Rare but relevant: Ibogaine and cardiovascular complications—prolonged QT interval and ventricular arrhythmias

Abstract

Revived interest in psychedelic‐assisted therapies has also renewed focus on ibogaine, a psychoactive alkaloid, for its notable anti‐addictive potential. Evidence from observational, open‐label, and limited randomized placebo‐controlled trials indicates that ibogaine and its metabolite noribogaine reduce craving and withdrawal symptoms in opioid and cocaine‐dependent individuals, primarily through multiple pharmacological mechanisms; however, ibogaine presents a rare yet clinically significant cardiotoxic risk: QTc prolongation and potentially fatal ventricular arrhythmias such as Torsades des Pointes. Case reports demonstrate that these events occur with therapeutic doses of ibogaine and in individuals without pre‐existing cardiac conditions. A large interindividual variability in CYP2D6 metabolism of ibogaine was shown and might contribute to higher cardiovascular risk in certain individuals. Recent efforts to improve safety of ibogaine include different dosing strategies, cardiovascular monitoring and the development of ibogaine analogues, which retain anti‐addictive efficacy while lacking cardiotoxicity in preclinical models. Future ibogaine‐assisted treatment should be conducted exclusively under controlled medical supervision, with CYP2D6 genotyping and rigorous monitoring of cardiovascular functioning. Future clinical trials should prioritize evaluation of safer analogues and personalized dosing strategies to optimize the benefit–risk profile of this emerging therapy.

INTRODUCTION

In the wake of a revival of interest in therapeutic use of classic psychedelics, the pharmacological mechanisms of these substances are also revisited, uncovering new knowledge and novel avenues for therapeutic benefits. Complex conditions like treatment resistant depression, post‐traumatic stress disorder or substance use disorders have been treated in several clinical trials with psychedelic drugs and, not seldom, with promising results. The spectrum of psychedelics under research is broadening, varying from isolated molecules, like esketamine and psylocybin to complex plant extracts, like ayahuasca or iboga. Because interest in psychedelics is continuously rising, it is of interest to focus on possible side‐effects some of these substances might have. This short clinical review gives an update on ibogaine, the psychoactive agent in iboga, its therapeutic potential, mechanism of action and its rare (but relevant) side effects on the cardiovascular system.

THERAPEUTIC APPLICATIONS: ANTI‐ADDICTIVE PROPERTIES

Ibogaine is derived from the African Tabernanthe Iboga shrub and isolated from the iboga root bark [1]. Anti‐addictive effects of ibogaine have been reported since the 1960s [2, 3], and in the decades that followed there have been multiple attempts to get approval to do clinical trials with ibogaine with substance‐dependent individuals [4, 5]. In a review by Koenig and Hilber [6] it was stated that there are ‘dozens of clinics worldwide’ that offer ibogaine treatment, some under licence, primarily for substance use disorders (SUD)s, for example, in South Africa, Canada, the Netherlands, Brazil and Mexico [7]. In 2006, it was estimated that over 3400 individuals had received ibogaine treatment [8], which was a fourfold increase over 5 years. In 2023, the estimate was that more than 10 thousand individuals sought ibogaine treatment for SUD [9], indicating that numbers are vastly increasing. However, prevalence of use in the general population is not known.

There have been some observational and open label studies done that have studied anti‐addictive effects and overall the results look promising [5, 10], mostly on opioid withdrawal [11, 12]. Whereas interest into ibogaine treatment was tempered for some period of time because of its side‐effects (mainly cardiovascular), it seems to have regained traction over recent years, partly because of the opioid epidemic in the United States (US) [10]. Therefore, more recently, there have been a number of open label clinical trials and a couple of placebo‐controlled randomized trials [5, 13, 14]. Doses of ibogaine or noribogaine HCl in the open label studies varied between 20 mg to 800 mg per os (p.o.) and reductions in craving and withdrawal symptoms were reported in most of them, mainly measured with the Clinical Opioid Withdrawal Scale (COWS) and Subjective Opioid Withdrawal Scale (SOWS) [5]. Most of these study populations were generally small. However, one study by Mash et al. [15] reported on 191 patients (144 males/47 females) with both cocaine‐ and opioid‐dependence, and oral doses of ibogaine (8–12 mg/kg) were well‐tolerated, without major clinical side‐effects and reduced cocaine and heroin craving (as measured with the clinical craving questionnaire ‐CCQ‐45‐ and the heroin craving questionnaire ‐HCQ‐29‐, respectively). In the placebo‐controlled randomized trials in opioid‐dependent patients, cravings and withdrawal symptoms decreased with noribogaine HCl (up to 180 mg p.o.) and reduced relapse rates up to at least 1 month were reported [13, 14].

