The Human Endocannabinoid System

endocannabinoidThe endogenous cannabinoid (or “endocannabinoid”) system is a complex, widely dispersed neuromodulatory system that some consider to have the ultimate responsibility for “homeostasis” (that is, the maintenance of “steady state,” or “normal”) in the human body. Homeostasis has also been called “biological harmony in response to changes in the environment.”1 In fact, the endocannabinoid system (ECS) is very old from an evolutionary perspective, and is present in all vertebrates. It is comprised of a receptor system (with at least two different specialized receptors, aptly named CB1 and CB2, “endocannabinoids” (natural, endogenous, cannabis-like substances), and a series of endogenous enzymes responsible for the synthesis and degradation of endocannabinoids. These “native” chemicals, present in all humans, are small molecules derived from arachidonic acid, and are termed anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG). These chemicals bind to a family of G-protein-coupled receptors.* The CB1 receptor is densely populated in areas of the brain linked to motor (muscle) control, cognition and reasoning, emotional responses and motivated behavior, and overall homeostasis. The CB2 receptor appears diffusely throughout the body, where it is integrally involved in modulating the autonomic nervous system, the immune response system, various inflammatory pathways, and the microcirculation. These receptors are found in skin, immune cells, bone, fat tissue, liver, pancreas, skeletal muscle, heart, blood vessels, kidney, gastrointestinal tract, and the female reproductive tract.

The endocannabinoid molecules—which in effect are neurotransmitters like dopamine or serotonin or acetylcholine–are released upon demand and then serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. These molecules normally have very short duration of activity, as they are avidly degraded by two well-characterized enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase.

The ECS is involved in an incredibly wide variety of bodily processes, including pain, memory, mood, appetite, stress, sleep, metabolism, immune function, and reproductive function. This makes the ECS a very attractive target for therapeutic agents. While we don’t understand the complex interactions between all of the components of the cannabis plant and these innate receptors that seem to have been “built” to accommodate the endogenous cannabinoids, we do know that manipulation of the ECS can have measurable consequences that go beyond the dissociative “high” associated with smoking pot. The primary psychoactive ingredient in the Cannabis plant—delta-(9)-tetrahydrocannabinol, or THC—is an agonist of the CB1 receptor. Exogenous agents can be ECS receptor agonists or antagonists, they can be partial agonists or antagonists, or they can block the action of the endocannabinoid degrading enzymes, giving the endocannabinoids a prolonged, supraphysiologic effect that may be similar to the administration of exogenous cannabinoids. In general, we think of the two main and best-characterized cannabinoids from the Cannabis plant—THC and cannabidiol (CBD)—as working in very different ways. THC is a direct CB1 agonist and has limited effects at the CB2 receptor. CBD is a weak antagonist at the CB1 receptor, and in fact may to some extent counteract the effects of THC there; CBD is an inverse agonist of the CB2 receptor, thus weakening its efficiency, and likely resulting in at least part of the anti-inflammatory effect ascribed to CBD. More than THC, however, it seems that CBD has diverse, pleiotropic effects—that is, it has the biologic potential to influence a wide range of various other regulatory systems in the body.

We’ll have separate and more detailed posts about THC and CBD, but just keep in mind that our understanding of their various effects in the body is vastly more sophisticated than it was even in the recent past, mainly because of our increased understanding of the body’s native system for reacting with Cannabis—the endocannabinoid system.

*G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell membrane receptors in higher animals. These cell surface receptors act like an inbox for messages that arrive as light energy, peptides, lipids, sugars, or proteins, informing cells of the presence or absence of life-sustaining light or nutrients in their environment, or they convey information sent by other cells (as in neurotransmitters conducting a nerve impulse). GPCRs play a role in an incredible variety of functions in the human body, and increased understanding of these receptors has greatly affected modern medicine. In fact, it is estimated that up to half of all marketed drugs act by binding to GPCRs.2


  1. McPartland JM, Matias I, Di Marzo V, Glass M. Evolutionary origins of the endocannabinoid system. Gene. 2006;370:64-74. doi:10.1016/j.gene.2005.11.004
  2. GPCR | Learn Science at Scitable. Accessed February 3, 2020.

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