1. Legislative and Analytical Update on Emerging Drugs of Abuse
Jeremiah Morris
Johnson County Sheriff’s Office Criminalistics Laboratory

2. 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

3. Heads up!
There is no value in just me talking

4. I am just the messenger

5. What is going on? Drug chemistry is not suppose to be this difficult
What happened to this quiet little section?

6. 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-081
JWH-307
JWH-073
WIN-55,212-2
CP 47,497 (C9)
JWH-250
JWH-370
AM-1220
JWH-200
CP 47,497 (C7)
RCS-4 (2-MeO)
JWH-210
AM-630
JWH-133
JWH-203
HU-210
RCS-4
JWH-122
AM-2201 (Cl)
RCS-4 (C4)
JWH-019
CP 47,497
RCS-8
JWH-015
Pravadoline
AM-2201
JWH-251
AM-1241
AM-694
JWH-398
JWH-051
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 This does not include the countless unpublished designer compounds which have also shown up in case submissions.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 , 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

9. 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

10. 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.

11. Cannabinoid control by chemical classes
Initiated in 2011 by several states
Modified version used federally in 2012
Currently most common legislative approach for cannabinoids
Most common controlled classes
Naphthoylindoles
Naphthylmethylindoles
Naphthoylpyrroles
Naphthylideneindenes
Phenylacetylindoles
Cyclohexylphenols
Benzoylindoles

12. One significant difference
Some class definitions contain only structural requirements while others have pharmacological components:

13. 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”

14. 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

15. Cannabinoid problem solved?

16. The next generation

17. This is not good

18. What does all this mean?

19. How bad can it get? Grand total of 252 possible cannabinoid classes
Ring system A
Linker
Ring system B
Indole
Indene
Indazole
Azaindole
Pyrrole
Pyrazole
Carbonyl
Methylene
Methine
Acetyl
Amide
Carboxyl
Naphthyl
Phenyl
Adamantyl
Tetramethylcyclopropyl
Piperidinyl
Quinolinyl
Amino-3-methyl-1-oxobutan-2-yl
Grand total of 252 possible cannabinoid classes

20. 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)

21. Substituted Cathinones

22. Substituted Cathinones
4-methylmethcathinone
3,4-methylenedioxypyrovalerone
4-fluoromethcathinone
3-fluoromethcathinone
4-methylethcathinone
3,4-dimethylmethcathinone
α-methylamino-butyrophenone
β-keto-ethylbenzodioxolylbutanamine
3,4-methylenedioxy-N-ethylcathinone
4-methoxymethcathinone
a-pyrrolidinopropiophenone
3,4-methlyenedioxymethcathinone
a-pyrrolidinopentiophenone
β-keto-N-methylbenzodioxolylpropylamine
naphthylpyrovalerone
4-’methyl-a-pyrrolidinopropiophenone
β-keto-methylbenzodioxolylpentanamine
4’-methyl-a-pyrrolidinohexanophenone
4’-methyl-a-pyrrolidinobutyrophenone
α-phthalimidopropiophenone,
N-ethylcathinone
4’-methyl-α-pyrrolidinohexanophenone
3,4-methylenedioxypyrrolidinobutyrophenone

23. Substituted cathinones
Unsubstituted
3- or 4-methyl
3- or 4-halo (F, Cl, Br, or I)
3- or 4-ethyl
3- or 4-hydroxy
3- or 4-methoxy
3,4-methylenedioxy
3,4-dimethyl
3,4-dihalo (F, Cl, Br, or I)
Replace phenyl with naphthyl
Propyl
Butyl
Pentyl
Hexyl
Unsubstituted
N-methyl
N-ethyl
N,N-dimethyl
Pyrrolidine
Phthalamido
N-benzyl
Grand total of 672 possible combinations

24. Legislative controls Mixed approach, starting in 2011
Listing individual compounds
Chemical class approach

25. 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

29. Arylcyclohexylamines
Comprise the most common class of dissociatives
Complex pharmacology
CNS appears dose dependent and spans entire range
Grand total of 54 possible combinations
Methoxy
Hydroxy
Halo
Carbonyl

30. Tryptamines Class of highly potent hallucinogens
Present in a diverse group of botanical materials
All contain substituted indole compound

31. Variations on a tryptamine theme
Methyl or ethyl with mono-N alkyl substitution
Hydroxyl, methoxy, acetoxy, halo a b
Alkyl or dialkyl substitution (methyl, ethyl, propyl, isopropyl, allyl
Grand total of 175 possible combinations

32. What about the analog law?

33. The Original
The Original - modified

34. Fentanyl Analogs
3-Methyl Fentanyl
Fentanyl

35. 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

36. 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

37. 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

38. 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?”

39. 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 or 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 or 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 or , 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 or , 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 or , and amendments thereto.

40. 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?

41. 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

42. 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?

43. 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)

44. 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

45. Considerations

46. 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

47. 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.

48. Indiana version
Sec (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 ).
(2) Alcohol (as defined in IC ).
(3) A legend drug (as defined in IC ).
(4) Tobacco.
(5) A dietary supplement (as defined in IC ).

49. Indiana version (continued)
(c) In determining whether a substance is a synthetic drug lookalike substance, the following factors 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 physical characteristics. (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 the substance's nature, use, or effect. (4) Any statement made to the buyer or recipient of the substance suggesting or implying that the substance is a synthetic drug. (5) Any statement made to the buyer or recipient of the substance suggesting or implying that the 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 as consideration; and (B) the amount of the consideration was substantially greater than the reasonable retail market value of the substance the seller claims the substance to be.

50. Thoughts?

51. 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

52. FDA approach
Most states likely have FDA-like statutes modeled after Federal statutes
Meant for pharmaceuticals
Never intended for drugs of abuse
But…

53. 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

54. FDA approach Definition for “drug” Definition for “new 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…”

55. 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

56.    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”?   

57. 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

58. 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

59. WARNING
The answers mean we have to talk about boring and confusing chemical technical stuff. Sorry.

60. Example
Any 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.

61. 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)

62. Example
Any 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.
M+ - 17

63. Other reporting issues
Confirming “AM-2201” locks in the fluorine at the 5-pentyl position

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”

66. Mass spectrum of flephedrone

67. But which isomer?

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
cm-1
1,3-disubstituted
cm-1
cm-1
1,4-disubstituted
cm-1

69. FTIR of fluoromethcathinones

70. Another issue… Schedule I reads: “Synthetic cannabinoid” defined as:
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”

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

72. 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.

73. Questions about legislation?

74. Analytical standards Two issues: Finding the standards (easy part)
Using the standards for casework (hard part)

75. 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

76. 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

77. 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

78. 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

79. 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

80. 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

81. Questions about analytical issues?

82. Thank you for your attention