The use of the illicit drug Ecstasy is a global phenomenon. Despite harsher legal sentencing and widely publicized reports of neurotoxicity and fatalities associated with Ecstasy exposure, the prevalence of its use in the United States is increasing among young adults (Johnston et al., 2000 (Figure). The U.S. Drug Enforcement Agency (DEA) has estimated that 750,000 tablets of Ecstasy are used every weekend in New York and New Jersey alone. Ecstasy culture has surpassed the LSD-centered psychedelic movement of the 1960s, in both its longevity and number of users. As was the case for LSD, media distortions and sensationalistic accounts of catastrophic reactions have contributed to misunderstandings about Ecstasy.
The principle constituent of Ecstasy -- 3,4-methylenedioxymethamphetamine (MDMA) -- can produce robust deleterious effects on serotonergic functioning in animals, including serotonin depletion and the degeneration of serotonergic nerve terminals (Ricaurte et al., 2000). Whether neurotoxicity also occurs in humans is unknown, but emerging evidence indicates that repeated Ecstasy exposure results in performance decrements in measures of neurocognitive function, which may be a manifestation of neurotoxicity (Morgan, 1999; Rodgers, 2000).
The specter of millions of Ecstasy users with severely disrupted serotonergic systems raises complicated public health issues with direct relevance to psychiatry. Given the neurotoxic potential and unknown long-term consequences of MDMA exposure, the recent approval by the U.S. Food and Drug Administration for a clinical trial of MDMA-assisted psychotherapy may be perplexing to those unfamiliar with its unique psychoactivity and history of therapeutic use. The purpose of this article is to provide psychiatrists with basic information about MDMA's pharmacology and addictive potential and to summarize data gathered from the clinical and recreational contexts of MDMA use that have particular relevance to clinical practice. In addition, a brief historical account of MDMA is presented to provide a context for understanding the complicated medical and social issues centered around MDMA.
History of MDMA
The first report of MDMA's pharmacological effects in humans appeared in 1978, which described an "easily controlled altered state of consciousness with emotional and sensual overtones" that was devoid of a hallucinatory component or psychological sequelae. The intoxication lasted several hours and was accompanied by sympathomimetic effects (Shulgin and Nichols, 1978). The drug's ability to reduce defensiveness and anxiety was recognized as potentially useful in therapy.
From the 1970s to the mid-1980s, MDMA was used legally as an adjunct to psychotherapy by a slowly expanding group of therapists. This therapeutic community was aware of the governmental restrictions imposed on research with LSD and other psychedelics once their use spread to a recreational context. Consequently, most therapists agreed to continue quietly using MDMA and only informal studies were performed.
However, by the early 1980s, MDMA was transformed into a commercial product marketed as "Ecstasy" that could be purchased by phone or at night clubs. Both the therapeutic community and politicians were alarmed by this uncontrolled, conspicuous consumption. In 1984, Sen. Lloyd Bentsen (D-Texas) formally requested that the DEA make MDMA illegal, and two years of public debate ensued during formal administrative law hearings. Advocates of MDMA testified to its relative safety and unique therapeutic utility, while witnesses for the DEA expressed concern over the abuse and neurotoxic potential of 3,4-methylenedioxyamphetamine (MDA), an analogue and metabolite of MDMA.
In July 1985, the DEA placed MDMA into Schedule I (the most restrictive category) of the Controlled Substances Act for one year on an emergency basis. On May 22, 1986, the DEA's administrative law judge recommended that MDMA be placed into Schedule III, concluding that there was sufficient evidence for an acceptable medical use and safe utilization under medical supervision. However, the DEA administrator overruled this advisement. In 1988, MDMA was placed permanently into Schedule I. This effectively ended its therapeutic use and severely curtailed controlled clinical studies. However, it had no effect on recreational use.
Chemistry and Pharmacology
MDMA is a phenethylamine, a chemical class based on a core molecular configuration of a benzene ring and an ethylamine side chain. The varied biological effects of phenethylamines are dependent on the specific chemical groups attached to this core structure. Examples of psychoactive phenethylamines are the monoamine neurotransmitters; the pharmaceuticals fenfluramine (Pondimin [voluntarily withdrawn from the U.S. market in 1997]), dextroamphetamine (Dexedrine) and venlafaxine (Effexor); and the hallucinogen mescaline.
