Safety of ibogaine administration in detoxification of opioid dependent individuals: a descriptive open-label observational study

This open-label observational study (n=14) investigated the safety profile of ibogaine (700mg/70kg) for patients with opioid use disorder who were undergoing acute opioid withdrawal. Although patients experienced mild withdrawal symptoms and transient well-tolerated psychomimetic effects, they exhibited abnormal patterns in heart rhythm that constituted an adverse level of cardiovascular risk. This study indicates that even a low-dose administration of ibogaine requires strict cardiac monitoring, and should be restricted to well-controlled settings.

Abstract

“Background and aims: Ibogaine is an indole alkaloid used in rituals of the Bwiti tribes of Africa. It is also used in non-medical settings to treat addiction. However, ibogaine has been linked to several deaths, mostly 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.

Design: A descriptive open-label observational study.

Setting: Department of psychiatry in university medical center, The Netherlands.

Participants: Patients 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 measurements: After conversion to morphine-sulphate, a single dose of ibogaine-HCl 10mg/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).

Findings: The maximum QTc prolongation was on average 100ms (range 40-168ms). 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).

Conclusions: An open-label observation study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.”

Authors: Thomas Knuijver, Arnt Schellekens, Maarten Belgers, Rogier Donders, Toon van Oosteren, C. Kramers & Robbert-Jan Verkes

Notes

A reply was written by Matthias Luz and Deborah Mash (respectively CMO and CEO of DemeRx) arguing for flaws in the analysis, though joining the conclusion that “ibogaine should only be administered to patients by astute clinicians who have knowledge of the pharmacokinetics, metabolism and potential safety risks for this investigational drug product.“

Summary

Ibogaine, an indole alkaloid used in rituals of the Bwiti tribes of Africa, has been linked to several deaths due to cardiac events and other safety concerns. A study of 14 patients with opioid use disorder found that ibogaine treatment can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.

Ibogaine is an entheogen found in the root of Tabernanthe iboga, a shrub found in Central Africa. Ibogaine has shown some promise in the treatment of addiction, but it is also associated with cardiac risks, such as torsades des pointes (TdP) and ataxia. Moreover, one case of suicide during ibogaine use has been published. Ibogaine treatment for opioid use disorder is widely offered across the world, often without medical supervision. The present study assessed the cardiac, cerebellar and behavioral effects of ibogaine treatment.

We conducted an open label observational study in patients with opioid use disorder in opioid substitution treatment. A total of 29 patients were included, and a post hoc poweranalysis showed that with 10 patients 80% power would be reached. Patients with a history of psychotic symptoms, severe major depressive disorder or suicidality were excluded from the study. Participants received 10mg/kg ibogaine-HCl orally, administered in a yoghurt mixture, at 8:30 AM. The purity was assessed using a validated liquid chromatography assay with ultraviolet detection.

Subjects were given 20mg of metoclopramide to prevent nausea before ibogaine administration. Substance use and addiction severity were assessed using the Addiction Severity Index (ASI), which scores the severity of problems experienced as well as a wish/request of the patient for help. The QTc prolongation was assessed using automatic twelve lead ECG measurements performed with a Philips Healthcare, multichannel TC50 . The correlation between the QTc intervals calculated by two independent researchers was moderate (r=0.64) and the Bland-Altman plot showed a non-significant mean difference of +7ms for the automatic measurement.

The heartrate and blood pressure were measured after each ECG assessment, and the cerebellar ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). The SARA has 8 items and a maximum score of 40. Psychomimetic effects were monitored using the Delirium Observation Screening (DOS) scale, and withdrawal was measured using the clinical opioid withdrawal scale. All subjects were converted from OST to oral morphine sulphate for 8 days, and detoxified of any other drugs for at least 8 days prior to participating in the study. ECGs were performed every half hour for the first twelve hours, and then every hour thereafter.

Participants received ibogaine for two hours, six hours, ten hours and twenty-four hours. Their SARA, COWS and DOS scales were assessed every hour for the first twelve hours after administration of ibogaine. We summarized demographics, type of substitution therapy, current substance use and addiction severity, and used descriptive statistics to calculate QTcMax and proportion of subjects with a QTc >500ms at any given time. Subjects were left sleeping in the evening and night, and fewer measurements were taken during the night. The number of subjects developing bradycardia or hypotension, and the mean maximum drop in heartrate and blood pressure during the first twelve hours were calculated.

