Xylazine Toxicity

Etiology

For veterinary usage, xylazine is available as a liquid solution for injection in concentrations of 20 mg/mL, 100 mg/mL, and 300 mg/mL. The liquid solution may be dried into a powder or salted. The powder may appear white or brown.

Xylazine may be added to other illicit substances for many reasons.

The powder can be used as a cutting agent in street drugs like heroin and fentanyl to increase the bulk of those drugs. It may be challenging to distinguish xylazine solely based on appearance since it can be blended with other powders or crushed into tablets to adulterate a drug supply. The availability, low cost, and ability of xylazine to potentiate the opioid effect make it a profitable addition to the opioid supply, decreasing the net amount of heroin or fentanyl sold and improving profits.[7] Although some individuals intentionally seek out xylazine-adultered opioids, a survey of the popular social media website Reddit found that xylazine is considered an unwanted adulterant in most situations.[8] When combined with stimulants, xylazine can decrease the adverse effects and withdrawal symptoms of the stimulant.[9] 

Acute xylazine toxicity can occur with an overdose of xylazine-mixed illicit substances, leading to severe central nervous system (CNS) depression, respiratory depression, bradycardia, hypotension, and, in extreme cases, cardiac arrest. Long-term use of xylazine-mixed illicit substances can result in cumulative toxic effects, leading to chronic complications in various organ systems, including chronic wounds and ulcers on the skin. The etiology of xylazine use in humans is complex, and further research is needed to understand the factors contributing to its abuse.

Epidemiology

The State Unintentional Drug Overdose Reporting System (SUDORS) has identified xylazine as an emerging adulterant in illicit drug mixtures, amplifying the already devastating opioid overdose crisis. Xylazine use substantially increased before adequate research on its effects was completed.

Before 2000, reports of xylazine intoxication in humans were infrequent.[4] It was found initially to be a more common additive in Puerto Rico and then more commonly seen in some Puerto Rican communities within the continental United States.[2][10] Persons who inject drugs (PWID) and public health professionals have observed xylazine as an increasingly common additive in the street opioid supply of Philadelphia since the mid-2010s.[6]

In 2014, xylazine was reported as an adulterant in recreational drugs such as heroin or combined opioid-stimulants, commonly called a "speedball." From 2015-2021, xylazine was reported to be coadministered primarily with fentanyl and cocaine, in addition to benzodiazepines, methamphetamine, and heroin. In Canada, flualprazolam, flubromazepam, flubromazolam, and etizolam were the most commonly co-occurring nonmedical benzodiazepines. A 2022 study by the Rhode Island government reported that in addition to cocaine, heroin, and fentanyl, xylazine was combined with reasonably prevalent drugs of abuse like Percocet (oxycodone plus acetaminophen) and Xanax (alprazolam). This pattern illustrates that xylazine is being combined with an increasing number of substances.

Furthermore, recent reports from Connecticut implicated xylazine in a rising fraction of overdose deaths during 2019–2020.[11] A study published in 2021 analyzed data from 38 states and Washington, D.C., and revealed that xylazine was present in 1.8% of overdose-related deaths in 2019.[12] Another study revealed that xylazine existed in ten jurisdictions throughout the four United States Census regions. Among these locations, Philadelphia had the highest prevalence of xylazine-related deaths at 25.8%, followed by Maryland at 19.3%, and Connecticut at 10.2%.[13] In 2021, the Philadelphia Department of Public Health reported that 91% of samples of purported heroin or fentanyl from the local area contained xylazine, making it the most common adulterant in the drug supply.

According to a study conducted in 2023, xylazine was detected in 413 out of 59,498 samples collected from individuals aged 20 to 73 across 25 states where physicians ordered testing. The study revealed that the most frequently identified substances were fentanyl (96%), buprenorphine, nicotine metabolites, cocaine, naloxone, D-methamphetamine, and delta-9-tetrahydrocannabinol. Additionally, xylazine was found to be prevalent. Among the designer benzodiazepines, etizolam and clonazolam metabolites were the most commonly detected.[9] Ethnographic accounts indicate that xylazine poses grave risks for PWID. Many recently published studies suggest that the percentage of deaths involving xylazine or found to have xylazine along with other drugs of abuse and overdose is steeply rising.

