snip

I see. Another unsupported claim from an anonymous coward.

Now, for a bit of review..

        George M. Carter

***
NATAP http://natap.org/
_______________________________________________

Club Drugs and HIV Infection: A Review

Clinical Infectious Diseases May 15 2006;42:1463-1469

Grant Colfax1,2 and Robert Guzman1

1AIDS Office, San Francisco Department of Public Health, and
2Department of Medicine, University of California, San Francisco,
California

Club drug use is common among populations with human immunodeficiency
virus (HIV) and populations at high risk for HIV infection. Club drugs
have a myriad of acute and chronic medical consequences. Club
drug-related visits to the emergency department and admissions for
treatment of substance use have increased dramatically over the past
15 years. Most epidemiological data support the role of club drugs in
increasing sexual risk behavior, with some studies demonstrating an
independent association between use of certain club drugs and HIV
infection. The direct influence of club drugs on progression of HIV
disease remains to be determined; however, club drugs may interact
with certain retroviral medications and have been associated with
decreased adherence to medication. Clinicians should ask all patients
about patterns of club drug use, counsel patients about the risks
associated with club drug use, and refer patients to appropriate
behavioral treatment programs for substance use when clinically
indicated.

Drugs that are frequently used in dance clubs or at circuit parties or
rave parties are known collectively as "club drugs" [1]. Because of
the frequent use of club drugs among persons who are at risk for HIV
infection or are infected with HIV, this review will include
3,4-methylenedioxymethamphetamine (MDMA; also known as "Ecstasy"),
methamphetamine, ketamine, y-hydroxybutyrate (GHB), and inhaled
nitrites (known as "poppers"). The present article provides a general
overview of the epidemiological profile and medical consequences of
club drugs and also provides recommendations for clinicians treating
patients who use club drugs, emphasizing the implications of club drug
use among persons with HIV infection and persons at high risk for HIV
infection.

OVERVIEW OF CLUB DRUGS

Use of club drugs is a public health concern. In 2004, according to
the population-based National Survey on Drug Abuse and Health, it was
estimated that, in the United States, 1.9 million persons aged >12
years used MDMA and 1.4 million used methamphetamine; in comparison,
1.3 million used crack cocaine and 398,000 used heroin [2]. The burden
of club drug use on the health care system is great: the Drug Abuse
Warning Network showed that, between 1994 and 2001, emergency
department visits associated with MDMA, ketamine, and GHB use
increased about 22-, 35-, and 60-fold, respectively [3].

As is the case with substance use in general, club drug use is more
prevalent among men who have sex with men (MSM), compared with the
general population [4]. A population-based study of urban gay men
found that, in the 6 months before being interviewed, 20% of the men
reported using poppers, 12% reported using MDMA, and 10% reported
using methamphetamines; HIV-infected men were more likely to report
use of multiple drugs and frequent drug use [5]. A probability-based
sample of young men (age range, 15-22 years) from 7 cities in the
United States found that, in the 6 months before interviews were
conducted, 14% of the men reported using poppers, 19% reported using
MDMA, and 20% reported using amphetamines [6]. Use of ketamine and GHB
is also high among MSM; one study found that 53% of young MSM reported
lifetime use of ketamine, and studies of MSM who were circuit-party
attendees reported that up to 25% of participants used GHB and 43%
used ketamine [7, 8]. There are considerably fewer studies of club
drug use among heterosexuals either infected with HIV or at high risk
for HIV infection, but some studies have shown high rates of club drug
use in these populations [9, 10].

SUMMARY DESCRIPTIONS OF CLUB DRUGS

Methamphetamine.     Methamphetamine is a synthetic stimulant derived
from ephedrine or pseudoephedrine, ingredients that are commonly found
in cold preparations and asthma medications [11]. Methamphetamine may
be ingested, snorted, smoked, injected, or administered as a rectal
suppository. The effects of methamphetamine, which last up to 10-12 h,
include increased energy and alertness, decreased appetite, and
endowment of users with feelings of power and invulnerability. These
effects can escalate until users develop severe insomnia and anxiety,
which sometimes develop into symptoms similar to those associated with
paranoia and schizophrenia. Additional acute effects include
tachycardia, hypertension, myocardial ischemia, cerebrovascular
accidents, and hyperthermia. Acute methamphetamine intoxication is
treated with supportive care and antipsychotics [12].

