TY - JOUR
AU - Esteve-Turrillas, Francesc A
AB - Abstract A procedure has been developed for the determination of third-generation synthetic cannabinoids in oral fluid samples by using a semi-automated microextraction by packed sorbent (MEPS) procedure and gas chromatography–mass spectrometry (GC–MS) determination. Five synthetic cannabinoids were employed as model compounds 5F-ADB, MMB-CHMICA, THJ-2201, CUMYL-4CN-BINACA and MDMB-CHMCZCA. The most adequate operative conditions for MEPS were evaluated giving quantitative recoveries, from 89 to 124%, in synthetic and field saliva samples spiked with 125 and 250 μg/L of the studied cannabinoids, with the exception of MDMB-CHMCZCA in field saliva samples that provided slightly lower recoveries from 62 to 66%. A high sensitivity was obtained for the proposed MEPS-GC–MS procedure with limits of detection from 10 to 20 μg/L. The obtained results demonstrate the high potential of MEPS-GC–MS combination for semi-automated, selective and sensitive determination of synthetic cannabinoids in oral fluid samples. Introduction Synthetic cannabinoids are substances designed to mimic the desired effects of cannabis, acting on cannabinoid type-1 (CB1) and cannabinoid type-2 (CB2) receptors (1). These substances, soaked into or sprayed onto plant material, are present in the market since 2004, being one of the main categories of substances reported as new psychoactive substances (NPS) at international markets by the United Nations Office on Drugs and Crime (UNODC) (2). JWH-018 (1-pentyl-3-(1-naphthoyl)indole) was one of the first synthetic cannabinoids identified; since then, wide-ranging and chemically diverse substances have been synthesized to circumvent legislation. In fact, 250 synthetic cannabinoids have been reported by the UNODC Early Warning Advisory between 2009 and 2017 (3). Currently, the third generation of synthetic cannabinoids is formed by a four-substructure pattern (tail–core–link–ring) resembling JWH-018, with an indole, indazole or carbazole core surrounded by different N-substituents like pentyl, 5-fluoropentyl, cyclohexylmethyl and 4-cianobutyl groups, and 3-acyl substituted by means of a methanone or carboxamide link with L-valinate, 3-methyl-L-valinate, adamantyl, naphthyl or cumyl substituents (4). Table I shows the molecular structure of the synthetic cannabinoids employed in this study. The prevalence of synthetic cannabinoids in the market is variable; however, substances like 5F-ADB and FUB-AMB show a continuous occurrence across several countries, being the most reported synthetic cannabinoids in both, 2017 and 2018 (5). Table I Molecular Structure, Formula and Molar Mass (M) of the Synthetic Cannabinoids Employed in This Study Open in new tab Table I Molecular Structure, Formula and Molar Mass (M) of the Synthetic Cannabinoids Employed in This Study Open in new tab Psychological effects of synthetic cannabinoids are similar to those reported during intoxication with cannabis, but additional effects like distorted perceptions of time, hallucinations and paranoia may also appear (6). In fact, 52 deaths have been reported in different countries between 2016 and 2018 involving synthetic cannabinoids (5). Consumption of synthetic cannabinoids is revealed by the analysis of these substances or their metabolites in biological fluids. Thus, the knowledge of metabolism pathways of synthetic cannabinoids is essential to focus their analysis in biological fluids. Urine is traditionally the most common biological fluid for drugs of abuse screening, but synthetic cannabinoids are quickly metabolized and parent compounds are rarely detected in urine (7). Moreover, misidentification of synthetic cannabinoids with similar molecular structure may occur because some of them provide the same metabolites in urine. Nevertheless, a more common occurrence of parent compounds has been observed in the analysis of synthetic cannabinoids in serum, blood and oral fluids (8). Furthermore, detection times are noticeably different depending on the target analyte and the analyzed fluid, being from hours to days for oral fluids, 1–2 days for blood and 2–3 days for urine (9). Even some