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K2 and the Synthetic Cannabinoids: Pharmacology, Effects and Chemical Analysis

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Presented September 16, 2010 by Dr. Barry K. Logan, PhD, DABFT, NMS Labs National Director of Forensic Services

NMS Labs has responded to the recent explosive growth in popularity of synthetic cannabinoid agonists in so-called “herbal blends” by developing new tests for the active chemicals in botanical material, and most recently for the parent drugs and their metabolites in blood and urine. This presentation describes the history and origin of the chemicals of concern, the composition of the various commercial products containing them, their known pharmacology, and the documented effects on drivers, and human test subjects. We also review the adverse effects that have resulted in hospitalization, and even allegedly in deaths. This presentation describes the challenges around providing a chemical test for these new drugs, information on their stability in biological fluids, and the validation of quantitative methods for their determination.

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K2 and the Synthetic Cannabinoids: Pharmacology, Effects and Chemical Analysis

  1. 1. Barry K Logan PhD, DABFT Director of Forensic Services NMS Labs online Seminar September 16, 2010 K2 and the Synthetic Cannabinoids: Pharmacology, Effects, and Chemical Analysis From the Premium Provider of Forensic Services
  2. 2. K2 Phenomenon
  3. 3. K2 Phenomenon
  4. 4. K2 Phenomenon
  5. 5. K2 Phenomenon
  6. 6. K2 Phenomenon
  7. 7. K2 Phenomenon
  8. 8. K2 Phenomenon <ul><li>Origins of synthetic cannabinoid agonists. </li></ul><ul><li>Contents of various. commercial “K2” type products. </li></ul><ul><li>Mechanism of Action and Pharmacology. </li></ul><ul><li>Analytical challenges. </li></ul><ul><li>Human pharmacodynamics. </li></ul><ul><li>A preview of the DUI environment. </li></ul>
  9. 9. Marijuana Most popular recreational drug after alcohol and tobacco. Main psychoactive component THC #1 Drug in the DRE program Some 25 million Americans have smoked marijuana in the past year, and more than 14 million do so regularly. Possession and use illegal under federal law, but states have variable policies on enforcement and prosecution. 6.8% of Friday and Saturday evening drivers test positive for use.
  10. 10. Synthetic Cannabinoids Synthetic drugs that mimic the effects of cannabis. Investigational use for appetite, blood pressure, nausea, etc First synthesized in the 1980’s Sprayed onto dried plant leaves, flowers and stems, and smoked. Legal or unregulated in most US states.
  11. 11. K2 Phenomenon Kansas, Georgia, Kentucky, Alabama, Tennessee, Louisiana, Missouri, Hawaii, Arkansas, Illinois Mississippi
  12. 12. Clemson Series - JWH JWH-018 JWH-073 JWH-250
  13. 13. Marijuana to Spice THC HU-210 CP 47,497 WIN 55,212
  14. 14. Cannabinoid Mechanism of Action Cerebral Cortex Higher Cognitive Function Basal Ganglia Cerebellum Movement Hippocampus Learning, Memory, Stress Hypothalamus Appetite Spinal Chord Pain, Peripheral sensation Medulla Nausea, Vomiting
