This presentation considers the latest intelligence on what drugs are out in the U.S. grey market of products being sold as novelties, legal highs, “Bath Salts” and research chemicals, including an update on the latest trends in synthetic cannabinoid use and detection. The proliferation of designer drugs in the last two years has made a remarkable change to the landscape of forensic toxicology and drug identification. The scope of compounds that require detection and measurement has grown from a few drugs that needed to be targeted in specific cases, to a wide range of esoteric compounds that arguably need to be included in general drug screens for forensic purposes. The growth continues as the industry that has built up around recreational drug manufacture adjusts in an attempt to stay one step ahead of the law. The presentation reviews the general chemical drug classes encountered in forensic toxicology and chemistry casework, including mephedrone, methylone and MDPV, recently scheduled by the US DEA, and related the cathinones, 2C compounds, tryptamines, and pyrovalerones. This includes a survey of the latest published research, and a review of resources for analytical testing and standards.

1. THE EXPANDING REACH OF THE DESIGNER
DRUG MOVEMENT IN 2011:
CHALLENGES FOR FORENSIC
TOXICOLOGY & CHEMISTRY
Barry K Logan PhD, DABFT,
National Director Forensic Services, NMS Labs
Willow Grove PA

2. History and Context

3. Designer Drugs
1980’s
α-methylfentanyl, MPPP, MDMA,
1990’s, early 2000’s
PMA, rise of methamphetamine
1991 Publication of PiHKAL
1997 Publication of TiHKAL
“Combat Methamphetamine Epidemic
Act of 2005”
Growth of the Internet
Beginnings of the “Research Chemicals”
or “New Psychedelic” Movement.

4. Designer Drugs
1980’s
α-methylfentanyl, MPPP, MDMA,
1990’s, early 2000’s
PMA, rise of methamphetamine
1991 Publication of PiHKAL
1997 Publication of TiHKAL
“Combat Methamphetamine Epidemic
Act of 2005”
Growth of the Internet
Beginnings of the “Research Chemicals”
or “New Psychedelic” Movement.

5. Designer Drugs
1980’s
α-methylfentanyl, MPPP, MDMA,
1990’s, early 2000’s
PMA, rise of methamphetamine
1991 Publication of PiHKAL
1997 Publication of TiHKAL
“Combat Methamphetamine Epidemic
Act of 2005”
Growth of the Internet
Beginnings of the “Research Chemicals”
or “New Psychedelic” Movement.

6. Designer Drugs
1980’s
α-methylfentanyl, MPPP, MDMA,
1990’s, early 2000’s
PMA, rise of methamphetamine
1991 Publication of PiHKAL
1997 Publication of TiHKAL
“Combat Methamphetamine Epidemic
Act of 2005”
Growth of the Internet 1995
Beginnings of the “Research Chemicals”
or “New Psychedelic” Movement.

7. Designer Drugs
1980’s
α-methylfentanyl, MPPP, MDMA,
1990’s, early 2000’s
PMA, rise of methamphetamine
1991 Publication of PiHKAL
1997 Publication of TiHKAL
“Combat Methamphetamine Epidemic
Act of 2005”
Growth of the Internet
Beginnings of the “Research Chemicals”
or “New Psychedelic” Movement.

8. Designer Drugs
Mid 2000’s
New tools for drug synthesis
Research Chemical Supply Industry
2C-B, 2C-E, 2C-T-7
AMT, DMT, 5-MeO-DiPT
2004 Operation Web Tryp
Khat, cathinone, methcathinone

9. Designer Drugs
2008-2011
Benzylpiperazines (6+)
BZP, TFMPP, m-CPP
Synthetic Cannabinoids (200+)
JWH series, AM Series, RCS Series
β -Keto amphetamines (30+)
Ephedrone, mephedrone, methylone, methedrone…
Phenethylamines (2C suite) (15+)
2C-B, 2C-E, 2C-I, 2C-B, 2C-T-7,…
Pyrrolidophenones (pyrovalerones) (20+)
α-PVP, MDPV, PPP,…

10. Legal Status

11. Legal Status
Title 21 United States Code (USC)
Controlled Substances Act
Schedules drugs according to their
medical use, liability for addiction, and
potential for abuse. Schedule I includes:
“…the following hallucinogenic substances, or
which contains any of their salts, isomers, and
salts of isomers whenever the existence of
such salts, isomers, and salts of isomers is
possible within the specific chemical
designation.”

