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{{Short description|Equine medication}} {{Short description|Veterinary anesthetic, sedative and analgesic}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 477868834 | verifiedrevid = 1147600369
| IUPAC_name = ''N''-(2,6-Dimethylphenyl)-5,6-dihydro-4''H''-1,3-thiazin-2-amine | IUPAC_name = ''N''-(2,6-Dimethylphenyl)-5,6-dihydro-4''H''-1,3-thiazin-2-amine
| image = Xylazine.svg | image = Xylazine.svg
| width = 160 | width = 160
| image2 = Xylazine ball-and-stick model.png | image2 = Xylazine ball-and-stick model.png
| width2 =


<!--Clinical data--> <!--Clinical data-->
| tradename = Rompun, Anased, Sedazine, Chanazine | tradename = Rompun, Anased, Sedazine, Chanazine, others
| Drugs.com = {{drugs.com|international|xylazine}} | Drugs.com = {{drugs.com|international|xylazine}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = Rx-only | legal_US = Rx-only
| DailyMedID = Xylazine
| legal_status = Veterinary Use | legal_status = Veterinary Use
| routes_of_administration = ], inhalation, or injection (intravenous, intramuscular, or subcutaneous) | routes_of_administration = ], inhalation, or injection (intravenous, intramuscular, or subcutaneous)
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| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 297362 | ChEMBL = 297362
| synonyms =


<!--Chemical data--> <!--Chemical data-->
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| StdInChIKey = BPICBUSOMSTKRF-UHFFFAOYSA-N}} | StdInChIKey = BPICBUSOMSTKRF-UHFFFAOYSA-N}}


'''Xylazine''' is a ] of ] and an ] ],<ref name="Greene" /> sold under many trade names worldwide, most notably the ] brand name '''Rompun''',<ref name=Xylazine/> as well as '''Anased''', '''Sedazine''' and '''Chanazine'''.<ref name=Ruiz! />
'''Xylazine''' is a pharmaceutical drug used for ], ], ], and ] in animals such as horses, cattle, and other non-human mammals.<ref name="Xylazine">{{cite web |url=https://techynewsblogs.com/this-drug-is-turning-people-into-zombies-xylazine|title=Xylazine |website=techynewsblogs.com}}</ref> Veterinarians also use xylazine as an ], especially in cats.<ref name="PDowling">{{cite book | vauthors = Dowling PM |orig-date=March 2015 |date=June 2016 |section=Drugs to control or stimulate vomiting (monogastric) |edition=professional |title=Merck Veterinary Manual |publisher=Merck & Co. |place=Rahway, NJ |section-url=https://www.merckvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-digestive-system/drugs-to-control-or-stimulate-vomiting-monogastric}}</ref> It is an ] of ] and an ] at the {{nobr|{{math|α}}{{sub|2}} class}} of ].<ref name="Greene" />


In ], xylazine is often used in combination with ]. It is sold under many brand names worldwide, most notably the ] brand name Rompun.<ref name=Xylazine/> It is also marketed as Anased, Sedazine, and Chanazine.<ref name=Ruiz! /> The drug interactions vary with different animals.<ref name=Haskins>{{cite journal |vauthors = Haskins SC, Patz JD, Farver TB |date = March 1986 |title = Xylazine and xylazine-ketamine in dogs |journal = American Journal of Veterinary Research |volume = 47 |issue = 3 |pages = 636–641 |pmid = 3963565}}</ref><ref name=Muir>{{cite journal |vauthors = Muir WW, Skarda RT, Milne DW |date = February 1977 |title = Evaluation of xylazine and ketamine hydrochloride for anesthesia in horses |journal = American Journal of Veterinary Research |volume = 38 |issue = 2 |pages = 195–201 |pmid = 842917}}</ref><ref name=Aithal>{{cite journal |vauthors = Aithal HP, Pratap AK, Singh GR |year = 1997 |title=Clinical effects of epidurally administered ketamine and xylazine in goats |journal = Small Ruminant Research |volume = 24 |issue = 1 |pages = 55–64 |doi = 10.1016/s0921-4488(96)00919-4}}</ref> Xylazine is a common veterinary drug used for ], ], ], and ] in animals such as horses, cattle, and other mammals.<ref name="Xylazine">{{cite web |url=https://www.drugs.com/international/xylazine.html |title=Xylazine |website=drugs.com}}</ref> In ], it is often used in combination with ]. Veterinarians also use xylazine as an ], especially in cats.<ref name="PDowling">{{cite book | vauthors = Dowling PM |orig-date=March 2015 |date=June 2016 |section=Drugs to control or stimulate vomiting (monogastric) |edition=professional |title=Merck Veterinary Manual |publisher=Merck & Co. |place=Rahway, NJ |section-url=https://www.merckvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-digestive-system/drugs-to-control-or-stimulate-vomiting-monogastric}}</ref> ]s vary with different animals.<ref name=Haskins>{{cite journal |vauthors = Haskins SC, Patz JD, Farver TB |date = March 1986 |title = Xylazine and xylazine-ketamine in dogs |journal = American Journal of Veterinary Research |volume = 47 |issue = 3 |pages = 636–641 |pmid = 3963565}}</ref><ref name=Muir>{{cite journal |vauthors = Muir WW, Skarda RT, Milne DW |date = February 1977 |title = Evaluation of xylazine and ketamine hydrochloride for anesthesia in horses |journal = American Journal of Veterinary Research |volume = 38 |issue = 2 |pages = 195–201 |pmid = 842917}}</ref><ref name=Aithal>{{cite journal |vauthors = Aithal HP, Pratap AK, Singh GR |year = 1997 |title=Clinical effects of epidurally administered ketamine and xylazine in goats |journal = Small Ruminant Research |volume = 24 |issue = 1 |pages = 55–64 |doi = 10.1016/s0921-4488(96)00919-4}}</ref>


Xylazine has become a commonly ] ] in the United States where it is known by the street name "'''tranq'''", particularly in the territory of Puerto Rico.<ref name="DEA-2023" /> The drug is being ] from stocks for ] ]s as well as trafficked in bulk from China to be used as a ] for ] and ], causing necrotic skin wounds leading to serious infections and limb amputations<ref>{{cite web |title=Recommendations for Caring for Individuals with Xylazine-Associated Wounds |url=https://hip.phila.gov/document/4148/Recommendations_for_Caring_for_People_with_Xylazine-Associated_Wounds_1.12.pdf/ |website=Department of Public Health - City of Philadelphia |access-date=11 August 2024}}</ref> as well as other health issues.<ref>{{cite news|last=Quynh|first=Jacqueline |date=October 4, 2023|title=Feds target Chinese based fentanyl supply chain with ties to Florida|url=https://www.cbsnews.com/miami/news/feds-target-chinese-based-fentanyl-supply-chain-with-ties-to-florida/|work=CBS News|location=Miami|access-date=May 24, 2024}}</ref><ref>{{cite news|last=Rowland|first=Brett |date=October 3, 2023|title=Justice Department goes after China-based companies in fentanyl fight |url=https://www.thecentersquare.com/national/article_c13a6bfe-622e-11ee-9699-13e10181f376.html|work=The Center Square|access-date=May 24, 2024}}</ref><ref name=Reyes/> Fentanyl mixed with xylazine is known by the street names "sleep-cut", "zombie drug", "Iso" and "tranq dope".<ref name="DEA-2023">{{Cite web |date=2023-03-21 |title=DEA Reports Widespread Threat of Fentanyl Mixed with Xylazine |url=https://www.dea.gov/alert/dea-reports-widespread-threat-fentanyl-mixed-xylazine |url-status=live |archive-url=https://web.archive.org/web/20230321002558/https://www.dea.gov/alert/dea-reports-widespread-threat-fentanyl-mixed-xylazine |archive-date=2023-03-21 |access-date=2023-04-12 |publisher=DEA}}{{PD-notice}}</ref><ref>{{Cite web |title=FDA warns about the risk of xylazine exposure in humans, November 8, 2022 |url=https://www.fda.gov/media/162981/download |url-status=live |archive-url=https://web.archive.org/web/20230321182338if_/https://www.fda.gov/media/162981/download |archive-date=2023-03-21 |access-date=2023-04-12 |website=fda.gov |quote=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.}}</ref><ref>{{Cite web |date=2023-03-21 |title=FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs.|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugs |url-status=live |archive-url=https://web.archive.org/web/20230321110941/https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugs |archive-date=2023-03-21 |access-date=2023-04-12 |publisher=www.fda.gov}}</ref><ref name="pmid37009634">{{cite journal | vauthors = Montero F, Bourgois P, Friedman J | title = Potency-Enhancing Synthetics in the Drug Overdose Epidemic: Xylazine ("Tranq"), Fentanyl, Methamphetamine, and the Displacement of Heroin in Philadelphia and Tijuana | journal = Journal of Illicit Economies and Development | volume = 4 | issue = 2 | pages = 204–222 | date = 2022 | pmid = 37009634 | pmc = 10065983 | doi = 10.31389/jied.122 }}</ref>
Xylazine has become a ] in the United States, where it is known by the street name "'''tranq'''", and particularly in ].<ref name=Torruella/> The drug is being ] from stocks used by equine ]s and used as a ] for ], causing skin sores and infections at injection sites, as well as other health issues.<ref name=Reyes/>


