Synthetic cannabinoids: Flying high under the RADAR Brett Ginsburg, Ph.D.

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1 Synthetic cannabinoids: Flying high under the RADAR Brett Ginsburg, Ph.D.

2 Introduction Brett Ginsburg, Ph.D. Associate Professor Department of Psychiatry

3 Introduction What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

4 Content What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

5 What are synthetic cannabinoids? NOT marijuana Dried flowers of Cannabis Over 400 cannabinoids Primary ingredient is THC Δ9-tetrahydrocannabinol Cannabidiol Smoked, eaten, vaporized

6 What are synthetic Synthetic chemicals Simple synthesis cannabinoids? Over 200 known Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents... The term cannabimimetic agents means any substance that is a cannabinoid receptor type 1 (CB1 receptor) agonist as demonstrated by binding studies and functional assays within any of [five designated] structural classes S (112th): Synthetic Drug Abuse Prevention Act of 2012 Smoked, vaporized

7 Manufacture 1940s Parahexyl Roger Adams Homologue of THC 1970s-1980s Non-classical cannabinoids WIN 55,212-2 CP55, s Huffman synthesis (aminoalkylindoles) JWH compounds Simple synthesis

8 Distribution Manufactured in large factories overseas Processed domestically Dissolved in acetone Sprayed over plant material (potpourri) Dried and packaged

9 Distribution

10 Distribution

11 Distribution

12 Consumers Males Reasons for use Novelty seeking Evade drug testing o Job o Probation Substitute for marijuana o Under age o No legal marijuana Psychedelic or dissociative effects

13 Content What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

14 Pharmacology Cannabinoid receptor CB1 agonist Two cannabinoid receptors o CB1 (central) o CB2 (peripheral) Feedback to end neurotransmitter signaling Normandin et al., J Cereb Blood Flow Metab Aug; 35(8):

15 Pharmacology Potency vs efficacy CP 55,940 JWH-018 THC Brents et al., PLoS One. 2011;6(7):e21917

16 Pharmacology Potency vs efficacy CP 55,940 JWH-018 THC Brents et al., PLoS One. 2011;6(7):e21917

17 Pharmacology Potency vs efficacy CP 55,940 JWH-018 THC Brents et al., PLoS One. 2011;6(7):e21917

18 Pharmacology Behavioral effects Animals Humans o Hypothermia o Hypothermia o Decreased movement o Sedation o Antinociception (analgesia) o Analgesia o Catalepsy o Lethargy o Increase eating o Munchies o Convulsions o Convulsions o Euphoria o Tachycardia o Hypertension

19 Ginsburg, et al. J Pharmacol Exp Ther Jan;340(1): Kinetics

20 Content What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

21 Toxicology Most common toxic effects reported to Texas Poison Control: Tachycardia Agitation Lethargy Nausea/Vomiting Confusion Hypertension Hallucinations Seizures Irritability Paranoia Delusions Dizziness Vertigo Chest pain Breathing difficulty Acute kidney injury

22 % Δ 9 -THC-Lever Toxicology Before 14 days THC treatment After 14 days THC treatment THC Hruba et al., J Pharmacol Exp Ther Sep;342(3):843-9 Dose (mg/kg)

23 % Δ 9 -THC-Lever Toxicology Before 14 days THC treatment After 14 days THC treatment JWH-018 Hruba et al., J Pharmacol Exp Ther Sep;342(3):843-9 Dose (mg/kg)

24 % Δ 9 -THC-Lever Toxicology Before 14 days THC treatment After 14 days THC treatment JWH-018 THC Hruba et al., J Pharmacol Exp Ther Sep;342(3):843-9 Dose (mg/kg)

25 Content What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

26 Detection Colorimetric Reagent changes color in presence of drug o o Tests sensitive to THC do not detect synthetic cannabinoids 2,4-dinitrophenylhydrazine Reacts with keto moiety Changes from yellow to orange High (~10mg/ml) LOD Marquis reagent Reacts with all nitrogen containing drugs Detects JWH-series

27 Detection Immunochemical ELISA (Enzyme-Linked Immunosorbent Assay) o o o o o Antibody targets specific molecule Enzyme produces signal when bound antibody is detected High specificity High sensitivity Limited cross-reactivity for new drugs entering the market

28 Detection Immunochemical ELISA (Enzyme-Linked Immunosorbent Assay)

29 Detection Chromatographic Gas chromatography mass spectrometry Highly specific Highly sensitive Requires a lab Requires a known sample

30 Content What are synthetic cannabinoids? Manufacture Distribution Who uses them? Pharmacology Cellular effects Behavioral effects Toxicology Cellular Organ Behavioral Detection Treatment Acute Chronic

31 Treatment Acute: Benzodiazepines/Quetiapine Agitation Irritability Anxiety Nausea/Vomiting Seizures Pentobarbital/Escitalopram/Clonidine Anxiety Seizures (prophylaxis) Pramipexole Insomnia due to agitation Cooper. Curr Psychiatry Report

32 Treatment No pharmacological treatment Cannabinoid replacement Opioid antagonists Antidepressants N-acetylcholine Cognitive Behavioral Therapy Lack of detection makes contingency management difficult

33 Conclusion Synthetic cannabinoid use is increasing Particularly among groups likely to join armed forces Synthetic cannabinoid use appears more dangerous than marijuana use Severe adverse effects Chronic use may be less prevalent Detection of synthetic cannabinoid use is difficult Treatment of acute intoxication is palliative Best treatment for chronic use is unclear

34 Brett Ginsburg, Ph.D. Department of Psychiatry The University of Texas Health Science Center at San Antonio

35 Thank you for attending. Please give us your feedback here! 08/09/16

Objectives. Why new drugs? New drugs of abuse: synthetic cannabinoids, stimulants, and 10/14/2015. Describe several new drugs of abuse

Objectives. Why new drugs? New drugs of abuse: synthetic cannabinoids, stimulants, and 10/14/2015. Describe several new drugs of abuse New drugs of abuse: synthetic cannabinoids, stimulants, and more Robert G. Hendrickson, MD Professor, Emergency Medicine, OHSU Program Director, Medical Toxicology Fellowship Associate Medical Director,