Pathophysiology

The chemical structure of xylazine closely resembles that of phenothiazines, tricyclic antidepressants, and clonidine. Xylazine is in the same drug class as clonidine, lofexidine, and dexmedetomidine and functions as an alpha-2 receptor agonist. Alpha-2 adrenoreceptors are found on the presynaptic and postsynaptic neurons of the central and peripheral nervous systems and are activated by norepinephrine and epinephrine. When the presynaptic receptors are activated, the release of norepinephrine onto the alpha-1 receptor in the postsynaptic neuron is inhibited due to a negative feedback mechanism. This lack of norepinephrine activity leads to the sympatholytic effects of hypotension, bradycardia, sedation, analgesia, and muscle relaxation. However, activation of postsynaptic receptors leads to sympathomimetic effects. Xylazine has a high affinity for presynaptic alpha-2 receptors, making its sympatholytic effects more pronounced clinically (see Image. Xylazine Mechanism of Action).

There are 3 alpha-2 adrenoreceptor subtypes: alpha-2a, alpha-2b, and alpha-2c. The activation of presynaptic alpha-2a and alpha-2c subtypes mediate the sympatholytic effects of sedation via the locus ceruleus and analgesia via the dorsal horn.[14] In contrast, the alpha-2b subtype, mainly located in vascular smooth muscles, mediates vasoconstriction and hypertension. The selectivity of xylazine for alpha-2/alpha-1 is 160:1; its selectivity and affinity for alpha-2a and alpha-2b are unclear.[15] 

However, in animal models, high doses of xylazine lead to intense alpha-1 and alpha-2b receptor activation, which can lead to adverse sympathomimetic effects such as hypertensive emergencies, cerebrovascular accidents, and myocardial infarctions. The direct vasoconstrictive effect of xylazine activating peripheral alpha-2b receptors in the vascular smooth muscles, leading to decreased skin perfusion, is thought to be the pathophysiology of skin ulcers that develop due to chronic use.[14] This vascular effect and resultant decreased skin perfusion are irrespective of the route of xylazine use; ulcerations can occur remotely from an injection site.[16][7] In addition, resultant hypotension, bradycardia, and respiratory depression further decrease tissue perfusion, decreasing wound healing and increasing the risk of secondary infection.

Histopathology

A single case report presents the findings of a punch biopsy of a patient presenting with an ulcerated lesion on the thigh after using intravenous fentanyl and xylazine. Histopathological evaluation revealed epidermal necrosis with focal fibrin thrombi within superficial small vessels; vasculitis was absent. However, this is a single case report, and more literature needs to be presented before definitive histopathological findings can be described for these lesions.[17] 

Toxicokinetics

Xylazine or xylazine-containing drugs can be injected into muscles or veins, insufflated, ingested, or smoked.[11] While the route of administration of xylazine is dictated by the substance it is mixed with, xylazine is known to exert its effects regardless of the route of administration. Pharmaceutical, pharmacokinetic, and toxicokinetic data for xylazine is limited. In veterinary medicine, these kinetic parameters are well-established for dogs, sheep, horses, and cattle. There are no significant kinetic differences among species.[4]

Xylazine is quickly absorbed.[18] Xylazine has a large volume of distribution due to its lipophilicity and is rapidly concentrated in the CNS and kidney. Xylazine is metabolized by cytochrome P450 enzymes in the liver and excreted through the kidney as 2,6-xylidine. Xylazine is quickly eliminated from the body, with an elimination half-life of 23 to 50 minutes. Xylazine is rapidly metabolized, and there is minimal elimination of intact xylazine by the kidney. In animal models, total drug elimination after administration of a therapeutic dose of xylazine for sedation occurs over 10 to 15 hours.[4] 

Depending on the dosage, route of administration, and combination with other substances, the effects of xylazine may begin within minutes and last for 8 or more hours. Xylazine can cause toxicity and death in humans at dosages ranging from 40 to 2400 mg, with plasma concentrations in nonfatal cases ranging from 0.03 to 4.6 mg/L and from trace to 16 mg/L in fatal cases.[19][20] This significant overlap between fatal and nonfatal doses indicates that there may be no "safe" blood concentration of xylazine.[4] Due to a lack of clear evidence regarding the pharmacokinetics of xylazine in humans, a preemptive correlation with animal studies is required; however, the authenticity of this correlation requires validation with further studies in humans.

History and Physical

Identification of xylazine toxicity is difficult due to its use as an adulterant and the inherent nature of polysubstance use. It is challenging to identify xylazine toxicity solely based on history and physical examination; many other substances with their specific toxidrome may be present. At this time, prudence dictates a low threshold of suspicion for coadministration of xylazine and any available illicit drug. 

