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The United States drug overdose crisis continues to evolve. Xylazine has been increasingly identified as an adulterant in illicit opioid supplies. The incorporation of novel adulterants, like xylazine, into the illicit drug supply adds complexity to post-mortem toxicology testing, public health messaging, substance use mitigation, and the treatment of people who use drugs. We assessed trends, decedent characteristics, drug co-detection, and blood concentrations of xylazine-positive post-mortem cases in Michigan. We utilized a toxicology testing program capable of detecting several opioids and non-opioids in post-mortem blood samples within 72 hours. A total of 279 deaths were xylazine-positive between October 2019 and June 2023, with 100 percent positive for fentanyl. Only 30 percent of xylazine-involved samples were positive for naloxone, while 21.2 percent of xylazine-negative and opioid-positive samples were positive for naloxone. The percentage of xylazine-positive deaths increased from 3.2 percent in 2021 to 4.7 percent in January–June 2023. A median of five total drug groups were present among xylazine-positive deaths. Post-mortem xylazine concentrations for 55 decedent blood samples ranged from 5.2 to 200 µg/L. Our study demonstrated increases in xylazine detection among post-mortem cases. Our findings are consistent with national trends of increasing xylazine presence among drug-involved deaths. Our range of detected post-mortem xylazine blood concentrations was consistent with what has been reported in previous literature. Fentanyl was detected in 100 percent of xylazine-positive overdose deaths. Naloxone detection was relatively low, highlighting the continued importance of increasing naloxone access and distribution. Deaths associated with xylazine often involved multiple other drugs. Limited human clinical xylazine research precludes accurate interpretation and attribution of causality from these data. Overdose-related deaths with xylazine detection are increasing in Michigan and across the United States. Further clinical and toxicological research can help contextualize the clinical significance of xylazine in opioid overdose, clarify epidemiologic and clinical research, and inform appropriate public health messaging. [ABSTRACT FROM AUTHOR]

Illicit opioids, consisting largely of fentanyl, novel synthetic opioids, and adulterants, are the primary cause of drug overdose fatality in the United States. Xylazine, an alpha-2 adrenergic agonist and veterinary tranquilizer, is being increasingly detected among decedents following illicit opioid overdose. Clinical outcomes in non-fatal overdose involving xylazine are unexplored. Therefore, among emergency department patients with illicit opioid overdose, we evaluated clinical outcome differences for patients with and without xylazine exposures. This multicenter, prospective cohort study enrolled adult patients with opioid overdose who presented to one of nine United States emergency departments between 21 September 2020, and 17 August 2021. Patients with opioid overdose were screened and included if they tested positive for an illicit opioid (heroin, fentanyl, fentanyl analog, or novel synthetic opioid) or xylazine. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect current illicit opioids, novel synthetic opioids, xylazine and adulterants. Overdose severity surrogate outcomes were: (a) cardiac arrest requiring cardiopulmonary resuscitation (primary); and (b) coma within 4 h of arrival (secondary). Three hundred and twenty-one patients met inclusion criteria: 90 tested positive for xylazine and 231 were negative. The primary outcome occurred in 37 patients, and the secondary outcome occurred in 111 patients. Using multivariable regression analysis, patients positive for xylazine had significantly lower adjusted odds of cardiac arrest (adjusted OR 0.30, 95% CI 0.10–0.92) and coma (adjusted OR 0.52, 95% CI 0.29–0.94). In this large multicenter cohort, cardiac arrest and coma in emergency department patients with illicit opioid overdose were significantly less severe in those testing positive for xylazine. [ABSTRACT FROM AUTHOR]