12. Legal Status
Section 812. Schedule I (c) 17
compounds including:
3,4-methylenedioxyamphetamine
3,4-methylenedioxymethamphetamine
5-methoxy-3,4-methylenedioxy
amphetamine.
3,4,5-trimethoxy amphetamine
Diethyltryptamine
Dimethyltryptamine.
4-methyl-2,5-diamethoxyamphetamine.

13. Legal Status
Temporary Scheduling
3/1/2011 – Synthetic Cannabinoids
JWH-018
JWH-073
JWH-200
CP47,497 (C7)
CP47,497 (C8)
10/21/2011 “Bath Salts”
MDPV
Mephedrone
Methylone

14. Legal Status
Federal Analog Act (1986)
The Federal Analogue Act defines an
analog as a substance which is
'substantially similar' to a scheduled
substance and has either an effect
'similar to or greater than' a controlled
Mephedrone
substance or is thought to have such an
effect.
21 U.S.C. § 813
Methcathinone

15. Analogs? Yes!
USA v Washam
(2002) 312 F.3d 926, 930
(i) 1,4-Butanediol and GHB are both
linear compounds containing four
carbons and that there is only one
difference between the substances on
one side of their molecules”, and (ii) that
1,4-B is metabolized into GHB by the
body and so produces substantially
similar physiological effects.

16. Analogs? No!
USA v. Damon S. Forbes et al.
(1992) 806 F.Supp. 232
(i) AET is a primary amine while DMT AET
and DET are tertiary amines,
(ii) AET cannot be synthesized from
either DMT or DET, and
(iii) the hallucinogenic or stimulant
DMT
effects of AET are not substantially
similar to the effects of DMT or DET.
DET

17. Synthetic Cannabinoids Update

18. Syn Canns Behavioral Effects

19. Syn Canns and Lethality

20. Syn Canns and Lethality

21. Syn Canns Prevalence
Calls to Poison Control Centers
NFLIS, Oct 2011

22. NMS Labs Blood Positivity Rates
US DEA Controls
JWH-018, 073, 200
and CP,47,497

23. NMS Blood Positivity Rates
August 2011-September 2011
JWH-018 JWH-073 JWH-250 AM-2201 RCS-4
Range (ng/mL) 0.10 – 26 0.93 – 1.7 0.11 – 6.5 0.13 – 10 0.25 – 1.8
Mean ± SD (ng/mL) 2.98 ± 6.69 1.32 ± 0.54 1.12 ± 1.7 2.36 ± 2.97 0.72 ± 0.64
Median (ng/mL) 0.36 1.3 0.67 0.69 0.49
% Positive 12.3 1.6 10.7 27.0 4.1
JWH-019 JWH-081 JWH-122 JWH-210 RCS-8
% Positive 4.9 7.4 40.2 19.7 0.8
No positives for JWH-200, AM-694
Graf, Kacinko & Logan, SOFT, October, 2011

24. Synn Cann Toxicity

25. Synn Cann Toxicity
Young AC, Schwarz E, Medina G, Obafemi A, Feng SY, Kane C, Kleinschmidt K.
Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory
confirmation. Am J Emerg Med. 2011 Jul 28.

26. Bath Salts Update

27. Bath Salts and Depression

28. Bath Salts Toxicity

29. Bath Salts and Violence

30. Bath Salts and Violence

31. Cathinones/MDPV prevalence
Calls to Poison Control Centers
NFLIS, Oct 2011

32. Cathinones/MDPV prevalence
NFLIS, Oct 2011

33. Mephedrone Toxicity

34. Mephedrone Toxicity

35. Bath Salts Toxicity

36. What to test for?

37. Designer Drug Scope
2009-2011
Peters FT, Martinez-Ramirez
JA. Analytical toxicology of
emerging drugs of abuse.
Ther Drug Monit. 2010
Oct;32(5):532-9.

38. Designer Drug Scope
2009-2011
Wohlfarth A, Weinmann W.
Bioanalysis of new designer
drugs. Bioanalysis. 2010
May;2(5):965-79.