Xylazine toxicity is characterized by CNS depression. Symptoms may include a "high" feeling, sedation, dry mouth, dysarthria, hyporeflexia, disorientation, dysmetria, miosis, hypotension, bradycardia, hypothermia, and hyperglycemia. When combined with other CNS depressants such as opioids, benzodiazepines, or alcohol, xylazine overdose causes severe CNS depression with signs and symptoms of obtundation, coma, muscle relaxation, hypotension or hypertension, respiratory depression, areflexia, asthenia or apnea, cardiac arrhythmias or cardiac arrest.[4] 

The xylazine high may last up to 6 hours, and users often feel driven to look for their next dosage while still high. This makes abstinence difficult. The lack of effective withdrawal treatment makes abstinence difficult, as standard medication-assisted therapies for opioid use disorder do not mitigate xylazine withdrawal symptoms.[7] The chronic use of heroin and fentanyl mixed with xylazine can lead to deep skin ulcers, abscesses, and infections.[16] These xylazine-associated wounds may increase the risk of bacteremia, endocarditis, sepsis, limb amputation, and death. Any patient with a nonhealing ulcer, regardless of the use of injection as the route of administration, should be assessed for xylazine use.

Fentanyl is the drug most commonly combined with xylazine. Patients under the influence of this combination of substances will present with opioid toxidrome, including miosis with CNS and respiratory depression. Nystagmus may be seen due to the xylazine. Fentanyl and xylazine have an additive effect on the CNS and respiratory depression that can lead to arrest and death. Patients exhibiting signs of a fentanyl overdose who have shown little to no improvement with the administration of naloxone should be suspected of a xylazine overdose or another etiology of their condition.

Patients using illicit substances should be educated on the signs, symptoms, and potential consequences of xylazine overdose. Patients should also be educated on the benefit of naloxone administration in cases of opioid overdose, even if the opioid is mixed with xylazine. While naloxone will not reverse the xylazine toxidrome, reversal of the opioid toxidrome can decrease overall mortality.

Evaluation

Evaluating a patient with suspected xylazine intoxication is similar to any other patient presenting after an overdose. The initial priority is establishing and maintaining an airway and ensuring adequate breathing and circulation. A mental status assessment should be performed, and a comprehensive medical history should be obtained if possible. A complete physical examination, bedside glucose, and, if applicable, a pregnancy test should be completed.  

In clinical settings, xylazine remains undetected in the most frequently performed urine drug screenings (UDS). These drug screenings are presumptive and use an immunoassay technique to test for the five most common substances of abuse: opiates, cannabinoids, amphetamines, cocaine, and phencyclidine (PCP).[21] Individuals treated with prescription pain drugs are tested additionally for benzodiazepines, barbiturates, and methadone using specialized testing methods. In cases of overdose, levels of lysergic acid (LSD), propoxyphene, buprenorphine, tramadol, fentanyl, and oxycodone can be assessed.[22] 

The presence of xylazine in urine samples must be confirmed using gas chromatography-mass spectrometry or liquid chromatography-tandem mass spectrometry. However, chromatography testing procedures are more expensive than typical immunoassays and do not result for 7 to 8 days.[23] Such testing would not provide real-time assistance with the care of an intoxicated patient. An experimental model comparing human and rat xylazine metabolites found no differences between the species; this may be an aid in developing urine detection assays in humans.[24] The rapid clearance of xylazine increases the possibility of false negative test results, complicating the development of effective testing methods. Creating xylazine detection assays that enhance sensitivity while lowering costs and processing times will require further research.

Due to the ongoing xylazine crisis, lateral flow immunoassay has been used to develop testing strips for xylazine with a detection sensitivity of up to 1000 ng/mL. The strips are used to test for xylazine within the drug supply. Testing strips used by patients with substance use disorder are available through common online marketplaces and harm-reduction programs but are currently rare in the healthcare setting. The use of this method in the healthcare setting would likely be limited; the ingested drug is rarely close to hand in the acute setting. However, these strips can play an eminent role as a harm-reduction tool.[25]

Treatment / Management

Management of Acute Xylazine Toxicity

Persons suspected of xylazine overdose in the field should be administered naloxone and placed in the "recovery position." Proper patient positioning is crucial in drug overdoses and is designed to maintain a clear airway and prevent aspiration in an unconscious, independently breathing person. The recovery position also prevents the person from rolling onto their stomach or back, which could restrict their breathing.

