BUY Uni mix I (SR-GW-YOHIMBINE) UAE

BUY Uni mix I (SR-GW-YOHIMBINE) UAE,1.1. Xylazine is a non-opioid tranquilizer approved for use as a sedative, muscle relaxant and analgesic in veterinary medicine, however is increasingly being used illicitly by humans internationally

1.2. Xylazine is a psychoactive adulterant which can be added to heroin or illicitly manufactured fentanyl (IMF), to produce a mixture which is known as FAAX (Fentanyl Adulterated or Associated with Xylazine), ‘tranq’ or ‘tranq dope’ in the USA. Xylazine, especially in combination with other sedatives, can dangerously lower an individual’s level of consciousness. In addition, it can lower an individual’s heart rate and, when injected, is reported to be associated with the development of skin ulcers. In November 2022, the United States Food and Drug Administration (FDA) issued an alert to healthcare professionals concerning the increased prevalence in illicit drug overdose deaths involving xylazine. [FDA 2022]

1.3. Xylazine was first detected in illicit drug markets in Puerto Rico around 2001 and subsequently in opioid-related deaths in mainland United States in 2006. Since then the detection of xylazine has been reported to mirror the IMF supply in the United States, starting in the North East and then spreading Southwards and Westward. Xylazine has now been detected in IMF in 48 States and is reported to have been identified in 23% of IMF powder and 7% of fentanyl tablets seized in 2022. [DEA Alert 2022] However, these rates vary widely by US state.

1.4. Data from the National Forensic Laboratory Information System (NFLIS) in the USA has shown an increase in the number of States that have reported xylazine-related deaths. In 2019, 16 states had zero NFLIS xylazine reports which decreased to only 2 States in 2022 (South Dakota and Wyoming). The highest rates of xylazine NFLIS reports per 100 000 residents in 2022 were concentrated in the North Eastern States (New Jersey (30.52), Rhode Island (22.82), Maryland (18.91), Virginia (15.47) and New Hampshire (13.10). [Cano 2024]

1.5. In Canada, xylazine identifications in samples submitted by law enforcement agencies increased from 5 in 2018 to 1350 in 2022, with most positive samples detected in Ontario and British Columbia. Almost all samples contained multiple other substances, most commonly cutting agents (e.g. caffeine or dimethylsulphone), opioids (especially fentanyls but also heroin) and benzodiazepines (e.g. flualprazolam, etizolam, bromazolam). [Health Canada 2023]

1.6. The US Drug Enforcement Administration (DEA) previously suggested xylazine was entering the drug market supply via misdirection of legitimate veterinary sources of xylazine; however, the detection of xylazine in fentanyl tablets produced outside the USA suggests that there may be a shift away from adulteration of IMF in the USA from misdirected veterinary supplies.

1.7. Xylazine may be added to illicit fentanyl supplies in North America due to low purity of fentanyl entering the drug market from Mexico and other areas. It is postulated the addition of the xylazine may enhance the sedative effects seen with fentanyl and potentially interfere with fentanyl metabolism, thereby directly prolonging the desired effects of the fentanyl.

1.8. To date xylazine has been much less frequently detected in Europe than in North America, however mixtures containing xylazine with the synthetic opioids protonitazene or metonitazene have been seized in Estonia. In a survey in Riga, Latvia, xylazine was co-detected in 13% of used syringes, with the synthetic opioids isotonitazene, metonitazene or carfentanil. [EMCDDA Annual Report 2023]

1.9. Currently, injecting drug users in Europe use heroin derived from Afghanistan, which has been of high quality and therefore there has been little use of other illicitly synthesised opioids such as fentanyl, or for the adulteration of illicit opioids with drugs such as xylazine, in contrast to the situation in North America.

1.10. As a result of the prohibition of cultivation of opium poppies and of all types of narcotics in Afghanistan by the Taliban in April 2022, there has been a 95% reduction in the areas cultivating opium poppies between 2022 and 2023. This resulted in a 95% decline in both the opium harvested and export heroin produced from 6,200 tons and 350-580 tons respectively in 2022 and to 333 tons and 24-38 tons respectively in 2023. [UNODC Afghanistan opium survey 2023] There is increasing concern that, with the reduction in availability of heroin from Afghanistan, the European and UK illicit opioid markets may shift to illicitly synthesised fentanyl. There is the potential that this would be associated with increased risk of xylazine in the UK illicit opioid market.

1.11. The first death in the UK involving xylazine was reported by the National Programme on Substance Abuse Deaths (NPSAD) in December 2022.

