The adverse events of ibogaine in humans: an updated systematic review of the literature (2015-2020)

Ona and colleagues situate ibogaine as the principal alkaloid of Tabernanthe iboga, historically used in West Central African rituals and later explored for stimulant and anti-addictive properties. Preclinical studies have shown dose- and route-dependent reductions in opioid self-administration in animals, but human evidence remains limited and largely observational. Prior systematic reviews documented multiple fatalities and serious adverse events associated with ibogaine/noribogaine, frequently occurring in uncontrolled settings and often involving co‑existing medical conditions, electrolyte disturbances, or concomitant drugs. Cardiotoxicity, notably QTc prolongation with risk of arrhythmia, has been a central safety concern highlighted in earlier work, and pharmacokinetic factors such as CYP2D6 metabolism and the longer half-life of noribogaine have been proposed as contributors to delayed adverse events. This paper aims to update the literature on adverse events and fatalities associated with ibogaine and noribogaine between July 2015 and July 2020. The investigators set out to identify human studies reporting adverse events, serious adverse events (SAEs), deaths, and potential drug–drug interactions, with particular attention to cases combining ibogaine with other substances. The review emphasises the need to characterise safety profiles across dosages and contexts given renewed interest in ibogaine for substance use disorders.

The researchers conducted a systematic review following PRISMA principles to capture human studies published from 2 July 2015 to 23 July 2020. Electronic searches were carried out in PubMed, Scopus, Web of Science, Scielo, Google Scholar, and Core.ac.uk using the terms ibogaine OR noribogaine AND humans OR addiction OR dependence, supplemented by manual reference checks. No language restrictions were applied. Inclusion criteria encompassed peer‑reviewed human studies reporting adverse events related to ibogaine or noribogaine, including case reports, case series, observational studies, letters, and clinical trials; preclinical work, reviews, abstracts, comments and editorials were excluded. All participants who received at least one dose of ibogaine or noribogaine were eligible. Outcomes included any reported adverse or negative effects, whether assessed systematically (scales, physiological or biological measures) or non‑systematically, plus reports of intoxication and death. Reviewers pre‑specified classifying adverse events as acute (< 24 h) or prolonged (> 24 h). Two independent reviewers screened records with disagreements resolved by a third reviewer. Extracted data included author, year, location, study design, setting, participant characteristics, intervention details (dose, formulation, route, concomitant drugs), and outcome measures. The NIH study‑quality checklists were applied to grade case series, observational cohort and controlled intervention studies; items present in each article contributed points to a proportional score ranging from 0 to 1. Where subjective checklist items were disputed, consensus was sought or a third reviewer adjudicated. Study selection produced 18 included articles after duplicates and ineligible reports were removed. The final set comprised primarily case reports/series (15), two randomised double‑blind clinical trials and one observational study. Because of heterogeneity in designs, doses, formulations, and frequently missing information on product purity, the authors confined their synthesis to qualitative analysis rather than quantitative pooling.

