MDMA (3,4-methylenedioxymethamphetamine) is popularly known as Ecstasy, XTC, and Adam. It is a ring-substituted derivative of the parent compound amphetamine and family member, methamphetamine. The addition of the methylenedioxy ring to the methamphetamine backbone confers its selectivity for binding to serotonin transporters over dopamine transporters. It is also structurally related to the hallucinogen mescaline. Consequently, the pharmacological effects of MDMA are a combination of the effects of the amphetamines and mescaline. These compounds are structurally related to the phenethylamine-type neurotransmitters dopamine, norepinepherine, and epinephrine. Many analogs of these compounds have been synthesized and are sometimes found on the street—the so-called designer drugs.
MDMA was first synthesized in 1912 by Merck; however, the first toxicology studies of the drug were not performed until the 1950s. It was first reported to be psychoactive in humans in 1978. During the 1980s MDMA began to be used in psychotherapy and was reported to increase patients' self-esteem and help facilitate communication with the therapist. Even with these positive effects, in 1985 the U.S. Drug Enforcement Agency classified MDMA as a Schedule I drug due to its high abuse potential, lack of clinical application, and the emerging evidence that it induced serotonergic nerve terminal degeneration in experimental animals. Despite these claims, and since the mid-1980s, MDMA has become a popular club drug, taken at rave parties because of its mild stimulant properties and the sense of euphoria, increased self-esteem, and heightened awareness it induces. Normally taken in tablet form, the average recreational dose of Ecstasy is one to two tablets each containing 60–120 milligrams of MDMA, or a dose of 0.75-4 milligrams/kilograms in a 70-kilogram individual.
Along with the positive subjective effects of MDMA, users have reported adverse physiological effects such as nausea, jaw clenching and teeth grinding, increased muscle tension, blurred vision, and panic attacks. It also causes amphetamine-like stimulation of the autonomic nervous system, producing increases in blood pressure, heart rate, and body temperature. While the drug does not typically result in a hangover, users have reported
experiencing midweek blues as well as headaches, insomnia, fatigue, drowsiness, sore jaw muscles, and loss of balance, any of which may last for several days after ingestion. In extreme cases MDMA is lethal due to the pathological consequences of severe hyper-thermia (elevated body temperature) as well as liver and cardiovascular toxicity.
Following ingestion, MDMA increases the release of the neurotransmitters serotonin and dopamine by interacting with nerve terminal transporters to cause the outflow of the neurotransmitters and the blockage of their reuptake. These interactions of MDMA with brain serotonergic and dopaminergic systems are likely responsible for its physical, psychological, and behavioral effects.
By the early 1990s increasing evidence indicated that MDMA could damage neurons in the brain. In laboratory animal experiments, MDMA was shown to produce long-lasting reductions in serotonin content in many regions of the brain. More advanced techniques have shown that MDMA causes a destruction of neuronal axon terminals while leaving the cell body intact. Single doses of the drug have been shown to deplete serotonin for several weeks and in some cases serotonin neuron terminals remain decreased for as long as one year after drug administration. In these experiments the extent of serotonin terminal loss appears to depend on the dose and the number of times the drug is administered. The exact mechanisms of MDMA-induced neurotoxicity are unknown at present but studies point to several contributing factors including excessive dopamine and serotonin release, the ability of MDMA to produce hyperthermia, the generation of harmful reactive oxygen species (very small molecules that are highly reactive and thereby damage tissue with which they come in contact), and the formation of neurotoxic breakdown products.
Controversy concerning whether findings from studies in laboratory animals can be applied to human MDMA users have been addressed by several groups. The concept of interspecies scaling suggests that neurotoxic doses of the drug in rodents correspond to recreational doses in humans, if one takes into account the differences in circulation time, organ blood flow and surface area, and liver metabolic enzymes between rodents and humans. Furthermore, increasing evidence suggests that brain function can be altered in humans exposed to the drug. Since the 1990s, considerable research has suggested the presence of cognitive and behavioral deficits associated with long-term MDMA use. Several studies have shown impairments in learning and memory as well as the development of depression and heightened anxiety after heavy MDMA use, all of which appear to correlate with decreases in the number of serotonin transporter sites in the brain as visualized with brain imaging techniques. Based on the implication of serotonergic systems in the control of cognition, sleep, food intake, sexual behavior, anxiety, mood, and the neuroendocrine system, loss of serotonin terminals after MDMA use can have major physical, psychological, and behavioral consequences in humans.
See also Complications: Mental Disorders; Dopamine; Methamphetamine; Serotonin.
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DANIEL X. FREEDMAN
R. N. PECHNICK
REVISED BY BETHANN N. JOHNSON (2009)
BRYAN K. YAMAMOTO (2009)