Generic placeholder image

Current Pharmaceutical Design

Author(s): Simona Zaami, Silvia Graziano, Roberta Tittarelli, Renata Beck and Enrico Marinelli*

DOI: 10.2174/1381612827666210917145636

DownloadDownload PDF Flyer Cite As
BDZs, Designer BDZs and Z-drugs: Pharmacology and Misuse Insights

Page: [1221 - 1229] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Benzodiazepines (BZDs) are a widely prescribed class of sedative-hypnotics compounds for the treatment of a broad range of conditions as anxiety and obsessive-compulsive disorders, phobias, sleep-related problems associated with insomnia, and for the management of alcohol and GHB withdrawal. Zolpidem, zopiclone and zaleplon, commonly known as Z-drugs, are non-benzodiazepine hypnotic drugs with pharmacology similar to BDZs. Despite their usefulness, BDZs and Z-drugs present a potential for abuse and dependence. Moreover, the non-medical use of BDZs is a well-known phenomenon and represents an increasingly widespread public health problem since it is associated with an elevated risk of serious health consequences or fatal overdose, especially among specific group of users. The spectrum of BDZs and Z-drugs misuse is extended by new synthetic BDZs, which may pose high risks to users, since the majority have never undergone clinical trials or tests and consequently their pharmacology and toxicology are largely unknown.

Keywords: BDZs, Z-drugs, new BDZs, diversion, abuse, misuse, pharmacology.

[1]
Schatzberg AF, DeBattista C. Manual of clinical psychopharmacology. (8th ed),. Arlington, VA, USA: American Psychiatric. Publishing 2015.
[http://dx.doi.org/10.1176/appi.books.9781615370047]
[2]
Beck R, Matanović SM, Zibar L. Gamma-hydroxybutyric acid, gamma-butyrolactone, and 1,4-butanediol addiction: A serious health threat. Arh Hig Rada Toksikol 2019; 70(2): 149-50.
[http://dx.doi.org/10.2478/aiht-2019-70-3295] [PMID: 31246568]
[3]
Licata SC, Rowlett JK. Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond. Pharmacol Biochem Behav 2008; 90(1): 74-89.
[http://dx.doi.org/10.1016/j.pbb.2008.01.001] [PMID: 18295321]
[4]
Guina J, Merrill B. BDZs I: Upping the care on downers: The evidence of risks, benefits and alternatives. J Clin Med 2018; 7: 17.
[http://dx.doi.org/10.3390/jcm7020017]
[5]
Batlle E, Lizano E, Viñas M. 1,4-BDZs and new derivatives: Description, analysis and organic synthesis. Medicinal Chemistry IntechOpen. 2019.
[http://dx.doi.org/10.5772/intechopen.79879]
[6]
Lader MH. Limitations on the use of benzodiazepines in anxiety and insomnia: Are they justified? Eur Neuropsychopharmacol 1999; 9(Suppl. 6): S399-405.
[http://dx.doi.org/10.1016/S0924-977X(99)00051-6] [PMID: 10622686]
[7]
Kaufmann CN, Spira AP, Depp CA, Mojtabai R. Long-Term Use of Benzodiazepines and Nonbenzodiazepine Hypnotics, 1999-2014. Psychiatr Serv 2018; 69(2): 235-8.
[http://dx.doi.org/10.1176/appi.ps.201700095] [PMID: 29089011]
[8]
National health and nutrition examination survey. Available from: http://www.cdc.gov/nchs/nhanes/index.htm
[9]
Blanco C, Han B, Jones CM. Prevalence and correlates of benzodiazepine use, misuse, and use disorders among adults in the united states. J Clin Psychiatry 2018; 79: 18m12174.
[10]
Donoghue J, Lader M. Usage of benzodiazepines: A review. Int J Psychiatry Clin Pract 2010; 14(2): 78-87.
[http://dx.doi.org/10.3109/13651500903447810] [PMID: 24922466]
[11]
World Drug Report 2019 (United Nations publication, Sales No. E.19.XI.8). 2019. Available from: https://wdr.unodc.org/wdr2019/prelaunch/WDR19_Booklet_3_DEPRESSANTS.pdf
[12]
Brunetti P, Giorgetti R, Tagliabracci A, Huestis MA, Busardò FP. Designer Benzodiazepines: A review of toxicology and public health risks. Pharmaceuticals (Basel) 2021; 14(6): 560.
[http://dx.doi.org/10.3390/ph14060560] [PMID: 34208284]
[13]
Agarwal SD, Landon BE. Patterns in outpatient benzodiazepine prescribing in the United states. JAMA Netw Open 2019; 2(1): e187399. [Erratum in: JAMA Netw Open. 2019; 2: e191203].
[http://dx.doi.org/10.1001/jamanetworkopen.2018.7399] [PMID: 30681713]
[14]
Kang M, Ghassemzadeh S. Benzodiazepine toxicity, NCBI Bookshelf, StatPearls Publishing 2020. Available from:https://www.ncbi.nlm.nih.gov/books/NBK482238/
[15]
Griffin CE III, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J 2013; 13(2): 214-23.
[PMID: 23789008]
[16]
da Silva AV, Meneghetti SMP, Meneghetti MR. Benzodiazepines: Drugs with chemical skeletons suitable for the preparation of metallacycles with potential pharmacological activity. Molecules 2021; 26(9): 2796.
[http://dx.doi.org/10.3390/molecules26092796] [PMID: 34068533]
[17]
Allison C, Pratt JA. Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharmacol Ther 2003; 98(2): 171-95.
[http://dx.doi.org/10.1016/S0163-7258(03)00029-9] [PMID: 12725868]
[18]
Vinkers CH, Olivier B. mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) Receptor modulators? Adv Pharmacol Sci 2012; 2012: 416864.
[http://dx.doi.org/10.1155/2012/416864] [PMID: 22536226]
[19]
Longo LP, Johnson B. Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives. Am Fam Physician 2000; 61(7): 2121-8.
[PMID: 10779253]
[20]
Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans and laboratory animals--implications for problems of long-term use and abuse. Psychopharmacology (Berl) 1997; 134(1): 1-37.
[http://dx.doi.org/10.1007/s002130050422] [PMID: 9399364]
[21]
Ibañez GE, Levi-Minzi MA, Rigg KK, Mooss AD. Diversion of benzodiazepines through healthcare sources. J Psychoactive Drugs 2013; 45(1): 48-56.
[http://dx.doi.org/10.1080/02791072.2013.764232] [PMID: 23662331]
[22]
Schmitz A. Benzodiazepine use, misuse, and abuse: A review. Ment Health Clin 2016; 6(3): 120-6.
[http://dx.doi.org/10.9740/mhc.2016.05.120] [PMID: 29955458]
[23]
Ait-Daoud N, Hamby AS, Sharma S, Blevins D. A Review of Alprazolam Use, Misuse, and Withdrawal. J Addict Med 2018; 12(1): 4-10.
[http://dx.doi.org/10.1097/ADM.0000000000000350] [PMID: 28777203]
[24]
European monitoring centre for drugs and drug addiction and europol. EU Drug Markets Report 2019, Publications Office of the European Union, Luxembourg. 2019. Available from:https://www.europol.europa.eu/publications/
[25]
Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry 2005; 18(3): 249-55.
[http://dx.doi.org/10.1097/01.yco.0000165594.60434.84] [PMID: 16639148]
[26]
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Perspective on drugs: The misuse of BDZs among high-risk opioids users in Europe, updated 14.11.2018. 2018. Available from:http://www.emcdda.europa.eu/topics/pods/BDZs_en
[27]
Wolff K, White J, Karch S. The SAGE handbook of drug & alcohol studies: biological approaches. SAGE Publishing Inc. 2016. [Online publication October 18, 2016]
[http://dx.doi.org/10.4135/9781473922143]
[28]
Ford C, Law F. Guidance for the use and reduction of misuse of BDZs and other hypnotics and anxiolytics in general practice. 2014; pp. 1-62. Available from: http://www.emcdda.europa.eu/attachements.cfm/att_248926_EN_UK59_benzos.pdf
[29]
Bentué-Ferrer D, Reymann JM, Tribut O, Allain H, Vasar E, Bourin M. Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam. Eur Neuropsychopharmacol 2001; 11(1): 41-50.
[http://dx.doi.org/10.1016/S0924-977X(00)00137-1] [PMID: 11226811]
[30]
Giardino L, Zanni M, Pozza M, Bettelli C, Covelli V. Dopamine receptors in the striatum of rats exposed to repeated restraint stress and alprazolam treatment. Eur J Pharmacol 1998; 344(2-3): 143-7.
[http://dx.doi.org/10.1016/S0014-2999(97)01608-7] [PMID: 9600648]
[31]
National Institute on Drug Abuse. Overdose Death Rates Available from:https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates
[32]
National Records of Scotland. Drug-related deaths in Scotland in 2018 Available from:https://www.nrscotland.gov.uk/statistics-and-data/statistics/statistics-by-theme/vital-events/deaths/drug-related-deaths-in-scotland/2018
[33]
Jouanjus E, Guernec G, Lapeyre-Mestre M. Medical prescriptions falsified by the patients: A 12-year national monitoring to assess prescription drug diversion. Fundam Clin Pharmacol 2018; 32(3): 306-22.
[http://dx.doi.org/10.1111/fcp.12356] [PMID: 29436015]
[34]
Johnson CF, Barnsdale LR, McAuley A. Investigating the role of BDZs in drug-related mortality. A systematic review undertaken on behalf of the Scottish National Forum on Drug-Related Deaths, NHS Health Scotland, Edinburgh. 2016. Available at:https://www.scotpho.org.uk/publications/reports-and-papers/investigating-the-role-of-BDZs-in-drug-related-mortality-a-systematic-review-undertaken-on-behalf-of-the-scottish-national-forum-on- drug-related-deaths/
[35]
National Institute for Health and Care Excellence (NICE). Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia 2004. [Published: 28 April 200] Available from: www.nice.org.uk/guidance/ta77
[36]
Schifano F, Chiappini S, Corkery JM, Guirguis A. An insight into z-drug abuse and dependence: An examination of reports to the european medicines agency database of suspected adverse drug reactions. Int J Neuropsychopharmacol 2019; 22(4): 270-7.
[http://dx.doi.org/10.1093/ijnp/pyz007] [PMID: 30722037]
[37]
Gunja N. The clinical and forensic toxicology of Z-drugs. J Med Toxicol 2013; 9(2): 155-62.
[http://dx.doi.org/10.1007/s13181-013-0292-0] [PMID: 23404347]
[38]
Matheson E, Hainer BL. Insomnia: Pharmacologic therapy. Am Fam Physician 2017; 96(1): 29-35.
[PMID: 28671376]
[39]
Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf 2009; 32(9): 735-48.
[http://dx.doi.org/10.2165/11312920-000000000-00000] [PMID: 19670914]
[40]
Gunja N. In the Zzz zone: The effects of Z-drugs on human performance and driving. J Med Toxicol 2013; 9(2): 163-71.
[http://dx.doi.org/10.1007/s13181-013-0294-y] [PMID: 23456542]
[41]
Agravat A. ‘Z’-hypnotics versus BDZs for the treatment of insomnia. Prog Neurol Psychiatry 2018; 22: 26-9.
[http://dx.doi.org/10.1002/pnp.502]
[42]
Israel AG, Kramer JA. Safety of zaleplon in the treatment of insomnia. Ann Pharmacother 2002; 36(5): 852-9.
[http://dx.doi.org/10.1345/aph.1A086] [PMID: 11978165]
[43]
Nutt DJ. NICE: The National Institute of Clinical Excellence -- or Eccentricity? Reflections on the Z-drugs as hypnotics. J Psychopharmacol 2005; 19(2): 125-7.
[http://dx.doi.org/10.1177/0269881105051988] [PMID: 15728430]
[44]
Wilson SJ, Nutt DJ, Alford C, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 2010; 24(11): 1577-601.
[http://dx.doi.org/10.1177/0269881110379307] [PMID: 20813762]
[45]
Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case reports and epidemiological data. Addiction 2003; 98(10): 1371-8.
[http://dx.doi.org/10.1046/j.1360-0443.2003.00491.x] [PMID: 14519173]
[46]
Schepis TS, Teter CJ, Simoni-Wastila L, McCabe SE. Prescription tranquilizer/sedative misuse prevalence and correlates across age cohorts in the US. Addict Behav 2018; 87: 24-32.
[http://dx.doi.org/10.1016/j.addbeh.2018.06.013] [PMID: 29940388]
[47]
Kapil V, Green JL, Le Lait C, Wood DM, Dargan PI. Misuse of benzodiazepines and Z-drugs in the UK. Br J Psychiatry 2014; 205(5): 407-8.
[http://dx.doi.org/10.1192/bjp.bp.114.149252] [PMID: 25061118]
[48]
Goodwin RD, Hasin DS. Sedative use and misuse in the United States. Addiction 2002; 97(5): 555-62.
[http://dx.doi.org/10.1046/j.1360-0443.2002.00098.x] [PMID: 12033656]
[49]
Victorri-Vigneau C, Feuillet F, Wainstein L, et al. Pharmacoepidemiological characterisation of zolpidem and zopiclone usage. Eur J Clin Pharmacol 2013; 69(11): 1965-72.
[http://dx.doi.org/10.1007/s00228-013-1557-x] [PMID: 23877252]
[50]
Rubio González V, Redondo Martín S, Ruíz López Del Prado G, Muñoz Moreno MF, Velázquez Miranda A. Urgencias hospitalarias asociadas al consumo de hipnóticos y sedantes, Castilla y León, 2009-2013. Rev Esp Salud Pública 2016; 90: e1-e12. [Hospital Emergencies Associated with the Consumption of Hypnotics and Sedatives, 2009-2013,Castilla y León, Spain]. [Spanish.]
[PMID: 27775683]
[51]
Grimsrud MM, Brekke M, Syse VL, Vallersnes OM. Acute poisoning related to the recreational use of prescription drugs: An observational study from Oslo, Norway. BMC Emerg Med 2019; 19(1): 55.
[http://dx.doi.org/10.1186/s12873-019-0271-0] [PMID: 31615421]
[52]
Brandt J, Leong C. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. Drugs R D 2017; 17(4): 493-507.
[http://dx.doi.org/10.1007/s40268-017-0207-7] [PMID: 28865038]
[53]
Lisa J, Geoff B, Mark B, Caryl B, et al. Department of Health of UK. A summary of the health harms of drugs 2011. [Published 25 August 2011] Available from:https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/215470/dh_129674.pdf
[54]
Zosel A, Osterberg EC, Mycyk MB. Zolpidem misuse with other medications or alcohol frequently results in intensive care unit admission. Am J Ther 2011; 18(4): 305-8.
[http://dx.doi.org/10.1097/MJT.0b013e3181d169ed] [PMID: 20458214]
[55]
Garnier R, Guerault E, Muzard D, Azoyan P, Chaumet-Riffaud AE, Efthymiou ML. Acute zolpidem poisoning--analysis of 344 cases. J Toxicol Clin Toxicol 1994; 32(4): 391-404.
[http://dx.doi.org/10.3109/15563659409011040] [PMID: 8057398]
[56]
Darke S, Deady M, Duflou J. Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001-2010. J Forensic Sci 2012; 57(5): 1259-62.
[http://dx.doi.org/10.1111/j.1556-4029.2012.02117.x] [PMID: 22444504]
[57]
Louis CJ, Fernandez B, Beaumont C, Pinillos MA, Bardom A, Encina Y. A case of zaleplon overdose. Clin Toxicol (Phila) 2008; 46(8): 782.
[http://dx.doi.org/10.1080/15563650701589417] [PMID: 19238743]
[58]
Hamad A, Sharma N. Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med 2001; 27(7): 1239.
[http://dx.doi.org/10.1007/s001340100972] [PMID: 11534578]
[59]
Lovett B, Watts D, Grossman M. Prolonged coma after eszopiclone overdose. Am J Emerg Med 2007; 25(6): 735.e5-6.
[http://dx.doi.org/10.1016/j.ajem.2006.12.021] [PMID: 17606111]
[60]
Anderson DT, Budd RD. Zaleplon (Sonata) analysis in postmortem specimens by gas chromatography-electron capture detection. J Anal Toxicol 2009; 33(8): 481-5.
[http://dx.doi.org/10.1093/jat/33.8.481] [PMID: 19874656]
[61]
Moore KA, Zemrus TL, Ramcharitar V, Levine B, Fowler DR. Mixed drug intoxication involving zaleplon (“Sonata”). Forensic Sci Int 2003; 134(2-3): 120-2.
[http://dx.doi.org/10.1016/S0379-0738(03)00130-0] [PMID: 12850405]
[62]
Advisory Council on the Misuse of Drugs (ACMD). Z-drugs: A review of the evidence of misuse and harm 2015 Professor Les I. [cited 12 March 2015] Available from:https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/411574/acmd_final_report_12_03_2015.pdf
[63]
García MG, Pérez-Cárceles MD, Osuna E, Legaz I. Drug-facilitated sexual assault and other crimes: A systematic review by countries. J Forensic Leg Med 2021; 79: 102151.
[http://dx.doi.org/10.1016/j.jflm.2021.102151] [PMID: 33773270]
[64]
Shbair MK, Eljabour S, Lhermitte M. Drugs involved in drug-facilitated crimes: part I: Alcohol, sedative-hypnotic drugs, gamma-hydroxybutyrate and ketamine. A review. Ann Pharm Fr 2010; 68(5): 275-85.
[http://dx.doi.org/10.1016/j.pharma.2010.05.002] [PMID: 20849998]
[65]
Shbair MK, Lhermitte M. Drug-facilitated crimes: definitions, prevalence, difficulties and recommendations. A review. Ann Pharm Fr 2010; 68(3): 136-47.
[http://dx.doi.org/10.1016/j.pharma.2010.03.005] [PMID: 20569770]
[66]
Goullé JP, Anger JP. Drug-facilitated robbery or sexual assault: problems associated with amnesia. Ther Drug Monit 2004; 26(2): 206-10.
[http://dx.doi.org/10.1097/00007691-200404000-00021] [PMID: 15228166]
[67]
Salvaggio J, Jacob C, Schmitt C. Consommation abusive de flunitrazépam par les toxicomanes aux opiacés [Abuse of flunitrazepam in opioid addicts] Ann Med Interne 2000; 151(Suppl A): A6-9.
[68]
Albrecht B. Benzodiazepine use of community-based violent offenders: A preliminary investigation. J Subst Use 2017; 22: 295-303.
[http://dx.doi.org/10.1080/14659891.2016.1195893]
[69]
EMCDDA Document Labrary. Sexual assaluts facilitated by drugs or alcohol 2008. Available from:http://www.emcdda.europa.eu/attachements.cfm/att_50544_EN_TDS_sexual_assault.pdf
[70]
LeBeau MA. Guidance for improved detection of drugs used to facilitate crimes. Ther Drug Monit 2008; 30(2): 229-33.
[http://dx.doi.org/10.1097/FTD.0b013e31816791d7] [PMID: 18367986]
[71]
Wang X, Johansen SS, Nielsen MKK, Linnet K. Hair analysis in toxicological investigation of drug-facilitated crimes in Denmark over a 8-year period. Forensic Sci Int 2018; 285: e1-e12.
[http://dx.doi.org/10.1016/j.forsciint.2018.01.021] [PMID: 29449106]
[72]
Gharedaghi F, Hassanian-Moghaddam H, Akhgari M. Drug-facilitated crime caused by drinks or foods. Egypt J Forensic Sci 2018; 8: 68.
[http://dx.doi.org/10.1186/s41935-018-0100-8]
[73]
Agence française de sécurité sanitaire des produits de santé (AFSSAPS). Résultats Enquête nationale sur la soumission chimique 2007. Available from: http://www.afssaps.fr/var/afssapssite/storage/original/application/9e5a4955f3462697342a561b06fb8292.pdf
[74]
European monitoring centre for drugs and drug addiction and europol. EU Drug Market Report 2019 EMCDDA, Europol Pages: 3. Luxembourg: Publications Office of the European Union 2019.
[75]
Zaami S. New psychoactive substances: concerted efforts and common legislative answers for stemming a growing health hazard. Eur Rev Med Pharmacol Sci 2019; 23(22): 9681-90.
[PMID: 31799633]
[76]
Schifano F, Napoletano F, Chiappini S, et al. New/emerging psychoactive substances and associated psychopathological consequences. Psychol Med 2021; 51(1): 30-42.
[http://dx.doi.org/10.1017/S0033291719001727] [PMID: 31327332]
[77]
United Nations Office on Drugs and Crime (UNODC). Current NPS threats 2019. Available from:https://www.unodc.org/pdf/opioids-crisis/Current_NPS_Threats_-_Volume_I.pdf
[78]
Schifano F, Chiappini S, Corkery JM, Guirguis A. Abuse of prescription drugs in the context of Novel Psychoactive Substances (NPS): A Systematic Review. Brain Sci 2018; 8(4): 73.
[http://dx.doi.org/10.3390/brainsci8040073] [PMID: 29690558]
[79]
Del Rio A, Graziano S, Tittarelli R, Umani-Ronchi F. Increasing diversion of prescribed benzodiazepines and Z-drugs to new psychoactive substances. Clin Ter 2021; 172(2): 116-8.
[http://dx.doi.org/10.7417/CT.2021.2296] [PMID: 33763670]
[80]
Graziano S, Anzillotti L, Mannocchi G, Pichini S, Busardò FP. Screening methods for rapid determination of new psychoactive substances (NPS) in conventional and non-conventional biological matrices. J Pharm Biomed Anal 2019; 163: 170-9.
[http://dx.doi.org/10.1016/j.jpba.2018.10.011] [PMID: 30316062]
[81]
Van Hout MC, Benschop A, Bujalski M, et al. Health and social problems associated with recent Novel Psychoactive Substance (NPS) use amongst marginalised, nightlife and online users in six european countries. Int J Ment Health Addict 2018; 16(2): 480-95.
[http://dx.doi.org/10.1007/s11469-017-9824-1] [PMID: 29674947]
[82]
Zaami S, Busardò FP, Pichini S, Pacifici R, Marinelli E. The value of toxicological and forensic analyses in the global challenge to health risks caused by new psychoactive substances. Eur Rev Med Pharmacol Sci 2019; 23(14): 6008-10.
[PMID: 31364102]
[83]
Gentili S, Mortali C, Mastrobattista L, Berretta P, Zaami S. Determination of different recreational drugs in sweat by headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME GC/MS): Application to drugged drivers. J Pharm Biomed Anal 2016; 129: 282-7.
[http://dx.doi.org/10.1016/j.jpba.2016.07.018] [PMID: 27442890]
[84]
Jemberie WB, Stewart Williams J, Eriksson M, et al. Substance use disorders and COVID-19: Multi-faceted problems which require multi-pronged solutions. Front Psychiatry 2020; 11: 714.
[http://dx.doi.org/10.3389/fpsyt.2020.00714] [PMID: 32848907]
[85]
Zaami S, Marinelli E, Varì MR. New trends of substance abuse during COVID-19 pandemic: An international perspective. Front Psychiatry 2020; 11: 700.
[http://dx.doi.org/10.3389/fpsyt.2020.00700] [PMID: 32765328]
[86]
Maskell PD, De Paoli G, Nitin Seetohul L, Pounder DJ. Phenazepam: The drug that came in from the cold. J Forensic Leg Med 2012; 19(3): 122-5.
[http://dx.doi.org/10.1016/j.jflm.2011.12.014] [PMID: 22390996]
[87]
Drug Enforcement Administration (DEA). PHENAZEPAM Expert Committee on Drug Dependence Thirty-seventh Meeting Geneva, 16-20 [cited on November 2015] Available from:https://www.deadiversion.usdoj.gov/drug_chem_info/phenazepam.pdf
[88]
World Health Organization (WHO). 37th Expert Committee on Drug Dependence, 2015. Phenazepam Pre-Review Report. 2015. Available from:https://www.who.int/medicines/access/controlled- substances/5.8_Phenazepam_PreRev.pdf
[89]
Ali A, Jerry JM, Khawam EA. Delirium induced by a new synthetic legal intoxicating drug: phenazepam. Psychosomatics 2015; 56(4): 414-8.
[http://dx.doi.org/10.1016/j.psym.2014.05.018] [PMID: 25555294]
[90]
United Nations Office on Drugs and Crime (UNODC). Seven substances "scheduled" at the 59th Session of the Commission on Narcotic Drugs. Available from:https://www.unodc.org/unodc/en/press/releases/2016/March/seven-substances-scheduled-at-the- 59th-session-of-the-commission-on-narcotic-drugs.html
[91]
Couch RA, Madhavaram H. Phenazepam and cannabinomimetics sold as herbal highs in New Zealand. Drug Test Anal 2012; 4(6): 409-14.
[http://dx.doi.org/10.1002/dta.349] [PMID: 22924168]
[92]
Drug Enforcement Administration (DEA). ETIZOLAM March 2020 Available from: https://www.deadiversion.usdoj.gov/drug_chem_info/etizolam.pdf
[93]
European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2020: Trends and Developments. Luxembourg: Publications Office of the European Union 2020.
[94]
EMCDDA-Europol. EMCDDA–Europol 2011 Annual report on the implementation of Council Decision 2005/387/JHA, 2011. Available fromh: ttps://www.emcdda.europa.eu/system/-files/publications/689/EMCDDA-Europol_Annual_Report_2011_ 2012_final_335568.pdf
[95]
Malaca S, Carlier J, Busardò FP. Advances in forensic toxicology. Curr Pharm Des 2020; 26(31): 3779-80.
[http://dx.doi.org/10.2174/138161282631200810123637] [PMID: 32942971]