Xylazine

Xylazine is a drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other non-human mammals.[1] It is an analog of clonidine and an agonist at the α2 class of adrenergic receptor.[2]

Xylazine
Clinical data
Trade namesRompun, Anased, Sedazine, Chanazine
AHFS/Drugs.comInternational Drug Names
License data
Routes of
administration		By mouth, inhalation, or injection (intravenous, intramuscular, or subcutaneous)
ATCvet code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • Veterinary Use
Identifiers
  • N-(2,6-Dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.028.093
Chemical and physical data
FormulaC12H16N2S
Molar mass220.33 g·mol−1
3D model (JSmol)
  • N\1=C(\SCCC/1)Nc2c(cccc2C)C
  • InChI=1S/C12H16N2S/c1-9-5-3-6-10(2)11(9)14-12-13-7-4-8-15-12/h3,5-6H,4,7-8H2,1-2H3,(H,13,14) ☒N
  • Key:BPICBUSOMSTKRF-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

In veterinary anesthesia, xylazine is often used in combination with ketamine. Veterinarians also use xylazine as an emetic, especially in cats.[3] It is sold under many brand names worldwide, most notably the Bayer brand name Rompun.[1] It is also marketed as Anased, Sedazine, and Chanazine.[4] The drug interactions vary with different animals.[5][6][7]

Xylazine has become a commonly used non-prescribed drug in the United States where it is known by the street name "tranq", particularly in Puerto Rico.[8] The drug is being diverted from stocks used by equine veterinarians and used as a cutting agent for heroin and fentanyl, causing skin sores and infections at injection sites, as well as other health issues.[9] Fentanyl mixed with xylazine is known by the street names "sleep-cut", "zombie drug", "Iso" and "tranq dope".[10][11][12][13]

History

Xylazine was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Leverkusen, Germany.[2] Accounts of the actions and uses of xylazine in animals were reported as early as the late 1960s and early 1970s.[2] Results from early human clinical studies confirmed that xylazine has several central nervous system depressant effects.[2] Xylazine administration is used for sedation, anesthesia, muscle relaxation, and analgesia.[1] It causes a significant reduction in blood pressure and heart rate in healthy volunteers.[14] Xylazine was also studied for use in human beings, but due to hazardous side-effects, including hypotension and bradycardia, it was not approved by the Food and Drug Administration (FDA) for human use.[9]

In the United States, xylazine was approved by the FDA only for veterinary use as a sedative, analgesic, and muscle relaxant in dogs, cats, horses, elk, fallow deer, mule deer, sika deer, and white-tailed deer.[2][4] The sedative and analgesic effects of xylazine are related to central nervous system depression. Xylazine's muscle relaxant effect inhibits the transmission of neural impulses in the central nervous system.[15]

In scientific research, xylazine is a component of the most common anesthetic, ketamine-xylazine (see rodent cocktail), which is used in rats, mice, hamsters, and guinea pigs.[16]

Veterinary use
As a veterinary anesthetic, xylazine is administered once for intended effect before surgical procedures (trade name: Rompun)

Xylazine is widely used in veterinary medicine as a sedative, muscle relaxant, and analgesic. It is frequently used in the treatment of tetanus.[2] It is not used in human medical treatment. Xylazine is similar to drugs such as phenothiazines, tricyclic antidepressants, and clonidine.[4] As an anesthetic, it is typically used in conjunction with ketamine.[14] In animals, xylazine may be administered intramuscularly or intravenously.[4] As a veterinary anesthetic, xylazine is typically only administered once for intended effect before or during surgical procedures.[2] Alpha-2 antagonists such as atipamezole and yohimbine may be used to reverse the effects of xylazine in animals.[17][18][19]

Side-effects

Side-effects in animals include transient hypertension, hypotension, and respiratory depression.[4] Further, the decrease of tissue sensitivity to insulin leads to xylazine-induced hyperglycemia and a reduction of tissue glucose uptake and utilization.[14] The effects in animals last up to 4 hours.[4]