The pharmacological effects of MDMA are complex, involving serotonergic, dopaminergic and noradrenergic systems. The primary effect is to acutely increase synaptic serotonin levels, followed by a prolonged course of serotonin depletion (White et al., 1996). It appears to simultaneously promote the release and block the reuptake of serotonin through serotonin transporter dependent mechanisms (Berger et al., 1992; Nichols et al., 1982; Rattray, 1991). It also promotes the release and blocks the reuputake of dopamine, although to a lesser extent (Nash and Brodkin, 1991; Pan and Wang, 1991). Amphetamine is six times more potent a dopamine releaser than MDMA in an in vitro assay of rat striatum (Kalix et al., 1988). MDMA has relatively high affinity for the 2 adrenoceptor and the noradrenergic transporter; this may account for sympathomimetic effects (such as the acute increases in systolic and diastolic blood pressure) seen after MDMA administration (Lavelle et al., 1999; Lester et al., 2000; Steele et al., 1987).
In addition, MDMA has weak affinity for 5-HT2A receptors and acutely inhibits tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Battaglia et al., 1988; Stone et al., 1986). The reversibility of TPH inhibition in reducing conditions provided the first clue that MDMA can promote oxidative changes in neuronal components (Stone et al., 1989). Oxidative stress is a process during which the structure and function of macromolecules are disrupted by highly energetic, unstable chemical species with unpaired electrons (free radicals). Free radicals are continuously made in vivo, and the body has multiple protective antioxidant mechanisms. When antioxidant capacity is overwhelmed, cell damage or death can occur. Accumulating evidence indicates that under some conditions, MDMA promotes oxidative stress, which may be an important mechanism of serotonergic neurotoxicity (Aguirre et al., 1999; Shankaran et al., 2001).
Although MDMA has been characterized as a hallucinogenic amphetamine due to its structural similarity to mescaline and amphetamine, it rarely induces hallucinatory experiences, nor is it as potent a psychostimulant as amphetamine. In controlled settings, 100 mg to 125 mg of oral MDMA induces a subjective experience of heightened mood, increased self-confidence, extroversion and emotional excitability. In addition, moderate derealization, depersonalization and intensified sensory perception commonly occur. Effects of MDMA typically peak 15 minutes to 30 minutes after administration and last between three hours to four hours.
Many of MDMA's psychological effects result from serotonin release. Pretreatment with an intravenous infusion of the selective serotonin reuptake inhibitor citalopram (Celexa) blocks many of the characteristic psychological effects, including heightened mood (Liechti et al., 2000a). Perceptual changes are not affected by citalopram but are reduced by the 5-HT2A/C antagonist ketanserin, suggesting that the mild hallucinogenic-like effects of MDMA are due to 5-HT2A agonist activity (Liechti et al., 2000b). Dopamine also contributes to MDMA's psychological effects, while the effects of noradrenergic modulation are unknown.
Commonly reported acute side effects include anorexia, sustained contraction of masticatory muscles (trismus), impaired balance and difficulty concentrating. Although the sample size in controlled experiments is small, the results corroborate the reports of a low incidence of acute or subacute psychiatric problems in patients treated during the era of MDMA-assisted psychotherapy.
Adamson S, ed. (1985), Through the Gateway of the Heart. Accounts and Experiences With MDMA and Other Empathogenic Substances. San Francisco: Four Trees Publications.
Aguirre N, Barrionuevo M, Ramirez MJ et al. (1999), Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity. Neuroreport 10(17):3675-3680.
Battaglia G, Brooks BP, Kulsakdinum C, De Souza EB (1988), Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur J Pharmacol 149(1-2):159-163.
Beardsley PM, Balster RL, Harris LS (1986), Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys. Drug Alcohol Depend 18(2):149-157.
Berger UV, Gu XF, Azmitia EC (1992), The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur J Pharmacol 215(2-3):153-160.
Curran HV, Travill RA (1997), Mood and cognitive effects of +/-3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'): week-end 'high' followed by mid-week low. Addiction 92(7):821-831.
Downing J (1986), The psychological and physiological effects of MDMA on normal volunteers. J Psychoactive Drugs 18(4):335-340.
Gerra G, Zaimovic A, Ferri M et al. (2000), Long-lasting effects of (+/-)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin function in humans. Biol Psychiatry 47(2):127-136.
Green AR, Cross AJ, Goodwin GM (1995), Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy). Psychopharmacology (Berl) 119(3):247-260.
Greer G, Tolbert R (1990), The therapeutic use of MDMA. In: Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA, Peroutka SJ, ed. Boston: Kluwer Academic Publishers.
Horan B, Gardner EL, Ashby CR Jr (2000), Enhancement of conditioned place preference response to cocaine in rats following subchronic administration of 3 ,4-methylenedioxymethamphetamine (MDMA). Synapse 35(2):160-162.
Jansen K (1999), Ecstasy (MDMA) dependence. Drug Alcohol Depend 53(2):121-124.
Johnston LD, O'Malley PM, Bachman JG (2000), Monitoring the Future: National Survey Results on Drug Abuse, 1975-1999, Vol. 1 Secondary School Students (NIH publication No. 00-4802). Bethesda, Md.: National Institute of Drug Abuse.
