Chemistry:Xylazine

From HandWiki

Xylazine is a structural analog of clonidine and an α2-adrenergic receptor agonist,[1] sold under many trade names worldwide, most notably the Bayer brand name Rompun,[2] as well as Anased, Sedazine and Chanazine.[3]

Xylazine is a common veterinary drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other mammals.[2] In veterinary anesthesia, it is often used in combination with ketamine. Veterinarians also use xylazine as an emetic, especially in cats.[4] Drug interactions vary with different animals.[5][6][7]

Xylazine was first investigated for human use in the 1960s in West Germany for antihypertensive effects before being discontinued and marketed as a veterinary sedative. Xylazine’s mechanism of action was discovered in 1981, which led to the creation of other α2-adrenergic receptor agonists such as medetomidine and dexmedetomidine.

Xylazine has become a commonly abused street drug in the United States where it is known by the street name "tranq", particularly in the territory of Puerto Rico.[8] The drug is used as a cutting agent for heroin and fentanyl.[9][10][11][12]

History

Xylazine was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Leverkusen, West Germany.[13][14] In human trials xylazine was found to depress the central nervous system leading to the discontinuation of further research for its use in humans and it was instead marketed as a veterinary sedative. Xylazine was first used for this purpose in the late 1960s. Xylazine proved popular and in the 1970s became one of the most common large animal sedatives.[14] In 1981 a study discovered that the cause sedation was due to xylazine's effect on the α2-adrenergic receptor.[15][14] This led to the development of other α2-adrenergic receptor agonists such as detomidine, medetomidine, dexmedetomidine, and romifidine.[14]

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.[1][3] 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.[16]

In scientific research using animal experiments, xylazine is a component of the most common anesthetic, ketamine-xylazine (see: Rodent cocktail), to anesthetize rats, mice, hamsters, and guinea pigs.[17]

Xylazine has not previously been a controlled substance; however, due to illicit abuse of xylazine legislative restrictions have been proposed in multiple countries.[14] Xylazine was made a class C drug in the UK on 15 January 2025.[18][19]

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.[1] It is not used in human medical treatment. Xylazine is similar to drugs such as phenothiazines, tricyclic antidepressants, and clonidine.[3] As an anesthetic, it is typically used in conjunction with ketamine.[20] In animals, xylazine may be administered intramuscularly, intravenously, and intraosseously.[14][3] Subcutaneous, oral transmusocal and intranasal have been investigated but are not standard routes for xylazine administration.[14] As a veterinary anesthetic, xylazine is typically only administered once for the intended effect before or during surgical procedures.[1] α2-Adrenergic receptor antagonists such as atipamezole and yohimbine may be used to reverse the effects of xylazine in animals.[14][21][22][23] Xylazine is licensed for use in non-meat horses. Off-label use in cattle is common with recommended withholding periods of 1–5 days for dairy cattle and 4–10 days for meat cattle. Cattle are more sensitive to xylazine than horses with the sensitivity being greater in meat cattle breeds than dairy cattle breeds.[14]

Xylazine's use in cats and dogs is being replaced with the more selective alpha2 adrenergic receptor agonists medetomidine and dexmedetomidine and in some countries xylazine is rarely used with cats and dogs.[14]

High amounts of catecholamines in a patient will require higher doses of xylazine to be administered to provide sedation. The heightened levels required may not be practical or possible to administer and regular doses may cause excitement.[14]

Side-effects

Side effects in animals include transient hypertension and hypotension.[3] Xylazine decreases both respiration rate and minute ventilation, although the changes to PaCO2 and PaO2 are minor and innocuous.[14]

Xylazine has been demonstrated as reducing the dose of epinephrine that causes arrythmia in dogs anaesthetised with isoflurane and halothane.[14][24][25]

Xylazine administration in sheep activates pulmonary macrophages that damage the capillary endothelium and alveolar type I cells. This in turns causes alveolar haemorrhage and oedema causing hypoxaemia.[14][26][27]

Intracarotid administration can cause seizures and excitement in horses.[14]

Xylazine has been shown to cause myometrial contractions in pregnant cattle.[28][14] Further evidence of xylazine's effect on pregnant animals is lacking and although other a2 adrenergic receptor agonists have been shown to not cause the same myometrial contraction the administration of a2 adrenergic receptor agonists is not recommended and should only be used in specific circumstances for animals near-term.[14]

