This review (2016) argues that the current doses of ibogaine administered as a treatment for drug dependence are too high and should be reconsidered to avoid toxicity and fatalities.

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.”

Authors: Leo J. Schep, R. J. Slaughter, S. Galea & D. Newcombe

Summary

Ibogaine, a plant extract from the Bwiti forest shrub Tabernanthe iboga, has been used as a treatment for drug dependence in Western jurisdictions since 1962, but has been associated with several side effects, including ataxia, gastrointesti- nal distress, ventricular arrhythmias and sudden and unexplained deaths.

Ibogaine has been shown to act on several types of receptors, including kappa- and mu-opioid receptors, nicotinic receptors, and the N-methyl-d-aspartic acid (NMDA) ion channel. This combination of receptor site activities may be responsible for the anti-addictive properties of ibogaine in animal models. Ibogaine acts upon 5-HT2 and 5-HT3 receptors, serotonin transporters, and other receptors, and is a serotonin-selective reabsorption inhibitor. Its IC50 concentrations range from 1 to 10 M, and its drug aversions are achieved at doses within this range.

Ibogaine causes acute toxicity in rats and mice at doses ranging from 145 mg/kg to 175 mg/kg. The lowest observable dose to cause observable neuronal injury was 50 mg/kg IP, and chronic administration of 10 mg/kg IP did not show evidence of neuropathology. Mild cardiotoxicity has also been evident in animal models. Doses of 100 and 200 mg/kg IP in rats demonstrated bradycardia without evidence of hypotension.

To establish the risk of toxicity to humans, animal studies can be converted to human equivalent doses (HEDs) by applying an appropriate safety factor.

There is limited information on the animal toxicity of ibogaine and even less so by the route of ingestion. A NOAEL for ibogaine has not been established for the oral route, and a theoretical dose of mg/kg could be considered acceptable for human clinical trials. To estimate a dose for humans, divide the lowest reported oral dose of ibogaine by several safety factors, including intra-species variability, inter-species variability, and susceptible people in a population.

Based on a 263 mg/kg oral investigation in mice, an initial starting dose of mg/kg is possibly acceptable for human exposure. However, a range of doses from 6 to 30 mg/kg has been used in unregulated treatments.

Animal models showed that marised various drugs of abuse were achieved at 40 and mg/kg IP, but patients have been administered doses ranging from 6 30 mg/kg. Nausea, vomiting, tremors and ataxia have been reported following oral doses of ibogaine at 500, 600 and 800 mg. These symptoms have also heralded the onset of more severe and, sometimes, life-threating clinical effects, including coma, respiratory difficulties and pulmonary aspiration.

Ibogaine has been shown to reduce currents through the hERG encoded subunit, which contributes to the electric activity of the voltage gated cardiac potassium channels, and may therefore reduce the risk of sudden cardiac death and torsades des pointes.

Ibogaine has been shown to block potassium voltage gated hERG channels in TSA-201 and HEK 293 cells in vitro, but doses used to treat patients may increase the risk of QT prolongation, which could prove fatal, due to chronic use of sympathomimetic agents such as cocaine and methamphetamine. Case reports are corroborating the findings that patients taking ibogaine have suffered QT prolongation and subsequent cardiac dysrhythmias.

In the absence of prompt resolution following moderate to severe clinical effects, deaths have ensued following ibogaine treatment. The risks of associated toxicity and death, particularly ibogaine-triggered cardiac dysrhythmias and cardiac related mortalities, will continue to be reported.

Although ibogaine has gained popularity, there is still very limited information on its toxicity. A maximum oral dosage limit of less than 1 mg/kg should be adhered to, and a moratorium should be put in place to prevent unnecessary deaths in patients seeking treatment for drug dependence.