Synthetic Cannabinoids, Synthetic Cathinones and Salvia Divinorum

Basic Chemistry and Lab Analysis

Acknowledgements

Synthetic Cannabinoids and Natural Highs Workshop

Sponsored by: Midwestern Association of Forensic Scientists Miami Valley Regional Crime Laboratory

Dayton, Ohio April 4 and 5, 2011

• “Synthetic Cannabinoids” - Jason Nawyn - US Army Lab • “Salvia Divinorum” - Pam Smith - Retired DEA Chemist

Synthetic Cannabinoids

Synthetic Cannabinoids Spice Silver Gorillaz Spice Gold Skunk Spice Diamond Genie Spice Arctic Synergy Galaxy Spice Tropical Synergy Gold Spice Egypt Space Truckin K2 Solar Flare Sence Moon Rocks Yucatan Fire Blue Lotus Smoke Aroma ChillX Scope Highdi’s Earth Impact Almdrohner

Synthetic Cannabinoids

• Components

– Herbal plant material – Psychoactive chemicals - synthetic cannabinoids

sprayed on to the herbal matter

Synthetic Cannabinoids

• Formulators will change their product to skirt the law.

• Formulators of these products can utilize any of a number of synthetic cannabinoids to spray on the herbal material.

• The specific synthetic cannabinoid used on any particular product (i.e.: Spice or K-2) could be changed at any time by the formulator.

Synthetic Cannabinoids • Attempts to control or regulate the new synthetic

cannabinoids is problematic on a number of fronts:

– Because of the structural dissimilarities between the synthetic cannabinoids, using the Controlled Substances Analog Act will most likely, have little success.

– Standards for most of these compounds are not available. – Mass spectral analysis of many of these compounds will be difficult if not

impossible. – Many of these compounds have multiple positional isomers. – Control of specific products is impractical since the composition of these

products can change from batch to batch both qualitatively and quantitatively.

Synthetic Cannabinoids • Synthetic Cannabinoid Agonists ≡ “Synthetic Cannabinoids”

– Definition: Agonist - A chemical that binds to a receptor of a cell and

triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance.

– Many of which are not actually cannabinoids in structure

– Synthetic Cannabinoids are CB1 receptor agonists

– CB1 receptors in the brain mediate the psychoactive effects of THC – Synthetic Cannabinoids mimic the effects of THC

Synthetic Cannabinoids

• Synthetic cannabinoid receptor agonists fall into 7 major groups: 1. Naphthoylindoles 2. Naphthylmethylindoles 3. Naphthoylpyrroles 4. Naphthylmethylindenes 5. Phenylacetylindoles 6. Cyclohexylphenols 7. Dibenzopyrans (classical cannabinoids)

Synthetic Cannabinoids

• Naming of chemical compounds (i.e.: JWH compounds, HU compounds, etc.)

When compounds are synthesized they are often uniquely named based on whomever synthesized the compound. – JWH, for John W. Huffman @ Clemson University – HU, for Hebrew University – CP compounds were developed by Pfizer.

Naphthoylindoles

R3

R4

C

O

NR2R1

1

31

2

Naphthoylindoles Compounds R1 R2 R3 R4 Ki ∆9-THC 10.2 JWH-007 Pentyl Methyl H H 2.9 JWH-018 Pentyl H H H 2.9 JWH-019 Hexyl H H H 9.8 JWH-048 Pentyl Methyl H Methyl 10.7 JWH-073 Butyl H H H 8.9 JWH-080 Butyl H Methoxy H 7.6 JWH-081 Pentyl H Methoxy H 1.2 JWH-082 Hexyl H Methoxy H 5.3 JWH-098 Hexyl H Methoxy H 4.5 JWH-122 Pentyl H Methyl H 0.69 JWH-149 Pentyl Methyl Methyl H 5 JWH-181 Pentyl Methyl Propyl H 1.3 JWH-182 Pentyl H Propyl H 0.65 JWH-193 MPE H Methyl H 6 JWH-198 MPE H Methoxy H 10 JWH-200 MPE H H H 42 JWH-210 Pentyl H Ethyl H 0.46 JWH-213 Pentyl Methyl Ethyl H 1.5 JWH-? Butyl H H H 8.9 JWH-387 Pentyl H Br H 1.2 JWH-394 Pentyl Methyl Br H 2.8 JWH-398 Pentyl H Cl H 2.3 JWH-412 Pentyl H F H 7.2 AM2201 Fluoropentyl H H H

Affinity Constant (Ki)

• A measure of the potency of the cannabinoids Low values are most potent, higher values have lower potency.

