Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine

Opioid use disorder (OUD) is described as an epidemic in the United States, with high overdose mortality and large numbers of people dependent on prescription and illicit opioids. Existing pharmacotherapies such as methadone and buprenorphine reduce some harms and improve retention in treatment but have limitations: they maintain opioid dependence, can have safety issues (for example QTc prolongation with methadone), and may be inaccessible to some patients. Non-opioid tapering and supportive approaches show high relapse rates driven by persistent craving, so additional strategies for managing opioid withdrawal and reducing craving are needed. Malcolm and colleagues frame ibogaine, a psychoactive alkaloid, as a candidate intervention because of preclinical and small human studies suggesting it can reduce both withdrawal and craving. The introduction summarises ibogaine’s complex pharmacology — including activity at κ opioid, NMDA, monoamine transporters, σ receptors and nicotinic receptors — and notes that its active metabolite noribogaine has a longer half-life and higher opioid receptor affinity. Interindividual variability in CYP2D6 metabolism and drug–drug interactions are highlighted as important for both efficacy and safety. Given a paucity of controlled human data, the investigators set out to evaluate withdrawal and craving scores using validated scales in participants with OUD undergoing a week-long ibogaine HCl detoxification protocol conducted in Mexico.

This study is a retrospective chart review of patients admitted to a single residential ibogaine treatment centre in Mexico during 2015. Participants were included if they presented primarily for management of OUD and carried a DSM-5 diagnosis of OUD made by clinic physicians. The study team excluded patients treated primarily for a non-opioid problem, polysubstance users whose primary problem was another drug class, and cases lacking complete Clinical Opioid Withdrawal Scale (COWS) data. The Institutional Review Board at Western University of Health Sciences determined the study exempt because it used de-identified retrospective data. The clinical programme comprises three phases: pre-treatment coaching and medical screening, a week-long ibogaine detoxification (the inpatient component occurring during the first four days and residential for the final three days), and optional aftercare. Prior to travelling to the clinic, applicants were converted to short-acting opioids and required to discontinue methadone or buprenorphine four weeks before treatment. On arrival, patients underwent physical examinations, 12-lead ECG, toxicology testing, and bloodwork. Patients were maintained on immediate-release (IR) morphine up until approximately four hours before ibogaine administration in order to prevent florid withdrawal during the initial medical evaluation; this regimen was intended to produce peak withdrawal 24–48 hours after cessation if ibogaine were ineffective. The ibogaine protocol delivered oral ibogaine hydrochloride at a total calculated dose of 18–20 mg/kg. A 100 mg test dose was given first, with the remainder administered within two hours. The product was Voacanga-derived and GMP-certified. Treatment was medically supervised with vital signs, telemetry, IV fluids/electrolytes and on-site emergency clinicians. If post-acute withdrawal symptoms persisted at 72 hours, supplemental smaller ibogaine doses (1–5 mg/kg) were permitted, with clonidine or gabapentin as adjuncts when indicated. Outcome measures were clinician-administered COWS (0–48, categorical cutoffs from no withdrawal to severe), self-reported SOWS (0–64), and the three-item Brief Substance Craving Scale (BSCS, 0–12). Scores were collected at roughly 48 and 24 hours prior to ibogaine administration and at about 24 and 48 hours after administration; measurement times followed the physician’s routine daily rounds. The primary outcome was change in COWS across those time points. Repeated measures analysis of variance (ANOVA) was used for COWS, SOWS, and BSCS with alpha set at 0.05, and pairwise comparisons performed to identify differences between pre- and post-ibogaine phases. Baseline demographic and Addiction Severity Index (ASI) composite scores were described; some participants lacked ASI, SOWS, or BSCS data, although COWS data were available for all included participants.

