Treatment of acute opioid withdrawal with ibogaine

Ibogaine is an indole alkaloid derived from the African shrub Tabernanthe iboga that has been claimed to possess anti-addictive properties, including efficacy in ameliorating acute opioid withdrawal. Earlier research supporting this claim comprises animal studies showing reduced morphine and heroin self-administration and attenuation of withdrawal signs, plus multiple anecdotal and case reports from an informal treatment network operating outside conventional research settings. The compound’s pharmacology is complex: it does not act as a classic dopamine or opioid agonist/antagonist or as an amine re-uptake inhibitor, but has affinities for NMDA, kappa opioid, sigma, and nicotinic receptors. Because its mechanism is unknown, NMDA antagonism and other interactions have been proposed as possible mediators of an effect on opioid withdrawal. This paper by Alper and colleagues aims to present a systematic series of open-label case observations drawn from that informal treatment network to assess ibogaine’s apparent effects on acute opioid withdrawal over the first 72 hours after the last opiate use. The authors focus on opioid withdrawal because it is a well-recognised, time-limited clinical syndrome that may provide clearer outcome measures than other substance withdrawal states and because opioid dependence has been the principal indication for which patients have sought ibogaine treatment.

The report is a descriptive case series. The cases derive from a subset of 41 patients treated with ibogaine between 1962 and 1993 and presented at a Medications Development Division (MDD-NIDA) meeting; 33 cases were selected for inclusion according to two criteria: (1) heroin dependence (with or without other substance use) meeting DSM-IV criteria for opioid dependence with physiological dependence at the time of treatment, and (2) continuous direct observation by one or both of the co-authors H.S.L. and G.M.N.F. for at least 48 hours after ibogaine administration. Eight of the original 41 cases were excluded because they were not opioid dependent or lacked post-treatment observation. Treatments were administered under open-label conditions in non-medical settings (hotel rooms or apartments). Seven treatments occurred in the United States in 1962–1963 and 26 in the Netherlands between 1989 and 1993. Observational coverage was provided by H.S.L. (23 cases), G.M.N.F. (9 cases), or both (1 case), with additional observers present when the co-authors slept. Jan Bastiaans, M.D., assessed and corroborated observations on many patients, typically being present for the first 4–8 hours and returning at 24 hours when available. Dosing and procedural details are reported as follows: patients received a mean ibogaine dose of 19.3 ± 6.9 mg/kg (range 6–29 mg/kg). Subjects were instructed to take their last food, fluids, heroin, or other substances the night before treatment and to receive ibogaine about 8–10 hours later in the morning; methadone-treated patients took their last methadone about 24 hours prior to ibogaine. During treatment subjects lay in a dim, quiet room. Observers kept journals and recorded objective signs of opioid withdrawal (for example, mydriasis, sweating, elevated pulse, shivering, piloerection, diarrhoea) and subjective complaints (chills, muscle and abdominal pain, nausea). Vomiting, which commonly occurs with ibogaine, was treated as a withdrawal sign only if it was sustained for more than 2 hours. No structured withdrawal rating scales or formal statistical analyses are reported; outcomes are described at 24, 48 and 72 hours post-administration.

Among the 33 cases included, 25 patients (76%) were reported to have no objective signs or subjective complaints of opioid withdrawal at both 24 and 48 hours and did not seek, obtain, or attempt to use opioids for at least 72 hours after ibogaine administration. For these patients the onset of symptomatic relief was reported to be rapid, typically within 1 to 3 hours of ingestion. An additional patient had sweating at 24 hours but not at 48 hours and likewise did not seek opioids over 72 hours; another patient had chills at both 24 and 48 hours but still refrained from seeking opioids over 72 hours. Four patients showed apparent resolution of withdrawal signs at 24 and 48 hours but returned to opioid use within 72 hours. Two of these were young males (aged 20 and 26) who continued to pursue a heroin-centred lifestyle despite apparent relief; both had received relatively low ibogaine doses of 8 mg/kg and reported low heroin use (approximately 0.1 g/day). The other two relapsed despite higher doses (23 and 25 mg/kg) and heavier baseline use (about 0.4 g/day and 0.75 g/day). One case (a 27-year-old female receiving 10 mg/kg and using ~0.4 g/day) exhibited clear objective and subjective withdrawal signs after ibogaine and left the treatment setting to use heroin roughly 8 hours after dosing; the authors suggest inadequate dosing relative to dependence level as a possible explanation. A single fatality occurred in a 24-year-old female treated in the Netherlands in 1993. Forensic examination did not yield a definitive cause of death; postmortem interpretation of ibogaine or noribogaine levels was considered problematic because of redistribution issues, and no analyses for heroin metabolites (for example, 6-monoacetylmorphine) or gastric contents were performed. The report notes evidence suggesting that opioid toxicity may be relatively greater after ibogaine, and indicates uncertainty about possible surreptitious opioid use in the fatality (charred tin foil was found among the patient’s possessions). The extracted text also reports that vomiting is common during ibogaine treatment but was not counted as a withdrawal sign unless persistent for more than 2 hours.

Alper and colleagues interpret the series as providing preliminary evidence that ibogaine may reduce the signs and symptoms of acute opioid withdrawal: 76% of cases were reportedly free of withdrawal signs at 24 hours and did not seek opioids during the 72-hour observation period, while another subset had relief of withdrawal but nonetheless resumed opioid use. The authors emphasise the methodological limitations of the data, notably the open-label, informal treatment context, the absence of structured withdrawal rating scales, and the lack of systematic follow-up; they nevertheless argue that the clinical recognition of the opioid withdrawal syndrome by experienced observers supports the validity of the observations. Corroboration by Dr Bastiaans in many cases is presented as additional support for the reliability of the assessments. Safety is identified as a principal concern. The single fatality in this series was influential in decisions not to proceed immediately to a clinical trial and highlights the need for dose-escalation studies, pharmacokinetic data, and medical supervision available in conventional research settings. The authors discuss preclinical neurotoxicity reports—cerebellar damage reported in rats at 100 mg/kg—but note that effects on withdrawal and self-administration were seen at much lower doses in animal studies and that other animal experiments have not demonstrated toxicity at lower dosing regimens. They also note that neurotoxic effects may be mediated via sigma-2 receptor activity and that congeners with less sigma-2 activity (for example, 18-methoxycoronaridine) produce similar anti-addiction effects in rodents without apparent neurotoxicity. Practical considerations are outlined as well: ibogaine’s wholesale cost was reported as roughly US$200 per treatment at the time of the report, but costs in a conventional medical setting would include supervisory personnel and other infrastructure; the substantial subjective psychoactive experience produced by ibogaine may not be acceptable or tolerable to all patients; and follow-up studies of tolerability and longer-term outcomes would be subject to self-selection bias among people who seek ibogaine in unconventional networks. The authors conclude that, despite the methodological disadvantages of this informal dataset, the observations merit systematic investigation in controlled clinical settings because confirmation would indicate a novel pharmacologic mechanism potentially useful for understanding and treating addiction.