39. 2011 Synthetic Cannabinoids
JWH-007 CP 47, 497 (C7) HU-210
JWH-015 CP 47,497 (C8) HU-211
JWH-018 CP 55,940 HU-308
JWH-018 methyl hexyl homolog AM-694 HU-331
JWH-019 AM-1220 JT-7770
JWH-073 AM-1241
JWH-073 methyl butyl homolog AM-2201
JWH-081 AM-2233
JWH-122 RCS-4
JWH-133 RCS-8
JWH-175 WIN 48,098 (Pravadoline)
JWH-200 WIN 55,212-2
JWH-201 WIN 55,212-3
JWH-203 CB-25
JWH-210 CB-52
JWH-250
JWH-251
JWH-302
JWH-398

40. Priority Analytical Targets
Designer Stimulants/Hallucinogens:
 Federal Schedules:
Mephedrone, MDPV, and Methylone
 State Schedule (PA)
4-Methoxymethcathinone
4-Fluoromethcathinone
3-Fluoromethcathinone
 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4

41. Priority Analytical Targets
Synthetic Cannabinoids:
 Federal Schedules:
HU-210, -211, JWH-018, -073, -200, CP47,497 (C7), (C8)
 State Schedule
JWH-019, JWH-250
 Other
JWH-120, -210, AM-2201, -694, RCS-4, - 8, JWH-081, WIN48,098

42. Priority Analytical Targets
Others:
 2C-B-FLY, 2-Bromo-dragonfly
 Tryptamines (5-MeO-DALT, 5-MeODiPT, AMT, DMT)
 Mitragynine (Kratom)
 Mesembrine/mesembrenol/hordenine (Kanna)
 Phenazepam
 Next: Aminoindanes, Benzofurans,
 Classical Hallucinogens
Psilocin
LSD
Salvinorin
A/B
Dextromethorphan

43. Designer Drugs/Hallucinogens
 Criminalistics Panel
 Comprehensive Stimulants and Hallucinogens Panel, Test
(7210LI/S)
• 2,5-Dimethoxy-4-chloroamphetamine
• 2,5-dimethoxy-4-iodophenethylamine
• 2,5-dimethoxy-4-n-propylthiophenethylamine
• 3, 4-methylenedioxyethamphetamine
• 3,4-Methylenedioxyamphetamine
• 3,4-Methylenedioxymethamphetamine
• 3-Trifluoromethylphenylpiperazine
• 4-Bromo-2,5-Dimethoxyphenethylamine
• 4-fluoroamphetamine
• 4-Fluorocathinone
• 4-methyl-N-ethylcathinone
• …

44. Designer Drugs/Hallucinogens
 Criminalistics Panel
 Comprehensive Stimulants and Hallucinogens Panel, Test
(7210LI/S)
• N-hydroxy-3,4-methylenedioxyamphetamine
• para-Chlorophenylpiperazine
• Pentylone
• Phencyclidine
• Psilocin
• Salvinorin A
• Scopolamine
• THC
• Thujone

45. Designer Drugs/Hallucinogens
 Toxicology LCTOF Panel
 Hallucinogens Screen - Expanded, Test (8755B/SP/U)

46. Designer Drugs/Hallucinogens
 Toxicology LCMSMS Panel
 Mephedrone & MDPV Stimulants Designer Drug Test,
(2623B/SP/U)
• Mephedrone
• MDPV
• Methylone (coming soon)

47. Choice of Matrix
 Cathinones, Phenethylamines,
Tryptamines, Pyrovalerones
 Blood/Urine – Parent Compound 10/100ng/mL
 Salvia
 Blood/Urine – Salvinorin A/B 0.1ng/mL
 Synthetic Cannabinoids
 Blood – Parent Compound 0.1 – 50ng/mL
 Urine – Metabolites 0.1 – 100ng/mL
 Lack of available reference materials
 Lack of labeled internal standards
requires careful validation.

