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Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when coadministered with alcohol and their sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl plus alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses when combined with fentanyl also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol\u2013induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol\u2013induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.<\/jats:p>","DOI":"10.1172\/jci.insight.198059","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T17:00:36Z","timestamp":1770138036000},"source":"Crossref","is-referenced-by-count":0,"title":["Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone"],"prefix":"10.1172","volume":"11","author":[{"given":"Emma V.","family":"Frye","sequence":"first","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyndsay E.","family":"Hastings","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aniah N.","family":"Matthews","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Gregory-Flores","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janaina C.M.","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay A.","family":"Kryszak","sequence":"additional","affiliation":[{"name":"Translational Analytical Core, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelley N.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Translational Analytical Core, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aidan J.","family":"Hampson","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapeutic Development, National Institute on Drug Abuse, Rockville, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora D.","family":"Volkow","sequence":"additional","affiliation":[{"name":"Laboratory for Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-8627","authenticated-orcid":true,"given":"Leandro F.","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"Stress and Addiction Neuroscience Unit, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Intramural Research Programs, NIH, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5040-7966","authenticated-orcid":true,"given":"Renata C.N.","family":"Marchette","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George F.","family":"Koob","sequence":"additional","affiliation":[{"name":"Neurobiology of Addiction Section and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"B1","unstructured":"US Centers for Disease Control and Prevention, National Center for Health Statistics. 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