Simultaneous Detection of Ten Psychedelic Phenethylamines in

Psychedelic phenethylamines are an emerging class of designerdrugs capable of producing a complex array of sought afteradrenergic and hallucinogenic effects. Toxicological detectionposes a number of challenges to laboratories. The purpose of thisstudy was to develop a procedure for the detection of psychedelicamphetamines using techniques that are widely accepted inforensic toxicology laboratories. In all, 10 target analytes wereselected: 2,5-dimethoxy-4-bromophenethylamine (2C-B),2,5-dimethoxyphenethylamine (2C-H), 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), 4-methylthioamphetamine(4-MTA), 2,5-dimethoxy-4-bromoamphetamine (DOB),2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoamphetamine (DOI), and 2,5-dimethoxy-4-methylamphetamine (DOM). Target drugs in urine were analyzedby gas chromatography in selected ion monitoring mode aftermixed-mode solid-phase extraction. Limits of detection for allanalytes were 2–10 ng/mL, and limits of quantitation were 10ng/mL or less. Precision evaluated at 50 and 500 ng/mL yieldedCVs of 0.4–7.9% and accuracy in the range 91–116%. Calibrationcurves were linear to 1500 ng/mL using mescaline-d9 as theinternal standard. No carryover was evident at 5000 ng/mL (thehighest concentration tested) and no interferences were observedfrom the presence of other structurally related compounds orendogenous bases.

Introduction

The psychedelic phenethylamines described in this studyare a series of psychoactive derivatives that produce soughtafter effects for recreational drug users. Many of these syntheticpsychotropics are not scheduled and bypass controlled sub-stance legislation in the United States. Hallucinogenicphenethylamines were first synthesized by Shulgin (1) andlater emerged as illicit drugs in Europe and Asia before makingan appearance in this country. Although the most widelyabused amphetamine in the United States is d-metham-phetamine, there is still significant interest in new designeramphetamines as the drug scene continues to evolve (2). Theseemerging designer drugs include the dimethoxyphenyl-ethanamine (2C, 2C-T) and dimethoxyphenylpropanamine(DO) series of psychedelics, which includes 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2,5-dimethoxyphenethylamine(2C-H), 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7),2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoampheta-mine (DOI), and 2,5-dimethoxy-4-methylamphetamine (DOM).4-Methylthioamphetamine (4-MTA) was also included in thestudy because of its structural similarity, toxicity, and reporteduse.

Methoxylated designer amphetamines are not new; para-methoxyamphetamine (PMA) and para-methoxymetham-phetamine (PMMA) were introduced in the late 1990s, andthese were associated with fatal intoxications and acute toxicity.Dimethoxy derivatives of phenyalkylamines are the subject ofthis study. These contain methoxy groups at positions 2 and 5of the aromatic system and often a lipophilic substituent in the4 position. Drugs in the 2C series contain two carbons sepa-rating the amine from the aromatic core. The 2C-T series of

Simultaneous Detection of Ten PsychedelicPhenethylamines in Urine by Gas Chromatography–Mass Spectrometry

Sarah Kerrigan1,2,*, Stephanie Banuelos1,†, Laura Perrella1, and Brittany Hardy1,‡1Forensic Science Program, College of Criminal Justice, Sam Houston State University, Box 2525, 1003 Bowers Blvd.,Huntsville, Texas 77341 and 2Sam Houston State University Regional Crime Laboratory, The Woodlands, Texas 77381

Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission. 459

Journal of Analytical Toxicology, Vol. 35, September 2011

* Author to whom correspondence should be addressed: Sarah Kerrigan, Ph.D., Director,Forensic Science Program, Sam Houston State University, Box 2525, 1003 Bowers Blvd.,Huntsville, TX 77341. Email: [email protected].

† Current address: Texas Department of Public Safety Crime Laboratory, McAllen, TX 78501.‡ Current address: Dallas County Institute of Forensic Sciences, Dallas, TX 75235.

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drug are sulfur containing, and many arederivatives of 4-thioamphetamine. Somedrugs within this class differ by just onesubstituent or atom, and share very sim-ilar chemical and physical properties.Molecular data and structures for thepsychedelic amphetamines described inthis study are depicted in Table I andFigure 1, respectively.