Methamphetamine causes increases in the release of epinephrine,
serotonin, and dopamine [11]. Most research has focused on the effects
of methamphetamine on dopamine levels. Methamphetamine increases
synaptic levels of dopamine through inhibiting dopamine reuptake
transporters and increasing release of vesicular dopamine stores [13].
The resulting high levels of dopamine are thought to be responsible
for the acute physiological and psychological effects of
methamphetamine. Prolonged exposure to methamphetamine is associated
with decreased dopamine levels, which are thought to be caused by
reductions in dopamine transporter activity and degeneration of
dopamine nerve terminals [13]. Long-term consequences of
methamphetamine use include weight loss, depression, and impaired
cognitive performance. Chronic methamphetamine use is associated with
severe dental disease, likely because of a convergence of
methamphetamine-related effects, including bruxism (excessive teeth
grinding), xerostomia (persistent dry mouth due to the sympathomimetic
properties of methamphetamine), poor dental hygiene, and diet [14].
The behavioral effects of methamphetamine include excessive picking
and scratching of skin, which put users at increased risk for skin
infections, including infection with methicillin-resistant
Staphylococcus aureus [15].

Methamphetamine withdrawal is associated with depression, anergia,
agitation, and insomnia. Symptoms can last from weeks to months, with
relapses to methamphetamine use common [16].

MDMA.     MDMA is chemically similar to amphetamine and the
hallucinogenic drug mescaline [17]. Usually ingested as a pill, MDMA
has empathogenic, euphoric, and stimulant effects that last for 3-6 h
[17]. Although the most serious medical consequences of MDMA use are
infrequent, the effects of MDMA include tachycardia, hypertension,
hyperthermia, hyponatremia, rhabdomyolosis, hepatic failure, and death
[18-21]. Although these sequelae may be a direct effect of the drug
itself, it should be noted that the long dance marathons often
associated with MDMA use, as well as the subsequent volume depletion
that occurs, may contribute to MDMA-associated morbidity and mortality
[22]. In addition, MDMA pills frequently contain other substances,
including methamphetamine and pseudoephedrine, that could either have
additional medical effects or compound the effects due to MDMA alone
[23]. Treatment of acute MDMA intoxication includes restoration of
fluid and electrolyte balance and careful evaluation and management of
hepatic function [18].

MDMA is thought to exert its acute psychological effects primarily
through increasing serotonin levels, by both increasing serotonin
release and inhibiting its reuptake [24, 25]. Although MDMA typically
is used only intermittently, MDMA dependence has been reported [26].
Animal studies have demonstrated that exposure to MDMA results in
reduced serotoninergic activity, possibly as a result of the
down-regulation of the serotoninergic neurons caused by
MDMA-associated toxicity [27, 28]. Although studies of the long-term
consequences of MDMA use in humans suffer from a number of design
flaws, evidence suggests that there are clinically significant
neurological consequences of MDMA use [29]. Some, but not all, studies
report high rates of depression, anxiety, insomnia, and impaired
cognitive performance among MDMA users [17, 26, 30, 31].

Ketamine.     Ketamine is a dissociative anesthetic frequently used in
veterinary medicine; ketamine for recreational use is therefore
usually illicitly obtained from medical sources [18]. A derivative of
phencyclidine hydrochloride, ketamine exerts strong hallucinogenic and
euphoric effects, and it is often combined with other club drugs [18,
32]. It may be snorted, injected, or ingested [33]. The effects
associated with ketamine have a rapid onset (1-30 min, depending on
the route of administration used) and last 30-180 min [18]. Overuse
can cause catatonia, inducing a dissociative state; users refer to
this state as falling into a "k-hole." Additional adverse effects
include delirium, amnesia, hypertension, depression, tachycardia,
rhabdomyolysis, vomiting, agitation, and respiratory depression [17,
18]. Treatment for acute complications involves supportive care,
including volume repletion. For cases of severe agitation, treatment
with benzodiazepines may be indicated [18].

