Serotonergic neurotoxicity of methylenedioxyamphetamine and methylenedioxymetamphetamine.

Abstract

3,4-(±)-Methylenedioxyamphetamine (MDA) and 3,4-(±)-methylenedioxymethamphetamine (MDMA, “Ecstasy”) are ring-substituted amphetamine derivatives that have stimulant and hallucinogenic properties (1,2). MDA and MDMA are popular recreational drugs and their abuse is increasing in both the United States (3) and Europe (4). In recent years their clandestine manufacture and appearance on the street have made them popular drugs of abuse (5,6) for their ability to induce “a state of sensory amplification and enhancement without appreciable sympathomimetic stimulation” (7) and have been reported as useful adjuncts to psychotherapy (8). After misuse, chronic paranoid psychosis has been reported, which is persistent and resistant to treatment with haloperidol (9). In experimental animals, including primates, toxicity is also manifest as a selective serotonergic neurotoxicity. The actions of MDA and MDMA are biphasic, initially causing an acute release of 5-hydroxytryptamine (5-HT) (10) followed by prolonged depletion of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), inhibition of tryptophan hydroxylase (TPH) (11,12), and structural damage to 5-HT terminal and preterminal axons in various regions of the central nervous system (11,13). The immediate 5-HT release caused by these compounds can be blocked in vitro by 5-HT uptake inhibitors (14). The long term neurotoxicity can also be blocked in vivo by 5-HT uptake inhibitors (15) and by 5-HT receptor antagonists, but is potentiated by L-dopa (16). The predominant adverse consequences of MDMA and MDA abuse in humans include convulsions, hyperthermia, rhabomyolysis, and acute liver and renal failure (17).KeywordsMercapturic AcidCytochrome P450 IsozymeCysteine ConjugateMDMA NeurotoxicityPreterminal AxonThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.