A number of these drugs are ScheduleI drugs in the Federal Controlled Sub-stances Act (CSA) because of the high po-tential for abuse and absence of eithermedical use or accepted safety. Althoughmost of these substances are considered“drugs or chemicals of concern” by theDrug Enforcement Administration (DEA),several remain unscheduled to date (2C-H, 2C-I, 2C-T-2, DOI, and 4-MTA). In-stead, they may be regulated by the Fed-eral Analogue Act, which states that anydrug substantially similar to a scheduleddrug may be treated as though it werescheduled, if intended for human con-sumption. Scheduling status, streetnames, dosages, and duration of actionfor the drugs included in this study aresummarized in Table II (3,4).

There is very limited published scien-tific literature concerning the pharma-cology or toxicology of these psychedelicamphetamines. A common route of ad-ministration is oral ingestion; however,insufflation, smoking, and rectal use arenot uncommon, and intravenous and in-tramuscular administrations have beenreported (2). Some of the psychedelicphenethylamines show affinity to 5HT2receptors, acting as potent and selective5HT2C receptor agonists and 5HT2A re-ceptor antagonists (5). Although thesedrugs are still the subject of ongoingstudy, it appears clear that their some-what unique properties are mediatedlargely by serotonergic and adrenergic re-ceptors. Many are capable of producingcentral nervous system effects, euphoriaand enhanced visual, auditory, olfactory,or physical sensations similar to LSD;however, reported effects are highly dose-dependent (1,6). Overdose and death areof concern, and fatal intoxications havebeen associated with the use of 2C-T-7,4-MTA, and DOB (7–12).

From 2004 through 2010, the DEApublished numerous reports of drugseizures throughout the United States(13–45). Reports are not geographically

Figure 1. Structures of target analytes and internal standard (mescaline-d9).

Table I. Chemical and Mass Spectral Data for Target Analytes

Base Molecular Ions m/z*Drug Formula Peak Weight (Ion Ratio)

2C-H C10H15NO2 152 181 152.1, 181.1 (19), 137.1 (53)4-MTA C10H15NS 44 181 138.0, 122.0 (31), 44.0 (497)DOM C12H19NO2 166 209 166.1, 151.1 (35), 44.1 (158)DOET C13H21NO2 180 223 180.1, 165.1 (32), 91.1 (11)2C-B C10H14BrNO2 232 261 232.0, 261.0 (11), 216.9 (24)DOB C11H16BrNO2 44 274 232.0, 216.9 (17), 77.1 (44)2C-I C10H14INO2 278 307 278.0, 307.0 (14), 262.9 (19)DOI C11H16INO2 44 321 278.0, 262.9 (12), 77.1 (19)2C-T-2 C12H19NO2S 212 241 212.1, 241.1 (29), 183.1 (39)2C-T-7 C13H21NO2S 226 255 226.1, 255.1 (41), 183.0 (60)Mescaline-d9, IS C11H8D9NO3 191 220 191.0, 220.0 (22), 173.0 (53)

* Quantitation ions are underlined, and ion ratios for qualifier ions are shown in parentheses.

Table II. Scheduling Status, Street Names, and Common Dosages

CSA Effective Street Common Dosage* DurationDrug Schedule Year Names (mg) (h)

2C-H Not scheduled† N/A N/A Unknown Unknown4-MTA Not scheduled† N/A Flatliner, Golden Eagle N/A N/ADOM I 1973 STP (Serenity, Tranquility, Peace) 3–10 14–20DOET I 1993 Hecate 2–6 14–202C-B I 1995 2’s, Bees, Bromo, Nexus, 12–24 4–8

Spectrum, Toonies, VenusDOB I 1973 Bob, Dr. Bob 1–3 18–302C-I Not scheduled† N/A i 14–22 6–10DOI Not scheduled† N/A N/A 1.5–3 16–302C-T-2 Not scheduled† N/A T2 12–25 6–82C-T-7 I 2004 Beautiful, Blue Mystic, T7, 10–30 8–15

Tripstasy, Tweety-Bird Mescaline

* Dosage and duration of action are reported from testimonial and nonscientific literature (1,3).† May be regulated under the Federal Analogue Act (4).


