Marijuana

Aka: Marijuana, Hashish, Cannabis, THC, THC Wax, THC Honey Oil, Cannabis Use Disorders, Cannabis Abuse, Cannabis Dependence, Cannabinoid, Tetrahydrocannabinol, Cannabichromene, Cannabidivarin, Cannabigerol, Cannabinol, Hemp Oil, Cannabinoid Receptor, CB1 Receptor, CB2 Receptor

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II. Definitions

  1. Cannabinoids
    1. Group of >100 chemicals derived from Cannabis sativa plant
    2. Cannabis sativa has different strains that include Marijuana and hemp
    3. Cannabinoids include Tetrahydrocannabinol (THC) and Cannabidiol (CBD)

III. Epidemiology

  1. Prevalence (U.S.)
    1. Marijuana is the second most abused substance in U.S. after Alcohol
    2. Adults: 17% (in 2017)
    3. High School Seniors: 37% (in 2017)
    4. Prevalence doubled for adults aged 18 to 39 between 2002 and 2012
    5. Cannabis Use Disorder: 19.5% lifetime risk for Cannabis users
      1. More likely in teens within 2 years of starting use

IV. Class

  1. Relaxant, Euphoriant, and Hallucinogen (high doses)
  2. Federal Schedule I Agent
    1. Medical use is permitted in more than half U.S. States (and D.C.)
    2. Recreational use has been approved by Colorado and Washington legislatures

V. Mechanism: Endocannabinoid System

  1. Cannabinoid Receptors (G-Protein Receptors, CB1 and CB2)
    1. CB1 Receptors (Central Cannabinoid)
      1. Dense representation throughout the brain
        1. CB1 bInding decreases intracellular cAMP and increases MAP kinase
        2. Elevates mood, increases feelings of well being and increases pain tolerance
        3. Affects time Perception and memory, as well as learning and cognition
      2. Cannabinoids have high affinity at CB1
        1. Brainstem has few CB1 Receptors, and therefore coma and respiratory depression are uncommon
    2. CB2 Receptors (Peripheral Cannabinoid)
      1. Present on Peripheral Nerves
        1. Binding results in presynaptic cell hyperpolarization with decreased Neurotransmitter release
      2. Present on T Cells, B Cells and Macrophages
        1. Binding has antiinflammatory activity
  2. Endogenous Cannabinoids bind at CB1 and CB2 Receptors
    1. 2-arachidonoyl-Glycerol
    2. Anandamide
  3. Delta-9-Tetrahydrocannabinol (THC)
    1. Primary psychoactive agent in Cannabis
    2. Mimics endogenous Cannabinoids
    3. Stimulates Central Nervous System CB1 and CB2 Receptors
    4. Contrast with the synthetic Delta-8-THC
      1. Associated with life threatening toxicity (see preparations below)
      2. Less potent psychoactive agent than Delta-9
  4. Cannabidiol (CBD)
    1. Stimulates Serotonin5-HT-1A receptors
    2. Antagonist or Weak binding at CB1 and CB2 Receptors
    3. Results in anxiolysis, anticonvulsant and sedation (but unlike THC, not psychoactive)

