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Raphael Mechoulam

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Raphael Mechoulam
רפאל משולם
Born(1930-11-05)5 November 1930[1]
Sofia, Bulgaria
Died9 March 2023(2023-03-09) (aged 92)
Jerusalem
NationalityIsraeli
CitizenshipIsrael
Known forTotal synthesis of tetrahydrocannabinol, major contributions to the chemistry of cannabinoids and discovery of endocannabinoids
AwardsHarvey Prize (2019)

Israel Prize (2000)
EMET Prize (2012)
Rothschild Prize (2012)
Heinrich Wieland Prize (2004)

NIDA Discovery Award (2011)
Scientific career
FieldsMedicinal Chemistry, Natural Products
InstitutionsWeizmann Institute of Science, Rockefeller University, Hebrew University of Jerusalem
Doctoral advisorProf. Franz Sondheimer

Raphael Mechoulam[a] (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[2][3] and served as its scientific chair from 2007-2013.[4] He was a recipient of the Israel Prize for Chemistry Research in 2000 and the Harvey Prize for 2019-2020.[5]

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.[1][6][7] 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.[8] His work has led to the discovery of the endocannabinoid system, which has effects on many important aspects of human health.[5][9]

Biography

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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.[7] 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.[7][10][1] After the communist takeover of hitherto pro-German Bulgaria in 1944 he studied chemical engineering, which he "disliked."[11]

In 1949 his family immigrated to Israel where he later studied chemistry.[11] 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 to 1956, he conducted research on insecticides.[8]

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 to 1960, he did a post-doctorate at the Rockefeller Institute in New York in research on the structure of terpenes. From 1960 to 1965, he worked as a researcher at the Weizmann Institute, and studied the chemistry of natural substances, including cannabinoids, terpenes, and alkaloids.[12]

In 1966, Mechoulam joined the faculty of the Hebrew University in Jerusalem.[1] In 1967, he received a research grant from the Institute of Mental Health in the United States to continue his research on hashish.[13][14] In 1968, he was appointed an associate professor,[3] and in 1972, a full professor, at Hebrew University.[12] In 1975 he was appointed to the Lionel Jacobson chair for medicinal chemistry.[3]

From 1979 to 1982, Mechoulam served as rector of the Hebrew University, and from 1983 to 1985 as pro-rector.[12][15] In 1982, he was a visiting professor at Ohio University, and in 1993–1994 he was a visiting professor in the Department of Pharmacology at the Richmond College of Medicine.[3] In 1994, he was elected a member of the Israel Academy of Sciences and Humanities.[2][3]

Mechoulam was a founding member of the International Association for Cannabinoid Medicines (IACM) and the International Cannabinoid Research Society.[16] He served as president of the International Cannabinoid Research Society from (1999–2002)[17] and Chairman of the Board of the International Association for Cannabinoid Medicines (2003–2005).[18] From 2007 to 2018, he served as the chairman of the Natural Sciences Division at the Israel National Academy of Sciences.[4]

Mechoulam died on 9 March 2023, at the age of 92.[16][19][20]

Research

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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.[21][22]

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.[21] They also isolated, characterized and synthetized cannabigerol (CBG, 1964), and showed that it was not psychoactive.[23] In 1970, Mechoulam's doctoral student Zvi Ben-Zvi reported the first isolation of an active THC metabolite in the human body.[24]

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.[25] 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.[26][25]

In 1989, Mechoulam established the concept that THC-style activity depends on a three-dimensional stereospecific structure.[27] This distinction is one of the factors that has led to the discovery (by other groups) of a specific cannabinoid receptor known as CB1.[28]

