5What is going on? Drug chemistry is not suppose to be this difficult What happened to this quiet little section?
6How we got here - cannabinoids First appearance in 2009JWH-018 and JWH-073Legislative responses in 2010Vendor responses in 2010
7Synthetic Cannabinoids JWH-018JWH-081JWH-307JWH-073WIN-55,212-2CP 47,497 (C9)JWH-250JWH-370AM-1220JWH-200CP 47,497 (C7)RCS-4 (2-MeO)JWH-210AM-630JWH-133JWH-203HU-210RCS-4JWH-122AM-2201 (Cl)RCS-4 (C4)JWH-019CP 47,497RCS-8JWH-015PravadolineAM-2201JWH-251AM-1241AM-694JWH-398JWH-051And 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 This does not include the countless unpublished designer compounds which have also shown up in case submissions.
8General chemical class Chemical structure Compounds currently marketed or identified in case submissionsNaphthoylindolesJWH-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-412NaphthoylpyrrolesJWH-307, JWH-370, JWH-030, JWH-147PhenylacetylindolesSR-18, RCS-8 (same as SR-18?), JWH-250, JWH-203, RCS-8 (C4 homolog), JWH-251, cannabipiperidiethanoneCyclohexylphenolsCP 47,497 (and homologs), cannabicyclohexanolBenzoylindolesAM-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-679Tricyclic benzopyransHU-210, JWH-051, JWH-133
9A different approachThe drug laws in the United Kingdom take a chemical class approach utilizing broad definitionsTryptaminesPhenethylaminesFentanylsPethidinesBarbituratesSteroidsPiperazinesCannabinoidsCathinones
10Cannabinoid examplesAny 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.
11Cannabinoid control by chemical classes Initiated in 2011 by several statesModified version used federally in 2012Currently most common legislative approach for cannabinoidsMost common controlled classesNaphthoylindolesNaphthylmethylindolesNaphthoylpyrrolesNaphthylideneindenesPhenylacetylindolesCyclohexylphenolsBenzoylindoles
12One significant difference Some class definitions contain only structural requirements while others have pharmacological components:
13Invoking pharmacology Oklahoma and Texas“Synthetic chemical compound that is a cannabinoid receptor agonist and mimics the pharmacological effect of naturally occurring substancesMinnesota“any quantity of a substance that is a cannabinoid receptor agonist”North Dakota“synthetic chemicals which have similar effects on cannabinoid receptors”
14What 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
19How bad can it get? Grand total of 252 possible cannabinoid classes Ring system ALinkerRing system BIndoleIndeneIndazoleAzaindolePyrrolePyrazoleCarbonylMethyleneMethineAcetylAmideCarboxylNaphthylPhenylAdamantylTetramethylcyclopropylPiperidinylQuinolinylAmino-3-methyl-1-oxobutan-2-ylGrand total of 252 possible cannabinoid classes
20How we got here – bath salts First appeared in 2009Based on the chemical structure of the naturally occurring cathinoneAll CNS stimulantsAct upon three different CNS receptorsPotency varies but most equal or greater than methamphetamineNo legitimate bath, beauty, or plant food purposeNo accepted medical use in the United StatesOften referred to as “beta-ketones” (i.e., bk-MDMA is methylone)
23Substituted cathinones 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 naphthylPropylButylPentylHexylUnsubstitutedN-methylN-ethylN,N-dimethylPyrrolidinePhthalamidoN-benzylGrand total of 672 possible combinations
24Legislative controls Mixed approach, starting in 2011 Listing individual compoundsChemical class approach
25Other kinds of “bath salts” Novelty products which originally contained just substituted cathinones now include a number of additional classes:Modified phenethylaminesStimulantsHallucinogenicArylcyclohexylaminesTryptaminesAnd so onWe have no reason to believe this cycle will stop anytime soon
26NBOME derivativesWork by Dr. Nichols et al discovered modifications of hallucinogenic phenethylamines increases potency
27NBOME derivativesN-benzyl ortho-methoxy (NBOME) derivatives were the most potent
28NBOME derivativesA number of these compounds are available on the web and have appeared in case submissions
29Arylcyclohexylamines Comprise the most common class of dissociativesComplex pharmacologyCNS appears dose dependent and spans entire rangeGrand total of 54 possible combinationsMethoxyHydroxyHaloCarbonyl
30Tryptamines Class of highly potent hallucinogens Present in a diverse group of botanical materialsAll contain substituted indole compound
31Variations on a tryptamine theme Methyl or ethyl with mono-N alkyl substitutionHydroxyl, methoxy, acetoxy, haloabAlkyl or dialkyl substitution (methyl, ethyl, propyl, isopropyl, allylGrand total of 175 possible combinations
35The Analog LawAny 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 analogApplication can be extremely difficult
36Your turnRespective of these approaches, how effective have they been? Prosecution issues? Legal challenges? Response from chemists? Effectiveness?Listing compounds individuallyChemical class (structure only)Chemical class (with pharmacology)Analog lawEmergency scheduling
37What we’ve learnedEducating prosecutors has made all of the differenceWhat the law actually saysCapabilities of the drug chemistry sectionHow to read reports
38Some other ideas Modifications to the analog law Additional chemical classesBroad class approach“Synthetic drug lookalike substance” approachFDA approachWe have to ask, “What are we trying to accomplish?”
