Closing the xylazine knowledge gap

In the 1960s, Bayer 1470, an alpha₂-adrenergic agonist similar to clonidine, was investigated as an antihypertensive in humans, only to be abandoned because it produced excessive sedation [1]. Extensive testing in animals confirmed this potent sedative effect across multiple species with minimal respiratory depression [1–3], which ultimately led to the marketing of Bayer 1470 as xylazine. For decades, xylazine has been used in veterinary medicine and animal research, and its pharmacology in animals is well defined [4,5]. Advantages in those settings [4,5] include rapid and deep sedation, analgesia, muscle relaxation, near lack of respiratory depression at appropriate doses, ease of administration by multiple routes (intravenous, intramuscular, and subcutaneous [6,7]), ability to be mixed with opioids or ketamine, and reversibility (with drugs such as yohimbine, tolazoline, or idazoxan [4,8]).

The first appearances of xylazine in the illicit drug market were reported in Puerto Rico in the early 2000s [9]. Two decades later, xylazine is increasingly found in illicit drug-related deaths across the United States (US) and often in combination with fentanyl or cocaine [10,11]. In a recent report of drug seizure data from the National Forensic Laboratory Information System [12] only three of the fifty US States reported no xylazine found. Although the vast majority of reports are from the US, other countries have detected xylazine in their local drug supply. Reports from Canada [13], the United Kingdom [14], throughout Europe [15], and Malaysia [16], for example, highlight a global phenomenon. With growing awareness and testing, cases are likely to be reported in many other regions.

Recent releases from usually trusted sources warn about xylazine. The US National Institutes of Health (NIH) [17] reported that in a small animal study, xylazine worsened the effects of opioids. Placed near the end of the release, the author of that animal study is quoted as saying, “Further research is needed to explore how these observations may apply in humans and to continue to parse the complex role of illicit drug combinations with xylazine and risk of overdose.” In contrast, the subtitle of the press release states “NIH study deepens understanding of possible mechanism through which xylazine impacts overdose risk” thus making clear implications to effects in man. Similarly, a US Drug Enforcement Administration release [18] stated that “xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier” and “people who inject drug mixtures containing xylazine also can develop severe wounds, including necrosis—the rotting of human tissue—that may lead to amputation.” Finally, The White House Office of National Drug Control Policy [19] recently designated fentanyl combined with xylazine an emergent threat to the United States with the justification stated as “xylazine combined with fentanyl is being sold illicitly and is associated with significant and rapidly worsening negative health consequences, including fatal overdoses and severe morbidity.” Do available human data support these assertions?

Although human controlled trials with xylazine for either hypertension or sedation are lacking, data exist from both intentional and unintentional toxicity from the approved veterinary drug. Hoffmann et al. [20] report a 27-year-old man with an intentional intramuscular injection of xylazine 1.5 g who abruptly developed bradycardia, coma, hypotension and hyperglycemia. Although endotracheal intubation was performed, there was no description of his respiratory status. A blood xylazine concentration was 4.6 mg/L, and serial concentrations allowed the calculation of an apparent half-life of 4.9 h. The authors mention eight previous non-fatal cases some of which are summarized here.

In a series that included three patients [21], an intramuscular dose of xylazine 2,400 mg produced apnea while 40 mg only produced sedation. In another report [22], ingestion of xylazine 400 mg resulted in coma, and the patient was intubated with a respiratory rate that was described as 8-12 shallow breaths/min. Following a subcutaneous injection of xylazine 200 mg a 19-year-old man developed respiratory depression requiring endotracheal intubation [23]. Neither doses nor toxicokinetics are reported in the other cases. Ruiz-Colón et al. [24] add an additional 11 cases to the literature but also included inhalational and ocular routes of exposure. Two cases had reported doses. A 23-year-old man who injected intramuscular xylazine 450 mg developed sedation without respiratory depression, and a blood xylazine concentration of 0.57 mg/L was reported [25]. A 36-year-old veterinarian who injected intramuscular ketamine 1,000 mg along with xylazine 1,500 mg developed toxicity without significant respiratory depression [26]. The authors of that report speculated that chronic use of both drugs produced some degree of tolerance. Although informative, these reports lack sufficient detail to allow an estimation of a dose-response curve for xylazine in humans.

The medical literature has also published images of skin necrosis associated with [27] or “induced” by [28] xylazine use. While these claims focus on xylazine, they neglect the fact that xylazine is routinely administered to animals intramuscularly or subcutaneously without causing skin necrosis [6,7] and that these human reports are associated with positive bacterial cultures [27,28] in the setting of unsterile injection drug use. While the association with xylazine is clear, the suggested causation is unsubstantiated. This sensationalism is reminiscent of the krokodil (desomorphine) reports [29–31], which were also published despite the fact that similar skin and soft tissue infections were common when the predominant injection drug was heroin (with or without a variety of other adulterants and contaminants) [32–34]. Similarly, while many reports of fatalities in people who use xylazine adulterated drugs use epidemiologically appropriate terms such as “xylazine-involved” [35], “fentanyl-involved” [10], or simply “detection” [11] denoting a clear association, terms such as “resulted in fatalities” [24] implying causation can easily be found in the medical literature. One public health response emphasizes the availability of xylazine test strips [36–38] so that properly informed users can presumably choose to avoid adulterated drug. This approach will have limited if any utility in regions where virtually all the accessible drug contains xylazine.