Xylazine affects the glucose level via the activation of alpha2A andrenergic receptors on beta cells, which prevents insulin release. alpha2 adrenergic receptors have been reported to cause transient hyperglycaemia with xylazine being reported as a cause in cattle and equine.[14][29][30] The renal threshold for glucose is not exceeded due to the hyperglycaemia with clinical doses. An alpha2 adrenergic receptor antagonist can reverse the effect.[14]

Emesis is the most common side effect in small animals; however, this can be a desired effect and xylazine is often used as an emetic in cats.[31]

Xylazine is contraindicated for pregnant animals as it impairs oxygen and blood circulation to the fetus and it can induce parturition

Pharmacokinetics

In dogs, sheep, horses, and cattle, the half-life is very short: only 1– 6 minutes. Complete elimination of the drug can take up to 23 minutes in sheep and up to 49 minutes in horses.[1][3] In young rats the half-life is one hour.[17] Xylazine has a large volume of distribution of Vd = 1.9 –2.5 for horses, cattle, sheep, and dogs.[3] Though the peak plasma concentrations are reached in 12 –14 minutes in all species, the bioavailability varies between species.[3] The half-life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time.[17] 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.[17]

Pharmacology

Pharmacodynamics

Xylazine synthesis adapted from Elliot & Ruehle (1986).[32]

Xylazine is a potent α2-adrenergic receptor agonist.[33][3][14] When xylazine and other α2-adrenergic receptor agonists are administered, they distribute throughout the body within 30 to 40 minutes.[16] Due to xylazine's highly lipophilic nature, it directly stimulates central α2-adrenergic receptors as well as peripheral α-adrenergic receptors in a variety of tissues.[1][3] As an agonist, xylazine reduces release of norepinephrine in the central nervous system.[3] It does so by mimicking norepinephrine in binding to the pre-synaptic surface autoreceptors, which leads to feedback inhibition of norepinephrine release.[34] Recent data suggests that xylazine treatment can induce dopamine release in the nucleus accumbens through an unresolved mechanism, and this effect is blocked by atipamezole.[35]

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.[34] This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site.[34] For example, xylazine and clonidine suppress uptake of iobenguane (MIBG), a norepinephrine analogue, in neuroblastoma cells.[34] Xylazine's chemical structure closely resembles clonidine.

It has also been reported that xylazine activates the κ-opioid receptors, with low potency, which may contribute to its effects.[36]

Unlike other α2-adrenergic receptor agonists xylazine does not have any imidazoline receptor activity. Xylazine binds at a ratio of 160:0, the lowest of all α2-adrenergic receptor agonists and 1/10th of that of medetomidine and dexmedotimidine.[14]

Xylazine is less selective than the other α2-Adrenergic receptor agonists.[14]

The analgesic effect of xylazine comes from binding to receptors at the substantia gelatinosa and locus coeruleus.[14]

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.[12][20] The most common route of administration is injection.[12]

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.[3] Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to enter the heart, lungs, liver, and kidney.[37] In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6 mg/L.[3] Xylazine diffuses extensively and penetrates the blood–brain barrier, as might be expected due to the uncharged, lipophilic nature of the compound.[3]

Xylazine is metabolized by the liver's cytochrome P450 enzymes.[17] When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted in urine.[38] Around 70% of a dose is excreted unchanged.[17] Thus, urine can be used in detecting xylazine administration because it contains many metabolites, which are the main targets and products in urine.[1][39] Within a few hours, xylazine decreases to undetectable levels.[3] Other factors can also significantly impact the pharmacokinetics of xylazine, such as sex, nutrition, environmental conditions, and prior diseases.[17]

Xylazine metabolites[39]
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 1 Xylazine-M (HO-) isomer 1 glucuronide Xylazine-M (HO-) isomer 2
Xylazine-M (HO-) isomer 2 glucuronide Xylazine-M (HO-oxo-) isomer Xylazine-M (HO-oxo-) isomer 1 glucuronide
Xylazine-M (HO-oxo-) isomer 2 Xylazine-M (HO-oxo-) isomer 2 glucuronide Xylazine-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 an injection of 1g of xylazine.[40]

