Ion trap tandem mass spectrometric evidence for the metabolism of 3,4-(methylenedioxy)methamphetamine to the potent neurotoxins 2,4,5-trihydroxymethamphetamine and 2,4,5-trihydroxyamphetamine

3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose

“…Nevertheless, attempts to identify this compound have as yet, been unsuccessful. There is evidence that MDMA is metabolised to catechol and quinone metabolites (Hiramatsu et al 1990;Lim and Foltz 1991;Lin et al 1992;Tucker et al 1994) and we have proposed that further metabolism of such compounds results in the formation of free radicals which induce oxidative stress and membrane damage Colado et al 1997). Another substituted amphetamine, p-chloroamphetamine (PCA), administered systemically also induces neurotoxic damage to 5-HT nerve terminals in the rat brain, but does not result in axonal degeneration when administered directly into the neocortex ).…”

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

“…) tonergic neurotoxicity. It has therefore been suggested that although the parent compound is probably responsible for the acute 5-HT and dopamine-releasing properties of MDMA it is unlikely to be responsible for the neurotoxic effects, and that systemic metabolism is required for the development of toxicity (Schmidt and Taylor, 1988;Hiramatsu et al, 1990;Lim and Foltz, 1991b;Miller et al, , 1996Miller et al, , 1997Bai et al, 1999Bai et al, , 2001Zhao et al, 1992). This hypothesis is supported by the fact that MDMA-induced 5-HT depletion is attenuated by pretreatment with the CYP450 inhibitor SKF-525A and potentiated by pretreatment with phenobarbital, which induces CYP450 isozymes and enhances N-demethylenation of MDMA in vitro (Gollamudi et al, 1989).…”

The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype

“…Tucker et al (1994) therefore suggested that persons deficient in CYP2D6 and who metabolize the drug more slowly (poor metabolizers or PM phenotypes) might have an exaggerated hyperthermic response. Tucker et al (1994) also proposed the corollary, namely that, given the evidence that the long term neurotoxicity is the result of the action of metabolites of MDMA (Molliver et al, 1986;Lim & Foltz, 1991;Paris & Cunningham, 1992;Johnson et al, 1992), rather than a consequence of released 5-HT (Hekmatpanah et al, 1989;Colado & Green, 1994), poor metabolizers might be at less risk of neurotoxic damage.…”