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  • Writer's pictureTravis Cesarone

What is the endocannabinoid system?

Updated: Feb 8, 2023


Historical literature documented the psychoactive components of cannabis thousands of years ago. Spiritual wisdom on nature’s compounds turned to quantitative endeavors within science. New analytical inventions exposed cannabis’s molecular structure centuries later, leading scientists to understand the plant’s mysterious effect on consumers. Discoveries tied together over two centuries now map an extensive endocannabinoid system found in nearly every animal.


Cannabinoid-specific receptors

Ingredients particular to cannabis are responsible for its predominant effects. Those ingredients, identified between 1869 (1) to 1964 (2), are known as phytocannabinoids due to their structure and cannabis origin. Allyn Howlett discovered a biological target preferred by tetrahydrocannabinol (THC) in 1988, known as the cannabinoid receptor. (3)


Howlett and her colleagues elucidated the gene that codes for CB1 receptors two years after publishing their initial discovery. (4) One year later, in 1993, researchers from Cambridge discovered a peripheral cannabinoid receptor. The discovery achieved by Sean Munro, Kerrie Yhonas, and Muna Abu-Shaar became known as the CB2 receptor. (5)


When were ‘endo’ cannabinoids elucidated?

Between discovering the two cannabinoid receptors, scientists discovered a blissful signaling molecule in mammals. N-arachidonoyl ethanolamine was found in a porcine brain specimen by a research team, published in late 1992. Coauthors included William Devane, Lumir Hanuš, Roger Pertwee, and seven colleagues, including Raphael Mechoulam. (6) Professor Mechoulam previously elucidated THC with Nuclear Magnetic Resonance (NMR) in 1964. (2)


The team named the molecule anandamide after the Sanskrit word for bliss — ananda. They discovered that, similar to THC, the endogenous molecule responds to CB1 receptors. Anandamide endogenously activates cannabinoid receptors inside mammals and most vertebrates. (7)



Does THC unlock 2-AG?

Three years after discovering the first endogenous cannabinoid, a dozen colleagues, including Hanuš, Pertwee, and Mechoulam,  found 2-Arachidonoyl-glycerol (2-AG) in canines. Their findings, published in 1995, confirmed that the new biological molecule activates simultaneous targets relative to THC. (8) Papers co-authored by Mechoulam and Hanuš between 1992 and 1995 used the verbiage — endogenous cannabinoid.


It was not, however, until September 1996 that Vincenzo Di Marzo, Petrocellis, Suigiura, and Waka published a study on cannabimimetic eicosanoids. The paper described the newly discovered transmitters as endocannabinoids. (9) Di Marzo and his co-authors were the first to document the compounded phrase, according to an in silico literary analysis by Uprooted Concepts.


Common knowledge interprets phytocannabinoids as keys that unlock their endogenous counterparts. A recent clinical trial confirmed the notion that anandamide correlates with THC. In contrast, 2-AG levels remained neutral after cannabinoid exposure. (10)


How are endocannabinoids made and destroyed?

2-AG and anandamide, alongside their associated receptors, are central in the endocannabinoid system. And these endocannabinoids come from different fatty acids. 2-AG can derive from lipids that protect cells, and anandamide comes from dietary fats.


A set of enzymes, tiny biological machines, must metabolize precursor fats (lipids) into endocannabinoids and their associated ligands. And different enzymes break down endocannabinoids into either pro or anti-inflammatory metabolites. Arachidonic acid, for example, is an inflammatory precursor and metabolite of 2-AG and anandamide.


Between biosynthesis and degradation, endocannabinoids exist as counterweights in an inflammatory pendulum. Several enzymes work to maintain a stable ECS, which activates on demand. FAAH, for example, is partially responsible for breaking down anandamide. (11, 12) Whereas a monoglycerol enzyme known as MAGl primarily deactivates 2-AG. (13)


What turns the ECS on and off?

