the expanding reach of the designer drug movement in 2011: challenges for forensic toxicology &...
DESCRIPTION
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.TRANSCRIPT
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 LabsWillow Grove PA
History and Context
Designer Drugs1980’s-methylfentanyl, MPPP, MDMA, 1990’s, early 2000’sPMA, rise of methamphetamine1991 Publication of PiHKAL1997 Publication of TiHKAL“Combat Methamphetamine Epidemic Act of 2005”Growth of the InternetBeginnings of the “Research Chemicals” or “New Psychedelic” Movement.
Designer Drugs1980’s-methylfentanyl, MPPP, MDMA, 1990’s, early 2000’sPMA, rise of methamphetamine1991 Publication of PiHKAL1997 Publication of TiHKAL“Combat Methamphetamine Epidemic Act of 2005”Growth of the InternetBeginnings of the “Research Chemicals” or “New Psychedelic” Movement.
Designer Drugs1980’s-methylfentanyl, MPPP, MDMA, 1990’s, early 2000’sPMA, rise of methamphetamine1991 Publication of PiHKAL1997 Publication of TiHKAL“Combat Methamphetamine Epidemic Act of 2005”Growth of the InternetBeginnings of the “Research Chemicals” or “New Psychedelic” Movement.
Designer Drugs1980’s-methylfentanyl, MPPP, MDMA, 1990’s, early 2000’sPMA, rise of methamphetamine1991 Publication of PiHKAL1997 Publication of TiHKAL“Combat Methamphetamine Epidemic Act of 2005”Growth of the InternetBeginnings of the “Research Chemicals” or “New Psychedelic” Movement.
1995
Designer Drugs1980’s-methylfentanyl, MPPP, MDMA, 1990’s, early 2000’sPMA, rise of methamphetamine1991 Publication of PiHKAL1997 Publication of TiHKAL“Combat Methamphetamine Epidemic Act of 2005”Growth of the InternetBeginnings of the “Research Chemicals” or “New Psychedelic” Movement.
Designer DrugsMid 2000’sNew tools for drug synthesisResearch Chemical Supply Industry2C-B, 2C-E, 2C-T-7AMT, DMT, 5-MeO-DiPT 2004 Operation Web TrypKhat, cathinone, methcathinone
Designer Drugs2008-2011Benzylpiperazines (6+)BZP, TFMPP, m-CPPSynthetic Cannabinoids (200+)JWH series, AM Series, RCS Series-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+)-PVP, MDPV, PPP,…
Legal Status
Legal StatusTitle 21 United States Code (USC) Controlled Substances ActSchedules 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.”
Legal StatusSection 812. Schedule I (c) 17 compounds including:3,4-methylenedioxyamphetamine 3,4-methylenedioxymethamphetamine 5-methoxy-3,4-methylenedioxy amphetamine. 3,4,5-trimethoxy amphetamineDiethyltryptamineDimethyltryptamine. 4-methyl-2,5-diamethoxyamphetamine.
Legal StatusTemporary Scheduling3/1/2011 – Synthetic CannabinoidsJWH-018JWH-073JWH-200CP47,497 (C7)CP47,497 (C8)10/21/2011 “Bath Salts”MDPVMephedroneMethylone
Legal StatusFederal 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 substance or is thought to have such an effect.
21 U.S.C. § 813
Mephedrone
Methcathinone
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.
Analogs? No!USA v. Damon S. Forbes et al. (1992) 806 F.Supp. 232
(i) AET is a primary amine while DMT and DET are tertiary amines, (ii) AET cannot be synthesized from either DMT or DET, and (iii) the hallucinogenic or stimulant effects of AET are not substantially similar to the effects of DMT or DET.
AET
DMT
DET
Synthetic Cannabinoids Update
Syn Canns Behavioral Effects
Syn Canns and Lethality
Syn Canns and Lethality
Syn Canns Prevalence
NFLIS, Oct 2011
Calls to Poison Control Centers
NMS Labs Blood Positivity Rates
US DEA Controls JWH-018, 073, 200 and CP,47,497
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
Graf, Kacinko & Logan, SOFT, October, 2011
No positives for JWH-200, AM-694
Synn Cann Toxicity
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 laboratoryconfirmation. Am J Emerg Med. 2011 Jul 28.