39Modified 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.
40Considerations for modified analog law Creates defined chemical modifications which automatically qualify compounds as an analogStructural only, no pharmacologyBased on accepted changes in medicinal drug designRetains previous approach for other structural modificationsWill this make the analog law more usable?
41Additional chemical classes Draft proposed definitions for the following chemical classes are available if you’re interested:Arylcyclohexylamines (PCP-like)Modified tryptaminesHallucinogenic phenethylamines (two versions)ConsiderationsSame benefits and analytical issues with existing classesStill reactionary and limited in scope
42Broad class approachIn 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 lawConsiderationsCatches all future “illicit” cannabinoidsBut what is a “synthetic cannabinoid”? Circular definition?
43Idaho approachAny 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)
44Idaho approachor (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
46Synthetic drug lookalike substance Broad-based approach which attempts to pre-empt new drugs of abuse which do not fall into specific control categoriesKind of creating a “looks like a duck” law
47Minnesota 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.
48Indiana versionSec (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 ).
49Indiana 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.
51FDA approachAll legislative approaches based upon the controlled substance act are:ReactionaryRestrictedIn the realm of chemicals consumed by people, DEA has jurisdiction over controlled substances, FDA has everything elseFDA has provided significant assistance
52FDA approachMost states likely have FDA-like statutes modeled after Federal statutesMeant for pharmaceuticalsNever intended for drugs of abuseBut…
53Mis-labeled products Basis for past cases in KS General approach These products contain a psychoactive substance“Not for human consumption” is a fraudNone of the packages are properly labeledCounty in Florida assesses vendors a fine of $500 per pack
54FDA 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…”
55The 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 thereofIf 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-dichloromethylphenidateNon-controlled substanceFDA approach requirementsMeets definition of “drug”?Meets definition of “new drug”?Verify vendor has no license for distributing “new drugs”?
57FDA approach considerations Laws already on the booksBroad enough to cover all future drugs of abuseNo need for pharmacological or structural comparisonsWill require more leg-work by allAddresses dealers, not personal possessionDifferent application than what intended?Violation may only be a misdemeanor
58Can it be supported? Legislators have controlled it Prosecutors wish to move forward with a caseDo 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 definitionsAlso an awareness of related isomers and instrument limitations
59WARNINGThe answers mean we have to talk about boring and confusing chemical technical stuff. Sorry.
60ExampleAny 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.
61The short answer The supporting data is likely there. Potentially long process between data collection and confident presentation of resultsUnderstanding theory of instrumentRe-introduction of organic chemistry (headaches)Knowing chemical structure of the compoundUnderstanding past work on structurally similar compoundsInterpretation of mass spectra (major headaches)
62ExampleAny 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
63Other reporting issues Confirming “AM-2201” locks in the fluorine at the 5-pentyl position
64Synthetic cannabinoids Do not under-estimate the value of retention times in GC/MS analyses!
65However…Reporting “Confirmed AM-2201” may require purchasing multiple standardsOnly one standard if reporting “Confirmed 1-fluoropentyl-3-(1-naphthoyl)indole”
68Infrared 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 bands1,2-disubstitutedcm-11,3-disubstitutedcm-1cm-11,4-disubstitutedcm-1
70Another 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”
71Analytical dataMass spec and retention time of single component in an item match the data for a known standard of JWH-018
72Report 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.
74Analytical standards Two issues: Finding the standards (easy part) Using the standards for casework (hard part)
75Analytical standard sources Cayman ChemicalMost common source~$100 to $200 for 10 mg“Traceable standards” are more expensiveToronto Research ChemicalsNational Measurement InstituteCerilliantGrace AnalyticalSigma
76Verifying the standards Most labs require verifying the standard prior to it being used in caseworkRequires published spectra from peer-reviewed sourceGenerally 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
77Issues with toxicology Analytical difficulties with emerging drugs of abuse are significantly greater in toxicologyExtraction from biological matricesMultiple metabolites rather than single compoundsLittle to no info on absorption, distribution, eliminationLittle to no info on human pharmcokineticsThese things take time – something not afforded
78Analytical difficulties with tox Immunoassay screening techniques are slow to evolveExpensive and labor intensiveAvailable screening kits deal with compounds long goneGC/MS screening techniques generally developed in-house and validated too late
79Analytical difficulties with tox ConfirmationLC/MS/MS best option (not a routine technique)Metabolite standards non-existent or expensivePublished 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
80So 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 issuesInstrumentation issuesBack-log issuesDrug life-cycle issues