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Table III. Summary of Published Procedures for Analysis

Drugs of Interest Matrix Extraction Internal Standard Instrumentation Derivatization Reference(s)

4-MTA NB* none none GC–MS, CE–DAD, ATR/FTIR, 1HNMR None 47

4-MTA Blood LLE Fenfluramine HPLC–DAD, GC–NPD None 7Urine Diethylpropion

4-MTA Blood LLE Phentermine LC–MS–MS None 9Urine

VitreousTissue

4-MTA Blood LLE Diphenylamine GC–MS, HPLC–DAD None 8

2C-B Urine LLE None GC–MS Isobutyric anhydride 48

2C-T-7 Blood LLE TMA GC–MS None 10UrineTissue

2C-B Urine LLE 2C-T-7 GC–MS N-Butyric anhydride 49

2C-T-2 Urine LLE None GC–MS None 50

2C-B, 4-MTA Urine SPE None HPLC–UV None 51

2C-B, 2C-T-7 Blood SPE Mescaline-d9 GC–MS, LC–MS PFPA 52Urine 5-Fluorotryptamine

DOB Blood LLE Brompheniramine GC–MS Acetic anhydride 12Urine

2C-B, 2C-I, DOB, Urine SPE None CE–MS None 53DOI, DOM

4-MTA Urine LLE None GC–MS Acetic anhydride 54

2C-B, 2C-I, Blood SPE AM-d5, MA-d5, MDA-d5,MDMA-d5, GC–MS HFBA 52C-T-2, 2C-T-7 MDEA-d5, mescaline-d9

2C-T-2, 2C-T-7 Urine LLE None GC–MS Acetic anhydride 55,56

DOB Urine LLE None GC–MS Acetic anhydride 57

2C-B, 2C-I, 2C-T-2, Urine SPE Medazepam GC–MS Acetic anhydride 582C-T-7, 4-MTA,Mescaline

2C-I Urine LLE None GC–MS, CE–MS Acetic anhydride 59

2C-B, 2C-I, Urine LLE None CE–NF, CE–LIF, GC–MS Fluorescence derivatization 602C-T-2, 2C-T-7

DOB NB None None CE–DAD, MSn, FTIR, GC–MS None 61

DOI Urine LLE None GC–MS Acetic anhydride 62

DOM, DOET Urine SPE None CE–MS None 63

2C-B Urine LLE None GC–MS Acetic anhydride 64

DOM Urine LLE None GC–MS Acetic anhydride 65

2C-B Blood SPE MBDB GC–MS Acetic anhydride 66Tissue

2C-B, 2C-H, 2C-I, Blood SPE AM-d5, MDMA-d5, LC–MS–MS None 672C-T-2, 2C-T-7, 4-MTA, MDEA-d5, cocaine-d3DOB, DOET, DOM

* Abbreviations: NB, nonbiological matrix; LLE, liquid extraction; SPE, solid-phase extraction; TMA, trimethoxyamphetamine; amphetamine-d5, AM-d5; methamphetamine-d5, MA-d5;3,4-methylenedioxyamphetamine-d5, MDA-d5; 3,4-methylenedioxymethamphetamine-d5, MDMA-d5; 3,4-methylenedioxy-N-ethylamphetamine-d5, MDEA-d5; 2-methylamino-1-(3,4-methylenedioxyphenyl)-butane, MBDB; GC, gas chromatography; MS, mass spectrometry; CE, capillary electrophoresis; DAD, diode-array detection; ATR/FTIR, attenuated totalreflectance/Fourier transform infrared spectroscopy; 1H-NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography; NPD, nitrogen-phosphorus detection;LC, liquid chromatography; UV, ultraviolet spectrometry; NF, native fluorescence detection; LIF, light emitting diode (LED)-induced fluorescence detection; MSn, tandem mass spectrometry;PFPA, pentafluoropropionic anhydride; and HFBA, heptafluorobutyric anhydride.


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isolated: they include Tennessee, Georgia, Arkansas, Kentucky,Florida, Pennsylvania, California, New Mexico, Wisconsin, Ok-lahoma, Oregon, Iowa, Michigan, New York, South Dakota,and Texas. Most of these designer amphetamines are recoveredin powder, tablet, or blotter form, although some have been en-countered as liquids and capsules. LSD-like “blotters” are par-ticularly common for 2C-I, DOB, and DOI. There are numerousreports of these psychedelic phenethylamines being sold asEcstasy mimic tablets and “acid” blotter mimics (13–46).

