Four decades after isolating THC, the founder of cannabinoid chemistry looked back on his field and argued that most cannabis compounds remained a neglected pharmacological treasure trove.
Anyone who wants to understand why cannabis science matters, told by the person who started it all.
~100 cannabinoidsidentified in cannabis by 2005 — most never pharmacologically evaluated
The Backstory
Jerusalem, 2005. Raphael Mechoulam is 75 years old and still working in the same lab at Hebrew University where he identified THC four decades earlier. The field he started with a two-page chemistry paper now spans thousands of laboratories across six continents. Two cannabinoid receptors have been cloned. Two endocannabinoids discovered. An entire biological system — the endocannabinoid system — has been mapped.
And yet, looking at the cannabis plant itself, Mechoulam sees something that troubles him. Of the roughly 100 cannabinoids identified in Cannabis sativa, the vast majority have never been properly studied. The plant that launched an entire field of neuroscience remains, in pharmacological terms, mostly unexplored.
He calls it a neglected treasure trove.
The Arc of a Field
To understand what Mechoulam was looking back on in 2005, you need to see the trajectory. In 1964, cannabis science didn't exist. By 2005, it had become one of the most active areas in pharmacology — but the path between those two points was anything but smooth.
Research Timeline
One Lab, One Career, One Field
Mechoulam & Gaoni isolate THC
The active molecule in cannabis is finally identified — a two-page paper in JACS that launches an entire scientific discipline
Total synthesis of THC and CBD
Mechoulam's lab creates both molecules from scratch, confirming their structures beyond doubt
CBD shown to reduce epileptic seizures
Cunha, Carlini & Mechoulam demonstrate CBD's anticonvulsant properties in a Brazilian trial. The finding is ignored for 37 years.
Allyn Howlett discovers THC binds specific receptors
Cannabis doesn't work by dissolving into cell membranes — there's a lock for this key
CB1 receptor cloned
The brain's cannabinoid receptor is identified at the genetic level. It turns out to be one of the most abundant receptors in the brain.
Anandamide discovered
Mechoulam's lab finds the brain's own THC — an endogenous cannabinoid named from the Sanskrit word for bliss
CB2 receptor cloned
A second cannabinoid receptor found, primarily in immune cells — the system is bigger than anyone thought
2-AG discovered
The second major endocannabinoid, 170x more abundant than anandamide. The ECS is now a full signaling system.
Entourage effect described
Mechoulam's lab shows that inactive compounds can enhance endocannabinoid activity
Mechoulam publishes 'Neglected Treasure Trove'
After 41 years: ~100 cannabinoids identified, most never studied. THCV shown to block CB1 — the opposite of THC.
FDA approves Epidiolex
The first cannabis-derived drug approved by the FDA — for the epilepsy indication Mechoulam's lab demonstrated in 1980
Mechoulam dies at 92, still working
Nearly 60 years of continuous cannabis research. He never used the substance he spent his life studying.
Multiple sources; Mechoulam (2005), Br J Pharmacol 146:913-915
The timeline reveals something remarkable: one lab in Jerusalem generated a disproportionate share of the field's foundational discoveries. THC isolation. Anandamide. 2-AG. The entourage effect. CBD's anticonvulsant properties. It's difficult to find a parallel in modern pharmacology — one scientist initiating an entire discipline and remaining at its center for six decades.
The Neglected Treasure Trove
The 2005 commentary's central argument was simple and devastating: cannabis contains roughly 100 identified cannabinoids, and the scientific community had only seriously investigated two of them.
~100
cannabinoids identified in Cannabis sativa by 2005 — of which only THC and CBD had been systematically studied for pharmacological activity. The remaining compounds represented what Mechoulam called a 'neglected pharmacological treasure trove.'
For comparison, the opium poppy contains roughly 80 alkaloids, and pharmaceutical development has explored dozens of them. Cannabis, despite being one of the oldest and most widely used medicinal plants, had received a fraction of that attention.
