This systematic review (2016) investigated the pharmacological properties of ibogaine with special attention to its potential toxicity for human subjects. The authors found that evidence of toxicity exists, and suggest that certain factors like pre-existing cardiac conditions and concurrent medications may pose an additional risk.

Abstract

“Context: Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine’s toxicity are cause for concern.

Objectives: To review ibogaine’s pharmacokinetics and pharmacodynamics, mechanisms of action and reported toxicity.

Methods: A search of the literature available on PubMed was done, using the keywords “ibogaine” and “noribogaine”. The search criteria were “mechanism of action”, “pharmacokinetics”, “pharmacodynamics”, “neurotransmitters”, “toxicology”, “toxicity”, “cardiac”, “neurotoxic”, “human data”, “animal data”, “addiction”, “anti-addictive”, “withdrawal”, “death” and “fatalities”. The searches identified 382 unique references, of which 156 involved human data. Further research revealed 14 detailed toxicological case reports.

Pharmacokinetics and pharmacodynamics: Ibogaine is metabolized mainly by CYP2D6 to the primary metabolite noribogaine (10-hydroxyibogamine). Noribogaine is present in clinically relevant concentrations for days, long after ibogaine has been cleared.

Mechanisms of action: Ibogaine and noribogaine interact with multiple neurotransmitter systems. They show micromolar affinity for N-methyl-D-aspartate (NMDA), κ- and μ-opioid receptors and sigma-2 receptor sites. Furthermore, ibogaine has been shown to interact with the acetylcholine, serotonin and dopamine systems; it alters the expression of several proteins including substance P, brain-derived neurotrophic factor (BDNF), c-fos and egr-1.

Neurotoxicity: Neurodegeneration was shown in rats, probably mediated by stimulation of the inferior olive, which has excitotoxic effects on Purkinje cells in the cerebellum. Neurotoxic effects of ibogaine may not be directly relevant to its anti-addictive properties, as no signs of neurotoxicity were found following doses lower than 25 mg/kg intra-peritoneal in rats. Noribogaine might be less neurotoxic than ibogaine.

Cardiotoxicity: Ether-a-go-go-related gene (hERG) potassium channels in the heart might play a crucial role in ibogaine’s cardiotoxicity, as hERG channels are vital in the repolarization phase of cardiac action potentials and blockade by ibogaine delays this repolarization, resulting in QT (time interval between the start of the Q wave and the end of the T wave in the electrical cycle of the heart) interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest. Twenty-seven fatalities have been reported following the ingestion of ibogaine, and pre-existing cardiovascular conditions have been implicated in the death of individuals for which post-mortem data were available. However, in this review, 8 case reports are presented which suggest that ibogaine caused ventricular tachyarrhythmias and prolongation of the QT interval in individuals without any pre-existing cardiovascular condition or family history. Noribogaine appears at least as harmful to cardiac functioning as ibogaine.

Toxicity from drug–drug interaction: Polymorphism in the CYP2D6 enzyme can influence blood concentrations of both ibogaine and its primary metabolite, which may have implications when a patient is taking other medication that is subject to significant CYP2D6 metabolism. Conclusions: Alternative therapists and drug users are still using iboga extract, root scrapings, and ibogaine hydrochloride to treat drug addiction. With limited medical supervision, these are risky experiments and more ibogaine-related deaths are likely to occur, particularly in those with pre-existing cardiac conditions and those taking concurrent medications.”

Authors: Ruud P. W. Litjens & Tibor M. Brunt

Summary

ARTICLE HISTORY

Introduction

Ibogaine is a psychoactive indole alkaloid derived from the root bark of the African rainforest shrub Tabernanthe Iboga, and was first isolated in 1901. It was never widely used in a clinical setting, but was made a Schedule I controlled substance in 1970.

In the 1940s, several articles were published about the pharmacological properties of ibogaine on the cardiovascular system and isolated tissues. In 1963, nine addicts to opioids engaged in an ibogaine experiment in a non-clinical setting and noted an apparent effect on withdrawal symptoms.