IBOGAINE: MECHANISM OF ACTION

Both ibogaine and its metabolite noribogaine are psychoactive, but their mechanism of action is complex and runs through simultaneous action at various neurotransmitter systems and via inducing neurotrophic factors [16]. First of all, ibogaine and noribogaine act as agonists of the κ opioid receptor, responsible for the hallucinatory states reached by ibogaine [17]. κ Opioid receptors are also located on the pre‐synaptic dopamine terminals of the striatum, inhibiting dopamine efflux, adding to the anti‐addictive properties of (nor)ibogaine [16]. In response to cocaine, ibogaine increased the dynorphin A concentration in the striatum, which can cause dysphoria via κ opioid receptors [18]. Ibogaine and its metabolite noribogaine act as weak antagonists of the μ opioid receptor, thereby also explaining some of its anti‐addictive potential [19, 20]. Ibogaine and noribogaine also interact with serotonin and dopaminergic transporters, which are believed to play a role in the visual and introspective effects [1]. Noribogaine particularly inhibits the serotonergic transporter [16], which might be responsible for anti‐depressive effects of iboga [15]. Furthermore, ibogaine is a competitive antagonist of N‐methyl‐D‐aspartate (NMDA) receptor at micromolar concentrations [21, 22], which is mainly responsible for its dissociative and dreamlike effects. It also adds to its anti‐addictive effects, as blockade of the NMDA receptor attenuates rewarding effects of drugs of dependence (e.g. morphine, cocaine) and suppresses symptoms of withdrawal [16, 23, 24]. Ibogaine and noribogaine induce cellular expression of brain‐/glial‐derived neurotrophic factors (BDNF and GDNF), especially in the ventral tegmental area (VTA) [25]. Mainly noribogaine induced neural plasticity and dendritic arbor complexity in a similar level as ketamine [26]. BDNF and GDNF expression in the VTA is able to extinguish rewarding and locomotor responses to morphine, so providing another route for anti‐addictive effects of iboga, however, the role of these neurotrophic factors in dependence and withdrawal still remains largely unknown [16]. Besides these mechanisms of action, other targets of ibogaine have also been identified, such as σ receptors and adenosine triphosphate‐binding cassette transporters [16].

COMPLICATIONS OF IBOGAINE USE

It has been well‐documented that the use of iboga/ibogaine has certain risks. A review in 2022 by Ona et al. [27] divided adverse events into acute and prolonged. Main acute adverse events consisted out of gastrointestinal (nausea, vomiting), but several studies also described ataxia, muscle weakness, diaphoresis, akathisia or tremors. Prolonged adverse events (after 3–13 days; mean = 7.8 days) included psychiatric complications, such as insomnia, alterations in speech, delusions, aggressiveness, irritability, dissociation and hallucinations [27, 28]. However, cardiovascular events were most prominently present in the majority of studies that were systematically reviewed in Ona et al. [27].

EFFECTS ON THE CARDIOVASCULAR SYSTEM

Notwithstanding ibogaine's therapeutic promise, treatment with (nor)ibogaine has a rare, but clinically very relevant side‐effect: it is known to cause a prolonged QT interval (≥450 ms for males, ≥460 ms for females; corrected for heart rate: QTc), affecting repolarization of the heart, causing ventricular tachyarrhythmias and Torsades des pointes, which can lead to death [1, 6, 27, 29]. The main mechanism by which ibogaine is responsible for this prolonged QTc interval and ventricular tachyarrhythmias is the blockade by noribogaine or ibogaine of ether‐a‐go‐go‐related gene (hERG) potassium channels in cardiomyocytes of the heart [30, 31]. The hERG channels cause repolarization of action potentials of the heart, therefore, blockade of these channels delays repolarization, leading to arrhythmias and, ultimately, cardiovascular failure and cardiac arrest. Additionally, action of ibogaine at L‐type calcium channels in ventricular cardiomyocytes in a computer model of the human heart has also been shown to prolong the QT interval [32]. See Figure 1 for an electrocardiogram (ECG) of ventricular arrhythmias with prolonged QT interval and Figure 2 for QT interval and Torsades des pointes.