  15. 15. Herbals - Botanical Substrate Glycyrrhiza glabra (Cultivated Liquorice) Astragalus membranaceus (Milk Vetch) Verbascum thapsus (Common Mullein) (Uchiyama et al, 2010)
  16. 16. Synthetic Cannabinoids – Drug ID <ul><ul><li>Agilent 5973 Mass Spectrometer </li></ul></ul><ul><ul><li>Agilent 6890 Gas Chromatograph </li></ul></ul><ul><ul><li>Electron Impact mode </li></ul></ul><ul><ul><li>Full scan </li></ul></ul><ul><ul><li>Total run time 10 minutes </li></ul></ul><ul><ul><li>Sensitivity 20-50 ug/g </li></ul></ul>
  17. 17. Synthetic Cannabinoids – Drug ID JWH-018 JWH-073 JWH-200 HU-210/11 JWH-019 JWH-200 WIN 55,212 JWH-015 JWH-133 JWH-250 CP55,940 CP 47,497 (n=7) CP 47,497 (n=8)
  18. 18. K2 Blends - Drug Content (* Uchiyama et al, 2010) JWH-018 (mg/g) JWH-073 (mg/g) CP47,497 (n=8) (mg/g) JWH-250 (mg/g) K2 Blonde 12 13 - - K2 Standard 9 9 - - K2 Citron 10 10 - - K2* (Unknown) - - 6 - K2 Summit 11 9 - - K2 Blue 15 - - - K2 Pink 11 - - - K2 Latte 16 0.28 - 14 K2 Mint 19 0.30 - - K2 Silver 8 - - 16 Spike Gold 20 11 - - Spike Maxx 17 - - 19 Spike Diamond 17 0.07 - - Spike Silver 9 16 - - Space 10 - - - Herbal blends* 2.0 – 35.9 - 1.1 – 16.9 -
  19. 19. Synthetic Cannabinoid Effects
  20. 20. Synthetic Cannabinoid Effects
  21. 21. Synthetic Cannabinoid Metabolism
  22. 22. Synthetic Cannabinoid Effects T. Sobolevsky, et al., Detection of JWH-018 metabolites in smoking mixture post-administration urine, Forensic Sci. Int. (2010), doi:10.1016/j.forsciint.2010.04.003
  23. 23. Synthetic Cannabinoid Disposition
  24. 24. Synthetic Cannabinoids at NMS Labs <ul><li>Synthetic Cannabinoids in Blood - $195 </li></ul><ul><ul><li>LCMSMS LOQ/LOQ - 0.1ng/mL </li></ul></ul><ul><ul><li>JWH-018, JWH-073 (screened, confirmed, quantitated). </li></ul></ul><ul><ul><li>JWH-018, JWH-073, JWH-019, JWH-250 (screened, confirmed) </li></ul></ul><ul><li>Synthetic Cannabinoids in Urine - $60 </li></ul><ul><ul><li>LCMSMS, LOD - 0.1ng/mL </li></ul></ul><ul><ul><li>JWH-018 mono-hydroxy and di-hydroxy metabolites (screened, confirmed) </li></ul></ul><ul><ul><li>JWH-018 tri-hydroxy metabolites (monitored) </li></ul></ul>
  25. 25. NMS Labs Special Projects Matrix Analytes Blood Serum Oral Fluid (Refrigerate) Parent Compounds – JWH-018, JWH-073, JWH-200, HU-210, HU-211, JWH-019, JWH-200 WIN 55,212, JWH-015, JWH-133, JWH-250, CP55,940, CP 47,497 (n=7) CP 47,497 (n=8) … Urine (Freeze) Ring monohydroxylated metabolites – glucuronidated Ring dihydroxylated metabolites – glucuronidated Desmethyl ring hydroxylated metabolites - glucuronidated
  26. 26. Missouri K2 Administration Study <ul><li>IRB Human subjects and ethical approval obtained by University of Central Missouri. </li></ul><ul><li>Six subjects smoked K2 Summit, Citron, or Standard </li></ul><ul><li>Each contained JWH-018, JWH-073, or CP47,497 </li></ul><ul><li>Subjects performed SFST’s, cognitive tests and DRE Exam. </li></ul><ul><li>Blood, urine and oral fluid collected. </li></ul>
