Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, unlike all other known inhibitors which compete with serotonin. It binds to a distinct site accessible from the cell exterior, not the substrate-binding site, and increases accessibility in the cytoplasmic permeation pathway. Ibogaine also noncompetitively inhibits the dopamine transporter (DAT) and blocks substrate-induced currents in both transporters. The inhibition is not reversed by increasing substrate concentration, and ibogaine does not form a long-lived complex with SERT but binds directly to the inward-open conformation. A kinetic model distinguishes ibogaine's noncompetitive action from cocaine's competitive action.
Amphetamines like speed, ice, and ecstasy are widely abused for their euphoric and stimulant effects. While animal studies show strong evidence that MDMA causes chronic neurotoxicity, the physiological consequences in humans remain unclear. Differences in metabolism and pharmacokinetics between species and animal strains make it difficult to design realistic human dose paradigms in animal research. This review examines amphetamine toxicity, especially MDMA toxicity, in the context of human disease, setting aside confounding factors such as polydrug use and drug purity.