White Paper by Emily Morgan

Peer Reviewed by Isobel Wright, Grace Chen, Bethany Medley, and Rachel Atterato

Introduction

Ibogaine is a plant-based medicine currently being explored as a treatment for opioid use disorder (OUD).​ ​It is a naturally occurring indole alkaloid extracted from the root bark of the ​Tabernanthe iboga​, a shrub native to rainforests in Western Africa (Schep,et al). Indigenous groups have used it safely for medicinal and religious purposes for centuries (Davis,et al). Currently, it is being investigated to remove cravings and help relieve withdrawals for opioid users (Schelp, Slaughter). However, the mechanisms of action are still novel, making it difficult to mitigate adverse side effects (Alper). While ibogaine has a history of therapeutic value, thorough clinical research is still lacking.

Brief History

Ibogaine was first introduced into Western countries in the late 1800s. It was brought from the Republic of Gabon to France and the alkaloid was isolated by 1901 (Alper). It was sold as ‘Lambarene’, a neuromuscular stimulant, and marketed to treat fatigue, depression, infectious diseases and as an antiseptic (Goutarel) (Alper, et al). However, its psychotropic effects were not explored until almost a century later (Alper, et al). In 1969, psychiatrist Dr. Claudio Naranjo was granted a French patent to use ibogaine during psychotherapy sessions (Brown). He prescribed doses between 4-5 mg/kg to help patients access repressed memories (Alper, et al). Nananjo found that when using this medicine his patients were better able to confront trauma and process the experiences (Gallo, et. al). He published his findings, which were corroborated by several psychiatrists also working with ibogaine in the United States (Aper, Lotsof) (Brown). It was soon found to have some other unexpected health benefits.

The discovery of ibogaine’s potential to help with OUD happened by accident. Howard Lotsof, who himself suffered from opioid abuse, took it in 1963 to experience the psychoactive effects (Alper). Afterwards, he found that he no longer withdrawals and/or cravings associated with opioid dependency (Alper, Beal). Lotsof recruited twenty of his friends, who were also drug users, to experiment with doses from .14-19 mg/kg (Alper). Out of these participants, seven reported a reduction in cravings and abstained from opioids for at least six months (Alper, Beal). Lotsof was so impressed by the results that he made it his life’s work to educate others about ibogaine’s benefits (Alper). Eventually he received a patent in the United States for its use in treating OUD, cocaine, amphetamine, alcohol, and nicotine dependence (Alper). In addition, he founded the Global Ibogaine Therapy Alliance, a non-profit that actively advocates using ibogaine to treat these dependencies.

Currently, the legality of ibogaine varies from country to country. In 1967, during “The War on Drugs” in the United States, it was classified as a Schedule 1 drug (Gallo, et al). This is defined as having a high potential for abuse with no medical use (Gallo et al). Around the same time, a third of the countries in the European Union classified it similarly (Brown, et al). However, ibogaine continues to be unregulated in other countries; some of which allow for its use medicinally (Alper, et al). Countries that have facilities with on-site medical staff include: Canada, Mexico, Panama, the Caribbean, and South Africa (Alper). Until ibogaine becomes unregulated, those suffering from OUD must travel abroad for treatment.

Detox

Often countries offering treatment lack regulations and some ibogaine clinics do not have on-site medical supervision (Alper). However there are a growing number of facilities with trained staff on location that have a standard procedure for treatment (Alper, et al). A single dose is given orally in the morning, preferably on an empty stomach (Alper, et al). ‘A flood dose’, or a large amount is administered; doses can range from 10-24 mg/kg (Alper et al). The medicine starts to take effect within 1-3 hours after ingestion and lasts anywhere from 24-72 hours (Kohek, et al). Once the detox is concluded, follow-up treatment is recommended which may include counseling, outpatient programs, and/or becoming involved in social support programs (Mash,et al).

Individuals treated with ibogaine report psychoactive effects; Kohek et al. completed a subjective study of these experiences with 20 participants. Each received a flood dose and self-reported the results, which are pictured left (Kohek,et al). Participants took the medicine either at home or in a clinical setting (Kohek, et al). Regardless of the setting, all involved found the experience to be deeply introspective (Kohek, et al). The majority of these participants also self-reported ‘substantial improvements in quality of life’, including feeling happier, more self aware, and sleeping better (Kohek,et al). The visualizations associated with the medicine are described as ‘a vivid waking dream state’ (Alper). This differs from other serotonin psychotropic drugs such as LSD and psilocybin, which are described as intense visual hallucinations (Kohek, et al). Ibogaine seems to create a sense of well-being in users but also has been shown to relieve opioid users of cravings.

