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Rapid Detection and Quantification of Hallucinogenic Salvinorin A in Commercial Salvia divinorum Products by DART-HRMS
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  • Megan I. Chambers
    Megan I. Chambers
    Department of Chemistry, University at Albany State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
    More by Megan I. Chambers
  • Justine E. Giffen-Lemieux
    Justine E. Giffen-Lemieux
    Department of Chemistry, University at Albany State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
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  • Rabi A. Musah*
    Rabi A. Musah
    Department of Chemistry, University at Albany State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
    *Email: [email protected]. Phone: 518-437-3740.
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    Orcidhttps://orcid.org/0000-0002-3135-4130
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ACS Omega

Cite this: ACS Omega 2023, 8, 1, 761–770
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https://doi.org/10.1021/acsomega.2c06106
Published December 21, 2022

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Abstract

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In recent years, national laboratories have identified several plant-derived materials as concerns to public health because of their psychoactive effects, potential for abuse, and the lack of federal regulation of their use. One of these is Salvia divinorum (aka Salvia), which has received focused attention due to its increasing recreational use and the ease by which it can be acquired. Traditional chromatographic approaches for the detection of the major psychoactive component of Salvia (i.e., salvinorin A) typically require time-consuming sample pretreatment prior to identifying the presence of salvinorin A in plant material unknowns. In this study, direct analysis in real time–high-resolution mass spectrometry (DART-HRMS) was used to rapidly screen for Salvia plant material. This approach facilitated the analysis of bulk material in its native form, thereby bypassing sample pretreatment steps. In addition, a validated DART-HRMS method was developed for the quantification of salvinorin A in commercial Salvia products (e.g., raw plant materials, enhanced leaf extracts). In this regard, cholesterol was found to be a suitable internal standard. The average salvinorin A content in raw Salvia leaves was determined to be 1.54 mg/g, while the salvinorin A quantified in enhanced Salvia leaf extracts was between 13.0 and 53.2 mg/g.

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Introduction

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In 2013, the United Nations Office on Drugs and Crime (UNODC) described several emerging new psychoactive substances (NPSs) identified by national laboratories between 2009 and mid-2012. (1) Eight percent of these NPSs, which is equivalent to 20 substances, were plant-based materials now classified as plants of abuse. (1) Their increased recreational use continues to raise public health concerns because of their dangerous health risks and their potential to result in dependence. Further exacerbating the issue is the difficulty of distinguishing these products from innocuous nonpsychoactive plant materials such as culinary items and medicinal herbs. Currently, only two of the plants on the list of 20 are federally classified as Schedule I Controlled Substances (and therefore considered illegal in the United States): (1) Catha edulis, commonly known as Khat; and (2) Lophophora williamsii, referred to as peyote or peyote cactus. (1) However, the unscheduled status of the other 18 species does not make them any less concerning. Salvia divinorum, commonly referred to simply as “Salvia”, serves as a case in point. It is a mint-family plant indigenous to Mexico, and is known for its powerful hallucinogenic properties. (2) Although several states in the United States have instituted various types of restrictions on Salvia use and possession (e.g., age restrictions, bans on certain product types, etc.), the lack of regulation at the federal level contributes to its ongoing use and abuse. (3)
Over the millennia, Salvia has been employed by various populations for medicinal, ceremonial, and religious purposes. (2) However, the recreational use of this plant has grown at an exponential pace primarily due in part to the ease of purchasing Salvia products online. (4) Salvia is typically sold as fresh or dried leaves, liquid tinctures, or plant extracts with strengthened potency. Enhanced leaf products are made by increasing the potency of raw Salvia leaves with a Salvia alcohol extract. (5) These are created by subjecting a large amount of raw Salvia leaves (e.g., 10 g) to solvent extraction and then applying the extract to a smaller amount of Salvia leaves (e.g., 1 g). The intense hallucinogenic effects of Salvia are experienced through: (1) smoking dried leaves or other enhanced products; (2) ingesting tinctures; and (3) chewing the leaves.
Because of the differences in S. divinorum cultivation conditions, as well as product enhancements that are designed to increase potency, the levels of the psychoactive salvinorin A (also referred to as divinorin A) to which users are exposed vary widely between products. Since the concentrations of this compound in the end product are not standardized, the psychoactive effects experienced by users can vary depending on the form of the material (e.g., tincture, dried or fresh leaves, etc.), and from batch to batch even for the same product. The experience that users have, which spans the extremes of peace and tranquility on the one hand, to paranoia and anxiety on the other, in addition to hallucinations and dyskinesia, is known to be dependent upon the salvinorin A levels ingested or inhaled, and the duration of use. (6) However, for the products available for purchase, active ingredient levels are not provided, which makes it impossible for users to gauge their level of exposure, or to make informed decisions about how much to use. Although there have been no reported instances of Salvia overdoses, several deaths have been linked to its use. (7,8) Because of the potential medical applications and/or toxicity of salvinorin A, and interest in this compound in forensic and toxicology contexts, a number of studies of its biological effects have been conducted. (4,6,9−11)
While S. divinorum contains several diterpenes, salvinorin A is the only one known to possess psychoactive properties. (12) This molecule is unique in that: (1) it is reported to be one of the most potent natural hallucinogens; (13−15) (2) it is the only known hallucinogen that is not an alkaloid; (14,16) and (3) it was the first non-nitrogenous diterpenoid with psychoactive properties discovered. (17) Heightened concerns over the potential of S. divinorum to result in dependence have resulted in attempts to restrict its use. However, the drafting of legislation to accomplish this hinges on the ability to not only accurately identify S. divinorum-derived material, but also to readily quantify the salvinorin A contained therein. Because S. divinorum cannot always be differentiated from other Salvia spp. through visual examination, forensic laboratories currently use the presence of salvinorin A to identify this plant material because it is only known to exist in S. divinorum. Studies have applied multivariate statistical procedures (e.g., principal component analysis (PCA)) to gas chromatography–mass spectrometry (GC-MS)-derived data obtained from Salvia spp. extracts, to distinguish S. divinorum plant materials. (18,19) There have also been investigations that have sought to develop approaches for the quantification of salvinorin A. (20−23) These methods have included GC-MS, liquid chromatography–mass spectrometry (LC-MS), thin-layer chromatography (TLC), and high-performance liquid chromatography (HPLC). While the developed procedures were functional for the analysis of the particular material that was analyzed in each case, it remains challenging to apply them to the full range of forms in which S. divinorum products appear. This impacts the extent to which such methods can be readily adopted for the analysis of each type of S. divinorum material that emerges on the market. Thus, it is highly desirable to have a more universal analysis approach that can better accommodate the wide range of sample types, and which, at the same time, enables incoming samples to be rapidly triaged and identified as being S. divinorum or not, so that informed decisions can be made about the necessity of subjecting the sample(s) to the more time-consuming salvinorin A quantification experiments.
The ambient ionization technique termed direct analysis in real time–high-resolution mass spectrometry (DART-HRMS) (24) has been demonstrated to readily enable qualitative and quantitative analyses of psychoactive molecules in complex plant matrices. (25−34) Samples can be screened in their native form for molecules of interest (i.e., no pretreatment required) by simply introducing them to the open-air gap between the DART ion source and the mass spectrometer inlet. DART-HRMS analyses are typically completed under either soft ionization conditions, which produce primarily protonated/deprotonated precursor molecules (depending on the ionization mode in which the DART ion source is operated) with minimal fragmentation, or collision-induced dissociation (CID) conditions, which result in varying levels of fragmentation. (24,35) More recently, DART-HRMS has shown utility in enabling the quantification of small molecules, with minimal sample preparation, using a semi-automated analysis approach. (25,27,30,31,33,34) Each of these advantages can be leveraged for effective analyses of Salvia.
Our laboratory previously demonstrated two successful investigations of Salvia-genus plant material by DART-HRMS: (1) species-level identification of culinary Salvia-genus plants using chemometric processing of DART-HRMS chemical profiles; (36) and (2) identification of S. divinorum headspace volatiles collected through the use of solid-phase microextraction (SPME). (37) The study presented here accomplishes the following: (1) rapid detection of salvinorin A in S. divinorum plant material and enhanced leaf products; (2) validation of a method for the quantification of salvinorin A, according to the U.S. Food and Drug Administration (FDA) Bioanalytical Method Validation: Guidelines for Industry; (38) and (3) application of the aforementioned protocol to eight commercial Salvia products (featured in Figure 1) acquired from online vendors. While salvinorin A is a unique chemical biomarker for S. divinorum, and there are other salvinorin derivatives present in Salvia, (39) the method does not aim to distinguish between salvinorin A isomers that are present in minor amounts in Salvia plant material. Therefore, although the salvinorin A concentrations reported here represent the upper limit of salvinorin A that could be present in the samples, the reported method will ultimately allow law enforcement and other laboratories to rapidly identify an unknown plant material as S. divinorum or S. divinorum-derived based on mass spectral data, and provide information regarding the amount of the psychoactive constituent a Salvia product contains.

Figure 1

Figure 1. Commercial Salvia products purchased from online vendors.

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Results and Discussion

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Rapid Screening of S. divinorum-Related Molecules in Salvia Products

This study commenced with confirmation that DART-HRMS was a suitable method for the detection of the psychoactive compound salvinorin A and rapid screening of Salvia plant materials. DART mass spectra [20 V (Panel A) and 90 V (Panel B)] of raw Salvia leaves (top) and an authentic salvinorin A standard (bottom) were compared in head-to-tail plot renderings such as those shown in Figure 2. Under soft ionization conditions (Panel A), a peak consistent with the protonated [M + H]+ mass of salvinorin A ([C23H28O8+H]+ calc. 433.1857) is detected in both spectra. Also detected under these conditions is a peak at nominal m/z 373, which is consistent with the fragment of salvinorin A that is formed following the loss of an acetate group (C21H25O6 calc. 373.1651), and which appears as the base peak in both mass spectra. Under CID conditions (Panel B), extensive fragmentation of the molecule(s) present in the samples was observed. Importantly, the salvinorin A fragments are well represented in the top S. divinorum spectrum, thereby confirming the presence of this biomarker. Similar analyses and comparisons were performed for an enhanced Salvia product (i.e., Salvia 20× leaf extract) to confirm the ability of DART-HRMS to screen for salvinorin A in different types of Salvia materials. Figure 3 illustrates the detection of salvinorin A in raw Salvia leaf (Panel A) and Salvia 20× (Panel B) products.

Figure 2

Figure 2. Head-to-tail renderings of the DART mass spectra of raw Salvia leaf and an authentic salvinorin A standard analyzed under soft ionization conditions at 20 V (A) and under CID conditions at 90 V (B).

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Figure 3

Figure 3. Representative DART mass spectra of two commercial Salvia products: raw Salvia leaf (A) and an enhanced Salvia leaf extract (B).

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Once it was demonstrated that DART-HRMS could detect salvinorin A in representative Salvia product types (i.e., raw plant materials and enhanced leaf extracts), the remaining six Salvia products were screened to confirm the presence of salvinorin A in each product and to ensure that all products were in fact derived from S. divinorum. The DART mass spectra for each of the eight Salvia products obtained for this study are displayed in Figure 4. A peak consistent with the protonated [M + H]+ mass of salvinorin A (within 5 mmu) at nominal m/z 433 was detected in each product.

Figure 4

Figure 4. DART-HR mass spectra for eight Salvia products, all of which contain a peak consistent with the protonated mass of salvinorin A.

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There are several molecules, in addition to salvinorin A, that are characteristic of Salvia spp., including salvinorins B–J (39) and divinatorins A–C. (40) Protonated masses consistent (within 10 mmu) with several of these molecules were detected throughout the DART-HRMS analysis of the acquired Salvia products. These molecules are listed in Table S1 and further confirm the identity of the Salvia plant materials as derived from S. divinorum.

Determining the Feasibility of Cholesterol as an Internal Standard for Quantification Studies

Deuterated internal standards have been used in previously reported DART-HRMS quantification investigations. (27,30,31,34) However, since no deuterium-labeled salvinorin A was commercially available, cholesterol was investigated as an alternative, given the similarity of some elements of its scaffold to that of salvinorin A. Because some plants are known to contain cholesterol, its presence in the various S. divinorum products was assessed. Although DART-HRMS soft ionization conditions often detect protonated precursors, there are occasions where adducts (e.g., +NH4+) or dehydrated (e.g., −H2O) versions of the molecule occur. This is influenced by the unique chemical structures of various molecules and the mechanisms by which they interact with the metastable helium (among other constituents present under ambient conditions). No peaks consistent with the protonated [M + H]+ ([C27H46O + H]+ calc. 387.3627) or the protonated-dehydrated [M – H2O + H]+ ([C27H46O – H2O + H]+ calc. 369.3516) masses of cholesterol were observed in any Salvia products. This finding supported its suitability as an internal standard in these quantification studies. Furthermore, based on the analyte response (i.e., relative abundance and ion counts) observed by DART-HRMS analysis of cholesterol, the ion (i.e., m/z value) consistent with [M – H2O + H]+ was used to generate peak area ratios throughout the quantification experiments.

