LEGISLATIVE AND ANALYTICAL UPDATE ON

EMERGING DRUGS OF ABUSE

Jeremiah MorrisJohnson County Sheriff’s Office

Criminalistics Laboratory

Overview Review of how we got into this mess Legislative topics

Various legislative approaches Providing data to support control criteria

Analytical topics Analytical standards Types of testing Toxicology

Heads up! There is no value in just me talking

I am just the messenger

What is going on? Drug chemistry is not suppose to be this

difficult What happened to this quiet little

section?

How we got here - cannabinoids

First appearance in 2009 JWH-018 and JWH-073 Legislative responses in 2010

Vendor responses in 2010

7

Synthetic Cannabinoids JWH-018 JWH-073 JWH-250 JWH-200 JWH-210 JWH-203 JWH-122 JWH-019 JWH-015 JWH-251 JWH-398

JWH-081 WIN-55,212-2 JWH-370 CP 47,497 (C7) AM-630 HU-210 AM-2201 (Cl) CP 47,497 Pravadoline AM-1241 JWH-051

JWH-307 CP 47,497 (C9) AM-1220 RCS-4 (2-MeO) JWH-133 RCS-4 RCS-4 (C4) RCS-8 AM-2201 AM-694 And so on…

Over 400 compounds have been identified in the literature with potencies at least twice that of THC.

This does not include the countless unpublished designer compounds which have also shown up in case

submissions.

8

General chemical class Chemical structure Compounds currently marketed or identified in case submissions

Naphthoylindoles

JWH-007, JWH-015, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-398, AM-2201, WIN 55-212, AM-2201 (Cl analog) AM-2201 (Br analog), AM-1220, 1-butyl-3-(1-(4-methyl)naphthoyl)indole; 4-methyl-AM-2201, 4-methyl AM-2201, AM-2232, JWH-412

Naphthoylpyrroles JWH-307, JWH-370, JWH-030, JWH-147

Phenylacetylindoles SR-18, RCS-8 (same as SR-18?), JWH-250, JWH-203, RCS-8 (C4 homolog), JWH-251, cannabipiperidiethanone

Cyclohexylphenols CP 47,497 (and homologs), cannabicyclohexanol

Benzoylindoles

AM-694, Pravadoline (WIN 48,098), RCS-4 (also called SR-19, BTM-4, and OBT-199), RCS-4 (C4 homolog), AM-630, AM-1241, RCS-4 (2-methoxy isomer), AM-2233, 3-(2-methoxybenzoyl)-1-butylindole, AM-679

Tricyclic benzopyrans HU-210, JWH-051, JWH-133

NH

O

O

NH

NH

O

OH

OH

NH

O

O

A different approach The drug laws in the United Kingdom take a

chemical class approach utilizing broad definitions Tryptamines Phenethylamines Fentanyls Pethidines Barbiturates Steroids Piperazines Cannabinoids Cathinones

9

Cannabinoid examples Any compound containing a ___________ structure with substitution at the

nitrogen atom of the indole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.

10

N

O

N

O

F

N

O

N

O

N

O

N

O

N

N

O

N

O

O

Cannabinoid control by chemical classes

Initiated in 2011 by several states Modified version used federally in 2012 Currently most common legislative approach

for cannabinoidsMost common controlled classes

NaphthoylindolesNaphthylmethylindoles

NaphthoylpyrrolesNaphthylideneindenesPhenylacetylindolesCyclohexylphenols

Benzoylindoles

One significant difference Some class definitions contain only

structural requirements while others have pharmacological components:

Invoking pharmacology Oklahoma and Texas

“Synthetic chemical compound that is a cannabinoid receptor agonist and mimics the pharmacological effect of naturally occurring substances

Minnesota “any quantity of a substance that is a

cannabinoid receptor agonist” North Dakota

“synthetic chemicals which have similar effects on cannabinoid receptors”

13

What is an agonist? What actually defines a “cannabinoid

receptor agonist”? Binding studies? Animal studies? Within expertise of a forensic chemist?

The answer(s) may impact the ability of the state to enforce the specific statute

14

Cannabinoid problem solved?

15

The next generation

N

O

N

O

NH

N

O

NH

NN

O

N

O

N

This is not good

What does all this mean?

