The xylazine-fentanyl nexus: A public health emergency

Abstract

The US opioid crisis has rapidly escalated over the past 4 decades, with a shifting profile of available substances contributing to rising fatalities. Leading this crisis is illicitly manufactured fentanyl, now increasingly adulterated with xylazine, a veterinary sedative not approved for human use. Despite a greater awareness in recent years regarding the vital role of naloxone in preventing fatal cases of overdose, xylazine has been associated with a sharp increase in overdose-related deaths due to its potent central nervous system effects. Recent data suggest a significant spread of xylazine, underscoring the importance of strategies to counteract fentanyl and implement aggressive supportive care for xylazine-fentanyl toxicity. This combination, often undetectable by standard drug tests, presents challenges in diagnosis and treatment of overdoses. These challenges have become relevant among young adults, a demographic particularly affected, underscoring the need for harm reduction measures and further research into the shifting patterns of fentanyl-related intoxication across the United States.

Introduction

The US overdose crisis has accelerated exponentially over the past 4 decades, with a constantly shifting profile of illicit drugs contributing to rising fatalities. Between 2000 and 2006, cocaine was the leading drug associated with overdose deaths, successively replaced by prescription opioid (2007–2013), heroin (2014–2015), and illicitly manufactured fentanyl (2016–present). ¹ Fentanyl is a potent synthetic opioid primarily used as an analgesic for cancer patients, those recovering from painful surgeries, and as a sedative. It is 50 times more potent than heroin and 100 times more potent than morphine, with similar side effects, including addiction, confusion, and respiratory depression.^2,3 Illicitly manufactured fentanyl-related adolescent overdose deaths nearly tripled from 2019 to 2021, contributing to 84% of total overdose-related deaths in the 15–19 year-old age group. ⁴ Among persons aged 14–18 years, overdose deaths in the US increased 94% from 2019 to 2020 and 20% from 2020 to 2021. ⁵ Geographically, drug overdose incidence in 2021 was found highest in Delaware (88%) followed by West Virginia (83%), Ohio (83%), Tennessee (80%), Pennsylvania (78%), Indiana (78%), Maine (67% to 77%), Kentucky (71%), and New Mexico (70%), respectively. ⁶ Analysis of death records data across the United States for 2020–2021 showed that men were significantly more vulnerable than women to overdose deaths involving opioid and stimulant drugs. ⁷ Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin, with the aim to increase product bulk and extend the euphoric effects. Since 2000, xylazine has become an increasingly common adulterant in heroin and fentanyl across the United States and Puerto Rico. Its growing prevalence is largely due to its undetectability by sight, smell, or touch, making it particularly difficult to identify. A structural analogue of clonidine, xylazine is exclusively approved for veterinary use as a sedative, analgesic, and muscle relaxant in animals due to its central nervous system depressive effects. Tolerance of xylazine varies widely, the exact lethal levels of the drug unclear due to overlap in blood concentrations of patients who suffered non-lethal xylazine poisoning and cases of lethal xylazine overdose. In cases of lethal xylazine overdose, blood concentration of xylazine ranged from 5 to 49 ng/mL, whereas blood or plasma concentrations ranging from 30 to 460 ng/mL were also detected in non-lethal xylazine overdose cases.^8–11 The ubiquitousness of xylazine is also attributed to its easy accessibility as a legitimate veterinary drug, in contrast to harder-to-obtain substances such as heroin or cocaine. The number of illicit manufactured drug (fentanyl-xylazine) overdose deaths have surged across the country in recent years. Thirty-one states and the District of Columbia ¹² detected 9% of fatal overdoses involving illicit fentanyl between January 2021 through June 2022. Of these states, Maryland had the highest state-wise rate of fentanyl xylazine deaths at 27.7%, followed by Connecticut (26.4%) and Pennsylvania (23.3%). ¹³ The Centers for Disease Control and Prevention (CDC) reported a 276% increase (from 2.9% to 10.9%) in the monthly share of illegally manufactured fentanyl-involved deaths from xylazine between January 2019 and June 2022. ⁷ From 2018 to 2021, the age-adjusted rate of such deaths increased from 0.03 to 1.06 per 100,000 of the population—a 35-fold increase—disproportionately affecting the non-Hispanic white male population in the 25–44 years old age group. ¹⁴ This was initially concentrated in the Northeast, particularly Philadelphia, but the presence of xylazine has since spread across all four U.S. geographic regions. This expansion correlates with a staggering rise in xylazine-positive overdose deaths, with increases of 1127% in the South, 750% in the West, and significant upticks in the Midwest and Northeast. ¹⁵ The isolation of drug users and related interventions during the COVID-19 pandemic further exacerbated the issue as highlighted by the Raidio Teilifis Eireann, demonstrating an 80% increase in fatal overdoses in New York from 2019 to 2021. ¹⁶ The ongoing opioid epidemic is expected to claim an estimated 1.2 million additional lives by 2029 unless policy reforms are implemented. However, newer data from Maryland suggested a decline in the xylazine-fentanyl associated overdose deaths after a peak in 2021. ¹⁷ A similar decline of approximately 10% was also noted in the preliminary data released by CDC in 2024. Although disparities remain, this suggests early signs of progress in combating the crisis. ¹⁸