Xylazine is not regulated as a controlled substance under the Controlled Substances Act. It is sold online through distributors often without requiring proof of a veterinary license. As a commonly used veterinary medicine xylazine is probably diverted from veterinary sources. The cost to purchase Xylazine from overseas suppliers is around $6–20 per kilogram. This low price makes it attractive for dealers looking for a cheap additive that is addictive and not treatable with opiate withdrawal medications.[41][42] The withdrawal can last for two weeks and has a quicker onset than fentanyl.[43]

Xylazine is most commonly ingested as an additive with fentanyl.[44] Xylazine has also been reported in combination with medetomidine, another potent α2-adrenergic receptor agonist.[45] It is unknown if drug users are ingesting it knowingly. As of 2024, Seattle police report that some users wrongly believe they are consuming higher-quality fentanyl.[46][47][39] Xylazine's street name in Puerto Rico is anestesia de caballo, which translates to "horse anesthetic".[3][48] From 2002 to 2008, its use was associated with a high number of inmate deaths at the Guerrero Correctional Institution in Aguadilla, Puerto Rico.[49]

Xylazine's street name in the United States, particularly when it is mixed with fentanyl, is "tranq", "tranq dope" and "zombie drug".[50]

As of 2012, xylazine users in Puerto Rico were more likely to be male, under age 30, living in a rural area, and injecting rather than inhaling xylazine. 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 a stimulant drug such as cocaine with a depressant drug such as heroin, morphine and/or fentanyl.[12] As of 2012, causal factors underlying xylazine's increasing popularity were still unknown.[48]

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.[51] From November 2021 until August 2022, 80% of drug paraphernalia which tested positive for fentanyl at needle exchange programs in Maryland also contained xylazine.[52] 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.[53][54]

In April 2023, the Biden administration declared xylazine-laced fentanyl an official emerging drug threat to the nation, the first time such a label has been given.[55] According to Gupta, xylazine is the deadliest drug threat the United States has ever faced. The Drug Enforcement Administration (DEA) has seized xylazine and fentanyl mixtures in most states, finding 23% of seized fentanyl powder and 7% of fentanyl pills adulterated with xylazine.[8]

In July 2023, the first death following xylazine use outside of North America was reported to have taken place in Solihull, England on May 22. A 43-year-old male was found dead at home with postmortem toxicology detecting heroin, cocaine, fentanyl and xylazine.[56]

Side effects

Xylazine overdose is often fatal in humans.[1] Because it is used as a drug adulterant, the symptoms caused by the drugs accompanying xylazine administration vary between individuals.[12]

The most common side-effects in humans associated with xylazine administration include bradycardia, respiratory depression, hypotension, transient hypertension secondary to α1-adrenergic receptor stimulation, and other central and hemodynamic changes.[1][12][57] Xylazine significantly decreases heart rate in animals that are not pre-medicated with medications that have anticholinergic effects.[1]

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.[3] Rarely, hypotonia, urinary incontinence, and nonspecific electrocardiographic ST segment changes occur.[3] Following a human overdose, symptoms can last for 8–72 hours, varying based on xylazine's combined usage with other drugs.[1][3]

Overdose

Human tolerance to xylazine varies widely, with toxicity and fatality occurring between doses of 40–2,400 mg (0.62–37.04 gr).[3] Non-fatal blood or plasma concentration ranges from 0.03 to 4.6 mg/L.[37] In fatalities, the blood concentration of xylazine ranges from trace to 16 mg/L.[37] 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.[3]

Hemodialysis has been suggested as a form of treatment, but is usually unfavorable due to the large volume of distribution of xylazine.[3]

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).[39][37] As of November 2022, detecting xylazine in a drug sample requires spectrophotometry.[58]

As of 1998, the α2-adrenergic receptor antagonist atipamezole was used to reverse the effects of xylazine or the related drug dexmedetomidine in veterinary medicine,[59] but this is not an approved medical treatment for humans, despite Phase I clinical trials in 2005.[60]

As of 2001, the effects of xylazine in animals were also reversed by the analeptics 4-aminopyridine, doxapram, and caffeine, which are physiological antagonists to central nervous system depressants.[61] The ways to accurately identify chronic xylazine usage are unknown, and the effective treatments, if any, are not standardized.[1][62] 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.[3]

