Download Club Drugs and HIV Infection: A Review

INVITED ARTICLE
HIV/AIDS
Kenneth H. Mayer, Section Editor
Club Drugs and HIV Infection: A Review
Grant Colfax1,2 and Robert Guzman1
1
AIDS 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, g-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
Received 20 October 2005; accepted 11 January 2006; electronically published 31 March
2006.
Reprints or correspondence: Dr. Grant Colfax, HIV/AIDS Statistics, Epidemiology, and
Intervention Research Section, San Francisco Dept. of Public Health, 25 Van Ness Ave., Ste.
710, San Francisco, CA 94102 ([email protected]).
Clinical Infectious Diseases 2006; 42:1463–9
2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4210-0019$15.00
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 ∼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 probabilitybased 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
HIV/AIDS • CID 2006:42 (15 May) • 1463
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
1464 • CID 2006:42 (15 May) • HIV/AIDS
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 (g-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 g-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 g-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 GHBrelated 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
HIV/AIDS • CID 2006:42 (15 May) • 1465
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
1466 • CID 2006:42 (15 May) • HIV/AIDS
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 reversetranscriptase 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 treatmentas-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].
5.
6.
7.
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.
Acknowledgments
Potential conflicts of interest. G.C. and R.G.: no conflicts.
References
1. Romanelli F, Smith KM, Pomeroy C. Use of club drugs by HIV-seropositive and HIV-seronegative gay and bisexual men. Top HIV Med
2003; 11:25–32.
2. Substance Abuse and Mental Health Services Administration
(SAMHSA). National survey on drug use and health. Washington, DC:
Office of Applied Studies, SAMHSA, 2004.
3. Kissin W, Ball J. The DAWN report. Washington, DC: Office of Applied
Studies, Substance Abuse and Mental Health Services Administration,
2003.
4. Cochran SD, Ackerman D, Mays VM, Ross MW. Prevalence of non-
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
medical drug use and dependence among homosexually active men
and women in the US population. Addiction 2004; 99:989–98.
Stall R, Paul JP, Greenwood G, et al. Alcohol use, drug use and alcoholrelated problems among men who have sex with men: the Urban Men’s
Health Study. Addiction 2001; 96:1589–601.
Thiede H, Valleroy LA, MacKellar DA, et al. Regional patterns and
correlates of substance use among young men who have sex with men
in 7 US urban areas. Am J Public Health 2003; 93:1915–21.
Mansergh G, Colfax GN, Marks G, Rader M, Guzman R, Buchbinder
S. The Circuit Party Men’s Health Survey: findings and implications
for gay and bisexual men. Am J Public Health 2001; 91:953–8.
Lee SJ, Galanter M, Dermatis H, McDowell D. Circuit parties and
patterns of drug use in a subset of gay men. J Addict Dis 2003; 22:
47–60.
Wohl AR, Johnson DF, Lu S, et al. HIV risk behaviors among African
American men in Los Angeles County who self-identify as heterosexual.
J Acquir Immune Defic Syndr 2002; 31:354–60.
Mitchell SJ, Kent CK, Stansell J, Klausner JD. Methamphetamine use
and sexual activity among HIV-infected patients in care—San Francisco, 2004. In: Program and abstracts of the National HIV Prevention
Conference (Atlanta). Atlanta: Centers for Disease Control and Prevention, 2005.
Ellinwood EH, King G, Lee TH. Chronic amphetamine use and abuse.
In: Watson SJ, ed. Psychopharmacology: the fourth generation of progress CD-ROM. Philadelphia: Lippincott, Williams & Wilkins, 1998.
Urbina A, Jones K. Crystal methamphetamine, its analogues, and HIV
infection: medical and psychiatric aspects of a new epidemic. Clin Infect
Dis 2004; 38:890–4.
Nordahl TE, Salo R, Leamon M. Neuropsychological effects of chronic
methamphetamine use on neurotransmitters and cognition: a review.
J Neuropsychiatry Clin Neurosci 2003; 15:317–25.
McGrath C, Chan B. Oral health sensations associated with illicit drug
abuse. Br Dent J 2005; 198:159–62; discussion 147; quiz 174.
Lee NE, Taylor MM, Bancroft E, et al. Risk factors for communityassociated methicillin-resistant Staphylococcus aureus skin infections
among HIV-positive men who have sex with men. Clin Infect Dis
2005; 40:1529–34.
Rawson RA, Gonzales R, Brethen P. Treatment of methamphetamine
use disorders: an update. J Subst Abuse Treat 2002; 23:145–50.
National Institute on Drug Abuse (NIDA). NIDA community drug
alert bulletin—club drugs. Vol. 2005. Bethesda, MD: NIDA, 2005.
Lin M. The underappreciated dangers of “club drugs”; what clinicians
need to know. Advanced Studies in Medicine 2004; 4:191–8.
Patel MM, Wright DW, Ratcliff JJ, Miller MA. Shedding new light on
the “safe” club drug: methylenedioxymethamphetamine (ecstasy)–
related fatalities. Acad Emerg Med 2004; 11:208–10.
Vuori E, Henry JA, Ojanpera I, et al. Death following ingestion of
MDMA (ecstasy) and moclobemide. Addiction 2003; 98:365–8.
Beitia G, Cobreros A, Sainz L, Cenarruzabeitia E. 3,4-Methylenedioxymethamphetamine (ecstasy)–induced hepatotoxicity: effect on cytosolic calcium signals in isolated hepatocytes. Liver 1999; 19:234–41.
Graeme KA. New drugs of abuse. Emerg Med Clin North Am 2000;
18:625–36.
Baggott M, Heifets B, Jones RT, Mendelson J, Sferios E, Zehnder J.
Chemical analysis of ecstasy pills. JAMA 2000; 284:2190.
Freese TE, Miotto K, Reback CJ. The effects and consequences of
selected club drugs. J Subst Abuse Treat 2002; 23:151–6.
Gudelsky GA, Nash JF. Carrier-mediated release of serotonin by 3,4methylenedioxymethamphetamine: implications for serotonin-dopamine interactions. J Neurochem 1996; 66:243–9.
Thomasius R, Petersen KU, Zapletalova P, Wartberg L, Zeichner D,
Schmoldt A. Mental disorders in current and former heavy ecstasy
(MDMA) users. Addiction 2005; 100:1310–9.
Ricaurte GA, Yuan J, McCann UD. ()3,4-Methylenedioxymethamphetamine (‘Ecstasy’)–induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 2000; 42:5–10.
Mechan A, Yuan J, Hatzidimitriou G, Irvine RJ, McCann UD, Ricaurte
HIV/AIDS • CID 2006:42 (15 May) • 1467
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
GA. Pharmacokinetic profile of single and repeated oral doses of
MDMA in squirrel monkeys: relationship to lasting effects on brain
serotonin neurons. Neuropsychopharmacology 2005;31:339–50.
Kish SJ. How strong is the evidence that brain serotonin neurons are
damaged in human users of ecstasy? Pharmacol Biochem Behav
2002; 71:845–55.
Sumnall HR, Cole JC. Self-reported depressive symptomatology in
community samples of polysubstance misusers who report Ecstasy use:
a meta-analysis. J Psychopharmacol 2005; 19:84–92.
Hanson KL, Luciana M. Neurocognitive function in users of MDMA:
the importance of clinically significant patterns of use. Psychol Med
2004; 34:229–46.
Colfax GN, Mansergh G, Guzman R et al. Drug use and sexual risk
behavior among gay and bisexual men who attend circuit parties: a
venue-based comparison. J Acquir Immune Defic Syndr 2001; 28:
373–9.
Swanson J, Cooper A. Dangerous liaison: club drug use and HIV/AIDS.