Use the following steps to place a person in the recovery position:

• Kneel beside the patient
• Extend the patient's arm that is closest to you above their head
• Fold their other arm across their body, placing the back of their hand against the cheek closest to you
• Bend the knee farthest from you and place the foot flat on the ground
• Roll the patient toward you onto their side
• Tilt their head back to open the airway; check for airway obstruction; clear any obstruction present if possible
• Adjust their top leg so the hip and knee are bent at right angles
• Monitor the patient until help arrives, performing airway maneuvers such as head or chin tilt and rescue breathing as needed 
• Be prepared to perform cardiopulmonary resuscitation as needed

As of June 2023, no pharmacological antidote for xylazine intoxication has been approved by the United States Food and Drug Administration (FDA). Management of xylazine intoxication involves supportive care, monitoring for adverse effects, and interventional management as symptoms present. Supportive care includes supplemental oxygen and airway management, intravenous fluid administration, vasopressor administration for hemodynamic instability, assessment and replenishment of electrolytes to prevent dysrhythmias, and management of hyperglycemia. The use of medications inducing CNS depression should be avoided. Naloxone should be administered to treat any concomitant opioid toxidrome. Prolonged sedation is a risk factor for thromboembolic disease, and patients should be monitored accordingly. Hemodialysis may not be effective in removing xylazine from the blood due to its lipophilic property.

Routine Care for Xylazine-induced Skin Ulcers

Routine wound care for xylazine-induced skin lesions comprises wound cleansing, evaluating potential secondary infection, applying a nonadherent gauze such as Xeroform to the wound bed, and applying a topical ointment. Daily dressing changes with layered dressings are optimum. Debridement may be necessary in cases where nonviable tissue covers the ulcer bed. Full-thickness wounds may require reconstruction or, in severe cases, limb amputation. Antibiotic coverage for secondary infection must cover methicillin-resistant Staphylococcus aureus, and coverage for group A streptococci should be considered.

Management of Xylazine Withdrawal Symptoms

Withdrawal symptoms have been reported in cases of chronic xylazine use. However, the literature regarding withdrawal symptom management is minimal. A single case report describes managing xylazine withdrawal using combined tizanidine, phenobarbital, and dexmedetomidine infusions followed by clonidine; the patient was discharged on clonidine, buprenorphine, and gabapentin. There is a possibility that these symptoms may not be due to isolated xylazine withdrawal.[26] (B3)

The Philadelphia Department of Public Health released recommendations for managing and alleviating xylazine withdrawal symptoms. The suggested approach includes replacement therapy with alpha-2 adrenergic agonists such as clonidine, dexmedetomidine, tizanidine, or guanfacine paired with symptom management for pain using short-acting opioids, ketamine, gabapentin, ketorolac, acetaminophen, or nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant insomnia can be managed with trazodone, quetiapine, or mirtazapine; anxiety can be addressed with hydroxyzine or benzodiazepines. Anxiety, irritability, and restlessness from xylazine withdrawal overlap with symptoms of opioid withdrawal; any coexisting opioid withdrawal symptoms must be addressed promptly. As xylazine is not an opioid, standard medication-assisted therapies such as methadone and buprenorphine will not be effective.

Differential Diagnosis

Acute conditions similar to xylazine overdose include syncope, hypoglycemia, hypothermia, seizure disorders, and cerebrovascular accidents.

Various toxidromes share the characteristics of xylazine overdose. 

Opioid overdose is the most common coexisting diagnosis. Naloxone can reverse opioid overdose but will not affect the clinical effects of xylazine. Overlooking concomitant opioid overdoses can result in fatal outcomes. Benzodiazepine overdose can lead to CNS depression. However, compared to xylazine toxicity, there is less respiratory depression and little cardiovascular derangement. Other toxidromes that may mimic xylazine toxicity include barbiturates and ethyl alcohol.

Xylazine is an alpha-2 adrenergic agonist, and an overdose of other drugs of this class, such as clonidine, tizanidine, guanfacine, and dexmedetomidine, will present similarly to xylazine overdose. Beta blockers and calcium channel blockers can also cause bradycardia and hypotension; calcium channel blockers may also induce hyperglycemia.