Mechoulam initiated a research project that led to the isolation of the first described endocannabinoid anandamide (N-arachidonoyl-ethanolamine, AEA) in 1992.[21][7] Anandamide, which is a fatty acid derivative, differs in its structure from the plant cannabinoid, and has the same activity profile as THC.[29] It was isolated and characterized by postdoctoral researchers William Devane and Lumír Ondřej Hanuš.[21][7][30] Another endogenous cannabinoid, 2-arachidonoylglycerol (2-AG), was discovered in 1995 by Shimon Ben-Shabat, one of his PhD students.[31][28] 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.[32]

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.[33][34]

The endocannabinoid system is a relatively newly discovered 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.[5][9][35][34]

Mechoulam published more than 425 scientific articles.[36] He is listed as a co-founder of the company 180 life sciences.[37]

Honours and awards

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See also

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Notes

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  1. ^ Hebrew: רפאל משולם, Bulgarian: Рафаел Мешулам

References

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  1. ^ a b c d Williams, Alex (March 22, 2023). "Raphael Mechoulam, 'Father of Cannabis Research,' Dies at 92". The New York Times.
  2. ^ a b c d "Hebrew University Prof. Raphael Mechoulam "Father of Cannabis Research" Dies at 92". American Friends of the Hebrew University. 10 March 2023. Retrieved 2 May 2023.
  3. ^ a b c d e f "Professor Raphael Mechoulam" (PDF). The Israel Academy of Sciences and Humanities. Retrieved 3 May 2023.
  4. ^ a b "Chairpersons, The Sciences". The Israel Academy of Sciences and Humanities. Retrieved 3 May 2023.
  5. ^ a b c d e "The Harvey Prize will be awarded this year for discovering the active molecules in the cannabis plant to Prof. Rafael Meshulam". Hebrew University of Jersulaem. 2020. Retrieved 2 May 2023.
  6. ^ Maccarrone, M (5 January 2022). "Tribute to Professor Raphael Mechoulam, The Founder of Cannabinoid and Endocannabinoid Research". Molecules (Basel, Switzerland). 27 (1): 323. doi:10.3390/molecules27010323. PMC 8746417. PMID 35011553.
  7. ^ a b c d e Mechoulam, Raphael (2023-01-20). "A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology". Annual Review of Pharmacology and Toxicology. 63 (1): 1–13. doi:10.1146/annurev-pharmtox-051921-083709. ISSN 0362-1642. PMID 35850522. S2CID 250642163.
  8. ^ a b Pertwee, RG (16 October 2020). "The 90th Birthday of Professor Raphael Mechoulam, a Top Cannabinoid Scientist and Pioneer". International Journal of Molecular Sciences. 21 (20): 7653. doi:10.3390/ijms21207653. PMC 7593926. PMID 33081122.
  9. ^ a b Alger, BE (November 2013). "Getting high on the endocannabinoid system". Cerebrum: The Dana Forum on Brain Science. 2013: 14. PMC 3997295. PMID 24765232.
  10. ^ Gerald, Eddie (May 3, 2023). "Raphael Mechoulam obituary". The Times. Retrieved 3 May 2023.
  11. ^ a b Mechoulam, R. (2007), "Conversation with Raphael Mechoulam", Addiction, 102 (6), Wiley: 887–893, doi:10.1111/j.1360-0443.2007.01795.x, PMID 17523982