Naphthylmethylindoles

R3

CH2

NR2R1

1

31

2

Naphthylmethylindoles Compounds R1 R2 R3 Ki JWH-175 Pentyl H H 22 JWH-184 Pentyl H Methyl 23 JWH-185 Pentyl H Methoxy 17 JWH-199 MPE H Methoxy 20

Naphthoylpyrroles

C

O

NR2R1

1

31

2

Naphthoylpyrroles Compounds R1 R2 Ki JWH-145 Pentyl Phenyl 14 JWH-146 Heptyl Phenyl 21 JWH-147 Hexyl Phenyl 11 JWH-292 Pentyl Methoxyphenyl 29 Unnamed JWH Propyl H >1000 JWH-030 Pentyl H 87 JWH-307 Pentyl 2-Fluorophenyl 7.7 JWH-368 Pentyl 3-Fluorophenyl 16 JWH-369 Pentyl 2-Chlorophenyl 7.9 JWH-370 Pentyl 2-methylphenyl 5.6

Naphthylmethylindenes

R3

R4

CH

R2R1

1

31

2

Naphthylmethylindenes Compounds R1 R2 Ki JWH-176 Pentyl H 26 Compound #7 MPE H 2.7 Compound #8 MPE Methyl 2.9

Phenylacetylindoles

C

O

NR1C5H11

R2

1

31

2

Phenylacetylindoles Compounds R1 R2 Ki JWH-203 H 2-Chlorophenyl 8 JWH-204 Methyl 2-Chlorophenyl 13 JWH-249 H 2-Bromophenyl 13 JWH-250 H 2-Methoxyphenyl 11 JWH-251 H 2-Methylphenyl 29 JWH-302 H 3-Methoxyphenyl 17 JWH-305 Methyl 2-Bromophenyl 15 JWH-306 Methyl 2-Methoxyphenyl 25 JWH-311 H 2-Fluorophenyl 23

Cyclohexylphenols

OH

R2

OH

R1

Cyclohexylphenols Compounds R1 R2 Ki CP-55,940 1,1-Dimethylheptyl Hydroxypropyl 0.34 CP-47,497 1,1-Dimethylheptyl H 9.4 CP-47,497 VII 1,1-Dimethyloctyl H 4.7 CP-47,497 XI* 1,1-Dimethylheptyl Methyl 6.2 CP-47,497 XII 1,1-Dimethylheptyl Methyl 7.7 CP-47,497 XVI 1,1-Dimethylheptyl Hydroxybutyl 1.6 * C1-α-OH analog of XII

Dibenzopyrans (classical cannabinoids)

R2

OH

R1O

A

Dibenzopyrans (classical cannabinoids)

Compounds R1 R2 Ki HU-210 1,1-Dimethylheptyl Hydroxymethyl 0.06 HU-211 1,1-Dimethylheptyl Hydroxymethyl >100 unnamed 1,1-Cyclopropylheptyl Methyl 0.44 unnamed 1,2-Dimethylheptyl Methyl < 1 unnamed 1,1-Dimethylheptyl Methyl < 1 ∆9-THC Pentyl Methyl 10.2 ∆8-THC Pentyl Methyl 16.5

Synthetic Cannabinoids Analysis:

• If we have the proper standard, we will identify the unknown sample by

comparing results with those of the standard reference material. • Currently we have the following ref. standards: AM2201 CP 47,497 CP 47,497 C8 homolog HU-210 HU-211 JWH-018 JWH-019 JWH-073 JWH-081 JWH-122 JWH-200 JWH-210 JWH-250 JWH-251 JWH-302 RCS-4 RCS-8

Synthetic Cannabinoids

• If we do not have a reference standard available, we may be able to compare the spectra for an unknown sample to a library spectra of a known reference standard, then report as “consistent with”.

Synthetic Cannabinoids

• Toxicology – The DCI Lab does not currently have the capability

to test for synthetic cannabinoids in urine or blood.