Pharmacokinetics

In dogs, sheep, horses, and cattle, the half-life is very short: only 1.21–5.97 minutes. Complete elimination of the drug can take up to 23 minutes in sheep and up to 49 minutes in horses.[2][4] In young rats the half life is one hour.[16] Xylazine has a large volume of distribution (Vd).[4] The Vd = 1.9–2.5 for horses, cattle, sheep, and dogs.[4] Though the peak plasma concentrations are reached in 12–14 minutes in all species, the bioavailability varies between species.[4] The half life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time.[16] Toxicity occurs with repeated administration, given that the metabolic clearance of the drug is usually calculated as 7–9 times the half-life, which is 4 to 5 days for the clearance of xylazine.[16]

Pharmacology

Pharmacodynamics
Xylazine synthesis adapted from Elliot & Ruehle (1986).[20]

Xylazine is a potent α2 adrenergic agonist.[4] When xylazine and other alpha-2 adrenergic receptor agonists are administered, they distribute throughout the body within 30–40 minutes.[15] Due to xylazine's highly lipophilic nature, xylazine directly stimulates central α2 receptors as well as peripheral α-adrenoceptors in a variety of tissues.[2][4] As an agonist, xylazine leads to a decrease in neurotransmission of norepinephrine and dopamine in the central nervous system.[4] It does so by mimicking norepinephrine in binding to pre-synaptic surface autoreceptors, which leads to feedback inhibition of norepinephrine.[21]

Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function through competitive inhibition of substrate transport. Accordingly, xylazine significantly increases Km and does not affect Vmax.[21] This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site.[21] For example, xylazine and clonidine suppress uptake of MIBG, a norepinephrine analog, in neuroblastoma cells.[21] Xylazine has varying affinities for cholinergic, serotonergic, dopaminergic, α1 adrenergic, H2-histaminergic and opiate receptors.[4] Its chemical structure closely resembles the phenothiazines, tricyclic antidepressants, and clonidine.

Pharmacokinetics in humans

Xylazine is absorbed, metabolized, and eliminated rapidly. Xylazine can be inhaled or administered intravenously, intramuscularly, subcutaneously, or orally either by itself or in conjunction with other anesthetics, such as ketamine, barbiturates, chloral hydrate, and halothane in order to provide reliable anesthesia effects.[9][14] The most common route of administration is injection.[9]

Xylazine's action can be seen usually 15–30 minutes after administration and the sedative effect may continue for 1–2 hours and last up to 4 hours.[4] Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to enter the heart, lungs, liver, and kidney.[22] In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6 mg/L.[4] Xylazine diffuses extensively and penetrates the blood–brain barrier, as might be expected due to the uncharged, lipophilic nature of the compound.[4]

Xylazine is metabolized by liver cytochrome P450 enzymes.[16] When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted as urine.[23] Around 70% of a dose is excreted by urine.[16] Thus, urine can be used in detecting xylazine administration because it contains many metabolites, which are the main targets and products in urine.[2][24] Within a few hours, xylazine decreases to undetectable levels.[4] Other factors can also significantly impact the pharmacokinetics of xylazine, such as sex, nutrition, environmental conditions, and prior diseases.[16]

Xylazine Metabolites [24]
Xylazine-M (2,6 dimethylaniline)Xylazine-M (N-thiourea-2,6-dimethylaniline)Xylazine-M (sulfone-HO-) isomer 2
Xylazine-M (HO-2,6-dimethylaniline isomer 1)Xylazine-M (HO-2,6-dimethylaniline isomer 2)Xylazine M (oxo-)
Xylazine-M (HO-) isomer 1Xylazine-M (HO-) isomer 1 glucuronideXylazine-M (HO-) isomer 2
Xylazine-M (HO-) isomer 2 glucuronideXylazine-M (HO-oxo-) isomerXylazine-M (HO-oxo-) isomer 1 glucuronide
Xylazine-M (HO-oxo-) isomer 2Xylazine-M (HO-oxo-) isomer 2 glucuronideXylazine-M (sulfone)
Xylazine-M (sulfone-HO-) isomer 1

Recreational use

In 1979, the first case of xylazine toxicity was reported in a 34-year-old male who had self-medicated for insomnia with injection of one gram of xylazine.[25] Intentional intoxication from ingesting, inhaling, or injecting xylazine has been reported. The intravenous route is the most common route of administration for those who use heroin or xylazine recreationally.