Users report a variety of sought after effects includingpsychedelic ideation, a sense of well being, emotional awak-ening, profound insight, closed and open-eyed visuals, in-creased appreciation of music, introspection and emphatho-genesis. Other effects include increased blood pressure, blurredvision, dehydration, nausea, vomiting, headache, dilated pupils,muscle tension, and tachycardia.

These recreational drugs are not routinely assayed inforensic toxicology laboratories and there is limited data con-cerning their prevalence in toxicological casework. Existingpublished studies are summarized in Table III (47–67). Somedescribe the analysis of non-biological samples (i.e., seizeddrugs), others use techniques that are not in widespread use intoxicology laboratories, and most target some, but not all, ofthe drugs described in this study. Gas chromatography–massspectrometry (GC–MS) is still the most widely used techniquefor confirmatory toxicology analysis. Most of the publishedmethods to date are limited in their ability to simultaneouslyidentify more than a few of the psychedelic phenethylamines ofinterest. Ishida et al. (58) developed a method for the detectionof 30 abused drugs in human urine using GC–MS, including2C-B, 2C-I, 2C-T-2, 2C-T-7, and 4-MTA. However, there is no lit-erature to date that describes a comprehensive screening pro-cedure for some of the most common 2C, 2C-T, and DO seriesdesigner drugs using GC–MS.

Some published methods utilizing GC–MS derivatize theseamphetamine-like drugs using acetic anhydride, n-butyric an-hydride, isobutyric anhydride, heptafluorobutyric anhydride,and pentafluoropropionic anhydride (Table III). Derivatizationhas many advantages from the standpoint of improved de-tectability, volatility, specificity, and chromatographic separa-tion. However, in this study drugs were not derivatized. Non-derivatized drugs can be advantageous if a laboratory is makingan identification using a commercial or widely used mass spec-tral library, particularly if the laboratory conducts full scanscreening by GC–MS. The purpose of this study was to estab-lish a simple procedure for the separation and identification ofthe 10 target drugs in urine, using techniques and instru-mentation already widely used in human performance andmedical examiner’s toxicology laboratories.

Experimental

Materials and methods2C-B, 2C-H, 2C-I, 2C-T-2, 2C-T-7, (±)-4-MTA, (±)-DOB, (±)-

DOET, and (±)-DOM were obtained from Lipomed (Cambridge,MA). DOI, phenethylamine, putrescine, tryptamine, and tyra-

mine were obtained from Sigma-Aldrich (St. Louis, MO).Mescaline-d9, (±)-amphetamine, (±)-methamphetamine, (±)-methylenedioxyamphetamine (MDA), (±)-methylene-dioxymethamphetamine (MDMA), (±)-methylenedioxyethyl-amphetamine (MDEA), (±)-methylbenzodioxolylbutanamine(MBDB), (–)-ephedrine, (+)-pseudoephedrine, phentermine,and (±)-phenylpropanolamine were obtained from Cerilliant(Round Rock, TX). PolyCrom Clin II (3 cc) solid-phase extrac-tion (SPE) columns (catalog #691-0353) containing 35 mgpolymeric sorbent were obtained from SPEware (Baldwin Park,CA). Deionized water was purified through a Millipore Milli Qwater system (Billerica, MA). Acetic acid, hexane, ethyl ac-etate, methanol, methylene chloride, and isopropyl alcoholwere obtained from Mallinckrodt-Baker (Hazelwood, MO). Am-monium hydroxide was obtained from Fisher Scientific (Pitts-burgh, PA). Sodium phosphate monobasic monohydrate (ACSgrade) and sodium phosphate dibasic heptahydrate (ACS grade)were purchased from Sigma-Aldrich (St. Louis, MO) and VWR(West Chester, PA), respectively, and used to prepare a 0.1 Mphosphate buffer solution (pH 6). All inorganic reagents andsolvents were ACS or HPLC grade or higher. A solution ofmethylene chloride and isopropyl alcohol was prepared at aratio of 95:5 (v/v). The elution solvent was prepared with 95:5v/v methylene chloride/isopropyl alcohol and ammonium hy-droxide at a ratio of 98:2 (v/v).

