Orsolini 2019-0112-MS CN
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Send Orders for Reprints to [email protected] Current Neuropharmacology, 2020, 18, 809-837 809 REVIEW ARTICLE ‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports Laura Orsolini1,2,3,*, John M. Corkery1, Stefania Chiappini1, Amira Guirguis1,4, Alessandro Vento5,6,7,8, Domenico De Berardis3,9,10, Duccio Papanti1 and Fabrizio Schifano1 1Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, Herts, UK; 2Department of Clinical Neurosciences/DIMSC, School of Medicine, Section of Psychiatry, Polytechnic University of Marche, Ancona, Italy; 3Polyedra, Teramo, Italy; 4Swansea University Medical School, Ysgol Feddygaeth Prifysgol Abertawe, UK; 5NESMOS Department (Neurosciences, Mental Health and Sensory Organs), Sapienza University - Rome, School of Medicine and Psychology; Sant’Andrea Hospital, Rome, Italy; 6School of psychology - G. Marconi Telematic University, Rome, Italy; 7Addictions Observatory (ODDPSS), Rome, Italy; 8Mental Health Department - ASL Roma 2, Rome, Italy; 9Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of “G. D’Annunzio”, Chieti, Italy; 10NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4 Teramo, Italy Abstract: Background: NPS belonging to the benzodiazepine (BZD) class, e.g., ‘legal/designer BZDs’/‘research chemicals’, have recently emerged in the drug (mainly online/virtual) market. Objective: While certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians’/public health knowledge/awareness, to incentive harm reduction strategies. Method: A comprehensive overview was carried out by using the EMCDDA/EDND database regu- A R T I C L E H I S T O R Y larly monitored by our research team, by specifically looking at the ‘new BZDs’ so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilin- gual qualitative netnographic study was conducted to obtain further clinical/pharmacological/ Received: October 17, 2019 Revised: December 08, 2019 toxicological data, including psychonauts’ online trip reports. Accepted: January 09, 2020 Results: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been DOI: notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are 10.2174/1570159X18666200110121333 sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably ad- ministered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds. Conclusion: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks. Keywords: New benzodiazepines, NPS, novel psychoactive substances, benzodiazepines, designer benzodiazepines, synthetic benzodiazepines. 1. INTRODUCTION the brain and plays an important role in modulating the activ- ity of many neurons, including those in the amygdala and Benzodiazepines (BZDs) act as positive allosteric modu- prefrontal cortex [1]. The GABA receptor is a ligand-gated lators on the gamma-aminobutyric acid (GABA) receptor A A chloride-selective ion channel build-up of five subunits: two [1]. GABA represents the main inhibitor neurotransmitter in α, two ß (the binding site for endogenous neurotransmitter) and one γ. BZDs bind to the pocket created by α and γ *Address correspondence to this author at the Psychopharmacology, Drug subunits and induce a conformational change in the GABAA Misuse and Novel Psychoactive Substances Research Unit, School of Life receptor. This alteration, in turns, induces a conformational and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, change in the GABAA receptor such as to increase the appar- Herts, UK; Villa Jolanda Hospital, Neomesia Mental Health, Villa Jolanda, ent affinity for channel gating by GABA at both agonist Italy; Polyedra, Teramo, Italy; Tel: (+39) 392 3244643; E-mail: [email protected] sites. As a result, maximal currents elicited by GABA re- 1570-159X/20 $65.00+.00 ©2020 Bentham Science Publishers 810 Current Neuropharmacology, 2020, Vol. 18, No. 9 Orsolini et al. main unaffected, and the GABA concentration channel open- profile are still unknown, posing serious health risks to con- ing curve is shifted to lower GABA concentrations’ chloride sumers [9, 10]. Furthermore, the risk of polydrug use involv- channel that hyperpolarizes the cell and accounts for ing BZDs and opioids (both traditional and synthetic ones) GABA’s inhibitory effect throughout the central nervous are furtherly intensified by NPS belonging to these system [1]. These complex pharmacological activities ex- new/designer BZDs [10]. Given the limited information on plain the different clinical effects (i.e., anxiolytic, hypnotic, the pharmacology and toxicity of these substances, variations anticonvulsant, amnestic, and muscle relaxant) of BZDs. The in the dosage, onset of effects, combinations with other sub- pharmacological activity of BZDs is determined by the type stances, potency, and general patient or individual variabil- of GABAA receptor α subunit to which they bind. Thus, the ity, the concomitant use of these substances with other drugs sedative, anterograde amnesic and anticonvulsant actions, as entails several and unpredictable risks, particularly amongst well as the addictive potential of these drugs, require the high-risk opioid users [11]. Interestingly, over the long-term presence of α1-containing GABAA receptors, while the anx- and in the last few years, a diverse range of NPS, including iolytic effects are mediated by GABAA receptors containing synthetic opioids and BZDs have been found [10]. In fact, by α2 subunits, and the myorelaxant actions by GABAA recep- the end of 2018, EMCDDA monitored more than 730 NPS, tors containing α2, α3, and α5 subunits [2]. of which 55 were reported for the first time in Europe in 2018, of which around 5% belonging to the BZD class [10]. Overall, BZDs are generally classified according to their So far, 29 NPS belonging to the BZD class have been re- pharmacokinetic characteristics, i.e. a) plasma half-life (t½); ported by the Member States to the UNODC Early Warning and, b) hepatic metabolism [1, 3] (Table 1). Plasma half-life Advisory (EWA), of which 23 were firstly detected in (t½) represents the hours required for the concentration of Europe during the last 5 years [10]. In 2008, phenazepam the drug in the body to be reduced to half of the maximum was the first new BZD to be reported to the EWA. In 2011, concentration. In detail, t½ represents the ‘phase distribu- α Germany, Norway and the United Kingdom were the first tion’ from the vascular system to the tissues; whilst t½ indi- β countries to report the emergence of another designer, BZD, cates the ‘elimination phase’ and represents, hence, an index etizolam. In the following years (2012-2013), a relatively of the metabolism and excretion of BZDs. This phase varies stable number of BZDs were reported to the EMCDDA; with significantly among different BZDs (from 2-3 hours up to an increased number in 2014-2016, a reduction in 2017 and a more than 100 hours) and is relevant for the accumulation of further increase in 2018 [10]. some BZDs in tissues after long-term use (see Table 1 for more details). Furthermore, BZDs may be classified accord- Some new BZDs were sold as tablets, capsules or pow- ing to their chemical structure and designer BZDs are mainly ders under their own names, marketed as ‘legal’ versions of classified as either 1,4-benzodiazepines (a structure shared authorised medicines. In other cases, counterfeiters used by most ‘traditional’ BZDs), triazolo-BZDs, or thienotria- these substances to produce ‘fake’ versions of commonly zolodiazepines (Table 1) [4]. BZD metabolism mainly oc- prescribed anti-anxiety drugs, such as diazepam and alprazo- curs in the liver, primarily by oxidative metabolism mediated lam, which were sold directly on the illicit online drug mar- by the cytochrome P450 (CYP450) family, i.e. CYP3A4, ket [10]. Furthermore, some new BZDs have been identified CYP3A5, CYP2C19, CYP2C18, CYP2C9 and CYP2B6 [5]. mixed with other NPS (i.e., synthetic cannabinoids) or have Tolerance and dependence may occur shortly after consump- been labeled as diazepam tablets but containing a new potent tion has started, which requires dose increase and may trig- synthetic opioid [11]. Overall, some of the new BZDs have ger drug-seeking behaviours [1, 3]. Acute intoxication may been historically approved and marketed for use in some cause respiratory and central nervous system depression, countries (i.e., phenazepam); whilst others have been previ- even though is rarely lethal if the BDZ is taken alone [6]. ously investigated and may be found