Since the early 2000s, xylazine has become popular as a drug in the United States and Puerto Rico.[24] Xylazine's street name in Puerto Rico is anestesia de caballo, which translates to "horse anesthetic".[4][8] From 2002 to 2008, its use was associated with a high number of inmate deaths at the Guerrero Correctional Institution in Aguadilla, Puerto Rico.[26]

Xylazine's street name in United States is "tranq", "tranq dope", and "zombie drug".[27] From 2010 to 2019, the proportion of xylazine in heroin and/or fentanyl deaths in Philadelphia rose from 3 to 28%.[28][29]

As of 2012, xylazine users in Puerto Rico were more likely to be male, under age 30, living in a rural area, and injecting versus inhaling xylazine. Because xylazine and heroin trigger similar behavioral outcomes, the former is often secretly mixed into illegal doses of heroin. The combination of heroin and xylazine produces a potentially more deadly high than administration of heroin alone. Xylazine is also frequently found in "speedball" (a mixture of several drugs – usually cocaine, heroin or morphine, and fentanyl).[9] As of 2012, causal factors underlying xylazine's increasing popularity were still unknown.[8]

As of 2022, more information on the distribution of xylazine in the body, physical symptoms, and factors predictive of chronic use was known: When used, frequency of use depended on social or economic factors, as well as each user's subjective response to the drug's addictive properties.[30] From November 2021 until August 2022, 80% of drug paraphernalia which tested positive for fentanyl at needle exchange programs in Maryland also contained xylazine.[31] As of 2022, xylazine was almost invariably combined with opioids when used recreationally, and the drug produced a characteristic withdrawal syndrome which complicates treatment of addicted users.[32][33]

In April 2023, the Biden administration declared xylazine-laced fentanyl an official emerging drug threat to the nation, the first time that label has been given. Rahul Gupta, director of the Office of National Drug Control Policy (ONDCP), said he was troubled about what he learned "about the devastating impact of the fentanyl xylazine combination, which is growing in youth across the nation".[34] According to Gupta, xylazine is the deadliest drug threat the United States has ever faced. The DEA has seized xylazine and fentanyl mixtures in most states, finding 23% of seized fentanyl powder and 7% of fentanyl pills adulterated with xylazine.[12]

In 2022, the first death following xylazine use outside of North America was reported to have taken place in Solihull, England, UK.[35] The 43-year-old male was found dead at home with postmortem detection of heroin, cocaine, fentanyl, and xylazine.

Side-effects

Xylazine overdose is often fatal in humans.[2] Because it is used as a drug adulterant, the symptoms caused by the drugs accompanying xylazine administration vary between individuals.[9]

The most-common side-effects in humans associated with xylazine administration include bradycardia, respiratory depression, hypotension, transient hypertension secondary to alpha-1 stimulation, and other central and hemodynamic changes.[2][9][36] Xylazine significantly decreases heart rate in animals that are not pre-medicated with medications that have anticholinergic effects.[2]

Xylazine administration can lead to diabetes mellitus and hyperglycemia.[14] Other possible side-effects are areflexia, asthenia, ataxia, blurred vision, disorientation, dizziness, drowsiness, dysarthria, dysmetria, fainting, hyporeflexia, slurred speech, somnolence, staggering, coma, apnea, shallow breathing, sleepiness, premature ventricular contraction, tachycardia, miosis, and dry mouth.[4] Rarely, hypotonia, urinary incontinence, and nonspecific electrocardiographic ST segment changes occur.[4] Following a human overdose, symptoms can last for 8–72 hours, varying based on xylazine's combined usage with other drugs.[2][4]

Chronic intravenous use of xylazine in combination with opioids is reported to be associated with physical deterioration, dependence, abscesses, and skin ulceration, sometimes progressing to necrosis with eschar formation, which can be physically debilitating and painful.[4][14][29] Hypertension followed by hypotension, bradycardia, and respiratory depression lower tissue oxygenation in the skin.[9] Thus, chronic use of xylazine can progress the skin oxygenation deficit, leading to severe skin ulceration.[9] Lower skin oxygenation is associated with impaired healing of wounds and a higher chance of infection.[9] The ulcers may ooze pus and have a characteristic odor.[8] In severe cases, amputations must be performed on the affected extremities.[8]

Overdose

While naloxone (Narcan) is only capable of reversing the effects of an opioid overdose, experts still recommend administering it during a suspected xylazine overdose because the drug is frequently mixed with opioids like fentanyl.[12]

