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Expecting the Unexpected: Clinical Effects of Synthetic Cannabinoids

Mark Su, MD, MPHClinical Associate ProfessorThe Ronald O. Perelman Department of Emergency MedicineNew York University School of MedicineDirector, New York City Poison Control Center

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Objective

• To describe the clinical toxicity of the synthetic cannabinoid receptor agonists (SCRAs)

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American Association of Poison Control Centers

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New York City Poison Control Center

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Where can we find cannabinoids?

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Endogenous Cannabinoids

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Phytocannabinioids -Marijuana (Cannabis Sativa)

• First record of use 2727 BC by Chinese Emperor Shen Nung

• More than 480 natural components

• 66 classified as cannabinoids

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Medicinal Cannabinoids

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SCRAs (Synthetic Cannabinoids)

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Cannabinoids

Synthetic Cannabinoids ≠ Marijuana

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Acute Marijuana Toxicity

• Severe toxicity uncommon• Adverse reactions: distrust, dysphoria, fear or

panic reactions• Case reports of significant toxicity

– Pancreatitis– Ventricular tachycardia– Atrial fibrillation– Myocardial infarction

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EAPCCT 2015

NO CONFIRMATION OF SCRA!

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N Engl J Med 2015;373:103-7

ALL CONFIRMED SCRA

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Synthetic Cannabinoid Receptor Agonist Toxicity

• Central Nervous System– Seizures– CVA

• Psychiatric• Cardiovascular• Renal

• Gastrointestinal• Pulmonary• Miscellaneous

– Metabolic– Muscular– Cutaneous

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Neurologic Toxicity - SeizuresReference Synthetic Cannabinoid(s)

(biological specimens)Notes

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

JWH-018 3 patients

McQuade D, et al: Eur J ClinPharmacol 2013;69:373-6

AM-2201 Single case

Lapoint J, et al: Clin Toxicol2011;49:760-4

JWH-018 Single case;ETOH; SVT

Hermanns-Clausen M, et al: Drug Test Anal 2013;5:790-4

JWH-018, JWH-122, JWH-210 4 patients; coma, apnea

Drenzek C, et al: Morbidity and Mortality Weekly Reports (Nov 22, 2013)

ADP-PINACA 3/22 patients

Simmons J, et al: Clin Toxicol2011;49:431-33

JWH-018, JWH-073 3 patients

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

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

Single patient; no biological confirmation

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Neurologic Toxicity - Seizures

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

Reduced seizure severity and mortality

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Neurologic Toxicity - Seizures• Mechanism unknown• Absence of cannabidiol in synthetic

cannabinoid products may result in increased risk of seizures

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

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Neurologic Toxicity - CVA

XLR-11Takematsu M, et al: Clin Toxicol2014;52:973-975

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Neuropsychiatric Effects

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Neuropsychiatric Effects

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

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Neuropsychiatric Effects

• 22 patients aged 16 – 57 years– Confusion/disorientation (32%)– Somnolence/unresponsiveness

(32%)– Aggression (32%)

• Toxicologic testing: ADB-PINACA

MMWR Morb Mortal Wkly Rep2013;62:939

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Cannabis

• “Hashish and Mental Illness” (1845)– Cannabis resin 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

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“Hashish and Mental Illness”(1845)

• Main features– Paranoid ideation– Illusions– Hallucinations– Delusions– Depersonalization– Confusion– Restlessness– Excitement

“Delirium”“Disorientation”

“Marked clouding of consciousness”

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Cannabis-induced Psychosis

Early Developmental Stages of Psychopathology StudyBaseline Assessment:1995; Follow-up: 1999

n = 2437

Cecile H, et al: BMJ 2005;330(7481):11 Epub 2004 Dec 1

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Cannabis-induced PsychosisEarly Developmental Stages of Psychopathology Study

Baseline Assessment:1995; Follow-up: 1999n = 2437

Cecile H, et al: BMJ 2005;330(7481):11 Epub 2004 Dec 1

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Cannabis-Induced Pyschosis

• Mechanism– Not clearly elucidated– Dopamine hypothesis of schizophrenia: 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

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Neuropsychiatric Effects from SCRAs

• Case series of 8 patients– Anxiety– Delirium – Psychosis– Aggressive behavior

• Confirmed ADB-PINACA

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

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Neuropsychiatric Effects of SCRAs

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

Hallucinations

Anxiety

Paranoia

Disorientation

Altered Mood/Perception

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Cardiovascular Toxicity

Hermanns-Clausen M, et al: Addiction 2013;108:534-44

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Cardiovascular Toxicity

Yeakel JK, Logan BK: J AnalToxicol 2013;37:547-551

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

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Cardiovascular Toxicity

• 22 patients aged 16 –57 years

• 13 (59%) had tachycardia

• 1 had Myocardial infarction

• Toxicologic testing of 5/7 patients tested:

• ADB-PINACA

MMWR Morb Mortal Wkly Rep2013;62:939

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Renal Toxicity

AKI in Multiple States2012

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Renal Toxicity

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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

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Gastrointestinal Effects

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

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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

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Pulmonary Toxicity (Marijuana)

Tashkin D, et al: Am Rev Respir Dis1987;135:209-216

MTS = marijuana + tobacco smokersMS = marijuana smokersTS = tobacco smokers

NS = non-smokers

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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

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Pulmonary Toxicity

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

Blood, Saliva, Urine Testing

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Miscellaneous Toxicity

• Metabolic– Hyperglycemia– Hypokalemia– Hyperthermia

• Muscular– Myalgias– CK elevation (rhabdo)

• Cutaneous– Xerostomia– Diaphoresis– Photosensitivity

Müller H, Kornhuber J, Sperling WBrain Res Bull 2015;pii:S0361-9230(15)30052-6

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Summary of Clinical Side Effects

Müller H, Kornhuber J, Sperling WBrain Res Bull 2015;pii:S0361-9230(15)30052-6

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Withdrawal Syndrome

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

J Addict Med 2013;7: 296-298

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Why are the clinical effects of SCRAs different from cannabis?

• Multiple factors– Dosing– Contents variable– Potential contaminants– Metabolic differences– Pharmacology

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Dosing of Marijuana

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Dosing of SCRAs (“Spice” or “K2”)

3g 4g 5g

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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)

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Sample of K2 Packets NYC (July 2015)

NYS Wadsworth Laboratory

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Human Metabolism of Cannabinoids

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

JWH-018

Δ9-THC

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Cytochrome p450 Enzyme System

• Enzymes involved in the metabolism of SCRAs have genetic polymorphisms– CYP 3A4

• Involved in metabolism of most drugs– CYP 1A2

• Wide range of expression and activity• Racial differences among gene expression• Affected by cigarette smoking

– CYP 2C9• More than 35 allelic variants

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Forensic Sci Rev2014;26:53-78

Binding Affinities of Synthetic Cannabinoids

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QUESTIONS?