The Endocannabinoid System

By Dr. Jessica Knox, MD, MBA, Medical Cannabis Expert

The claims seem too good to be true — the cannabis plant is a natural panacea that can cure chronic pain, cancer, and PTSD; it relieves anxiety, tremors, and seizures; it rids the body of migraines, spasms, insomnia, and much more! Before you brush off the claims as hype — even if you already have — please consider the human body’s innate cannabinoid-driven circuitry.

At the heart of the cannabis plant’s wide-ranging effects on the human body is the endogenous cannabinoid or endocannabinoid system. Hardly unique to humans, the endocannabinoid system (henceforth: ECS) is common to most complex animals.1,2 Composed of cannabinoid (pronounced “kuh-nab-in-oid”) receptors, endogenous lipid-derived ligands, and the enzymes that synthesize and degrade those ligands, the ECS is a powerful communication system that drives survival and homeostasis.3

The roles of the ECS are frequently and briefly summarized as “relax, eat, sleep, forget, and protect.”4 Indeed, the ECS is involved in body processes as varied as pain relief, mood management, movement, blood pressure control, appetite and feeding, blood sugar control, sleep cycles, extinction of traumatic memories, inflammation, immunomodulation,5 neuroprotection,6 cancer immunosurveillance,7,8 and yes, even more.9 If our organs and organ systems make up the body’s symphony, the ECS is the maestro conducting the harmony.

CANNABINOID RECEPTORS (CB)

A key to cannabis’ diverse impact on the body is the distribution of the receptors with which the plant’s active components interact. CB1 receptors are the most abundant receptors in the brain.10 CB1 is also widely distributed throughout the spinal cord, fatty tissue, pancreas, liver, GI tract, skeletal muscles, heart, and the reproduction system.11,12 A second cannabinoid receptor, CB2, is distributed primarily in immune tissues,13 but can also be found in blood-producing cells, the pancreas, liver,14 and brainstem.15 There appear to be other receptors with which cannabinoids also interact, particularly in the vasculature and visceral organs.16

Importantly, there is only very low-level cannabinoid activity at the brain stem, which explains the significant safety of cannabis compared to opioids and alcohol, which can and do heavily impact brain stem activity. Because cannabis has very little, if any impact on the brain stem, it does not depress vital respiratory or cardiovascular functions.1

CANNABINOIDS

Cannabinioids are the molecules that interact directly with CB receptors, or indirectly by interacting with the molecules that bind to the receptors (the ligands). Endocannabinoids are those molecules synthesized by the body, while phytocannabinoids are plant-produced molecules that mimic the structure of endocannabinoids and interact with the ECS.

ENDOCANNABINOIDS

Many people are surprised to learn that our bodies produce their own cannabinoid molecules. However, the discovery of the CB receptors practically demanded the existence of our own cannabinoids, as it seems unlikely our bodies would express receptors solely attuned to plant molecules. Indeed, the identification of the two primary endocannabinoids swiftly followed that of the two primary CB receptors.16

Anandamide was the first identified endocannabinoid and was named after the Sanskrit word for “bliss” (“ananda”).17 Anandamide is broken down by fatty-acid amide hydrolase (FAAH).

2-AG (2-Arachidonoyl glycerol) was identified several years after anandamide.18

2-AG is degraded by monoacylglycerol lipase (MGL).

Anandamide and 2-AG are produced on-demand in the body in response to signaling between cells. These molecules bind to the CB1 and CB2 receptors like a key in a lock to turn on or off the signals that prompted their production. Once these ligands bind to the receptors, their degrading enzymes quickly break them down. This feedback loop controls crucial signaling patterns throughout the body.

There are several other endogenous molecules that mimic or support the effects of the endocannabinoids. Two of these molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), inhibit the action of FAAH in turn inhibiting the breakdown and enhancing the effect of anandamide.

CLINICAL RELEVANCE OF THE ECS

The ECS plays a central role to so many physical and psychological functions, and proper “endocannaboid tone” is vital to maintaining optimal health and wellness. You can likely imagine that a poorly functioning ECS might translate into a poorly functioning body. Indeed, numerous diseases, including several that are often poorly managed by conventional medicine, have been suggested to be associated with a dysfunctional or deficient ECS.19,20 Migraines, fibromyalgia, irritable bowel syndrome,21 obesity,12,22 and uncompensated schizophrenia are just some of the conditions connected to a suboptimal ECS.23

Replacement of deficient endocannabinoids or refinement of endocannabinoid activity by administration of exogenous cannabinoids (from the cannabis plant or other plant sources) can provide immense symptomatic relief and disease management or reversal.3,24,25 The cannabis plant provides phytocannabinoids and supporting molecules that act directly and indirectly on the ECS to restore and maintain its critical balance.11

This overview of the endocannabinoid system barely scrapes the surface of the physiologic function and importance of the ECS. I encourage you to continue reading about the ECS and learning about how cannabis can become a powerful medicine in your health toolkit. And look out for the MCBA Medical Committee’s ECS webinar coming out in March 2017!

References

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13. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65. doi:10.1038/365061a0.

14. Mallat A, Teixeira-Clerc F, Deveaux V, Manin S, Lotersztajn S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br J Pharmacol. 2011;163(7):1432–1440. doi:10.1111/j.1476–5381.2011.01397.x.

15. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310(5746):329–332. doi:10.1126/science.1115740.

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17. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949. http://www.ncbi.nlm.nih.gov/pubmed/1470919. Accessed January 10, 2015.

18. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83–90. http://www.ncbi.nlm.nih.gov/pubmed/7605349. Accessed December 7, 2015.

19. Glass M. The role of cannabinoids in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(4):743–765. http://www.ncbi.nlm.nih.gov/pubmed/11383976. Accessed January 10, 2016.

20. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 25(1–2):31–39. http://www.ncbi.nlm.nih.gov/pubmed/15159679. Accessed January 10, 2016.

21. Storr MA, Yüce B, Andrews CN, Sharkey KA. The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol Motil. 2008;20(8):857–868. doi:10.1111/j.1365–2982.2008.01175.x.

22. Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009;14(1):43–65. doi:10.1517/14728210902736568.

23. Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2014;35(3):198–201. http://www.ncbi.nlm.nih.gov/pubmed/24977967. Accessed January 10, 2016.

24. Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. 2006;46:101–122. doi:10.1146/annurev.pharmtox.46.120604.141254.

25. Baron EP. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache. 2015;55(6):885–916. doi:10.1111/head.12570.

Dr. Jessica Knox, MD, MBA, MPH

Co-founder of The Canna MDs and The American Cannabinoid Clinics

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