• Xylazine is a quickly-spreading, veterinary sedative in the illicit drug supply. • We synthesized trends in all-time U.S. policy responses to human xylazine consumption. • We identified 58 unique policy measures; 9 federal and 49 in 24 states. • 64 % (n = 37) were introduced in 2023. Most proposed penalties for possession (n = 34, 59 %). • Policy measures also proposed new surveillance methods and resources and public awareness campaigns. Xylazine is a veterinary sedative that is quickly spreading in the U.S. illicit drug supply and is increasingly associated with fatal overdoses and severe wounds. In response, xylazine has been deemed an emerging public health threat and several policy initiatives have been introduced to combat its spread and negative broad health impact. We aimed to synthesize trends in all-time U.S. policy responses to xylazine in the drug supply. In April 2024, we systematically identified and categorized proposed and enacted policy initiatives that related to human xylazine consumption by searching LexisNexis and Thomas Reuters Westlaw legal databases. Of 58 unique policy initiatives, most were introduced in 2023 (n = 37/58, 64 %) and concentrated in Northeastern states. Penalties for xylazine possession, often tied to state drug scheduling changes, were the most common provision (n = 34/58; 59 %) and Schedule III was the most frequently proposed scheduling level (n = 17/30; 57 %). Other provisions included proposals to enhance: test strip access (n = 11/58; 19 %), public awareness and education (n = 3/58; 5 %), xylazine-specific research (n = 4/58; 7 %), and surveillance (n = 8/58; 14 %). U.S. state and federal policy responses to xylazine grew rapidly in 2023, were most concentrated in states affected most by xylazine, and scheduling was the most commonly proposed policy approach. Research measuring policy effects should be prioritized as policies are implemented. [ABSTRACT FROM AUTHOR]

Xylazine has been increasingly detected in illegally manufactured fentanyl (IMF) products and overdose deaths in the United States; most xylazine-involved overdose deaths involve IMF. A convenience sample of U.S. adults aged ≥18 years was identified from those evaluated for substance use treatment during July 2022-September 2023. Data were collected using the Addiction Severity Index-Multimedia Version clinical assessment tool. Among 43,947 adults, 6,415 (14.6%) reported IMF or heroin as their primary lifetime substance-use problem; 5,344 (12.2%) reported recent (i.e., past-30-day) IMF or heroin use. Among adults reporting IMF or heroin as their primary lifetime substance-use problem, 817 (12.7%) reported ever using xylazine. Among adults reporting recent IMF or heroin use, 443 (8.3%) reported recent xylazine use. Among adults reporting IMF or heroin use recently or as their primary lifetime substance-use problem, those reporting xylazine use reported a median of two past nonfatal overdoses from any drug compared with a median of one overdose among those who did not report xylazine use; as well, higher percentages of persons who reported xylazine use reported other recent substance use and polysubstance use. Provision of nonjudgmental care and services, including naloxone, wound care, and linkage to and retention of persons in effective substance use treatment, might reduce harms including overdose among persons reporting xylazine use., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

The article discusses the detection and involvement of the drug xylazine in drug overdose deaths in the United States in 2019. Xylazine, not approved for human use, was found as an adulterant in illicit opioids, potentially increasing the risk of fatal overdose. The study shows that xylazine was present in a small percentage of overdose deaths, highlighting the need for continued surveillance and standardized testing protocols to understand its impact on the overdose epidemic.

Importance: Xylazine is increasingly reported in street drugs and fatal overdoses in the US, yet state-level data are limited, hampering local public health responses., Objective: To gather available state-level data on xylazine involvement in overdose deaths and in forensic drug reports., Design, Setting, and Participants: This cross-sectional study was a secondary analysis of 2019 to 2022 data from the National Forensic Laboratory Information System (NFLIS), National Center for Health Statistics, and individual states' medical examiner or public health agency reports. Data were analyzed from August to October 2023., Exposure: State., Main Outcomes and Measures: Yearly xylazine-related overdose deaths per 100 000 residents; xylazine NFLIS drug reports, both per 100 000 residents and as a percentage of all NFLIS drug reports (from samples of drugs seized by law enforcement and analyzed by NFLIS-participating laboratories)., Results: A total of 63 state-years were included in analyses of mortality rates, while 204 state-years were included in analyses of NFLIS reports. According to the publicly available data compiled in this study, at least 43 states reported at least 1 xylazine-related overdose death from 2019 to 2022, yet yearly totals of xylazine-related deaths were available for only 21 states. Of states with data available, xylazine-involved overdose death rates were highest in Vermont (10.5 per 100 000 residents) and Connecticut (9.8 per 100 000 residents) in 2022. In 2019, 16 states had zero xylazine reports included in NFLIS reports; in 2022, only 2 states had zero xylazine reports and all but 3 states had recorded an increase in xylazine's representation in NFLIS reports. In 2022, xylazine represented 16.17% of all NFLIS reports in Delaware and between 5.95% and 7.00% of NFLIS reports in Connecticut, Maryland, District of Columbia, New Jersey, and Rhode Island, yet less than 1.0% of NFLIS reports in 35 different states., Conclusions and Relevance: In this cross-sectional study of publicly available data on fatal overdoses and drugs analyzed by forensic laboratories, xylazine's reported presence in overdose deaths and forensic reports was concentrated in the eastern US yet extended across the country to encompass nearly all states. In spite of xylazine's geographic reach, yearly state-level numbers of xylazine-related overdose deaths were publicly available for less than half of all states.

Abstract: In response to the rapid escalation in the detection of xylazine in the unregulated drug supply, in April 2023, the White House designated fentanyl contaminated with xylazine an "emerging threat." The National Institute on Drug Abuse Center for Clinical Trials Network convened a multidisciplinary meeting of stakeholders, federal staff members, researchers, and clinicians caring for patients with fentanyl and xylazine exposures. This convening focused on the most critical areas of concern with the goal of describing current practices and a xylazine-fentanyl research agenda. Discussions focused on the domains of epidemiology and laboratory detection, xylazine withdrawal and overdose, and dermal manifestations. The authors were involved in planning and moderating the program and providing a summary of the proceedings., Competing Interests: KH’s spouse is eligible for a defined benefit plan through Pfizer from previous employment. The other authors report no conflicts of interest., (Copyright © 2023 American Society of Addiction Medicine.)

Xylazine, a sedative analgesic drug approved as an animal tranquilizer but not for human use, has become an adulterant in the illicit opioid marketplace in North America. Recently declared an emerging health threat in the U.S., the prevalence of xylazine in overdose deaths increased 5.5-fold between 2019 and 2021. More information is needed about the impact of xylazine on opioid users and harm reduction service providers. The impact of xylazine adulteration was triangulated through examination of (1) opioid overdose fatalities in Connecticut between 2017 and 2021 reported by the Office of the Chief Medical Examiner data, (2) a convenience survey of people in Connecticut who use drugs (PWUD) regarding their knowledge of and attitude about the local illicit drug supply, and (3) semi-structured interviews of harm reduction service providers in Connecticut and Philadelphia in response to prompts on the impacts of and responses to xylazine adulteration. The presence of fentanyl or its analogues in fatal opioid overdoses was a statistically significant predictor of xylazine presence [OR = 25.0, 95%CI (10.7,81.1)] as was being Hispanic [OR = 1.36, 95%CI (1.03,1.77)]. A survey of people who used drugs revealed that 43% (n = 286) were concerned that the drug supply was always unpredictable. Three-quarters of respondents were aware of xylazine and two-thirds would use a xylazine test strip if one was available. Respondents who identified as White, Hispanic were most likely to be aware of xylazine, to have used a fentanyl test strip, and to be interested in a xylazine test strip. Respondents who injected drugs were 3.6-fold more likely than those who did not inject to endorse an interest in a xylazine test strip. Harm reduction service providers were cognizant of a range of problems surrounding the use and injection of xylazine. Although they reported implementing practices to better respond to xylazine harms, they recognized the absence of solutions to many of the problems encountered. The prevalence of xylazine has expanded, especially in combination with fentanyl. Harm reduction education efforts with fidelity to best practices have emerged, but the harms persist and community prevention needs are largely unmet. [ABSTRACT FROM AUTHOR]

The article discusses the detection and involvement of xylazine, a drug primarily used in veterinary medicine, in drug overdose deaths in the United States in 2019. It mentions that Xylazine, when mixed with illicit opioids like fentanyl or heroin, may potentiate sedation and respiratory depression, leading to an increased risk of fatal overdose. The study found that xylazine was detected in a small percentage of overdose deaths.drug overdose.

