MDMA and Ecstasy
By Gerald Valentine, M.D.
February 1, 2002
Dr. Valentine is a fourth-year psychiatry resident in the Neuroscience Research Training Program at Yale University.
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(Drug information on ketamine), MDA, amphetamine, dextromethorphan(Drug information on 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(Drug information on 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.
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