I Smell A RatCannabinoids and Contaminants Kirk Moberg

I Smell A Rat—Cannabinoids and Contaminants Kirk Moberg, MD, Ph. D, FACP, FASAM Executive Medical Director, Unity. Point Health Illinois Institute for Addiction Recovery Clinical Professor of Internal Medicine and Psychiatry University of Illinois College of Medicine Annual Conference of the Illinois Chapter of the American College of Physicians East Peoria, IL November 9, 2018

Disclosures • Dr. Moberg has no conflicts of interest to disclose.

Objectives • The participant will compare and contrast synthetic cannabinoids and phytocannabinoids. • The participant will list several substances that contaminate the “street drug” supply. • The participant will discuss the recent epidemic of brodifacoum induced coagulopathy.

Agenda • Cannabis • Synthetic Cannabinoids • Trends in additives

Agenda • Cannabis • Synthetic Cannabinoids • Trends in additives

Anandamide (AEA) 2 -arachidonoyl glycerol (2 -AG)

Cannabinoid Receptors CB 1 AEA—partial agonist 2 -AG—full agonist CB 2 AEA—minimal activity 2 -AG—full agonist Zou & Kumar. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018; 19: 833.

CB 1 Zou & Kumar. 2018.

CB 2 Receptors Zou & Kumar. 2018.

Cannabinoid Receptors Zou & Kumar. 2018.

Capsaicin Receptor Palazzo et al. Role of TRPV 1 Receptors in the Descending Modulation of Pain. Mol Cell Endo. 2008; 286 Suppl 1: S 79 -S 83.

p-AP = p-aminophenol AA = arachidonic acid FAAH = fatty acid amide hydrolase Mallet et al. TRPV 1 in Brain is Involved in Acetaminophen-Induced Antinociception. PLOSOne. 2010; 5(9): e 12748.

Dronabinol and Nabilone Schedule III AIDS associated anorexia/weight loss Schedule II Chemotherapy associated nausea and vomiting

Cannabidiol Oral Solution Lennox-Gastaut syndrome Dravet syndrome Schedule V fda. gov; 6/25/2018 Hudak. The FDA Just Opened the Door to Transforming Marijuana Policy. Washington Post, 6/27/2018.

Nabiximols THC/CBD 1: 1

Increases over Time in the Potency of Tetrahydrocannabinol (THC) in Marijuana and the Number of Emergency Department Visits Involving Marijuana, Cocaine, or Heroin. Volkow et al. 2014.

Edibles

There’s a reason there’s an entire public education campaign around starting with an edible that equals just 5 milligrams of THC. Warner. 8 Things You Need to Know About Eating Marijuana Edibles. Fresh Toast, 10/31/2017.

There’s a reason there’s an entire public education campaign around starting with an edible that equals just 5 milligrams of THC. Warner. 8 Things You Need to Know About Eating Marijuana Edibles. Fresh Toast, 10/31/2017. Marijuana Edibles: Yi. Lo Gummy Bears, 10/22/2013.

2005 -2011 0/790 14/588 unintentional ingestions Tanner. Edible Medical Pot Sickens Kids. Peoria Journal Star, 5/28/2013. Wang et al. Pediatric Marijuana Exposures in a Medical Marijuana State. JAMA Pediatrics. 2013; 167(7): 630 -633.

Concentrates

Hash oil derivatives can be 80% THC

Agenda • Cannabis • Synthetic Cannabinoids • Trends in additives

John W. Huffman— 1984 Professor Emeritus, Organic Chemistry Clemson University Mc. Coy. How This Chemist Unwittingly Help Spawn the Synthetic Drug Industry. Washington Post, 8/9/2015. Seely et al. Spice Drugs are more than Harmless Herbal Blends: A Review of the Pharmacology and Toxicology of Synthetic Cannabinoids. Prog Neuro-Psychopharm Biol Chem. 2012; 39: 234 -243.

JWH-018

HU-210

XLR-11

Damiana Leaf Ciolino. Quantitation of Synthetic Cannabinoids in Plant Materials Using High Performance Liquid Chromatography with UV Detection (Validated Method). J For Sci. 2015; 60(5): 1171 -1181.

Adverse Clinical Effects Seizures Agitation Tachycardia Cardiovascular Hypertension Central Irritation Chest pain Nervous Loss of consciousness Cardiac Ischemia System Anxiety Confusion Gastrointestinal Nausea Paranoia Metabolic Hypokalemia Vomiting Autonomic Hyperglycemia Fever Mydriasis Other Conjunctivitis Seely et al. Marijuana-based Drugs: Innovative Therapeutics or Designer Drugs of Abuse? Mol Interv. 2011; 11(1): 36 -51.

