CANNABINOIDS
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.
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