ReviewIbogaine for treating drug dependence. What is a safe dose?
Introduction
The indole alkaloid ibogaine is the most abundant hallucinogenic constituent present in the root bark of the West African rain forest shrub Tabernanthe iboga. Extracts derived from this plant have a long history of traditional medicinal and ceremonial use by local Bwiti people (Alper et al., 2008). Since approximately 1962, ibogaine has been employed in Western jurisdictions, such as Europe and the United States (Alper et al., 2001), as a treatment for drug dependence particularly to treat the cravings and withdrawal that accompany opioid and cocaine dependence (Lotsof and Alexander, 2001).
Nevertheless, evidence of its efficacy has been restricted to case studies in patients withdrawing from drug dependence, suggesting apparent reduction in withdrawal severity (symptoms) and drug seeking for up to 72 h post-treatment (Alper, 2001, Alper et al., 2008, Galea et al., 2011). Ibogaine appears to have a dose-dependent effect with low doses reportedly acting as a stimulant and higher doses being hallucinogenic (Alper et al., 2008, Mash et al., 2000). Patients undergoing treatment report oneirophrenic effects that can endure for 4–8 h post-ingestion followed by an evaluation phase, during which patients report a high level of mental activity, terminating with a residual stimulation state that may last up to 72 h (Lotsof and Alexander, 2001).
However, in addition to ibogaine’s hallucinogenic properties, which allegedly contribute to its efficacy in treating drug addiction, case reports consistently report evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths (Alper et al., 2012). Given the risks associated with its use, this paper seeks to explore the drug’s toxicity and show that doses employed in recovery clinics to treat patients are within values that demonstrate mammalian toxicity.
Section snippets
Mechanism of action
Ibogaine has a complex pharmacology and the underlying mechanisms that mediate its physiological and psychological effects are not well elucidated. Investigations of the pharmacological activity of ibogaine and its putative anti-addictive properties suggest that its action involves mediation of several classes of neurological receptors and transporters, including the sigma-2, kappa- & mu-opioid, 5HT2 and 5HT3 receptors, α3β4 nicotinic receptors, and the N-methyl-d-aspartic acid (NMDA) ion
Toxicity
There is limited information available on the toxicity of ibogaine in mammalian species. A summary of the investigations involving acute toxicity to ibogaine are presented in Table 1. Investigations have been undertaken with rats and mice, and, depending on the route of exposure, lethal doses varied from 145 to 175 mg/kg and 263 to 327 mg/kg body weight by the intraperitoneal (IP) and oral routes, respectively. The no observable adverse effect level (NOAEL), defined as the highest dose of a
Correlating animal toxicity to human clinical trials
Animal investigations can assist in assessing the toxicology of a drug in living systems. To establish the risk of toxicity to humans in clinical trials, for example, animal studies that establish a NOAEL can be applied to human investigations, following the application of an appropriate safety factor. This is determined by converting the animal NOAEL to a human equivalent dose (HED). Suggested values are derived by dividing the NOAEL by a safety factor that can range from 10 through to 50,
Human toxicity
Doses necessary to achieve efficacy in rodents are within those that cause observable toxicity. A number of studies, such as summarised by Zubaran (2000), for example, suggest aversions to various drugs of abuse were achieved in animal models at 40 and 80 mg/kg IP; these are, however, within doses that have been shown to cause neuronal injury by the same route of exposure (Xu et al., 2000).
To achieve efficacy in patients seeking interruption from drug dependency, doses administered to patients
Conclusion
Ibogaine, an indole alkaloid obtained from the West African rain forest shrub Tabernanthe iboga, is used as a recreational drug and as an alternate therapy for drug dependence. Despite its widespread popularity, there still remains very limited information on its toxicity. Investigations with animal models, however, suggest doses necessary to obtain dependence aversion have been shown to cause degeneration of purkinje cells and block potassium voltage gated hERG channels. High doses of ibogaine
Conflict of interest
No conflict declared.
Role of funding source
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Contributors
LS conducted the literature search and review and wrote the first draft of the manuscript. RS provided toxicological input and reviewed and revised subsequent drafts of the document. SG and DN provide clinical and addiction input and reviewed and revised drafts of the document. All authors have approved the final submission.
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A systematic literature review of clinical trials and therapeutic applications of ibogaine
2022, Journal of Substance Abuse TreatmentCitation Excerpt :Individuals in this review received between 0.28 mg/kg (Glue, Lockhart, et al., 2015) and up to 55 mg/kg of ibogaine (Noller et al., 2018). Severe adverse events and fatal outcomes associated with the ingestion of iboga/ibogaine have appeared in the literature (dos Santos et al., 2016; Schep et al., 2016; Alper et al., 2012; Corkery, 2018; Grogan et al., 2019; Steinberg & Deyell, 2018). Among the 24 studies included here, we identified two reported fatalities (Alper et al., 1999; Noller et al., 2018).
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2022, Actualites PharmaceutiquesIbogaine Consumption With Seizure-Like Episodes, QTc-Prolongation, and Captured Cardiac Dysrhythmias
2019, Journal of Emergency MedicineCitation Excerpt :It acts as a mixed agonist of κ1 and κ2 and is an antagonist of nicotinic and N-methyl-D-aspartate (NMDA) receptors. Ibogaine modulates serotonin activity, increasing its release and inhibiting its reuptake (8,9). Notably, the modulation of μ-opioid receptor activity is thought to suppress symptoms of withdrawal from opioids.
Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers
2018, Progress in Brain ResearchCitation Excerpt :In mice the LD50 of ibogaine is 263 mg/kg, whereas that for noribogaine is 630 mg/kg; thus, the toxicity of ibogaine is 2.4 times higher than that of noribogaine (Kubiliene et al., 2008). After factoring in considerations such as intra- and inter-species variability and for susceptible people in a population (such as drug users), Schep et al. (2016) have estimated that an initial dose to treat patients should be about 0.87 mg/kg body mass. This is much lower than that used currently in the treatment of drug dependence.
Identifying setting factors associated with improved ibogaine safety: a systematic review of clinical studies
2023, European Archives of Psychiatry and Clinical Neuroscience