Ivermectin Toxicity in Humans and Animals: Clinical Spectrum, Mechanisms, and Management

ABSTRACT Ivermectin is a widely used macrocyclic lactone with established efficacy against a broad range of parasitic infections in humans and animals and a long‐standing reputation for clinical safety. However, increasing evidence indicates that ivermectin can produce clinically relevant toxicity under specific conditions, particularly involving the central nervous system. This review integrates findings from controlled human trials, pharmacovigilance data, clinical case reports, experimental animal studies, and environmental investigations to comprehensively characterize the toxicological profile of ivermectin. Early randomized, placebo‐controlled studies in healthy volunteers demonstrated that ivermectin is generally well tolerated, even at doses substantially exceeding approved therapeutic levels, with predominantly mild and transient adverse events and no significant neurological toxicity under controlled conditions. In contrast, post‐marketing surveillance and real‐world clinical reports have identified rare but severe neurotoxic events, including encephalopathy, seizures, coma, and death, occurring after supratherapeutic exposure and, in susceptible individuals, even at standard therapeutic doses. Converging human and animal evidence highlights impairment or saturation of blood–brain barrier protection, particularly dysfunction of P‐glycoprotein (ABCB1/MDR1)–mediated efflux, as a central determinant of ivermectin neurotoxicity. Animal studies further demonstrate marked species‐, breed‐, age‐, dose‐, and route‐dependent susceptibility, with neonatal animals, genetically predisposed dog breeds, and models exposed to transporter inhibition or repeated high‐dose regimens showing pronounced vulnerability. While neurotoxicity is often functional and reversible at lower exposures, high or cumulative dosing can lead to structural neuropathology and multi‐organ injury. The COVID‐19 pandemic amplified these risks through widespread off‐label use, especially of veterinary formulations, resulting in a substantial increase in toxic exposures without demonstrated clinical benefit. Overall, ivermectin toxicity emerges as a predictable consequence of interactions between pharmacokinetics, transporter biology, exposure patterns, and host‐specific factors rather than an inherent contradiction of its therapeutic value.