According to a survey carried out by Medical Cannabis Evaluation in 2013, only 13% of medical schools in the United States teach the endocannabinoid system (ECS) as part of their curriculum. Why have medical institutions taken so little interest in such a vital system? The simple answer is “ignorance.” Decades of cannabis prohibition did a lot to hinder research on medicinal cannabis, even though the plant has been used as medicine since time immemorial.
The Long Trek to Freedom: Discovery of the Endocannabinoid System
The journey commenced in the middle of the 20th century and was a joint effort by a group of scientists. In the 1960s, Robert Mechoulam, an Israeli scientist, was keen on finding the healing compounds in the cannabis plant. Indeed, the use of cannabis traces its roots back to ancient civilizations that sprouted along banks of great rivers such as the Indus River in India, Hwang-Ho in China, and the rivers Tigris and Euphrates in Mesopotamia. Ancient communities acknowledged that cannabis had healing properties, the same properties that Dr. Mechoulam was studying in the 1960s.
In 1964, Dr. Mechoulam made a milestone discovery when he isolated the first cannabinoid in cannabis Sativa, which was named Delta-9 tetrahydrocannabinol (THC). He continued his research, and a few years later, he was able to isolate the second cannabinoid, which was named cannabidiol (CBD). In 1986, Mechoulam published the book “Cannabinoids as Therapeutic Agents.” Here he outlined the therapeutic benefits of the cannabis plant, but at this point, it still was not clear how this plant was able to interact with the human body to perform healing.
Around 1988, Allyn Howlett and William Devane, through a US government-funded study, discovered endocannabinoid receptors in the mammalian brain. These receptors happened to be more abundant than any neurotransmitter in the brain.
Two years later, another team of scientists led by Lisa A. Matsuda isolated the DNA sequence of the first cannabinoid receptor – CB1 – in a rat’s brain. Note that the ’90s was referred to as “the decade of the brain,” because of the numerous advances in neuroscience that happened in this decade. The CB1 receptor was found to be concentrated in regions that control memory, motor coordination, appetite, thinking, emotions, and movement.
The CB2 receptor was identified soon after, and it was found predominantly in the immune system and peripheral nervous system. This includes the gut, spleen, liver, lymph glands, endocrine glands, and reproductive organs.
In 1992, a team led by Israeli professor Dr. Mechoulam identified an endogenous molecule that interacts with the CB1 receptor. They named this endocannabinoid anandamide, which means bliss. In 1995, the second endocannabinoid was isolated and called – 2-arachidonoylglycerol, or “2-AG”; this molecule binds to both the CB1 and CB2 receptors. A third receptor has been identified and named GPR55; it has been associated with anti-cancer effects. The endocannabinoid system has been found in all mammals, reptiles, and other animals apart from insects.
In summary, Robert Mechoulam wraps this journey up in such a beautiful way:
“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.”
Metabolic Enzymes Play a Role
To complete the picture, scientists identified metabolic enzymes, abbreviated as FAAH and MAGL, that degrade the endocannabinoids. An enzyme called FAAH is responsible for breaking down anandamide, while another called MAGL is responsible for breaking down 2-AG. This means that endocannabinoids, unlike phytocannabinoids, do not accumulate in the body. Endocannabinoids are released on an as-needed basis.
Putting all this together, they identified a molecular signaling system spread through the entire body whose primary role is to maintain physiological balance in the body. This is called the endocannabinoid system.
Therefore, the endocannabinoid system is made up of:
ï Endocannabinoid receptors located in various parts of the body: CB1 and CB2
ï Endocannabinoids: anandamide and 2-AG
- Metabolic enzymes: FAAH and MAGL
Endocannabinoids work in a retrograde manner, which is different from how other neurotransmitters work. Most neurotransmitters are released from a cell known as a presynaptic cell, and they cross a synapse (gap) to get to postsynaptic cells, triggering an action. Endocannabinoids work in the opposite manner. They are released from the postsynaptic cells, cross the synaptic junction and get to the presynaptic cells, where they bind to endocannabinoid receptors. This is what is referred to as a retrograde mechanism.
Unlike other neurotransmitters, endocannabinoids are manufactured on demand. Acting in a retrograde fashion allows endocannabinoids to have control over the release of other neurotransmitters. They work as a “dimmer switch” to regulate the release and functioning of other neurotransmitters.
The Endocannabinoid System and Homeostasis
Britannica defines homeostasis as “any self-regulating process by which biological systems tend to maintain stability while adjusting to conditions that are optimal for survival.”
Homeostasis is the balance of the internal environment of the body. This means when the external conditions fluctuate, the internal mechanism adjusts to ensure that the internal environment remains in check. For example, when the external temperatures increase, the body initiates mechanisms such as sweating so that the body temperature remains moderate. The same applies to hormonal levels, hunger, and other important functions in the body.
Through the interactions of endocannabinoids with endocannabinoid receptors, the body is able to keep all systems in check. Some important functions regulated by the ECS are:
- Motor control
What’s Next for the Endocannabinoid System?
Now that there are fewer restrictions on cannabis research, we hope that the ECS will be demystified even more. This may mean more funding for cannabis research, larger clinical trials, and more evidence-based guidelines in the use of cannabis as a potential treatment for various diseases.
- Mediawix (2013): A Survey of American Medical School’s Acceptance of the Science of the ECS. Retrieved from http://media.wix.com/ugd/b72a4e_e88348b93436e74dea366be39a6b47e2.pdf
- Beyond THC: The Discovery of the Endocannabinoid System. Retrieved from https://www.beyondthc.com/wp-content/uploads/2012/07/eCBSystemLee.pdf
- Drug Library. org: Marijuana – The First Twelve Thousand Years. Retrieved from http://www.druglibrary.org/schaffer/hemp/history/first12000/1.htm
- NCBI (2013): Modulating the endocannabinoid system in human health and disease–successes and failures. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23551849/
- NCBI (2018): Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877694/