Cannabis was used medicinally in the Western world from the mid-1800s through 1940, even though doctors did not understand cannabis’s mechanisms of action. The Marijuana Tax At of 1937 Federally banned the use of cannabis in the US for either medical or recreational uses, and it restricted scientific studies of cannabis. Nonetheless, from 1937 through the late 1970s, cannabis research proceeded internationally, as did illegal uses of cannabis for both recreational and medical purposes.

Grass roots activists in the US have been demonstrating to legalize cannabis for medical use at least since the 1970s.[1] Yet, medical cannabis remained uniformly illegal until 1978, when the US Government was legally forced to make medical marijuana available to select patients, initially for use in treating glaucoma, and later for treatment of patients with HIV/AIDS. This compassionate use program was shut down in 1991.[2] The AIDS epidemic and Gulf War ushered in the 1990s. America’s focus shifted away from the War on Drugs and toward medical cannabis and the Middle East. [3] Soon thereafter, in 1996, California legalized cannabis for medical uses within the State. Over the next two and a half decades, 32 more states, together with the District of Columbia, Guam, Puerto Rico and U.S. Virgin Islands, followed California’s lead in legalizing cannabis for medical use.[4]

The AIDs crisis created an urgent, medical rationale for more overt use of medical cannabis. However, it was the discovery of the endocannabinoid system (ECS) during the late 1980s and early 1990s that truly legitimized cannabis for medical use and paved the way for the current flood of medical cannabis research. An influx of new research is discovering the pervasive workings of the ECS in our bodies. These new discoveries provide a glimpse into the tremendous potential of cannabis for enhancing our health and well-being.

This sequence of events begs the question: If medical cannabis research had not been restricted in 1937, would the ECS – together with its wealth of associated health and wellness benefits – have been discovered earlier?

To answer the question, we must examine the state of science and technology during the 20^th century. Restrictions on research surely caused difficulties in securing funding and/or cannabis samples for research. And if these restrictions were the primary constraints on the advancement of discovery, then we may conclude that the ECS may very well have been discovered earlier than it was. If, however, limitations on advancements in complementary science and technology played a role in delaying the course of discoveries on the ECS, then we cannot conclude that but-for restrictions on cannabis research, the ECS likely would have been discovered sooner.

Adding Context to the Investigation

The purpose of this investigation is to better understanding the path of discovery of the endocannabinoid system (ECS). The ECS was discovered in the course of trying to understand THC’s mechanism of action (MOA) – how THC works to create its psychoactive effects. To provide further context to this investigation, let’s compare the discovery paths of the MOAs for three major, plant-derived, drugs: opium, cocaine, and cannabis.

People have used plants for medical applications throughout history. Yet, it’s only been relatively recently that we’ve understood how many of our medications generate their effects. Before the 1800s, science and technology had not yet advanced enough for researchers to be able to determine the MOAs through which different substances address our health and well-being. Since that time, science and technology have both slowly progressed in fits and starts. New discoveries and innovations have built upon previous discoveries, providing new opportunities for better understanding of the complex functioning of our bodies. Comparing the discoveries of the MOAs for opium, cocaine, and cannabis may provide some insights into the nature of the discovery process for cannabis, and specifically, whether or not the ban on use delayed the discovery of the ECS.

Opium, coca, and cannabis are all plants that contain psychoactive substances that have been used by man for thousands of years or more. All three were exploited by man for their psychoactive effects long before researchers understood how the substances generated their effects. Furthermore, medicinal properties of morphine, cocaine, and cannabis were also recognized early on (during the 1800s in the US). However, while morphine and cocaine continue to be legal for medical uses, cannabis was banned in 1937. Furthermore, all three drugs were relatively unusual in the medical industry for having been used to treat patients long before their MOAs were understood. In fact, it was peoples’ use of these drug that drove discoveries about their MOAs, rather than the understanding of their MOAs that drove medical use.

Indeed, opiates are in the rare position where their clinical pharmacology preceded the development of corresponding animal models and molecular mechanisms of action. Thus, the clinical pharmacology of opiates has driven much of the basic preclinical research into their mechanism of action.[5]

Paths of Discovery

Scientists’ understanding of the MOA for all three substances, morphine, cocaine, and THC, followed a similar path: First, researchers succeeded in isolating the active ingredient from the plant. Second, the chemical structure of the active ingredient was synthesized. Third, the receptors with which the substances bind were discovered: Morphine was discovered to act on opioid receptors, cocaine on dopamine receptors, and cannabis on cannabinoid receptors. And last, scientists determined the endogenous chemicals manufactured in our bodies that the plant-derived substances mimic.

