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Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids
 

Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids

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Presented on February 21, 2012 at the AAFS 64th Annual Scientific Meeting by Barry K. Logan, PhD, DABFT, NMS Labs National Director of Forensic Services and Wendy R. Adams, Ph.D., DABFT, Forensic ...

Presented on February 21, 2012 at the AAFS 64th Annual Scientific Meeting by Barry K. Logan, PhD, DABFT, NMS Labs National Director of Forensic Services and Wendy R. Adams, Ph.D., DABFT, Forensic Toxicologist

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  • Begin with financial disclosure
  • Synthetic drugs that mimic the effects of cannabis through binding at the same receptors, principally the CB1 receptor, more of which about momentarily. The drugs were developed in the 1980’s and 1990’s as potential cannabinoid agonists that might possess some of the advantageous effects of cannabis, appetite stimulation, and anti- nausea properties, blood pressure, and much flaunted as adjuncts in cancer pain therapy, without the euphoric intoxicating effects for which the drug was popular recreationally. Now the drugs are sold widely on the internet and convenience stores and gas stations, smoke shops and head shops. The compounds that we will discuss are largely unregulated in most o the US but there is a rapid trend towards state or even local regulation as public concern grows. The DEA is looking to develop controls for these drugs and recently appealed for information through the SOFT newsletter.
  • Just some introductory historical perspective. Slides are self explanatory.
  • Effects are characteristic of marijuana and predicted to also result from synthetic cannabinoid use based on CB1 activity.
  • CB1 regulates both excitatory and inhibitory neurotransmission, depending on the site of action. Therefore, the location of receptors is very important for understanding the effect.
  • There is some uncertainty about whether CB2 may also be involved in neurotransmission. JWH designed compounds to target CB2 in order to avoid CNS effects. In the process, he discovered ways to enhance CB1 bindings. Drug abusers use these in vitro results to choose compounds that have predominantly CB1 binding.
  • This paper details the requirements for optimal CB1 binding and is a good source for structures of compounds that may be abused in the future. Thus far, the easiest to synthesize have been the most popular.
  • Schedule I have been replaced by non-controlled compounds. Preference is given to compounds with evidence of high potency at CB1. We may expect this trend to continue. Also, JWH-018 appears to be a metabolite of AM-2201; these are frequently detected together. The structures are very similar, so analog law may apply.
  • Positivity data from NMS Labs shows that there is a decrease in positive findings after compounds are scheduled.
  • Positivity data from NMS Labs shows controlled compounds are replaced by non-controlled substitutes.
  • Unlikely to cause a rush or high based on mechanism, although this is a concern of the investigators.
  • Marijuana, the most popular recreational drug in the United states after alcohol is enjoying growing popularity and seeing increasing efforts for its legalization. MJ is the number 1 drug in the DRE program, some 25 million Americans have smoked it in the past year, and a recent national roadside drug test survey showed that 6.8% of Friday and Saturday evening drivers tested positive for its use.
  • Sobolevsky and coworkers reported urine profiles of three subjects in Russia who had smoked a product containing JWH-018. The effect profile was again similar to that expected of marijuana.
  • Teske and coworkers conducted self administration of a product containing JWH-018. They reported sickness, sedation and dry mouth, hot flushes, burning eyes, and thought disruption. No change in pupil size. But pulse and blood pressure were noticeably elevated.
  • They reported quantitative concentrations in in serum, with peak concentrations occurring in the range of 8-10 ng/mL within a few minutes of smoking, and concentrations falling below 1ng/mL within 3 hours. Trace concentrations were reported at 24 hours (<0.1ng/mL)
  • Challenges to laboratories tasked with keeping up.
  • This study was done in support of clinical development of CB2 targeted therapeutics. It has been used as a basis to predict metabolism of other, similar compounds.
  • These metabolite predictions are very much just shots in the dark. Wouldn’t it be great to have some human data?
