IDENTIFICATION OF A PRIMARY METABOLITE OF IBOGAINE THAT TARGETS SEROTONIN TRANSPORTERS AND ELEVATES SEROTONIN

Ibogaine is a hallucinogenic indole with putative efficacy for the tre atment of cocaine, stimulant and opiate abuse. The purported efficacy of ibogaine following single dose administrations has led to the sugge stion that a long-acting metabolite of ibogaine may explain in part ho w the drug reduces craving for psychostimulants and opiates. We report here that 12-hydroxyibogamine, a primary metabolite of ibogaine, disp lays high affinity for the 5-HT transporter and elevates extracellular 5-HT. In radioligand binding assays, 12-hydroxyibogamine was 50-fold more potent at displacing radioligand binding at the 5-HT transporter than at the DA transporter. Ibogaine and 12-hydroxyibogamine were equi potent at the dopamine transporter. In vivo microdialysis was used to evaluate the acute actions of ibogaine and 12-hydroxyibogamine on the levels of DA and 5-HT. Administration of 12-hydroxyibogamine produced a marked dose-related elevation of extracellular 5-HT. Ibogaine and 12 -hydroxyibogamine failed to elevate DA levels in the nucleus accumbens over the dose range tested. The elevation in synaptic levels of 5-HT by 12-hydroxyibogamine may heighten mood and attenuate drug craving. T he effects of the active metabolite on 5-HT transmission may account i n part for the potential of ibogaine to interrupt drug-seeking behavio r in humans.