Ketamine is thought to exert its effects primarily through its effects
on the N-methyl-D-aspartate receptor, where it functions as an
antagonist [34]. N-methyl-D-aspartate dysfunction has been associated
with psychoses and schizophrenia; similar symptoms are seen in
association with ketamine use [18]. Ketamine dependence has been
reported, with symptoms of craving and tolerance but with no
physiological withdrawal symptoms reported [35, 36]. Although data are
inconclusive, they suggest that memory deficits and perception
distortions associated with acute ketamine use may persist [37].

GHB.     GHB is a naturally occurring metabolite in the human brain.
Synthetic GHB and its precursors (y-butyrolactone and 1,4-butanediol)
are used for their euphoria-inducing effects [38]. GHB typically is
taken orally as a liquid, begins to affect users within 10-20 min, and
has effects that can last for up to 4 h [17]. GHB has been used to
treat narcolepsy and alcohol withdrawal [39]. A controlled substance,
GHB is manufactured using readily available chemicals and instructions
available on the Internet. Small doses of GHB can induce nausea and
vomiting and can cause a comalike state in users, particularly when
GHB is combined with alcohol. Because of these effects, GHB has been
implicated as a date-rape drug [17]. Other documented adverse effects
of GHB include depression, confusion, alternating states of agitation
and coma, amnesia, syncope, hypotonia, ataxia, nystagmus, random
clonic movements of the face and extremities, and seizures [40-43].
GHB-related deaths have been attributed to respiratory depression,
aspiration, and pulmonary edema. Treatment for acute GHB intoxication
involves mainly supportive care, often involving intubation for airway
support [18].

GHB binds to both GHB and y-aminobutyric acid receptors, which
modulate sleep and memory; the drug-induced effects of exogenous GHB
are thought to occur primarily as a result of its interaction with
y-aminobutyric acid type B receptors [44]. GHB has been associated
with changes in dopaminergic activity in the CNS, and there exists
evidence of GHB causing increases in dopamine levels in brain tissue
[45]. GHB has a narrow safety index, with small increases in dosages
resulting in a switch from a euphoric, relaxed state to a drug-induced
coma and respiratory depression in users [18]. This is especially of
concern because the purity of GHB preparations varies by as much as
10-fold, so persons may inadvertently overdose by taking highly
concentrated preparations of the drug. These variations in drug
concentrations, as well as the fact that the safety index narrows
considerably when alcohol is used in conjunction with GHB, probably
account for the numerous cases of GHB-related comas seen in emergency
departments.

GHB dependence is well-documented, with acute withdrawal symptoms
(tremors, vomiting, and insomnia) lasting up to 2 weeks and prolonged
withdrawal (characterized by dysphoria, memory problems, and anxiety)
lasting several months [38, 44]. Acute withdrawal is treated with
benzodiazepines and supportive care [44].

Poppers.     Although they are not always included in the definition
of club drugs, we include poppers in our definition in the present
review because they are frequently used in party settings and by
populations at risk for HIV infection or infected with HIV [7]. This
inhaled drug may consist of various forms of amyl, alkyl, or butyl
nitrites. Poppers are readily available for purchase via the Internet,
where they are legally sold as cleaning products, although their use
as a drug is acknowledged and even encouraged on some Internet sites.
Nitrites are usually nasally inhaled and cause rapid onset of
vasodilation, resulting in light-headedness and euphoria that may
progress to severe headaches; these symptoms are accompanied by
decreased blood pressure and tachycardia [46]. Poppers are rapidly
metabolized, with their effects generally lasting only a few minutes.

The popularity of poppers in sexual settings is attributable to their
orgasm-enhancing effects and to the belief that they relax the anal
sphincter, making receptive anal sex more comfortable [46].
Coadministration of poppers with sildenafil citrate (Viagra; Pfizer)
or other phosphodiesterase inhibitors is contraindicated, given the
potential for the combination of these vasodilators to cause
cardiovascular collapse [47]. Negative consequences of popper use
include allergic reactions, methemoglobinemia, and hemolytic anemia
[48]. Popper use has also been associated with an increased risk of
human herpesvirus 8 infection [49]. Although the reasons for this
association remain to be determined, it is likely that this
association results from the sexual practices associated with popper
use [46].

CLUB DRUGS, SEXUAL RISK BEHAVIOR, AND SEXUALLY TRANSMITTED INFECTIONS
(STIS)

Studies of club drug use, sexual risk behavior, and STIs are
complicated by a myriad of factors. Because many of these studies have
a cross-sectional design, it is difficult to ascertain whether club
drug use in general preceded high-risk sexual behavior. Even in
longitudinal studies, the timing of club drug use in relation to
sexual behavior is not always ascertained; in such cases, the
potential causal pathway between club drug use and sexual risk
behavior cannot be determined. Among most club drug users, polydrug
use is common, making it difficult to measure the effect of any single
drug on outcomes. Furthermore, many studies do not control for other
contextual factors, such as partner type, the location(s) where club
drug use and sexual behavior occurred, and the presence of other
comorbid conditions that may be expected to contribute to sexual risk,
such as depression.

Despite the aforementioned limitations, most, but not all, studies
show significant associations between increased sexual risk behavior
and methamphetamine and popper use; these drugs have also been
independently associated with HIV infection and other STIs [50-54].
Popper use has been associated with a doubling of the risk for HIV
infection in several studies; similarly, an increased risk for HIV
infection has been noted in association with methamphetamine use
[55-57]. A recent study of MSM tested for HIV found that the
seroincidence of HIV was 6.3% among methamphetamine users, compared
with 2.1% among nonusers [58].

MDMA, ketamine, and GHB have also been associated with increased
sexual risk, although less consistently than have methamphetamine or
poppers. Use of MDMA has been associated with unprotected anal sex and
an increased number of sexual partners in some, but not all, studies
[59-64]. Frequent ketamine use and any ketamine use have also been
associated with sexual risk behaviors, but not all studies demonstrate
such an association [61, 65]. GHB has also been associated with
unprotected anal sex [64, 65].

Although not all studies have controlled for the multiple factors that
may confound the association between club drug use and heightened
sexual risk, the disinhibitory effects of the drugs are believed to
result in greater numbers of sex partners, an increased frequency of
sex, and decreased condom use. However, other factors, including
prolongation of sexual encounters while taking club drugs, increased
mucosal trauma, and the possible immunosuppressive effects of club
drugs have been postulated as additional factors that may increase the
risks for STI found to be associated with club drug use, even after
controlling for sexual behavior [66]. Some club drugs have also been
associated with increased rates of condom failure, which suggests
that, even in settings where safer sex practices are attempted, club
drugs may lead to increases in risk [67].

CLUB DRUGS AND HIV DISEASE

No studies have demonstrated conclusively that club drugs directly
influence the progression of HIV disease; the challenges of examining
the effects of drug use on HIV disease have been reported elsewhere
[68]. Methamphetamine, MDMA, and poppers have been shown to influence
cellular immune responses, but the clinical implications of these
findings are unknown [69-72]. Recent studies have demonstrated that
methamphetamine increases cytokine levels; this finding suggests that
these drugs may play a role in enhancing the immune activation seen in
subjects with chronic HIV disease [73-75]. Methamphetamine also
increases rates of viral replication and mutation in cells infected
with feline immunodeficiency virus, a retrovirus closely related to
HIV [76, 77]. Nevertheless, most natural history studies do not report
significant associations between club drug use and HIV-disease
progression. However, these analyses were limited with regard to their
examination of the effects of particular club drugs on HIV-disease
progression, because composite club drug variables were often
examined, or because club drugs were combined with other drug-use
variables [78, 79]. One study found that methamphetamine use was
associated with higher viral loads and decreased effectiveness of
antiretroviral therapy (ART), after controlling for self-reported
medication adherence [80].

Club drugs and medication adherence.     Although substance users
report suboptimal adherence to ART, relatively little research has
focused specifically on ART adherence among club drug users [81-83].
Methamphetamine users have reported decreased adherence to ART during
episodic methamphetamine "binges" that last for many days; similar
binging patterns have also been noted among users of other club drugs
[7, 81]. Such sporadic treatment interruptions could lead to the
development of drug-resistant HIV and, potentially, to treatment
failure. However, patterns of drug resistance among club drug users
remain to be determined.

