What are the documented cases of ivermectin‑related neurotoxicity in humans and what were the contributing factors?
Executive summary
Documented human cases of ivermectin‑related neurotoxicity are rare but well described in the literature and fall into three broad patterns: mass‑treatment encephalopathies linked to parasitic coinfections, individual genetic susceptibility that impairs the blood–brain efflux transporter ABCB1 (P‑glycoprotein), and overdose—often from veterinary formulations or high self‑administered doses during the COVID‑19 pandemic [1] [2] [3].
1. Mass‑treatment encephalopathy: Loa loa and community campaigns
Large community ivermectin campaigns for onchocerciasis in Africa produced clusters of severe neurological events—confusion, coma and death—in persons heavily infected with the filarial parasite Loa loa, and investigators debated whether the drug itself, the rapid killing of microfilariae, or host responses caused the encephalopathy; these events are documented in post‑marketing surveillance and case series from mass administration programs [1] [4]. While ivermectin is usually safe in mass use, the epidemiologic signal around Loa‑endemic areas indicates a host/disease interaction that precipitates neurologic harm in a small subset of treated people [1] [4].
2. Genetic vulnerability: ABCB1 (MDR1/P‑glycoprotein) loss‑of‑function
A clear human mechanism emerged from case reports and genetic work: the ABCB1 efflux transporter normally prevents ivermectin accumulation in the brain, and nonsense mutations or deficiency of this transporter can permit neurotoxic concentrations even at therapeutic doses; a high‑profile pediatric case with coma after a standard scabies dose implicated this mechanism and mirrors veterinary examples in collie dogs with MDR1 mutations [2] [5] [6]. Experimental and clinical reviews underscore that individuals with impaired P‑glycoprotein function—whether genetic or pharmacologically inhibited—are at elevated risk for ivermectin neurotoxicity [7] [8].
3. Overdose and veterinary formulations: COVID‑era poisonings
Toxicology surveillance during the COVID‑19 pandemic recorded a surge of ivermectin poisonings, predominantly in older men who ingested doses above recommended human regimens, with rapid‑onset neurotoxicity particularly common among those taking veterinary formulations that contain much higher concentrations and non‑pharmaceutical excipients [3]. U.S. poison centers and case series described neurologic symptoms—altered mental status, ataxia, coma—after single large doses or repeated high doses, and many affected patients required hospitalization [3].
4. Pharmacologic contributors: drug interactions and impaired blood–brain barrier
Beyond genetic mutations and overdose, pharmacologic inhibition of P‑glycoprotein or hepatic enzymes (e.g., CYP3A4) that alter ivermectin metabolism can raise CNS exposure, and animal models show marked brain accumulation and neurotoxicity when P‑glycoprotein is absent or inhibited [7] [8]. Review articles caution that co‑administration of inhibitors of the ABCB1 transporter, or other factors that impair the blood–brain barrier, plausibly convert ordinarily safe doses into neurotoxic exposures [7] [6].
5. Clinical pattern, prognosis and gaps in reporting
Reported human cases span reversible confusion and ataxia to prolonged coma; many reports describe symptom resolution after discontinuation (positive dechallenge), but some mass‑campaign events were fatal and the literature stresses rarity compared with tens of millions treated safely [1] [9]. Important gaps remain: many case reports lack measured ivermectin blood or CSF concentrations, comprehensive toxicologic workups, or genetic testing, limiting definitive attribution in some clustered events [5] [1].
6. Competing explanations and implicit agendas in reporting
Scientific debate has focused on whether parasite‑related inflammatory responses (e.g., rapid Loa loa killing) versus direct drug neurotoxicity explain mass‑campaign encephalopathies, and some reporting—particularly during COVID‑19—blurred overdose toxicology with politicized claims about ivermectin’s efficacy, which risked amplifying misuse and veterinary product ingestion [1] [3]. The academic literature emphasizes measured, mechanism‑based risk assessment (genotype, interactions, overdose) rather than broad claims that ivermectin is inherently neurotoxic in ordinary therapeutic use [9] [8].
Conclusion: what is documented and why it matters
Documented human ivermectin neurotoxicity occurs in clearly definable contexts—Loa loa coinfection during mass treatment, ABCB1 transporter deficiency, and overdose (notably veterinary product misuse)—with contributing factors including impaired P‑glycoprotein function, drug interactions, and extremely high ingested doses; despite these documented risks, ivermectin remains broadly safe at recommended doses, and the literature calls for targeted risk mitigation (screening in Loa‑endemic areas, avoidance of veterinary formulations, awareness of drug interactions) and improved surveillance and genetic testing in unexplained severe cases [1] [2] [3] [7].