Ibogaine, a hallucinogenic drug being studied for opioid use disorder, shows highly variable pharmacokinetics strongly linked to CYP2D6 genotype. In 14 patients given a single 10 mg/kg dose, ibogaine clearance increased by 30.7 L/h per point of CYP2D6 activity score, from a baseline of 0.82 L/h. Higher ibogaine plasma concentrations correlated significantly with QTc prolongation and cerebellar ataxia, while noribogaine did not. Neither ibogaine nor its metabolite correlated with opioid withdrawal severity. These findings suggest that cardiac and neurological side effects are driven more by ibogaine itself, and that lower or genotype-personalized dosing may improve safety.
Ibogaine, a psychedelic alkaloid used orally for substance use disorders despite being unlicensed, is rapidly converted to noribogaine and noribogaine glucuronide in mice. The drug efflux transporters ABCB1 and ABCG2 modestly restrict ibogaine's oral availability, possibly through hepatobiliary or intestinal excretion, and ABCB1 limits its brain penetration. In wild-type mice, the brain-to-plasma ratio was 3.4, increasing 1.5-fold in mice lacking both transporters. Human OATP transporters and CYP3A4 had no major impact on ibogaine pharmacokinetics, suggesting low risk of drug interactions or interindividual variation from these pathways.