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Using a randomized, double-blind, crossover trial, we then showed that prophylactic treatment with 400 mg caffeine mitigates systemic hypercapnia and headache during graded CO<jats:sub>2<\/jats:sub> exposure. Overall, these novel findings establish caffeine as the first evidence-based countermeasure to mitigate adverse effects associated with CO<jats:sub>2<\/jats:sub> exposure. <\/jats:p>","DOI":"10.1152\/japplphysiol.01024.2024","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T16:10:47Z","timestamp":1740759047000},"page":"881-890","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prophylactic caffeine mitigates systemic hypercapnia and headache during graded carbon dioxide exposure in healthy males and females: a randomized crossover trial"],"prefix":"10.1152","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-6988","authenticated-orcid":false,"given":"Benjamin J.","family":"Ryan","sequence":"first","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-9196","authenticated-orcid":false,"given":"Thomas A.","family":"Mayer","sequence":"additional","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6503-6053","authenticated-orcid":false,"given":"Billie K.","family":"Alba","sequence":"additional","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7115-8684","authenticated-orcid":false,"given":"Karleigh E.","family":"Bradbury","sequence":"additional","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaun C.","family":"Brazelton","sequence":"additional","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]},{"name":"Oak Ridge Institute for Science and Education","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-5279","authenticated-orcid":false,"given":"Nisha","family":"Charkoudian","sequence":"additional","affiliation":[{"name":"U.S. Army Research Institute of Environmental Medicine","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. 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