Open Chemistry 2021; 19: 60–106 Review Article Vera Lukić,Ružica Micić, Biljana Arsić*, Bojan Nedović, Živana Radosavljević Overview of the major classes of new psychoactive substances, psychoactive effects, analytical determination and conformational analysis of selected illegal drugs https://doi.org/10.1515/chem-2021-0196 received May 26, 2020; accepted August 20, 2020 Abbreviations Abstract: Themisuseofpsychoactivesubstancesis NMR nuclear magnetic resonance attracting a great deal of attention from the general public. MS mass spectrometry An increase use of psychoactive substances is observed NPS new psychoactive substances among young people who do not have enough awareness USA United States of America of the harmful effects of these substances. Easy access to GABA γ-aminobutyric acid illicit drugs at low cost and lack of effective means of rou- EU European Union tine screening for new psychoactive substances (NPS) LSD lysergic acid diethylamide have contributed to the rapid increase in their use. New LSA lysergamide research and evidence suggest that drug use can cause a UK United Kingdom variety of adverse psychological and physiological effects DMT N,N-dimethyltryptamine on human health (anxiety, panic, paranoia, psychosis, NE norepinephrine and seizures). We describe different classes of these NPS 5-HT 5-hydroxytryptamine drugs with emphasis on the methods used to identify them ENT ears, nose and throat and the identification of their metabolites in biological IV intravenous specimens. This is the first review that thoroughly gives GC-MS gas chromatography-mass spectrometry the literature on both natural and synthetic illegal drugs IR infra-red with old known data and very hot new topics and investi- CNS central nervous system gations, which enables the researcher to use it as a starting MEA microelectrode arrays point in the literature exploration and planning of the own hDAT human dopamine reuptake transporter research. For the first time, the conformational analysis hNET human norepinephrine reuptake was done for selected illegal drugs, giving rise to the transporter search of the biologically active conformations both the- SPE solid-phase extraction oretically and using lab experiments. QuEChERS quick (Qu), easy (E), cheap (Ch),effective ( ) ( ) ( ) Keywords: illegal drugs, cathinones, phenethylamines, E , rugged R and safe S – cannabinoids, tryptamines LLE liquid liquid extraction dSPE dispersive solid phase extraction ELISA enzyme-linked immunosorbent assay UHPLC ultrahigh-performance liquid chromatography - -fl TOF time of ight * Corresponding author: Biljana Arsić, Department of Chemistry, UV-Vis ultraviolet-visible Faculty of Sciences and Mathematics, University of Niš,Niš, PDA photodiode array detector Republic of Serbia, e-mail: [email protected] HPLC high-performance liquid chromatography Vera Lukić: Institute of Forensic Medicine, Faculty of Medicine, LC-HRMS liquid chromatography–high-resolution University of Belgrade, Belgrade, Republic of Serbia Ružica Micić, Živana Radosavljević: Department of Chemistry, mass spectrometry Faculty of Sciences and Mathematics, University of Priština, CYP2D6 cytochrome P450 2D6 Kosovska Mitrovica, Republic of Serbia FMO3 flavin-containing monooxygenase 3 Bojan Nedović: Faculty of Medicine, University of Niš,Niš, Republic NAT1 N-acetyltransferase 1 š š of Serbia; Mental Health Center, Clinical Center Ni ,Ni , Republic of NAT2 N-acetyltransferase 2 Serbia Open Access. © 2021 Vera Lukić et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. Overview of the major classes of NPS 61 SGK1 serum/glucocorticoid regulated HSCCC high-speed counter-current kinase 1 chromatography PER2 period circadian regulator 2 4-MMC 4-methylmethcathinone CB cannabinoid receptor MDPV 3,4-methylenedioxypyrovalerone EMCDDA European monitoring centre for drugs 4-MEC 4-methylethcathinone and drug addiction 4-MePPP 4′-methyl-α- CBD cannabidiol pyrrolidinopropiophenone CBN cannabinol α-PVP α-pyrrolidinopentiophenone GPCR G protein-coupled receptor 4-FMC 4-fluoromethcathinone CB1R cannabinoid receptor type 1 3-FMC 3-fluoromethcathinone CB2R cannabinoid receptor type 2 α-PBP α-pyrrolidinobutiophenone pHLM pooled human liver microsome assay 3-MMC 3-methylmethcathinone SARs structure–activity relationships MDMA 3,4-methylenedio- AAI aminoalkylindole xymethamphetamine SCs synthetic cannabinoids ′ ′- -α- UGT UDP glucuronosyl transferase MDPBP 3 ,4 methylenedioxy HEK293 human embryonic kidney 293 pyrrolidinobutyrophenone - - HNK hydroxy-norketamine 3,4 DMMC 3,4 dimethylmethcathinone NPD nitrogen–phosphorus detector PV9 1-phenyl-2-(pyrrolidin-1-yl)octan- CIMS chemical ionization mass 1-one spectrometry IS internal standard HS-SPME headspace-solid phase TM5 transmembrane helix 