All subjects had a history of polysubstance abuse, and their heart-rate, blood pressure and QTc were within normal range. The QTcMax varied greatly, with a median of 102ms, and the proportion of subjects with a QTc >500ms varied between 7-28%.

During the first 12 hours after administration mild bradycardia and a decrease in blood pressure occurred, and all subjects developed clinical signs of cerebellar ataxia. Five patients scored above zero after 24 hours, they were tested again 24 hours later, with full remission of ataxia.

Most subjects experienced low withdrawal severity after ibogaine ingestion, with only three subjects requesting a return to morphine substitution. Ibogaine-HCl (10mg/kg) produced a clinically relevant QTc prolongation in patients with OUD in OST undergoing acute opioid withdrawal. Although reversible, this QTc prolongation is a clinically relevant cardiac safety risk, including risk of TdP, even after a relatively small dose of ibogaine. In vitro studies strongly suggest that ibogaine and its metabolite noribogaine prolong the QTc by inhibiting cardiac hERG-potassium channels, which results in prolonged depolarization of cardiomyocytes. Inter-individual variation in the extent, timing, and duration of QTc prolongation might result from several inter-individual pharmacokinetic and pharmacodynamic differences, including genetic variation in the CYP2D6 genotype, which can cause variation in the first pass effect, bioavailability, and elimination of ibogaine and availability of noribogaine. Ibogaine causes ataxia in the distal limbs and balance, which is in accordance with the higher susceptibility of the vermis to toxicity as opposed to the cerebellar cortex. However, future studies should investigate whether cerebellar effects of ibogaine play a role in its alleged anti-addictive properties. No subjects had substantial increases on the DOS-scale, but some reported having psychomimetic experiences. However, literature and internet fora suggest that longer lasting disturbing behavioral changes can occur after ibogaine ingestion.

The observed serious side effects of ibogaine, including cardiac risk, hamper the clinical utility of ibogaine in the treatment of substance use disorders. The current findings should be interpreted in the light of several limitations, including that only 14 patients were included, that the study is underpowered to detect rare, severe adverse events, and that the provided dose is on the lower bound of dosages in previous research settings. Patients received metoclopramide to prevent nausea and vomiting, and a mild QTc-prolonging effect was observed. However, given the lack of a placebo control group, any confounding effects of metoclopramide or opioid withdrawal itself cannot be fully ruled out.

In conclusion, ibogaine induces clinically relevant reversible QTc prolongation and bradycardia in patients with OUD in opioid substitution treatment in acute withdrawal.

We thank several people for their help in conducting our research, as well as NISPA, the nursing staff and RadboudUMC.

Ibogaine, an anti-addiction drug, is used in the treatment of opioid and cocaine addiction. It has been shown to inhibit the activity of certain receptors in the brain, including those involved in the regulation of heart rate and rhythm. Ibogaine, a psychoactive indole alkaloid, inhibits voltage-gated ionic currents in the heart, and may be used to treat addiction to drugs such as heroin. Ibogaine treatment for opioid use disorder can lead to manic symptoms, hallucinations, and a prolonged QT interval. The Mini-International Neuropsychiatric Interview is a structured diagnostic psychiatric interview for DSM-IV and ICD-10 that was developed by the Clinical Pharmacology Research Institute IU.

A retrospective study of ibogaine treatment outcomes for opiate dependence from a twelve-month follow-up observational study. Ibogaine is a psychoactive drug used to treat addiction to opioids. The Addiction Severity Index (ASI) is a reliable and valid measure of addiction severity that was developed by McLellan, Luborsky, Cacciola, Griffith, Evans, Barr, et al. The SARA is a useful tool for assessing and rating ataxia. Responsiveness of different rating instruments in spinocerebellar ataxia patients was evaluated in a systematic review. A new rating scale for opiate withdrawal was developed in 1987, and a report was published in 2005 on the clinical evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.

Ibogaine and its O-desmethyl metabolite, noribogaine, have been shown to induce Torsade de Pointes in healthy volunteers. Ibogaine, an anti-addictive drug, has been studied in detail. Noribogaine is a biologically active metabolite of ibogaine. Subject characteristics, baseline measurements, and primary and secondary outcomes are shown in Table 1. Ibogaine treatment induces a phenomenological analysis of the subjective experience elicited by iboga in the context of a drug dependence treatment.