II. Pharmacology

  1. Synthetic Cannabinoids
    1. Originally produced as research chemicals to study receptor binding in the 1980s
      1. Synthetic Cannabinoids have 5-10 fold higher bindings affinity at specific receptor sites
    2. Produced by spraying dried, shredded herbal plant leaves with cannabinoid receptor agonists
    3. Synthetic agonists are THC-like agents based on one of four synthetic parent agents
    4. Synthetic agonists are small, lipid soluble, non-polar molecules (22 to 26 carbons)
    5. Many current generation substances are indazoles (fused benzene and pyrene rings)
  2. Agents act at two cannabinoid receptors (with high affinity to CB1)
    1. CB1 (Central Cannabinoid)
      1. CNS receptors (decrease intracellular cAMP and increase MAP kinase)
      2. Elevates mood and increases feelings of well being
      3. Affects pain tolerance, time perception, memory
    2. CB2 (Peripheral Cannabinoid)
      1. T Cells, B Cells and Macrophages as well as peripheral nerves
  3. Most agents are pure agonists at cannabinoid CB1 cerebral receptor (contrast with THC as a partial agonist)
    1. Synthetics result in more intense, and unpredictable Intoxication than THC
    2. Synthetic THC lacks the Cannabidiol (Antipsychotic, anticonvulsant) effects of Cannabis sativa (Marijuana)
      1. Hence the unpredictable psychotic effects and Seizures with synthetic THC
      2. In addition, formulations frequently change to overcome detection
  4. Typically smoked in pipe or Cigarette paper
    1. Has also been vaporized and inhaled, as well as ingested

III. Preparations

  1. Sold in 1-3 gram foil pouches of dried Herbals
    1. Typically labeled as "not for human consumption" or marketed as incense or potpourri
    2. Often sold in gas stations and head shops
    3. More than 50 distinct products have been identified in the U.S.
    4. Various Herbals and crushed leaves are added for appearance only
      1. Synthetic Cannabinoids dissolved in acetone is dripped onto the leaves and allowed to dry
      2. Concentration and potency varies considerably even within the same package
    5. Inconsistent effects across products as well as within the same brand (unpredictable)
      1. Even different effects in the same package shared by different users
      2. May occur with concentrated portions within the package
  2. Street Names
    1. K2 (U.S.)
    2. Kronic
    3. Spice (Europe and UK)
    4. JWH (John W. Huffman)
    5. Legal Marijuana
    6. Fake Weed
    7. Black Mamba
    8. Mojo
    9. Scooby Snax
    10. Death Ride
    11. Intensely aromatic incense
    12. Cloud-9 (AB-PINACA)
      1. Liquid form vaporized and resulted in multiple hospitalizations in 2014

IV. Symptoms: Intoxication

  1. Marijuana-like Intoxication (sought effects)
    1. Euphoria, elevated mood or intense "high"
    2. Uncontrolled laughter
    3. Disinhibition
  2. Other effects often with severe mood changes
    1. Hyperadrenergic effects
    2. Agitated Delirium (with possible Seizures)
    3. Altered Mental Status with sedation
    4. Anxiety
    5. Psychosis

V. Signs: Intoxication

  1. Diaphoresis
  2. Hyperreflexia
  3. Nystagmus
  4. Conjunctival injection

VI. Symptoms: Withdrawal

  1. Headache
  2. Anxiety
  3. Depressed Mood
  4. Irritability

VII. Adverse Effects

  1. Effects vary due to the ever changing formulations and compositions of Synthetic Cannabinoids and contaminants
    1. Small modifications in cannabinoid chemical structures may have drastically different physiologic effects
    2. Even the same formulation, may have widely different potency due to manufacturing practices
  2. Life threatening bleeding (2018)
    1. Related to Anticoagulant-laced Synthetic Cannabinoids in 2018
    2. Cannabinoids were laced with Brodifacoum (rat poison) with effects that last for months
    3. May require high dose Vitamin K (50 mg PO three times daily) for months (at up to $45,000 per month)
    4. (2018) Presc Lett 25(6):35 [PubMed]
  3. Neuropsychiatric effects (central Serotonin and Dopamine receptor binding)
    1. Confusion
    2. Agitation, irritation or Violent Behavior
    3. Severe anxiety
    4. Memory loss
    5. Loss of consciousness and other central depressant effects (esp. fourth generation agents)
    6. Generalized Seizures (4% of cases)
    7. "Zombie Intoxication" (fourth generation agents)
      1. Blank stare, groaning and purposeless movements
  4. Acute Psychosis ("Spiceophrenia")
    1. Severe paranoia and Hallucinations (auditory and visual)
    2. May persist for days to months
    3. May occur after a single dose
  5. Gastrointestinal effects
    1. Nausea or Vomiting
    2. Diarrhea
  6. Cardiovascular effects (cardiac Potassium channel binding)
    1. Chest Pain (including due to cardiac ischemia)
    2. Palpitations
    3. Cardiac Arrhythmia (including Ventricular Tachycardia and Ventricular Fibrillation)
    4. Heart Rate changes (Tachycardia or Bradycardia)
    5. Blood Pressure changes (Hypertension or Hypotension)
  7. Endocrine and renal effects
    1. Hypokalemia
    2. Metabolic Acidosis
    3. Hyperglycemia
    4. Acute Kidney Injury
    5. Rhabdomyolysis
  8. Withdrawal symptoms with regular use
    1. Anxiety, irritability, Insomnia
    2. Chills
    3. Profuse diaphoresis
    4. Tremors
    5. Myalgias
    6. Headaches
    7. Anorexia, Nausea, Vomiting

