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. 2025 Jun 6;34(6):589–602. doi: 10.1111/ajad.70051

Management of xylazine toxicity, overdose, dependence, and withdrawal: A systematic review

Philipa Owusu‐Antwi 1,✉, Priya Atodaria 2, Edmund Appiah‐Kubi 3, Zainab Shah 1, Elpidio Marlon Garcia 1
PMCID: PMC12555106  PMID: 40476542

Abstract

Background and Objectives

Xylazine, an alpha‐2‐adrenergic agonist, has been increasingly implicated in substance use and overdose crises. However, little is known about its effects on humans. With the growing public health crisis surrounding xylazine, it has become important to recognize and promptly manage symptoms of xylazine toxicity, withdrawal, and overdose. We conducted a systematic review to consolidate the existing literature on the topics, aiming to identify gaps and propose evidence‐based actions for managing patients.

Methods

Published literature from 1957 to 2024 was searched to identify studies focusing on the management of xylazine intoxication, withdrawal, overdose, and dependence in humans. PRISMA guidelines and JBI critical appraisal tools were used to ensure the methodological quality of the included studies and reduce bias in study selection. Thirty‐four studies were included in this review.

Results

Xylazine misuse was common among men aged 19–45 years and was more likely to be used with other substances than alone. The doses ranged from 40 to 4300 mg, with no established toxic dosing. Supportive care included treatment with naloxone, alpha‐2 agonists, and GABAergic medications. There is no antidote or evidence‐based treatment recommendations.

Discussion and Conclusions

This systematic review consolidated the outcomes and proposed guidelines from xylazine management trials. It can serve as a reference for providers to promptly manage xylazine toxicity, withdrawal, and overdose symptoms to improve patient outcomes.

Scientific Significance

Although there is currently no standardized treatment or antidote, this review will aid ongoing research to address these gaps in xylazine management.

Short abstract

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INTRODUCTION

Xylazine is a potent alpha‐2 adrenergic agonist that is marketed as a veterinary sedative. Its action on alpha‐2 receptors in the central nervous system (CNS) reduces the release of norepinephrine and dopamine, resulting in sedation, decreased pain perception, and muscle relaxation. In humans, xylazine can cause CNS and respiratory depression, bradycardia, hypotension, and even death. 1 Unique effects associated with xylazine include hyperglycemia and QT interval prolongation. 2 The drug also shows affinity for cholinergic, serotonergic, dopaminergic, alpha‐1 adrenergic, histaminergic, and opioid receptors. 3 , 4

While the pharmacokinetics of xylazine are well studied in animals, data in humans remains limited. Animal studies indicate that the drug undergoes extensive metabolism, has a high volume of distribution, and is rapidly distributed and eliminated. Its effects begin within minutes and can last up to 4 h. 2 , 5 Limited human studies have identified xylazine's metabolites in urine samples. 3

Xylazine is currently a noncontrolled substance, 6 but it is frequently mixed with cocaine and heroin. It has been a subject of misuse in various contexts, including attempted sexual assault, horse‐doping, and both accidental and intended overdoses. 1 According to Hoffman, 2 xylazine is increasingly contributing to the fentanyl crisis. It has been linked to severe wounds, necrosis, and amputation. The risk of fatal overdose increases when xylazine is combined with fentanyl or heroin, as it can potentiate both sedative effects and respiratory depression. 7 Management of acute xylazine toxicity primarily focuses on supportive treatment, such as maintaining the airways and blood pressure. In opioid overdose involving xylazine, naloxone is ineffective against respiratory depression, although it remains effective in reversing opioid effects. 3 Kariisa et al. 7 highlight the need for further research to understand the role of xylazine in the evolving United States (U.S.) overdose crisis.

OBJECTIVES

  • 1.

    To synthesize, clarify, and consolidate the existing literature on xylazine toxicity, withdrawal, and overdose management.

  • 2.

    To identify existing gaps in the literature on xylazine misuse sequelae management and proposed actions.

  • 3.

    To propose management for xylazine toxicity, withdrawal, and overdose based on the review findings, thereby informing clinical practice by helping clinicians develop a literature‐informed protocol for assessment and stabilization.

METHODS

We independently screened eligible publications across all study designs following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations. We evaluated primary studies, such as cohort, case‐control, randomized clinical trials, case series, and reports published between 1957 and 2024, to investigate the proposed management for xylazine intoxication, withdrawal, overdose, and dependence. Publications with participants of all ages, genders, races, ethnicities, or nationalities were included. Exclusion criteria were nonevidence‐based expert recommendations, studies involving nonhuman subjects or in vitro studies, studies with unreliable data extraction, studies with duplicate or overlapping data, abstract‐only papers published before primary papers, editorials, author response theses, and articles without full text.

We searched PubMed, PubMed Central (PMC), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Google Scholar, and Embase using search terms and Boolean operators, including “xylazine toxicity,” “xylazine toxicity management,” “xylazine intoxication,” “xylazine intoxication treatment,” “xylazine overdose,” “xylazine overdose treatment,” “xylazine dependence treatment,” “xylazine AND dependence,” “(‘xylazine’/exp OR ‘xylazine’) AND toxicity AND (‘treatment’/exp OR treatment) AND human NOT animals,” “xylazine AND (intoxication OR withdrawal) AND [humans]/lim.”

The studies were selected based on title screening, abstract review, and full‐text synthesis of all relevant papers that met the inclusion criteria. A third team member performed a blind independent search and review to ensure that no critical studies were missed and conflicts were resolved through discussion. Figure 1 shows the PRISMA flow diagram.

Figure 1.

Figure 1

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PRISMA flow diagram. Source: Page MJ, et al. BMJ 2021;372:n71. 10.1136/bmj.n71. This study is licensed under CC BY 4.0.

We independently evaluated the studies that met our inclusion criteria using the Joanna Briggs Institute (JBI) critical appraisal tools. 8 Table 1 summarizes and reviews the matrices of the included studies. A gap analysis was conducted, highlighting areas requiring further research on this public health crisis and potential actions to address them (Figure 2).

Table 1.

Summary of included studies.

