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. 2016 Sep 28;1:3–10. doi: 10.1016/j.clinms.2016.08.003

Rapid screening and identification of novel psychoactive substances using PaperSpray interfaced to high resolution mass spectrometry

Joseph Kennedy a,⁎, Kevin G Shanks b, Kristine Van Natta c, Maria C Prieto Conaway c, Justin M Wiseman a, Brian Laughlin a, Marta Kozak c
PMCID: PMC11322720  PMID: 39193420

Highlights

  • •

    PaperSpray-MS has been applied to the detection and identification of novel psychoactive substance (NPS) in consumer products using minimal sample preparation.

  • •

    PaperSpray-MS provides a rapid screening tool and, interfaced to high resolution accurate mass (HRAM), a powerful identification technique for obtaining chemically-relevant information.

  • •

    Identification of second and third generation synthetic cannabinoids was accomplished by accurate mass interpretation and interpretation of spectra from data dependent MS2 analyses.

  • •

    The combination of these techniques provides a simplified work flow for detection and identification of NPS by accurate mass and confirmation by MS2 without the necessity of reference standards.

  • •

    HRAM also allows the identification of unknown compounds outside the target compound class.

  • •

    Analysis times for PS–MS are less than two minutes rather than the greater than 12 min with UPLC used here.

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    PaperSpray with HRAM detection provided results which were comparable to those from UPLC-MS.

Keywords: Synthetic cannabinoids, Novel psychoactive substances, PaperSpray ionization

Abstract

The simple and rapid detection and identification of designer drugs is of substantial importance to forensic scientists and law enforcement. Although synthetic cathinones, cannabinoids, and other common novel psychoactive substances (NPS) are produced for purposes that do not include human consumption, they are regularly abused. The analysis of these compounds is often achieved using mass spectrometry, but can be complicated by the lack of spectral libraries and the scarcity of simple and reliable sample introduction techniques. PaperSpray® ionization is a new, automated technique for rapid analysis of samples, without chromatography or prior purification. Matrix, such as powder or plant material, is dissolved or extracted with common solvents and deposited directly on disposable PaperSpray® cartridges for high-throughput, automated analysis. The combination of PaperSpray® sample introduction and High Resolution Accurate Mass Spectrometry (HRAM) provides a powerful and simple tool for identification of new substances, without requiring reference standards.

1. Introduction

Forensic drug analysis has many challenges; one of them is staying ahead of synthetic chemists. New, pharmacologically active, compounds are being created and made available to the public in inconspicuous ways. Synthetic cannabinoids and cathinones, two common classes of novel psychoactive substances (NPS), have been detected in many herbal incense products and powdered bath salts [1], [2]. These compounds mimic the effects of tetrahydrocannabinol (THC), but often elude detection by current drug screening techniques that require standards or reference spectra. NPS are typically dissolved and sprayed onto plants or powders to facilitate their use. The majority of NPS are synthetic cannabinoids from the Far East and Southeast Asia [3]. Their structures are readily modified, without loss of physiological activity, resulting in new NPS-type compounds that evade regulation as controlled substances. In the United States, many cannabinoids have been regulated via legislation, and sixteen of the first and second generation cannabinoids are listed as Schedule 1 controlled substances [4], [5], [6], [7]. The emergence of these novel compounds mandates the development of testing approaches that incorporate simplicity, structural selectivity, robustness and qualitative reproducibility, as the most critical attributes; requirements that are addressable using mass spectrometric methods. The use of mass spectrometry (MS) and tandem MS interfaced to Ultra-Performance Liquid Chromatography (UPLC) and ambient ionization techniques, such as Direct Analysis in Real Time (DART), for the identification of these emerging compounds has been reported [8], [9], [10]. The use of High-Resolution Mass Spectrometry (HRMS) for non-targeted analysis of designer drugs has been proposed to keep pace with their continual evolution [11], [12], [13]. HRMS offers enhanced specificity over conventional MS, and improvements in software expedite data mining [14]. Analytical standards are required for confirmation, but when standards are not available, these approaches narrow the list of possible compounds. Several investigators have proposed Gas Chromatography–Tandem Mass Spectrometry (GC–MS/MS) methods as a means for differentiation of isomeric cannabinoids [15], [16]. JWH-250, JWH302, and JWH-201 are all isomeric and difficult to distinguish by GC alone. In these cannabinoids, the methoxy group differs in its position on the aromatic ring versus the indole substituent. However, some common fragments in each cannabinoid were found to have different ratios and, thus, ortho methoxy (JWH-250), meta methoxy (JWH-302) and para methoxy (JWH-201) could be individually distinguished [17]. Ultimately, in an attempt at standardization, a recommended methodology has been provided by the United Nations Office on Drugs and Crime for identification and analysis of synthetic cannabinoid agonists in seized materials [18]. In this report, Thin-Layer Chromatography (TLC) developing systems with Rf values for cannabinoids, Ion Mobility Spectrometry (IMS) data with cannabinoid drift times, and GC–MS conditions with retention times for selected cannabinoids, are presented. A Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS) methodology, with quantitation using internal standards and 5-point calibration curves is detailed, as well as sample preparation techniques for cannabinoids in herbal blends.