FIGURE 1.

Ventricular arrhythmias and prolonged QT‐interval.

FIGURE 2.

QT‐interval (upper panel) and Torsades des pointes (lower panel).

In 2012, a forensic case series review of post‐mortem data on 27 cases led to the conclusion that pre‐existing cardiovascular morbidity was a leading cause of fatalities of individuals taking iboga or ibogaine [33]. From the cases where this information was available, mean dose was 14.3 ± 6.1 mg/kg. Cardiomyopathy, myocardial infarct, arrhythmias and cardiac hypertrophy were conditions identified in pathology examination and some fatalities occurred many hours to even days after the ingestion of ibogaine, which could point toward metabolites of ibogaine as cardiotoxic, like noribogaine. Equipotent retarded action potential repolarization by noribogaine was shown in stem cell‐derived human ventricular‐like cardiomyocytes [34]. Blockade of hERG channels and subsequent QT interval prolongation and arrhythmias of (nor)ibogaine was determined at less or equivalent doses used for addiction treatment (8–10 mg/kg) [14]. However, the finding that pre‐existing cardiovascular morbidity is a pre‐requisite for ibogaine‐related cardiac events has been since then refuted by several case studies (e.g. Hoelen et al. [35], Vlaanderen et al. [36] and Pleskovic et al. [37]), and for an overview see Litjens [29]. Since this overview, even more (case) studies have reported prolonged QTc interval, ventricular arrhythmias, including Torsades des pointes in patients without cardiovascular history after Iboga/ibogaine ingestion (sometimes fatal), and ages in the various reported cases to date varied between 19 and 64 years [28, 38, 39, 40, 41, 42]. Where the information was available, doses taken varied considerably (2.6 mg/kg–70 mg/kg), and plasma ibogaine levels measured ranged from 1.45 mg/L–3.26 mg/L. Furthermore, it has to be taken into consideration that in all of these cases it was taken in uncontrolled and unmonitored conditions.

In the light of ibogaine‐assisted addiction therapy, several studies have addressed the issue of dosing and safety in ibogaine therapy. For instance, a study by Kuijver et al. [43] carefully monitored opioid‐dependent patients (n = 14) after administration of ibogaine HCl (10 mg/kg). QTc interval of >500 ms was seen in half of the patients and after 24 hours, QTc was still >450 ms in 29% of subjects, but no serious cardiac events or Torsades des pointes were observed on ECG, and QTc normalized in all patients eventually. The same research group has recently investigated the relationship between ibogaine plasma levels and QTc prolongation, and the half‐maximum concentration (EC₅₀) for QTc prolongation was estimated to be 0.195 μM, with no difference between sex (n = 14; 12 males/2 females) [44]. The participants received the regular treatment dose of 10 mg/kg ibogaine. In this study, it was found that the peak effects (Cmaxs) of ibogaine (4.77 μM/L) and noribogaine (1.33 μM/L) were more than 10‐fold higher than the EC₅₀, so Knuijver et al. [44] concluded that the treatment dose should be 10‐fold reduced to be on the safe side. However, such a dose might not have any therapeutic effects. This study also showed an anti‐clockwise hysteresis if QTc was plotted against ibogaine plasma concentrations, whereas noribogaine showed clockwise hysteresis, implying that QTc prolongation is most likely driven by ibogaine [44]. In support of the findings by Knuijver et al. [45], another study correlated results from animal toxicity studies to humans and concluded that the ‘safe’ dose for ibogaine is approximately 0.87 mg/kg, which is at least a factor 10 lower than doses used in addiction treatment. In these studies and others, pharmacokinetics of ibogaine was emphasized, which has important implications, because clearance of ibogaine is dependent on genotype, mainly via the CYP2D6 enzyme, and plasma levels show strong intersubject variance [9, 46], therefore, poor metabolizers are likely to run greater risks of adverse cardiac events.