Validation of DART-HRMS Protocol for the Quantification of Salvinorin A

Method validation for the DART-HRMS quantitative investigations of Salvia products was conducted in accordance with the U.S. FDA Bioanalytical Method Validation: Guidelines for Industry. (38) Following these recommendations, a standard curve was developed with seven nonzero calibrators covering the quantification range. Accompanying the curve were two additional calibrators: (1) a blank calibrator, defined as containing no analyte or internal standard; and (2) a zero calibrator classified as a blank calibrator with internal standard at the concentration used throughout the quantification experiments. To demonstrate the reproducibility and consistency of the developed method, the curve was prepared and analyzed by DART-HRMS on three separate days. The requirements that the blank and zero calibrators not produce any peaks that may interfere with the analyte of interest or that might interfere with quantification efforts were met. Thus, the analyte response of the lowest nonzero calibrator (5 mg/L) was greater than 5 times the response produced by the zero calibrator. This demonstrates method sensitivity, in addition to enabling the determination that the 5 mg/L calibrator coincided with the lower limit of quantification (LLOQ).
The guidelines indicate that two sets of quality control (QC) standards at four concentration levels must span the quantification range, including at the LLOQ, and that these should accompany the curve during each DART-HRMS acquisition. These standards were each analyzed in triplicate at the following levels: 175 mg/L (high), 80 mg/L (medium), 15 mg/L (low), and 5 mg/L (LLOQ). According to the FDA guidelines, for a run to be considered validated, the nonzero calibrators must be within ±15% of their nominal (theoretical) concentration. The one exception is that the LLOQ calibrator can be within ±20% of the nominal concentration. Regarding QCs, ≥50% of the replicates at each level must be within ±15% of their nominal concentrations and ≥67% of the total QC replicates must be within ±15% of the nominal concentrations.
For each of the 3 days that the curve was analyzed, and for all subsequent plant material analyses, all of the recommended validation guidelines were met. In addition, it is worth noting that each of the three validated curves had an R2 value of ≥0.9977. The three curves used to validate the method are shown in Figure 5.

Figure 5

Figure 5. Validated standard curves for salvinorin A quantification developed from DART-HRMS data.

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Quantification of Salvinorin A in Commercial Salvia Products

Qualitative and quantitative investigations of salvinorin A in Salvia products and plant materials have been conducted using several common approaches, including GC-MS, LC-MS, TLC, and HPLC. Additional studies have applied other techniques for the analysis of Salvia plant materials including liquid chromatography/electrospray ionization multistage ion trap mass spectrometry (LC/ESI-IT-MSn) (41) and two-dimensional gas chromatography–time-of-flight mass spectrometry (GCxGC-TofMS). (42) Products analyzed in these studies ranged from raw plant materials to leaves with strengthened potency, with samples acquired through various means (e.g., smartshops, online vendors, or grown on-site). (41,42) However, the chromatography-based methods employed typically require time-consuming sample preparation, lengthy run times, and extensive method development.
The concentrations of salvinorin A in raw Salvia leaves reported in previous studies range from 0.89 to 7.8 mg/g. (20−22,41,43) Salvia stems have also been investigated and were found to contain less than 0.63 mg/g of salvinorin A. (21) Significant effort has been dedicated to quantifying salvinorin A in enhanced Salvia leaf products. Concentrations or concentration ranges published to date and organized according to the potency listed on the product labels are as follows: 4.10 mg/g (2×), 1.64 mg/g (3×), 0.13–18.2 mg/g (5×), 6.60 mg/g (7×), 0.56–35.8 mg/g (10×), 15.50 mg/g (14×), 20.9–33.18 mg/g (15×), 0.46–44.5 mg/g (20×), 38.90 mg/g (25×), 28.91–155.6 mg/g (40×), 521.2 mg/g (60×), 36.32 mg/g (70×), and 54.80 mg/g (100×). (20−23,43,44)
The study presented here features raw Salvia leaves and multiple enhanced leaf products of various potency levels. Salvia extracts were spiked with internal standard (cholesterol) and analyzed by DART-HRMS alongside calibrators and two sets of QC standards. The peak area ratios developed between the salvinorin A [M + H]+ peak ([C23H28O8+H]+ calc. 433.1857) and the cholesterol ([C27H46O – H2O + H]+ calc. 369.3516) were used to determine the concentration of salvinorin A in the plant extracts, and by extension, the original amount in the enhanced plant materials and raw leaf. To consider an extract concentration accurate, the peak area ratio between the analyte and internal standard peaks must fall within the linear range of quantification established by the calibration curve; this was the case for all eight of the experimentally acquired peak area ratios. The observed salvinorin A concentrations are listed in Table 1. The product with the lowest salvinorin A content (1.54 mg/g) was the raw leaves from Arena Ethnobotanicals, which was expected considering that all seven of the other products were purchased as enhanced materials. The enhanced leaf products yielded concentrations ranging from 13.0 to 53.2 mg/g. These concentrations represent the average results obtained from three separate runs of the calibration curve and QCs (prepared fresh each day).
Table 1. Salvinorin A Concentrations Measured in Commercial Salvia Products and Plant Materials
commercial Salvia productvendoraverage salvinorin A concentration (mg/g)
Salvia LeavesArena Ethnobotanicals1.54
Salvia 5×Arena Ethnobotanicals13.0
Salvia 10×Salvia Dragon32.4
Salvia 15×Arena Ethnobotanicals20.9
Salvia 20×Salvia Dragon16.7
Salvia 40×Salvia Dragon24.6
Salvia 50×Arena Ethnobotanicals53.2
Salvia 60×Salvia Dragon29.3
These salvinorin A results, which are shown in bar chart form in Figure 6, are fairly similar to those appearing in the reports published to date. (20−23,43,44) In particular, the salvinorin A concentration in the raw Salvia leaves and Salvia 5×, 10×, 15×, and 20× products all fall within the ranges reported in the literature. Nevertheless, there were some deviations between the experimentally determined and literature values of salvinorin A, for the Salvia 40× and Salvia 60× products, in that they fell below previously reported values or ranges. To the authors’ knowledge, this is the first report of the analysis of a commercial Salvia product with a labeled potency of “50×”, and therefore there are no literature-reported values to which to compare the results obtained for analysis of this potency.

Figure 6

Figure 6. Salvinorin A concentrations measured in commercial Salvia products illustrated in bar chart form, demonstrating the trends between products of different strengthened potency.

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Although the Salvia 10× product fell within the range of reported literature concentrations of other 10× products, this material had a higher salvinorin A concentration than the Salvia 20×, Salvia 40×, and Salvia 60× products that were purchased from the same online vendor. This observation may be a consequence of the use of S. divinorum leaves with a very high natural concentration of salvinorin A for the preparation of the Salvia 10× extract, while the Salvia 20×, 40×, and 60× extracts may have been derived from leaves with lower natural concentrations of salvinorin A. In addition to the fact that they were purchased from different vendors, this explanation may also account for the differences between the Salvia 50× and 60× products, where the Salvia 60× had a significantly lower salvinorin A concentration than the Salvia 50×.
It is also notable that while S. divinorum is the only known Salvia species to contain salvinorin A, there are other known salvinorin derivatives. (39) These include salvinorin B (also referred to as divinorin B), for which an authentic chemical standard is available, and salvinorins D and E which share the same molecular formula as salvinorin A ([C23H28O8+H]+ calc. 433.1857). Therefore, the salvinorin A concentrations reported here represent the upper limit of salvinorin A that could be present in the various samples. Based on previous studies, (41) in comparison to salvinorin A, the contribution of these isomers (i.e., salvinorins D and E) is minor. Although their exact contributions to the signal observed at m/z 433 could not be confirmed due to the lack of available chemical standards for most salvinorin and divinatorin derivatives, it can be inferred that the majority of the total signal produced at m/z 433 is contributed by the salvinorin A content in the plant material that was analyzed here. While this supposition could not be confirmed in this study, it should be noted that the method presented here is nevertheless useful because it provides rapid assessment of whether confirmatory testing (e.g., GC-MS) is required to determine the extent of any contributions from salvinorins B–J.

Conclusions

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The increasing popularity of Salvia, the ease of purchasing and obtaining its related products, and its association with several deaths, all support the UNODC’s decision to include Salvia as one of the 20 plants of concern. Therefore, a method to facilitate laboratory identification of otherwise indistinguishable plant materials as S. divinorum or S. divinorum-derived, as well as the ability to quantify the psychoactive constituent, is highly desirable. The validated DART-HRMS method presented here meets the demand by providing a means by which to rapidly screen for Salvia plant material and quantify salvinorin A. In comparison to other published methods, it proved to be simple, fast, and effective, following a straightforward extraction procedure. The use of a nondeuterated internal standard offers an added benefit. These results further support the use of DART-HRMS protocols for the quantification of psychoactive small molecules in plant species of concern. In addition, the developed method reveals the ability to create additional validated DART-HRMS protocols to aid investigations across multiple fields (e.g., environmental science, forensics, food chemistry, toxicology, etc.).

Materials and Methods

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Salvia Products

All Salvia products were purchased from online vendors. Salvia Leaf, Salvia 5×, Salvia 15×, and Salvia 50× products were purchased from Arena Ethnobotanicals (Del Mar, CA). Salvia 10×, Salvia 20×, Salvia 40×, and Salvia 60× products were purchased from Salvia Dragon (Los Angeles, CA).

Chemical Standards

Salvinorin A was purchased from Cayman Chemical (Ann Arbor, MI). Cholesterol was purchased from Fisher Scientific (Pittsburgh, PA). Methanol was acquired from Pharmco (Brookfield, CT). Nitrogen and ultra high purity helium gases were obtained from AirGas (Albany, NY).

Preparation of Stock Solutions and Calibrators

To quantify the salvinorin A in Salvia products, standard curves were developed using salvinorin A calibrators. Cholesterol was used as an internal standard. Stock solutions of salvinorin A and cholesterol (500 mg/L each) were made by dissolving 10.0 mg in 20 mL of methanol. Seven salvinorin A calibrators ranging from 10 to 400 mg/L with final volumes of 250 μL were prepared by serial dilution. After diluting the 500 mg/L cholesterol stock solution to 50 mg/L, this internal standard was added in 250 μL aliquots to each calibrator, bringing the final volume to 500 μL for each (diluting the original concentrations by half). The final standard curve range was 5 to 200 mg/L, with an internal standard concentration of 25 mg/L. A blank calibrator of 500 μL of methanol and zero calibrator composed of 250 μL of methanol and 250 μL of 50 mg/L cholesterol accompanied the seven calibrators for validation purposes (see below). All calibrators and controls were analyzed by DART-HRMS in triplicate.

Preparation of Quality Control Standards

In accordance with the U.S. FDA Bioanalytical Method Validation: Guidelines for Industry, (38) two QC stock solutions of salvinorin A were prepared independent of the salvinorin A stock solution used to make the curve calibrators. These were created by dissolving 10.0 mg of salvinorin A in 20 mL of methanol and were labeled QC 1 and QC 2 to represent the two sets of QC standards. To follow the validation guidelines, QC standards at four levels (i.e., high, medium, low, and the LLOQ) must accompany the curve in each DART-HRMS acquisition. The concentrations selected for this validation, prepared in the same manner as the curve calibrators, were as follows: 175 mg/L (high), 80 mg/L (medium), 15 mg/L (low), and 5 mg/L (LLOQ). Furthermore, in accordance with the guidelines, the QC standards from each set were freshly prepared each day from their respective stock solutions on the three days the curve was run. All QC standards were analyzed in replicates of five.

Sample Preparation and Data Acquisition for Salvia Plant Materials

All Salvia plant materials were analyzed in replicates of three, meaning that in a single DART-HRMS acquisition, three replicates of the analyzed product were introduced to the DART gas stream independently. Sampling was performed by either holding the material with tweezers (for whole dried leaves) or dipping the closed end of a glass melting point capillary tube into the plant material (for enhanced Salvia leaf products), and presenting it to the open-air gap between the mass spectrometer inlet and DART ion source for approximately 5 s.
Once the DART-HRMS quantification method had been validated, the eight Salvia products were prepared for quantification experiments. Approximately 1 g of the whole dried Salvia leaf was ground using a mortar and pestle to increase the surface area exposed to the solvent during the extraction. The crushed leaves were suspended in 10 mL of methanol in a 20 mL scintillation vial. Approximately 200 mg of the remaining seven enhanced Salvia leaf products was suspended in 5 mL of methanol in a 20 mL scintillation vial. The eight product samples were sonicated for 20 min and placed on a 3D Rotator Mixer (Benchmark Scientific, Inc., Edison, NJ) overnight. The solution was decanted into a 10 mL volumetric flask and diluted accordingly. A 2 mL aliquot was removed and placed into a 2 mL plastic Eppendorf tube (Fisher Scientific, Pittsburgh, PA). All plant samples were centrifuged at 1000 g for 5 min. A 250 μL aliquot of the supernatant was added to a new 2 mL plastic tube and diluted to 500 μL with 250 μL of the 50 mg/L cholesterol internal standard solution. To confirm that the salvinorin A was exhaustively extracted from the plant material, the remaining plant samples were subjected to a second round of extraction and the supernatant was analyzed by DART-HRMS. The first round of extraction was considered sufficient because no peak consistent with the protonated mass of salvinorin A was detected in the solutions collected from the second round of extractions.

DART-HRMS Mass Spectral Acquisition and Data Processing

DART-HRMS-derived data for all chemical standards and Salvia products were obtained using a DART-SVP ion source (IonSense, Saugus, MA) coupled to a JEOL AccuTOF high-resolution time-of-flight (TOF) mass spectrometer (JEOL USA, Peabody, MA) in positive-ion mode. The following parameters were used to perform DART-HRMS soft ionization experiments: ring lens voltage, 5 V; orifice 1 voltage, 20 V; orifice 2 voltage, 5 V; peak voltage, 600 V; detector voltage, 2000 V; and resolving power, 6000 FWHM (full width at half-maximum). When experiments were conducted under collision-induced dissociation (CID) conditions, the orifice 1 voltage (which controls the extent to which fragmentation of the molecules occurs) was adjusted to 90 V to increase the extent to which the molecule(s) present fragment. All mass spectra were collected over the range m/z 60–1000 at a rate of 1 spectrum/s. The DART ion source was operated using the following parameters: helium flow rate, 2 L/min; grid voltage, 250 V; and heater temperature, 350 °C. Poly(ethylene glycol) (PEG 600) (Sigma-Aldrich, St. Louis, MO) was used as the mass calibrant for all DART-HRMS acquisitions. Calibration of mass spectral data, spectral averaging, background subtraction, peak centroiding, and peak integration were performed using TSSPro 3.0 software (Shrader Software Solutions, Grosse Point, MI). Analysis of mass spectral data was conducted using the Mass Mountaineer software suite (RBC Software, Portsmouth, NH).

DART-HRMS Semiautomated Quantification of Salvinorin A in Salvia Products

DART-HRMS allows for semiautomated quantification through the use of a 12 DIP-it Holder (IonSense, Saugus, MA) device that is mounted on a linear rail system. The calibrators, standards, and extracts were deposited onto DIP-it Tips (IonSense, Saugus, MA) (referred to as tips) using a dipping method. The tips were inserted into the 2 mL plastic tubes containing the various calibrators and extracts until the tip touched the bottom of the tube. The tips were then removed from the 2 mL plastic tubes and affixed to the holder. A visual assessment was conducted to ensure consistency in the height of the tips. The holder was moved across the DART-HRMS linear rail system at a speed of 1 mm/s. This optimal speed introduced each of the tips to the DART ion stream independently and avoided carryover and cross-contamination from one replicate to the next.
The same calibrators created to validate the standard curve were used to quantify the amount of salvinorin A in the Salvia products. As was performed in the method validation, QC standards were prepared fresh on each of the three days that the curve was run. The calibrators were analyzed in replicates of three, while the QC standards and Salvia extracts were analyzed in replicates of five.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06106.

  • Mass measurements and relative intensities of salvinorins and divinatorins in Salvia products (PDF)

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  • Corresponding Author
  • Authors
    • Megan I. Chambers - Department of Chemistry, University at Albany State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
    • Justine E. Giffen-Lemieux - Department of Chemistry, University at Albany State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This project was supported by grant nos. 2015-DN-BX-K057, 2017-R2-CX-0020, and 2019-BU-DX-0026 awarded by the National Institute of Justice (NIJ), Office of Justice Programs, U.S. Department of Justice (DOJ) to R.A.M. The support of the U.S. National Science Foundation (NSF) under grant no. 1429329 to R.A.M. is also gratefully acknowledged. The opinions, findings, and conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect those of the NIJ, DOJ, or NSF.

References

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This article references 44 other publications.