The growing use of illicitly manufactured drugs in the United States is based on several factors, including geographical location, socioeconomic factors, and behavior patterns among adolescents and young adults. Other variables include individuals with a history of prior substance abuse, those with chronic pain, a history of mental health issues, and people in areas affected by the opioid crisis. ¹⁹ Environmental factors such as peer pressure, physical and sexual abuse, early exposure to drugs, stress, and lack of parental guidance can greatly affect one’s likelihood of drug use and addiction. ²⁰ The aim of this review is to discuss the harmful effects of xylazine-fentanyl use in humans, outline the factors that make it one of the most dangerous medications, unpack its growing use in younger populations in the United States, and shed light on reasons for drug abuse, and current management and an action plan to counteract drug abuse in Americans with opioid use disorder (OUD).

To provide clarity regarding the scope and methodology of this review, the following details are offered. This is a narrative review, which synthesizes information from a variety of sources to provide a comprehensive overview of the emerging crisis posed by the combination of xylazine and fentanyl. A systematic search of the literature was conducted using PubMed, Scopus, Web of Science, Medline, and Google Scholar. The search strategy focused on identifying relevant articles published from 2010 onward and was limited to English-language publications. Keywords used in the search included “xylazine,” “fentanyl,” “OUP,” “addiction,” and “xylazine mixed fentanyl.” The review included a range of paper types, including observational studies, case reports, forensic toxicology reports, news articles, and government press releases/articles. This approach allowed for the inclusion of diverse perspectives and data sources, acknowledging the multifaceted nature of this public health issue.

Pathophysiology

Xylazine

Xylazine, also known as N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine, was initially approved by the U.S. Food and Drug Administration for animal sedation due to its sedative and muscle relaxant properties (Figure 1).^21,22

Figure 1.

Two-dimensional chemical structure of xylazine. ²³

It is a potent alpha-2 receptor agonist, both at central and peripheral receptors, causing sympatholytic effects on the body such as hypotension, bradycardia, and respiratory depression. ²² Xylazine activates the receptors in the locus coeruleus and dorsal horn, leading to its sedating and analgesic effects. ²⁴ In addition, it has been suggested that xylazine may have some affinity for cholinergic, serotonergic, dopaminergic, H2-histaminergic, and opiate receptors, which would explain its euphoric effects and associated addictive behaviors. ²⁵ It is administered through various routes, including intravenous, intramuscular, subcutaneous, inhalation, or oral administration. It is often used alone or in combination with other anesthetics such as ketamine, chloral hydrate, halothane, and barbiturates to ensure effective anesthesia. ¹⁰ Studies have indicated that xylazine doses ranging from 40 to 2400 mg can cause toxicity in humans (Figure 2).^26,27

Figure 2.

