Key Milestones in Medical Use of Cannabis: the Discovery of the Endocannabinoid System

  • “By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” Raphael Mechoulam

For anybody interested in the increasing use of cannabis to treat medical conditions, it is worth recalling some of the scientific events underpinning this situation.

These events have not only helped to change our understanding of how cannabis exerts its effects in the human body, but also on our way of thinking about the potential uses of cannabis.

It began with a scientific breakthrough by a distinguished Israeli scientist, Raphael Mechoulam, who in 1964 was the first to isolate tetrahydrocannabinol [THC], one of the main constituents of cannabis, and describe its properties, and in particular its psychoactive potential.
Interestingly, Mechoulam had previously identified Cannabidiol [CBD]. Being able to isolate these cannabinoids was the first stepping stone in discovering the endocannabinoid system – a biological system that can be found in just about all vertebrates.
Endocannabinoids [those existing within the body] can be thought of as a bridge between body and mind. By understanding this system, scientists are better able to see the mechanisms that could connect brain and states of physical health and disease.
A key discovery in the 1980s was that of a receptor system in rats, which interacted with cannabinoid molecules.
In 1988, the first cannabinoid receptor was found in the brain of a rat. Initially found by Allyn Howlett and William Devane, these cannabinoid receptors turned out to be plentiful in the brain – more so than any other neurotransmitter receptor.
The existence of a cannabinoid receptor system in all mammals was thereafter recognised.
Cannabinoid receptors
Two years went by before the next significant development occurred in 1990 when Lisa Matsuda announced at the National Academy of Science’s Institute of Medicine that she and her colleagues at the National Institute of Mental Health had managed to analyse the DNA sequence that defines a THC-sensitive receptor in a rat’s brain.

“I believe that small, regular doses of cannabis might act as a tonic to our most central physiological healing system.”
– Dustin Sulak

In humans, these receptors are located in specific areas of the brain (basal ganglia, hippocampus, and cerebellum) where cognition and motion are controlled but notably absent in those areas of the lower brain controlling heart and lung functions.
Not long after this announcement they were able to clone successfully a receptor, thus enabling them to create molecules that “fit” or “activate” the receptors.
In 1993, a second cannabinoid receptor was found – as a part of the immune and nervous systems.
Named CB2 receptors (the CB receptors in the brain are termed CB1 receptors) they are found to control mental and physiological processes including memory, higher cognition, motor coordination, appetite and emotions among others.
Receptors for cannabinoids
These receptors sites bind cannabinoids and with nothing else, as was clearly pointed out in a detailed review published in 1993. n parallel, but independently of the research into the basic elements of the receptor system, it was realised that the pain reduction produced by cannabinoids occurred both within the spinal and supraspinal levels of the central nervous system.
In parallel, but independently of the research into the basic elements of the receptor system, it was realised that the pain reduction produced by cannabinoids occurred both within the spinal and supraspinal levels of the central nervous system.
A complementary development started in 1992, when the first naturally occurring
endocannabinoid, Anandamide, was discovered by Raphael Mechoulam as well as NIMH researchers William Devane and Dr. Lumir Hanus.
thc and anadamide molecule
This is one of two relatively well-understood endocannabinoids. It attaches to the same CB receptors as THC and it was named after the Sanskrit word for bliss.
A second endocannabinoid was subsequently discovered and identified in 1995, by none other than Mechoulam’s group yet again.
This second major endocannabinoid was termed 2-arachidonoylglycerol or “2-AG” to keep it simple. This particular endocannabinoid attaches to both CB1 and CB2 receptors.
It was these discoveries which allowed scientists to discover a hitherto unknown molecular signalling system that resides within us and within thousands of other biological lifeforms.
As a result of the diligent work of these pioneers we now understand the endocannabinoid system to be comprised of the following:
  • Endogenous arachidonate-based lipids, [anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG)]; these are known as “endocannabinoids” and are physiological ligands for the cannabinoid receptors (ligands are substances that form complexes with biomolecules to serve a biological purpose).  
  • The enzymes that synthesise and degrade the endocannabinoids, such as fatty acid amide hydrolase or monoacylglycerol lipase.
  • The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems.
  • The neurons, neural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all co-localised from the endocannabinoid system.
As such the endocannabinoid system is possibly the single-most important system within our body, responsible for maintaining homeostasis.
Endocannabinoid System
This one system helps to regulate almost every aspect of our well-being – meaning if we can learn to manipulate these receptors (with the use of cannabinoids from cannabis) we could possibly have the answer not only to curing diseases but also preventing them all together.
By supplementing naturally occurring endocannabinoids with the cannabinoids from cannabis could one manage, relieve or control the symptoms of a disease (such as Parkinson’s or Alzheimer’s) and even alter the pathology of cancer?
Might it be possible to use the same process to prevent such conditions in the first place? More research is needed as stated by Dustin Sulak of the American Academy of Cannabinoid Medicine:
“Research has shown that small doses of cannabinoids from cannabis can signal the body to make more endocannabinoids and build more cannabinoid receptors. This is why many first-time cannabis users don’t feel an effect, but by their second or third time using the herb they have built more cannabinoid receptors and are ready to respond. More receptors increase a person’s sensitivity to cannabinoids; smaller doses have larger effects, and the individual has an enhanced baseline of endocannabinoid activity. I believe that small, regular doses of cannabis might act as a tonic to our most central physiological healing system.”

References and further Reading

1. Gaoni, Y. and Mechoulam, R. (1964). Isolation, structure and partial synthesis of an active constituent of Hashish. Journal of the American Chemical Society 86, 1646–1647.

2. Devane, W.A., Dysarz, F.A. 3rd, Johnson, M.R., Melvin, L.S. and Howlett, A.C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology 34, 605–613.

3. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. and Bonner, T.I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.

4. Munro, S., Thomas, K.L. and Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65.

5. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A. and Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258, 1946–1949.
(1995). Pertwee, R.G., Griffin, G., Bayewitch, M., Barg, J. and Vogel, Z.

6. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology 50, 83–90.

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