Clinical Manifestations of Xylazine Exposure Among People Who Use Drugs: Overdose, Wounds, and Withdrawal

Introduction: Xylazine, a non-opioid veterinary sedative, has been increasingly detected in the illicit drug supply in the United States, creating clinical challenges for people who use drugs (PWUD). Although xylazine exposure has been linked to naloxone-resistant overdose, chronic skin wounds, and withdrawal symptoms, little is known about how these manifestations co-occur in community samples. Methods: A community-based cross-sectional survey was administered to 948 PWUD recruited through harm reduction programs, community health centers, and street outreach in Cumberland County, North Carolina. The survey assessed suspected xylazine-related overdose, naloxone reversal difficulty, skin wound presence and severity, and withdrawal symptoms. Results: Approximately 50% reported at least one suspected xylazine-related overdose. Among those reporting overdose, over 80% reported difficulty reversing overdose with naloxone. Nearly 40% reported persistent skin wounds associated with suspected xylazine exposure, with about 70% rating wounds as moderate or severe. Withdrawal symptoms were common across symptom categories. Overdose frequency was positively associated with withdrawal severity, wound presence and severity, whereas overdose reversal difficulty was negatively associated with withdrawal severity and positively associated with wound presence and severity. However, all associations were small in magnitude. Conclusions: These findings indicate high rates of suspected xylazine-related overdose, naloxone reversal difficulty, skin wounds, and withdrawal symptoms among PWUD, with weak intercorrelations across clinical domains. Current opioid-focused management approaches may be insufficient in the context of xylazine contamination, highlighting the need for targeted clinical guidelines for overdose response, wound care, and withdrawal management.