The antiaddictive effects of ibogaine: A systematic literature review of human studies

Ibogaine is a naturally occurring indole alkaloid obtained from the root bark of Tabernanthe iboga, traditionally used in Central African rituals. Earlier research and anecdotal reports suggested that ibogaine and its major metabolite noribogaine may reduce drug craving, withdrawal and self-administration across several substances, and animal studies showed reduced opiate/opioid, cocaine and ethanol self-administration. However, the pharmacology of ibogaine/noribogaine is complex and incompletely understood, involving multiple receptor systems (for example NMDA antagonism, modulation of serotonin and dopamine systems, κ- and μ-opioid activity) and putative neurotrophic effects; safety concerns including cardiac arrhythmias, psychosis and fatalities have also been reported, particularly in uncontrolled settings. Santos and colleagues therefore undertook a systematic literature review to identify and synthesise human studies that evaluated the antiaddictive effects of ibogaine or noribogaine. The aim was to compile available clinical evidence, characterise study designs, doses and outcomes, and evaluate safety signals, given the absence of a prior systematic review on this topic and the growing interest in these compounds for treating substance dependence.

The investigators conducted a systematic review in line with Systematic Reviews and Meta-Analyses guidelines. Electronic searches of PubMed, LILACS and SciELO were performed for studies published up to 2 July 2016, using the keywords: ibogaine OR noribogaine AND humans OR addiction OR dependence. Manual reference‑list searches supplemented the electronic search and no language restrictions were applied. Inclusion criteria comprised case reports and clinical studies (peer‑reviewed articles and books/book chapters indexed in the searched databases) that reported human administration of ibogaine or noribogaine and evaluated dependence or abuse symptoms. Excluded materials were preclinical studies, reviews, abstracts, letters, comments and editorials. Outcomes of interest were measures of dependence/abuse symptoms, including withdrawal, craving and substance use. Screening and data extraction were performed by two independent reviewers with a third reviewer resolving discrepancies. Extracted items included author, year, location, study design, participant characteristics (sample size, age, gender), dose and type of intervention, response criteria and outcome measures. The literature search returned 259 references; after screening and handsearching one additional report, eight studies met the pre‑defined criteria and were included: seven open‑label case series and one randomized, placebo‑controlled clinical trial with noribogaine.