Human tolerance to xylazine varies widely with toxicity and fatality occurring between doses of 40–2400 mg.[4] Non-fatal blood or plasma concentration ranges from 0.03 to 4.6 mg/L.[22] In fatalities, the blood concentration of xylazine ranges from trace to 16 mg/L.[22] It is reported that there is no defined safe or fatal concentration of xylazine because of the significant overlap between the non-fatal and postmortem blood concentrations of xylazine.[4]

As of 2014, there is no specific antidote to treat humans who overdose on xylazine. Hemodialysis has been suggested as a form of treatment, but is usually unfavorable due to the large volume of distribution of xylazine.[4]

There are no standardized screenings to determine if an overdose has occurred. Detection of xylazine in humans involves various screening methods, such as urine screenings, thin layer chromatography (TLC), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).[24][22] As of November 2022, detecting xylazine in a drug sample requires spectrophotometry.[37]

As of 1998, the alpha-2 antagonist atipamezole was used to reverse the effects of xylazine or the related drug dexmedetomidine in veterinary medicine,[38] but this is not an approved medical treatment for humans, despite Phase I clinical trials in 2005.[39]

As of 2001, the effects of xylazine were also reversed by the analeptics 4-aminopyridine, doxapram, and caffeine, which are physiological antagonists to central nervous system depressants.[40] Further research is needed to accurately identify chronic xylazine usage and standardize effective treatments.[2] As of 2014, multiple drugs have been used for therapeutic intervention, including lidocaine, naloxone, thiamine, lorazepam, vecuronium, etomidate, propofol, tolazoline, yohimbine, atropine, orciprenaline, metoclopramide, ranitidine, metoprolol, enoxaparin, flucloxacillin, insulin, and irrigation of both eyes with saline.[4]

The treatment after a xylazine overdose primarily involve maintaining respiratory function and blood pressure.[4] In cases of intoxication, physicians recommend intravenous fluid infusion, atropine, and hospital observation.[2] Severe cases may require tracheal intubation, mechanical ventilation, gastric lavage, activated charcoal, bladder catheterization, electrocardiographic (ECG) and hyperglycemia monitoring.[4] Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highly perfused organs, such as the liver and kidney.[22]

In 2022, the FDA issued an alert to American health care providers on the risks patients face if exposed to xylazine in illicit drugs.[41]

