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

on reinforcing cocaine-free urine tests, result in significant improvement
in the majority of cocaine users (Alterman et al., 1994; Higgins
et al., 1994). Nonetheless, there is great interest in finding a medication
that can aid in the rehabilitation of cocaine addicts.
Numerous medications have been tried in placebo-controlled
clinical trials with cocaine addicts, but no medication has yet consistently
improved upon the results of behavior therapy alone. Animal
models suggest that enhancing GABAergic inhibition can reduce
reinstatement of cocaine self-administration, and a controlled clinical
trial of topiramate (TOPAMAX) showed a significant reduction in
cocaine use. Topiramate also reduced the relapse rate in alcoholics,
prompting current studies in patients dually dependent on cocaine
and alcohol. Baclofen (LIORESAL, others), a GABA B
agonist, was
found in a single-site trial to reduce relapse in cocaine addicts, but
was not effective in a multisite trial. A different approach was taken
using modafinil (PROVIGIL), a medication that increases alertness and
is approved for the treatment of narcolepsy. This medication was
found to reduce the euphoria produced by cocaine and to relieve
cocaine withdrawal symptoms. Modafinil is currently being tested in
clinical trials of cocaine, methamphetamine, alcohol, and other substance
abuse disorders. A novel approach to cocaine addiction employs
a vaccine that produces cocaine-binding antibodies. Preliminary studies
showed some success in reducing cocaine use. Larger trials are
in progress. For now, behavioral therapy remains the treatment of
choice, with medication indicated for specific co-existing disorders
such as depression.
Amphetamine and Related Agents. Subjective effects
similar to those of cocaine are produced by amphetamine,
dextroamphetamine, methamphetamine, phenmetrazine,
methylphenidate, and diethylpropion. Amphetamines
increase synaptic DA, NE, and 5-HT primarily by stimulating
pre-synaptic release rather than by blockade of
reuptake, as is the case with cocaine. Intravenous or
smoked methamphetamine produces an abuse/dependence
syndrome similar to that of cocaine, although clinical
deterioration may progress more rapidly. In animal
studies, methamphetamine in doses comparable with
those used by human abusers produces neurotoxic effects,
as reflected by histologic changes in dopaminergic and
serotonergic neurons.
Methamphetamine can be synthesized from ephedrine in small,
clandestine laboratories. Methamphetamine addiction has become a
major public health problem, particularly in the western half of the
U.S. Behavioral and medical treatments for methamphetamine addiction
are similar to those used for cocaine. Until recently, ephedrine
was a widely available nonprescription stimulant (a “wake-up” pill).
Oral stimulants, such as those prescribed in a weight-reduction program,
have short-term efficacy because of tolerance development.
Only a small proportion of patients introduced to these appetite suppressants
subsequently exhibits dose escalation or drug-seeking from
various physicians; such patients may meet diagnostic criteria for
abuse or addiction.
Caffeine. Caffeine, a mild stimulant, is the most widely
used psychoactive drug in the world. It is present in
soft drinks, coffee, tea, cocoa, chocolate, and numerous
prescription and over-the-counter drugs. It mildly
increases NE and DA release and enhances neural activity
in numerous brain areas. Caffeine is absorbed from
the digestive tract and is distributed rapidly throughout
all tissues and easily crosses the placental barrier. Many
of caffeine’s effects are believed to occur by means of
competitive antagonism at adenosine receptors; as a
methylxanthine, caffeine also inhibits cyclic nucleotide
phosphodiesterases. Adenosine is a neuromodulator that
influences a number of functions in the CNS, as is cyclic
AMP (Chapter 14). The mild sedating effects that occur
when adenosine activates particular adenosine-receptor
subtypes can be antagonized by caffeine.
Tolerance occurs rapidly to the stimulating effects
of caffeine. Thus, a mild withdrawal syndrome has been
produced in controlled studies by abruptly discontinuing
the intake of as little as one to two cups of coffee per
day. Caffeine withdrawal consists of feelings of
fatigue and sedation. With higher doses, headaches
and nausea have been reported during withdrawal;
vomiting is rare (Silverman et al., 1992). Although a
withdrawal syndrome can be demonstrated, few caffeine
users report loss of control of caffeine intake or
significant difficulty in reducing or stopping caffeine,
if desired (Dews et al., 1999). Thus, caffeine is not
listed in the category of addicting stimulants (American
Psychiatric Association, 2000).
Cannabinoids (Marijuana)
The cannabis plant has been cultivated for centuries both
for the production of hemp fiber and for its presumed
medicinal and psychoactive properties. The smoke from
burning cannabis contains many chemicals, including 61
different cannabinoids that have been identified. One of
these, Δ-9-tetrahydrocannabinol (Δ-9-THC), produces
most of the characteristic pharmacological effects of
smoked marijuana.
Marijuana is the most commonly used illegal
drug in the U.S. Surveys over the period 2006-2009
report that ~32% of highschool seniors have tied marijuana,
down from a high of 51% in 1974, but up from
22% in 1992 (Johnston et al., 2010).
Cannabinoid receptors CB 1
(mainly CNS) and CB 2
(peripheral) have been identified and cloned. An arachidonic acid
derivative, anandamide, has been proposed as an endogenous ligand
for CB receptors. While the physiological function of these receptors
and their endogenous ligands are incompletely understood, they are
likely to have important functions because they are dispersed widely
with high densities in the cerebral cortex, hippocampus, striatum,
and cerebellum (Iversen, 2003). Specific CB 1
antagonists have been
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CHAPTER 24
DRUG ADDICTION