What are the short-term and long-term side effects of high-dose ivermectin in humans?

1. Short-term harms seen after high doses — overt toxicity and neuropsychiatric events

Acute or “high-dose” ivermectin exposure in humans commonly produces gastrointestinal complaints (nausea, vomiting, abdominal pain, diarrhea) and skin reactions (pruritus, rash); more worrisome are neurologic and psychiatric effects reported in case series and reviews, including dizziness, ataxia, seizures, confusion, disorientation, and acute psychosis — several case reports link these outcomes to high-dose self-treatment for COVID-19 ^{[1] [2] [3]}. National-consensus drug summaries list serious allergic reactions (laryngeal edema, difficulty breathing) and note that overdose can cause breathing difficulties and severe neurologic symptoms ^{[7] [1]}.

2. Cardiac, hepatic and fatal outcomes reported at extreme exposures

Available clinical reports and reviews warn that very large ivermectin doses can cause hypotension, tachycardia, altered consciousness and, in rare reports, liver failure and death; a review of cases tied extremely high, nonstandard dosing to these severe outcomes ^{[2] [1]}. Animal lethality data and human-equivalent extrapolations show LD50 ranges manyfold above therapeutic doses but within reach if veterinary or massively increased human dosing occurs; authors caution that achieving in vitro antiviral levels would require doses likely to produce poisoning ^{[4] [3]}.

3. What “high-dose” means — dose comparisons and trial experience

Typical approved human dosing for parasitic infections is weight-based single doses around 150–200 μg/kg; some clinical trials tested higher regimens for COVID‑19 (for example, 400 μg/kg daily for 3 days) and found no meaningful clinical benefit and no increase in adverse events in that trial, but these regimens are still modest compared with the multiples implicated in poisoning reports ^{[8] [5]}. Pharmacokinetic and in vitro analyses indicate the antiviral concentrations that inhibit SARS‑CoV‑2 in cell culture would require oral doses tens of times higher than approved human dosing — a level identified by researchers as “high enough to be considered ivermectin poisoning” ^{[4] [2]}.

4. Long-term effects — limited human evidence; population programs offer partial reassurance

Long-term adverse-event data from controlled human studies of repeated or sustained high-dose ivermectin are sparse in current reporting. Mass drug-administration campaigns using recommended doses (e.g., annual 0.4 mg/kg in some filariasis programs) indicate the drug is generally well tolerated when used as directed, but those program doses are not “high-dose” by the definitions used in poisoning cases; the literature states that ivermectin’s long- and short-term toxicological properties are “very clear” for approved uses, but it does not document chronic toxicity from repeated supratherapeutic exposure in humans ^{[9] [10] [6]}. Available sources do not mention robust, controlled human data demonstrating chronic sequelae from single high-dose ivermectin exposures.

5. Biological plausibility — blood‑brain barrier, metabolism, and risk modifiers

Ivermectin normally has limited penetration of the mammalian blood–brain barrier, which helps explain its safety at therapeutic doses, but at high doses crossing can increase and raise risk of central nervous system toxicity; genetic and pharmacologic differences in CYP3A4 metabolism and MDR1 transporters may alter individual susceptibility ^{[6] [3]}. Drug–food interactions (higher absorption after a high‑fat meal) and drug interactions that affect CYP3A4 could raise systemic levels and thus toxicity risk ^{[6] [3]}.

6. Conflicting viewpoints and limitations in the evidence

Clinical trial data for higher, but still modest, ivermectin regimens (e.g., 400 μg/kg × 3 days) found no significant increase in adverse events compared with placebo, suggesting short-term safety at those levels in trial populations ^[5]. However, case reports of severe neurotoxicity and hepatic failure come from uncontrolled settings where massively excessive dosing, veterinary product use, or co‑morbidities may have contributed — meaning causality and generalizability are imperfectly defined ^{[2] [1]}. Sources differ on how much margin exists between therapeutic and toxic doses; animal LD50 extrapolations provide context but are not direct human evidence ^{[4] [3]}.

7. Practical takeaways and reporting gaps

Do not self‑administer veterinary ivermectin or take doses above approved, weight‑based prescriptions; overdose risks include GI distress, neurologic and psychiatric events, liver injury and death, per clinical reviews and case reports ^{[7] [1] [2]}. Major gaps remain: controlled human long‑term follow‑up after supratherapeutic exposure is not reported in the sources, and more pharmacovigilance data would help quantify chronic sequelae from high‑dose exposure (available sources do not mention controlled long‑term human studies of supratherapeutic ivermectin).