Raphael Mechoulam
Raphael Mechoulam (, ; 5 November 1930 – 9 March 2023) was a Bulgarian-born Israeli organic chemist and a professor in the Department of Natural Materials at the School of Pharmacy in the Faculty of Medicine of the  Hebrew University of Jerusalem. Mechoulam served as Rector of the university from 1979-1982.  He was elected to the Israel Academy of Sciences and Humanities in 1994 and served as its scientific chair from 2007-2013.  He was a recipient of the Israel Prize for Chemistry Research in 2000 and the Harvey Prize for 2019-2020.

Known as "the godfather of cannabis research", Mechoulam is best known for his work (together with Y. Gaoni) in the isolation of tetrahydrocannabinol, or THC, the main active principle of cannabis. He was also successful in the isolation and identification of the endogenous cannabinoids anandamide from the brain and 2-arachidonoyl glycerol, or 2-AG, from peripheral organs.
His work has led to the discovery of the endocannabinoid system, which has effects on many important aspects of human health.

Biography
Mechoulam was born in Sofia, Bulgaria on 5 November 1930, to a Sephardic Jewish family. Both parents were well-educated: his father was a physician and head of a local hospital and his mother had studied in Berlin. He attended an "American grade school" in Sofia until the enactment of antisemitic laws and the beginning of World War II.  The school was closed.   Mechoulam's parents left Berlin, removing to a small village in the Balkans, where they hoped they would be safer. In spite of being the only doctor in the area,   Mechoulam's father was subsequently sent to a concentration camp, which he survived. After the communist takeover of hitherto pro-German Bulgaria in 1944 he studied chemical engineering, which he "disliked."

In 1949 his family immigrated to Israel where he later studied chemistry.  Mechoulam received his M.Sc. in biochemistry from the Hebrew University of Jerusalem in 1952. During his military service in the  Israeli Army from 1953-1956, he conducted research on  insecticides.

In the years 1956-1958 Mechoulam did his doctorate at the Weizmann Institute of Science, and was one of the first to be awarded a doctorate by the Weizmann Institute. The topic of his doctoral thesis was the synthesis of steroids and it was conducted under the guidance of Franz Sondheimer. From 1959-1960 he did a post-doctorate at the Rockefeller Institute in New York in research on the structure of terpenes. From 1960-1965 he worked as a researcher at the Weizmann Institute, and studied the chemistry of natural substances, including cannabinoids, terpenes, and alkaloids.

In 1966 Mechoulam joined the faculty of the Hebrew University in Jerusalem. In 1967 he received a research grant from the Institute of Mental Health in the United States to continue his research on hashish. In 1968 he was appointed an associate professor and in 1972 a full professor at Hebrew University. In 1975 he was appointed to the Lionel Jacobson chair for medicinal chemistry.

From 1979-1982 Mechoulam served as rector of the Hebrew University, and from 1983-1985 as pro-rector. In 1982 he was a visiting professor at Ohio University, in 1993-1994 he was a visiting professor in the Department of Pharmacology at the Richmond College of Medicine.  In 1994 he was elected a member of the Israel Academy of Sciences and Humanities.

Mechoulam was a founding member of the International Association for Cannabinoid Medicines (IACM) and the International Cannabinoid Research Society.
He served as president of the International Cannabinoid Research Society from 1999-2002 and Chairman of the Board of the International Association for Cannabinoid Medicines from 2003–2005.  From 2007 to 2018, he served as the chairman of the Natural Sciences Division at the Israel National Academy of Sciences.

Mechoulam died on 9 March 2023, at the age of 92.

Research
Raphael Mechoulam's major scientific interest was the chemistry and pharmacology of cannabinoids. 
In 1963 Mechoulam began working on the components of the cannabis plant, from which hashish and marijuana are produced. Although cannabis had been the most widely used illegal drug in many parts of the world for centuries, its chemistry and biology were unknown, in contrast to morphine and cocaine, the two other common illegal drugs, which had been isolated as early as the 19th century.  While some research had been done, the psychoactive components of cannabis had not been isolated in their pure form, and their chemical structure had not been explained.