Mechoulam (2005), Br J Pharmacol 146:913-915
To prove his point, Mechoulam highlighted new research published in the same issue of the British Journal of Pharmacology: delta-9-tetrahydrocannabivarin (THCV), a minor cannabinoid that had been sitting in the plant all along, turned out to be a potent antagonist of the CB1 receptor. That meant a cannabis compound could block the same receptor that THC activates. If nobody had bothered to test it, nobody would have known.
How many other surprises were hiding in the unstudied 98?
The Frustration
The gap between Mechoulam's science and its clinical application haunted him. In 1980, his collaborators in Brazil — Cunha, Carlini, and colleagues — published a controlled trial showing CBD reduced seizures in epilepsy patients. The results were clear. Nobody followed up.
For 25 years.
It wasn't that the science was wrong — it was eventually vindicated by the Devinsky trials and the FDA's approval of Epidiolex in 2018. The problem was political. Cannabis was Schedule I in the United States — classified alongside heroin as having "no accepted medical use and a high potential for abuse." Researchers who wanted to study it needed DEA licenses, NIDA-approved cannabis supply (from a single farm at the University of Mississippi), and multiple layers of bureaucratic approval that existed for no other drug class.
The pharmaceutical industry, meanwhile, showed almost no interest. Cannabis couldn't be patented. Its components were difficult to formulate. Its association with recreational use made corporate boards nervous. For decades, the world's most promising source of novel pharmacology was essentially off-limits to the institutions best equipped to develop it.
“We have just scratched the surface. The endocannabinoid system is involved in essentially all human diseases.”
— Raphael Mechoulam
Hebrew University of Jerusalem
Reflecting on 41 years of cannabinoid research, 2005
This wasn't hyperbole. By 2005, the endocannabinoid system had been implicated in pain modulation, appetite regulation, immune function, mood disorders, neurodegeneration, cardiovascular health, bone metabolism, and reproductive biology. It was present in every vertebrate animal studied. Yet the number of approved drugs targeting it could be counted on one hand.
What He Predicted
Mechoulam's "neglected treasure trove" argument proved prophetic on nearly every count.
Evidence Matrix
Mechoulam's Predictions vs. What Happened
| Study | Design | N | Finding | |
|---|---|---|---|---|
| ↑ | THCV(2005) | Prediction | — | Highlighted as a potent CB1 antagonist deserving serious pharmacological investigation |
| ↑ | THCV(2020) | Outcome | — | Now commercially available in consumer products. Clinical trials for metabolic disorders. Research confirms appetite-suppressing and energizing properties. |
| ↔ | CBD(2005) | Prediction | — | Anti-epileptic potential known since 1980 but no approved drug existed |
| ↑ | CBD(2018) | Outcome | — | FDA approves Epidiolex for Dravet and Lennox-Gastaut syndromes — 38 years after Mechoulam's lab demonstrated the effect |
| ○ | CBG/CBN/CBC(2005) | Prediction | — | Essentially unstudied minor cannabinoids with unknown potential |
| ↑ | CBG/CBN/CBC(2023) | Outcome | — | Active research programs in antibacterial (CBG), sleep (CBN), and anti-inflammatory (CBC) applications. Consumer products already on market. |
Multiple sources
The compound Mechoulam specifically highlighted — THCV — turned out to have a unique pharmacological profile. At low doses it blocks CB1 (potentially useful for appetite suppression and metabolic disorders). At higher doses it can activate CB1. This biphasic behavior would have been impossible to predict without testing — exactly Mechoulam's point about why the unstudied cannabinoids needed attention.
The Man
Myth vs. Reality
Mechoulam was a cannabis advocate who wanted the drug legalized.
Mechoulam was a chemist and pharmacologist who never used cannabis and never campaigned for legalization. He wanted the compounds studied scientifically and, where evidence supported it, developed into medicines. He was frustrated not by prohibition per se but by the way prohibition prevented research.
