Elsevier

Drug and Alcohol Dependence

Volume 166, 1 September 2016, Pages 1-5
Drug and Alcohol Dependence

Review
Ibogaine for treating drug dependence. What is a safe dose?

https://doi.org/10.1016/j.drugalcdep.2016.07.005Get rights and content

Highlights

  • Review of the toxicology of ibogine as a treatment for drug dependence.

  • Treatment of drug dependence requires large doses of ibogaine.

  • Animal models demonstrate toxicity at doses necessary to achieve aversion.

  • Findings suggest doses used should be substantially lower to avoid adverse effects.

  • Safety factors need to be applied to animal data to find a safe dose for humans.

Abstract

The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient’s treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263 mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87 mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients.

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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