==History== ==History==
⚫ Xylazine was discovered as an ] agent in 1962 by Farbenfabriken Bayer in ].<ref name=Greene>{{cite journal |vauthors = Greene SA, Thurmon JC |date = December 1988 |title = Xylazine—a review of its pharmacology and use in veterinary medicine |journal = Journal of Veterinary Pharmacology and Therapeutics |volume = 11 |issue = 4 |pages = 295–313 |pmid = 3062194 |doi = 10.1111/j.1365-2885.1988.tb00189.x}}</ref> Accounts of the actions and uses of xylazine in animals were reported as early as the late 1960s and early 1970s.<ref name=Greene/> Results from early human clinical studies confirmed that xylazine has several ] ] effects.<ref name=Greene/> Xylazine administration is used for sedation, anesthesia, muscle relaxation, and analgesia.<ref name=Xylazine /> It causes a significant reduction in ] and ] in healthy volunteers.{{failed verification|31 Nar 2023|date=March 2023}}<ref name=Xiao>{{cite journal |vauthors = Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX |date = October 2013 |title = Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys |journal = BMC Anesthesiology |volume = 13 |issue = 1 |pages = 33 |pmid = 24138083 |pmc = 4016475 |doi = 10.1186/1471-2253-13-33 |doi-access = free }}</ref> Xylazine was also studied for use in human beings, but due to hazardous ]s, including ] and ], it was not approved by the ] (FDA) for human use.<ref name=Reyes>{{cite journal |vauthors = Reyes JC, Negrón JL, Colón HM, Padilla AM, Millán MY, Matos TD, Robles RR |date = June 2012 |title = The emerging of xylazine as a new drug of abuse and its health consequences among drug users in Puerto Rico |journal = Journal of Urban Health |volume = 89 |issue = 3 |pages = 519–526 |pmid = 22391983 |pmc = 3368046 |doi = 10.1007/s11524-011-9662-6}}</ref>


⚫ In the United States, xylazine was approved by the FDA only for veterinary use as a ], analgesic, and muscle relaxant in dogs, cats, horses, elk, ], ], ], and ].<ref name=Greene/><ref name=Ruiz!/> 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.<ref name=Delehant>{{cite journal |vauthors = Delehant TM, Denhart JW, Lloyd WE, Powell JD |year = 2003 |title = 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 |journal = Veterinary Therapeutics |volume = 4 |issue = 2 |pages = 128–134 |pmid = 14506588}}</ref>
⚫ Xylazine was discovered as an ] agent in 1962 by Farbenfabriken Bayer in Leverkusen, Germany.<ref name=Greene>{{cite journal |vauthors = Greene SA, Thurmon JC |date = December 1988 |title = Xylazine—a review of its pharmacology and use in veterinary medicine |journal = Journal of Veterinary Pharmacology and Therapeutics |volume = 11 |issue = 4 |pages = 295–313 |pmid = 3062194 |doi = 10.1111/j.1365-2885.1988.tb00189.x}}</ref> Results from early human clinical studies confirmed that xylazine has several ] ] effects.<ref name=Greene/> Xylazine administration is used for sedation, anesthesia, muscle relaxation, and analgesia.<ref name=Xylazine /> It causes a significant reduction in ] and ] in healthy volunteers.{{failed verification|31 Nar 2023|date=March 2023}}<ref name=Xiao>{{cite journal |vauthors = Xiao YF, Wang B, Wang X, Du F, Benzinou M, Wang YX |date = October 2013 |title = Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys |journal = BMC Anesthesiology |volume = 13 |issue = 1 |pages = 33 |pmid = 24138083 |pmc = 4016475 |doi = 10.1186/1471-2253-13-33}}</ref> Due to hazardous side effects, including ] and ], xylazine was not approved by the ] (FDA) for human use.<ref name=Reyes>{{cite journal |vauthors = Reyes JC, Negrón JL, Colón HM, Padilla AM, Millán MY, Matos TD, Robles RR |date = June 2012 |title = The emerging of xylazine as a new drug of abuse and its health consequences among drug users in Puerto Rico |journal = Journal of Urban Health |volume = 89 |issue = 3 |pages = 519–526 |pmid = 22391983 |pmc = 3368046 |doi = 10.1007/s11524-011-9662-6}}</ref> As a result, xylazine's mechanism of action in humans remains unknown.<ref name=Ruiz!>{{cite journal |vauthors = Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, Martínez MA |date = July 2014 |title = Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature |journal = Forensic Science International |volume = 240 |pages = 1–8 |pmid = 24769343 |doi = 10.1016/j.forsciint.2014.03.015}}</ref>


⚫ In scientific research using ]s, xylazine is a component of the most common anesthetic, ketamine-xylazine {{crossreference|(see: ])}}, to anesthetize rats, mice, hamsters, and guinea pigs.<ref name=Veilleux-Lemieux>{{cite journal |vauthors = Veilleux-Lemieux D, Castel A, Carrier D, Beaudry F, Vachon P |date = September 2013 |title = Pharmacokinetics of ketamine and xylazine in young and old Sprague-Dawley rats |journal = Journal of the American Association for Laboratory Animal Science |volume = 52 |issue = 5 |pages = 567–570 |pmid = 24041212 |pmc = 3784662}}</ref>
⚫ Xylazine was approved by the FDA for veterinary use and is now used as an animal ].<ref name=Reyes/> In the United States, xylazine was only approved by the FDA for veterinary use as a sedative, analgesic, and muscle relaxant in dogs, cats, horses, elk, ], ], ], and ].<ref name=Greene/><ref name=Ruiz!/> 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.<ref name=Delehant>{{cite journal |vauthors = Delehant TM, Denhart JW, Lloyd WE, Powell JD |year = 2003 |title = 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 |journal = Veterinary Therapeutics |volume = 4 |issue = 2 |pages = 128–134 |pmid = 14506588}}</ref>

⚫ In scientific research, xylazine is a component of the most common anesthetic, ketamine-xylazine (see ]), which is used in rats, mice, hamster, and guinea pigs.<ref name=Veilleux-Lemieux>{{cite journal |vauthors = Veilleux-Lemieux D, Castel A, Carrier D, Beaudry F, Vachon P |date = September 2013 |title = Pharmacokinetics of ketamine and xylazine in young and old Sprague-Dawley rats |journal = Journal of the American Association for Laboratory Animal Science |volume = 52 |issue = 5 |pages = 567–570 |pmid = 24041212 |pmc = 3784662}}</ref> The accounts of the actions and uses of xylazine in animals were reported as early as the late 1960s and early 1970s.<ref name=Greene/>

==Medical uses==
Xylazine is widely used in veterinary medicine as a sedative, muscle relaxant, and analgesic. It is frequently used in the treatment of ].<ref name=Greene/> However it is rarely if ever used in human medical treatment. Xylazine is similar to drugs such as ], ]s, and clonidine.<ref name=Ruiz!/> As an anesthetic, it is typically used in conjunction with ketamine.<ref name=Xiao/>


==Veterinary use== ==Veterinary use==
] ]
In animals, xylazine may be administered ] or ].<ref name=Ruiz!/> As a veterinary anesthetic, xylazine is typically only administered once for intended effect before or during surgical procedures.<ref name=Greene/> Alpha-2 antagonists such as ] and ] may be used to reverse the effects of xylazine in animals.<ref>Kollias-Baker CA, Court MH, Williams LL. Influence of yohimbine and tolazoline on the cardiovascular, respiratory, and sedative effects of xylazine in the horse. ''J Vet Pharmacol Ther''. 1993 Sep;16(3):350-8. {{doi|10.1111/j.1365-2885.1993.tb00182.x}} {{pmid|8230406}}</ref><ref>Murahata Y, Miki Y, Hikasa Y. Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. ''Can J Vet Res''. 2014 Oct;78(4):304-15. {{pmid|25356000}}</ref><ref>Janssen CF, Maiello P, Wright MJ Jr, Kracinovsky KB, Newsome JT. Comparison of Atipamezole with Yohimbine for Antagonism of Xylazine in Mice Anesthetized with Ketamine and Xylazine. ''J Am Assoc Lab Anim Sci''. 2017 Mar 1;56(2):142-147. {{pmid|28315642}}</ref>


Xylazine is widely used in veterinary medicine as a sedative, muscle relaxant, and analgesic. It is frequently used in the treatment of ].<ref name=Greene/> It is not used in human medical treatment. Xylazine is similar to drugs such as ], ]s, and clonidine.<ref name=Ruiz!/> As an anesthetic, it is typically used in conjunction with ketamine.<ref name=Xiao/> In animals, xylazine may be administered ] or ].<ref name=Ruiz!>{{cite journal | vauthors = Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, Martínez MA | title = Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature | journal = Forensic Science International | volume = 240 | pages = 1–8 | date = July 2014 | pmid = 24769343 | doi = 10.1016/j.forsciint.2014.03.015 }}</ref> As a veterinary anesthetic, xylazine is typically only administered once for the intended effect before or during surgical procedures.<ref name=Greene/> ]s such as ] and ] may be used to reverse the effects of xylazine in animals.<ref>{{cite journal | vauthors = Kollias-Baker CA, Court MH, Williams LL | title = Influence of yohimbine and tolazoline on the cardiovascular, respiratory, and sedative effects of xylazine in the horse | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 16 | issue = 3 | pages = 350–358 | date = September 1993 | doi = 10.1111/j.1365-2885.1993.tb00182.x | pmid = 8230406 }}</ref><ref>{{cite journal | vauthors = Murahata Y, Miki Y, Hikasa Y | title = Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats | journal = Canadian Journal of Veterinary Research | volume = 78 | issue = 4 | pages = 304–315 | date = October 2014 | pmid = 25356000 | pmc = 4170770 }}</ref><ref>{{cite journal | vauthors = Janssen CF, Maiello P, Wright MJ, Kracinovsky KB, Newsome JT | title = Comparison of Atipamezole with Yohimbine for Antagonism of Xylazine in Mice Anesthetized with Ketamine and Xylazine | journal = Journal of the American Association for Laboratory Animal Science | volume = 56 | issue = 2 | pages = 142–147 | date = March 2017 | pmid = 28315642 | pmc = 5361038 }}</ref>
⚫ ===Side effects===


===Side-effects===
Side effects in animals include transient hypertension, hypotension, and respiratory depression.<ref name=Ruiz!/> Further, the decrease of tissue sensitivity to insulin leads to xylazine-induced hyperglycemia and a reduction of tissue glucose uptake and utilization.<ref name=Xiao/> The duration of effects in animals lasts up to 4&nbsp;hours.<ref name=Ruiz!/> ]s in animals include transient ], ], and ].<ref name=Ruiz!/> Further, the decrease of tissue sensitivity to insulin leads to xylazine-induced ] and a reduction of tissue glucose uptake and utilization.<ref name=Xiao/> The effects in animals last up to 4{{nbsp}}hours.<ref name=Ruiz!/>


===Pharmacokinetics=== ===Pharmacokinetics===
⚫ In dogs, sheep, horses, and cattle, the ] is very short: only 1.21–{{hsp}}5.97 minutes. Complete elimination of the drug can take up to 23{{spaces}}minutes in sheep and up to 49{{spaces}}minutes in horses.<ref name=Greene/><ref name=Ruiz!/> In young rats the half-life is one hour.<ref name=Veilleux-Lemieux/> Xylazine has a large ] of {{mvar|V}}{{sub|d}} = {{nowrap|1.9{{hsp}}–}}2.5 for horses, cattle, sheep, and dogs.<ref name=Ruiz!/> Though the peak ] concentrations are reached in {{nowrap|12{{hsp}}–}}14 minutes in all species, the ] varies between species.<ref name=Ruiz!/> The half-life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time.<ref name=Veilleux-Lemieux/> Toxicity occurs with repeated administration, given that the metabolic clearance of the drug is usually calculated as 7–{{hsp}}9 times the half-life, which is 4{{spaces}}to 5 days for the clearance of xylazine.<!--This seems to conflict with the half-life info at beginning of the section.--><ref name=Veilleux-Lemieux/>

⚫ In dogs, sheep, horses, and cattle, the ] is very short: only 1.21–5.97&nbsp;minutes. Complete elimination of the drug can take up to 23.11&nbsp;minutes in sheep and up to 49.51&nbsp;minutes in horses.<ref name=Greene/><ref name=Ruiz!/> In young rats, the half life is one hour.<ref name=Veilleux-Lemieux/> Xylazine has a large ] (''V''<sub>d</sub>).<ref name=Ruiz!/> The {{mvar|V}}{{sub|d}} = 1.9–2.5 for horses, cattle, sheep, and dogs.<ref name=Ruiz!/> Though the peak ] concentrations are reached in 12–14&nbsp;minutes in all species, the ] varies between species.<ref name=Ruiz!/> The half life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time.<ref name=Veilleux-Lemieux/> Toxicity occurs with repeated administration, given that the metabolic clearance of the drug is usually calculated as 7–9&nbsp;times the half-life, which is 4 to 5&nbsp;days for the clearance of xylazine.<!--This seems to conflict with the half-life info at beginning of section.--><ref name=Veilleux-Lemieux/>


==Pharmacology== ==Pharmacology==


===Pharmacodynamics=== ===Pharmacodynamics===
⚫ [[File:Xylazine synthesis.png|thumb|Xylazine synthesis adapted from Elliot & Ruehle (1986).<ref>{{cite patent |invent1=Elliott, Richard L. |invent2=Ruehle, Paul H. |number=4614798A |fdate=9 April 1985 |gdate=30 September 1986 |assign1=Vetamix |status=expired |title=Process for the production of xylazine |country=US}} (expired 9 April 2005).</ref>

⚫ [[File:Xylazine synthesis.png|thumb|Xylazine synthesis adapted from Elliot & Ruehle (1986).<ref>{{cite patent |invent1=Elliott, Richard L. |invent2=Ruehle, Paul H. |number=4614798A |fdate=9 April 1985 |gdate=30 September 1986 |assign1=Vetamix |status=expired |title=Process for the production of xylazine |country=US}} (expired 9&nbsp;April 2005).</ref>
]] ]]