Mechanism of action of xylazine. Xylazine acts primarily as an alpha-2 adrenergic receptor agonist. Binding to the alpha-2A and alpha-2C receptors on presynaptic neurons inhibits the release of norepinephrine. This, in turn, reduces activation of postsynaptic alpha-1 receptors, leading to a decrease in sympathetic outflow. At high doses, xylazine can also bind to alpha-2B receptors on vascular smooth muscle, causing vasoconstriction. Xylazine’s sedative and analgesic effects are largely due to alpha-2 receptor-mediated hyperpolarization via potassium efflux, with G protein-coupled inwardly-rectifying potassium (GIRK) channel activation playing a critical role.^28,29

Fentanyl

Fentanyl, an N-phenyl-N-[1-(2-phenylmethyl) piperidin-4-yl] propanamide, is a potent synthetic opioid belonging to the phenylpiperidine family with 50 times greater potency than heroin and around 100 times greater potency than morphine (Figure 3).^3,30

Figure 3.

Two-dimensional chemical structure of fentanyl. ³¹

Fentanyl exerts its physiological effects via its action on opioid receptors, with a high affinity for the mu(µ)-opioid receptor and a weak affinity for the delta and kappa receptors. Upon binding to mu-receptors, fentanyl induces inhibitory physiological effects by reducing cyclic adenosine monophosphate (cAMP) production, increasing efflux of potassium, and decreasing influx of calcium. ³² Mu receptor activation is responsible for analgesia, respiratory depression, sedation, drowsiness, constipation, euphoria, and hypotension. ³³ Additionally, it elevates dopamine levels, contributing to its potential for addiction and abuse. ³⁴ Its acute toxicity generally presents with severe respiratory depression, cardiac arrest, and potentially death. However, chronic use and overdose often include signs of opioid toxidrome, including symptoms such as miotic (pin-point) pupils, respiratory depression, bradycardia, hypothermia, cold and clammy skin, drowsiness, sedation, or loss of consciousness (Figure 4). ³⁵

Figure 4.

Mechanism of action of fentanyl. Fentanyl binds to the opioid receptor, a G-protein coupled receptor. This binding triggers a decrease in cAMP production, a decrease in calcium influx, and an increase in potassium efflux.^29,32

Xylazine + fentanyl

Xylazine is often consumed with illicit drugs like fentanyl due to its greater availability from the veterinary industry and lower cost, ³⁶ with the resultant combination offering a synergistic effect in terms of abuse potential as xylazine extends the duration of the euphoric effects of fentanyl. ³⁷ This combination presents significant dangers, resulting in a prolonged state of opioid toxicity, respiratory and CNS depression, nystagmus due to xylazine, with potential for cardiac arrest and death. ²² Xylazine use has also been found to increase and prolong the brain hypoxia associated with fentanyl use. ³⁸ Chronic xylazine use can lead to peculiar skin manifestations which are not fully understood but are believed to result from multiple overlapping mechanisms; the alpha-2b adrenergic agonist activity of xylazine is believed to induce peripheral vasoconstriction, leading to tissue ischemia and necrosis, while its sedative properties contribute to prolonged immobility and pressure ulcers. ³⁹ Recent studies have elucidated a similar mechanism to clonidine, though xylazine induces greater vasodilation in peripheral tissues through inhibition of sympathetic outflow. This vasodilation contributes to ulcer formation through tissue hypoperfusion. ⁴⁰ Chronic hypoxia impairs wound healing, further exacerbating ulcer formation. ³⁸ Direct cytotoxic effects of xylazine – mediated by an increase in the reactive oxygen species and DNA fragmentation – have also been implicated in skin injury, potentially accelerating necrosis and secondary infections.^41,42 These lesions typically begin as ulcers, before progressing to deep, necrotic wounds prone to superinfection. ⁴³ Without early intervention, patients face an increased risk of sepsis, endocarditis, limb amputation, and death. ³⁷ The combination of these drugs has been linked to increased cardiovascular instability, with reports of severe hypotension and bradycardia requiring intensive medical intervention. Unfortunately, overdose patients show little to no improvement with the administration of naloxone, ⁴⁴ and consequently are susceptible to more overdose deaths. ⁴⁵ The presence of xylazine in illicit fentanyl has thus complicated overdose management, necessitating more comprehensive emergency response strategies. ⁴⁵

