Cannabinoids, a group of C21 compounds present in Cannabis sativa L., their carboxylic acids, analogs, and transformation products, are the active ingredients found in hasish and marihuana. (-)-trans-D9-tetrahydrocannabinol (D9-THC) is the major psychopharmacologically active component of cannabis. Cannabis affect cognition and memory, euphoria and sedation, and antinociception (analgesia) without the respiratory depression problems associated with opioid analgesics. D9-THC is also immunosuppressive and impairs cell-mediated and humoral immunity. To date, two sub-types of the G-protein coupled cannabinoid receptor, CB1 and CB2, have been identified. CB1 (rat/mouse 473 aa, human 472 aa, ~95% sequence homology) has 7 TM domains with an extracellular N-terminus and cytoplasmic C-terminus. An alternative spliced N-terminal variant, CB1A, has also been reported. The CB1 receptor has been shown to inhibit adenylate cyclase activity in a pertussis-toxin sensitive manner and to be more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. CB1 also couples to a pertussis-toxin sensitive G-protein to regulate Ca2+ currents, to activate inward rectifying K+ channels, and to activate MAP Kinases. CB1 receptor is distributed throughout the brain, with higher representation in the hippocampus, a brain region essential for storage of newly acquired information and changes of mood and behavioral state. In the cerebellum, CB1 is most dense in the molecular layer, consistent with the effects of cannabinoids on the coordination of motor function and motor learning. Outside the CNS, CB1 expression is found in testes, endothelial cells, and ileum longitudinal smooth muscle.

CB2 (rat 410 aa, mouse 347aa, human 360 aa; ~45% homology with CB1) also inhibit adenylate cyclase activity. Unlike CB1, CB2 does not modulate the activity of either Q-type Ca2+ or inwardly rectifying K+ channels. High level of CB2 expression was found in HL60 cells that had been differentiated into granulocytes or macrophages. It is also expressed in splenic macrophages and monocytes, but not in splenic T cells, mature blood neutrophils, thymus, liver, brain, lung, or kidney. High levels of CB2 mRNA was found in B-cells and natural killer cells, to a moderate extent in monocytes and only minimally in polymorphonuclear leukocytes, T4- and T8- cells. CNS responses to cannabinoid compounds are believed to be mediated largely by the CB1 receptor.

The first brain-derived endogenous cannabinoids, an unsaturated fatty acid ethanolamide, arachidonylethanolamide (AEA, also called anandamide) was found in brain. AEA has higher affinity for the CB1 than for the CB2. AEA inhibits electrically evoked twitch response of the MVD, antinociception, hypothermia, hypomotility, and catalepsy in mice. The synthesis and release of anandamide is stimulated in intact cortical and striatal neurons (but not astrocytes) by treatment with membrane depolarizing agents. Neurons and astrocytes re-uptake and hydrolyze anandamide rapidly, resulting in the formation of arachidonic acid and ethanolamine. The uptake mechanism is mediated by a saturable, selective, temperature-dependent and Na+-independent transporter. Aanandamide analog, AM 404 acts as a competitive inhibitor of anandamide transport. AM 404 had no effect on FAAH activity or on uptake of arachidonate or ethanolamine. Anandamide hydrolysis is catalyzed by a membrane-bound amidohydrolase (called anandamide amidohydrolase or fatty acid amide hydrolase, FAAH). FAAH (rat/mouse/human 579 aa; chromosome 1p34-p35; mol wt ~67 kDa) sequence analyses suggest a single predicted transmembrane domain at the extreme N-terminus of the enzyme. Distribution of FAAH parallels CB1 in rat brain suggesting that FAAH participates in cannabinoid signaling mechanisms. The sn-2-Arachidonylglycerol (2-AG), initially isolated from intestine, appears to be the second endogenous CB ligand. 2-AG concentration in the brain is 170 times greater than anandamide. FAAH hydrolyzes 2-AG at a rate four times faster than that for anandamide hydrolysis