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    The bicyclic diterpene salvinorin (I) was isolated from the leaves of S. divinorum and characterized by spectral and x-ray crystallog. anal.
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    Salvia divinorum is a hallucinogenic herb that is internationally regulated. In this study, salvinorin A, the active compd. in S. divinorum, was extd. from S. divinorum plant leaves using a 5-min extn. with dichloromethane. Four addnl. Salvia species (Salvia officinalis, Salvia guaranitica, Salvia splendens, and Salvia nemorosa) were extd. using this procedure, and all exts. were analyzed by gas chromatog.-mass spectrometry. Differentiation of S. divinorum from other Salvia species was successful based on visual assessment of the resulting chromatograms. To provide a more objective comparison, the total ion chromatograms (TICs) were subjected to principal components anal. (PCA). Prior to PCA, the TICs were subjected to a series of data pretreatment procedures to minimize non-chem. sources of variance in the data set. Successful discrimination of S. divinorum from the other four Salvia species was possible based on visual assessment of the PCA scores plot. To provide a numerical assessment of the discrimination, a series of statistical procedures such as Euclidean distance measurement, hierarchical cluster anal., Student's t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores. The statistical procedures were then compared to det. the advantages and disadvantages for forensic applications.
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    Determination of salvinorin A and salvinorin B in Salvia divinorum-related products circulated in Japan
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    Gruber, John W.; Siebert, Daniel J.; Der Marderosian, Ara H.; Hock, Rick S.
    Phytochemical Analysis (1999), 10 (1), 22-25CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
    A reversed-phase HPLC method for the detn. of salvinorin A, a psychotropic diterpene isolated from the Mexican sage S. divinorum, was developed. Exts. from several plant collections were examd. on a C-18 column with UV detection and isocratic elution with MeCN-H2O (45:55). This assay allowed quantification of salvinorin A in exts. of leaves and stems of S. divinorum and was also applied to the screening of related species for the prodn. of salvinorin A. Levels of salvinorin A in leaves range from 0.89 to 3.70 mg/g dry wt.
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  22. 22
    Lin, P.-X.; Li, J.-H.; Chen, S.-H.; Chang, H.-C.; McKetin, R. Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan. J. Food Drug Anal. 2014, 22, 370– 378,  DOI: 10.1016/j.jfda.2014.01.017
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    Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan
    Lin, Po-Xiang; Li, Jih-Heng; Chen, Su-Hwei; Chang, Hsien-Chang; McKetin, Rebecca
    Journal of Food and Drug Analysis (2014), 22 (3), 370-378CODEN: JFDAAF; ISSN:1021-9498. (Elsevier B.V.)
    In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum and its related concd. ext. products are available via the Internet. Besides S. divinorum, there are many endemic Salvia species whose salvinorin A content is yet unknown. To understand the abuse liability of these products, the aim of this study was to assess the concn. of salvinorin A in endemic Salvia species and Internet-available salvinorin A-related products. Samples of S. divinorum were purchased via the Internet and samples of eight endemic species of Salvia were collected in Taiwan, including S. arisanensis Hayata, S. coccinea Juss. ex Murr, S. hayatana Makino ex Hayata, S. japonica Thumb. ex Murr, S. nipponica Miq. Var. formosana (Hayata) Kudo, S. scapiformis Hance, S. tashiroi Hayata. IconΠFormosan, and S. keitaoensis Hayata. The content of salvinorin A was detd. by high performance liq. chromatog. (HPLC). Salvinorin A was extd. from the dry leaves of S. divinorum and endemic species of Salvia with methanol and analyzed on a C-18 column by isocratic elution with a mobile phase of acetonitrile-water. Salvinorin A was detected in S. divinorum, but not in the endemic Salvia species of Taiwan. Therefore, endemic species of Salvia in Taiwan may not possess hallucinogenic potential. However, the potential harm from S. divinorum available via the Internet should be thoroughly assessed in Taiwan, and control measures similar to those implemented in many other countries should be considered.
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  23. 23
    Hernández-Bello, R.; García-Rodríguez, R. V.; García-Sosa, K.; Peña-Rodríguez, L. M.; Vázquez-Hernández, M.; Ramos-Morales, F. R.; Corcoran, O.; Sánchez-Medina, A. Salvinorin A content in legal high products of Salvia divinorum sold in Mexico. Forensic Sci. Int. 2015, 249, 197– 201,  DOI: 10.1016/j.forsciint.2015.01.038
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    Salvinorin A content in legal high products of Salvia divinorum sold in Mexico
    Hernandez-Bello, Rafael; Garcia-Rodriguez, Rosa Virginia; Garcia-Sosa, Karlina; Pena-Rodriguez, Luis Manuel; Vazquez-Hernandez, Maribel; Ramos-Morales, Fernando Rafael; Corcoran, Olivia; Sanchez-Medina, Alberto
    Forensic Science International (2015), 249 (), 197-201CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf exts. of S. divinorum are sold in different strengths, claiming to correlate with increasing amts. of salvinorin A. In order to det. the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in com. products available in Mexico using an HPLC method. The HPLC anal. method showed a correlation coeff. R2 > 0.99, with LOD of 0.44 μg/mL and LOQ of 1.34 μg/mL. The retention time for salvinorin A was 23.09 ± 0.95 min and the measured concns. ranged between 8.32 ± 0.65 and 56.52 ± 3.77 mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calcd. amt. of salvinorin A. Addnl., the emergence in Mexico of high strength salvia products (100×), the lack of regulation and the obsd. variability of salvinorin A content between brands of com. legal highs products of S. divinorum could result in a health problem for consumers.
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  24. 24
    Cody, R. B.; Laramée, J. A.; Durst, H. D. Versatile new ion source for the analysis of materials in open air under ambient conditions. Anal. Chem. 2005, 77, 2297– 2302,  DOI: 10.1021/ac050162j
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    24
    Versatile new ion source for the analysis of materials in open air under ambient conditions
    Cody, Robert B.; Laramee, James A.; Durst, H. Dupont
    Analytical Chemistry (2005), 77 (8), 2297-2302CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    A new ion source was developed for rapid, noncontact anal. of materials at ambient pressure and at ground potential. The new source, termed DART (for Direct Anal. in Real Time), is based on the reactions of electronic or vibronic excited-state species with reagent mols. and polar or nonpolar analytes. DART was installed on a high-resoln. time-of-flight mass spectrometer (TOFMS) that provides improved selectivity and accurate elemental compn. assignment through exact mass measurements. Although DART was applied to the anal. of gases, liqs., and solids, a unique application is the direct detection of chems. on surfaces without requiring sample prepn., such as wiping or solvent extn. DART demonstrated success in sampling hundreds of chems., including chem. agents and their signatures, pharmaceutics, metabolites, peptides and oligosaccharides, synthetic orgs., organometallics, drugs of abuse, explosives, and toxic industrial chems. These species were detected on various surfaces, such as concrete, asphalt, human skin, currency, airline boarding passes, business cards, fruits, vegetables, spices, beverages, body fluids, horticultural leaves, cocktail glasses, and clothing. DART employs no radioactive components and is more versatile than devices using radioisotope-based ionization. Because its response is instantaneous, DART provides real-time information, a crit. requirement for screening or high throughput.
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  25. 25
    Lesiak, A. D.; Fowble, K. L.; Musah, R. A. A rapid, high-throughput validated method for the quantification of atropine in Datura stramonium seeds using direct analysis in real time-high resolution mass spectrometry (DART-HRMS). In Methods in Molecular Biology; Springer, 2018; Vol. 1810, pp 207– 215.
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  26. 26
    Lesiak, A. D.; Cody, R. B.; Ubukata, M.; Musah, R. A. Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration-The case of Kanna. Forensic Sci. Int. 2016, 260, 66– 73,  DOI: 10.1016/j.forsciint.2015.12.037
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    Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration - The case of Kanna
    Lesiak, Ashton D.; Cody, Robert B.; Ubukata, Masaaki; Musah, Rabi A.
    Forensic Science International (2016), 260 (), 66-73CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    We demonstrate the utility of direct anal. in real time ionization coupled with high resoln. time-of-flight mass spectrometry (DART-HRTOFMS) in revealing the adulteration of com. available Sceletium tortuosum, a mind-altering plant-based drug commonly known as Kanna. Accurate masses consistent with alkaloids previously isolated from S. tortuosum plant material enabled identification of the products as Kanna, and in-source collision-induced dissocn. (CID) confirmed the presence of one of these alkaloids, hordenine, while simultaneously revealing the presence of an adulterant. The stimulant ephedrine, which has been banned in herbal products and supplements, was confirmed to be present in a sample through the use of in-source CID. High-throughput DART-HRTOFMS was shown to be a powerful tool to not only screen plant-based drugs of abuse for psychotropic alkaloids, but also to reveal the presence of scheduled substances and adulterants.
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  27. 27
    Fowble, K. L.; Musah, R. A. A validated method for the quantification of mitragynine in sixteen commercially available Kratom (Mitragyna speciosa) products. Forensic Sci. Int. 2019, 299, 195– 202,  DOI: 10.1016/j.forsciint.2019.04.009
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    A validated method for the quantification of mitragynine in sixteen commercially available Kratom (Mitragyna speciosa) products
    Fowble, Kristen L.; Musah, Rabi A.
    Forensic Science International (2019), 299 (), 195-202CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    The recent rise in the recreational use of plant-based "legal highs" has prompted the development of methods for the identification of the bulk material, and quantification of their psychoactive components. One of these plants is Mitragyna speciosa, commonly referred to as Kratom. While traditional use of this plant was primarily for medicinal purposes, there has been a rise in its recreational use, and as a self-prescribed medication for opioid withdrawal. Although Kratom contains many alkaloids, mitragynine and 7-hydroxymitragynine are unique psychoactive biomarkers of the species, and are responsible for its psychoactive effects. A rapid validated method for the quantification of mitragynine in Kratom plant materials by direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS) is presented. It has a linear range of 5-100μg mL-1, and a lower limit of quantification of 5μg mL-1. The protocol was applied to detn. of the mitragynine content of 16 com. available Kratom plant products purchased online. The mitragynine amts. in these materials ranged from 2.76 to 20.05 mg g-1 of dried plant material. The utilization of DART-HRMS affords a mechanism not only for the preliminary identification of bulk plant material as being M. speciosa-derived (with no sample prepn. required), but also provides the opportunity to quantify its psychoactive components using the same technique.
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  28. 28
    Lesiak, A. D.; Cody, R. B.; Dane, A. J.; Musah, R. A. Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: the case of Mitragyna speciosa aka “Kratom”. Forensic Sci. Int. 2014, 242, 210– 218,  DOI: 10.1016/j.forsciint.2014.07.005
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    Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: The case of Mitragyna speciosa aka "Kratom"
    Lesiak, Ashton D.; Cody, Robert B.; Dane, A. John; Musah, Rabi A.
    Forensic Science International (2014), 242 (), 210-218CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    Mitragyna speciosa, also known commonly as "Kratom" or "Ketum", is a plant with psychoactive properties that have been attributed to the presence of various indole alkaloids such as mitragynine and 7-hydroxymitragynine. M. speciosa use is gaining popularity internationally as a natural and legal alternative to narcotics. As a drug of abuse, its detection and identification are not straightforward, since M. speciosa plant material is not particularly distinctive. Here, we show that direct anal. in real time-mass spectrometry (DART-MS) can be used not only to rapidly identify M. speciosa plant material and distinguish it from other plants, but also to distinguish between M. speciosa plant varieties, based on differences between their chem. profiles. The method is rapid and the anal. expeditious. Plant material such as that found at a crime scene can be analyzed directly with no sample pre-prepn. steps. Furthermore, we show that the basis set of principal components that permit characterization of the plant material can be used to pos. identify M. speciosa.
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  29. 29
    Lesiak, A. D.; Musah, R. A. More than just heat: Ambient ionization mass spectrometry for determination of the species of origin of processed commercial products─application to psychoactive pepper supplements. Anal. Methods 2016, 8, 1646– 1658,  DOI: 10.1039/C5AY02570B
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    There is no corresponding record for this reference.
  30. 30
    Chambers, M. I.; Osborne, A. M.; Musah, R. A. Rapid detection and validated quantification of psychoactive compounds in complex plant matrices by direct analysis in real time-high resolution mass spectrometry - Application to “Kava” psychoactive pepper products. Rapid Commun. Mass Spectrom. 2019, 33, 1915– 1925,  DOI: 10.1002/rcm.8532
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    Rapid detection and validated quantification of psychoactive compounds in complex plant matrices by direct analysis in real time-high resolution mass spectrometry - application to "Kava" psychoactive pepper products
    Chambers, Megan I.; Osborne, Amy M.; Musah, Rabi A.
    Rapid Communications in Mass Spectrometry (2019), 33 (24), 1915-1925CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
    Rationale : Classified by the UNODC as a top 20 plant of concern, Piper methysticum (also known as Kava) is being increasingly abused recreationally for its mind-altering effects. It is of significant forensic relevance to establish methods to rapidly identifyand quantify psychoactive compds., esp. those yet to be scheduled as controlled substances and which have exhibited various noteworthy health concerns. Methods : Direct anal. in real time high-resoln. mass spectrometry (DART-HRMS) demonstrated the ability to detect a range of kavalactones in Piper methysticum derived products and plant material with no sample prepn. Inaddn., a validated method using calibration curves developed with a deuteratedinternal std. was used for the quantification of the psychoactive mol. yangonin in various products. Results : DART-HRMS detected the protonated masses of six major kavalactonesand three flavokavains in 18 com. Kava products. A method consistent with FDA validation guidelines was established for the quantification of yangonin in the various complex matrixes. Implementation of this method, with an LLOQ of 5 mg/mL, enabled successful quantification of yangonin in 16 Kava products. Concns. for solid products ranged from 2.71 to 8.99 mg/g, while that forliquid products ranged from 1.03 to 4.59 mg/mL. Conclusions : Rapid identification and quantification of psychoactive small mols. in plant material can be accomplished using a validated DART-HRMS protocol. This work illustrates an approach to qual. and quant. analyzes of a wide variety of complex matrixes derived from plants, and demonstrates that the com. available products analyzed are P. methysticum derived and do contain psychoactive yangonin at quantifiable levels.
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  31. 31
    Longo, C. M.; Musah, R. A. An efficient ambient ionization mass spectrometric approach to detection and quantification of the mescaline content of commonly abused cacti from the Echinopsis genus. J. Forensic Sci. 2020, 65, 61– 66,  DOI: 10.1111/1556-4029.14134
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    An Efficient Ambient Ionization Mass Spectrometric Approach to Detection and Quantification of the Mescaline Content of Commonly Abused Cacti from the Echinopsis Genus
    Longo, Cameron M.; Musah, Rabi A.
    Journal of Forensic Sciences (2020), 65 (1), 61-66CODEN: JFSCAS; ISSN:0022-1198. (John Wiley & Sons, Inc.)
    Unregulated cacti from the genus Echinopsis are used recreationally as mescaline-contg. alternatives to the outlawed peyote. Echinopsis-derived plant materials appear in a variety of nondescript forms, making rapid assessment of whether they are mescaline-contg. materials or simply innocuous plant-derived food products, very challenging. Reported here is a DART-HRMS approach for the rapid detection of mescaline in whole plant material and a validated method for the quantification of mescaline in cactus tissue, using mescaline-d9 as the internal std. Calibration curves exhibited R2 values of ≥0.995, and the method exhibited a LLOQ and a linear range of 1 ppm and 1-100 ppm, resp. Application of the method to com. available Echinopsis spp. yielded results consistent with previous studies performed by GC- and LC-MS, with mescaline levels of <2% dry wt. in all cases. Therefore, DART-HRMS is a suitable technique for the rapid screening of mescaline and its subsequent quantification within complex plant-derived matrixes.
