Ibogaine in the treatment of substance dependence

This review article (2013) reviews the progress and obstacles of ibogaine in the treatment of substance dependence (e.g. opioids, alcohol) from ‘underground’ to controlled clinical trials.

Abstract

“Ibogaine is a psychoactive alkaloid derived from Tabernanthe iboga, a plant used in initiatory rituals in West Central Africa. Largely because of ibogaine’s status as a Schedule I substance in the U.S., the development of ibogaine’s use in the treatment of drug addiction took place outside conventional clinical and medical settings. This article reviews the history of ibogaine’s use in the treatment of drug addiction, and discusses progress made towards, and obstacles blocking, the establishment of controlled clinical trials of ibogaine’s efficacy. Preclinical research has generally supported anecdotal claims that ibogaine attenuates withdrawal symptoms and reduces drug cravings. Concerns about ibogaine’s safety, as well as a dearth of solid data from human studies, have hampered progress in its development as an approved medication. This article outlines major findings from preclinical studies, discusses concerns about ibogaine’s safety, and details previous and ongoing research on ibogaine’s use as an anti-addictive treatment for humans.”

Summary

Ibogaine is a naturally occurring psychoactive indole alkaloid found in the rainforest shrub Tabernanthe iboga. It has been used for many centuries in West Central Africa for the treatment of addiction to opiates and other substances.

Although there is substantial evidence from preclinical studies and open-label clinical studies that ibogaine can interrupt addiction to opiates and other substances of abuse, there have not yet been any complete controlled clinical trials.

In West Central Africa, initiates of the Bwiti religion chew iboga root bark during overnight rituals. This often facilitates visionary experiences.

T. iboga was first introduced to the Western world in 1864, and its ritual usage was first described in print in 1885. In the first decade of the 20th Century, ibogaine was recommended as a treatment for “asthenia” at a dosage of 10 to 30 mg per day.

Howard Lotsof, a habitual user of heroin, discovered that ibogaine had anti-addictive properties when he and other members of a group ingested ibogaine at dosage levels up to 19 mg/kg. After this discovery, Lotsof made it his life’s work to advocate for policy changes and research geared towards making ibogaine available as an anti-addictive medicine.

Ibogaine was patented in 1957 for enhancing the analgesic effects of opiates. It works by increasing opiate signaling.

Ibogaine was used in psychiatric treatment in the late 1950’s and 1960’s, and was characterized as particularly effective in enabling patients to recognize psychological “blocks” that they had previously denied. Ibogaine was classified as a Schedule I drug in the U.S. in 1970.

Lotsof created the Dora Weiner Foundation and launched NDA International to support research on ibogaine and opiate addiction. This research led to the first publication showing evidence of ibogaine’s efficacy.

Lotsof’s efforts to legitimize ibogaine’s medical use failed due to a lack of interest from the pharmaceutical industry and the fact that addiction was an unprofitable area for drug development.

In 1989, ibogaine treatments for drug dependence started in non-medical settings in the Netherlands with support from NDA International and DASH, the Dutch Addict Self-Help organization, as well as ICASH, the International Coalition of Addict Self-Help. In 1993, the US FDA approved a phase I trial for cocaine dependence.

Within a few short years, however, all promising avenues for ibogaine treatment were blocked, including the NDA-funded treatments in the Netherlands, the dose escalation trials at the University of Miami, and the NIDA-funded clinical trials in Rotterdam.

Ibogaine became increasingly available outside of West Central Africa in the wake of the denial of official approval for the study of ibogaine in Europe and the United States. A sizeable minority of individuals took ibogaine for the purpose of promoting personal psycho-spiritual growth.

The study identified four distinct scenes, including the medical model scene, the lay provider/treatment guide scene, the activist/self-help scene, and the religious/spiritual scene, in which a lay provider provides ibogaine treatment for psycho-spiritual growth.

Internet social media sites provide information on and discussion of ibogaine and support for patients seeking treatment. Many people treated at ibogaine clinics in Mexico first learn about ibogaine treatment via the Internet.

Typically, 15 to 20 mg/kg of body weight is used for clinical usage of ibogaine, with dosages half as strong for psycho-spiritual purposes. Ibogaine is produced by 13-step synthesis from nicotinamide or voacangine.

Ibogaine is most commonly administered in the morning in a non-hospital setting for the treatment of substance dependence. Patients report sustained resolution of the withdrawal syndrome within 1218 hours.