A retrospective study conducted by Davis et, al. found a positive correlation between ibogaine treatment and continued abstinence from opioid use. Data was collected online from 88 participants, the majority self-reported using opioids every day for four years or more (Davis et al). Each received a flood dose at a treatment center in Mexico, which had medical staff present (Davis, et al). Among the participants; 61% felt the experience was effective in treating their OUD; 85% would make the same choice to do it again (Davis et al.) Over half of the participants had a reduction in opioid cravings for up to three months; 41% reported remaining abstinent from all opioids for six months (Davis et al). Overall, 31% reported remaining abstinent for a year or more (Davis et al). While 70% of participants did end up returning to opioid use, 48% said they used less than they did before treatment (Davis et al). While few studies have been conducted on the long term benefits of ibogaine, the preliminary results appear promising.

​Pharmacology
Ibogaine has a diverse pharmacological profile that has yet to be clearly defined. Preliminary studies have found that the drug acts as a noncompetitive antagonist to N-methyl-D-aspartate (NMDA) receptors (Kang et al.). It is postulated that ibogaine blocks the binding of glutamate, which was observed in a study by Kang et al. Using a rat model he noticed this effect, specifically in the hippocampus. It is also proposed that ibogaine may inhibit NMDA by blocking MG2+, which is needed to open the voltage dependent channels (Kang et al.). This is important because, while not proven, there are several studies linking NDMA regulation to various forms of addiction. Further research is needed to better understand the specific actions ibogaine has on the human body.

Studies are being conducted in Canada with the metabolite noribogaine and the synthetic version 18-MC; both have similar chemical structures to ibogaine (Carnicella et al). While ibogaine and noribogaine have psychoactive effects, 18-MC does not, thus it is desirable to pharmaceutical companies (Glick et al). In addition 18-MC lacks ibogaine’s adverse side effects including: bradycardia, tremors and hallucinations, making it a safer medicine (Carnicella et al). Results of using 18-MC in rats found that even at high doses, no negative effects were present (Carnicella, et al.). Research on noribogaine has found it to be two times less toxic than ibogaine (Carnicella, et al.) In addition, it lacks adverse side effects, most notably tremors (Carnicella, He). However noribogaine, like ibogaine, can be lethal at high doses (Carnicella, He). Little is known about the mechanism of action in these two variations and more research is needed to gain a better understanding of their benefits and drawbacks.

​Adverse effects
Initial adverse effects often include nausea, headaches, and impaired coordination, known as ataxia (Wasco et al). These can last for twenty-four hours or less and the experience has been described as ‘physically and mentally taxing’ (Corkery). A key development noted is a potential link between ibogaine and deaths due to cardiac arrest (Corkery). This has occurred particularly in individuals who have pre-existing heart conditions (Corkery). It is speculated that the medication can further any present arrhythmias that could potentially be fatal, especially if the dosage isn’t monitored (Corkery). At high doses it can cause convulsions, paralysis, and death (Gallo, et al). There have been 33 reported deaths in association with ibogaine use (Corkey). Yet side effects and potential for fatalities may be lessened with further research (Corkery). This is arguably the primary obstacle that ibogaine treatment faces (Corkey). The lack of clinical research and treatment standardization limits the potential for widespread use (Marta et al.) This medicine requires development of regulations to ensure that clinicians know how to treat their patients (Marta et al.). Further understanding of the drug is essential to understand therefore to reduce risk factors.

Current

Ibogaine has a history of being a promising treatment for OUD. The chart below shows the outcome of a nonmedical study done in the Netherlands, which was shared with the National Institute on Drug Abuse (NIDA) (Alper). The positive results prompted the NIDA to conduct a study of it’s own in the United States, which was approved by the FDA in 1995 (Mash).

Unfortunately, the study was discontinued during phase 1, not due to concerns of efficacy or safety, but lack of funding (Alper). After this, few clinical studies were conducted until recently (Alper). Organizations such as the Multiple Association for Psychedelics Studies (MAPS) and MindMed have picked up where the NIDA left off. These companies are advocating for the medical use of ibogaine as well as other psychoactive compounds to treat depression, PTSD, OUD, and other drug dependencies.

Discussion

Ibogaine is a plant-based medicine currently being investigated to treat opioid addiction. It originates from Western Africa and has been used for centuries medicinally and in religious ceremonies. As use of the medicine widened, it was found to be helpful in treating withdrawals associated with OUD. Recent studies have shown that it is both safe and effective in reducing post acute withdrawal syndrome. However, due to its psychoactive properties, ibogaine has been classified as a Schedule 1 drug. This brought a halt to all research within the United States and most clinical trials take place abroad. Preliminary results of these studies have appeared promising. The mechanisms of action are still novel, making it difficult to reduce negative side effects. More research is needed to determine its clinical significance in treating OUD.

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