Kalivas PW, Duffy P, White SR (1998), MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology 18(6):469-479.
Kalix P, Yousif MY, Glennon RA (1988), Differential effects of the enantiomers of methylenedioxymethamphetamine (MDMA) on the release of radioactivity from (3H)dopamine-prelabeled rat striatum. Research and Communications in Substance Abuse 9:45-52.
Lamb RJ, Griffiths RR (1987), Self-injection of d,l-3,4-methylenedioxymethamphetamine (MDMA) in the baboon. Psychopharmacology (Berl) 91(3):268-272.
Lavelle A, Honner V, Docherty JR (1999), Investigation of the prejunctional alpha2-adrenoceptor mediated actions of MDMA in rat atrium and vas deferens. Br J Pharmacol 128(5):975-980.
Lester SJ, Baggot M, Welm S et al. (2000), Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial. Ann Intern Med 133(12):969-973.
Liechti ME, Baumann C, Gamma A, Vollenweider FX (2000a), Acute psychological effects of 3,4-methylenedioxymethamphetaine (MDMA, Ecstasy) are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology 22(5):513-521.
Liechti ME, Saur MR, Gamma A et al. (2000b), Psychological and physiological effects of MDMA (Ecstasy) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology 23(4):396-404.
McCann UD, Eligulashvili V, Mertl M et al. (1999), Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in 3,4-methylenedioxymethamphetamine (MDMA) users. Psychopharmacology (Berl) 147(1):56-65.
Morgan MJ (1999), Memory deficits associated with recreational use of Ecstasy (MDMA). Psychopharmacology (Berl) 141(1):30-36.
Morgan AE, Horan B, Dewey SL, Ashby CR Jr (1997), Repeated administration of 3,4-methylenedioxymethamphetaine augments cocaine's action on dopamine in the nucleus accumbens: a microdialysis study. Eur J Pharmacol 331(1):R1-R3.
Nash JF, Brodkin J (1991), Microdialysis studies on 3,4-methylenedioxymethamphetamine-induced dopamine release: effect of dopamine uptake inhibitors. J Pharmacol Exp Ther 259(2):820-825.
Nichols DE, Lloyd DH, Hoffman AJ et al. (1982), Effects of certain hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain synaptosomes. J Med Chem 25(5):530-535.
Nichols DE, Oberlender R (1990), Structure-activity relationships of MDMA and related compounds: a new class of psychoactive drugs? Ann N Y Acad Sci 600:613-623 [discussion pp623-625].
Pan HS, Wang RY (1991), The action of (+/-)-MDMA on medial prefronatal cortical neurons is mediated through the serotonergic system. Brain Res 543(1):56-60.
Parrott AC, Sisk E, Turner JJ (2000), Psychobiological problems in heavy 'ecstasy' (MDMA) polydrug users. Drug Alcohol Depend 60(1): 105-110.
Rattray M (1991), Ecstasy: towards an understanding of the biochemical basis of the actions of MDMA. Essays Biochem 26:77-87.
Ratzenboeck E, Saria A, Kriechbaum N, Zernig G (2001), Reinforcing effects of MDMA (ecstasy) in drug-naive and cocaine-treated rats. Pharmacology 62(3):138-144.
Ricaurte GA, Yuan J, McCann UD (2000), (+/-)3,4-methylenedioxymethamphetamine ('Ecstasy')-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 42(1):5-10.
Rodgers J (2000), Cognitive performance amongst recreational users of ecstasy. Psychopharmacology (Berl) 151(1):19-24.
Schifano F, Di Furia L, Forza G et al. (1998), MDMA ('ecstasy') consumption in the context of polydrug abuse: a report on 150 patients. Drug Alcohol Depend 52(1):85-90.
Shankaran M, Yamamoto B, Gudelsky GA (2001), Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5HT. Synapse 40(1):55-64.
Shulgin AT, Nichols DE (1978), Characterization of three new psychotomimetics. In: The Psychopharmacology of Hallucinogens, Stillman RC, Willette RE, eds. New York: Pergamon Press.
Steele TD, Nichols DE, Yim GK (1987), Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monamines into synaptosomes from different regions of the rat brain. Biochem Pharmacol 36(14):2297-2303.
Stone DM, Johnson M, Hanson GR, Gibb JW (1989), Acute inactivation of tryptophan hydroxylase by amphetamine analogs involves the oxidation of sulfhydryl sites. Eur J Pharmacol 172(1):93-97.
Stone DM, Stahl DC, Hanson GR, Gibb JW (1986), The effects of 3,4-methyelene dioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 128(1-2):41-48.
White SR, Obradovic T, Imel KM, Wheaton MJ (1996), The effects of methylenedioxymethamphetamine (MDMA, Ecstasy) on monoaminergic neurotransmission in the central nervous system. Prog Neurobiol 49(5):455-479.