The clinical study reviewed open-label case series (n=191) of human volunteers to review in-patient ibogaine (0.5-0.8g) detoxification using multi-dimensional craving questionnaires. It was found that Ibogaine therapy in a “safe dose range” decreases opioid withdrawal symptoms and drug cravings. The study proposed the development of a single oral dose of ibogaine to treat opioid withdrawal during medically monitored detoxification to help drug-dependent individuals in abstinence.

Abstract

“Ibogaine may be effective for transitioning opioid and cocaine dependent individuals to sobriety. American and European self-help groups provided public testimonials that ibogaine alleviated drug craving and opioid withdrawal symptoms after only a single dose administration. Preclinical studies in animal models of addiction have provided proof-of-concept evidence in support of these claims. However, the purported therapeutic benefits of ibogaine are based on anecdotal reports from a small series of case reports that used retrospective recruitment procedures. We reviewed clinical results from an open label case series (N = 191) of human volunteers seeking to detoxify from opioids or cocaine with medical monitoring during inpatient treatment. Whole blood was assayed to obtain pharmacokinetic measures to determine the metabolism and clearance of ibogaine. Clinical safety data and adverse events (AEs) were studied in male and female subjects. There were no significant adverse events following administration of ibogaine in a dose range that was shown to be effective for blocking opioid withdrawal symptoms in this study. We used multi-dimensional craving questionnaires during inpatient detoxification to test if ibogaine was effective in diminishing heroin and cocaine cravings. Participants also completed standardized questionnaires about their health and mood before and after ibogaine treatment, and at program discharge. One-month follow-up data were reviewed where available to determine if ibogaine’s effects on drug craving would persist outside of an inpatient setting. We report here that ibogaine therapy administered in a safe dose range diminishes opioid withdrawal symptoms and reduces drug cravings. Pharmacological treatments for opioid dependence include detoxification, narcotic antagonists and long-term opioid maintenance therapy. Our results support product development of single oral dose administration of ibogaine for the treatment of opioid withdrawal during medically supervised detoxification to transition drug dependent individuals to abstinence.”

Authors: Kathleen Allen-Ferdinand, Bryan Page, Linda Duque & Deborah C. Mash

Summary

INTRODUCTION

Ibogaine is an indole alkaloid isolated from the roots of the West African shrub Tabernanthe iboga. It is used ceremonially and medicinally in Africa, where 2 – 3 million members of the Bwiti religion take large doses.

Ibogaine was marketed in France in the early 20th century as a neuromuscular stimulant at a dose of 2 – 4 tablets/day. Several groups reported on the potential benefit of ibogaine for the treatment of drug dependence.

Ibogaine was never approved as a medicine for the treatment of drug addiction in most western countries, but human experience suggested its effectiveness. Self-treating heroin addicts discovered that ibogaine eliminated the signs and symptoms of opioid withdrawal. A small case series of patients who had undergone pre-treatment screening and physical evaluation reported diminished opioid craving and significantly improved mood after treatment.

Although ibogaine has been used to treat opioid use disorder in 1000s of patients, there have yet to be any clinical trials to demonstrate efficacy of the drug for opioid dependence.

Heroin and prescription opioid dependence are growing concerns that have great societal impact and rising health care costs. Medically assisted ibogaine detoxification is a safe and effective method to discontinue substance dependence and misuse.

Inclusion and Exclusion Criteria

Individuals self-referred for inpatient detoxification from opioids or cocaine were subject to a physician’s review of their history and physical examination, clinical laboratory results and electrocardiograms to determine the safety and open-label efficacy of ibogaine as a pharmacological treatment for managing withdrawal symptoms.

Oral Dose Ibogaine

Participants included 191 self-referred treatment seeking opioid and cocaine dependent men (n = 144) and women (n = 47). Ibogaine HCl (8 – 12 mg/kg) was administered oral doses under open-label conditions, and morphine sulfate was used for opioid withdrawal control prior to ibogaine detoxification.

On admission, participants completed the Addiction Severity Index, a Structured Clinical Interview for DSM-IV Axis I Disorders, a comprehensive psychosocial assessment, and were assessed for opioid withdrawal signs and symptoms.

Participants completed a series of standardized self-report instruments to assess their current level of craving for cocaine or opioids. The instruments were designed to capture five theoretically distinct conceptualizations of drug craving.

Mood and Craving Measures

Subjects’ depressive symptoms were measured using the Beck Depression Inventory version II (BDI-II), Profile of Moods (POMS), and Symptoms Checklist-90 scales. A repeated measures mixed model analysis of variance with time post-treatment was performed on Days 5 (discharge) and Day 30 (1 month follow up) with days as a repeated measure on subject.

Elicitation Narratives

A licensed therapist worked with the subjects to provide psychological support during and after administration of ibogaine HCL. Subjects narrated their subjective experience to oral doses of ibogaine HCL within 3 days after receiving an oral dose of ibogaine HCL.

Demographics of Opioid and Cocaine Dependent Subjects

The demographic characteristics of the opioid and cocaine dependent subjects are shown in Tables 1, 2. The opioid abusers had an average age of 35.8 years and were habitual users with a high rate of depressive disorders.

This observational case series included mostly male opioid (67%) and cocaine (85%) dependent subjects that were admitted for ibogaine treatment. They had a high rate of relapse and a higher rate of comorbidity for bipolar disorder and attention deficit disorder compared to opioid dependent subjects.