An alternative ambient method for ionization and sample introduction into the mass spectrometer is PaperSpray [19], [20]. Initially described in 2010, PaperSpray (PS) uses a cellulosic substrate shaped to a fine tip that produces a spray when solvent and high voltage are applied [21], [22]. Applications of PS–MS include the analysis of dried blood spots for monitoring drugs of abuse, immunosuppressant drugs (e.g. tacrolimus) or cocaine residue on different surfaces [23], [24]. A comprehensive review of PS–MS applications as well as limitations of the technique has been recently published [25]. Although PS–MS is capable of detecting drugs and metabolites directly in biofluids, it is performed without chromatography and, thus, HRMS, MS/MS or a combination of both is necessary for structural confirmation. As with other ambient ionization techniques, selectivity and specificity are heavily dependent on the capabilities of the mass spectrometer. In many cases, direct methods cannot distinguish diastereomers, or closely related structural isomers that fragment in a similar manner, without prior HPLC separation, which prevents labile metabolites such as acyl glucuronides from decomposing in the source region resulting in an inflated concentration of the parent drug. Methodology adjustments to improve the selectivity of PS–MS without significantly increasing the analysis time include the addition of derivatization agents to the paper substrate prior to analysis [26], [27]. Such modifications are intended to derivatize specific functional groups to aid in distinguishing closely related structural isomers. One emerging technique that may improve selectivity for PS–MS analysis is Ion Mobility Spectrometry–Mass Spectrometry (IMS–MS), which separates analytes in the gas phase prior to entering the mass spectrometer. Alternatively, FAIMS–PS–MS/MS was recently reported to have been used for the separation of the structurally similar opiate isomers: morphine, norcodeine and hydrocodone [28].

In this report, we combine PS with High Resolution Accurate Mass (HRAM) and Full Scan-data-dependent MS2 (FS-ddMS2) as a high throughput screening technique for identification of the NPS in herbal matrices. The sample preparation employed involves dissolution with or without extraction from the matrix. Combining PS ionization with HRAM and FS-ddMS2 provides a powerful and potentially high-throughput tool for identification and quantification of synthetic cannabinoids, as well as other drugs, without extensive sample preparation or chromatographic separation. PS is demonstrated to address some of the principal needs of the qualitative screens for NPS in crude sample preparations, including simplicity, availability of structural information, comparable mass spectra to reference standards, and high correlation with LCMS results, but with considerable time savings (i.e. 2 min vs. 12 min).

2. Experimental

2.1. Materials

Acetonitrile and methanol were HPLC grade and purchased from VWR Scientific. Acetic acid (A.R. grade) was purchased from VWR scientific. Reference standards for XLR-11, UR-144, A-796260, PB-22, AB-PINACA, and MAM-2201 were purchased from Cerilliant Analytical Reference Standards, Round Rock TX. Specimens of herbal incense and powders were acquired from local sources and were stored at ambient temperature. Samples for UPLC-ToF-MS were transferred to a glass tube, a 1:1 mixture of methanol/acetonitrile was added, sonicated 10 min, and then diluted 1:50 with acetonitrile: DI water (20:80). Aliquots were transferred to auto sampler vials for analysis. Extracts were stored under refrigeration for future use. Ten microliters of refrigerated extract were deposited on Velox™ Sample Cartridges (Prosolia, Indianapolis, IN) and allowed to dry under ambient conditions. The PS cartridges were stored with drying agent at room temperature prior to analysis. Samples were prepared in Indianapolis, Indiana and shipped to San Jose, California for analysis.

