A systematic literature review of clinical trials and therapeutic applications of ibogaine

This systematic review (2021) explores clinical trials involving ibogaine and noribogaine. Across the number of trials included, a total of 705 individuals were treated with either ibogaine or noribogaine. It was found that such interventions may be useful for treating substance use disorders, alleviating withdrawal symptoms and cravings. Importantly, a number of severe side effects, including death, that have been recorded in the trials are discussed.

Abstract

“Background: Iboga and its primary alkaloids, ibogaine and noribogaine, have been of interest to researchers and practitioners, mainly due to their putative efficacy in treating substance use disorders (SUDs). For many SUDs, still, no effective pharmacotherapies exist. Distinct psychoactive and somatic effects of the iboga alkaloids set them apart from classic hallucinogens like LSD, mescaline, and psilocybin.

Aims: The study team performed this systematic review focusing on clinical data and therapeutic interventions involving ibogaine and noribogaine.

Methods: The team conducted a search for all publications up to December 7, 2020, using PubMed and Embase following PRISMA guidelines.

Results: In total, we identified 743 records. In this review, we consider 24 studies, which included 705 individuals receiving ibogaine or noribogaine. This review includes two randomized, double-blind, controlled clinical trials, one double-blind controlled clinical trial, 17 open-label studies or case series (including observational or retrospective studies), three case reports, and one retrospective survey. The published data suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and cravings. Data also point toward a beneficial impact on depressive and trauma-related psychological symptoms. However, studies have reported severe medical complications and deaths, which seem to be associated with neuro- and cardiotoxic effects of ibogaine. Two of these fatalities were described in the 24 studies included in this review.

Conclusion: Treatment of SUDs and persisting comorbidities requires innovative treatment approaches. Rapid-onset therapies such as the application of ibogaine may offer novel treatment opportunities for specific individuals. Rigorous study designs within medical settings are necessary to warrant safe application, monitoring, and, possibly, medical intervention.“

Authors: Patrick Köck, Katharina Frölich, Marc Waller, Undine Lang & Kenneth M. Dürsteler

Authors Highlights

• This review provides an overview of the therapeutic uses of ibogaine and noribogaine
• Data suggests effectiveness in the treatment of substance use disorders
• Data suggests potential benefits for depressive and post-traumatic symptoms
• Fatalities have been reported among the screened literature
• Due to potentially lethal consequences, rigorous medical settings may increase safety
• Global consensus regarding legal status of ibogaine and noribogaine is absent
• Eligible individuals may benefit from rapid-onset therapies like ibogaine

Summary

A systematic review of clinical trials and therapeutic applications of ibogaine in the treatment of substance use disorder.

Iboga and its primary alkaloids have been of interest to researchers and practitioners due to their putative efficacy in treating substance use disorders.

The study team performed a systematic review of 24 studies involving 705 individuals receiving ibogaine or noribogaine. The results suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and craving, but also pointing toward a beneficial impact on depressive and trauma-related psychological symptoms.

Iboga and its main active alkaloids, ibogaine, and noribogaine, have gained increasing scientific attention over the last decades, mainly due to their proposed “anti-addictive” properties. However, several case reports have been published about fatalities or adverse events associated with the ingestion of iboga plant material or ibogaine. Ibogaine is an indole alkaloid found in the shrub Tabernanthe iboga and in the plant Voacanga africana. Several other plants in the Apocynaceae family also contain iboga alkaloids.

Researchers have investigated the use of ibogaine, an alkaloid found in the Tabernanthe iboga plant, for different medical purposes and pharmacologic profiles. Ibogaine has been used in West Central Africa for ceremonial rites and has been banned in the United States and the International Olympic Committee. Ibogaine is used in medical and nonmedical settings to treat addictive disorders, most commonly opiate detoxification. A synthetic ibogaine alkaloid, 18-methoxycoronaridine (18-MC), has been found to be safer than ibogaine regarding cardiotoxicity.

Ibogaine, noribogaine,18-MC, and the novel analog tabernanthalog decrease self-administration of various addictive substances. GDNF up-regulation, NMDA receptor antagonism, and nicotinic acetylcholine receptor blockade may be involved in the effects of ibogaine. The exact role of serotonin (5-HT) receptor agonism and serotonin transporter inhibition in hallucinogenic or putative antidepressant effects remains unclear, but ibogaine and noribogaine interact with several central nervous receptors, including the sigma2-receptor, the opioid receptors, SERT, and DAT.

