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Expecting the Unexpected: Clinical Effects of Synthetic

Mark Su, MD, MPH Clinical Associate Professor The Ronald O. Perelman Department of Emergency New York University School of Medicine Director, New York City Poison Control Center

1 Objective

• To describe the clinical of the synthetic (SCRAs)

2 American Association of Poison Control Centers

3 New York City Poison Control Center

4 Where can we find cannabinoids?

5 Endogenous Cannabinoids

6 Phytocannabinioids - ( Sativa) • First record of use 2727 BC by Chinese Emperor Shen Nung • More than 480 natural components • 66 classified as cannabinoids

7 Medicinal Cannabinoids

8 SCRAs ()

9 Cannabinoids

Synthetic Cannabinoids ≠ Marijuana

10 Acute Marijuana Toxicity

• Severe toxicity uncommon • Adverse reactions: distrust, dysphoria, fear or panic reactions • Case reports of significant toxicity – Pancreatitis – Ventricular – Atrial fibrillation –

11 NO CONFIRMATION OF SCRA!

EAPCCT 2015 12 ALL CONFIRMED SCRA

N Engl J Med 2015; 373:103-7

13 Synthetic Toxicity

• Central Nervous • Gastrointestinal System • Pulmonary – • Miscellaneous – CVA – Metabolic • Psychiatric – Muscular • Cardiovascular – Cutaneous • Renal

14 Neurologic Toxicity - Seizures

Reference Synthetic Cannabinoid(s) Notes (biological specimens)

Gunderson EW, et. al: JWH-018 3 patients Am J Addict 2012;21:320-6

McQuade D, et al: Eur J Clin AM-2201 Single case Pharmacol 2013;69:373-6 Lapoint J, et al: Clin Toxicol JWH-018 Single case;ETOH; SVT 2011;49:760-4 Hermanns-Clausen M, et al: Test JWH-018, JWH-122, JWH-210 4 patients; coma, apnea Anal 2013;5:790-4 Drenzek C, et al: Morbidity and ADP-PINACA 3/22 patients Mortality Weekly Reports (Nov 22, 2013) Simmons J, et al: Clin Toxicol JWH-018, JWH-073 3 patients 2011;49:431-33 Schneir A, Baumbacher T: J Med JWH-018, JWH-081, JWH-250, AM- Single patient; no biological Toxicol 2012;8:62-64 2201 confirmation

15 Neurologic Toxicity - Seizures

Reduced severity and mortality

Jones NA, et al. J Pharmacol Exp Ther 2010;332:569-577

16 Neurologic Toxicity - Seizures

• Mechanism unknown • Absence of in synthetic cannabinoid products may result in increased risk of seizures

Schneir A, Baumbacher T: J Med Toxicol 2012;8:62-64

17 Neurologic Toxicity - CVA

XLR-11 Takematsu M, et al: Clin Toxicol 2014;52:973-975 18 Neuropsychiatric Effects

19 Neuropsychiatric Effects

• SCRAs associated with: – Confusion – – Agitation – Loss of or memory – Seizures

20 Neuropsychiatric Effects

• 22 patients aged 16 – 57 • Toxicologic testing: years ADB-PINACA – Confusion/disorientation (32%) – Somnolence/unresponsiveness (32%) – Aggression (32%)

MMWR Morb Mortal Wkly Rep 2013;62:939

21 Cannabis

• “ and Mental Illness” (1845) – Cannabis could precipitate “acute psychotic reactions, generally lasting but a few hours, but occasionally as long as a week; the reaction seemed dose-related” Jacques-Joseph Moreau (de Tours) 1804 - 1884

22 “Hashish and Mental Illness” (1845) • Main features – Paranoid ideation – “Delirium” – “Disorientation” – Delusions “Marked clouding of consciousness” – – Confusion – Restlessness – Excitement

23 Cannabis-induced Psychosis

Early Developmental Stages of Psychopathology Study Baseline Assessment:1995; Follow-up: 1999 n = 2437

Cecile H, et al: BMJ 2005; 330(7481):11 Epub 2004 Dec 1 24 Cannabis-induced Psychosis Early Developmental Stages of Psychopathology Study Baseline Assessment:1995; Follow-up: 1999 n = 2437

Cecile H, et al: BMJ 2005; 330(7481):11 Epub 2004 Dec 1 25 Cannabis-Induced Pyschosis

• Mechanism – Not clearly elucidated – hypothesis of : increase in DP into limbic system and neocortex – Stimulation of CB receptors by THC alters release of dopamine – May occur more frequently in patients with previous psychosis

