Ascending-dose study of noribogaine in healthy volunteers: Pharmacokinetics, pharmacodynamics, safety, and tolerability

Abstract

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.

Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine

“…The slightly higher logP for ibogaine compared to noribogaine indicates that ibogaine is slightly more lipophilic than noribogaine. We found a much higher half-life of noribogaine in our patient than the authors of a dose-ascending study investigating the PK/PD in healthy volunteers: 2540 h vs. 28-49 h [9]. However, the toxicokinetic parameters in our patient revealed a much higher C max , which may account for the difference in these evaluated parameters.…”

“…However, the toxicokinetic parameters in our patient revealed a much higher C max , which may account for the difference in these evaluated parameters. In literature, due to fluctuations in individual distribution-phase concentration-time profiles, the presence of enterohepatic recirculation for noribogaine was suggested as a factor for prolonged elimination [9]. In our patient, we measured fluctuating noribogaine plasma-concentrations.…”

“…The halflife of noribogaine is much longer than ibogaine, resulting in relevant plasma-concentrations of noribogaine long after clearance of ibogaine [9,10]. They also described a post-mortem analysis of a patient following ingestion of ibogaine, which revealed high tissue concentrations of ibogaine and noribogaine in liver, spleen, lung and brain, implicating high lipophilicity of both ibogaine and its metabolite [11].…”

Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers

“…The use of higher doses (eg, ∼500–800 mg or higher, which might be used for treatment of opioid withdrawal or craving) was not considered acceptable, because of the population being tested (healthy volunteers), likely hallucinatory effects, and unknown ECG safety profile. An earlier noribogaine pharmacokinetic study indicated acceptable assay sensitivity around this dose range.…”

Ascending Single‐Dose, Double‐Blind, Placebo‐Controlled Safety Study of Noribogaine in Opioid‐Dependent Patients

“…2 To date, ibogaine has not been evaluated in randomized controlled trials. 5 The objectives of the present study were to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of single-dose noribogaine in patients seeking to discontinue methadone opioid substitution treatment (OST). Subsequent research has identified ibogaine as being rapidly converted oxidatively to an active metabolite, noribogaine, 3 which is eliminated much more slowly than ibogaine and thus might contribute to its antiwithdrawal and anticraving effects.…”