Eighteen studies met inclusion criteria: 15 case reports or case series, two clinical trials (a Phase I ibogaine pharmacokinetic/safety study and a randomised, double‑blind noribogaine trial), and one observational study. Most case reports described single subjects; one case series included 191 patients. Trial sample sizes described in the extract include groups of 21 and 27 participants; the observational study contained 30 subjects. Ages in case reports ranged from 22 to 60 years and males were over‑represented across several study types. The principal indication for use was opioid dependence; two cases sought spiritual cleansing. Formulation and dosing were highly heterogeneous and often poorly documented. Reported ibogaine exposures ranged from 725 mg to administration of 38 g of dried root bark; only five of 15 case reports confirmed presence of ibogaine analytically, and only one measured its quantity. Root bark, ibogaine HCl and unknown preparations were all mentioned. This uncertainty limited dose–response interpretation. Acute adverse events (< 24 h) most commonly involved cardiac abnormalities, with QTc prolongation repeatedly reported; individual QTc values cited included 527 ms, 730 ms, 647 ms, 516 ms, 714 ms, 788 ms and 512 ms. Other acute cardiac findings were tachycardia, hypotension, wide QRS complexes, and Torsades de Pointes. Gastrointestinal symptoms (nausea, vomiting), altered consciousness and perceptual changes (visions, hallucinations, disorientation), a range of autonomic and motor symptoms (ataxia, diaphoresis, akathisia, tremor) and neurological events (seizures, dysmetria, anoxic brain injury, unconsciousness) were also reported. In the Phase I pharmacokinetic study (21 healthy volunteers divided by placebo or paroxetine pretreatment), a 20 mg dose showed rapid noribogaine peaks at about 3–4 h; paroxetine pretreatment doubled exposure to ibogaine + noribogaine, indicating potential pharmacokinetic interactions via CYP2D6 inhibition. The noribogaine trial (n = 27) tested 60, 120 and 180 mg doses versus placebo in patients discontinuing methadone; noribogaine produced non‑significant reductions in opioid withdrawal symptoms and exhibited slow elimination (24–30 h). Both trials reported that low doses were generally well tolerated with only transient mild/moderate effects (light perceptual changes, headache, nausea) and no serious adverse events in these controlled settings. Prolonged adverse events (> 24 h) included persistent psychiatric (insomnia, delusions, irritability, hallucinations), neurological (psychomotor slowing, ptosis, dysarthria, amnesia) and cardiac alterations, with some reports of QTc prolongation persisting up to 7 days. Mean hospitalisation among cases was 7.8 days (range 3–13). Laboratory abnormalities noted in two studies included transient increases in C‑reactive protein, white blood cell count and creatinine, plus hypokalemia and hypomagnesaemia on the day after admission. Management of serious events in case reports frequently required intensive care interventions. Benzodiazepines and antipsychotics were the most commonly administered medications; anticonvulsants, atropine, isoprenaline, magnesium sulfate, intravenous fluids, antiemetics, and, in some cases, invasive measures (intubation, electrical cardioversion, pacemaker insertion, defibrillation) were used. One fatality occurred after administration of naloxone in the field followed by morphine and vasopressors in hospital; the authors noted possible iatrogenic or interaction contributions. Toxicology screens in several cases revealed concomitant drugs (benzodiazepines, opioids, methadone, cannabinoids, cocaine) but in five reports no toxicology was performed. Quality assessment yielded average scores of roughly 80% for case series, 78% for controlled intervention studies, and 64% for observational cohort assessment. Given the predominance of case reports and heterogeneity across reports, the synthesis remained qualitative.

Ona and colleagues interpret the assembled evidence as consistent with prior reviews: ibogaine and noribogaine are associated with gastrointestinal, motor and cardiovascular effects, plus psychedelic‑like perceptual changes, and in some uncontrolled settings with more severe neurological and cardiac adverse events. The authors stress that serious adverse events and fatalities occur predominantly in unsupervised, non‑clinical contexts where dose, purity and concomitant drug use are uncertain. They highlight multiple contributors to risk: variable and often unknown alkaloid content in root bark and commercial products, high doses used in non‑medical settings, pre‑existing medical conditions (notably cardiovascular disease), electrolyte disturbances (earlier reviews found hypokalemia in all fatalities and hypomagnesaemia in 50% of cases), and concomitant use of other drugs including CYP2D6 inhibitors and P‑glycoprotein substrates. Pharmacokinetic and pharmacodynamic mechanisms are discussed as plausible explanations for delayed cardiotoxicity: noribogaine’s longer half‑life and both compounds’ inhibitory effects on hERG potassium channels may prolong cardiac repolarisation and raise arrhythmia risk. The Phase I data showing increased exposure when CYP2D6 is inhibited (paroxetine pretreatment) support concerns about drug–drug interactions. The authors also note the occurrence of seizures in three case reports and consider possible mechanistic links via 5‑HT2A agonism, glutamatergic disinhibition, or dose‑related phenomena; preclinical neurotoxicity findings are mixed, with some high‑dose animal studies showing Purkinje cell degeneration but other studies and a neuropathological evaluation of a human volunteer showing no clear cerebellar damage. Key limitations acknowledged include the predominance of case reports and small uncontrolled studies, substantial heterogeneity in formulations and doses, and frequent lack of analytical confirmation of ibogaine exposure. These factors impede causal inference and dose–response characterisation. As implications, the authors call for properly powered Phase I–II clinical trials using standardised products to define safety, tolerability, dose–effect relationships and drug–drug interactions, and they recommend rigorous pre‑treatment screening (electrocardiography, electrolyte panels, drug screening and consideration of CYP2D6 status) plus continued cardiovascular monitoring in any clinical use to mitigate risk.