Rapid changes in the illicit drug supply, including additives and contaminants, can have profound clinical impacts. Xylazine is a veterinary sedative that has been added to opioids since 2001 to intensify the euphoric effects and is implicated in sedation, withdrawal, and chronic skin wounds.¹ Since 2024, a new additive, medetomidine, has increasingly replaced xylazine and has been implicated in overdose and complicated withdrawal in several major metropolitan areas (eg, Chicago, Pittsburgh, Philadelphia) and is likely spreading to other regions.²

Like xylazine, medetomidine is a veterinary sedative and synthetic alpha-2 adrenoreceptor agonist but is up to 300 times more potent.³ Medetomidine is related to the human medication dexmedetomidine, a commonly used sedative and anesthetic in the intensive care unit (ICU). Medetomidine does not appear to cause the wounds typically seen with xylazine use. Xylazine and medetomidine are not included in standard urine drug testing. The levels of adulterants in the drug supply can fluctuate, causing unexpected intoxication and withdrawal.⁴

Medetomidine intoxication is similar to, but more potent than, other alpha-2 adrenoreceptor agonist intoxications (eg, from clonidine), causing hypotension, bradycardia, and prolonged sedation. Medetomidine is metabolized by the liver, and plasma levels peak within 10 to 30 minutes of ingestion. Its effects can last several hours but can be prolonged by concurrent opioid exposure.

Naloxone administration is the foundation of acute opioid overdose response, even if concurrent medetomidine intoxication is suspected. Given the risks of sedation and respiratory suppression related to medetomidine, ongoing airway protection and other supportive care measures may be required after opioid reversal from naloxone administration.⁴

Medetomidine withdrawal symptoms can begin abruptly within hours of use, peaking within 18 to 36 hours. Medetomidine withdrawal can cause profound tachycardia, hypertension, vomiting, and altered mental status. Vital signs can fluctuate rapidly from hypotension and bradycardia caused by direct alpha-2 effects to hypertension and tachycardia a few hours later as withdrawal occurs. Hospitalization may be required for abnormal vital signs that occur during withdrawal. ICU-level care may become necessary due to neurologic changes requiring more frequent monitoring, inability to tolerate medications by mouth, or hypertensive emergency with end-organ damage (eg, posterior reversible encephalopathy syndrome, non–ST elevation myocardial infarction).⁵

Treatment of medetomidine withdrawal includes alpha-2 agonist therapy with oral and/or transdermal clonidine, oral tizanidine, oral guanfacine (Intuniv), and escalation to intravenous dexmedetomidine, which often requires ICU monitoring. Doses required may exceed typical upper limits of prescribing. Optimal tapering strategies are unknown but may take days to weeks. Severe nausea and vomiting are common with medetomidine withdrawal and can be treated with antiemetics such as ondansetron and prochlorperazine or antipsychotics such as olanzapine (Zyprexa). Treatment of medetomidine withdrawal does not replace treatment of opioid withdrawal using medications for opioid use disorder (MOUD), opioid agonists, and supportive medications.⁶

There are no prediction rules based on patient characteristics or quantity of substances used to determine who is at higher risk of severe medetomidine withdrawal. In our clinical setting, where medetomidine contamination is ubiquitous, we routinely prescribe oral alpha-2 agonists for outpatient initiation of MOUD to proactively treat alpha-2 agonist withdrawal. We also counsel patients on which signs and symptoms of medetomidine withdrawal should prompt escalation of care.

The adage that opioid withdrawal is uncomfortable but not dangerous is no longer always accurate in the context of a contaminated and poisoned drug supply, and people who primarily use opioids can have dangerous withdrawal from nonopioid contaminants. The most important intervention for opioid use disorder is MOUD, and treating medetomidine withdrawal safely and proactively can support patients in the transition to MOUD.

Physicians working with a population that actively uses illicit drugs should consider reaching out to the local public health department and social services organizations to learn about real-time changes in the local drug supply. Drug checking is increasingly available and provides a way for people who use drugs to find out what contaminants are present in their drugs. This can be done using testing strips for a single contaminant or laboratory techniques that test for multiple contaminants and provide early detection for new clinically relevant contaminants.⁷

Patients who continue to use drugs should be educated on the risks associated with a changing supply such as complicated withdrawal, in addition to other important tenets of safety such as naloxone use; sterile syringes; safer injection techniques; not using drugs alone; hepatitis C testing and treatment; HIV testing, treatment, and prevention; and connections to community resources.⁸