Evaluating the toxicity and therapeutic potential of ibogaine in the treatment of chronic opioid abuse

KEYWORDS:

• Adverse event
• cytochrome p450 2d6
• hallucinogen
• hERG channel
• noribogaine
• opioid use disorder
• opioid withdrawal
• qt prolongation

1. Introduction

Ibogaine is a psychoactive indole alkaloid isolated from the West African shrub Tabernanthe iboga. It has been used by indigenous cultures to combat fatigue, hunger, and thirst, and to induce hallucinations during religious ceremonies. First isolated in 1901, ibogaine was initially recommended for use in asthenia at doses of 10 to 30 mg per day [1,2]. Semi-synthetic ibogaine came into use in 1939 and was marketed in France through 1970 under the trade name Lambarène as a ‘neuromuscular stimulant’ in 8-mg tablets for indications including fatigue, depression, and recovery from infectious illnesses [1]. Anecdotal reports concerning the beneficial effects of ibogaine for the treatment of opioid abuse and other drug dependencies appeared starting in the early 1960s [2], while the World Health Assembly classified ibogaine as a ‘substance likely to cause dependency or endanger human health’ and the Food and Drug Administration (FDA) assigned ibogaine to Schedule I classification. Despite these restrictions, ibogaine became available as an ‘addiction interrupter’ in countries that had not specifically prohibited its use. Although the benefit-risk ratio in opioid withdrawal management appears to be favorable if ibogaine is administered under qualified medical supervision [1], reports on drug-related deaths and other safety concerns in the published literature continue to hinder drug development.

2. Pharmacokinetics and pharmacology

Given orally, ibogaine is absorbed rapidly and undergoes extensive first-pass metabolism to 12-hydroxyibogamine (noribogaine) by cytochrome P450 2D6 (CYP2D6) in the gut wall and liver [3]. Plasma protein binding is in the range of 65–70% and consistent with its lipophilic nature, ibogaine accumulates in fat [4]. Maximum ibogaine concentrations in whole blood are estimated to be around 1,000 ng/mL with therapeutic doses are reached within approximately 2 hours. The plasma half-life of ibogaine is in the range of 2–6 hours depending on CYP2D6 genotype, while the metabolite noribogaine is eliminated with a half-life of 24–30 hours [1].

Circuit mechanisms driving opioid withdrawal and the protracted aversive state of the opioid abstinence syndrome involve dysregulated receptor signaling in neurotransmitter systems in the 5 main reward–aversion brain centers (nucleus accumbens, ventral tegmental area, amygdala, habenula, and raphe nucleus), all of which express mu opioid receptors [5]. Although the mechanism of action of ibogaine is not yet fully understood, it is likely related to the clinically relevant polypharmacology of the drug at receptor and transporter proteins in these addiction circuits. Blockade of the N-methyl-D-aspartate (NMDA) receptor presumably contributes to the oneiric effects of ibogaine, whereas different receptors, or combinations of receptors, may mediate the anti-addictive effects of ibogaine across different classes of abused substances [6]. We suggest that the multi-target actions of ibogaine and noribogaine cause a rapid reset of mu opioid expressing neurons in the reward-aversion centers of the brain [5].

3. Therapeutic potential

Ibogaine blocks addiction-like behavior in preclinical models, including opioid withdrawal, and opioid, alcohol, cocaine and nicotine self-administration. In a recent meta-analysis of 27 published animal studies, drug self-administration was most significantly reduced in the first 24 hours after treatment with ibogaine, and these effects were sustained for more than 72 hours [7].

In early 2006, more than 3,400 individuals had taken ibogaine worldwide, primarily for the treatment of substance use disorder (68%) with more than half specifically for opioid withdrawal (53%) [8]. Since commercial ibogaine clinics have been established in several countries (e.g. Netherlands, Portugal, New Zealand, Mexico, Bahamas, and the West Indies) and ibogaine is widely available through online channels, we estimate today’s total number of patients treated with ibogaine to be over 10,000 worldwide.

