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

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

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

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

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

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. 3190 (112th): Synthetic Drug Abuse Prevention Act of 2012 Smoked, vaporized

Manufacture 1940s Parahexyl Roger Adams Homologue of THC 1970s-1980s Non-classical cannabinoids WIN 55,212-2 CP55,940 2000s Huffman synthesis (aminoalkylindoles) JWH compounds Simple synthesis

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

Distribution

Consumers Males 18-24 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

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. 2015 Aug; 35(8): 1313 1322.

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

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

Ginsburg, et al. J Pharmacol Exp Ther. 2012 Jan;340(1):37-45. Kinetics

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

% Δ 9 -THC-Lever Toxicology Before 14 days THC treatment After 14 days THC treatment THC Hruba et al., J Pharmacol Exp Ther. 2012 Sep;342(3):843-9 Dose (mg/kg)

% Δ 9 -THC-Lever Toxicology Before 14 days THC treatment After 14 days THC treatment JWH-018 Hruba et al., J Pharmacol Exp Ther. 2012 Sep;342(3):843-9 Dose (mg/kg)

% 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. 2012 Sep;342(3):843-9 Dose (mg/kg)

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

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

Detection Immunochemical ELISA (Enzyme-Linked Immunosorbent Assay)

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

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. 2016. 18

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

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

Brett Ginsburg, Ph.D. Department of Psychiatry The University of Texas Health Science Center at San Antonio ginsburg@uthscsa.edu 210-567-0871

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