What clinical trials have evaluated ivermectin for COVID-19 and what adverse events did they report?
Executive summary
Randomized and non-randomized clinical trials have tested ivermectin across a range of doses and disease severities for COVID-19; most peer‑reviewed randomized controlled trials (RCTs) and several meta‑analyses found no consistent clinical benefit and did not show a clear increase in overall adverse events compared with control, but individual trials and pharmacovigilance reports documented gastrointestinal, neurological, dermatological and occasional serious events including deaths in non‑COVID contexts and rare encephalopathy in Loa‑loa co‑infection—leaving safety signals that require careful context and better data [1] [2] [3] [4].
1. Trials landscape: how many and what kinds of studies measured safety
Clinical investigation of ivermectin for COVID-19 included pilot randomized, controlled, open‑label trials, multiple small RCTs (some double‑blind, some open), retrospective observational studies and many registered but unpublished trials; systematic reviewers identified dozens of trials but highlighted that only a subset reported usable safety data for pooled analysis—WHO’s expert review summarized data from 16 RCTs involving about 2,407 participants when making guidance statements [5] [6] [2].
2. Notable randomized trials and their adverse‑event findings
A pilot high‑dose trial led by Krolewiecki reported adverse events in 13 of 30 patients (43%) in the ivermectin arm versus 5 of 15 controls (33%) but found no relationship between plasma ivermectin levels and the events [7] [8]. A JAMA‑reported randomized trial of a 5‑day course for mild COVID‑19 found adverse events in 77% of the ivermectin group versus 81.3% of placebo, with headache the most common complaint, and concluded no meaningful clinical benefit [9]. Other controlled trials have reported no adverse events or no severe adverse events in small samples, including double‑blind placebo‑controlled trials that found no significant safety signals in the populations studied [10] [9].
3. What pooled analyses and reviews say about overall safety
Systematic reviews and meta‑analyses that pooled trial safety data have generally concluded that ivermectin was not associated with a statistically significant increase in adverse events or serious adverse events compared with standard care or placebo, supporting continued study in trials rather than routine clinical use (QJM review) [1]. A focused safety meta‑analysis reported a range of events across organ systems but concluded overall tolerability in COVID‑19 trials without clear excess harm in pooled comparisons [2].
4. Reports of severe, neurological and fatal events: scattered but important
Outside the controlled COVID‑19 RCT record, toxicology and pharmacovigilance literature documents rare but serious ivermectin‑linked outcomes—encephalopathy after mass treatment in Loa‑loa co‑endemic settings, isolated fatal reports attributed to ivermectin in case reviews, and regulatory databases noting neurologic and hepatic events—creating a plausible mechanism for rare severe toxicity under certain circumstances [3] [4] [5]. Systematic reviewers caution that high‑dose exposures and vulnerable co‑infections or co‑medications can change safety profiles [11] [5].
5. Why safety signals are hard to interpret: heterogeneity and reporting gaps
Heterogeneity in dose (single low dose up to multi‑day high doses), trial size (many small trials), inconsistent adverse‑event collection and reporting, and confounding by COVID‑19 itself (which can cause gastrointestinal, hepatic and neurologic manifestations) make attribution difficult; many reviewers explicitly note limited data on high‑dose regimens and call for larger standardized trials to resolve remaining uncertainty [11] [6] [5].
6. Conclusion: what the clinical record supports and what remains unsettled
The peer‑reviewed RCT record and aggregated analyses do not show a consistent increase in overall adverse events for ivermectin at commonly tested doses in COVID‑19 trials, but isolated trials reported higher event counts and separate toxicology and case reports document rare but serious neurologic, hepatic and fatal events in specific contexts—therefore safety cannot be declared settled and further large, rigorously reported trials with standardized adverse‑event monitoring are required to define rare risks, especially for high‑dose regimens or in patients with co‑infections or interacting medications [1] [2] [3] [4].