2.2. Instrumentation

2.2.1. PS MS

A Velox 360™ PaperSpray System (Prosolia) was interfaced to a Thermo Scientific™ Q-Exactive™ Focus high-resolution, accurate-mass (HRAM) mass spectrometer (Thermo Fisher Scientific, San Jose, CA) for analysis. A solvent mixture consisting of acetonitrile/water/acetic acid (90/10/0.1 v/v/v) was used as the eluting solvent and spray solvent for the PaperSpray source. Voltages for the mass spectrometer in the PS experiment were set using tune files from the mass spectrometer. The Q-Exactive MS was operated in full-scan data-dependent MS2 mode. In confirmation mode, data-dependent MS2 scans are triggered based on detection of compounds in an inclusion list. Data were acquired with Thermo Scientific TraceFinder™ software (v 3.2) over a mass range of m/z 175–500 and resolution of 70,000. During sample analysis, the source voltage was provided by the mass spectrometer and was ramped from 0 kV (0.1 min) to 5 kV (hold for 0.7 min) then back to 0 kV (0.1 min) followed by a negative pulse of −4.5 kV (0.1 min).

2.2.2. UPLC-ToF

Chromatographic separation was completed using a Waters (Milford, MA) Acquity UltraPerformance® Liquid Chromatograph. The UPLC separations were performed using BEH C18 column (2.1 × 100 mm, 1.8 μm particle size) with a gradient elution at a flow rate of 0.5 ml/min. The UPLC mobile phase consisted of DI water containing 0.05% formic acid (solvent A) and acetonitrile (solvent B). The gradient profile was 42% B for 0.3 min, linear increase to 97% B in 11 min, hold for 0.5 min, then reverse to 42%B. Electrospray ionization mass spectrometry was performed using a Waters LCT Premier XE Time of Flight mass spectrometer. Low voltage scan was used for precursor mass identification followed by collision induced dissociation (CID).

3. Results and discussion

The herbal samples were analyzed and chronograms were obtained similar to that in Fig. 1 for the Tranquility sample. Integration or summation of the resultant signal across time allowed for extraction of MS or MS/MS spectra. Methylone, the mass spectrum of which is included in Fig. 1, was ultimately identified as a major component in this specimen based on accurate mass. This mass spectrum represents an average over the entire chronogram from 0.10 to 0.83 min. Cannabinoid identification was facilitated by use of an inclusion list and MS2 data. Table 1 provides a summary of [m/z] for suspected cannabinoids as well as [m/z] values for the detected cannabinoids found in the herbal mixtures. Several suspected cannabinoids were not detected in the herbal mixes. Identification and confirmation of the cannabinoids were based on accurate mass matching (tolerance of 10 ppm) and formula confirmation derived from the HRAM data followed by data dependent fragmentation for any compounds detected on the inclusion list. Two additional compounds, methalone and 5/6 APB, were not contained within in the original inclusion table used for analysis. However, both compounds were tentatively identified post-analysis based on HRAM. Both of these structures were subsequently identified in the herbal blends using UPLC-ToF-MS. As many of these compounds are not in spectral libraries, comparative identification of the compounds was to be inferred from the MS2 experimental data. This can be achieved by comparison of the spectra from unknowns with those from knowns and inferring structural homology.

Fig. 1.

Fig. 1

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Chronogram from Tranquility (Top) with average HRAM Spectrum for Methylone (bottom).

Table 1.

Inclusion list of compounds.

