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MDMA was first synthesized in Germany early in the 20th century and patented for use as an appetite suppressant, but because of its unacceptably high incidence of severe side effects it was never marketed for that indication. During the 1960s and 1970s, it was used experimentally as an adjunct to psychotherapy. Its administration has never been legal in the U.S., except as a Schedule I investigational drug. At present no medical indications for its use are recognized. Since the late 1980s, it has been an increasingly popular drug of abuse among white middle-class adolescents and young adults in metropolitan and suburban communities. More than 2 million tablets are smuggled into the U.S. each week from Belgium, Israel, and the Netherlands. It is also produced in illicit laboratories in this country. Known as "ecstasy" and by a number of other street synonyms (X, E, XTC, M&M, ADAM, Clarity, Lover's Speed, Hug Drug, Bean, Roll), it is usually dispensed as compressed tablets bearing various logos, particularly butterflies, lightning bolts, and four-leaf clovers. Tablets vary in concentration and purity and may contain substances other than MDMA, including caffeine and dextromethorphan, as adulterants or substitutes. MDMA is a club drug, that is, an agent sold and ingested at all-night dance parties ("raves," "techno parties," "trances") where most or all participants use the drug and where decor, entertainment, and ambiance are intended to enhance its psychotropic effects. Pharmacologically MDMA acts as a monoaminergic agonist, promoting copious serotonin release in midbrain centers. Taken orally a dose of 100 mg induces euphoria, loquacity, and a sense of increased energy and heightened social intimacy lasting 4-6 hours. Some users experience perceptual distortion and hallucinations, delirium, anxiety, panic attacks, aggressiveness, paranoia, or seizures. Physiologic effects include elevation of pulse and blood pressure, hyperthermia, dehydration, and muscular twitching and spasms (particularly jaw clenching) sometimes resulting in rhabdomyolysis. Excessive water consumption can lead to water intoxication. After the acute effects wear off, the user may experience depression, flashbacks, or amnesia. Some of these effects can persist or recur for weeks after use is discontinued. MDMA is frequently used in combination with other drugs, especially marijuana. Serially repeated dosing ("piggy-backing") increases the risk of acute psychosis, life-threatening cardiovascular emergencies, and malignant hyperthermia. Use of MDMA accounts for 5000-6000 emergency department visits yearly. Human and animal studies have documented a neurotoxic effect of MDMA on serotonin pathways. A single dose induces significant long-term neurochemical changes and repetitive use has been shown to cause selective and permanent brain damage manifested by irreversible cognitive impairment and memory loss.