The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients
This pharmacokinetic study (n=14) on ibogaine (700mg/70kg) for opioid use disorder (OUD) finds significant variability in ibogaine clearance, strongly correlated with CYP2D6 genotype. Ibogaine plasma concentrations correlate with QTc prolongation and cerebellar effects, while neither ibogaine nor noribogaine correlate with the severity of opioid withdrawal symptoms.
Authors
- Robbert-Jan Verkes
- Arnt Schellekens
Published
Abstract
Objective
Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine.
Methods
The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity.
Results
The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms.
Conclusions
The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.
Research Summary of 'The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients'
Introduction
Ibogaine is an alkaloid from the rootbark of Tabernanthe iboga historically used in unregulated settings to treat addiction, including opioid use disorder (OUD). Earlier, non-controlled studies suggested ibogaine can mitigate opioid withdrawal and reduce craving and relapse, but dosing regimens have varied widely and no formal dose–effect studies exist. Major safety concerns remain, in particular ibogaine- and noribogaine-associated prolongation of the corrected QT interval (QTc), which raises the risk of torsades de pointes, and cerebellar ataxia observed in animal and human reports. Metabolism of ibogaine to noribogaine is largely mediated by cytochrome P450 2D6 (CYP2D6), with subsequent glucuronidation to noribogaine glucuronide (NIG); interindividual genetic variation in CYP2D6 activity could therefore drive exposure differences and safety risk, but the impact of genotype on PK and exposure–response relationships had not been fully characterised. Knuijver and colleagues designed a pharmacokinetic–pharmacodynamic (PKPD) study to address these gaps. Their primary aims were to quantify how CYP2D6 genetic variation affects ibogaine, noribogaine and NIG pharmacokinetics after a single oral dose, and to explore exposure–response relationships between plasma levels and three pharmacodynamic outcomes: QTc prolongation, cerebellar ataxia (assessed by SARA), and opioid withdrawal severity (OOWS and SOWS). The study was conducted in patients with OUD undergoing detoxification and monitored intensively for 24 hours after dosing.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Knuijver, T., ter Heine, R., Schellekens, A. F. A., Heydari, P., Lucas, L., Westra, S., Belgers, M., van Oosteren, T., Verkes, R. J., & Kramers, C. (2024). The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients. Journal of Psychopharmacology, 38(5), 481-488. https://doi.org/10.1177/02698811241237873
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Knuijver, T., Schellekens, A., Belgers, M. et al. · Addiction (2021)
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Koenig, X., Hilber, K. · Journal of Humanistic Psychology (2015)
Litjens, R. P. W., Brunt, T. M. · Clinical Toxicology (2016)
Malcolm, B., Polanco, M., Barsuglia, J. P. · Journal of Psychoactive Drugs (2018)
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Ona, G., Rocha, J. M., Bouso, J. C. et al. · Psychopharmacology (2021)
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Rodríguez-Cano, B. J., Kohek, M., Ona, G. et al. · Drug and Alcohol Review (2022)
Schenberg, E. E., de Castro Comis, M. A., Chaves, T. V. et al. · Journal of Psychopharmacology (2014)
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