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  32. 32
    Musah, R. A.; Domin, M. A.; Cody, R. B.; Lesiak, A. D.; Dane, A. J.; Shepard, J. R. Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids. Rapid Commun. Mass Spectrom. 2012, 26, 2335– 42,  DOI: 10.1002/rcm.6354
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    Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids
    Musah, Rabi A.; Domin, Marek A.; Cody, Robert B.; Lesiak, Ashton D.; John Dane, A.; Shepard, Jason R. E.
    Rapid Communications in Mass Spectrometry (2012), 26 (19), 2335-2342CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
    RATIONALE: The emergence of numerous cannabinoid designer drugs has been tied to large spikes in emergency room visits and overdoses. Identifying these substances is difficult for the following reasons: (1) the compds. are novel, closely structurally related, and do not usually test pos. in drug screens; (2) novel analogs rapidly appear on the market; (3) no std. protocols exist for their identification; and (4) customized and extensive sample prepn./extn. and anal. procedures are required to demonstrate their presence. METHODS: Direct anal. in real time mass spectrometry (DART-MS) employing collision-induced dissocn. (CID) provided confirmatory structural information that was useful in characterizing the various cannabinoid analogs, including those contained in mixts. CID anal. illustrated that, although closely related compds. fragment in a similar fashion, their structural differences still resulted in multiple diagnostic peaks that provided addnl. confidence towards structural identification. RESULTS: DART-MS spectra were acquired under CID conditions to rapidly differentiate among five synthetic cannabinoids contained within 'herbal' products purchased locally in New York State (USA). The spectra exhibited [M+H]+ ions and product ions unique to each cannabinoid that corresponded to major structural features. Five different cannabinoid analogs, alone and as mixts. of at least two cannabinoids, were identified in six herbal products and differentiated by their CID product ion patterns. CONCLUSIONS: Illicit synthetic cannabinoid products continue to be readily available despite national and international restrictions. These products contain a wide range of active components, and, in many cases, multiple active ingredients. DART-MS allows rapid analyses of these synthetic cannabinoids based on the exact masses of their [M+H]+ ions and product ion peaks generated using CID. Copyright © 2012 John Wiley & Sons, Ltd.
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  33. 33
    Chambers, M. I.; Appley, M. G.; Longo, C. M.; Musah, R. A. Detection and quantification of psychoactive N,N-dimethyltryptamine in ayahuasca brews by ambient ionization high-resolution mass spectrometry. ACS Omega 2020, 5, 28547– 28554,  DOI: 10.1021/acsomega.0c03196
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    Detection and Quantification of Psychoactive N,N-Dimethyltryptamine in Ayahuasca Brews by Ambient Ionization High-Resolution Mass Spectrometry
    Chambers, Megan I.; Appley, Meghan G.; Longo, Cameron M.; Musah, Rabi A.
    ACS Omega (2020), 5 (44), 28547-28554CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    The United Nations Office on Drugs and Crime designated twenty psychoactive botanical species as "plants of concern" because of their increased recreational abuse. Four of these are used to prep. ayahuasca brews. The complexity of the plant matrixes, as well as the beverage itself, make the identification and quantification of the Schedule I component, N,N-dimethyltryptamine (DMT), a time-consuming and resource-intensive endeavor when performed using conventional approaches previously reported. Reported here is the development of a rapid validated method for the quantification of DMT in ayahuasca by direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS). This ambient ionization approach also enables identification of ayahuasca through detection of the secondary metabolites assocd. with its plant constituents. Anal. of six ayahuasca brews created using different combinations of DMT/harmala alkaloid-contg. plants resulted in beverages with DMT levels of 45.7-230.5 mg/L. The detected amts. were consistent with previously reported values detd. by conventional approaches.
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  34. 34
    Appley, M. G.; Chambers, M. I.; Musah, R. A. Quantification of hordenine in a complex plant matrix by direct analysis in real time–high-resolution mass spectrometry: Application to the “plant of concern” Sceletium tortuosum. Drug Test. Anal. 2022, 14, 604– 612,  DOI: 10.1002/dta.3193
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    Quantification of hordenine in a complex plant matrix by direct analysis in real time-high-resolution mass spectrometry: Application to the "plant of concern" Sceletium tortuosum
    Appley, Meghan Grace; Chambers, Megan Isabella; Musah, Rabi Ann
    Drug Testing and Analysis (2022), 14 (4), 604-612CODEN: DTARBG; ISSN:1942-7603. (John Wiley & Sons Ltd.)
    Recently, there has been an increase in the recreational abuse of several psychoactive plants, resulting in the United Nations Office on Drugs and Crime creating a list of "plants of concern.". One such material is Sceletium tortuosum and products derived from it. Regulation of these materials is challenging because of their innocuous appearance, the cumbersome sample prepn. steps required to render the material into a form amenable to anal. by conventional techniques, the requirement for nuanced sample anal. protocols, and lengthy anal. times. It is demonstrated here that direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS) can be used to not only identify S. tortuosum material based on the detection of characteristic biomarkers including hordenine and several mesembrine alkaloids, but also quantify the amt. of hordenine present. Using hordenine-d6 as an internal std., a protocol, validated according to US Food and Drug Administration (FDA) Guidelines for the Development and Validation of Bioanal. ,methods was devised for the quantification of the psychoactive component hordenine. The method was then applied to the quantification of hordenine in six com. available products derived from the foliage and stems of S. tortuosum. By this method, the lower limit of quantification (LLOQ) was found to be 1μg/mL. Obsd. hordenine concns. ranged from 0.02738 to 1.071 mg of hordenine per g of plant material. The developed technique provides an effective and quick means for the detection and quantification of hordenine in S. tortuosum, which can be extended to anal. of other hordenine-contg. products.
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  35. 35
    Cody, R. B. Observation of molecular ions and analysis of nonpolar compounds with the direct analysis in real time ion source. Anay. Chem. 2009, 81, 1101– 1107,  DOI: 10.1021/ac8022108
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    Observation of molecular ions and analysis of nonpolar compounds with the direct analysis in real time ion source
    Cody, Robert B.
    Analytical Chemistry (Washington, DC, United States) (2009), 81 (3), 1101-1107CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Pos. ions in the direct anal. in real time (DART) ion source are commonly formed by proton transfer. However, the DART source is similar to atm. pressure photoionization (APPI) in that it can produce mol. ions as well as protonated mols., although the two sources differ in the initial ion formation process. This report discusses some of the factors that influence mol. ion formation in DART and shows how the DART source can be used to analyze difficult or nonpolar compds. such as alkanes and cholesterol. Trace reagent ions including NO+ and O2+· formed from atm. gases play important roles in DART ionization. The use of the DART source as a gas chromatog./mass spectrometry (GC/MS) interface is demonstrated to show the difference between mass spectra obtained using conditions that favor proton transfer and those that favor mol. ion formation.
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  36. 36
    Giffen, J. E.; Lesiak, A. D.; Dane, A. J.; Cody, R. B.; Musah, R. A. Rapid species-level identification of Salvias by chemometric processing of ambient ionisation mass spectrometry-derived chemical profiles. Phytochem. Anal. 2017, 28, 16– 26,  DOI: 10.1002/pca.2639
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    Rapid Species-level Identification of Salvias by Chemometric Processing of Ambient Ionisation Mass Spectrometry-derived Chemical Profiles
    Giffen, Justine E.; Lesiak, Ashton D.; Dane, A. John; Cody, Robert B.; Musah, Rabi A.
    Phytochemical Analysis (2017), 28 (1), 16-26CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
    Introduction : The Salvia genus contains numerous economically important plants that have horticultural, culinary and nutraceutical uses. They are often similar in appearance, making species detn. difficult. Species identification of dried Salvia products is also challenging since distinguishing plant morphol. features are no longer present. Objective : The development of a simple high-throughput method of anal. of fresh and dried Salvia leaves that would permit rapid species-level identification and detection of diagnostic biomarkers. Methodol. : Plant leaves were analyzed in their native form by DART-MS without the need for any sample prepn. steps. This furnished chem. fingerprints characteristic of each species. In the same expt., in-source collision-induced dissocn. was used to identify biomarkers. Biomarker presence was also independently confirmed by GC-MS. Chemometric processing of DART-MS profiles was performed by kernel discriminant anal. (KDA) and soft independent modeling of class analogy (SIMCA) to classify the fingerprints according to species. Results : The approach was successful despite the occurrence of diurnal cycle and plant-age related chem. profile variations within species. In a single rapid expt., the presence of essential oil biomarkers such as 3-carene, α-pinene, β-pinene, β-thujone, β-caryophyllene, camphor and borneol could be confirmed. The method was applied to rapid identification and differentiation of Salvia apiana, S. dominica, S. elegans, S. officinalis, S. farinacea and S. patens. Conclusion : Species-level identification of Salvia plant material could be accomplished by chemometric processing of DART-HRMS-derived chem. profiles of both fresh and dried Salvia material. Copyright © 2016 John Wiley & Sons, Ltd.
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    ACS Omega (2019), 4 (13), 15636-15644CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    The United Nations Office on Drugs and Crime has designated several "legal highs" as "plants of concern" because of the dangers assocd. with their increasing recreational abuse. Routine identification of these products is hampered by the difficulty in distinguishing them from innocuous plant materials such as foods, herbs, and species. It is demonstrated here that several of these products have unique but consistent headspace chem. profiles and that multivariate statistical anal. processing of their chem. signatures can be used to accurately identify the species of plants from which the materials are derived. For this study, the headspace volatiles of several species were analyzed by direct anal. in real-time high-resoln. mass spectrometry (DART-HRMS). These species include Althaea officinalis, Calea zacatechichi, Cannabis indica, Cannabis sativa, Echinopsis pachanoi, Lactuca virosa, Leonotis leonurus, Mimosa hostilis, Mitragyna speciosa, Ocimum basilicum, Origanum vulgare, Piper methysticum, Salvia divinorum, Turnera diffusa, and Voacanga africana. The results of the DART-HRMS anal. revealed intraspecies similarities and interspecies differences. Exploratory statistical anal. of the data using principal component anal. and global t-distributed stochastic neighbor embedding showed clustering of like species and sepn. of different species. This led to the use of supervised random forest (RF), which resulted in a model with 99% accuracy. A conformal predictor based on the RF classifier was created and proved to be valid for a significance level of 8% with an efficiency of 0.1, an obsd. fuzziness of 0, and an error rate of 0. The variables used for the statistical anal. processing were ranked in terms of the ability to enable clustering and discrimination between species using principal component anal.-variable importance of projection scores and RF variable importance indexes. The variables that ranked the highest were then identified as m/z values consistent with mols. previously identified in plant material. This technique therefore shows proof-of-concept for the creation of a database for the detection and identification of plant-based legal highs.
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    A review. Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzon de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolyzed smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT2A receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biol. processes responsible for its obsd. psychol. effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.
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    Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry
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    Salvinorin A is the most potent naturally occurring hallucinogen known and rivals synthetic LSD in potency. Structurally it belongs to the neoclerodane diterpenoids, and it is the only known non-nitrogenous kappa-opioid-selective agonist. Salvia divinorum (Diviner's sage) is a member of the mint family that was used in ancient Mexican traditional practices. Today it is widely cultivated in Europe as a recreational marijuana substitute; it is illegal to buy, sell or possess the plant or the active principle in some countries. Six different salvinorins and three divinatorins have been isolated from Salvia divinorum leaves. The ion fragmentation, separation and quantitation of these diterpenes by liquid chromatography/electrospray ionization multistage mass spectrometry (LC/ESI-MS(n)) are described. The importance of LC in herbal extract determination and the chemical diagnostic power of MS(n) in the analysis of classes of natural organic products are discussed.
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    Analysis of Salvinorin A in plants, water, and urine using solid-phase microextraction-comprehensive two-dimensional gas chromatography-time of flight mass spectrometry
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    Salvinorin A, a psychoactive hallucinogen, and related compds., were analyzed in plants, water, and urine using liq.-liq. extn. (LLE), solid-phase microextn. (SPME) and comprehensive 2-dimensional gas chromatog.-time of flight mass spectrometry (GC × GC-ToFMS). A semi-qual. study of the extn. of Salvinorin A and analogs from Salvia divinorum plants by LLE showed ppb levels of Salvinorin A and several analogs in the leaves and stems of S. divinorum plants, much lower than expected. Quant. anal. of Salvinorin A spiked into water and urine showed much better figures of merit for SPME than LLE, with limit of detection of about 5 ng/mL, linear range from 8 to 500 ng/mL, and precision about ±10% for the SPME-based analyses using external std. quantitation. GC × GC-ToFMS was esp. effective in sepg. the peaks of interest from matrix and chromatog. interferences.
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    Analysis of the psychoactive terpenoid salvinorin A content in five Salvia divinorum herbal products
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    Xavier Moreira, F.; Carvalho, F.; de Lourdes Bastos, M.; Guedes de Pinho, P. Analytical investigation of legal high products containing Salvia divinorum traded in smartshops and internet. Forensic Sci. Int. 2014, 242, 255– 260,  DOI: 10.1016/j.forsciint.2014.07.009
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    Analytical investigation of legal high products containing Salvia divinorum traded in smartshops and internet
    Xavier Moreira, Fernando; Carvalho, Felix; de Lourdes Bastos, Maria; Guedes de Pinho, Paula
    Forensic Science International (2014), 242 (), 255-260CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
    Lately, the hallucinogenic plant Salvia divinorum has been considered a popular recreational product among adolescents, being legally sold in several countries in "smartshops" and in internet websites. Sellers frequently omit the safety information about the plant, encouraging its use for recreational purposes, without providing adequate qual. and quant. details. The principal hallucinogenic compd. of the plant, salvinorin A, alongside with three other isomeric compds., salvinorin B, C and D were evaluated in 10 products contg. S. divinorum. These products were obtained in smartshops and from internet websites, and contained concd. exts. of salvinorin A, with potencies labeled between "5x" and "60x". For that purpose a simple and rapid extn. protocol and a GC-MS methodol. were developed and applied to the purchased samples. The anal. of S. divinorum samples allowed the identification of four salvinorins, salvinorin A being the most prevalent hallucinogen. In the tested samples, there were several unreliable data provided to consumers. Frequently, there was no information on salvinorin A concn., but when it existed, it generally did not correspond to the true amt. present in products. On the other hand, the concn. of salvinorin A in each product far exceeded the amt. needed to produce hallucinogenic effects.
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  • Abstract

