Drug Abuse

Addiction (1994) 89, 539-551

REVIEW

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans

THOMAS D. STEELE,*t UNA D. McCANNt & GEORGE A.
RICAURTE*

* Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD,
and Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, National
Institute of Mental Health, Bethesda, MD, USA

Abstract
(--)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a ring-substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDAM produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDAIA has been demonstrated in a variety of experimental animals (including non-human primates). In monkeys, the neurotoxic dose of MDAIA closely approaches that used by humans. While the possibility that MDAIA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDAM involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDAM use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDAIA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDA4A, with the hope that improved recognition of MDAIArelated syndromes will Provide insight into the function of serotonin in the human brain, in health as well as disease.

Introduction

Recreational use of 3,4-methylenedioxyinethamphetamine (MDMA, "Ecstasy") has increased despite recent legislative actions in several countries to limit its use, and despite compelling evidence that MDMA is a potent
toxin to brain serotonin neurones in animals. Unlike many other popular psychoactive agents (e.g., LSD , mescaline and peyote), MDNiA has been recreationally used for only the last decade., hence, many health professionals may be unfamiliar with MDMA and potential consequences of its use. This article will review the history, chemistry, pharmacology and toxicology of MDMA in animals and humans, and characterize possible adverse clinical consequences of MDMA use. In addition, this article will seek to identify future research directions with the overall aim of using MDMA as a tool for elucidating the functional role of serotonin in ilie human brain.


History

MDMA, synthesized and patented by Merck in 1914, never generated commercial interest for its intended use as an appetite suppressant (Shulgin, 1986). MDMA was largely ignored by the scientific community until the 1970s when, as part of a larger study of mescaline analogs, Hardman, Haavik & Seevers (1973) examined some of MDMA's behavioral effects and determined its lethal dose in several animal species. In 1978, Shulgin & Nichols (1978) reported that MDMA produced "an easily controlled altered state of consciousness with emotional and sensual overtones", and suggested that MDMA might be useful as psychotherapeutic adjunct. Except for these two reports and a smaller number of related publications (Anderson et al., 1978; Braun, Shulgin & Braun, 1980), MDMA received little attention until the last decade. In 1985, intense scientific and social interest in MDNL6, was generated by a decision on the part of the Drug Enforcement Administration (DEA) in the Unitad States to severely restrict MDMA use by placing it on schedule I of controlled substances (Lawn, 1986). In taking this action, the DEA cited reports of increasing recreational MDM.A use and expressed concern that MDMA might pose a threat to public health, since one of its congeners, 3,4-methylenedioxyamphetamine (MDA), had recently been found to produce toxic effects on brain serotonin neurones in todents (Ricaurte et al., 1985). In addition, the DEA maintained that MDMA had no medical utility, an assertion that drew a quick challenge from some mental health specialists who were of the opinion that MDMA facilitated psychotherapy (Greer, 1985; Greer & Tolbert, 1986; Greer & Strassman, 1985). Coincidentally, MDM.A became popular on college campuses (Peroutka, 1987a) in spite of emerging evidence that MDMA, like MDA, was toxic to brain serotonin neurones in animals (Schmidt, Wu & Lovenberg, 1986; Stone et al,, 1986; Commins et al., 1987). Much of the scientific interest in MDMA is focused on its neurotoxicity, although recently the Food and Drug Administration in the United States has given approval for limited human MDMA studies to go forward. Such studies, sanctioned by the authorities, have been ongoing in Switzerland for approximately the last five years, but results from Swiss studies have not yet been reported.