Mescaline-d9 internal standard solution was prepared inmethanol at a concentration of 0.01 mg/mL. Working stan-dards of 2C-B, 2C-H, 2C-I, 2C-T-2, 2C-T-7, 4-MTA, DOB, DOET,DOI, and DOM were prepared in methanol at concentrationsappropriate for the fortification of calibrators and controls. Anamphetamine interference solution consisted of am-phetamine, methamphetamine, MDA, MDMA, MDEA, MBDB,ephedrine, pseudoephedrine, phentermine, and phenyl-propanolamine in methanol. An endogenous interference so-lution consisted of phenethylamine, putrescine, tryptamine,and tyramine in methanol. Pooled drug-free urine containing1% sodium fluoride (w/v) was used to prepare all calibratorsand controls.

InstrumentationGC–MS analysis was performed using an Agilent HP 5975

MSD/6890 GC (Santa Clara, CA) with a DB-5MS (30 m × 0.25mm × 0.25 μm) capillary column purchased from VWR (WestChester, PA). The injector and interface were both set at 280°C.Injections (2 μL) were made in split mode with a 5:1 splitratio. Ethyl acetate was used as the wash solvent, with a totalof six pre-and post injection syringe washes between samples.The oven temperature was held at 130°C for 0.50 min, rampedto 170°C at a rate of 15°C/min with a hold time of 1 min,ramped to 180°C at a rate of 5°C/min with a hold time of 9 min,ramped to 200°C at a rate of 15°C/min and then ramped to290°C at a rate of 30°C/min with a final hold time of 1 min. Thetotal run time was 20.0 min. Helium was used as the carrier gasat a flow rate of 1.3 mL/min. The MS was operated in the elec-tron impact (EI) ionization mode. The ion source andquadrupole were set at 230°C and 150°C, respectively. Data wasacquired using selected ion monitoring (SIM) using quantita-tion and qualifier ions shown in Table I.


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ExtractionA methanolic working standard was used to prepare all cal-

ibrators and controls. In the absence of deuterated analoguesfor each of the target drugs, a number of alternatives wereevaluated. These included deuterated analogues of MDMA,MBDB, and mescaline. Mescaline-d9 was structurally similarand yielded the most promising results during method devel-opment. After addition of internal standard (IS) solution to 2mL urine (250 ng/mL, IS), 2 mL phosphate buffer (0.1M, pH6.0) was added. Buffered urine samples were added to Poly-Crom Clin II columns (catalog #691-0353) and successivelyrinsed using 1 mL deionized water and 1 mL 1 M acetic acid.Columns were dried under full vacuum for 5 min and thenrinsed with 1 mL hexane, 1 mL ethyl acetate, and 1 mLmethanol. Drugs of interest were eluted using 1 mL of 2%ammonium hydroxide in 95:5 (v/v) methylene chloride/iso-propyl alcohol in silanized conical borosilicate glass tubes. Ex-tracts were evaporated to dryness under nitrogen at 50°C, re-constituted in 20 μL of ethyl acetate, and transferred toautosampler vials for analysis.

Assay performanceAlthough quantitative analyses are not routinely performed

on urine samples, the new procedure was evaluated qualita-tively and quantitatively in order to determine overall assay per-formance. The analytical recovery was estimated by compar-ison of the relative peak areas of target analytes. Urinecontaining internal standard was extracted with (250 ng/mL)and without target drugs. The extract containing internal stan-dard alone was fortified with target drugs (250 ng/mL) imme-diately after the extraction, prior to the evaporation step. Sam-ples were reconstituted and analyzed by GC–MS. The analyticalrecovery (extraction efficiency) was calculated from the relativepeak area (drug/IS) of extracted and non-extracted samples.

The limit of detection (LOD) was defined as the lowest con-centration of analyte that met the following criteria: signal-to-noise (S/N) ratio of at least 3:1 for the total ion chromatogram;ion ratios for both qualifiers within acceptable ranges (±20%);and a retention time within 2% of the expected value. Thelimit of quantitation (LOQ) was defined as the lowest concen-

tration of analyte that met the following criteria: S/N ratio ofat least 10:1 for the total ion chromatogram; ion ratios forboth qualifiers within acceptable ranges (±20%); the retentiontime within 2% of the expected value; and a calculated con-centration within 20% of the expected value. The LOD andLOQ were assessed using urine fortified with psychedelic am-phetamine working standard. For the purpose of the LOQ, theurine calibrators were prepared using independently preparedstock solutions at to give final concentrations of 2, 10, and 20ng/mL.