Bath Salts Update
Bath Salts and Depression
Bath Salts Toxicity
Bath Salts and Violence
Bath Salts and Violence
Cathinones/MDPV prevalence
NFLIS, Oct 2011
Calls to Poison Control Centers
Cathinones/MDPV prevalence
NFLIS, Oct 2011
Mephedrone Toxicity
Mephedrone Toxicity
Bath Salts Toxicity
What to test for?
Designer Drug Scope2009-2011
Peters FT, Martinez-Ramirez JA. Analytical toxicology of emerging drugs of abuse. Ther Drug Monit. 2010 Oct;32(5):532-9.
Designer Drug Scope2009-2011
Wohlfarth A, Weinmann W. Bioanalysis of new designer drugs. Bioanalysis. 2010 May;2(5):965-79.
2011 Synthetic CannabinoidsJWH-007JWH-015JWH-018JWH-018 methyl hexyl homologJWH-019JWH-073JWH-073 methyl butyl homologJWH-081JWH-122JWH-133JWH-175JWH-200JWH-201JWH-203JWH-210JWH-250JWH-251JWH-302JWH-398
CP 47, 497 (C7)CP 47,497 (C8) CP 55,940AM-694AM-1220AM-1241AM-2201AM-2233RCS-4RCS-8WIN 48,098 (Pravadoline)WIN 55,212-2WIN 55,212-3CB-25CB-52
HU-210HU-211HU-308HU-331JT-7770
Priority Analytical TargetsDesigner Stimulants/Hallucinogens:
Federal Schedules:Mephedrone, MDPV, and Methylone
State Schedule (PA)4-Methoxymethcathinone4-Fluoromethcathinone3-Fluoromethcathinone 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4
Priority Analytical TargetsSynthetic Cannabinoids:
Federal Schedules:HU-210, -211, JWH-018, -073, -200, CP47,497 (C7), (C8)
State ScheduleJWH-019, JWH-250
OtherJWH-120, -210, AM-2201, -694, RCS-4, - 8, JWH-081, WIN48,098
Priority Analytical TargetsOthers:
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
PsilocinLSDSalvinorin A/BDextromethorphan
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• …
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
Designer Drugs/Hallucinogens Toxicology LCTOF Panel Hallucinogens Screen - Expanded, Test (8755B/SP/U)
Designer Drugs/Hallucinogens Toxicology LCMSMS Panel Mephedrone & MDPV Stimulants Designer Drug Test,
(2623B/SP/U)
• Mephedrone• MDPV• Methylone (coming soon)
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.
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
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.
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
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
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
Synthetic Cannabinoids Urine - Synthetic Cannabinoids Synthetic Cannabinoid Metabolites Screen - Expanded,
Urine (Forensic) Test (9562U) JWH-018 N-(4-hydroxypentyl) metabolite JWH-018 N-(5-hydroxypentyl) metabolite JWH-019 N-(5-hydroxyhexyl) metabolite JWH-073 N-(3-hydroxybutyl) metabolite JWH-073 N-(4-hydroxybutyl) metabolite JWH-250 N-(4-hydroxypentyl) metabolite* AM-2201 N-(4-hydroxypentyl) metabolite
OO
N
OH
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
Analytical Technique LCMSMS
Superior sensitivity Limited fragmentation Shared transitions for close relatives Requires separation in time/good chromatography
N
O
OH
N
O
OH
OH
358 374
155 155
127 127
JWH-018 monohydroxy JWH-018 dihydroxy
JWH-018 Metabolism
NMS Labs, June 2011
JWH-018/073 Metabolism
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.
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.
ACKNOWLEDGEMENTS
Staff of NMS Labs
Criminalistics
Toxicological Services
Research and Development Department
LC-MS/MS Department
QUESTIONS?