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • Provided to remind audience of relative affinity of these compounds at CB1. 18 and 73 are both relatively easy to synthesize and have good affinity.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • The data show the rapid rise, distribution and decline of the parent compounds in blood, combined with the rapid rise in blood pressure, systolic shown here. Importantly within one hour of this pharmacologically significant dose, the concentrations had dropped to less than 1ng.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • In July 2010 the University of Missouri sponsored a K2 administration study. Following approval by the University’s IRB, six subjects were administered low doses of smokeable products containing JWH-018, JWH-073 or CP-47,497. Subjects completed SFST’s and a DRE exam, some cognitive tests, and underwent medical assessments. Blood urine and oral fluid were collected, refrigerated or frozen and shipped to NMS labs for analysis. The K2 was analyzed for SC content and the presence of any other drugs before administration.
  • Synthetic drugs that mimic the effects of cannabis through binding at the same receptors, principally the CB1 receptor, more of which about momentarily. The drugs were developed in the 1980’s and 1990’s as potential cannabinoid agonists that might possess some of the advantageous effects of cannabis, appetite stimulation, and anti- nausea properties, blood pressure, and much flaunted as adjuncts in cancer pain therapy, without the euphoric intoxicating effects for which the drug was popular recreationally. Now the drugs are sold widely on the internet and convenience stores and gas stations, smoke shops and head shops. The compounds that we will discuss are largely unregulated in most o the US but there is a rapid trend towards state or even local regulation as public concern grows. The DEA is looking to develop controls for these drugs and recently appealed for information through the SOFT newsletter.

Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids Presentation Transcript

  • Wendy R. Adams, Ph.D., DABFT Barry K. Logan, Ph.D., DABFT NMS Labs, Willow Grove, PA February 21, 2012
  • Synthetic Cannabinoids • Chemicals designed to have CB1/CB2 binding properties • Chemically diverse structure classes • First synthesized as investigational drugs in the 1980’s • Adopted by the “Research Chemical” movement in 2000’s • Sold as “Legal highs”, “Incense blends”, “Potpourri” Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 2
  • What’s in Herbal Incense?"The stuff thats been put into the incense was originally made in our lab 15 years ago." John W. Huffman, ABC News, 3/17/10 Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 3
  • Nomenclature  Initially synthesized for medicinal research  JWH compounds are named for John W. Huffman at Clemson University for research on the relationship between the structure of drugs and brain receptor activity  HU prefaced compounds are named for Hebrew University  CP 47,497 was initially developed by Pfizer as an analgesic  AM prefaced compounds are halogenated and named for Northeastern University professor Alexandros Makriyannis  WIN compounds were developed by Sterling Winthrop
  • CB1 Cannabinoid ReceptorCentral and Peripheral EffectsBeneficial Effects Undesirable EffectsReduced nausea/Increased appetite Increased appetiteImproved mood, euphoria High abuse potential, dysphoria Vasodilation and tachycardia, increased risk of cardiac events Impaired memory and cognition, altered perception Impaired coordination and psychomotor performance Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 5
  • CB1 and Neurotransmission Presynaptic GABA or Postsynaptic glutamate CB1 Endocannabinoid Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 6
  • Pharmacodynamics and Pharmacokinetics ofSynthetic Cannabinoids 7
  • CB2 Cannabinoid ReceptorSuggested Peripheral EffectsBeneficial Effects Undesirable EffectsReduced inflammation ImmunosuppressionLack of psychoactive effects (?)Improved bone strengthDecreased pain perception Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 8
  • Structure Activity Relationships CP-47,497 Δ9-THC Classical CB1 Binding Non-Classical CB1 Binding Poso & Huffman, Br J Pharm 153:335-346, 2008. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 9
