Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes

This observational field study (n=30) investigated the effects of ibogaine on opioid detoxification amongst individuals who sought addiction treatment at a private clinic and found that the treatment had a substantiative effect of reducing drug use up to 1 month, or even up to 12 months amongst select individuals.

Abstract

“Background: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. 

Objectives: To study outcomes following opioid detoxification with ibogaine. 

Methods: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. 

Results: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. 

Conclusion: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.”

Authors: Thomas Kingsley Brown & Kenneth Alper

Summary

In this observational study, 30 subjects with DSM-IV Opioid Dependence received a mean total dose of 1,540 920 mg ibogaine HCl. They showed significant improvement in Subjective Opioid Withdrawal Scale (SOWS) scores and Addiction Severity Index Composite (ASIC) scores following opioid detoxification with ibogaine.

Accessed 16 April 2017.

Ibogaine, 18-methoxycoronaridine, noribogaine, heroin, oxycodone, opioid use disorder

Introduction

Ibogaine, a monoterpene indole alkaloid, is used for the treatment of substance use disorders. It has been associated with controversy and is illegal in the US and 9 of the 28 countries in the European Union.

Ibogaine is used most frequently for detoxification from opioids, and has been shown to have a substantive effect in 33 individuals treated in nonmedical settings with single mean dosages of 19.3 6.6 mg/kg (4). Unpublished data include a series of 53 treatment episodes that were presented to the National Institute on Drug Abuse (NIDA), and an academic thesis on a Web-based survey of 21 individuals who had used ibogaine.

Ibogaine, administered intraperitoneally or intracerebrally to animals, reduces naloxone- or naltrexone-precipitated opioid withdrawal signs, and diminishes self-administration of multiple abused substances including morphine, heroin, cocaine, amphetamine, and alcohol.

Ibogaine, its major metabolite noribogaine, and 18-MC do not act as orthosteric opioid receptor (MOR) agonists, but instead potentiate morphine analgesia without producing analgesia when administered alone. This suggests that ibogaine may modify neuroadaptations associated with chronic exposure to opioids.

Ibogaine is an NMDA receptor antagonist that diminishes signs of opioid withdrawal in preclinical models and humans, however 18-MC lacks significant affinity for the NMDA receptor.

Ibogaine is proposed to reduce drug self-administration by increasing the expression of glial-derived neurotrophic factor (GDNF). Its action as an allosteric antagonist of the nicotinic acetylcholine receptor (nAChR) is also suggested to mediate its effect on drug self-administration.

Treatment setting, inclusion and exclusion criteria, and subject enrollment

The Human Research Review Committee at the California Institute of Integral Studies approved this observational study, which assessed detoxification and drug use outcomes in two private clinics in Baja California, Mexico.

The study sample consisted of 30 individuals who sought treatment with ibogaine for detoxification from opioids. They were required to have a reliable method of communication with the researchers and provide the name and contact information of at least one other individual.

30 people signed up for the study, 9 were rejected, and 4 declined to participate. They were given $10 for each follow-up phone interview.

Study sample

The demographic, drug use, and treatment history characteristics of the study sample are summarized in Table 1. The subjects were heavy users of opioids and reported no stimulant use or alcohol use in the previous 30 days.

The subjects had been regularly using at least one opioid substance for an average of 5.2 3.1 years before presenting for treatment. Twenty-nine of the 30 subjects had previously received treatment for SUD.

Treatment

Subjects were stabilized on a short acting opioid, most often oxycodone, for two to three days prior to the administration of ibogaine. A total dose of 1,540 920 mg ibogaine HCl, 94% purity by certificate of analysis was administered to each subject.

Ibogaine treatment is initiated with a test dose of 3 mg/kg, and a flood dose of 4 mg/kg is given approximately 2 to 12 hours after the test dose. A booster dose is sometimes given to alleviate residual or re-emergent withdrawal symptoms.

A group of physician and lay ibogaine treatment providers published clinical guidelines for detoxification from opioids with ibogaine. The guidelines were followed by the providers of treatment in this study.

Assessment and rating

A baseline pretreatment interview was conducted with participants, and follow-up interviews were conducted with participants and their significant others 1, 3, 6, 9 and 12 months after treatment with ibogaine.

Subjects were evaluated using the Addiction Severity Index (ASI) at pretreatment baseline and at follow-up intervals of 1, 3, 6, 9 and 12 months after treatment with ibogaine. The ASIC has seven composite measures with distinct item content.

The 16-item Subjective Opioid Withdrawal Scale (SOWS) was used to assess withdrawal symptoms. The baseline SOWS was administered within one hour prior to the test dose.

Statistical tests

Paired t-tests were used to compare ASIC scores at 1, 3, 6, 9 and 12 months to their pretreatment baseline. A noninferiority test was performed to determine if a treatment effect observed at 1 month was sustained at subsequent 3-, 6-, 9-, and 12-month time points.