Morphine

Coincidentally the isolation of morphine from opium by Friedrich Sertürner in 1805 was “the first isolation of a natural product from a plant,” which “kick-started natural product chemistry.” As researcher Eyan Huxtable notes,

The isolation of morphine from opium —the first isolation of a natural product—was a seminal event in the development of pharmacology as an independent discipline. The purification kick-started natural product chemistry and quickly led to the isolation of a host of other alkaloids [including strychnine, caffeine, quinine, nicotine, and codeine].

…

As a consequence of his studies, Sertürner established the principle that plants contain active substances that, on isolation, carry the therapeutic properties of the plant.[6]

The development of the hypodermic syringe during the mid 1800s enabled opiates to be injected into the blood for immediate relief of symptoms, but by the early 1900s, opiate abuse had become problematic in society. Particularly troublesome was the fact that too much morphine caused people to stop breathing.[7]

The first morphine total synthesis was achieved by Marshall D. Gates, Jr. and Gilg Tschudi in 1952. Presumably, it was the “stereochemical complexity” of the “polycyclic structure”[8] that delayed synthesis of the drug. The complexity of the molecular structure of morphine makes it expensive to synthesize, so the natural poppy continues to be the primary source of supply.[9]

In 1973, 21 years after it was first synthesized, researchers discovered opiates’ MOA, acting on the opioid receptors. The discovery of opioid receptors was enabled by a recently-developed technology, the radioimmunoassay, which was developed in the 1960s and released in the early 1970s. Soon after the discovery of opioid receptors, scientists discovered our bodies’ own versions of morphine. [10]

In short, pure morphine was first isolated in 1805, but it took another 168 years for its MOA to be discovered, in 1973, where the long delay was (largely) due to lack of knowledge (science) and equipment (technology) needed to figure things out.

Cocaine

The next of our three plant-based psychoactive substances to be isolated was cocaine. While it had been long-known that South American natives chew on coca leaves for its effects, it was decades before Europeans could investigate the substances responsible for the activity. The delay was due to two problems. First, the active ingredients in coca leaves degrade quickly; so by the time shipments of coca leaves arrived in Europe from South America, there was little activity left to investigate:

The coca leaf doesn't travel well. By the time leaves sent by early colonists in South America reached Europe, they had lost much of their potency. So for centuries the plant remained little more than a curiosity of interest only to obscure European botanists.[11]

And second, knowledge of chemistry was lacking.

By the mid 1850s, a couple of researchers managed to extract crude solutions from coca leaves, and in 1860, Albert Niemann was the first to isolate a pure extract, which he named cocaine.[12] It wasn’t until several decades later, in 1898, that Richard Willstatter was able to synthesize and elucidate the first cocaine molecule.[13]

Cocaine gained popularity for medical use as an anesthetic during the late 1800s.[14] By the early 1900s, cocaine’s addictive properties were becoming problematic, and the 1914 Harrison Narcotics Act staunched its use recreationally. However, the field of cocaine biosynthesis “has been a focus of biochemists for over a century.”[15]

It appears the first dopamine receptor may have been discovered in 1975.[16] In 1985, 125 years after cocaine was first isolated, researchers discovered its MOA was inhibition of dopamine uptake;[17] that is, cocaine increases the amount of dopamine in the body.

It’s clear that delays in isolating cocaine were due to lack of scientific knowledge. Given the substantial amount of research into cocaine during the 20^th century – one pair of researchers claims cocaine is “the most studied and discussed alkaloid in the scientific literature”[18] – presumably, it is simply a complex MOA. In fact, less than five years ago, in 2016, researchers “uncovered what cocaine does to the body and the brain to make it so addictive.”[19]

THC

In 1842, WB O'Shaughnessy, “a young professor at the Medical College of Calcutta, who had observed its use in India” was the first person to introduce medical cannabis (Cannabis indica) to the West. O'Shaughnessy was impressed by cannabis’s effectiveness as an analgesic, a muscle-relaxant, and an anticonvulsant. By the end of the 19^th century, physicians were using cannabis tinctures for:

tetanus, neuralgia, dysmenorrhea (painful menstruation), convulsions, the pain of rheumatism and childbirth, asthma, postpartum psychosis, gonorrhea, and chronic bronchitis … [a]s a hypnotic (sleep-inducing drug) … to stimulate appetite … to subdue restlessness and anxiety and distract a patient's mind in terminal illness ... [as] a pain reliever … for senile insomnia … [for] various forms of neuralgia, including tic douloureux (a painful facial neurological disorder), and … [for] preventing migraine attacks.[20]

According to Raphael Mechoulam, "CBD was isolated in the 1930's, by [Roger] Adams in the US and Todd in the UK. We reisolated it in 1963 and elucidated its structure."[21] Then in 1964 Mechoulam first isolated pure THC, and in the following year, 1965, Mechoulam synthesized THC.