Research suggests that pharmaceuticals displaying agonist and antagonist qualities upon KOPR can treat CUD, and noribogaine seems to possess these qualities. The involvement of multiple receptor systems and pharmacokinetic mechanisms might explain postulated effects upon substance craving, withdrawal symptoms, and post-withdrawal depression. Ibogaine has been studied for its effects on SUD symptoms. It has been shown to have high interindividual variability in blood concentrations, with poor metabolizers showing higher blood concentrations of ibogaine relative to noribogaine over time.

Ibogaine seems to be cleared quickly from the blood, while noribogaine concentrations could be measured 24 hours after oral ingestion. The ibogaine experience can be divided into three phases, with phase I being an oneiric state, phase II an evaluative state, and phase III a residual state.

Ibogaine has been linked to several fatalities and severe toxic adverse events in humans, including seizures, comas, pulmo- nary difficulties, and fatal outcomes.

Ibogaine can cause cardiac abnormalities, including QTc-prolongation, ventricular tachycardia, and cardiac arrest. Eighteen of 33 previously analyzed fatality reports had preexisting medical conditions, and twelve of 33 cases report concomitant drug or medication use.

We searched for studies on iboga, ibogaine, or noribogaine in peer-reviewed journals and other databases. We included studies with pre-post and placebo-controlled effects, as well as studies with demographic data, study intention, substances used, dose, administration route, safety measures, serious adverse events, and main results.

We performed a systematic review of the literature and identified 1,038 records. Of those, we included 33 full-text articles, eight of which were excluded due to the absence of clinical data or redundant information, and three were double-blind, placebo-controlled clinical trials.

In 1994, seven individuals were treated with ibogaine for opioid withdrawal symptoms. All seven showed an immediate reduction of opioid withdrawal symptoms, and three remained abstinent for at least 14 weeks. A case series of 33 individuals with OUD who were treated in informal, nonmedical settings with ibogaine (9 – 29 mg/kg) between 1962 and 1993 was published in 1999. One participant died 19 hours after treatment, and a remission of severe OUD with ibogaine was reported in 2016.

A patient with opioid use disorder (OUD) received ibogaine HCl (2300 mg) over four days, and hydromorphone 32 mg and 45 mg orally on the first and second day, respectively. She maintained opioid abstinence for 18 months, and returned neither to OAT nor to the use of other illicit substances or benzodiazepines. Barsuglia et al. performed SPECT imaging on a human receiving ibogaine and found changes in several relevant brain regions associated with SUDs.

13 studies were reviewed, 6 of which used ibogaine as a treatment for OUD. One study used ibogaine in combination with 5-MeO-DMT to treat trauma-related psychological symptoms and cognitive impairment in U.S. veterans. Eight studies were conducted on individuals with substance use disorders (SUDs). Most studies found that ibogaine and 5-MeO-DMT reduced withdrawal symptoms and substance cravings, and that a ratio of responders vs. non-responders was 3:1. A 45-year-old woman died during ibogaine treatment in a medical setting. The Health & Disability Commissioner of New Zealand investigated the death.

We identified six open-label clinical trials that investigated the effects of ibogaine on opioid use disorder (OUD) or cocaine use disorder (CUD). The studies found that ibogaine reduced heroin or cocaine craving, and depressive symptoms were significantly reduced. Another study found that individuals who received ibogaine experienced significant reductions in multiple opiate withdrawal symptoms, including the HCQ, CCQ, MCCS, SCL-90-R Depression Subscale, the BDI, and the POMS.

This review included three double-blind placebo-controlled clinical trials. One trial evaluated the pharmacological profile and the safety of noribogaine in ascending doses, and the other two trials evaluated the effects of noribogaine on opioid withdrawal in opioid-dependent patients.

Across the selected studies, 55% of individuals participated in ibogaine treatments for opioid use disorder or assessment of changes in opioid use symptoms. 24% of individuals participated in ibogaine treatments for cocaine use disorder. In this systematic review, we have found that most of the reviewed studies assessed the effects of ibogaine for the treatment of SUDs. However, there are several additional reports of ibogaine toxicity or fatalities that did not meet eligibility criteria for this review.