Xylazine is a potent {{math|α}}{{sub|2}} ].<ref name=Ruiz!/> When xylazine and other {{math|α}}{{sub|2}} adrenergic receptor agonists are administered, they distribute throughout the body within 30–40&nbsp;minutes.<ref name=Delehant/> Due to xylazine's highly ] nature, xylazine directly stimulates central {{math|α}}{{sub|2}} receptors as well as peripheral {{math|α}}-adrenoceptors in a variety of tissues.<ref name=Greene/><ref name=Ruiz!/> As an agonist, xylazine leads to a decrease in neurotransmission of ] and ] in the central nervous system.<ref name=Ruiz!/> It does so by mimicking norepinephrine in binding to presynaptic surface ]s, which leads to feedback inhibition of norepinephrine.<ref name=Park>{{cite journal |vauthors = Park JW, Chung HW, Lee EJ, Jung KH, Paik JY, Lee KH |date = April 2013 |title = {{math|α}}{{sub|2}}-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells |journal = Neuroscience Letters |volume = 541 |pages = 184–189 |pmid = 23485735 |doi = 10.1016/j.neulet.2013.02.022 |s2cid = 46338840}}</ref> Xylazine is a ] ].<ref>{{cite journal | vauthors = Hsu WH | title = Xylazine-induced depression and its antagonism by alpha adrenergic blocking agents | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 218 | issue = 1 | pages = 188–192 | date = July 1981 | pmid = 6113279 | url = https://jpet.aspetjournals.org/content/218/1/188 }}</ref><ref name=Ruiz!/> When xylazine and other ] agonists are administered, they distribute throughout the body within 30 to 40 minutes.<ref name=Delehant/> Due to xylazine's highly ] nature, it directly stimulates central α<sub>2</sub>-adrenergic receptors as well as peripheral ]s in a variety of tissues.<ref name=Greene/><ref name=Ruiz!/> As an agonist, xylazine reduces release of ] and ] in the ].<ref name=Ruiz!/> It does so by mimicking norepinephrine in binding to the pre-synaptic surface ]s, which leads to feedback inhibition of norepinephrine release.<ref name=Park>{{cite journal |vauthors = Park JW, Chung HW, Lee EJ, Jung KH, Paik JY, Lee KH |date = April 2013 |title = {{math|α}}{{sub|2}}-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells |journal = Neuroscience Letters |volume = 541 |pages = 184–189 |pmid = 23485735 |doi = 10.1016/j.neulet.2013.02.022 |s2cid = 46338840}}</ref>


Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function through ] of substrate transport. Accordingly, xylazine significantly increases ] and does not affect ].<ref name=Park /> This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site.<ref name=Park/> For example, xylazine and clonidine suppress uptake of MIBG, a norepinephrine analog, in ] cells.<ref name=Park/> Xylazine has varying affinities for ], ], ], ], ] and ] receptors.<ref name=Ruiz!/> Its chemical structure closely resembles the ], ], and clonidine. Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function through ] of substrate transport. Accordingly, xylazine significantly increases ] and does not affect ].<ref name=Park /> This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site.<ref name=Park/> For example, xylazine and ] suppress uptake of ] (MIBG), a norepinephrine analogue, in ] cells.<ref name=Park/> Xylazine's chemical structure closely resembles clonidine.

It has also been reported that xylazine activates the ]s, with low potency, which may contribute to its effects.<ref>{{Cite journal | vauthors = Bedard ML, Huang XP, Murray JG, Nowlan AC, Conley SY, Mott SE, Loyack SJ, Cline CA, Clodfelter CG, Dasgupta N, Krumm B |date=2024-05-03 |title=Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism |journal=Addiction Neuroscience |language=en |volume=11 |pages=100155 |doi=10.1016/j.addicn.2024.100155|doi-access=free |pmc=11290297 }}</ref>


===Pharmacokinetics in humans=== ===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, ], ], and ] in order to provide reliable anesthesia effects.<ref name=Reyes/><ref name=Xiao/> The most common route of administration is ].<ref name=Reyes/>


Xylazine is absorbed, metabolized, and eliminated rapidly. Xylazine can be inhaled or administered intravenously, ]ly, subcutaneously, or orally either by itself or in conjunction with other anesthetics, such as ketamine, ], ], and ] in order to provide reliable anesthesia effects.<ref name=Reyes/><ref name=Xiao/> The most common route of administration is ].<ref name=Reyes/> The drug is used as a veterinary anesthetic and the recommended dose varies between species.<ref name=Silva-Torres>{{cite journal |vauthors = Silva-Torres L, Veléz C, Alvarez L, Zayas B |year = 2014 |title = 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 = Journal of Toxicology |volume = 2014 |page = 492609 |pmid = 25435874 |pmc = 4243599 |doi = 10.1155/2014/492609 |doi-access = free}}</ref> 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.<ref name=Ruiz!/> Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to enter the heart, lungs, liver, and kidney.<ref name=Silva-Torres>{{cite journal |vauthors = Silva-Torres L, Veléz C, Alvarez L, Zayas B |year = 2014 |title = 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 = Journal of Toxicology |volume = 2014 |page = 492609 |pmid = 25435874 |pmc = 4243599 |doi = 10.1155/2014/492609 |doi-access = free}}</ref> In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6&nbsp;mg/L.<ref name=Ruiz!/> Xylazine diffuses extensively and penetrates the ], as might be expected due to the uncharged, lipophilic nature of the compound.<ref name=Ruiz!/>


⚫ Xylazine is metabolized by the liver's ] enzymes.<ref name=Veilleux-Lemieux/> When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted in urine.<ref name=Barroso>{{cite journal |vauthors = Barroso M, Gallardo E, Margalho C, Devesa N, Pimentel J, Vieira DN |date = April 2007 |title = Solid-phase extraction and gas chromatographic–mass spectrometric determination of the veterinary drug xylazine in human blood |journal = Journal of Analytical Toxicology |volume = 31 |issue = 3 |pages = 165–169 |pmid = 17579964 |doi = 10.1093/jat/31.3.165 |doi-access = free}}</ref> Around 70% of a dose is excreted by urine.<ref name=Veilleux-Lemieux /> Thus, urine can be used in detecting xylazine administration because it contains many ]s, which are the main targets and products in urine.<ref name=Greene/><ref name=Meyer/> Within a few hours, xylazine decreases to undetectable levels.<ref name=Ruiz!/> Other factors can also significantly impact the pharmacokinetics of xylazine, such as sex, nutrition, environmental conditions, and prior diseases.<ref name=Veilleux-Lemieux/>
Xylazine's action can be seen usually 15–30&nbsp;minutes after administration and the sedative effect may continue for 1–2&nbsp;hours and last up to 4&nbsp;hours.<ref name=Ruiz!/> Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to perfuse target organs including the heart, lungs, liver, and kidney.<ref name=Silva-Torres/> In nonfatal cases, the blood plasma concentrations range from 0.03–4.6&nbsp;mg/L.<ref name=Ruiz!/> Xylazine diffuses extensively and penetrates the ], as might be expected due to the uncharged, lipophilic nature of the compound.<ref name=Ruiz!/>