Safety and Cardiovascular Changes in Vital Signs

In this study, male and female subjects tolerated ibogaine well, with nausea and vomiting and ataxia of gait as the most common side effects. Headache was a common complaint reported post dose in 7% of the subjects. There were no serious AEs in this study, but several subjects developed orthostatic hypotension and bradycardic heart rate early after ibogaine administration in cocaine dependent subjects. This effect of ibogaine was not observed in our study in opioid abusers.

There were no ocular or visual side effects noted in this study, and laboratory test results were unchanged from baseline measures.

Ibogaine Pharmacokinetics and Opioid Withdrawal

Ibogaine and noribogaine produced similar pharmacokinetic profiles and OOWS ratings in opioid dependent subjects, but ibogaine caused less acute withdrawal symptoms in subjects switching from methadone to oral morphine.

Ibogaine is metabolized in the gut wall and liver by cytochrome P4502D6 and converted to 12-hydroxyibogamine (noribogaine) with a T max observed between 0.5 and 4 h. Subjects 8 (M5, male) and 10 (F2, female) were ultra-rapid metabolizers, resulting in blood levels below the level of assay detection for ibogaine.

Drug Craving and Mood Following Ibogaine Detoxification

Subjects undergoing ibogaine-induced opioid detoxification reported significantly decreased drug craving on five measures taken from the heroin (HCQ-29) craving questionnaire post-treatment and 1 month follow up assessments compared to baseline measures.

Ibogaine detoxification was effective in blocking drug craving in opioid and cocaine dependent subjects. Follow-up assessments demonstrated beneficial after effects of ibogaine detoxification on drug cravings reported at 1-month assessments.

Ibogaine administration resulted in a reduction in the severity of depression in acutely abstinent subjects after detoxification from cocaine. The Beck Depression Inventory total score means were significantly decreased at 1-month follow up assessments compared to pre-ibogaine baseline and program discharge.

Self-Reports of Ibogaine Treatment

Oral doses of ibogaine produce a period of active visualizations lasting 30 – 45 min, followed by a quiet period of deep introspection.

We used a narrative elicitation protocol to gather information about the ibogaine experience in opioid and cocaine dependent subjects. Many subjects reported having a “waking dream state” or feeling like they were “watching a film or a movie”.

Subjects reported that they felt a benefit of the ibogaine experience and that ibogaine was useful as a treatment for drug abuse. Many reported that they felt “cleansed” or “reborn” and that they were given a second chance at life.

DISCUSSION

Howard Lotsof was issued a patent describing a rapid method for interrupting the narcotic addiction syndrome by administering an oral dose of ibogaine. This method involved the administration of ibogaine in dosage ranges of 500 – 1000 mg.

Safety of Ibogaine

The safety of oral doses of ibogaine was evaluated in 191 subjects who elected to undergo detoxification from opioids and cocaine. The subjects were closely monitored for vital signs for 24 h and side effects up to 7 days after ibogaine administration.

Mild ataxia of gait, nausea and vomiting were seen during the acute drug phase. The period of active oneirophrenic visualization usually resolved within 6 – 12 h post dose, and there were no serious AEs or deaths that occurred from administration of ibogaine to drug dependent patients.

Deaths related to ibogaine have been described for persons seeking detoxification from drugs and alcohol involving variable product purities of ibogaine (HCl or extract), and multiple doses of ibogaine “stacked” over time following the initial “flood” dose. Advanced drug-related comorbidities and contributing conditions may have contributed to the AEs and possible drug related fatalities.

Ibogaine and noribogaine interact with hERG channels in vitro and may cause QTc prolongation in some subjects. Persons with a bradycardic heart rate below 50 bpm or a long QT syndrome were excluded from the study.

Opioid Withdrawal Blockade

Lotsof (1985) described the effects of ibogaine that were time dependent and suggested that the effects lasted for days to weeks. We identified 12-hydroxyibogamine (noribogaine) as the active metabolite of ibogaine and provided evidence that genetic polymorphisms influence the biotransformation of ibogaine in humans.

Physician ratings of the objective signs of opioid withdrawal demonstrated that ibogaine brings about a rapid detoxification from heroin and methadone. Subjects’ self-reports of withdrawal symptoms 72 h after recovery from ibogaine treatment were significantly decreased from the pre-ibogaine rating.

Ibogaine has significant differences among the populations of fast and intermediate metabolizers with regard to maximal concentration, half-life for elimination and the area under the curve of the parent drug and metabolite. The CYP2D6 phenotype may be an important determinant in the clinical pharmacology and safety of ibogaine.

CONCLUSION

Ibogaine has been reported to help people transition from heroin and cocaine to sobriety. Its oneiric effects and complex pharmacokinetics make it a better choice for opioid detoxification than methadone or buprenorphine taper, and may have a lasting effect on mood and drug cravings.

High rates of depressive disorders are reported among people seeking treatment for substance abuse disorders. Ibogaine may offer an additional benefit for opioid detoxification by improving depressive mood following administration.

Ibogaine may help opioid dependent patients to transition to sobriety and to establish a substance-free recovery by promoting harm reduction following detoxification from opioids and by diminishing the intractable cravings and desire to use opioids that set into motion the addiction relapse cycle.

Ibogaine is a psychoactive drug that has never been licensed as a therapeutic drug. However, open-label observations in patient volunteers support its use for detoxification from opioids.

Opioid use disorder costs the US healthcare system hundreds of billions of dollars each year. Ibogaine may be a non-addictive alternative that deserves fast-track review.

ACKNOWLEDGMENTS

The authors acknowledge the contribution of Frank Ervin MD, Manuel R Mayor MD, Izben C. Williams MD, and Rachel Tyndale Ph.D. to the study.