The Evidence
In interviews throughout his career, Mechoulam consistently described himself as a scientist, not an advocate. He supported medical cannabis research but did not take public positions on recreational legalization. His famous quote — 'an addiction from which I did not want to be cured' — referred to his research, not to cannabis.
Multiple interviews; Mechoulam obituaries (2023)
What makes the 2005 retrospective compelling isn't just the science — it's the voice. This was a man who had spent 41 years producing discoveries that governments, pharmaceutical companies, and medical institutions had largely ignored. He watched families move across state lines to access a compound his lab had shown was anticonvulsant in 1980. He watched the pharmaceutical industry develop drugs for every receptor system except the one he helped discover.
“Who cared about our findings? No one! Did we have to wait 30 years? We could have helped thousands of children, and we didn't!”
— Raphael Mechoulam
On the decades-long delay between his CBD epilepsy research and the approval of Epidiolex
He never stopped working. In his 80s, he was investigating cannabidiolic acid methyl ester for nausea and anxiety. In his early 90s, he was still publishing. He died on March 9, 2023, at age 92, in Jerusalem — the city where he had arrived as a young immigrant in 1949 and where he would spend the next seven decades quietly building one of the most consequential research programs in modern pharmacology.
He described his life's work as "an addiction from which he did not want to be cured."
The Treasure Trove Today
Twenty years after Mechoulam's commentary, the treasure trove is finally being opened — though unevenly. CBD has become a multibillion-dollar industry. THCV, CBG, CBN, and CBC are finding their way into consumer products and clinical pipelines. The endocannabinoid system is now a target for drug development in dozens of disease areas.
But Mechoulam's core criticism still applies. Of the ~100 plant cannabinoids, the vast majority remain poorly characterized. Most consumer products contain only THC and CBD. The systematic pharmacological investigation Mechoulam called for in 2005 is still incomplete.
The neglected treasure trove is less neglected than it was. But it's far from fully explored.
Related Research
Mechoulam's Legacy in the Research Record
The studies that trace directly to Mechoulam's work — and the ones he was reflecting on when he wrote this retrospective.
Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish
Gaoni & Mechoulam (1964)
Where it all started. Two pages. 2,200+ citations. Every cannabis product on earth traces back to this structural identification.
Isolation and structure of a brain constituent that binds to the cannabinoid receptor
Devane, Hanus & Mechoulam (1992)
The discovery of anandamide — the brain's own THC. Mechoulam's second landmark paper, 28 years after the first.
A second endogenous cannabinoid that modulates long-term potentiation
Stella, Schweitzer & Piomelli (1997)
2-AG — the second endocannabinoid, 170x more abundant than anandamide. Confirmed the ECS was a full signaling system.
Chronic administration of cannabidiol to healthy volunteers and epileptic patients
Cunha, Carlini & Mechoulam (1980)
The CBD epilepsy trial that was ignored for 37 years — Mechoulam's deepest frustration.
An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-AG cannabinoid activity
Ben-Shabat, Mechoulam et al. (1998)
The original entourage effect — showing that inactive compounds modify endocannabinoid activity.
Who was Raphael Mechoulam?
Raphael Mechoulam (1930-2023) was a Bulgarian-born Israeli chemist who isolated THC in 1964, co-discovered anandamide (the brain's own THC) in 1992, and spent over 50 years at Hebrew University of Jerusalem building the field of cannabinoid science. He published more than 400 papers and is widely considered the father of cannabis research. He never used cannabis himself.
What did Mechoulam mean by 'neglected pharmacological treasure trove'?
Cannabis contains roughly 100 identified cannabinoids beyond the well-known THC and CBD. By 2005, the vast majority had never been systematically tested for pharmacological activity. Mechoulam argued this represented an enormous untapped resource for drug discovery — compounds with potentially valuable properties that nobody had bothered to investigate.
What is THCV and why is it significant?
