New benzodiazepines in Europe – a review I Legal notice This publication of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is protected by copyright. The EMCDDA accepts no responsibility or liability for any consequences arising from the use of the data contained in this document. The contents of this publication do not necessarily reflect the official opinions of the EMCDDA’s partners, any EU Member State or any agency or institution of the European Union. Luxembourg: Publications Office of the European Union, 2021 PDF ISBN 978-92-9497-641-3 doi:10.2810/725973 TD-02-21-596-EN-N © European Monitoring Centre for Drugs and Drug Addiction, 2021 Reproduction is authorised provided the source is acknowledged. Photo credits for cover images from left to right: Finnish customs; Slovenian National Forensic Laboratory; Slovenian National Laboratory of Health, Environment and Food, Police Scotland. For any use or reproduction of photos or other material that is not under the European Monitoring Centre for Drugs and Drug Addiction copyright, permission must be sought directly from the copyright holders. Recommended citation: European Monitoring Centre for Drugs and Drug Addiction (2021), New benzodiazepines in Europe – a review, Publications Office of the European Union, Luxembourg. Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, Portugal Tel. +351 211210200 [email protected] I www.emcdda.europa.eu twitter.com/emcdda I facebook.com/emcdda I Contents 2 I Methods and information sources 4 I Executive summary 5 I Background 5 I History of the development of benzodiazepines 5 I Legitimate uses of benzodiazepines 5 I International control measures 6 I New benzodiazepines in Europe 6 I Emergence of new benzodiazepines 7 I Availability, size of the market 12 I International legal response to new benzodiazepines 13 I Replacement 13 I Physical, chemical and pharmacological properties 13 I Physical and chemical description 15 I Physical and pharmaceutical form 15 I Pharmacology 19 I Health and social risks 19 I Acute toxicity 21 I Chronic toxicity 22 I Psychological and behavioural effects 22 I Dependence and abuse potential 22 I Effects on the ability to drive and operate machines 23 I Social risks 23 I Extent and patterns of use, availability and potential for diffusion 23 I Prevalence of use 24 I Patterns of use 24 I Availability, supply and involvement of organised crime 27 I Conclusion 28 I References 36 I Annex – Profiles of selected new benzodiazepines New benzodiazepines in Europe – a review Authors I Methods and information sources Volker Auwärter (*), Joanna de Morais (**), Ana In the context of this report, ‘new benzodiazepines’ are Gallegos (**), Michael Evans-Brown (**), Rachel defined as new psychoactive substances (NPS) that Christie (**), Rita Jorge (**) and Roumen Sedefov (**) contain a benzodiazepine core, including structurally closely related compounds (e.g. thienodiazepines), and (*) Forensic Toxicology Department, Institute of Forensic Medicine, Medical Center, University of Freiburg, Germany that are not controlled under the international drug control (**) European Monitoring Centre for Drugs and Drug Addiction system. They also include three benzodiazepines – (EMCDDA), Lisbon, Portugal phenazepam, etizolam and flualprazolam – that Funding were formerly classed as NPS but have recently been controlled under the international drug control system. Part of this work was supported by EMCDDA Other common names for this category are ‘designer contracts CT.18.SAS.0085.1.0 with Dr Volker benzodiazepines’, ‘NPS benzodiazepines’ and, less Auwärter and CT.18.SAS.0089.1.0 with Dr Simon frequently, ‘synthetic benzodiazepine analogues’. Brandt. Acknowledgements English-language articles were selected from a search of the PubMed and Web of Science databases performed on The EMCDDA would like to extend its sincere thanks 18 June 2018 using the following search strings: (1) ‘(NPS and appreciation to the Early Warning System OR “new psychoactive substance*”) AND benzodiazepine*’ correspondents of the Reitox national focal points and (2) ‘designer benzodiazepine*’. Additional articles and experts from their national early warning were identified from a review of the references cited in system networks, and the Europol national units. retrieved publications (snowball technique). Searches The authors would like to thank Spanish customs; of selected medical specialty society and international, Police Scotland; and the Welsh Emerging Drugs national and local government agency websites were and Identification of Novel Substances Project, conducted to identify clinical guidelines, position Public Health Wales, for the images used in this statements and reports. Search strings were introduced publication. The authors