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

Ibogaine is a naturally occurring psychoactive compound derived from the Tabernanthe iboga plant that has been used traditionally and, more recently, investigated for its ability to attenuate opioid withdrawal and reduce craving. Subsequent research identified noribogaine as ibogaine's principal active metabolite that is formed rapidly and eliminated more slowly, and which shares many pharmacological targets with ibogaine including interaction with NMDA receptors, opioid receptors and the serotonin transporter. Preclinical data suggested noribogaine might have lower acute toxicity than ibogaine and therefore could have therapeutic potential in managing opioid withdrawal. Glue and colleagues set out to characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single oral doses of noribogaine in healthy volunteers as the first step in a clinical development programme. The study aimed to define absorption and elimination kinetics, dose proportionality, metabolic profiles including glucuronidation and urinary excretion, and to screen for mu-opioid agonist effects using sensitive PD measures relevant to opioid activity.

This was a Phase I, ascending single-dose, placebo-controlled, randomised, double-blind, parallel-group study conducted in 36 healthy drug-free male volunteers aged 18–55 years at a clinical trials unit. The trial was approved by an ethics committee and registered in a national registry. Participants were screened by medical history, examination, laboratory tests and ECG, provided written informed consent, and were confined to the study site from 12 hours prior to dosing until 72 hours after dosing with additional outpatient follow-up to 216 hours. Four sequential cohorts (n = 9 per cohort) received oral noribogaine capsules or matching placebo at dose levels of 3, 10, 30 or 60 mg, with six active and three placebo participants per cohort. Dose escalation proceeded only after blinded review of safety, tolerability and PK data by an independent Data Safety Monitoring Board. Study drug was administered after an overnight fast and food was withheld for at least five hours post-dose. Extensive PK sampling was performed: plasma at numerous time points from predose to 216 hours, and 24-hour urine collections for the 30 mg and 60 mg cohorts. Noribogaine and noribogaine glucuronide concentrations in plasma and urine were quantified using validated LC–MS/MS assays; multiple sample-preparation methods were used depending on dose cohort. Reported lower limits of quantification included 0.025 ng/mL for the low-dose plasma method, 0.50 ng/mL for the higher-dose plasma method, 0.050 ng/mL for plasma glucuronide, and 20.0 ng/mL and 2.0 ng/mL for urine noribogaine and glucuronide respectively. Pharmacodynamic assessments targeted sensitivity to mu-opioid agonists and included pupillometry (dark-adapted pupil diameter), cold-pressor testing (time to hand removal and VAS pain score), continuous pulse oximetry and capnography, and serial ECGs. PK parameters (Cmax, Tmax, t1/2, AUC0–∞, CL/F, Vd/F) were calculated using model-independent methods; terminal half-life was derived from the terminal elimination rate constant. Dose proportionality of AUC and Cmax was assessed by linear regression. The effect of dose on PD parameters over time was analysed with two-factor ANOVA and pairwise comparisons versus placebo using Tukey–Kramer adjustments, implemented with mixed models in SAS.

All 36 enrolled healthy male volunteers completed the study. Mean (SD) age was 22.0 (3.3) years; mean (SD) weight was 78.0 (9.2) kg. The sample included predominantly Caucasian participants with small numbers of other ethnicities. Pharmacokinetics: Noribogaine was rapidly absorbed with mean Tmax approximately 2–3 hours post-dose. Both Cmax and AUC increased linearly with dose across the 3–60 mg range. The compound was eliminated slowly, with mean terminal half-lives of roughly 28–49 hours across dose groups. Apparent volume of distribution was large (mean Vd/F range 1417–3086 L), consistent with extensive tissue distribution. Individual concentration–time profiles showed fluctuations in the distribution phase suggestive of possible enterohepatic recirculation. For the 30 mg and 60 mg cohorts, noribogaine glucuronide was detectable by 0.75 hours with a mean Tmax about 3–4 hours (approximately 1 hour later than parent), and a mean half-life of 21–23 hours. The glucuronide-to-parent ratios for mean Cmax and AUC were small (about 3–4%). Urinary recovery of total noribogaine (parent plus glucuronide) was minimal: mean total urine elimination was 1.16 mg (3.9% of dose) for the 30 mg group and 0.82 mg (1.4% of dose) for the 60 mg group. Pharmacodynamics: No dose-related effects consistent with mu-opioid agonism were observed. Pupillometry showed no between-group differences over time after baseline adjustment (ANOVA P > .9), and there was no evidence of drug-induced miosis. Cold-pressor testing revealed no noribogaine-related analgesic effect in either time to hand removal (ANOVA P > .9) or VAS pain scores (ANOVA P = .17) compared with placebo. Continuous oximetry, capnography and respiratory rate were unchanged. Safety and tolerability: Thirteen treatment-emergent adverse events were reported by seven participants. Six events occurred in three placebo subjects, five in two subjects in the 3 mg group, and one each in single subjects in the 10 mg and 30 mg groups. The most frequent events were headache (4 reports) and epistaxis (2 reports). All adverse events were mild or moderate and resolved before study completion. No clinically meaningful changes were observed in vital signs or laboratory tests. There were no QTcF values >500 ms; one subject in the 10 mg group had a single QTcF increase >60 ms at 24 hours post-dose.

Glue and colleagues report the first clinical administration of noribogaine to humans and conclude that single oral doses from 3 to 60 mg were safe and well tolerated in healthy male volunteers. The investigators highlight that noribogaine displayed rapid absorption, slow elimination, extensive distribution and dose-linear increases in AUC and Cmax across the examined range. The absence of pharmacodynamic effects typical of mu-opioid agonists in sensitive measures (pupillometry, cold-pressor testing, respiratory monitoring) led the authors to interpret their findings as consistent with a lack of mu-agonist activity for noribogaine at doses up to 60 mg. They note that noribogaine interacts most potently with the serotonin transporter (SERT) and uniquely acts noncompetitively at SERT, which may relate to its tolerability; anticipated serotonergic adverse effects such as nausea and insomnia were not observed at the doses tested. The authors also cite recent in vitro work suggesting noribogaine's mu-opioid interactions may reflect antagonism or weak partial agonism rather than robust agonism, a view compatible with the negative PD results obtained here. Potential mechanisms for the prolonged elimination observed include enterohepatic recirculation (supported by distribution-phase profile fluctuations), a high lipophilicity (predicted logP ~3.88) yielding large apparent volume of distribution, and slow metabolic clearance. The small proportion of exposure represented by noribogaine glucuronide and the low urinary recovery are consistent with limited renal elimination and the in vitro metabolic data presented. The authors acknowledge that serotonergic side effects might still occur at doses higher than 60 mg and that the study's conclusions about mu-agonist activity are confined to the dose range tested. They also position their data in the context of limited prior human PK information on noribogaine and conclude that the safety, tolerability and PK/PD profile observed support further clinical development of noribogaine as a treatment candidate for drug dependence.