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THE CHEMISTRY OF CANNABINOIDS

Updated: Mar 10, 2023

Over the past century, science has made enormous strides in identifying and understanding the hundreds of chemical compounds in the cannabis plant and how they affect our physiology. And no man has done more to advance that noble cause than the internationally recognized “Father of Cannabis Research,” Israeli chemist Dr. Raphael Mechoulam.



EARLY CANNABIS RESEARCH

During the birth of modern medicine in the 19th century, scientific study of the chemical composition of cannabis began to take off.


In the 1840s, researchers like French pharmacist (and Club de Hashischin affiliate) Edmond DeCourtive began making cannabis extracts using ethanol – a concentrate he dubbed cannabin. From these kinds of extracts, chemists began identifying the molecules that would later come to be known as cannabinoids. In 1895, researchers Thomas Wood, W.T. Spivey, and Thomas Easterfield discovered and isolated the first cannabinoid, which they called cannabinol (CBN) – publishing a paper about it in the Journal of Chemical Society in 1899 (though its chemical structure wasn’t fully identified until the 1930s, by British chemist Robert S. Cahn).


The scientists who first discovered and studied cannabinoids.
The scientists who first discovered and studied cannabinoids.

Unfortunately, the enactment of America’s Marihuana Tax Act of 1937 stymied cannabis research for decades, with one notable exception: A Harvard-trained chemist named Roger Adams, who, in 1939, was actually tasked by the newly-formed Bureau of Narcotics with exploring the plant’s composition. In 1940, using the wild Minnesota hemp supplied by the Bureau, he became the first person to identify, isolate and synthesize cannabidiol, or CBD (the method for which he was awarded a patent). Adams – who published 27 studies on cannabis in the American Journal of Chemistry throughout the 1940s – also synthesized CBN and even identified tetrahydrocannabinol (THC), though he lacked the technology or technique to isolate it.



It would be 20 years before another scientist would grab Adams’ academic baton and run with it: That scientist was Dr. Raphael Mechoulam.


Father of cannabis research, Dr. Raphael Mechoulam.

FROM REFUGEE TO RESEARCHER

Born in Bulgaria in 1930, Raphael Mechoulam was the son of an upper-middle-class Sephardic Jewish couple. His father was a physician and head of the Jewish hospital in their town of Sofia. At the start of World War II, the family was forced to flee and move from village to village to escape the Nazis (his father later spent time in a concentration camp but survived).


Mechoulam originally studied chemical engineering but later switched to chemistry after his family emigrated to Israel in 1949. There, he got his first experience with scientific research when he studied insecticides during his stint in the Israeli Defense Forces (IDF).


“I first tasted the sweet taste of research in the Army,” Mechoulam told Tablet magazine in 2016. “I found the independence of research to be an addiction from which I do not want to be cured.”

After his service, Mechoulam earned a Master of Science in biochemistry from the Hebrew University of Jerusalem (1952), followed by a Ph.D. from the Weizmann Institute in Rehovot (near Tel Aviv) and postdoctoral studies at the Rockefeller Institute in New York before returning to Israel to begin what would become his life’s work—the exploration of cannabis chemistry.



CANNABIS CURIOSITY

“I realized the scarce chemical knowledge about the compounds in cannabis. I found it very surprising: While morphine had been isolated from opium and cocaine from the coca leaf, no one had studied the chemistry of the marijuana plant. It was very odd.”


“I realized the scarce chemical knowledge about the compounds in cannabis. I found it very surprising: While morphine had been isolated from opium and cocaine from the coca leaf, no one had studied the chemistry of the marijuana plant. It was very odd.”

Due to prohibition, academics couldn’t get research grants involving cannabis and even feared prosecution for studying it. Luckily, that didn’t deter Mechoulam – despite the fact that cannabis was illegal in Israel, he came up with an idea on how to get some. In 1962, he asked the director at the Weizmann Institute – where he was working as a junior faculty member – if he knew of any police who could supply hashish for research. As it turned out, the head of investigations at the national police happened to be one of the director’s old army buddies … and after vouching for the young scientist, the officer agreed.


Mechoulam hopped on a bus to a police station in Tel Aviv, where he was given five kilos of Moroccan hashish that had been intercepted while being smuggled in from Lebanon. He thanked the officers, put the hash in his bag, and got back on the bus. Of course, his parcel made for an interesting bus ride home, as he amusedly recalls in the award-winning 2015 documentary about him, The Scientist: “People on the bus after 15, 20 minutes started asking, ‘What the hell is this very unusual smell?’”


Soon after, Mechoulam and the police learned that any requests for illegal substances required a permit from the Ministry of Health and that their transaction could actually land them all in prison. Nevertheless, after apologies were made, the matter was forgiven and Mechoulam continued to obtain hashish from the police (with a permit) for decades thereafter.

CBD, THC & THE NIH

After procuring the hash, the next step was to secure some funding. Mechoulam applied for a research grant from the National Institutes of Health in America but was rejected out of hand.


“They told me, ‘It’s not relevant. Nobody smokes marijuana in the U.S. – people do it in Mexico,’” he recalls.


Dr. Mechoulam & colleague Dr. Gaoni examining some data.
Dr. Mechoulam & colleague Dr. Gaoni examining some data.

