Objectives. Synthetic Cannabinoids. Disclosure. Recreational Drug Use in the US. Classic Recreational Drugs 8/29/2017 I. RECREATIONAL DRUG USE

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Synthetic Cannabinoids Update for Healthcare Professionals Dayne Laskey, PharmD, DABAT Objectives Describe the

trends associated with synthetic cannabinoid use in the U.S.

Disclosure Dr Laskey has no actual or potential conflict of interest associated with this presentation I.

Center for Behavioral Health Statistics and Quality. (2015).

1 Synthetic Cannabinoids Update for Healthcare Professionals Dayne Laskey, PharmD, DABAT Objectives Describe the epidemiology of recreational drug use Explain the pharmacologic and health effects of synthetic cannabinoid use Discuss trends associated with synthetic cannabinoid use in the U.S. Communicate effective strategies that support pharmacy's role in recreational drug abuse prevention and education Disclosure Dr Laskey has no actual or potential conflict of interest associated with this presentation I. RECREATIONAL DRUG USE Recreational Drug Use in the US Classic Recreational Drugs 1. Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA , NSDUH Series H 50). 2. Swift, A. In US, 45% Say They Have Tried Marijuana. Gallup. July 19, Available at: tried marijuana.aspx 1

Synthetics: Alexander Shulgin Phenethylamines American pharmacologist, chemist 1961: Develops Zectran (mexacarbate) for Dow Chemical DEA schedule 1 license Godfather

Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila). 2011;49(8):705 19.

31 of these were cathinones 30 were cannabinoids Mechanism(s) presynap c release of catecholamines Inhibit breakdown of neurotransmitters (e.g.

2 Synthetics: Alexander Shulgin Phenethylamines American pharmacologist, chemist 1961: Develops Zectran (mexacarbate) for Dow Chemical DEA schedule 1 license Godfather of psychedelics PIHKAL (1991), TIHKAL (1997) Together describe synthesis of over 250 psychoactive compounds Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila). 2011;49(8): Bath Salts Bath Salts In 2014, 101 new recreational substances were identified by EMCDDA. 31 of these were cathinones 30 were cannabinoids Mechanism(s) presynap c release of catecholamines Inhibit breakdown of neurotransmitters (e.g. MAOi) Inhibit catecholamine reuptake (DAT, NAT, SERT) Clinical effects Paranoia, agitation, psychosis, tachycardia, hypertension, hyperthermia, seizures, coma, death. European Monitoring Centre for Drugs and Drug Addiction (2015), New psychoactive substances in Europe. An update from the EU Early Warning System (March 2015), Publications Office of the European Union, Luxembourg. 2

3 Marijuana Δ 9 Tetrahydrocannabinol II. PHARMACOLOGY AND EFFECTS Mechanism Complex combination of 86 active components Δ9 Tetrahydrocannabinol (THC), Cannabidiol (CBD), cannabinol (CBN), cannabavarin (THCV), cannabigerol (CBG), cannabichromene (CBC), delta 8 THC, cannabicyclol (CBL) Partial agonist CB1: CNS CB2: Peripheral NS, immune cells Legal status 7 states recreational (plus D.C.) 14 states decriminalized 29 states allow medical (plus D.C.) Marijuana Potency Marijuana Potency Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades ( ): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7): Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades ( ): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7): Unintentional Pediatric Exposures Unintentional Pediatric Exposures Clinical Effects Lethargy, ataxia, irritability, vomiting, respiratory depression, bradycardia, hypotension Several cases requiring hospitalization and admission to ICU Contrast with adults Agitation, paranoia, tachycardia, nausea/vomiting Wang GS, Roosevelt G, Le lait MC, et al. Association of unintentional pediatric exposures with decriminalization of marijuana in the United States. Ann Emerg Med. 2014;63(6): Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167(7):

Cannabinoid hyperemesis syndrome Occurs in users with regular cannabis use > 1 year (74.8%) Severe n/v with accompanying abdominal pain, cycling over months (100%) Compulsive hot baths (92.

2017;13(1):71 87. 2. Dezieck L, Hafez Z, Conicella A, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol (Phila).

