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

Ibogaine, an indole alkaloid used sacramentally in West African Bwiti practice, has long been reported in case series and lay reports to reduce opioid withdrawal symptoms and cravings, but has not been evaluated in randomized controlled trials. Subsequent pharmacology showed ibogaine is rapidly converted to an active metabolite, noribogaine, which is eliminated more slowly and may mediate anti‑withdrawal or anticraving effects. Earlier work included a single‑ascending dose study of noribogaine in healthy volunteers. Glue and colleagues designed the present study to evaluate single‑dose noribogaine in opioid‑dependent patients seeking to discontinue methadone opioid substitution therapy (OST). The primary objectives were to characterise safety and tolerability, and to describe pharmacokinetics (PK) and pharmacodynamics (PD), including effects on opioid withdrawal and cardiac repolarisation (QT interval). This was the first trial of noribogaine in this patient population and aimed to inform the safety profile for future multiple‑dose studies.

This was an ascending single‑dose, randomized, double‑blind, placebo‑controlled, parallel‑group study performed at a clinical trials unit in Dunedin, New Zealand. Ethics approval and trial registration were obtained. Twenty‑seven participants established on methadone OST (25–80 mg/day for ≥30 days) were enrolled; inclusion required age ≥18 years and absence of clinically significant acute or chronic medical conditions. Within each dose cohort, six participants were assigned to noribogaine and three to matching placebo using a computer‑generated random code. Three planned dose levels were 60, 120, and 240 mg, but blinded safety review after the first two cohorts identified QT prolongation at 120 mg; the DSMB recommended reducing the top dose to 180 mg, which was implemented. In the week before dosing, methadone was switched to controlled‑release morphine for six days and then to immediate‑release morphine on the day before dosing. On dosing day participants fasted overnight; the last morphine dose was given at 06:00 and blinded study drug at approximately 08:00, with confinement from 24 hours pre‑dose to 72 hours postdose and follow‑up to 35 days. Pharmacokinetic sampling was intensive up to 144 hours postdose and analysed by validated LC‑MS/MS with an LLOQ of 0.50 ng/mL. PK parameters (Cmax, Tmax, AUC, t1/2, CL/F, Vd/F) were calculated by noncompartmental methods. Pharmacodynamic assessments included pupillometry, continuous pulse oximetry and capnography, and opioid withdrawal ratings: Subjective, Objective, and Clinical Opioid Withdrawal Scales (SOWS, OOWS, COWS). Time to resumption of OST was recorded. Cardiac safety included continuous Holter ECG and serial 12‑lead ECGs; QT correction used QTcF and an individualized QT correction (QTcI) derived from each subject’s 24‑hour baseline QT/RR relationship. The primary QT endpoint used the correction method that best removed heart‑rate dependence. Safety monitoring also recorded adverse events, vital signs, labs and physical and ophthalmological examinations. Statistical analyses comprised descriptive summary statistics, linear regression to assess dose proportionality of Cmax and AUC, and linear mixed‑effects models for change‑from‑baseline QTc with time, treatment and time-by‑treatment interaction; subjects were modelled as random intercepts. Exposure‑response models relating plasma noribogaine concentration to placebo‑corrected QTc change were fitted using several linear formulations, and model fit was assessed graphically and with standard residual diagnostics.