Eight studies were included: seven open‑label case series/reports and one randomized, double‑blind, placebo‑controlled single ascending‑dose study of noribogaine. The case series varied in setting (non‑medical clinics, specialised clinics and retrospective datasets), sample size, dosing regimens and outcome assessments. Small open‑label reports: In an Amsterdam non‑medical setting seven opiate‑dependent individuals (mean age 29.3 years; doses 700–1,800 mg ibogaine HCl, given as a trial dose of 100–200 mg followed 1–2 hr later by the remainder) were followed up to 14 weeks. No subject showed significant opiate withdrawal at 24–38 hr; two subjects who received the lowest dose (700 mg) relapsed within 2 days, two who received >1,000 mg relapsed after weeks, one reverted to intermittent use and three remained drug‑free for >14 weeks. Adverse effects included transient ataxia, nausea, vomiting and sensitivity to light and sound. Another small, unidentified open‑label report described three cocaine‑dependent cases treated with 20–25 mg/kg ibogaine HCl; participants underwent medical and neurological monitoring and reported absence of withdrawal or craving at 24 hr, with normal EEG and ECG during and after treatment, but demographic details were not provided. Retrospective series and clinic reports: A retrospective set of 33 subjects (22 men; mean age 27.3 years) treated in non‑medical settings with an average dose of 19.3 ± 6.9 mg/kg reported that 25/33 (76%) had complete resolution of opiate/opioid withdrawal 24 hr after administration, sustained for 72 hr. Four subjects used opiates within 72 hr despite not reporting withdrawal; two reported attenuated withdrawal but remained drug‑free; one reported no effect. One fatality was described in this dataset (a 24‑year‑old female who died 19 hr after ibogaine; the report states this was apparently due to heroin use in the hours after treatment). A clinic in St Kitts treated more than 150 drug‑dependent subjects with single doses of 500–800 mg ibogaine HCl under open‑label conditions. Within this setting a 2‑week inpatient Phase I dose‑escalation subset (n = 27; 23 men; mean ages ~34–37 years for opiate and cocaine groups) received single fixed doses of 500, 600 or 800 mg and completed structured self‑reports of depression (Beck Depression Inventory, BDI) and craving (HCQN‑29 for heroin; CCQN‑45 for cocaine) at baseline, 36 hr and 14 days, with BDI also at 1 month. Ibogaine was associated with statistically significant reductions across all five HCQN‑29 subscales at 36 hr and 14 days (all subscales p < .0001), significant reductions in two CCQN‑45 subscales (Relief of Negative States, p < .0005; Lack of Control, p < .002) at 36 hr and 14 days, and reduced BDI scores at 1 month (p < .0005). A related subset of 32 opiate‑dependent patients who received a single 800 mg dose showed significant reductions in physician‑rated Objective Opiate Withdrawal Scale (OOWS) scores at 12 and 24 hr (p < .05) and in self‑rated Opiate‑Symptom Checklist (OP‑SCL) scores at <72 hr and at 6–9 days (p < .05). The report states that many subjects maintained abstinence over the months following treatment, but specific abstinence data were not shown. A larger retrospective assessment of 41 individuals treated between 1962 and 1993 reported abstinence durations as follows: 15 (29%) abstinent <2 months, 15 (29%) abstinent ≥2 and <6 months, seven (13%) abstinent ≥6 and <12 months, 10 (19%) abstinent >1 year, and five (10%) indeterminate. A Brazilian private hospital retrospective study (n = 75; 67 males, 8 females) combined open‑label ibogaine sessions (mean 3.8 sessions in males, 5.4 in females) with cognitive behavioural therapy. Doses were 17–20 mg/kg ibogaine HCl, with domperidone pre‑treatment to reduce nausea; patients were required to abstain for 30–60 days at home or at least 24 hr prior to treatment. Single and multiple doses were associated with significant increases in abstinence duration (p < .001), with 61% of participants reported abstinent after treatment: median 5.5 months for single‑dose patients and median 8.4 months for those receiving multiple doses. Acute adverse effects were transient (nausea, ataxia, vomiting, tremors, headaches, confusion) and no serious cardiac arrhythmias or fatalities were reported in this cohort. Adverse events across case reports included transient neurological and gastrointestinal symptoms; the authors note more than 25 fatalities have been associated with ibogaine in the literature, often linked to cardiac arrhythmias, pre‑existing cardiovascular disease, or concomitant drug use in uncontrolled settings. Randomized clinical trial: The single randomized, double‑blind, placebo‑controlled single ascending‑dose study enrolled 27 patients on methadone substitution (21 men; mean age 41.2 years) who were switched to morphine prior to dosing and received noribogaine 60, 120 or 180 mg. Withdrawal was assessed by pupillometry, oximetry/capnography, time to resumption of methadone and withdrawal scales (SOWS, OOWS, COWS) up to 144 hr. Noribogaine was generally well tolerated with no deaths or serious adverse events, but it produced dose‑ and concentration‑dependent QT interval prolongation that reached clinically concerning levels at 180 mg. Noribogaine did not produce significant reductions on subjective or objective withdrawal scales and did not increase time to resumption of methadone compared with placebo; the 120 mg group showed the longest time to resumption and the lowest withdrawal scores, but this was not a consistent dose–response effect.

Santos and colleagues conclude that available human data are limited and heterogeneous: seven open‑label case series suggest rapid reductions in withdrawal and craving and periods of abstinence lasting from 24 hr to weeks or months after single or a few ibogaine treatments, yet the only controlled clinical trial with noribogaine failed to demonstrate significant efficacy for opioid withdrawal. The authors therefore urge caution in interpreting apparent therapeutic effects. They discuss several explanations for the discordant findings. Dose equivalence between ibogaine and noribogaine is uncertain, and the noribogaine trial may have employed insufficient doses to reproduce the effects reported after ibogaine. Differences in patient populations are also relevant: many case series involved heroin‑dependent subjects treated in non‑medical contexts, whereas the clinical trial recruited methadone‑substituted patients; methadone has a long elimination half‑life, and methadone dependence may require repeated dosing strategies to achieve detoxification. Pharmacokinetic and pharmacodynamic factors are raised as potentially important, since noribogaine is longer‑lasting and both compounds act at multiple receptor sites implicated in addiction. Safety and implementation concerns form a major part of the authors' interpretation. They note reports of fatalities, cardiac arrhythmias and neuropsychiatric adverse events associated with ibogaine/noribogaine, and highlight the trial's finding of dose‑dependent QT prolongation with noribogaine. The investigators warn that many treatments occur in unsupervised, non‑medical settings with variable preparations and inadequate screening, increasing the risk of harm. Given these uncertainties, they argue that the current evidence does not permit causal claims about efficacy and that controlled clinical trials of ibogaine and noribogaine are necessary to establish safety, dosing, and therapeutic benefit. The authors position their review as supportive of further research, noting consistency with animal data but emphasising the need for rigorous randomised studies before clinical use can be recommended.