Fergusson DM, et al. BMJ 2006;332:172-6 26 Neuropsychiatric Effects from SCRAs

• Case series of 8 patients – – Delirium – Psychosis – Aggressive behavior • Confirmed ADB- PINACA

Schwartz MD, et al. J Emerg Med;2015;48:573-580

27 Neuropsychiatric Effects of SCRAs

Paranoia

Anxiety

Hallucinations

Disorientation

Altered Mood/ Perception

Gunderson ED, et al. Am J Addict 2012;21:320-6 28 Cardiovascular Toxicity

Hermanns-Clausen M, et al: 2013;108:534-44 29 Cardiovascular Toxicity

JWH-018, JWH-081, JWH-122, JWH-210, JWH-250, AM-2201

Yeakel JK, Logan BK: J Anal Toxicol 2013;37:547-551 30 Cardiovascular Toxicity

• 22 patients aged 16 – • Toxicologic testing of 57 years 5/7 patients tested: • 13 (59%) had • ADB-PINACA tachycardia • 1 had Myocardial infarction

MMWR Morb Mortal Wkly Rep 2013;62:939

31 Renal Toxicity

AKI in Multiple States 2012

32 Renal Toxicity

33 Renal Toxicity

• Renal biopsy – 6 out of 8 patients had acute tubular necrosis (ATN) – 3 out of 8 patients had acute interstitial nephritis • Kidney function – Returned in 3 days in most patients – 5 out of 16 patients required HD • Other causes AKI not found – Infectious, Autoimmune, Pharmacologic

34 Gastrointestinal Effects

• Cannabinoid hyperemesis syndrome (CHS) – Recurrent bouts of abdominal pain – Nausea/vomiting – Relieved by frequent hot baths – Resolve when cannabis use is discontinued

35 Gastrointestinal Effects

• 30-year-old man previous marijuana user • Frequent visits to ED • Abdominal pain, nausea, vomiting • CT Scan, US, endoscopy, barium swallow… • Urine (LC/MS): JWH-018, JWH-073, AM-2201; negative THC • Symptoms resolved after two weeks

Hopkins CY, Gilchrist BL: J Emerg Med 2013;45:544-6 36 Pulmonary Toxicity (Marijuana)

MTS = marijuana + smokers MS = marijuana smokers TS = tobacco smokers NS = non-smokers

Tashkin D, et al: Am Rev Respir Dis 1987;135:209-216 37 Pulmonary Toxicity

• 21-year-old male involved in MVC • Smoked synthetic cannabinoids for 4 months prior to presentation

Alhadi S, et al: J Med Toxicol 2013;9:199-206

38 Pulmonary Toxicity

Blood, Saliva, Urine Testing

Alhadi S, et al: J Med Toxicol 2013;9:199-206

39 Miscellaneous Toxicity

• Metabolic • Cutaneous – Hyperglycemia – – Hypokalemia – Diaphoresis – Hyperthermia – Photosensitivity • Muscular – Myalgias – CK elevation (rhabdo)

Müller H, Kornhuber J, Sperling W Brain Res Bull 2015;pii:S0361- 9230(15)30052-6 40 Summary of Clinical Side Effects

Müller H, Kornhuber J, Sperling W Brain Res Bull 2015;pii:S0361- 9230(15)30052-6 41 Withdrawal Syndrome

• Δ9-THC Syndrome – Anxiety – Myalgias – Chills –

J Addict Med 2013; 7: 296-298

42 Why are the clinical effects of SCRAs different from cannabis? • Multiple factors – Dosing – Contents variable – Potential contaminants – Metabolic differences – Pharmacology

43 Dosing of Marijuana

44 Dosing of SCRAs (“Spice” or “K2”)

3g 4g 5g 45 Spice/K2 Contents

• One gram of spice can contain up to 202 mg of SCRA • High variability in content of individual packets • Potential contaminants

– β2 agonists (e.g., clenbuterol)

46 Sample of K2 Packets NYC (July 2015)

NYS Wadsworth Laboratory 47 Human Metabolism of Cannabinoids

JWH-018

Δ9-THC

Su MK, et al: Clin Pharmacol Ther 2015;97:562-4

48 Cytochrome p450 System

• involved in the metabolism of SCRAs have genetic polymorphisms – CYP 3A4 • Involved in metabolism of most – CYP 1A2 • Wide range of expression and activity • Racial differences among gene expression • Affected by – CYP 2C9 • More than 35 allelic variants

49 Binding Affinities of Synthetic Cannabinoids

Forensic Sci Rev 2014;26:53-78 50 QUESTIONS?

51