The antiaddictive effects of ibogaine: A systematic literature review of human studies

This systematic review (2017) examined the antiaddictive effects of ibogaine (420 – 2030mg/70kg) in humans and identified seven open-label studies that indicated that ibogaine/noribogaine significantly reduced opiate/opioid withdrawal symptoms and that many subjects remained drug-free for several days after treatment. However, these results were largely heterogeneous and the only additional clinical trial performed failed to find significant reductions in opiate/opioid withdrawal symptoms in response to noribogaine.

Abstract

Background and aims: Ibogaine is a naturally occurring hallucinogenic alkaloid with a therapeutic potential for reducing drug craving and withdrawal. To the best of our knowledge, no systematic review was previously performed assessing these effects. Thus, we conducted a systematic literature review of human studies assessing the antiaddictive effects of ibogaine.

Methods: Papers published up to July 2, 2016 were included from PubMed, LILACS, and SciELO databases following a comprehensive search strategy and a pre-determined set of criteria for article selection.

Results: Two hundred and fifty-nine studies were identified, of which eight met the established criteria. Seven studies were open-label case series with ibogaine and one study was a randomized, placebo-controlled clinical trial with noribogaine. Case series suggest that a single dose or a few treatments with ibogaine may significantly reduce drug withdrawal, craving, and self-administration in dependent individuals lasting from 24 h to weeks or months. No significant effects of noribogaine on opiate/opioid withdrawal were observed in the clinical trial.

Conclusions: Considering the necessity of new drugs that may produce fast-acting and sustained effects in opiate/opioid and cocaine dependence, the potential beneficial effects of ibogaine/noribogaine should be further investigated in controlled trials.

Authors: Rafael G. dos Santos, José C. Bouso & Jaime E. C. Hallak

Summary

INTRODUCTION

Ibogaine is a naturally occurring indole alkaloid derived from the root barks of Tabernanthe iboga, a plant native to western Central African countries such as Gabon and Cameroon, where it has been used traditionally by the Pygmies and other African ethnic groups for several centuries.

In the 1960s, Lotsof et al. showed that ibogaine could reduce heroin withdrawal. They proposed ibogaine as a new method to treat dependence to opiates/opioids, stimulants, and ethanol.

Ibogaine is ingested orally in the form of extracts/hydrochloride (HCl) in doses ranging from 4 to 25 mg/kg. It produces psychoactive effects such as decreased muscular coordination, increased sensitivity to light and sound, nausea and vomiting if they move, and visual effects similar to dreams.

Ibogaine administration has been associated with several fatalities, but most of these deaths happened in uncontrolled/non-medical settings, using unknown doses of ibogaine of variable purity. When administered in more controlled/supervised contexts, to individuals without previous cardiovascular diseases or under the acute effects of drugs, ibogaine appears to be relatively safe.

Animal studies showed that ibogaine is neither reinforcing nor aversive, and that it reduces opiate/opioid (morphine and heroin), cocaine, and ethanol self-administration, as well as nicotine and amphetamine self-administration. Human case reports have also described significant reductions in drug craving and withdrawal symptoms.

Although some narrative and non-systematic reviews analyzing the antiaddictive effects of ibogaine in humans were published, no systematic review analyzing the antiaddictive effects of noribogaine in humans was previously performed.

Search strategy

Electronic searches were performed using PubMed, LILACS, and SciELO databases. Reference lists were also searched.

Data extraction

All studies were screened by two independent reviewers and discrepancies resolved by a third reviewer. They were then classified into open label and controlled studies.

Study selection

A literature search yielded 259 separate references, seven of which were potentially relevant. After detailed evaluation of the reports, all citations were included, and the study comprised seven case series involving the administration of ibogaine and one randomized, placebo-controlled clinical trial with noribogaine.

Case series

Seven opiate-dependent individuals were treated with single oral doses of 700 – 1800 mg (11.7 – 25.0 mg/kg) ibogaine HCl. Two subjects relapsed to opiate usage within 2 days, two subjects relapsed after a number of weeks, and three subjects remained drug-free for >14 weeks after treatment. Ibogaine was well tolerated, but did not reduce cannabis use. No medical or psychiatric screening was performed, and no control of drug use prior, during, or after treatment was performed.

Three subjects were treated with ibogaine HCl (20 – 25 mg/kg) for cocaine dependence. After 24 hours, all subjects reported an absence of subjective or objective signs of withdrawal or craving, and all neurologic/EEG examinations were normal.