  27. 27. Missouri K2 Administration Study <ul><li>Onset of effects in about 2-3 minutes </li></ul><ul><ul><li>Dry mouth </li></ul></ul><ul><ul><li>Light headedness </li></ul></ul><ul><ul><li>Blurred vision </li></ul></ul><ul><ul><li>Agitation, Motor restlessness </li></ul></ul><ul><ul><li>Time dilation </li></ul></ul><ul><li>DRE Exam </li></ul><ul><ul><li>Increased pulse and blood pressure </li></ul></ul><ul><ul><li>Lack of convergence </li></ul></ul><ul><ul><li>No HGN, or VGN </li></ul></ul><ul><ul><li>Pupils normal, muscle tone normal </li></ul></ul><ul><li>SFST’s </li></ul><ul><ul><li>3-4 inches of sway, leg body tremors </li></ul></ul><ul><ul><li>Loss of balance </li></ul></ul><ul><ul><li>Loss of motor coordination </li></ul></ul>
  28. 28. Missouri K2 Administration Study <ul><li>Reported effects: </li></ul><ul><ul><li>Tachycardia (increased heart rate, 5-30mm/Hg) </li></ul></ul><ul><ul><li>Dry Mouth </li></ul></ul><ul><ul><li>Felt Impaired, subjective thought disruption </li></ul></ul><ul><ul><li>Changes in perception </li></ul></ul><ul><ul><li>Impaired sense of time </li></ul></ul><ul><ul><li>Mild anxiety, paranoia </li></ul></ul><ul><ul><li>Sedation </li></ul></ul><ul><ul><li>Post-intoxication exhaustion </li></ul></ul>
  29. 29. K2 use and the DRE Matrix * High doses Drug Symptom Matrix                   CNS Depressant Inhalants Dissociative Drugs CNS Stimulants Hallucinogens Narcotic analgesics Cannabis K2                   Horizontal nystagmus Yes Yes Yes No No No No No Vertical Nystagmus Present * Present* Present No No No No No Lack of Convergence Present Present Present No No No Present Present Pupil Size Normal Normal Normal Dilated Dilated Constricted Dilated* Normal Reaction to Light Slow Slow Normal Slow Normal Little to none Normal Normal Pulse Rate Down Up Up Up Up Down Up Up Blood Pressure Down Up/Down Up Up Up Down Up Up Body Temperature Normal Up/Down/Normal up Up Up Down Normal Normal
  30. 30. NMS Labs Blood JWH-018 and -073 L/L extraction JWH-073 d-9 Istd Quantitative LOD/LOQ 0.1ng/mL Waters TQD Acquity Gradient 4 minute run Formic acid vs ACN 2 Transitions per analyte
  31. 31. NMS Labs Blood JWH-018 and -073
  32. 32. Missouri K2 Administration Study Subject BM Smoked “K2 Citron” 10mg/g JWH-018/073 0.3g in water pipe 3 inhalations over 30 minutes
  33. 33. Synthetic Cannabinoid Disposition
  34. 34. Synthetic Cannabinoid Disposition * *
  35. 35. NMS Labs Urine JWH-018 and -073 L/L extraction Qualitative JWH-073 d-9 Istd Method 1: hydrolyzed – Waters TQD Mono and Di hydroxy metabolites 2 transitions per analyte Method 2: unhydrolyzed – ABI 5000 Monohydroxy glucuronide – daughter – grandaughter 2 transitions per analyte and precursor
  36. 36. NMS Labs Urine SC metabolites
  37. 37. Missouri K2 Administration Study Subject BM - Urine Time JWH-018 Mono-OH Di-OH Tri-OH Glucuronides Pre-dose X X X X X 1:15 +/- √ √ X √ 2:07 X √ √ √ √ 2:40 X √ √ √ √ Time JWH-073 Mono-OH Di-OH Tri-OH Glucuronides Pre-dose X X X X X 1:15 X √ √ X √ 2:07 X √ √ √ √ 2:40 X √ √ √ √
  38. 38. York County PA, DRE Case <ul><ul><li>Vehicle crashed into snowbank </li></ul></ul><ul><ul><li>Subject appeared drunk or high, difficulty speaking, incoherent, mumbling, slow slurred speech, nonsense, giggling. </li></ul></ul><ul><ul><li>Had smoked “Space” less than 2 hours before. </li></ul></ul><ul><ul><li>“ I’m not a DUI. The stuff I smoked is legal. You can’t arrest me” </li></ul></ul><ul><ul><li>Courtesy Cpl Brian Torkar, PSP </li></ul></ul>