5 microextraction TM6 transmembrane helix 6 - AMT alpha methyltryptamine r5-HT2AR rat HT2A receptor DIPT diisopropyltryptamine BZP benzylpiperazine MAO monoamine oxidase NSO new synthetic opioids LOD limit of detection DBZD designer benzodiazepines 1 Introduction US-LDS-DLLME ultra-assisted low-density solvent dis- persive liquid–liquid microextraction The number of health-related incidents caused by the use QSAR quantitative structure–activity of illegal drugs is increasing rapidly, and so is the need relationship for better understanding of their physiological effects and DFT density functional theory fast identification [1]. UPLC ultra-performance liquid These substances can be grouped depending on the chromatography chemical structure into synthetic cannabinoids, synthetic DART direct analysis in real time cathinones, phenethylamines, arylcyclohexylamines, trypt- TLC thin layer chromatography amines, indolalkylamines, new synthetic opioids, pipera- EIA enzyme immunoassay zines and designer benzodiazepines [2,3], and on the basis APCI atmospheric pressure chemical of their origin on psychoactive drugs of natural origin and ionization synthetic molecules. Previous studies have been limited to NACE nonaqueous capillary electrophoresis the analytical and toxicological data related to only some UPC2 SFC-PDA ultraperformance convergence chro- classes, and their representatives [4–30], reviews of the matography supercritical fluid chro- particular group [31–35],orparticulartopic[36], but failed matography–photodiode array to address all aspects: identification, quantification, synth- NIRS near-infrared spectroscopy esis, case reports, and statistics. The last few years have HPTLC high-performance thin-layer witnessed research on origin and the trafficking route for chromatography various psychoactive molecules (using both 13C NMR spec- FID flame-ionization detection trometry and 13C, 15NMS)[37], and the use of machine ECD electrochemical detection learning to predict the similarity of new psychoactive sub- DESI-MS desorption electrospray ionization stances (NPS) with the classical NPS [38]. This article seeks mass spectrometry to address the topic in the broadest spectrum available. 62 Vera Lukić et al. 2 Psychoactive drugs of natural subtropical America [43]. The psychoactive alkaloids origin (isoergine and ergine) are mainly found in the plant seeds, and they show psychoactive effects quite similar to lysergic acid diethylamide (LSD), but not so intensive Numerous plants possess psychoactive properties. Areca [3,44]. Similarly to ergot alkaloids, ergine is assumed to catechu, Argyreia nervosa, Ayahuasca, Catha edulis, bind to D2-dopamine receptors [45]. The available data Ipomoea violacea, Mandragora officinarum, Mitragyna on the analytical determination of the active components speciosa, Pausinystalia johimbe, Piper methisticum, are presented in Table 1. Psilocybe, Rivea corymbosa, Salvia divinorum, Sceletium There are specific national regulations regarding LSA tortuosum, Lactuca virosa, and Lophophora williamsii in Italy and UK. In the USA, the LSA and its related pro- have been receiving much attention due to their common ducts are controlled (Schedule III drug in the Controlled misuse [34]. Mainly found in Asia and South America, the Substances Act) as a depressant, and LSA is also on the misuse of these plants is underestimated due to religious list of U.S. Code of Federal Regulations as a possible LSD and traditional practices [34]. Catha edulis (common forerunner, but the plant and the seeds can be bought name: khat; mainly in the USA and the Netherlands), without any problem [34]. Mitragyna speciosa (common name: kratom; mainly in Asia), and Salvia divinorum are monitored by the United Nation Office on Drugs and Crime [34]. 2.3 Banisteropsis caapi and Psychotria viridis 2.1 Areca catechu Ayahuasca (Quechua word meaning “soul rope”) is a brew Areca catechu belongs to Arecaceae family, and it is a characteristic for the South America used for religious and native palm tree in Sri Lanka and Malaysia, abounded therapeutic purposes in Northwestern Amazonian coun- in Asia and Africa and exported to USA and Europe by tries for many centuries, and now by some religious sects the Asian communities. The fruit of this plant (areca nut) (Santo Daime, Baraquinha; prepared from Banisteropsis is traditionally chewed and represents one of the most caapi stems mixed with P. viridis, Mimosa hostiles, ( ff )[ ] used drugs after ca eine, ethanol, and nicotine 32 .It Mimosa tenuiflorea, Anadenanthera spp., and/or other is consumed either in combination with other substances plants with psychoactive compounds)[10,46]. The psy- (“ ”) - betel quid or alone giving the stimulation and relaxa choactive compound