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Xylazine

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

Xylazineis astructural analogofclonidineand anα2-adrenergic receptoragonist,[1]sold under many trade names worldwide, most notably theBayerbrand nameRompun,[2]as well asAnased,SedazineandChanazine.[3]

Xylazine is a common veterinary drug used forsedation,anesthesia,muscle relaxation,andanalgesiain animals such as horses, cattle, and other mammals.[2]Inveterinary anesthesia,it is often used in combination withketamine.Veterinarians also use xylazine as anemetic,especially in cats.[4]Drug interactionsvary with different animals.[5][6][7]

Xylazine has become a commonlyabusedstreet drugin the United States where it is known by the street name "tranq",particularly in the territory of Puerto Rico.[8]The drug is beingdivertedfrom stocks forequineveterinariansas well as trafficked in bulk from China to be used as acutting agentforheroinandfentanyl,causing necrotic skin wounds leading to serious infections and limb amputations[9]as well as other health issues.[10][11][12]Fentanyl mixed with xylazine is known by the street names "sleep-cut", "zombie drug", "Iso" and "tranq dope".[8][13][14][15]

History

[edit]

Xylazine was discovered as anantihypertensiveagent in 1962 by Farbenfabriken Bayer inLeverkusen, Germany.[1]Accounts of the actions and uses of xylazine in animals were reported as early as the late 1960s and early 1970s.[1]Results from early human clinical studies confirmed that xylazine has severalcentral nervous systemdepressanteffects.[1]Xylazine administration is used for sedation, anesthesia, muscle relaxation, and analgesia.[2]It causes a significant reduction inblood pressureandheart ratein healthy volunteers.[failed verification][16]Xylazine was also studied for use in human beings, but due to hazardousside effects,includinghypotensionandbradycardia,it was not approved by theFood and Drug Administration(FDA) for human use.[12]

In the United States, xylazine was approved by the FDA only for veterinary use as asedative,analgesic, and muscle relaxant in dogs, cats, horses, elk,fallow deer,mule deer,sika deer,andwhite-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.[17]

In scientific research usinganimal experiments,xylazine is a component of the most common anesthetic, ketamine-xylazine(see:Rodent cocktail),to anesthetize rats, mice, hamsters, and guinea pigs.[18]

Veterinary use

[edit]
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 oftetanus.[1]It is not used in human medical treatment. Xylazine is similar to drugs such asphenothiazines,tricyclic antidepressants,and clonidine.[3]As an anesthetic, it is typically used in conjunction with ketamine.[16]In animals, xylazine may be administeredintramuscularlyorintravenously.[3]As a veterinary anesthetic, xylazine is typically only administered once for the intended effect before or during surgical procedures.[1]α2-Adrenergic receptor antagonistssuch asatipamezoleandyohimbinemay be used to reverse the effects of xylazine in animals.[19][20][21]

Side-effects

[edit]

Side effectsin animals include transienthypertension,hypotension,andrespiratory depression.[3]Further, the decrease of tissue sensitivity to insulin leads to xylazine-inducedhyperglycemiaand a reduction of tissue glucose uptake and utilization.[16]The effects in animals last up to 4hours.[3]

Pharmacokinetics

[edit]

In dogs, sheep, horses, and cattle, thehalf-lifeis very short: only 1.21– 5.97 minutes. Complete elimination of the drug can take up to 23minutes in sheep and up to 49minutes in horses.[1][3]In young rats the half-life is one hour.[18]Xylazine has a largevolume of distributionofVd=1.9 –2.5 for horses, cattle, sheep, and dogs.[3]Though the peakplasmaconcentrations are reached in12 –14 minutes in all species, thebioavailabilityvaries 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.[18]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 4to 5 days for the clearance of xylazine.[18]

Pharmacology

[edit]

Pharmacodynamics

[edit]
Xylazine synthesis adapted from Elliot & Ruehle (1986).[22]