IAPAC Mon 2002; 8:330–8.
Haas DA, Harper DG. Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog 1992; 39:61–8.
Pal HR, Berry N, Kumar R, Ray R. Ketamine dependence. Anaesth
Intensive Care 2002; 30:382–4.
Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamine,
part two: a review of problem use and dependence. J Psychoactive
Drugs 2001; 33:151–8.
Morgan CJ, Monaghan L, Curran HV. Beyond the K-hole: a 3-year
longitudinal investigation of the cognitive and subjective effects of
ketamine in recreational users who have substantially reduced their
use of the drug. Addiction 2004; 99:1450–61.
Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R. Gammahydroxybutyric acid: patterns of use, effects and withdrawal. Am J
Addict 2001; 10:232–41.
Dupont P, Thornton J. Near-fatal gamma-butyrolactone intoxication—
first report in the UK. Hum Exp Toxicol 2001; 20:19–22.
Mamelak M. Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neurosci Biobehav Rev 1989; 13:187–98.
Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jakobs C. 4Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism.
Neuropediatrics 1998; 29:14–22.
Lettieri J, Fung HL. Improved pharmacological activity via pro-drug
modification: comparative pharmacokinetics of sodium g-hydroxybutyrate and gamma-butyrolactone. Res Commun Chem Pathol Pharmacol 1978; 22:107–18.
Li J, Stokes SA, Woeckener A. A tale of novel intoxication: a review
of the effects of g-hydroxybutyric acid with recommendations for management. Ann Emerg Med 1998; 31:729–36.
Snead OC 3rd, Gibson KM. g-Hydroxybutyric acid. N Engl J Med
2005; 352:2721–32.
Teter CJ, Guthrie SK. A comprehensive review of MDMA and GHB:
two common club drugs. Pharmacotherapy 2001; 21:1486–513.
Romanelli F, Smith KM, Thornton AC, Pomeroy C. Poppers: epidemiology and clinical management of inhaled nitrite abuse. Pharmacotherapy 2004; 24:69–78.
Romanelli F, Smith KM. Recreational use of sildenafil by HIV-positive
and -negative homosexual/bisexual males. Ann Pharmacother 2004;
38:1024–30.
Newell GR, Adams SC, Mansell PW, Hersh EM. Toxicity, immunosuppressive effects and carcinogenic potential of volatile nitrites: possible relationship to Kaposi’s sarcoma. Pharmacotherapy 1984; 4:
284–91.
Pauk J, Huang ML, Brodie SJ, et al. Mucosal shedding of human
herpesvirus 8 in men. N Engl J Med 2000; 343:1369–77.
Wong W, Chaw JK, Kent CK, Klausner JD. Risk factors for early syphilis
among gay and bisexual men seen in an STD clinic: San Francisco,
2002–2003. Sex Transm Dis 2005; 32:458–63.
1468 • CID 2006:42 (15 May) • HIV/AIDS
51. Molitor F, Truax SR, Ruiz JD, Sun RK. Association of methamphetamine use during sex with risky sexual behaviors and HIV infection
among non-injection drug users. West J Med 1998; 168:93–7.
52. Myers T, Rowe CJ, Tudiver FG, et al. HIV, substance use and related
behaviour of gay and bisexual men: an examination of the Talking Sex
project cohort. Br J Addict 1992; 87:207–14.
53. Ostrow DG, VanRaden MJ, Fox R, Kingsley LA, Dudley J, Kaslow RA.
Recreational drug use and sexual behavior change in a cohort of homosexual men. The Multicenter AIDS Cohort Study (MACS). AIDS
1990; 4:759–65.
54. Purcell DW, Parsons JT, Halkitis PN, Mizuno Y, Woods WJ. Substance
use and sexual transmission risk behavior of HIV-positive men who
have sex with men. J Subst Abuse 2001; 13:185–200.