⚫ Xylazine is metabolized by liver ] enzymes.<ref name=Veilleux-Lemieux/> When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted as urine.<ref name=Barroso>{{cite journal |vauthors = Barroso M, Gallardo E, Margalho C, Devesa N, Pimentel J, Vieira DN |date = April 2007 |title = Solid-phase extraction and gas chromatographic–mass spectrometric determination of the veterinary drug xylazine in human blood |journal = Journal of Analytical Toxicology |volume = 31 |issue = 3 |pages = 165–169 |pmid = 17579964 |doi = 10.1093/jat/31.3.165 |doi-access = free}}</ref> Around 70% of a dose is excreted by urine.<ref name=Veilleux-Lemieux /> Thus, urine can be used in detecting xylazine administration because it contains many ]s, which are the main targets and products in urine.<ref name=Greene/><ref name=Meyer/> Within a few hours, xylazine decreases to undetectable levels.<ref name=Ruiz!/> Other factors can also significantly impact the pharmacokinetics of xylazine, including sex, nutrition, environmental conditions, and prior diseases.<ref name=Veilleux-Lemieux/>
:{| class="wikitable" style = "text-align:center" :{| class="wikitable" style = "text-align:center"
|+Xylazine Metabolites <ref name=Meyer/> |+Xylazine Metabolites <ref name=Meyer/>
|- |-
| Xylazine-M (2,6 dimethylaniline) || Xylazine-M (''N''-thiourea-2,6-dimethylaniline) || Xylazine-M (sulfone-HO-) isomer&nbsp;2 | Xylazine-M (]) || 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&nbsp;2) || Xylazine M (oxo-) | Xylazine-M (HO-2,6-dimethylaniline isomer 1) || Xylazine-M (HO-2,6-dimethylaniline isomer 2) || Xylazine M (oxo-)
|- |-
| Xylazine-M (HO-) isomer&nbsp;1 || Xylazine-M (HO-) isomer&nbsp;1 glucuronide || Xylazine-M (HO-) isomer&nbsp;2 | Xylazine-M (HO-) isomer 1 || Xylazine-M (HO-) isomer 1 glucuronide || Xylazine-M (HO-) isomer 2
|- |-
| Xylazine-M (HO-) isomer&nbsp;2 glucuronide || Xylazine-M (HO-oxo-) isomer&nbsp;1 || Xylazine-M (HO-oxo-) isomer 1 glucuronide | Xylazine-M (HO-) isomer 2 glucuronide || Xylazine-M (HO-oxo-) isomer || Xylazine-M (HO-oxo-) isomer 1 glucuronide
|- |-
| Xylazine-M (HO-oxo-) isomer&nbsp;2 || Xylazine-M (HO-oxo-) isomer&nbsp;2 glucuronide || Xylazine-M (sulfone) | Xylazine-M (HO-oxo-) isomer 2 || Xylazine-M (HO-oxo-) isomer 2 glucuronide || Xylazine-M (sulfone)
|- |-
| || Xylazine-M (sulfone-HO-) isomer 1 || | || Xylazine-M (sulfone-HO-) isomer 1 ||
Line 119: Line 119:


==Recreational use== ==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.<ref>{{cite journal | vauthors = Carruthers SG, Nelson M, Wexler HR, Stiller CR | title = Xylazine hydrochloridine (Rompun) overdose in man | journal = Clinical Toxicology | volume = 15 | issue = 3 | pages = 281–285 | date = October 1979 | pmid = 509891 | doi = 10.3109/15563657908989878 }}</ref>


Xylazine is not regulated as a controlled substance under the ]. 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.<ref>{{cite web |title=Xylazine in Minnesota |url=https://www.health.state.mn.us/communities/opioids/documents/2023xylazinebrief.pdf |website=Minnesota Department of Health}}</ref><ref>{{cite web |title=The Growing Threat of Xylazine and its Mixture with Illicit Drugs |website=Drug Enforcement Administration |publisher=USDOJ |url=https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf}}</ref> The withdrawal can last for two weeks and has a quicker onset than fentanyl.<ref name=masslive>{{cite news |title=What is ‘tranq’ and why do police carry wound care kits because of it? |url=https://www.masslive.com/news/2024/05/what-is-tranq-and-why-do-police-carry-wound-care-kits-because-of-it.html |access-date=11 August 2024 |work=Masslive |date=May 9, 2024}}</ref>
Since the early 2000s, xylazine has become popular as a drug of abuse in the United States and Puerto Rico.<ref name=Meyer>{{cite journal | vauthors = Meyer GM, Maurer HH | title = 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 | journal = Analytical and Bioanalytical Chemistry | volume = 405 | issue = 30 | pages = 9779–9789 | date = December 2013 | pmid = 24141317 | doi = 10.1007/s00216-013-7419-7 | s2cid = 23164588 }}</ref> Xylazine's street name in Puerto Rico is ''anestesia de caballo'', which translates to "horse anesthetic".<ref name=Ruiz!/><ref name=Torruella>{{cite journal | vauthors = Torruella RA | title = Xylazine (veterinary sedative) use in Puerto Rico | journal = Substance Abuse Treatment, Prevention, and Policy | volume = 6 | pages = 7 | date = April 2011 | pmid = 21481268 | pmc = 3080818 | doi = 10.1186/1747-597x-6-7 }}</ref> Xylazine's street name in United States is "tranq", "tranq dope", and "zombie drug".<ref>{{cite web |title=Opioid Epidemic Updates: “Frankenstein Opioids” and Xylazine-Induced Skin Ulcers |url=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. |website=] |access-date=23 February 2023}}</ref><ref name="injuryprev-2020-043968">{{cite journal | vauthors = Johnson J, Pizzicato L, Johnson C, Viner K | title = Increasing presence of xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010-2019 | journal = Injury Prevention | volume = 27 | issue = 4 | pages = 395–398 | date = August 2021 | pmid = 33536231 | doi = 10.1136/injuryprev-2020-043968 }}</ref><!-- <ref>{{cite news |title=Skin-rotting drug 'tranq' infiltrates big cities: 'Zombifying bodies' |url=https://nypost.com/2023/02/21/skin-rotting-drug-tranq-infiltrates-big-cities-zombifying-bodies/ |access-date=23 February 2023 |date=21 February 2023}}</ref> --><ref name="nytimes/Tranq-Dope">{{cite news | vauthors = Hoffman J |title=Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones |url=https://www.nytimes.com/2023/01/07/health/fentanyl-xylazine-drug.html |access-date=23 February 2023 |work=The New York Times |date=7 January 2023}}</ref> While xylazine is almost invariably combined with opioids when used recreationally, it can produce a characteristic ] in its own right which can complicate treatment of addicted users.<ref>Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. ''Drug Alcohol Depend''. 2022 Apr 1;233:109380. {{doi|10.1016/j.drugalcdep.2022.109380}} {{pmid|35247724}}</ref><ref>Ehrman-Dupre R, Kaigh C, Salzman M, Haroz R, Peterson LK, Schmidt R. Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report. ''J Addict Med''. 2022 Sep-Oct 01;16(5):595-598. {{doi|10.1097/ADM.0000000000000955}} {{pmid|35020700}}</ref>