1.12. As a result of horizon scanning, the ACMD self-commissioned a review into the potential harms of xylazine, and this was followed by a formal government commission in June 2023.

1.13. This report reviews the evidence of use and harms of xylazine in the UK and considers whether it should be controlled via the Misuse of Drugs Act 1971. Evidence of illicit use in the UK of the related compounds medetomidine and detomidine was also sought, as this has been reported in other countries. [CSFRE 2023a; CSFRE 2023b; Sisco 2023]

2. Legal Control

2.1. In the UK, xylazine, detomidine and medetomidine are veterinary medicines licensed for use as sedatives, muscle relaxants and analgesics in animals; more information on their use as veterinary medicines is described in Section 6 below. Only dexmedetomidine (one of the stereoisomers of medetomidine) is approved by the Medicines and Health care products Regulatory Agency (MHRA) for human use, as a sedative for use by infusion in critical care areas.

2.2. Xylazine, detomidine and medetomidine are not currently controlled under the Misuse of Drugs Act 1971. They are, however, likely to be subject to the 2016 Psychoactive Substances Act (PSA) because they have psychoactive effects, given that they are licensed for use as sedatives and/or anaesthetics in veterinary medicine. Whilst these are all veterinary medicines, the list of ‘exempted substances’ in Schedule 1 of the PSA includes only medicinal products approved for human use and the list of ‘exempted activities’ in Schedule 2 includes only human applications. Therefore, their import, supply, possession with the intent to supply and possession in a custodial institution for human use are likely to be offences under the PSA. To confirm this and initiate any prosecutions for such offences, the compounds would have to be tested against a panel of receptors as part of the two-stage in vitro testing process conducted by the Defence Science and Technology Laboratory (DSTL). Alternatively, a statement confirming psychoactivity from an expert witness, such as a pharmacologist, pharmacist, or registered veterinary surgeon, could be used to support a prosecution.

3. Chemistry

3.1. Xylazine consists of a 2,6-dimethylphenyl ring linked via an amine bridge to a 5,6-dihydro-1,3-thiazine ring (thiazine being a six-membered heterocycle containing 4 carbon atoms, 1 sulphur and 1 nitrogen).

3.2. A number of structurally similar compounds, which also feature a phenyl ring linked via an amine bridge to a five-membered heterocycle, are pharmaceuticals approved for human use, including clonidine (2,6- dichlorophenylimidazole-2-amine) which is also an alpha-2 receptor agonist although less potent than xylazine. Other similar pharmaceuticals include apraclonidine (licensed in the UK for reducing intra-ocular pressure) and romifidine (approved as a veterinary drug).

3.3. A range of other pharmaceutical compounds have some structurally similarity, featuring a phenyl ring linked via a methyl bridge to an imidazole ring. These include dexmedetomidine, a stereoisomer of medetomidine, which is significantly more potent than clonidine but less potent than xylazine; levomedetomidine, the other stereoisomer of medetomidine is inactive. [Kuusela 2001; Siegenthaler 2020] Others include detomidine, which is also an alpha-2 receptor agonist, and xylometazoline, a nasal decongestant. Lofexidine, used in the management of opioid withdrawal, has a similar structure to clonidine, except that the nitrogen link between the two rings is replaced by a link consisting of an oxygen atom attached to the phenyl ring joined to the 1-position of an ethyl group attached to the imidazole ring.

3.4. The chemical structures for xylazine, medetomidine and detomidine, along with clonidine and lefoxidine are shown in Appendix A.

4. International control

Xylazine control in the USA

4.1. As of December 2023, xylazine had not yet been brought under the control of the Controlled Substances Act in the USA. However, some individual states have used legislation to schedule at the state level, including Florida, Ohio, West Virginia, Pennsylvania and Illinois.

4.2. Following the designation of fentanyl adulterated and/or associated with xylazine as an emerging drug threat in April 2023, a number of further actions have occurred:

4.2.1. The US Food and Drug Administration issued Import Alert 68-20 in June 2023, permitting the seizure of importations of xylazine and finished products containing xylazine from a ‘red list’ of suppliers or which appear to have been mis-declared;

4.2.2. The White House released the “Fentanyl adulterated or associated with xylazine emerging threat response plan” in July 2023; and

4.2.3. The US Congress is currently considering Federal legislation (S. 993/H.R. 1839, The Combating Illicit Xylazine Act), which would seek to classify xylazine as a Schedule III Controlled Substance.

Xylazine control in other countries

4.3. Outside the USA, xylazine continues to be considered as a veterinary medicine, subject to national veterinary prescription requirements, rather than as a Controlled Drug.