Theoretical (m/z) [M+H]+ Measured (m/z) [M+H]+ Molecular formula Compound
176.2270 176.1069 C11H14ON 5/6 APB⁎
195.1254 – C11H16NO2 MDMA
208.2258 208.0968 C11H14O3N Methylone⁎
232.1696 232.1696 C15H21NO a-PVP
248.1645 248.1645 C15H21NO2 Methoxetamine
276.1594 – C16H21NO3 MDPV
312.2322 312.2325 C21H29NO UR-144
319.2632 – C21H34O2 CP 47 497
322.1802 – C21H23NO2 RCS-4
323.2118 – C21H26N2O Acetylfentanyl
328.1696 328.1696 C23H21NO JWH-015
328.1696 328.1696 C23H21NO JWH-073
329.2111 – C21H28O3 HU-331
330.2228 330.2226 C21H28FNO XLR-11
331.2129 331.2258 C18H26N4O2 AB-PINACA
336.1361 336.1360 C18H22ClNO3 25C-NBOMe
336.1958 336.1951 C22H25NO2 JWH-250
339.1703 – C20H22N2O3 URB597
340.1463 340.1908 C21H22ClNO JWH-203
342.1852 342.1693 C24H23NO JWH-018
345.2285 – C19H28N4O2 ADB-PINACA
348.9738 348.9737 C15H10BrClN2O Phenazepam
355.2380 355.2380 C22H30N2O2 A796,260
356.2009 356.2207 C25H25NO JWH-019
356.2009 356.2207 C25H25NO JWH-122
357.2285 357.2281 C20H28N4O2 AB Chminaca
359.1754 359.1753 C23H22N2O2 QUPIC (PB-22)
360.1758 360.1759 C24H22FNO AM-2201
369.1721 369.1718 C20H21FN4O2 AB-FUBINACA
370.2165 370.2165 C26H27NO JWH-210
372.1958 372.3621 C25H25NO2 JWH-081
374.1915 374.2408 C25H24FNO MAM-2201
376.2271 376.2250 C25H29NO2 RCS-8
377.1660 377.1656 C23H21FN2O2 5F-PB-22
380.0856 – C18H22BrNO3 25B-NBOMe
383.1878 – C21H23FN4O2 ADB-FUBINACA
385.1911 – C25H24N2O2 JWH-200
387.2894 – C25H38O3 HU-211
427.2016 – C27H26N2O3 WIN 55-212-2
428.0717 428.0717 C18H22INO3 25I-NBOMe
459.0928 459.0913 C22H23IN2O AM-2233
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⁎

Compounds were not included in original Inclusion List. (–) indicates compound was not detected in blends.

The structural similarities among the first and second generation cannabinoids [11] (Fig. 2) and the newly emerging third generation [8] (Fig. 3) are apparent and will be leveraged in interpreting spectral information and identifying the compounds detected in the consumer products analyzed here. MAM-2201 (second generation synthetic cannabinoid) is similar to typical naphthoylindole structure observed in earlier cannabinoids with a fluorine added to the alkyl chain. However, A796260, UR-144 and XLR-11 (Fig. 3) contain completely new chemical moieties adjacent to the keto-indole core. In the MS2 experiment, the cannabinoids studied here all fragment in a predictable manner allowing MS2 data to more readily identify the location and nature of the substituent in the new compound. JWH-018 is one of the most commonly found and well-studied cannabinoids [12]. This allows its MS2 behavior (Fig. 4) to facilitate the interpretation of other spectra with fragmentation on either side of the central carbonyl to yield m/z 155.0491 (C11H7O) and m/z 214.1224 (C14H16NO) being diagnostic of substituents. Consequently, it would be predicted that XLR-11 would produce fragment ions at m/z 125.0961 (C8H13O) and m/z 232.1128 (C14H15ONF). These ions are, in fact, observed in the MS2 spectrum of this compound as illustrated in Fig. 5. The sample containing XLR-11 also contains QUPIC or PB-22. PB-22 is an analog of JWH-018 with an ester at the indole-3 position and 8-hydroxyquinoline replacing the naphthalene group. Fragmentation is similar to JWH-018 with m/z 214.1226 (C14H16ON) and 144.0444 (C9H6ON) being predominant. Mass spectral data from analysis of the Black Magic Smoke specimen is illustrated in Fig. 6. The data from this specimen were consistent with a mix of UR-144, A796,260, and MAM-2201. Specifically, UR-144 fragments are m/z 125.0963 (C8H13O) and 214.1227 (C14H16ON), representing cleavage at the ketone to generate the epoxide containing fragments. The common m/z 125.0963 and unique m/z 214.1227 and 232.1128 ions are consistent with the purported structural difference minus F for H substitution between UR-144 and XLR-114. UR-144 does not contain a fluorine as seen in XLR-11 and thus m/z 214.1227 versus m/z 232.1128 is present. The primary fragments observed in A796260 were m/z 114.0917 (C6H12ON), m/z 125.0964 (C8H13O) and also m/z 257.1278 (C15H17O2N2). MAM-2201 fragments were as expected m/z 169.0647 (C12H9O) as well as m/z 232.1133 (C14H15ONF). Additional confirmation of structure was obtained by comparison of mass spectral data from selected reference standard cannabinoids summarized in Table 2. In all of these compounds, the mass spectrum from extracted samples and reference standards were comparable. Overall, the analysis using PS included 42 samples from post-mortem crime scenes and resulted in the detection of numerous designer cannabinoids including: AM-2201, JWH-210, JWH-250, MAM-2201, RCS-8, A796260, UR-144, JWH-122, JWH-019, AM-2233, XLR11, PB-22.

