"Xylazine, an alpha-2 receptor agonist, is used in veterinary medicine as a sedative and muscle relaxant; it is not approved for use in humans. However, reports of adulteration of illicit opioids with xylazine have been increasing in the United States (1–3). In humans, xylazine can cause respiratory depression, bradycardia, and hypotension (4).

"In June 2020, the presence of xylazine, a veterinary sedative, was first detected as an active cut in heroin/fentanyl MADDS samples but in very low or trace quantities from 2 sites. By fall 2020, the ratio of xylazine to other active drugs had increased, and by the end of the year, xylazine was identified in 6.3% of MADDS samples (13.4% of fentanyl, 22.2% of heroin) and detected at all sites. At the close of 2020, some samples were found to contain more xylazine than fentanyl (eg, https://DrugsData.org/9661).

"Globally, community drug checking programs (CDCPs) allow people to submit drug samples for chemical analysis.

"The Massachusetts Drug Supply Data Stream (MADDS) is the country's first statewide community drug checking program. Founded on public health-public safety partnerships, MADDS collects remnant drug packaging and paraphernalia with residue from people who use drugs and noncriminal samples from partnering police departments. MADDS tests samples using simultaneous immunoassay fentanyl test strips, Fourier-transform infrared spectrometry (FTIR), and off-site laboratory testing by gas chromatography-mass spectrometry (GC/MS).

"Xylazine is currently not a scheduled substance under the United States Controlled Substances Act, though some efforts are underway to change this (Drug Enforcement Administration, 2021; Murphy, n.d.).

"We summarize longitudinal, recent, and geographically specific evidence describing how xylazine is increasingly implicated in overdose deaths in jurisdictions spanning all major US regions and link it to detailed ethnographic observations of its use in Philadelphia open-air narcotics markets. Xylazine presence in overdose deaths grew exponentially during the observed period, rising nearly 20-fold between 2015 and 2020.

"In overdose data from 10 jurisdictions – representing all four major US census regions – xylazine was found to be increasingly present in overdose mortality (Fig. 1). The highest prevalence was observed in Philadelphia, (with xylazine present in 25.8% of overdose deaths in 2020), followed by Maryland (19.3% in 2021) and Connecticut (10.2% in 2020). In 2021, xylazine prevalence also grew substantially in Jefferson County, Alabama, reaching 8.4% of overdose fatalities.

"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.

"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.

"Importantly, our results show that evidence of injection was more prevalent among decedents with xylazine and heroin and/or fentanyl detections.