Xylazine, an Emerging Adulterant

Andrew McAward, MS
Joan C. Edwards School of Medicine – Marshall University Medical Student, Class of 2024

What is xylazine?

Xylazine (Rompum, AnaSed, Sedazine) is a sedative with analgesic and muscle relaxant properties approved for use in veterinary medicine only. It is, however, increasingly found in illicit drugs of abuse. The drug comes as a clear liquid solution (20, 100, and 300 mg/mL). In the veterinary setting, xylazine is often administered concomitantly with ketamine or barbiturates. Due to effects of sedation, bradycardia, and hypotension, it has not been approved by the FDA for human use (1). However, xylazine is not considered a federally controlled substance, requiring only a veterinarian’s prescription (2). Some states have begun tightening legislation around the drug; New York State Senate passed a bill to designate xylazine as a controlled substance in 2017 (3).

How is xylazine used illicitly?

Drugs such as cocaine, fentanyl, and heroin are often adulterated to increase bulk size or modify effects of other drugs. Xylazine is especially commonly used as an adulterant in a mixture of heroin and cocaine, colloquially known as a “speedball.” Xylazine has been used for multiple illicit purposes: attempted sexual assault, accidental or intentional poisoning, drug abuse.

Xylazine is also abused independently from other drugs. Routes of administration include smoking, snorting, swallowing, inhaling, or injecting (4). Street names for xylazine include “tranq,” “tranq dope,” or “sleep cut” in the United States and “Anestecia de Caballo” in Puerto Rico.

What is the prevalence of xylazine?

Illicit use of xylazine as an additive has been well documented in Puerto Rico since the early 2000s (5), but cases of overdoses due to this mixture have been rapidly increasing in a growing number of states (1)(4)(6). In one study examining the incidence of xylazine in overdose deaths from heroin and/or fentanyl over a ten-year period, the presence of xylazine rose from <2% of cases between 2010-2015 to 31% in 2019 (6). The most common co-ingested drugs found in overdose deaths with xylazine are cocaine and fentanyl followed by benzodiazepines, methamphetamine, and heroin. Due to the lack of both legislative action and resources available to identify the drug, xylazine is likely underreported in its national prevalence.

What is the pharmacology of xylazine?

Xylazine is an α2-adrenergic agonist that acts via stimulation of central α2-receptors. Its chemical configuration is similar to tricyclic antidepressants, phenothiazines, and clonidine. Xylazine inhibits neurotransmitter release of both dopamine and norepinephrine at the neuronal synapse, resulting in depression of the central nervous system (7). In animals, it has been studied to provide analgesia for 15-30 minutes and sedation for 1-4 hours. Due to the drug’s secondary site of action, xylazine use as an

adulterant may potentiate the effects of heroin, leading to increased risk of overdose. The dose of xylazine required to produce toxicity in humans is between 40 to 2400 mg. Serum concentrations of xylazine in fatal overdose cases were seen from trace to 16 mg/L. This significant overlap between fatal and non-fatal doses indicates that there may be no defined “safe” blood concentration of xylazine (7).

What are the symptoms of xylazine overdose?

Xylazine overdose should be suspected in patients presenting like an opioid overdose (miosis, apnea, hypotension, bradycardia) and who are poorly responsive to naloxone treatment (4). Xylazine can be picked up in a comprehensive (gas chromatography-mass spectrometry) toxicology screen, however, rapid drug screens available in the emergency department will not routinely test for or detect xylazine.

Xylazine has similar pharmacological effects to heroin in humans, resulting in bradycardia, hypotension, depression of central nervous system, and respiratory depression (4). The clinical presentation of xylazine overdose also resembles other α2 agonists, such as clonidine, in causing: miosis, apnea, bradycardia, hypothermia, dry mouth, and coma. Although the effects of xylazine on animals lasted for up to 4 hours, there have been reported xylazine overdoses in humans that have lasted from 8 to 72 hours (7).

Heroin users with chronic use of xylazine as an additive may be more likely to develop skin lesions and ulcers when compared to those that only use heroin (5).

What is the treatment for xylazine overdose?

There is no approved antidote for xylazine overdose in humans and the mainstay of treatment remains supportive. There are mixed reports on the effectiveness of naloxone in reversing the symptoms of xylazine overdose. In fact, poor response to naloxone is suggestive of concomitant xylazine or other non-opioid ingestion. Since xylazine is usually used in combination with opioids, naloxone may help treat the confounding symptoms related to the opioids.

Yohimbine, a natural α2 adrenergic antagonist, has been shown to reverse the antihypertensive effects of xylazine in dogs and elephants, but this is not approved for human usage (8).