Ibogaine ingestion produces 3 distinct phases, the acute phase lasting 1-2 hours and the chronic phase lasting 4-8 hours. The chronic phase is characterized by emotional intensity and the experience of location and interaction within a “waking dream”. With ibogaine, the acute stage is characterized by visions of ancestral or archetypal persons or beings, placement in and movement within a dream-like visual landscape, and panoramic recall of personal experiences or past events.

The “evaluative” stage begins 4-8 hours after ingestion and lasts 8-20 hours. During this time, the patient’s attention continues to be inwardly directed rather than towards external stimuli, and the emotional tone tends to diminish in intensity.

The final stage of ibogaine use is called residual stimulation, and lasts for 24-72 hours or even longer. Patients report a diminished need for sleep for days or weeks after use.

The subjective experience of ibogaine is often described as unpleasant or even harrowing by patients receiving the drug in the treatment setting. However, for some people, the experience may reap psychological benefits, such as insight into destructive behaviors and a sense of having a second chance at life.

There have been few rigorous studies of treatment outcomes for patients at ibogaine clinics. These studies provide some important data on short-term outcomes, in particular regarding the resolution of withdrawal signs.

Beginning in the mid-1980’s, scientists began using animal models of addiction to test the claims made within Lotsof’s patents, which stated that ibogaine eliminates withdrawal symptoms and drug cravings. These claims were largely supported by preclinical studies.

Ibogaine, noribogaine and 18-methoxycoronaridine have been studied for their anti-addictive effects in animals. 18-MC has been developed as a medicine without the aversive and dangerous side effects of ibogaine.

Evidence from animal models of addiction indicates that ibogaine reduces self-administration of morphine, heroin, cocaine, alcohol, and preference for nicotine, and that a regimen of multiple doses over a period of time may be optimal for achieving persistent reductions in drug self-administration.

Ibogaine has a prolonged effect on self-administration of drugs, outlasting the presence of ibogaine, and may be mediated by ibogaine’s longer-lived metabolite, noribogaine. Ibogaine and related compounds have also been shown to alleviate withdrawal-like symptoms in animal models.

Ibogaine, noribogaine, and 18-MC have been shown to attenuate withdrawal signs in 13 of 14 independent investigations involving two rodent and two primate species. The mechanisms of efficacy of ibogaine and 18-MC are not fully understood, but they appear to involve complex interactions across multiple receptor systems.

Ibogaine and its active metabolite, noribogaine, have different pharmacological profiles and act on different receptors in the central nervous system. They also have different effects on the serotonin reuptake transporter.

Ibogaine has a greater potency at NMDA receptors than does noribogaine, but neither has a greater affinity for mu-opioid receptors than does the parent compound. Ibogaine is more highly lipophilic and is released slowly, which accounts for its prolonged anti-addictive effects.

Ibogaine and noribogaine have been shown to increase GDNF activity in the ventral tegmental area (VTA), but 18-MC has not. This suggests that 18-MC and ibogaine may work at different sites and by different mechanisms.

Ibogaine increases brain serotonin levels and is thought to act at least in part by its activity at 5-HT2A and 5-HT2c receptors. However, evidence suggests that its activity at sigma-2 and opiate receptors may be responsible for its therapeutic activity.

Noribogaine is believed to be responsible for the psychoactive effects of ibogaine, and 18-MC is predicted to have no hallucinogenic activity.

Despite its association with the psychedelic counterculture of the 1960’s, there is no evidence that ibogaine is physiologically or psychologically addictive, and its subjective experience is often unsettling.

Evidence suggests that ibogaine use may be associated with significant health risks, especially when used to treat substance abuse disorders in conjunction with pre-existing medical comorbidities, high dosages, or when opioids or cocaine are used in close temporal proximity with ibogaine.

Ibogaine has been shown to cause body tremor in rats and mice, bradycardia in humans, and anti-addictive activities in animal models without producing body tremors or bradycardia.

Ibogaine has been linked to sudden death in at least 19 cases since 1990. The most likely cause of death in these cases was preexisting heart disease, but an interaction between ibogaine and the patient’s preexisting heart disease was possible.

A 24-year-old woman died 19 hours after she started treatment with ibogaine for detoxification from heroin in the Netherlands in 1993. The cause of death was not determined, but there was evidence suggesting the possibility of surreptitious opiate use.

