The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy").
The amphetamine derivative (+/-)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug among young people, particularly those involved in the dance culture. MDMA produces an acute, rapid enhancement in the release of both serotonin (5-HT) and dopamine from nerve endings in the brains of experimental animals. It produces increased locomotor activity and the serotonin behavioral syndrome in rats. Crucially, it produces dose-dependent hyperthermia that is potentially fatal in rodents, primates, and humans. Some recovery of 5-HT stores can be seen within 24 h of MDMA administration. However, cerebral 5-HT concentrations then decline due to specific neurotoxic damage to 5-HT nerve endings in the forebrain. This neurodegeneration, which has been demonstrated both biochemically and histologically, lasts for months in rats and years in primates. In general, other neurotransmitters appear unaffected. In contrast, MDMA produces a selective long-term loss of dopamine nerve endings in mice. Studies on the mechanisms involved in the neurotoxicity in both rats and mice implicate the formation of tissue-damaging free radicals. Increased free radical formation may result from the further breakdown of MDMA metabolic products. Evidence for the occurrence of MDMA-induced neurotoxic damage in human users remains equivocal, although some biochemical and functional data suggest that damage may occur in the brains of heavy users. There is also some evidence for long-term physiological and psychological changes occurring in human recreational users. However, such evidence is complicated by the lack of knowledge of doses ingested and the fact that many subjects studied are or have been poly-drug users.
Green
A Richard
AR
AstraZeneca R&D Charnwood, Loughborough, LE11 5RH, UK. richard.green@astrazeneca.com
Mechan
Annis O
AO
Elliott
J Martin
JM
O'Shea
Esther
E
Colado
M Isabel
MI
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006213:Hallucinogens / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D009638:Norepinephrine / Q000378:metabolism; D011323:Primates; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D005609:Free Radicals; D006213:Hallucinogens; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D009638:Norepinephrine