studies have revealed that synthetic cannabinoids can be accumulated in adipose tissue for heavy users with half-lives in serum higher than 40 days (10). Typical synthetic cannabinoid intake is in the low mg range; thus, very low concentrations are expected to be found in biological fluids, requiring the use of highly sensitive techniques. Regarding the analytes under study (see Table I), parent compounds and their metabolites have been analyzed by liquid chromatography–mass spectrometry (LC–MS) in different biological fluids, such as 5F-ADB metabolites in urine (7, 11–15) and in blood (16, 17); THJ-2201 in urine (18); CUMYL-4CN-BINACA in urine (19–21) and postmortem blood samples (22); and MDMB-CHMCZCA in urine (23). Thus, in our knowledge there are no existing studies in the literature for the determination of the studied synthetic cannabinoids in oral fluids or saliva. Even no precedents have been found in the literature for the determination of MMB-CHMICA in any biological fluid. Analytical procedures for the determination of synthetic cannabinoids in oral fluids are mainly based on a conventional sample preparation step, such as liquid–liquid or solid-phase extraction (SPE), followed by a chromatographic analysis coupled to mass spectrometry detectors (9). In this frame, the use of microextraction by packed sorbent (MEPS), a simple, fast and miniaturized extraction procedure, has shown a high potential for psychoactive compound analysis in liquid matrices (24). The use of microscale volumes in MEPS greatly reduces both sample and reagent consumption without compromising the extraction efficiency. MEPS has been previously employed in the determination of NPS in oral fluids in combination with different techniques such as LC–MS (25, 26) and ion mobility spectrometry (27, 28). Thus, the objective of the present study is to develop MEPS-based procedure for the determination of third-generation synthetic cannabinoids in oral fluids. Working conditions for MEPS have been selected, and the method has been validated in terms of linearity, selectivity, sensitivity, trueness and precision. Experimental Apparatus and reagents Analysis of synthetic cannabinoids was performed using an Agilent 7890A GC coupled to an Agilent 53975C inert XL EI/CI MSD with triple-axis single quadrupole detector and an Agilent HP-5 MS (30 m, 0.25 mm, 0.25 μm) capillary column, obtained from Agilent Technologies (Palo Alto, CA, USA). Extraction of oral fluid samples by MEPS was performed using a SGE Analytical Science (Victoria, Australia) eVol XR digitally controlled positive displacement dispensing system, with a 100-μL syringe (22-gauge needle, 0.72-mm outside diameter and 55.5 mm in length) working at the lowest plunger speed (10 μL/s) and an octadecyl (C18) packed sorbent (4-mg silica with 45-μm mean particle size). 5F-ADB (methyl (s)-2-[1-(5-fluoropentyl)-1h-indazole-3-carboxamido]-3,3-dimethylbutanoate), MMB-CHMICA (methyl (n-{[1-(cyclohexylmethyl)-1h-indol-3-yl]carbonyl}-l-valinate)), THJ-2201 ([1-(5-fluoropentyl)-1h-indazol-3-yl](1-naphthyl)methanone), CUMYL-4CN-BINACA (1-(4-cyanobutyl)-n-(2-phenylpropan-2-yl)-1h-indazole-3-carboxamide) and MDMB-CHMCZCA (methyl (s)-2-(9-(cyclohexylmethyl)-9h-carbazole-3-carboxamido)-3,3-dimethylbutanoate) standards were provided by the Unidad de Inspección de Farmacia y Control de Drogas (Valencia, Spain). Deuterated synthetic cannabinoids were not commercially available to be employed as internal standard for GC–MS acquisitions. Thus, triphenyl phosphate (TPP), provided by Sigma (St. Louis, MO, USA), was employed as internal standard. Standard working solutions were prepared in 2-propanol and stored at 4°C in amber glass vials. Methanol, 2-propanol, chloroform and buffer constituents were obtained from Scharlab (Barcelona, Spain). Buffer solutions were prepared at 0.1 and 2.5 M with sodium acetate (pH 5.0), dipotassium hydrogen phosphate (pH 7.0) and sodium carbonate (pH 9.0) salts. Synthetic saliva was prepared following the Centre for Applied Science and Technology guidelines (29), using buffer salts and mucin from porcine stomach type II, obtained from Merck (Darmstadt, Germany). Field oral fluid samples