How bad can it get?Linker Ring

system BRing

system A

IndoleIndeneIndazoleAzaindolePyrrolePyrazole

CarbonylMethyleneMethineAcetylAmideCarboxyl

NaphthylPhenylAdamantylTetramethylcyclopropylPiperidinylQuinolinylAmino-3-methyl-1-oxobutan-2-yl

Grand total of 252 possible cannabinoid classes

How we got here – bath salts First appeared in 2009 Based on the chemical structure of the naturally

occurring cathinone All CNS stimulants

Act upon three different CNS receptors Potency varies but most equal or greater than

methamphetamine No legitimate bath, beauty, or plant food

purpose No accepted medical use in the United States Often referred to as “beta-ketones” (i.e., bk-

MDMA is methylone)

Substituted Cathinones

O

NH2

Cathinone

O

NH

Methcathinone(Ephedrone)

O

NH

4-Methylmethcathinone(Mephedrone)

O

NH2O

4-methoxymethcathinoneMethedrone

O

NH

4-Methylethcathinone

O

NHF

4-Fluoromethcathinone(Flephedrone)

N

O

O

O

3,4-Methylenedioxypyrovalerone(MDPV)

O

NH

O

O

3,4-Methylenedioxymethcathinone(Methylone)

O

NH

O

O

Butylone

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Substituted Cathinones

4-methylmethcathinone 3,4-methylenedioxypyrovalerone4-fluoromethcathinone 3-fluoromethcathinone4-methylethcathinone 3,4-dimethylmethcathinoneα-methylamino-butyrophenone β-keto-

ethylbenzodioxolylbutanamine3,4-methylenedioxy-N-ethylcathinone

4-methoxymethcathinone

a-pyrrolidinopropiophenone 3,4-methlyenedioxymethcathinone

a-pyrrolidinopentiophenone β-keto-N-methylbenzodioxolylpropylamine

naphthylpyrovalerone 4-’methyl-a-pyrrolidinopropiophenoneβ-keto-methylbenzodioxolylpentanamine

4’-methyl-a-pyrrolidinohexanophenone

4’-methyl-a-pyrrolidinobutyrophenone α-phthalimidopropiophenone,N-ethylcathinone 4’-methyl-α-

pyrrolidinohexanophenone3,4-methylenedioxypyrrolidinobutyrophenone

23

Substituted cathinones

O

NH2

Cathinone

Unsubstituted3- or 4-methyl3- or 4-halo (F, Cl, Br, or I)3- or 4-ethyl3- or 4-hydroxy3- or 4-methoxy3,4-methylenedioxy3,4-dimethyl3,4-dihalo (F, Cl, Br, or I)Replace phenyl with naphthyl

UnsubstitutedN-methylN-ethylN,N-dimethylPyrrolidinePhthalamidoN-benzyl

PropylButylPentylHexyl

Grand total of 672 possible combinations

Legislative controls Mixed approach, starting in 2011

Listing individual compounds Chemical class approach

SO

NH2

O

NH2

O

NH2

1

2

31

2

31

2

3

Other kinds of “bath salts” Novelty products which originally

contained just substituted cathinones now include a number of additional classes: Modified phenethylamines

Stimulants Hallucinogenic

Arylcyclohexylamines Tryptamines And so on

We have no reason to believe this cycle will stop anytime soon

26

NBOME derivatives Work by Dr. Nichols et al discovered

modifications of hallucinogenic phenethylamines increases potency

27

NBOME derivatives N-benzyl ortho-methoxy (NBOME)

derivatives were the most potent

28

NBOME derivatives A number of these compounds are

available on the web and have appeared in case submissions

NH

O

H

O

O

NH

O

CH3

O

O

NH

O

Br

O

O

NH

O

I

O

O

2C-H-NBOMe 2C-C-NBOMe

2C-B-NBOMe 2C-I-NBOMe

29

Arylcyclohexylamines Comprise the most common class of

dissociatives Complex pharmacology CNS appears dose dependent and spans

entire range

N ArylR

R'

R

SR

S

R

NR

RNH

RNH

MethoxyHydroxyHalo

Carbonyl

Grand total of 54 possible combinations

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Tryptamines Class of highly potent hallucinogens

Present in a diverse group of botanical materials

All contain substituted indole compoundNH

NOH

NH

N

OH

NH

N

Dimethyltryptamine Bufotenine Psilocin

31

Variations on a tryptamine theme

NH

NH2

1

2

3

4

5

6

7Hydroxyl, methoxy, acetoxy, halo

Alkyl or dialkyl substitution (methyl, ethyl, propyl, isopropyl, allyl

Methyl or ethyl with mono-N alkyl substitution

a

b

Grand total of 175 possible combinations

What about the analog law?

