Exogenous cannabinoids, eg, in marijuana, which when smoked contains thousands of organic and inorganic chemical compounds, exert their pharmacologic effects through active substances including Δ9-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 euphoria and relaxation. Users also report feelings of well-being, grandiosity, 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 medicinal use of marijuana was comprehensively examined by the Institute of Medicine (IOM) of the National Academy of Sciences in its 1999 report, Marijuana & Medicine. Today, medical use of botanical marijuana has been legalized in 25 states and the District of Columbia. Nevertheless 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 syndrome that includes restlessness, irritability, mild agitation, insomnia, nausea, and cramping. The relative risk for addiction is 2.
The synthetic Δ9-THC analog dronabinol is a US Food and Drug Administration (FDA) -approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial Δ9-THC analog, was recently reintroduced in the USA for treatment of chemotherapy-induced emesis. Nabiximols is a botanical drug obtained by standard extraction. Its active principles are Δ9-THC and cannabidiol. Initially only marketed in the United Kingdom, it is now widely available to treat symptoms of multiple sclerosis. In the USA, nabiximols is in phase III testing for cancer pain. The cannabinoid system is likely to emerge as an important drug target in the future because of its apparent involvement in several therapeutically desirable effects.
Gamma-hydroxybutyric acid (GHB, or sodium oxybate for its salt form) is produced during the metabolism of GABA, but the function of this endogenous agent is unknown at present. The pharmacology of GHB is complex because there are two distinct binding sites. The protein that contains a high-affinity binding site (1 μM) for GHB has been cloned, but its involvement in the cellular effects of GHB at pharmacologic concentrations remains unclear. The low-affinity binding site (1 mM) has been identified as the GABAB receptor. In mice that lack GABAB receptors, even very high doses of GHB have no effect; this suggests that GABAB receptors are the sole mediators of GHB’s pharmacologic action.