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?