What are the documented adverse effects in humans at ivermectin doses ≥1 mg/kg or with parenteral administration?

1. What has been observed in real-world overdoses and misuse

Case series and poison‑center reports from the COVID‑era document people ingesting veterinary and incorrect human products who developed vomiting, diarrhea, transient neurologic dysfunction, and in some instances enough toxicity to require hospital admission; the New England Journal of Medicine series reported doses taken from veterinary pastes and solutions (examples: 6.8 mg–125 mg paste, 20–50 mg solution) and found six of 21 patients hospitalized for toxic effects after preventive use ^[1], while public health advisories warn that animal products are much more concentrated and can cause overdose ^{[5] [6]}.

2. Neurologic toxicity is the clearest documented risk at high exposure

Product labeling and clinical reviews list alteration of consciousness ranging from somnolence and confusion to stupor, coma, seizures, ataxia and, rarely, death after ivermectin exposure; these neurologic events have been reported both in routine human use and in overdose contexts and form the bulk of the severe adverse‑event signal in pharmacovigilance databases ^{[2] [3] [7]}.

3. The role of dose, parasites and host factors in severe encephalopathy

Large‑scale pharmacovigilance and case reports emphasize that severe encephalopathies have been seen not only in apparent overdoses but also in people with high Loa loa microfilarial loads after standard doses; this complicates simple dose–response conclusions because host infection status (and possibly genetic variants affecting the MDR‑1/P‑glycoprotein transporter) can permit ivermectin to penetrate the CNS and produce severe neurologic effects even at lower relative doses ^{[4] [8] [7]}.

4. Evidence specifically at ≥1 mg/kg in humans: limited and mixed

Conclusive, large human studies documenting systematic adverse effects at or above 1 mg/kg are lacking in the provided reporting; small safety investigations have reported no clear CNS toxicity up to roughly 10× the licensed 200 µg/kg in a limited cohort (68 subjects), but that sample was small and not broadly representative, and pharmacovigilance still records idiosyncratic severe neurologic events—so absence of consistent signal in small trials does not negate reported severe case reports ^{[7] [4]}.

5. Non‑neurologic adverse effects and severe systemic presentations

Common, generally milder reactions known from standard use—pruritus, fever, rash, myalgia, headache—can be more pronounced during heavy parasite die‑offs, while overdose and misuse reports add vomiting, diarrhea, hypotension and in rare cases multiorgan dysfunction (notably when Strongyloides hyperinfection is present after immunosuppression); supportive care is the recommended management for severe presentations ^{[9] [3] [10]}.

6. Parenteral administration: reporting gap and clinical caveats

None of the supplied sources offer systematic human data describing parenteral (non‑oral) ivermectin administration as an approved route; the literature and product labeling focus on oral and topical human formulations and report severe neurologic and systemic adverse events with excess exposure, but the absence of documented parenteral‑route safety/outcome data in these sources is a meaningful limitation that prevents definitive statements about parenteral‑specific risks ^{[3] [2]}.

7. Synthesis and practical inference

Taken together, the documented adverse effects associated with high ivermectin exposure in humans are dominated by central‑nervous‑system depression (ranging to coma and seizures), gastrointestinal symptoms, hypotension and rarely multiorgan dysfunction or death; although individual small studies reported no CNS toxicity at several‑fold higher doses, pharmacovigilance and case reports—including hospitalizations after misuse—establish that idiosyncratic severe toxicity occurs and that host factors (co‑infections and possible genetic variants) materially affect risk, while direct, high‑quality human data specifically at ≥1 mg/kg or for parenteral use are limited in the sources reviewed ^{[1] [2] [7] [4] [3]}.