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New Psychoactive Substances (Npss) Abuse in Romania: Analytical Strategies for Drug Screening in Biological Samples Using High Resolution Mass Spectrometry

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New Psychoactive Substances (Npss) Abuse in Romania: Analytical Strategies for Drug Screening in Biological Samples Using High Resolution Mass Spectrometry Rom J Leg Med [26] 173-182 [2018] DOI: 10.4323/rjlm.2018.173 © 2018 Romanian Society of Legal Medicine FORENSIC TOXICOLOGY New psychoactive substances (NPSs) abuse in Romania: analytical strategies for drug screening in biological samples using high resolution mass spectrometry Carmen Lidia Chiţescu1,2,*, Ana Doina Radu3, Florina Aciu3, Monica Moraru1,2, Iuliu Fulga1,2 _________________________________________________________________________________________ Abstract: New psychoactive substances (NPSs) are rapidly spreading among Romanian youth, and toxicology laboratories are requested to identify such compounds in biological samples as blood, urine, or gastric content. In this work, LC-HRMS/MS technique represented by Q Exactive -Orbitrap was applied in addition to GC-MS, for the identification of the NPSs. Different extraction methods such as liquid-liquid extraction, solid phase extraction were applied to samples from deceased or living persons. The results were compared and discussed. Although the reference standards were not always available, the identification of the NPSs was successfully achieved, via LC- HRMS in both full scan and targeted ion fragmentation (t-MS2) modes using a predictive approach. Key Words: forensic sciences, toxicology, new psychoactive substances, screening, HRMS, predictive approach. INTRODUCTION The governmental measures wasn’t followed by a significant decline of consumption, as, according to fifth Due to its geographical location, Romania is ESPAD Survey 2015, about 5% of the Romanian adult part of the Balkan route of drugs traffic. If in the past population had experimented with NPSs (compared Romania was mainly a transit area, drug consumption to 2% at the fourth ESPAD Survey conducted in 2011) has more than doubled in the last years, according to the [1]. According to the last ANA report on drug situation, fifth general population survey conducted by European 20172, NPSs are the second consumed drugs after School Survey Project on Alcohol and Other Drugs cannabis [2]. In Romania, NPSs are currently being (ESPAD) in 2015 [1]. purchased online or on illegal market as drug of choice New psychoactive substances are designer drugs and their availability and use has been increased. that intend to mimic controlled substances and are not Therefore, there is a growing concern about the yet covered by international laws. Those “legal-highs” associated issues: drug-related intoxications, deaths, appeared on the Romanian drug market in 2008, and infectious disease or criminality. Regarding drug related were legally commercialized in “smart” or “dreams” emergency room visits in 2016, from 4518 cases, 6% were shops. In 2 years, in 2010, Romania was ranked fourth diagnosed as intoxication due to ingestions of an unknown in the EU, regarding NPSs use. As a response, by drug [2]. Regarding the NPSs drug related deaths, these government control laws in 2010, 36 new psychoactive were likely to be underestimated due to the difficulties of substances were placed under control and new drugs analytical confirmation of exposures, since only two cases commercialization was banned. are reported in 2015 and four cases in 2016 [2, 3]. 1) Emergency Hospital of Galati, Department of Legal Medicine, Galati, Romania 2) “Dunarea de Jos” University of Galaţi, Faculty of Medicine and Pharmacy, Galaţi, Romania * Corresponding author: “Dunarea de Jos” University of Galaţi, Faculty of Medicine and Pharmacy, 35 Alexandru Ioan Cuza street, 80010, Galaţi, Romania E-mail: [email protected] 3) “Mina Minovici” National Institute of Legal Medicine, Bucharest, Romania 173 Chiţescu C.L. et al. New psychoactive substances (NPSs) abuse in Romania This brings up the problem of drug testing diethyl ether. Formic acid (98%), Tris(hydroxymethyl) methods for NSPs. Only a few of toxicology laboratories aminomethane, acetic acid, ammonium acetate, are able to detect and confirm the drug consumption ammonia, ultrapure water (LC-MS grade) were purchased in Romania, most of them engaged in legal medicine from Merck Romania. As derivatization agents: acetic structures. Furthermore, forensic toxicology laboratories anhydride/pyridine, trifluoroacetic acid (TFA), and are required to identify NSPs in biological samples or pentafluoropropanol (PFPOH) were purchased seized materials without the availability of a reference from Sigma-Aldrich (Germany). β-Glucuronidase/ standard. Arylsulfatase from Helix Pomatia for urine hydrolysis, Gas chromatography coupled with mass was purchased from Sigma-Aldrich (Germany). spectrometry (GC–MS) has been the most used