For statistical tests, missing values were set to their baseline pretreatment value. Paired t-tests were performed on subjects with follow-up data available at 1 month, 3, 6, 9 and 12 months.

Sows

The mean score for the entire study sample decreased from 31.0 11.6 to 14.0 9.8 following ibogaine treatment.

The effect of methadone on SOWS scores was similar in opioid-dependent subjects with comorbid substance use, and 16.8 versus 17.2 points decreased in the group with comorbid substance use.

Tests of difference on ASIC scores relative to baseline at 3-, 6-, 9-, and 12-month follow-up

The results of paired t-tests of difference on ASIC scores showed that the scores decreased significantly at all posttreatment time points for Drug Use, Family/ Social Status, and Legal Status. The scores did not differ significantly from baseline at any time point for Alcohol Use and Medical Status.

Tests of noninferiority on ASIC scores relative to 1 month over the subsequent posttreatment interval of 3 to 12 months

The improvement in Family/Social and Legal Status scores at the 1-month posttreatment interval was sustained at the 3-, 6-, 9-, and 12-month posttreatment follow-ups.

The results suggest that the treatment effect on Drug Use persists across the 12-month follow-up interval in a subset of subjects, although the group noninferiority result becomes nonsignificant under the conservative assumption that all missing subjects have relapsed to their baseline.

Relationship of baseline characteristics to subsequent outcome

A subset of 12 subjects had favorable outcomes, and did not differ significantly from the remaining subjects with regard to their rates of use of non-opioid substances, opioids other than methadone, or the predominant route of heroin self-administration.

Exposure to methadone was associated with less favorable outcome, whereas exposure to buprenorphine did not differ between the two groups. Subjects with histories of methadone treatment had more prior treatment episodes than subjects without a history of methadone treatment.

Subjects receiving other SUD treatment during follow-up

Nine subjects received additional treatment during the 12 months following opioid detoxification with ibogaine, including drug-free residential treatment, opioid agonist maintenance treatment, and an additional subsequent ibogaine treatment.

Subjects in residential treatment were assumed to have missed a test, and their missing scores were set to pretreatment values.

Discussion

This observational study reports on follow-up data subsequent to detoxification with ibogaine of 30 individuals with OUD. The data indicate that ibogaine has a significant effect on opioid withdrawal symptoms, and that this effect is sustained over the subsequent posttreatment interval of up to 12 months.

Ibogaine had a substantive effect on drug use at 1 month, with 50% reporting no opioid use during the previous 30 days at 1 and 3 months respectively.

Group statistics indicated that Drug Use scores were improved at all posttreatment time points, although the noninferiority tests suggest that the improvement was sustained over the subsequent 3 to 12 months.

The subset of subjects with favorable outcomes averaged 2.0 1.6 prior treatment episodes for OUD, indicating that ibogaine may have provided distinctive benefit for individuals with histories of previously unsuccessful treatment.

Although no adverse cardiovascular events were observed in this study, ibogaine has been associated with fatalities. 18-MC has been found to have less hERG blockade than ibogaine or noribogaine, and has not produced bradycardia in the animal model.

Qualitative perspective

Participants reported having a panoramic, rapid readout of long-term visual memory, and equanimity regarding the material retrieved. Family/Social was the most improved ASIC factor apart from Drug Use, in apparent consonance with the themes of “one heartedness” and “binding” to family and ancestors.

Limitations of this study

This study looked at the effects of ibogaine on substance use in a challenging setting. It lacked a control group and relied on self-report without laboratory verification.

Laboratory verification of self-reports is necessary in future clinical research on SUDs to prevent biasing the data due to underreporting of drug use.

The mean time interval between baseline and second SOWS for the entire sample was 76.5 hours, which suggests that an inactive agent might yield falsely positive results if the eventual resolution of withdrawal symptoms with unassisted opioid withdrawal were considered.

The subjects in this study had substantial rates of previous 30-day use of buprenorphine or methadone, and withdrawal from long-acting opioids may have increased the time interval required for detoxification.

The test-flood-booster protocol used in this observational study may have prolonged the treatment, because the subjects were using twice as large amounts of heroin and methadone as in prior studies, and the providers used total dosages of ibogaine that are similar to those used in prior studies.

The qualitative descriptions and comments from the subjects in this study suggest that ibogaine is tolerable and may be effective in alleviating withdrawal symptoms in individuals with a one gram/day heroin or 200 mg/day oxycodone habit.

Conclusion

Ibogaine appeared to have a clinical effect in some subjects with histories of failure of other treatments for opioid use disorder. It may provide an interesting prototype for discovery and development of fundamentally innovative pharmacotherapy.