were obtained by expectoration into 1.5-mL Eppendorf tubes from volunteers who provided their consent after appropriate information about the study following the ethical guidelines established by the University of Valencia (H1454687358321—drug analysis in biofluids). Fifteen saliva samples from different volunteers were pooled in order to obtain representative field saliva sample, and it was employed for recovery studies. Extraction of oral fluid samples Samples were previously centrifuged at 10,000 rpm for 4 min to remove solids that may provide any syringe clogging. Sample pH was adjusted by adding 20-μL buffer (pH 7, 2.5 M) to 480-μL sample. Spiked samples were prepared using 455-μL blank saliva, 20-μL buffer (pH 7, 2.5 M) and 25-μL synthetic cannabinoid standard of 5 and 10 mg/L in 2-propanol. Extraction of synthetic cannabinoids from oral fluid samples was carried out by MEPS using a C18 sorbent. Sorbent was previously conditioned with 100-μL 2-propanol plus 100-μL deionized water. 100-μL sample was loaded using five charge/discharge cycles, washed with 100-μL deionized water, dried with 100-μL clean air and eluted with 50-μL 2-propanol, using five charge/discharge cycles. Before GC–MS determination, 5-μL TPP at 5 mg/L was added to the MEPS extract. GC–MS determination of synthetic cannabinoids Synthetic cannabinoids were determined by GC–MS by the injection of 1-μL extract at 300°C, in splitless mode, using 1-mL min−1 helium as carrier in a constant flow mode. Oven temperature program was as follows: initial temperature 150°C for 1 min, increased at a rate of 10°C/min up to 300°C and held 10 min. Transfer line and ion source temperatures were 300 and 250°C, respectively. Electron impact ionization was performed at 70 eV in selected ion monitoring (SIM) mode. Table II shows retention times and ions employed for SIM determination for each studied compound. Table II Analytical Features for the Determination of Synthetic Cannabinoids by the Proposed Method Analyte . RT (min) . SIM (m/z) . R2 . LOD (μg/L) . LOQ (μg/L) . RSD (%) . TPP (IS) 9.49 326, 325 - - - - 5F-ADB 12.01 233, 145 0.996 10 30 3.6 MMB-CHMICA 14.61 240, 256 0.999 10 30 4.8 THJ-2201 14.91 127, 271 0.991 20 60 7.8 CUMYL-4CN-BINACA 15.07 226, 345 0.990 20 60 8.9 MDMB-CHMCZCA 19.73 290, 179 0.996 20 60 6.8 Analyte . RT (min) . SIM (m/z) . R2 . LOD (μg/L) . LOQ (μg/L) . RSD (%) . TPP (IS) 9.49 326, 325 - - - - 5F-ADB 12.01 233, 145 0.996 10 30 3.6 MMB-CHMICA 14.61 240, 256 0.999 10 30 4.8 THJ-2201 14.91 127, 271 0.991 20 60 7.8 CUMYL-4CN-BINACA 15.07 226, 345 0.990 20 60 8.9 MDMB-CHMCZCA 19.73 290, 179 0.996 20 60 6.8 Abbreviations: IS, internal standard; LOD, limit of detection; LOQ, limit of quantification; RSD, relative standard deviation; RT, retention time; SIM, selected ion monitoring. Open in new tab Table II Analytical Features for the Determination of Synthetic Cannabinoids by the Proposed Method Analyte . RT (min) . SIM (m/z) . R2 . LOD (μg/L) . LOQ (μg/L) . RSD (%) . TPP (IS) 9.49 326, 325 - - - - 5F-ADB 12.01 233, 145 0.996 10 30 3.6 MMB-CHMICA 14.61 240, 256 0.999 10 30 4.8 THJ-2201 14.91 127, 271 0.991 20 60 7.8 CUMYL-4CN-BINACA 15.07 226, 345 0.990 20 60 8.9 MDMB-CHMCZCA 19.73 290, 179 0.996 20 60 6.8 Analyte . RT (min) . SIM (m/z) . R2 . LOD (μg/L) . LOQ (μg/L) . RSD (%) . TPP (IS) 9.49 326, 325 - - - - 5F-ADB 12.01 233, 145 0.996 10 30 3.6 MMB-CHMICA 14.61 240, 256 0.999 10 30 4.8 THJ-2201 14.91 127, 271 0.991 20 60 7.8 CUMYL-4CN-BINACA 15.07 226, 345 0.990 20 60 8.9 MDMB-CHMCZCA 19.73 290, 179 0.996 20 60 6.8 Abbreviations: IS, internal standard; LOD, limit of detection; LOQ, limit of quantification; RSD, relative standard deviation; RT, retention time; SIM, selected ion monitoring. Open in new tab A calibration curve was prepared from 60 to 1000 μg/L synthetic cannabinoids in 2-propanol, containing 500-μg/L TPP. Results and Discussion Selection of extraction parameters Extraction parameters for MEPS were evaluated for the extraction of synthetic cannabinoids from oral fluid samples. As in the case of standard SPE, the main parameters to evaluate were type of sorbent, pH of the loading step and nature of elution solvent. However, because