  39. 39. York County PA, DRE Case <ul><ul><li>Pulse 96-88, BP 150/80 </li></ul></ul><ul><ul><li>Eyes watery, red, bloodshot, pupils dilated </li></ul></ul><ul><ul><li>Eyelids droopy, HGN present, no VGN </li></ul></ul><ul><ul><li>Lack of convergence </li></ul></ul><ul><ul><li>SFST’s </li></ul></ul><ul><ul><ul><li>4 inches of sway on Romberg </li></ul></ul></ul><ul><ul><ul><li>Lost balance, used arms on WAT </li></ul></ul></ul><ul><ul><ul><li>Swayed, used arms on OLS </li></ul></ul></ul><ul><ul><ul><li>Poor finger to nose performance </li></ul></ul></ul><ul><ul><li>Courtesy Cpl Brian Torkar, PSP </li></ul></ul>
  40. 40. York County PA, DRE Case <ul><ul><li>Drug Identification </li></ul></ul><ul><ul><ul><li>“ Space” contained JWH-018, traces of JWH-200 </li></ul></ul></ul><ul><ul><li>Toxicology </li></ul></ul><ul><ul><ul><li>Blood collected approximately 4 hours after use. </li></ul></ul></ul><ul><ul><ul><li>Positive for diphenydramine <50ng/mL </li></ul></ul></ul><ul><ul><ul><li>0.2 ng/mL for JWH-018 by directed analysis, LC-TOF </li></ul></ul></ul>
  41. 41. Death Investigation Case <ul><ul><li>19 yo male out for a night of partying with friends. </li></ul></ul><ul><ul><li>Smoking marijuana and K2. </li></ul></ul><ul><ul><li>Becomes disoriented. </li></ul></ul><ul><ul><li>Returned home late in evening. </li></ul></ul><ul><ul><li>Found dead in bed the following morning. </li></ul></ul><ul><ul><li>No anatomic cause of death. </li></ul></ul><ul><ul><li>Toxicology (cardiac) </li></ul></ul><ul><ul><ul><li>Delta-9-carboxy THC 13ng/mL </li></ul></ul></ul><ul><ul><ul><li>JWH-018 0.71ng/mL </li></ul></ul></ul><ul><ul><li>Cause of Death – currently undetermined </li></ul></ul>
  42. 42. Conclusions <ul><ul><li>Synthetic cannabinoids have great toxicological significance. </li></ul></ul><ul><ul><li>The range of synthetics is likely to be a moving target. </li></ul></ul><ul><ul><li>Effect profile very similar to marijuana </li></ul></ul><ul><ul><li>Should be considered in “marijuana” cases where no THC or metabolites present. </li></ul></ul><ul><ul><li>Blood analysis should target parent drugs <1ng/mL </li></ul></ul><ul><ul><li>Urine analysis must look for multiple points of identification, as standards are unavailable. </li></ul></ul>
  43. 43. Acknowledgments <ul><ul><li>Analysis </li></ul></ul><ul><ul><ul><li>NMS Labs </li></ul></ul></ul><ul><ul><ul><ul><li>Allan Xu </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Matt McMullin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lindsay Reinhold </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Donna Warrington </li></ul></ul></ul></ul><ul><ul><ul><li>Webinar </li></ul></ul></ul><ul><ul><ul><ul><li>Amanda Panepinto </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Julie Ruth </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Sherri Kacinko </li></ul></ul></ul></ul><ul><ul><li>Dosing Study </li></ul></ul><ul><ul><ul><ul><li>Bob Welsh </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Tracey Durbin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>DRE’s and subjects </li></ul></ul></ul></ul><ul><ul><ul><li>WSLH </li></ul></ul></ul><ul><ul><ul><ul><li>Amy Miles </li></ul></ul></ul></ul>www.NMSLabs.com 1.866.522.2216

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