Xylazine exacerbates fentanyl-induced respiratory depression and prevents rescue by naloxone in mice

Acosta-Mares P, Violante-Soria V, Browne T Jr., Cruz SL (2023) Xylazine potentiates the lethal but not the rewarding effects of Fentanyl in mice. Drug Alcohol Depend 253:110993

Article  CAS  PubMed  Google Scholar 

Alexander RS, Canver BR, Sue KL, Morford KL (2022) Xylazine and overdoses: Trends, Concerns, and recommendations. Am J Public Health 112:1212–1216

Article  PubMed  PubMed Central  Google Scholar 

Ayub S, Parnia S, Poddar K, Bachu AK, Sullivan A, Khan AM, Ahmed S, Jain L (2023) Xylazine in the opioid epidemic: A systematic review of case reports and clinical implications. Cureus 15:e36864

PubMed  PubMed Central  Google Scholar 

Ball NS, Knable BM, Relich TA, Smathers AN, Gionfriddo MR, Nemecek BD, Montepara CA, Guarascio AJ, Covvey JR, Zimmerman DE (2022) Xylazine poisoning: a systematic review. Clin Toxicol (Phila) 60:892–901

Article  PubMed  Google Scholar 

Bateman JT, Saunders SE, Levitt ES (2023) Understanding and countering opioid-induced respiratory depression. Br J Pharmacol 180:813–828

Article  CAS  PubMed  Google Scholar 

Bedard ML, Huang X-P, Murray JG, Nowlan AC, Conley SY, Mott SE, Loyack SJ, Cline CA, Clodfelter CG, Dasgupta N, Krumm B, Roth BL, McElligott ZA (2024) Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism. Addict Neurosci 11:100155

Article  PubMed  PubMed Central  Google Scholar 

Biancardi V, Bícego KC, Almeida MC, Gargaglioni LH (2008) Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch 455:1119–1128

Article  CAS  PubMed  Google Scholar 

Buajordet I, Næss A-C, Jacobsen D, Brørs O (2004) Adverse events after Naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med 11:19–23

Article  PubMed  Google Scholar 

Bünemann M, Bücheler MM, Philipp M, Lohse MJ, Hein L (2001) Activation and deactivation kinetics of alpha 2A- and alpha 2 C-adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents. J Biol Chem 276:47512–47517

Article  PubMed  Google Scholar 

Bylund DB (2007) Characterization of adrenoceptors. Curr Protocols Pharmacol 36:151–1518

Article  Google Scholar 

Canada Go (2023) Spotlight: the emergence of Xylazine in Canada. In: Service HCDA (ed)

Cano M, Daniulaitye R, Marsiglia F (2023) Xylazine in drug seizure reports and overdose deaths in the US, 2018–2022. medRxiv

Cano M, Daniulaityte R, Marsiglia F (2024) Xylazine in overdose deaths and forensic drug reports in US States, 2019–2022. JAMA Netw Open 7:e2350630

Article  PubMed  PubMed Central  Google Scholar 

Capraro AJ, Wiley JF 2nd, Tucker JR (2001) Severe intoxication from xylazine inhalation. Pediatr Emerg Care 17:447–448

Article  CAS  PubMed  Google Scholar 

Chabot-Doré AJ, Millecamps M, Naso L, Devost D, Trieu P, Piltonen M, Diatchenko L, Fairbanks CA, Wilcox GL, Hébert TE, Stone LS (2015a) Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors. Neuropharmacology 99:285–300

Article  PubMed  PubMed Central  Google Scholar 

Chabot-Doré AJ, Schuster DJ, Stone LS, Wilcox GL (2015b) Analgesic synergy between opioid and α2 -adrenoceptors. Br J Pharmacol 172:388–402

Article  PubMed  Google Scholar 

Choi S, Irwin MR, Kiyatkin EA (2023) Xylazine effects on opioid-induced brain hypoxia. Psychopharmacology 240:1561–1571

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi S, Irwin MR, Noya MR, Shaham Y, Kiyatkin EA (2024) Combined treatment with Naloxone and the alpha2 adrenoceptor antagonist Atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model. Neuropsychopharmacology 49:1104–1112

Article  CAS  PubMed  Google Scholar 

Crystal R, Ellison M, Purdon C, Skolnick P (2024) Pharmacokinetic properties of an FDA-approved intranasal Nalmefene formulation for the treatment of opioid overdose. Clin Pharmacol Drug Dev 13:58–69