– Referring to private labs that have the capability

Synthetic Cannabinoids

• Approximately 231 Items analyzed to date – Probably more were reported as “No controlled

substances” prior to the law going into effect. – 101 of those were JWH-18 (67 of which were

received in 2010. 2nd most common was JWH-250.

– The lab is seeing a progression of compounds submitted. As one is identified and regulated, it slowly disappears and another compounds take it’s place.

Synthetic Cannabinoids

– No clear favorite recently. – We have seen the following:

JWH-18 JWH-210 JWH-19 JWH-250 JWH-73 JWH-302 JWH-81 AM-2201 JWH-122 RCS-4 JWH-203

Synthetic Cathinones

Synthetic Cathinones

• Central Nervous System (CNS) Stimulants – Increased blood pressure – Increased heart rate – Agitation – Hallucinations – Extreme paranoia – Delusions

Synthetic Cathinones

• Falsely marketed as: “bath salts”, “plant food”, “insect repellant”, “pond cleaner”, and “research chemical” • Labeled “not for human consumption” to

evade FDA scrutiny

• More accurately referred to as: – Substituted cathinones or cathinone derivatives

Synthetic Cathinones

• Product names: Artic Blasting Station Atomic Blaze Blitz Blue Moon Blue Silk Bohemian Bath Salts Bolivian Bath Salts Cloud 9 Cloud 10 Columbian Odorizer Cotton Cloud Dr. Booga Shooga Dream Dynamite Euphoria Hurricane Charlie Ivory Wave Ivory Wave Ultra Kush Blitz Lady Bubbles Legal Love Potion 69 Moon Dust Night Cap NRG-1 Q Concentrated Red Dove Resin Scar Face Super Clean Stain Remover Serenity White Cloud White Diamonds White Dove White Lightening White Girls Bath Salts Zoom others?

Natural Cathinone?

• Schedule I controlled substance • Found naturally in Khat

Synthetic Cathinones

• New compounds regulated in Iowa: – Mephedrone – 3,4-Methlenedioxypyrovalerone (MDPV)

• Recently emergency controlled by USDEA – Mephedrone – Methylone – 3,4-Methlenedioxypyrovalerone (MDPV) – These 3 substances represent 98% of the synthetic

cathinones encountered by law enforcement (NFLIS)

Cathinone Derivatives

R1 R2 R3 R4 R5 Name H H H H H Cathinone

Methyl H H H H Methcathinone (ephedrone)

Methyl Methyl H H H N,N-Dimethylcathinone (metamfepramone)

Ethyl H H H H N-Ethylcathinone (EC) Methyl H H Methyl H Buphedrone Ethyl H 4-Methyl H H 4-Methyl-N-ethylcathinone

R1 R2 R3 R4 R5 Name Methyl H 4-Methyl H H Mephedrone (4-MMC; M-CAT) Ethyl Ethyl H H H Amfepramone t-Butyl H 3-CI H H Bupropion Methyl H 3,4-Methylenedioxy H H Methylone (βk-MDMA) Ethyl H 3,4-Methylenedioxy H H Ethylone (βk-MDEA) Methyl H 4-Methyl Methyl H Butylone (βk-MBDB) Methyl H 4-Methoxy H H Methedrone (βk-PMMA) Methyl H 4-F H H Flephedrone (4-FMC) Methyl H 3-F H H 3-Fluoromethcathinone (3-FMC) {pyrrolidino} H H H α-Pyrrolidinopropiophenone (PPP)

{pyrrolidino} 4-Methyl H H 4-Methyl-α-pyrrolidinopropiophenone (MPPP)

{pyrrolidino} 4-MeO H H 4-methoxy-α-pyrrolidinopropiophenone (MOPPP)

{pyrrolidino} 4-Methyl Propyl H 4-Methyl-α-pyrrolidino-hexanophenone (MPHP)

{pyrrolidino} 4-Methyl Ethyl H Pyrovalerone

{pyrrolidino} 4-Methyl Methyl H 4-Methyl-α-pyrrolidino-butyrophenone (MPBP)

{pyrrolidino} 4-Methyl H Methyl 4-Methyl-α-pyrrolidino-α-methylpropiophenone

{pyrrolidino} 3,4-Methylenedioxy H H 3,4-Methylenedioxy-α-pyrrolidinopropiophenone (MDPPP)

{pyrrolidino} 3,4-Methylenedioxy Ethyl H 3,4-Methylenedioxypyrovalerone (MDPV)

Synthetic Cathinones Analysis:

• If we have the proper standard, we will identify the

unknown sample by comparing results with those of the standard reference material.