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N

O

N

O

JWH-018 UR-144

The Original

The Original - modified

Fentanyl Analogs

N

N

O

N

N

O

Fentanyl 3-Methyl Fentanyl

The Analog Law Any new substance can be considered a

controlled “analog” if: It has a substantially similar structure to a

Schedule I or II hallucinogen, stimulant, or opiate, AND,

It has the same CNS effects as the related Schedule I or II hallucinogen, stimulant, or opiate, OR,

It was possessed or sold with the knowledge of being an analog

Application can be extremely difficult

Your turn Respective of these approaches, how

effective have they been? Prosecution issues? Legal challenges? Response from chemists? Effectiveness? Listing compounds individually Chemical class (structure only) Chemical class (with pharmacology) Analog law Emergency scheduling

What we’ve learned Educating prosecutors has made all of

the difference What the law actually says Capabilities of the drug chemistry section How to read reports

Some other ideas Modifications to the analog law Additional chemical classes Broad class approach “Synthetic drug lookalike substance”

approach FDA approach

We have to ask, “What are we trying to accomplish?”

Modified Analog Law"Controlled substance analog" means any of the following:

A substance that differs in its chemical structure to a controlled substance listed in or added to the scheduled designated in K.S.A. 65-4105 or 64-4107 only by substituting one or more hydrogens with halogens or by substituting one halogen with a different halogen or,

  A substance that is an alkyl homolog of a controlled substance listed in or added to the

scheduled designated in K.S.A. 65-4105 or 64-4107 or  (C) A substance intended for human consumption, and: 

(i) The chemical structure of which is substantially similar to the chemical structure of a controlled substance listed in or added to the schedules designated in K.S.A. 65-4105 or 65-4107, and amendments thereto;

(ii) which has a stimulant, depressant or hallucinogenic effect on the central nervous system substantially similar to the stimulant, depressant or hallucinogenic effect on the central nervous system of a controlled substance included in the schedules designated in K.S.A. 65-4105 or 65-4107, and amendments thereto; or (iii) with respect to a particular individual, which the individual represents or intends to have a stimulant, depressant or hallucinogenic effect on the central nervous system substantially similar to the stimulant, depressant or hallucinogenic effect on the central nervous system of a controlled substance included in the schedules designated in K.S.A. 65-4105 or 65-4107, and amendments thereto.

Considerations for modified analog law

Creates defined chemical modifications which automatically qualify compounds as an analog Structural only, no pharmacology Based on accepted changes in medicinal drug

design

Retains previous approach for other structural modifications

Will this make the analog law more usable?

Additional chemical classes

Draft proposed definitions for the following chemical classes are available if you’re interested: Arylcyclohexylamines (PCP-like) Modified tryptamines Hallucinogenic phenethylamines (two versions)

Considerations Same benefits and analytical issues with existing

classes Still reactionary and limited in scope

Broad class approach In addition to specific chemical classes,

Kentucky has this statement: Any other synthetic cannabinoid or piperazine

which is not approved by the United States Food and Drug Administration or, if approved, which is not dispensed or possessed in accordance with state and federal law

Considerations Catches all future “illicit” cannabinoids But what is a “synthetic cannabinoid”?

Circular definition?

Idaho approach Any compound structurally derived from (1H-

indole-3-yl)(cycloalkyl, cycloalkenyl, aryl)methanone, or (1H-indole-3yl)(cycloalkyl, cycloalkenyl, aryl)methane, or (1H-indole-3-yl)(cycloalkyl, cycloalkenyl, aryl)carboxamide by substitution at the nitrogen atoms of the indole ring or carboxamide to any extent, whether or not further substituted in or on the indole ring to any extent, whether or not substituted in the naphthyl ring to any extent in or on the cycloalkyl, cycloalkenyl, aryl ring(s) (substitution in the ring may include, but is not limited to, heteroatoms such as nitrogen, sulfur and oxygen)

Idaho approach or (1H-indole-3yl)(cycloalkyl, cycloalkenyl,

aryl)methane, or (1H-indole-3-yl)(cycloalkyl, cycloalkenyl, aryl)carboxamide by substitution at the nitrogen atoms of the indole ring or carboxamide to any extent

N

R1

R2

O

N

R1

NH

O

R2

N

Considerations

N

NH

ON

F

N

N

O O

O

N

O

NH

NN

O

F

NH

NN

O

N

N

OH

O

Synthetic drug lookalike substance

Broad-based approach which attempts to pre-empt new drugs of abuse which do not fall into specific control categories

Kind of creating a “looks like a duck” law

Minnesota version(a) For the purposes of this section, "synthetic drug look-alike substance" means one or more of the following:

(1) a substance that a reasonable person would believe is a synthetic drug;

(2) a substance that a reasonable person would believe is being purchased or sold as a synthetic drug; or

(3) a substance that a person knows or should have known was intended to be consumed by injection, inhalation, ingestion, or any other immediate means, and consumption was intended to cause or simulate a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in Schedule I.