55. Page-Shafer K, Veugelers PJ, Moss AR, Strathdee S, Kaldor JM, van
Griensven GJ. Sexual risk behavior and risk factors for HIV-1 seroconversion in homosexual men participating in the Tricontinental Seroconverter Study, 1982–1994. Am J Epidemiol 1997; 146:531–42.
56. Buchbinder SP, Vittinghoff E, Heagerty PJ, et al. Sexual risk, nitrite
inhalant use, and lack of circumcision associated with HIV seroconversion in men who have sex with men in the United States. J Acquir
Immune Defic Syndr 2005; 39:82–9.
57. Seage GR 3rd, Mayer KH, Horsburgh CR Jr, Holmberg SD, Moon
MW, Lamb GA. The relation between nitrite inhalants, unprotected
receptive anal intercourse, and the risk of human immunodeficiency
virus infection. Am J Epidemiol 1992; 135:1–11.
58. Buchacz K, McFarland W, Kellogg TA, et al. Amphetamine use is
associated with increased HIV incidence among men who have sex
with men in San Francisco. AIDS 2005; 19:1423–4.
59. Tardieu S, Poirier Y, Micallef J, Blin O. Amphetamine-like stimulant
cessation in an abusing patient treated with bupropion. Acta Psychiatr
Scand 2004; 109:75–8; discussion 77–8.
60. Klitzman RL, Pope HGJ, Hudson JI. MDMA (“Ecstasy”) abuse and
high-risk sexual behaviors among 169 gay and bisexual men. Am J
Psychiatry 2000; 157:1162–4.
61. Mattison AM, Ross MW, Wolfson T, Franklin D. Circuit party attendance, club drug use, and unsafe sex in gay men. J Subst Abuse 2001;13:
119–26.
62. Colfax G, Vittinghoff E, Husnik MJ, et al. Substance use and sexual
risk: a participant- and episode-level analysis among a cohort of men
who have sex with men. Am J Epidemiol 2004; 159:1002–12.
63. Colfax G, Mansergh G, Vittinghoff E, Guzman R, Marks G, Buchbinder
S. Drug use and high risk sexual behavior among circuit party participants [abstract TuPeC3422]. In: Program and abstracts of the XIIIth
International AIDS Conference (Durban, South Africa). Durban, South
Africa: XIIIth International AIDS Conference, 2000.
64. Purcell DW, Moss S, Remien RH, Woods WJ, Parsons JT. Illicit substance use, sexual risk, and HIV-positive gay and bisexual men: differences by serostatus of casual partners. AIDS 2005; 19:S37–S47.
65. Rusch M, Lampinen TM, Schilder A, Hogg RS. Unprotected anal intercourse associated with recreational drug use among young men who
have sex with men depends on partner type and intercourse role. Sex
Transm Dis 2004; 31:492–8.
66. Colfax G, Shoptaw S. The methamphetamine epidemic: implications
for HIV prevention and treatment. Curr HIV/AIDS Rep 2005; 2:194–9.
67. Stone E, Heagerty P, Vittinghoff E, et al. Correlates of condom failure
in a sexually active cohort of men who have sex with men. J Acquir
Immune Defic Syndr Hum Retrovirol 1999; 20:495–501.
68. Kapadia F, Vlahov D, Donahoe RM, Friedland G. The role of substance
abuse in HIV disease progression: reconciling differences from laboratory and epidemiologic investigations. Clin Infect Dis 2005; 41:
1027–34.
69. Soderberg LS, Barnett JB. Inhalation exposure to isobutyl nitrite inhibits macrophage tumoricidal activity and modulates inducible nitric
oxide. J Leukoc Biol 1995; 57:135–40.
70. Connor TJ. Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’): a
stressor on the immune system. Immunology 2004; 111:357–67.
71. Nunez-Iglesias MJ, Castro-Bolano C, Losada C, et al. Effects of amphetamine on cell mediated immune response in mice. Life Sci 1996;58:
PL 29–33.