  12. ^ a b c Crowther, S M; Reynolds, L A; Tansey, E M (2010). The medicalization of cannabis : the transcript of a Witness Seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 24 March 2009 (PDF). Wellcome Witnesses to Twentieth Century Medicine. Vol. 40. London: Wellcome Trust Centre for the History of Medicine at UCL. p. 92. ISBN 9780854841295.
  13. ^ Mechoulam, R; Ben-Zvi, Z; Gaoni, Y (August 1968). "Hashish--13. On the nature of the Beam test". Tetrahedron. 24 (16): 5615–24. doi:10.1016/0040-4020(68)88159-1. PMID 5732891.
  14. ^ Jorisch, Avi (June 19, 2018). "A higher calling: How Israeli marijuana research changed the world". The Jerusalem Post. Retrieved 3 May 2023.
  15. ^ Siegel-Itzkovich, Judy (March 11, 2023). "Prof. Raphael Mechoulam, father of Israeli cannabis research, dies at 92". The Jerusalem Post. Retrieved 3 May 2023.
  16. ^ a b Silow-Carroll, Andrew (11 March 2023). "Raphael Mechoulam, Israel's 'father of cannabis research,' dies at 92: Esteemed scientist led pioneering research into psychoactive substance, with findings that helped ease its shift out of counterculture and into the mainstream". The Times of Israel. Retrieved 14 March 2023.
  17. ^ a b "'Father of cannabis research': Prof. Raphael Mechoulam dies at 92". Israel National News. 12 March 2023. Retrieved 3 May 2023.
  18. ^ a b c Grotenhermen, F; Müller-Vahl, KR (April 2021). "Two Decades of the International Association for Cannabinoid Medicines: 20 Years of Supporting Research and Activities Toward the Medicinal Use of Cannabis and Cannabinoids". Cannabis and Cannabinoid Research. 6 (2): 82–87. doi:10.1089/can.2020.0044. PMC 8064956. PMID 33912675.
  19. ^ Cermak, Timmen L. (13 March 2023). "Raphael Mechoulam, Father of Cannabis Research, Dead at 92: Gratitude for the man and the researcher". Psychology Today. Retrieved 14 March 2023.
  20. ^ Scopel, Joana (10 March 2023). "Renowned Scientist And Father Of THC Dr. Raphael Mechoulam Dies At 92". Benzinga. Retrieved 10 March 2023.
  21. ^ a b c d Pertwee, RG (January 2006). "Cannabinoid pharmacology: the first 66 years". British Journal of Pharmacology. 147 (Suppl 1): S163-71. doi:10.1038/sj.bjp.0706406. PMC 1760722. PMID 16402100.
  22. ^ Appendino, Giovanni (1 December 2020). "The early history of cannabinoid research". Rendiconti Lincei. Scienze Fisiche e Naturali. 31 (4): 919–929. doi:10.1007/s12210-020-00956-0. ISSN 1720-0776. S2CID 222179431.
  23. ^ Navarro, G; Varani, K; Reyes-Resina, I; Sánchez de Medina, V; Rivas-Santisteban, R; Sánchez-Carnerero Callado, C; Vincenzi, F; Casano, S; Ferreiro-Vera, C; Canela, EI; Borea, PA; Nadal, X; Franco, R (2018). "Cannabigerol Action at Cannabinoid CB(1) and CB(2) Receptors and at CB(1)-CB(2) Heteroreceptor Complexes". Frontiers in Pharmacology. 9: 632. doi:10.3389/fphar.2018.00632. PMC 6021502. PMID 29977202.
  24. ^ Ben-Zvi, Zvi; Mechoulam, Raphael; Burstein, Sumner (June 1970). "Identification through synthesis of an active .DELTA.1(6)-tetrahydrocannabinol metabolite". Journal of the American Chemical Society. 92 (11): 3468–3469. doi:10.1021/ja00714a043. ISSN 0002-7863. PMID 4987240.
  25. ^ a b Jones, Nicola (31 January 2023). "Scientific highs and lows of cannabinoids". Knowable Magazine. doi:10.1146/knowable-013123-1. Retrieved 3 May 2023.
  26. ^ Parker, LA; Rock, EM; Limebeer, CL (August 2011). "Regulation of nausea and vomiting by cannabinoids". British Journal of Pharmacology. 163 (7): 1411–22. doi:10.1111/j.1476-5381.2010.01176.x. PMC 3165951. PMID 21175589.