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    Figure 1

    Figure 1. Commercial Salvia products purchased from online vendors.

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    Figure 2

    Figure 2. Head-to-tail renderings of the DART mass spectra of raw Salvia leaf and an authentic salvinorin A standard analyzed under soft ionization conditions at 20 V (A) and under CID conditions at 90 V (B).

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    Figure 3

    Figure 3. Representative DART mass spectra of two commercial Salvia products: raw Salvia leaf (A) and an enhanced Salvia leaf extract (B).

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    Figure 4

    Figure 4. DART-HR mass spectra for eight Salvia products, all of which contain a peak consistent with the protonated mass of salvinorin A.

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    Figure 5

    Figure 5. Validated standard curves for salvinorin A quantification developed from DART-HRMS data.

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    Figure 6

    Figure 6. Salvinorin A concentrations measured in commercial Salvia products illustrated in bar chart form, demonstrating the trends between products of different strengthened potency.

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      The American journal of drug and alcohol abuse (2012), 38 (1), 108-13 ISSN:.
      BACKGROUND: Salvia divinorum has known hallucinogenic effects and is legal in most parts of the United States. Given that this psychoactive substance has a potential of misuse and abuse, further data regarding the clinical and psychosocial factors associated with use are needed. OBJECTIVES: To examine the clinical and psychosocial characteristics associated with use of salvia. METHODS: The study uses data from the National Survey on Drug Use and Health, 2008 (N = 55,623). RESULTS: The results of this study suggest that salvia use is most common among young adults aged 18-25 years as well as individuals who had engaged in risk-taking behaviors (selling illicit drugs, stealing) or illicit drug use (especially other hallucinogens/ecstasy). Self-reported depression and anxiety were also associated with salvia use. CONCLUSIONS/SCIENTIFIC SIGNIFICANCE: The results provide evidence that salvia use is part of a broader constellation of psychosocial and behavioral problems among youth and young adults. The accessibility, legal status, and psychoactive effects of salvia can be a potentially complicating health risk to young people, especially among those with existing substance use problems.
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      OBJECTIVE: The illicit use of hallucinogens is reemerging in the United States, especially among well-educated adults and teenagers. These same groups are also frequent users of the Internet. The authors sought to characterize the extent of information about hallucinogens available to Internet users. METHOD: Using standard Internet search techniques, the authors located 81 hallucinogen-related sites and categorized the information provided. RESULTS: Internet sites offer thousands of pages of information-albeit of questionable accuracy-on how to obtain, synthesize, extract, identify, and ingest hallucinogens. Much of this information has yet to appear in textbooks. By contrast, the authors found few U.S. government agency sites offering cautionary material about hallucinogen use. CONCLUSIONS: Using the Internet, potential hallucinogen users can bypass traditional channels of medical information and learn in great detail how to obtain and use numerous drugs with unknown hazards.
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      Johnson, Matthew W.; MacLean, Katherine A.; Reissig, Chad J.; Prisinzano, Thomas E.; Griffiths, Roland R.
      Drug and Alcohol Dependence (2011), 115 (1-2), 150-155CODEN: DADEDV; ISSN:0376-8716. (Elsevier Ireland Ltd.)
      Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychol. and phys. healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 μg/kg to 21 μg/kg. Subject-rated drug strength was assessed every 2 min for 60 min after inhalation. Orderly time- and dose-related effects were obsd. Drug strength ratings peaked at 2 min (first time point) and definite subjective effects were no longer present at approx. 20 min after inhalation. Dose-related increases were obsd. on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects assocd. with classic serotonergic (5-HT2A) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepd. and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.
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    10. 10
      Coyle, J. R.; Presti, D.; Baggot, M. Quantitative analysis of narrtive reports of psychedelic drugs. 2012. arXiv:1206.0312, arXiv.org e-Print archive. https://arxiv.org/abs/1206.0312.
      There is no corresponding record for this reference.
    11. 11
      Siebert, D. J. Salvia divinorum and salvinorin A: New pharmacologic findings. J. Ethnopharmacol. 1994, 43, 53– 56,  DOI: 10.1016/0378-8741(94)90116-3
      11
      Salvia divinorum and salvinorin A: New pharmacologic findings
      Siebert, Daniel J.
      Journal of Ethnopharmacology (1994), 43 (1), 53-6CODEN: JOETD7; ISSN:0378-8741.
      The diterpene salvinorin A from Salvia divinorum (Epling and Jativa-M), in doses of 200-500 μg, produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed.
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    12. 12
      Hanson, J. R. Natural products from the hallucinogenic sage. Sci. Prog. 2010, 93, 171– 180,  DOI: 10.3184/003685010X12626983776947
      12
      Natural products from the hallucinogenic sage
      Hanson, James R.
      Science Progress (St. Albans, United Kingdom) (2010), 93 (2), 171-180CODEN: SCPRAY; ISSN:0036-8504. (Science Reviews 2000 Ltd.)
      A review. The isolation, structures and biol. activity of the neoclerodane and other natural products obtained from the Mexican hallucinogenic sage, Salvia divinorum are reviewed.
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    13. 13
      ValdÉs, L. J., III; Hatfield, G. M.; Koreeda, M.; Paul, A. G. Studies of Salvia divinorum (Lamiaceae), an hallucinogenic mint from the Sierra Mazateca in Oaxaca, Central Mexico. Econ. Bot. 1987, 41, 283– 291,  DOI: 10.1007/BF02858975
      There is no corresponding record for this reference.
    14. 14
      Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.; Steinberg, S.; Ernsberger, P.; Rothman, R. B. Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11934– 11939,  DOI: 10.1073/pnas.182234399
      14
      Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist
      Roth, Bryan L.; Baner, Karen; Westkaemper, Richard; Siebert, Daniel; Rice, Kenner C.; Steinberg, SeAnna; Ernsberger, Paul; Rothman, Richard B.
      Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (18), 11934-11939CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum exts. and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3H-bremazocine binding to cloned κ opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent κ opioid agonist at cloned κ opioid receptors expressed in human embryonic kidney-293 cells and at native κ opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT2A serotonin receptor, the principal mol. target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for κ opioid receptors, κ opioid-selective antagonists may represent novel psychotherapeutic compds. for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Addnl., these results suggest that κ opioid receptors play a prominent role in the modulation of human perception.
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    15. 15
      Sheffler, D. J.; Roth, B. L. Salvinorin A: The “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol. Sci. 2003, 24, 107– 109,  DOI: 10.1016/S0165-6147(03)00027-0
      15
      Salvinorin A: the 'magic mint' hallucinogen finds a molecular target in the kappa opioid receptor
      Sheffler, Douglas J.; Roth, Bryan L.
      Trends in Pharmacological Sciences (2003), 24 (3), 107-109CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Science Ltd.)
      A review. Salvinorin A, a neoclerodane diterpene, is the most potent naturally occurring hallucinogen known and rivals the synthetic hallucinogen lysergic acid diethylamide in potency. Recently, the mol. target of salvinorin A was identified as the kappa opioid receptor (KOR). Salvinorin A represents the only known non-nitrogenous KOR selective agonist. Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential mol. target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder.
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    16. 16
      Chavkin, C.; Sud, S.; Jin, W.; Stewart, J.; Zjawiony, J. K.; Siebert, D. J.; Toth, B. A.; Hufeisen, S. J.; Roth, B. L. Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious kappa-opioid receptor agonist: Structural and functional considerations. J. Pharmacol. Exp. Ther. 2004, 308, 1197– 1203,  DOI: 10.1124/jpet.103.059394
      16
      Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious κ-opioid receptor agonist: Structural and functional considerations
      Chavkin, Charles; Sud, Sumit; Jin, Wenzhen; Stewart, Jeremy; Zjawiony, Jordan K.; Siebert, Daniel J.; Toth, Beth Ann; Hufeisen, Sandra J.; Roth, Bryan L.
      Journal of Pharmacology and Experimental Therapeutics (2004), 308 (3), 1197-1203CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective κ-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivs. were found to be potent and efficacious agonists in several measures of agonist activity using cloned human κ-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP prodn. Addnl. studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective κ-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was crit. for κ-opioid receptor binding and activation. Because issues of receptor reserve complicate ests. of agonist efficacy and potency, we also examd. the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K+ channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate (U69593) (two std. κ-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for κ-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at κ-opioid receptors.
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    17. 17
      Ortega, A.; Blount, J. F.; Manchand, P. S. Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae). J. Chem. Soc., Perkin Trans. 1 1982, 2505– 2508,  DOI: 10.1039/p19820002505
      17
      Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum (Labiatae)
      Ortega, Alfredo; Blount, John F.; Manchand, Percy S.
      Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1982), (10), 2505-8CODEN: JCPRB4; ISSN:0300-922X.
      The bicyclic diterpene salvinorin (I) was isolated from the leaves of S. divinorum and characterized by spectral and x-ray crystallog. anal.
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    18. 18
      Bodnar Willard, M. A.; McGuffin, V. L.; Smith, R. W. Forensic analysis of Salvia divinorum using multivariate statistical procedures. Part I: Discrimination from related Salvia species. Anal. Bioanal. Chem. 2012, 402, 833– 842,  DOI: 10.1007/s00216-011-5479-0
      18
      Forensic analysis of Salvia divinorum using multivariate statistical procedures. Part I: discrimination from related Salvia species
      Bodnar Willard, Melissa A.; McGuffin, Victoria L.; Waddell Smith, Ruth
      Analytical and Bioanalytical Chemistry (2012), 402 (2), 833-842CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      Salvia divinorum is a hallucinogenic herb that is internationally regulated. In this study, salvinorin A, the active compd. in S. divinorum, was extd. from S. divinorum plant leaves using a 5-min extn. with dichloromethane. Four addnl. Salvia species (Salvia officinalis, Salvia guaranitica, Salvia splendens, and Salvia nemorosa) were extd. using this procedure, and all exts. were analyzed by gas chromatog.-mass spectrometry. Differentiation of S. divinorum from other Salvia species was successful based on visual assessment of the resulting chromatograms. To provide a more objective comparison, the total ion chromatograms (TICs) were subjected to principal components anal. (PCA). Prior to PCA, the TICs were subjected to a series of data pretreatment procedures to minimize non-chem. sources of variance in the data set. Successful discrimination of S. divinorum from the other four Salvia species was possible based on visual assessment of the PCA scores plot. To provide a numerical assessment of the discrimination, a series of statistical procedures such as Euclidean distance measurement, hierarchical cluster anal., Student's t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores. The statistical procedures were then compared to det. the advantages and disadvantages for forensic applications.
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    19. 19
      Bodnar Willard, M. A.; Hurd, J. E.; Smith, R. W.; McGuffin, V. L. Statistical comparison of mass spectra of salvinorins in Salvia divinorum and related Salvia species. Forensic Chem. 2020, 17, 100192  DOI: 10.1016/j.forc.2019.100192
      There is no corresponding record for this reference.
    20. 20
      Tsujikawa, K.; Kuwayama, K.; Miyaguchi, H.; Kanamori, T.; Iwata, Y. T.; Yoshida, T.; Inoue, H. Determination of salvinorin A and salvinorin B in Salvia divinorum-related products circulated in Japan. Forensic Sci. Int. 2008, 180, 105– 109,  DOI: 10.1016/j.forsciint.2008.07.008
      20
      Determination of salvinorin A and salvinorin B in Salvia divinorum-related products circulated in Japan
      Tsujikawa, Kenji; Kuwayama, Kenji; Miyaguchi, Hajime; Kanamori, Tatsuyuki; Iwata, Yuko T.; Yoshida, Takemi; Inoue, Hiroyuki
      Forensic Science International (2008), 180 (2-3), 105-109CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      Two major salvinorins, salvinorin A (SalA) and salvinorin B (SalB), in three Salvia divinorum dried leaf products and nine of its "concd. ext." products circulated in Japan were detd. These ingredients were extd. twice with acetonitrile and decolored with graphite carbon powder. SalA and SalB were confirmed by liq. chromatog.-tandem mass spectrometry in product ion scan mode, and quantified by high-performance liq. chromatog. with UV detection (for SalA) and by mass spectrometry in single ion monitoring mode (for SalB). The SalA/SalB contents (μg/mg) were in the range of 3.2-5.0/0.10-0.17 in the dried leaf products and 4.1-38.9/0.26-2.42 in the "concd. ext." products. These findings would be useful for anal. of S. divinorum-related products circulated in the drug market.
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    21. 21
      Gruber, J. W.; Siebert, D. J.; Der Marderosian, A. H.; Hock, R. S. High performance liquid chromatographic quantification of salvinorin a from tissues of Salvia divinorum Epling & Játiva-m. Phytochem. Anal. 1999, 10, 22– 25
      21
      High performance liquid chromatographic quantification of salvinorin A from tissues of Salvia divinorum Epling & Jativa-M
      Gruber, John W.; Siebert, Daniel J.; Der Marderosian, Ara H.; Hock, Rick S.
      Phytochemical Analysis (1999), 10 (1), 22-25CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
      A reversed-phase HPLC method for the detn. of salvinorin A, a psychotropic diterpene isolated from the Mexican sage S. divinorum, was developed. Exts. from several plant collections were examd. on a C-18 column with UV detection and isocratic elution with MeCN-H2O (45:55). This assay allowed quantification of salvinorin A in exts. of leaves and stems of S. divinorum and was also applied to the screening of related species for the prodn. of salvinorin A. Levels of salvinorin A in leaves range from 0.89 to 3.70 mg/g dry wt.
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    22. 22
      Lin, P.-X.; Li, J.-H.; Chen, S.-H.; Chang, H.-C.; McKetin, R. Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan. J. Food Drug Anal. 2014, 22, 370– 378,  DOI: 10.1016/j.jfda.2014.01.017
      22
      Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan
      Lin, Po-Xiang; Li, Jih-Heng; Chen, Su-Hwei; Chang, Hsien-Chang; McKetin, Rebecca
      Journal of Food and Drug Analysis (2014), 22 (3), 370-378CODEN: JFDAAF; ISSN:1021-9498. (Elsevier B.V.)
      In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum and its related concd. ext. products are available via the Internet. Besides S. divinorum, there are many endemic Salvia species whose salvinorin A content is yet unknown. To understand the abuse liability of these products, the aim of this study was to assess the concn. of salvinorin A in endemic Salvia species and Internet-available salvinorin A-related products. Samples of S. divinorum were purchased via the Internet and samples of eight endemic species of Salvia were collected in Taiwan, including S. arisanensis Hayata, S. coccinea Juss. ex Murr, S. hayatana Makino ex Hayata, S. japonica Thumb. ex Murr, S. nipponica Miq. Var. formosana (Hayata) Kudo, S. scapiformis Hance, S. tashiroi Hayata. IconΠFormosan, and S. keitaoensis Hayata. The content of salvinorin A was detd. by high performance liq. chromatog. (HPLC). Salvinorin A was extd. from the dry leaves of S. divinorum and endemic species of Salvia with methanol and analyzed on a C-18 column by isocratic elution with a mobile phase of acetonitrile-water. Salvinorin A was detected in S. divinorum, but not in the endemic Salvia species of Taiwan. Therefore, endemic species of Salvia in Taiwan may not possess hallucinogenic potential. However, the potential harm from S. divinorum available via the Internet should be thoroughly assessed in Taiwan, and control measures similar to those implemented in many other countries should be considered.
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    23. 23
