What are the documented neurologic and hepatic adverse events reported in high‑dose ivermectin studies in humans?
Executive summary
High‑dose ivermectin studies in humans and pharmacovigilance analyses document a spectrum of neurologic events—from common, mild symptoms such as dizziness and somnolence observed in trials to rare but severe encephalopathies, coma, and ataxia reported in case series and overdoses—while hepatotoxicity appears uncommon but has been reported as isolated serious hepatitis and transient aminotransferase elevations [1] [2] [3] [4]. Interpretation is complicated by confounders (Loa loa infection), genetic susceptibility (ABCB1/ MDR1 loss‑of‑function), variable dosing including veterinary products, and limited sample sizes in formal high‑dose trials [1] [3] [4] [2].
1. High‑dose clinical trials: tolerability and mild neurologic signals
A randomized, double‑blind dose‑escalation trial that administered up to ten times the highest approved ivermectin dose reported that adverse experiences were similar between ivermectin and placebo and did not increase with dose, finding no indication of central nervous system toxicity in that cohort; common labeled neurologic events across trials remained dizziness (2.8%), somnolence (0.9%), vertigo (0.9%) and tremor (0.9%) [2] [1]. That controlled trial, however, included only 68 subjects with limited ethnic diversity and was underpowered to detect rare idiosyncratic events, so absence of serious events there does not rule out uncommon severe toxicity at higher or repeated dosing [2] [1].
2. Pharmacovigilance and population‑level signal detection: mixed findings
Large pharmacovigilance analyses mining VigiBase and WHO adverse‑event records documented reports of encephalopathies, seizures, confusional disorders, toxidermias and hepatic and renal events after ivermectin exposure, yet disproportionality analyses did not detect consistent increases for many categories (including encephalopathies, seizures and hepatic disorders) when comparing sub‑Saharan Africa and the rest of the world, leaving an ambiguous population‑level signal [5] [6]. These studies highlight reported serious adverse drug reactions (sADRs) but also underscore that routine surveillance did not uniformly show a strong statistical association across all syndromes [5] [6].
3. Severe neurologic reactions in mass treatment settings and the Loa loa confounder
Serious neurologic adverse events, including encephalopathy and deaths, occurred during large community ivermectin campaigns in West/Central Africa and were tightly associated with very high Loa loa microfilarial loads prior to treatment; investigators have debated whether the pathology is drug‑directed toxicity or a consequence of rapid parasitic killing and inflammatory CNS injury [3] [1]. Those programmatic events remain a canonical example of severe neurologic outcomes temporally related to ivermectin, but they are contextually linked to coinfection and parasite burden rather than simple high dosing alone [3] [1].
4. Case reports, genetic susceptibility and overdose patterns
Individual case reports have documented dramatic neurologic toxicity—coma, ataxia, pyramidal signs, diplopia and prolonged impaired consciousness—after doses within or modestly above therapeutic ranges in patients identified with nonsense mutations in ABCB1 (P‑glycoprotein), a transporter that normally limits ivermectin CNS penetration; these cases demonstrate a biologically plausible mechanism for severe CNS toxicity in susceptible humans [4]. Separately, poison‑center series during the COVID‑19 era describe predominantly older men ingesting supratherapeutic and veterinary formulations who developed rapid neurotoxicity (confusion, stupor, seizures), linking misuse/overdose to neurologic harm [7] [8].
5. Hepatic events: rare but documented
Ivermectin is generally associated with minor, transient aminotransferase elevations in clinical use, but isolated reports of clinically apparent hepatitis and severe hepatic injury exist, including a published case of severe hepatitis after a single dose with markedly elevated transaminases that resolved over months [3] [9]. Pharmacovigilance extractions identified a small number of serious hepatic events among thousands of reports, indicating hepatotoxicity is possible but appears rare in humans based on available data [9] [6].
6. Bottom line, uncertainties and research gaps
Documented neurologic adverse events range from mild dizziness and tremor in trials to rare severe encephalopathy, coma and movement disorders in contexts of high parasite burden, genetic ABCB1 defects, or overdose with veterinary products, while hepatic injury manifests mostly as transient enzyme rises with rare reports of clinical hepatitis; population studies give mixed signals and controlled high‑dose trials are underpowered to detect rare idiosyncratic reactions, leaving substantive uncertainty about the true incidence of severe neurologic or hepatic toxicity at high or repeated human doses [1] [2] [3] [4] [5]. Future safety assessments must couple larger controlled dosing studies with genetic screening and careful pharmacovigilance, especially where co‑infections or off‑label high‑dose use occur, because current evidence is heterogeneous and context‑dependent [2] [3] [5].