What adverse events and safety signals have been reported in clinical trials and poison‑control data for high‑dose or veterinary ivermectin use?
Executive summary
High-dose and veterinary-use ivermectin have been linked repeatedly to neurological toxicity, gastrointestinal upset, and rising poison‑control calls during the COVID‑19 era, while pharmacovigilance databases also record rare but serious dermatologic, hepatic, and renal reactions; randomized and meta‑analytic trial data report generally tolerable adverse‑event profiles for defined high‑dose regimens but carry limits when extrapolating to unsupervised veterinary or extreme overdoses [1] [2] [3] [4]. The evidence therefore splits along two realities: regulated clinical dosing (including some trials up to 800 µg/kg) shows mostly mild–moderate and comparable adverse events to standard doses [5] [3], whereas misuse—especially ingestion of veterinary formulations or large single doses—has produced clear signals of severe neurotoxicity and emergency presentations captured by poison centers and case series [1] [6] [2].
1. Poison‑control surge and the clinical picture of misuse
Poison‑control centers in the United States documented a dramatic rise in calls about human exposures to ivermectin in 2021 compared with baseline, with some centers reporting jumps from fractions of a call per month to dozens in a single month, and public‑health agencies issued alerts linking that surge to increased adverse‑event reports [7] [6] [8]. Clinical effects reported to these centers and academic toxico‑surveillance networks centered on neurologic symptoms—confusion, altered consciousness, hallucinations, seizures and, in severe cases, coma—alongside more common gastrointestinal complaints such as nausea and vomiting; these presentations were particularly associated with ingestion of veterinary products or doses higher than recommended [2] [9] [10] [6].
2. Neurological toxicity: frequency, context, and special risks
Multiple case series and pharmacovigilance reviews identify neurologic adverse events as the dominant signal for serious ivermectin‑associated harm outside approved uses, including encephalopathy, loss of consciousness, tremor, abasia and coma; some reports implicate ivermectin penetrating the brain and producing depressed levels of consciousness [11] [4]. Serious neurologic reactions have long been documented in patients with high Loa loa microfilarial loads after mass ivermectin campaigns, and pharmacovigilance analyses also find cases not explained by loiasis—suggesting host, parasite, dose, formulation or genetic susceptibility factors in rare severe outcomes [5] [4] [12].
3. Dermatologic, hepatic, renal and immune‑mediated signals from surveillance
Beyond the central‑nervous‑system effects, global pharmacovigilance data and case reports have flagged rare but severe cutaneous adverse reactions (including DRESS and generalized pustulosis), as well as reports of hepatic and renal disorders temporally associated with ivermectin exposure; these were identified in VigiBase and regional safety reviews and may not have been captured in clinical trials due to rarity [4] [13] [12]. Pharmacovigilance analyses explicitly call out novel toxidermias and distinct serious adverse drug reactions that warrant clinician awareness when assessing causality [12] [4].
4. What clinical trials and meta‑analyses say about controlled high‑dose use
Systematic reviews and randomized‑trial safety reporting for ivermectin used as a repurposed therapy for COVID‑19 or in other experimental settings generally found no large increase in adverse‑event rates for higher, defined dosing regimens compared with standard doses; a meta‑analysis cited trials up to several hundred µg/kg and concluded adverse‑event profiles were similar across groups [3]. Another systematic review and individual study reports concluded that doses up to 800 µg/kg produced mainly mild‑to‑moderate events comparable to standard 150–200 µg/kg regimens, but these trial contexts involved controlled dosing, monitoring, and selection criteria that limit direct comparison to unsupervised overdoses or veterinary product ingestion [5] [3].
5. Synthesis: regulated dosing vs. real‑world misuse and evidence gaps
The strongest, consistent safety signal is that misuse—especially ingestion of veterinary formulations or repeated large doses—causes neurotoxicity and emergency presentations well documented by poison centers and case series [1] [2] [6]. Pharmacovigilance systems extend that picture to rare dermatologic and organ‑system reactions [12] [4]. Conversely, controlled trials and systematic reviews provide evidence that specified high‑dose regimens can be tolerated with mostly mild–moderate adverse events, but those data do not negate the documented harms of unsupervised overdosing, nor fully resolve which patient‑level risk factors (co‑medications, genetic variants, parasite co‑infections) predict severe outcomes; these remain areas where surveillance and rigorous trials must be reconciled with real‑world poison‑control experience [5] [3] [4].