Given the significant cardiac risks involved in ibogaine treatment, clinical management of ibogaine administration mainly relies on stringent monitoring, administration in controlled settings with comprehensive medical, psychiatric and cardiac monitoring, including continuous ECG surveillance, to detect and manage these life‐threatening complications, as was concluded in a systematic review by Rocha et al. [47]. The systematic review by Ona et al. [27] summarized some medical interventions that were applied in hospitalized patients in several case studies, such as anticonvulsants, isoproterenol and atropine in the management of clinical symptoms. They also described some case studies whereby electrical cardioversion, a pacemaker, defibrillation and intubation were necessary. Two studies reported on magnesium/sodium and saline suppletion after ibogaine treatment to manage adverse cardiac events [28, 38]. However, aside from placing the pacemaker in some patients to reduce ventricular arrhythmias, most of the other clinical interventions treatments were not effective in resolving ventricular arrhythmias or Torsades des pointes [38, 48].

CLINICAL CONSIDERATIONS AND IMPLICATIONS

When looking through literature, ibogaine therapy seems a risky endeavor bound by many precautions, on the other hand, it appears very effective in addiction treatment, as most studies report favorable long term effects on craving and withdrawal. Where do we go from here?

First of all, in an attempt to harness the efficacy of ibogaine in anti‐addiction treatment while mitigating the cardiotoxic side‐effects, analogues have been developed, such as the iboga alkaloid congener 18‐methoxycoronaridine (18‐MC) [30, 49]. Recently, another analogue type has been developed, ‘oxa‐iboga’ (created via structural editing of the ibogaine and noribogaine molecules) [50]. Oxa‐iboga is an alkaloid compound that lacks the adverse cardiac effects in primary human cardiomyocytes and maintains high efficacy in animal models of opioid use disorder [50]. After a single dose or a short treatment regimen, persistent opioid‐induced hyperalgesia was reversed and opioid drug seeking suppressed in rodent relapse models. However, both 18‐MC and oxa‐iboga have only been tested in animal models and pre‐clinical research, but clinical trials can be expected to be underway [51]. Another route to counteract cardiotoxic effects of ibogaine was undertaken in a study of war veterans (n = 30) with traumatic brain injury to lower depression and post‐traumatic stress disorder with ibogaine therapy [52]. In this study, doses of ibogaine HCl up to 14 mg/kg were administered and followed by an intravenous dose of magnesium sulfate and antioxidants, which successfully mitigated cardiac events, like QTc‐prolongation. Finally, because of the large intersubject variance of both ibogaine and noribogaine plasma levels, which are strongly dependent on pharmacokinetic clearance by CYP2D6 [9, 44, 46], screening for metabolizer genotype before commencing treatment is commendable, which was also stated in a recent review on psychedelic‐assisted therapy [53].

CONCLUSIONS

Psychedelic‐assisted therapies, like ibogaine in addiction treatment, are on the rise. Given ibogaine's (rare) cardiotoxic side‐effects, more casualties are to be expected if uncontrolled and unmonitored experiments ensue. Therefore, it is critical that this form of therapy happens under strict conditions, with monitoring of vital parameters, ECG, doses and genotyping. Moreover, therapies with ibogaine analogues deserve more attention, and clinical trials are recommended to harness the promising anti‐addictive potential of this drug without its dangerous cardiovascular side‐effects.

AUTHOR CONTRIBUTIONS

Tibor M. Brunt: Conceptualization (lead); writing—original draft (lead);writing—review and editing (lead); supervision (lead).

DECLARATION OF INTERESTS

None.

Brunt TM. Rare but relevant: Ibogaine and cardiovascular complications—prolonged QT interval and ventricular arrhythmias. Addiction. 2026;121(6):1616–1621. 10.1111/add.70319

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.