also thank Laura Huppertz into Google and Google Scholar and the first 100 hits were (Institute of Forensic Medicine, Medical Center, screened to find additional relevant content. Although the University of Freiburg, Germany) and Dr Björn systematic searches were conducted in 2018, information Moosmann (Institute of Forensic Medicine, St Gallen, from the scientific papers and reports published in 2019 Switzerland) for their support; Dr Simon Brandt and 2020 was also included in this report. In particular, (School of Pharmacy and Biomolecular Sciences, the most recent data on flualprazolam and etizolam were Liverpool John Moores University, United Kingdom) added. All the references in the European Database on for peer-reviewing this report; and Regina Kühnl, IFT New Drugs for substances listed in the benzodiazepine Institut für Therapieforschung München, German category were also included, except patents. Monitoring Centre for Drugs and Drug Addiction, for reviewing parts of this report.. MEDLINE, PubMed, Google and internet platforms (e.g. Erowid, Bluelight, Eve and Rave) were searched for the Statement on the United Kingdom terms ‘designer benzodiazepines’, ‘NPS benzodiazepines’, The United Kingdom left the European Union on ‘legal benzodiazepines’, ‘flubromazolam’, ‘flualprazolam’, 1 February 2020. For the purpose of this report, the ‘fluclotizolam’, ‘diclazepam’, ‘clonazolam’, ‘clonitrazolam’, United Kingdom is not included in the term ‘Member ‘norfludiazepam’ and ‘bromazolam’, alone or in combination, States’. in May 2019. In addition, colleagues within our scientific network were contacted to obtain further information. 2 New benzodiazepines in Europe – a review Information from the European Union Early Warning System on NPS (EWS), operated by the European Monitoring Centre for Drugs and Drug Addiction, has been included as relevant. The EWS is composed of a multiagency and multidisciplinary network, which includes the EMCDDA, 29 national early warning systems (27 EU Member States, Turkey, and Norway), Europol and its law enforcement networks, the European Medicines Agency (EMA), the European Commission, and other partners. Information from the United Nations system (the United Nations Office on Drugs and Crime and the World Health Organization), as well as from non-EU countries such as Canada, the United Kingdom and the United States, has also been included as relevant. 3 New benzodiazepines in Europe – a review I Executive summary of new benzodiazepines is largely unknown, and the risks associated with their use may be higher than those Benzodiazepines are one of the most important groups associated with the use of authorised benzodiazepine of medicines that are specifically used for sedation and medicines. In addition, the very nature of unregulated to aid sleep. They are the most widely prescribed group markets means that these risks may be amplified by the of medicines in the world and are used to treat a range uncertain doses that are used. In some cases, users may of conditions, including anxiety, insomnia, epilepsy and not be aware that they are using these substances, and alcohol withdrawal. Benzodiazepines were introduced into therefore might be at higher risk of severe poisoning, clinical medicine in the early 1960s. They rapidly replaced particularly if taken in combination with other central barbiturates as sedative-hypnotics because they were nervous system depressants, such as alcohol and safer and less likely to cause fatal central nervous system opioids. Of particular concern is the growing use of depression. Benzodiazepines act as central nervous new benzodiazepines to make falsified (fake) tablets of system depressants by enhancing the actions of the commonly prescribed benzodiazepine medicines, such neurotransmitter gamma-aminobutyric acid (GABA) on the as diazepam (Valium) and alprazolam (Xanax), and the benzodiazepine site of the GABA type A (GABAA) receptor. involvement of criminal groups in producing such tablets. Their effects include anxiolytic and sedative effects, In some cases, the fake tablets are packaged in blister muscle relaxation and anticonvulsive activity. packs resembling legitimate products, which makes it more difficult for consumers to spot the fakes. Serious Since the mid 2000s, new benzodiazepines, which are not adverse events, such as severe poisonings, involving such controlled under the international drug control system, fake medicines have been reported in Europe. Other risks have been sold as ‘legal’ replacements for controlled might be related to the potential presence of adulterants, benzodiazepines in Europe. A small number of these new other substances or synthesis by-products from illicit benzodiazepines, such as phenazepam and etizolam, are manufacture