PROJECT ABSTRACT People who use opioids (PWUO) from the unregulated drug market have little control over the presence of unwanted substances within the drug products they obtain. Xylazine, an animal tranquilizer, has been increasingly detected in opioids throughout the eastern United States, Puerto Rico, and Canada. Xylazine produces a more potent high than heroin alone, potentiates and prolongs the effects of opioids, and may increase the risk of opioid-related overdose or death. Xylazine decreases the release of excitatory neurotransmitters in the central nervous system (CNS) and peripherally acts as a vasoconstrictor. This can lead to sedation, muscle relaxation, respiratory depression, and hypotension. Moreover, the long, sedating effects of the drug places PWUO at increased risk of sexual assault. Xylazine is also linked to development of severe infected ulcerating skin lesions in both injection and non-injection sites. Of concern, xylazine is rapidly spreading across the United States, with a five times higher presence in national overdose deaths in 2020 compared with 2015. Spread has been particularly rapid in the Eastern and Northeast parts of the country. To date, the United States lacks a robust national public health response to xylazine. As xylazine emerges in drug markets in other parts of the country, there is an urgent need for a rapid response to prevent adverse outcomes for PWUO nationally. In response to this rapid rise of xylazine in Philadelphia, PWUO have been seeking strategies to mitigate xylazine harms. To date, these have not been rigorously explored nor disseminated. Our research indicates that PWUO in Philadelphia desire tailored harm reduction strategies to avoid xylazine. The objective of this proposal is to leverage the knowledge and experiences of PWUO in Philadelphia, an early locus of xylazine emergence, alongside national content experts to develop and test person-centered approaches to mitigate the impact of xylazine as it emerges as an adulterant in other markets nationally. We will do this through 1) engaging PWUO and other content experts to explore current experiences with xylazine adulteration, 2) developing actionable interventions to address emerging xylazine adulterations, and 3) presenting these draft interventions in emerging xylazine markets in Massachusetts for purposes of feedback and to inform refinement. Our long-term goal is to translate PWUO needs into PWUO- centered interventions, creating key harm reduction messaging to mitigate the public health harms of xylazine adulteration observed in Philadelphia. The proposed work is expected to significantly contribute to informing optimal harm reduction interventions to mitigate harms associated with xylazine adulteration that can be rapidly implemented. It is urgent and timely, as xylazine is currently rapidly spreading across the country, and thus these interventions are imminently needed to prevent unnecessary harm.

PROJECT NARRATIVE Xylazine, an animal tranquilizer, has been increasingly detected in opioids throughout the eastern United States, Puerto Rico, and Canada. Xylazine may increase the risk of opioid-related overdose or death and is associated with the development of severe infected ulcerating skin lesions in both injection and non-injection sites. This project is expected to significantly contribute to informing optimal harm reduction interventions that can be rapidly implemented to mitigate harms associated with xylazine adulteration.