Synthetic Cannabinoids History Structurally unrelated to THC CB1/CB2 agonists Many times more potent First synthesized in the 1960s for research into the endocannabinoid system JWH XXX John William

4 Cannabinoid hyperemesis syndrome Occurs in users with regular cannabis use > 1 year (74.8%) Severe n/v with accompanying abdominal pain, cycling over months (100%) Compulsive hot baths (92.3%) Pathology is unclear 1. Sorensen CJ, Desanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment a Systematic Review. J Med Toxicol. 2017;13(1): Dezieck L, Hafez Z, Conicella A, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol (Phila). 2017;55(8): Synthetic Cannabinoids History Structurally unrelated to THC CB1/CB2 agonists Many times more potent First synthesized in the 1960s for research into the endocannabinoid system JWH XXX John William Huffman AM XXX Alexandros Makriyannis HU XXX Hebrew University CP XXX Pfizer Synthetic Cannabinoids History Sources 2004 Internet, head shop sales begin in Europe 2008 First law enforcement seizure in US synthetic cannabinoids placed on Schedule I 2012 Synthetic Drug Abuse Prevention Act Defines SCs pharmacologically rather than structurally 2015 Largest outbreak of SCs in history DEA estimates there are at least 75 additional synthetic cannabinoids that remain unscheduled Some may still be subject to prosecution under Federal Analogue Act of 1986 Synthetic Cannabinoids Synthetic Cannabinoids Clinical Effects Excited delirium Acute kidney injury Seizures Psychosis Hallucinations Cardiotoxic effects Respiratory depression Coma Death 1. Monte AA, Calello DP, Gerona RR, et al. Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study. J Med Toxicol. 2017;13(2): Image: politics/why synthetic drugs could become washingtons next drug horror/2015/07/18/32530cfc 2bc8 11e5 a250 42bd812efc09_story.html?utm_term=.f8c2affde36e 4

5 Clinical effects by type JWH Series (11/2010) AMS, seizures, hyperthermia, tachycardia XLR 11 (5/2013) Tachycardia, hypertension, psychosis, AKI AB FUBINACA (1/2014) MAB CHMINACA (10/2015), AB CHMINACA (1/2015) Bradycardia, hypotension, obtundation ADB PINACA (1/2015), Hallucinations, psychosis, tachycardia, agitated delirium AMB FUBINACA Severe CNS depression in absence of other features Synthetics: Treatment Supportive care Intravenous fluids Treatment of hyperthermia Talkdown measures, calming environment Monitoring Vitals, EKG, renal function, CK Sedation (benzodiazepines preferred) Role for neuroleptics? Synthetics: Why the demand? Curiosity Feeling good/getting high Lack of toxicological screening Availability Internet and retail stores Perceived legality Cost Fraction of the price of conventional marijuana Poor perception of the risk 1. Lauritsen KJ, Rosenberg H. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana. Am J Drug Alcohol Abuse. 2016;42(4): Bonar EE, Ashrafioun L, Ilgen MA. Synthetic cannabinoid use among patients in residential substance use disorder treatment: prevalence, motives, and correlates. Drug Alcohol Depend. 2014;143: III. SYNTHETIC CANNABINOID TRENDS Riederer AM, Campleman SL, Carlson RG, et al. Acute Poisonings from Synthetic Cannabinoids 50 U.S. Toxicology Investigators Consortium Registry Sites, MMWR Morb Mortal Wkly Rep 2016;65: A Growing Public Health Threat 644 NPS identified by UN Office of Drugs and Crime Synthetic cannabinoids are the fastest growing class >177 novel SCs identified in 2014 alone Second most common illicit substance among US high school students in 2014 and 2015 Third most common in 2016 United Nations Office on Drugs and Crime, World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7). Timeline Wiley JL, Marusich JA, Lefever TW, et al. AB CHMINACA, AB PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9 Tetrahydrocannabinol Like Effects in Mice. J Pharmacol Exp Ther. 2015;354(3):

Laboratory Trends Timeline NMS Labs, 2017 Adams AJ, Banister

"Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB

Laboratory Trends Poison Center Trends NMS Labs, 2017 American

Synthetic Cannabinoids. July 31, 2017. http://www.aapcc.

