R EVIEWS _ F T HERAPEUTICS A Comprehensive Review of MDMA and GHB: Two Common Club Drugs Christian J. Teter, Pharm.D., and Sally K. Guthrie, Pharm.D., FCCP “Club drugs” have become alarmingly popular. The use of 3,4- methylenedioxymethamphetamine (MDMA, Ecstasy) and g-hydroxybutyrate (GHB), in particular, has increased dramatically from 1997–1999. The pharmacokinetics of MDMA and GHB appear to be nonlinear, making it difficult to estimate a dose-response relationship. The drug MDMA is an amphetamine analog with sympathomimetic properties, whereas GHB is a g- aminobutyric acid analog with sedative properties. Symptoms of an MDMA toxic reaction include tachycardia, sweating, and hyperthermia. Occasional severe sequelae include disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Treatment includes lowering the body temperature and maintaining adequate hydration. Symptoms of GHB intoxication include coma, respiratory depression, unusual movements, confusion, amnesia, and vomiting. Treatment includes cardiac and respiratory support. Because of the popularity of these agents and their potentially dangerous effects, health care professionals must be familiar with these substances and the treatment options for patients who present with symptoms of a toxic reaction. (Pharmacotherapy 2001;21(12):1486–1513) OUTLINE GHB MDMA History History Availability Availability Pharmacokinetics Chemistry Pharmacology Pharmacokinetics Therapeutic Applications Pharmacology Adverse Effects and Acute Toxic Reactions Compound Lethality Treatment Preclinical Neurotoxic Reactions Conclusion Clinical Neurotoxic Reactions The increase in the popularity of a socially Subjective Effects designated class of drugs known as “club drugs” Pharmacologic Pretreatment has been alarming. These drugs acquired this Adverse Effects and Acute Toxic Reactions label because they are used most often at all- Treatment night dance parties known as “raves” or in dance Summary clubs and bars. Drugs commonly included in From the College of Pharmacy, the University of this group are 3,4-methylenedioxymetham- Michigan, Ann Arbor, Michigan (both authors). phetamine (MDMA, “Ecstasy”), g-hydroxybutyrate Address reprint requests to Christian J. Teter, Pharm.D., College of Pharmacy, the University of Michigan, 428 (GHB), flunitrazepam (“Roofies”), ketamine, Church Street, Room 4017, Ann Arbor, MI 48109-1065; e- methamphetamine, and lysergic acid diethyl- mail: [email protected]. amide (LSD). Many of these drugs are colorless, MDMA AND GHB, TWO COMMON CLUB DRUGS Teter and Guthrie 1487 tasteless, and odorless and can be placed covertly report,3 emergency department episodes into beverages. Therefore, some of these drugs, significantly increased for MDMA (p<0.01), GHB in particular GHB and flunitrazepam, have been (p<0.01), and ketamine (p<0.05) from used to intoxicate or sedate unsuspecting 1994–1999. These increases were especially individuals to facilitate sexual assault and have dramatic from 1997–1999 for MDMA and GHB been given the name “date rape” drugs.1 (Figures 1 and 2). Apparent increases in the use Epidemiologic studies have shown that use of of flunitrazepam over the same time period were club drugs is on the rise.2, 3 According to the not statistically significant. Methamphetamine Monitoring the Future Study,2 the use of MDMA and LSD account for the largest number of has risen sharply over the last couple of years. In emergency department “mentions” in this report 2000, 8.2% of 12th graders reported taking overall; however, mentions of methamphetamine MDMA in the prior 12 months, an increase from dropped significantly from 1994–1999, whereas 5.6% in 1999. Use also increased markedly mentions of LSD remained stable over these 6 among American college students, from 0.5% in years. (A mention refers to a specific substance 1994 to 5.5% in 1999. According to the principal that was mentioned in a drug abuse episode.) investigator for the Monitoring the Future Study, The use of these drugs poses a serious public two reasons explain why MDMA use may still be health problem, and health care professionals on the rise despite a great deal of attention in the need to be familiar with these substances. media. First, young people may not yet see MDMA as a dangerous drug. Second, the MDMA perceived availability of MDMA has increased dramatically. By 2000, 51% of 12th graders History stated that they could buy MDMA fairly or very The drug MDMA (Ecstasy, “E”) is a ring- easily. The same study reported that the substituted amphetamine analog commonly prevalence rates of GHB and ketamine use are taken as a recreational drug of abuse. It was 1–2.5% in grades 8, 10, and 12. Ketamine and synthesized in 1912 by Merck Pharmaceuticals GHB were added to the ongoing Monitoring the and patented in 1914.4 However, MDMA did not Future Study in 2000, so it is not possible to become popular until the 1970s when it was obtain usage trends for these drugs. The use of promoted as a useful adjunct to psychotherapy. flunitrazepam, crystal