Chemistry Chemically, MDMA can be designated as N-methyl- 1-(3,4-methylenedioxyphenyl)-2aminopropane and structurally, it is related to the psychomotor stimulant amphetamine and the hallucinogen mescaline, Like amphetamine, MDMA has a chiral center at the alpha carbon, and thus exists as a pair of optical isomers. Absolute configurations for the dextrorotatory and levorotatory isomers are S-( + ) and R-( - ), respectively, with the dextrorotatory isomer having higher central activity (Anderson et al., 1978). The aromatic methylenedioxy substituent of MDMA is similar to that found in oils of natural products, safrole and myristicin, once proposed as the intoxicants of sassafras and nutmeg (Shulgin, Sargent & Naranjo, 1967). The ring substitution pattern of MDMA differs, however, from that of potent hallucinogenic amphetamines (e.g., 2,5-dimethoxy-4-methylamphetamine,DOM), which invariably are more active in their levorotatory form (Snyder, Faillace & Hollister, 1967; Nichols, 1986).

Anirnal studies
Neurochemical effects

In vitro studies indicate that MDMA evokes calcium-independent release of brain monoamines (Johnson, Hoffman & Nichols, 1986), and inhibits their reuptake inactivation (Steele, Nichols & Yim, 1987). These "indirect" effects of MDMA appear to be related to its interaction with vesicular and plasma membrane biogenic amine transporters, resulting in amine-MDMA exchange at the membrane level (Rudnick & Wall, 1992). Although dopamine-releasing effects of MDMA have been demonstrated (Yamamoto & Spanos, 1988; Hiramatsu & Cho, 1990; Nash, 1990), MDMA's serotonergic effects appear to be more prominent (Johnson et Steele et al., 1987, Schmidt, 1987). al.,1986,

The stereochernical profile for MDMAs neurochemical effects is similar to related amphetamines in that S-(+)-MDMA is more active than R-(-)-MDNiA (Johnson et al., 1986; Steele et al., 1987, Hiramatsu & Cho, 1990). The primarily indirect effects of MDMA on monoamingergic mechanisms contrast with those of hallucinogenic amphetamines whose actions are probably due to activation of serotonergic receptors (Titeler, Lyon & Glennon, 1988) for which MDMA has a very low affinity (Lyon, Glerinon & Titeler, 1986, Battaglia et al., 1988). Little is known about the effects of MDNLA, on other brain neurotransmitter systems (i.e., acetylcholine, GABA, glutarnate).

Behavioral effects
In rats, MDMA increases locomotor activity, heart rate and body temperature (Gordon et al., 1991). These effects are not unlike those of other amphetamines and, at least in part, most probably reflect activation of the sympathetic nervous system. Administration of MDMA to dogs and monkeys also produces a spectrum of signs
characteristic of sympathomimetic stimulation including mydriasis, salivation, piloerection and hyperthermia (Hardman et al., 1973; Frith et al., 1987).
In drug discrimination studies, MDMA substitutes for d-amphetamine in rats (Glennon & Young, 1984), pigeons (Evans & Johanson, 1986) and monkeys trained to discriminate d-amphetamine from saline (Kamien et al., 1986).
However, MDMA does not substitute for the potent hallucinogen, DOM, in animals trained to discriminate DOM from saline (Glennon et al., 1982; Nichols et al., 1986). Thus, MDMA appears to have significant stimulant activity but little or no hallucinogenic activity (Glennon, Yousif & Patrick, 1988,- Nichols & Oberlender, 1989), at least at the doses tested. Since the MDMA cue can be partially blocked by the dopamine receptor antagonist haloperidol (Schecter, 1989), it would seem that some of MDMA's discriminative stimulus effects are mediated by dopamine. However, substantial evidence also implicates serotonin in the discriminative stimulus effect of MDMA. MDMA substitutes completely for the potent serotonin releaser, fenfluramine (Schecter, t 1986). Moreover, norfenfluramine and TFMPP (a 5-HT1 receptor agonist) generalize to IMDMA, and the MDMA cue is blocked by pirenperone, a 5-HT receptor antagonist (Schechter, 1989). These findings, along with the observation that MDMA substitutes for N methyl-i-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) (Oberlender & Nichols, 1990), a 5-HT releasing agent with little or no in vitro dopaminergic activity (Johnson et al., 1986; Steele et al., 1987), suggest that serotonin is also involved in the discriminative stimulus effects of MDMA.