Fifty participants had complete COWS data and were included in the primary analysis; demographic analyses used 40 participants because 10 were missing baseline ASI data. The sample mean age was 31.28 ± 8.38 years (range 19–51) and 39% were female. Regarding primary opioid problem, 60% (n = 24) reported heroin and 37.5% (n = 15) reported prescription opioids; among heroin users 66.7% usually injected while almost all prescription opioid users did not. Polysubstance use was common (82.5%); 75% reported prior treatment and 85% reported prior methadone or buprenorphine exposure. Participants reported an average of US$1666.85 spent on drugs in the prior 30 days (S.D. $1833.99). ASI composite scores indicated, on average, a medium-level problem in the drug domain (mean 0.206 ± 0.06) with 47.5% scoring in the severe range for drug problems. Other domains with notable severity included family/social, medical, and psychiatric. Objective withdrawal (COWS) scores averaged 8.2 ± 5.21 at 48 hours pre-ibogaine and 7.64 ± 5.27 at 24 hours pre-ibogaine, consistent with mild withdrawal while patients were maintained on IR morphine. Group means decreased to 5.26 ± 4.31 at 24 hours post-ibogaine and 3.30 ± 3.13 at 48 hours post-ibogaine (the latter in the non-clinical range). Repeated measures ANOVA showed a significant time effect on COWS (Wilk’s Lambda = 0.463, F(3,47) = 18.71, p < 0.01, η2 = 0.537). At 48 hours after ibogaine administration, 78% (n = 39) of patients exhibited no clinical signs of opioid withdrawal, 20% (n = 10) had mild signs, and 2% (n = 1) had moderate signs. Subjective withdrawal (SOWS) scores were higher at baseline (20.51 ± 13.66 at −48 hours and 17.09 ± 12.95 at −24 hours) and declined to 12.63 ± 11.95 at +24 hours and 10.04 ± 11.65 at +48 hours. The SOWS repeated measures ANOVA was significant (Wilk’s Lambda = 0.572, F(3,45) = 11.24, p < 0.01, η2 = 0.428). At 48 hours post-ibogaine, 68% (n = 34) rated withdrawal as mild, 10% (n = 5) as moderate, and 22% (n = 11) as severe on the SOWS. Craving (BSCS) scores averaged 6.58 ± 3.08 and 5.98 ± 2.98 at −48 and −24 hours respectively, and fell to 2.69 ± 2.68 at +24 hours and 1.92 ± 2.83 at +48 hours. The BSCS ANOVA demonstrated a strong time effect (Wilk’s Lambda = 0.314, F(3,45) = 32.80, p < 0.01, η2 = 0.69). At 48 hours post-ibogaine, 79.2% (n = 38) of participants had minimal craving (score 0–3), 14.6% (n = 7) moderate craving (4–6), and 6.3% (n = 3) severe craving (7–12). The extracted text notes that safety data such as vital signs and telemetry were not available for review in this study. The sample included some missing SOWS, BSCS or ASI data for subsets of participants; COWS data were complete for the 50 included cases.

Malcolm and colleagues conclude that, in their largest observed sample to date, ibogaine administration during a week-long detoxification protocol was associated with statistically significant and clinically meaningful reductions in clinician-rated withdrawal (COWS), self-reported withdrawal (SOWS), and self-reported craving (BSCS) scores within 48 hours. They place these findings in the context of few prior human reports and suggest the results are consistent with earlier case series and pilot studies indicating that ibogaine can attenuate both withdrawal and craving, potentially within a relatively brief treatment window. The investigators emphasise that simultaneous reduction of withdrawal and craving could be an important advantage compared with some existing approaches because unaddressed craving contributes to high relapse risk and subsequent overdose. They also note that ibogaine treatment typically requires psychological support before, during and after the psychedelic experience to maximise benefit and reduce risks, and that aftercare remains important since ibogaine is not viewed as a stand-alone cure. Safety concerns are highlighted: ibogaine’s subjective effects differ from classical psychedelics and it has been associated with serious adverse outcomes, including fatalities with suspected or confirmed cardiac causes, as reported in the literature. The authors acknowledge that the present dataset lacked detailed safety data (for example telemetry reports) and therefore could not contribute to that aspect of the evidence base. They also note that patients seeking ibogaine often have complex medical and addiction histories, which may increase medical risk during detoxification. Methodological limitations are clearly acknowledged: the study’s retrospective, open-label design and absence of a control group introduce the possibility of placebo effects, observer bias, and other confounders. The study team argues the likelihood of a pure placebo explanation is reduced by the timing of measurements (when peak withdrawal would be expected) and the large effect sizes observed, but they do not rule out continued pharmacologic effects from ibogaine metabolites such as noribogaine, nor the influence of clinician or participant reporting biases. The authors recommend future research with greater methodological rigour, including controlled trials, investigation of predictive factors of response (for example CYP2D6 genotype and metabolic capacity), and improved safety monitoring. Given the public-health burden of OUD, they call for reduced barriers to legitimate medical research on ibogaine’s addiction-interrupting properties.