Which drug–drug interactions and patient conditions increase the risk of serious neurologic adverse events with ivermectin?
Executive summary
Serious neurologic adverse events (encephalopathy, seizures, coma, persistent coma, ataxia) after ivermectin are uncommon but documented, and risk clusters around particular parasitic coinfections (notably Loa loa), host defects in the ABCB1/P‑glycoprotein blood–brain barrier pump, pharmacologic interactions that raise CNS ivermectin levels, and situations of overdose or impaired drug clearance [1] [2] [3]. The literature and pharmacovigilance databases point to a mix of infectious, genetic, pharmacokinetic and exposure‑related drivers rather than a single universal mechanism [4] [5].
1. Loa loa coinfection and high microfilarial density — the classic driver
Large community ivermectin campaigns for onchocerciasis revealed a reproducible signal: patients with high Loa loa microfilarial loads developed severe neurologic syndromes after ivermectin, and the risk correlates with pre‑treatment microfilarial density, making coinfection a primary, well‑documented risk factor in endemic areas [1] [2] [6].
2. ABCB1 (P‑glycoprotein) loss‑of‑function — a human genetic vulnerability
Ivermectin normally is kept out of the CNS by the ABCB1 (MDR1/P‑gp) transporter at the blood‑brain barrier; human nonsense mutations in ABCB1 have been reported in patients who developed severe neurotoxicity even at usual doses, mirroring the well‑known susceptibility in collie dogs and Abcb1‑knockout mice [3] [7].
3. Drug–drug interactions that increase brain ivermectin — P‑gp inhibitors and substrates
Drugs that inhibit P‑glycoprotein or compete as P‑gp substrates can raise brain concentrations of ivermectin; verapamil is explicitly noted as an example that can increase CNS ivermectin, and coadministration of other ABCB1 substrates or inhibitors is mechanistically plausible to amplify neurotoxicity risk [8] [5].
4. Overdose, age and physiologic states that lower P‑gp activity
Supratherapeutic doses predictably increase neurologic adverse events: case reports describe encephalopathy after massive overdoses, and children—who may have lower P‑gp expression—are highlighted as potentially higher‑risk for CNS effects [5] [8]. Impaired drug clearance or coexisting conditions that alter blood–brain barrier integrity could similarly raise CNS exposure, although specific comorbidity datasets are limited in the reviewed literature [6] [4].
5. Neurologic disease, concomitant CNS‑active drugs, and epilepsy patients — interaction concerns
Ivermectin has CNS depressant and tremor‑producing potential at higher doses and was judged unsuitable for epilepsy development in part because of its CNS adverse effects and the “high potential of drug–drug interactions” with antiepileptic regimens; patients on multiple CNS‑active drugs or with seizure disorders therefore represent a practical cautionary group [9] [6].
6. How common, and what remains uncertain — data, reporting bias and competing explanations
Pharmacovigilance analyses identify clusters of serious neurologic adverse reactions but conclude they are rare relative to global ivermectin use; some case series suggest events occur even without Loa loa, implying additional host or pharmacologic risk factors such as ABCB1 mutations, P‑gp‑modulating co‑drugs, or overdoses, yet underreporting, regional reporting practices, and incomplete individual‑level data limit firm incidence estimates and causal attributions [2] [4] [10]. Alternative viewpoints emphasize ivermectin’s overall safety in approved parasitic indications, but the literature converges on specific, actionable risks—Loa loa burden, ABCB1 dysfunction, P‑gp interactions, overdose, and possibly young age or compromised BBB—as the chief drivers of severe neurologic events [1] [3] [8].