methamphetamine, and It allegedly improved self-esteem and enhanced LSD has actually declined from peak levels in the communication within significant emotional mid-1990s through 2000. relationships.5 Therapeutic applications for The increase in the use of club drugs has been observed by medical care providers. According to the Drug Abuse Warning Network (DAWN) 3000 2500 3000 2000 2500 2000 1500 1500 1000 1000 500 500 of Emergency Department Mentions of GHB No. No. of Emergency Department Mentions of MDMA No. 0 0 1994 1995 1996 1997 1998 1999 1994 1995 1996 1997 1998 1999 Year Year Figure 1. Drug Abuse Warning Network (DAWN) statistics Figure 2. Drug Abuse Warning Network (DAWN) statistics of the number of emergency department mentions of 3,4- of the number of emergency department mentions of g- methylenedioxymethamphetamine (MDMA) from hydroxybutyrate (GHB) from 1994–1999. (From reference 1994–1999. (From reference 3.) 3.) 1488 PHARMACOTHERAPY Volume 21, Number 12, 2001 MDMA were not well established, however, and users of MDMA to control their dose. Larger- the Drug Enforcement Administration (DEA) than-expected doses of MDMA may be taken classified MDMA as a schedule I drug in 1985 accidentally, leading to adverse effects.11 after its recreational use became more widespread Furthermore, because of the variety of substances and publicized.6 It also was shown that 3,4- that may be found in any given MDMA tablet, the methylenedioxyamphetamine (MDA), an analog clinical presentation of acute intoxication may and metabolite of MDMA, had a neurotoxic effect vary significantly. in animals.7 Chemistry Availability The chemical designation of MDMA is N- The drug MDMA is commonly distributed as methyl-1-(3,4-methylenedioxyphenyl)-2- small tablets, capsules, or white powder. Ecstasy aminopropane (Figure 3). Structurally it tablets may contain various chemicals other than resembles both the stimulant amphetamine and pure MDMA, including MDA, 3,4-methylene- the hallucinogen mescaline.12 The drug MDMA dioxyethylamphetamine (MDEA), caffeine, is optically active, with the dextrorotatory isomer dextromethorphan, ephedrine, phenyl- (S+) having higher central activity than the propanolamine, methamphetamine, ampheta- levorotatory isomer.4, 13 mine, diphenhydramine, ketamine, cocaine, and diazepam. Some have contained no active drugs Pharmacokinetics at all.8 Results of analyses of tablets from all over the United Kingdom, given to the Leeds Pharmacokinetic Parameters Addiction Unit, confirm that there are many The pharmacokinetics of MDMA after oral ingredients in Ecstasy tablets other than MDMA.9 ingestion have been studied by various In another report, MDMA concentrations in 25 researchers.14–17 The time to maximum tablets varied 70-fold, and 9 of the tablets did not concentration (Tmax) is 2 hours after oral contain either MDMA or any related MDMA ingestion of MDMA 50, 75, or 125 mg.14–17 The analog.10 Furthermore, MDMA tablets collected half-life shows little variation after a wide range by the Haight Ashbury Free Medical Clinic of doses. After a 50-, 75-, or 125-mg dose, the contained from 16–150 mg of MDMA/tablet. half-life is 8 hours.16, 17 Other studies found the Owing to the great variability in the dose of half-life to be 9.53 hours after a 75-mg dose and MDMA in any given tablet, it is very difficult for 9.12 hours after a 125-mg dose.14 The maximum Figure 3. Mechanism of MDMA elimination. The parent compound MDMA and its metabolites are excreted in the urine to varying degrees (see text). Also, MDMA may be metabolized by ring hydroxylation and demethylenation to potential serotonergic neurotoxins. MDMA AND GHB, TWO COMMON CLUB DRUGS Teter and Guthrie 1489 19 concentration (Cmax) after oral ingestion appears methyl-a-methyldopamine). The metabolite to be dose dependent. A Cmax of 105.6 ng/ml was DHMA is the major metabolite of MDMA in rat reported in a single subject who took a 50-mg liver19, 20 and in rat brain microsomes.21 16 dose, whereas a Cmax of 330 ng/ml was found in Microsomes from yeast expressing human another subject who took MDMA 135 mg.18 In a CYP2D6 demethylenate MDMA to the metabolite 22, 23 group of eight subjects, the Cmax values after DHMA. ingestion of MDMA 75 mg and 125 mg were Furthermore, using human liver microsomes, 126.5 and 226.3 ng/ml, respectively,14 whereas in CYP2D6 is the primary isoenzyme responsible 24 another group of eight subjects, Cmax values of for the demethylenation of MDMA. If CYP2D6 130.9 ng/ml and 236.4 ng/ml were obtained after is the isoenzyme responsible for the majority of ingestion of MDMA 75 mg and 125 mg, MDMA metabolism in humans, then poor 17 respectively. In these studies, the Cmax exhibits metabolizers could be sensitive to the acute a slightly greater-than-expected increase physiologic effects of MDMA, but less prone to compared with the increase in dose. According any long-term toxic effects of MDMA arising to these observations, after the usual recreational from metabolites.