Legislative and Analytical Update on Emerging Drugs of Abuse

1. Legislative and Analytical Update on Emerging Drugs of Abuse Jeremiah Morris Johnson County Sheriff’s OfficeCriminalistics 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-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 This does not include the countless unpublished designer compounds which have also shown up in case submissions.

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

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? 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 Ring system B Ring system A Linker 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

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 Methoxy Hydroxy Halo Grand total of 54 possible combinations 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 Grand total of 175 possible combinations Alkyl or dialkyl substitution (methyl, ethyl, propyl, isopropyl, allyl

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. 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.

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. 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).

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) Anystatement 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?