VIII. Labs

  1. Serum Creatinine
  2. Serum Glucose
  3. Creatine Kinase (CK)
  4. Serum Lactic Acid
  5. Serum Troponin
  6. Coagulation studies (INR, PTT)
  7. Urine Drug Screening
    1. Does not typically detect Synthetic Cannabinoids (producers frequently modify formulations)

IX. Diagnostics

X. Differential Diagnosis

XI. Management: Acute

  1. See Unknown Ingestion
  2. See Agitated Delirium
  3. Precautions
    1. Consult with poison control
    2. Some Synthetic Cannabinoid forms have had paradoxical Anticholinergic Reactions and Agitation to Naloxone
  4. Aggressive supportive care management
    1. No specific antidotes
    2. Avoid unnecessary intubation
    3. Protect patients and staff
      1. See Agitated Delirium
      2. Sedation allows for IV Access, patient exposure, labs and diagnostics
  5. IV crystalloid fluid Resuscitation
    1. Indicated for dehydration
  6. Benzodiazepines
    1. First-line agent
    2. Indicated for Agitation and Seizures
  7. Diphenhydramine
    1. Indicated for Dystonia
  8. Evaporative Cooling
    1. Indicated for hyperthermia
    2. Antipyretics are typically ineffective (fever is unrelated to hypothalamic set point)
  9. Antipsychotics (e.g. Zyprexa, Haloperidol)
    1. Indicated for acute Psychosis, esp. refractory to Benzodiazepines
    2. Avoid prophylactically due to theoretical risk of Seizure
  10. Rhabdomyolysis
    1. Aggressive intravenous hydration
  11. Seizures
    1. First-line: Benzodiazepines
    2. Second-line: Phenobarbital
    3. Avoid Sodium channel blocking agents (e.g. Phenytoin)

XII. Management: Chemical Dependency

  1. Cognitive Behavioral Therapy
  2. Motivational Enhancement Therapy with abstinence-based incentives
  3. No medication is supported with sufficient evidence

XIII. Management: Disposition

  1. Acute Intoxication typically resolves within 6 hours of ingestion
  2. May discharge home when Clinical Sobriety and no serious complications identified
    1. Complex presentations may require hospital observation or admission

XIV. Precautions

  1. Agents are unregulated and unpredictable with variable components, potency and toxicity
  2. Acute Psychosis lasting months may occur after only a single dose
  3. Intentionally adulterated products with life threatening effects have been reported
    1. Life threatening bleeding due to Anticoagulant-laced Synthetic Cannabinoids in 2018
      1. See Adverse Effects as above
    2. Associated with 24 deaths in Mississippi in 2015

XVI. References

  1. Tomaszewski (2016) Drugs of Abuse, ACEP PEM Conference, Orlando, attended 3/8/2016
  2. Fattore (2011) Front Behav Neurosci 5: 60
    1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187647/
  3. Haynes, Meadors and Yuan (2016) Crit Dec Emerg Med 30(2): 3-9
  4. Rosenbaum (2012) J Med Toxicol 8(1): 15–32
    1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550220/
  5. Swaminathan and LaPoint in Herbert (2019) EM:Rap 19(5): 6-7
  6. Trautmann (2021) Crit Dec Emerg Med 35(3): 15-20
  7. Kemp (2016) Am J Med 129(3):240 [PubMed]
  8. Khullar (2014) J Gen Intern Med 29(8):1200-4 +PMID:24553958 [PubMed]
  9. Klega (2018) Am Fam Physician 98(2): 85-92 [PubMed]

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Ontology: Cannabinoids.synthetic (C3260252)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
LNC LP130276-1, MTHU041061
English Cannabinoids.synthetic