Three recent publications in this Journal improve our understanding of xylazine toxicity using different methodologies. In a systematic review, Ball et al. [39], expand on the previous reviews [20,24] described above. The review confirms exposures and toxicity from ocular, oral, and inhalational exposures (which are not relevant to the current discussion) and identifies one additional unique case worth highlighting in detail. Following the intravenous injection of xylazine 1,000 mg, a 65-year-old man developed hypotension, bradycardia, and required endotracheal intubation [40]. His original electrocardiogram revealed a heart rate of 54 beats/min with a QT interval of 490 msec. By the second day, his QT interval continued to prolong, which at its worst was reported as an uncorrected QT interval of 714 msec (heart rate not specified) with a corrected QT interval of 664 msec (formula for QT correction not specified). His potassium concentration was normal. Additional information was derived from a case series from one poison center collected over five years [41]. Of note, hypertension was present in 9% of reported cases. Although hypertension was reported in some of the individual cases described above [20,24,39] and is characteristic of an early clonidine overdose, only this larger poison center series allows an estimation of a percentage.

In the second article in this Journal, Love et al. [42] report on 90 patients from the Toxicology Investigators Consortium (ToxIC) who had confirmed xylazine concentrations in the setting of opioid use. Although this population was clinically less ill than the patients reported following veterinary xylazine injection (possibly related to dose used and publication bias in the individual reports), and interpretation of the contribution of xylazine in these ToxIC patients is confounded by co-used drugs, the value of this report is that every patient had analytically confirmed xylazine use. Most importantly, among patients who used opioids and tested positive for xylazine, both coma and cardiac arrest occurred less often than in those patients who used opioids and tested negative for xylazine. While no cause for this finding can be derived from the data, it is reasonable to speculate that either the presence of xylazine offers some protection or more likely that xylazine is less toxic than the opioids and the greater the xylazine adulteration, the less opioid received by the user. Either way, these data cast doubt on the public health implications of xylazine in the illicit drug supply and suggest areas for future research.

The third paper in this Journal describes the impact of xylazine in forensic medicine. Vohra et al. [43] report on 279 xylazine-positive deaths in Michigan that were collected between October 2019 and June 2023. Decedents tended to be young white men whose toxicology was suggestive of poly-substance use disorder, and fentanyl was present in all the samples. Post-mortem blood concentrations (available in 55 decedents) ranged from 5.2 to 200.0 μg/L, but the authors correctly caution against comparison with the living because the post-mortem properties of xylazine, especially redistribution, are unknown. Most notably, only 30% of xylazine-positive fatalities tested positive for naloxone.

What are the facts about xylazine? Clinical effects of xylazine toxicity mirror those produced by similar drugs (e.g., clonidine) with early hypertension in some patients, followed by miosis, hypotension, bradycardia, coma, and respiratory depression. Hyperglycemia and QT interval prolongation seem to be more unique to this drug. It is noteworthy that no cases of skin or soft tissue necrosis are reported in any of the cases of exposure to veterinary-grade xylazine [20,24,39]. Taken together with the extensive intramuscular and subcutaneous use in animals [4–7], it is more likely that contaminated drugs and needle use cause the cutaneous findings associated by too many sources with xylazine.

While it is certain that xylazine is prevalent in the illicit drug supply and, therefore, commonly found in opioid-related deaths, the contribution of xylazine to those fatalities is undetermined. It is unclear that xylazine exacerbates opioid toxicity within the construct of how drugs are adulterated, sold, and used in humans. In fact, the substitution of xylazine for potent lethal opioids may be protective. While it is also uncertain whether naloxone reverses xylazine toxicity (data not discussed here), it seems apparent that not enough patients who present with miosis, central nervous system depression, and hypoventilation receive naloxone to reverse their co-used opioid.

While there is no single best approach to patients with opioid use disorder and no easy solution to prevent deaths from opioid use, little will be gained by the unsubstantiated demonizing of a particular drug or adulterant. Rather a multi-pronged public health approach is required that, at the present time, includes prevention education, community-level naloxone, clean needles, access to uncontaminated and unadulterated drugs, supervised injection sites, access to substance treatment programs, assisted therapy with buprenorphine (preferably) or methadone, and possibly test strips and smart devices. All of these actions and potential novel approaches should be directed by data rather than speculation and fear. These reports highlight that no single data source provides an adequate description of the role of xylazine adulteration in the toxicity that occurs in patients who use opioids. Rather, an integrated approach across multiple data streams is required.

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