The endocannabinoid system maintains homeostasis throughout the body and brain. At the same time, the ECS further keeps itself in check. It responds to stress and activates in selective environments rich in ionic activity. Specifically, acute quantities of calcium ions flowing through various nerves and receptors can turn on the endocannabinoid system.


In contrast, two hormones turn down ECS tone by picking up the FAAH enzyme, which degrades anandamide. Leptin, involved in diet, and the sex hormone, progesterone, separately upregulate FAAH. (14) Turning off the peripheral ECS is, in essence, part of the body’s natural rhythm.


CBD also inhibits FAAH. Contrary to popular biochemical interpretations, though, CBD might not protect anandamide. Participants in a clinical trial funded by Medical Research Council in the United Kingdom received 30 milligram doses of CBD. Endocannabinoid tone was not affected by the dose. (10)



Cannabinoid receptors in the peripheral and central nervous systems (CNS) must remain constantly activated by their associated endogenous cannabinoids. Otherwise, THC can exogenously turn on the ECS. Too much presynaptic activity by THC or 2-AG can, however, cause CB1 receptors throughout the nervous system to build a tolerance by shutting down.


Their endogenous purpose

The endocannabinoid system, comprised of a few key receptors and bio-active lipids, is a primary regulator of many organs and biological processes. Endocannabinoid depletion leads to many diseases and ailments, both physical and mental. Huntington’s Disease depends on a degenerative gene that destroys CB1 receptors to induce neurological symptoms.


The endocannabinoid system itself is part of a deep network known as the endocannabinoidome. Anandamide’s family, for example, has several members with various physiological properties. Microbiota and most endogenous systems depend on the network’s adaptation and many mechanisms to sustain homeostasis.


Sources

  1. Cahn RS. Cxxi. —cannabis indica resin. Part i. The constitution of nitrocannabinolactone(Oxycannabin). J Chem Soc. 1930;(0):986-992.

  2. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86(8):1646-1647.

  3. Devane, W. A., Dysarz, F. A., 3rd, Johnson, M. R., Melvin, L. S., & Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular pharmacology, 34(5), 605–613.

  4. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346(6284), 561–564.

  5. Munro, S., Thomas, K. L., & Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365(6441), 61–65.

  6. Devane, W. A., Hanus, L., Breuer, A., Pertwee, R. G., Stevenson, L. A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., & Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (New York, N.Y.), 258(5090), 1946–1949.

  7. McPartland, J. M., Agraval, J., Gleeson, D., Heasman, K., & Glass, M. (2006). Cannabinoid receptors in invertebrates. Journal of evolutionary biology, 19(2), 366–373.

  8. 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. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical pharmacology, 50(1), 83–90.

  9. Di Marzo, V., De Petrocellis, L., Sugiura, T., & Waku, K. (1996). Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochemical and biophysical research communications, 227(1), 281–288.

  10. Chester, L. A., Englund, A., Chesney, E., Oliver, D., Wilson, J., Sovi, S., Dickens, A. M., Oresic, M., Linderman, T., Hodsoll, J., Minichino, A., Strang, J., Murray, R. M., Freeman, T. P., & McGuire, P. (2022). Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study. Cannabis and cannabinoid research, 10.1089/can.2022.0174. Advance online publication.

  11. Deutsch, D. G., & Chin, S. A. (1993). Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochemical pharmacology, 46(5), 791–796.

  12. Cravatt, B., Giang, D., Mayfield, S. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996).

  13. Di Marzo, V., & Maccarrone, M. (2008). FAAH and anandamide: is 2-AG really the odd one out?. Trends in pharmacological sciences, 29(5), 229–233.

  14. Gasperi, V., Fezza, F., Spagnuolo, P., Pasquariello, N., & Maccarrone, M. (2005). Further insights into the regulation of human FAAH by progesterone and leptin implications for endogenous levels of anandamide and apoptosis of immune and neuronal cells. Neurotoxicology, 26(5), 811–817.


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