Xylazine potentiates the lethal but not the rewarding effects of fentanyl in mice

• Published in: Drug and alcohol dependence 2023-12, Vol.253, p.110993-110993, Article 110993
• Main Authors: Acosta-Mares, Palmira, Violante-Soria, Valeria, Browne, Thom, Cruz, Silvia L.
• Format: Article
• Language: English
• Subjects: Conditioned-place preference; Fentanyl; Naloxone; Opioid Overdose; Xylazine; Yohimbine
• ISSN: 0376-8716; 1879-0046
• DOI: 10.1016/j.drugalcdep.2023.110993

Fentanyl is commonly laced with xylazine. People who use this combination report heightened effects, but it also increases death risk. Although no medication has been approved to counteract overdoses produced by fentanyl and xylazine, naloxone is frequently used. This paper studies the preclinical rewarding and lethal effects of fentanyl combined with xylazine and the efficacy of yohimbine or naloxone to prevent death. Male Swiss Webster mice were treated with (in mg/kg, i.p.) xylazine (0.3, 1, 3, or 5.6), fentanyl (0.01, 0.3, or 0.1), or 1 xylazine plus 0.01 (non-effective) or 0.1 (effective) fentanyl doses during the conditioned-place preference (CPP) test. In addition, independent groups received (in mg/kg, i.p.): xylazine (31.6, 60, 74.2, or 100), fentanyl (3.1 or 10), or both substances at two doses: 31.6 xylazine + 3.1 fentanyl, or 60 xylazine + 10 fentanyl to analyze lethal effects. We determined whether yohimbine or naloxone (each medication tested at 10 or 30mg/kg) could prevent the lethality produced by fentanyl/xylazine combinations. Female mice were also tested in key experiments. Xylazine neither induced CPP nor altered fentanyl’s rewarding effects. In contrast, lethality was potentiated when fentanyl was combined with xylazine. Naloxone, but not yohimbine, effectively prevented the lethality of the fentanyl/xylazine combinations. At the doses tested, xylazine does not increase the rewarding effect of fentanyl on the CPP in male mice but potentiates the risk of fatal overdose in male and female mice. A high naloxone dose prevents death induced by coadministration of fentanyl and xylazine in both sexes. •Xylazine was not rewarding, nor did it alter fentanyl-induced reward in the CPP test.•Xylazine significantly potentiates fentanyl’s lethal effects in male and female mice.•Yohimbine does not prevent death induced by a fentanyl + xylazine combination.•A high naloxone dose prevents death induced by fentanyl + xylazine.