{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:10:47Z","timestamp":1791648647613,"version":"4.3.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Opioid related fatalities remain a public health crisis in the US. Currently, the only way to restore breathing following an opioid induced persistent apnea is with the administration of the opioid antagonist naloxone, but it also reverses analgesia, euphoria, and induces precipitated withdrawal in opioid dependent individuals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using whole-body plethysmography, we assessed changes in breathing frequency in awake behaving mice resulting from a single fentanyl dose (50\u202fmg\/kg\u202fi.p.) that followed i.p. pretreatment with saline, vehicle, naloxone (100\u202fmg\/kg), cannabidiol (CBD) (250\u202fmg\/kg), or CBD\u202f+\u202fnaloxone. Then we assessed the delay to opioid-induced persistent apnea (OIPA) and the median lethal dose (LD<jats:sub>50<\/jats:sub>) of fentanyl during a continuous i.c.v. infusion of fentanyl (100\u202fng\/min), in urethane anesthetized mice, following pretreatment with saline, vehicle, naloxone (100\u202fmg\/kg), CBD (250\u202fmg\/kg), or CBD\u202f+\u202fnaloxone i.p.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here we show acute pretreatment with CBD is as effective as naloxone at preventing opioid-induced respiratory depression from fentanyl in awake mice, and increasing LD<jats:sub>50<\/jats:sub> of fentanyl in urethane anesthetized mice. When pre-administered together, CBD\u202f+\u202fnaloxone, increased LD<jats:sub>50<\/jats:sub> of fentanyl even more than CBD or naloxone alone in urethane anesthetized mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CBD may be an effective preventative therapy for OIPA by increasing the time before apnea onset and potentially enhancing the efficacy of naloxone as an additional strategy to save lives.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1654787","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T05:41:21Z","timestamp":1759902081000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Proof of concept for high-dose Cannabidiol pretreatment to antagonize opioid induced persistent apnea in mice"],"prefix":"10.3389","volume":"19","author":[{"given":"Beth M.","family":"Wiese","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny","family":"Bondarenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack L.","family":"Feldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.neuron.2020.02.005","article-title":"Emergent elements of inspiratory rhythmogenesis: network synchronization and synchrony propagation","volume":"106","author":"Ashhad","year":"2020","journal-title":"Neuron"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"52694","DOI":"10.7554\/eLife.52694","article-title":"Opioids depress breathing through two small brainstem sites","volume":"9","author":"Bachmutsky","year":"2020","journal-title":"eLife"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"9466","DOI":"10.1021\/acs.jmedchem.3c00061","article-title":"Structure-activity relationship study of Cannabidiol-based analogs as negative allosteric modulators of the \u03bc-opioid receptor","volume":"66","author":"Bosquez-Berger","year":"2023","journal-title":"J. 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Neurosci."},{"key":"ref11","first-page":"25","article-title":"Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings","volume-title":"Prog Mol Biol Transl Sci","author":"Elsaid","year":"2019"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1152\/jn.00711.2020","article-title":"Respiratory effects of low and high doses of fentanyl in control and \u03b2-arrestin 2-deficient mice","volume":"125","author":"Haouzi","year":"2021","journal-title":"J. Neurophysiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1176\/appi.ajp.2019.18101191","article-title":"Cannabidiol for the reduction of Cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial","volume":"176","author":"Hurd","year":"2019","journal-title":"Am. J. Psychiatry"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s13311-015-0373-7","article-title":"Early phase in the development of Cannabidiol as a treatment for addiction: opioid relapse takes initial center stage","volume":"12","author":"Hurd","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1089\/can.2016.0034","article-title":"An update on safety and side effects of Cannabidiol: a review of clinical data and relevant animal studies","volume":"2","author":"Iffland","year":"2017","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1113\/jphysiol.2005.098848","article-title":"Distinct rhythm generators for inspiration and expiration in the juvenile rat","volume":"570","author":"Janczewski","year":"2006","journal-title":"J. Physiol."},{"key":"ref17","volume-title":"Epidiolex (cannabidiol) dosing for US healthcare professionals","year":"2024"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"6429","DOI":"10.1038\/s41598-022-09601-2","article-title":"Naloxone's dose-dependent displacement of [(11)C]carfentanil and duration of receptor occupancy in the rat brain","volume":"12","author":"Kang","year":"2022","journal-title":"Sci. Rep."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"11229","DOI":"10.1073\/pnas.1711351114","article-title":"Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome","volume":"114","author":"Kaplan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1007\/s00210-006-0033-x","article-title":"Cannabidiol is an allosteric modulator at mu-and delta-opioid receptors","volume":"372","author":"Kathmann","year":"2006","journal-title":"Naunyn Schmiedeberg's Arch. Pharmacol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s12954-024-00994-z","article-title":"High-dose naloxone formulations are not as essential as we thought","volume":"21","author":"Lemen","year":"2024","journal-title":"Harm Reduct. J."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1177\/07067437231183525","article-title":"Cannabidiol as a harm reduction strategy for people who use drugs: a rapid review","volume":"68","author":"Lo","year":"2023","journal-title":"Can. J. 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Neurobiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1111\/bcpt.13710","article-title":"A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD)","volume":"130","author":"Peng","year":"2022","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/phar.2469","article-title":"CBD and THC: do they complement each other like yin and Yang?","volume":"40","author":"Pennypacker","year":"2020","journal-title":"Pharmacotherapy"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"14764","DOI":"10.1523\/JNEUROSCI.4291-09.2009","article-title":"Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances","volume":"29","author":"Ren","year":"2009","journal-title":"J. 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Neurosci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1089\/can.2021.0090","article-title":"Brain penetrant, but not peripherally restricted, synthetic cannabinoid 1 receptor agonists promote morphine-mediated respiratory depression","volume":"5","author":"Wiese","year":"2021","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1089\/can.2020.0076","article-title":"Cannabinoid-2 agonism with AM2301 mitigates morphine-induced respiratory depression","volume":"5","author":"Wiese","year":"2020","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1111\/j.1476-5381.2009.00521.x","article-title":"Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors","volume":"159","author":"Zanelati","year":"2010","journal-title":"Br. J. 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