(b) Synthetic drug look-alike substance does not include:(1) food and food ingredients;(2) alcohol;(3) legend drugs;(4) tobacco; or(5) dietary supplements.

Indiana versionSec. 321.5. (a) "Synthetic drug lookalike substance", except as provided in subsection (b), means one (1) or more of the following:

(1) A substance, other than a synthetic drug, which any of the factors listed in subsection (c) would lead a reasonable person to believe to be a synthetic drug.

(2) A substance, other than a synthetic drug:(A) that a person knows or should have known was intended to be consumed; and(B) the consumption of which the person knows or should have known to be intended to cause intoxication.

(b) The term "synthetic drug lookalike substance" does not include the following:(1) Food and food ingredients (as defined in IC 6-2.5-1-20).(2) Alcohol (as defined in IC 7.1-1-3-4).(3) A legend drug (as defined in IC 16-18-2-199).(4) Tobacco.(5) A dietary supplement (as defined in IC 6-2.5-1-16).

Indiana version (continued)

(c) In determining whether a substance is a synthetic drug lookalike substance, the followingfactors may be considered:

(1) The overall appearance of a dosage unit of the substance, including its shape, color, size,markings or lack of markings, taste, consistency, and any other identifying physicalcharacteristics.(2) How the substance is packaged for sale or distribution, including the shape, color, size,markings or lack of markings, and any other identifying physical characteristics of the packaging.(3) Any statement made by the owner or person in control of the substance concerning thesubstance's nature, use, or effect.(4) Any statement made to the buyer or recipient of the substance suggesting or implying thatthe substance is a synthetic drug.(5) Any statement made to the buyer or recipient of the substance suggesting or implying thatthe substance may be resold for profit.(6) The overall circumstances under which the substance is distributed, including whether:

(A) the distribution included an exchange of, or demand for, money or other property asconsideration; and(B) the amount of the consideration was substantially greater than the reasonable retail market value of the substance the seller claims the substance tobe.

Thoughts?

FDA approach All legislative approaches based upon the

controlled substance act are: Reactionary Restricted

In the realm of chemicals consumed by people, DEA has jurisdiction over controlled substances, FDA has everything else

FDA has provided significant assistance

FDA approach Most states likely have FDA-like statutes

modeled after Federal statutes Meant for pharmaceuticals Never intended for drugs of abuse But…

Mis-labeled products Basis for past cases in KS General approach

These products contain a psychoactive substance

“Not for human consumption” is a fraud

None of the packages are properly labeled

County in Florida assesses vendors a fine of $500 per pack

FDA approach Definition for “drug”

“articles, other than food, intended to affect the structure or any function of the body of man or other animals.”

Definition for “new drug” “any drug the composition of which is such that

such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof…”

The critical piece Must be licensed to deal with “new drugs”

No person shall sell, deliver, offer for sale, hold for sale or give away any new drug unless (1) an application with respect thereto has been approved and such approval has not been withdrawn under 21 U.S.C.A. 355, or (2) when not subject to the federal act, unless such drug has been tested and has been found to be safe for use and effective in use under the conditions prescribed, recommended, or suggested in the labeling thereof

If neither of the two requirements are met, then the person can be charged with unlawful distribution of a new drug

Example Local smoke shop selling

packets of “3,4-CTMP pellets” Analysis confirms 3,4-

dichloromethylphenidate Non-controlled substance

FDA approach requirements Meets definition of “drug”? Meets definition of “new

drug”? Verify vendor has no license

for distributing “new drugs”?

FDA approach considerations

Laws already on the books Broad enough to cover all future drugs of

abuse No need for pharmacological or structural

comparisons Will require more leg-work by all Addresses dealers, not personal

possession Different application than what intended? Violation may only be a misdemeanor

Can it be supported? Legislators have controlled it Prosecutors wish to move forward with a

case

Do we have sufficient data to conclude that a compound detected in an item of evidence meets the criteria to be a controlled substance? Primarily an issue with chemical class

definitions Also an awareness of related isomers and

instrument limitations

WARNING The answers mean we have to talk about

boring and confusing chemical technical stuff. Sorry.

ExampleAny compound containing a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.