A study examined 19 deaths that occurred in close proximity to ibogaine ingestion outside of West Central Africa from 1990 through 2008. It determined that in 12 of the 14 cases, a pre-existing medical condition or the concurrent use of other drugs adequately explained or contributed to the sudden death.

The authors discuss the possible relevance of prolongation of the QT interval during ibogaine treatments, and the nutritionally compromised state typical of people with long-term addictions to opiates, as well as the use of methadone, cocaine, and alcohol, to sudden deaths following the ingestion of ibogaine.

Ibogaine may have been a causal factor in some deaths, because it potentiates both the analgesia and the toxicity of opiates and stimulants such as cocaine. In addition, the study cited the user’s lack of experience and knowledge regarding the use and dosage of such preparations.

Ibogaine patients are at significant risk, in part due to the lack of clinical and pharmaceutical standards and the absence of regulations pertaining to the manufacture and storage of ibogaine. Providers have become increasingly aware of the risks to patients and have implemented practices for minimizing such risks.

A focus group of college-educated Caucasian men in their late teens and 20’s experimented with ibogaine in 1962 and 1963. The group discussed the subjective effects of the drugs.

Twenty group participants, all ibogaine-nave, ingested ibogaine HCl in doses ranging from 0.14 to 19 mg/kg. Seven of those 20 were heroin dependent, and all seven reported an alleviation of opiate withdrawal symptoms and cravings.

The results of this study are based entirely on self-report from a small subject pool, which constitutes a significant weakness of this study. However, the study was conducted in a non-judgmental environment and participants were not subject to legal persecution for using ibogaine.

Seven opiate-dependent individuals were treated with ibogaine HCl, and none showed signs of opiate withdrawal. Two relapsed within two days, two others within a few months, and three others remained abstinent for at least 14 weeks.

Neurologist Daniel Luciano observed and reported on three cases of persons treated with ibogaine for cocaine dependence. No subjective or objective signs of drug withdrawal were seen within the 24 hours.

Bob Sisko discussed four case studies of New York City residents who were treated for heroin and cocaine addiction with ibogaine in the Netherlands. He argued that success should be defined not by a “drug-free” life but by an “addiction-free” life.

Dr. Charles Kaplan reported on the results of a study of heroin addicts treated with ibogaine and participating in a focus group in the Netherlands. The patients reported an extended period of abstinence following treatment from ibogaine, and suggested that the group provided an “exogenous” means of effecting positive health outcomes.

The seven cases from the early work by the Lotsof group were combined with the results from 26 patients treated in the Netherlands between 1989 and 1993 for purposes of opioid detoxification. Eight other subjects were excluded from the retrospective study because they were not opiate-dependent or because there was inadequate follow-up data.

Eight to ten hours after each subject’s most recent use of heroin, ibogaine HCl was administered to the subjects. Self-reports of withdrawal signs and drug craving were observed and recorded.

In 25 of the patients, ibogaine completely resolved opiate withdrawal symptoms without drug-seeking behavior. Four patients showed no signs of withdrawal but nevertheless sought and used opiates within 72 hours of treatment.

The authors acknowledge that the assessment of the resolution of withdrawal signs rested upon the expertise and knowledge of two investigators, and that a structured methodology would improve the validity of the results.

Howard Lotsof’s report at the NIDA Ibogaine Review Meeting in 1995 based on data gleaned from eight cases that were excluded from the retrospective study.

Thirty-eight of the 41 individuals in the study reported using opiates, and ten were also dependent on other substances. Thirty-one were treated just once with ibogaine, nine were treated twice each, and one was treated three times.

Deborah Mash’s team treated more than 150 patients at a freestanding clinic in St. Kitts, West Indies, and conducted the earliest research in a conventional research setting on ibogaine administration in humans. Twenty-seven heroin- or cocaine-dependent individuals participated in a 12-14 day inpatient Phase I dose escalation study.

Compared to pre-treatment scores, self-report depression and opiate and cocaine cravings were reduced at post-treatment and at discharge, and significantly reduced at the 1-month follow-up for both groups.

A subset of 32 opiate users was given a single fixed dose of 800 mg of ibogaine and showed significant reductions in withdrawal symptoms, heroin craving, and Beck Depression Inventory scores at discharge and at the 1-month follow-up.

The 12-14 day treatment program provided motivational counseling and referrals to aftercare programs and community support groups. All patients were successful in the detoxification process, but no follow-up data has been published.

