Xylazine

Xylazine is a structural analog of clonidine and an α₂-adrenergic receptor agonist, sold under many trade names worldwide, most notably the Bayer brand name Rompun, as well as Anased, Sedazine and Chanazine.
Xylazine is a common veterinary drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other mammals. In veterinary anesthesia, it is often used in combination with ketamine. Veterinarians also use xylazine as an emetic, especially in cats. Drug interactions vary with different animals.
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. The drug is used as a cutting agent for heroin and fentanyl.

History

Xylazine was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Leverkusen, West Germany. 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. In 1981 a study discovered that the cause sedation was due to xylazine's effect on the α2-adrenergic receptor. This led to the development of other α₂-adrenergic receptor agonists such as detomidine, medetomidine, dexmedetomidine, and romifidine.
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. 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.
In scientific research using animal experiments, xylazine is a component of the most common anesthetic, ketamine-xylazine, to anesthetize rats, mice, hamsters, and guinea pigs.
Xylazine has not previously been a controlled substance; however, due to illicit abuse of xylazine legislative restrictions have been proposed in multiple countries. Xylazine was made a class C drug in the UK on 15 January 2025.

Veterinary use

Xylazine is widely used in veterinary medicine as a sedative, muscle relaxant, and analgesic. It is frequently used in the treatment of tetanus. It is not used in human medical treatment. Xylazine is similar to drugs such as phenothiazines, tricyclic antidepressants, and clonidine. As an anesthetic, it is typically used in conjunction with ketamine. In animals, xylazine may be administered intramuscularly, intravenously, and intraosseously. Subcutaneous, oral transmusocal and intranasal have been investigated but are not standard routes for xylazine administration. As a veterinary anesthetic, xylazine is typically only administered once for the intended effect before or during surgical procedures. α₂-Adrenergic receptor antagonists such as atipamezole and yohimbine may be used to reverse the effects of xylazine in animals. 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.
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.
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.

Side-effects

s in animals include transient hypertension and hypotension. Xylazine decreases both respiration rate and minute ventilation, although the changes to PaCO₂ and PaO₂ are minor and innocuous.
Xylazine has been demonstrated as reducing the dose of epinephrine that causes arrythmia in dogs anaesthetised with isoflurane and halothane.
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.
Intracarotid administration can cause seizures and excitement in horses.
Xylazine has been shown to cause myometrial contractions in pregnant cattle. 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.
Xylazine affects the glucose level via the activation of alpha_2A 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. The renal threshold for glucose is not exceeded due to the hyperglycaemia with clinical doses. An alpha₂ adrenergic receptor antagonist can reverse the effect.
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.
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. Complete elimination of the drug can take up to 23minutes in sheep and up to 49minutes in horses. In young rats the half-life is one hour. Xylazine has a large volume of distribution of = for horses, cattle, sheep, and dogs. Though the peak plasma concentrations are reached in minutes in all species, the bioavailability varies between species. The half-life depends on the age of the animal, as age is related to prolonged duration of anesthesia and recovery time. Toxicity occurs with repeated administration, given that the metabolic clearance of the drug is usually calculated as times the half-life, which is 4 to 5 days for the clearance of xylazine.

Pharmacology

Pharmacodynamics

Xylazine is a potent α₂-adrenergic receptor agonist. When xylazine and other α₂-adrenergic receptor agonists are administered, they distribute throughout the body within 30 to 40 minutes. 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. As an agonist, xylazine reduces release of norepinephrine in the central nervous system. It does so by mimicking norepinephrine in binding to the pre-synaptic surface autoreceptors, which leads to feedback inhibition of norepinephrine release. 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.
Xylazine also serves as a transport inhibitor by suppressing norepinephrine transport function through competitive inhibition of substrate transport. Accordingly, xylazine significantly increases K_m and does not affect V_max. This likely occurs by direct interaction on an area that overlaps with the antidepressant binding site. For example, xylazine and clonidine suppress uptake of iobenguane, a norepinephrine analogue, in neuroblastoma cells. 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.
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.
Xylazine is less selective than the other α₂-Adrenergic receptor agonists.
The analgesic effect of xylazine comes from binding to receptors at the substantia gelatinosa and locus coeruleus.

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. The most common route of administration is injection.
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. Once xylazine gains access to the vascular system, it is distributed within the blood, allowing xylazine to enter the heart, lungs, liver, and kidney. In non-fatal cases, the blood plasma concentrations range from 0.03 to 4.6 mg/L. Xylazine diffuses extensively and penetrates the blood–brain barrier, as might be expected due to the uncharged, lipophilic nature of the compound.
Xylazine is metabolized by the liver's cytochrome P450 enzymes. When it reaches the liver, xylazine is metabolized and proceeds to the kidneys to be excreted in urine. Around 70% of a dose is excreted unchanged. Thus, urine can be used in detecting xylazine administration because it contains many metabolites, which are the main targets and products in urine. Within a few hours, xylazine decreases to undetectable levels. Other factors can also significantly impact the pharmacokinetics of xylazine, such as sex, nutrition, environmental conditions, and prior diseases.