Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients

This randomized, double-blind, placebo-controlled study (n=27) evaluated the safety, tolerability, and pharmacokinetics of noribogaine 60, 120, or 180mg/70kg administered to opioid-dependent patients withdrawing from methadone. Noribogaine was well tolerated across the entire dose range and a statistically nonsignificant trend toward decreased total score in opioid withdrawal ratings. The ascending noribogaine dose was correlated to prolongation of heart contractions (longer QT intervals) to a degree that would be concerning in a clinical setting, which indicates the need for ECG monitoring to enable dose adjustment or discontinuation to mitigate cardiovascular risk in future studies.

Abstract

“Introduction: Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine’s active metabolite, in patients established on methadone opioid substitution therapy (OST).

Methods: In this randomized, double‐blind, placebo‐controlled single ascending‐dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level).

Results: Noribogaine was well tolerated. The most frequent treatment‐emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose‐linear increases for AUC and C_max and was slowly eliminated (mean t_1/2 range, 24–30 hours). There was a concentration‐dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60‐, 120‐, and 180‐mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120‐mg dose; however, the study design may have confounded evaluations of time to resumption of OST.

Discussion: Future exposure‐controlled multiple‐dose noribogaine studies are planned that will address these safety and design issues.”

Authors: Paul Glue, Gavin Cape, Donna Tunnicliff, Michelle Lockhart, Fred Lam, Noelyn Hung, C. Tak Hung, Sarah Harland, Jane Devane, R. S. Crockett, John Howes, Borje Darpo, Meijian Zhou, Holger Weis & Lawrence Friedhoff