In 2006, Roger Pertwee — who had been working in cannabinoid pharmacology since 1968 — published a concise historical narrative of the entire field, from the first cannabinoid isolation in 1940 through six decades of receptor discoveries, endocannabinoid identification, and therapeutic development.
Anyone wanting to understand how cannabis science developed from the first cannabinoid isolation to the modern endocannabinoid system — told as a narrative rather than an encyclopedia.
66 yearsof cannabinoid pharmacology compressed into one narrative — from the first cannabinoid isolation in 1940 to the therapeutic frontier of 2006, told by a researcher who was personally involved for 38 of those years
The Backstory
In 2006, a pharmacologist at the University of Aberdeen sat down to write a history of his field. It began in 1940, with the first isolation of a cannabinoid from cannabis. It ended in 2006, with selective receptor drugs entering clinical trials and an entire signaling system mapped across the body.
Sixty-six years. And Roger Pertwee had been in the field for thirty-eight of them.
This wasn't a historian reviewing archives. It was a builder surveying the house he helped construct — from a postdoc extracting cannabinoids from legal cannabis tincture in 1968 Oxford, to a co-founder of the field's professional society, to the developer of one of its most important research tools. When Pertwee wrote the history, he was writing partly from memory.
The Man in the Story
Roger Pertwee holds three degrees from Oxford — a BA in biochemistry, a DPhil in pharmacology, and a DSc in physiological sciences. He entered cannabinoid research in 1968, four years after Mechoulam characterized THC, as a postdoctoral researcher in Sir William Paton's pharmacology laboratory at Oxford.
When Pertwee began his work, cannabis tincture was still a legal medicine in the United Kingdom. His early research used THC and CBD extracted directly from pharmaceutical-grade cannabis tincture — a supply chain that would be unimaginable in most countries just a few years later as drug scheduling tightened worldwide. He worked with the crude plant material before most of the synthetic tools that define modern cannabinoid pharmacology existed.
His initial contributions included demonstrating that CBD potently inhibits liver enzymes (hepatic microsomal enzymes) and developing the "ring immobility test" — a behavioral assay for measuring cannabinoid effects in rodents that is still used today, over fifty years later.
In 1974, Pertwee moved to Aberdeen, where he would spend the rest of his career. And it was in Aberdeen that he made his most lasting methodological contribution — by borrowing a tool from another field entirely.
Hans Kosterlitz's laboratory at the University of Aberdeen was famous for opioid pharmacology — Kosterlitz had co-discovered the endogenous opioids enkephalins. His lab used the mouse isolated vas deferens as a standard bioassay for opioid receptor agonists: apply the compound, measure the inhibition of electrically-stimulated muscle contractions.
Pertwee realized this same tissue preparation might work for cannabinoids. He was right. The mouse vas deferens turned out to be an extraordinarily sensitive and quantitative functional bioassay for CB1 receptor agonists — far more precise than behavioral tests. It became the gold standard for measuring cannabinoid receptor activation and was used by labs worldwide for over two decades.
The connection between opioid and cannabinoid research tools, forged in the same Aberdeen corridor, would prove symbolically appropriate: the two systems would later be found to interact extensively in pain processing.
In 1990, at a scientific meeting in Kolympari, Crete, Pertwee was among a small group of cannabinoid researchers who decided to formalize their community. They founded the International Cannabinoid Research Society (ICRS) — the field's first dedicated professional organization. Pertwee would serve as its president twice.
A year later, at a 1991 conference in Palm Beach, Florida, Pertwee met Raphael Mechoulam. Mechoulam's lab had just discovered anandamide. Using his vas deferens bioassay, Pertwee and his colleague Graeme Griffin provided the first functional evidence that anandamide doesn't just bind the cannabinoid receptor — it activates it. Binding had been shown in the original 1992 paper. Functional activation was Pertwee's contribution.
66 Years in Nine Pages
The review itself is concise — nine pages in the British Journal of Pharmacology. But it covers six and a half decades of discovery with a clarity that only a participant could achieve. Where Pacher's 74-page review mapped diseases and Piomelli's review mapped mechanisms, Pertwee mapped time. The field as a narrative, each chapter building on the last.