Xylazine is apotentα2-adrenergic receptor agonist.[23][3]When xylazine and otherα2-adrenergic receptoragonists are administered, they distribute throughout the body within 30 to 40 minutes.[17]Due to xylazine's highlylipophilicnature, it directly stimulates central α2-adrenergic receptors as well as peripheralα-adrenergic receptorsin a variety of tissues.[1][3]As an agonist, xylazine reduces release ofnorepinephrineanddopaminein thecentral nervous system.[3]It does so by mimicking norepinephrine in binding to the pre-synaptic surfaceautoreceptors,which leads to feedback inhibition of norepinephrine release.[24]

Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function throughcompetitive inhibitionof substrate transport. Accordingly, xylazine significantly increasesKmand does not affectVmax.[24]This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site.[24]For example, xylazine andclonidinesuppress uptake ofiobenguane(MIBG), a norepinephrine analogue, inneuroblastomacells.[24]Xylazine's chemical structure closely resembles clonidine.

It has also been reported that xylazine activates theκ-opioid receptors,with low potency, which may contribute to its effects.[25]

Pharmacokinetics in humans

[edit]

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,andhalothanein order to provide reliable anesthesia effects.[12][16]The most common route of administration isinjection.[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.[26]In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6 mg/L.[3]Xylazine diffuses extensively and penetrates theblood–brain barrier,as might be expected due to the uncharged, lipophilic nature of the compound.[3]

Xylazine is metabolized by the liver'scytochrome P450enzymes.[18]When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted in urine.[27]Around 70% of a dose is excreted by urine.[18]Thus, urine can be used in detecting xylazine administration because it contains manymetabolites,which are the main targets and products in urine.[1][28]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.[18]

Xylazine Metabolites[28]
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

[edit]

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.[29]

Xylazine is not regulated as a controlled substance under theControlled 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.[30][31]The withdrawal can last for two weeks and has a quicker onset than fentanyl.[32]

Xylazine is most commonly ingested as an additive with fentanyl.[33]Xylazine has also been reported in combination withmedetomidine,another potentα2-adrenergic receptoragonist.[34]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.[35][36][28]Xylazine's street name in Puerto Rico isanestesia de caballo,which translates to "horse anesthetic".[3][37]From 2002 to 2008, its use was associated with a high number of inmate deaths at theGuerrero Correctional InstitutioninAguadilla, Puerto Rico.[38]

Xylazine's street name in the United States, particularly when it is mixed withfentanyl,is "tranq", "tranq dope" and "zombie drug".[39]

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]The combination of heroin and xylazine produces a potentially more deadlyhighthan administration of heroin alone. Xylazine is also frequently found in "speedball",a mixture of a stimulant drug such ascocainewith a depressant drug such asheroin,morphineand/orfentanyl.[12]As of 2012, causal factors underlying xylazine's increasing popularity were still unknown.[37]

As of 2022, more information on thedistributionof 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.[40]From November 2021 until August 2022, 80% of drug paraphernalia which tested positive for fentanyl at needle exchange programs in Maryland also contained xylazine.[41]As of 2022, xylazine was almost invariably combined withopioidswhen used recreationally, and the drug produced a characteristicwithdrawal syndromewhich complicates treatment of addicted users.[42][43]

In April 2023, theBiden administrationdeclared xylazine-lacedfentanyl an official emerging drug threat to the nation, the first time such a label has been given.Rahul Gupta,director of theOffice of National Drug Control Policy(ONDCP), said he was troubled about what he learned "about the devastating impact of the fentanyl-xylazine combination, which is growing in youth across the nation".[44]According to Gupta, xylazine is the deadliest drug threat the United States has ever faced. TheDrug 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 inSolihull,England in May 22. A 43-year-old male was found dead at home withpostmortemtoxicologydetecting heroin, cocaine, fentanyl and xylazine.[45]Xylazine is anticipated to make inroads in the European illicit drug market once the most recent Afghanistanopium poppyharvest has been produced and delivered, theTalibanhaving banned poppy cultivation in 2023.[46]

