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8/29/2017
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Update for Healthcare ProfessionalsDayne Laskey, PharmD, DABAT
Synthetic Cannabinoids
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
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 15‐4927, NSDUH Series H‐50).
2. Swift, A. In US, 45% Say They Have Tried Marijuana. Gallup. July 19, 2017. Available at: http://www.gallup.com/poll/214250/say‐tried‐marijuana.aspx
“Classic” Recreational Drugs
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Synthetics: Alexander Shulgin
• 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
Phenethylamines
Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila). 2011;49(8):705‐19.
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.
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II. PHARMACOLOGY AND EFFECTS
Δ9‐Tetrahydrocannabinol
Marijuana
• 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
Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades (1995‐2014): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7):613‐9.
Marijuana ‐ Potency
Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades (1995‐2014): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7):613‐9.
Unintentional Pediatric Exposures
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):684‐9.
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/vomitingWang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167(7):630‐3.
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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):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). 2017;55(8):908‐913.
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
• 2004 – Internet, head shop sales begin in Europe• 2008 – First law enforcement seizure in US • 2011 – 15 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
Sources
Synthetic Cannabinoids Synthetic Cannabinoids – Clinical Effects
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):146‐152.
2. Image: https://www.washingtonpost.com/local/dc‐politics/why‐synthetic‐drugs‐could‐become‐washingtons‐next‐drug‐horror/2015/07/18/32530cfc‐2bc8‐11e5‐a250‐42bd812efc09_story.html?utm_term=.f8c2affde36e
• Excited delirium• Acute kidney injury• Seizures• Psychosis• Hallucinations• Cardiotoxic effects• Respiratory depression• Coma• Death
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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):377‐84.2. 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;143:268‐71.
III. SYNTHETIC CANNABINOID TRENDSRiederer AM, Campleman SL, Carlson RG, et al. Acute Poisonings from Synthetic Cannabinoids — 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:692–695.
A Growing Public Health Threat
• 644 NPS identified by UN Office of Drugs and Crime 2008‐2015
– 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):328‐39.
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Laboratory Trends
NMS Labs, 2017
Timeline
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 EnglJ Med. 2017;376(3):235‐242.
Laboratory Trends
NMS Labs, 2017
Poison Center Trends
American Association of Poison Control Centers (AAPCC) Press Release: Synthetic Cannabinoids. July 31, 2017.http://www.aapcc.org/alerts/synthetic‐cannabinoids/
Outbreaks occur in clusters
Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid‐Related Illnesses and Deaths. N Engl J Med. 2015;373(2):103‐7.
IV. OUR ROLE Created by Photoroyalty ‐ Freepik.com
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• No clear toxidrome
• No readily available diagnostic tools
• No antidote
• No pharmacologic/pharmacokinetic data
• Unpredictable and severe effects
• Unknown long‐term effects
Clinical Challenges
• Difficult for law enforcement to track
• Cases are often underreported
• Baseline use patterns are difficult to track
Other Challenges
• Takes weeks‐months to complete• Requires collaboration between healthcare providers, law
enforcement, clinical laboratories, organic chemists,
Challenges in the Laboratory
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
Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid‐Related Illnesses and Deaths. N Engl J Med. 2015;373(2):103‐7.
• National Poison Data System
• >62 million exposures dating back to 1983
• The only real‐time public health surveillance tool in the US
NPDS
What is the role of the pharmacist?
• Prevention
• Education
• AssistanceASHP Statement on the Pharmacist's Role in Substance Abuse Prevention, Education, and Assistance. Am J Health Syst Pharm. 2016;73(9):e267‐70.
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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):235‐242.• ASHP Statement on the Pharmacist's Role in Substance Abuse Prevention, Education, and Assistance. Am J Health
Syst Pharm. 2016;73(9):e267‐70.• 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;143:268‐71.• 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; 2015. HHS Publication No. SMA 15‐4927, 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):908‐913.
• Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades (1995‐2014): Analysis of Current Data in the United States. Biol Psychiatry. 2016;79(7):613‐9.
• 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):705‐19.
References• Lauritsen KJ, Rosenberg H. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana. Am J Drug Alcohol Abuse.
2016;42(4):377‐84.• 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):146‐152.• 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):586‐90.• Riederer AM, Campleman SL, Carlson RG, et al. Acute Poisonings from Synthetic Cannabinoids —50 U.S. Toxicology Investigators Consortium Registry
Sites, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:692–695.• 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):71‐87.• Swift, A. In US, 45% Say They Have Tried Marijuana. Gallup. July 19, 2017. Available at: http://www.gallup.com/poll/214250/say‐tried‐
marijuana.aspx• Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid‐Related Illnesses and Deaths. N Engl J Med. 2015;373(2):103‐7.• 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):15‐
45.• Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167(7):630‐3.• 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):684‐9.• 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):328‐39.