[15] A neurotransmitter for a possible endocannabinoid system in the brain and peripheral nervous system, anandamide (from 'ananda', Sanskrit for 'bliss'), was first characterized in 1992,[18][19][20] followed by discovery of other fatty acid neurotransmitters that behave as endogenous cannabinoids having a low-to-high range of efficacy for stimulating CB1 receptors in the brain and CB2 receptors in the periphery.

One mechanism through which they function is endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of retrograde signaling, in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission.

), the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, fibroblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous systems (2011).

[8] The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol that produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2.

[23][24] Recent research strongly supports the hypothesis that the N-arachidonoyl glycine (NAGly) receptor GPR18 is the molecular identity of the abnormal cannabidiol receptor and additionally suggests that NAGly, the endogenous lipid metabolite of anandamide (also known as arachidonoylethanolamide or AEA), initiates directed microglial migration in the CNS through activation of GPR18.

At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).

[33] Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors.

Prenatal cannabis exposure (PCE) has been shown to perturb the fetal endogenous cannabinoid signaling system.

[34] Additionally, PCE may alter the wiring of brain circuitry in foetal development and cause significant molecular modifications to neurodevelopmental programs that may lead to neurophysiological disorders and behavioural abnormalities.

THC is also an active ingredient in nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.