Endocannabinoids: An Origin Story

Loren DeVito, PhD
Written by Loren DeVito, PhD

From plant to receptor to discovery of a novel system in the body

A seminal paper published by arguably the most influential cannabis scientist of all time, Raphael Mechoulam, PhD, identified a chemical that binds to cannabinoid (CB) receptors 1 and 2.[1] This finding was quite impactful, as discovering that an endogenous substance (now known as an “endocannabinoid”) binds to CB receptors opened up a world previously unknown. But this finding was built upon many years of research on how exogenous cannabinoids, or phytochemicals, produce their effects.

While the behavioral and medicinal benefits of the cannabis plant had been well known for centuries, less was known about the mechanisms behind these actions. The first step in elucidating this mystery included identifying the individual phytochemicals, the multitude of compounds that exist within a single cannabis plant. [2] Then, scientists could learn to understand how these chemicals interacted with the brain.

If you think of chemicals (or neurotransmitters) as little triangular chemical spacecrafts within the brain, then V-shaped “docks” represent their receptors. When these two elements lock together, a cascade of electrical and chemical events are initiated that propagate the ‘docking’ signal to another dock far away. [3] These docks sit at the ends of neurons and carry messages from cell to cell, setting off a long chain of signaling that eventually results in physiological and behavioral effects.

In the late 1980s, advances in genetics made it possible to characterize cannabis receptors (the docks) and identify their agonists and antagonists (spacecrafts), naturally-occurring or man-made chemicals that either increase or decrease their function. Through this work, the structure and function of the two main cannabinoid receptors – CB1 and CB2 – were carved out. [4, 5] However, it wasn’t until 15 years later that Mechoulam et al identified 2-arachidonoylglycerol (2-AG) as the first endocannabinoid. [1]

But if scientists had already resolved CB1 and CB2, why was this discovery so important? Well, Mechoulam’s research not only revealed the identity of 2-AG but also ushered in recognition of a natural circuit within the body that responded to both internal and external cannabinoids called the endocannabinoid system (ECS).[6] No longer could cannabis be considered a “recreational” plant alone – this finding was proof that the body has its own system that relies on cannabinoids for optimal function. And this system, it was found, can be effectively and selectively targeted by therapeutics.

Since this seminal finding, additional endocannabinoids have been identified, including an and amide, Oarachidonoyl-ethanolamine (virodhamine), and N-arachidonoyl-dopamine. [7]

Endocannabinoids work to promote balance with the ECS through their effects on inflammation, pain, and immune regulation. A greater understanding of these naturally-occurring compounds within the body has led to additional studies of how exogenous phytochemicals can bolster the effects of endocannabinoids to promote health. And thanks to this body of work, the United States FDA has approved several therapies that target the endocannabinoid system, as well a recent therapy derived from the cannabis plant. In fact, there are over 400 clinical trials underway evaluating the effects of cannabis on a multitude of conditions.

None of this progress would have been possible without a greater understanding of how our internal cannabis system was built to receive the multitude of benefits from both endogenous and exogenous cannabinoids. One study really can make a difference in driving scientific progress.


  1. Mechoulam, R., Ben-Shabat, S., Hanus, L., et al., “Identification of an Endogenous 2-monoglyceride, Present in Canine Gut, That Binds to Cannabinoid Receptors”, Biochemical Pharmacology, 1995, Volume 50, pg. 83-90 (impact factor: 5.009; cited by: 2,677)
  1. Ligresti, A., De Petrocellis, L., Di Marzo, V., “From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology”, Physiol Rev,2016, Volume 96, pg. 1593-1659. (impact factor: 27.23; cited by: 82)
  1. Avery, M.C.,Krichmar, J.L., “Neuromodulatory Systems and Their Interactions:
    A Review of Models, Theories, and Experiments”, Front Neural Circuits, 2017, Volume 11, pg. 1-18. (impact factor: 3.005; cited by: 4)
  1. Devane, W.A., Dysarz, F.A., Johnson, M.R., Melvin, L.S., Howlett, A.C., “Determination and Characterization of a Cannabinoid Receptor in Rat Brain”, Mol Pharmacol, 1988, Volume 34, pg. 605-613. (impact factor: 4.556; cited by: 2,530)
  1. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I., “Structure of a Cannabinoid Receptor And Functional Expression of the cloned cDNA”, Nature, 1990, Volume 346, pg. 561-564. (impact factor: 41.577 cited by: 4,948)
  1. Mechoulam, R., Parker, L.A., “The Endocannabinoid System and the Brain”, Ann Rev Psychol, 2013, Volume 64, pg. 21-47. (impact factor: 12.22; cited by: 497)
  1. Grotenhermen, F., “Cannabinoids and the Endocannabinoid System”, Cannabinoids, 2006, Volume 1, pg. 10-14. (impact factor: N/A ; cited by: 46)

About the author

Loren DeVito, PhD

Loren DeVito, PhD

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