The Endocannabinoid System 101

WRITTEN BY TRANG TRAN AND DR. SWATHI

The endocannabinoid system (ECS) is involved in various processes including learning and memory, pain, inflammation, appetite regulation, digestion, energy balance, sleep-wake cycle, and regulation of stress and emotions. It consists of three components: cannabinoid receptors, endogenous cannabinoids (i.e., cannabinoids that are produced inside the body, also known as endocannabinoids), and the enzymes (proteins) responsible for creating and breaking down the endocannabinoids.

What are cannabinoid receptors?

As of early 2022, two cannabinoid receptors have been discovered: cannabinoid type receptor 1 (CB1) and cannabinoid type receptor 2 (CB2). CB1 and CB2 mediate the effects of endocannabinoids.

In particular, CB1 receptor plays an important role in the central nervous system including emotional behavior (stress, fear, or anxiety) and cognition, and CB2 receptor seems to be a part of a general protective system (immune system). Whereas CB1 receptors are found abundantly in the brain, CB2 receptors are found primarily in cells of the immune systems. That being said, CB1 is also expressed in peripheral organs and non-brain cells such as fat cells, liver cells, and musculoskeletal tissues, and CB2 receptors are also expressed in the brain but at much lower levels compared to CB1.

Interestingly, cannabidiol (CBD), a well-known compound derived from the cannabis plant, does not have a direct interaction with CB1 or CB2 receptors. But the discovery of the cannabinoid receptors suggested that molecules that may stimulate or inhibit these receptors in the body are present.

What are endocannabinoids?

The two most studied cannabinoids that are produced in the body are N-arachidonylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG). Both AEA and 2-AG mediate the activation of CB1 and CB2. 2-AG is from peripheral tissues and favors CB2 receptors, AEA (also known as the bliss molecule) is a compound named after the Sanskrit word ananda meaning 'joy' or 'happiness' and favors CB1 receptors. Unlike chemical substances such as acetylcholine, dopamine, and serotonin, AEA and 2-AG are released on demand. The activation of the CB1 receptor by the endocannabinoids inhibits the release of various chemical substances in the brain. 

Are CBD and THC endocannabinoids?

The term endocannabinoid means 'cannabinoid' created in the body 'endo-'. CBD and tetrahydrocannabinol (THC) are created in the cannabis plant, and are therefore not endocannabinoids. They are sometimes referred to in research as exocannabinoids, meaning 'cannabinoid' created outside of the body 'exo-'.

What's the role of the ECS in health and disease?

An increase or decrease in ECS tone is associated with various disease-causing states. For example, individuals with obesity seem to exhibit an increased endocannabinoid tone, driving CB1 activation. Rimonabant, designed to block CB1 receptor, was approved for the treatment of obesity but was subsequently withdrawn from the market due to psychiatric side effects such as anxiety and depression.

In contrast to CB1 signaling which contributes to increased cardiovascular risk in humans with obesity, CB2 signaling in the heart may protect the heart. As can be seen, ECS seems to play a role in health and disease and thus emerges as a potential target of drug therapy.

References

1. Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 2017;22(1):105-110. doi:10.1016/j.drudis.2016.08.005
2. Fowler CJ. The endocannabinoid system - current implications for drug development. J Intern Med. 2021;290(1):2-26. doi:10.1111/joim.13229
3. Kruk-Slomka M, Dzik A, Budzynska B, Biala G. Endocannabinoid System: the Direct and Indirect Involvement in the Memory and Learning Processes-a Short Review. Mol Neurobiol. 2017;54(10):8332-8347. doi:10.1007/s12035-016-0313-5
4. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-525. doi:10.1016/j.biopsych.2015.07.028
5. McPartland JM, Guy GW, Di Marzo V. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014;9(3):e89566. Published 2014 Mar 12. doi:10.1371/journal.pone.0089566
6. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. doi:10.1146/annurev-psych-113011-143739
7. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389-462. doi:10.1124/pr.58.3.2
8. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease--successes and failures. FEBS J. 2013;280(9):1918-1943. doi:10.1111/febs.12260

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This article was edited by Dr. Swathi and was written by Element Apothec Scientific Communications Intern, Trang Tran. She is a Doctor of Pharmacy (PharmD) student at Oregon State University and Oregon Health & Science University College of Pharmacy in Portland, Oregon.