In self-administration studies, animals show propensity to selfadminister MDMA, consistent with the occurrence of recreational human MDMA use. In baboons trained to self-administer cocaine, low doses of MDMA (0.32-1.0 mg/ kg) were self-administered to a greater extent than higher doses (3.2 mg/kg) (Lamb & Griffiths, 1987). In rhesus monkeys trained to self-administer cocaine, three of four animals selfadministered MDMA at a rate greater than saline, and two of four selfadministered MDMA at a higher rate than cocaine (Beardsley, Balster & Harris, 1986). In addition, MDMA has been shown to lower the threshold for intracranial self-stimulation (Hubner et al., 1988), another model system used to gauge a drug's abuse potential.

Some behavioral studies suggest that MDMA possesses pharmacological activity that may be distinct from that of typical stimulants or hallucinogens. For instance, qualitative differences in the locomotor hyperactivity produced by MDMA and amphetamine have been reported (Gold, . Koob & Geyer, 1988; Spanos & Yamamoto, 1989) and in a complex behavioral paradigm, MDMA disrupted locomotor activity in a manner more characteristic of hallucinogens than stimulants (Gold et al., 1988). Such observations, considered in conjunction with stereochemical considerations and human subjective reports, form the basis for the hypothesis that MDMA and its analogs represent a new drug category (Nichols, 1986).

Biodisposition

The metabolism of MDMA has been characterized extensively in vitro and in vivo in several species, and is of particular interest in view of the potential involvement of certain metabolites in its pharmacological and toxicological actions. Identified in vivo metabolic pathways of MDMA in the rat include N-demethylation, O-dealkylation, deamination and conjugation (0-methylation, O-glucuronidation and O-sulfation) (Lim & Foltz, 1988). In vivo stereochernical studies have suggested a more rapid (Cho et al., 1990) and extensive (Fitzgerald et al., 1989) metabolism of the S-( + )-MDMA. Half-life estimates in rats for the enantiomers are 73.8 and 100.7 min for S-(+) and R-(-)-MDNLA, respectively (Cho et al., 1990). Quantitative assessments have not been made, but nonconjugated metabolites are present in blood, brain, liver, feces and urine over a 24-hour period, except for the O-dealkylated catechol metabolite, which appears only in the brain (Lim & Foltz, 1988). 'ne latter pathway is mediated via constitutive cytochrome P450 isozymes and is a primary route of metabolism in rat brain microsomes (Lin, Kumagai & Cho, 1992), but probably does not generate neurotoxic metabolites (Steele et al., 1991). 2-Hydroxy-4,5-methylenediocymethamphetamine (6-OH-MI)MA) has also been detected in rat brain following MDMA administration (Lim & Foltz, 1991a) but is not neurotoxic Uohnson et al., 1992; Zhao et al., 1992). A trihydroxylated metabolite of MDMA structurally similar to the well-studied neurotoxin 6-hydroxydopamine is an in vitro product of 6-OH-MDMA metabolism (Lim & Foltz, 1991b) and is neurotoxic (Johnson et al., 1992; Zhao et al., 1992), but has yet to be identified in the brain of MDNIA-treated animals.

General toxicology

In high doses, MDMA may cause convulsions in rats, dogs and monkeys (Hardman et al., 1973; Frith et al., 1987; Gordon et al., 1991). Routine necropsy of dogs treated orally with MDMA (15 mg/kg) for 28 days revealed testicular atrophy and prostatic hypertrophy (Frith et al., 1987). The LD50 of MDMA in mice has been estimated between 80-115 mglkg (Hardman et al.., 1973; Davis, Hatourn & Waters, 1987) and is enhanced upon aggregation, characteristic of amphetamine-like compounds (Davis et al., 1987).