Detomidine and medetomidine control

4.4. Detomidine and medetomidine are considered as veterinary medicines, subject to national veterinary prescription requirements, rather than as Controlled Drugs.

5. Misuse

5.1. Xylazine, medetomidine and detomidine are not specifically named as compounds/drugs in the Crime Surveys in England, Northern Ireland, Scotland or Wales; therefore, there is no information in regards to their prevalence of use in these administrations.

5.2. Qualitative research in the USA with individuals who inject opioids has provided some insight into the experience of those who are exposed to xylazine when injecting opioids. [Reed 2022; Freidman 2022] This research suggests that with the changing opioid market in the USA from heroin to illicit fentanyl, which has a shorter duration of action, xylazine (along with other sedatives) have been added to prolong the desired effects of the illicit fentanyl being injected. However, many individuals do not like the sedative effects reported with xylazine, and so may try to re-sell on any opioids they believe contain xylazine.

5.3. There is very limited information on user discussion fora relating to the intentional recreational use of xylazine, detomidine and/or medetomidine. The information available describes use by a variety of routes; it appears that the onset of desired effects tends to occur more rapidly when used by injection, followed by rectal insertion and then sublingual administration or oral ingestion. The effects are often described as being unpleasant and sedative in nature and their duration is between 3 and 5 hours. There are insufficient reports reporting doses used to comment on any relationship between dose and effects and/or duration of effects.

5.4. In an anonymous Reddit survey posted seventeen times (between March to August 2022) in the seven subreddits identified as having the highest number of Reddit posts on xylazine, respondents reported on their pattern of use. The majority of respondents were from the USA (44), but 2 were from the UK, 2 from Canada, 1 from Sweden and 1 from Ecuador (the location was not disclosed for 11 respondents). Of the 61 respondents, 74% of reported that they do not seek out to buy/acquire drugs that contain xylazine. The route of use of xylazine-containing drugs were inhalational 20%, nasal insufflation 57%, injection 43% or oral ingestion 3%. Xylazine was most frequently used daily (39% of respondents), but 19% reported use 1-6 times/week, 15% reported 1-4 times per month and 27% reported use a few times a year. [Spadaro 2023]

6. Legitimate Uses

6.1. The ACMD Secretariat contacted the Medicines and Healthcare products Regulatory Agency (MHRA) for any information on the legitimate use, clinical trials and/or marketing authorisation applications of xylazine, medetomidine and detomidine.

6.2. The MHRA confirmed that there were no granted, lapsed, cancelled or pending marketing authorisations for xylazine, detomidine or medetomidine. There have been no clinical trial authorisations for xylazine and there has only been one clinical trial authorisation for detomidine/medetomidine (as dexmedetomidine) in 2006 to 2007, with no clinical trial authorisations since then. Dexmedetomidine (one of the two stereoisomers medetomidine) is approved for use in humans in the UK for sedation in intensive care.

6.3. Xylazine, medetomidine and detomidine are prescription only veterinary medicines (POM-V) licensed for sedation and/or use as pre-medication prior to use of alternative injectable or inhalational anaesthetics. The veterinary medicinal products authorised for use in Great Britain and Northern Ireland are:

i) Xylazine: 13 products containing xylazine for use by injection (intravenous, intramuscular or subcutaneous) routes in horses, cattle, dogs and cats;

ii) Detomidine: 18 products for use by injection (intravenous/intramuscular) or oro-mucosal routes in horses and cattle;

iii) Medetomidine: 15 products for use by injection (intravenous, intramuscular or subcutaneous) in dogs and cats.

Of note, veterinary medicines in the UK are authorised for both specific species AND specific conditions. Where there is no authorised veterinary medicine for a specific species and/or condition, veterinarians are permitted to prescribe/use other authorised veterinary or human medicines based on clinical judgement using a risk-based decision tree called the Cascade.

6.4. The authorised veterinary medicines containing xylazine, detomidine or medetomidine are not currently classified as Controlled Drugs. As such, they are subject only to standard storage, record keeping and destruction requirements in accordance with The Veterinary Medicines Regulations (2013).

7. Pharmacology

7.1. There are three subtypes of alpha-2 adrenoceptors – designated α2A, α2B and α2C. [Listik 2023] Sedation and hypotension appear to result from activation of α2A receptors in the brain, whereas peripheral vasoconstriction likely results from activation of α2B receptors located on the smooth muscle of small diameter blood vessels. Xylazine, detomidine and medetomidine are non- selective α-2 adrenoceptor agonists that activate both central and peripheral α-2 adrenoceptors.

7.2. Xylazine is chemically related to phenothiazine antipsychotics and tricyclic antidepressants. Detomidine is an imidazole derivative. Medetomidine is an equal mixture of two optical isomers: dexmedetomidine and levomedetomidine. [Lamont 2009] All of these compounds are analogues of clonidine.

7.3. Xylazine, detomidine and medetomidine are rapidly absorbed following use by a variety of routes, including oral ingestion, nasal insufflation, rectal insertion and ocular exposure. Injection (intravenous, subcutaneous or intramuscular) of these compounds avoids first-pass metabolism, leading to higher initial peak concentrations. [Capraro 2001; Velez 2006; Ball 2022; Gao 2015; Potoukian 2023]. These compounds have large volumes of distribution related to their high lipophilicity (lipid solubility), as discussed in section 7.5.

7.4. All these compounds have a short half-life of minutes, with overall elimination from the body within a few hours of exposure. The half-life of xylazine is reported as 23-50 minutes [Ruiz-Colon et al, 2014]. The metabolism of xylazine in humans is not well understood, but the main xylazine biotransformation pathway is most likely thiazine ring breakdown leading to formation of 2,6-dimethylaniline (DMA) also known as 2,6-xylidine. The main metabolite of medetomidine is N-methyldexmetomidine. [Malayala 2022; Baselt 2017; Kaur 2011, Gao 2015]

7.5. As these compounds are highly lipophilic (high lipid solubility), they can easily cross the blood-brain barrier. Actions of these compounds at central α-2 receptors lead to sedation, muscle relaxation, reduced pain response and depressed respiratory drive. [Fyffe 1994]

7.6. The overlap between blood concentrations associated with non-fatal and fatal intoxications of xylazine; similar to other drugs and NPS this indicates that there is no defined safe, toxic, or lethal concentration. [Potoukian 2023]

7.7. Several α-2 adrenoceptor antagonists are available that could potentially reverse toxicity associated with α-2 adrenoceptor agonists. Yohimbine, an indole alkaloid derived from the bark of the African tree Pausinystalia johimb, and atipamezole, are α-2 adrenoceptor antagonists. Of the two, atipamezole has the highest preference for α-2 over α-1 receptors. Although atipamezole is licensed for the reversal of sedation produced by dexmedetomidine and its racemic mixture medetomidine in dogs and cats, yohimbine is not licensed for the reversal of xylazine sedation in veterinary practice. [Van Metre 1992; Choon 2023] Tolazoline is an α-2 receptor antagonist licensed for use in the treatment for pulmonary vasospasm in neonates, and the antidepressant mirtazapine is an α-2 receptor antagonist with activity at other types of receptors as well. [Guide to Pharmacology 2023] None of these drugs are currently licensed for the reversal of sedation or other unwanted effects in humans produced by xylazine, medetomidine or detomidine.

8. Health harms

Acute toxicity: Xylazine

8.1. Adverse effects reported with human exposure to xylazine include central nervous system depression, hypotension, bradycardia or tachycardia (slow or fast heart rate), respiratory depression, miosis, hyperglycaemia, and hypothermia. [Ruiz-Colon 2014]

8.2. A systematic review identifying published English language cases of xylazine related toxicity identified from Web of Science, PubMed, Embase, Google Scholar and grey literature sources were published in 2023. Of the initial 1,238 articles identified, 34 were assessed to meet the systematic review inclusion criteria. [Ayub 2023] However, on review of this report, one of the included articles was a conference poster presentation where xylazine was mentioned in the title of the presentation but there was no mention in the text of the poster that xylazine had been used.

8.3. Of the remaining 33 publications, 1 was a drug-driving related report, 2 related to xylazine withdrawal, 7 related to deaths where xylazine was detected and/or implicated in the cause of death and 23 related to acute xylazine toxicity. The 23 publications relating to acute xylazine toxicity described a total of 33 individual cases (23 male, 8 female, 2 unknown sex; age range 19 days to 76 years old), of which 9 were accidental exposures, 7 were self- harm/suicide attempts, 7 were recreational/misuse related, 4 were malicious and in 6 the intent was not clear from the publication. The route of exposure was known in 27 patients: injection (IV/IM/SC) in 15, oral ingestion in 6, inhalation in 4, ocular in 1 and combined oral ingestion/injection in 1. The majority of individuals (28, 85%) were drowsy following exposure and 12 of those had associated respiratory depression. Nine patients had a trial of naloxone with no significant clinical effect in 7 patients and a response likely related to concurrent opioid toxicity in 2 patients. Nine individuals with coma and respiratory depression and 5 with coma without respiratory depression required intubation. Hypotension occurred in 9 and bradycardia in 17.

8.4. Four cases of the administration of xylazine to individuals for malicious criminal intent have been reported: i) a 4-year-old child presented with drowsiness in Germany following xylazine administered in an attempted drug- facilitated sexual assault by his god-father and ii) three individuals in their 70s were found drowsy in a hospital in Bangkok, Thailand after consumption of drinks offered to them by strangers. [Andresen-Streichert 2017, Krongvorakul 2018]

8.5. There were 76 xylazine exposures reported to the Texas Poison Center Network (TPCN) between 2000 and 2014. Twenty-eight (36.8%) involved other substances [ketamine (9 cases); tiletamine/zolazepam (5); alcohol (3); detomidine (3); butorphanol (2), cocaine (2), and pentobarbital/phenytoin (2). Forty-nine (64.5%) were unintentional (17 occupational-related and 10 were drug misuse); 24 were intentional (12 suspected attempted suicide; 10 abuse of the drug). Forty-one (53.9%) were male. Symptoms in the 48 patients without reported exposure to other substances were: i) drowsiness/lethargy in 43.8%; ii) bradycardia in 27.1%; iii) hypotension in 10.4%; iv) hypertension in 8.3%; v) slurred speech in 6.3%; vi) Coma in 2.1%; vii) ocular irritation/pain in 8.3%; and viii) respiratory depression in 2.1%. [Forrester 2016]

8.6. In the anonymous Reddit survey conducted between March and August 2022, 48 respondents reported unwanted effects from xylazine; 81% reported increased overdoses/passing out and 17% increased emergency room (ED) visits. [Spadaro 2023]

8.7. Nine Emergency Departments (EDs) in California, Oregon, Michigan, Missouri, Pennsylvania, New Jersey and New York enrolled consecutive patients with suspected opioid overdose between 21 September 2020 and 17 August 2021. [Love 2023] Enrolled patients had serum and/or blood samples taken for routine clinical care and these were subsequently analysed to detect whether opioids and/or other drugs had been used before presentation. Illicit opioid use was defined as the detection of “heroin, fentanyl or its analogs, nitazene or its analogs or other new synthetic opioids”; the authors did not state if this was parent drug and/or metabolites. Of the 1,006 patients screened, 395 were enrolled into two groups: i) presence of illicit opioid without xylazine (231 patients); ii) presence of illicit opioid with xylazine (90 patients). There were no differences in the demographics (proportion male and median age), initial observations (systolic blood pressure, heart rate, respiratory rate) and use of naloxone between the two groups. The primary outcomes in this study were cardiac arrest requiring CPR or coma. Cardiac arrest requiring CPR occurred in 4 (4.4%) of the 90 xylazine cases and 33 (14.3%) of the no xylazine cases (p=0.13); modelling demonstrated that the detection of xylazine was associated with a reduced risk of this outcome (adjusted odds ratio 0.30, 95% CI 0.10-0.92). There was no significant difference in the frequency of coma within 4 hours (seen in 26.7% of xylazine cases and 37.7% of no xylazine cases, p=0.063) or coma after 4 hours (seen in 13.3% of xylazine cases and 15.2% of no xylazine cases). Modelling demonstrated that the detection of xylazine was associated with an overall lower risk of developing coma (adjusted odds ratio 0.52, 95% CI 0.29-0.94). The explanation for this finding is uncertain, but one possibility acknowledged by the authors is that those exposed to xylazine had used a lower opioid dose.

8.8. The European Drug Emergencies Network Plus (Euro-DEN Plus) project has had a total of 62,613 cases reported to its registry from October 2013 to December 2021. There have been two reports of acute toxicity related to self- reported use of xylazine, both in November 2021 from Riga, Lativa. A 37-year- old male presented with coma (GCS 4) requiring intubation with a heart of 95 bpm, blood pressure 111/61 mmHg and temperature of 37.8°C following the use of xylazine, benzodiazepines and ketamine. He was treated with naloxone pre-hospital and medically discharged from the ED 41 hours after presentation. A 42-year-old female presented with drowsiness (GCS 10), a heart rate of 85 bpm, blood pressure 90/60 mmHg and temperature of 37.0°C following the use of xylazine and benzodiazepines. She did not require any specific treatment and was medically discharged from the ED 27 hours after presentation. In both cases urine immunoassay testing confirmed only the reported drugs used; nothing else was detected.