title: Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.
abstract: 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). 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). 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 Cmaxand was slowly eliminated (mean t1/2range, 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. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Paul
authors.initials: P
authors.lastname: Glue
authors.affiliation: Southern District Health Board, Dunedin, New Zealand.
authors.forename: Gavin
authors.initials: G
authors.lastname: Cape
authors.affiliation: Southern District Health Board, Dunedin, New Zealand.
authors.forename: Donna
authors.initials: D
authors.lastname: Tunnicliff
authors.affiliation: University of Auckland, Auckland, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lockhart
authors.affiliation: Zenith Technology Ltd, Dunedin, New Zealand.
authors.forename: Fred
authors.initials: F
authors.lastname: Lam
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Noelyn
authors.initials: N
authors.lastname: Hung
authors.affiliation: Zenith Technology Ltd, Dunedin, New Zealand.
authors.forename: C Tak
authors.initials: CT
authors.lastname: Hung
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Harland
authors.affiliation: DemeRx, Inc, Fort Lauderdale, FL, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Devane
authors.affiliation: Design and Analysis of Trials Associates, Inc, Grand Bay, AL, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Crockett
authors.affiliation: DemeRx, Inc, Fort Lauderdale, FL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Howes
authors.affiliation: iCardiac Technologies, Rochester, NY, USA.|Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: iCardiac Technologies, Rochester, NY, USA.
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: DemeRx, Inc, Fort Lauderdale, FL, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Weis
authors.affiliation: Pharmaceutical Special Projects Group, LLC.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Friedhoff
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007050:Ibogaine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008691:Methadone; D009294:Narcotics; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders / Q000188:drug therapy; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy
chemical_list: D009294:Narcotics; D007050:Ibogaine; C094385:noribogaine; D008691:Methadone
keywords: QTc; first-in-patient; noribogaine; opioid withdrawal; pharmacokinetics