VI. Preparations: Marijuana (THC)

  1. Formulations derived from dried flowers (buds) and leaves of the Cannabis sativa plant
  2. Street Names
    1. Pot, Grass, Tea
    2. Dagga, Kif
    3. Joint, Reefer
    4. Weed, Dope
  3. Modes of use
    1. Smoking (Marijuana bud or resin rolled, or in a pipe or bong)
    2. Vaping (bud, resin or liquid heated)
    3. Dabbing (high THC concentrate inhaled)
  4. Formulations
    1. Concentrate (high THC concentration, up to 90%)
      1. See Hemp Oil below
    2. Edibles (Gummies, teas or infused drinks, hash brownies, candies)
      1. Added to foods via oils used to extract THC
    3. Marijuana (bud or flower)
      1. Typically purchased as an eighth (3.5 g)
      2. Used via smoking or Vaping
      3. Typical joint contains 0.5 to 1 g or Marijuana
        1. THC concentration has increased from 1.5% in 1970s, 8.9% in 2008, to 21% in 2018
        2. Chandra (2019) Eur Arch Psychiatry Clin Neurosci 269(1): 5-15 [PubMed]
    4. Topical Oils (15 to 50% THC concentration)
      1. Extracted with various solvents that have resulted in significant lung injury when inhaled
    5. Resin (trichome flower protrusions, 2-8% THC)
      1. Smoked or vaped
    6. Tincture
      1. Contains Ethanol
      2. Taken by mouth or sublingual
    7. Vape Pen
      1. Vaping of THC concentrate
  5. Synthetic Delta-8 Tetrahydrocannabinol (Delta-8-THC)
    1. Synthetic THC associated with life threatening Intoxication complications (coma, Seizure, apnea)
      1. Parodoxical increased use as of 2022, despite its toxicity as well as growing Marijuana legalization
      2. Contrast with Delta-9-Tetrahydrocannabinol, which is natural form of THC extracted from Cannabis
        1. Delta-8-THC varies from Delta-9-THC, in only the location of a single double bond
        2. Small synthetic change, results in a dramatic increase in toxic effects including death
    2. Oil tinctures
      1. Typically contain 30 to 40 mg/ml (1 to 1.5 mg/gtt) of Delta-8-THC
    3. Gummies
      1. Typically contain 10 to 25 mg per gummy
    4. Vape liquid
    5. References
      1. Jackson and Fisher (2022) Crit Dec Emerg Med 36(4): 16-7
  6. Other Cannabinoid extracts (>100 different Cannabinoids in Marijuana)
    1. Cannabichromene (cbc)
    2. Cannabidivarin (CBDV)
    3. Cannabigerol (CBG)
    4. Cannabinol (CBN)

VII. Preparations: Hemp Oil

  1. Background
    1. Pulverized Marijuana placed for 8 minutes in PVC pipe filled with butane and capped at each end
    2. Results in 90% THC solution (honey oil) or wax (after exposure to Rubbing Alcohol)
    3. Production associated with explosions and fires (related to use of butane)
  2. Street Names
    1. Honey Oil
      1. Concentrated THC in Butane solvent
      2. Smoked (or placed on a Cigarette)
    2. Wax
      1. Solidified honey oil (after exposure to Rubbing Alcohol)
      2. Similar appearance to honeycomb or ear wax
      3. Smoked
  3. References
    1. Nordt and Swadron in Herbert (2014) EM: Rap 14(6):6

VIII. Preparations: Prescription Cannabinoid

  1. See Prescription Cannabinoid
  2. See Synthetic Cannabinoids
    1. Refer to illicit formulations (e.g. K2, spice) with serious adverse effects
  3. Dronabinol (Marinol)
    1. THC formulation Indicated for intractable Nausea, Vomiting (e.g. Chemotherapy, AIDS-related Anorexia)
    2. Dosed 2.5 mg orally twice daily (max: 20 mg/day)
    3. DEA Schedule 3
  4. Nabilone (Cesamet)
    1. THC analogue used to treat intractable Nausea, Vomiting (e.g. Chemotherapy)
    2. Dosed 1 mg orally twice daily (max: 6 mg/day in divided doses)
    3. DEA Schedule 2
  5. Cannabidiol (Epidiolex)
    1. CBD formulation used to treat rare forms of childhood Epilepsy
      1. Dravet Syndrome
      2. Lennox-Gastaut Syndrome
      3. Tuberous Sclerosis
    2. Dosed 2.5 mg/kg twice daily (max: 20 mg/kg/day)
    3. DEA Schedule 5
  6. Nabiximols (Sativex)
    1. Approved outside U.S. for neuropathic pain and spasticity (e.g. Multiple Sclerosis)
    2. Buccal Spray contains THC and CBD and used on average for 5 sprays daily (max: 14/day)

IX. Pathophysiology

  1. Similar to highly addictive "hard" drugs or Opioids
    1. Cannabinoid use results in Dopamine release and is blocked by Naloxone
    2. As with other substances of abuse, Cannabinoids are addictive
  2. Marijuana considered a gateway drug
    1. Use may lead to Opiate Abuse
  3. References
    1. Tanda (1997) Science 276:2048-50 [PubMed]