17 studies have reviewed 259 records on ibogaine and noribogaine and found that both have beneficial effects on opioid withdrawal symptoms and depressive symptoms in patients who seek opioid abstinence. A preliminary review of the safety of ibogaine use in humans found that an initial dose of 0.87 mg/kg bodyweight is considered safe. However, two fatalities have been reported and inadequate medical monitoring and vague instructions concerning the cessation of the patient’s antidepressant medication were highlighted.

We identified 58 ibogaine-associated emergencies and deaths, most of which were accompanied by cardiac arrhythmias. However, one patient with schizophrenia experienced an exacerbation of psychotic symptoms, and two individuals experienced symptoms of mania following ibogaine ingestion. Research has made efforts to provide clinical recommendations for ibogaine treatments, yet global consensus about the legal status and scientific investigation of ibogaine is lacking. In recent years, some studies evaluated the effects of microdosing of other hallucinogenic compounds like LSD, psilocybin, or ketamine.

19 OAT is the first-line treatment for OUD, but some individuals wish to stop OAT and attain opioid abstinence. Moreover, insufficient evidence still exists for routine pharmacological management of CUD or stimulant use disorders. The authors of this review suggest that more rigorously designed studies could clarify the therapeutic benefits of ibogaine in human patients with SUD, and that increased public and medical awareness could potentially prevent unnecessary fatalities or other severe adverse events.

Ibogaine, a plant from the genus Iboga, is used in traditional medicine to treat pain. A review of the research shows that ibogaine has several benefits, but also has some side effects.

Ibogaine, noribogaine, and their metabolites are promising new treatments for addiction. These treatments include ibogaine, 5-MeO-DMT, and mixed Kappa/Mu partial opioid agonists, and they are currently being tested in clinical trials for opioid use disorder.

A non-hallucinogenic psychedelic analogue with therapeutic potential was discovered by Cameron, Woolf, J., Polanco, M., Malcolm, B., Kelmendi, B., Dickens, C., & Barsuglia, J. P. in 2020.

Ibogaine treatment for problematic opioid consumption: Short- and long-term outcomes and current psychological functioning. Corkery, J. M., Crits-Christoph, P., Wadden, S., Gaines, A., Rieger, A., Gallop, R., McKay, J. R., & Gibbons, M. B. C. (2018).

Ibogaine is a psychedelic substance used in the treatment of addiction. A systematic review of human studies has been conducted on the effects of ibogaine on addiction and psychomotor performance.

A multiple-dose study of noribogaine in opioid-dependent subjects was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of a noribogaine alkaloid congener. The study was conducted by Geoffroy, P., Weis, H., and Maisonneuve, I. M.

In a study of opioid-dependent patients, noribogaine was found to be safe and effective at treating infection. In another study, ketamine and psilocybin were found to enhance motivation and attention in poor performing rats, suggesting an antidepressant property.

Ibogaine, an anti-addiction drug, inhibits hERG channels, which may be a risk factor for cardiac arrhythmia. Koenig, X., Kovar, M., Boehm, S., Sandtner, W., & Hilber, K. (2014) reported on this finding.

Ibogaine, an anti-addictive drug, has been used in several studies and may be a useful treatment for a variety of addictions. It is still under development and more research needs to be done into its potential.

Ibogaine is a G-protein biased kappa-opioid receptor agonist that has been used for the treatment of opioid use disorder. It can be used in combination with other treatments to help people stop using opioids.

A study of 31 patients with opioid and cocaine addiction found that ibogaine detoxification transitioned them between dependence and abstinence, and that ibogaine treatment outcomes were positive.

Ibogaine, a psychedelic drug, has been shown to reduce alcohol intake and nicotine self-administration in rats. Schellekens, A., Oosteren, T., Knuijver, T., verkes, R. J., & Belgers, M. have also reported successful treatment of heroin dependence with ibogaine.

Ibogaine is a psychedelic substance that has been used for treating addiction. There have been several studies on the use of ibogaine, including a case report of a patient who successfully detoxified from methadone using ibogaine.

This review provides an overview of the therapeutic uses of ibogaine and noribogaine, including data suggesting effectiveness in the treatment of substance use disorders and potential benefits for depressive and post-traumatic symptoms.