Author JBI score Reported past psychiatric history Route Dose Toxicology/reported substances Symptoms Management used or recommended Outcome After care
Carruthers et al. 9 100% Depression Injection 10 mL of a 100 mg/mL solution Not reported Comatose, apneic, areflexic, moderate‐sized/sluggish pupils, flexor plantar responses sinus bradycardia. Widespread T wave flattening, CPK 597 u/L, LDH 529 u/L, premature ventricular contractions Endotracheal intubation, ventilation with a Bird respirator, IV fluids, bladder catheterization, central venous pressure monitoring, lidocaine infusion Resolution None reported
Gallanosa et al. 10 100% Case 1 ‐ chronic depression with two previous suicidal attempts Oral 4 mL Xylazine Drowsy, incontinent of urine, difficult to arouse, dizziness and weakness, bradycardia, temperature of 36.8 C, bradypnea, miosis, generalized hyporeflexia, hyperglycemia Naloxone (2 mg), endotracheal intubation, mechanical ventilation, saline cathartics, activated charcoal Resolution None reported
Case 2 ‐ none Injection 1 g Not reported Areflexia, apnea, coma, sinus tachycardia w/multifocal PVCs, hyperglycemia, CNS depression Lidocaine infusion Resolution None reported
Mackintosh et al. 11 100% None for all cases Case 1‐ injection 0.5 mL (30 mg xylazine, 5 mg fentanyl, and 40 mg azaperone) Toxicology: not reported Reported: 30 mg xylazine, 5 mg fentanyl, and 40 mg azaperone Unconscious Naloxone, tolazoline, yohimbine 0.125 mg/kg IV Resolution None reported
Spoerke et al. 12 100% None for all cases Case 1 ‐ IM 0.73 mg/kg Not reported Bradycardia, hypotension, miosis, disorientation, hypotension Spontaneous resolution before treatment Resolution None reported
Case 2 ‐ IM 22 mg/kg Bradycardia, hypertension, somnolent but arousable, apneic Intubation, mechanical ventilation, oxygen, naloxone 1.6 mg Psychiatric treatment
Case 3 ‐ IV Undertemined Apneic, hypertension, bradycardia Intubation, mechanical ventilation, naloxone 2 mg None reported
Samanta et al. 13 100% None Subcutaneous 2 mL Not reported Comatose, hypotensive, bradycardic, acidotic, sluggish and small pupils, bradycardia, hypotension, bradypnea, cyanosis, hyporeflexic, downgoing plantar responses Naloxone 1.2 mg, IV fluids, assisted ventilation Resolution None reported
Mittleman et al. 14 75% None for all cases Injection & hypodermic dart gun 18 mL Toxicology: xylazine, ethanol Reported: ethanol Not reported Not reported Death None reported
Capraro et al. 15 100% None Inhalation Unknown Toxicology: Benzodiazepine Reported: Alcohol Coma, unresponsiveness, miosis, shallow respirations, apnea, bradycardia, hypothermia, hypotonia, reduced reflexes, dry mouth 2 mg naloxone, IV fluids, thiamine, and activated charcoal, intubation Resolution None reported
Hoffmann et al. 4 100% None IM 1.5 g/75 mL Toxicology: Xylazine Comatose, hypotensive, bradycardic, and mildy glycemic, HR 88 bmp BP 180/100 mmHg, miosis Intubation, mechanical ventilation, gastric lavage, activated charcoal, cathartics, etomidate, propofol, orciprenaline, metoclopramide, ranitidine, IV fluids Resolution Psychiatry consult
Elejalde et al. 16 100% None Inhalation Unknown Negative Chills, dizziness, sweating, gait instability, palpitations, syncope, sinus bradycardia, hypotension, disorientation, dysarthria, dysmetria, ataxia, intermediate‐sized reactive pupils Intravenous fluids Resolution None reported
Arican et al. 17 100% None IM 15 mL xylazine, 10 mL ketamine Negative Vomiting, hypersalivation, constipation, dizziness, narrow pupils, diminished reflexes, sluggish movements, creatine kinase 1548 U/L and glucose 148 mg/dL, sinus tachycardia at 130/bpm, inverted T waves in D2‐ D3‐AVF and V1‐6 leads IV fluid, close monitoring, telemetry, 100 mg metoprolol succinate, transfer to psych Resolution Phone call after 1 month
Velez et al. 18 100% None Accidental eye irrigation 800 mg of xylazine (8 mL of the 100 mg/mL solution) Not reported Bradycardia, hypotension, decreased level of consciousness Extensive eye irrigation, cardiovascular monitoring, IV fluids, telemetry Resolution None reported
Liu et al. 19 100% Chronic use of antacids and sulpiride IV 762 mg/L Toxicology: Xylazine Reported: Sulpiride, 582 mg/L of Ketamine, 448 mg/L of Norketamine, 745 mg/L of Phenobarbital Syncope, blurred vision, ataxia, dizziness, sinus bradycardia, orthostatic hypotension Echocardiography, 24‐h Holter ECG, nerve conduction test, sympathetic skin response, IV fluids Resolution None reported
Bayramoglu et al. 6 100% Multiple suicide attempts IV 500 mg ethanol unconscious, GCS of 3, pulseless electrical activity, tachycardia, VF, hypocapnea CPR, monitoring, defibrillation Death Not applicable
Mizerova et al. 20 100% None Oral Unknown Not reported Case 1 ‐ bradycardia, mildly altered consciousness (GCS 11) 1.5 mg Atropine for bradycardia Resolution None reported
Case 2 ‐ altered consciousness (GCS ‐ 8), hypoventilation, gastrointestinal symptoms, mild hyperglycemia Intubated and mechanical ventilation
Meyer et al. 21 100% None Accidental Injection 0.3 mg/L Toxicology: Xylazine, Ketamine. Reported: Ketamine Loss of consciousness (GCS ‐ 3) Intubated, ventilated Resolution None reported
Snow et al. 22 100% None IV 10 mL of the 50 mL bottle Not reported Heart rate 45 bpm, sinus bradycardia with persisting QT prolongation (490 ‐ 714 msec), serum potassium was 5 mEq/L, diffuse T wave flattening or inversion, and frequent premature ventricular contractions Intubated, intensive care unit admission Resolution None reported
Forrester et al. 23 100% None Injection, oral, dermal, ocular, inhalation Not reported Reported: ketamine, tiletamine, zolazepam, alcohol, butorphanol, cocaine, pentobarbital, phenytoin, xylazine Drowsiness, lethargy, bradycardia, hypotension, hypertension, puncture or wound, slurred speech IV fluids, dilution or irrigation or wash, oxygen, naloxone Resolution None reported
Mulders et al. 24 100% Chronic methylphenidate (mild) and xylazine use (severe), mild depressive episode Injection Unknown Not reported Clenching of the jaw and grinding of his teeth, depressed mood, muscle twitching and restlessness at onset, and later mild fatigue and increased appetite, blood pressure and pulse were stable at approximately 130/85 mmHg and 60–70 bpm; severe cognitive impairments Dutch detoxification, clonidine, other alpha‐two agonists, MRI, LP Resolution with severe cognitive deficits None reported