Objectives: Xylazine is a tranquilizer commonly added into the illicit drug supply and a likely contributor to overdoses because it does not respond to naloxone reversal. The objective of this study was to perform a retrospective data analysis on xylazine-positive samples collected from patients in various outpatient healthcare settings to illustrate geographic distribution and common copositive substances, which may also contribute to risk of adverse events., Methods: Samples for which providers ordered testing for xylazine were subjected to enzymatic hydrolysis, extracted, and analyzed using liquid chromatography-tandem mass spectrometry. Retrospective analysis was performed on xylazine-positive samples collected from April 2021 to March 2022, to include geographic location and copositive substances., Results: Xylazine was identified in 413 of 59,498 samples from adults aged 20-73 years and originated from 25 of the 39 states where xylazine testing was ordered. The most common routine substances detected with xylazine were fentanyl, buprenorphine, naloxone, cocaine, d -methamphetamine, and delta-9-tetrahydrocannabinol. The most common designer drugs detected included fentanyl analogs, isotonitazene, and designer benzodiazepines., Conclusions: Xylazine is geographically spread throughout the United States, indicative of a wide incorporation into the illicit drug supply. These findings differ from previous studies in that these samples originated from healthcare providers in routine care settings, where other reports typically involve overdose deaths. This analysis illustrates that routine testing for xylazine in outpatient settings can afford providers the opportunity to educate individuals and adjust harm reduction measures to potentially mitigate overdose risk., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

In 2022, provisional data indicated that more than two thirds (68%) of the reported 107,081 drug overdose deaths in the United States involved synthetic opioids other than methadone, principally illicitly manufactured fentanyls (IMFs) (1). Xylazine, a nonopioid sedative not approved for human use and with no known antidote, has been increasingly detected in IMF products in the U.S. drug supply* and in IMF-involved overdose deaths (2). Limited studies suggest xylazine can cause central nervous system depression, respiratory depression, bradycardia, and hypotension in humans (3,4); chronic use might lead to severe withdrawal symptoms † as well as skin ulcerations (4). This report uses data from CDC's State Unintentional Drug Overdose Reporting System (SUDORS) to describe IMF-involved § overdose deaths with and without xylazine detected that occurred during January 2019-June 2022. Among 21 jurisdictions, which included 20 states and the District of Columbia, the monthly percentage of IMF-involved deaths with xylazine detected increased 276%, from 2.9% to 10.9%. Among IMF-involved deaths during January 2021-June 2022 in 32 jurisdictions, xylazine was detected in a higher percentage of jurisdictions in the Northeast U.S. Census Bureau region; listing detected xylazine as a cause of death varied across jurisdictions. Expanded postmortem and illicit drug product testing for xylazine is needed to clarify prevalence in drug supplies; further investigation of xylazine's effects on humans is necessary to characterize morbidity and overdose risk. It is important for overdose prevention and response messages to highlight the potential presence of xylazine in IMF products and emphasize the need for respiratory and cardiovascular support to address the sedative effects of xylazine., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Xylazine is a nonopioid veterinary anesthetic and sedative that is increasingly detected in the illicit drug supply in the United States. Data indicate a striking prevalence of xylazine among opioid-involved overdose deaths. The emergence of xylazine in the illicit drug supply poses many unknowns and potential risks for people who use drugs. The public health system needs to respond by increasing testing to determine the prevalence of xylazine, identifying its potential toxicity at various exposure levels, and taking mitigating action to prevent harms. Currently, there is little testing capable of identifying xylazine in drug supplies, which limits the possibility of public health intervention, implementation of harm reduction strategies, or development of novel treatment strategies. ( Am J Public Health . 2022;112(8):1212-1216. https://doi.org/10.2105/AJPH.2022.306881).

