Noribogaine, the active metabolite of ibogaine, was tested for the first time in patients on methadone opioid substitution therapy. In a randomized, double-blind, placebo-controlled trial with 27 patients, doses of 60, 120, or 180 mg were well tolerated, with common side effects including temporary changes in light perception, headache, and nausea. The drug showed dose-linear increases in blood concentration and a slow elimination half-life of 24–30 hours. Noribogaine caused a concentration-dependent increase in heart rate–corrected QT interval (QTcI), with average increases of about 16, 28, and 42 milliseconds at the three doses. There was a nonstatistically significant trend toward reduced opioid withdrawal symptoms, most notably at 120 mg, but study design issues may have affected results.
Conversion of ibogaine to its active metabolite noribogaine is primarily mediated by the CYP2D6 enzyme. In a study of 21 healthy subjects given a single 20 mg oral dose of ibogaine after 6 days of pretreatment with either placebo or the CYP2D6 inhibitor paroxetine, those pretreated with paroxetine showed rapid absorption of ibogaine, with detectable levels lasting up to 72 hours and an elimination half-life of 10.2 hours. Noribogaine exposure was similar between groups, but the active moiety (ibogaine plus noribogaine) exposure was about 2-fold higher in paroxetine-pretreated subjects. CYP2D6 phenotype correlated strongly with ibogaine AUC and Cmax. The findings suggest genotyping patients before ibogaine treatment and halving the dose in CYP2D6 poor metabolizers to ensure safety.