Club drugs and interactions with ARTs.     The combination of club
drugs with ART may produce serious and even fatal interactions.
Patients starting retroviral therapy should be advised that their
"normal" doses of club drugs may produce untoward effects when
coadministered with ART. MDMA, GHB, ketamine, and methamphetamine are
all at least partially cleared through the cytochrome P-450 system, as
are a variety of retroviral medications [1]. Thus, concomitant use of
club drugs and antiretrovirals can delay clearance of club drugs,
dramatically increasing blood levels and leading to adverse events. In
case reports, ritonavir has been implicated in increasing both MDMA
and GHB levels, with at least 1 death attributed to the effect of
ritonavir on delaying MDMA clearance [84, 85]. The interactive effects
of nucleoside reverse-transcriptase inhibitors and nonnucleoside
reverse-transcriptase inhibitors on club drug levels remain less
understood, although ketamine levels may increase when individuals are
taking nonnucleoside reverse-transcriptase inhibitors [86].

TREATMENT OF CHRONIC CLUB DRUG USE

Few studies have evaluated the efficacy of approaches to treating
abuse of and dependence on club drugs or club drug-related sexual risk
behavior. One study found that, compared with users of alcohol and
other drugs, users of club drugs were more likely to complete
treatment, but they had higher addiction indices, even at discharge
[87]. Most research has focused on the treatment of methamphetamine
use, for which interventions have been adapted mainly from alcohol and
cocaine treatment programs. Greater duration of and patient retention
in treatment are correlated with better outcomes, although relapse
rates are high [16]. One recently completed randomized trial involving
a large sample of methamphetamine-dependent persons compared intensive
behavioral counseling with treatment-as-usual outpatient treatment;
reductions in methamphetamine use were noted in both groups, with no
differences noted at 6 months of follow-up [88]. Current
harm-reduction approaches to methamphetamine use exist, but they have
not been rigorously evaluated [89]. Contingency management, a
behavioral intervention that involves providing vouchers if
individuals have drug-negative urine samples, has been used
successfully among methamphetamine-using MSM, and it compares
favorably with intensive behavioral counseling [90].

To our knowledge, there have not been rigorous evaluations of the
effects of behavioral interventions for use of other club drugs or for
club drug-related sexual risk behavior. The Centers for Disease
Control and Prevention-funded Project MIX intervention is a
randomized, controlled group intervention for MSM who are substance
users, including those who use club drugs. Project MIX will determine
whether a risk-reduction approach will reduce substance use and
substance use-associated risk behavior. This 4-city study is currently
completing subject enrollment. Finally, despite widespread interest in
the development of pharmacologic interventions for substance
dependence, there are no currently approved medical treatments for
club drug use [91].

RECOMMENDATIONS FOR PROVIDERS

Providers should ask all their patients about club drug use, keeping
in mind that patients frequently use multiple club drugs and that club
drug use may vary in intensity throughout a week or month, with
weekends and party events noted as periods during which particularly
high use occurs. Patients should be informed of the acute and
long-term consequences of club drug use; those who continue to use
club drugs should be provided with information on how to reduce the
risks of use, such as ensuring adequate, but not excessive, hydration
during party events; avoidance of mixing club drugs with alcohol; and
knowing the risks of combining poppers with sildenafil citrate or
other phosphodiesterase inhibitors. Patients who inject club drugs
should be referred to needle-exchange programs. All club drug users
should be informed of the sexual risk behaviors and STIs associated
with club drug use, and they should be provided with safer-sex
counseling and condoms. For patients receiving ART, a frank discussion
about plans for adherence and possible interactions of ART with club
drugs is warranted. Comorbidities, including skin infections, dental
disease, and depression, should be evaluated and treated.

Patients who are dependent on club drugs should be referred for
behavioral treatment. Clinicians should become familiar with
substance-use treatment programs within their communities, and they
should pay particular attention to determining whether staff are
familiar with club drugs and are comfortable accepting a club drug
user for treatment. Programs that serve specific populations (e.g.,
MSM and HIV-infected persons) may be particularly familiar with the
management of individuals who use club drugs.

_______________________________________________