Xylazine is most commonly ingested as an additive with fentanyl.<ref name="Hoffman et al.">{{Cite journal | vauthors=Hoffman GR, Giduturi C, Cordaro NJ, Yoshida CT, Schoffstall AM, Stabio ME, Zuckerman MD | date=May 15, 2024 | title=Classics in Chemical Neuroscience: Xylazine | journal=ACS Chem Neurosci | volume=15 | issue=11 | pages=2091–2098 | doi=10.1021/acschemneuro.4c00172}}</ref> Xylazine has also been reported in combination with ], another potent ] ].<ref name="de Andrade Horn">{{Cite journal | vauthors=de Andrade Horn P, Berida TI, Parr LC, Bouchard JL, Jayakodiarachchi N, Schultz DC, Lindsley CW, Crowley ML | date=October 2024 | title= Classics in Chemical Neuroscience: Medetomidine | journal=ACS Chem Neurosci | doi=10.1021/acschemneuro.4c00583| doi-access=free | pmc=11587509 }}</ref> 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.<ref name=fox13>{{cite web |last=Rose |first=David |title=Seattle Police warn that base ingredient in 'zombie drug' tranq is being sold as standalone pill |date=April 7, 2024 |work=Fox 13 Seattle |url=https://www.fox13seattle.com/news/tranq-zombie-drug-seattle}}</ref><ref>{{cite web |title=Xylazine |url=https://oasas.ny.gov/xylazine |website=Office of Addiction Services and Supports (OASAS) - New York |publisher=OASAS |access-date=11 August 2024}}</ref><ref name="Meyer">{{cite journal | vauthors = Meyer GM, Maurer HH | title = 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 | journal = Analytical and Bioanalytical Chemistry | volume = 405 | issue = 30 | pages = 9779–9789 | date = December 2013 | pmid = 24141317 | doi = 10.1007/s00216-013-7419-7 | s2cid = 23164588 }}</ref> Xylazine's street name in Puerto Rico is ''anestesia de caballo'', which translates to "horse anesthetic".<ref name="Ruiz!" /><ref name="Torruella">{{cite journal | vauthors = Torruella RA | title = Xylazine (veterinary sedative) use in Puerto Rico | journal = Substance Abuse Treatment, Prevention, and Policy | volume = 6 | pages = 7 | date = April 2011 | pmid = 21481268 | pmc = 3080818 | doi = 10.1186/1747-597x-6-7 | doi-access = free }}</ref> From 2002 to 2008, its use was associated with a high number of inmate deaths at the ] in ].<ref name="boston">{{Cite news | vauthors = Melia M |date=5 August 2010 |title=ACLU probes prisoner deaths in Puerto Rico |publisher=Boston.com |agency=Associated Press |url=http://archive.boston.com/news/world/latinamerica/articles/2010/08/05/aclu_probes_prisoner_deaths_in_puerto_rico/ |access-date=24 August 2016}}</ref>
Xylazine users in Puerto Rico are more likely to be male, under age&nbsp;30, living in a rural area, and injecting versus inhaling xylazine. Xylazine has similar behavioral consequences as heroin, thus it is commonly used as an adulterant. Xylazine is also frequently found in "]" (a mixture of several abused drugs – usually ], ] or ], and ]).<ref name=Reyes/> The combination of heroin and xylazine produces a potentially more deadly high than administration of heroin alone. Use of xylazine in combination with "speedball" may potentiate or prolong the effects of ], which can lead to adverse consequences.


Xylazine's street name in the United States, particularly when it is mixed with ], is "tranq", "tranq dope" and "zombie drug".<ref>{{cite web |title=Opioid Epidemic Updates: "Frankenstein Opioids" and Xylazine-Induced Skin Ulcers |url=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. |website=] |access-date=23 February 2023}}</ref>
⚫ 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 1&nbsp;g of xylazine.<ref>{{cite journal | vauthors = Carruthers SG, Nelson M, Wexler HR, Stiller CR | title = Xylazine hydrochloridine (Rompun) overdose in man | journal = Clinical Toxicology | volume = 15 | issue = 3 | pages = 281–285 | date = October 1979 | pmid = 509891 | doi = 10.3109/15563657908989878 }}</ref> Intentional intoxication from ingesting, inhaling, or injecting xylazine has been reported. The intravenous route is the most common route of administration for those who abuse heroin or xylazine recreationally. In Puerto Rico, xylazine has increased in popularity. Its use was associated with a high number of inmate deaths at the Guerrero Correctional Institution in ], from 2002 to 2008.


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. Because xylazine and heroin trigger similar behavioral outcomes, the former is often secretly mixed into illegal doses of heroin.{{Citation needed|date=September 2024}} The combination of heroin and xylazine produces a potentially more deadly ] than administration of heroin alone. Xylazine is also frequently found in "]", a mixture of a stimulant drug such as ] with a depressant drug such as ], ] and/or ].<ref name=Reyes/> As of 2012, causal factors underlying xylazine's increasing popularity were still unknown.<ref name=Torruella/>
When abused by humans, frequency of xylazine use depends on social or economic factors, as well as each user's subjective response to the drug's addictive properties. ] can reverse the effect of opioid overdose, but has no effect on xylazine.<ref>{{cite web |title=Research Topics - Xylazine |url=https://nida.nih.gov/research-topics/xylazine |website=National Institute on Drug Abuse |publisher=U.S. Department of Health and Human Services |access-date=25 January 2023}}</ref> As of November 2022, its detection in the bloodstream requires a ]-based test.<ref>{{cite web |title=Xylazine Public Health Advisory, November 2022 |url=https://content.boston.gov/sites/default/files/file/2023/01/BPHC%2BXylazine%2BPublic%2BHealth%2BAdvisory_November%2B2022_1.pdf |website=Boston Public Health Commission |publisher=City of Boston |access-date=25 January 2023}}</ref>


As of 2022, more information on the ] 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.<ref>{{cite web |title=Research Topics - Xylazine |url=https://nida.nih.gov/research-topics/xylazine |website=National Institute on Drug Abuse |date=21 April 2022 |publisher=U.S. Department of Health and Human Services |access-date=25 January 2023}}</ref> From November 2021 until August 2022, 80% of drug paraphernalia which tested positive for fentanyl at needle exchange programs in Maryland also contained xylazine.<ref>{{cite journal | vauthors = Russell E, Sisco E, Thomson A, Lopes J, Rybak M, Burnett M, Heilman D, Appley MG, Gladden RM | title = 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 | language = en-us | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 72 | issue = 17 | pages = 458–462 | date = April 2023 | pmid = 37104171 | doi = 10.15585/mmwr.mm7217a2 | s2cid = 258354168 | doi-access = free }}</ref> As of 2022, xylazine was almost invariably combined with ]s when used recreationally, and the drug produced a characteristic ] which complicates treatment of addicted users.<ref>{{cite journal | vauthors = Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C | title = Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis | journal = Drug and Alcohol Dependence | volume = 233 | pages = 109380 | date = April 2022 | pmid = 35247724 | pmc = 9128597 | doi = 10.1016/j.drugalcdep.2022.109380 }}</ref><ref>{{cite journal | vauthors = Ehrman-Dupre R, Kaigh C, Salzman M, Haroz R, Peterson LK, Schmidt R | title = Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report | journal = Journal of Addiction Medicine | year = 2022 | volume = 16 | issue = 5 | pages = 595–598 | doi = 10.1097/ADM.0000000000000955 | pmid = 35020700 | s2cid = 245907730 }}</ref>
Causal factors underlying xylazine's increasing popularity are still unknown. Further research is needed to gain more information on the distribution of xylazine in the body, physical symptoms, potential treatments, and factors predictive of chronic use.<ref name=Torruella/>


In April 2023, the ] declared xylazine-] fentanyl an official emerging drug threat to the nation, the first time such a label has been given. ], director of the ] (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".<ref>{{Cite web | vauthors = Weixel N |date=2023-04-12 |title=White House says fentanyl laced with 'tranq' drug is 'emerging threat' |url=https://thehill.com/policy/healthcare/3945198-white-house-says-fentanyl-laced-with-tranq-drug-is-emerging-threat/ |access-date=2023-04-13 |website=The Hill |language=en-US}}</ref> 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.<ref name="DEA-2023"/>
⚫ ===Side effects===


In July 2023, the first death following xylazine use outside of North America was reported to have taken place in ], England in May 22. A 43-year-old male was found dead at home with ] ] detecting heroin, cocaine, fentanyl and xylazine.<ref>{{Cite journal | vauthors = Rock KL, Lawson AJ, Duffy J, Mellor A, Treble R, Copeland CS |date= July 2023 |title=The first drug-related death associated with xylazine use in the UK and Europe |journal=Journal of Forensic and Legal Medicine |language=en |volume=97 |pages=102542 |doi=10.1016/j.jflm.2023.102542 |pmid= 37236142 |s2cid= 258859939 |issn=1752-928X|doi-access=free }}</ref> Xylazine is anticipated to make inroads in the European illicit drug market once the most recent Afghanistan ] harvest has been produced and delivered, the ] having banned poppy cultivation in 2023.<ref>{{Cite web|url=https://www.euronews.com/health/2023/05/26/xylazine-what-to-know-about-the-flesh-eating-zombie-drug-spreading-from-the-us-to-europe|title=Xylazine: Flesh-rotting 'zombie' drug claims first victim in Europe|date=May 26, 2023|website=euronews}}</ref>
⚫ Xylazine overdose is often fatal in humans.<ref name=Greene/> Because it is used as a drug ], the symptoms caused by the drugs accompanying xylazine administration vary between individuals.<ref name=Reyes/>