Serotonin neurotoxicity

In animals, there is extensive evidence that MDMA causes dose-related reductions of brain serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations (Stone et al., 1986; Schmidt, Wu & Lovenberg, 1986; Commins et al., 1987a; Schmidt, 1987), the density of 5-HT uptake sites (Battaglia et al., 1987; Commins et al., 1987a, Battaglia, Yeh & DeSouza, 1988) and the activity of tryptophan hydroxylase activity (Stone et al., 1986, Schmidt & Taylor, 1987; Stone et al., 1987a). These neurochemical deficits, which last well beyond the period of drug administration have been correlated with the disappearance of serotonin immunoreactive axons (O'Hearn et al., 1988; Molliver et aL, 1990; Wilson, Ricaurte & Molliver, 1989), suggesting that they are related to axonal damage. This suspicion has been confirmed by studies using the Fink-Heimer method (Commins et al., 1987a), a silver degeneration that allows for the silver impregnation of degenerating axons. Mamounas and colleagues (1991) have also presented evidence that MDMA damages only those serotonergic axons that arise from the dorsal raphe nucleus.

The profile of neurodegenerative changes produced by MDMA is remarkably consistent across a variety of species, including rats (Battaglia et al., 1987; Commins et al., 1987a; - Schmidt, 1987; Stone et O'Hearn et al., 19883 al., 1986), guinea pigs (Commins et al., 1987a; Battaglia, Yeh & DeSouza, 1988), and non-human primates (Ricaurte et al., 1988a, Insel et al., 1989; Wilson et al., 1989). Mice appear to be less sensitive to MDMA neurotoxicity, but at high doses also have evidence of serotonergic deficits (Stone, Hanson & Gibb, 1987; Steele, Nichols & Yim, 1990). The magnitude and duration of MDNIA's effects are dependent on the dose and the number of injections given. Single doses as low as 5 mg/kg produce marked transient depletions of 5-HT and 5-HIAA (Schmidt et al., 1986; Schmidt & Taylor, 1987). Changes that persist for one week or longer are produced by administration of single doses of 10-40 mg/kg MDMA (Schmidt et al., 1986; Stone et al., 1987, Commins et al., 1987a; Battaglia et al., 1988). Brain levels of dopamine and its metabolites are not reduced by low doses of MDMA but are depleted after higher doses (Commins et al., 1987a), suggesting that while MDMA is more toxic to 5-HT than DA systems, it can also damage DA neurones. With regard to regional brain sensitivity, areas rich in 5-HT terminals such as the cerebral cortex show more severe 5-HT deficits than brain regions containing either fibers of passage (hypothalamus) or cell bodies (brain stem) (Commins et al., 1987a; O'Hearn et al., 1988). Some evidence exists that the serotonergic system of rats is able to recover within six months to one year following repeated injections with 10 (Scanzello et al., 1993) or 20 mg/kg MDMA (Battaglia et al., 1988). In nonhuman primates, the neurotoxic effects of high doses of MDMA appear to be permanent (Ricaurte et al., 1992a,b).

Studies on the mechanism of MDMA neurotoxicity have focused on two general themes: (1) the generation of a toxic drug metabolite, and (2) the role of endogenous neurotransmitters (dopamine or serotonin) or their reactive intermediates. The former hypothesis has been tested extensively using drug interaction strategies and by directly assessing the neurotoxic potential of putative metabolites. Inhibition of N- (Schmidt et al., 1987) or O-dealkylation (Steele et al., 1991) does not block the long-term effects of MDMA on serotonergic parameters. Direct central administration of catechol metabolites of MDMA (Steele et al., 199 1) and MDA (McCann & Ricaurte, 1991) does not reproduce the 5-HT-depleting effects of MDMA. The 6hydroxydoparnine analog 2,4,5-trihydroxymethamphetamine, an in vitro metabolite of MDMA (Lim et al., 1991b), persistently depletes 5-HT (Zhao et al., 1991) and reduces TPH activity (Johnson et al., 1992) after direct injection into the brain but, unlike MDM.A, also damages doparninergic neurones.

