MDMA and Ecstasyby Gerald Valentine, M.D.
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. 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 a2 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.
Many Ecstasy users may be exposing themselves to neurotoxic regimens that result in long-lasting serotonergic degeneration or, at the very least, acutely depleted serotonin levels. The potential for increased serotonergically mediated psychopathology is apparent.
The most commonly reported psychiatric problems in individual case reports are psychosis, anxiety, panic disorder and depression. Dysphoria and memory disturbances have been reported at two and five days after binge Ecstasy use (Curran and Travill, 1997). In a study of 150 Ecstasy users presenting for substance-abuse treatment, 53% were diagnosed with a neuropsychiatric problem (Schifano et al., 1998). A study comparing heavy and light Ecstasy users to controls found higher levels of paranoid ideation, psychoticism, somatization, obsessionality, anxiety, hostility, phobic anxiety, appetite disturbance, restless sleep and impulsiveness in Ecstasy users (Parrott et al., 2000).
Although these studies are suggestive of increased psychopathology secondary to Ecstasy use, establishing cause and effect relationships is problematic due to significant methodological limitations. Subjects are mainly polysubstance users without established premorbid functioning. These studies often have poorly matched or absent comparison groups and rely on self-reported estimates of the amount of Ecstasy used.
Most studies lack toxicological or chemical analyses that identify the actual drugs ingested, further complicating the attribution of acute psychiatric problems to a specific drug. In addition, the actual composition of the ingested drug may be uncertain. Although most Ecstasy tablets contain MDMA, other commonly identified ingredients include ketamine, MDA, amphetamine, dextromethorphan or combinations of these drugs. Some tablets contain inert ingredients, while others contain phencyclidine (PCP).
These same limitations apply to most studies on cognitive performance in Ecstasy users. To date, a clearly defined psychiatric or neurological syndrome has not been attributed to Ecstasy abuse. While it is a statistical certainty that some Ecstasy users will present for psychiatric services, the current available data shed little light on whether Ecstasy use is a precipitant, modifier or consequence of psychiatric illness.
Another clinical concern is the potential for diminished or absent therapetic responses to psychotropic medications. Several studies have demonstrated blunted serotonergic neuroendocrine responses in Ecstasy users, suggesting that central serotonergic dysfunction may also result in subpopulations who are or will become treatment refractory (Gerra et al., 2000; McCann et al., 1999). There have been no studies examining treatment responses in psychiatrically ill Ecstasy users, and the risks of using psychiatric medications in these patients are unknown. In cases of acute Ecstasy intoxication with psychosis, neuroleptics should be avoided, as they could accentuate hyperthermic reactions or promote conditions favorable to the formation of neuroleptic malignant syndrome (Green et al., 1995).
Self-administration in animals is of direct relevance to understanding MDMA's abuse potential. Baboons and rhesus monkeys will self-administer MDMA if they have been pretreated with cocaine, and drug-naive rats will self-administer MDMA but to a lesser extent than cocaine (Beardsley et al., 1986; Lamb and Griffiths, 1987; Ratzenboeck et al., 2001). Pretreatment with MDMA in rats sensitizes cocaine-induced behavioral responses, increases cocaine-stimulated place preference and enhances cocaine-stimulated dopamine release in the nucleus accumbens (Horan et al., 2000; Kalivas et al., 1998; Morgan et al., 1997).
Extrapolation to humans suggests that MDMA has less addictive potential than psychostimulants but may sensitize Ecstasy users to the reinforcing effects of stimulants. A small subset of compulsive Ecstasy users is likely to meet criteria for dependence (Jansen, 1999). However, Ecstasy use does not appear to result in a clearly defined dependence or withdrawal syndrome for most users. Tolerance to the euphoric effects quickly develops, with repeated use leaving unpleasant sympathomimetic side effects from escalating doses. This generally limits frequent dosing. Chronic, high-dose Ecstasy use is likely to have a withdrawal syndrome similar to that observed in cocaine and amphetamine abusers.
Last November, the FDA approved a Phase II clinical trial designed to study the safety and efficacy of MDMA-assisted psychotherapy in the treatment of chronic posttraumatic stress disorder (PTSD). This is the first approved protocol designed to explore the therapeutic use of MDMA. Researchers at the Medical University of South Carolina intend to employ a treatment model that evolved during the hundreds of MDMA-assisted therapeutic sessions performed prior to MDMA's criminalization. Unlike earlier psychedelic treatment models, which used potent hallucinogenic drugs that radically changed the patient's state of consciousness in unpredictable ways, the subjective state associated with MDMA is fairly predictable and easily controlled.
Commonly reported psychological effects of MDMA include feeling states of empathy, compassion, acceptance, forgiveness, openness and caring (Adamson, 1985). MDMA appears to mitigate conditioned fear responses to perceived emotional threats, allowing patients to examine their own lives and interpersonal relationships from a position of security and love. Patients experience a state of reduced defensiveness that promotes self-disclosure and trust for several hours after ingestion, thereby strengthening the therapeutic alliance (Greer and Tolbert, 1990).
MDMA may be the prototype for a novel category of psychoactive drugs characterized as "enactogens," based on their unique psychological and pharmacological profile (Nichols and Oberlender, 1990). The descriptor enactogen, derived from the Latin root tactus (touch) and the Greek roots gen (to produce) and en (within), attempts to capture the apparent ability of these drugs to facilitate a patient's access to painful emotional states that are ordinarily heavily defended.
In addition to PTSD, a variety of other psychiatric difficulties including depression, anxiety, addiction, eating disorders and chronic interpersonal problems were reported to be safely and effectively treated with MDMA (Downing, 1986; Greer and Tolbert, 1990). These claims await corroboration from controlled, clinical studies.
The widespread use of Ecstasy has direct and profound implications for psychiatry. The millions of youths ingesting unknown combinations of powerful drugs in conditions that are likely to accentuate adverse reactions and neurotoxicity is a daunting public health problem. The true extent of psychiatric morbidity associated with Ecstasy use remains to be determined. Presently, an empirically based foundation for guiding treatment decisions in Ecstasy-using patients does not exist and should be a focus of future investigation.
Likewise, MDMA's treatment efficacy and tolerability has not been empirically established. It is critical for psychiatrists to keep contexts of use in mind when evaluating both patients and the scientific literature. In some situations, MDMA appears to be a human neurotoxin while in others, a unique and useful medicine. Carefully designed prospective clinical experiments are needed for a truly objective evaluation of MDMA's risks and therapeutic potential.
Dr. Valentine is a fourth-year psychiatry resident in the Neuroscience Research Training Program at Yale University.
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