The Discovery of the THC molecule and Raphael Mechoulam 

Brief History of Cannabis Chemistry 

Cannabis use has been documented as far back as 10,000 years at a variety of archeological sites around the world. Used for medicinal and spiritual purposes, cannabis plants are known to affect humans in numerous ways such as pain relief and euphoria inducement.  

As alchemists in apothecaries gave way to pharmaceutical chemists, their scientific investigation of medicinal plants actively pursued the discovery of natural chemical properties. One of the first was German pharmacist assistant Freidrich Serturner who isolated morphine from resinous gum of opium poppy in 1806. Another German scientist Dr. Albert Nieman successfully published his 1860 work elucidating the isolation of the alkaloid cocaine from Erythroxylum coca leaves.  

Known attempts to identify and isolate ingredients within cannabis plants are documented as early as 1840 in Europe. Experiments proved unsuccessful for many years. In 1933 British scientist R.S. Cahn came close with Cannabis indica resin experiments but published incomplete cannabinol chemical structures. Then, in 1939, Roger Adams had a breakthrough while heading a team of graduate students working on a natural products project, with permission from the U.S. government, only two years after the 1937 Marihuana Tax Act. 

Early Discovery of Cannabinoids 

In 1942, Roger Adams (left) won a patent for his method of isolating CBD and was also the first researcher to identify THC. 

Roger Adams, and his University of Illinois team, identified cannabidiol (CBD) and cannabinol (CBN) from plants. CBD was isolated, but its chemical makeup could not be immediately described, as certain technologies were not yet developed. Adams and his team did determine there were parts of the cannabis sativa plant that did not contain psychotropic qualities.  

Adams actively pursued identifying the psychoactive cannabinoid he believed to exist. In his laboratory, he synthetically created tetrahydrocannabinol (THC) molecules from other cannabinoids. Unable to isolate and identify the molecule within the cannabis plant, Adams’ name is often not attributed to this discovery.  

In 1946 British scientist Lord Alexander Todd resolved the structure of tetrahydrocannabinol (THC), the active component of cannabis, using chromatography and spectroscopy instead of the older methods of crystallization and distillation for purifying compounds as Adams used.  

 Raphael Mechoulam: Father of Cannabis Research 

Publishing the paper “Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish” in 1964, the person most associated with the discovery of THC is undoubtably Raphael Mechoulam. At the Weizmann Institute of Science in Rehovot, Israel, Dr. Raphael Mechoulam with his colleagues, Dr. Yehiel Gaoni and pharmacologist Habib Edery, succeeded in the very first isolation and elucidation of the active constituent of cannabis,  Δ 9-tetrahydrocannabinol (delta-9-THC) from Cannabis sativa L. 

Рафаэль Мешулам — Циклопедия

Mechoulam, lead scientist at the Laboratory of Natural Products, School of Pharmacy, The Hebrew University in Jerusalem, showing the stereochemistry of CBD in 1970. 

From a 2011 interview Mechoulam explains why the discovery of THC was so difficult: 

“If you look at the other illicit drugs that are throughout the world, morphine came out of opium or poppy plants, and cocaine came out of cocoa leaves – and these were discovered 150 years ago. Morphine was isolated in the early 19th century, and cocoa and cocaine in the middle 19th century. And surprisingly, THC – the active component of cannabis – was not known, which seemed very strange. 

And I know why it was not isolated: because the techniques were very complicated. See, morphine and cocaine are so-called alkaloids, namely a natural product that contains a nitrogen [atom] on the molecule, and it can give us salt; it precipitates as a salt. And so you have salt: Cocaine is a salt, morphine is a salt – very easy to prepare. It turned out that THC does not have a nitrogen, and it is present in a mixture of compounds…[others] didn’t have the techniques to isolate them in the past. So a few people tried here and there, actually some very good people – one of them [Lord Alexander Todd] got the Nobel Prize for something else. But they never succeeded in isolating the pure substance, and so they never knew whether they had one compound or many compounds, and so on.”

Mechoulam and his team used Nuclear Magnetic Resonance (NMR) in the discovery of the chemical structure of both CBD and THC. Without NMR spectroscopy development, in the 1940’s and 1950’s Mechoulam’s work may not have progressed as far as it did. 

During his life Raphael Mechoulam authored over 450 papers. In a 2018 interview, he expressed three highlights of his extensive career “The identification of THC in the 1960s, the identification of the endogenous cannabinoids in the 1990s, and our work now on the third phase of cannabinoid research – endogenous anandamide-like compounds of importance in numerous areas.” 

In the 2019 video interview, Professor Mechoulam expressed his satisfaction with his contributions to science by quoting a poem by Rainer Maria Rilke, titled “Widening Circles”: 

I live my life in widening circles 
that reach out across the world. 
I may not complete this last one 
but I give myself to it. 

“Well,” Professor Mechoulam said, “it is as if in some way he is describing what is going on with the cannabinoids. It started with a small circle, and expanded, and the expansion is going on and on and on.” 

Mechoulam accomplished this expansion and beyond based upon this sentiment from his obituary

“Beyond his scientific achievements, Raphi was known for his commitment to promoting scientific curiosity and discovery, and for his generosity in mentoring and supporting other researchers in the field, including many members of our ICRS society. His work inspired, and continues to inspire, a generation of successful cannabinoid researchers. As such, he will be not only remembered for his specific contributions to Cannabis and cannabinoid research, but also for his far-reaching impact on the scientific community and more broadly our global society.” 

Raphael Mechoulam (Hebrew: רפאל משולם , Bulgarian: Рафаел Мешулам) 

 5 November 1930 – 9 March 2023 

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Written by Dana Neverdousky, MT(ASCP) and Veronica Martinez April 2023