The Human Endocannabinoid System (ECS): A Guide

Ever wondered why cannabis has certain effects on the human body? The answer relates to the endocannabinoid system—it’s probably our most significant physiological system for moderating and maintaining human health. 

The discovery of the human endocannabinoid system itself might never have happened if people didn’t consume cannabis. Questions about the plant’s impact on people have driven researchers to study cannabis, which has resulted in many unexpected learnings about our own bodies. (Kind of amazing, right?) [Source] 

If you want to learn more, keep reading our go-to guide of the human endocannabinoid system (ECS). We’ll cover exactly how it was discovered, what it is, what it does, and how cannabis interacts with it. 

Highlights 

• The endocannabinoid system is a complex and widespread network that plays an important role in the central nervous system. 
• ESC is responsible for maintaining physiological homeostasis or a balance that helps us function on a daily basis. 
• An interesting paradox: Humans might have never discovered the ECS if we had no cannabis—and if humans had no ECS, we might have never discovered cannabis.

How the human endocannabinoid system was discovered 

It all begins with cannabis. Human use of the plant in a variety of applications dates back thousands of years and spans many cultures across the globe. [Source] 

However, it wasn’t until 1964 that we took the first steps toward discovering the ECS. That year, in Rehovot, Israel, Dr. Raphael Mechoulam and his colleagues at the Weizmann Institute of Science successfully isolated and synthesized the psychoactive cannabinoid in cannabis: delta-9-tetrahydrocannabinol, also known as THC. Next, they synthesized cannabidiol or CBD found in hemp. [Source] 

This cannabinoid research continued in earnest from the 1970s through the 1990s, when Mechoulam isolated the first endogenous cannabinoid. This discovery of endocannabinoids existing in our bodies opened the door to a previously unknown and exciting new physiological system, the endocannabinoid system. [Source] 

For launching a cannabis revolution that continues to this day and shows no signs of slowing, Mechoulam has become known as the “Father of Cannabis Research.”

What is the endocannabinoid system? 

Scientists are currently investigating the vast and very complex cell-signaling endocannabinoid system. There are still many unknowns, but they’ve confirmed the ECS is responsible for moderating and maintaining a proper operating balance or homeostasis within nearly every physiological process employed by our bodies to keep us functioning on a moment-to-moment, 24/7 basis. [Source] 

And the ECS is not unique to humans. In fact, all mammals, fish, birds, and reptiles have an ECS for maintaining physiological homeostasis, a term derived from the Greek words for “same” and “steady.” [Source] 

Homeostasis is the primary mission of the endocannabinoid system. Some of the many processes maintained by the ECS include appetite, cardiovascular function, energy, pain, reproduction, reward perception, sleep, and stress, as well as responding to endogenous (inside the body) and exogenous (outside the body) environmental conditions. [Source] 

Key components of the endocannabinoid system 

The ECS contains three key components: endocannabinoid molecules that send signals, cannabinoid receptors found on the surface of cells that receive those signals, and metabolic enzymes that destroy the endocannabinoids after their signals have been received by the endocannabinoid receptors. These three components are present throughout our bodies, including our nervous systems, virtually every brain cell, the immune cells in our blood, across the full axis of the spinal cord, and even on our skin cells. [Source] 

Make sense so far? Great! Now, let’s look at the key components of the ECS in greater detail. 

Endocannabinoids 

Endocannabinoids are small fatty acid neurotransmitter molecules produced within the membranes of our cells. The ECS creates them on-demand, meaning they are produced precisely where and only when they are needed. As soon as they are created, endocannabinoids seek out cannabinoid receptors and bind to them. 

There are two key endocannabinoids found in the ECS: 

• Anandamide: Also known as the “bliss molecule.” The name is derived from ananda, a Sanskrit word for bliss, delight, or joy. Its chemical compound name is N-arachidonoylethanolamine (AEA), first identified and named by Mechoulam, Devane and Lumír Hanuš in 1992. Anandamide is believed to have an impact on the early stages of embryo development and on memory functions, but studies may reveal more details.[Source]
• 2-AG: Abbreviated from 2-Arachidonoyl Glycerol, 2-AG was identified as an endocannabinoid by Mechoulam and his student, Shimon Ben-Shabat in 1994-1995. Although the presence of 2-AG was previously recorded, it was Mechoulam and Ben-Shabat who discovered its interaction with cannabinoid receptors in the ECS. A high level of 2-AG is found in the central nervous system (CNS), and it’s also present in human and bovine maternal milk.[Source]