Fig. 2.

Fig. 2

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Structures of first and second generation synthetic cannabinoids.

Fig. 3.

Fig. 3

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Structures of third generation synthetic cannabinoids.

Fig. 4.

Fig. 4

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Structure and MS2 spectrum from JWH-018.

Fig. 5.

Fig. 5

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FSddMS2 spectra from Bizarro specimen. [a] XLR-11 m/z 330.2228 C21H29ONF and PB-22 m/z 359.1754 C23H33O2N2, [b] MS2 for XRL-11, and [c] MS2 for PB-22.

Fig. 6.

Fig. 6

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FSddMS2 spectra from Black Magic Smoke showing the predictable fragmentation behavior of the cannabinoids. [a] UR-144 m/z 312.2322 C21H30ON, A796,260 m/z 355.2380 C22H31O2N2, and MAM 2201 m/z 374.1914 C25H25ONF, [b] MS2 for UR-144, [c] MS2 for A796,260, [d] MS2 for MAM 2201.

Table 2.

Parent and product ions from selected cannabinoid reference standards.

Compound Molecular formula Theoretical (m/z) [M+H]+ Observed (m/z) [M+H]+ Fragment 1 (m/z) [M+H]+ Fragment 2 (m/z) [M+H]+
UR-144 C21H29NO 312.2322 312.2318 214.1226 125.0963
XLR-11 C21H28FNO 330.2228 330.2222 232.1130 125.0962
AB-PINACA C18H26N4O2 331.2129 331.2121 233.1281 215.1177
A796260 C22H30N2O2 355.2380 355.2374 125.0963 114.0917
PB-22 C23H22N2O2 359.1754 359.1748 214.1224 144.0442
MAM2201 C25H24FNO 374.1915 374.1910 232.1131 169.0646
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These samples were also analyzed by UPLC-ToF-MS methodology [8]. The total run time per sample was 12 min as compared to <2 min using PS-MS. In-source, collision-induced dissociation of precursor was used in the UPLC-ToF-MS experiments to identify the compounds in the different blends. A summary of results from PS–MS and UPLC-ToF-MS is presented in Table 3. These data show a strong correlation between the two techniques in which NPS were detected and in the identification capabilities of the two techniques. Differences in the number of synthetic cannabinoids in several blends were obvious and were attributed to differences in concentration of analyzed sample or, possibly, sample stability. The UPLC-ToF-MS data were obtained from fresh extracts and diluted (1:50) prior to analysis. The PS–MS analysis was performed on extract solutions that had been refrigerated several months prior to analysis and solutions were not diluted.

Table 3.

Summary of NPS detected by UPLC-ToF-MS and PS–MS data.