Management and prevention

The diagnosis of combined xylazine and fentanyl intoxication can be particularly challenging because, despite newer development of the first immunoassay test designed to detect xylazine, most standard and ubiquitous 5-drug urine tests do not detect these drugs. Moreover, rapid metabolization of xylazine can often lead to false negative results. Gas chromatography-mass spectrometry is often employed in the diagnosis of xylazine intoxication, but it is often costly and takes approximately 7–8 days for results to return. Fentanyl can be detected using a specialized opioid test with a turnaround time of minutes; emergency department clinicians should maintain a high index of suspicion for xylazine intoxication, especially in patients with history of polydrug abuse, to facilitate early anticipation and management of complications. ²² Once xylazine with fentanyl intoxication is suspected, treatment primarily involves administering IV or intranasal naloxone every 3–5 min to counteract the effects of fentanyl. Supportive care for xylazine-induced symptoms includes intubation or supplemental oxygenation for respiratory failure, atropine for bradycardia, vasopressors and IV fluids for shock, lidocaine or defibrillation for arrhythmias, and regular electrolyte monitoring.^45–47

Patients who abuse fentanyl and xylazine often become dependent on these drugs, such that The White House Office of National Drug Control Policy (ONDCP) has labeled the drug combination an emerging threat to the United States. In response, various strategies to address this crisis have been put forth, including greater emphasis on community-based stakeholders and allocating funds toward centers with point-of-care testing for xylazine with xylazine test strips, Quadruple time of Flight Spectroscopy Fourier-Transform Infrared Spectroscopy.^48–50 Point-of-care testing centers are often equipped with reformed addicts, who foster a more empathetic and collaborative approach to rehabilitation and serve to implement additional harm reduction measures, such as educating patients about dangers of syringe sharing, measures to stay safe, and promoting regular health maintenance. These centers also provide adequate resources to implement these measures such as HIV rapid test kits and single-use syringes. ⁵¹ Furthermore, ONDCP has taken significant steps to encourage the use of community-based naloxone by approving naloxone as a nonprescription over-the-counter drug in 2023, along with the social media campaign “Real Deal on Fentanyl.” The campaign, offered in English and Spanish, encourages public settings such as airports and music festivals to carry opioid reversal kits and provide naloxone free of cost. ⁵²

Additionally, the ONDCP has taken multiple steps in providing rehabilitation centers equipped with withdrawal treatments for people battling addiction; unfortunately, given the novelty of xylazine intoxication in humans, research on its effects and antidotes is limited and ongoing. For xylazine withdrawal, the current regimen consists of buprenorphine or methadone used in combination with alpha-2 agonists (dexmedetomidine, tizanidine, or clonidine).^45,47 Atipamezole and yohimbine, both alpha-2 receptor antagonists, have also demonstrated potential as antidotes for xylazine overdose. Atipamezole combined with naloxone has shown promise in reversing xylazine-fentanyl effects in animals, although yohimbine’s efficacy with naloxone has been unsatisfactory.^53–55 Undertreatment of opioid overuse disorder may be due to gaps in knowledge and awareness in both healthcare workers and people who use drugs (PWUDs). However, appropriate utilization of novel therapeutics (Table 1) for OUD by primary care physicians in innovative models such as mobile methadone units and technology-assisted buprenorphine clinics can help minimize gaps in awareness and overcome barriers to OUD undertreatment. ⁵⁶

Table 1.

Drugs for treatment of OUD.