Research Timeline
The First 66 Years of Cannabinoid Pharmacology
Cannabinol (CBN) first isolated from cannabis
First phytocannabinoid identified — but not the psychoactive one
Adams (US) and Todd (UK) independently isolate CBD
Year zero of cannabinoid pharmacology — the '66 years' starts here
First crude THC fractions extracted
Active compound detected but couldn't be purified or characterized
Mechoulam & Gaoni characterize THC structure
The breakthrough — pure THC enables pharmacological research
Total synthesis of THC and CBD
Synthetic production enables controlled studies
Pertwee begins cannabinoid research at Oxford
Working with cannabis tincture — still a legal medicine in the UK
Structure-activity relationships, mouse tetrad, ring test developed
Tools for systematically studying cannabinoid pharmacology
Howlett & Devane prove cannabinoid receptor binding sites exist
Not membrane disruption — a real receptor with specific binding
CB1 receptor cloned (Matsuda, Bonner, NIH)
The molecular identity revealed — most abundant GPCR in the brain
ICRS founded at meeting in Crete
The field gets a professional society — Pertwee among co-founders
Anandamide discovered (Devane, Hanuš, Mechoulam)
The brain's own cannabinoid found
CB2 receptor cloned (Munro, Cambridge)
A second receptor — in immune cells, not brain
SR141716A (rimonabant) announced — first selective CB1 antagonist
Pharmacological tools for blocking specific receptors
2-AG discovered independently by two groups
A second, more abundant endocannabinoid
FAAH identified — the enzyme that degrades anandamide
The off-switch mapped — a new drug target
SR144528 — first selective CB2 antagonist
Complete pharmacological toolkit for both receptors
This review published — the field has therapeutic candidates
66 years from first isolation to the edge of clinical application
Pertwee (2006), Br J Pharmacol 147(S1):S163-171
A Chain of Dependencies
The review's most important insight isn't any single discovery — it's the structure of how the field developed. Each breakthrough depended specifically on the one before it. You couldn't skip steps.
Biological Mechanism
Why Each Discovery Required the Previous One
Isolate cannabinoids (1940s)
You can't study a drug's pharmacology if you don't have the pure compound. Adams and Todd isolated CBD; Mechoulam isolated THC.
Develop bioassays (1960s-70s)
You need ways to measure cannabinoid effects systematically. The mouse tetrad, ring test, and eventually the vas deferens assay provided quantitative tools.
Prove a receptor exists (1988)
Howlett & Devane showed stereoselective, saturable binding — not just membrane disruption. This proved a specific molecular target exists.
Clone the receptor (1990)
Matsuda & Bonner sequenced CB1. Now you could make knockout mice, design selective drugs, and map distribution at the gene level.
Find the endogenous ligands (1992-95)
Anandamide and 2-AG — the brain's own cannabinoids. Their discovery proved the ECS is a fundamental regulatory system, not just a cannabis-response pathway.
Develop selective tools (1994-98)
Selective agonists and antagonists for CB1 and CB2 — enabling researchers to study each receptor independently and develop drug candidates.
Pertwee (2006), Br J Pharmacol
This chain explains something that frustrates cannabis advocates: why did it take so long? The answer isn't politics (though that didn't help). It's science. Each step required specific technical capabilities that didn't exist until the previous step was completed. You couldn't discover anandamide in 1964 because the receptor hadn't been found yet. You couldn't find the receptor in 1940 because pure THC didn't exist. The 66 years weren't wasted time — they were the minimum path through a chain of dependencies.
The Tools He Built
Pertwee's personal contribution to this chain was primarily methodological. He didn't discover a molecule or clone a gene. He built tools — ways to measure what cannabinoids do, precisely and reproducibly.
