The endocannabinoid system

First published April 2023, revised and referenced September 2026

The endocannabinoid system (ECS) is a signalling system with a major influence on how the body works. It modulates appetite, sleep, pain, memory, mood and the response to inflammation, among much else.¹ By helping to keep these processes in balance, it keeps the parts of the body working in harmony with one another.

Homeostasis

Homeostasis is how the body regulates things like water content, temperature and blood sugar. For the body to function properly it must stay within a narrow range, and it does so through feedback: it constantly monitors itself and corrects what drifts. The endocannabinoid system is one of the systems that does this correcting, particularly in the nervous and immune systems.^1,2

A recent discovery

The ECS was characterised only in the early 1990s, so it has been known for roughly 35 years. The first cannabinoid receptor, CB1, was cloned in 1990 at the National Institutes of Health in the United States,³ and the second, CB2, in Cambridge in 1993.⁵ The first compound the body makes to act on these receptors, anandamide, was isolated in Jerusalem in 1992 by Raphael Mechoulam’s group, with the Czech chemist Lumír Hanuš among its discoverers,⁴ and the second, 2-AG, was identified independently in Israel and Japan in 1995.^6,7 The work began as an attempt to explain how THC acts on the body, and ended by revealing a signalling system of its own.

The three main parts of the system are endocannabinoids, cannabinoid receptors, and the enzymes that make and break down endocannabinoids.

Endocannabinoids

Like neurotransmitters such as dopamine and serotonin, endocannabinoids act as chemical messengers, and they are produced throughout the body. The two best known are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Anandamide was named by its discoverers in Mechoulam’s laboratory after the Sanskrit word ananda, meaning bliss.⁴ It is involved in memory, appetite and mood, and endocannabinoids, rather than endorphins, are now the leading candidate explanation for the runner’s high: in a placebo-controlled study, the euphoria and reduced anxiety after 45 minutes of running persisted when opioid receptors were blocked, while blood levels of anandamide and 2-AG rose.^8,9

Cannabinoid receptors

If endocannabinoids are messengers, receptors are the sentries waiting for them. They sit on the surface of cells throughout the body. CB1 is concentrated in the brain, where it affects mood, memory, movement and pain perception, and is one of the most abundant receptors of its kind in the central nervous system.¹⁰ CB2 is most abundant in immune tissues, with lower expression elsewhere, and influences inflammatory processes.^5,1 THC activates CB1 directly, which is what produces its psychoactive effects. CBD works differently: it has a low affinity for the receptor itself, dampens CB1 signalling rather than switching it on, and acts on a range of other targets in the nervous system.^11,12

Enzymes

Endocannabinoids are lipids, formed from fats in the cell membrane. Unlike most neurotransmitters they are not stored in advance but made on demand, and are then broken down quickly by dedicated enzymes, mainly FAAH for anandamide and MAGL for 2-AG. That short life is part of why the system works as a fine-tuning mechanism rather than a switch.¹

Cannabinoids from the plant

Well over 100 cannabinoids have been identified in cannabis (125 in the most recent systematic inventory), among more than 500 compounds in total.^13,14 Because they are produced by the plant they are called phytocannabinoids. Their effects mimic or modulate those of the body’s own endocannabinoids: put simply, they can act on the same system when there is a problem that adjusting it could address.

THC

THC is the most abundant cannabinoid in THC-dominant medical varieties and the one responsible for the characteristic high. It is also the cannabinoid with the most clinical trial evidence. The two largest independent syntheses, a 2015 meta-analysis of 79 randomised trials and the 2017 report of the US National Academies, found the strongest evidence for chronic pain in adults, for chemotherapy-induced nausea and vomiting, and for patient-reported spasticity in multiple sclerosis, with weaker evidence for short-term sleep improvement.^15,16 Some patients use it for post-traumatic stress disorder, but the trial evidence there is limited and inconclusive.^16,17

Its psychotropic effects can be an obstacle for some patients. Depending on dose it can cause dizziness, confusion, anxiety, impaired coordination and thinking, and an altered sense of time.¹⁵ Under medical supervision these are usually minimised by the rule of start low, go slow: begin with a small dose and increase it gradually over days or weeks, preferably with CBD alongside it.¹⁸

CBD

CBD is the main non-psychoactive cannabinoid, though it can alter mood by easing anxiety. The World Health Organization’s Expert Committee on Drug Dependence concluded in 2018 that CBD has been shown in clinical trials to be an effective treatment for several forms of epilepsy, that it is generally well tolerated, and that it shows no effects indicative of abuse or dependence. For other conditions, including Parkinson’s disease, Alzheimer’s disease and psychosis, the committee described the evidence as preliminary and largely from laboratory and animal studies.¹⁹ Its therapeutic potential is still being mapped.

The entourage effect

Each cannabinoid has its own effects, and the proposal that cannabinoids and terpenes administered together work better than each does separately is known as the entourage effect.^24,20 It is a plausible hypothesis with some laboratory support, but it has not been established in controlled clinical trials, and its pharmacological basis is still debated.^21,22

Endocannabinoid deficiency

If the body produces its own endocannabinoids, why supplement them? One proposal is that the body can have difficulty producing enough, or regulating the system properly. Ethan Russo, a neurologist and psychopharmacologist, has argued that a clinical endocannabinoid deficiency could underlie conditions such as fibromyalgia, irritable bowel syndrome and migraine.²³ It remains a hypothesis, supported by some biochemical findings, rather than an established diagnosis.

References

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16. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press; 2017. doi:10.17226/24625
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Adapted from material originally written for Motagon by Lukáš Hurt, revised and referenced September 2026. Reviewed by [name, role], Motagon s.r.o. Last reviewed 21 September 2026.