DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

664 developed and tested in controlled clinical trials. One of these,
rimonabant, was found to reduce relapse in cigarette smokers and to
produce weight loss in obese patients; however, its development has
been abandoned because of depressive and neurologic side effects.
The pharmacological effects of Δ-9-THC vary with the dose,
route of administration, experience of the user, vulnerability to psychoactive
effects, and setting of use. Intoxication with marijuana
produces changes in mood, perception, and motivation, but the effect
most frequently sought is the “high” and “mellowing out.” This
effect is described as different from the high produced by a stimulant
or opiate. Effects vary with dose, but typically last ~2 hours. During
the high, cognitive functions, perception, reaction time, learning, and
memory are impaired. Coordination and tracking behavior may be
impaired for several hours beyond the perception of the high, with
obvious implications for the operation of a motor vehicle and performance
in the workplace or at school.
Marijuana also produces complex behavioral changes such as
giddiness and increased hunger. There are unsubstantiated claims of
increased pleasure from sex and increased insight during a marijuana
high. Unpleasant reactions such as panic or hallucinations and even
acute psychosis may occur; several surveys indicate that 50-60% of
marijuana users have reported at least one anxiety experience. These
reactions are seen commonly with higher doses and with oral ingestion
rather than smoked marijuana, because smoking permits the titration
of dose according to the effects. While there is no convincing
evidence that marijuana can produce a lasting schizophrenia-like syndrome,
association studies suggest a correlation of early marijuana use
with an increased risk of later developing schizophrenia. Numerous
clinical reports suggest that marijuana use may precipitate a recurrence
of psychosis in people with a history of schizophrenia.
One of the most controversial of the reputed effects of marijuana
is the production of an “amotivational syndrome.” This syndrome
is not an official diagnosis, but it has been used to describe
young people who drop out of social activities and show little interest
in school, work, or other goal-directed activity. When heavy marijuana
use accompanies these symptoms, the drug often is cited as
the cause, even though there are no data that demonstrate a causal
relationship between marijuana smoking and these behavioral characteristics.
There is no evidence that marijuana damages brain cells
or produces any permanent functional changes, although there are
animal data indicating impairment of maze learning that persists for
weeks after the last dose. These findings are consistent with clinical
reports of gradual improvement in mental state after cessation of
chronic high-dose marijuana use.
SECTION II
NEUROPHARMACOLOGY
Marijuana has medicinal effects, including antiemetic
properties that relieve side effects of anticancer
chemotherapy. It also has muscle-relaxing effects, anticonvulsant
properties, and the capacity to reduce the
elevated intraocular pressure of glaucoma. These medical
benefits come at the cost of the psychoactive effects
that often impair normal activities. Thus, there is no
clear advantage of marijuana over conventional treatments
for any of these indications (Joy et al., 1999).
An oral capsule containing Δ-9-THC (dronabinol;
MARINOL, others) is approved for anorexia associated
with weight loss in patients with HIV infection and for
cancer chemotherapy-induced nausea and vomiting.
With the cloning of cannabinoid receptors, the discovery
of endogenous ligands, and the synthesis of specific
agonists and antagonists, it is likely that new orally
effective medications will be developed without the
undesirable properties of smoked marijuana and without
the deleterious effects of inhaling smoke particles
and the chemical products of high-temperature combustion.
Tolerance, Dependence, and Withdrawal. Tolerance to most of the
effects of marijuana can develop rapidly after only a few doses, but
also disappears rapidly (Martin et al., 2004). Tolerance to large doses
persists in experimental animals for long periods after cessation of
drug use. Withdrawal symptoms and signs typically are not seen in
clinical populations. In fact, few patients ever seek treatment for marijuana
addiction. Human subjects develop a withdrawal syndrome
when they receive regular oral doses of the agent (Table 24–9). This
syndrome, however, is only seen clinically in persons who use marijuana
on a daily basis and then suddenly stop.
Pharmacological Interventions. Marijuana abuse and addiction have
no specific treatments. Heavy users may suffer from accompanying
depression and thus may respond to antidepressant medication, but
this should be decided on an individual basis considering the severity
of the affective symptoms after the marijuana effects have dissipated.
The residual drug effects may continue for several weeks. The CB 1
receptor antagonist rimonabant has been reported to block the acute
effects of smoked marijuana, but development of this drug has been
halted due to safety concerns (discussed under “Pharmacological
Interventions” in the nicotine section earlier in the chapter).
Psychedelic Agents
Perceptual distortions that include hallucinations, illusions,
and disorders of thinking such as paranoia can be
produced by toxic doses of many drugs. These phenomena
also may follow withdrawal from toxic sedatives
such as alcohol. There are, however, certain drugs that
have as their primary effect the production of disturbances
of perception, thought, or mood at low doses
with minimal effects on memory and orientation. These
are commonly called hallucinogenic drugs, but their
Table 24–9
Marijuana Withdrawal Syndrome
Restlessness
Irritability
Mild agitation
Insomnia
Sleep EEG disturbance
Nausea, cramping