Evidence Matrix
Key Tools Developed During the 66 Years
| Study | Design | Finding | |
|---|---|---|---|
| ↑ | Paton/Pertwee(1968) | Behavioral assay | Ring immobility test — measuring catalepsy induced by cannabinoids in mice |
| ↑ | Martin et al.(1991) | Behavioral battery | Mouse tetrad — four tests (catalepsy, hypothermia, analgesia, hypolocomotion) defining cannabinoid activity |
| ↑ | Pertwee/Griffin(1992) | Functional bioassay | Mouse vas deferens — quantitative CB1 agonist assay adapted from Kosterlitz's opioid lab |
| ↑ | Rinaldi-Carmona(1994) | Selective antagonist | SR141716A (rimonabant) — first selective CB1 antagonist/inverse agonist |
| ↑ | Cravatt et al.(1996) | Enzyme identification | FAAH — enzyme that degrades anandamide, enabling targeted enzyme inhibitor design |
| ↑ | Rinaldi-Carmona(1998) | Selective antagonist | SR144528 — first selective CB2 antagonist, completing the receptor-specific toolkit |
Pertwee (2006), Br J Pharmacol; various primary sources
Without tools like these, the discoveries in the timeline above couldn't have been made — and the therapeutic applications couldn't have been explored. The glamorous history is the discoveries (THC! receptors! anandamide!). The enabling history is the tools. Pertwee understood this better than most because he was, fundamentally, a tool-builder.
Where History Stood in 2006
The review was published at a specific moment: the endocannabinoid system was fully characterized, selective drugs existed for both receptors, and therapeutic applications were entering clinical trials. Rimonabant had just been approved in Europe. FAAH inhibitors were in development. The field felt like it was on the verge of delivering medicines.
38
years of personal involvement in the field (1968-2006) by the time Pertwee wrote this review. He started when cannabis tincture was still a legal UK medicine. He wrote the history at the moment the field pivoted from discovery to application.
Of the 66 years covered, Pertwee was an active researcher for more than half. He's not reviewing history — he's recounting it.
University of Aberdeen faculty profile; Pertwee (2006)
What the review couldn't know was what would happen next. Rimonabant would be withdrawn within two years due to psychiatric side effects. A FAAH inhibitor trial would cause a death in 2016. CB2 drugs would fail Phase 2. The therapeutic promise would prove harder to fulfill than anyone in 2006 imagined.
But the basic science — the 66 years of pharmacology Pertwee documented — held firm. Every receptor, every endocannabinoid, every enzyme, every signaling pathway he described has been confirmed and extended. The foundation was solid. Only the translational path was harder than expected.
Pertwee continued active research for years after the review, eventually receiving the ICRS Lifetime Achievement Award in 2018 — recognizing more than half a century of contributions to a field he helped build from nearly the beginning.
Related Research
The Milestones in the Story
Pertwee's 66-year history covers discoveries that are themselves pillar studies. These are the key events he narrates.
Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish
Gaoni & Mechoulam (1964)
The central event of the narrative — the moment cannabis chemistry caught up to morphine and cocaine
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Matsuda et al. (1990)
The pivot from pharmacology to molecular biology — the receptor gets a gene
Isolation and structure of a brain constituent that binds to the cannabinoid receptor
Devane, Hanuš, Mechoulam et al. (1992)
Pertwee personally provided the first functional evidence that anandamide activates CB1
The endocannabinoid system as an emerging target of pharmacotherapy
Pacher, Bátkai & Kunos (2006)
Published the same year — where Pertwee narrates history, Pacher maps the therapeutic future
Why is a history paper ranked among the most important studies in cannabis science?
Because it's the only concise narrative history of the entire field written by someone who was personally involved for most of it. Roger Pertwee started in cannabinoid research in 1968, developed key laboratory tools, co-founded the International Cannabinoid Research Society, and helped prove that anandamide activates cannabinoid receptors. His review shows how each discovery depended on the one before it — a 66-year chain of dependencies that explains why progress took decades and why the endocannabinoid system wasn't recognized until the 1990s despite cannabis being used for millennia.
What does 'the first 66 years' refer to?
