Skip to main content
SpringerLink
Log in

Designer Benzodiazepines: Another Class of New Psychoactive Substances

  • Chapter
  • First Online:
New Psychoactive Substances

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 252))

Abstract

Benzodiazepines have been introduced as medical drugs in the 1960s. They replaced the more toxic barbiturates, which were commonly used for treatment of anxiety or sleep disorders at the time. However, benzodiazepines show a high potential of misuse and dependence. Although being of great value as medicines, dependence to these drugs is a concern worldwide, in part due to overprescription and easy availability. Therefore, the phenomenon of benzodiazepines sold via Internet shops without restrictions at low prices is alarming and poses a serious threat to public health. Most of these compounds (with the exception of, e.g., phenazepam and etizolam) have never been licensed as medical drugs in any part of the world and are structurally derived from medically used benzodiazepines. Strategies of clandestine producers to generate new compounds include typical structural variations of medically used 1,4-benzodiazepines based on structure-activity relationships as well as synthesis of active metabolites and triazolo analogs of these compounds. As they were obviously designed to circumvent national narcotics laws or international control, they can be referred to as “designer benzodiazepines.” The majority of these compounds, such as diclazepam, clonazolam, and nitrazolam, have been described in scientific or patent literature. However, little is known about their pharmacological properties and specific risks related to their use. This chapter describes the phenomenon of designer benzodiazepines and summarizes the available data on pharmacokinetics and pharmacodynamics as well as analytical approaches for their detection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Ameline A, Richeval C, Gaulier J-M, Raul J-S, Kintz P (2018) Characterization of flunitrazolam, a new designer benzodiazepine, in oral fluid after a controlled single administration. J Anal Toxicol. https://doi.org/10.1093/jat/bky01

  • Archer GA, Sternbach LH (1968) Chemistry of benzodiazepines. Chem Rev 68:747–784

    Article  CAS  Google Scholar 

  • Barnard EA, Darlison MG, Seeburg P (1987) Molecular biology of the GABAA receptor: the receptor/channel superfamily. Trends Neurosci 10:502–509

    Article  CAS  Google Scholar 

  • Baselt RC (2011) Disposition of toxic drugs and chemicals in man, 9th edn. Biomedical Publications, Seal Beach

    Google Scholar 

  • Bauer TM, Ritz R, Haberthür C, Haefeli W, Scollo-Lavizzari G, Ha H, Hunkeler W, Sleight A (1995) Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 346:145–147

    Article  CAS  PubMed  Google Scholar 

  • Bo LD, Marcucci F, Mussini E, Perbellini D, Castellani A, Fresia P (1980) Plasma levels of chlorodesmethyldiazepam in humans. Biopharm Drug Dispos 1:123–126

    Article  Google Scholar 

  • Bönisch H (2007) Pharmakologie der Benzodiazepine: Allosterische Aktivatoren an GABAA-Rezeptoren. Pharm Unserer Zeit 36:186–194

    Article  PubMed  Google Scholar 

  • Breimer DD (1979) Pharmacokinetics and metabolism of various benzodiazepines used as hypnotics. Br J Clin Pharmacol 8:7S–13S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chebib M, Johnston GA (2000) GABA-activated ligand gated ion channels: medicinal chemistry and molecular biology. J Med Chem 43:1427–1447

    Article  CAS  PubMed  Google Scholar 

  • Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry 65:7–12

    CAS  PubMed  Google Scholar 

  • Coller JK, Somogyi AA, Bochner F (1999) Flunitrazepam oxidative metabolism in human liver microsomes: involvement of CYP2C19 and CYP3A4. Xenobiotica 29:973–986

    Article  CAS  PubMed  Google Scholar 

  • El Balkhi S, Chaslot M, Picard N, Dulaurent S, Delage M, Mathieu O, Saint-Marcoux F (2017) Characterization and identification of eight designer benzodiazepine metabolites by incubation with human liver microsomes and analysis by a triple quadrupole mass spectrometer. Int J Legal Med 131:979–988

