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

use does not always result in frank hallucinations. In
the late 1990s, the use of “club drugs” at all-night dance
parties became popular. Such drugs include methylenedioxymethamphetamine
(MDMA, “ecstasy”), lysergic
acid diethylamide (LSD), phencyclidine (PCP), and
ketamine (KETALAR). They often are used in association
with illegal sedatives such as flunitrazepam (ROHYPNOL)
or γ-hydroxybutyrate (GHB). The latter drug has the
reputation of being particularly effective in preventing
memory storage, and has been implicated in “date rapes.”
While psychedelic effects can be produced by a
variety of different drugs, there are two main categories
of psychedelic compounds, indoleamines and phenethylamines.
The indoleamine hallucinogens include LSD,
N,N-dimethyltryptamine (DMT), and psilocybin. The
phenethylamines include mescaline, dimethoxymethylamphetamine
(DOM), methylenedioxyamphetamine
(MDA), and MDMA. Both groups have a relatively high
affinity for 5-HT 2
receptors (Chapter 13), but they differ
in their affinity for other subtypes of 5-HT receptors.
There is a good correlation between the relative affinity
of these compounds for 5-HT 2
receptors and their
potency as hallucinogens in humans (Titeler et al., 1988).
The 5-HT 2
receptor is further implicated in the mechanism
of hallucinations by the observation that antagonists
of that receptor, such as ritanserin, are effective in
blocking the behavioral and electrophysiological
effects of hallucinogenic drugs in animal models.
However, LSD interacts with many receptor subtypes
at nanomolar concentrations, and it is not possible to
attribute the psychedelic effects to any single 5-HT
receptor subtype (Peroutka, 1994).
LSD. LSD is the most potent hallucinogenic drug and produces significant
psychedelic effects with a total dose of as little as 25-50 μg.
This drug is > 3000 times more potent than mescaline. LSD is sold
on the illicit market in a variety of forms. A popular contemporary
system involves postage stamp-sized papers impregnated with varying
doses of LSD (50-300 μg or more). While most street samples
sold as LSD actually contain LSD, samples of mushrooms and other
botanicals sold as sources of psilocybin and other psychedelics have
a low probability of containing the advertised hallucinogen.
The effects of hallucinogenic drugs are variable, even in the
same individual on different occasions. LSD is absorbed rapidly after
oral administration, with effects beginning at 40-60 minutes, peaking
at 2-4 hours, and gradually returning to baseline over 6-8 hours. At a
dose of 100 μg, LSD produces perceptual distortions and sometimes
hallucinations; mood changes, including elation, paranoia, or depression;
intense arousal; and sometimes a feeling of panic. Signs of
LSD ingestion include pupillary dilation, increased blood pressure
and pulse, flushing, salivation, lacrimation, and hyperreflexia. Visual
effects are prominent. Colors seem more intense, and shapes may
appear altered. The subject may focus attention on unusual items
such as the pattern of hairs on the back of the hand.
A “bad trip” usually consists of severe anxiety, although at
times it is marked by intense depression and suicidal thoughts. Visual
disturbances usually are prominent. The bad trip from LSD may be
difficult to distinguish from reactions to anticholinergic drugs and
phencyclidine. There are no documented toxic fatalities from LSD
use, but fatal accidents and suicides have occurred during or shortly
after intoxication. Prolonged psychotic reactions lasting 2 days or
more may occur after the ingestion of a hallucinogen. Schizophrenic
episodes may be precipitated in susceptible individuals, and there is
some evidence that chronic use of these drugs is associated with the
development of persistent psychotic disorders (McLellan et al., 1979).
Claims about the potential of psychedelic drugs for enhancing
psychotherapy and for treating addictions and other mental disorders
have not been supported by controlled treatment outcome
studies. Consequently, there is no current indication for these drugs
as medications.
Tolerance, Physical Dependence, and Withdrawal. Frequent, repeated
use of psychedelic drugs is unusual, and thus tolerance is not commonly
seen. Tolerance does develop to the behavioral effects of LSD
after three or four daily doses, but no withdrawal syndrome has been
observed. Cross-tolerance among LSD, mescaline, and psilocybin
has been demonstrated in animal models.
Pharmacological Intervention. Because of the unpredictability of psychedelic
drug effects, any use carries some risk. Dependence and addiction
do not occur, but users may require medical attention because of
“bad trips.” Severe agitation may respond to diazepam (20 mg orally).
“Talking down” by reassurance also is effective and is the management
of first choice. Antipsychotic medications (Chapter 16) may intensify
the experience and thus are not indicated.
A particularly troubling after-effect of the use of LSD and
similar drugs is the occasional occurrence of episodic visual disturbances.
These originally were called “flashbacks” and resembled the
experiences of prior LSD trips. Flashbacks belong to an official diagnostic
category called the hallucinogen persisting perception disorder
(HPPD; American Psychiatric Association, 1994). The symptoms
include false fleeting perceptions in the peripheral fields, flashes of
color, geometric pseudohallucinations, and positive afterimages
(Abraham and Aldridge, 1993). The visual disorder appears stable in
half the cases and represents an apparently permanent alteration of
the visual system. Precipitants include stress, fatigue, emergence into
a dark environment, marijuana, antipsychotic agents, and anxiety
states.
MDMA (“Ecstasy”) and MDA. MDMA and MDA are phenylethylamines
that have stimulant as well as psychedelic effects. MDMA
became popular during the 1980s on college campuses because of testimonials
that it enhances insight and self-knowledge. It was recommended
by some psychotherapists as an aid to the process of therapy,
although no controlled data exist to support this contention. Acute
effects are dose-dependent and include feelings of energy, altered
sense of time, and pleasant sensory experiences with enhanced perception.
Negative effects include tachycardia, dry mouth, jaw clenching,
and muscle aches. At higher doses, visual hallucinations, agitation,
hyperthermia, and panic attacks have been reported. A typical oral dose
is one or two 100-mg tablets and lasts 3-6 hours, although dosage and
potency of street samples are variable (~100 mg per tablet).
MDA and MDMA produce degeneration of serotonergic
nerve cells and axons in rats. While nerve degeneration has not been
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CHAPTER 24
DRUG ADDICTION