New Haven Green Fentanyl Neuman. Dozens Overdose in Connecticut Park on Tainted Synthetic Marijuana. npr. org. 8/16/2018. Investigation Into K 2 Overdoses in New Haven Reveals Drug Contaminated With Fubinaca. nbc. com. 8/17/2018.

Adams et al. “Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. NEJM. 2017; 376: 235 -242.

Drug Testing

Agenda • Cannabis • Synthetic Cannabinoids • Trends in additives

Definitions Adulterant Cole et al. Adulterants in Illicit Drugs: A Review of Empirical Evidence. Drug Testing and Analysis. 2011; 3: 89 -96

Definitions Adulterant Contaminant Cole et al. Adulterants in Illicit Drugs: A Review of Empirical Evidence. Drug Testing and Analysis. 2011; 3: 89 -96

Definitions Adulterant Contaminant Diluent Cole et al. Adulterants in Illicit Drugs: A Review of Empirical Evidence. Drug Testing and Analysis. 2011; 3: 89 -96

Additives Drug Adulterant • Illicit Drugs • • • Cole et al. 2011. Sugars Lead Caffeine Procaine Acetaminophen Strychnine

Additives Drug Adulterant • Heroin • • • Cocaine Cole et al. 2011. Phenobarbital Quinine Clenbuterol Scopolamine • Lidocaine • Phenacetin • Levamisole

Additives Drug Adulterant • Methamphetamine • Methylsulfonylmethane • MDMA • Amphetamine • Methamphetamine Cole et al. 2011.

Opioids

Fentanyl combinations 7 patients Vo et al. Counterfeit Norco Poisoning Outbreak—San Francisco Bay Area, California, March 25 April 5, 2016. MMWR. 2016; 65(16): 420 -423.

Fentanyl DRUG OVERDOSE HEALTH ALERT: Fentanyl-Contaminated Street Norco March 25, 2016 Deadly fentanyl-laced pills emerge in Central Florida, agents say May 7, 2016 The Sacramento County Division of Public Health has received reports from local hospital emergency departments of at least 12 poisoning overdoses within the past 48 hours associated with ingestion of street Norco tablets that may be contaminated with fentanyl. Vo et al. MMWR, 4/26/2016. Oxycodone/acetaminophen Alprazolam LA oxycodone Will County, Illinois April 14, 2016 Heroin plus fentanyl 53 overdoses, 18 deaths Fentanyl disguised as oxycodone WSJ, 9/3/2016.

Pill Synthesis 2018 National Drug Threat Assessment. US Department of Justice Drug Enforcement Administration. October 2018.

Pill Press Equipment Seized in Richmond, Texas 2018 National Drug Threat Assessment Fraudulent Oxycodone Tablets Containing Fentanyl Seized in Richmond, Texas

Levamisole 69 % of cocaine in 2008 -2009 78% in 2011 Centers for Disease Control and Prevention. Agranulocytosis Associated With Cocaine Use—Four States, March 2008 -November 2009. MMWR. 2009; 58: 1381 -5. Buchanan et al. Prevalence of Levamisole in Urine Toxicology Screens Positive for Cocaine in an Inner-City Hospital. JAMA. 2011; 305(16): 1657 -8. Muirhead & Eide. Toxic Effects of Levamisole in a Cocaine User. NEJM. 2011; 364: 424

Manifestations Leukocytoclastic Vasculitis Agranulocytosis Ching and Smith. Levamisole-Induced Necrosis of Skin, Soft Tissue and Bone: Case Report and Review of Literature. J Burn Care Res. 2012; 33(1): e 1 -5.

Ching and Smith. 2012.

Proposed explanations • Adds bulk and weight • Stimulant effect • Looks “pure” – White powder • Survives purification process – Other contaminants are removed in the free base process • Can pass street drug purity tests—bleach test – Lidocaine—yellow – Procaine—reddish-brown – Other contaminants precipitate Morris et al. Levamisole Adulterated Cocaine: A Case Series. J Am Board Fam Med. 2012; 25(4): 531 -5.

Serum levels (ng/m. L) Patient Fentanyl Cocaine BE Levamisole A - - B 0. 9 ND 1 1 C 0. 5 0 65 13 D 0. 6 0 1 1 E 11 ND ND - F 4. 6 2 15 2 G 2. 3 1 63 4 H 1. 9 26 144 5 I 13 79 680 - J 3 26 68 6 K 9. 5 3 172 2 L 3. 6 4 712 64 Tomassoni et al. Multiple Fentanyl Overdoses—New Haven, Connecticutt, June 23, 2016. MMWR. 2017; 66: 107 -11.