of the particularities of MEPS, which operates with volumes in the microliter scale, additional operative parameters must be evaluated such as volume of sample and elution solvent and number of charge/discharge cycles in loading and elution steps. Commercially available sorbents for MEPS bins are amino-propyl silane for ion exchange purposes and C2, C8 and C18 functionalized silica for reverse phase extraction (30). Among these, C18 was selected because it was typically employed for MEPS application for forensic drug analysis (24). A 100-μL syringe was selected in order to reduce the sample amount required to perform the analysis and to afford a slow flow of sample through the sorbent to enhance analyte/sorbent interactions. The initial procedure for MEPS extraction was a pre-conditioning step with 100-μL 2-propanol and 100-μL deionized water, a loading step using 100-μL sample using a single charge/discharge cycle, a washing step with 100-μL deionized water and an elution step with 100 μL using one charge/discharge cycle. These working conditions were evaluated by means of monoparametric studies by the evaluation of the effect of the selected parameter on the recovery obtained for a buffer solution spiked with 250 μg/L of the studied synthetic cannabinoids. Loading pH value is not a critical parameter because the evaluated synthetic cannabinoids do not show any protonation/deprotonation at physiological pH, and in our knowledge, no pKa values have been reported for these compounds. Nevertheless, 0.1-M buffer solutions at pH 5.0, 7.0 and 9.0 were spiked and extracted by MEPS in order to evaluate the effect of pH. Figure 1A shows the effect of the pH on the obtained recoveries of the studied compounds, which ranged from 52 to 95%. As it was expected, there were no significant changes in the obtained recovery values for the studied compounds at different pH. Thus, pH 7.0 was proposed for the loading step and it was employed for further experiments. Figure 1 Open in new tabDownload slide Selection of extraction parameters for the analysis of synthetic cannabinoids in oral fluid samples using a buffer solution spiked with 250 μg/L of the studied synthetic cannabinoids (A, sample pH; B, number of loading cycles; C, elution solvent and D, elution solvent volume). See the text for more details. Figure 1 Open in new tabDownload slide Selection of extraction parameters for the analysis of synthetic cannabinoids in oral fluid samples using a buffer solution spiked with 250 μg/L of the studied synthetic cannabinoids (A, sample pH; B, number of loading cycles; C, elution solvent and D, elution solvent volume). See the text for more details. The number of charge/discharge cycles in the loading step, from 1 to 20, was also evaluated (see Figure 1B). The use of a single charge/discharge cycle provides low recoveries for the studied compounds (from 65 to 86%) that reach a plateau at five cycles with quantitative recoveries (from 77 to 95%). Thus, five charge/discharge cycles were selected in order to obtain high recoveries and low analysis time. Methanol, 2-propanol and chloroform were evaluated as elution solvents. Figure 1C shows the obtained results, showing a high dependence with the employed solvent. The use of chloroform provided a reduced recovery for THJ-2201 and MDMB-CHMCZA, and high variability in the results, with relative standard deviation (RSD) values from 11 to 23%. Methanol is an adequate extraction solvent for the evaluated compounds, except for MMB-CHMICA and THJ-2201. The use of 2-propanol provided the best results with RSDs from 2 to 11% and quantitative recoveries from 78 to 105%. Thus, 2-propanol was selected for further experiments. The number of charge/discharge cycles was fixed to five in order to achieve the highest elution of the studied synthetic cannabinoids. The volume of 2-propanol was decreased to 75 and 50 μL in order to increase pre-concentration factors (see Figure 1D). As it can be seen, the use of 50-μL 2-propanol provided pre-concentration factors from 1.27 to 1.87 with quantitative recoveries for evaluated compounds. Thus, 50-μL 2-propanol, in five charge/discharge cycles, was proposed as an elution