Nevertheless, Mechoulam and his colleagues (Dr. Yehiel Gaoni and Dr. Haviv Edery) began their in-depth study of the hash’s various compounds and cannabinoids (a term which Mechoulam coined). First, in 1963, they isolated CBD and mapped its molecular structure. Then, the following year, using a nuclear magnetic resonance spectrometer, they were able for the first time to isolate and map the structure of delta-9-tetrahydrocannabinol, better known as THC – which, as their experimentation on monkeys soon revealed, was the only compound that produced a psychoactive effect.


Illustration of Mechoulam observing the various reactions of his guests after eating THC-laced cake
Illustration of Mechoulam observing and recording the various reactions of his guests after eating THC-laced cake (from the documentary film "The Scientist").

To be sure, though, they’d need to test it on humans. So Mechoulam took a bunch of pure THC powder home and invited a group of friends over for cake – dosing some of the slices with 10 mg of THC. While the effects on each individual differed, there was little doubt that they’d identified the correct compound.

On April 1, 1964, they revealed their findings in a paper entitled “Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish,” published in the Journal of the American Chemical Society. After that, the NIH was suddenly very interested in their “irrelevant” research – sending representatives to Israel to meet with them.


“To the world’s surprise, they [NIH] came over to see our work," Mechoulam recounts. “We had 10 grams of THC isolated from hashish, so they took it back with them, and most of the initial research in the US was done with our THC.”


According to Mechoulam, there was also a more personal reason behind the unexpected reversal regarding their research, though. As he told High Times in 2011:


“I get a phone call from the head of pharmacology at NIH, and they’re now interested. So I asked him: “What happened, all of a sudden, that you have great interest?” Well, it turned out that a senator had called NIH – his son smoked pot, and he wanted to know whether it would destroy his mind! And just like that, the government got NIH to change direction. They don’t want to fight the senators because they need their support, and they looked around and [said] “Aha!” – they don’t support grants on marijuana, so they asked me if I was still working. We had just isolated THC, and that was it."


THE ENDOCANNABINOID SYSTEM

& THE ENTOURAGE EFFECT

In the decades that followed, Mechoulam and his team at the Hebrew University of Jerusalem continued to make groundbreaking discoveries about cannabis – identifying and synthesizing over 100 compounds, including cannabinoids like cannabigerol (CBG) and cannabichromene (CBC), as well as Delta 8 and Delta 10 THC.


In the early 1980s, they conducted the first experiments with CBD oil for epilepsy. In the mid-‘80s, their research led to the discovery of two cannabinoid receptors in the human body (dubbed CB1 and CB2) by St. Louis University School of Medicine neuroscientist Dr. Allyn Howlett … which, in turn, led to their discovery of the first endocannabinoid (a cannabinoid-like chemical produced internally by the human body) in December 1992 —a compound which they named anandamide (aka the “bliss molecule”).


“Basically, if you have a receptor in the body, it’s not because there is a plant out there—it doesn’t work that way,” Mechoulam explains. “It works only because there is something in your body which will activate that receptor. So we went after those compounds that activated it, and we found the compound in the brain that activated it: anandamide.”


Raphael Mechoulam
Photo by Madison Margolin

These discoveries eventually led to the most game-changing revelation of all — the realization that those receptors were part of a complex, pervasive, and previously unknown biological network within human anatomy that Mechoulam’s team aptly named the endocannabinoid system. Ostensibly the missing link between the body and the mind, the endocannabinoid system is believed to be responsible for maintaining homeostasis (regulating the stability of all of the body’s other systems).


“The endocannabinoid system is very important,” Mechoulam told Vice. “Almost all illnesses we have are linked to it in some way or another. And that is very strange. We don’t have many systems which get involved with every illness.”

Based on his research, Mechoulam was also the first to propose the concept of the so-called “entourage effect” (also referred to as the “ensemble effect”) in 1998. This is the hypothesis that, when it comes to the various active compounds in cannabis, the whole is greater than the sum of its parts—that is, that the combination of various cannabinoids and terpenes act synergistically to provide benefits they wouldn’t necessarily provide in isolation.

FOUNDATION FOR THE FUTURE

Thanks to the work of Mechoulam and his team, Israel has become the global leader in medical cannabis research. In the early 1990s, the Israel Ministry of Health began offering medical marijuana to patients suffering from certain debilitating ailments. And in 2004, they launched an experimental program to study the effectiveness of cannabis on veterans suffering from PTSD.


Speaking at a medical Cannabis conference in Israel in 2018.
Speaking at a medical cannabis conference in Israel in 2018.

Dr. Mechoulam has now published nearly 400 scientific articles and has been awarded several honorary degrees. He’s a member of the Israel Academy of Sciences and Humanities and a founding member of both the International Cannabinoid Research Society and the International Association for Cannabinoid Medicines. He’s been nominated for over 25 academic awards, several of which he won – including the esteemed Israel Prize and Harvey Prize in 2020, as well as two lifetime achievement awards: from the European College of Neuropsychopharmacology (2005) and from CannMed (2016). There’s even talk that he’s destined to win the Nobel Prize.


Still, the legacy that the now 92-year-old “father of cannabis research” seems most concerned with is ensuring that cannabis is fully accepted and integrated into traditional Western medicine.



“I have spent the better part of my life decoding the mysteries that lie within this incredible plant,” Mechoulam has said. “I believe that cannabinoids represent a medicinal treasure trove which waits to be discovered.”



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