X. Pharmacokinetics

  1. Tetrahydrocannabinol (THC)
    1. Highly lipophilic
    2. Crosses blood brain barrier
    3. Duration: 5-20 mg of THC has a 2-4 hour duration
    4. Long half life
    5. Metabolized by Cytochrome P450 (CYP3A4, CYP2C9, CYP2C19)
    6. THC psychoactive doses
      1. Dose >25 mg in adults is enough to alter cognitive and psychomotor performance
      2. Dose >5 mg in children is enough to result in Intoxication
      3. Delta-9 THC concentrations have dramatically increased in Marijuana since 2000
        1. Freeman (2021) Addiction 116(5):1000-10 +PMID: 33160291 [PubMed]
  2. Smoking Marijuana
    1. Bioavailability: 20-50%
    2. Onset: Rapid (5-10 minutes)
    3. Duration: 2 to 4 hours
  3. Edible maijuana
    1. Bioavailability: 4-12%
    2. Onset: 1 to 3 hours
    3. Peaks: 2 to 6 hours
    4. Duration: 6 to 8 hours (up to 12 hours)
    5. Lower peak serum concentration than if smoked (give the same quantity of Marijuana)
    6. However edible products may be associated with greater toxicity for a longer duration
      1. Edible preparations are unregulated and often contain higher potency Marijuana
      2. Marijuana products may be adulterated or replaced completely with Synthetic Marijuana
      3. A single THC serving (e.g. 10 mg) may be contained in one gummy bear
        1. Patients may eat more than a serving as effects are delayed

XI. Indications: Medical Marijuana

  1. Precautions
    1. See Contraindications, Adverse Effects and Complications
    2. There are no FDA approved indications for inhaled Cannabis
  2. Anti-emetic (especially Chemotherapy related)
    1. Most established use
    2. Consider Dronabinol (Marinol) or Nabilone (Cesamet) instead
    3. However, Cannabinoid Hyperemesis Syndrome may result with increased, sustained use
  3. AIDS Anorexia
    1. Consider Nabilone (Cesamet) instead
  4. Neuropathic pain
    1. Modest reduction in pain (30%) compared with Placebo
      1. Stockings (2018) Pain 159(10): 1932-54 [PubMed]
    2. Cannabinoids do not appear to reduce Opioid use in Chronic Pain
      1. Nielsen (2017) Neuropsychopharmacology 42(9): 1752-65 [PubMed]
  5. Multiple Sclerosis related spasticity and pain
    1. Lim (2017) Clin Psychophamacol Neurosci 15(4): 301-12 [PubMed]
  6. Intractable Seizure Disorder
    1. Consider Cannabidiol (CBD) instead (see synthetics as above)
  7. References
    1. Allan (2018) Can Fam Physician 64(2): e78-94 [PubMed]

XII. Contraindications: Patients at High Risk for Adverse Events

  1. Age <21 years old (without medical indication)
    1. Risk of Cannabis use disorder
    2. Affects brain development (may adversely affect IQ, educational outcomes)
      1. Scott (2018) JAMA Psychiatry 75(6): 585-95 [PubMed]
    3. Risk of future Anxiety Disorder
      1. Degenhardt (2013) Addiction 108(1): 124-33 [PubMed]
    4. Increased risk of Suicidality and all-cause mortality
      1. Fontanella (2021) JAMA Pediatr 175(4): 377-84 [PubMed]
    5. Increased physical Violence
      1. Dellazizzo (2020) Am J Psychiatry 177(7): 619-26 [PubMed]
  2. Substance Use Disorder
    1. Risk of Cannabis use disorder
  3. Longterm Opioid or Benzodiazepine use
    1. Risk of Drug Interactions, sedation
  4. Age >65 years (and on 2 or more psychoactive drugs on Beer's Criteria)
    1. Risk of increased confusion, Memory Loss and falls
  5. Pregancy and Lactation
    1. Increased risk of preterm birth, low birth weight and future Psychopathology (insufficient data)
      1. Paul (2021) JAMA Psychiatry 78(1): 64-76 [PubMed]
    2. May impact neurologic development in Breast Feeding infants (insufficient data)
      1. THC is present in Breast Milk for up to 6 days after last use
  6. Psychosis history or Family History
    1. Increased risk of Psychosis episode or recurrence (4 to 5 fold increased risk)
      1. Di Forti (2014) Schizophr Bull 40(6): 1509-17 [PubMed]
      2. Schoeler (2016) Lancet Psychiatry 3(3): 215-25 [PubMed]
  7. Cardiopulmonary Disease (moderate to severe disease)
    1. Risk of exacerbation