72. Pacifici R, Zuccaro P, Farre M, et al. Effects of repeated doses of MDMA
(“ecstasy”) on cell-mediated immune response in humans. Life Sci
2001; 69:2931–41.
73. Rofael HZ, Turkall RM, Abdel-Rahman MS. Immunomodulation by
cocaine and ketamine in postnatal rats. Toxicology 2003; 188:101–14.
74. Kubera M, Filip M, Basta-Kaim A, et al. The effect of amphetamine
sensitization on mouse immunoreactivity. J Physiol Pharmacol 2002;
53:233–42.
75. Yamada K, Nabeshima T. Pro- and anti-addictive neurotrophic factors
and cytokines in psychostimulant addiction: mini review. Ann N Y
Acad Sci 2004; 1025:198–204.
76. Phillips TR, Billaud JN, Henriksen SJ. Methamphetamine and HIV-1:
potential interactions and the use of the FIV/cat model. J Psychopharmacol 2000; 14:244–50.
77. Gavrilin MA, Mathes LE, Podell M. Methamphetamine enhances cellassociated feline immunodeficiency virus replication in astrocytes. J
Neurovirol 2002; 8:240–9.
78. Kaslow RA, Blackwelder WC, Ostrow DG, et al. No evidence for a role
of alcohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1-positive individuals: a report from the Multicenter
AIDS Cohort Study. JAMA 1989; 261:3424–9.
79. Buchbinder SP, Katz MH, Hessol NA, O’Malley PM, Holmberg SD.
Long-term HIV-1 infection without immunologic progression. AIDS
1994; 8:1123–8.
80. Ellis RJ, Childers ME, Cherner M, Lazzaretto D, Letendre S, Grant I.
Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral
therapy. J Infect Dis 2003; 188:1820–6.
81. Reback CJ, Larkins S, Shoptaw S. Methamphetamine abuse as a barrier
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
to HIV medication adherence among gay and bisexual men. AIDS Care
2003; 15:775–85.
Metsch LR, Pereyra M, Brewer TH. Use of HIV health care in HIVseropositive crack cocaine smokers and other active drug users. J Subst
Abuse 2001; 13:155–67.
Zaccarelli M, Barracchini A, De Longis P, et al. Factors related to
virologic failure among HIV-positive injecting drug users treated with
combination antiretroviral therapy including two nucleoside reverse
transcriptase inhibitors and nevirapine. AIDS Patient Care STDS
2002; 16:67–73.
Henry JA, Hill IR. Fatal interaction between ritonavir and MDMA.
Lancet 1998; 352:1751–2.
Harrington RD, Woodward JA, Hooton TM, Horn JR. Life-threatening
interactions between HIV-1 protease inhibitors and the illicit drugs
MDMA and g-hydroxybutyrate. Arch Intern Med 1999; 159:2221–4.
Antoniou T, Tseng AL. Interactions between recreational drugs and
antiretroviral agents. Ann Pharmacother 2002; 36:1598–613.
Maxwell JC, Spence RT. Profiles of club drug users in treatment. Subst
Use Misuse 2005; 40:1409–26.
Rawson RA, Marinelli-Casey P, Anglin MD, et al. A multi-site comparison of psychosocial approaches for the treatment of methamphetamine dependence. Addiction 2004; 99:708–17.
Tong J, Ross BM, Schmunk GA, et al. Decreased striatal dopamine D1
receptor-stimulated adenylyl cyclase activity in human methamphetamine users. Am J Psychiatry 2003; 160:896–903.
Shoptaw S, Reback CJ, Peck JA, et al. Behavioral treatment approaches
for methamphetamine dependence and HIV-related sexual risk behaviors among urban gay and bisexual men. Drug Alcohol Depend
2005;78:125–34.
Vocci FJ, Acri J, Elkashef A. Medication development for addictive
disorders: the state of the science. Am J Psychiatry 2005; 162:1432–40.
HIV/AIDS • CID 2006:42 (15 May) • 1469