The treatment after a xylazine overdose primarily involves maintaining respiratory function and blood pressure.[3] In cases of intoxication, physicians recommend intravenous fluid infusion, atropine, and hospital observation.[1] Severe cases may require tracheal intubation, mechanical ventilation, gastric lavage, activated charcoal, bladder catheterization, electrocardiographic (ECG) and hyperglycemia monitoring.[3] Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highly perfused organs such as the liver and kidneys.[37]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Xylazine–a review of its pharmacology and use in veterinary medicine". Journal of Veterinary Pharmacology and Therapeutics 11 (4): 295–313. December 1988. doi:10.1111/j.1365-2885.1988.tb00189.x. PMID 3062194. 
  2. ↑ 2.0 2.1 "Xylazine". https://www.drugs.com/international/xylazine.html. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 "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. July 2014. doi:10.1016/j.forsciint.2014.03.015. PMID 24769343. 
  4. ↑ Merck Veterinary Manual (professional ed.). Rahway, NJ: Merck & Co.. June 2016. 
  5. ↑ "Xylazine and xylazine-ketamine in dogs". American Journal of Veterinary Research 47 (3): 636–641. March 1986. doi:10.2460/ajvr.1986.47.03.636. PMID 3963565. 
  6. ↑ "Evaluation of xylazine and ketamine hydrochloride for anesthesia in horses". American Journal of Veterinary Research 38 (2): 195–201. February 1977. doi:10.2460/ajvr.1977.38.02.195. PMID 842917. 
  7. ↑ "Clinical effects of epidurally administered ketamine and xylazine in goats". Small Ruminant Research 24 (1): 55–64. 1997. doi:10.1016/s0921-4488(96)00919-4. 
  8. ↑ 8.0 8.1 "DEA Reports Widespread Threat of Fentanyl Mixed with Xylazine". DEA. 2023-03-21. https://www.dea.gov/alert/dea-reports-widespread-threat-fentanyl-mixed-xylazine. Public Domain This article incorporates text from this source, which is in the public domain.
  9. ↑ "Recommendations for Caring for Individuals with Xylazine-Associated Wounds". https://hip.phila.gov/document/4148/Recommendations_for_Caring_for_People_with_Xylazine-Associated_Wounds_1.12.pdf/. 
  10. ↑ "Feds target Chinese based fentanyl supply chain with ties to Florida". CBS News (Miami). October 4, 2023. https://www.cbsnews.com/miami/news/feds-target-chinese-based-fentanyl-supply-chain-with-ties-to-florida/. 
  11. ↑ "Justice Department goes after China-based companies in fentanyl fight". The Center Square. October 3, 2023. https://www.thecentersquare.com/national/article_c13a6bfe-622e-11ee-9699-13e10181f376.html. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 "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. June 2012. doi:10.1007/s11524-011-9662-6. PMID 22391983. 
  13. ↑ "Xylazine--a review of its pharmacology and use in veterinary medicine". Journal of Veterinary Pharmacology and Therapeutics 11 (4): 295–313. December 1988. doi:10.1111/j.1365-2885.1988.tb00189.x. PMID 3062194. 
  14. ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 14.11 14.12 14.13 14.14 14.15 14.16 14.17 14.18 14.19 14.20 14.21 14.22 "Sedatives and Tranquilizers". Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. 11 September 2024. pp. 338–344. ISBN 978-1-119-83027-6. 
  15. ↑ "Xylazine-induced depression and its antagonism by alpha adrenergic blocking agents". The Journal of Pharmacology and Experimental Therapeutics (J Pharmacol Exp Ther) 218 (1): 188–192. July 1981. doi:10.1016/S0022-3565(25)32650-9. PMID 6113279. 
  16. ↑ 16.0 16.1 "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. 2003. PMID 14506588. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 "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. September 2013. PMID 24041212. 
  18. ↑ "Britain working at pace to curb rising synthetic drugs threat" (in en). https://www.gov.uk/government/news/britain-working-at-pace-to-curb-rising-synthetic-drugs-threat. 