In April 2024, xylazine was reported to be present in illicit ] ] in the UK.<ref>{{Cite journal | vauthors = Copeland CS, Rice K, Rock KL, Hudson S, Streete P, Lawson AJ, Couchman L, Holland A, Morley S |date= April 2024 |title=Broad evidence of xylazine in the UK illicit drug market beyond heroin supplies: Triangulating from toxicology, drug-testing and law enforcement |journal=Addiction |language=en |doi=10.1111/add.16466 |doi-access=free }}</ref><ref>{{Cite web|url=https://www.bbc.co.uk/news/health-68760301|title='Zombie' drug xylazine found in cannabis THC vapes in UK|date=Apr 10, 2024|website=BBC News}}</ref>
⚫ The most common side effects in humans associated with xylazine administration include ], ], ], transient ] secondary to ], and other central and hemodynamic changes.<ref name=Greene/><ref name=Reyes/><ref>Ball NS, Knable BM, Relich TA, Smathers AN, Gionfriddo MR, Nemecek BD, Montepara CA, Guarascio AJ, Covvey JR, Zimmerman DE. Xylazine poisoning: a systematic review. ''Clin Toxicol (Phila)''. 2022 Aug;60(8):892-901. {{doi|10.1080/15563650.2022.2063135}} {{pmid|35442125}}</ref> Xylazine significantly decreases heart rate in animals that are not premedicated with medications that have ] effects.<ref name=Greene/>


In April 2024, Seattle police reported that "tranq" was being sold as a standalone narcotic, something they had not seen before. According to Seattle police officials, their patrol officers are now on alert for people collapsing due to tranq consumption.<ref name=fox13/> As of May 2024, over 90% of illegally purchased opiates were adulterated with Xylazine in Philadelphia. In Massachusetts, the percentage of samples containing xylazine increased to 42%.<ref name=masslive/>
⚫ Xylazine administration can lead to ] and ].<ref name=Xiao /> Other possible side effects that can occur are ], ], ], blurred vision, ], dizziness, drowsiness, ], ], fainting, ], slurred speech, ], staggering, ], ], shallow breathing, sleepiness, ], ], ], and dry mouth.<ref name=Ruiz!/> Rarely, ], dry mouth, ] and nonspecific electrocardiographic ] changes occur.<ref name=Ruiz!/> It has been reported that the duration of symptoms after human overdose is 8–72&nbsp;hours.<ref name=Ruiz!/> Further research is necessary to categorize the side effects that occur when xylazine is used in conjunction with heroin and cocaine.<ref name=Greene/>


Police departments in 45 US states are preparing for wound care, overdose response, and creating educational materials for communities. There are still surveillance blind spots and, according to one police officer conducting educational outreach with first responders, drug-addicted high school students " more about xylazine than paramedics, nurses, and police officers."<ref name=masslive/>
⚫ Chronic intravenous use of xylazine in combination with opioids is reported to be associated with physical deterioration, dependence, ], and ]ation, sometimes progressing to ] with ] formation, which can be physically debilitating and painful.<ref name=Ruiz!/><ref name=Xiao/><ref name="nytimes/Tranq-Dope">{{cite news | vauthors = Hoffman J |title=Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones |url=https://www.nytimes.com/2023/01/07/health/fentanyl-xylazine-drug.html |access-date=23 February 2023 |work=The New York Times |date=7 January 2023}}</ref> Hypertension followed by hypotension, bradycardia, and respiratory depression lower tissue oxygenation in the skin.<ref name=Reyes /> Thus, chronic use of xylazine can progress the skin oxygenation deficit, leading to severe skin ulceration.<ref name=Reyes/> Lower skin oxygenation is associated with impaired healing of wounds and a higher chance of infection.<ref name=Reyes/> The ulcers may ooze pus and have a characteristic odor.<ref name=Torruella/> In severe cases, amputations must be performed on the affected extremities.<ref name=Torruella/>

⚫ ===Side effects===
⚫ Xylazine ] is often fatal in humans.<ref name=Greene/> Because it is used as a drug ], the symptoms caused by the drugs accompanying xylazine administration vary between individuals.<ref name=Reyes/>

⚫ The most common ]s in humans associated with xylazine administration include ], ], ], transient ] secondary to ], and other central and ] changes.<ref name=Greene/><ref name=Reyes/><ref name="ball">{{cite journal | vauthors = Ball NS, Knable BM, Relich TA, Smathers AN, Gionfriddo M, Nemecek BD, Montepara CA, Guarascio AJ, Covvey JR, Zimmerman DE | title = Xylazine poisoning: a systematic review | journal = Clinical Toxicology | volume = 60 | issue = 8 | pages = 892–901 | date = August 2022 | pmid = 35442125 | doi = 10.1080/15563650.2022.2063135 | s2cid = 248264717 }}</ref> Xylazine significantly decreases ] in animals that are not pre-medicated with medications that have ] effects.<ref name=Greene/>

⚫ Xylazine administration can lead to ] and ].<ref name=Xiao /> Other possible side-effects are ], ], ], ], ], dizziness, drowsiness, ], ], fainting, ], ], ], staggering, ], ], shallow breathing, sleepiness, ], ], ] and ].<ref name=Ruiz!/> Rarely, ], ], and nonspecific electrocardiographic ] changes occur.<ref name=Ruiz!/> Following a human overdose, symptoms can last for 8–72 hours, varying based on xylazine's combined usage with other drugs.<ref name="Greene" /><ref name=Ruiz!/>

⚫ Chronic intravenous use of xylazine in combination with opioids is reported to be associated with ], ], dependence, ], and ]ation, sometimes progressing to ] with ] formation, which can be physically debilitating and painful.<ref name=Ruiz!/><ref name=Xiao/><ref name="nytimes/Tranq-Dope">{{cite news |date=7 January 2023 |title=Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug Zones |url=https://www.nytimes.com/2023/01/07/health/fentanyl-xylazine-drug.html |access-date=23 February 2023 |work=The New York Times |vauthors=Hoffman J}}</ref> Hypertension followed by hypotension, bradycardia, and respiratory depression lower tissue oxygenation in the skin.<ref name=Reyes /> Thus, chronic use of xylazine can progress the skin oxygenation deficit, leading to severe skin ulceration.<ref name=Reyes/> Lower skin oxygenation is associated with impaired healing of wounds and a higher chance of infection.<ref name=Reyes/> The ulcers may ooze pus and have a characteristic odor.<ref name=Torruella/> In severe cases, ] ]s must be performed on the affected extremities.<ref name=Torruella/>


===Overdose=== ===Overdose===
Since xylazine is not an ], it cannot be neutralized by ] (Narcan). However, experts still recommend administering naloxone during suspected xylazine ] because the drug is very frequently mixed with opioids like ].<ref name="DEA-2023"/>

⚫ Human tolerance to xylazine varies widely, with toxicity and fatality occurring between doses of {{cvt|40|-|2400|mg}}.<ref name=Ruiz!/> Non-fatal blood or plasma concentration ranges from 0.03 to 4.6&nbsp;mg/L.<ref name=Silva-Torres/> In fatalities, the blood concentration of xylazine ranges from trace to 16&nbsp;mg/L.<ref name=Silva-Torres/> 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.<ref name=Ruiz!/>

As of 2014, there is no specific ] to treat humans who overdose on xylazine. ] has been suggested as a form of treatment, but is usually unfavorable due to the large ] of xylazine.<ref name=Ruiz!/>