IV. OUR ROLE Trecki J, Gerona RR, Schwartz MD.

6 Laboratory Trends Timeline NMS Labs, 2017 Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. "Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB FUBINACA in New York. N Engl J Med. 2017;376(3): Laboratory Trends Poison Center Trends NMS Labs, 2017 American Association of Poison Control Centers (AAPCC) Press Release: Synthetic Cannabinoids. July 31, cannabinoids/ Outbreaks occur in clusters IV. OUR ROLE Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid Related Illnesses and Deaths. N Engl J Med. 2015;373(2): Created by Photoroyalty Freepik.com 6

Clinical Challenges No clear toxidrome No readily available diagnostic tools No antidote No pharmacologic/pharmacokinetic data Unpredictable and severe effects Unknown long term effects Other

collected, sent to specialty lab for preliminary identification Analytical standard synthesized Metabolites predicted and synthesized Reanalysis of biological samples Reference standards sent to

Schwartz MD. Synthetic Cannabinoid Related Illnesses and Deaths. N Engl J Med. 2015;373(2):103 7.

7 Clinical Challenges No clear toxidrome No readily available diagnostic tools No antidote No pharmacologic/pharmacokinetic data Unpredictable and severe effects Unknown long term effects Other Challenges Difficult for law enforcement to track Cases are often underreported Baseline use patterns are difficult to track Challenges in the Laboratory NPDS Illness cluster identified Samples collected, sent to specialty lab for preliminary identification Analytical standard synthesized Metabolites predicted and synthesized Reanalysis of biological samples Reference standards sent to other laboratories for validation Takes weeks months to complete Requires collaboration between healthcare providers, law enforcement, clinical laboratories, organic chemists, Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid Related Illnesses and Deaths. N Engl J Med. 2015;373(2): National Poison Data System >62 million exposures dating back to 1983 The only real time public health surveillance tool in the US What is the role of the pharmacist? Prevention Education Assistance ASHP Statement on the Pharmacist's Role in Substance Abuse Prevention, Education, and Assistance. Am J Health Syst Pharm. 2016;73(9):e

8 References References Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. "Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB FUBINACA in New York. N Engl J Med. 2017;376(3): ASHP Statement on the Pharmacist's Role in Substance Abuse Prevention, Education, and Assistance. Am J Health Syst Pharm. 2016;73(9):e Bonar EE, Ashrafioun L, Ilgen MA. Synthetic cannabinoid use among patients in residential substance use disorder treatment: prevalence, motives, and correlates. Drug Alcohol Depend. 2014;143: Center for Behavioral Health Statistics and Quality (CBHSQ). Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration; HHS Publication No. SMA , NSDUH Series H 50. Dezieck L, Hafez Z, Conicella A, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol (Phila). 2017;55(8): Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades ( ): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7): European Monitoring Centre for Drugs and Drug Addiction (2015), New psychoactive substances in Europe. An update from the EU Early Warning System (March 2015), Publications Office of the European Union, Luxembourg. German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci. 2014;97(1):2 8. Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila). 2011;49(8): Lauritsen KJ, Rosenberg H. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana. Am J Drug Alcohol Abuse. 2016;42(4): Monte AA, Calello DP, Gerona RR, et al. Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study. J Med Toxicol. 2017;13(2): Patrick ME, O'malley PM, Kloska DD, et al. Novel psychoactive substance use by US adolescents: Characteristics associated with use of synthetic cannabinoids and synthetic cathinones. Drug Alcohol Rev. 2016;35(5): Riederer AM, Campleman SL, Carlson RG, et al. Acute Poisonings from Synthetic Cannabinoids 50 U.S. Toxicology Investigators Consortium Registry Sites, MMWR Morb Mortal Wkly Rep 2016;65: Sorensen CJ, Desanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment a Systematic Review. J Med Toxicol. 2017;13(1): Swift, A. In US, 45% Say They Have Tried Marijuana. Gallup. July 19, Available at: triedmarijuana.aspx Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid Related Illnesses and Deaths. N Engl J Med. 2015;373(2): United Nations Office on Drugs and Crime, World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7). Valente MJ, Guedes de pinho P, De lourdes bastos M, Carvalho F, Carvalho M. Khat and synthetic cathinones: a review. Arch Toxicol. 2014;88(1): Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167(7): Wang GS, Roosevelt G, Le lait MC, et al. Association of unintentional pediatric exposures with decriminalization of marijuana in the United States. Ann Emerg Med. 2014;63(6): Wiley JL, Marusich JA, Lefever TW, et al. AB CHMINACA, AB PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9 Tetrahydrocannabinol Like Effects in Mice. J Pharmacol Exp Ther. 2015;354(3):

Conflict of Interest Disclosure

Conflict of Interest Disclosure None Street Drugs: What s out there and just how bad is it? Kathy Vo, MD Medical Toxicology Fellow Department of Emergency Medicine California Poison Control System 2 Objectives