Atipamezole is an α2-antagonist that is used as a reversal agent for α2-agonist toxicity in animals. It is currently not FDA-approved for human use; however, studies have shown its effectiveness in reversing sedative and cardiovascular effects of α2-agonists in human trials. Providers should consider legal and ethical implications before administering this drug (9).

The focus of the care team for a suspected xylazine overdose should be two-fold: supporting respiratory function, and blood pressure stability. Emergency care may include endotracheal intubation, IV fluid resuscitation, vasopressors, ECG monitoring, and monitoring blood glucose and electrolytes. Bradycardia and hypotension can be treated with atropine, pacing, IVF and vasopressors. Avoid aggressively treating hypertension as initial hypertension may be followed by severe hypotension.

What is the risk of exposure to xylazine for First Responders?

There is little peer-reviewed data on prior LEO or EMS exposure to xylazine while on duty. Accidental injection is the most common method of unintentional xylazine exposure. Other documented routes of exposure include ingestion, dermal route, ocular route, and inhalation (10). One case report of

ocular exposure involves a 38-year-old veterinarian technician who accidentally irrigated his eyes with xylazine. The patient subsequently developed symptoms of hypotension, bradycardia, and decreased levels of consciousness approximately two hours after exposure. Treatment was limited to normal saline eye irrigation, IV fluids, and observation in the telemetry unit. The patient was released from the hospital 25 hours after initial exposure (11).

Why is xylazine overdose important for LEO/EMS to recognize?

1. As the rate of cutting illicit drugs with substances such as xylazine increases, emergency medical responders must be aware of their side effects and how their presence in illicit drug combinations may complicate clinical presentation and treatment.
2. Concomitant xylazine use with heroin and cocaine may have synergistic effects that may increase risk of death (5).
3. Naloxone may not reverse xylazine toxicity, but it may reverse respiratory depression associated with concomitant opioid usage.

REFERENCES

1. Drug Enforcement Administration. Xylazine. Feb. 2021, https://www.deadiversion.usdoj.gov/drug_chem_info/Xylazine.pdf.
2. “Xylazine: A Toxic Adulterant Found in Illicit Street ” Nevada State Opioid Response, Oct. 2020, https://www.nvopioidresponse.org/wp-content/uploads/2020/10/u-public-alert- xylazine-003.pdf.
3. “Slaying the Monster: Senate Passes Murphy’s Bill Designating Xylazine as a Controlled ” NY State Senate, 24 Apr. 2017, https://www.nysenate.gov/newsroom/press- releases/terrence-murphy/slaying-monster-senate-passes-murphys-bill-designating.
4. “Xylazine.” Michigan Regional Poison Control Center, Children’s Hospital of Michigan,
5. Silva-Torres, L. A., et al. “Toxic Effects of Xylazine on Endothelial Cells in Combination with Cocaine and 6-Monoacetylmorphine.” Toxicology in Vitro, vol. 28, no. 7, Oct. 2014, pp. 1312– DOI.org (Crossref), https://doi.org/10.1016/j.tiv.2014.06.013.
6. Johnson, Jewell, et al. “Increasing Presence of Xylazine in Heroin and/or Fentanyl Deaths, Philadelphia, Pennsylvania, 2010–2019.” Injury Prevention, 27, no. 4, Aug. 2021, pp. 395–98 injuryprevention.bmj.com, https://doi.org/10.1136/injuryprev-2020-043968.
7. “Xylazine Intoxication in Humans and Its Importance as an Emerging Adulterant in Abused Drugs: A Comprehensive Review of the ” Forensic Science International, vol. 240, July 2014, pp. 1–8. www.sciencedirect.com, https://doi.org/10.1016/j.forsciint.2014.03.015.
8. Tina Jansson, B. Vijitha Perera, Anna Edner, Åsa Fahlman “Standing Sedation with Xylazine and Reversal with Yohimbine in Juvenile Asian Elephants (Elephas Maximus)," Journal of Zoo and Wildlife Medicine, 52(2), 437-444, (11 June 2021)
9. M Greenberg, A Rama, J R Zuba. A Protocol for the Emergency Treatment of Alpha-2 Agonist Overdose using Atipamezole, a Selective Alpha-2 Antagonist. The Internet Journal of Toxicology. 2017 Volume 12 Number
10. Forrester, Mathias B. “Xylazine Exposures Reported to Texas Poison Centers.” The Journal of Emergency Medicine, vol. 51, no. 4, Oct. 2016, pp. 389–393., doi:10.1016/j.jemermed.2015.09.051.
11. Velez LI, Shepherd G, Mills LD, Rivera W. Systemic toxicity after an ocular exposure to xylazine hydrochloride. J Emerg Med. 2006 May;30(4):407-10. doi: 1016/j.jemermed.2006.02.042. PMID: 16740450.