With other members of his research group including Yehiel Gaoni, Mechoulam elaborated the structures and stereochemistry of the major plant cannabinoids cannabidiol (CBD, 1963) and Δ9-tetrahydrocannabinol (THC, 1964) and succeeded in their total synthesis in 1965. They also isolated, characterized and synthetized cannabigerol (CBG, 1964), and showed that it was not psychoactive. 
In 1970, Mechoulam's doctoral student Zvi Ben-Zvi reported the first isolation of an active THC metabolite in the human body.

During the 1980s, Mechoulam continued to study the active structure of the cannabinoids and began to work with clinicians on clinical trials with THC and CBD in animal models. In 1987, Mechoulam and A. Abrahamov initiated a clinical trial with Δ8-THC (a more stable isomer of Δ9-THC) in children who were undergoing chemotherapy treatments against cancer. The substance prevented nausea and vomiting and has since been used clinically against nausea and vomiting in chemotherapy patients.

In 1989, Mechoulam established the concept that THC-style activity depends on a three-dimensional stereospecific structure.  This distinction is one of the factors that has led to the discovery (by other groups) of a specific cannabinoid receptor known as CB1.

Mechoulam initiated a research project that led to the isolation of the first described endocannabinoid anandamide (N-arachidonoyl-ethanolamine, AEA) in 1992.  Anandamide, which is a fatty acid derivative, differs in its structure from the plant cannabinoid, and has the same activity profile as THC.  It was isolated and characterized by postdoctoral researchers William Devane and Lumír Ondřej Hanuš.  Another endogenous cannabinoid, 2-arachidonoylglycerol (2-AG), was discovered in 1995 by Shimon Ben-Shabat, one of his PhD students.
In 2006, Mechoulam's group identified another endocannabinoid, arachidonoyl L-serine. It is not related to the known cannabinoid receptors, but is probably an endogenous ligand of a novel cannabinoid receptor, which causes vasodilation.

In 1998,  Mechoulam and Ben-Shabat posited the “entourage effect”, the idea that a variety of metabolites working together can result in increased activity compared to individual endogenous cannabinoids.

The endocannabinoid system is a relatively new neurotransmission system, which  influences a variety of functions and systems in the human body. The discovery of the endocannabinoid system and the study of its functions in the body has helped to open a new field in biochemistry and brain research. The research in Mechoulam's laboratory, in collaboration with other groups in Israel and abroad, has helped to clarify the importance of the plant's cannabinoids and endocannabinoids in many physiological processes and has furthered research into their possible use in the treatment of pathological conditions.

Mechoulam published more than 425 scientific articles. He is listed as a co-founder of the company 180 life sciences.

Honours and awards
 2019–2020: Harvey Prize of the Technion
 2019: Doctor of Philosophy, Honoris causa, Weizmann Institute of Science
 2014: IACM Special Award, International Association for Cannabinoid Medicines (IACM)
 2012: Rothschild Prize in Chemical Sciences and Physical Sciences,
 2012: EMET Prize in Exact Sciences—Chemistry
 2011: NIDA Discovery Award
 2006: Degree Honoris causa, Complutense University of Madrid
 2003–2005: Chairman of the Board, International Association for Cannabinoid Medicines (IACM)
 2002: Honorary Member of the Israel Society for Physiology and Pharmacology
 2001: Honorary doctorate from Ohio State University
 2000: Israel Prize in Exact Sciences - Chemistry
 1999–2002: President, International Cannabinoid Research Society (ICRS)
 1994: Member of the Israel Academy of Sciences and Humanities

References

External links
 The Scientist—A documentary about the life and work of Raphael Mechoulam

1930 births
2023 deaths
Academic staff of the Hebrew University of Jerusalem
Bulgarian emigrants to Israel
Bulgarian Jews in Israel
Cannabis in Israel
Cannabis researchers
HU cannabinoids
Israel Prize in chemistry recipients
Israeli chemists
Israeli people of Bulgarian-Jewish descent
Members of the Israel Academy of Sciences and Humanities
Members of the Israel Society for Physiology and Pharmacology
Scientists from Sofia