      Hernández-Bello, R.; García-Rodríguez, R. V.; García-Sosa, K.; Peña-Rodríguez, L. M.; Vázquez-Hernández, M.; Ramos-Morales, F. R.; Corcoran, O.; Sánchez-Medina, A. Salvinorin A content in legal high products of Salvia divinorum sold in Mexico. Forensic Sci. Int. 2015, 249, 197– 201,  DOI: 10.1016/j.forsciint.2015.01.038
      23
      Salvinorin A content in legal high products of Salvia divinorum sold in Mexico
      Hernandez-Bello, Rafael; Garcia-Rodriguez, Rosa Virginia; Garcia-Sosa, Karlina; Pena-Rodriguez, Luis Manuel; Vazquez-Hernandez, Maribel; Ramos-Morales, Fernando Rafael; Corcoran, Olivia; Sanchez-Medina, Alberto
      Forensic Science International (2015), 249 (), 197-201CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf exts. of S. divinorum are sold in different strengths, claiming to correlate with increasing amts. of salvinorin A. In order to det. the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in com. products available in Mexico using an HPLC method. The HPLC anal. method showed a correlation coeff. R2 > 0.99, with LOD of 0.44 μg/mL and LOQ of 1.34 μg/mL. The retention time for salvinorin A was 23.09 ± 0.95 min and the measured concns. ranged between 8.32 ± 0.65 and 56.52 ± 3.77 mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calcd. amt. of salvinorin A. Addnl., the emergence in Mexico of high strength salvia products (100×), the lack of regulation and the obsd. variability of salvinorin A content between brands of com. legal highs products of S. divinorum could result in a health problem for consumers.
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    24. 24
      Cody, R. B.; Laramée, J. A.; Durst, H. D. Versatile new ion source for the analysis of materials in open air under ambient conditions. Anal. Chem. 2005, 77, 2297– 2302,  DOI: 10.1021/ac050162j
      24
      Versatile new ion source for the analysis of materials in open air under ambient conditions
      Cody, Robert B.; Laramee, James A.; Durst, H. Dupont
      Analytical Chemistry (2005), 77 (8), 2297-2302CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      A new ion source was developed for rapid, noncontact anal. of materials at ambient pressure and at ground potential. The new source, termed DART (for Direct Anal. in Real Time), is based on the reactions of electronic or vibronic excited-state species with reagent mols. and polar or nonpolar analytes. DART was installed on a high-resoln. time-of-flight mass spectrometer (TOFMS) that provides improved selectivity and accurate elemental compn. assignment through exact mass measurements. Although DART was applied to the anal. of gases, liqs., and solids, a unique application is the direct detection of chems. on surfaces without requiring sample prepn., such as wiping or solvent extn. DART demonstrated success in sampling hundreds of chems., including chem. agents and their signatures, pharmaceutics, metabolites, peptides and oligosaccharides, synthetic orgs., organometallics, drugs of abuse, explosives, and toxic industrial chems. These species were detected on various surfaces, such as concrete, asphalt, human skin, currency, airline boarding passes, business cards, fruits, vegetables, spices, beverages, body fluids, horticultural leaves, cocktail glasses, and clothing. DART employs no radioactive components and is more versatile than devices using radioisotope-based ionization. Because its response is instantaneous, DART provides real-time information, a crit. requirement for screening or high throughput.
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    25. 25
      Lesiak, A. D.; Fowble, K. L.; Musah, R. A. A rapid, high-throughput validated method for the quantification of atropine in Datura stramonium seeds using direct analysis in real time-high resolution mass spectrometry (DART-HRMS). In Methods in Molecular Biology; Springer, 2018; Vol. 1810, pp 207– 215.
      There is no corresponding record for this reference.
    26. 26
      Lesiak, A. D.; Cody, R. B.; Ubukata, M.; Musah, R. A. Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration-The case of Kanna. Forensic Sci. Int. 2016, 260, 66– 73,  DOI: 10.1016/j.forsciint.2015.12.037
      26
      Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration - The case of Kanna
      Lesiak, Ashton D.; Cody, Robert B.; Ubukata, Masaaki; Musah, Rabi A.
      Forensic Science International (2016), 260 (), 66-73CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      We demonstrate the utility of direct anal. in real time ionization coupled with high resoln. time-of-flight mass spectrometry (DART-HRTOFMS) in revealing the adulteration of com. available Sceletium tortuosum, a mind-altering plant-based drug commonly known as Kanna. Accurate masses consistent with alkaloids previously isolated from S. tortuosum plant material enabled identification of the products as Kanna, and in-source collision-induced dissocn. (CID) confirmed the presence of one of these alkaloids, hordenine, while simultaneously revealing the presence of an adulterant. The stimulant ephedrine, which has been banned in herbal products and supplements, was confirmed to be present in a sample through the use of in-source CID. High-throughput DART-HRTOFMS was shown to be a powerful tool to not only screen plant-based drugs of abuse for psychotropic alkaloids, but also to reveal the presence of scheduled substances and adulterants.
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    27. 27
      Fowble, K. L.; Musah, R. A. A validated method for the quantification of mitragynine in sixteen commercially available Kratom (Mitragyna speciosa) products. Forensic Sci. Int. 2019, 299, 195– 202,  DOI: 10.1016/j.forsciint.2019.04.009
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      A validated method for the quantification of mitragynine in sixteen commercially available Kratom (Mitragyna speciosa) products
      Fowble, Kristen L.; Musah, Rabi A.
      Forensic Science International (2019), 299 (), 195-202CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      The recent rise in the recreational use of plant-based "legal highs" has prompted the development of methods for the identification of the bulk material, and quantification of their psychoactive components. One of these plants is Mitragyna speciosa, commonly referred to as Kratom. While traditional use of this plant was primarily for medicinal purposes, there has been a rise in its recreational use, and as a self-prescribed medication for opioid withdrawal. Although Kratom contains many alkaloids, mitragynine and 7-hydroxymitragynine are unique psychoactive biomarkers of the species, and are responsible for its psychoactive effects. A rapid validated method for the quantification of mitragynine in Kratom plant materials by direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS) is presented. It has a linear range of 5-100μg mL-1, and a lower limit of quantification of 5μg mL-1. The protocol was applied to detn. of the mitragynine content of 16 com. available Kratom plant products purchased online. The mitragynine amts. in these materials ranged from 2.76 to 20.05 mg g-1 of dried plant material. The utilization of DART-HRMS affords a mechanism not only for the preliminary identification of bulk plant material as being M. speciosa-derived (with no sample prepn. required), but also provides the opportunity to quantify its psychoactive components using the same technique.
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    28. 28
      Lesiak, A. D.; Cody, R. B.; Dane, A. J.; Musah, R. A. Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: the case of Mitragyna speciosa aka “Kratom”. Forensic Sci. Int. 2014, 242, 210– 218,  DOI: 10.1016/j.forsciint.2014.07.005
      28
      Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: The case of Mitragyna speciosa aka "Kratom"
      Lesiak, Ashton D.; Cody, Robert B.; Dane, A. John; Musah, Rabi A.
      Forensic Science International (2014), 242 (), 210-218CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      Mitragyna speciosa, also known commonly as "Kratom" or "Ketum", is a plant with psychoactive properties that have been attributed to the presence of various indole alkaloids such as mitragynine and 7-hydroxymitragynine. M. speciosa use is gaining popularity internationally as a natural and legal alternative to narcotics. As a drug of abuse, its detection and identification are not straightforward, since M. speciosa plant material is not particularly distinctive. Here, we show that direct anal. in real time-mass spectrometry (DART-MS) can be used not only to rapidly identify M. speciosa plant material and distinguish it from other plants, but also to distinguish between M. speciosa plant varieties, based on differences between their chem. profiles. The method is rapid and the anal. expeditious. Plant material such as that found at a crime scene can be analyzed directly with no sample pre-prepn. steps. Furthermore, we show that the basis set of principal components that permit characterization of the plant material can be used to pos. identify M. speciosa.
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    29. 29
      Lesiak, A. D.; Musah, R. A. More than just heat: Ambient ionization mass spectrometry for determination of the species of origin of processed commercial products─application to psychoactive pepper supplements. Anal. Methods 2016, 8, 1646– 1658,  DOI: 10.1039/C5AY02570B
      There is no corresponding record for this reference.
    30. 30
      Chambers, M. I.; Osborne, A. M.; Musah, R. A. Rapid detection and validated quantification of psychoactive compounds in complex plant matrices by direct analysis in real time-high resolution mass spectrometry - Application to “Kava” psychoactive pepper products. Rapid Commun. Mass Spectrom. 2019, 33, 1915– 1925,  DOI: 10.1002/rcm.8532
      30
      Rapid detection and validated quantification of psychoactive compounds in complex plant matrices by direct analysis in real time-high resolution mass spectrometry - application to "Kava" psychoactive pepper products
      Chambers, Megan I.; Osborne, Amy M.; Musah, Rabi A.
      Rapid Communications in Mass Spectrometry (2019), 33 (24), 1915-1925CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
      Rationale : Classified by the UNODC as a top 20 plant of concern, Piper methysticum (also known as Kava) is being increasingly abused recreationally for its mind-altering effects. It is of significant forensic relevance to establish methods to rapidly identifyand quantify psychoactive compds., esp. those yet to be scheduled as controlled substances and which have exhibited various noteworthy health concerns. Methods : Direct anal. in real time high-resoln. mass spectrometry (DART-HRMS) demonstrated the ability to detect a range of kavalactones in Piper methysticum derived products and plant material with no sample prepn. Inaddn., a validated method using calibration curves developed with a deuteratedinternal std. was used for the quantification of the psychoactive mol. yangonin in various products. Results : DART-HRMS detected the protonated masses of six major kavalactonesand three flavokavains in 18 com. Kava products. A method consistent with FDA validation guidelines was established for the quantification of yangonin in the various complex matrixes. Implementation of this method, with an LLOQ of 5 mg/mL, enabled successful quantification of yangonin in 16 Kava products. Concns. for solid products ranged from 2.71 to 8.99 mg/g, while that forliquid products ranged from 1.03 to 4.59 mg/mL. Conclusions : Rapid identification and quantification of psychoactive small mols. in plant material can be accomplished using a validated DART-HRMS protocol. This work illustrates an approach to qual. and quant. analyzes of a wide variety of complex matrixes derived from plants, and demonstrates that the com. available products analyzed are P. methysticum derived and do contain psychoactive yangonin at quantifiable levels.
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    31. 31
      Longo, C. M.; Musah, R. A. An efficient ambient ionization mass spectrometric approach to detection and quantification of the mescaline content of commonly abused cacti from the Echinopsis genus. J. Forensic Sci. 2020, 65, 61– 66,  DOI: 10.1111/1556-4029.14134
      31
      An Efficient Ambient Ionization Mass Spectrometric Approach to Detection and Quantification of the Mescaline Content of Commonly Abused Cacti from the Echinopsis Genus
      Longo, Cameron M.; Musah, Rabi A.
      Journal of Forensic Sciences (2020), 65 (1), 61-66CODEN: JFSCAS; ISSN:0022-1198. (John Wiley & Sons, Inc.)
      Unregulated cacti from the genus Echinopsis are used recreationally as mescaline-contg. alternatives to the outlawed peyote. Echinopsis-derived plant materials appear in a variety of nondescript forms, making rapid assessment of whether they are mescaline-contg. materials or simply innocuous plant-derived food products, very challenging. Reported here is a DART-HRMS approach for the rapid detection of mescaline in whole plant material and a validated method for the quantification of mescaline in cactus tissue, using mescaline-d9 as the internal std. Calibration curves exhibited R2 values of ≥0.995, and the method exhibited a LLOQ and a linear range of 1 ppm and 1-100 ppm, resp. Application of the method to com. available Echinopsis spp. yielded results consistent with previous studies performed by GC- and LC-MS, with mescaline levels of <2% dry wt. in all cases. Therefore, DART-HRMS is a suitable technique for the rapid screening of mescaline and its subsequent quantification within complex plant-derived matrixes.
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    32. 32
      Musah, R. A.; Domin, M. A.; Cody, R. B.; Lesiak, A. D.; Dane, A. J.; Shepard, J. R. Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids. Rapid Commun. Mass Spectrom. 2012, 26, 2335– 42,  DOI: 10.1002/rcm.6354
      32
      Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids
      Musah, Rabi A.; Domin, Marek A.; Cody, Robert B.; Lesiak, Ashton D.; John Dane, A.; Shepard, Jason R. E.
      Rapid Communications in Mass Spectrometry (2012), 26 (19), 2335-2342CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
      RATIONALE: The emergence of numerous cannabinoid designer drugs has been tied to large spikes in emergency room visits and overdoses. Identifying these substances is difficult for the following reasons: (1) the compds. are novel, closely structurally related, and do not usually test pos. in drug screens; (2) novel analogs rapidly appear on the market; (3) no std. protocols exist for their identification; and (4) customized and extensive sample prepn./extn. and anal. procedures are required to demonstrate their presence. METHODS: Direct anal. in real time mass spectrometry (DART-MS) employing collision-induced dissocn. (CID) provided confirmatory structural information that was useful in characterizing the various cannabinoid analogs, including those contained in mixts. CID anal. illustrated that, although closely related compds. fragment in a similar fashion, their structural differences still resulted in multiple diagnostic peaks that provided addnl. confidence towards structural identification. RESULTS: DART-MS spectra were acquired under CID conditions to rapidly differentiate among five synthetic cannabinoids contained within 'herbal' products purchased locally in New York State (USA). The spectra exhibited [M+H]+ ions and product ions unique to each cannabinoid that corresponded to major structural features. Five different cannabinoid analogs, alone and as mixts. of at least two cannabinoids, were identified in six herbal products and differentiated by their CID product ion patterns. CONCLUSIONS: Illicit synthetic cannabinoid products continue to be readily available despite national and international restrictions. These products contain a wide range of active components, and, in many cases, multiple active ingredients. DART-MS allows rapid analyses of these synthetic cannabinoids based on the exact masses of their [M+H]+ ions and product ion peaks generated using CID. Copyright © 2012 John Wiley & Sons, Ltd.
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    33. 33
      Chambers, M. I.; Appley, M. G.; Longo, C. M.; Musah, R. A. Detection and quantification of psychoactive N,N-dimethyltryptamine in ayahuasca brews by ambient ionization high-resolution mass spectrometry. ACS Omega 2020, 5, 28547– 28554,  DOI: 10.1021/acsomega.0c03196
      33
      Detection and Quantification of Psychoactive N,N-Dimethyltryptamine in Ayahuasca Brews by Ambient Ionization High-Resolution Mass Spectrometry
      Chambers, Megan I.; Appley, Meghan G.; Longo, Cameron M.; Musah, Rabi A.
      ACS Omega (2020), 5 (44), 28547-28554CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      The United Nations Office on Drugs and Crime designated twenty psychoactive botanical species as "plants of concern" because of their increased recreational abuse. Four of these are used to prep. ayahuasca brews. The complexity of the plant matrixes, as well as the beverage itself, make the identification and quantification of the Schedule I component, N,N-dimethyltryptamine (DMT), a time-consuming and resource-intensive endeavor when performed using conventional approaches previously reported. Reported here is the development of a rapid validated method for the quantification of DMT in ayahuasca by direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS). This ambient ionization approach also enables identification of ayahuasca through detection of the secondary metabolites assocd. with its plant constituents. Anal. of six ayahuasca brews created using different combinations of DMT/harmala alkaloid-contg. plants resulted in beverages with DMT levels of 45.7-230.5 mg/L. The detected amts. were consistent with previously reported values detd. by conventional approaches.
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    34. 34