Ibogaine has been studied in animals but little in humans. This review will focus on its pharmacokinetics and pharmacodynamics, possible mechanisms of action, and toxicity in humans.

Methods

A search of PubMed was done using the keywords ”ibogaine” and ”noribogaine”. 156 references were found that related to human data, and four reports were excluded because they contained no reliable information on clinical course or cause of death.

Pharmacokinetics

Ibogaine is metabolized mainly by CYP2D6 to noribogaine, which has psychoactive properties and its own pharmacological profile. A polymorphism in the CYP2D6 enzyme can influence blood concentrations of both ibogaine and its primary metabolite, noribogaine, which has a much longer half-life than ibogaine.

Ibogaine and noribogaine are highly lipophilic compounds that accumulate in brain and fat tissue. In a person who died from iboga poisoning, the ratio of ibogaine to noribogaine was exceptionally high.

Mechanisms of action

Ibogaine interacts with multiple neurotransmitter systems, including NMDA, kand m-opioid receptors, sigma-2 receptor sites, and alters the expression of several proteins, including substance P, brain-derived neurotrophic factor, c-fos and egr-1.

Ibogaine is a competitive antagonist of NMDA receptor-coupled ion channels and may be involved in the anti-addictive effects of addictive drugs by increasing dynorphin A concentrations in the striatum.

Ibogaine increases glial cell line-derived neurotrophic factor (GDNF) transcription in midbrain regions, including the ventral tegmental area (VTA), and may promote regrowth and survival of dopaminergic neurons following injury.

Experimental studies

Neurodegeneration was observed in the intermediate and lateral cerebellum and the vermi following the administration of ibogaine 100 mg/kg or three doses of 100 mg/kg to rats. However, no signs of neurotoxicity were found following the administration of a 40 mg/kg single dose.

Ibogaine caused tremors in rats and mice, and these tremors were similar to harmaline-induced tremors. However, the tremors were only briefly present and were more likely to be ibogaine rather than noribogaine mediated.

Human studies

Ibogaine may be neurotoxic in humans at therapeutic dosages, but a woman who received four doses of ibogaine over a period of 15 months died of natural causes without signs of damage to the cerebellum.

After ibogaine administration under open-label conditions in 30 drug-dependent subjects using three fixed-dose regiments of 500 , 600 and 800 mg, early nausea and mild tremors were reported frequently. Many neurological symptoms were also reported in case reports.

Three different patients suffered from psychotic symptoms following ingestion of ibogaine, but it remains unclear if any long-term neurological damage occurred.

Human studies

Ibogaine administration has been associated with a rise in blood pressure and a decline in pulse rate in several patients. A fatality resulting from acute heart failure has been described.

A recent review of ibogaine fatalities concluded that pre-existing medical conditions were an important factor contributing to the death of individuals for which adequate post-mortem data were available. In several cases patients had pre-existing cardiac problems.

Maas and Strubelt [37] suggest that during the ”ibogaine experience”, where participants experience ”visions”, there is a parasympathetic dominance which protects the cardiac system. The risk is thought to be highest in the period afterwards.

Ibogaine can cause cardiac arrhythmias and sudden deaths. Many case reports have been published describing similar cardiotoxicity in patients who ingested ibogaine, and none of these patients had any pre-existing medical problems or family history of cardiac-rhythm abnormalities.

Although evidence for ibogaine’s cardiotoxic effects has been accumulating, ibogaine and noribogaine appear to have been well-tolerated in open-label trials. The doses of ibogaine used in case reports of cardiotoxicity are higher than those described in the open-label trials.

Koenig and colleagues suggested that ibogaine may cause cardiac arrhythmias by inhibiting hERG potassium channels, which delays the repolarization phase of cardiac action potentials, resulting in QT interval prolongation and sudden cardiac death.

Conclusions

Alternative therapists and drug users are still using iboga extract, root scrapings and ibogaine hydrochloride to treat drug addiction. These are risky experiments.