A retrospective report on 33 subjects treated with ibogaine HCl for opiate/opioid dependence between 1962 and 1993 found that eight were also using methadone and eight were using cocaine on a daily basis. 25 subjects reported complete resolution of opiate/opioid withdrawal without drug-seeking behavior after ibogaine administration, 4 subjects did not report withdrawal signs but used opiates/opioids within 72 hr after ibogaine administration, and 2 subjects reported attenuated signs of withdrawal but remained drug-free.

In a conventional research setting (clinic), more than 150 drug-dependent subjects were treated with single doses of 500 – 800 mg ibogaine HCl under open-label conditions.

In a Phase I dose-escalation study, 27 opiate/opioid- and cocaine-dependent subjects received ibogaine HCl and completed self-reports relating to depression symptoms and craving for heroin or cocaine. Ibogaine administration was associated with significant reductions in craving for opiates/opioids, cocaine, and depressive symptoms 36 hr and 14 days after drug intake.

A subset of 32 patients who were opiate/opioid dependent were given a single 800 mg of ibogaine, and their withdrawal and craving symptoms were assessed with the OOWS and OP-SCL. The results showed that the subjects’ symptoms were significantly reduced after ibogaine intake.

A retrospective study assessed the long-term effects of ibogaine in 41 individuals treated in non-medical settings under open-label conditions between 1962 and 1993, mainly for opiate/ opioid or stimulant dependence.

In a retrospective study conducted in a private hospital in Santa Cruz do Rio Pardo, Brazil, 75 drug-dependent patients underwent ibogaine treatment combining the administration of the drug with cognitive behavioral therapy. They received oral doses of 17 – 20 mg/kg ibogaine HCl, preceded 30 – 45 min before by 20 mg of the dopamine D2/3 receptor antagonist domperidone. Single and multiple doses of ibogaine were associated with significant increases in abstinence duration. No serious adverse reactions were observed.

Clinical trials

27 patients on methadone substitution therapy received noribogaine doses of 60, 120, or 180 mg. They were evaluated for withdrawal symptoms, and safety and tolerability measures were performed from baseline to 144 hr after noribogaine/placebo administration.

Noribogaine was well tolerated and did not induce significant changes in vital signs, safety laboratory tests, oximetry or capnography, respiratory rate, or physical examinations. However, it did induce significant dose- and concentration-dependent QT interval prolongation and increased opiate/opioid withdrawal symptoms.

DISCUSSION

In this systematic review, eight studies were identified that investigated the antiaddictive effects of ibogaine in humans. The results suggest that ibogaine/noribogaine significantly reduced opiate/opioid withdrawal symptoms, but the only clinical trial performed failed to find significant reductions.

The absence of effects of noribogaine could be related to several factors, such as the administration of low doses of noribogaine, which would not be enough to achieve anti-withdrawal effects. The case series described the treatments of subjects mostly dependent on heroin, with fewer patients reporting the use of methadone. Methadone has a longer half-life than heroin, and patients may need repetitive doses of ibogaine/noribogaine to detoxify from methadone.

The reviewed studies are open-label case series, and the results cannot be concluded that ibogaine/noribogaine are effective treatments for drug dependence. However, animal studies consistently show that ibogaine significantly reduces opiate/opioid and cocaine self-administration, and the pattern of results observed in all case series is very similar.

Researchers speculate that the therapeutic effects of ibogaine may be due to the pharmacokinetics of its main metabolite, noribogaine, and to the multiple receptor profile of both compounds. Ibogaine may also have effects on the NMDA receptor, the -2-opioid receptor, and the 5-HT2A receptor.

The use of ibogaine/noribogaine in clinical settings is limited by the possible toxicity of these alkaloids, which include fatalities, cardiac arrhythmias, psychosis, mania, and seizures. Moreover, patients should be warned of the risks of using drugs during or immediately after ibogaine/noribogaine intake.

The results of this systematic review suggest that ibogaine/noribogaine have antiaddictive properties, but no controlled clinical trials have been performed with ibogaine or noribogaine.

In Europe, the use of heroin and synthetic opiates has reached an alarming level, and 44 people die every day from overdose of prescription painkillers. Ibogaine/noribogaine could provide new pharmacological treatments for patients suffering drug dependence.

RGDS, JCB and JECH are members of ICEERS, a non-profit organization that promotes the scientific research of ibogaine. None of the authors received any specific funding for participating in this investigation.

Study details

Compounds studied
Ibogaine

Topics studied
Addiction Opioid Use Disorder

Study characteristics
Meta-Analysis Literature Review

Participants
406

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