An Expanding World of New Psychoactive Substances—Designer Benzodiazepines T ⁎ Jolanta B
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Neurotoxicology 73 (2019) 8–16 Contents lists available at ScienceDirect Neurotoxicology journal homepage: www.elsevier.com/locate/neuro Review An expanding world of new psychoactive substances—designer benzodiazepines T ⁎ Jolanta B. Zawilska , Jakub Wojcieszak Department of Pharmacodynamics, Medical University of Łódź, 90-151 Łódź, Muszynskiego 1, Poland ARTICLE INFO ABSTRACT Keywords: The abuse of new psychoactive substances (NPS) has been increasing dramatically since the late 2000s world- Benzodiazepines wide. Between 2009 and 2017, a total of 803 individual NPS were reported to the United Nations Office of Drugs New psychoactive substances and Crime by 111 countries and territories. Although the most popular compounds are synthetic cannabino- Toxicity mimetics and psychostimulatory derivatives of cathinone (so-called β-keto-amphetamines), novel benzodiaze- Metabolism pines have recently emerged on the recreational drug market. The misuse/abuse of “designer benzodiazepines” Impaired driving (DBZD), a common name for the benzodiazepine class NPS, has become an increasing problem in many coun- tries. The DBZD group includes pharmaceutical drug candidates that have never been approved for medical use, compounds that were synthesized by a simple structural modification of a registered drug, and some active metabolites of registered benzodiazepines. This survey presents members of the DBZD group, describes the epidemiological trends and clinical effects associated with DBZD use, and discusses available data on their metabolism. Special emphasis is given to cases of intoxications involving these compounds. 1. Introduction the influence of drugs (e.g., Bertol et al., 2018; Drummer et al., 2012; Kriikku et al., 2012; Valen et al., 2017; Xiang et al., 2015). Benzodiazepines were introduced as therapeutic drugs in the early Over the last decade, an increasing number of new benzodiazepines 1960s. They act as positive allosteric modulators of γ-aminobutyric acid that are not registered as medical products have been introduced into (GABA)-A receptors, which are composed of heteropentameric multi- the recreational drug market (see Table 1). Currently, new psychoactive subunit proteins. The drugs bind to a specific high affinity binding site substances (NPS) belonging to the benzodiazepine class are commonly of GABA-A receptors, located at the α/γ subunit interface. The phar- referred to as “designer benzodiazepines” (DBZD), and their misuse or macological activity of the benzodiazepines is determined by the type abuse has become an increasing problem in many countries. This survey of GABA-A receptor α subunit to which they bind. Thus, the sedative, presents members of the DBZD group, describes the epidemiological anterograde amnesic and anticonvulsant actions, as well as the addic- trends and clinical effects associated with DBZD use, and discusses tive potential of these drugs, require the presence of α1-containing available data on their metabolism. GABA-A receptors, while the anxiolytic effects are mediated by GABA-A receptors containing α2 subunits, and the myorelaxant actions by 2. Methodology GABA-A receptors containing α2, α3, and α5 subunits (Tan et al., 2011). Benzodiazepines are nowadays widely applied in the therapy of Review of the literature was based on the exhaustive search carried psychiatric and neurological disorders, including anxiety and panic out in PubMed (U.S. National Library of Medicine), using “designer attacks, insomnia, muscle spasms, epilepsy and alcohol withdrawal. benzodiazepines” and each of the compound name listed in Table 1 as Some are also used as a premedication prior to surgery and intra-op- keywords. Only papers written in English and with full texts available erative medications. In addition, benzodiazepines are commonly used by December 2018 were included. Additionally, official reports pub- in self-medication, and misused in combination with other psychoactive lished by the United Nations O ffice on Drugs and Crime (UNODOC), substances, namely opioids, psychostimulants and alcohol (EMCDDA, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2018a; Griffin et al., 2013; UNODC, 2017a). There are also reports on and World Health Organization (WHO), and governmental acts were the use of benzodiazepines in drug-facilitated crime and driving under reviewed. Furthermore, in each article and report retrived, references ⁎ Corresponding author. E-mail address: [email protected] (J.B. Zawilska). https://doi.org/10.1016/j.neuro.2019.02.015 Received 4 January 2019; Received in revised form 12 February 2019; Accepted 21 February 2019 Available online 23 February 2019 0161-813X/ © 2019 Elsevier B.V. All rights reserved. J.B. Zawilska and J. Wojcieszak Neurotoxicology 73 (2019) 8–16 Table 1 Table 1 (continued) Chemical structures and names of designer benzodiazepines. Chemical structure Names Chemical structure Names 1,4-BENZODIAZEPINES Cloniprazepam A likely prodrug of clonazepam. IUPAC name: 5-(2-Chlorophenyl)-1-(cyclopropylmethyl)-7- nitro-1,3-dihydro-2H-benzo[e][1,4]diazepin-2- one Phenazepam1 IUPAC name: 7-Bromo-5-(2-chlorophenyl)-1,3-dihydro-2H- fl Desmethyl unitrazepam (also known as 1,4-benzodiazepin-2-one fl nor unitrazepam, Ro-4435 and fonazepam) Trade names: BD98, Elzepam, Fenazepam, The active metabolite of the potent drug Phenazef, Phenazepam, Phezipam, fl unitrazepam. Phenorelaxan, Trankvezipam IUPAC name: Street names: Bonsai, Bonsai Supersleep, Fenaz, fl 5-(2- uorophenyl)-7-nitro-1,3-dihydro-2H-1,4- Soviet Benzo, Panda benzodiazepin-2-one 3-Hydroxyphenazepam The active metabolite of phenazepam. IUPAC name: Diclazepam (2-Chlorodiazepam, Ro5-3448) 7-Bromo-5-(2-chlorophenyl)-3-hydroxy-1,3- IUPAC name: dihydro-2H-1,4-benzodiazepin-2-one 7-Chloro-5-(2-chlorophenyl)-1-methyl-1,3- dihydro-2H-1,4-benzodiazepin-2-one TRIAZOLOBENZODIAZEPINES Adinazolam (Deracyn®, Adinazolamum) IUPAC name: 1-(8-Chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a] [1,4]benzodiazepin-1-yl)-N,N- 4’-Chlorodiazepam (Ro5-4864) dimethylmethanamine IUPAC name: 7-Chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4- benzodiazepin-2-one Bromazolam IUPAC name: 8-Bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo [4,3-a][1,4]benzodiazepine Flubromazepam IUPAC name: 7-Bromo-5-(2-fluorophenyl)-1,3-dihydro-2H- 1,4-benzodiazepin-2-one Clonazolam (Clonitrazolam) IUPAC name: Meclonazepam [(S)-3-methylclonazepam] 6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-[1,2,4] IUPAC name: triazolo[4,3-a][1,4]benzodiazepine (3S)-5-(2-Chlorophenyl)-3-methyl-7-nitro-1,3- dihydro-2H-1,4-benzodiazepin-2-one Flualprazolam Nifoxipam (3- IUPAC name: fl hydroxydesmethylflunitrazepam, DP 370) 8-Chloro-6-(2- uorophenyl)-1-methyl-4H-benzo IUPAC name: [f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-Fluorophenyl)-3-hydroxy-7-nitro-2,3- dihydro-1H-1,4-benzodiazepin-2-one Nitemazepam Flubromazolam IUPAC name: IUPAC name: 3-Hydroxy-1-methyl-7-nitro-5-phenyl-2,3- 8-Bromo-6-(2-fluorophenyl)-1-methyl-4H- dihydro-1H-1,4-benzodiazepin-2-one (continued on next page) 9 J.B. Zawilska and J. Wojcieszak Neurotoxicology 73 (2019) 8–16 Table 1 (continued) Table 1 (continued) Chemical structure Names Chemical structure Names [1,2,4]triazolo[4,3-a][1,4]benzodiazepine Street name: liquid Xanax Flunitrazolam IUPAC name: Metizolam (desmethyletizolam) 6-(2-Fluorophenyl)-1-methyl-8-nitro-4H-[1,2,4] A metabolite of etizolam. triazolo[4,3-a][1,4]benzodiazepine IUPAC name: 4-(2-Chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine Nitrazolam (NitrazolaM) IUPAC name: 1-Methyl-8-nitro-6-phenyl-4H-[1,2,4]triazolo Fluclotizolam [4,3-a][1,4]benzodiazepine IUPAC name: 2-Chloro-4-(2-fluorophenyl)-9-methyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a]diazepine Pyrazolam IUPAC name: 8-Bromo-1-methyl-6-(pyridin-2-yl)-4H-[1,2,4] triazolo[4,3-a][1,4]benzodiazepine 1 Phenazepam is used as a prescription medicine in the Russian Federation, Estonia, Latvia, Lithuania and Belarus (WHO, 2015). 2 Etizolam is used as a prescription medicine in Japan, India and Italy (WHO, 2017). were checked carefully in order to find possible additional publications, Zapizolam missed during the initial search. IUPAC name: 8-Chloro-6-(2-chlorophenyl)-4H-pyrido[2,3-f] [1,2,4]triazolo[4,3-a][1,4]diazepine 3. Legal status of designer benzodiazepines In Canada, all benzodiazepines are classified as schedule IV drugs (Ministry of Justice, Canada, 2018). In the United Kingdom, broma- zolam, 4-chlorodiazepam, clonazolam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, fonezepam, 3-hydro- xyphenazepam, meclonazepam, metizolam, nifoxipam, nitrazolam and THIENOTRIAZOLOBENZODIAZEPINES 2 pyrazolam have been classified as Class C drugs by the May 2017 Etizolam IUPAC name: amendment to The Misuse of Drugs Act 1971 (Advice Council on Misuse 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno of Drugs, 2017). Several DBZD have been placed under national control [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine in other countries (UNODC, 2017c; WHO, 2015, 2017): International trade names: Arophalm, Capsafe, Depas, Dezolam, Eticalm, Etidrale, Etisedan, Etizolan, Guperies, Medipeace, Mozun, • China: phenazepam; Nonnerv, Palgin, Pasaden, Sedekopan, • Denmark: clonazolam, deschloroetizolam, diclazepam, flu- Sylazepam bromazepam, flubromazolam, metizolam, nifoxipam, phenazepam Street names: Etiz, Eitizzy, Etizest and pyrazolam; • Finland: clonazolam, deschloroetizolam, diclazepam, etizolam, flu- Deschloroetizolam bromazepam, flubromazolam, meclonazepam, nifoxipam, phena- IUPAC name: zepam and pyrazolam; 4-Phenyl-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine