{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:55:28Z","timestamp":1790873728472,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Ivermectin is a widely used macrocyclic lactone with established efficacy against a broad range of parasitic infections in humans and animals and a long\u2010standing 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\u2010controlled 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\u2010marketing surveillance and real\u2010world 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\u2013brain barrier protection, particularly dysfunction of P\u2010glycoprotein (ABCB1\/MDR1)\u2013mediated efflux, as a central determinant of ivermectin neurotoxicity. Animal studies further demonstrate marked species\u2010, breed\u2010, age\u2010, dose\u2010, and route\u2010dependent susceptibility, with neonatal animals, genetically predisposed dog breeds, and models exposed to transporter inhibition or repeated high\u2010dose 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\u2010organ injury. The COVID\u201019 pandemic amplified these risks through widespread off\u2010label 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\u2010specific factors rather than an inherent contradiction of its therapeutic value.<\/jats:p>","DOI":"10.1002\/jat.70166","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:24:54Z","timestamp":1773656694000},"page":"1856-1870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ivermectin Toxicity in Humans and Animals: Clinical Spectrum, Mechanisms, and Management"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-9475","authenticated-orcid":false,"given":"Serkan","family":"Yilmaz","sequence":"first","affiliation":[{"name":"Faculty of Nursing Ankara University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0126-4801","authenticated-orcid":false,"given":"Bayram","family":"G\u00f6kta\u015f","sequence":"additional","affiliation":[{"name":"Haymana Vocational School Ankara University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130lker","family":"Ate\u015f","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Department of Pharmaceutical Toxicology Ankara University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"\u00c7elik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology Kahramanmaras Sutcu \u0130mam University  Kahramanmaras Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.21608\/ejvs.2023.221045.1537"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1917344"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.31196\/huvfd.1348411"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70430"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2021.106516"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104787"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6308762"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.17\u20100042"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2006.11.006"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12639\u2010016\u20100837\u20102"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10646\u2010015\u20101608\u20100"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13256\u2010023\u201003799\u20100"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.42603"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rvsc.2010.05.020"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127002401382731"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2024.107248"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12551\u2010023\u201001080\u20107"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10139"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2022.2107517"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1939\u20101676.2002.tb01609.x"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2024.115383"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/jfmpc.jfmpc_1229_22"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166294"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2012.00060"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.26873\/SVR\u20101861\u20102024"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvp.13102"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.10.010"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2017.06.029"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2021.07.648"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13736"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.07.001"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD015017.pub3"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2115869"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph18101459"},{"issue":"9","key":"e_1_2_13_36_1","first-page":"735","article-title":"Ivermectin Overdose and Toxicosis in Neonatal Pigs","volume":"29","author":"Sanford S. E.","year":"1988","journal-title":"Canadian Veterinary Journal"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.21608\/EJVS.2024.277901.1816"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2114907"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.19080\/JDVS.2017.02.555594"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/03000605251318724"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.70166","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jat.70166","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.70166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:16:51Z","timestamp":1777864611000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.70166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/jat.70166"],"URL":"https:\/\/doi.org\/10.1002\/jat.70166","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]},"assertion":[{"value":"2026-01-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}