Mechoulam explains why it took researchers so long to isolate and synthesize THC: Isolation was difficult because cannabinoids “are present in cannabis as a mixture of a large number of closely related constituents, which were apparently difficult to separate by the methods available in the 19th and early 20th centuries.” Mechoulam was able to finally synthesize THC (others synthesized other cannabinoids soon thereafter) using a newly developed technology, a nuclear magnetic resonance (NMR) spectrometrometer to which he had access.[22]

The isolation and synthesis of THC led to a flurry of pharmacological research activity on cannabis during the mid-1960s and early 1970s.

Pharmacological research at this time was also directed at seeking out and characterizing the effects of cannabis or individual cannabinoids on particular biological systems, at comparing the effects of cannabis with those of other recreational drugs and at exploring the dependence liability of cannabis and D9-THC. This early research provided a more complete description of the pharmacological effects of cannabis and D 9-THC, but did little to explain the mechanisms by which these effects were produced.[23]

Mechoulam explains that during the 1970s and 1980s, cannabis’s MOA remained an enigma. For both conceptual and technical reasons, researchers were not looking for the cell receptors, which, in the end, turned out to be the actual MOA. Pfizer had recently created “a much more active synthetic cannabinoid, HU-210, which is at least 100 times more active than THC.”[24] It was this new synthetic that finally led the researchers to the discovery of the endocannabinoid receptors in 1988, and confirmation came with the cloning of CB1 in 1990 and CB2 in 1993.[25]

Mechoulam notes, "We isolated, elucidated the structure and synthesized anandamide in 1992 and 2-AG in 1995 - thus contributing to the establishment of the endocannabinoid system."[26]

In short, cannabis’s MOA was discovered 92 years after the isolation of CBD, but only 26 years after the isolation of THC, where delays in discoveries were due to lack of needed technologies.

Mechoulam's comment on the question this analysis investigates:

Did the legal system delay this advance? Not in my case. But 'if' has minor importance in science as well as in history.[27]

Discussion

I entered the world of cannabis in 2016 to help my brother figure out how to use the plant to treat his pain. Soon thereafter, I learned about a system in our bodies, the endocannabinoid system (ECS), that’s fundamental for maintaining homeostasis throughout our bodies, yet that I had never heard of before. As I delved deeper into the history of scientific research into cannabis, I began to appreciate the implications of the ECS for our health and well-being. And when I thought about how recent the discovery had been, during the early 1990s, I assumed that, surely, the discovery had been so recent only because medical cannabis had been banned. I figured that but-for the ban on cannabis, researchers would surely have discovered the ECS earlier, say, back in the 1970s, and we would have had an additional 50 years to learn about how to use the ECS to improve our health.

It was only after conducting this analysis that I realized how much I had taken our current knowledge of science and technology for granted. In the world of scientific discoveries, a hundred years passes in the blink of an eye, as researchers grapple to understand natural phenomena. In particular, I am continually awe-struck by the complexity of our bodies and how little we actually know about how our bodies function.

A summary of the timelines for morphine, cocaine, and THC discoveries is presented in Figure 1. From the analysis and the timeline display in the figure, it is clear to me that the discovery of the ECS was not, in fact, hampered by legal bans on use. Rather, it was the lack of sufficient scientific knowledge and technology that delayed its discovery. And in fact, compared with our understanding of how morphine and cocaine work in our bodies, the length of time it took to discover cannabis’s MOA is relatively short. It appears that cannabis’s late start in researchers’ laboratories might actually have given the science and technology a bit of time to catch up, and had research on cannabis started earlier than it did, or if medical cannabis had never been banned, the discovery of the ECS probably still would not have occurred before it did, in the early 1990s.