condition for additional experiments. Analytical features of the method Figure 2 shows the chromatogram for a 250-μg/L synthetic cannabinoids standard measured by GC–MS. The five evaluated synthetic cannabinoids were adequately resolved by the chromatographic method, and quantification was performed in SIM mode in order to avoid interferences with close retained peaks. The obtained chromatogram for a blank oral fluid spiked with 250-μg/L synthetic cannabinoids and analyzed by the proposed MEPS-GC–MS methodology is also shown in Figure 2. As it can be seen, the analysis of oral fluids did not provide any additional peak or interferences, demonstrating the usefulness of the proposed extraction and determination procedures. Figure 2 Open in new tabDownload slide GC–MS chromatograms obtained for (A) an oral fluid blank, (B) a 250 μg/L synthetic cannabinoids standard and (C) an oral fluid blank spiked with 125 μg/L synthetic cannabinoids. Chromatograms have been shifted for clarification purposes. Note: 1, TPP (internal standard); 2, 5F-ADB; 3, MMB-CHMICA; 4, THJ-2201; 5, CUMYL-4CN-BINACA and 6, MDMB-CHMCZCA. Figure 2 Open in new tabDownload slide GC–MS chromatograms obtained for (A) an oral fluid blank, (B) a 250 μg/L synthetic cannabinoids standard and (C) an oral fluid blank spiked with 125 μg/L synthetic cannabinoids. Chromatograms have been shifted for clarification purposes. Note: 1, TPP (internal standard); 2, 5F-ADB; 3, MMB-CHMICA; 4, THJ-2201; 5, CUMYL-4CN-BINACA and 6, MDMB-CHMCZCA. Linearity of GC–MS acquisitions was established from 60- to 1000-μg/L synthetic cannabinoid standards with coefficients of determination (R2) ranged from 0.990 to 0.999. Limit of detection (LOD) and limit of quantification (LOQ) were calculated as 3 and 10 times, respectively, the standard deviation (n = 3) of a 100-μg/L synthetic cannabinoid standard, divided by the slope of the calibration curve. The obtained LOD and LOQ values ranged from 10 to 20 μg/L and from 30 to 60 μg/L, respectively. Precision was established as the RSD (n = 3) of a 100-μg/L synthetic cannabinoid, with values ranging from 3.6 to 8.9%. Individual values for each studied synthetic cannabinoid can be seen in Table II. Previous reports on the determination of synthetic cannabinoids in oral fluids established concentrations up to 40, 80, 381, 460 and 2036 μg/L for AB-FUBINACA, AM-2201, JWH-122, JWH-210 and JWH-018, respectively (8, 31–34). Thus, trueness of the method was established by the analysis of synthetic and field oral fluids spiked with synthetic cannabinoid at 125 and 250 μg/L concentration levels. Quantitative recoveries were obtained for all the synthetic cannabinoids evaluated (see Table III), ranging from 90 to 124% and from 89 to 103%, for spiked synthetic and field oral fluids, respectively, with the exception of MDMB-CHMCZCA that provided low recoveries from 62 to 66%. Thus, the proposed MEPS-GC–MS procedure provides a high extraction efficiency and adequate sensitivity for the determination of new-generation synthetic cannabinoids in oral fluids. Table III Recoveries Obtained for Synthetic and Field Oral Fluids Spiked with Synthetic Cannabinoids and Extracted by the Proposed MEPS Method Analyte . Recovery (% ± s, n = 3) . . Synthetic . Field . . 125 μg/L . 250 μg/L . 125 μg/L . 250 μg/L . 5F-ADB 120 ± 7 124 ± 4 100 ± 2 102 ± 5 MMB-CHMICA 116 ± 10 121 ± 11 91 ± 6 103 ± 3 THJ-2201 110 ± 1 112 ± 9 89 ± 6 93 ± 1 CUMYL-4CN-BINACA 118 ± 16 121 ± 13 97 ± 11 104 ± 4 MDMB-CHMCZCA 108 ± 13 90 ± 9 62 ± 14 66 ± 9 Analyte . Recovery (% ± s, n = 3) . . Synthetic . Field . . 125 μg/L . 250 μg/L . 125 μg/L . 250 μg/L . 5F-ADB 120 ± 7 124 ± 4 100 ± 2 102 ± 5 MMB-CHMICA 116 ± 10 121 ± 11 91 ± 6 103 ± 3 THJ-2201 110 ± 1 112 ± 9 89 ± 6 93 ± 1 CUMYL-4CN-BINACA 118 ± 16 121 ± 13 97 ± 11 104 ± 4 MDMB-CHMCZCA 108 ± 13 90 ± 9 62 ± 14 66 ± 9 Open in new tab Table III Recoveries Obtained for Synthetic and Field Oral Fluids Spiked with Synthetic Cannabinoids and Extracted by the Proposed MEPS Method Analyte . Recovery (% ± s, n = 3) . . Synthetic . Field . . 125 μg/L . 250 μg/L . 125 μg/L . 250 μg/L . 