  

Cannabinoid receptors 

Cannabinoid (CB) receptors are G proteins residing on cell surfaces, continuously monitoring external conditions. When an Anandamide or 2-AG endocannabinoid binds with a CB receptor, signals are transmitted into the cell on which the cannabinoid receptor resides. This initiates an appropriate response, determined by the location and type of CB receptor, as well as the type of endocannabinoid that binds with it. Endocannabinoids may also bind to TRPV proteins that function similarly to cannabinoid receptors in the ECS. [Source] 

Here’s what we know about CB1, CB2, and TRPV receptors in the ECS: 

• CB1 Receptor:Found mostly in the central nervous system and highly expressed throughout the brain, CB1 receptors serve as targets for both endogenous cannabinoids produced by our bodies and phytocannabinoids produced by the cannabis plant. CB1 is the psychotropic/psychoactive CB receptor responsible for producing the state-altering effect associated with THC in cannabis products. 
• CB2 receptor:Also serving as targets for both endocannabinoids and phytocannabinoids, CB2 receptors are found throughout the body but are more abundant in the peripheral nervous system and on immune cells circulating in the brain and body via the bloodstream. 
• TRPV:Acting as “ionotropic cannabinoid receptors,” members of the transient receptor potential (TRP) ion channel family interact with the ECS to modulate skin-based sensory processes like pain, temperature, itch perception, and dermatitis conditions. 

Metabolic enzymes 

The third key component of the ECS is metabolic enzymes responsible for destroying endocannabinoids when they are no longer needed by the ECS. There are two primary ECS enzymes: 

• FAAH: Fatty Acid Amide Hydrolase, which metabolizes Anandamide (AEA) 
• MAGL: MonoAcylGlycerol Acid Lipase, which breaks down 2-AG [Source]

Key functions of the endocannabinoid system 

Driven by the overarching mission of homeostasis, the endocannabinoid system has evolved incredibly dynamic and complex mechanisms for achieving and maintaining optimum physiological performance. Scientists around the world are beginning to rigorously investigate the many functions of the mysterious ECS. 

Less than 30 years have passed since the discovery of the ECS, but researchers have already achieved remarkable success identifying many key roles and functions. Certainly, there are more great discoveries still waiting in the wings, but the list of scientifically identified physiological functions moderated by the ECS on a 24/7 basis is impressive, to say the least. 

Bodily functions under ECS control via activation of CB1 receptors: 

• Appetite and weight 
• Bone physiology 
• Bronchodilation 
• Cardiovascular function 
• Digestion 
• Emotional behavior 
• Energy Metabolism 
• Inflammation 
• Intraocular pressure 
• Liver function 
• Memory and cognition 
• Motor control 
• Muscle fiber formation 
• Nausea and vomiting 
• Neural development 
• Neuroprotection 
• Pain relief 
• Reproductive functions 
• Reward sensation 
• Sensory perception 
• Sleep processes 
• Temperature control 
• Tumor surveillance 

Bodily functions under ECS control via interaction with CB2 receptors: 

• Cramps and pain in inflammatory bowel conditions 
• Immune functions 
• Inflammation 
• Kidney functions 
• Liver functions 
• Nausea and vomiting 
• Neuroprotection 
• Pain relief 

[Source] 

How the ECS interacts with phytocannabinoids 

Phytocannabinoids are cannabinoids produced naturally in cannabis plants. As it turns out, our ECS interacts with the phytocannabinoids in cannabis almost identically as with our own endocannabinoids. 

Researching the psychoactive effects of phytocannabinoids led us to the ECS, which in turn led us to endocannabinoids. Now we are returning to the source, researching how phytocannabinoids might interact with the ECS to potentially benefit human health. 

Astoundingly, our need to know why marijuana has such interesting effects on us has produced a wealth of compelling research and inspired an entirely new market sector for cannabis pharmaceuticals and pharmacotherapeutics. A May 2020 market analysis report predicts the global cannabis pharmaceuticals market will grow at a compound annual rate of 76.8% from 2020 through 2027. 