Krongvorakul et al. 25 100% None Oral Unknown Xylazine Case 1 ‐ drowsy, bradycardia, RR 20 breaths/min, pupils 1 mm diameter Gastric lavage, activated charcoal, supportive care Resolution None reported
Case 2 ‐ drowsy, hypotension, pupils 1 mm diameter, sinus bradycardia IV fluids, 0.6 mg of atropine IV Resolution with persisting bradycardia for one month
Case 3 ‐ hypertension, tachypnea pupils 2 mm diameter, slurred speech, atrial fibrillation, suspected stroke, orthostatic hypotension CT Head, ICU admit Resolution
Johnson et al. 26 100% None Not reported Not reported Toxicology: Xylazine General symptoms discussed Intubation, ventilation, IV fluids, naloxone Not applicable Not applicable
Gill et al. 27 100% None Unspecified accidental exposure Unknown Toxicology: Immunoassay Drug of abuse ‐ negative. GC‐MS ‐ xylazine and fentanyl. Reported: Fentanyl Loss of consciousness, altered mental state, respiratory distress, hypopnea, pinpoint pupils, brief desaturations, headache Bag valve mask ventilation, nasal cannula; cardiology, pulmonary, and neurology consultations Resolution Neurology, repeat MRI and electroencephalogram
Ehrman‐Dupre et al. 28 100% Opioid use disorder and chronic xylazine use IV 10 mg/L Toxicology: Tramadol, fentanyl, xylazine Reported: Heroin, fentanyl Restlessness, rigors, dysphoria, bilateral lower extremity exudative wounds, tissue loss, necrosis, pain Dexmedetomidine, tizanidine, clonidine, buprenorphine, phenobarbital, hydromorphone, gabapentin, ketamine Resolution with wound pain Follow‐up with the Addiction Medicine and General Surgery teams
Jiang et al. 29 100% None Oral, inhalation, smoking, injection Not reported Reported: polysubstance use; majority xylazine alongside illicitly manufactured fentanyl or heroin Not reported Naloxone Not reported None reported
D'orazio et al. 30 100% None Not reported Not reported Not reported General symptoms discussed Supportive airway management, pulse oximetry, and/or capnometry. Opioid withdrawal management; Primary ‐ clonidine. Secondary ‐ Olanzapine, Gabapentin, Phenobarbital, Dexmedetomidine Not applicable Not applicable
Deutsch et al. 31 100% Case 1 ‐ maternal use of amphetamines, fentanyl, cocaine, methadone and neonatal opioid withdrawal syndrome. Prenatal exposure Unknown Toxicology: morphine, noroxymorphone metabolites, xylazine Reported: morphine, noroxymorphone metabolites Unresponsive, limp, blue, bradycardia, apnea Naloxone Resolution Child Protective Services
Case 2 ‐ maternal use of amphetamines and methamphetamines Toxicology: fentanyl, norfentanyl, xylazine Reported: fentanyl, norfentanyl Unresponsive, pinpoint pupils, agonal respirations, mild tachycardia, bradypnea, episodic tachycardia, hypertension Naloxone
Case 3 ‐ maternal opioid use and neonatal opioid withdrawal syndrome Toxicology: acetyl fentanyl Reported: acetyl fentanyl Labored breathing, cyanotic, hypothermic, hypotensive LP, antibiotics, intubation
Boyce et al. 32 100% Opioid use disorder Not reported Not reported Reported: fentanyl Febrile (102.3 F), hypertensive, tachycardia, agitated with poor ventilator synchrony, carboxyhemoglobin level of 31.7% Emergent hyperbaric oxygen therapy, fentanyl, propofol infusions, intubation, mechanical ventilation, dexmedetomidine infusion, clonidine Resolution None reported
Knopf 33 100% None Not reported Not reported Reported: opioids and/or stimulants CNS depression, hypotension, bradycardia, chronic skin lesions Not reported Not reported None reported
Robbins‐Welty 34 100% Polysubstance use (opioids, cocaine, benzodiazepines, Tetrahydrocannabinol, methamphetamine, and tobacco) Not reported Unknown Toxicology: Xylazine, Fentanyl, and Bromazolam Reported: Benzodiazepine/Heroin Cyanosis Naloxone, Buprenorphine, Lorazepam Resolution with persisting asymptomatic bradycardia Substance use rehabilitation treatment center
London et al. 35 100% None Not reported Unknown Toxicology: fentanyl, cocaine, and amphetamine use Psychomotor agitation and anxiety Alpha‐2 agonists, GABAergic agents, guanfacine Mild and self‐resolving complications, severe acute medical pathology, and concomitant polysubstance withdrawal None reported
Nwodim et al. 36 100% Opioid Use Disorder Not reported Unknown Toxicology: Fentanyl, Xylazine, Benzodiazepine (prescribed), and Tetrahydrocannabinol Left lower extremity pain, weakness, new acute bilateral hearing loss, electrolyte derangements, tachycardia, creatine kinase was 149,000 U/L, headache, lethargy, and bradycardia. Acute hydrocephalus, and mass effect with signs of impending herniation. 4 L of intravenous crystalloid fluid, insulin, D50, calcium gluconate, bicarbonate, vancomycin, piperacillin‐tazobactam, and morphine. Emergent sub‐occipital decompressive craniectomy and external ventricular drain (EVD) placement, followed by hypertonic saline therapy Resolution Rehabilitation
Wu et al. 37 100% None Not reported Not reported Not reported General symptoms discussed Clonidine, benzodiazepines, or gabapentin. Specialized addiction care Not reported None reported
Morris et al. 38 100% Substance use (unknown) IM 2cc at 100 mg/mL Toxicology: amphetamines. Reported: amphetamines Difficult to arouse, hypertension Naloxone 2 mg Resolution None reported
Haroz et al. 39 100% None Unknown Unknown Toxicology: not reported Reported: fentanyl Anxiety, restlessness, associated wounds Clonidine, tizanidine, dexmedetomidine, supportive care, methadone, buprenorphine Not reported None reported
Dai et al. 40 100% Depression Injection Unknown Not reported 36.8°C (increased to 41C and never resolved), GCS score is 2‐1‐5‐8, constricted pupils, hypotension, diaphoretic, tachycardia, arm scars Torsemide, alanyl‐glutamine, nalmefene hydrochloride injection, insulin, nutritional support, norepinephrine, intubation, mechanical ventilation, flucloxacillin, moxifloxacin, rehydration, IV betamethasone, cooling blanket Death None reported
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Figure 2.

Figure 2

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Gap analysis comparing the current state to desired states, highlighting areas requiring attention and recommended actions.

RESULTS

The search yielded 5219 records, 188 of which were duplicates. A total of 34 studies were selected based on the inclusion criteria. Most studies were case reports (n = 20). The selection also included case series (n = 6), retrospective studies (n = 4), educational letters with recommendations (n = 1), informational articles (n = 2), and narrative reviews with management recommendations (n = 1). Most case reports and series featured male patients (n = 26). Ten cases were younger than 19 years, four were older than 65 years, and three were older than 70 years. Thirteen patients were aged 19–65 years. Cases involving children younger than 10 years and adults older than 70 years were more likely to be accidental, by proxy with criminal intent, or via prenatal exposure (in pediatric cases). For instance, Krongvorakul et al. 25 reported three cases in a population of more than 70. All cases were by proxy with the criminal intent of robbing people of their belongings. Eleven patients had a past psychiatric history, eight had substance use disorders (SUD), and three had more than one psychiatric diagnosis. Opioid use disorder was the most common diagnosis of substance use. This finding is consistent with those in the current literature. According to the Substance Abuse and Mental Health Services Administration (SAMHSA) 2022 national survey, approximately 21.5 million adults in the U.S. with SUD have a co‐occurring mental health disorder. 41 Among the reported cases, fentanyl and heroin were the most frequently detected substances in toxicology tests. Literature shows an increasing number of deaths secondary to the polysubstance overdose crisis in Philadelphia, Maryland and Connecticut. 7 , 42 , 43 Seventeen cases involved intravenous (IV) or intramuscular (IM) injections; five were inhaled, and the rest were oral, with one case involving irrigation.

Toxicology, dosing and route

Toxicology was reported in 18 of 34 studies. Accessible toxicology is essential for managing cases of substance use, including xylazine use, amid increasing adulteration. Studies by Gill et al. 27 and Capraro et al. 15 highlighted toxicology omissions from initial diagnoses due to limited awareness and presentation. Capraro et al., 15 Elejalde et al., 16 and Velez et al. 18 noted that xylazine was often not tested due to its exclusion from standard toxicology and the unavailability of commercial immunoassays. Although the aforementioned cases were nonfatal, toxicity and overdose caused deaths occur and are likely preventable with evidence‐based assessment and management or harm reduction. Currently, there is no FDA‐approved treatment for xylazine misuse sequelae; however, this systematic review presents the recommended guidelines.

According to Ayub et al., 44 overall dose ranged from 40 to 4300 mg. Toxicity and fatality in humans may occur in doses ranging from 40 to 2400 mg, with plasma concentrations from trace to 16 mg/L and 0.03 to 4.6 mg/L in nonfatal cases. The average fatal dose was 1200 mg compared with 525 mg in nonfatal cases. Because there is a significant overlap between nonfatal and postmortem blood concentrations, there appears to be no defined safe, toxic, or fatal concentration of xylazine in humans. 1 , 44 , 45 Intravenous administration remains the most common route of xylazine exposure. 44 In the majority of case reports and series, ingested doses were in the lower range, with symptoms generally resolving without long‐term sequelae. Notable exceptions include cases reported by Hoffman et al. 4 and Liu et al., 19 in which individuals ingested 1.5, 800, and 762 mg/L of xylazine, and experienced significant symptoms such as bradycardia and hypotension, and in the former case, coma necessitating intubation. Dai et al. 40 and Mittleman et al. 14 reported xylazine‐related fatalities due to hyperpyrexia and homicide, respectively, although dosages were not specified.

Adulteration and symptomatology

According to Edinoff et al., 3 Habib et al., 46 and the case reports we reviewed, xylazine was frequently used in combination with fentanyl and other opioids. The opioid‐like effects of xylazine in the CNS may enhance respiratory depression and increase the risk of fatality. 46 This was evidenced by the rising number of xylazine‐related overdose deaths, from 2% to 26% in Philadelphia and 19% and 10% in Maryland and Connecticut, respectively. 46

Nearly all patients exhibited drowsiness, impaired consciousness, and autonomic instability. Electrocardiography often revealed sinus bradycardia. Nwodim et al. 36 presented a unique case of bilateral hearing loss, elevated creatine kinase levels, and multiple electrolyte abnormalities that appeared to be secondary to acute hydrocephalus, requiring craniectomy for decompression and drainage. The authors of this study hypothesized that patients developed these symptoms due to xylazine's ability to cause microvascular obstruction, leading to ischemia in areas such as the auditory processing center. The patient's toxicology test was also positive for fentanyl. Opioids have been shown to cause hydrocephalus, spontaneous abortion, and hearing loss in some cases. 47 , 48 , 49 , 50 Respiratory compromise due to anoxia and encephalopathy can cause edema and hydrocephalus. Considering these effects, one can hypothesize that xylazine overdose may decrease or disrupt cerebral blood flow, potentially leading to hypoxic or ischemic brain damage, edema, or hydrocephalus. 51

Management

The reviewed publications presented different management strategies. All received supportive care, including IV fluids or continuous monitoring. Robbins‐Wetty et al., 34 Johnson et al., 26 Spoerke et al., 12 Deutsch et al., 31 and Forrester et al. 23 administered naloxone due to possible co‐occurrence or suspected opioid toxicity. On the other hand, Nwodim et al. 36 reported that insulin, D50, calcium gluconate, and some antibiotics were given as the patient incidentally tested positive for COVID‐19. Some patients required airway protection via valve mask ventilation, intubation, and mechanical ventilation, whereas others underwent gastric lavage and were administered atropine (Table 1). Eye irrigation was used to manage two cases of xylazine eye exposure. 18 , 23 Alpha‐2 agonists and GABAergic medications were frequently used in the cases reviewed. Dexmedetomidine, clonidine, tizanidine, and gabapentin were used or recommended in previous studies (Table 1).

For the management of xylazine withdrawal, Wu et al. 37 and D'Orazio et al. 30 recommended adjunctive treatments such as benzodiazepine, clonidine, and gabapentin, along with addressing co‐occurring substance use. The goals were to achieve complete well‐being and symptom remission. It was recognized that all symptoms should be addressed, either in inpatients or outpatients. Some studies lacked outpatient follow‐up, while others advised patients to return if symptoms recurred (Table 1). D'Orazio et al. 30 recommended prioritizing opioid withdrawal in xylazine toxicity management as xylazine misuse often co‐occurs with other opioids. Clonidine was recommended as the primary treatment, with alpha‐2 agonist alternatives, such as tizanidine, lofexidine, and guanfacine. Clonidine is a partial and selective alpha‐2 adrenergic agonist that differs from xylazine in its structure, toxicity, and clinical use. It may compete with the shared receptors to reduce the effects of xylazine. Clinically, clonidine stabilizes the autonomic function and supports the treatment of rebound hypertension and withdrawal symptoms, particularly in xylazine dependence. 5 , 52 The recommended starting dose of clonidine is 0.1 mg every 8 h (as the standing dose/prophylaxis), as tolerated by blood pressure. Symptoms requiring caution included sedation, bradycardia, and hypotension. Secondary treatments included olanzapine (2.5 mg starting dose; 2.5–10 mg daily), lorazepam (1–2 mg orally, IV/IM; titrated when in effect), gabapentin (300–600 mg every 8 h and 300 mg once daily at bedtime), phenobarbital (130 mg IV), and dexmedetomidine (≥0.2–1 mcg/kg/h). Dexmedetomidine was administered in a monitored setting once oral alpha‐2 agonists are maximized. Other treatment options included ropinirole (starting dose 0.25–0.5 mg every 8 h), ketamine (10 mg postoperatively every 6 h; 0.3 mg/kg IV over 15 min), and pregabalin (100 mg 3 times per day up to 600 mg 3 times per day). 30 Ropinirole can aid anxiety, muscle relaxation, and motor restlessness (myoclonus), whereas pregabalin is used to treat neuropathic pain and anxiety. Naloxone was commonly administered because xylazine is frequently co‐detected with fentanyl or other opioids in cases of overdose. Most patients in the reviewed cases received naloxone doses from 1.2 to 2 mg (Table 1). The potential synergism is unclear; however, naloxone, although ineffective against xylazine sedation, can treat poisoning from combined opioid‐xylazine use. 45 Table 1 presents a review matrix summarizing the included studies.

DISCUSSION

This is the first review to critically assess and consolidate existing literature on the management of xylazine withdrawal, intoxication, overdose, and dependence. Although there is no current evidence‐based management, multiple recommendations and guidelines have been described, and case reports have shown different management strategies and outcomes. This review summarizes this information and identifies the gaps in knowledge that require further research. Different factors have led to an increase in xylazine overdose, toxicity, and withdrawal, including a lack of knowledge, resources, and primordial and primary interventions.

Numerous studies have explored and evaluated the consequences of xylazine toxicity, withdrawal, dependence, and overdose in animals; however, there is limited literature available focusing on humans. Some studies have shown that xylazine use can lead to cardiac abnormalities such as necrosis, biventricular failure, and valve dysfunction. Another study showed that xylazine use increased reactive oxygen species production in umbilical vein endothelial cells. Diabetes mellitus and pulmonary edema have also been observed. 53 There have been increasing reports of xylazine‐related deaths and an alarming number of fentanyl overdoses amplified by xylazine. 54 Two case reports in Mittleman et al. 14 highlight how xylazine can lead to death. A report showed that xylazine doses of 40 mg or greater can lead to toxicity in humans. This is a consequence of xylazine's alpha‐2 central agonism and a decrease in norepinephrine and dopamine, causing loss of consciousness, bradycardia, hypotension, and CNS depression. Miosis, hypothermia, and hyporeflexia may also be observed. In these cases, higher concentrations of xylazine were found in the patients' liver, brain, and kidneys. Based on the hypothesis and the available evidence, 1800 mg of xylazine may have been used in these cases.

Studies by Gallanosa et al., 10 Mackintosh, 11 as well as Zuba and Greenberg 55 have identified potential antidotes or approaches for symptomatic relief, such as yohimbine, tolazoline, atropine, and atipamezole. In veterinary medicine, alpha‐2 antagonists, such as idaxozan, atipamezole, and yohimbine, have been tested and reported to reverse the effects of xylazine. Atipamezole has been found to be more effective in reversing the effects of xylazine, even in smaller animals. 56 , 57 Moreover, some animal studies have suggested potential strategies for managing combined fentanyl and xylazine toxicity, including the combination of naloxone and atipamezole or the use of naloxone alone. 58 , 59 These findings provide valuable insights for the development of effective treatment approaches. These potential antidotes have also been shown to provide smooth reversal and recovery processes, even at high doses. 55 Zuba and Greenberg 55 highlighted the possibility of reversing the harmful effects of alpha‐2 agonists using naltrexone and atipamezole. However, few studies have tested the efficacy and safety of these potential antidotes in humans. Gallanosa et al. 10 reported that atropine was effective in reversing the bradycardia and hypotension seen in some cases of intoxication, while Mackintosh 11 showed that yohimbine (0.125 mg/kg or less) can be effective in reversing the toxic effects of xylazine as quickly as 15 min after IM administration and approximately 2 min after IV administration. Spoerke et al. 12 showed that tolazoline may also be useful in managing hypotension and unresponsive bradycardia, particularly in unresponsive cases. It is important to note the adverse effects of these potential antidotes. For example, tolazoline can cause arrhythmias, hypertension, and tachycardia; thus, it should be used cautiously in xylazine toxicity, predominantly in severe and treatment‐resistant cases as a last resort. 12 This highlights the importance of further studies to determine its safety and efficacy in humans. The recommended management guidelines for xylazine toxicity, withdrawal, and overdose are shown in Figure 3.

Figure 3.

Figure 3

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Outlines a recommended step‐by‐step process for managing xylazine overdose toxicity and withdrawal. 60 , 61 , 62 , 63 , 64 , 65

LIMITATIONS

Data collection may have been restricted by limited access to certain studies. In addition, critical details were missing from some case studies, such as the route and dosing of xylazine. Furthermore, some studies had to be translated into English; specifically, Mizerová et al. 20

CONCLUSION

The misuse of xylazine is increasing and presents a significant public health concern. This review may serve as a reference for clinicians encountering xylazine‐induced symptoms and making critical decisions to improve patient outcomes. Additionally, the pediatric cases in our review, particularly those involving prenatal exposure, lacked precise dosing and concentration data. There is limited insight into toxic ranges and age‐specific effects, highlighting the need for further research across varied demographics and dosages.

AUTHOR CONTRIBUTIONS

Philpa Owusu‐Antwi: Conceptualization; data curation; formal analysis; investigation; methodology; project management; software; supervision; validation; visualization; writing (original draft, review and editing); appraisal. Priya Atodaria: Data curation; investigation; writing (original draft, editing); appraisal. Edmund Appiah‐Kubi: Data curation; appraisal; investigation; writing (original draft, review). Zainab Shah: Appraisal; writing (review and editing). Elpidio Marlon Garcia: Writing (review and editing); supervision.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

ACKNOWLEDGMENTS

Thank you to Dr. Gyimah, Dr. Smalls‐Mantey, Dr. Bowe, and Dr. Serpa for all the support.

Owusu‐Antwi P, Atodaria P, Appiah‐Kubi E, Shah Z, Garcia EM. Management of xylazine toxicity, overdose, dependence, and withdrawal: a systematic review. Am J Addict. 2025;34:589‐602. 10.1111/ajad.70051

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