The first drug-related death associated with xylazine use in the UK and Europe.

BACKGROUND AND AIMS: On November 8th, 2022, the United States Food and Drug Administration (FDA) issued a statement alerting healthcare professionals to the increasing prevalence of xylazine in illicit drug overdoses in the country. Xylazine is a veterinary medicine with sedative, analgesic and muscle relaxant properties that is used as a heroin/fentanyl adulterant on the illicit drug market in North America. Here we report the first drug-related death associated with xylazine in the United Kingdom. METHODS: The National Programme on Substance Abuse Deaths (NPSAD) receives reports on drug-related deaths from coroners In England, Wales and Northern Ireland on a voluntary basis. The NPSAD was searched for cases with xylazine detections in cases received by December 31, 2022. RESULTS: One drug-related death associated with xylazine use was reported to NPSAD by December 31, 2022. The deceased was a 43-year-old male who was found dead at home with drug paraphernalia located at the property in May 2022. The post-mortem examination identified recent puncture wounds to the groin. Coronial documentation reports that the deceased had a history of illicit drug use. A number of drugs were detected by post-mortem toxicology and xylazine was implicated in death alongside heroin, fentanyl and cocaine. CONCLUSIONS: To the best of our knowledge, this is the first death associated with xylazine use reported in the UK, and even Europe, and indicates the entry of xylazine into the UK drug supply. This report highlights the importance of monitoring changes in illicit drug markets and the emergence of new drugs.

The First Fatal Intoxication with 3-MeO-PCP in the UK and a Review of the Literature.

The phencyclidine derivative 3-methoxyphencyclidine (3-MeO-PCP) is a potent dissociative hallucinogen. Sought for recreational use as a novel psychoactive substance, it can also induce acute psychological agitation and pathophysiological cardiorespiratory effects. Due to the harms associated with its use, 3-MeO-PCP was added to the "Green List" of materials covered by the 1971 Convention on Psychotropic Substances as a Schedule II substance by the United Nations Commission on Narcotic Drugs in April 2021. There have been 15 previous reports of fatal intoxications following 3-MeO-PCP use, but only one was attributable to 3-MeO-PCP intoxication alone. In this report, we detail the first fatality due to 3-MeO-PCP intoxication to be reported in the UK, along with a review of the surrounding literature. While the blood concentrations associated with 3-MeO-PCP toxicity and fatality remain unclear, by providing details of sample collection and storage conditions, this case will aid in future interpretations. Furthermore, this case suggests that 3-MeO-PCP toxicity may be exacerbated by exercise. Users of 3-MeO-PCP should be cautioned against its use as a "club drug" or in a similar setting where elevations in heart rate, body temperature and blood pressure may occur.

Correction: The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor.

[This corrects the article DOI: 10.1371/journal.pone.0059334.].

Designer psychostimulants: pharmacology and differences.

More than 200 novel psychoactive drugs have been reported in Europe, with 73 added in 2012 and additional compounds encountered every week in 2013. Many of these are "designer psychostimulants" which aim to mimic the subjective effects of amphetamines, cocaine or 3,4-methylenedioxymethylamphetamine (MDMA; "Ecstasy"). Several drugs are based on the beta-ketoamphetamine cathinone chemical structure, others include aminoindanes, aminotetralins, piperazines, amphetamine analogues and pipradrol derivatives. Although a detailed analysis of the pharmacology of these novel drugs is largely lacking, a number of scientific studies have been reported in 2011-2013 and these are reviewed. All of the novel psychostimulants activate monoamine systems in the brain - with differing dopamine (DA) v serotonin (5-HT) preferences. Those activating principally DA systems are amphetamine-like stimulants, such as naphyrone, desoxypipradrol, 3,4-methylenedioxypyrovalerone (MDPV), and benzylpiperazine while those preferentially activating 5-HT mechanisms are MDMA-like or cocaine-like stimulants, such as mephedrone, methylone and other substituted cathinones, aminoindanes, aminotetralins and piperazines. The ability of mephedrone and other novel psychostimulants to substitute for methylamphetamine or cocaine in drug discrimination tests in rats, and the ability of mephedrone to induce conditioned place preference and to sustain self-administration behaviour suggests that this and other cocaine/methylamphetamine-like drugs have dependence liability. This article is part of the Special Issue entitled 'CNS Stimulants'.

An analysis of the synthetic tryptamines AMT and 5-MeO-DALT: emerging 'Novel Psychoactive Drugs'.

Novel Psychoactive Drugs (NPD) can be sold without restriction and are often synthetic analogues of controlled drugs. The tryptamines are an important class of NPD as they bind to the various serotonin (5-HT) receptor subtypes and cause psychosis and hallucinations that can lead to injury or death through misadventure. Here we report on the structure elucidation and receptor binding profiles of two widely marketed tryptamine-derived NPDs, namely alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine.

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

Neurochemical profiles of some novel psychoactive substances.

Fourteen substances from the class of drugs sometimes known as "legal highs" were screened against a battery of human receptors in binding assays, and their potencies as inhibitors of monoamine uptake determined in functional in vitro assays. Thirteen of the test substances acted as inhibitors of monoamine uptake at submicromolar concentrations, including 9 potent inhibitors of the dopamine transporter (DAT), 12 potent inhibitors of the norepinephrine transporter (NET) and 4 potent inhibitors of the serotonin transporter (SERT). Seven compounds acted as submicromolar inhibitors of both DAT and NET, and three substances 1-(benzofuran-5-yl)propan-2-amine (5-APB), 1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one hydrochloride ("naphyrone") and 1-naphthalen-1-yl-2-pyrrolidin-1-ylpentan-1-one hydrochloride ("1-naphyrone") were submicromolar inhibitors of all three monoamine transporters. There was a lack of correlation between results of functional uptake experiments and in vitro binding assays for the monoamine transporters. There was also no correlation between the human behavioral effects of the substances and the results of bindings assays for a range of receptor targets, although 1-(benzofuran-5-yl)propan-2-amine (5-APB), 1-(benzofuran-6-yl)propan-2-amine hydrochloride (6-APB) and 5-iodo-2,3-dihydro-1H-inden-2-amine hydrochloride (5-iodo-aminoindane) exhibited <100 nM affinities for 5HT(2B) and α(2C) receptors. Functional assays revealed that 5-APB and 6-APB were potent full agonists at 5HT(2B) receptors.

Reference materials for new psychoactive substances.

Historically, the appearance of new psychoactive materials (and hence the requirement for new reference standards) has been relatively slow. This position has now changed, with 101 new psychoactive substances reported to EMCDDA-Europol since 2006. The newly reported materials, and associated metabolites, require properly certified reference materials to permit reliable identification and quantification. The traditional approach and timescales of reference material production and certification are being increasingly challenged by the appearance of these new substances. Reference material suppliers have to adopt new strategies to meet the needs of laboratories. This situation is particularly challenging for toxicology standards as the metabolism of many of these substances is initially unknown. Reference material production often involves synthesis from first principles. While it is possible to synthesis these materials, there can be significant difficulties, from synthetic complexities through to the need to use controlled materials. These issues are examined through a discussion of the synthesis of cathinones. Use of alternative sources, including pharmaceutical impurity materials or internet sourced products, as starting materials for conversion into appropriately certified reference materials are also discussed. The sudden appearance and sometimes brief lifetime in the market place of many of these novel legal highs or research chemicals present commercial difficulties for reference material producers. The need for collaboration at all levels is highlighted as essential to rapid identification of requirements for new reference materials. National or international commissioning or support may also be required to permit reference material producers to recover their development costs.