The adverse events of ibogaine in humans: an updated systematic review of the literature (2015-2020)

This review (s=18) did a qualitative analysis of studies with ibogaine and describes the acute adverse events (cardiac, gastrointestinal, neurological) and long-lasting effects (persistent cardiac, psychiatric, neurological). The authors note that phase I studies with standardized products are necessary as the products quantity and mix was widely varied.

Abstract

“Context: Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga. It produces hallucinogenic and psychostimulant effects, but it is currently known for the anti-addictive properties. Despite the potential therapeutic effects, several cases of fatalities and serious adverse events related to ibogaine/noribogaine use can be found in the literature. Most studies consist in case reports or were conducted under non-controlled settings, so causation cannot be clearly established.

Objectives: To update (2015-2020) the literature on the adverse events and fatalities associated with ibogaine/noribogaine administration.

Methods: Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results: Eighteen studies were included in the final selection. Highly heterogeneous results were found in terms of kind of product used or the known dosages. The adverse events were classified in acute effects (< 24 h), mainly cardiac (the most common was QTc prolongation), gastrointestinal, neurological, and clinical alterations, and long-lasting effects (> 24 h), mainly persistent cardiac alterations, psychiatric, and neurological signs.

Conclusions: There is a high need of phase I clinical trials that can describe the safety of different dosages of ibogaine with standardized products. Further research should perform clinical profiling of vulnerable populations, and design effective screening methods and clinical procedures.“

Authors: Genís Ona, Juliana M. Rocha, José C. Bouso, Jaime E. C. Hallak, Tre Borràs, Maria T. Colomina & Rafael G. dos Santos

Notes

Psychedelics don’t come without risks. Most are physiologically safe, with for instance virtually no risks of overdosing, for instance with magic mushrooms (psilocybin) unless one stomachs 20kg in one sitting. But, not every psychedelic is made equally and there are known differences within this class of compounds. Ibogaine is one notable exception with known cardiovascular risks. Reports of seizures, gastrointestinal issues, loss of balance (ataxia), and heart failure are not uncommon.

Before we dive into the most recent review of adverse events with ibogaine, let’s first ask why it is being used in the first place. Ibogaine is known to disrupt the opioid system and thus can reduce, and temporarily eliminate, withdrawal symptoms and drug cravings. Many clinics around the world are currently treating those with substance use disorders, such as addictions to cocaine or opioids (e.g. heroin). Although promising, there hasn’t been much study on the considerable risks of ibogaine ingestion. This study lays out what we know.

The top risks of ibogaine:

• Acute effects (<24 hours): QTc prolongation, where the time between contraction and relaxation of the heart chambers (cardiac ventricals)
• Prolonged adverse events (>24 hours): psychiatric alterations, with insomnia for up to two weeks, delusions, agressiveness, and hallucinations being some of the most often mentioned events
• Interactions with other drugs: where one case of ‘standard practice’ medications led to a fatal interaction

Although the risks of ibogaine alone can be characterized as graver than other psychedelics, it should be known that many (if not most) of the participants in the studies had pre-existing medical conditions and most a dependence on a variety of drugs (sometimes still present in their bodies during treatment). Or in other words, the participants don’t reflect the average population and although they may be most helped by ibogaine treatment, they are also the ones with heightened health risks.

One factor that makes finding out the risk of ibogaine treatment difficult is the variability of the amount of ibogaine and the exact substance administered (sometimes noribogaine, the active metabolite of ibogaine, was used directly). An earlier study found that the amount of ibogaine in root bark (of the Tabernanthe iboga bush) ranged from 0.6% to 11.2% (a 19-fold difference). The study analyzed both case reports from private clinics and clinical trials in hospitals. The former reported the most severe adverse events, whilst the latter only reported mild to moderate adverse events.

Although promising, ibogaine treatment doesn’t come without significant risks. For some, the risks are worth it to potentially break free from addiction. Future clinical trials should be able to better differentiate the risk at which dose level. Or second generation psychedelics such as 18-MC and Tabernanthalog could provide anti-addictive properties with lower to no cardiovascular risks. We will find out in the coming years.

The data comes from studies conducted between 2015 and 2020 and most were case studies.

Summary

Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga and produces hallucinogenic and psychostimulant effects. However, several cases of fatalities and serious adverse events are associated with ibogaine/noribogaine use.

Introduction

Ibogaine is the main alkaloid of the African shrub Tab ernanthe iboga, and it has been used for centuries for medicinal and religious purposes. It was discovered in 1962 that ibogaine had anti-addictive effects, and since then, many studies have been conducted assessing its potential effects in animal models of substance use disorders.

Ibogaine has been observed to reduce the self-administration of morphine and heroin in rats and to eliminate the withdrawal syndrome induced by naloxone or naltrexone. However, ibogaine’s pharmacokinetics is relevant for its antiaddictive effects in non-human primates. Ibogaine has been found to have significant anti-addictive properties, however, most studies are open label and therefore causation cannot be established. A randomized, double-blind, placebo-controlled, single-dose clinical trial was conducted, but no reductions in the opioid withdrawal syndrome were observed.

Two systematic reviews evaluated reports of fatalities or serious adverse events related to iboga/ibogaine use, while a third review also analyzed the anti-addictive potential of ibogaine. All the cases came from case reports in which ibogaine were used in non-controlled settings, including private residences or private ibogaine clinics. Both reviews found that the main metabolite of ibogaine (noribogaine) could be more directly involved in fatalities and adverse events, and that pre-existing medical conditions and the presence of one or more drugs of abuse explained or contributed to most deaths.

Dos Santos et al. (2016) performed a systematic review of human studies assessing the anti-addictive potential of ibogaine. They found that most subjects could remain drug-free for several days after treatment, but there was no detailed information on how adverse events were measured. Regarding the clinical trial in which noribogaine was administered to methadone-dependent patients, non-significant effects on withdrawal syndrome were found. However, the subjects included in this clinical trial showed dose-dependent QT prolongation, raising concerns regarding the safety profile of noribogaine.

The manuscript was to perform an updated systematic review of literature of serious adverse events and fatalities associated with ibogaine administration.

Data acquisition

We reviewed all human studies of adverse events related to ibogaine and noribogaine from July 2, 2015 to July 23, 2020.

Search strategy

A search was performed using PubMed, Scopus, Web of Science, Scielo, Google Scholar, and Core.ac.uk databases for studies on ibogaine and humans.

Data extraction

Two independent reviewers screened all studies with discrepancies resolved by a third reviewer. They recorded the names of authors, year of publication, study location, study design, characteristics of the context and participants, response criteria, and outcome measures.

NIH evaluation of selected studies

We used the NIH (National Heart, Lung and Blood Institute) checklists and guidelines for clinical trials as a template to grade and compare the studies found in our search. The overall grade of each article was calculated by dividing the positive points by the difference of the total number of points less the not applicable points.

Selected studies

A bibliographic search was performed in several databases, and 23 articles were selected for full reading. Five articles were excluded since they did not report adverse events. The systematic review included 18 articles, 15 of which were case reports or case series. Two randomized, double-blind clinical trials and one observational study were also included, with a higher number of males in the clinical trials and observational study. Ibogaine was used in clinical trials to treat opioid dependence and in two cases for spiritual cleansing. It was also used in observational studies to evaluate the efficacy of ibogaine in the treatment of opioid dependence.

The dose of ibogaine used in the case reports ranged from 725 mg of ibogaine to 38 g of dried T. iboga root bark. The adverse events were divided between acute and long-lasting effects, and most cases required hospital intervention. This review will discuss the results of the studies on ibogaine, which were heterogeneous in design, dosage, and quality.

Characteristics of the subjects

Among 15 case reports, 163 had a history of drug abuse/dependence, 5 had a history of polysubstance use, 89 had a history of cocaine use disorder, and 1 had a history of alcohol use disorder. Five subjects had a history of psychiatric diagnosis.

Ibogaine/noribogaine information

In five out of 15 case reports the presence of ibogaine could be determined, and in one case both the presence and the quantity of ibogaine were measured. In the remaining cases where toxicological analyses were performed, the presence of ibogaine/noribogaine was not specifically measured.