An unpublished Dutch doctorandus thesis collected outcomes data from 21 subjects who had taken ibogaine to treat drug dependence. The study differentiated itself from previous studies that focused on only short-term outcomes directly related to drug use.

Nineteen out of twenty-one respondents indicated that they abstained from all drug use for at least 1 week following treatment with ibogaine, corroborating data from previous studies showing ibogaine’s capacity to attenuate withdrawal symptoms and to reduce cravings for drugs.

Based on the reports, the respondents were categorized into three groups: those who quit all substance use, those who quit for a short period of time, and those who returned to using their primary and secondary drugs of abuse shortly after treatment.

Most participants reported post-treatment improvements in medical health, relationships with significant others, and psychological well being.

This study has limitations, but the respondents had no reason to lie about their substance use.

The ibogaine medical subculture continues to grow in Mexico, and two new clinics have opened in Baja California, Mexico within the past nine months. The subculture gained legitimacy in July of 2010 when New Zealand categorized ibogaine as a nonapproved prescription medicine.

Though much has been learned about ibogaine as an anti-addictive agent, there is a clear need for further research into the safety and efficacy of ibogaine treatment in humans. The few scientific studies with humans demonstrate significant effects by ibogaine.

We have learned much about the complex pharmacology of the iboga alkaloids, but questions about the mechanism of action of these substances remain to be answered.

Ibogaine’s serotonergic activity appears to account, at least in part, for its hallucinogenic properties, although other receptor systems also seem to be involved in producing an altered state of consciousness. Ibogaine is not currently known whether its psychoactive effects play an important therapeutic role.

Ibogaine and other hallucinogens are thought to generate introspection and facilitate psychological growth, and may have therapeutic value in addiction therapy and the rational design of anti-addiction drugs.

Even if ibogaine is determined to be therapeutically useful, lingering questions regarding the safety of ibogaine treatment may continue to hamper progress towards its development as a certified medicine for the treatment of substance use disorders.

The dangers of ibogaine treatment should be taken seriously, but should also be weighed against the dangers of chronic addiction to substances such as heroin and the problems associated with commonly attendant conditions such as malnutrition, depression, and social and legal difficulties.

Despite limitations, we have gained a great deal from the studies of ibogaine treatment, including a better sense of how to move forward with our research. The only other data on long-term outcomes for ibogaine treatment comes from Lotsof’s 1995 report at the NIDA hearings, but Bastiaan’s data provides a clearer sense of the wide degree of variation in long-term outcomes following ibogaine treatment, and suggests that the definition of success of addiction treatment should be re-examined.

Bastiaan’s study broke new ground in considering the importance of assessing the efficacy of ibogaine treatment not only in terms of substance use, but also in terms of overall quality of life. However, there have been no published studies of quality of life changes associated with ibogaine treatment for addiction.

The human studies of ibogaine treatment provide preliminary support for the efficacy of ibogaine in alleviating the discomforts of withdrawal from opiates and other addictive drugs, and thereby facilitating detoxification from these substances in a comparatively painless manner.

A substantial minority of patients remain abstinent for several months following treatment for opiate and cocaine cravings. It is important to look carefully at long-term outcomes.

Careful documentation of treatment measures and long-term outcomes regarding substance use and related quality of life measures may yield invaluable information about the predictors of optimal long-term success. The patient’s pre-treatment expectations may play an important role in determining outcomes, as may the treatment team’s interactions with the patient.

The conditions to which the patient returns after treatment may have an impact on outcomes. The assistance of the patient’s social support network may be a key to the ongoing success of treatment.

Two research studies are currently underway to address some of the unanswered questions about ibogaine treatment for opiate dependence. The studies will follow 20 to 30 patients monthly over the course of one year.

The Mexico study began in September of 2010 and will continue for 18-24 months. Thirty subjects were obtained through continuous enrollment attempts for all eligible patients seeking treatment at the clinics.

The primary objective of both studies is to assess the effectiveness of ibogaine-assisted treatment for opiate addiction by tracking changes in substance use and related quality of life measures, and by determining the effectiveness of ibogaine to alleviate symptoms of depression for extended periods.

Investigators gather baseline measures on the ASI-lite, BDI – II, and SOWS prior to treatment, and again two to three days after treatment. Patients are contacted monthly for twelve months after treatment to monitor substance use and depressive symptoms.

These two studies should provide much-needed information about the long-term efficacy of ibogaine and about the variability among individual outcomes.