References
  1. "Xylazine". techynewsblogs.com. 23 March 2023.
  2. Greene SA, Thurmon JC (December 1988). "Xylazine—a review of its pharmacology and use in veterinary medicine". Journal of Veterinary Pharmacology and Therapeutics. 11 (4): 295–313. doi:10.1111/j.1365-2885.1988.tb00189.x. PMID 3062194.
  3. Dowling PM (June 2016) [March 2015]. "Drugs to control or stimulate vomiting (monogastric)". Merck Veterinary Manual (professional ed.). Rahway, NJ: Merck & Co.
  4. Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, Martínez MA (July 2014). "Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature". Forensic Science International. 240: 1–8. doi:10.1016/j.forsciint.2014.03.015. PMID 24769343.
  5. Haskins SC, Patz JD, Farver TB (March 1986). "Xylazine and xylazine-ketamine in dogs". American Journal of Veterinary Research. 47 (3): 636–641. PMID 3963565.
  6. Muir WW, Skarda RT, Milne DW (February 1977). "Evaluation of xylazine and ketamine hydrochloride for anesthesia in horses". American Journal of Veterinary Research. 38 (2): 195–201. PMID 842917.
  7. Aithal HP, Pratap AK, Singh GR (1997). "Clinical effects of epidurally administered ketamine and xylazine in goats". Small Ruminant Research. 24 (1): 55–64. doi:10.1016/s0921-4488(96)00919-4.
  8. Torruella RA (April 2011). "Xylazine (veterinary sedative) use in Puerto Rico". Substance Abuse Treatment, Prevention, and Policy. 6: 7. doi:10.1186/1747-597x-6-7. PMC 3080818. PMID 21481268.
  9. Reyes JC, Negrón JL, Colón HM, Padilla AM, Millán MY, Matos TD, Robles RR (June 2012). "The emerging of xylazine as a new drug of abuse and its health consequences among drug users in Puerto Rico". Journal of Urban Health. 89 (3): 519–526. doi:10.1007/s11524-011-9662-6. PMC 3368046. PMID 22391983.
  10. "FDA warns about the risk of xylazine exposure in humans, November 8, 2022". fda.gov. Archived from the original on 2023-03-21. Retrieved 2023-04-12. Reports from social media and news outlets suggest that xylazine-containing products may be sold under the street names tranq, tranq dope, sleep-cut, Philly dope and zombie drug.
  11. "FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs". www.fda.gov. 2023-03-21. Archived from the original on 2023-03-21. Retrieved 2023-04-12.
  12. "DEA Reports Widespread Threat of Fentanyl Mixed with Xylazine". DEA. 2023-03-21. Archived from the original on 2023-03-21. Retrieved 2023-04-12.Public Domain This article incorporates text from this source, which is in the public domain.
  13. Montero F, et al. "Potency-Enhancing Synthetics in the Drug Overdose Epidemic: Xylazine ('Tranq'), Fentanyl, Methamphetamine, and the Displacement of Heroin in Philadelphia and Tijuana". Journal of Illicit Economies and Development 2022; 4(2): 204-222. doi:10.31389/jied.122
  14. Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX (October 2013). "Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys". BMC Anesthesiology. 13 (1): 33. doi:10.1186/1471-2253-13-33. PMC 4016475. PMID 24138083.
  15. Delehant TM, Denhart JW, Lloyd WE, Powell JD (2003). "Pharmacokinetics of xylazine, 2,6-dimethylaniline, and tolazoline in tissues from yearling cattle and milk from mature dairy cows after sedation with xylazine hydrochloride and reversal with tolazoline hydrochloride". Veterinary Therapeutics. 4 (2): 128–134. PMID 14506588.
  16. Veilleux-Lemieux D, Castel A, Carrier D, Beaudry F, Vachon P (September 2013). "Pharmacokinetics of ketamine and xylazine in young and old Sprague-Dawley rats". Journal of the American Association for Laboratory Animal Science. 52 (5): 567–570. PMC 3784662. PMID 24041212.
  17. Kollias-Baker CA, Court MH, Williams LL (September 1993). "Influence of yohimbine and tolazoline on the cardiovascular, respiratory, and sedative effects of xylazine in the horse". Journal of Veterinary Pharmacology and Therapeutics. 16 (3): 350–358. doi:10.1111/j.1365-2885.1993.tb00182.x. PMID 8230406.
  18. Murahata Y, Miki Y, Hikasa Y (October 2014). "Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats". Canadian Journal of Veterinary Research. 78 (4): 304–315. PMC 4170770. PMID 25356000.
  19. Janssen CF, Maiello P, Wright MJ, Kracinovsky KB, Newsome JT (March 2017). "Comparison of Atipamezole with Yohimbine for Antagonism of Xylazine in Mice Anesthetized with Ketamine and Xylazine". Journal of the American Association for Laboratory Animal Science. 56 (2): 142–147. PMC 5361038. PMID 28315642.
  20. US expired 4614798A, Elliott, Richard L. & Ruehle, Paul H., "Process for the production of xylazine", issued 30 September 1986, assigned to Vetamix (expired 9 April 2005).