5F-ADB 120 ± 7 124 ± 4 100 ± 2 102 ± 5 MMB-CHMICA 116 ± 10 121 ± 11 91 ± 6 103 ± 3 THJ-2201 110 ± 1 112 ± 9 89 ± 6 93 ± 1 CUMYL-4CN-BINACA 118 ± 16 121 ± 13 97 ± 11 104 ± 4 MDMB-CHMCZCA 108 ± 13 90 ± 9 62 ± 14 66 ± 9 Analyte . Recovery (% ± s, n = 3) . . Synthetic . Field . . 125 μg/L . 250 μg/L . 125 μg/L . 250 μg/L . 5F-ADB 120 ± 7 124 ± 4 100 ± 2 102 ± 5 MMB-CHMICA 116 ± 10 121 ± 11 91 ± 6 103 ± 3 THJ-2201 110 ± 1 112 ± 9 89 ± 6 93 ± 1 CUMYL-4CN-BINACA 118 ± 16 121 ± 13 97 ± 11 104 ± 4 MDMB-CHMCZCA 108 ± 13 90 ± 9 62 ± 14 66 ± 9 Open in new tab Conclusions The consumption of synthetic cannabinoids has increased in the last decade with a great social incidence due to the high number of undesirable episodes of intoxications and deaths reported in many countries. In this study a novel procedure has been developed for the determination of third-generation synthetic cannabinoids in saliva based on MEPS extraction and GC–MS analysis. Experimental conditions for MEPS of the target analytes have been evaluated in order to obtain quantitative extraction recoveries with a high sensitivity with LOD values in the 10–20 μg/L range. The use of MEPS shows a high potential automation to perform routinely analysis of a high number of samples and a reduced consumption of solvents and reagents. Moreover, the analysis of oral fluid allows the identification of the parent compounds instead of their respective metabolites, which reduces potential misidentification that often occurs in urine analysis. Conflict of interest The authors declare that have no competing financial interests in this investigation. Funding Authors gratefully acknowledge the financial support of the Generalitat Valenciana (AICO/2019/099 and ACIF-2017/386) and the Spanish Ministerio de Ciencia e Innovación (PID2019-110788GB-I00). References 1. Longworth , M. , Reekie , T.A., Blakey , K., Boyd , R., Connor , M., Kassiou , M. ( 2019 ) New-generation azaindole-adamantyl-derived synthetic cannabinoids . Forensic Toxicology , 37 , 350 – 365 . Google Scholar Crossref Search ADS WorldCat 2. United Nations. World Drug Report United Nations Publication, Sales No. E.19.XI.8 . United Nations Office on Drugs and Crime : Vienna, Austria , 2019 ; ISBN: 978-92-1-148314-7 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 3. United Nations Office on Drugs and Crime Early warning advisory of new psychoactive substances (2020). Synthetic Cannabinoids, UNODC Laboratory and Scientific Section, Vienna International Centre, Vienna, Austria . https://www.unodc.org/LSS/SubstanceGroup/Details/ae45ce06-6d33-4f5f-916a-e873f07bde02. OpenURL Placeholder Text WorldCat 4. United Kingdom Government MIL-OSI UK Circular 009/2019: third generation synthetic cannabinoids update , 15 November 2019 , https://www.gov.uk/government/publications/circular-0092019-third-generation-synthetic-cannabinoids-update/circular-0092019-third-generation-synthetic-cannabinoids-update. 5. United Nations Office on Drugs and Crime ( 2019 ). Current NPS threats, Vol I, March 2019 , UNODC Laboratory and Scientific Section, Vienna International Centre, Vienna, Austria . https://www.unodc.org/pdf/opioids-crisis/Current_NPS_Threats_-_Volume_I.pdf. 6. Lamy , F.R. , Daniulaityte , R., Nahhas , R.W., Barratt , M.J., Smith , A.G., Sheth , A., et al. ( 2017 ) Increases in synthetic cannabinoids-related harms: results from a longitudinal web-based content analysis . International Journal of Drug Policy , 44 , 121 – 129 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Minakata , K. , Yamagishi , I., Nozawa , H., Hasegawa , K., Suzuki , M., Gonmori , K., et al. ( 2017 ) Sensitive identification and quantitation of parent forms of six synthetic cannabinoids in urine samples of human cadavers by liquid chromatography–tandem mass spectrometry . Forensic Toxicology , 35 , 275 – 283 . Google Scholar Crossref Search ADS WorldCat 8. Coulter , C. , Garnier , M., Moore , C. ( 2011 ) Synthetic cannabinoids in oral fluid . Journal of Analytical Toxicology , 35 , 424 – 430 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Øiestad , E.L. , Karinen , R.A., Haugland , K., Øiestad , M.L. Chapter 101 screening of synthetic cannabinoids. In: Preedy V.R. (ed). Handbook of Cannabis and Related Pathologies . Academic