"Here, we report the first xylazine dose-response locomotor study in male and female mice as well as the first assessment of adrenergic- and opioid-receptor antagonist-precipitated withdrawal symptoms following, xylazine, fentanyl, and xylazine/fentanyl administration in mice. These experiments show that male and female mice are differentially sensitive to xylazine. We find female mice are less sensitive to the motor-suppressing effects of xylazine contrary to the recent findings in rats reported by Khatri et al.

"Naloxone has been used as an antidote to opioids for over 50 years, and the drug has been readily available as a parenteral formula. Naloxone acts as a pure μ-opioid receptor competitive antagonist and is instrumental in preventing accidental overdose of opioids. Due to its effectiveness in preventing death due to opioid overdose, the federal government has recommended that naloxone should be available over-the-counter at most pharmacies.

"Rescue breathing for persons suspected of having an opioid overdose has considerable support among harm reduction programs and in the medical literature.¹⁸ This preference is based on the physiology of an opioid overdose. Opioids suppress the autonomic respiratory response to declining oxygen saturation and rising carbon dioxide levels. If this response remains suppressed, the consequences are hypoxia, acidosis, organ failure and death. The majority, if not all, of the community-based naloxone programs in the United States train responders in a rescue breathing technique.

"Relevant literature on overdose response included 3 clinical guidelines,1,21,32 3 grey literature reports (a rapid review,36 an evidence brief37 and a report of a technical working group on resuscitation tra

"Historically, there have been a number of US overdose events where a fentanyl was implicated [14▪▪,15▪]. However, the wave of overdose deaths attributed to illicit fentanyls since 2013 is unprecedented. The current rise of fentanyls is considered a positive supply shock, i.e., a supply driven more than demand-driven event [16].

"Our findings suggest that the increase in the state’s fatal drug overdose rate after implementation of M110 should not be attributed to drug decriminalization, and the state’s contemporaneous transition to a fentanyl-based unregulated drug market is the more plausible explanation. We also observed that the contemporaneous recriminalization of drug possession in Washington coincided with increased drug overdose deaths.

"This study examined the performance of BTNX XTS [Xylazine Test Strips] for testing drug residue. The detection of xylazine’s presence was lower than expected although increased if xylazine was the sample major psychoactive component. Our findings suggest further research and field testing are needed to develop rapid XTS and procedures for residue testing in point-of-care DCS.

"Xylazine is a non-opiate sedative, analgesic, and muscle relaxant that shares its drug class (α2-adrenoreceptor agonists) with medications such as clonidine, lofexidine, tizanidine, and dexmedetomidine [6].

"Prior to the widespread availability of xylazine in the Philadelphia drug supply, it was often mentioned in passing by residents of the majority Puerto Rican neighborhood where our fieldwork was based as a powerfully psychoactive additive ‘“back on the Island”.’ Xylazine was occasionally detected in fatal overdoses in Philadelphia as early as 2006 (Wong et al., 2008), but it was not common knowledge among PWID.

"At least a decade after Xylazine became a fixture in Puerto Rico, it entered the street opioid supply in Philadelphia as a more prevalent additive in the mid-2010s. The shift was noted by PWID, as well as harm reductionists and city public health officials (Johnson et al., 2021). PWID began to describe xylazine – often referred to as tranq – as a known element of specific ‘stamps’ or brands of opioid products in the illicit retail market.