A better speedball? Kravetz. Fentanyl-laced Cocaine adds to Opioid Crisis in Peoria Journal Star, December 9, 2017. Loria. The Killer Drug at the Heart of the Opioid Crisis is being Cut into Cocaine and Killing Users. Business Insider. June 16, 2017.

Synthetic Cannabinoids

Clenbuterol

“Unintentional exposure to superwarfarins was also reported to occur…Fortunately, these incidents appear to be sparse. ” Feinstein et al. The Emerging Threat of Superwarfarins: History, Detection, Mechanisms, and Countermeasures. Ann N Y Acad Sci. 2016; 137(1): 111 -122.

Feinstein et al. 2016.

Vitamin K cycle 1) g-glutamyl carboxylase 2) Vitamin K epoxide reductase Shearer & Newman. Recent Trends in the Metabolism and Cell Biology of Vitamin K with Special Reference to Vitamin K Cycling and MK-4 Biosynthesis. J Lipid Res. 2014; 55: 345 -362.

Vitamin K 600 mg/day Months Feinstein. Brodifacoum Poisoning: A Clear and Present Danger to Public Health in the USA. Toxicol Letters. 2017; 268: 71 -72.

“This is very normal, synthetic weed contains rat poison very often. It's the way it is. ” Man Accused of Mixing Rat Poison into Synthetic Marijuana. Tuscaloosanews. com. 6/5/2014.

March 7, 2018 Illinois Department of Public Health. 5/31/2018.

Epidemiology County Chicago Cook County Du. Page County Fulton County Kane County Kankakee County Mc. Lean County Madison County Mason County Peoria County Stark County Stephenson County Tazewell County Winnebago County Woodford County Total Illinois Department of Public Health Number of Cases 40 10 2 2 1 1 2 35 1 1 49 1 9 7 164

Fourth Death Related to Synthetic Cannabinoids Illinois Department of Public Health. 4/24/2018.

Illinois Indiana Kentucky Maryland Missouri Pennsylvania Virginia Florida Wisconsin CDC: Rat Poison Found in Synthetic Marijuana in 8 States. Fox 13 News. May 2, 2018.

Outbreak of Life-threatening Coagulopathy Associated with Synthetic Cannabinoids Use Outbreak of Life-Threatening Coagulopathy Associated with Synthetic Cannabinoids Use. CDC Health Alert Network. May 25, 2018.

“At least seven people in Wisconsin have been hospitalized with severe bleeding in the last three months after using synthetic marijuana containing rat poison. ” Type of Cases Confirmed Probable Total cases reported to DPH Number of Cases 15 21 36 Wisconsin Case Counts: March 30 - June 27, 2018 Counties with confirmed cases: Dane, Milwaukee, Outagamie, and Rock. Mueller. 7 Wisconsin Residents Hospitalized after Using Synthetic Marijuana Containing Rat Poison. Appleton Post Crescent, 6/21/2018. Synthetic Cannabinoids. Wisconsin Department of Public Health. 6/28/2018. dhs. wisconsin. gov

“additional cases” More Synthetic Cannabinoids Cases. Illinois Department of Public Health. 6/25/2018.

Region Number of Cases Central Maryland 21 Western Maryland 9 Eastern Maryland 1 Southern Maryland 1 Maryland’s Synthetic Cannabinoids Statistics. Maryland Poison Center. 6/28/2018.

34 patients Kelkar et al. An Outbreak of Synthetic Cannabinoid-Associated Coagulopathy in Illinois. NEJM. 2018; 379: 1216 -1223.

1 5 15 Bromadiolone 2 Feinstein et al. 2016.

Eitenmiller. Police seize deadly fake pot, three arrested in Pekin man’s death. Tazewell Chronicle. 4/13/2013.

WHY?

PROLONG THE HIGH Powell. The Spice of Death: The Science Behind Tainted “Synthetic Marijuana. ” Scientific American. 4/17/2018.

La Rosa et al. Brodifacoum Intoxication With Marijuana Smoking. Arch Path Lab Med. 1997; 121: 67 -69. Waien et al. Severe Coagulopathy as a Consequence of Smoking Crack Cocaine Laced with Rodenticide. NEJM. 2001; 345(9): 700 -701. Feinstein. 2017.

Conclusions • The cannabinoid neurotransmitter system is one of most widespread in the CNS.

Conclusions • The cannabinoid neurotransmitter system is one of most widespread in the CNS. • Cannabis comes in a variety of formulations.

Conclusions • The cannabinoid neurotransmitter system is one of most widespread in the CNS. • Cannabis comes in a variety of formulations. • Synthetic cannabinoids are risky.

Conclusions • The cannabinoid neurotransmitter system is one of most widespread in the CNS. • Cannabis comes in a variety of formulations. • Synthetic cannabinoids are risky. • Additives in street drugs are common.