Accuracy and precision were assessed by replicate analysis(n = 4) of drug-free urine fortified with target drugs at 50 and500 ng/mL. Linear regression analysis was used to determinethe limit of linearity of the assay, and carryover was evaluatedusing drug-free matrix injected immediately after extracts con-taining high concentrations of target drugs.

Interferences were evaluated using a number of structurallyrelated substances, endogenous bases, and common drugs.From a quantitative standpoint, an interference was defined asa substance that caused the calculated concentrations of atarget drug to deviate from the expected value by more than±20%. The potential interference of other abused am-phetamine-like drugs was investigated. Negative and positive(250 ng/mL) controls were assayed in the presence of 1 mg/Lof amphetamine-like drugs (amphetamine, methamphetamine,MDA, MDMA, MDEA, MBDB, ephedrine, pseudoephedrine,phentermine, phenylpropanolamine); endogenous bases(phenethylamine, putrescine, tryptamine, tyramine); andcommon basic drugs, including dextromethorphan, zolpidem,ketamine, diphenhydramine, cocaine, amitriptyline, diazepam,nordiazepam, oxycodone, hydrocodone, alprazolam, phency-clidine (PCP), methadone, tramadol, and codeine.

Results and Discussion

Analytical recovery, LOD, and LOQAnalytical recoveries for each of the target drugs were 63–

94% (Table IV). The lowest recoveries were generally observed

Table IV. Summary of Analytical Specifications Including Recovery, Limit of Detection (LOD), Limit of Quantitation (LOQ),and Correlation Coefficients (r2) for the Linear Range

Calculated Concentration LinearRecovery LOD LOQ at the LOQ Range

Drug (%) (ng/mL) (ng/mL) (ng/mL) (ng/mL) r2

2C-H 70 10 10 11.1 0–1500 0.9974-MTA 71 2 10 9.9 0–1500 0.994DOM 63 2 5 5.8 0–1500 0.995DOET 64 2 2 2.1 0–1500 0.9932C-B 94 2 5 4.8 0–1500 0.997DOB 74 2 2 1.9 0–1500 0.9922C-I 92 2 5 5.1 0–1500 0.990DOI 72 2 10 10.8 0–1500 0.9882C-T-2 86 5 10 8.6 0–1500 0.9902C-T-7 78 5 10 8.1 0–1500 0.993


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for the DO series of drugs. During the method developmentstage it was necessary to increase the polarity of the elution sol-vent (using isopropanol) in order to optimize recovery. An elu-tion solvent consisting of 2% ammonium hydroxide in 95:5 v/v

methylene chloride/isopropyl alcohol was optimal for methoxy-lated drugs. LODs ranged from 2 to 10 ng/mL, and LOQs were10 ng/mL or less for all analytes (Table IV). Calculated con-centrations for controls run at the quantitation limits are alsoshown, and Table V shows the corresponding signal-to-noise ra-tios for the total ion chromatogram (TIC) and acquired ions.Low LODs are preferable for this class of drug because of thelimited pharmacological data in humans and the absence ofmetabolites from commercial sources.

The most challenging drugs to separate and identify were thefollowing pairs of structurally related compounds: 2C-B andDOB; 2C-I and DOI. Despite the structural similarity, chro-matographic and spectroscopic resolution was achieved for all10 target drugs. Representative urine extracts containing 10and 100 ng/mL of each drug are depicted in Figure 2 and ex-tracted ion chromatograms are shown in Figure 3.

Precision, accuracy, and linearityPrecision and accuracy data are summarized in Table VI.

Accuracy was 91–116% and 98–109% at 50 and 500 ng/mL, re-spectively. Corresponding CVs were 0.9–6.5% and 0.4–5.6%, re-spectively. Calibrations were linear from 0 to 1500 ng/mL forall drugs, and correlation coefficients are given in Table IV. Nocarryover was evident following injection of an extract con-taining 5000 ng/mL of target drugs. During method develop-ment, a comparison of silanized and non-silanized glasswareindicated the former to be preferable. This suggests that someof the methoxylated species may have a tendency to adsorb tothe surface of glass.

