Discovery Of The Endocannabinoid System

The endocannabinoid system (ECS) has emerged as a fascinating physiological target over the last few decades. Research has identified associated receptors, ligands, and enzymes of the system all throughout the body—from the immune system and nervous system to the skin and bone. More and more research suggests that the ECS plays a fundamental role in human physiology; namely, in helping other systems maintain a state of balance or “homeostasis”.

Science has shown modulation of this system using phytocannabinoids (like CBD, CBN, etc.) to hold promise in numerous contexts. But where did this all begin?

Continue reading to find out who discovered the ECS, and when they stumbled across this vital system.

Discovery of the ECS

Interestingly, the discovery of cannabinoids predates that of the ECS. In fact, these molecules were vital tools in unveiling the homeostatic network. The cannabinoid CBN is believed to have first been isolated in the late 19th century, followed by CBD and THC in the mid-20th century, yet researchers didn't pinpoint the exact cellular mechanism of these cannabinoids until decades later.

THC occupied the limelight in the early years of cannabinoid research, largely because of its psychoactive effect. It didn’t take long for researchers to discover the hydrophobic nature of the molecule—it doesn’t absorb well into water. This led them to the hypothesis that THC was drawn to fat in the body, and probably exerted a non-specific action in cell membranes instead of directly at specialised binding sites.

Although this hypothesis made sense, further research soon turned it on its head. After conducting experiments with synthetic analogues of THC, researchers started to put forth the idea of “cannabinoid” binding sites.

Then, in 1988, researchers identified the first specific binding site^[1] of a THC analogue using radiolabeled molecules. William Devane and his colleagues at the Department of Pharmacology at St. Louis University Medical School conducted the experiment in rat brains. This research paved the way for research conducted by Lisa Matsuda and others that identified^[2] the CB1 receptor in the 1990s. They made the groundbreaking discovery by cloning a “complementary” DNA that encodes the G protein-coupled receptor (CB1).

The discovery of the CB2 receptor soon followed. Sean Munro and colleagues^[3] hypothesised that non-psychoactive cannabinoids must produce their effects through another unidentified cannabinoid receptor. In 1993, the team reported their cloning of the CB2 receptor. However, they noted a lack of receptor expression in the brain, instead finding it primarily in immune cells.

The discovery of these molecular targets is certainly helpful to understanding the ECS, but how does it operate in the first place? Much like the endogenous opioid system, which utilises endorphins, the ECS features its own set of signalling molecules—endocannabinoids.

Lumir Hanus and fellow researchers at the Hebrew University of Jerusalem discovered the first endocannabinoid in 1992^[4]. The team was working in close proximity with Raphael Mechoulam, the man who first isolated THC. They utilised mass spectrometry and nuclear magnetic resonance spectroscopy to identify a molecule they named “anandamide”, meaning “bliss” in Sanskrit. They found anandamide to function as a natural ligand for the CB1 receptor.

It wasn’t until 1995^[5] that researchers discovered the cannabinoid receptor binding affinity of a previously known molecule. Mechoulam and his team found 2-arachidonoyl glycerol (2-AG) to bind to these receptor sites, and confirmed it as the second major endocannabinoid. Since then, other novel endocannabinoids have been discovered, but pharmacological interest lies in the first two identified.

Discovery is just the beginning

The discovery of major components of the endocannabinoid system has led to a new paradigm of addressing human physiology and homeostasis. Researchers are now exploring ways to target the ECS to alter endocannabinoid signalling^[6] for human benefit.

The discovery of the ECS has also given rise to theories such as clinical endocannabinoid deficiency, which suggests humans require an appropriate “endocannabinoid tone” for optimal function. Although still early, research into the ECS and its chemical activators holds great promise. No doubt, many more discoveries on the ECS are soon to appear.