Article  CAS  PubMed  Google Scholar 

Di Trana A, Di Giorgi A, Carlier J, Serra F, Busardò FP, Pichini S (2024) Tranq-dope: the first fatal intoxication due to xylazine-adulterated heroin in Italy. Clin Chim Acta 561:119826

Article  PubMed  Google Scholar 

Drug Enforcement Agency UDoJ (2023) DEA reports widespread threat of Fentanyl mixed with Xylazine

Duong C, Lovett C, Downes MA, Isbister GK (2023) Reality of clonidine poisoning in children and adolescents. J Paediatr Child Health 59:827–832

Article  PubMed  PubMed Central  Google Scholar 

Edinoff AN, Sall S, Upshaw WC, Spillers NJ, Vincik LY, De Witt AS, Murnane KS, Kaye AM, Kaye AD (2024) Xylazine: A drug adulterant of clinical concern. Curr Pain Headache Rep 28:417–426

Article  PubMed  PubMed Central  Google Scholar 

Ellison M, Hutton E, Webster L, Skolnick P (2024) Reversal of Opioid-Induced respiratory depression in healthy volunteers: comparison of intranasal Nalmefene and intranasal Naloxone. J Clin Pharmacol 64:828–839

Article  CAS  PubMed  Google Scholar 

Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C (2022) Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend 233:109380

Article  PubMed  PubMed Central  Google Scholar 

Friedman J, Molina CA, Koncsol AJ, Romero R, Godvin ME, Jalayer E, Davila S, Arellano O, Cowan A, Hurley B, Shover CL (2025) Xylazine prevalence and concentration in the Los Angeles Fentanyl market, 2023–2025. Drug Alcohol Depend Rep 16:100364

Article  PubMed  PubMed Central  Google Scholar 

Gallanosa AG, SD A, R. SJ, and, Morris DL (1981) Human xylazine overdose: A comparative review with Clonidine, Phenothiazines, and tricyclic antidepressants. Clin Toxicol 18:663–678

Article  CAS  PubMed  Google Scholar 

Glass MJ, Pickel VM (2002) Alpha(2A)-adrenergic receptors are present in mu-opioid receptor containing neurons in rat medial nucleus tractus solitarius. Synapse 43:208–218

Article  CAS  PubMed  Google Scholar 

Hoffman RS (2023) Closing the xylazine knowledge gap. Clin Toxicol 61:1013–1016

Article  CAS  Google Scholar 

Hoffmann U, Meister CM, Golle K, Zschiesche M (2001) Severe intoxication with the veterinary tranquilizer xylazine in humans. J Anal Toxicol 25:245–249

Article  CAS  PubMed  Google Scholar 

Holt AC, Schwope DM, Le K, Schrecker JP, Heltsley R (2023) Widespread distribution of xylazine detected throughout the united States in healthcare patient samples. J Addict Med 17:468–470

Article  PubMed  PubMed Central  Google Scholar 

Iacopetta D, Catalano A, Aiello F, Andreu I, Sinicropi MS, Lentini G (2025) Xylazine, a drug adulterant whose use is spreading in the human population from the U.S. To the U.K. and all europe: an updated review. Appl Sci 15:3410

Article  CAS  Google Scholar 

James JC, Thrush JR, Yusufali TM, Shaw HE, Avram M, Moran JH, Fantegrossi WE (2025) Synthetic cannabinoid receptor agonists exacerbate fentanyl-elicited respiratory depression and confer resistance to Naloxone rescue in mice. Drug Alcohol Depend 272:112672

Article  CAS  PubMed  PubMed Central  Google Scholar 

Johnson J, Pizzicato L, Johnson C, Viner K (2021) Increasing presence of xylazine in heroin and/or Fentanyl deaths, Philadelphia, Pennsylvania, 2010–2019. Inj Prev 27:395–398

Article  PubMed  Google Scholar 

Justice Department DEA (2022) Growing threat of xylazine and its mixture with illicit drugs. DEA Joint Intelligence Report

Kacinko SL, Mohr ALA, Logan BK, Barbieri EJ (2022) Xylazine: Pharmacology review and prevalence and drug combinations in forensic toxicology casework. J Anal Toxicol 46:911–917

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