The majority of the clinical data that are currently available to support the use of ibogaine for the treatment of opioid or other substance use disorders stem from case reports or open-label clinical trials [1,9–11]. Although there is still a complete lack of adequate and well-controlled clinical trials, published efficacy results are consistent in showing rapid resolution of opioid withdrawal symptoms, reduced cravings, and extended abstinence over weeks, often months, and sometimes years. The single largest study performed to date is an open-label case series in opioid- (N = 102) or cocaine- (N = 89) dependent patients conducted in St. Kitts, West Indies [1]. In both cohorts, medically supervised and tightly monitored treatment with single oral doses of ibogaine (approximately 8–12 mg/kg or 600–1,200 mg total) in a controlled clinical environment was associated with significant reductions in opioid withdrawal symptoms at 24–36 hours after the last opioid dose. Significant decreases in drug cravings and standard scores of depression and anxiety were observed both at the end of the inpatient stay and at 30 days post treatment.

4. Safety

A total of 33 ibogaine-related deaths have been publicly reported to date. Thirty-two cases (33 including a double-counted case [12]) have been summarized in a review article by Corkery [13]; one additional case has been published more recently [14]. The deaths occurred between 1990 and 2020. Twenty-five (76%) of the decedents were male and 8 (24%) were female. Their age was 38.4 ± 9.7 years (mean ± SD; range 24–60 years). On average, the reported time between ibogaine ingestion and death was approximately 24 hours (range 1.5–76 hours) with an estimated dose range (when reported) between 4.5–55 mg/kg.

The ibogaine-related fatalities occurred mostly in unsafe settings without proper medical monitoring and advanced cardiac life support capabilities, including ‘treatment facilities’ (15 cases), patients’ homes (6 cases), and undisclosed environments (12 cases). Most patients were at an increased risk for adverse events due to use of supra-therapeutic and sometimes toxic ibogaine doses, concomitant use of CYP2D6-inhibitors or QT-prolonging drugs, polydrug abuse or alcohol withdrawal, presence of cardiovascular disease and other predisposing comorbidities, and/or electrolyte dysbalances (Mg⁺⁺ and K⁺). Furthermore, impure, crude alkaloidal extracts or adulterated drug product was used in many cases [15].

The recent report from Aćimović et al. illustrates the difficulties when assessing the causality of ibogaine fatalities based on incomplete information from forensic and toxicologic investigations [14]. The patient, a 27-year-old male heroin addict, was found dead in a rented apartment, where he had spent 3 days with a ‘therapist’ to undergo an ‘addiction treatment.’ The treatment, a powder labeled Tabernanthe iboga of unknown source and purity, was purchased online. The decedent’s use of heroin, codeine or other drugs in the days before death was undisclosed. Very high ibogaine concentrations were measured in femoral blood (3,260 ng/mL) and urine (28,870 ng/mL). Unfortunately, noribogaine concentrations were not quantified, although this would have been especially important for determining the relationship between time of ingestion, death and drug or metabolite exposures. However, as the patient purportedly died 5–12 hours after oral ingestion of the powder, the ibogaine concentrations support the conclusion of massive over-dosing.

Many of the reported deaths were attributed to drug-induced QT prolongation and Torsades de Pointes (TdP) resulting from blockade of potassium channels (hERG). Low micromolar concentrations of ibogaine inhibit various cardiac voltage-gated ion channels, including hERG potassium, Nav1.5 sodium, and Cav1.2 calcium channels [4]. The IC₅₀ for hERG channels is around 4 µM (corresponding to free ibogaine concentrations in plasma of approximately 1,200 ng/mL, approximately 4 times above estimated therapeutic levels [1]. However, ibogaine does not induce action potential prolongation in adult ventricular guinea pig cardiomyocytes and even leads to a shortening of the action potential at higher concentrations, through L-type calcium channel blockade [4].