XIII. History: Cannabis Use Disorder Screening

  1. See Cannabis Use Disorder Identification Test - Revised (CUDIT-R)
  2. Do you use Cannabis at times?
  3. How much do you use and how often?
  4. Is there polysubstance use or abuse?
  5. Are there psychiatric comorbidities?
  6. Is there a medical indication for the Cannabinoid use?
    1. Is it FDA-approved?
    2. Do benefits outweigh risks?
    3. Are there reasonable, effective alternatives to recommend?
  7. Are there contraindications for use (see above)?
  8. Are there findings of Cannabinoid use disorder (see diagnosis below)?

XIV. Symptoms

  1. Acute Effects
    1. Euphoria
    2. Relaxed inhibitions
    3. Increased appetite
    4. Decreased alertness
    5. Disoriented behavior
  2. Chronic Use: Amotivational syndrome
    1. Aimless
    2. Uncommunicative

XV. Signs: Adults

  1. Cardiopulmonary findings
    1. Tachycardia
    2. Hypertension
    3. Tachypnea
  2. Miscellaneous findings
    1. Conjunctival Injection
    2. Dry Mouth
    3. Decreased coordination

XVI. Signs: Children

  1. Exposures
    1. Severe toxicity (including cardiovascular effects) occurs at ingestion of >1.7 mg/kg
      1. Some available products have 500 mg THC in a single package
    2. Accidental Ingestion of joint or edible Marijuana (most common)
      1. Significantly increased exposures resulting in emergency, hospital and poison control contacts since legalization
      2. Bennett (2022) Acad Pediatr 22(4):592-7 +PMID: 34325061 [PubMed]
      3. Leubitz (2021) Pediatr Emerg Care 37(12):e969-73 +PMID: 34908380 [PubMed]
      4. Myran (2022) JAMA Netw Open 5(1):e2142521 +PMID: 34994796 [PubMed]
    3. Other possible exposures
      1. Breastfeeding may lead to THC exposure
      2. Secondhand Smoke is unlikely to cause significant effects
  2. Timing
    1. Maximal effects occur within first 10 minutes of inhalation, but not for 2-4 hours of ingestion
    2. Ingested Marijuana effects may persist up to 6-12 hours
      1. Typically admit children (esp. under age 6 years) for observation
  3. Central Nervous System effects (esp. under age 6 years old)
    1. CNS depression (somnolent, lethargic to obtunded)
    2. Cerebellar dysfunction (e.g. Ataxia)
    3. Horizontal Nystagmus may be present
    4. Agitation or fussiness
    5. Nausea or Vomiting
    6. Respiratory depression may occur
    7. Seizures may occur with ingested THC edible
  4. Other effects
    1. Borderline low Blood Pressure (Hypertension may occur in some cases)
    2. Normal Heart Rate (although Tachycardia may occur)
  5. Management
    1. See Unknown Ingestion
    2. Bedside Glucose
    3. Urine Drug Screen (confirm with spectrometry if legal case)
      1. THC will be positive for 3-7 days in urine after single exposure
    4. Supportive care
      1. Advanced Airway is rarely needed
      2. Symptoms typically improve in first 4 to 6 hours after use
    5. Seizures
      1. Benzodiazepines
    6. Agitation
      1. Benzodiazepines
      2. Dexmedotomidine
    7. Intoxication under Age <10 years is typically unintentional (consult Child Abuse and neglect specialists)
  6. References
    1. Claudius and Levine in Herbert (2018) EM: Rap 18(5): 5-6
    2. Claudius, Friedrich and Jimenez in Swadron (2021) EM:Rap 21(12): 17-8
    3. Tomaszewski (2022) Crit Dec Emerg Med 36(2): 27

XVII. Labs

  1. Urine Drug Screening detects 11-nor-9-carboxy-THC (THCCOOH)
    1. Inactive metabolite
    2. Positive in urine for 4-5 days after single use (up to 30 days with chronic use)
    3. Second hand smoke in a poorly ventilated area may result in positive test for <24 hours
    4. Urine results may be confirmed with gas chromatography or mass spectrometry

XVIII. Diagnosis: Cannabis Use Disorder

  1. Screening Tools
    1. Cannabis Use Disorder Identification Test - Revised (CUDIT-R)
  2. Criteria (two or more of the following) over a 12 month period
    1. Used in larger amounts or over longer period than intended
    2. Persistent desire or unable to cut-down or control use
    3. Excessive time spent in activities needed to obtain, use or recover from Cannabis
    4. Craving or strong desire or urge to use Cannabis
    5. Recurrent Cannabis use resulting in failed major role obligations at work, school or home
    6. Cannabis use continues despite persistent or recurrent social or interpersonal problems
    7. Important social, occupational or recreational activities are reduced due to Cannabis use
    8. Recurrent Cannabis use in situations where it is physically hazardous
    9. Continued use despite knowledge of persistent or recurrent physical or psychological related problems
    10. Tolerance (markedly increased amounts to achieve desired effect or decreased effects at same dose)
    11. Withdrawal symptoms or Cannabis use to avoid withdrawal symptoms
  3. Severity
    1. Mild: 2-3 criteria
    2. Moderate: 4-5 criteria
    3. Severe: 6 or more criteria

XIX. Adverse Effects: General

  1. See Cannabinoid Hyperemesis Syndrome
  2. Dizziness
  3. Dry Mouth
  4. Fatigue
  5. Respiratory symptoms (when smoked)
  6. Drowsiness
  7. Cognitive Impairment
    1. Cognitive Impairment and behavioral effects are more significant in teens (and children)
    2. Murray (2022) Neuropsychopharmacology 47(7):1331-8 +PMID: 35110688 [PubMed]

XX. Adverse Effects: Withdrawal

  1. Occurs in 47% of regular users
  2. Three or more criteria are consistent with diagnosis
    1. Decreased appetite or weight loss
    2. Sleep difficulty (Insomnia, disturbing dreams)
    3. Nervousness or Anxiety
    4. Depressed Mood or dysphoria
    5. Irritability, anger or aggression
    6. Restlessness
    7. Physical symptom (e.g. Abdominal Pain, Tremors, diaphoresis, fever, chills, Headaches)
  3. Course
    1. Anxiety may begin as early as 4 hours from last use
    2. Other symptoms have onset qithin 1-2 days of last use
    3. Withdrawal symptoms may persist for 3-4 weeks
  4. Management
    1. Physical Activity and Exercise
    2. Relaxation Technique
    3. Analgesics (e.g. Acetaminophen, Ibuprofen)
    4. Other agents that have been used (not FDA approved)
      1. Gabapentin (Neurontin)
      2. Quetiapine (Seroquel)
      3. Mirtazapine (Remeron)

XXI. Adverse Effects: Toxicity

  1. Dysphoria
  2. Sinus Tachycardia
  3. Orthostatic Hypotension
  4. May increase Myocardial Infarction risk
  5. Cannabinoid Hyperemesis Syndrome with frequent use
  6. May precipitate psychiatric illness (esp. at high dose)
    1. Latent or controlled Schizophrenia
    2. Anxiety Disorder
    3. Dysphoria
    4. Paranoia
    5. Acute Psychosis

XXII. Drug Interactions

  1. CNS Depressants (increased sedation, Dizziness)
    1. Opioids
    2. Benzodiazepines
    3. Alcohol
  2. Antithrombotics
    1. Increased bleeding risk
  3. Other interactions
    1. Statins
    2. Anidepressants

XXIII. Management: Cannabis Use Disorder

  1. See HIstory and Diagnosis as above
  2. See Withdrawal Management as above
  3. Counsel about excessive use
  4. Encourage reduced use
    1. Decrease THC concentrations
    2. Avoid daily use
    3. Reduce inhalation frequency
    4. Taper use
    5. Limit purchases to regulated, legal dispensaries (where available)
  5. Refer for Chemical Dependency counseling if patient is ready to reduce use or quit
    1. Cognitive Behavioral Therapy
    2. Motivational enhancement therapy
    3. Gates (2016) Cochrane Database Syst Rev (5): CD005336 [PubMed]
  6. N-Acetylcysteine (NAC)
    1. Early study showed improved Cannabis sobriety in teens (in combination with counseling)
    2. Dose: 1200 mg orally twice daily (well tolerated)
    3. Gray (2012) Am J Psychiatry 169(8):805-12 +PMID: 22706327 [PubMed]