S.no.	Drugs for OUD treatment	Special features
1.	Methadone (synthetic opioid agonist)	Stabilizes mu receptors and has been shown to decrease opioid overuse along with all-cause mortality in OUD patients
2.	Buprenorphine (semisynthetic, partial opioid agonist)	High affinity to mu receptors, increases compliance of treatment, and reduces all-cause mortality in OUD patients
3.	Extended release naloxone (opioid receptor antagonist)	Used mainly in preventing relapse in newly reformed PWUD needs a 7–10 day drug-free period to initiate treatment

Source: Lui et al. ⁵⁶

Limitations

While this narrative review provides a comprehensive analysis of the emerging crisis posed by the xylazine-fentanyl combination, it has several limitations. First, the rapidly evolving nature of illicit drug-use patterns presents challenges in maintaining the most up-to-date epidemiological data. The prevalence of xylazine-adulterated fentanyl varies regionally, and real-time surveillance mechanisms are still being developed. Second, the lack of randomized controlled trials and extensive clinical studies on xylazine-fentanyl intoxication limits the availability of high-quality evidence regarding effective treatment strategies. Much of the existing knowledge is derived from case reports, observational studies, and forensic toxicology reports, which may introduce selection bias and inconsistencies in clinical data. Third, as a narrative review, this study is inherently susceptible to potential biases in the selection and interpretation of the literature, as it does not follow the rigorous, predefined methodological approach of a systematic review. This could affect the comprehensiveness and objectivity of the findings. Fourth, the variability in toxicological screening methods and reporting standards across different states and healthcare institutions further complicates a standardized understanding of xylazine-related fatalities. The review’s scope, while aiming to be broad, may not have captured every nuance of the complex interplay between xylazine and fentanyl due to the dynamic nature of the available research and the constraints of synthesizing a large body of information. Lastly, although we discuss potential harm reduction strategies and policy interventions, the effectiveness of these measures remains difficult to quantify due to limited longitudinal studies. Future research should focus on developing targeted antidotes, refining overdose management protocols, and improving surveillance systems to combat this growing public health emergency effectively.

Conclusions

The growing epidemic of illicitly manufactured fentanyl, especially when combined with xylazine, poses a severe public health risk in the United States. This combination not only increases the risk of fatal overdoses but also complicates clinical management due to unique pharmacological interactions and the limitations of standard overdose treatments. The surge in xylazine-fentanyl–related deaths underscores the need for expanded public health initiatives, more widespread drug testing, improved treatment methods, and enhanced surveillance, particularly for adolescents and young adults. The rapid geographic spread of these substances, initially concentrated in the Northeast, now affects all U.S. states and correlates with a notable increase in overdose mortality nationwide.

Conventional toxicological testing frequently fails to identify xylazine, making prompt medical intervention more difficult and necessitating more sophisticated diagnostic methods. A multifaceted strategy is needed to address this issue, including increased availability of life-saving medications like naloxone, harm reduction strategies, and robust public health surveillance. Government programs have been essential, especially those run by the White House ONDCP. The ONDCP advocates for more community-based interventions, such as making naloxone available over-the-counter, as the fentanyl-xylazine combination remains an emerging hazard. Efforts also have included the establishment of testing centers with point-of-care diagnostics and launching educational campaigns to raise public awareness. Additionally, long-term prevention of substance abuse involves addressing the underlying socioeconomic and environmental conditions that contribute to its prevalence. Innovative treatments, such as opioid agonists and antagonists, are essential for management of addiction and decreasing the rising percentage of Americans with OUD. Coordinated action by the government and healthcare systems is paramount so these extensive measures can be implemented in such a way that they can curb this public health emergency.

This article highlights the importance of ongoing research, policy reform, and public health initiatives in addressing the escalating crisis and protecting vulnerable populations from the devastating consequences of these illicit drug combinations. Advancing our understanding of the pathophysiology behind biological interactions with drug combinations like fentanyl and xylazine offers hope for more targeted and effective treatments. This involves a continued evolution in research and policy, with a focus on root causes of drug abuse, and an emphasis on vigilance and adaptability in public health strategies to combat this complex and evolving threat.