Press : San Diego , 2017 ; pp 981 – 997 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC 10. Kneisel , S. , Teske , J., Auwarter , V. ( 2014 ) Analysis of synthetic cannabinoids in abstinence control: long drug detection windows in serum and implications for practitioners . Drug Testing and Analysis , 6 , 135 – 136 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Barceló , B. , Pichini , S., López-Corominas , V., Gomila , I., Yates , C., Busardò , F.P., et al. ( 2017 ) Acute intoxication caused by synthetic cannabinoids 5F-ADB and MMB-2201: a case series . Forensic Science International , 273 , e10 – e14 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Kusano , M. , Zaitsu , K., Taki , K., Hisatsune , K., Nakajima , J., Moriyasu , T., et al. ( 2018 ) Fatal intoxication by 5F–ADB and diphenidine: detection, quantification, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q-TOFMS . Drug Testing and Analysis , 10 , 284 – 293 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Richter , L.H.J. , Maurer , H.H., Meyer , M.R. ( 2019 ) Metabolic fate of the new synthetic cannabinoid 7’N-5F-ADB in rat, human, and pooled human S9 studied by means of hyphenated high-resolution mass spectrometry . Drug Testing and Analysis , 11 , 305 – 317 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Yeter , O. , Ozturk , Y.E. ( 2019 ) Metabolic profiling of synthetic cannabinoid 5F-ADB by human liver microsome incubations and urine samples using high-resolution mass spectrometry . Drug Testing and Analysis , 11 , 847 – 858 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Yeter , O. , Öztürk , Y.E. ( 2019 ) Detection and quantification of 5F-ADB and its methyl ester hydrolysis metabolite in fatal intoxication cases by liquid chromatography–high resolution mass spectrometry . Forensic Science International , 302 , 109866. Google Scholar OpenURL Placeholder Text WorldCat 16. Ivanov , I.D. , Stoykova , S., Ivanova , E., Vlahova , A., Burdzhiev , N., Pantcheva , I., et al. ( 2019 ) A case of 5F-ADB / FUB-AMB abuse: drug-induced or drug-related death? Forensic Science International , 297 , 372 – 377 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Ong , R.S. , Kappatos , D.C., Russell , S.G.G., Poulsen , H.A., Banister , S.D., Gerona , R.R., et al. ( 2020 ) Simultaneous analysis of 29 synthetic cannabinoids and metabolites, amphetamines, and cannabinoids in human whole blood by liquid chromatography–tandem mass spectrometry - a New Zealand perspective of use in 2018 . Drug Testing Analysis , 12, 195 – 214 . Google Scholar OpenURL Placeholder Text WorldCat 18. Diao , X. , Wohlfarth , A., Pang , S., Scheidweiler , K.B., Huestis , M.A. ( 2016 ) High-resolution mass spectrometry for characterizing the metabolism of synthetic cannabinoid THJ-018 and its 5-fluoro analog THJ-2201 after incubation in human hepatocytes . Clinical Chemistry , 62 , 157 – 169 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Staeheli , S.N. , Poetzsch , M., Veloso , V.P., Bovens , M., Bissig , C., Steuer , A.E., et al. ( 2018 ) In vitro metabolism of the synthetic cannabinoids CUMYL-PINACA, 5F–CUMYL-PINACA, CUMYL-4CN-BINACA, 5F–CUMYL-P7AICA and CUMYL-4CN-B7AICA . Drug Testing and Analysis , 10 , 148 – 157 . Google Scholar Crossref Search ADS PubMed WorldCat 20. Öztürk , Y.E. , Yeter , O., Öztürk , S., Karakus , G., Ates , I., Buyuk , Y., et al. ( 2018 ) Detection of metabolites of the new synthetic cannabinoid CUMYL-4CN-BINACA in authentic urine samples and human liver microsomes using high-resolution mass spectrometry . Drug Testing and Analysis , 10 , 449 – 459 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Åstrand , A. , Vikingsson , S., Lindstedt , D., Thelander , G., Gréen , H., Kronstrand , R., et al. ( 2018 ) Metabolism study for CUMYL-4CN-BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway . Drug Testing and Analysis , 10 , 1270 – 1279 . Google Scholar Crossref Search ADS WorldCat 22. Yeter , O. ( 2017 ) Identification of the synthetic cannabinoid 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1Hindazole- 3-carboxamide (CUMYL-4CN-BINACA) in plant material and quantification in post-mortem blood samples . Journal