There are no standardized ]s to determine if an overdose has occurred. Detection of xylazine in humans involves various screening methods, such as urine screenings, ] (TLC), ] (GC-MS) and ] (LC-MS).<ref name=Meyer/><ref name=Silva-Torres/> As of November 2022, detecting xylazine in a drug sample requires ].<ref>{{cite web |title=Xylazine Public Health Advisory, November 2022 |url=https://content.boston.gov/sites/default/files/file/2023/01/BPHC%2BXylazine%2BPublic%2BHealth%2BAdvisory_November%2B2022_1.pdf |website=Boston Public Health Commission |publisher=City of Boston |access-date=25 January 2023}}</ref>


As of 1998, the ] ] ] was used to reverse the effects of xylazine or the related drug ] in veterinary medicine,<ref>{{cite journal | vauthors = Scheinin H, Aantaa R, Anttila M, Hakola P, Helminen A, Karhuvaara S | title = Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers | journal = Anesthesiology | volume = 89 | issue = 3 | pages = 574–584 | date = September 1998 | doi = 10.1097/00000542-199809000-00005 | pmid = 9743392 | s2cid = 25346350 | doi-access = free }}</ref> but this is not an approved medical treatment for humans, despite ]s in 2005.<ref>{{cite journal | vauthors = Pertovaara A, Haapalinna A, Sirviö J, Virtanen R | title = Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist | journal = CNS Drug Reviews | year = 2005 | volume = 11 | issue = 3 | pages = 273–288 | doi = 10.1111/j.1527-3458.2005.tb00047.x | pmid = 16389294 | pmc = 6741735 }}</ref>
⚫ The known doses of xylazine that produce toxicity and fatality in humans vary from 40 to 2400&nbsp;mg.<ref name=Ruiz!/> Small doses may produce toxicity and larger doses may be survived with medical assistance.<ref name=Ruiz!/> Non-fatal blood or plasma concentration ranges from 0.03 to 4.6&nbsp;mg/L.<ref name=Silva-Torres/> In fatalities, the blood concentration of xylazine ranges from trace to 16&nbsp;mg/L.<ref name=Silva-Torres/> 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.<ref name=Ruiz!/>


As of 2001, the effects of xylazine in animals were also reversed by the ]s ], ], and ], which are physiological antagonists to ]s.<ref name=Ndeereh>{{cite journal |vauthors = Ndeereh DR, Mbithi PM, Kihurani DO |date = June 2001 |title = The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats |journal = Journal of the South African Veterinary Association |volume = 72 |issue = 2 |pages = 64–67 |pmid = 11513261 |doi = 10.4102/jsava.v72i2.618 |doi-access = free}}</ref> Further research is needed to accurately identify chronic xylazine usage and standardize effective treatments.<ref name=Greene/> As of 2014, multiple drugs have been used for therapeutic intervention, including ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], and irrigation of both eyes with ].<ref name=Ruiz!/>
Currently, there is no specific ] to treat humans who overdose on xylazine. ] has been suggested as a form of treatment, but is usually unfavorable due to the large ] of xylazine.<ref name=Ruiz!/> In addition, due to lack of research in humans, there are no standardized screenings to determine if an overdose has occurred. The detection of xylazine in biological fluids in humans involves various screening methods, such as urine screenings, ] (TLC), ] (GC-MS) and ] (LC-MS).<ref name=Meyer/><ref name=Silva-Torres/> In veterinary medicine, the alpha-2 antagonist ] is used to reverse the effects of xylazine or the related drug ], but while this has been tested in humans in Phase I trials, it is not an approved medical treatment for xylazine overdose.<ref>Scheinin H, Aantaa R, Anttila M, Hakola P, Helminen A, Karhuvaara S. 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''. 1998 Sep;89(3):574-84. {{doi|10.1097/00000542-199809000-00005}} {{pmid|9743392}}</ref><ref>Pertovaara A, Haapalinna A, Sirviö J, Virtanen R. Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist. ''CNS Drug Rev''. 2005 Autumn;11(3):273-88. {{doi|10.1111/j.1527-3458.2005.tb00047.x}} {{pmid|16389294}}</ref>


⚫ The treatment after a xylazine overdose primarily involves maintaining respiratory function and blood pressure.<ref name=Ruiz!/> In cases of intoxication, physicians recommend intravenous fluid infusion, atropine, and hospital observation.<ref name=Greene/> Severe cases may require ], ], ], ], bladder ], ] (ECG) and hyperglycemia monitoring.<ref name=Ruiz!/> Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highly ] organs such as the liver and kidneys.<ref name=Silva-Torres/>
Multiple drugs have been used as supportive therapeutic intervention such as ], ], ], ], ], ], ], ], yohimbine, atropine, ], ], ], ], ], ], insulin, and irrigation of both eyes with ].<ref name=Ruiz!/> Effects of xylazine are also reversed by the ]s ], ], and ], which are physiological ] to central nervous system depressants.<ref name=Ndeereh>{{cite journal |vauthors = Ndeereh DR, Mbithi PM, Kihurani DO |date = June 2001 |title = The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats |journal = Journal of the South African Veterinary Association |volume = 72 |issue = 2 |pages = 64–67 |pmid = 11513261 |doi = 10.4102/jsava.v72i2.618 |doi-access = free}}</ref> Research initiatives may be necessary in order to standardize treatment and determine effective measures for identifying chronic xylazine usage and intoxication.<ref name=Greene/>


In 2022, the ] (FDA) issued an alert to American healthcare providers on the risks patients face if exposed to xylazine in illicit drugs.<ref>{{Cite web | work = Center for Drug Evaluation and Research|date=2022-11-08 |title=FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugs |publisher = U.S. Food and Drug Administration |language=en}}</ref>
⚫ The treatment after xylazine overdose should primarily involve maintaining respiratory function and blood pressure.<ref name=Ruiz!/> In cases of intoxication, physicians recommend intravenous fluid infusion, atropine, and hospital observation.<ref name=Greene/> Severe cases may require ], ], ], ], bladder ], ] (ECG) and hyperglycemia monitoring.<ref name=Ruiz!/> Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highly ] organs, such as the liver and kidney.<ref name=Silva-Torres/>


== References == == References ==
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== Further reading == == Further reading ==
{{refbegin}} {{refbegin}}
* {{cite book |vauthors = McCurnin DM, Bassert JM |year = 2002 |title = Clinical Textbook for Veterinary Technicians |edition = 5th |publisher = Saunders |location = Philadelphia, PA}} * {{cite book |vauthors = McCurnin DM, Bassert JM |year = 2002 |title = Clinical Textbook for Veterinary Technicians |edition = 5th |publisher = Saunders |location = Philadelphia}}
* {{cite web | work = Bayer Healthcare | title = Rompun Homepage | url = http://www.rompun.com:80/ | archive-url = https://web.archive.org/web/20070302155131/http://www.rompun.com:80/ | url-status = dead | archive-date = 2007-03-02 | date = 2005 }} * {{cite web | publisher = Bayer Healthcare | title = Rompun Homepage | url = http://www.rompun.com:80/ | archive-url = https://web.archive.org/web/20070302155131/http://www.rompun.com:80/ | url-status = dead | archive-date = 2007-03-02 | date = 2005 }}
* {{cite web | vauthors = Wright B | url = http://www.omafra.gov.on.ca/english/livestock/horses/facts/00-063.html | title = Human health concerns when working with medications around horses | work = Agdex# 460. Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA) | date = 2000 }} * {{cite web | vauthors = Wright B |url=https://www.omafra.gov.on.ca/english/livestock/horses/facts/00-063.html|archive-url=https://web.archive.org/web/20060907095904/https://www.omafra.gov.on.ca/english/livestock/horses/facts/00-063.html|archive-date=7 September 2006|url-status=dead|title = Human health concerns when working with medications around horses | work = Agdex# 460 |publisher=Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA) | date = 2000 }}
{{refend}} {{refend}}


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] ]
] ]
] <!-- 2,6-Xylidine -->
] ]
]
] ]