The emergence of new psychoactive substance (NPS) benzodiazepines: a review

The market for new psychoactive substances has increased markedly in recent years and there is now a steady stream of compounds appearing every year. Benzodiazepines consist of only a fraction of the total number of these compounds but their use and misuse has rapidly increased. Some of these benzodiazepines have only been patented, some of them have not been previously synthesised and the majority have never undergone clinical trials or tests. Despite their structural and chemical similarity, large differences exist between the benzodiazepines in their pharmacokinetic parameters and metabolic pathways and so they are not easily comparable. As benzodiazepines have been clinically used since the 1960s many analytical methods exist to quantify them in a variety of biological matrices and it is expected that these methods would also be suitable for the detection of benzodiazepines that are new psychoactive substances. Illicitly obtained benzodiazepines have been found to contain a wide range of compounds such as opiates which presents a problem since the use of them in conjunction with each other can lead to respiratory depression and death. The aim of this review is to collate the available information on these benzodiazepines and to provide a starting point for the further investigation of their pharmacokinetics which is clearly required

Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism

Designer benzodiazepines provide an attractive alternative to prescribed benzodiazepines for abuse purposes as they are readily available via the Internet without control. Metizolam was ordered via the Internet and a 2 mg blue tablet was orally administered to a 54-year-old man. Urine samples were collected over 6 days in polypropylene tubes. After liquid/liquid extraction at pH 9.5, metizolam was analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) using a standard method devoted to benzodiazepines, and ions transitions, at m/z 328.9 > 275.0 and 328.9 > 300.0. Metizolam was detectable in hydrolyzed urine during the 46-h period, with concentrations always lower than 11 ng/mL. About 0.3% of the initial dose was excreted in urines as total unchanged metizolam during the first 24 h. The most relevant potential CYP- and UGT-dependent metabolites of metizolam were investigated in vitro using human liver microsome incubation and, subsequently, liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS) analysis. Three mono-hydroxylated metabolites were produced including a hydroxylation compound at the 2-ethyl moiety of metizolam (M1) as quantitatively main metabolite, and a N-hydroxymetiazolam (M2). The structure of the third metabolite (M3) could not be elucidated because of a too low experimental production rate. Two authentic urine samples were analyzed using the same analytical method to search for metabolites of metizolam. M1, together with its glucuronide (M1-Glu), and M2 were observed in urine at the 8 h mark, whereas only M1 and M1-Glu were still detected in urine at 30 h post administration. Copyright © 2016 John Wiley & Sons, Ltd