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Using three mouse models, we examined the impact of CBD and THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), and 3) cortical spreading depolarization (CSD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Both male and female CD1 mice were treated with CBD (100 mg\/kg) or THC (1 mg\/kg) alone or in combinations of CBD (1, 30 or 100 mg\/kg) and THC (1 mg\/kg) prior to injection of CGRP or SNP. The mice were assessed for light aversion (photophobia), squint (non-evoked pain), and periorbital tactile hypersensitivity, as well as possible adverse effects. In a separate set of experiments, CSD events were optogenetically induced in familial hemiplegic migraine 1 (FHM1) mutant and wildtype littermates (WT) mice (C57BL\/6 background), followed by grimace and motor assessments with and without combinations of CBD (30 or 100 mg\/kg) and THC (1 mg\/kg).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In CD1 mice, a 100:1 CBD:THC combination mitigated light aversion induced by CGRP and SNP in males and females. Rescue of CGRP- and SNP-induced squint was observed only in male mice with 100:1 CBD:THC. None of the treatments rescued periorbital tactile hypersensitivity in either sex. In FHM1 mutant and WT mice, the 100:1 CBD:THC ratio did not affect CSD characteristics but did reduce CSD-induced grimace features (i.e., head pain mimic). No adverse effects of any of the cannabinoid treatments were observed using cognitive, emotional, or motor tests.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A 100:1 ratio of CBD:THC has a beneficial effect on some of the most bothersome migraine-related symptoms in three mouse models. Our findings support a potential therapeutic efficacy of combined CBD and THC treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03331024251314487","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T01:47:48Z","timestamp":1740361668000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Combined effects of cannabidiol and \u03949-tetrahydrocannabinol alleviate migraine-like symptoms in mice"],"prefix":"10.1177","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-9959","authenticated-orcid":false,"given":"Erik","family":"Zorrilla","sequence":"first","affiliation":[{"name":"University of Iowa"},{"name":"University of 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