Another hypothesis holds that MDMA neurotoxicity results from the combined effects of transmitter release and monoamine oxidase inhibition, engendering elevated synaptic levels of transmitter which spontaneously auto-oxidize to known neurotoxic intermediates. In this regard, 6-hydroxydopamine and 5,6-dihydroxytryptamine have been detected in the brains of rats treated with high doses of substituted amphetamines (Seiden & Vosmer, 1984; Commins et al., 1987b). Support for the notion that doparnine is an endogenous mediator of MDMA neurotoxicity has been obtained on several fronts. Depletion of central dopamine stores (Stone et al., 1988; Schmidt, Black & Taylor, 1990) prevents MDMA-induced declines in serotonergic markers. Conversely, pretreatment With I-DOPA, the immediate precursor to dopamine, potentiates MDMA-induced serotonergic deficits (Schmidt, Black & Taylor, 1991). Combined administration of dopamine-releasing agents and non-neurotoxic MDMA analogs produces persistent changes similar to those produced by MDMA itself (Johnson, Huang & Nichols, 1991). Finally, protection afforded by serotonin antagonists may be related to blockade of 5-HT2 receptors, which modulate dopamine synthesis and are activated by MDMA-induced release of 5-HT (Schmidt et al., 1991b; Nash, Meltzer & Gudelsky, 1990).

More recently, a number of studies have implicated excitatory amino acid pathways in the  neurotoxic effects of methamphetamine (Sonsalla, Nicklas & Heikkila, 1989). Conflicting evidence exists with respect to the involvement of NMDA receptors in MDMA neurotoxicity - Johnson, Hanson & (Finnegan et al., 1989, Gibb, 1989; Sonsalla, pers. comm.).

Human experience

Use patterns

There have been no formal epidemiological studies of human MDMA use patterns. However, there have been reports of MDMA use in at least three types of settings: as a psychotherapeutic adjunct; as a recreational drug in small social  gatheringsand as a recreational drug for use in large organized social settings ("raves"). Each of these will be discussed in turn.

In psychotherapeutic sessions, MDAAA is typically ingested at a dose ranging from 50 mg to 200 mg (usually 100-150 nig). Several hours later, as the effects of the first dose begin to wane, the patient is often offered a booster dose of 50-15 mg (Eisner, 1989; Downing, 1986; Greer & Tolbert, 1986). The frequency of M13M.A psychotherapeutic sessions varies depending on the individual patient and therapist involved, but are typically spaced at least two weeks apart. The number of therapists who continue to use MDMA as psychotherapeutic adjunct is not known, but it can be reasonably assumed that it has decreased considerably since MDMA use was restricted.

When used recreationally, the typical dose ranges from 75-150 mg, and as in psychotherapeutic MDMA "sessions", sometimes involves a booster dose of 50-100 mg several hours later (Peroutka, Newman & Harris, 1988; Eisner, 1989; Leister et al., 1992). Individuals generally report that they use M13MA twice a month or less frequently, and that drug use is usually restricted to weekends, although exceptions of more frequent use are encountered.

A more recently reported use pattern for MDMA has been in the context of large, organized social settings known as "raves", which are typically held in large warehouses or dance halls and involve all-night dancing to high-tech music, computer-generated video and laser light shows. (Randall, 1992; Abbot & Concar,1992). Partygoers, who number hundreds or thousands, drink amino acid-laced beverages ("smart drinks") and use MD.MA as their drug of choice. The amount of 1ADMA typically consumed by a single individual during a "rave", or the frequency that single individuals attend "raves" is not known.

