Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin.

Ibogaine, a hallucinogenic indole, is thought to help treat cocaine, stimulant, and opiate abuse, possibly through a long-acting metabolite. This study reports that 12-hydroxyibogamine, a primary metabolite of ibogaine, binds with high affinity to the serotonin (5-HT) transporter and increases extracellular 5-HT levels. In binding assays, 12-hydroxyibogamine was 50-fold more potent at the 5-HT transporter than at the dopamine transporter, while ibogaine and the metabolite were equally potent at the dopamine transporter. Microdialysis showed that 12-hydroxyibogamine dose-dependently elevated extracellular 5-HT, but neither ibogaine nor its metabolite raised dopamine levels in the nucleus accumbens. The metabolite's enhancement of 5-HT transmission may improve mood and reduce drug craving, potentially explaining ibogaine's ability to interrupt drug-seeking behavior.

Study at a glance

Abstract

Ibogaine is a hallucinogenic indole with putative efficacy for the treatment of cocaine, stimulant and opiate abuse. The purported efficacy of ibogaine following single dose administrations has led to the suggestion that a long-acting metabolite of ibogaine may explain in part how the drug reduces craving for psychostimulants and opiates. We report here that 12-hydroxyibogamine, a primary metabolite of ibogaine, displays 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 equipotent 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. The effects of the active metabolite on 5-HT transmission may account in part for the potential of ibogaine to interrupt drug-seeking behavior in humans.