  • Schedule I as of 3/1/11CP47,497(non-classical)CP 47,497 (C8 analog) – Cannabicyclohexanol(non-classical)HU-210 (and HU-211)(classical, schedule I as THC analog)JWH-018(non-classical)JWH-073(non-classical)JWH-200(non-classical)
  • The Chemical Arms Race Compound Positivity in Blood (%) CB1 Ki (nM) AM-2201 61 1.0 JWH-122 58 0.7 JWH-210 30 0.5 JWH-018* 18 9.5 JWH-250 12 11.0 JWH-081 11 1.2 RCS-4 6 RCS-8 3 JWH-019 2 9.8 JWH-073* 1 8.9 AM-694 0 0.1 JWH-200* 0 42.0 D9-THC* N/A 41.0 *Schedule I Controlled Substance, NMS Labs data Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 11
  • US DEA Controls JWH-018, 073Pharmacodynamics and Pharmacokinetics ofSynthetic Cannabinoids 12
  • Pharmacodynamics and Pharmacokinetics ofSynthetic Cannabinoids 13
  • The Next Wave?Fatty acid amide hydrolase (FAAH) functions at the synapse to breakdown anandamideInhibition is predicted to enhance the effects of endogenous cannabinoidsIn development as a treatment for pain Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 14
  • Human StudiesEffectsMetabolismDuration Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 15
  • Marijuana and Driving Cognitive and psychomotor effects: Relaxation, mild euphoria, laughter, time change effects, possible hallucinations, divided attention impairment. Physiological Effects: Increased pulse and blood pressure, conjunctival injection, xerostomia/dry mouth, head movements and jerks, blinking, increased appetite. Adverse Effects on Driving: Increase in Standard Deviation of Lateral Position (weaving), estimation of time to impact, lower arousal, increased sleepiness, increased risk of crash involvement/culpability Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 16
  • Synthetic Cannabinoid EffectsSobolevsky T, Prasolov I, Rodchenkov G. Forensic SciInt. 2010 Jul 15;200(1-3):141-7. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 17
  • Teske J, Weller JP, Fieguth A, Rothämel T, Schulz Y, Tröger HD. JChromatogr B Analyt Technol Biomed Life Sci. 2010 Oct1;878(27):2659-63.
  • Synthetic Cannabinoid EffectsTeske J, Weller JP, Fieguth A, Rothämel T, Schulz Y, Tröger HD. JChromatogr B Analyt Technol Biomed Life Sci. 2010 Oct1;878(27):2659-63.
  • Toxicology • Limited immunoassay screens • Not detectable in GCMS screens • Blood – detect parent compounds • Urine – Need to look for metabolites Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 20
  • MetabolismIdentification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS. Zhang Q, Ma P, Cole RB, Wang G. Anal Bioanal Chem. 2006 Nov;386(5):1345-55 Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 21
  • Pharmacodynamics and Pharmacokinetics ofZhang et al. Fig. 9 Synthetic Cannabinoids 22
  • JWH-018 StudiesWintermeyer et al, Analy Bio Chem, 398(5): 1241-53, 2010 Incubation with human liver microsomes Analysis by LC-MS/MSSobolevsky et al, Forensic Sci Int, 200(1-3):141-47, 2010 Urine from 3 persons known to have smoked JWH-018 Analysis of hydrolyzed urine by GC-MS/MS and LC-MS/MS Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 23
  • Pharmacodynamics and Pharmacokinetics ofWintermeyer et al, Fig. 2 Synthetic Cannabinoids 24
  • Pharmacodynamics and Pharmacokinetics ofSobolevsky et al, Fig. 6 Synthetic Cannabinoids 25
  • Missouri K2 Administration Lab• Spring 2010, UCMO plans DRE training to include K2 smoking Lab• NMS Labs contacted regarding ability to test urine• Study expanded to include additional DRE staff, and six subjects Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 26
  • Missouri K2 Administration Study• IRB approval from University of Central Missouri• Subjects smoked incense products containing JWH-018, JWH-073• Subjects performed SFST’s, cognitive tests and DRE Exam• Blood, urine and oral fluid collected Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 27
  • K2 K2 K2 Herbal Standard Citron Summit Blend JWH-018 (mg/g) 9 10 11 - JWH-073 (mg/g) 9 10 9 -CP47,497 (C7) (mg/ g) - - - 6 Free from other known drugs or chemicals Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 28
  • Percent of Bloods Compound Submitted CB1 Ki (nM) AM-2201 61 1.0 JWH-122 58 0.7 JWH-210 30 0.5 JWH-018* 18 9.5 JWH-250 12 11.0 JWH-081 11 1.2 RCS-4 6 RCS-8 3 JWH-019 2 9.8 JWH-073* 1 8.9 AM-694 0 0.1 JWH-200* 0 42.0 D9-THC* 41.0*Schedule I Controlled Substance, NMS Labs data, n=310, 12/9/11 Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 29
