Therapeutic Drug Monitoring
March 19, 2004
Terrence J. Monks, Douglas C. Jones, Fengju Bai et al.
123 citations
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.
Chemical Research in Toxicology
November 19, 1999
Fengju Bai, Serrine S. Lau, Terrence J. Monks
109 citations
Injecting MDMA or MDA directly into the brain does not cause the serotonin nerve damage seen when these drugs are given peripherally, indicating that a toxic metabolite is responsible. A major metabolite, alpha-methyldopamine (alpha-MeDA), forms thioether conjugates with glutathione or N-acetylcysteine. When injected directly into the striatum or cortex of rats, certain conjugates—5-(glutathion-S-yl)-alpha-MeDA, 5-(N-acetylcystein-S-yl)-alpha-MeDA, and 2,5-bis(glutathion-S-yl)-alpha-MeDA—significantly reduced serotonin concentrations in those regions seven days later, without affecting dopamine or norepinephrine levels. The damage was limited to serotonin nerve terminals, sparing cell body regions. These conjugates are selective serotonergic neurotoxicants, but whether they cause the toxicity seen after systemic MDMA or MDA administration remains unproven.
Chemical Research in Toxicology
May 31, 2001
Fengju Bai, Douglas C. Jones, Serrine S. Lau et al.
56 citations
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.