History of the Endocannabinoid System

Today, I wanted to go more in-depth into the history of the endocannabinoid system. In my last post, we learned all about cannabinoids. We learned the three different types of cannabinoids (phyto, endo, and synthetic) as well as some fun facts surrounding them. For me, it made sense to start there, because that is essentially where the science and research started. In my next post, we will dive into what the “endocannabinoid system” is and how it works, but in this post, we will talk about the history of how it was discovered.

In 1964, the very first cannabinoid was identified, and isolated. Raphael Mechoulam was a scientist from Israel studying the Cannabis Sativa plant and trying to identify the active component inside it. He wanted to learn more about the Cannabis Sativa plant because he knew it had been used for thousands of years as a drug and as a recreational agent but the active compound had never been isolated in pure form. It wasn’t long before Dr. Mechoulam had isolated tetrahydrocannabinol (THC), the first known and isolated phytocannabinoid!

Photo by ThisisEngineering RAEng on Unsplash

After isolating THC, Dr. Mechoulam continued his research on the cannabis plant and continued isolating other compounds found within the plant. The next compound he isolated was a phytocannabinoid named cannabidiol (CBD). After isolating and discovering this compound, he started to test it on patients with epilepsy. He and his team of scientists in Sao Paulo conducted a study on 10 epileptic patients that did not respond to traditional medicines. In his documentary, The Scientist, he says “We gave the patients 200mg per day. We were happy to note that, indeed, they had no seizures while they were taking cannabidiol. And it was published, and nothing happened afterward… So far, 34 years later (2009) this is the only publication of cannabidiol in humans against epilepsy.”

After years and years of studying cannabinoids isolated from the cannabis plant, Raphael believed he was onto something and wrote a book. In 1986, in his book, Cannabinoids As Therapeutic Agents, Dr. Mechoulam talks about the extensive amount of information they had been collecting on plant cannabinoids (phytocannabinoids) and the many therapeutic effects they displayed in mammals. At this point, they knew cannabinoids were beneficial, but they knew nothing about why cannabinoids had such a profound therapeutic effect on mammals.

In comes Professor Allyn Howlett, a researcher based in the USA. Professor Howlett began studying THC in the mid-1980s. While studying THC and it effects on the human body, she discovered a complex network of receptors in the brain and central nervous system. She named the receptor, the CB1 receptor, cannabinoid receptor number 1. These receptors seemed to be a perfect fit for the THC compound. This was a major discovery.

“On July 18, 1990, at a meeting of the National Academy of Science’s Institute of Medicine, Lisa Matsuda announced that she and her colleagues at the National Institute of Mental Health (NIMH) had achieved a major breakthrough — they had pinpointed the exact DNA sequence that encodes the CB1 receptor in a rat’s brain.”

Researchers soon discovered a second type of cannabinoid receptor that they named “CB2” which was found prevalent in the immune system and peripheral nervous system. At this point, we knew there was an entire network of receptors (CB1 and CB2) found in large amounts embedded within the human body.

Photo by ThisisEngineering RAEng on Unsplash

Once we found out there are receptors in the human brain and throughout the body that binds to phytocannabinoids, the next obvious question was, “Why are there receptors in the human brain for a plant compound that comes from cannabis?”

In 1992, Dr. Mechoulam and his team of scientists believed they knew the answer to that question. They believed that the receptors existed for compounds that we produce in the human body, not for compounds found in a plant.  This leads them on a search to find endogenous cannabinoids. After two years of research, they found a compound in the brain that acts on these receptors and named the compound anandamide, the first known endocannabinoid! They named it anandamide because they believed that this compound would have an effect on mood and emotion and could potentially create happiness. In Sanskrit, the word ananda means “supreme joy” or “bliss”. They combined the Sanskrit word ananda, with the chemical name of the compound “Arachidonoyl Ethanolamide” to create the word anandamide. That is why it is now known as “The Bliss Molecule”.

In 1995, Mechoulam’s group discovered a second major endogenous cannabinoid, 2-arachidonoylglycerol or “2-AG”. The second known endocannabinoid! They discovered that this endocannabinoid locks on to both the CB1 and CB2 receptors.

By tracing the metabolic pathways of THC, scientists stumbled upon a unique and unknown molecular signaling system that is involved in regulating a broad spectrum of biological functions. Scientists call it “the endocannabinoid system,” (Shortened from Endogenous Cannabinoid System) after the plant that helped them discover it. The name suggests that the plant came first, but in fact, as Dr. John McPartland has explained, this ancient, internal system started evolving over 600 million years ago (long before cannabis appeared) when the most complex life form was sponges.

“By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance. We wouldn’t have been able to get there if we had not looked at the plant.” – Raphael Mechoulam, Dean of the Transnational Cannabinoid Research Community




The Scientist“: a documentary published by Fundación CANNA


McPartland, M, Guy G. “The evolution of Cannabis and coevolution with the cannabinoid receptor – a hypothesis,” in Guy, et al, eds., The Medicinal Uses of Cannabinoids; and McPartland JM et al “Evolutionary origins of the endocannabinoid system,” Gene. 2006;370:64-74.

“The Discovery of the Endocannabinoid System” by Martin Lee


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