  • Missouri K2 Administration Lab• Onset of subjective effects within 2-3 minutes.• Subjectively peaking 5-10 minutes.• Taste tobacco/burning garbage/unpleasant Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 30
  • K2 Standard: Subject Pm• 39 y.o. Male, 190 lbs, Naive user• Quiet, cooperative, low key• Smoked “K2 Standard”, JWH-018, JWH-073 (~1%)• Excellent baseline performance in DRE/SFST assessment• 15:02 dosing • 1 inhalation of K2 Standard smoked in a small water pipe, 300 mg of material on the screen Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 31
  • K2 Standard: Subject Pm• 15:05 Effects coming on, head high, buzzed, shaking leg, some anxiety, feels impaired.• 15:40 SFSTs • Marked sway, staggering, loss of balance. • Walk and Turn: Lost balance during instructions, trouble placing foot on line, stepped off line, lost balance on turn, marked muscle tremors. • One Leg Stand: Lost balance several times, swayed, used arms for balance. • Lack of Convergence Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 32
  • K2 Observations Subjective Effects: Dry mouth Light headedness/Buzzed Blurred vision Sedation Motor agitation/restlessness Time dilation Mild anxiety/paranoia Post intoxication fatigue Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 33
  • K2 Observations• Psychomotor Effects• Highly variable response• DRE Exam  Increased pulse and blood pressure  Lack of convergence  No HGN, or VGN  Pupils normal, muscle tone normal Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 34
  • K2 Observations• Standard Field Sobriety Tests  3-4 inches of sway, leg body tremors  Loss of balance  Loss of motor coordination Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 35
  • Sobolevsky et al, Auwater et al, Elsohly, This Study - subject number Teske et al, 2010 2010 2009 2008 1 2 3 4 5 6 3 DUIs, positive 2 subjects smoked 2 subjects THC K2 K2 K2 K2 K2 K2 for JWH-018 JWH-018 Cannabicyclohexa Standard Citron Standard Summit Citron Summit nol + JWH-018 Red eyes / Yes - Yes Yes Yes Yes Yes Yes Yes Yes bloodshotBurning of the eyes - Yes - - - Yes - - - - Xerostomia (dry - Yes Yes Yes Yes Yes - - Yes Yes mouth) Increased pupil - Yes - Yes Equiv Equiv Equiv Equiv Equiv Equiv diameter Tachycardia Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Anxiety Yes - - Yes Yes - Yes - Yes Yes Hallucinations Yes - - Yes - - - - - - Paranoia Yes - - Yes - - - - Yes Yes Sickness - Yes - - - - - - - - Sedation - Yes - Yes Yes - Yes - - Yes Changes in - - Yes Yes Yes Yes Yes - Yes Yes perception/mood Loss of - Yes - Yes Yes Yes - - Yes Yes concentration Impaired sense of Yes - - Yes Yes Yes Yes - - Yes time Tiredness - 6-12 hours 6-24 hours - Yes Yes Yes - - - Self assessed - - Yes Yes Yes Yes Yes - Yes 36 Yes impairment
  • Missouri K2 Administration Study Smoked “K2 Citron” 10 mg/g JWH-018/073 0.3 g in water pipe 3 inhalations over 30 minutes Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 37
  • K2 Conclusions• Blood concentrations of the parent drug were typically less than 1 ng/mL within 2 hours of smoking• Urine was positive within 1 hour of administration, for mono-and di-hydroxy metabolites Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 38
  • K2 Administration Phase II• IRB approval from University of Central Missouri• Subjects smoked one of 6 herbal incense products• Subjects performed SFST’s, cognitive tests and DRE Exam• Blood, urine and oral fluid collected Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 39
  • Legal UK Eagle 8-Ball Blend I Freedom C4 SOHIJWH-019 +JWH-081 + +JWH-122 +JWH-210 +JWH-250 + + + RCS-4 + RCS-8 +AM-2201 + Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 40
  • Legal Eagle: Subject Cm• Male, Previous Marijuana/K2 Smoker, 150lbs• Outgoing, loud, laughing, joking• Smoked “Legal Eagle” containing JWH-250, JWH-019, JWH-081, RCS-4 (~1%)• Good baseline performance in DRE/SFST assessment• 12:19 dosing • 4 inhalations of Legal Eagle smoked in a small water pipe, 300 mg of material on the screen Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 41
  • Legal Eagle: Subject Cm Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 42
