MDA and MDMA (ecstasy) are amphetamine derivatives that combine stimulant and hallucinogenic effects and are used recreationally despite warnings of irreversible damage to the central nervous system. They are primarily serotonergic neurotoxicants. Because neither drug causes neurotoxicity when injected directly into the brain, and certain major metabolites also fail to reproduce this effect, researchers investigated the role of thioether metabolites of alpha-methyldopamine and N-methyl-alpha-methyldopamine. These thioether conjugates stimulate acute release of serotonin, dopamine, and norepinephrine, produce behavioral signs of serotonin syndrome, and when injected into rat brain cause long-term serotonin depletion, increased GFAP expression, and microglial activation. The evidence suggests these thioether metabolites contribute to the neurotoxicity of the parent amphetamines.
Reactive metabolites, particularly 5-(glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA), contribute to the serotonergic neurotoxicity caused by the drugs MDA and MDMA (ecstasy). Inhibiting the enzyme gamma-glutamyl transpeptidase (gamma-GT) at the blood-brain barrier with acivicin increased the brain uptake of these thioether metabolites and worsened the depletion of serotonin and its metabolite 5-HIAA in brain regions rich in serotonin nerve terminals. Acivicin pretreatment also increased glial fibrillary acidic protein (GFAP) expression in the striatum when combined with MDA, indicating enhanced neurotoxicity. The findings suggest that thioether metabolites formed from MDA and MDMA are key contributors to the serotonergic damage seen after peripheral drug administration.