Postmortem Detection of Xylazine in Fentanyl- and Opioid-related Overdose Deaths: A Systematic Review of Medicolegal Evidence

Xylazine, a veterinary α2-adrenergic agonist with no approved human use, has increasingly emerged as an adulterant in illicit fentanyl-containing drug supplies in the United States and is now frequently detected in overdose fatalities, raising important clinical, forensic, and public health concerns related to polysubstance toxicity and medico-legal cause-of-death determination. Evidence regarding postmortem xylazine detection remains fragmented across jurisdictions and study designs, prompting this systematic review to synthesize medico-legal findings on its prevalence, polysubstance patterns, temporal and geographic trends, and forensic interpretation. A systematic review was conducted following PRISMA 2020 guidelines, with searches of PubMed/MEDLINE, Embase, Scopus, and Web of Science for observational studies published from 2018 onward that reported postmortem detection of xylazine in opioid- or fentanyl-involved overdose deaths based on medico-legal investigations. Two reviewers independently screened studies, extracted data, and assessed risk of bias, and due to substantial heterogeneity in study design, testing practices, and outcome definitions, findings were synthesized narratively. Eleven observational studies conducted in the United States, covering data from 2010 to 2023, met inclusion criteria. Xylazine was detected almost exclusively in fentanyl-involved overdose deaths, with prevalence varying widely by jurisdiction and time period, increasing from approximately 2% in earlier years to over 30% in some regions by 2019–2021. Xylazine-positive deaths consistently demonstrated extensive polysubstance involvement, including near-universal fentanyl co-detection and frequent presence of stimulants, benzodiazepines, alcohol, and other opioids. Reported xylazine concentrations showed wide variability and overlapped with non-fatal exposures, limiting causal inference. Temporal analyses indicated rapid increases in detection after 2019, while spatial patterns showed geographic clustering. Definitions of xylazine exposure varied substantially, with inconsistent differentiation between analytical detection and causal involvement in death certification. Overall, postmortem evidence indicates that xylazine has become a significant and geographically heterogeneous component of fentanyl-related overdose mortality in the United States, typically occurring within complex polysubstance profiles. Interpretation of its contribution to death is limited by inconsistent testing practices, variable definitions, and insufficient quantitative data, highlighting the need for standardized postmortem toxicosurveillance, routine inclusion of xylazine in toxicology panels, and clearer distinction between detection and causal involvement to improve forensic interpretation, surveillance accuracy, and public health response.