  19. ↑ "The Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2024 and The Misuse of Drugs and Misuse of Drugs (Designation) (England and Wales and Scotland) (Amendment) (No. 2) Regulations 2024" (in en). https://www.gov.uk/government/publications/circular-0022025-the-misuse-of-drugs-act-1971-order-2024/the-misuse-of-drugs-act-1971-amendment-no-2-order-2024-and-the-misuse-of-drugs-and-misuse-of-drugs-designation-england-and-wales-and-scotland. 
  20. ↑ 20.0 20.1 "Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys". BMC Anesthesiology 13 (1). October 2013. doi:10.1186/1471-2253-13-33. PMID 24138083. 
  21. ↑ "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. September 1993. doi:10.1111/j.1365-2885.1993.tb00182.x. PMID 8230406. 
  22. ↑ "Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats". Canadian Journal of Veterinary Research 78 (4): 304–315. October 2014. PMID 25356000. 
  23. ↑ "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. March 2017. PMID 28315642. 
  24. ↑ "Alteration in the arrhythmogenic dose of epinephrine (ADE) following xylazine administration to halothane-anesthetized dogs". Journal of Veterinary Pharmacology and Therapeutics 9 (2): 198–203. June 1986. doi:10.1111/j.1365-2885.1986.tb00030.x. PMID 3723662. 
  25. ↑ "Alterations in epinephrine-induced arrhythmogenesis after xylazine and subsequent yohimbine administration in isoflurane-anesthetized dogs". American Journal of Veterinary Research 49 (7): 1072–1075. July 1988. doi:10.2460/ajvr.1988.49.07.1072. PMID 3421530. 
  26. ↑ "Histopathologic alterations induced in the lungs of sheep by use of alpha2-adrenergic receptor agonists". American Journal of Veterinary Research (Am J Vet Res) 60 (2): 154–161. February 1999. doi:10.2460/ajvr.1999.60.02.154. PMID 10048544. 
  27. ↑ "The comparative hypoxaemic effect of four alpha 2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep". Journal of Veterinary Pharmacology and Therapeutics 20 (6): 464–471. December 1997. doi:10.1046/j.1365-2885.1997.00097.x. PMID 9430770. 
  28. ↑ "The effects of xylazine hydrochloride on intrauterine pressure in the cow". Theriogenology 21 (5): 681–690. May 1984. doi:10.1016/0093-691X(84)90014-1. PMID 16725917. 
  29. ↑ "Xylazine causes transient dose-related hyperglycemia and increased urine volumes in mares". American Journal of Veterinary Research (Am J Vet Res) 45 (2): 224–227. February 1984. doi:10.2460/ajvr.1984.45.02.224. PMID 6711946. 
  30. ↑ "Xylazine-induced hyperglycemia in cattle: a possible involvement of alpha 2-adrenergic receptors regulating insulin release". Endocrinology 109 (3): 825–829. September 1981. doi:10.1210/endo-109-3-825. PMID 6266810. 
  31. ↑ Saunders Handbook of Veterinary Drugs (4th ed.). Elsevier. 2016. ISBN 978-0-323-24485-5. 
  32. ↑ Elliott RL, Ruehle PH, "Process for the production of xylazine", US patent expired 4614798A, issued 30 September 1986, assigned to Vetamix (expired 9 April 2005).
  33. ↑ "Xylazine-induced depression and its antagonism by alpha adrenergic blocking agents". The Journal of Pharmacology and Experimental Therapeutics 218 (1): 188–192. July 1981. doi:10.1016/S0022-3565(25)32650-9. PMID 6113279. 
  34. ↑ 34.0 34.1 34.2 34.3 "α2-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells". Neuroscience Letters 541: 184–189. April 2013. doi:10.1016/j.neulet.2013.02.022. PMID 23485735. 
  35. ↑ "Xylazine induces dopamine release and augments the effects of fentanyl". The Journal of Clinical Investigation 134 (22). November 2024. doi:10.1172/JCI183354. PMID 39545408. 
  36. ↑ "Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism". Addiction Neuroscience 11. June 2024. doi:10.1016/j.addicn.2024.100155. PMID 39086495. 
  37. ↑ 37.0 37.1 37.2 37.3 37.4 "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. 2014. doi:10.1155/2014/492609. PMID 25435874. 
  38. ↑ "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. April 2007. doi:10.1093/jat/31.3.165. PMID 17579964. 
  39. ↑ 39.0 39.1 39.2 39.3 "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. December 2013. doi:10.1007/s00216-013-7419-7. PMID 24141317. 
  40. ↑ "Xylazine hydrochloridine (Rompun) overdose in man". Clinical Toxicology 15 (3): 281–285. October 1979. doi:10.3109/15563657908989878. PMID 509891. 
