How toxic is ibogaine?

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.

Keywords: Cardiotoxicity; deaths; ibogaine; neurotoxicity; noribogaine.