XXIV. Management: Toxicity

  1. See Synthetic Cannabinoid (e.g. K2, JWH, Spice)
  2. Usually no specific treatment needed
  3. Benzodiazepines for severe reactions
  4. Toxicity may be related to polysubstance abuse (consider other Drugs of Abuse combined with THC)
  5. Marijuana Intoxication in children may present with greater CNS depression
  6. Toxicity may be associated with masking agent Overdose
    1. Some THC users have Overdosed on Niacin (Vitamin B3) in attempt to mask the Urine Drug Screen (UDS)
    2. No evidence Niacin actually masks THC in the urine, but this has resulted in emergency department visits
      1. Mittal (2007) Ann Emerg Med 50:587-590 [PubMed]
  7. Legalized Marijuana in 4 U.S. States (CO, OR, WA, AL) as of 2015 has been associated with increased ED visits
    1. Increased cyclic Vomiting (2x) and accidental childhood Poisonings
    2. Kim (2016) Ann Emerg Med 68(1): 71-5 [PubMed]

XXV. Complications

  1. See Adverse Effects above
  2. See Contraindications above
  3. Background
    1. Legalization of recreational Cannabis has increased related U.S. emergency department visits (esp. age <29 years)
      1. Mullen (2022) Am Fam Physician 106(3): 322-3 [PubMed]
  4. Acute Serious Complications
    1. Myocardial Infarction
    2. Acute Kidney Injury
    3. Seizure
  5. Intoxication impairs memory, judgment and coordination
    1. Increases MVA risk by 3 to 7 fold
  6. Longterm effects from excessive and persistent use
    1. Cannabinoid Hyperemesis Syndrome
    2. Psychosis and increased risk of Bipolar Disorder and Schizophrenia
      1. Khan (2009) 6(12):44-8 +PMID: 20104292 [PubMed]
      2. Cheng (2023) Lancet Psychiatry 10(6):441-51 +PMID: 37208114 [PubMed]
    3. Suicidality in adults
      1. History of teenage Marijuana use may increase risk of Suicidality in adults as much as 50%
      2. Gobbi (2019) Psychiatry 76(4): 426-34 [PubMed]
    4. Neuropsychological decline in older adults
      1. Cognitive deficits (IQ decline of 5.5 points) and smaller hippocampal volume by midlife
      2. Meier (2022) Am J Psychiatry 179(5):362-74 +PMID: 35255711 [PubMed]
    5. Cardiac Toxicity
      1. Premature atherosclerosis (e.g. CAD, CVA)
      2. Increased Acute Coronary Syndrome within first hour of use
        1. May be related to acutely increased sympathetic tone, Hypertension and Tachycardia
      3. Arrhythmia association (e.g. Atrial Fibrillation in teens)
      4. Congestive Heart Failure
      5. Swaminathan and Mattu in Herbert (2019) EM:Rap 19(8): 7-8
      6. Rezkalla (2018) Cardiovasc Med S1050-1738(18)30141-5 +PMID:30447899 [PubMed]
  7. Pregnancy related effects
    1. Hypertensive Disorders of Pregnancy
    2. Neonatal Respiratory Distress
    3. Preterm birth
    4. Small for Gestational Age
    5. Infant death
    6. Increased neonatal Intensive Care unit (NICU) admissions
    7. Prewitt (2022) J Addict Med 17:e192-98 [PubMed]
  8. References
    1. Volkow (2014) N Engl J Med 37(23): 2219-27 [PubMed]

XXVI. References

  1. Moore, Behar, Claudius and Farrah in Herbert (2018) EM:Rap 18(5):11-2
  2. (2017) Presc Lett 24(9): 51
  3. (2012) Presc Lett 20(2): 11
  4. Fontes (2014) Crit Dec Emerg Med 28(1): 14-24
  5. Mason (2016) EM:Rap 16(8): 5
  6. Sazegar (2021) Am Fam Physician 104(6): 598-608 [PubMed]

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