Systematic studies of electrocardiographic effects associated with the use of ibogaine have not been conducted to date. The clinical evidence of drug-related QT prolongation (N = 11) with or without Torsades de Pointes (N = 6) and/or ventricular tachyarrhythmias is based on previously reviewed case reports [4,13,16–18]. These nonfatal cases presented with many of the same accompanying risk factors that have been identified for the ibogaine-related deaths, including abnormal electrolytes and dosing of impure, ‘large’ or multi-gram amounts of iboga-derived powders (3.11 ± 1.65; N = 6; mean ± SEM, 95% CI) These contributing factors make it difficult to determine the relative contributions of the ibogaine itself when cases are reported as single individual events.

There was no drug-related mortality or reported clinically relevant QT prolongation in the 191-patient study from St. Kitts which excluded relevant comorbidities and used high-quality ibogaine HCl drug product, a partially weight-based dosing scheme, and 24-hour telemetry post-dosing to maximize patient safety [1].

5. Expert opinion

Drug safety and effectiveness assessments of ibogaine for the management of opioid withdrawal have been hindered by its highly diverse regulatory status around the globe, ranging from strictly illegal/controlled in countries like the United States, France and Belgium to unregulated and/or commercially available in Canada, Spain, Mexico and New Zealand. Open-label studies have demonstrated that ibogaine has the potential to be a safe, effective and transformative therapy for patients seeking to break their intractable cycle of opioid dependence. However, the lack of controlled clinical trials conducted by qualified investigators remains a major obstacle, especially when unregulated use in unsafe settings by unskilled practitioners leads to reported cardiac arrhythmias and other adverse events that can turn lethal if untreated. Today, the vast underground ibogaine experiment is ongoing, because desperate patients will continue to exercise their ‘right to try’ ibogaine for opioid detoxification, most often in unsafe settings without medical supervision.

To objectively determine the benefit-risk ratio of ibogaine, adequate and well-controlled clinical trials of ibogaine for opioid detoxification and withdrawal management are urgently needed. The UK Medicines and Healthcare products Regulatory Agency (MHRA) recently granted approval to commence subject enrollment in a Phase 1/2a clinical trial of ibogaine HCl (clinicaltrials.gov). The Phase 1 part of the study will provide an assessment of safety at escalating doses of ibogaine in recreational opioid users. Extensive cardiac and other safety monitoring, CYP2D6 genotyping, and pharmacokinetic profiling will provide an understanding of what role QT prolongation or other adverse events may play on the way forward to full-scale clinical testing. The randomized, placebo-controlled Phase 2 part of the study is designed to provide proof of concept in patients who seek to detoxify from opioids. If successful, the study will lay the foundation for ibogaine to ultimately become available as a registered product that represents an important first step for patients seeking a non-opioid alternative to long-term opioid substitution therapy. While methadone and buprenorphine are important medicines, substitution therapies unfortunately have not ended the opioid crisis which resurged during the coronavirus pandemic.

Declaration of interest

M Luz is the Chief Medical Officer at DemeRx, Inc., a company which is advancing clinical trials of ibogaine and noribogaine for opioid detoxification and maintenance therapy, among other indications. He is also a consultant at atai Life Sciences, a joint venture partner with DemeRx. M Luz is holding stock options in both companies.

DM is an inventor on patents pertaining to the active metabolite of ibogaine. She is the CEO, founder and a shareholder in DemeRx, Inc.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from EOMT for their review work but have no other relevant financial relationships to disclose.

Additional information

Funding

The retrospective review of life-threatening adverse events temporally associated with ibogaine cited in the published literature were conducted as part of the reporting requirements for IND submissions. Funds for these activities were provided by DemeRx Inc. (M Luz and D Mash). D Mash has conducted clinical and nonclinical ibogaine research studies supported by contributions to the Addiction Research Fund, University of Miami Miller School of Medicine.