Acute adverse events (< 24 h)

Ibogaine/noribogaine caused QTc prolongation as the most common acute adverse event, but tachycardia, hypotension, wide QRS complex were also reported.

A high number of physical symptoms were reported in the case series, including ataxia, muscle tension, weakness, diaphoresis, akathisia, or tremors. Moreover, neurological alterations including seizures, dysmetria, anoxic brain injury, and unconsciousness were also reported.

The first clinical study included in this review evaluated the pharmacokinetics of ibogaine and noribogaine in 21 healthy individuals divided into two groups previously treated with placebo or paroxetine. The second clinical study evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients undergoing treatment to discontinue treatment of opioid substitution with methadone.

Prolonged adverse events (> 24 h)

Ibogaine/noribogaine prolonged adverse events were mainly associated with psychiatric, neurological, and cardiac alterations. In two studies, elevated C- reactive protein, white blood cell, and creatinine levels were observed, and hypokalemia and hypomagnesaemia the day after admission were reported.

Potential drug‑drug interactions

A positive test for benzodiazepines, opioids, methadone, and cannabinoids was found in Marta et al. (2015), Meisner et al. (2016), Grogan et al. (2019), and Cloutier-Gill et al. (2016). Medications used at hospital or medical settings might also have caused potentially dangerous interactions, such as the case of Meisner et al. (2016), where vasopressors and morphine were administered upon arrival at hospital, after the administration of naloxone (2 mg) in the field, which resulted in a fatality.

Quality assessment

In the current review, we considered the evidence of most studies with moderate-to-high quality. However, we noted that case series, controlled interventions, and observational cohort studies have limitations that should be considered before reporting results.

Discussion

We have collected the adverse events and fatalities associated with ibogaine and noribogaine reported in the last 5 years.

Case reports are the first source of evidence for new therapies and rare adverse effects, and help in the formulation of new questions. However, the main disadvantages of this study design are related to the difficulty of drawing wide conclusions and translating the results to the general population.

Clinical trials were carried out in a hospital context, under the supervision of professionals, using low doses of pure ibogaine or noribogaine. Adverse events were mild/moderate, but serious events were also observed.

Ibogaine doses varied widely between cases, and thus it is difficult to describe adverse events associated with certain doses. In addition, the safety of root bark extracts is unknown, making this practice especially risky.

A recently published study of 16 products used by treatment providers found that the concentration of ibogaine in the products ranged from 0.6 to 11.2%, and that other alkaloids and unknown substances were present in almost all samples.

The high degree of uncertainty, unknown dosages, high doses commonly used in non-medical settings, medical conditions, and concomitant use of other drugs are risk factors that can contribute to adverse events. Previous health conditions, especially cardiac alterations, should be considered when taking ibogaine or noribogaine. Ibogaine and noribogaine have the potential to inhibit hERG potassium channels and prolong the cardiac action potential, which can lead to serious adverse events.

Ibogaine and noribogaine have different half-lives, which could be related to the observation of persistent QT prolongation and cardiac arrhythmia following ibogaine ingestion.

The reported adverse events were mainly associated with gastrointestinal, motor, and cardiovascular alterations, but psychedelic-like effects were also commonly reported. Generalized seizures were reported in three cases, which could be associated with the agonistic effect of ibogaine at 5-HT2A receptors. Previous preclinical research has shown that ibogaine causes degeneration of Purkinje cells in rats and monkeys, but no evidence of neurotoxicity after low doses or oral administration. Moreover, most ibogaine-associated SAEs occur when the drug is administered by unskilled people in unsafe settings. Previous reports confirmed that other drugs/medications were present in fatalities associated with ibogaine. In this case, the combination of ibogaine with methadone and diazepam was considered the most probable cause of death.

Ibogaine should be used with caution when combined with substrates of cytochrome P450 liver isoforms or P-glycoprotein.

Health professionals may encounter intoxications related to ibogaine and noribogaine at emergency departments. Naloxone may be administered under the suspicion of an opioid overdose, but morphine and vasopressors may not be indicated.

Conclusion

Adverse events and fatalities associated with ibogaine/ noribogaine are still a major concern that is challenging to address. Phase I – II trials are urgently needed to assess their tolerance and safety.