Thirty‑four subjects were screened and 27 enrolled and completed the study (21 male, 6 female). Mean age was 41.2 years, mean BMI 27.0 kg/m2; 20 participants were white, 5 Maori and 2 other. Comorbid diagnoses and concomitant medications were reported but are listed elsewhere in the extracted text. Pharmacokinetics: Noribogaine was rapidly absorbed with mean Tmax of 3.0–4.4 hours (range 1–8 hours) across dose groups, and both Cmax and AUC increased approximately linearly with dose. Individual concentration‑time profiles suggested possible enterohepatic recirculation. The mean terminal elimination half‑life was approximately 24–30 hours and apparent volume of distribution was large (means ~1,032–2,106 L across dose groups). Pharmacodynamics and withdrawal measures: Time to resumption of OST was presented by treatment arm and cohort; when analysed by cohort, placebo results closely matched corresponding active arms (Pearson’s r = 0.993). Opioid withdrawal scores (COWS, OOWS, SOWS) typically rose 1–2 hours prior to OST resumption and declined 1–3 hours after restarting OST. Pupillometry showed mean pupil diameter increased by 0.47 mm in the 2 hours prior to OST resumption (group range 0.3–0.64 mm); changes in pupil diameter over time did not differ between treatment groups. Electrocardiographic effects: QTcI was selected as the primary correction method because it reduced heart‑rate dependence more than QTcF in on‑treatment data. Noribogaine produced a clear, dose‑ and concentration‑dependent prolongation of the QTc interval. Peak mean placebo‑corrected QTcI effects were 16 ms at 4 hours for 60 mg, 28 ms at 3 hours for 120 mg, and 42 ms at 3 hours for 180 mg. The exposure‑response slope was estimated at 0.17 ms per ng/mL (90% CI 0.14 to 0.20 ms/ng/mL). Using the model, the projected QTcI effect at observed geometric mean Cmax values was 30 ms (90% CI 26–35 ms) for 120 mg and 42 ms (90% CI 36–48 ms) for 180 mg. In the 180 mg group one subject had QTcI > 480 ms at one time and another subject had QTcI > 500 ms at four time points; one subject in each of the 120 mg and 180 mg groups had a QTcI change > 60 ms at a single time point. Small changes in heart rate and PR interval were observed overall; the 180 mg group showed a placebo‑corrected heart rate reduction reaching −11 bpm at 6 hours. Safety and adverse events: Across all groups 78 adverse events were reported by 22 participants. The most common events were noneuphoric visual changes described as alterations in light perception, headache and nausea. Visual changes typically began within 1 hour of dosing, were mild, and resolved by 2.5–3 hours; no hallucinations were reported. Three events were rated severe (nausea, vomiting, headache); there were no deaths or serious adverse events and all AEs resolved before study completion. No notable changes in vital signs, respiratory measures (oximetry, capnography) or laboratory tests were observed.

Glue and colleagues interpret these results as showing that single doses of noribogaine up to 180 mg were generally tolerated but produced dose‑ and concentration‑dependent prolongation of the QTc interval that reached levels considered clinically concerning at the higher doses. The investigators emphasise that QT prolongation was the principal safety signal and that future trials should include ECG monitoring capable of rapid detection of pronounced QT prolongation to allow dose adjustment or discontinuation. Pharmacokinetic findings mirrored those in healthy volunteers: rapid absorption, slow elimination, dose‑linear increases in AUC and Cmax, and extensive distribution; Tmax in this patient population was delayed by 1–2 hours and Cmax at 60 mg was lower, possibly because predose morphine slowed gastric emptying. The observed exposure‑response relationship for QTc enables prediction of QT effects in future studies to help optimise benefit/risk. The authors note the QT effect diminished as plasma levels fell and that this decline preceded the emergence of methadone’s QT effect when methadone was reintroduced in most subjects 24 hours later. Mechanistically, noribogaine inhibits hERG (reported IC50 ≈ 5 μM, ~1,500 ng/mL), but the QT prolongation observed at much lower plasma concentrations was unexpected; the investigators suggest contributions from interactions with other cardiac ion channels are possible, analogous to published data for ibogaine. Translating to ibogaine, the authors estimate that commonly used ibogaine doses could produce noribogaine concentrations similar to those that prolonged QTc here and therefore recommend ECG monitoring and individual risk assessment for torsades de pointes in any clinical use of ibogaine. Regarding pharmacodynamics against opioid withdrawal, no clear benefit was demonstrated in this single‑dose design: time to OST resumption and withdrawal scores were similar between active and placebo within cohorts. The authors acknowledge study design limitations that likely confounded assessment of withdrawal efficacy — notably confinement of mixed treatment groups in a single ward that may have influenced participants’ decisions about when to resume OST, the small sample size, and the single‑dose regimen. They state that multiple‑dose, exposure‑controlled studies are planned to address these safety and design issues. The investigators also recognise the study may have been underpowered to detect uncommon or subtle safety signals.