The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity

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.

Study at a glance

Abstract

3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are ring-substituted amphetamine derivatives with stimulant and hallucinogenic properties. The recreational use of these amphetamines, especially MDMA, is prevalent despite warnings of irreversible damage to the central nervous system. MDA and MDMA are primarily serotonergic neurotoxicants. Because (1) neither MDA nor MDMA produces neurotoxicity when injected directly into brain, (2) intracerebroventricular (i.c.v.) administration of some major metabolites of MDA and MDMA fails to reproduce their neurotoxicity, (3) alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-MeDA are metabolites of both MDA and MDMA, (4) alpha-MeDA and N-methyl-alpha-MeDA are readily oxidized to the corresponding ortho-quinones, which can undergo conjugation with glutathione (GSH), and (5) quinone thioethers exhibit a variety of toxicologic activities, we initiated studies on the potential role of thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA in the neurotoxicity of MDA and MDMA. Our studies have revealed that the thioether conjugates stimulate the acute release of serotonin, dopamine, and norepinephrine and produce a behavioral response commensurate with the "serotonin syndrome." Direct injection of the conjugates into rat brain also produces long-term depletions in serotonin (5-HT) concentrations, elevations in GFAP expression, and activation of microglial cells. The data are consistent with the view that thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA contribute to the neurotoxicity of the parent amphetamines.