• Currently we have the following ref. standards:

– Mephedrone – 3,4-Methlenedioxypyrovalerone (MDPV)

Synthetic Cathinones

• If we do not have a reference standard available, we may be able to compare the spectra for an unknown sample to a library spectra of a known reference standard, then report as “consistent with”.

Synthetic Cathinones

• Toxicology –The DCI Lab is currently analyzing for

MDPV and Mephedrone in urine.

Salvia Divinorum

Salvia Divinorum - aka Diviner’s Sage or Seer’s Sage Plant Classification - Family: Lamiaceae (lah-MAY-see-ay) “mint family” Genus: Salvia (sage) Species: Divinorum

Salvia Divinorum • Native to the Sierra Mazateca region in the state of Oaxaca, Mexico

• Traditionally used by Mazatec Shaman for spiritual healing, by chewing fresh leaves or drinking the juice of the leaves.

Salvia divinorum

Oaxaca (wah-HAH-kah)

Salvia Morphology • Net-veined Leaves • Square/Hollow

Stems • Opposite

stems/leaves

BUT: • 900 – 1200 plants

in genus: salvia

Typical Lab Submissions

• Chopped, it might look a little like marijuana, but under closer examination it has different morphological characteristics.

• Still, it is not distinguishable from other species of salvia using microscopy or chemical color tests.

• Rather than identifying using plant morphology, it’s better to identify the psychoactive chemical, Salvinorin A.

• Psychoactive chemical = Salvinorin A • Very potent natural Hallucinogen, but not particularly toxic • Not an alkaloid (no N), unlike other natural hallucinogens • Active at a different receptor site than other psychedelics, like LSD and

mescaline • Soluble in organic solvents, but not very solvent in water • Metabolizes quickly – falls below detection levels in a short period of time

Analysis

• Salvia Divinorum – Difficult to distinguish from other Salvia species

visually or using microscopy and chemical color tests

• Salvinorin A – Gas Chromatography – Gas Chromatography/Mass Spectrometry

Salvia Divinorum

• Just two submission items analyzed to date. – More could have been submitted that were reported

as “No controlled substances” prior to the law going into effect.

• Toxicology

– The DCI Lab does not currently have the capability to test for synthetic cannabinoids in urine or blood.

– Referring to private labs that have the capability

References

• Jason Nawyn, U.S. Army Lab, “Synthetic Cannabinoids,” Synthetic Cannabinoids and Natural Highs Workshop, Midwestern Association of Forensic Scientists, Dayton, Ohio, April 4-5, 2011.

• David Nutt, “Consideration of the major cannabinoid agonists,” Advisory Council on the Misuse of Drugs (ACMD), 2009.

• “Synthetic Cathinones (Bath Salts): An Emerging Domestic Threat,” Situation Report – U.S. Department of Justice National Drug Intelligence Center, July 2011.

References

• “Background, Data, and Analysis of Synthetic Cathinones: Mephedrone (4-MMC), Methyllone (MDMC) and 3,4-Methylenedioxypyrovalerone (MDPV),” Office of DiversionControl, Drug and Chemical Evaluation Section, U.S. Department of Justice Drug Enforcement Administration, August 2011.

• Henry A. Spiller et al., “Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States,” Clinical Toxicology (2011), 49, 499-505.

References

• Pam Smith, USDEA (retired), “Salvia Divinorum,” Synthetic Cannabinoids and Natural Highs Workshop, Midwestern Association of Forensic Scientists, Dayton, Ohio, April 4-5, 2011.

• John D. Jermain et al., “Analyzing Salvia Divinorum and its Active Ingredient Salvinorin A Utilizing Thin Layer Chromatography and Gas Chromatography/Mass Spectrometry,” Journal of Forensic Science, May 2009, Vol. 54, No. 3, 612-616.