  41. ↑ "Xylazine in Minnesota". https://www.health.state.mn.us/communities/opioids/documents/2023xylazinebrief.pdf. 
  42. ↑ "The Growing Threat of Xylazine and its Mixture with Illicit Drugs". USDOJ. https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf. 
  43. ↑ "What is 'tranq' and why do police carry wound care kits because of it?". Masslive. May 9, 2024. https://www.masslive.com/news/2024/05/what-is-tranq-and-why-do-police-carry-wound-care-kits-because-of-it.html. 
  44. ↑ "Classics in Chemical Neuroscience: Xylazine". ACS Chemical Neuroscience 15 (11): 2091–2098. June 2024. doi:10.1021/acschemneuro.4c00172. PMID 38747710. 
  45. ↑ "Classics in Chemical Neuroscience: Medetomidine". ACS Chemical Neuroscience 15 (21): 3874–3883. November 2024. doi:10.1021/acschemneuro.4c00583. PMID 39405508. 
  46. ↑ "Seattle Police warn that base ingredient in 'zombie drug' tranq is being sold as standalone pill". Fox 13 Seattle. April 7, 2024. https://www.fox13seattle.com/news/tranq-zombie-drug-seattle. 
  47. ↑ "Xylazine". OASAS. https://oasas.ny.gov/xylazine. 
  48. ↑ 48.0 48.1 "Xylazine (veterinary sedative) use in Puerto Rico". Substance Abuse Treatment, Prevention, and Policy 6. April 2011. doi:10.1186/1747-597x-6-7. PMID 21481268. 
  49. ↑ "ACLU probes prisoner deaths in Puerto Rico". Associated Press. Boston.com. 5 August 2010. http://archive.boston.com/news/world/latinamerica/articles/2010/08/05/aclu_probes_prisoner_deaths_in_puerto_rico/. 
  50. ↑ "Opioid Epidemic Updates: "Frankenstein Opioids" and Xylazine-Induced Skin Ulcers". https://www.aafp.org/pubs/afp/afp-community-blog/entry/opioid-epidemic-updates-frankenstein-opioids-and-xylazine-induced-skin-ulcers.html#:~:text=Xylazine%2C%20which%20goes%20by%20the,is%20already%20a%20staggering%20epidemic.. 
  51. ↑ "Research Topics - Xylazine". U.S. Department of Health and Human Services. 21 April 2022. https://nida.nih.gov/research-topics/xylazine. 
  52. ↑ "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" (in en-us). MMWR. Morbidity and Mortality Weekly Report 72 (17): 458–462. April 2023. doi:10.15585/mmwr.mm7217a2. PMID 37104171. 
  53. ↑ "Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis". Drug and Alcohol Dependence 233. April 2022. doi:10.1016/j.drugalcdep.2022.109380. PMID 35247724. 
  54. ↑ "Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report". Journal of Addiction Medicine 16 (5): 595–598. 2022. doi:10.1097/ADM.0000000000000955. PMID 35020700. 
  55. ↑ "White House says fentanyl laced with 'tranq' drug is 'emerging threat'" (in en-US). 2023-04-12. https://thehill.com/policy/healthcare/3945198-white-house-says-fentanyl-laced-with-tranq-drug-is-emerging-threat/. 
  56. ↑ "The first drug-related death associated with xylazine use in the UK and Europe". Journal of Forensic and Legal Medicine 97. July 2023. doi:10.1016/j.jflm.2023.102542. PMID 37236142. 
  57. ↑ "Xylazine poisoning: a systematic review". Clinical Toxicology 60 (8): 892–901. August 2022. doi:10.1080/15563650.2022.2063135. PMID 35442125. 
  58. ↑ "Xylazine Public Health Advisory, November 2022". City of Boston. https://content.boston.gov/sites/default/files/file/2023/01/BPHC%2BXylazine%2BPublic%2BHealth%2BAdvisory_November%2B2022_1.pdf. 
  59. ↑ "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. September 1998. doi:10.1097/00000542-199809000-00005. PMID 9743392. 
  60. ↑ "Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist". CNS Drug Reviews 11 (3): 273–288. 2005. doi:10.1111/j.1527-3458.2005.tb00047.x. PMID 16389294. 
  61. ↑ "The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats". Journal of the South African Veterinary Association 72 (2): 64–67. June 2001. doi:10.4102/jsava.v72i2.618. PMID 11513261. 
  62. ↑ "Xylazine in the Opioid Epidemic: A Systematic Review of Case Reports and Clinical Implications". Cureus 15 (3). March 2023. doi:10.7759/cureus.36864. PMID 37009344. 

Further reading



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