Download 11/10/2014 Synthetic Cannabinoids – Research Compounds

11/10/2014
Synthetic Cannabinoids – Research Compounds
Synthesis of > 400 cannabinoid compounds by John W. Huffman, Clemson University
targeting the endocannabinoid system, for HIV, MS, chemotherapy indications
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JWH‐200
JWH‐073
JWH‐018
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Research funded by NIDA (National Institute on Drug Abuse).
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Synthetic Cannabinoids – Research Compounds
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THC
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Other notable compounds prepared by pharmaceutical companies and universities CP‐47,497
Pfizer, 1980s
analgesic
Cannabicyclohexanol
Pfizer, 1979
5x more potent than THC
HU‐210
Prof. Ralph Mechoulam
Hebrew University
100‐800x more potent than THC
Longer half‐life than THCz
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Synthetic Cannabinoids (SCBs) Illicitly Marketed as “Incense"
Late 2000s, two of Huffman's cannabinoid compounds began being sold in Germany as
marijuana alternatives, marketed as “incense” under names K2 and Spice. "I figured once it got started in Germany it was going to spread. I'm concerned that it could hurt people," Huffman said. "I think this was something that was more or less inevitable. It bothers me that people are so stupid as to use this stuff."
John William Huffman (1932 ‐ ) Professor Emeritus, Clemson University
Synthetic Cannabinoids (SCBs) Illicitly Marketed as “Incense”
SCBs dissolved in volatile organic solvent (e.g. ethanol, acetone) then sprayed on
plant leaves (e.g. Indian Warrior, Lion’s Ear, Dog Rose, Marshmallow leaves).
Smoked or vaporized similar to cannabis.
Brents, L. K.; Prather, P. L. The K2/Spice Phenomenon: Emergence, Identification, Legislation and Metabolic Characterization of Synthetic Cannabinoids in Herbal Incense Products. Drug Metab. Rev. 2014, 46, 72‐85.
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Synthetic Cannabinoids (SCBs) Illicitly Marketed as Incense
“Not for Human Consumption” label to avoid subjection to the Federal Analogue Act of 1986
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“A controlled substance analogue shall, to the extent intended for human consumption, be
treated, for the purposes of any Federal law as a controlled substance in schedule I”
Brents, L. K.; Prather, P. L. The K2/Spice Phenomenon: Emergence, Identification, Legislation and Metabolic Characterization of Synthetic Cannabinoids in Herbal Incense Products. Drug Metab. Rev. 2014, 46, 72‐85.
Scheduling of Synthetic Cannabinoids and Resulting Changes to “Incense”
March 1, 2011: JWH‐018, JWH‐073, CP‐ 47,497, JWH‐200 listed as Schedule I
July 9, 2012: Obama signed Synthetic Drug Abuse Prevention Act of 2012
15 SCBs named in Act
Composition of SCB “incense” products frequently changes to avoid detection.
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Risks of “Synthetic Marijuana” Use
• Highly variable and unpredictable drug composition
Highly variable and unpredictable drug composition
• Uneven distribution of drugs sprayed onto plant matter results in drug “hot spots”
• Relatively few studies performed on the pharmacological and toxicological effects of SCDs
Medical Issues Associated with “Synthetic Marijuana” Use
• Tachycardia
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• Hypertension
• Nausea
• Vomiting
• Convulsions
• Agitation
• Hallucinations
• Psychosis
• Aggression
• Rhabdomyoloysis
• Respiratory depression
• Kidney failure
• Deaths including suicide
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Medical Issues Associated with “Synthetic Marijuana” Use
Cannabis versus SCDs
Cannabis versus SCDs
Effects differ substantially between cannabis and SCDs, potentially due to:
1. SCBs more potent than THC
2. SCB activity at non‐cannabinoid receptors
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3. SCB metabolite activity (versus THC metabolites)
4. Cannabis contains modulators such as CBD; SCBs lack such modulation
“Synthetic Cannabis” – One of Many Designer Drugs
Designer Drug
Designer Drug
Structural or functional analog of a controlled substance designed to mimic pharmacological effects of original drug while avoiding illegal status or evading detection. Examples
• Analogs of many psychoactive compounds (e.g. opiods, psychostimulants, dissociatives)
• Synthetic cannabis
• Designer steroids
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Gas Chromatography Mass Spectrometry (GC‐MS) Used in Drug Urinalysis
Gas chromatography separates compounds primarily based on boiling point; also polarity
Mass spectrometry provides molecular weight of compounds plus information on structure based on fragmentation pattern generated via ionization
Gas Chromatography (GC)
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Sample GC‐MS Trace
Mixture of cyclohexane (1.54 min) and toluene (2 43 min)
and toluene (2.43 min)
MS of peak at 2.43 (toluene)
High Performance Liquid Chromatography – Mass Spectrometry (HPLC‐MS)
HPLC can be used for separation of compounds that are non‐volatile ‐ e.g. ionic compounds
Compounds generally detected via UV light absorbance (254 nm common)
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High Performance Liquid Chromatography (HPLC)
Testosterone – An Anabolic Steroid
Testosterone
Endogenous steroid hormone
Testosterone: performance enhancing via muscle development, strength or endurance
Increases muscle’s protein synthesis
Supplemental testosterone is deemed as doping in most athletic competitions
Testosterone levels often measured in urine via GC‐MS
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T/E Ratio in Urine is Measured by GC‐MS to Determine Doping
Testosterone (T)
Epitestosterone (E)
Inactive though present naturally in adult males
Ca. 1:1 ratio T/E (variable)
Testosterone/epitestosterone
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((T/E) ratio in urine is tested by GC‐MS.
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Excess of 6:1 is considered “doping.”
Administration of testosterone does not affect the levels of epitestosterone.
Epitestosterone is banned in competitive sports, even though it’s inactive. Why?
Gas Chromatography (GC) Spectrum of Testosterone Derivatives
Reference samples
Analyte (other components present)
Muller et al. J. Chromatography A. 1999, p 275
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Designer Drugs ‐ Anabolic Steroids
Testosterone
Endogenous steroid hormone
Androstenedione
“Andro”
Endogenous testosterone precursor, also supplement
Used by Mark McGuire
Nandrolone
Drug previously used for osteoporosis
Used by Linford Christie
Tetrahydrogestrinone
(THG, “The Clear”)
Used by Marion Jones, Jason Giambi
BALCO (Victor Conte) scandal
Reference Samples Required for GC‐MS and LC‐MS Analysis
THG was designed and synthesized to evade detection, since reference sample (analytical standard) was lacking
standard) was lacking.
Tetrahydrogestrinone
(THG, “The Clear”)
Used syringe with “The Clear” (THG) submitted to USADA for analytical testing.
Gestrinone
Known anabolic steroid
Prescribed for endometriosis
MS fragmentation showed peaks 4 amu higher than gestrinone
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