    Article  PubMed  Google Scholar 

  • EMCDDA (2017) European drug report 2017: trends and developments. Publications Office of the European Union, Lisbon

    Google Scholar 

  • EMCDDA (2018) Early warning system alert. Accessible via EDND database of the EMCDDA, Lisbon

    Google Scholar 

  • Fracasso C, Confalonieri S, Garattini S, Caccia S (1991) Single and multiple dose pharmacokinetics of etizolam in healthy subjects. Eur J Clin Pharmacol 40:181–185

    CAS  PubMed  Google Scholar 

  • Franz F, Angerer V, Jechle H, Pegoro M, Ertl H, Weinfurtner G, Janele D, Schlögl C, Friedl M, Gerl S, Mielke R, Zehnle R, Wagner M, Moosmann B, Auwärter V (2017) Immunoassay screening in urine for synthetic cannabinoids – an evaluation of the diagnostic efficiency. Clin Chem Lab Med 55:1375–1384

    Article  CAS  PubMed  Google Scholar 

  • Fraser AD, Isner AF, Bryan W (1993) Urinary screening for adinazolam and its major metabolites by the Emit® d.a.u:™ and FPIA benzodiazepine assays with confirmation by HPLC. J Anal Toxicol 17:427–431

    Article  CAS  PubMed  Google Scholar 

  • Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (1999) Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 51:629–650

    CAS  PubMed  Google Scholar 

  • Golovenko NY, Larionov V (2014) Pharmacodynamical and neuroreceptor analysis of the permeability of the blood-brain barrier for derivatives of 1,4-benzodiazepine. Neurophysiology 46:199–205

    Article  CAS  Google Scholar 

  • Gorski JC, Jones DR, Hamman MA, Wrighton SA, Hall SD (1999) Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily. Xenobiotica 29:931–944

    Article  CAS  PubMed  Google Scholar 

  • Greenblatt D (1981) Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 6:89–105

    Article  CAS  PubMed  Google Scholar 

  • Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW (1976) Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam. Clin Pharmacol Ther 20:329–341

    Article  CAS  PubMed  Google Scholar 

  • Hester JB, Von Voigtlander P (1979) 6-Aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines. Influence of 1-substitution on pharmacological activity. J Med Chem 22:1390–1398

    Article  CAS  PubMed  Google Scholar 

  • Hester JB, Rudzik AD, Kamdar BV (1971) 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. J Med Chem 14:1078–1081

    Article  CAS  PubMed  Google Scholar 

  • Høiseth G, Tuv SS, Karinen R (2016) Blood concentrations of new designer benzodiazepines in forensic cases. Forensic Sci Int 268:35–38

    Article  PubMed  Google Scholar 

  • Hümpel M, Illi V, Milius W, Wendt H, Kurowski M (1979) The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C. Eur J Drug Metab Pharmacokinet 4:237–243

    Article  PubMed  Google Scholar 

  • Huppertz L, Bisel P, Westphal F, Franz F, Auwärter V, Moosmann B (2015) Characterization of the four designer benzodiazepines clonazolam, deschloroetizolam, flubromazolam, and meclonazepam, and identification of their in vitro metabolites. Forensic Toxicol 33:388–395

    Article  CAS  Google Scholar 

  • Huppertz LM, Moosmann B, Auwärter V (2018) Flubromazolam – basic pharmacokinetic evaluation of a highly potent designer benzodiazepine. Drug Test Anal 10:206–211

    Article  CAS  PubMed  Google Scholar 

  • Hyland R, Osborne T, Payne A, Kempshall S, Logan YR, Ezzeddine K, Jones B (2009) In vitro and in vivo glucuronidation of midazolam in humans. Br J Clin Pharmacol 67:445–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, Sellers EM (2001) Flunitrazepam metabolism by cytochrome P450s 2C19 and 3A4. Drug Metab Dispos 29:460–465

    CAS  PubMed  Google Scholar 

  • Kintz P, Jamey C, Ameline A, Richeval C, Raul J-S (2017a) Characterization of metizolam, a designer benzodiazepine, in alternative biological specimens. Toxicol Anal Clin 29:57–63

    Google Scholar 

  • Kintz P, Richeval C, Jamey C, Ameline A, Allorge D, Gaulier JM, Raul JS (2017b) Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism. Drug Test Anal 9:1026–1033

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa H, Esumi Y, Kurosawa S, Sekine S, Yokoshima T (1979) Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl- 4H-s-triazolo [4,3-a] [1,4] benzodiazepine, triazolam, a new central depressant. I. Absorption, distribution and excretion in rats, dogs and monkeys. Xenobiotica 9:415–428

    Article  CAS  PubMed  Google Scholar 

  • Kleemann A, Engel J, Kutscher B, Reichert D (2014) Pharmaceutical substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme, Stuttgart

    Google Scholar 

  • Lahti RA, Sethy VH, Barsuhn C, Hester JB (1983) Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine. Neuropharmacology 22:1277–1282

    Article  CAS  PubMed  Google Scholar 

  • Lim WJ, Yap AT, Mangudi M, Koh H, Tang AS, Chan K (2017) Detection of phenazepam in illicitly manufactured Erimin 5 tablets. Drug Test Anal 9:293–305

    Article  CAS  PubMed  Google Scholar 

  • Łukasik-Głębocka M, Sommerfeld K, Teżyk A, Zielińska-Psuja B, Panieński P, Żaba C (2016) Flubromazolam – a new life-threatening designer benzodiazepine. Clin Toxicol 54:66–68

    Article  Google Scholar 

  • Manchester KR, Maskell PD, Waters L (2018) Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances. Drug Test Anal. https://doi.org/10.1002/dta.2387

    Article  CAS  Google Scholar 

  • Masica AL, Mayo G, Wilkinson GR (2004) In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam. Clin Pharmacol Ther 76:341–349

    Article  CAS  PubMed  Google Scholar 

  • Maskell PD, De Paoli G, Nitin Seetohul L, Pounder DJ (2012) Phenazepam: the drug that came in from the cold. J Forensic Legal Med 19:122–125

    Article  Google Scholar 

  • Mattila MAK, Larni HM (1980) Flunitrazepam: a review of its pharmacological properties and therapeutic use. Drugs 20:353–374

    Article  CAS  PubMed  Google Scholar 

  • Meng L, Zhu B, Zheng K, Fu S (2017) Ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction for the determination of 4 designer benzodiazepines in urine samples by gas chromatography-triple quadrupole mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1053:9–15

    Article  CAS  PubMed  Google Scholar 

  • Meyer MR, Bergstrand MP, Helander A, Beck O (2016) Identification of main human urinary metabolites of the designer nitrobenzodiazepines clonazolam, meclonazepam, and nifoxipam by nano-liquid chromatography-high-resolution mass spectrometry for drug testing purposes. Anal Bioanal Chem 408:3571–3591

    Article  CAS  PubMed  Google Scholar 

  • Mohsin N, Qadir M (2015) Recent structure activity relationship studies of 1,4-benzodiazepines. Peertechz J Med Chem Res 1(1):008–0012

    Google Scholar 

  • Moosmann B, Huppertz LM, Hutter M, Buchwald A, Ferlaino S, Auwärter V (2013a) Detection and identification of the designer benzodiazepine flubromazepam and preliminary data on its metabolism and pharmacokinetics. J Mass Spectrom 48:1150–1159

    Article  CAS  PubMed  Google Scholar 

  • Moosmann B, Hutter M, Huppertz L, Ferlaino S, Redlingshöfer L, Auwärter V (2013b) Characterization of the designer benzodiazepine pyrazolam and its detectability in human serum and urine. Forensic Toxicol 31:263–271

    Article  CAS  Google Scholar 

  • Moosmann B, Bisel P, Auwärter V (2014) Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics. Drug Test Anal 6:757–763

    Article  CAS  PubMed  Google Scholar 

  • Moosmann B, King LA, Auwärter V (2015) Designer benzodiazepines: a new challenge. World Psychiatry 14:248

    Article  PubMed  PubMed Central  Google Scholar 

  • Moosmann B, Bisel P, Franz F, Huppertz LM, Auwärter V (2016) Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines – an update comprising adinazolam, cloniprazepam, fonazepam, 3-hydroxyphenazepam, metizolam and nitrazolam. J Mass Spectrom 51:1080–1089

    Article  CAS  PubMed  Google Scholar 

  • Mortelé O, Vervliet P, Gys C, Degreef M, Cuykx M, Maudens K, Covaci A, van Nuijs AL, Lai FY (2018) In vitro phase I and phase II metabolism of the new designer benzodiazepine cloniprazepam using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal 153:158–167

    Article  PubMed  Google Scholar 

  • Nakamae T, Shinozuka T, Sasaki C, Ogamo A, Murakami-Hashimoto C, Irie W, Terada M, Nakamura S, Furukawa M, Kurihara K (2008) Case report: etizolam and its major metabolites in two unnatural death cases. Forensic Sci Int 182:e1–e6

    Article  PubMed  Google Scholar 

  • Noble C, Mardal M, Bjerre Holm N, Stybe Johansen S, Linnet K (2017) In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples. Drug Test Anal 9:1182–1191

    Article  CAS  PubMed  Google Scholar 

  • O’Connor LC, Torrance HJ, McKeown DA (2015) ELISA detection of phenazepam, etizolam, pyrazolam, flubromazepam, diclazepam and delorazepam in blood using Immunalysis® Benzodiazepine Kit. J Anal Toxicol 40:159–161

    Article  PubMed  Google Scholar 

  • Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60:243–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peter R, Wicht A, Moosmann B, Huppertz L-M, Kempf J, Joly R (2017) Semi-quantitative determination of designer benzodiazepines in serum by adaption of an automated LC-MSn screening approach. Toxicol Anal Clin 29:S59–S60

    Google Scholar 

  • Pettersson Bergstrand M, Helander A, Beck O (2016) Development and application of a multi-component LC-MS/MS method for determination of designer benzodiazepines in urine. J Chromatogr B Analyt Technol Biomed Life Sci 1035:104–110

    Article  CAS  PubMed  Google Scholar 

  • Pettersson Bergstrand M, Helander A, Hansson T, Beck O (2017a) Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays. Drug Test Anal 9:640–645

    Article  CAS  PubMed  Google Scholar 

  • Pettersson Bergstrand M, Meyer MR, Beck O, Helander A (2017b) Human urinary metabolic patterns of the designer benzodiazepines flubromazolam and pyrazolam studied by liquid chromatography-high resolution mass spectrometry. Drug Test Anal. https://doi.org/10.1002/dta.2243

    Article  PubMed  Google Scholar 

  • Rudolph W, Remane D, Moosmann B, Lemke S, Auwärter V, Peters FT (2015) First reported intoxication involving the four designer benzodiazepines, flubromazepam, diclazepam, pyrazolam, and etizolam. Toxichem Krimtech 82:91

    Google Scholar 

  • Sanna E, Pau D, Tuveri F, Massa F, Maciocco E, Acquas C, Floris C, Fontana SN, Maira G, Biggio G (1999) Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions. Arzneimittelforschung 49:88–95

    CAS  PubMed  Google Scholar 

  • Schwartz MA, Koechlin BA, Postma E, Palmer S, Krol G (1965) Metabolism of diazepam in rat, dog, and man. J Pharmacol Exp Ther 149:423–435

    CAS  PubMed  Google Scholar 

  • Sternbach LH (1971) 1,4-Benzodiazepines. Chemistry and some aspects of the structure-activity relationship. Angew Chem Int Ed 10:34–43

    Article  CAS  Google Scholar 

  • Sternbach LH (1979) The benzodiazepine story. J Med Chem 22:1–7

    Article  CAS  PubMed  Google Scholar 

  • Sternbach LH, Fryer RI, Metlesics W, Reeder E, Sach G, Saucy G, Stempel A (1962a) Quinazolines and 1,4-benzodiazepines. VI.1a halo-, methyl-, and methoxy-substituted 1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones1b,c. J Org Chem 27:3788–3796

    Article  CAS  Google Scholar 

  • Sternbach LH, Fryer RI, Metlesics W, Sach G, Stempel A (1962b) Quinazolines and 1,4-benzodiazepines. V. o-aminobenzophenones1a,b. J Org Chem 27:3781–3788

    Article  CAS  Google Scholar 

  • Sternbach LH, Randall LO, Banziger R, Lehr H (1968) Structure-activity relationships in the 1,4-benzodiazepine series. In: Burger A (ed) Drugs affecting the central nervous system, vol 2. Edward Arnold, London

    Google Scholar 

  • Švidrnoch M, Boráňová B, Tomková J, Ondra P, Maier V (2018) Simultaneous determination of designer benzodiazepines in human serum using non-aqueous capillary electrophoresis – tandem mass spectrometry with successive multiple ionic – polymer layer coated capillary. Talanta 176:69–76

    Article  PubMed  Google Scholar 

  • Tomkova J, Svidrnoch M, Maier V, Ondra P (2017) Analysis of selected designer benzodiazepines by ultra high performance liquid chromatography with high-resolution time-of-flight mass spectrometry and the estimation of their partition coefficients by micellar electrokinetic chromatography. J Sep Sci 40:2037–2044

    Article  CAS  PubMed  Google Scholar 

  • Tripsit (2018.) https://tripsit.me/. Accessed 1 Feb 2018

  • UNODC (1997) Recommended methods for the detection and assay of barbiturates and benzodiazepines in biological specimens. Manual for use by National Laboratories. UN document ID number: ST/NAR/28 edn. United Nations Office on Drugs and Crime, New York

    Google Scholar 

  • UNODC (2018) Thirty-seventh meeting of the Expert Committee on Drug Dependence. http://www.who.int/medicines/access/controlled-substances/ecdd_37_meeting/en/. Accessed 1 Feb 2018

  • Vikingsson S, Wohlfarth A, Andersson M, Green H, Roman M, Josefsson M, Kugelberg FC, Kronstrand R (2017) Identifying metabolites of meclonazepam by high-resolution mass spectrometry using human liver microsomes, hepatocytes, a mouse model, and authentic urine samples. AAPS J 19:736–742

    Article  CAS  PubMed  Google Scholar 

  • Waters L, Manchester KR, Maskell PD, Haider S, Haegeman C (2017) The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines. Sci Justice. https://doi.org/10.1016/j.scijus.2017.12.004

    Article  Google Scholar 

  • Wohlfarth A, Vikingsson S, Roman M, Andersson M, Kugelberg FC, Green H, Kronstrand R (2017) Looking at flubromazolam metabolism from four different angles: metabolite profiling in human liver microsomes, human hepatocytes, mice and authentic human urine samples with liquid chromatography high-resolution mass spectrometry. Forensic Sci Int 274:55–63

    Article  CAS  PubMed  Google Scholar 

  • Zherdev VP, Caccia S, Garattini S, Ekonomov AL (1982) Species differences in phenazepam kinetics and metabolism. Eur J Drug Metab Pharmacokinet 7:191–196

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Forensic Medicine, Forensic Toxicology, Kantonsspital St. Gallen, St. Gallen, Switzerland

    Bjoern Moosmann

  2. Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Volker Auwärter

Authors
  1. Bjoern Moosmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Auwärter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bjoern Moosmann .

Editor information

Editors and Affiliations

  1. Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany

    Hans H. Maurer

  2. School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK

    Simon D. Brandt

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Moosmann, B., Auwärter, V. (2018). Designer Benzodiazepines: Another Class of New Psychoactive Substances. In: Maurer, H., Brandt, S. (eds) New Psychoactive Substances . Handbook of Experimental Pharmacology, vol 252. Springer, Cham. https://doi.org/10.1007/164_2018_154

Download citation

Publish with us

Policies and ethics

Search

Navigation