Xylazine, an alpha-2 receptor agonist used in veterinary medicine for its sedative and muscle relaxant effects, has been reported periodically in forensic toxicology casework since the 1980s. Xylazine is not approved for human use but has seen more widespread positivity as a result of its use as an adulterant in illicit opioids, known as “Tranq Dope”, in the United States. Xylazine has been designated a toxic adulterating substance, due to its causation of hypotension and bradycardia, CNS and respiratory depression, and the development of skin lesions, slowed wound healing and frequent, persistent or worsening skin infections in chronic intravenous drug users. These effects have contributed to a marked increase poly drug deaths over the last three years involving xylazine. The aim of this study was to evaluate xylazine positivity in death investigation casework, document concentrations of the drug in fatalities and compare those to concentrations in living subjects in impaired driving cases, evaluate patterns of combined drug use, and to provide guidance on the incorporation of xylazine as a finding into cause of death determination in drug overdose fatalities. Xylazine is a basic drug with a molecular weight of 220.34 Daltons, and is easily recovered in basic blood extracts, and detected either in gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry (LCMSMS) workflows. In our laboratory, screening was performed by liquid chromatography time of flight mass spectrometry (LCTOF), with confirmation and quantitation by LCMSMS, with screening and confirmatory cut-offs of 5 ng/mL. he prevalence and concentrations of xylazine in 2.5-years of driving-under-the-influence-of-drugs (DUID) and medicolegal-death-investigation (MDI) cases (January 2019-June 2021) was investigated. Of over 170,000 cases screened for xylazine during this time frame, 97% were classified as MDI. During the study period, quantitative xylazine results were reported for 3,215 of the 3,691 cases which screened positive. The prevalence and geographical spread of xylazine increased and included 37 US States, three Canadian provinces and Puerto Rico. Overall, 2.8% of DUID, and 2.1% of MDI cases screened positive for xylazine with concentrations of 5.1–450 ng/mL (mea n = 36 ng/mL) and 5.0–11,000 ng/mL (mea n = 41 ng/mL), respectively. Two MDI cases which had xylazine concentrations of 9,100 and 11,000 ng/mL were drug overdose suicides that did not involve any opioids. Opioids, primarily fentanyl and/or a fentanyl byproduct/metabolite were detected in 100% of xylazine positive DUID cases, and all but two MDI cases. After opioids, stimulants, phyto-cannabinoids and benzodiazepines were the most common drug classes detected in conjunction with xylazine in both DUID and MDI casework. The primary difference in these cases was the type of stimulant detected with cocaine (including cocaine metabolites) being the most commonly detected stimulant in MDI cases, while methamphetamine was more commonly detected in DUID cases. In summary, xylazine exposure in opioid drug users continued to increase during the study period, with most exposure resulting from the adulteration of illicit opioids, although suicide cases involving ingestion of xylazine alone were reported. There is extensive overlap in the concentrations of xylazine between living and deceased individuals making it challenging to interpret the role of the drug in MDI or DUID cases without careful consideration of other case information. The interaction of effects of xylazine and opioids however make it advisable to include xylazine in the drugs contributing to death in cases where both are detected.
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