Figure 1

References

[1] Cara Wietstock Profile: Dennis Peron, Patient Activist. Ganjapreneur. Retrieved from https://www.ganjapreneur.com/profiles-in-cannabis-history-dennis-peron-front-line-activist/

[2] Mohamed Ben Amar (2006). Cannabinoids in medicine: A review of their therapeutic potential. Journal of Ethnopharmacology. Retrieved from http://doctordeluca.com/Library/WOD/WPS3-MedMj/CannabinoidsMedMetaAnalysis06.pdf

[3] Erich Goode and Nachman Ben-Yehuda (1994). The American Drug Panic of the 1980s. Schaffer Library of Drug Policy. Retrieved from http://www.druglibrary.org/special/goode/drugpanic.htm

[4] State Medical Marijuana Laws (2020). National Conference of State Legislatures. Retrieved from http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx

[5] Pasternak and Pan (2013). Mu Opioids and Their Receptors: Evolution of a Concept. Pharmacological Reviews. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799236/pdf/pr.112.007138.pdf

[6] Ryan Huxtable (2001). The Isolation of Morphine—First Principles in Science and Ethics. Indian J Anaesth. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125194/

[7] Pasternak and Pan (2013). Mu Opioids and Their Receptors: Evolution of a Concept. Pharmacological Reviews. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799236/pdf/pr.112.007138.pdf

[8] https://en.wikipedia.org/wiki/Morphine#Chemical_synthesis

[9] Morphine. Chemical and Engineering News. http://pubsapp.acs.org/cen/coverstory/83/8325/8325morphine.html?

[10] Pasternak and Pan (2013). Mu Opioids and Their Receptors: Evolution of a Concept. Pharmacological Reviews. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799236/pdf/pr.112.007138.pdf t

[11] David Pearce. A Spoonful of Sugar? Cocaine.org. Retrieved from https://cocaine.org/cokespoon.htm; Brian Silber, History of Cocaine. Brian Silber Law. Retrieved from https://www.briansilberlaw.com/history-of-cocaine/

[12] Alan Dronsfield and Pete Ellis (2007, Aug 31). Cocaine - a short trip in time. RSC Education. Retrieved from

[13] Brian Silber, History of Cocaine. Brian Silber Law. Retrieved from https://www.briansilberlaw.com/history-of-cocaine/

[14] Amy Sue Biondich and Jeremy David Joslin (2016). Coca: The History and Medical Significance of an Ancient Andean Tradition. Emergency Medicine International. Retrieved from http://downloads.hindawi.com/journals/emi/2016/4048764.pdf

[15] Lindsey Drake and Peter Scott (2018). Dark Classics in Chemical Neuroscience: Cocaine. ACS Chem Neurosci. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197930/pdf/nihms971587.pdf

[16] Bertha K Madras (2013). History of the Discovery of the Antipsychotic Dopamine D2 Receptor: A Basis for the Dopamine Hypothesis of Schizophrenia https://pubmed.ncbi.nlm.nih.gov/23323533/

[17] Cristina Missale at al (1985). Dopamine Uptake is Differentially Regulated in Rat Striatum and Nucleus Accumbens. Journal of Neurochemistry.

[18] Amy Sue Biondich and Jeremy David Joslin (2016). Coca: The History and Medical Significance of an Ancient Andean Tradition. Emergency Medicine International. Retrieved from http://downloads.hindawi.com/journals/emi/2016/4048764.pdf

[19] Siobhan Fenton (2016, Aug 3). Scientists Discover What Cocaine Does to the Brain to Make It So Addictive. Independent. Retrieved from https://www.independent.co.uk/life-style/health-and-families/health-news/cocaine-effects-on-body-brain-why-is-it-so-addictive-scientists-study-addiction-drugs-a7169556.html

[20] Lester Grinspoon, (2005, Aug 16). History of Cannabis as a Medicine. Retrieved from https://maps.org/research-archive/mmj/grinspoon_history_cannabis_medicine.pdf

[21]Raphael Mechoulam. Personal Communication. June 12, 2020.

[22] Raphael Mechoulam, Lumír Hanusˇ (2000). A historical overview of chemical research on cannabinoids. Chemistry and Physics of Lipids. Retrieved from https://mybestbudca.com/wp-content/uploads/A-historical-overview-of-chemical-research-on-cannabinoids.pdf

[23] Roger G. Pertwee (2006). Cannabinoid pharmacology: the first 66 years. British Journal of Pharmacology. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760722/pdf/147-0706406a.pdf

[24] Conversation with Raphael Mechoulam (2007). Addiction.

[25] Roger G. Pertwee (2006). Cannabinoid pharmacology: the first 66 years. British Journal of Pharmacology. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760722/pdf/147-0706406a.pdf

[26]Raphael Mechoulam. Personal Communication. June 12, 2020.

[27]Raphael Mechoulam. Personal Communication. June 12, 2020.