Xylazine Exposure and Association With Early Physiological and Withdrawal Symptoms in People With Opioid Use Disorder

OBJECTIVES: The prevalence of xylazine, an agonist at the alpha-2 adrenergic receptor often used in veterinary medicine, has increased in the illicit opioid drug supply. Case series and survey data suggest that xylazine may increase the nature and severity of opioid withdrawal. We sought to evaluate the association between quantified levels of xylazine exposure and withdrawal symptoms in people undergoing opioid withdrawal. METHODS: People (n=36; 11 female) with opioid use disorder and physical dependence were enrolled in two harmonized clinical trials. Urine specimens were collected at admission to a residential unit and were analyzed for xylazine, fentanyl, and its inactive metabolite norfentanyl. Opioid withdrawal and physiological effects were collected during stabilization on oral hydromorphone without illicit opioid access. RESULTS: Urinary xylazine was detected in 69% of samples with concentrations ranging from 5.7 to 15481.1 ng/mL. Among participants with detectable urinary xylazine, higher xylazine concentrations were significantly associated with higher systolic blood pressure (b=7.68 [2.03, 13.33], P=0.011) and COWS total scores (b=1.53 [0.17, 2.88], P=0.029). No significant differences in blood pressure or COWS were observed between participants with and without xylazine detected. CONCLUSIONS: Potential rebound hypertensive effects following xylazine exposure were observed, consistent with alpha-2 adrenergic mechanisms, which may be accompanied by an exacerbated withdrawal syndrome. Continued preclinical and clinical evaluation of strategies are needed to understand how co-exposure to drug adulterants like xylazine influences withdrawal expression and the utility of existing pharmacological approaches for withdrawal management in clinical settings.