      Appley, M. G.; Chambers, M. I.; Musah, R. A. Quantification of hordenine in a complex plant matrix by direct analysis in real time–high-resolution mass spectrometry: Application to the “plant of concern” Sceletium tortuosum. Drug Test. Anal. 2022, 14, 604– 612,  DOI: 10.1002/dta.3193
      34
      Quantification of hordenine in a complex plant matrix by direct analysis in real time-high-resolution mass spectrometry: Application to the "plant of concern" Sceletium tortuosum
      Appley, Meghan Grace; Chambers, Megan Isabella; Musah, Rabi Ann
      Drug Testing and Analysis (2022), 14 (4), 604-612CODEN: DTARBG; ISSN:1942-7603. (John Wiley & Sons Ltd.)
      Recently, there has been an increase in the recreational abuse of several psychoactive plants, resulting in the United Nations Office on Drugs and Crime creating a list of "plants of concern.". One such material is Sceletium tortuosum and products derived from it. Regulation of these materials is challenging because of their innocuous appearance, the cumbersome sample prepn. steps required to render the material into a form amenable to anal. by conventional techniques, the requirement for nuanced sample anal. protocols, and lengthy anal. times. It is demonstrated here that direct anal. in real time-high-resoln. mass spectrometry (DART-HRMS) can be used to not only identify S. tortuosum material based on the detection of characteristic biomarkers including hordenine and several mesembrine alkaloids, but also quantify the amt. of hordenine present. Using hordenine-d6 as an internal std., a protocol, validated according to US Food and Drug Administration (FDA) Guidelines for the Development and Validation of Bioanal. ,methods was devised for the quantification of the psychoactive component hordenine. The method was then applied to the quantification of hordenine in six com. available products derived from the foliage and stems of S. tortuosum. By this method, the lower limit of quantification (LLOQ) was found to be 1μg/mL. Obsd. hordenine concns. ranged from 0.02738 to 1.071 mg of hordenine per g of plant material. The developed technique provides an effective and quick means for the detection and quantification of hordenine in S. tortuosum, which can be extended to anal. of other hordenine-contg. products.
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    35. 35
      Cody, R. B. Observation of molecular ions and analysis of nonpolar compounds with the direct analysis in real time ion source. Anay. Chem. 2009, 81, 1101– 1107,  DOI: 10.1021/ac8022108
      35
      Observation of molecular ions and analysis of nonpolar compounds with the direct analysis in real time ion source
      Cody, Robert B.
      Analytical Chemistry (Washington, DC, United States) (2009), 81 (3), 1101-1107CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Pos. ions in the direct anal. in real time (DART) ion source are commonly formed by proton transfer. However, the DART source is similar to atm. pressure photoionization (APPI) in that it can produce mol. ions as well as protonated mols., although the two sources differ in the initial ion formation process. This report discusses some of the factors that influence mol. ion formation in DART and shows how the DART source can be used to analyze difficult or nonpolar compds. such as alkanes and cholesterol. Trace reagent ions including NO+ and O2+· formed from atm. gases play important roles in DART ionization. The use of the DART source as a gas chromatog./mass spectrometry (GC/MS) interface is demonstrated to show the difference between mass spectra obtained using conditions that favor proton transfer and those that favor mol. ion formation.
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    36. 36
      Giffen, J. E.; Lesiak, A. D.; Dane, A. J.; Cody, R. B.; Musah, R. A. Rapid species-level identification of Salvias by chemometric processing of ambient ionisation mass spectrometry-derived chemical profiles. Phytochem. Anal. 2017, 28, 16– 26,  DOI: 10.1002/pca.2639
      36
      Rapid Species-level Identification of Salvias by Chemometric Processing of Ambient Ionisation Mass Spectrometry-derived Chemical Profiles
      Giffen, Justine E.; Lesiak, Ashton D.; Dane, A. John; Cody, Robert B.; Musah, Rabi A.
      Phytochemical Analysis (2017), 28 (1), 16-26CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
      Introduction : The Salvia genus contains numerous economically important plants that have horticultural, culinary and nutraceutical uses. They are often similar in appearance, making species detn. difficult. Species identification of dried Salvia products is also challenging since distinguishing plant morphol. features are no longer present. Objective : The development of a simple high-throughput method of anal. of fresh and dried Salvia leaves that would permit rapid species-level identification and detection of diagnostic biomarkers. Methodol. : Plant leaves were analyzed in their native form by DART-MS without the need for any sample prepn. steps. This furnished chem. fingerprints characteristic of each species. In the same expt., in-source collision-induced dissocn. was used to identify biomarkers. Biomarker presence was also independently confirmed by GC-MS. Chemometric processing of DART-MS profiles was performed by kernel discriminant anal. (KDA) and soft independent modeling of class analogy (SIMCA) to classify the fingerprints according to species. Results : The approach was successful despite the occurrence of diurnal cycle and plant-age related chem. profile variations within species. In a single rapid expt., the presence of essential oil biomarkers such as 3-carene, α-pinene, β-pinene, β-thujone, β-caryophyllene, camphor and borneol could be confirmed. The method was applied to rapid identification and differentiation of Salvia apiana, S. dominica, S. elegans, S. officinalis, S. farinacea and S. patens. Conclusion : Species-level identification of Salvia plant material could be accomplished by chemometric processing of DART-HRMS-derived chem. profiles of both fresh and dried Salvia material. Copyright © 2016 John Wiley & Sons, Ltd.
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    37. 37
      Appley, M. G.; Beyramysoltan, S.; Musah, R. A. Random forest processing of direct analysis in real-time mass spectrometric data enables species identification of psychoactive plants from their headspace chemical signatures. ACS Omega. 2019, 4, 15636– 15644,  DOI: 10.1021/acsomega.9b02145
      37
      Random Forest Processing of Direct Analysis in Real-Time Mass Spectrometric Data Enables Species Identification of Psychoactive Plants from Their Headspace Chemical Signatures
      Appley, Meghan Grace; Beyramysoltan, Samira; Musah, Rabi Ann
      ACS Omega (2019), 4 (13), 15636-15644CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      The United Nations Office on Drugs and Crime has designated several "legal highs" as "plants of concern" because of the dangers assocd. with their increasing recreational abuse. Routine identification of these products is hampered by the difficulty in distinguishing them from innocuous plant materials such as foods, herbs, and species. It is demonstrated here that several of these products have unique but consistent headspace chem. profiles and that multivariate statistical anal. processing of their chem. signatures can be used to accurately identify the species of plants from which the materials are derived. For this study, the headspace volatiles of several species were analyzed by direct anal. in real-time high-resoln. mass spectrometry (DART-HRMS). These species include Althaea officinalis, Calea zacatechichi, Cannabis indica, Cannabis sativa, Echinopsis pachanoi, Lactuca virosa, Leonotis leonurus, Mimosa hostilis, Mitragyna speciosa, Ocimum basilicum, Origanum vulgare, Piper methysticum, Salvia divinorum, Turnera diffusa, and Voacanga africana. The results of the DART-HRMS anal. revealed intraspecies similarities and interspecies differences. Exploratory statistical anal. of the data using principal component anal. and global t-distributed stochastic neighbor embedding showed clustering of like species and sepn. of different species. This led to the use of supervised random forest (RF), which resulted in a model with 99% accuracy. A conformal predictor based on the RF classifier was created and proved to be valid for a significance level of 8% with an efficiency of 0.1, an obsd. fuzziness of 0, and an error rate of 0. The variables used for the statistical anal. processing were ranked in terms of the ability to enable clustering and discrimination between species using principal component anal.-variable importance of projection scores and RF variable importance indexes. The variables that ranked the highest were then identified as m/z values consistent with mols. previously identified in plant material. This technique therefore shows proof-of-concept for the creation of a database for the detection and identification of plant-based legal highs.
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    38. 38
      FDA (Food and Drug Adminstration). Bioanalytical method validation guidance for industry 2018. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf (accessed Aug 22, 2018).
      There is no corresponding record for this reference.
    39. 39
      Cunningham, C. W.; Rothman, R. B.; Prisinzano, T. E. Neuropharmacology of the naturally occurring κ-opioid hallucinogen salvinorin A. Pharmacol. Rev. 2011, 63, 316– 347,  DOI: 10.1124/pr.110.003244
      39
      Neuropharmacology of the naturally occurring κ-opioid hallucinogen salvinorin A
      Cunningham, Christopher W.; Rothman, Richard B.; Prisinzano, Thomas E.
      Pharmacological Reviews (2011), 63 (2), 316-347CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)
      A review. Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzon de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolyzed smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT2A receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biol. processes responsible for its obsd. psychol. effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.
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    40. 40
      Bigham, A. K.; Munro, T. A.; Rizzacasa, M. A.; Robins-Browne, R. M. Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum. J. Nat. Prod. 2003, 66, 1242– 1244,  DOI: 10.1021/np030313i
      40
      Divinatorins A-C, New Neoclerodane Diterpenoids from the Controlled Sage Salvia divinorum
      Bigham, Andrea K.; Munro, Thomas A.; Rizzacasa, Mark A.; Robins-Browne, Roy M.
      Journal of Natural Products (2003), 66 (9), 1242-1244CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
      Three new neoclerodane diterpenoids, divinatorins A-C (7-9), have been isolated from the leaves of Salvia divinorum. The compds. were identified by spectroscopic methods as derivs. of the antibiotic (-)-hardwickiic acid (10), which was also isolated, along with four other known terpenoids. Neither the crude ext. nor 7-9 displayed antimicrobial activity.
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    41. 41
      Medana, C.; Massolino, C.; Pazzi, M.; Baiocchi, C. Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry. Rapid Comm. Mass Spectrom. 2006, 20, 131– 136,  DOI: 10.1002/rcm.2288
      41
      Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry
      Medana Claudio; Massolino Cristina; Pazzi Marco; Baiocchi Claudio
      Rapid communications in mass spectrometry : RCM (2006), 20 (2), 131-6 ISSN:0951-4198.
      Salvinorin A is the most potent naturally occurring hallucinogen known and rivals synthetic LSD in potency. Structurally it belongs to the neoclerodane diterpenoids, and it is the only known non-nitrogenous kappa-opioid-selective agonist. Salvia divinorum (Diviner's sage) is a member of the mint family that was used in ancient Mexican traditional practices. Today it is widely cultivated in Europe as a recreational marijuana substitute; it is illegal to buy, sell or possess the plant or the active principle in some countries. Six different salvinorins and three divinatorins have been isolated from Salvia divinorum leaves. The ion fragmentation, separation and quantitation of these diterpenes by liquid chromatography/electrospray ionization multistage mass spectrometry (LC/ESI-MS(n)) are described. The importance of LC in herbal extract determination and the chemical diagnostic power of MS(n) in the analysis of classes of natural organic products are discussed.
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    42. 42
      Barnes, B. B.; Snow, N. H. Analysis of salvinorin A in plants, water, and urine using solid-phase microextraction-comprehensive two-dimensional gas chromatography-time of flight mass spectrometry. J. Chromatogr. A 2012, 1226, 110– 115,  DOI: 10.1016/j.chroma.2011.09.056
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      Analysis of Salvinorin A in plants, water, and urine using solid-phase microextraction-comprehensive two-dimensional gas chromatography-time of flight mass spectrometry
      Barnes, Brian B.; Snow, Nicholas H.
      Journal of Chromatography A (2012), 1226 (), 110-115CODEN: JCRAEY; ISSN:0021-9673. (Elsevier B.V.)
      Salvinorin A, a psychoactive hallucinogen, and related compds., were analyzed in plants, water, and urine using liq.-liq. extn. (LLE), solid-phase microextn. (SPME) and comprehensive 2-dimensional gas chromatog.-time of flight mass spectrometry (GC × GC-ToFMS). A semi-qual. study of the extn. of Salvinorin A and analogs from Salvia divinorum plants by LLE showed ppb levels of Salvinorin A and several analogs in the leaves and stems of S. divinorum plants, much lower than expected. Quant. anal. of Salvinorin A spiked into water and urine showed much better figures of merit for SPME than LLE, with limit of detection of about 5 ng/mL, linear range from 8 to 500 ng/mL, and precision about ±10% for the SPME-based analyses using external std. quantitation. GC × GC-ToFMS was esp. effective in sepg. the peaks of interest from matrix and chromatog. interferences.
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    43. 43
      Wolowich, W. R.; Perkins, A. M.; Cienki, J. J. Analysis of the psychoactive terpenoid salvinorin A content in five Salvia divinorum herbal products. Pharmacotherapy 2006, 26, 1268– 12672,  DOI: 10.1592/phco.26.9.1268
      43
      Analysis of the psychoactive terpenoid salvinorin A content in five Salvia divinorum herbal products
      Wolowich, William R.; Perkins, Alisha M.; Cienki, John J.
      Pharmacotherapy (2006), 26 (9), 1268-1272CODEN: PHPYDQ; ISSN:0277-0008. (Pharmacotherapy Publications)
      The study objective was to det. the content of the hallucinogen salvinorin A in a variety of Salvia divinorum herbal products and to compare the content with the label claims of potency and purity. Five herbal products contg. Salvia divinorum were analyzed. High-performance liq. chromatog. and thin-layer chromatog.-gas chromatog.-mass spectroscopy were used for the anal. All five samples contained salvinorin A, a psychoactive compd. found in Salvia divinorum; however, the salvinorin A, concns. we measured were much lower than those claimed on the product label. Vitamin E was also found in two samples and caffeine in one sample. The five salvinorin A herbal products were concluded to be subpotent, and three products contained adulterants. Any discrepancy between the advertised salvinorin A concn. and their actual concn. may pose a potential risk of both misuse and overdose. These concerns, and the recently reported teenage suicide that could have been related to salvia consumption, underscore the need for practitioners to become familiar with the signs and symptoms of salvia use.
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    44. 44
      Xavier Moreira, F.; Carvalho, F.; de Lourdes Bastos, M.; Guedes de Pinho, P. Analytical investigation of legal high products containing Salvia divinorum traded in smartshops and internet. Forensic Sci. Int. 2014, 242, 255– 260,  DOI: 10.1016/j.forsciint.2014.07.009
      44
      Analytical investigation of legal high products containing Salvia divinorum traded in smartshops and internet
      Xavier Moreira, Fernando; Carvalho, Felix; de Lourdes Bastos, Maria; Guedes de Pinho, Paula
      Forensic Science International (2014), 242 (), 255-260CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
      Lately, the hallucinogenic plant Salvia divinorum has been considered a popular recreational product among adolescents, being legally sold in several countries in "smartshops" and in internet websites. Sellers frequently omit the safety information about the plant, encouraging its use for recreational purposes, without providing adequate qual. and quant. details. The principal hallucinogenic compd. of the plant, salvinorin A, alongside with three other isomeric compds., salvinorin B, C and D were evaluated in 10 products contg. S. divinorum. These products were obtained in smartshops and from internet websites, and contained concd. exts. of salvinorin A, with potencies labeled between "5x" and "60x". For that purpose a simple and rapid extn. protocol and a GC-MS methodol. were developed and applied to the purchased samples. The anal. of S. divinorum samples allowed the identification of four salvinorins, salvinorin A being the most prevalent hallucinogen. In the tested samples, there were several unreliable data provided to consumers. Frequently, there was no information on salvinorin A concn., but when it existed, it generally did not correspond to the true amt. present in products. On the other hand, the concn. of salvinorin A in each product far exceeded the amt. needed to produce hallucinogenic effects.
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    • Mass measurements and relative intensities of salvinorins and divinatorins in Salvia products (PDF)


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