Skin Lesions

Skin ulcers resulting from xylazine use may result regardless of the method of drug use. Consideration of other etiologies of the lesion is a must, and multifactorial etiologies must be considered. A comprehensive medical history, physical examination, and diagnostic testing with wound cultures, biopsies, or imaging studies may be necessary to correctly determine the etiology of any ulcerated skin lesion.

Skin lesions may occur secondary to a host of infectious processes; bacterial cellulitis, necrotizing fasciitis, bullous impetigo, fungal dermatoses, and viral infections are common. Ulcerated skin lesions may also be due to heroin or methamphetamine use. Cocaine adulterated with levamisole may induce ulcerated skin lesions, most often on the ears and nose.

Vascular pathologies such as chronic venous stasis, peripheral arterial disease, poorly-controlled diabetes, vasculitides, and autoimmune diseases may result in ulcerated skin lesions.

Pressure ulcers, pyoderma gangrenosum, and advanced squamous cell carcinoma of the skin may also rarely present as chronic nonhealing skin ulcers.

Pertinent Studies and Ongoing Trials

Developing a xylazine-specific antidote is the need of the hour. Some case reports and studies describe efforts to identify an antidote for xylazine; an antidote that meets the FDA-approval standards remains elusive. Although the results from these studies cannot be used as clinical treatment guidelines, they can guide antidote research and development.

For example, atropine reversed xylazine-induced bradycardia and hypotension in humans in some case reports.[27] The alpha-2 antagonist yohimbine was used alone or with 4-aminopyridine in several animal studies to block the effects of xylazine and was used to antagonize the sedative effects of xylazine in humans in doses up to 0.125 mg/kg. Yohimbine can be effective within 15 minutes of intramuscular administration and 1 to 2 minutes of intravascular administration.[28] 

Tolazoline may be administered in cases of unresponsive bradycardia and hypotension.[29] However, tolazoline is known to cause hypertension, tachycardia, and arrhythmias and may be used only in cases unresponsive to other interventions. Atipamezole, a potent alpha-2 antagonist approved for use in humans from 1970 to 2017, is no longer available; when comparing the dose requirements in humans and animals, studies suggest atipamezole may be a life-saving drug in overdose emergencies.[30]

Xylazine use is spreading rapidly. To effectively reduce harm, any xylazine-specific antidote must be readily available, safer than xylazine itself, conducive to mass production, efficacious, and nonaddictive. Ideally, such an antidote would also be compatible with or effective against the concomitant opioids usually mixed with xylazine.

Prognosis

The clinical implications of human use of xylazine are significant, with a range of potential health outcomes. Various factors influence the prognosis of individuals with xylazine toxicity, including the dose of xylazine, the fraction of xylazine if it was mixed with other opioids, the overall health condition of the individual, and the promptness of medical intervention. Early identification of symptoms and the time to medical intervention can determine the outcome; timely medical assistance and avoidance of severe respiratory depression or other complications portend a more favorable recovery. However, sustained xylazine exposure or use can precipitate grave health outcomes, including death.

Avoiding xylazine use and providing prompt and appropriate treatment for xylazine-induced skin ulcers may result in wound healing. However, if the ulcers are not adequately cared for and get infected, the chances of acquiring sepsis from infection, the need for limb amputation, and mortality are very high.

Complications

An overdose of xylazine or its toxicity may have substantial clinical implications, including death. The consequences specific to each organ system have not been adequately studied in humans. The few existing studies on humans and animals indicate potentially life-threatening complications of xylazine use, including biventricular failure, pulmonary edema, cardiac necrosis, valvular dysfunction, and insulin-dependent diabetes mellitus.

The primary metabolite of xylazine, 2,6-xylidine, has carcinogenic and genotoxic effects; long-term users of xylazine appear to be at increased risk for malignancies.[31] One study showed that xylazine increases the generation of reactive oxygen species (ROS) in human umbilical vein endothelial cells, increasing DNA fragmentation. More studies on this mechanism are needed, as this process can induce or potentiate malignancy.[20]

There are no human data on the effect of xylazine on embryogenesis and pregnancy. Studies performed in the veterinary field have revealed increased uterine contractions, decreased uterine blood flow, and fetal loss when xylazine is used in pregnant cattle and goats.[3][32]

It has been reported that xylazine addiction is even stronger than opioid addiction, including fentanyl. The prolonged effects of xylazine may promote addiction and dependency, complicating recovery.[7] In addition, there are no effective treatments for xylazine withdrawal or prolonged therapy for xylazine addiction.