of Analytical Toxicology , 41 , 720 – 728 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Mogler , L. , Franz , F., Wilde , M., Huppertz , L.M., Halter , S., Angerer , V., et al. ( 2018 ) Phase I metabolism of the carbazole-derived synthetic cannabinoids EG-018, EG-2201, and MDMB-CHMCZCA and detection in human urine samples . Drug Testing and Analysis , 10 , 1417 – 1429 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Pereira , J.A.M. , Gonçalves , J., Porto-Figueira , P., Figueira , J.A., Alves , V., Perestrelo, et al. ( 2019 ) Current trends on microextraction by packed sorbent - fundamentals, application fields, innovative improvements and future applications . Analyst , 144 , 5048 – 5074 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Ares , A.M. , Fernández , P., Regenjo , M., Fernández , A.M., Carro , A.M., Lorenzo , R.A. ( 2017 ) A fast bioanalytical method based on microextraction by packed sorbent and UPLC–MS/MS for determining new psychoactive substances in oral fluid . Talanta , 174 , 454 – 461 . Google Scholar Crossref Search ADS PubMed WorldCat 26. Rocchi , R. , Simeoni , M.C., Montesano , C., Vannutelli , G., Curini , R., Sergi , M., et al. ( 2018 ) Analysis of new psychoactive substances in oral fluids by means of microextraction by packed sorbent followed by ultra-high performance liquid chromatography–tandem mass spectrometry . Drug Testing Analysis , 10 , 865 – 873 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Sorribes-Soriano , A. , Monedero , A., Esteve-Turrillas , F.A., Armenta , S. ( 2019 ) Determination of the new psychoactive substance dichloropane in saliva by microextraction by packed sorbent – Ion mobility spectrometry . Journal of Chromatography A , 1603 , 61 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Sorribes-Soriano , A. , Sánchez-Martínez , S., Arráez-González , R., Esteve-Turrillas , F.A. and Armenta S. ( 2020 ) Methylone determination in oral fluid using microextraction by packed sorbent coupled to ion mobility spectrometry, Microchemical Journal , 153, 104504. Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 29. Centre for Applied Science and Technology (2012). Preliminary drug testing devices: A guide to type approval procedures for preliminary drug testing devices used for transport law enforcement in great Britain , Alcohol and Drugs Type Approval Manager, Centre for Applied Science and Technology, St. Albans, United Kingdom. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/190174/Guide_to_Type_Approval_Preliminary_Drug_Testing_Devices__2_.pdf. 30. Fischer Scientific website (2020). Trajan Scientific and Medical™ MEPS BINs for XCHANGE/eVol Syringes , https://www.fishersci.es/shop/products/meps-bins-xchange-evol-syringes-12/p-7114334. 31. Blandino , V. , Wetzel , J., Kim , J., Haxhi , P., Curtis , R., Concheiro , M. ( 2017 ) Oral fluid vs. urine analysis to monitor synthetic cannabinoids and classic drugs recent exposure . Current Pharmaceutical Biotechnology , 18 , 796 – 805 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Rodrigues , W.C. , Catbagan , P., Rana , S., Wang , G., Moore , C. ( 2013 ) Detection of synthetic cannabinoids in oral fluid using ELISA and LC–MS-MS . Journal of Analytical Toxicology , 37 , 526 – 533 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Kneisel , S. , Auwärter , V., Kempf , J. ( 2013 ) Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography–electrospray ionization tandem mass spectrometry . Drug Testing Analysis , 5 , 657 – 669 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Toennes , S.W. , Geraths , A., Pogoda , W., Paulke , A., Wunder , C., Theunissen , E.L., et al. ( 2018 ) Pharmacokinetic properties of the synthetic cannabinoid JWH-018 in oral fluid after inhalation . Drug Testing Analysis , 10 , 644 – 650 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Determination of Third-Generation Synthetic Cannabinoids in Oral Fluids
JF - Journal of Analytical Toxicology
DO - 10.1093/jat/bkaa091
DA - 2020-07-18
UR - https://www.deepdyve.com/lp/oxford-university-press/determination-of-third-generation-synthetic-cannabinoids-in-oral-PuE4VRAdS0
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -