Raphael Mechoulam and the Cannabis Story

The cannabis story

Arguably, cannabis is one of the most controversial natural products around, with different campaigns and policies regulating its cultivation, marketing, and use. With an origin traced back 10,000-12,000 years ago in Taiwan, cannabis has grown to become a universally known plant cutting across different industries. Before the global popularity of cannabis and cannabis-derived products currently seen, different natural product experts have made several discoveries and published tons of reports detailing the results of these experiments. Of all researchers to have worked on the cannabis plant, Raphael Mechoulam was exceptional, setting a platform for significant subsequent cannabis discoveries.

Raphael Mechoulam’s contribution

Professor Raphael Mechoulam is known as the Father of Cannabis for his contributions to medical cannabis research. An organic chemist born in Bulgaria who moved to Israel during the Holocaust, Mechoulam is a professor of Medicinal Chemistry at the Hebrew University of Jerusalem. The professor has received many awards for his contributions to medicine and science. As a member of the Institute for Drug Research at the Hebrew University of Jerusalem, Professor Mechoulam serves as the Co-Chair of the Scientific Advisory Board at Kalytera Therapeutics, Inc. 

His other collaborations and service record include Member of the Israel Academy of Science, Member of Scientific Advisory Board at Therapix Biosciences, and Member of the Israeli Academy of Science and Humanities. Mechoulam’s research interests are focused on the biological chemistry profile of the natural product and medicinal agents. He has published extensive reports on the constituents of cannabis and the pharmacology of the endogenous cannabinoids found in the brain and periphery. Raphael Mechoulam’s contribution to the science of the cannabis plant include: 

• Discovery and isolation of 9-delta-tetrahydrocannabinol (THC)

There are over 113 natural compounds in the cannabis plant. Before the discovery of THC, cannabis was known to cause a characteristic high and a mind-altering effect. Mechoulam research into the cannabis plant started in the 1960s. Mechoulam was puzzled that there exist research details about the chemical analysis of plant-based drugs, including morphine, but none exists for cannabis. After an official request to the Israeli police department, a large consignment of confiscated Moroccan hashish was donated to him for research purposes. With a well-outlined methodical analysis, Mechoulam was able to isolate a few distinct compounds from the cannabis plant. 

To examine the properties of these compounds, clinical research on primates was carried using the monkey as subjects. Of all the compounds extracted, only THC was found to exert a sedating effect on the subjects—a parameter used to determine biochemical activity. As narrated by Mechoulam, he observed the effect of THC on himself and a group of friends. Effects noticed during this informal test range from euphoria to paranoia to hyperactivity. This ultimately confirmed that THC is the psychoactive component of the cannabis plant and exhibits a different level of response in users. Subsequently, in 1964, Mechoulam published a scientific paper on the isolation and complete elucidation of the structure of THC. 

• Discovery of anandamide

Mechoulam was quoted to have said, “Receptors are made for compounds that we produce, not because there is a plant out there.” This notion led to research interest in the study of endogenous cannabinoids. As reported by different accounts, Mechoulam worked on big brains supplied by a butcher in Tel Aviv. Assisted by two other scientists—Lumir Hanus and Aviva Breuer—Mechoulam and the team attempted to discover endogenous cannabinoids by working with a thin slice of pig brain and silica sand column. The team repeatedly isolated extracts of an unknown chemical structure and conducted a test on how the extracts bounds to the cannabinoid receptor. 

Cannabinoid receptors were initially discovered in 1988 by Allyn Howlett and colleagues at the Saint Louis University School of Medicine. In 1992, Mechoulam’s team isolated a few droplets of a new compound identified as arachidonoyl ethanolamide. The newly discovered compounds were evaluated by Roger Pertwee—a University of Aberdeen pharmacologist who confirmed that the new compound was indeed an endogenous cannabinoid. Subsequently, the compound was named after the Sanskrit word for bliss: “Ananda”. Reflecting on the fact that the compound was characterized as an ethanolamide, the name was officially modified to “anandamide” and became the first endogenous cannabinoid to be discovered.

• Study and description of the “entourage effect”

With the continued use of cannabis plants for different medical purposes, anecdotal reports from different users suggest that the cannabis plant by an unknown mechanism exerts a better therapeutic effect in humans when compared with isolates of THC and CBD. Mechoulam proceeded to research this claim and discovered the “entourage effect”—a proposed mechanism by which THC acts in synergy with other components of the cannabis plant to modulate biochemical effects on the cells. 

In 2011, a report published by the British Journal of Pharmacology concluded that selective breeding of cannabis chemotypes rich in phytocannabinoids offers the complementary pharmacological effect that may strengthen and improve the therapeutic index of cannabis extracts. In addition to other studies, this report confirms early observations of the entourage effect as described by Mechoulam.
  

• Discovery of a synthetic cannabinoid: cannabidiolic acid methyl ester

This is considered the most recent contribution of Raphael Mechoulam’s contribution to cannabis science. In 2019, Mechoulam was quoted to have said that “there are many things that are still unknown in the field of cannabis.” Cannabidiol acids produced by the cannabis plant were discovered to have potential health benefits. However, it was hard to study these compounds as they were relatively unstable. These cannabinoids are cannabinoid receptor agonists that are functionally similar to THC. At a medical cannabis conference in 2018, Mechoulam and a group of researchers announced that they had developed a chemical process for stabilizing cannabinoid acids. The new compounds are available for licensing to companies for drug discovery.

In addition, Mechoulam is credited for the discovery of the endocannabinoid system and the ant-epileptic properties of the cannabis plant. He has also arranged for different research studies and clinical trials investigating the anti-cancer properties of THC and other cannabinoid extracts. 

REFERENCES

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/#!po=2.10280
• https://beyondthc.com/raphael-mechoulam-gets-the-biopic-he-deserves/
• https://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids_en
• https://www.healtheuropa.eu/dr-raphael-mechoulam-revolutionary-cannabis-research/93049/
• https://patientsoutoftime.org/raphael-mechoulam-phd/
• https://www.nbsnews.com/news/amp/ncna1059116