomnia and neurological diseases. In Europe, it was popularized by the Irish physician William O'Shaughnessy, who conducted studies on animals and humans in India in the 1830s. In the mid-19th century and early 20th century, cannabis was included in hundreds of patented medicines, including tinctures, powders and syrups. They were prescribed as remedies for gout, rheumatism, migraine, cough, asthma, “women’s problems”, pain, sleep problems, epilepsy… This knowledge was a great challenge for the young researcher. He developed a project that is a milestone in revealing the unnecessaryness and harmfulness of cannabis prohibition, and at the same time was amazed at the fact that it was introduced before the plant had even been scientifically studied. He found that the legislation regarding cannabis was based neither on knowledge nor on data about its effects on our bodies. The story of how the young Mechoulam first obtained the hated, stigmatized and banned cannabis for research is interesting. In interviews, he repeatedly revealed to journalists how he bypassed the bureaucracy in obtaining initial cannabis samples for research on what makes cannabis psychoactive, and in doing so, unintentionally broke the law. It turned out that he would have to get permission from the Ministry of Health to do his research first. Regardless, officials gave him 5 kg of Lebanese hashish. Since he did not have a car, he simply took a public bus from the police station to the laboratory in a plastic bag to bring the amount of the illegal substance. From this material, he managed to synthesize THC in 1964, something no scientist had ever done before. Cannabis, which at the time was associated only with drug addicts and criminals and condemned as a dangerous “devil’s herb,” led the scientist on a path to better understanding the human body and revealing a biological system that was then only assumed to be involved in modulating everything from the sensation of pain to reproduction and appetite. With the discovery of THC, research into cannabinoids took off worldwide. In parallel, the popularity of cannabis (“marijuana”) as a recreational drug also expanded. The isolation and synthesis of THC proved to be one of the most important events in the history of psychopharmacology. Although he did not realize it at the time, Mechoulam lit a slow-burning fuse that would revolutionize medical science. Together with his colleagues, he later isolated, elucidated, and synthesized several other cannabinoids, including cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and several other cannabinoids. CBD, which is non-intoxicating and has a number of promising therapeutic effects, such as treating seizures, relieving chronic pain and inflammation, and may have beneficial effects against Parkinson's disease, Alzheimer's disease, and multiple sclerosis, has also shown promise as an antidepressant because of its ability to affect the brain's receptors for serotonin, a neurotransmitter that helps regulate mood and social behavior. Today, it is also safely used to relieve stress, anxiety, and insomnia. These discoveries laid the foundation for chemical and clinical research on cannabinoids and helped spur future discoveries, such as the elucidation of the body's own (endogenous) cannabinoid receptors.

Endocannabinoid system (ECS)

The ECS is a complex cell signaling system that was discovered in 1988 by Mechoulam and his colleagues at Saint Louis University School of Medicine. They first discovered CB1 receptors, which are located primarily in the cerebral cortex, cerebellum, and basal ganglia. These are parts of the brain responsible for thinking, memory, pleasure, coordination, and movement. In 1992, the first endocannabinoid was discovered, which they named anandamide, also known as N-arachidonoylethanolamine (AEA). The name “anandamide” is taken from the Sanskrit word “ananda,” which means joy, bliss, or pleasure. Anandamide is present in the brain at very low concentrations. Endocannabinoids behave differently from other neurotransmitters. Most
neurotransmitters are synthesized and stored in vesicles. The body keeps them waiting until they are needed, when they are released by the presynaptic neuron and act postsynaptically. In contrast, endocannabinoids are formed on demand, when and where needed; they are released from the postsynaptic neuron and act presynaptically. According to Mechoulam, the ECS is part of “the body’s general protective network that works in conjunction with the immune system and various other physiological systems.” “One of the main effects of endogenous cannabinoids is to regulate the release of dopamine, serotonin, and other neurotransmitters,” he taught. He called them “master regulators” and compared their action to the immune system. He pointed out that the ECS is very complex and regulates many processes, paralleling other known systems, such as the adrenergic, cholinergic, and dopaminergic systems. He considered it unacceptable to neglect the potential clinical use of such a system—given the very low toxicity and generally benign side effects of cannabinoids. We need to look for more selective agonists/antagonists, distinguish between the desired clinical action and psychoactivity, and carefully monitor these side effects. He cited the example of the effect of ECS on appetite regulation. Mice with blocked endocannabinoid receptors will starve to death. They developed the drug rimonabant, a CB1 receptor blocker that was approved in Europe in 2006 for the treatment of obesity, but was withdrawn from the market in 2008 due to very serious psychiatric side effects. They did not take into account the complexity of ECS. “If you block appetite, you can also increase anxiety,” Mechoulam explained. Endocannabinoids have been found to play a role in memory, mood, appetite and metabolism, sleep, pain response, thermoregulation, and immunity. ECS is also thought to regulate reproduction. Mechoulam believed that ECS is involved in many physiological reactions and almost all human diseases.

Why did we have to wait over 30 years?

In 1982, Mechoulam said that if cannabis were legal, it could replace ten to twenty percent of all drugs. Since most research on cannabinoids has focused on the plant’s psychoactive properties, other non-psychoactive cannabinoids have been largely overlooked. Mechoulam has repeatedly warned that knowledge about cannabinoids and ECS is generally insufficiently integrated into medical education systems. His discoveries have posed a direct challenge to scientific orthodoxy, including by revealing that the brain has built-in mechanisms of protection and regeneration that can repair damaged nerves and brain cells. At a 2019 conference on cannabis therapy in California, the then 88-year-old announced another cannabis-based discovery: cannabidiol acid (CBDA), suitable for clinical use due to its anti-inflammatory, anticonvulsant and anti-cancer properties. This is likely just the tip of the iceberg of the therapeutic potential of this green plant cannabinoid. He also used his time on stage to encourage politicians and the scientific community to support more research. He lamented the time already lost due to obstacles in researching the therapeutic potential of cannabis, especially CBD, and expressed sympathy for the deaf who could benefit if cannabis were more widely available. He wondered why we had to wait decades when we could have helped thousands of children with epilepsy and we didn't. In the 1980s, Mechoulam, along with colleagues from Brazil and elsewhere, published findings that cannabis effectively treats epilepsy, as was already stated in the medical literature of the 19th century. However, the publications did not stimulate larger clinical trials and the development of appropriate drugs. For more than 30 years, nothing happened in medicine, until some parents in the United States and elsewhere in the world discovered for themselves that plants containing large amounts of CBD effectively helped their children's epilepsy. It was only because of parental pressure that the research was approved and today children with epilepsy have an approved drug called Epidiolex.

Scientist

Mechoulam shared his life story in the heart-warming 2015 documentary The Scientist, which follows his life from his childhood during the Holocaust in Bulgaria and his emigration to Israel to his career as an extraordinary scientist studying one of the most medicinal, yet stigmatized and misunderstood plants in the world. Director Zach Klein met Professor Mechoulam when he was seeking help for his mother, who had breast cancer and was suffering from severe side effects from chemotherapy, which she was treating with cannabis. In 2017, Mechoulam helped found the Hebrew University’s multidisciplinary center for cannabinoid research. He initiated scientific collaborations between researchers from around the world. The center brought together Jews, Muslims, Christians, Israelis, Arabs, and others connected to science, under the guidance of a charismatic leader. He was a fierce lecturer and critic of the “war on cannabis” and an advocate for the use of cannabis in medicine. He continued to research and innovate until his death. It is impossible to summarize all of Mechoulam’s contributions. He also investigated the role of cannabinoids in the treatment of schizophrenia and post-traumatic stress disorder (PTSD), as well as the role of ECS in the maternal-infant bond. He received numerous scientific awards and was nominated for the Nobel Prize. Many scientists consider the discovery of ECS and the subsequent use of cannabinoids in medicine to be equivalent to the discovery of DNA. Despite these accolades, Mechoulam’s name is not well-known outside the cannabis and cannabinoid research community. Mechoulam once called cannabis “a neglected pharmacological treasure trove.” He helped to alleviate misconceptions and ideological hatred of the “devil’s herb,” and paved the way for other scientists to harness its treasure trove for medical use and share it around the world. His discoveries and belief that cannabis opens the door to new insights into the functioning of the human brain and body, represent the possibility of developing a wide range of new medicines for humanity and have led to a renaissance of cannabis in medicine. His work has inspired and continues to inspire a generation of successful cannabis and cannabinoid researchers. As such, he will be remembered not only for his pioneering contributions to cannabis research, but also for his far-reaching impact on the scientific community and, more broadly, on our global society.

Resources

1. Gaoni Y., Mechoulam R. Isolation, structure and partial synthesis of the active constituent of hashish. J Am Chem Soc. 1964;86:1646–1647.
2. Lee MA Smoke Signals: A Social History of Marijuana- Medical, Recreational and Scientific. New York City Scribner, 2012.
3. The Scientist. Documentary, 2015. Available at https://www.youtube.com/ watch?v=5BGS5JzLlvs
4. Mechoulam R. Cannabinoid chemistry. In: Mechoulam R, ed. Marijuana. New York, NY; London, UK: Academic Press. 1973:1–99.
5. Mechoulam R., Hanus L. A historical overview of chemical research on cannabinoids. Chem Phys Lipids. 2000;108:1–13.
6. Mechoulam R. Conversation with Raphael Mechoulam. Addiction, 2007 102(6):887-93.

Text: Prim. mag. Dušan Nolimal, MD, public health specialist, Ljubljana

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