Xylazine is a veterinary sedative used to anesthetize large animals. It is not approved for human use, has no antidote, and cannot be reversed by naloxone. Beginning around 2019 in Philadelphia and spreading rapidly to every region of the United States, xylazine began appearing as an adulterant in the illicit fentanyl supply — creating a new and more dangerous drug combination that emergency physicians were not trained to treat and that existing overdose response protocols were not designed to handle.
The opioid epidemic has moved in waves. The first wave was prescription opioids. The second was heroin. The third was illicitly manufactured fentanyl. The fourth — the one that emergency physicians are now confronting — is fentanyl adulterated with xylazine, a veterinary tranquilizer that prolongs sedation, causes severe necrotic skin wounds, and cannot be reversed by the drug that has saved hundreds of thousands of opioid overdose victims. Each wave has been deadlier than the last. This one may be the most difficult to treat.
Xylazine (pronounced ZY-luh-zeen) is an alpha-2 adrenergic agonist used in veterinary medicine as a sedative, analgesic, and muscle relaxant. It is commonly used to anesthetize horses, cattle, and other large animals for procedures. It is not approved by the FDA for human use, and its effects in humans differ significantly from its effects in animals.
In humans, xylazine causes profound sedation, respiratory depression, bradycardia, and hypotension. It also causes severe, distinctive skin wounds — necrotic ulcers that can appear at injection sites and, unusually, at sites distant from the injection point, suggesting a systemic vascular mechanism. These wounds can progress to deep tissue necrosis requiring surgical debridement and, in severe cases, amputation.
Critically, xylazine is not an opioid and is not reversed by naloxone (Narcan). When a person overdoses on a fentanyl-xylazine combination, naloxone will reverse the fentanyl component — but the xylazine sedation will persist. A patient who receives naloxone and does not wake up, or who wakes up briefly and then loses consciousness again, may be experiencing xylazine toxicity. Emergency physicians who are not aware of this distinction may administer repeated doses of naloxone without effect, delaying recognition of the true clinical picture.
Xylazine first appeared in significant quantities in the illicit drug supply in Puerto Rico in the early 2000s, where it was used as an adulterant in heroin. It remained largely confined to Puerto Rico for more than a decade. Beginning around 2019, it began appearing in the fentanyl supply in Philadelphia — a city that was already experiencing one of the highest per-capita overdose death rates in the United States.
The spread from Philadelphia was rapid. By 2021, xylazine was detected in the drug supply in more than 30 states. By 2023, the DEA reported that xylazine-fentanyl combinations had been detected in all 50 states. The Drug Enforcement Administration designated xylazine-fentanyl as an "emerging threat" in 2022, and the White House Office of National Drug Control Policy declared it a "serious threat to public health" in 2023.
The reasons for xylazine's spread are not fully understood, but several factors appear to have contributed. Xylazine is cheap and widely available — it is used in veterinary practices across the country and is not a controlled substance, meaning it can be purchased without the regulatory scrutiny that applies to opioids. Drug suppliers appear to add it to fentanyl to extend the duration of the high, since xylazine's sedative effects last longer than fentanyl's. Users who become dependent on the xylazine component may seek out xylazine-containing products specifically.
The Naloxone Problem
Naloxone (Narcan) is the cornerstone of opioid overdose response — a drug that reverses opioid toxicity within minutes and has saved hundreds of thousands of lives. It does not work on xylazine. When a person overdoses on fentanyl-xylazine, naloxone will reverse the fentanyl component, but the xylazine sedation will persist. Bystanders and first responders who administer naloxone and see partial or no response may not recognize that xylazine is involved. The clinical guidance is to administer naloxone regardless — it will still help with the fentanyl component — but to recognize that persistent sedation after naloxone suggests xylazine involvement and requires additional supportive care.
The most distinctive and devastating clinical feature of xylazine exposure is the skin wounds it causes. These wounds — deep, necrotic ulcers that can appear at injection sites and at distant sites — are unlike the wounds caused by other injected drugs. They are slow to heal, prone to infection, and can progress to osteomyelitis (bone infection) and sepsis. In severe cases, they require surgical debridement, skin grafting, and amputation.
The mechanism of xylazine-associated wounds is not fully understood. The leading hypothesis is that xylazine causes vasoconstriction — narrowing of blood vessels — that reduces blood flow to the skin and underlying tissue, causing ischemic necrosis. The appearance of wounds at sites distant from injection points supports a systemic vascular mechanism rather than a purely local one.
Emergency departments in cities with high xylazine prevalence — Philadelphia, Baltimore, New York, and increasingly cities across the South and Midwest — have seen a significant increase in patients presenting with severe skin and soft tissue infections related to xylazine use. These patients require wound care, antibiotics, and often surgical consultation — a level of care that is resource-intensive and that many patients, who are unhoused or lack stable housing, cannot access on an outpatient basis.
The wound crisis has created a new challenge for harm reduction programs. Needle exchange programs, which were designed to reduce the transmission of bloodborne infections, have had to adapt to provide wound care supplies and education. Several cities have established dedicated wound care clinics for people who use drugs, recognizing that the standard wound care infrastructure is not accessible to this population.
Emergency physicians have had to rapidly adapt their approach to opioid overdose to account for xylazine. The key clinical changes include: recognizing that persistent sedation after adequate naloxone dosing suggests xylazine involvement; providing supportive care (airway management, ventilatory support) for xylazine-related respiratory depression; and assessing for and treating the skin wounds that are a hallmark of xylazine exposure.
ACEP issued guidance on xylazine management in 2023, recommending that emergency physicians maintain a high index of suspicion for xylazine in any patient presenting with opioid overdose who does not respond fully to naloxone, and that they assess all patients with known or suspected xylazine exposure for skin wounds even if the patient does not report them.
The treatment of xylazine toxicity is supportive — there is no antidote. Atipamezole, an alpha-2 antagonist used in veterinary medicine to reverse xylazine in animals, has been studied in small case series in humans, but there is insufficient evidence to recommend its routine use. Research into xylazine antidotes is ongoing, but the timeline for an approved human antidote is uncertain.
The federal response to the xylazine crisis has been complicated by the fact that xylazine is not a controlled substance. Scheduling xylazine under the Controlled Substances Act would restrict its availability for legitimate veterinary use — a significant concern given its importance in large animal medicine. The DEA has proposed scheduling xylazine as a Schedule III controlled substance, but as of 2026 the scheduling process has not been completed.
The White House ONDCP's 2023 "Xylazine Action Plan" called for enhanced surveillance, development of point-of-care testing for xylazine, research into antidotes, and expansion of wound care services. The FDA has approved a rapid fentanyl test strip for use in harm reduction settings; similar test strips for xylazine are in development but not yet widely available.
The xylazine crisis illustrates a recurring pattern in the opioid epidemic: the drug supply evolves faster than the regulatory and clinical response. Fentanyl replaced heroin before the healthcare system had adapted to fentanyl. Xylazine entered the fentanyl supply before the healthcare system had adapted to xylazine. The next adulterant — nitazenes, a class of synthetic opioids more potent than fentanyl, have already been detected in the drug supply — may arrive before the response to xylazine is complete.
50
States where xylazine-fentanyl has been detected (2023)
2019
Year xylazine first appeared significantly in Philadelphia drug supply
0
FDA-approved antidotes for xylazine in humans
36%
Of fentanyl samples in Philadelphia containing xylazine (2022)
~25%
Of overdose deaths in some Eastern cities involving xylazine (2023)
N/A
Xylazine scheduling status — not yet a controlled substance (2026)
Key signs suggesting xylazine involvement:
Management: