The Evolution Toward Designer Benzodiazepines in Drug-Facilitated Sexual Assault Cases

Abstract Drug-facilitated sexual assault (DFSA) is a crime where the victim is unable to provide sexual consent due to incapacitation resulting from alcohol or drug consumption. Due to the large number of substances possibly used in DFSA, including illicit, prescription and over-the-counter drugs, DFSA faces many toxicological challenges. Benzodiazepines (BZDs) are ideal candidates for DFSA, as they are active at low doses, have a fast onset of action and can be easily administered orally. The last decade has seen the emergence of designer benzodiazepines (DBZDs), which show slight modifications compared with BZDs and similar pharmacological effects but are not controlled under the international drug control system. DBZDs represent an additional challenge due to the number of new entities regularly appearing in the market, their possibly higher potency and the limited knowledge available on their pharmacokinetic and pharmacodynamics properties. Many BZDs and DBZDs have a short half-life, leading to rapid metabolism and excretion. The low concentrations and short time windows for the detection of BZD in body fluids require the use of highly sensitive analysis methods to enable the detection of drugs and their respective metabolites. This review discusses the current state of the toxicological analysis of BZDs and DBZDs in forensic casework and their pharmacokinetic properties (i.e., absorption, distribution, metabolism, and elimination), as well as their analysis in biosamples typically encountered in DFSA (i.e., blood, urine and hair).

[1]  M. Huestis,et al.  Designer Benzodiazepines: A Review of Toxicology and Public Health Risks , 2021, Pharmaceuticals.

[2]  New benzodiazepines in Europe – a review , 2021 .

[3]  Béatrice Garneau,et al.  A comprehensive analytical process, from NPS threat identification to systematic screening: Method validation and one-year prevalence study. , 2020, Forensic science international.

[4]  C. Campobasso,et al.  Long-Term Detection In Hair Of Zolpidem, Oxazepam And Flunitrazepam In A Case Of Drug-Facilitated Sexual Assault. , 2020, Journal of analytical toxicology.

[5]  L. Couchman,et al.  Flubromazolam: Detection in five post-mortem cases , 2020, Medicine, science, and the law.

[6]  M. Huestis,et al.  Development and Validation of an LC-MS-MS Method for the Detection of 40 Benzodiazepines and Three Z-Drugs in Blood and Urine by Solid-Phase Extraction. , 2020, Journal of analytical toxicology.

[7]  Stefânia N Lavorato,et al.  Violence against women and drug-facilitated sexual assault (DFSA): A review of the main drugs. , 2020, Journal of forensic and legal medicine.

[8]  G. Høiseth,et al.  Blood Concentrations of Designer Benzodiazepines: Relation to Impairment and Findings in Forensic Cases , 2020, Journal of analytical toxicology.

[9]  Etizolam , 2020, Reactions Weekly.

[10]  H. Moir,et al.  Toxicological assessment of the role of alcohol and drugs in drug-facilitated sexual assault cases in New Zealand. , 2020, Journal of analytical toxicology.

[11]  Sascha K. Manier,et al.  Toxicokinetics and analytical toxicology of flualprazolam: metabolic fate, isozyme mapping, human plasma concentration, and main urinary excretion products. , 2020, Journal of analytical toxicology.

[12]  T. Kraemer,et al.  Large scale consumption monitoring of benzodiazepines and z-drugs by hair analysis. , 2020, Journal of pharmaceutical and biomedical analysis.

[13]  F. Hérault,et al.  Designer benzodiazepines’ pharmacological effects and potencies: How to find the information , 2020, Journal of psychopharmacology.

[14]  L. Orsolini,et al.  ‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports , 2020, Current neuropharmacology.

[15]  Jorrit van den Berg,et al.  New psychoactive substances (NPS) in the Netherlands: occurrence in forensic drug samples, consumer drug samples and poisons center exposures between 2013 and 2017 , 2020, Addiction.

[16]  Carmen García-Ruiz,et al.  Multi-target methodology for the screening of blood specimens in drug-facilitated sexual assault cases , 2019, Microchemical Journal.

[17]  M. Concheiro,et al.  Validation of an LC-MS/MS Method for the Quantification of 13 Designer Benzodiazepines in Blood. , 2019, Journal of analytical toxicology.

[18]  J. Zawilska,et al.  An expanding world of new psychoactive substances-designer benzodiazepines. , 2019, Neurotoxicology.

[19]  C. Locatelli,et al.  Analytical protocol for the screening of psychotropic/incapacitating drugs in alleged drug-facilitated crimes , 2019, Forensic Chemistry.

[20]  Yunli Zhao,et al.  A retrospective analysis of data from forensic toxicology at the Academy of Forensic Science in 2017. , 2019, Forensic science international.

[21]  V. Angerer,et al.  Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam, norflurazepam, and 4'-chlorodiazepam (Ro5-4864). , 2019, Drug testing and analysis.

[22]  B. Logan,et al.  Toxicological findings in 1000 cases of suspected drug facilitated sexual assault in the United States. , 2019, Journal of forensic and legal medicine.

[23]  Z. Kazzi,et al.  Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014–2017 , 2018, Clinical toxicology.

[24]  A. Helander,et al.  Occurrence and time course of NPS benzodiazepines in Sweden – results from intoxication cases in the STRIDA project , 2018, Clinical toxicology.

[25]  J. Raul,et al.  Detection of the designer benzodiazepine flunitrazolam in urine and preliminary data on its metabolism. , 2018, Drug testing and analysis.

[26]  M. Meyer,et al.  In vitro glucuronidation of designer benzodiazepines by human UDP-glucuronyltransferases. , 2018, Drug testing and analysis.

[27]  P. Kintz Hair analysis in forensic toxicology , 2018, WIREs Forensic Science.

[28]  M. Cole,et al.  A multifactorial critical appraisal of substances found in drug facilitated sexual assault cases. , 2018, Forensic science international.

[29]  J. Pascali,et al.  Proactive drugs in DFSA cases: Toxicological findings in an eight-years study. , 2018, Forensic science international.

[30]  L. Waters,et al.  Experimental versus theoretical log D 7 . 4 , pK a and plasma protein binding values for 1 benzodiazepines appearing as new psychoactive substances 2 3 , 2018 .

[31]  S. Pedersen‐Bjergaard,et al.  Rapid determination of designer benzodiazepines, benzodiazepines, and Z-hypnotics in whole blood using parallel artificial liquid membrane extraction and UHPLC-MS/MS , 2018, Analytical and Bioanalytical Chemistry.

[32]  S. Johansen,et al.  Hair analysis in toxicological investigation of drug-facilitated crimes in Denmark over a 8-year period. , 2018, Forensic science international.

[33]  M. Meyer,et al.  Human urinary metabolic patterns of the designer benzodiazepines flubromazolam and pyrazolam studied by liquid chromatography-high resolution mass spectrometry. , 2018, Drug testing and analysis.

[34]  S. Haider,et al.  The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines. , 2017, Science & justice : journal of the Forensic Science Society.

[35]  V. Auwärter,et al.  Designer Benzodiazepines: Another Class of New Psychoactive Substances. , 2018, Handbook of experimental pharmacology.

[36]  Bai-Hsiun Chen,et al.  Simultaneous drug identification in urine of sexual assault victims by using liquid chromatography tandem mass spectrometry. , 2018, Forensic science international.

[37]  V. Auwärter,et al.  Flubromazolam - Basic pharmacokinetic evaluation of a highly potent designer benzodiazepine. , 2018, Drug testing and analysis.

[38]  L. Waters,et al.  The emergence of new psychoactive substance (NPS) benzodiazepines: A review. , 2018, Drug testing and analysis.

[39]  M. Mardal,et al.  In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples. , 2017, Drug testing and analysis.

[40]  K. McCartan,et al.  Drug facilitated sexual assault and chemical submission , 2017 .

[41]  J. Raul,et al.  Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism. , 2017, Drug testing and analysis.

[42]  Oscar Quintela Jorge,et al.  Alleged drug-facilitated sexual assault in a Spanish population sample , 2017 .

[43]  H. Gréen,et al.  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. , 2017, Forensic science international.

[44]  J. Pilgrim,et al.  A global epidemiological perspective on the toxicology of drug-facilitated sexual assault: A systematic review. , 2017, Journal of forensic and legal medicine.

[45]  A. Helander,et al.  Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays. , 2017, Drug testing and analysis.

[46]  N. Picard,et al.  Characterization and identification of eight designer benzodiazepine metabolites by incubation with human liver microsomes and analysis by a triple quadrupole mass spectrometer , 2017, International Journal of Legal Medicine.

[47]  J. Raul,et al.  Characterization of metizolam, a designer benzodiazepine, in alternative biological specimens , 2017 .

[48]  H. Gréen,et al.  Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples , 2017, The AAPS Journal.

[49]  V. Auwärter,et al.  Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines - an update comprising adinazolam, cloniprazepam, fonazepam, 3-hydroxyphenazepam, metizolam and nitrazolam. , 2016, Journal of mass spectrometry : JMS.

[50]  L. Aguayo,et al.  Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected? , 2016, Front. Cell. Neurosci..

[51]  Madeleine Pettersson Bergstrand,et al.  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 , 2016, Analytical and Bioanalytical Chemistry.

[52]  Chetna K. Desai Meyler's side effects of drugs: The international encyclopedia of adverse drug reactions and interactions , 2016, Indian Journal of Pharmacology.

[53]  Bai-Hsiun Chen,et al.  Simultaneous identification of abused drugs, benzodiazepines, and new psychoactive substances in urine by liquid chromatography tandem mass spectrometry , 2016, The Kaohsiung journal of medical sciences.

[54]  D. McKeown,et al.  ELISA Detection of Phenazepam, Etizolam, Pyrazolam, Flubromazepam, Diclazepam and Delorazepam in Blood Using Immunalysis® Benzodiazepine Kit. , 2016, Journal of analytical toxicology.

[55]  O. Drummer,et al.  Review: Drug concentrations in hair and their relevance in drug facilitated crimes. , 2015, Journal of forensic and legal medicine.

[56]  Wojciech Piekoszewski,et al.  Analytical methodologies for the determination of benzodiazepines in biological samples. , 2015, Journal of pharmaceutical and biomedical analysis.

[57]  Do Steve Louvet,et al.  The Current Role of Long-Term Benzodiazepines for the Treatment of Generalized Anxiety , 2015 .

[58]  S. Dulaurent,et al.  Identification and quantification of 35 psychotropic drugs and metabolites in hair by LC-MS/MS: application in forensic toxicology , 2015, International Journal of Legal Medicine.

[59]  V. Auwärter,et al.  Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics. , 2014, Drug testing and analysis.

[60]  Frank T. Peters,et al.  Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedure for screening of urine specimens for 100 analytes relevant in drug-facilitated crime (DFC) , 2014, Analytical and Bioanalytical Chemistry.

[61]  V. Auwärter,et al.  Detection and identification of the designer benzodiazepine flubromazepam and preliminary data on its metabolism and pharmacokinetics. , 2013, Journal of mass spectrometry : JMS.

[62]  Sandra Furlanetto,et al.  Cross-reactivities and structure-reactivity relationships of six benzodiazepines to EMIT(®) immunoassay. , 2013, Journal of pharmaceutical and biomedical analysis.

[63]  N. Samyn,et al.  Drug-facilitated sexual crime by use of ketamine and diazepam by a gynaecologist. , 2013, Drug testing and analysis.

[64]  O. Spigset,et al.  Ethanol and drug findings in women consulting a Sexual Assault Center--associations with clinical characteristics and suspicions of drug-facilitated sexual assault. , 2013, Journal of forensic and legal medicine.

[65]  Alan D Kaye,et al.  Benzodiazepine pharmacology and central nervous system-mediated effects. , 2013, The Ochsner journal.

[66]  Ming-Tsang Wu,et al.  Simultaneous quantification of urine flunitrazepam, nimetazepam and nitrazepam by using liquid chromatography tandem mass spectrometry. , 2013, Clinica chimica acta; international journal of clinical chemistry.

[67]  V. Auwärter,et al.  Characterization of the designer benzodiazepine pyrazolam and its detectability in human serum and urine , 2013, Forensic Toxicology.

[68]  Serge Rudaz,et al.  Dispersive liquid-liquid microextraction combined with capillary electrophoresis and time-of-flight mass spectrometry for urine analysis. , 2013, Journal of pharmaceutical and biomedical analysis.

[69]  R. Ferner Handbook of Drug Interactions: a Clinical and Forensic Guide , 2012 .

[70]  M. Andreasen,et al.  Screening analysis for medicinal drugs and drugs of abuse in whole blood using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS)--toxicological findings in cases of alleged sexual assault. , 2012, Forensic science international.

[71]  M. Schulz,et al.  Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics , 2012, Critical Care.

[72]  G. De Paoli,et al.  Phenazepam: the drug that came in from the cold. , 2012, Journal of forensic and legal medicine.

[73]  S. Johansen,et al.  A drug rape case involving triazolam detected in hair and urine , 2012, International Journal of Legal Medicine.

[74]  M. Gennaro,et al.  A fast liquid chromatography-tandem mass spectrometry method for determining benzodiazepines and analogues in urine. Validation and application to real cases of forensic interest. , 2011, Journal of pharmaceutical and biomedical analysis.

[75]  I. Bosman,et al.  Toxicological Findings in Cases of Sexual Assault in the Netherlands * , 2011, Journal of forensic sciences.

[76]  Qiran Sun,et al.  Segmental hair analysis using liquid chromatography-tandem mass spectrometry after a single dose of benzodiazepines. , 2011, Forensic science international.

[77]  J. Du Mont,et al.  Drug-facilitated sexual assault in Ontario, Canada: toxicological and DNA findings. , 2010, Journal of forensic and legal medicine.

[78]  M. Kała,et al.  Simultaneous screening for and determination of 128 date-rape drugs in urine by gas chromatography-electron ionization-mass spectrometry. , 2010, Forensic science international.

[79]  S. Johansen,et al.  Simultaneous screening and quantification of 52 common pharmaceuticals and drugs of abuse in hair using UPLC-TOF-MS. , 2010, Forensic science international.

[80]  F. Questel,et al.  Chemical submission: results of 4-year French inquiry , 2009, International Journal of Legal Medicine.

[81]  J. Ahlner,et al.  Occurrence of ethanol and other drugs in blood and urine specimens from female victims of alleged sexual assault. , 2008, Forensic science international.

[82]  M. Raggi,et al.  Benzodiazepine metabolism: an analytical perspective. , 2008, Current drug metabolism.

[83]  H. Parker,et al.  The epidemiology of drug facilitated sexual assault. , 2006, Journal of clinical forensic medicine.

[84]  T. Ohshima A case of drug-facilitated sexual assault by the use of flunitrazepam. , 2006, Journal of clinical forensic medicine.

[85]  P. Kintz,et al.  Identification of alprazolam in hair in two cases of drug-facilitated incidents. , 2005, Forensic science international.

[86]  M. Scott-ham,et al.  Toxicological findings in cases of alleged drug-facilitated sexual assault in the United Kingdom over a 3-year period. , 2005, Journal of clinical forensic medicine.

[87]  L. Raymon,et al.  Handbook of Drug Interactions: A Clinical and Forensic Guide, 2nd Edition , 2012 .

[88]  B. Ludes,et al.  Hair to document drug-facilitated crimes: four cases involving bromazepam. , 2004, Journal of analytical toxicology.

[89]  Laurent Galichet,et al.  Clarke's analysis of drugs and poisons in pharmaceuticals, body fluids and postmortem material , 2004 .

[90]  M. Odell,et al.  The Forensic Pharmacology of Drugs of Abuse , 2001 .