Psychoactive effects

As might be anticipated from previously described behavioral studies in animals, MDMA possesses CNS stimulant activity, in addition to psychoactive properties apparently distinct from both stimulants and hallucinogens. The stimulant effects of MDMA are typically noted shortly after drug ingestion, and include increased heart rate, increased blood pressure, dry mouth, decreased appetite, increased alertness, elevated mood and jaw clenching (Downing, 1986; McCann & Ricaurte, 1993). When taken at typical doses, MDMA is not frankly hallucinogenic (i.e., most individuals do not experience visual or auditory hallticinations). Instead what is typically described is, as phrased by Shulgin & Nichols (1978), an alteration in consciousness with "sensual and emotional over-tones". The unique qualities of MDMA have also been described in a variety of research settings, as described below.

There have been two studies which prospectively evaluated the behavioral effects of MDMA (Downing, 1986; Greer & Tolbert, 1986), both of which were conducted prior to government restrictions on its use. The study by Downing was designed to provide data on cardiovascular, biochemical and neurobehavioral effects of a single dose of MDMA. Twenty-one healthy volunteers with previous MDMA experience received a pre-selected dose of MDMA, ranging between 1.75 and 4.18 mg/kg of body weight (average dose 2.5 mg/kg or 175 mg for an individual weighing 70kg). Following drug ingestion, subjects were asked to report both positive and negative physical and emotional experiences. In addition, 10 subjects underwent repeated preand post-drug neurological examinations, with six of these subjects also evaluated neurologically 24 hours post-drug ingestion. Acute effects (time of drug ingestion until 3 hours post-drug) included euphoria, increased physical and emotional energy, heightened sensual awareness and decreased appetite. The majority of subjects experienced trismus, and exhibited increased deep tendon reflexes and gait instability. Four of 10 subjects demonstrated impaired judgement one to two hours following drug ingestion, as demonstrated by giving "idiosyncratic" responses to hypothetical questions requiring decision-making. Three of 10 subjects had difficulty performing mathematical calculations during the same period. No significant or lasting untoward physical symptoms were noted in this group.

The report by Greer & Tolbert (1986) was a summary of 29 separate clinical sessions during which MDMA was utilized as a psychotherapeutic adjunct. Data consisted of phenomenologic descriptions of the therapists' observations and the patients' experiences before, during and after the MDMA-assisted therapeutic sessions. In this study, patients received an oral dose of MDMA ranging from 75-150 mg, after a 6 hour fast (one subject, at his request, received a higher dose). A second dose of 50 or 75mg was offered when the effects of the first dose began to subside. Reported effects in this group were similar to those reported in normal volunteers. All patients who were in therapy sessions with their mate (21) reported increased closeness or enhanced communication. All 29 patients reported positive attitudinal and emotional changes, and 22 of 29 subjects reported cognitive benefits (defined as "an expanded mental perspective, insight into personal patterns or problems, improved selfexamination or "intrapsychic communication" skills, or "issue resolution"). All patients also reported some adverse effects associated with MDMA ingestion. Following the acute effects of MDMA, one patient developed chronic intermittent episodes of panic (he had also experienced panic in the remote past, but the MDMA session appeared to re-trigger them), which ultimately caused him to enter biweekly long-term psychotherapy. Other more acute undesirable symptoms mentioned were similar to those found in the study by Downing (1986), and included fatigue, jaw-clenching, nausea, transient gait disturbance (while under the influence of MDMA) and sympathornimet . c symptoms.

In addition to these two prospective studies, two studies have reported on MDMA's effects using retrospective methodology (Peroutka et al., 1988, Liester et al., 199"ata from the Peroutka study was collected from college students who had used MDMA for recreational purposes.

Subjects completed questionnaires regarding the acute (less than 24 hours) and sub-acute (greater than 24 hours) effects of MDMA. Acutely, most students reported, in decreasing order of frequency, a sense of "closeness" with others, trismus, tachycardia, bruxism, dry mouth, increased alertness. Sub-acute effects were less frequent, and included drowsiness and muscle aches (reported by 36% of subjects) and fatigue (reported by 32% of subjects). Lingering effects reported by less than 25% of individuals included a sense of "closeness" with others, depression, tight jaw muscles and difficulty concentrating.