Purpose: Xylazine is an alpha-2-adrenergic agonist used for its sedative and analgesic properties in veterinary medicine. While not approved by the Food and Drug Administration for use in humans, anecdotal evidence suggests that exposures in humans is on the rise. We sought to systematically review and synthesize the evidence on xylazine exposure in humans focusing on the clinical presentation, management, and outcomes., Methods: We conducted a systematic review of the literature including PubMed, Embase, and Scopus from their inception to September 9, 2021. We searched abstracts from selected emergency medicine and toxicology conferences from 2011 through 2021. We included clinical reports of xylazine exposure in humans. We excluded animal studies, in vitro studies, laboratory studies, or articles in a language other than English. From each included article, we extracted subjective and objective data that focused on clinical presentation, management, and outcomes of patients exposed to xylazine., Results: We evaluated a total of 1409 records, rendering a final set of 17 articles and 2 abstracts meeting inclusion criteria. We identified a total of 98 patients amongst reports ranging from 1979 to 2020 and across nine countries. The most common types of xylazine exposures reported were unintentional exposure and intentional misuse/abuse. Common symptoms on presentation included hypotension, bradycardia, drowsiness, lethargy, while apnea with intubation and death were less frequently reported., Conclusion: Human exposure to xylazine appears to be a rising concern within the prehospital and emergency medicine setting. Although a standardized treatment algorithm cannot be recommended at this time, further research is needed to improve the care of patients exposed to xylazine.

Field workers handling bears continually strive to improve their field methods and reduce risks to animals during capture. Zolazepam tiletamine (ZT) is the standard anesthesia currently used in bear captures, but has a prolonged recovery because there is no antagonist. Researchers are increasingly using xylazine, zolazepam, and tiletamine (XZT) in combination an improvement to ZT alone. Because xylazine provides excellent analgesic qualities and can antagonized, XZT has the potential for effective anesthesia and faster recovery time for bears. assessed recovery times and considered physiological parameters to asses the quality of anesthesia of grizzly (Ursus arctos) and American black (U. americanus) bears anesthetized XZT, for which the xylazine portion was antagonized by yohimbine (XZT/Y). I compared these recovery times with unpublished recovery time data on bears anesthetized with ZT only. My XZT/Y samples came from research projects in western Montana, northern Idaho, and southeast British Columbia; bears anesthetized with ZT only came from Alberta, Canada, and the Greater Yellowstone Project of Montana, Wyoming, and Idaho, USA. Bears administered the XZT/Y protocol recovered from anesthesia 1.61 (95% CI = 1.28 2.01) times faster than bears anesthetized with ZT combinations. Bears administered XZT/Y at dosage rates presented here received adequate anesthesia for humane handling as indicated by the physiological parameters monitored. [ABSTRACT FROM AUTHOR]

Xylazine is commonly used in veterinary medicine as a tranquillizer or adjunct to surgical anaesthesia. Although its use is approved in companion animals and certain species of deer, xylazine remains unapproved for use in food-producing animals in the United States. This paper reviews existing toxicological and residue chemistry information on xylazine in food animals, particularly cattle, and discusses the regulatory status of the drug in the US, as well as the conclusions reached by the Joint FAO/WHO Expert Committee on Food Additives in its recent evaluation of xylazine. [ABSTRACT FROM AUTHOR]

Reports from active drug users state that xylazine, the veterinary tranquilliser, has been increasing in the illicit drug supply in Philadelphia. To describe trends and characteristics of unintentional deaths from heroin and/or fentanyl overdose with xylazine detections occurring in Philadelphia, Pennsylvania, the Philadelphia Department of Public Health analysed data on deaths from unintentional heroin and/or fentanyl overdose from the Philadelphia Medical Examiner's Office over a 10-year period (2010-2019). Xylazine went from being detected in less than 2% cases of fatal heroin and/or fentanyl overdose between 2010 and 2015 to 262 (31%) of the 858 fatal heroin and/or fentanyl overdose cases in 2019. Currently, information is limited on the presence of xylazine in continental United States. Xylazine's association with adverse outcomes in other locations indicates that potential health consequences should also be monitored in the USA. Whenever possible, jurisdictions should consistently test for xylazine., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)