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.

Hoewel de richtlijnen terughoudendheid adviseren, heeft het gebruik van oxycodon in Nederland een hoge vlucht genomen. Dat is zorgelijk, want opioïden zijn verslavend en je mag ze alleen voorschrijven als het echt niet anders kan. In de regio Arnhem heeft een transmuraal initiatief het gebruik van kortwerkend oxycodon in 3 jaar tijd sterk teruggedrongen door protocollen te stroomlijnen en nascholing te geven. Hopelijk kan het Arnhemse initiatief een voorbeeld zijn voor andere regio’s.

AbstractBackground and aimsIbogaine is an indole alkaloid used in rituals of the African Bwiti tribe. It is also used in non‐medical settings to treat addiction. However, ibogaine has been linked to several deaths, mainly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder.DesignA descriptive open‐label observational study.SettingDepartment of psychiatry in a university medical center, the Netherlands.ParticipantsPatients with opioid use disorder (n = 14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care.Intervention and measurementsAfter conversion to morphine‐sulphate, a single dose of ibogaine‐HCl 10 mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, scale for the assessment and rating of ataxia (SARA) to assess cerebellar side effects and the delirium observation scale (DOS) to assess psychomimetic effects.FindingsThe maximum QTc (Fridericia) prolongation was on average 95ms (range 29‐146ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well‐tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold).ConclusionsThis open‐label observational study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.

We thank Luz & Mash for their valuable thoughts [1] regarding our pilot study [2] on the effects of a single ibogaine administration in patients with opioid use disorder (OUD). Below we respond to the issues raised in order to substantiate the conclusion that administration of ibogaine has profound cardiac risks. First, our pilot study, registered at EudraCT (2014–000354-11), was designed to investigate clinical effects of ibogaine in healthy OUD patients, including safety issues (secondary objective). The trial register does not detail statistical analyses on the secondary outcome measures. Analyses are described in detail in the research protocol approved by the medical ethical board and in the published article (page 4). Secondly, we applied standard electrocardiogram (ECG) methodology and QTc-corrections, in line with Food and Drug Administration (FDA) guidelines [3]. Fridericia correction is more reliable in bradycardic conditions [3], thus correcting for potential confounding effects of heart-rate variability during oneirogenic experiences after ibogaine. Because Bazett's formula was the standard at study initiation we also report those results, showing very similar findings. As outlined in the Methods section, ECG measures were taken every 30 minutes in supine position. Doing so, we observed robust QTc-prolongation (median maximum QTc-prolongation = 95 ms; QTc > 500 ms in half of patients) [2]. The clinically most relevant point refers to potential drug–drug interactions of ibogaine. Potential confounding effects of metoclopramide (putative pharmacokinetic interactions with ibogaine through CYP2D6) and residual methadone (given its QTc-prolonging effects) are suggested. However, in-vitro metoclopramide showed no to little inhibition of CYP2D6 [4], and no interactions are reported for metoclopramide with known CYP2D6 substrates (e.g. IBM–micromedex). Note that more potent CYP2D6 inhibitors and inducers, e.g. paroxetine and fluoxetine, are commonly used by OUD patients who might apply for ibogaine treatment. The suggested pharmacodynamic interaction between ibogaine and residual methadone weeks after the last dose is also theoretically viable. However, baseline ECG measures did not show QTc-prolongation. Furthermore, any potential residual methadone after 9 days cannot account for the observed systematic acute QTc-prolongation in all participants, commencing within 60 minutes after ibogaine ingestion. Note that in non-research settings patients might receive ibogaine without proper ECG-monitoring prior to ibogaine ingestion and without tapering of QTc-prolonging agents, such as methadone, antipsychotics and antidepressants. Finally, Luz & Mash call for linking ibogaine plasma levels with the observed QTc-effects. We fully agree that this is a relevant next step, as pharmacokinetic–pharmacodynamic (PK–PD) modelling can shed further light on a dose–response relationship (causality) between ibogaine plasma levels, its metabolites (a.o. nor-ibogaine) and the observed impressive QTc-prolongation. Indeed, our study suggests that the QTc-prolongation observed after ibogaine administration may persist even after 24 hours, potentially reflecting a relationship with ibogaine metabolites or a long-lasting effect on cardiomyocytes. In the PK-PD model genetic variability in CYP2D6 activity can also be addressed, which may contribute to heterogeneity in the severity of QTc-prolongation. The clear safety issues encountered with the current small-scale, well-carried-out study are in line with other studies and clinical observations on cardiac toxicity and acute deaths after ibogaine [5-8], and observed in-vitro effects on repolarization in cardiomyocytes [9, 10]. We acknowledge that new effective treatments for OUD patients are urgently needed. However, patient safety is key in medication development. Based on our findings we recommend application of ibogaine only in well-monitored research settings and exploration of safe alternatives, such as ibogaine micro-dosing or synthetic ibogaine analogues [11]. We thank participants for their willingness to participate in the original study. Stichting Hoogeland provided financial support for the original study that this letter refers to. AS wrote the first draft, all authors commented on this draft and contributed to the final version of the manuscript.

Knuijver, Thomas MD, PhD; Belgers, Maarten MD, PhD; Markus, Wiebren MA; Verkes, Robbert-Jan MD; van Oosteren, Toon MD; Schellekens, Arnt MD Author Information