N

O

N

O

NH

O

The short answer The supporting data is likely there. Potentially long process between data

collection and confident presentation of results Understanding theory of instrument Re-introduction of organic chemistry

(headaches) Knowing chemical structure of the compound Understanding past work on structurally

similar compounds Interpretation of mass spectra (major

headaches)

ExampleAny compound containing a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by a alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.

N

O

N

O

NH

O

O

M+ - 17

N

O

63

Other reporting issues Confirming “AM-2201” locks in the

fluorine at the 5-pentyl position

N

O

F

N

O

F

N

O

F

N

O

F

N

O

F

64

Synthetic cannabinoids

Do not under-estimate the value of retention times in GC/MS analyses!

65

However… Reporting “Confirmed AM-2201” may

require purchasing multiple standards Only one standard if reporting “Confirmed

1-fluoropentyl-3-(1-naphthoyl)indole”

N

O

F

N

O

F

N

O

F

N

O

F

N

O

F

66

Mass spectrum of flephedrone

67

But which isomer?

NH

O

FNH

O

F

NH

OF

68

Infrared spectral comparison

If the compound contains a benzene ring and no other aromatic groups (e.g., indole system), di-substituted compounds can be differentiated by specific infrared absorbance bands

1,2-disubstituted 735-770 cm-1

1,3-disubstituted690-710 cm-1

810-850 cm-1

1,4-disubstituted 810-840 cm-1

R

X

RX R

X

R

X

RX R

X

R

X

RX R

X

69

FTIR of fluoromethcathinones

4-fluoromethcathinone

3-fluoromethcathinone

2-fluoromethcathinone

NH

O

FNH

O

F

NH

OF

NH

O

FNH

O

F

Another issue… Schedule I reads:

Any compound structurally derived from 3-(1-naphthoyl)indole or 1H-indol-3-yl-(1-naphthyl)methane by substitution at the nitrogen atom of the indole ring by alkyl , haloalkyl , alkenyl , cycloalkyl methyl , cycloalkyl ethyl , 1-(N-methyl-2-piperidinyl)methyl or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent, whether or not substituted in the naphthyl ring to any extent. Including, but not limited to: JWH-018, or 1-pentyl-3-(1-naphthoyl)indole;

“Synthetic cannabinoid” defined as: “any natural or synthetic material, compound, mixture, or

preparation that contains any quantity of a substance that is a cannabinoid receptor agonist, including but not limited to any substance listed in paragraph (ll) of subdivision (4) of subsection 2”

Analytical dataMass spec and retention time of single component in an item match the data for a known standard of JWH-018

N

O

N

O

NH

O

Report wording What do you think about the following

report wording?

Analysis confirmed the presence of 1-pentyl-3-(1-naphthoyl)indole (JWH-018), a Schedule I controlled substance.

Questions about legislation?

Analytical standards Two issues:

Finding the standards (easy part) Using the standards for casework (hard part)

Analytical standard sources

Cayman Chemical Most common source ~$100 to $200 for 10 mg “Traceable standards” are more expensive

Toronto Research Chemicals National Measurement Institute Cerilliant Grace Analytical Sigma

Verifying the standards Most labs require verifying the standard

prior to it being used in casework Requires published spectra from peer-reviewed

source Generally GC/MS (sufficient for 10 mg standards) Positional isomer determination (3- or 4-

fluoroamphetamine) requires FTIR analysis (can be an issue for 10 mg standards)

Biggest obstacles are finding a reference spectrum and sufficient sample for FTIR

Issues with toxicology Analytical difficulties with emerging drugs

of abuse are significantly greater in toxicology Extraction from biological matrices Multiple metabolites rather than single

compounds Little to no info on absorption, distribution,

elimination Little to no info on human pharmcokinetics These things take time – something not

afforded

Analytical difficulties with tox Immunoassay screening techniques are

slow to evolve Expensive and labor intensive Available screening kits deal with compounds

long gone GC/MS screening techniques generally

developed in-house and validated too late

Analytical difficulties with tox Confirmation

LC/MS/MS best option (not a routine technique)

Metabolite standards non-existent or expensive

Published data on metabolite standards? Interpretation of any obtained results is very

difficult (i.e., “Were they impaired?”)

Essentially, the compounds in these products and the resultant laws are changing faster than toxicology sections can keep up

So what to do with Tox? If the toxicology results are critical to the

case, often times the best option will be using a private laboratory. Budget issues Instrumentation issues Back-log issues Drug life-cycle issues

Questions about analytical issues?

Thank you for your attention