Over 400 chemical compounds produced in cannabis have been identified to date. At least 104 of these compounds are phytocannabinoids unique to cannabis. Scientists have identified potentially promising improvements in healthcare with synthesized cannabinoid-based pharmaceuticals. [Source] 

• THC (delta-9-tetrahydrocannabinol): One of the two most abundant cannabinoids found in cannabis, THC interacts with the ECS by binding to both CB1 and CB2 receptors. THC is the phytocannabinoid that gets you intoxicated upon binding with the CB1 receptor in ways similar to anandamide, the “bliss” endocannabinoid molecule, but THC lasts much longer in our systems.[Source]
• THCV (delta-9-tetrahydrocannabivarin): THCV is a naturally occurring phytocannabinoid analog of THC which, unlike THC, isn’t psychotropic/psychoactive. It interacts with the ECS via CB1 antagonist / reverse agonist, producing decreased appetite effects of potential value in obesity management.[Source]
• CBD (cannabidiol): The second of the two most abundant cannabinoids found in cannabis, CBD doesn’t bind well with CB1 or CB2. It may interact with the ECS by binding with an unknown receptor.[Source]
• CBC (cannabichromene): CBC binds with CB2, TRPA1, and TRPV1 receptors in the ECS and helps release increased levels of endocannabinoids for enhanced health benefits.[Source]
• CBG (cannabigerol): Although there is far less CBG in cannabis than CBD, CBG binds directly to both CB1 and CB2 receptors, so it might interact more efficiently with the ECS and potentially deliver more beneficial therapeutic effects.[Source]

Looking ahead: the ECS and healthcare 

“We are truly at the dawn of an age of discovery,” writes Dr. Peter Grinspoon of Harvard Medical School, referring to the development of new medicines targeting the ECS to “help alleviate some of the cruelest diseases that people (and animals) suffer from.” [Source] 

Echoing the sentiments of so many in the science and medical communities, Dr. Grinspoon adds, “I am incredibly excited to see what discoveries await us as we continue to untangle the mysteries of the ECS.” 

Curious about cannabis? 

Do you have questions about specific cannabinoids, or cannabis in general? Would you like a consultation? Visit your local RISE Dispensary—our friendly, knowledgeable staff is here happy to help!

Sources:

• Brand EJ, Zhao Z. Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids?. Front Pharmacol. 2017;8:108. Published 2017 Mar 10. doi:10.3389/fphar.2017.00108
• Crocq MA. History of cannabis and the endocannabinoid system
. Dialogues Clin Neurosci. 2020;22(3):223-228. doi:10.31887/DCNS.2020.22.3/mcrocq
• Did You Know… Marijuana Was Once a Legal Cross-Border Import? | U.S. Customs and Border Protection
• Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish Y. Gaoni and R. Mechoulam Journal of the American Chemical Society 1964 86 (8), 1646-1647 DOI: 10.1021/ja01062a046
• Mechoulam, R, Marihuana Chemistry, Science 168: 1159 (1970)
• Silver RJ. The Endocannabinoid System of Animals. Animals (Basel). 2019;9(9):686. Published 2019 Sep 16. doi:10.3390/ani9090686
• Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International Journal of Molecular Sciences. 2018; 19(3):833. https://doi.org/10.3390/ijms19030833
• 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
• Hanus LO. Discovery and isolation of anandamide and other endocannabinoids. Chem Biodivers. 2007;4(8):1828-1841. doi:10.1002/cbdv.200790154
• 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. doi:10.1016/0006-2952(95)00109-d
• Basavarajappa BS. Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett. 2007;14(3):237-246. doi:10.2174/092986607780090829
• Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3):833. Published 2018 Mar 13. doi:10.3390/ijms19030833
• Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241-254. doi:10.1177/2045125312457586
• Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi:10.1007/978-3-319-45541-9_4
• 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
• The endocannabinoid system: Essential and mysterious – Harvard Health
• Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147 Suppl 1(Suppl 1):S163-S171. doi:10.1038/sj.bjp.0706406
• Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol. 1998;359(1):1-18. doi:10.1016/s0014-2999(98)00649-9
• Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. doi:10.1146/annurev-psych-113011-143739
• Pier Vincenzo Piazza, Daniela Cota, Giovanni Marsicano, The CB1 Receptor as the Cornerstone of Exostasis, Neuron, Volume 93, Issue 6, 2017, Pages 1252-1274, ISSN 0896-6273, https://doi.org/10.1016/j.neuron.2017.02.002. (https://www.sciencedirect.com/science/article/pii/S0896627317300594)
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