48. Screening
 Immunoassay – Benzylpiperazines
 Trazodone, meta-chlorophenylpiperazine (an
hallucinogenic drug and trazodone metabolite),
and the hallucinogen
trifluoromethylphenylpiperazine cross-react with
the EMIT®II ecstasy immunoassay in urine.
 Logan BK, et al.
 J Anal Toxicol. 2010 Nov;34(9):587-9.
 Development of a Novel Benzylpiperazine ELISA
Assay for Urine and Blood.
 Rodrigues* WC et al.
 SOFT/TIAFT 2011

49. Analytical Technique
 Immunoassay – Phenethylamines
 Evaluation of commercial enzyme-linked immunosorbent
assays to identify psychedelic phenethylamines.
 Kerrigan S, et al.
 J Anal Toxicol. 2011;35(7):444-51.

50. Analytical Technique
 Immunoassay – Synthetic Cannabinoids
 NMS Labs data
 No cross-reactivity of synthetic cannabinoids or metabolites
with Immunalysis Cannabinoids ELISA assay, or EMIT II
Cannabinoids assay, at 10,000ng/mL
 Development of New Polyclonal Antibodies for the Screening of
JWH Synthetic Cannabinoids and Metabolites
 Benchikh, ME et al.
 SOFT/TIAFT 2011

51. JWH-018/073 Urine ELISA
 Immunoassay – Synthetic Cannabinoids
 Synthetic Cannabinoid Metabolites Screen, Urine Test
(9563U)
 September 20th, 2011 NMS Labs releases JWH-018 and
JWH-073 ELISA.
 Cross reacts with 4-OH-JWH-018, 5-OH-JWH-018, 4-OH-
JWH-073, 4-OH-JWH-073
 Does not cross react with THC-COOH
 Cutoff = 5 ng/mL

52. Synthetic Cannabinoids
 Blood - Synthetic Cannabinoids
 Synthetic Cannabinoids, Blood (Forensic) Test (9560B)
 JWH-018
 JWH-073
 JWH-019
 JWH-250
 JWH-081
 JWH-122
 JWH-200
 AM-2201
 AM-694
 RCS-4
 RCS-8 RCS-4

53. Synthetic Cannabinoids
 Urine - Synthetic Cannabinoids
 Synthetic Cannabinoid Metabolites Screen - Expanded,
Urine (Forensic) Test (9562U)
 JWH-018 N-(4-hydroxypentyl) metabolite
O
 JWH-018 N-(5-hydroxypentyl) metabolite O
 JWH-019 N-(5-hydroxyhexyl) metabolite
N
 JWH-073 N-(3-hydroxybutyl) metabolite
OH
 JWH-073 N-(4-hydroxybutyl) metabolite
 JWH-250 N-(4-hydroxypentyl) metabolite*
 AM-2201 N-(4-hydroxypentyl) metabolite

54. Analytical Technique
 GCMS
 Good candidate for parent compounds
 Limited sensitivity in full scan
 Most information for structural discrimination of
closely related compounds.
 Some synthetic cannabinoids and amphetamine
compounds require derivatization.
CP47,497 (C7) DOM

55. Analytical Technique
 LCMSMS
 Superior sensitivity
 Limited fragmentation
 Shared transitions for close relatives
 Requires separation in time/good chromatography
155 155
127 OH 127 OH
N N
O O OH
358 374
JWH-018 monohydroxy JWH-018 dihydroxy

56. JWH-018 Metabolism
NMS Labs, June 2011

57. JWH-018/073 Metabolism

58. Analytical Technique
 High Resolution/LCTOF
 Superior sensitivity
 Molecular formula identification
 Many pairs of isobaric compounds exist
 HU-210/HU-211
 3-fluoromethcathinone/4-fluoromethcathinone
 MDMA/3,4-BDB/p-MeO-MMA, etc
 JWH-007/JWH-019
 JWH-122/180
 JWH-049/JWH-182
Hudson et al. J Anal Toxicol. 2010 Jun;34(5):252-60.

59. Summary
 Rapidly changing market.
 Regulation always a step behind the market.
 Analog definitions will be fought out in court.
 Growing evidence of adverse effects.
 Violence, paranoia, psychosis, possible cardiotoxicity,
and unexplained deaths.
 Laboratories should update their scope and keep it
targeted to most prevalent compounds.
 LCMSMS/LCTOF are the most versatile
techniques for detecting biomarkers.
 Innovative strategies required for
identification of metabolites and
acquisition of standards.

60. ACKNOWLEDGEMENTS
Staff of NMS Labs
Criminalistics
Toxicological Services
Research and Development Department
LC-MS/MS Department
QUESTIONS?