Identification and quantification of synthetic cathinones in blood and urine using liquid chromatography-quadrupole/time of flight (LC-Q/TOF) mass spectrometry.

Synthetic cathinones are commonly abused novel psychoactive substances (NPS). We present a comprehensive systematic review addressing in vitro and in vivo synthetic cathinone pharmacokinetics, analytical methods for detection and quantification in biological matrices, and toxicological findings from human performance and postmortem toxicology cases. Few preclinical administration studies examined synthetic cathinone pharmacokinetic profiles (absorption, distribution, metabolism, and excretion), and only one investigated metabolite pharmacokinetics. Synthetic cathinone metabolic profiling studies, primarily with human liver microsomes, elucidated metabolite structures and identified suitable biomarkers to extend detection windows beyond those provided by parent compounds. Generally, cathinone derivatives underwent ketone reduction, carbonylation of the pyrrolidine ring, and oxidative reactions, with phase II metabolites also detected. Reliable analytical methods are necessary for cathinone identification in biological matrices to document intake and link adverse events to specific compounds and concentrations. NPS analytical methods are constrained in their ability to detect new emerging synthetic cathinones due to limited commercially available reference standards and continuous development of new analogs. Immunoassay screening methods are especially affected, but also gas-chromatography and liquid-chromatography mass spectrometry confirmation methods. Non-targeted high-resolution-mass spectrometry screening methods are advantageous, as they allow for retrospective data analysis and easier addition of new synthetic cathinones to existing methods. Lack of controlled administration studies in humans complicate interpretation of synthetic cathinones in biological matrices, as dosing information is typically unknown. Furthermore, antemortem and postmortem concentrations often overlap and the presence of other psychoactive substances are typically found in combination with cathinones derivatives, further confounding result interpretation.

Synthetic cathinone pharmacokinetics, analytical methods, and toxicological findings from human performance and postmortem cases.

Psychoactive compounds that contain a phenylethylamine structure (such as amphetamine-type stimulants and synthetic cathinones) are one of the major classes of stimulants on the recreational drug market. Approximately 670 new psychoactive substances (NPS) are monitored only in Europe; however, new psychoactive compounds are being developed for illicit trade each year. In this context, the development of new analytical procedures for the determination of such compounds in biological specimens for forensic toxicology is of great importance. Gas chromatography–tandem mass spectrometry (GC–MS/MS) technique was applied for analysis of amphetamines and synthetic cathinones. The volumes of 200 µL of each whole blood sample and 1 mL of liquid-liquid extraction solvent were used for extraction, followed by pentafluoropropionyl derivatization. A high-throughput, robust, rapid, and sensitive procedure involving a simple liquid-liquid extraction for the simultaneous determination of 45 amphetamine-type stimulants and synthetic cathinones in whole blood was developed. The assay was validated based on its recovery (83.2–106%), interday accuracy (89.0–108%), and interday precision (≤ 8.1%). In view of the low limits of detection (ranged between 0.02 and 0.72 ng/mL) and limits of quantification (1 and 2.5 ng/mL), the developed method can serve as a less expensive and more ecologically friendly alternative to the liquid chromatography–tandem mass spectrometric methods. To the best of our knowledge, this is the first work presenting a GC–MS/MS method for the determination of NPS in blood samples. The presented procedure was applied to authentic samples from forensic cases, demonstrating its utility in the quantification of a wide number of psychoactive substances in routine toxicological analyses. The developed procedure can also be easily expanded to additional compounds.

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Development and validation of a GC–MS/MS method for the determination of 11 amphetamines and 34 synthetic cathinones in whole blood

Stability of synthetic cathinones in blood and urine.

Distinguishing drug isomers in the forensic laboratory: GC-VUV in addition to GC-MS for orthogonal selectivity and the use of library match scores as a new source of information

The synthetic cathinones represent an important class of designer drugs. The widespread attention and publicity associated with these psychostimulants have resulted in numerous legislative actions at state and federal levels throughout the USA. These amphetamine-like compounds are characterized by a β-keto functional group. Although the synthetic cathinones share many properties of their phenethylamine counterparts, the presence of the ketone moiety is responsible for a number of unique and distinct differences in terms of their chemical characteristics and properties. Thermal degradation of methcathinone was first reported several decades ago but has received limited attention. In this study, we identified in situ thermal degradation products for 18 cathinones during gas chromatography-mass spectrometry (GC-MS) analysis. Oxidative degradation arises from the loss of two hydrogens, yielding a characteristic 2 Da mass shift. Degradation products were characterized by prominent iminium base peaks with mass-to-charge ratios 2 Da lower than the parent drug, and in the case of the pyrrolidine-containing cathinones, prominent molecular ions arising from the 2,3-enamine. Chromatographic and mass spectroscopic data are described for 4-ethylmethcathinone, 4-methylethcathinone, buphedrone, butylone, ethcathinone, ethylone, flephedrone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 3,4-methylenedioxypyrovalerone, mephedrone, methcathinone, methedrone, methylone, 4-methyl-α-pyrrolidinobutiophenone, naphyrone, pentedrone, pentylone and pyrovalerone. Degradation was minimized by lowering injection temperatures, residence time in the inlet and eliminating active sites during chromatographic analysis. Chromatographic and mass spectral data for the cathinone degradation products are presented and discussed within the context of forensic toxicological analysis, selection of appropriate instrumental methods and implications for the interpretation of results.

Paige Bella

Papers

Thermal Degradation of Synthetic Cathinones: Implications for Forensic Toxicology