  27. ^ Mechoulam, R; Feigenbaum, JJ; Lander, N; Segal, M; Järbe, TU; Hiltunen, AJ; Consroe, P (15 September 1988). "Enantiomeric cannabinoids: stereospecificity of psychotropic activity". Experientia. 44 (9): 762–4. doi:10.1007/BF01959156. PMID 3416993. S2CID 19589995.
  28. ^ a b Marzo, Vincenzo Di (29 June 2004). Cannabinoids. Springer Science & Business Media. ISBN 978-0-306-48228-1.
  29. ^ Scherma, M; Masia, P; Satta, V; Fratta, W; Fadda, P; Tanda, G (March 2019). "Brain activity of anandamide: a rewarding bliss?". Acta Pharmacologica Sinica. 40 (3): 309–323. doi:10.1038/s41401-018-0075-x. PMC 6460372. PMID 30050084.
  30. ^ Solomon, Shoshanna (15 October 2018). "Israeli lab set up to give clinical validation to cannabis research". The Times of Israel. Retrieved 2 May 2023.
  31. ^ Justinová, Zuzana; Yasar, Sevil; Redhi, Godfrey H.; Goldberg, Steven R. (11 May 2011). "The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys". Journal of Neuroscience. 31 (19): 7043–7048. doi:10.1523/JNEUROSCI.6058-10.2011. ISSN 0270-6474. PMC 3123903. PMID 21562266. Retrieved 2 May 2023.
  32. ^ Guo, Juan; Williams, Damian J.; Ikeda, Stephen R. (August 2008). "N -Arachidonoyl l -Serine, a Putative Endocannabinoid, Alters the Activation of N-Type Ca 2+ Channels in Sympathetic Neurons". Journal of Neurophysiology. 100 (2): 1147–1151. doi:10.1152/jn.01204.2007. PMC 2652135. PMID 18234973.
  33. ^ Russo, Ethan B. (2019). "The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain". Frontiers in Plant Science. 9: 1969. doi:10.3389/fpls.2018.01969. ISSN 1664-462X. PMC 6334252. PMID 30687364.
  34. ^ a b Ferber, SG; Namdar, D; Hen-Shoval, D; Eger, G; Koltai, H; Shoval, G; Shbiro, L; Weller, A (2020). "The "Entourage Effect": Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders". Current Neuropharmacology. 18 (2): 87–96. doi:10.2174/1570159X17666190903103923. PMC 7324885. PMID 31481004.
  35. ^ Zou, S; Kumar, U (13 March 2018). "Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System". International Journal of Molecular Sciences. 19 (3): 833. doi:10.3390/ijms19030833. PMC 5877694. PMID 29533978.
  36. ^ "User profiles for author:Raphael author:Mechoulam". Google Scholar. Retrieved 2 May 2023.
  37. ^ DelMonico, Kim (June 28, 2021). "New Drug Family Targets Dupuytren's, Frozen Shoulder | Orthopedics This Week". RRY Publications. Retrieved 2 May 2023.
  38. ^ "Technion Harvey Prize Honors Pioneers in Chemical Engineering and Medical Sciences". www.newswise.com. Retrieved 3 May 2023.
  39. ^ "Ph.D. Honoris Causa | Academic Affairs Office". Weizmann Institute of Science. Retrieved 4 May 2023.
  40. ^ "Raphael Mechoulam". International Alliance for Cannabinoid Medicines. Retrieved 4 May 2023.
  41. ^ "The Rothschild Prize". Yad Hanadiv. Retrieved 4 May 2023. Search for MECHOULAM
  42. ^ Denman, Michael (2007). "MECHOULAM, RAPHAEL". Encyclopaedia Judaica. Vol. 13 (2nd ed.). Thomson Gale. pp. 711–712.
  43. ^ "Raphael Mechoulam Faculty of Medicine". Complutense University of Madrid. Retrieved 4 May 2023.
  44. ^ Wingard, Shannon (August 21, 2001). "Six honored at SU commencement". Ohio State News. Retrieved 3 May 2023.
[edit]
  • The Scientist—A documentary about the life and work of Raphael Mechoulam
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