Liester and colleagues (1992) retrospectively studied 20 psychiatrists who had taken MDMA previously, using a semi-structured interview. These subjects reported the following subjective experiences, in decreasing frequency: altered time perception (90%), increased ability to communicate (85%), decreased defensiveness (80%), decreased fear (65%) decreased sense of alienation from others (60%), changes in visual perception (50%), increased awareness of emotions (50%) and decreased aggression (50%). Neuropsychiatric consequences experienced by less than half but greater than 25% of subjects included altered speech, awareness of unconscious memories, decreased obsessiveness, cognitive changes, decreased restlessness and decreased impulsivity. Adverse effects reported in the majority of subjects included decreased desire to perform mental or physical tasks (70%), decreased appetite (65%) and trismus (50%).

Tolerance/dependence

There is little pre-clinical or clinical data to suggest that repeated use of MDMA is associated with increased tolerance or dependence. However, anecdotal reports suggest that in some individuals, increasing amounts of MDMA are used in order to achieve the same reinforcing Psychoactive effects (McCann & Ricaurte, 1991; McGuire & Fahy, 1991).

Systemic toxic effects

In recent years, as MDMA's popularity has increased, the number of reports of adverse medical sequelae associated with MDMA has also increased. Cardiac abnormalities reported following MDMA use have included arrhythmias and asystole (Dowling et al., 1987; Henry, Jeffreys & Dawling, 1992) and cardiovascular collapse (Suarez & Reimersma, 1988). There have also been several reports of rhabdomyalysis, disseminated intravascular coagulation, hyperthermia and acute renal failure following MDMA use (Brown & Osterloh, 1987, Chadwick et al., 1991; Campkin & Davies, 1992, Screaton et al., 1992; Henry et al., 1992). In addition, a number of individuals have been reported who developed hepatotoxicity following MDMA ingestion (Henry et al , 1992). Given the illicit source of MDMA in all of these case reports, it is possible that contaminants of the MDMA preparation played a role in the genesis of medical complications.

Untoward neuropsychiatric effects

Reports of adverse neuropsychiatric manifestations associated with MDMA use have included acute (within 24 hours of drug ingestion), subacute (greater than 24 hours and less than one month) and chronic (greater than one month) syndromes. In addition to the adverse effects  described in the four studies previously mentioned (Downing, 1986; Greer & Tolbert, 1986; Peroutka et al., 1988, Liester et al. 1992), reported acute adverse effects of MDMA have included flashbacks, anxiety, insomnia (Greer & Strassman, 1985), panic attacks (Whitaker Azmitia & Aronson, 1989; McCann & Ricaurte, 1991) and psychosis (Creighton, Black & Hyde, 1991). Sub-acute adverse effects which have  been reported following MDMA use have included drowsiness, depression, anxiety and irritability (Peroutka et al., 1988). Chronic neuropsychiatric difficulties seen following  MDMA use include panic disorder (Pallanti &  Mazzi, 1992; McCann & Ricaurte, 1992), psychosis (McGuire & Fahy, 1991; Creighton,  Schifano, 199 1), flashbacks Black & Hyde, 199 1 3(Creighton et al., 1991), major depressive disorder (McCann et al., 1991; Benazzi & Mazzoli, 1991) and memory disturbance (McCann et al., 1991). The observation that only certain individuals develop neuropsychiatric disturbances following MDMA use suggests that certain predisposing psychiatric factors (or high dose regimens) may make some individuals more vulnerable to these untoward effects.