  • Legal Eagle: Subject Cm• 12:19 Inhaled, held 6 seconds• 12:20 Inhaled, held 12 seconds• 12:20 “Pretty stoned”, Feels the high coming on. “This stuff is pretty potent”.• 12:24 Inhaled ~20 seconds, held 3 seconds• 12:24 Some unease, paranoia, feels “Chill, relaxed”• 12:30 Inhaled, held 2 seconds• 12:30 Euphoria is subsiding, eyes glassy/bloodshot Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 43
  • Legal Eagle: Subject Cm• ~12:45 Subject thought he could drive OK, but, “wouldn’t want to take the risk of a DUI.” • Feels relaxed, content, chill, head-high • Paranoia was transient, during smoking • Talkative, “ranting”, short attention span Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 44
  • Legal Eagle: Subject Cm• 12:45 ~30 minutes post dose SFST • Euphoric, talkative • Lack of convergence • Reddened bloodshot eyes • Pulse 102 vs 78 pre dose • Minimal sway on SFST, some leg tremors, generally good performance, good balance. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 45
  • Legal Eagle: Subject Cm Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 46
  • 8 Ball: Subject Am• 24y.o., Male, Previous Marijuana Smoker, 153 lbs• Quiet, calm, relaxed, passive.• Smoked “8 Ball” containing JWH-081, JWH-250 (~1%)• Good baseline performance in DRE/SFST assessment• 10:54 dosing • 3 inhalations of UK Blend smoked in a small water pipe, 300 mg of material on the screen Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 47
  • 8 Ball: Subject Am Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 48
  • 8 Ball: Subject Am• 10:54 Inhaled, held 8 seconds• 10:55 Inhaled, held 10 seconds• 10:56 A little light headed, “heart is speeding up”• 10:57 Inhaled deeply, held 23 seconds• 10:59 “..more focused...vision is delayed”. Smiling, fixed gaze• 11:01 “Wow, its hitting me now… like I blacked out”• 11:02 Subject becomes uncomfortable, folds arms, becomes tense, not relaxed Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 49
  • 8 Ball: Subject Am• 11:03 Feeling dizzy, scared, emotional, depressed, claustrophobic, doesn’t understand why people smoke K2, feels like he’s not in control of his emotions. Says he’s angry for losing control.• 11:06 Tense, eyes closed, holding his head, crossing arms, apprehensive, breathing faster.• 11:07 Expected alcohol buzz, but feels “oppressed”• 11:11 “I’m getting good, more coherent” “I can’t believe it caused claustrophobia” “Objects are moving left and uphill” Nursing staff are making him nervous Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 50
  • 8 Ball: Subject Am• 11:41 Getting more clarity, “shaking”, 7 on distress scale compared to 1 at the peak of effect. Stated if he drove now he would crash into a tree.• 11:57 More relaxed, laughing, difficulty focusing.• 13:23 Still residual negative mood, dazed, confused, irritable. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 51
  • 8 Ball: Subject Am• SFST Performance – 70 minutes post dose • Extreme Leg and Body Tremors, Hard to stand • Terminated Romberg test • Walk and Turn: missed numbers, tremors, stepped off the line, used arms for balance – Impaired. • One Leg Stand: Numerous errors in counting, very poor balance. • Problems focusing on the tests, fixated on distractions, poor attitude, became uncomfortable in the dark room. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 52
  • 8 Ball: Subject Am• Evaluations stopped at 16:00 hrs, five hours post dose.• Some residual effects Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 53
  • 8 Ball: Subject Am Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 54
  • Phase II Conclusions• Effects were qualitatively similar to marijuana with some additional anxiety/paranoia• Subjects reported a noticeable hangover effect• Short time to peak effects after smoking Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 55
  • Synthetic Cannabinoids  Potential to cause physiological and psychomotor effects consistent with DRE cannabis category  Effects include Lack of Convergence, reddened conjunctivae, intoxication, time dilation effects, laughter, agitation, anxiety and paranoia  Blood concentrations below 1 ng/mL within an hour or two after smoking  Detectable in oral fluid  Urine concentrations may be detectable for 24 hours Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 56
  • Acknowledgements Sherri Kacinko, Ph.D. Pharmacodynamics and Pharmacokinetics of Synthetic Cannabinoids 57