Post on 24-Feb-2016
description
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This does not include the countless unpublished designer compounds which have also shown up in case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
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
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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
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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
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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
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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