In April 2024, xylazine was reported to be present in illicitTHCe-cigarettesin the UK.[47][48]

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.[35]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%.[32]

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 "[know] more about xylazine than paramedics, nurses, and police officers."[32]

Side effects

[edit]

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

The most commonside-effectsin humans associated with xylazine administration includebradycardia,respiratory depression,hypotension,transienthypertensionsecondary toα1-adrenergic receptor stimulation,and other central andhemodynamicchanges.[1][12][49]Xylazine significantly decreasesheart ratein animals that are not pre-medicated with medications that haveanticholinergiceffects.[1]

Xylazine administration can lead todiabetes mellitusandhyperglycemia.[16]Other possible side-effects areareflexia,asthenia,ataxia,blurred vision,disorientation,dizziness, drowsiness,dysarthria,dysmetria,fainting,hyporeflexia,slurred speech,somnolence,staggering,coma,apnea,shallow breathing, sleepiness,premature ventricular contraction,tachycardia,miosisanddry mouth.[3]Rarely,hypotonia,urinary incontinence,and nonspecific electrocardiographicST segmentchanges 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]

Chronic intravenous use of xylazine in combination with opioids is reported to be associated withmuscle atrophy,physical deterioration,dependence,abscesses,andskin ulceration,sometimes progressing tonecrosiswithescharformation, which can be physically debilitating and painful.[3][16][50]Hypertension followed by hypotension, bradycardia, and respiratory depression lower tissue oxygenation in the skin.[12]Thus, chronic use of xylazine can progress the skin oxygenation deficit, leading to severe skin ulceration.[12]Lower skin oxygenation is associated with impaired healing of wounds and a higher chance of infection.[12]The ulcers may ooze pus and have a characteristic odor.[37]In severe cases,surgicalamputationsmust be performed on the affected extremities.[37]

Overdose

[edit]

Since xylazine is not anopioid,it cannot be neutralized bynaloxone(Narcan). However, experts still recommend administering naloxone during suspected xylazineoverdosebecause the drug is very frequently mixed with opioids likefentanyl.[8]

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.[26]In fatalities, the blood concentration of xylazine ranges from trace to 16 mg/L.[26]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]

As of 2014, there is no specificantidoteto treat humans who overdose on xylazine.Hemodialysishas been suggested as a form of treatment, but is usually unfavorable due to the largevolume of distributionof xylazine.[3]

There are no standardizedscreeningsto 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) andliquid chromatography–mass spectrometry(LC-MS).[28][26]As of November 2022, detecting xylazine in a drug sample requiresspectrophotometry.[51]

As of 1998, theα2-adrenergic receptorantagonistatipamezolewas used to reverse the effects of xylazine or the related drugdexmedetomidinein veterinary medicine,[52]but this is not an approved medical treatment for humans, despitePhase I clinical trialsin 2005.[53]

As of 2001, the effects of xylazine in animals were also reversed by theanaleptics4-aminopyridine,doxapram,andcaffeine,which are physiological antagonists tocentral nervous system depressants.[54]Further research is needed to accurately identify chronic xylazine usage and standardize effective treatments.[1]As of 2014, multiple drugs have been used for therapeutic intervention, includinglidocaine,naloxone,thiamine,lorazepam,vecuronium,etomidate,propofol,tolazoline,yohimbine,atropine,orciprenaline,metoclopramide,ranitidine,metoprolol,enoxaparin,flucloxacillin,insulin,and irrigation of both eyes withsaline.[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 requiretracheal intubation,mechanical ventilation,gastric lavage,activated charcoal,bladdercatheterization,electrocardiographic(ECG) and hyperglycemia monitoring.[3]Physicians typically recommend which detoxification treatment should be used to manage possible dysfunction involving highlyperfusedorgans such as the liver and kidneys.[26]

In 2022, theFood and Drug Administration(FDA) issued an alert to American healthcare providers on the risks patients face if exposed to xylazine in illicit drugs.[55]

References

[edit]
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Further reading

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