It counts from 1940, when Roger Adams and Alexander Todd first isolated cannabinoids from cannabis, to 2006, when the review was published. During those 66 years, the field went from not knowing what the active ingredient in cannabis was to having two cloned receptors, two identified endocannabinoids, a complete enzyme toolkit, selective drugs for each receptor, and the first wave of therapeutic candidates entering clinical trials.
What the researchers found
The review traces cannabinoid pharmacology through five eras: (1) Early chemistry (1940s): isolation of CBN, CBD, and crude THC by Cahn, Adams, and Todd; (2) Structural characterization (1960s): Mechoulam determines THC structure, enables pharmacological research; (3) Receptor discovery (1980s-90s): Howlett proves receptor binding, Matsuda clones CB1, Munro clones CB2; (4) Endocannabinoid era (1990s): discovery of anandamide and 2-AG, identification of synthesis and degradation enzymes; (5) Therapeutic development (2000s): selective agonists, antagonists, enzyme inhibitors, and the recognition that the endocannabinoid system plays roles in both health and disease. The review emphasizes how each discovery depended on the one before it — a chain of dependencies spanning 66 years.
Why it matters
This review provides the only concise narrative history of cannabinoid pharmacology written by a participant-observer — someone who lived through most of the discoveries described. It demonstrates how the field developed through a chain of dependent discoveries: you couldn't find the receptor without first identifying THC; you couldn't find the endocannabinoids without first cloning the receptor; you couldn't develop targeted drugs without first characterizing the endocannabinoid pathways. Understanding this chain explains why progress took decades and why each breakthrough depended on specific prior knowledge.
How the study worked
Historical narrative review synthesizing published pharmacological, biochemical, and clinical literature from 1940-2006. The author draws on personal experience spanning 38 years of active cannabinoid research (1968-2006), incorporating both published evidence and first-hand knowledge of the field's development.
What this study cannot tell us
As a 9-page review, the historical narrative is necessarily concise and selective. It prioritizes key milestones over comprehensive coverage. Published in a special supplement of the British Journal of Pharmacology, it assumes pharmacological literacy. The review reflects the state of knowledge in 2006 and does not address subsequent developments (rimonabant withdrawal, FAAH inhibitor failures, CBD drug approval). As the author was an active participant in the field, the narrative may emphasize contributions from his own network.
How to read the evidence
Rated strong because this historical review is written by one of the field's most authoritative figures (Pertwee has 50+ years of active research, co-founded ICRS, received the Mechoulam Award and ICRS Lifetime Achievement Award). Published in the British Journal of Pharmacology, the review synthesizes well-established historical facts and the author's personal knowledge of the field's development.
When this study was published
Published in 2006, this review covers the period 1940-2006. The historical account is complete and accurate for the period it covers. Subsequent developments (rimonabant failure 2008, BIA 10-2474 disaster 2016, Epidiolex approval 2018) are not included but do not contradict the narrative — they extend it.
The bigger picture
Pertwee's review captures a moment of transition. By 2006, the basic science was mature — receptors cloned, endocannabinoids found, enzymes mapped, selective tools developed. The field was pivoting from discovery to application. Rimonabant was being approved. FAAH inhibitors were entering trials. The review serves as both a history and a turning-point marker: this is where we came from, and this is where we're going. The subsequent decades proved the therapeutic path was harder than expected, but the basic science foundation described in this review has held firm.
Questions still open
- Now that the basic science is mature, which therapeutic applications will actually reach patients?
- Can the endocannabinoid system be therapeutically modulated without the side effects that have derailed early drug candidates?
- What remains undiscovered — are there more cannabinoid receptors, more endocannabinoids, more enzymes?
Common questions
Why is a history paper ranked among the most important studies in cannabis science?
What does "the first 66 years" refer to?
Read the original research
Cannabinoid pharmacology: the first 66 years
British Journal of Pharmacology, 147(S1), S163-171
Citation
Pertwee, R G. (2006). Cannabinoid pharmacology: the first 66 years. British Journal of Pharmacology, 147(S1), S163-171. https://doi.org/10.1038/sj.bjp.0706406