Possible neurotoxic effects

The neurotoxic dose of MDMA in non-human primates approaches the dose of MDMA typically taken by recreational MDMA users (Ricaurte & McCann, 1992). This raises the concern that human MDMA users might also incur MDMA-induced serotonin damage. Since there are no currently available methods for directly evaluating the status of serotonin neurones in living humans, studies of N4DMA's neurotoxic potential in humans rely on indirect methods, including measurements of 5-HIAA in cerebrospinal fluid (CSF), and neuroendocrine challenge techniques. To date,, there have been two published studies which have used lumbar CSF 5-HIAA measurements to screen for possible MDMA-induced neurotoxicity in humans. One of these reported reductions in CSF 5-HIAA (Ricaurte et al., 1990), while the other did not (Peroutka, Pascoe & Faull, 1987). A third study, which used a neurcendocrine challenge test with L-tryptophan as a probe for serotonergic function suggested that MDMA users may have altered serotonindependent neuroendocrine function (Price eo al., 1988). None of these studies were conducted in controlled settings, so meaningful interpretation of these conflicting findings is problematic. Ongoing controlled studies evaluating MDMA users who have taken significant amounts of the drug in the past should help to clarify whether MDMA users, like MDMA-treated animals, incur damage to serotonin systems in the central nervous system.

A promising, though as yet unrealized, technique for evaluating the status of serotonergic systems in living patients is through the use of neuroirnaging techniques such as positron emission tomographv (PET) and single photon emission computed tomography (SPECT). If sensitive and specific presynaptic serotonin ligands were available for use with these methods, it would be possible to visualize diminished serotonergic activity in MDMA users, if it exists. Unfortunately, efforts to develop such a sensitive and specific ligand have thus far been unsuccessfu1.

Questions/future directions

The mechanism(s) of MDMA action remain to be identified. This is true for both its pharmacologic and neurotoxic actions. Insight into how M13MA damages 5-HT neurones may shed light on basic mechanisms underlying neuronal degeneration in various human neurologic disorders, including Alzheimer's disease and Parkinson's disease.

In view of reports of MDMA's growing popularity as a recreational drug, it will be important to determine whether MDMA is neurotoxic to serotonin neurones in humans. Although controlled studies measuring serotonin metabolites in the CSF of MDMA users will be suggestive, it is important to continue efforts to develop direct methods for evaluating the status of serotonin systems in living humans. In addition to studies of CSF, until direct methods are available, it will be necessary to rely on converging lines of evidence to determine MDMA's neurotoxic potential, including neuroendocrine evaluation, psychiatric and neuropsychiatric assessments and case reports of individuals who have taken large amounts of MDMA.

More information is needed on the functional consequences of MIDMA exposure in both animals and humans. This information will probably provide important clues regarding the functional role of brain serotonin neurones.

It also remains to be determined whether M13MA has utility as a psychotherapeutic adjunct and if so, whether the benefits incurred by MDMA use outweigh the risks of serotonin neurotoxicity. These questions can only be answered using controlled, prospective methodology, which is currently difficult (but not impossible) given MDMA's restricted status. A related question is whether non-toxic analogs of MDMA can be developed (Nichols & Oberlender, 1989). If the unique reinforcing properties of MDMA can be dissociated from its neurotoxic properties, as has been suggested in an anecdotal report (McCann & Ricaurte, 1993), then prospective controlled therapeutic trials might be possible, and may help in determining whether drugassisted psychotherapy is indeed effective.

Finally, MDMA may play a role in elucidating the role of serotonin in normal brain function and in neuropsychiatric illness. Specifically, if it is deten-nined that MDMA is toxic to serotonin neurones in humans, it may provide a better opportunity to determine the nature of serotonin's influence on a variety of behavioral functions, including mood, anxiety, pain, sleep, appetite, personality and cognition. To this end, it is important that clinicians who encounter individuals with disturbances in one or more of these behavioral domains obtain thorough drug use histories, with particular vigilance regarding possible exposure to MDMA. Until large prospective studies of MDMA in human populations are possible, scholarly contributions from observant clinicians may be the primary source of information regarding lasting consequences of human MDMA use. Such information may provide valuable clues regarding the role of serotonin in human brain function.

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