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

This ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study (n=36) investigated the safety and pharmacokinetic profile of orally ingested noribogaine (3, 10, 30, or 60mg), and found that it was rapidly absorbed and slowly eliminated, and generally safe and well-tolerated in healthy male volunteers.

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

Discussion: 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.”

Authors: Paul Glue, Michelle Lockhart, Fred Lam, Noelyn Hung, Cheung‐Tak Hung & Lawrence Friedhoff

Summary

Noribogaine, the active metabolite of ibogaine, was studied in 36 healthy drug-free male volunteers. It 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.

Ibogaine, a naturally occurring psychoactive chemical from the roots of the Tabernanthe iboga plant, has been used for centuries to combat hunger, thirst, and fatigue, and to provoke dream-like hallucinations for spiritual rituals. Noribogaine, a metabolite of ibogaine, may have advantages over ibogaine in terms of acute stress effects and acute toxicity in mice.

Methods

This study was conducted in 36 healthy male volunteers to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of noribogaine in healthy volunteers. All participants provided signed informed consent prior to enrollment, and were assessed as suitable to participate based on medical history, physical examination, and safety laboratory tests. A blinded study drug was administered as a capsule with 240 mL of water after an overnight fast of at least 10 hours.

Noribogaine’s mu-opioid agonist pharmacology was assessed using pupillometry, cold-pressor testing, oximetry, and capnography. Additional oximetry and capnography data were collected at 120, 168, and 216 hours post-dose.

Noribogaine Capsules (3 and 10 mg Doses)

Plasma noribogaine concentrations were determined using a validated, sensitive LCMSMS method. The samples were prepared using tert-butyl methyl ether, dried under a stream of nitrogen, and reconstitution with acetonitrile:B.P. water. Noribogaine-d4 was used as the internal standard. The concentration of noribogaine was measured by comparing the peak area of noribogaine to that of noribogaine-d4.

Plasma Noribogaine Glucuronide Assay (30 and 60 mg Doses)

Noribogaine glucuronide concentrations were determined in plasma samples from 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method. Noribogaine-d4 was used as the internal standard, and the concentration of noribogaine glucuronide was measured by comparing the peak area of noribogaine glucuronide to the peak area of noribogaine d4. The LLOQ was 0.050 ng/mL, and the run time was 7 minutes.

Urine Noribogaine and Noribogaine Glucuronide Assay (for 30 and 60 mg Doses)

Summary statistics were determined for safety laboratory test data, ECG and pharmacokinetic parameters, and pharmacodynamic variables for each dose group. The effect of dose on pharmacodynamic parameter values over time was assessed using two-factor analysis of variance.

Pharmacokinetics

Noribogaine was rapidly absorbed and rapidly eliminated from the body, with mean plasma elimination half-lives of approximately 28 – 49 hours across dose groups. Noribogaine glucuronide was detected in all subjects by 0.75 hours and was slowly eliminated from the body, with mean half-life estimates of 21 – 23 hours.

Pharmacodynamics

No between-dose group differences in pupil diameter were detected over time, and no evidence of noribogaine-related analgesic effect was observed in the cold-pressor test.

Safety

The most common adverse events were headache and epistaxis. There were no changes in vital signs or safety laboratory tests of note, except for one subject who had an increase in QTcF of >60 milliseconds at 24 hours post-dosing.

Discussion

Noribogaine doses from 3 to 60 mg were safe and well tolerated. Noribogaine had a large volume of distribution and increased linearly with dose.

Noribogaine is an antagonist of the serotonin transporter, but no side effects were reported. It is possible that the unique pharmacology of noribogaine at SERT affects its clinical tolerability.

Noribogaine was rapidly absorbed and slowly eliminated, with dose-linear increases in AUC and Cmax. It was well tolerated in healthy male volunteers, and there was no evidence of mu-opioid agonist effects at doses up to 60 mg.

Study details

Compounds studied
Ketamine

Topics studied
Safety

Study characteristics
Placebo-Controlled Double-Blind Randomized

Participants
36