InterferencesInterferences were evaluated qualitatively and quantitatively

using negative and positive controls fortified with potentialinterferants. None of the amphetamine-like drugs (am-

Table V. Signal-to-Noise (S/N) Ratios and CalculatedConcentrations at the LOQ

Drug m/z S/N Ratio*

2C-H 152 79:1181 110:1137 35:1TIC 10:1

4-MTA 138 103:1122 13:1

44 20:1TIC 31:1

DOM 166 570:1151 151:1

44 20:1TIC 34:1

DOET 180 430:1165 103:1

91 18:1TIC 119:1

2C-B 232 212:1261 122:1217 24:1TIC 52:1

DOB 232 398:1217 19:1

77 18:1TIC 63:1

2C-I 278 100:1307 84:1263 16:1TIC 32:1

DOI 278 184:1263 21:1

77 15:1TIC 39:1

2C-T-2 212 67:1241 76:1183 10:1TIC 10:1

2C-T-7 226 49:1255 46:1183 10:1TIC 17:1

* S/N ratios were evaluated for the total ion chromatogram (TIC) and for eachacquired ion.

Figure 2. Total ion chromatograms of target drugs in urine at 10 ng/mL (A)and 100 ng/mL (B). All extracts contain 250 ng/mL of mescaline-d9 (internalstandard).


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phetamine, methamphetamine, MDA,MDMA, MDEA, MBDB, ephedrine, pseu-doephedrine, phentermine, and phenyl-propanolamine) or endogenous bases(phenethylamine, putrescine, tryptamine,and tyramine) interfered with the assay.With the exception of MDMA, all am-phetamine-like and endogenous baseseluted prior to data acquisition (solventdelay 5 min). Negative controls remainedblank and quantitative controls con-taining target drugs at 250 ng/mL pro-duced calculated concentrations within82–104% of expected values for stimu-lants, and 81–116% for endogenousamines. In the presence of common alka-line drugs, both 2C-I and 2C-T-7 quanti-tated outside of the acceptable ±20%range (79% for both). Although this ap-peared marginal, negative controls werealways drug-free, indicating the absenceof interfering ions from these species. Al-though the quantitative discrepancy wasvery small, it was reproducible. There wasno obvious source of the possible inter-ference because none of the commondrugs coeluted with the target analyteswith the exception of 2C-I and phency-clidine at relative retention times of 1.80and 1.79, respectively (Table VII).

LimitationsPharmacological and toxicological data

for many of these drugs are still some-what limited. However, animal and, to alesser extent human, studies for selectdrugs within the class suggest a numberof common metabolic pathways. The DOseries of drugs may undergo hydroxyla-tion of the 4 methyl, followed by conju-gation or oxidation to the correspondingacid, deamination (to a ketone), reduc-tion to an alcohol, O-demethylation, orcombinations of these pathways (57,62,65). In a somewhat similar fashion, pro-posed pathways for the 2C series includeO-demethylation, deamination, alcoholformation, acid formation, reduction, andacetylation (48,49,59,64,66). Sulfur-con-taining drugs in the 2C-T series likely un-dergo similar transformations, in addi-tion to S-depropylation followed bymethylation of the resulting thiol(50,55,56). Conjugation (glucuronidationand sulfation) takes place and severalmetabolic studies employ a deconjuga-tion step prior to the identification of pro-posed metabolites.

Figure 3. Extracted ion chromatograms for target analytes and internal standard in urine at 10 ng/mL (A)and 100 ng/mL (B). Internal standard (mescaline-d9) was present at 250 ng/mL.


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A significant limitation, however, is the absence of com-mercial standards for these metabolites. From a practicalstandpoint, this limits most laboratories to the identification ofthe parent drug alone. Although concentrations of 2C-T-7 inheart blood and urine were 57 ng/mL and 1120 ng/mL fol-lowing a fatality (10), concentrations in recreational drug usersare not well established. DOB concentrations in serum fol-lowing a fatal overdose were particularly low (19 ng/mL) (12),but this is perhaps not surprising considering the very lowdose (1–3 mg) of this drug (Table II). Au-thors of this study tentatively identifiedurinary metabolites in addition to DOB,but were unable to identify them becauseof the absence of a commercial standard.