  21. Park JW, Chung HW, Lee EJ, Jung KH, Paik JY, Lee KH (April 2013). "α2-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells". Neuroscience Letters. 541: 184–189. doi:10.1016/j.neulet.2013.02.022. PMID 23485735. S2CID 46338840.
  22. Silva-Torres L, Veléz C, Alvarez L, Zayas B (2014). "Xylazine as a drug of abuse and its effects on the generation of reactive species and DNA damage on human umbilical vein endothelial cells". Journal of Toxicology. 2014: 492609. doi:10.1155/2014/492609. PMC 4243599. PMID 25435874.
  23. Barroso M, Gallardo E, Margalho C, Devesa N, Pimentel J, Vieira DN (April 2007). "Solid-phase extraction and gas chromatographic–mass spectrometric determination of the veterinary drug xylazine in human blood". Journal of Analytical Toxicology. 31 (3): 165–169. doi:10.1093/jat/31.3.165. PMID 17579964.
  24. Meyer GM, Maurer HH (December 2013). "Qualitative metabolism assessment and toxicological detection of xylazine, a veterinary tranquilizer and drug of abuse, in rat and human urine using GC-MS, LC-MSn, and LC-HR-MSn". Analytical and Bioanalytical Chemistry. 405 (30): 9779–9789. doi:10.1007/s00216-013-7419-7. PMID 24141317. S2CID 23164588.
  25. Carruthers SG, Nelson M, Wexler HR, Stiller CR (October 1979). "Xylazine hydrochloridine (Rompun) overdose in man". Clinical Toxicology. 15 (3): 281–285. doi:10.3109/15563657908989878. PMID 509891.
  26. Melia M (5 August 2010). "ACLU probes prisoner deaths in Puerto Rico". Boston.com. Associated Press. Retrieved 24 August 2016.
  27. "Opioid Epidemic Updates: "Frankenstein Opioids" and Xylazine-Induced Skin Ulcers". aafp.org. Retrieved 23 February 2023.
  28. Johnson J, Pizzicato L, Johnson C, Viner K (August 2021). "Increasing presence of xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010-2019". Injury Prevention. 27 (4): 395–398. doi:10.1136/injuryprev-2020-043968. PMID 33536231. S2CID 231804394.
  29. Hoffman J (7 January 2023). "Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones". The New York Times. Retrieved 23 February 2023.
  30. "Research Topics - Xylazine". National Institute on Drug Abuse. U.S. Department of Health and Human Services. 21 April 2022. Retrieved 25 January 2023.
  31. Russell E, Sisco E, Thomson A, Lopes J, Rybak M, Burnett M, et al. (April 2023). "Rapid Analysis of Drugs: A Pilot Surveillance System To Detect Changes in the Illicit Drug Supply To Guide Timely Harm Reduction Responses - Eight Syringe Services Programs, Maryland, November 2021-August 2022". MMWR. Morbidity and Mortality Weekly Report. 72 (17): 458–462. doi:10.15585/mmwr.mm7217a2. PMID 37104171. S2CID 258354168.
  32. Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C (April 2022). "Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis". Drug and Alcohol Dependence. 233: 109380. doi:10.1016/j.drugalcdep.2022.109380. PMC 9128597. PMID 35247724.
  33. Ehrman-Dupre R, Kaigh C, Salzman M, Haroz R, Peterson LK, Schmidt R (2022). "Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report". Journal of Addiction Medicine. 16 (5): 595–598. doi:10.1097/ADM.0000000000000955. PMID 35020700. S2CID 245907730.
  34. Weixel N (2023-04-12). "White House says fentanyl laced with 'tranq' drug is 'emerging threat'". The Hill. Retrieved 2023-04-13.
  35. Rock KL, Lawson AJ, Duffy J, Mellor A, Treble R, Copeland CS (July 2023). "The first drug-related death associated with xylazine use in the UK and Europe". Journal of Forensic and Legal Medicine. 97: 102542. doi:10.1016/j.jflm.2023.102542. ISSN 1752-928X. PMID 37236142. S2CID 258859939.
  36. Ball NS, Knable BM, Relich TA, Smathers AN, Gionfriddo M, Nemecek BD, et al. (August 2022). "Xylazine poisoning: a systematic review". Clinical Toxicology. 60 (8): 892–901. doi:10.1080/15563650.2022.2063135. PMID 35442125. S2CID 248264717.
  37. "Xylazine Public Health Advisory, November 2022" (PDF). Boston Public Health Commission. City of Boston. Retrieved 25 January 2023.
  38. Scheinin H, Aantaa R, Anttila M, Hakola P, Helminen A, Karhuvaara S (September 1998). "Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers". Anesthesiology. 89 (3): 574–584. doi:10.1097/00000542-199809000-00005. PMID 9743392. S2CID 25346350.
  39. Pertovaara A, Haapalinna A, Sirviö J, Virtanen R (2005). "Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist". CNS Drug Reviews. 11 (3): 273–288. doi:10.1111/j.1527-3458.2005.tb00047.x. PMC 6741735. PMID 16389294.
  40. Ndeereh DR, Mbithi PM, Kihurani DO (June 2001). "The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats". Journal of the South African Veterinary Association. 72 (2): 64–67. doi:10.4102/jsava.v72i2.618. PMID 11513261.
  41. "FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs". Center for Drug Evaluation and Research. U.S. Food and Drug Administration. 2022-11-08.

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