technique Solid phase extraction (SPE) Chromabond for general unknown screening in toxicological analysis Drug 200 mg/3 ml were purchased from Chromabond [4]. (Macherey-Nagel GmbH & Co., Germany). However this method is generally not suitable Analytical standards: diazepam, methadone, for NPSs the identification because it is based on library benzoylecgonine, morphine, codeine, THC, THC- spectra or reference standards and spectra information COOH, α-PVP and prolintane were purchased from on NPSs are not always available. Lipomed GmbH, Germany as solutions 1 mg ml-1 in From this perspective, high-resolution mass methanol. spectrometry (HRMS) analyses allowed for the accurate Analysed samples mass determination of the analytes and therefore of their Biological samples in 17 forensic cases were empirical formulas and molecular structures directing collected between January 2015 and December 2016, the investigation to one compound or to a limited due to suspicion of NPSs ingestion. Urine and blood number of compounds [5-7]. MS-MS methods applied specimens were provided by police department for in addition to HRMS screening can raise the reliability the persons involved in traffic events (2 cases) or two of screening at the level of confirmation analysis [7,8]. attempts of rape. Blood, urine, gastric content from Because the lack of reference standards, approaches patients presented to the emergency department were based on theoretical and predicted reference data proved provided by clinic laboratories in (2 cases). Post-mortem to be useful [9]. specimens (blood, urine, gastric content) were obtained The presented study was conducted in two during the autopsy for 11 cases of drug related death. All forensic toxicology laboratories of National Institute samples were stored frozen (-20°C) until were analysed. of Legal Medicine, Bucharest and Legal Medicine Blank urine and blood samples and spiked samples Service of Galati, Romania with the technical support for the available analytical standards were analysed as of the Laboratory of Chromatography and Imagistic of control samples. “Dunarea de Jos” University of Galati, Romania. GC-MS and HRMS techniques were both Methods applied. The manuscript presents analytical strategies, Sample preparation for HRMS analysis emphasizing the potential of the HRMS/MS approach, LL extraction for blood samples: blood samples which allows the identification of a large number of were extracted with an ethyl acetat/methylene chloride/ compounds including NPSs in one single analysis. isopropanol (3/1/1) mixture in both basic condition Different sample preparation methods as: liquid-liquid (pH 9, with Tris solution) and acidic condition (pH 3, extraction (LL), solid-phase extraction (SPE), enzymatic with acetic acid 4%). After centrifugation, the extract hydrolysis, and derivatization were applied to blood, was evaporated under a high purity nitrogen flow at urine, and gastric content. The results were compared 40°C (Thermo Scietific, Germany). The residue was and the key role of HRMS-MS analysis in identifying reconstituted in methanol and filtrated thru 0.2 µm NPSs was discussed. micro-filter. In the context of the currently poor official Urine enzymatic hydrolysis followed by LL reporting of drug abuse in Romania, the aim of the extraction: urine was adjusted to pH 5.5 with acetate buffer presented manuscript is to describe our experiences and incubated for 2.5 h at 37°C with β-glucuronidase. The regarding the analytical challenge of NPSs identification urine was then extracted by liquid-liquid extraction with in biological samples and to discuss some methodological diethyl ether/methylene chloride (1/1). After evaporation issues raising analysing new psychoactive substances. at 40°C under a high purity nitrogen flow, the residue was dissolved in methanol and filtrated (0.2 µm). Experimental Gastric content LL extraction: a volume of Chemicals, reagents and materials gastric content was filtered and extracted with methylene Organic solvents used were purchased from chloride/ diethyl ether (70/30). After evaporations of the Merck Romania: methanol, acetonitrile, methylene solvents at 40°C under high purity nitrogen flow, the chloride, ethyl acetate, isopropanol, ethyl acetate, residue was dissolved in methanol. 174 Romanian Journal of Legal Medicine Vol. XXVI, No 2(2018) Sample preparation for GC-MS analysis An ultra-performance Accucore U-HPLC SPE extraction for blood/serum/plasma sample: Column C18 (150 x 2.1 mm, 2.6 µm), (Thermo Scientific) 1 ml of sample was applied on Chromabond Drug was used. A flow rate of 0.4 ml min−1 was set for cartridge previously preconditioned with methanol and separation of the selected compounds in the U-HPLC water. The analytes were eluted with methylene chloride/ system. The mobile phase consisted of: water at pH 3.5 isopropanol/ammonia mixture (80/20/2). The eluate was with formic acid (A) and methanol (B). A 15 minutes concentrated
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