Specimen UPLC-ToF-MS PS–MS
Purple Diesel MAM-2201 MAM-2201
Diablo MAM-2201 MAM-2201
Funky Green Stuff UR-144 JWH-081, MAM-2201, A796,260, UR-144
Assassin MAM-2201, UR-144 UR-144, MAM-2201
Black Magic Smoke UR-144 MAM-2201, A796,260, UR-144
Darkness Blueberry UR-144 MAM-2201, A796,260, UR-144
Gorilla Pro GD JWH-081, JWH-210, MAM-2201, UR-144 MAM-2201, A796,260, UR-144
Black Rooster AM-2201 MAM-2201, AM-2201
Funky Monkey AM-2201, JWH-210, JWH-250 AM-2201, JWH-210, JWH-250, MAM-2201, RCS-8
Matrix JWH-122 JWH-122
Bayou Blaster AM-2201, AM-2233, JWH-210 AM-2201, AM-2233, JWH-210
K2 XXX Chronic JWH-122, JWH-203 JWH-122, JWH-203
Cloud 9 AM-2201, JWH-019, JWH-122, JWH-250 AM-2201, JWH-019, JWH-122, JWH-250
Demon 5F-PB-22, PB-22 PB-22, AM2201
Colorado AM-2201 AM2201, XLR11, A796,260
iBlown 4G XLR11, XLR11 N-4-pentenyl derivative XLR11, A796,260, AM-2201
Sunshine Daydream UR-144, XLR11 UR-144, XLR11
Joker 5F-PB-22, PB-22 PB-22
Sunshine Nightmare UR-144, XLR11 UR-144, XLR11, PB-22
Ultra-Zombie Matter AM-2201, JWH-210, Phenazepam JWH-210
Crazy Monkey AM2201 AM-2201
No Mames AB-PINACA AB-PINACA, AM-2201
Brain Freeze AB-FUBINACA, AB-PINACA AB-PINACA
Unspecified Blotter Paper 25C-NBOMe, 25H-NBOMe, 25I-NBOMe 25C-NBOMe, 25I-NBOMe
Crystal Clean Hookah Cleaner Alpha-PVP Alpha-PVP
Bliss Ultra Methoxetamine Methoxetamine
Super Flame 5F-PB-22, FUB-PB-22, PB-22 5F-PB-22, FUB-PB-22, PB-22
Inferno 5F-PB-22, PB-22 5F-PB-22, PB-22
Bizarro XLR11 XLR11, PB-22
Black Diamond 5F-PB-22, AB-FUBINACA, AB-PINACA, PB-22, XLR11 5F-PB-22, AB-FUBINACA, AB-PINACA, PB-22, XLR11
E-cigarette Liquid 2 5F-PB-22, AB-CHMINACA, PB-22, XLR11 AB-CHMINACA, PB-22
OMG XLR11 XLR11
WTF XLR11 XLR11
Scooby Snax None Detected None Detected
Mr. Nice Guy AM-2201, JWH-018, JWH-081, JWH-210, MAM-2201 AM-2201, JWH-018, JWH-210, MAM-2201
Caution Yellow UR-144, XLR11 UR-144, XLR11
Mind Candy 5/6-APB 5/6-APB
Speed Rush Alpha-PVP Alpha-PVP
Tranquility Methylone Methylone
K2 Blonde – JWH-018. JWH-073
White Dragon – JWH-018
Spike Silver – JWH-018
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4. Conclusions

PS–MS has been applied to the detection and identification of NPS compounds in consumer products using minimal sample preparation. PS–MS interfaced to HRAM provides a rapid screening tool and a useful technique for obtaining chemically-relevant structural information without chromatographic separation. Chromatography is necessary for conformation of isobaric compounds or other structural isomers, although this is a limitation for all ambient ionization techniques, as these types of compounds cannot be distinguished by mass spectrometry alone. Future combinations of IMS–MS with PS ionization may eliminate the need for prior separation of isobars. Identification of the synthetic cannabinoids was accomplished by accurate mass interpretation and inference and interpretation of spectra from data dependent MS2 analyses. The combination of these techniques provides a simplified work flow for detection and identification of NPS by accurate mass and MS2 fragmentation when reference standards are not readily available. The full scan and MS2 spectrum from selected cannabinoids were compared to reference standards for additional confirmation. HRAM also allows the identification of unknown compounds outside the target compound class, as in the case of methylone in the Tranquility sample and 5/6 APB in Mind Candy samples (both confirmed by UPLC-ToF-MS). Methylone and its isomers could not be distinguished individually using PS–MS. However, isomeric forms were not detected in the UPLC-ToF-MS analysis and, as of April 12, 2013, all forms of methylone were listed as Schedule 1 in the Federal register. These data demonstrate the possibility of the combined techniques for targeted, as well as non-targeted, analysis. Analysis times for PS–MS are <2 min, rather than the >12 min with UPLC used here. PS–MS with HRAM detection provided results that were comparable to those obtained from UPLC-ToF-MS, but with a shorter analysis time and without chromatographic separation.

Conflict of interest

The authors wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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