Xylazine

"Xylazine, also called “tranq” or “tranq dope,” is a non-opioid veterinary tranquilizer. Although not approved by the United States (US) Food and Drug Administration for human use, xylazine is increasingly being identified as an adulterant in illicitly manufactured fentanyl and heroin, and occasionally in other drugs such as cocaine and methamphetamine in the US [1, 2]. Xylazine overdose has no known antidote and can cause central nervous system and respiratory depression, hypotension, and bradycardia in humans [3, 4]. This has led to concern that xylazine could worsen the cardiorespiratory depressive effects and lethality of opioids when the drugs are combined, but its impact on overdose risk and symptoms is still being explored [2, 5–9]. The sedating effects of xylazine, which can last for hours, may also put individuals at greater risk for victimization or injury from assault or exposure to the elements [10]. In addition to its sedating properties, xylazine can also cause severe skin ulcers in humans, regardless of route of use (e.g., injection, smoking, snorting) [2, 11]."

"Xylazine is a veterinary tranquilizer, which is not approved for human use in the United States, but is commonly used for sedating large animals (Reyes et al., 2012; Ruiz-Colón et al., 2014). Although human intoxication with xylazine has been reported sporadically over the past several decades in a number of case studies (Ruiz-Colón et al., 2014; Forrester, 2016), it was first described as a more prevalent additive in the unregulated drug supply of Puerto Rico (Reyes et al., 2012; Rodríguez et al., 2008; Torruella, 2011). It was also noted in the literature describing drug overdose deaths in Philadelphia as early as 2006, yet it did not appear in high prevalence at that time (Wong et al., 2008). However, since the mid-2010s, xylazine has been noticed by people who inject drugs (PWID) and public health practitioners as an increasingly commonplace additive in the street opioid supply of Philadelphia (Johnson et al., 2021). Further, recent reports from Connecticut implicated xylazine in a rising fraction of overdose deaths in 2019–2020 (Nunez et al., 2021; Thangada, 2021). A report released in September 2021 leveraged data from 38 states and Washington DC representing the year 2019, and found xylazine to be present in 1.8% of overdose deaths (Kariisa, 2021). However, no time trends were provided, and results were not disaggregated below the level of US Census Region, with limits the usefulness of the results for frontline providers and harm reductionists. Additionally, reports from Philadelphia and Connecticut, as well as media reports from numerous cities, suggest that xylazine-present overdose have increased sharply in 2020–2021."

"This study examined the performance of BTNX XTS [Xylazine Test Strips] for testing drug residue. The detection of xylazine’s presence was lower than expected although increased if xylazine was the sample major psychoactive component. Our findings suggest further research and field testing are needed to develop rapid XTS and procedures for residue testing in point-of-care DCS.

"Few studies have evaluated the performance of XTS in the community. One small laboratory study on samples from Philadelphia found no false-negatives compared to confirmatory results (i.e., a sensitivity of 100 %). Notably, the Philadelphia study tested samples rather than residue using a 1 mg:1 mL dilution factor (Krotulski et al., 2023), compared to our procedure of dissolving an unquantified amount of residue in 5 mL of water. A second study using 100 residue samples from Maryland and Nevada assessed crossreactivity of 77 different compounds found only lidocaine produced false-positives (Sisco et al., 2023). Each study tested different XTS batch lots which may have contributed to result discrepancies; quality and accuracy of lateral flow strips can vary between lots (Hayden et al., 2014).

"This study's limitations include its small sample size, limited collection radius and timeframe, and non-random collection procedure. Tested samples primarily contained fentanyl or other opioids; further research should explore the performance of testing non-opioids. Additionally, no validated procedure existed for testing drug residue at the time of the study. While collecting larger amounts of drugs to test would likely increase generalizability and confidence in findings, non-laboratory DCS fall into a legal gray area due to the Controlled Substances Act and resultantly often rely on drug refuse residue. Finally, while quantification was outside the scope of this study, it would provide stronger evidence of whether XTS perform in accordance with their stated detection limit in a community setting and should be considered for future studies. Given these uncertainties, our findings, while initial, caution against reliance upon the XTS alone for xylazine detection in drug residue and, if used, should be accompanied by a thorough discussion of the test’s limitations when interpreting the results or coupled with laboratory testing."

"At least a decade after Xylazine became a fixture in Puerto Rico, it entered the street opioid supply in Philadelphia as a more prevalent additive in the mid-2010s. The shift was noted by PWID, as well as harm reductionists and city public health officials (Johnson et al., 2021). PWID began to describe xylazine – often referred to as tranq – as a known element of specific ‘stamps’ or brands of opioid products in the illicit retail market. Opioid formulations containing xylazine, (e.g.,“tranq dope”) became largely sought-after, as the addition of xylazine was reported to improve the euphoria and prolong the duration of fentanyl injections, in particular, solving “the problem” of the “short legs” of the otherwise euphoric effects of illicitly manufactured fentanyl."

"Xylazine is a non-opiate sedative, analgesic, and muscle relaxant that shares its drug class (α2-adrenoreceptor agonists) with medications such as clonidine, lofexidine, tizanidine, and dexmedetomidine [6]. It was initially developed as an antihypertensive agent by Farbenfabriken Bayer AG in 1962; however, subsequent testing revealed severe adverse events related to hypotension and central nervous system (CNS) depression [6, 7]. Consequently, xylazine never gained approval for human use; however, it was approved by the US Food and Drug Administration (FDA) in 1972 exclusively for use in veterinary medicine [6, 7]. At present, xylazine remains unregulated under both the Controlled Substances Act (CSA) in the USA [8] and the Controlled Drugs and Substances Act (CDSA) in Canada [9].

"Fatal xylazine-positive overdoses, often co-occurring with synthetic compounds such as IMF and its analogs, surged dramatically in the past decade in North America. These overdoses have increased approximately 12-fold between 2018 and 2021 in the USA [6]. Importantly, naloxone—an opioid antagonist medication that is safe and effective for reversing opioid-induced respiratory depression during overdose—does not directly address the effects of xylazine as it is not an opioid, thereby introducing new challenges regarding overdose response best practices within clinical- and community-based settings [8, 10]. Altogether, this pressing issue has prompted The White House Office of National Drug Control Policy (ONDCP) to designate fentanyl associated or adulterated with xylazine (FAAX) as an emergent health threat to the USA in April 2023 and issue a comprehensive response plan in July 2023 [11, 12]. Similar cases are also on the rise in Canada and other countries such as the UK, marking the first xylazine-involved overdose outside of North America [9, 13]. Against the backdrop of this global health crisis, it is imperative to renew efforts in delivering evidence-based public health and harm reduction programs to facilitate secondary and tertiary prevention of adverse health outcomes following xylazine exposure."

