Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors. These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and dif-fuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of such backward signaling, endocannabinoids are called retrograde messengers. In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation.
Exogenous cannabinoids, eg in marijuana, include several pharmacologically active substances including D9-tetra-hydrocannabinol (THC), a powerful psychoactive substance.Like opioids, THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the VTA. The half-life of THC is about 4 hours. The onset of effects of THC after smoking marijuana occurs within minutes and reaches a maximum after 1–2 hours. The most prominent effects are eupho-ria and relaxation. Users also report feelings of well-being, grandios-ity, and altered perception of passage of time. Dose-dependent perceptual changes (eg, visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, eg, in hashish, result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, eg, increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics. The justification of medic-inal use of marijuana was comprehensively examined by the Institute of Medicine (IOM) of the National Academy of Sciences in its 1999 report, Marijuana & Medicine. This continues to be a controversial issue, mainly because of the fear that cannabinoids may serve as a gateway to the consumption of “hard” drugs or cause schizophrenia in individuals with a predisposition.
Chronic exposure to marijuana leads to dependence, which is revealed by a distinctive, but mild and short-lived, withdrawal syn-drome that includes restlessness, irritability, mild agitation, insom-nia, nausea, and cramping. The relative risk for addiction is 2.
The synthetic 9-THC analog dronabinol is a Food and Drug Administration (FDA)-approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial 9-THC analog, was recently reintroduced in the USA for adjunctive therapy in chronic pain management. The cannabinoid system is likely to emerge as an important drug target in the future because of its apparent involvement in several thera-peutically desirable effects.