Delta-9-tetrahydrocannabivarin (THCV) is a minor cannabinoid that Mechoulam highlighted in his 2005 commentary. Unlike THC, which activates the CB1 receptor, THCV acts as a CB1 antagonist at certain doses — it blocks the receptor. This was a striking example of Mechoulam's argument: a compound sitting in the plant for millennia with pharmacological properties nobody knew about until someone finally tested it.
Why was cannabis research so difficult for so long?
In the United States, cannabis's Schedule I classification (alongside heroin) created extraordinary barriers. Researchers needed DEA licenses, had to source cannabis from a single government-approved farm, and faced multiple layers of bureaucratic review that applied to no other drug. The pharmaceutical industry avoided cannabis because the compounds couldn't be easily patented and the association with recreational use made corporate boards nervous. These barriers persisted for decades despite mounting scientific evidence of therapeutic potential.
What the researchers found
Writing four decades after isolating THC, Raphael Mechoulam argued that most of the ~100 cannabinoids identified in Cannabis sativa had never been properly evaluated pharmacologically. He highlighted new research showing THCV acts as a potent CB1 antagonist — meaning a cannabis compound blocks the same receptor that THC activates — and predicted that systematic investigation of the remaining plant cannabinoids would yield significant biological and therapeutic discoveries.
Why it matters
This was the founder of cannabinoid chemistry arguing that the field he created had barely scratched the surface. After 40 years of research, most cannabis compounds remained unstudied. The commentary served as both a retrospective on a remarkable career and a call to action for the next generation of researchers.
The numbers in context
~100 cannabinoids identified in cannabis, most never pharmacologically evaluated
400+ publications over Mechoulam's career
41 years since THC isolation (1964-2005)
Only 2 FDA-approved cannabinoid drugs by 2005 (dronabinol, nabilone)
25 years since Mechoulam's lab showed CBD was anticonvulsant (1980)
How the study worked
Commentary/editorial by Raphael Mechoulam in the British Journal of Pharmacology, responding to new research on THCV and reflecting on the state of cannabinoid pharmacology after four decades of research.
What this study cannot tell us
A brief 3-page commentary rather than a systematic review. Reflects one researcher's perspective, though that researcher founded the field. Does not provide a formal evidence assessment of therapeutic applications.
How to read the evidence
A commentary by the most authoritative voice in cannabinoid chemistry. Not a systematic review, but carries unique weight as the perspective of the field's founder after four decades of work.
When this study was published
Published in 2005. Mechoulam continued working for another 18 years until his death in 2023. Many of his predictions about unexplored cannabinoids have since been validated.
The bigger picture
Mechoulam's 2005 retrospective proved prophetic. In the years that followed, CBD went from an obscure plant compound to an FDA-approved epilepsy drug (Epidiolex, 2018). THCV, the compound he highlighted, became commercially available in consumer products. Cannabis legalization swept across dozens of jurisdictions. And the endocannabinoid system he helped discover became relevant to cardiovascular, metabolic, psychiatric, immunological, and oncological research. He continued working until his death in 2023 at age 92 — still arguing that we had barely scratched the surface.
Questions still open
- How many of the ~100 plant cannabinoids have therapeutic potential?
- Could THCV's CB1 antagonism be developed into treatments for obesity or addiction?
- Why did the pharmaceutical industry ignore cannabinoids for so long?
- What discoveries remain in the 'neglected treasure trove' of unstudied plant cannabinoids?
Common questions
Who was Raphael Mechoulam?
What did Mechoulam mean by 'neglected pharmacological treasure trove'?
What is THCV and why did Mechoulam highlight it?
Did Mechoulam ever use cannabis himself?
Read the original research
Plant cannabinoids: a neglected pharmacological treasure trove.
British journal of pharmacology, 146(7), 913-915
One of the world's leading pharmacology journals. Published by the British Pharmacological Society since 1946.
Citation
Mechoulam, Raphael. (2005). Plant cannabinoids: a neglected pharmacological treasure trove.. British journal of pharmacology, 146(7), 913-915. https://doi.org/10.1038/sj.bjp.0706415
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