"Here, we report the first xylazine dose-response locomotor study in male and female mice as well as the first assessment of adrenergic- and opioid-receptor antagonist-precipitated withdrawal symptoms following, xylazine, fentanyl, and xylazine/fentanyl administration in mice. These experiments show that male and female mice are differentially sensitive to xylazine. We find female mice are less sensitive to the motor-suppressing effects of xylazine contrary to the recent findings in rats reported by Khatri et al. (2023), potentially due to their use of repeated dosing of xylazine or species differences [27]. Using a modified version of our 3-day precipitated withdrawal model [40,41,46], we show xylazine is indeed responsive to naloxone, contrary to common assumptions made by both health professionals and in the media [7]. Both sexes exhibited some level of somatic withdrawal behaviors to xylazine and naloxone, though females showed sensitized behavioral responding. Indeed, females appear to be as sensitive, if not more sensitive to xylazine withdrawal than fentanyl withdrawal at tested doses, while males remain much more responsive to fentanyl withdrawal conditions. At the doses tested in our study, the effect of naloxone precipitated withdrawal on xylazine/fentanyl combination was synergistic as compared to each drug in isolation. This was especially apparent when examining increased bouts of paw tremors, which may represent a more passive coping behavior that we have previously observed is sexually dimorphic in opioid withdrawal [41]. In contrast, we did not observe similar findings when withdrawal was precipitated by atipamezole, an α2-AR antagonist used anesthesia reversal in veterinary medicine. These intriguing findings led us to consider the possibility of direct xylazine activity on opioid receptors. Previous studies have shown that xylazine is antinociceptive, results in a cross-tolerance to some mechanisms of opioid induced antinociception, and that these effects are naloxone-sensitive, but surprisingly not sensitive to the κOR selective antagonist nor-BNI [57–60]. Congruent with this data, we did not observe significant expression of withdrawal behavior to nor-BNI precipitated withdrawal, and pretreatment with nor-BNI exacerbated naloxone precipitated withdrawal in female mice. Until now, xylazine was thought to exert these effects through promotion of endogenous opioid release and xylazine has not been directly tested as a potential opioid agonist. We are the first to report definitive evidence that xylazine acts as a full agonist at κOR and is biased towards G-protein signaling pathways."

"Originally developed as an anti-hypertensive agent by Farbenfabriken Bayer AG (now Bayer AG) in 1962, xylazine was found to cause severe hypotension and central nervous system depression.7,8 Xylazine was never approved for human use but was instead approved in 1967 as a sedative in large animal anesthesia.7,9 Shortly after its development, xylazine’s danger became quickly evident from multiple reported suicide attempts, accidental injections or ingestions, and illicit production and abuse.10, 11, 12, 13

"Years later, medical providers in Puerto Rico first reported chronic wound issues in patients using xylazine.14 Around this same time, medical examiners in Philadelphia found xylazine in samples of seven patients who had experienced overdose deaths.15 More recently, as testing specifically for xylazine has been introduced in certain areas, the prevalence of xylazine has increased and become more widespread throughout the entire US.16"

"In 2019, relatively low rates of xylazine NFLIS [National Forensic Laboratory Information System] reports were observed; all states had a rate below 6 xylazine NFLIS reports per 100,000 residents, and 16 states had zero NFLIS xylazine reports (Figure 1; eTable 4 in Supplement 1). In contrast, in 2022, only 2 states had zero xylazine NFLIS drug reports, and the highest rates of xylazine NFLIS reports (per 100,000 residents) were observed in New Jersey (30.52), Rhode Island (22.82), Maryland (18.91), Virginia (15.47), New Hampshire (13.10), and Ohio (10.87). In 2019, xylazine NFLIS reports were limited to a few northeastern states; by 2022, xylazine NFLIS reports were still concentrated in northeastern states yet had extended to states south and west.

"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, DC, New Jersey, and Rhode Island, yet less than 1.00% of NFLIS reports in 35 different states (Figure 2; eTable 5 in Supplement 1). Delaware, Maryland, Rhode Island, New Jersey, Connecticut, DC, and Virginia had the highest absolute change in xylazine reports as a percentage of all NFLIS drug reports (2019-2022), while Virginia, Maryland, North Carolina, Michigan, Kansas, Alabama, Minnesota, and Tennessee had the highest relative change. Only 1 state, Wisconsin, recorded a decrease in xylazine’s representation in NFLIS drug reports from 2019 (0.56% of drug reports) to 2022 (0.48% of drug reports), and 2 states reported no increase (0% in 2019 to 0% in 2022; South Dakota and Wyoming) yet in 30 states, across all regions, xylazine reports (as a percentage of all NFLIS drug reports) more than doubled."

"Importantly, our results show that evidence of injection was more prevalent among decedents with xylazine and heroin and/or fentanyl detections. Despite limited literature on the health effects of chronic xylazine use, regular injection of xylazine has been associated with skin ulcers, abscesses and lesions in Puerto Rico.^{2 3} Semistructured interviews with people who use xylazine in Puerto Rico revealed that regular use of xylazine leads to skin ulcers.⁴ As skin ulcers are painful, people may continually inject at the site of the ulcer to alleviate the pain as xylazine is a potent α2-adrenergic agonist that mediates via central α2-receptors, which decreases perception of painful stimuli.¹ People may self-treat the wound by draining or lancing it, which can exacerbate negative outcomes.⁸ While Philadelphia has seen a rise in skin and soft tissue infections relating to injection drug use, it is not yet clear whether or not this is due to increased presence of xylazine in the drug supply.⁹"

"Xylazine (also known as “tranq, tranq dope, Philly dope, sleep-cut, or zombie drug”) is a non-opioid veterinary tranquilizer that has become a common additive with illicit fentanyl and other opioids.1 When xylazine is injected with fentanyl, the result can be severe soft tissue injury ranging from superficial irritation to deep tissue necrosis and even bony involvement (Fig. 1). The pathogenesis of the skin changes from xylazine is multifactorial but most akin to a burn from local tissue injury. Theoretical causes for the tissue toxicity from xylazine include injury from the concentrated acidity, the vasoconstrictive effect on local blood vessels, and overall decreased tissue oxygenation from central nervous tissue depression.2 However, the enhanced and prolonged euphoric effect xylazine adds to injected fentanyl will likely only increase the potential for abuse."

"The emergence of xylazine has led to several unintended consequences for PWUD [People Who Use Drugs] across North America, such as tissue necrosis and heightened sedation, the latter of which has potential implications for elevated risk of overdose and social consequences (such as being robbed or assaulted) [5, 21]. Here, we identified how the emergence of xylazine has also precipitated a range of behavioral responses among PWUD, with implications for their individual health and the broader healthcare system [22].

"We identified dynamic communication processes through which information about xylazine emerged and spread among SSP staff and clients, ultimately leading to a formal response by the SSP via the use of XTS [17]. Notably, the initial identification of xylazine was driven by clients’ firsthand experiences with the unregulated opioid supply. Clients then shared their observations and experiences with SSP staff, underscoring the importance of building trust and listening to client expertise, which can serve as an early warning system for emerging adulterants prior to adverse consequences. In contrast, many of the official accounts of xy-lazine adulteration are based on overdose surveillance data or medical examiner reports [9, 13–15, 23], which can take time to process. In addition, most official early warning systems focus on mass spectrometry or drug seizure data, which may involve a time lag and is resource intensive [24, 25], especially in the Southern U.S. where comprehensive drug-checking services are sparse [26, 27]. Integrating qualitative insights from PWUD into current early warning systems may provide another avenue for proactive intervention that can indicate the presence of a novel adulterant using relatively few resources and can be scaled locally via SSPs or other settings that serve PWUD (e.g., drug treatment facilities). Indeed, improved collaboration between harm reduction programs and surveillance professionals, including medical examiners and crime laboratory personnel, could circumvent and augment delays in reporting systems. Of course, caution is needed in the development and deployment of warning systems to avoid sensationalizing harms or generating “alert fatigue,” where PWUD and their communities are inundated with information [28, 29]. These findings also emphasize the benefit of embedding research within harm reduction settings to further empower these organizations in responding to emerging challenges."

"PWUD demonstrated a predominantly protective approach to xylazine emergence by modifying their drug consumption routes and reducing injection drug use, aiming to mitigate potential harms associated with xylazine adulteration. While often discussed in the context of xylazine here, this echoes a broader literature that reveals an elevated prevalence of smoking among people who previously injected opioids on the West Coast of North America [30–32].

"Xylazine use has been associated with severely necrotizing skin infections that produce wounds even distal to the injection site or when individuals are smoking [10, 12, 33]. While more research is needed on the health implications of transitioning away from injection drug use towards other routes of administration (e.g., smoking) and its consequences, it is possible that transitioning away from injecting could reduce the likelihood of tissue necrosis or subsequent SSTIs [34]. However, it is still unclear if transitioning from injecting to smoking opioids (especially those adulterated with xylazine) decreases one’s risk for overdose and what the impacts are on cardiovascular health [35].

"While clients’ reliance on alternative consumption routes and peer networks for safety highlights the importance of peer-based harm reduction approaches, increased stimulant use and ‘human testing’ practices, intended to counteract xylazine’s sedative effects and verify drug safety, raises concerns about heightened susceptibility to overdose and other adverse outcomes [3, 36]. Increased polysubstance use with stimulants may increase clients’ overall drug consumption, thereby increasing their risk for additional adverse events (e.g., cardiac arrest, overdose, and SSTIs) [37–39]. Also, reports of using drugs alone underscore the need for additional interventions to address social isolation and enhance safety while people consume unregulated substances. One such intervention that may overcome these challenges could be implementing a phone-based overdose response service, as seen in Canada [40].

"The phenomenon of clients seeking out xylazine for its unique effects challenges existing literature on individuals’ preferences for xylazine and has implications for addiction treatment in the context of an evolving drug supply [41–43]. For example, more research is needed to develop guidelines for managing buprenorphine initiation while individuals are using xylazine-adulterated opioids to help mitigate anxiety and xylazine-related withdrawal symptoms [44]. On the other hand, despite efforts to reduce exposure to xylazine, some clients reported increasing their consumption of opioids, driven by the need to counteract diminished opioid availability and withdrawal symptoms associated with xylazine’s short half-life [45]. This finding contradicts previous hypotheses suggesting xylazine’s role in extending the duration of opioids’ effects [12, 46], indicating a nuanced interplay between substance availability, dependence, and desired effects."

"Xylazine, an alpha-2 receptor agonist, is used in veterinary medicine as a sedative and muscle relaxant; it is not approved for use in humans. However, reports of adulteration of illicit opioids with xylazine have been increasing in the United States (1–3). In humans, xylazine can cause respiratory depression, bradycardia, and hypotension (4). Typical doses of naloxone are not expected to reverse the effects of xylazine; therefore, persons who use xylazine-adulterated opioids are at high-risk for fatal overdose. Although some regions of the United States have reported increases in xylazine-involved deaths, xylazine was involved in <2% of overdose deaths nationally in 2019 (2,5). Most xylazine-involved deaths are associated with fentanyls, including fentanyl analogs (1,5)."

"A xylazine-associated death was defined as a positive postmortem xylazine serum toxicology test result in an unintentional, undetermined, or pending intent substance-related death during January 2017–October 2021. Routine postmortem tests were conducted for other substances including fentanyl, fentanyl analogs, cocaine, and naloxone. Xylazine testing is standard in Cook County for suspected drug overdose deaths. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.*

"A total of 236 xylazine-associated deaths were reported during the study period. Xylazine-associated deaths increased throughout the study period; incidence peaked during July 2021 (Figure). The percentage of fentanyl-associated deaths involving xylazine also increased throughout the study period, rising to a peak of 11.4% of fentanyl-related deaths assessed by the Cook County Medical Examiner’s Office during October 2021. Fentanyl or fentanyl analogs were detected on forensic testing in most xylazine-involved deaths (99.2%). Other common co-occurring substances included diphenhydramine (79.7%), cocaine (41.1%), and quinine (37.3%). Naloxone was detected in 32.2% of xylazine-associated deaths."

"Prior to the widespread availability of xylazine in the Philadelphia drug supply, it was often mentioned in passing by residents of the majority Puerto Rican neighborhood where our fieldwork was based as a powerfully psychoactive additive ‘“back on the Island”.’ Xylazine was occasionally detected in fatal overdoses in Philadelphia as early as 2006 (Wong et al., 2008), but it was not common knowledge among PWID. Significantly, however, many of our long-term informants recently immigrating/returning from Puerto Rico spoke with a mix of intrigue and apprehension about the psychoactive effects and health risks of “anastesia de caballo [horse tranquilizer]”."