Conclusions

The 2C, 2C-T, and DO series of designerdrugs pose a number of challenges toforensic toxicology laboratories. Althoughthese drugs are seized by law enforcementagencies throughout the United States,they are not readily detected in forensictoxicology laboratories. It is not clearwhether these drugs are rarely encoun-tered due to overall low prevalence or lim-itations with respect to detectability.Commercial immunoassays have limitedcross-reactivity towards these am-phetamine-like drugs. As a consequence,laboratories that rely upon immunoassayrather than more broad spectrum chro-matographic screening techniques mayfail to detect these and other similar sub-

stances. In this study, we report a simple alkaline SPE to iso-late drugs of interest, followed by GC–MS analysis of under-ivatized extracts. Although the metabolic transformation ofthese drugs has been preliminarily investigated and likely in-volves a number of common pathways, commercial standardsare not readily available. Toxicology laboratories performingroutine human performance or postmortem investigationsmust therefore rely upon detection of the parent drug. Usingthe approach described here, a total of 10 designer drugs were

Table VI. Precision and Accuracy at 50 and 500 ng/mL

50 ng/mL 500 ng/mL

Calculated Calculated Calculated CalculatedConcentration Concentration Concentration Concentration

(ng/mL) (ng/mL) (ng/mL) (ng/mL)Mean ± SD Mean ± 95% CI Accuracy %CV Mean ± SD Mean ± 95% CI Accuracy %CV

Drug (n = 4) (n = 4) (%) (n = 4) (n = 4) (n = 4) (%) (n = 4)

2C-H 46.2 ± 0.5 46.2 ± 0.9 93 1.2 494.2 ± 20.3 494.2 ± 32.3 99 4.14-MTA 50.8 ± 4.0 50.8 ± 6.4 102 7.9 488.3 ± 26.5 488.3 ± 42.1 98 5.4DOM 50.4 ± 1.3 50.4 ± 2.1 101 2.6 499.4 ± 14.5 499.4 ± 23.1 100 2.9DOET 49.2 ± 1.3 49.2 ± 2.0 98 2.5 498.7 ± 9.7 498.7 ± 15.4 100 1.92C-B 47.4 ± 0.4 47.4 ± 0.7 95 0.9 524.2 ± 2.3 524.2 ± 3.7 105 0.4DOB 46.3 ± 1.5 46.3 ± 2.3 93 3.1 502.1 ± 7.4 502.1 ± 11.7 100 1.52C-I 47.7 ± 0.5 47.7 ± 0.8 95 1.1 522.5 ± 8.4 522.5 ± 13.4 105 1.6DOI 45.4 ± 1.3 45.4 ± 2.1 91 2.9 508.6 ± 5.3 508.6 ± 8.5 102 1.02C-T-2 48.0 ± 3.1 48.0 ± 4.9 96 6.52 518.4 ± 15.7 518.4 ± 25.0 104 3.02C-T-7 57.8 ± 0.9 57.8 ± 1.5 116 1.67 545.4 ± 30.7 545.4 ± 48.8 109 5.6

Figure 3 (continued). Extracted ion chromatograms for target analytes and internal standard in urine at10 ng/mL (A) and 100 ng/mL (B). Internal standard (mescaline-d9) was present at 250 ng/mL.


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targeted in one assay with very low detection limits, sufficientto identify parent drug in urine samples. Using this approach,2C, 2C-T, and DO series drugs could be incorporated somewhatreadily into a laboratory’s existing analytical procedures wherenecessary.

Acknowledgments

This project was supported by Award No. 2008-DN-BX-K126awarded by the National Institute of Justice, Office of JusticePrograms, U.S. Department of Justice. The opinions, findings,and conclusions or recommendations expressed in this publi-cation are those of the author(s) and do not necessarily reflectthose of the Department of Justice.

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Table VII. Relative Retention Times of Target Analytesand Other Drugs

Drug Relative Retention Time

MDMA 0.71

2C-H 0.72

4-MTA 0.76

MDEA 0.78

DOM 0.83

MBDB 0.86

DOET 0.94

Mescaline-d9 1.00

Tryptamine 1.13

2C-B 1.35

DOB 1.38

Ketamine 1.60

Diphenhydramine 1.66

PCP 1.79

2C-I 1.80

DOI 1.84

2C-T-2 1.95

Tramadol 2.07

2C-T-7 2.23

Methadone 2.41

Dextromethorphan 2.42

Amitriptyline 2.47

Cocaine 2.47

Codeine 2.62

Diazepam 2.66

Hydrocodone 2.67

Nordiazepam 2.72

Oxycodone 2.73

Zolpidem 2.98

Alprazolam 2.82


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