II. Definitions
- Cannabinoids
- Group of >100 chemicals derived from Cannabis sativa plant
- Cannabis sativa has different strains that include Marijuana and hemp
- Cannabinoids include Tetrahydrocannabinol (THC) and Cannabidiol (CBD)
III. Epidemiology
-
Prevalence (U.S.)
- Marijuana is the second most abused substance in U.S. after Alcohol
- Adults: 17% (in 2017)
- High School Seniors: 37% (in 2017)
- Prevalence doubled for adults aged 18 to 39 between 2002 and 2012
- Cannabis Use Disorder: 19.5% lifetime risk for Cannabis users
- More likely in teens within 2 years of starting use
IV. Class
- Relaxant, Euphoriant, and Hallucinogen (high doses)
- Federal Schedule I Agent
- Medical use is permitted in more than half U.S. States (and D.C.)
- Recreational use has been approved by Colorado and Washington legislatures
V. Mechanism: Endocannabinoid System
- Cannabinoid Receptors (G-Protein Receptors, CB1 and CB2)
- CB1 Receptors (Central Cannabinoid)
- Dense representation throughout the brain
- CB1 bInding decreases intracellular cAMP and increases MAP kinase
- Elevates mood, increases feelings of well being and increases pain tolerance
- Affects time Perception and memory, as well as learning and cognition
- Cannabinoids have high affinity at CB1
- Brainstem has few CB1 Receptors, and therefore coma and respiratory depression are uncommon
- Dense representation throughout the brain
- CB2 Receptors (Peripheral Cannabinoid)
- Present on Peripheral Nerves
- Binding results in presynaptic cell hyperpolarization with decreased Neurotransmitter release
- Present on T Cells, B Cells and Macrophages
- Binding has antiinflammatory activity
- Present on Peripheral Nerves
- CB1 Receptors (Central Cannabinoid)
- Endogenous Cannabinoids bind at CB1 and CB2 Receptors
- 2-arachidonoyl-Glycerol
- Anandamide
- Delta-9-Tetrahydrocannabinol (THC)
- Primary psychoactive agent in Cannabis
- Mimics endogenous Cannabinoids
- Stimulates Central Nervous System CB1 and CB2 Receptors
- Contrast with the synthetic Delta-8-THC
- Associated with life threatening toxicity (see preparations below)
- Less potent psychoactive agent than Delta-9
-
Cannabidiol (CBD)
- Stimulates Serotonin5-HT-1A receptors
- Antagonist or Weak binding at CB1 and CB2 Receptors
- Results in anxiolysis, anticonvulsant and sedation (but unlike THC, not psychoactive)
VI. Preparations: Marijuana (THC)
- Formulations derived from dried flowers (buds) and leaves of the Cannabis sativa plant
- Street Names
- Pot, Grass, Tea
- Dagga, Kif
- Joint, Reefer
- Weed, Dope
- Modes of use
- Smoking (Marijuana bud or resin rolled, or in a pipe or bong)
- Vaping (bud, resin or liquid heated)
- Dabbing (high THC concentrate inhaled)
- Formulations
- Concentrate (high THC concentration, up to 90%)
- See Hemp Oil below
- Edibles (Gummies, teas or infused drinks, hash brownies, candies)
- Added to foods via oils used to extract THC
- Marijuana (bud or flower)
- Typically purchased as an eighth (3.5 g)
- Used via smoking or Vaping
- Typical joint contains 0.5 to 1 g or Marijuana
- THC concentration has increased from 1.5% in 1970s, 8.9% in 2008, to 21% in 2018
- Chandra (2019) Eur Arch Psychiatry Clin Neurosci 269(1): 5-15 [PubMed]
- Topical Oils (15 to 50% THC concentration)
- Extracted with various solvents that have resulted in significant lung injury when inhaled
- Resin (trichome flower protrusions, 2-8% THC)
- Smoked or vaped
- Tincture
- Contains Ethanol
- Taken by mouth or sublingual
- Vape Pen
- Vaping of THC concentrate
- Concentrate (high THC concentration, up to 90%)
- Synthetic Delta-8 Tetrahydrocannabinol (Delta-8-THC)
- Synthetic THC associated with life threatening Intoxication complications (coma, Seizure, apnea)
- Parodoxical increased use as of 2022, despite its toxicity as well as growing Marijuana legalization
- Contrast with Delta-9-Tetrahydrocannabinol, which is natural form of THC extracted from Cannabis
- Delta-8-THC varies from Delta-9-THC, in only the location of a single double bond
- Small synthetic change, results in a dramatic increase in toxic effects including death
- Oil tinctures
- Typically contain 30 to 40 mg/ml (1 to 1.5 mg/gtt) of Delta-8-THC
- Gummies
- Typically contain 10 to 25 mg per gummy
- Vape liquid
- References
- Jackson and Fisher (2022) Crit Dec Emerg Med 36(4): 16-7
- Synthetic THC associated with life threatening Intoxication complications (coma, Seizure, apnea)
- Other Cannabinoid extracts (>100 different Cannabinoids in Marijuana)
- Cannabichromene (cbc)
- Cannabidivarin (CBDV)
- Cannabigerol (CBG)
- Cannabinol (CBN)
VII. Preparations: Hemp Oil
- Background
- Pulverized Marijuana placed for 8 minutes in PVC pipe filled with butane and capped at each end
- Results in 90% THC solution (honey oil) or wax (after exposure to Rubbing Alcohol)
- Production associated with explosions and fires (related to use of butane)
- Street Names
- Honey Oil
- Concentrated THC in Butane solvent
- Smoked (or placed on a Cigarette)
- Wax
- Solidified honey oil (after exposure to Rubbing Alcohol)
- Similar appearance to honeycomb or ear wax
- Smoked
- Honey Oil
- References
- Nordt and Swadron in Herbert (2014) EM: Rap 14(6):6
VIII. Preparations: Prescription Cannabinoid
- See Prescription Cannabinoid
- See Synthetic Cannabinoids
- Refer to illicit formulations (e.g. K2, spice) with serious adverse effects
-
Dronabinol (Marinol)
- THC formulation Indicated for intractable Nausea, Vomiting (e.g. Chemotherapy, AIDS-related Anorexia)
- Dosed 2.5 mg orally twice daily (max: 20 mg/day)
- DEA Schedule 3
-
Nabilone (Cesamet)
- THC analogue used to treat intractable Nausea, Vomiting (e.g. Chemotherapy)
- Dosed 1 mg orally twice daily (max: 6 mg/day in divided doses)
- DEA Schedule 2
-
Cannabidiol (Epidiolex)
- CBD formulation used to treat rare forms of childhood Epilepsy
- Dravet Syndrome
- Lennox-Gastaut Syndrome
- Tuberous Sclerosis
- Dosed 2.5 mg/kg twice daily (max: 20 mg/kg/day)
- DEA Schedule 5
- CBD formulation used to treat rare forms of childhood Epilepsy
- Nabiximols (Sativex)
- Approved outside U.S. for neuropathic pain and spasticity (e.g. Multiple Sclerosis)
- Buccal Spray contains THC and CBD and used on average for 5 sprays daily (max: 14/day)
IX. Pathophysiology
- Similar to highly addictive "hard" drugs or Opioids
- Marijuana considered a gateway drug
- Use may lead to Opiate Abuse
- References
X. Pharmacokinetics
- Tetrahydrocannabinol (THC)
- Highly lipophilic
- Crosses blood brain barrier
- Duration: 5-20 mg of THC has a 2-4 hour duration
- Long half life
- Metabolized by Cytochrome P450 (CYP3A4, CYP2C9, CYP2C19)
- THC psychoactive doses
- Dose >25 mg in adults is enough to alter cognitive and psychomotor performance
- Dose >5 mg in children is enough to result in Intoxication
- Delta-9 THC concentrations have dramatically increased in Marijuana since 2000
- Smoking Marijuana
- Bioavailability: 20-50%
- Onset: Rapid (5-10 minutes)
- Duration: 2 to 4 hours
- Edible maijuana
- Bioavailability: 4-12%
- Onset: 1 to 3 hours
- Peaks: 2 to 6 hours
- Duration: 6 to 8 hours (up to 12 hours)
- Lower peak serum concentration than if smoked (give the same quantity of Marijuana)
- However edible products may be associated with greater toxicity for a longer duration
- Edible preparations are unregulated and often contain higher potency Marijuana
- Marijuana products may be adulterated or replaced completely with Synthetic Marijuana
- A single THC serving (e.g. 10 mg) may be contained in one gummy bear
- Patients may eat more than a serving as effects are delayed
XI. Indications: Medical Marijuana
- Precautions
- See Contraindications, Adverse Effects and Complications
- There are no FDA approved indications for inhaled Cannabis
-
Anti-emetic (especially Chemotherapy related)
- Most established use
- Consider Dronabinol (Marinol) or Nabilone (Cesamet) instead
- However, Cannabinoid Hyperemesis Syndrome may result with increased, sustained use
- AIDS Anorexia
- Neuropathic pain
- Modest reduction in pain (30%) compared with Placebo
- Cannabinoids do not appear to reduce Opioid use in Chronic Pain
- Multiple Sclerosis related spasticity and pain
- Intractable Seizure Disorder
- Consider Cannabidiol (CBD) instead (see synthetics as above)
- References
XII. Contraindications: Patients at High Risk for Adverse Events
- Age <21 years old (without medical indication)
- Risk of Cannabis use disorder
- Affects brain development (may adversely affect IQ, educational outcomes)
- Risk of future Anxiety Disorder
- Increased risk of Suicidality and all-cause mortality
- Increased physical Violence
-
Substance Use Disorder
- Risk of Cannabis use disorder
- Longterm Opioid or Benzodiazepine use
- Risk of Drug Interactions, sedation
- Age >65 years (and on 2 or more psychoactive drugs on Beer's Criteria)
- Risk of increased confusion, Memory Loss and falls
- Pregancy and Lactation
- Increased risk of preterm birth, low birth weight and future Psychopathology (insufficient data)
- May impact neurologic development in Breast Feeding infants (insufficient data)
- THC is present in Breast Milk for up to 6 days after last use
-
Psychosis history or Family History
- Increased risk of Psychosis episode or recurrence (4 to 5 fold increased risk)
- Cardiopulmonary Disease (moderate to severe disease)
- Risk of exacerbation
XIII. History: Cannabis Use Disorder Screening
- See Cannabis Use Disorder Identification Test - Revised (CUDIT-R)
- Do you use Cannabis at times?
- How much do you use and how often?
- Is there polysubstance use or abuse?
- Are there psychiatric comorbidities?
- Is there a medical indication for the Cannabinoid use?
- Is it FDA-approved?
- Do benefits outweigh risks?
- Are there reasonable, effective alternatives to recommend?
- Are there contraindications for use (see above)?
- Are there findings of Cannabinoid use disorder (see diagnosis below)?
XIV. Symptoms
- Acute Effects
- Euphoria
- Relaxed inhibitions
- Increased appetite
- Decreased alertness
- Disoriented behavior
- Chronic Use: Amotivational syndrome
- Aimless
- Uncommunicative
XV. Signs: Adults
- Cardiopulmonary findings
- Miscellaneous findings
- Conjunctival Injection
- Dry Mouth
- Decreased coordination
XVI. Signs: Children
- Exposures
- Severe toxicity (including cardiovascular effects) occurs at ingestion of >1.7 mg/kg
- Some available products have 500 mg THC in a single package
- Accidental Ingestion of joint or edible Marijuana (most common)
- Significantly increased exposures resulting in emergency, hospital and poison control contacts since legalization
- Bennett (2022) Acad Pediatr 22(4):592-7 +PMID: 34325061 [PubMed]
- Leubitz (2021) Pediatr Emerg Care 37(12):e969-73 +PMID: 34908380 [PubMed]
- Myran (2022) JAMA Netw Open 5(1):e2142521 +PMID: 34994796 [PubMed]
- Other possible exposures
- Breastfeeding may lead to THC exposure
- Secondhand Smoke is unlikely to cause significant effects
- Severe toxicity (including cardiovascular effects) occurs at ingestion of >1.7 mg/kg
- Timing
- Maximal effects occur within first 10 minutes of inhalation, but not for 2-4 hours of ingestion
- Ingested Marijuana effects may persist up to 6-12 hours
- Typically admit children (esp. under age 6 years) for observation
- Central Nervous System effects (esp. under age 6 years old)
- Other effects
- Borderline low Blood Pressure (Hypertension may occur in some cases)
- Normal Heart Rate (although Tachycardia may occur)
- Management
- See Unknown Ingestion
- Bedside Glucose
- Urine Drug Screen (confirm with spectrometry if legal case)
- THC will be positive for 3-7 days in urine after single exposure
- Supportive care
- Advanced Airway is rarely needed
- Symptoms typically improve in first 4 to 6 hours after use
- Seizures
- Agitation
- Benzodiazepines
- Dexmedotomidine
- Intoxication under Age <10 years is typically unintentional (consult Child Abuse and neglect specialists)
- References
- Claudius and Levine in Herbert (2018) EM: Rap 18(5): 5-6
- Claudius, Friedrich and Jimenez in Swadron (2021) EM:Rap 21(12): 17-8
- Tomaszewski (2022) Crit Dec Emerg Med 36(2): 27
XVII. Labs
-
Urine Drug Screening detects 11-nor-9-carboxy-THC (THCCOOH)
- Inactive metabolite
- Positive in urine for 4-5 days after single use (up to 30 days with chronic use)
- Second hand smoke in a poorly ventilated area may result in positive test for <24 hours
- Urine results may be confirmed with gas chromatography or mass spectrometry
XVIII. Diagnosis: Cannabis Use Disorder
- Screening Tools
- Cannabis Use Disorder Identification Test - Revised (CUDIT-R)
- Criteria (two or more of the following) over a 12 month period
- Used in larger amounts or over longer period than intended
- Persistent desire or unable to cut-down or control use
- Excessive time spent in activities needed to obtain, use or recover from Cannabis
- Craving or strong desire or urge to use Cannabis
- Recurrent Cannabis use resulting in failed major role obligations at work, school or home
- Cannabis use continues despite persistent or recurrent social or interpersonal problems
- Important social, occupational or recreational activities are reduced due to Cannabis use
- Recurrent Cannabis use in situations where it is physically hazardous
- Continued use despite knowledge of persistent or recurrent physical or psychological related problems
- Tolerance (markedly increased amounts to achieve desired effect or decreased effects at same dose)
- Withdrawal symptoms or Cannabis use to avoid withdrawal symptoms
- Severity
- Mild: 2-3 criteria
- Moderate: 4-5 criteria
- Severe: 6 or more criteria
XIX. Adverse Effects: General
- See Cannabinoid Hyperemesis Syndrome
- Dizziness
- Dry Mouth
- Fatigue
- Respiratory symptoms (when smoked)
- Drowsiness
-
Cognitive Impairment
- Cognitive Impairment and behavioral effects are more significant in teens (and children)
- Murray (2022) Neuropsychopharmacology 47(7):1331-8 +PMID: 35110688 [PubMed]
XX. Adverse Effects: Withdrawal
- Occurs in 47% of regular users
- Three or more criteria are consistent with diagnosis
- Decreased appetite or weight loss
- Sleep difficulty (Insomnia, disturbing dreams)
- Nervousness or Anxiety
- Depressed Mood or dysphoria
- Irritability, anger or aggression
- Restlessness
- Physical symptom (e.g. Abdominal Pain, Tremors, diaphoresis, fever, chills, Headaches)
- Course
- Anxiety may begin as early as 4 hours from last use
- Other symptoms have onset qithin 1-2 days of last use
- Withdrawal symptoms may persist for 3-4 weeks
- Management
- Physical Activity and Exercise
- Relaxation Technique
- Analgesics (e.g. Acetaminophen, Ibuprofen)
- Other agents that have been used (not FDA approved)
XXI. Adverse Effects: Toxicity
- Dysphoria
- Sinus Tachycardia
- Orthostatic Hypotension
- May increase Myocardial Infarction risk
- Cannabinoid Hyperemesis Syndrome with frequent use
- May precipitate psychiatric illness (esp. at high dose)
- Latent or controlled Schizophrenia
- Anxiety Disorder
- Dysphoria
- Paranoia
- Acute Psychosis
XXII. Drug Interactions
- CNS Depressants (increased sedation, Dizziness)
- Antithrombotics
- Increased bleeding risk
- Other interactions
- Statins
- Anidepressants
XXIII. Management: Cannabis Use Disorder
- See HIstory and Diagnosis as above
- See Withdrawal Management as above
- Counsel about excessive use
- Encourage reduced use
- Decrease THC concentrations
- Avoid daily use
- Reduce inhalation frequency
- Taper use
- Limit purchases to regulated, legal dispensaries (where available)
- Refer for Chemical Dependency counseling if patient is ready to reduce use or quit
- Cognitive Behavioral Therapy
- Motivational enhancement therapy
- Gates (2016) Cochrane Database Syst Rev (5): CD005336 [PubMed]
-
N-Acetylcysteine (NAC)
- Early study showed improved Cannabis sobriety in teens (in combination with counseling)
- Dose: 1200 mg orally twice daily (well tolerated)
- Gray (2012) Am J Psychiatry 169(8):805-12 +PMID: 22706327 [PubMed]
XXIV. Management: Toxicity
- See Synthetic Cannabinoid (e.g. K2, JWH, Spice)
- Usually no specific treatment needed
- Benzodiazepines for severe reactions
- Toxicity may be related to polysubstance abuse (consider other Drugs of Abuse combined with THC)
- Marijuana Intoxication in children may present with greater CNS depression
- Toxicity may be associated with masking agent Overdose
- Some THC users have Overdosed on Niacin (Vitamin B3) in attempt to mask the Urine Drug Screen (UDS)
- No evidence Niacin actually masks THC in the urine, but this has resulted in emergency department visits
- Legalized Marijuana in 4 U.S. States (CO, OR, WA, AL) as of 2015 has been associated with increased ED visits
- Increased cyclic Vomiting (2x) and accidental childhood Poisonings
- Kim (2016) Ann Emerg Med 68(1): 71-5 [PubMed]
XXV. Complications
- See Adverse Effects above
- See Contraindications above
- Background
- Legalization of recreational Cannabis has increased related U.S. emergency department visits (esp. age <29 years)
- Acute Serious Complications
-
Intoxication impairs memory, judgment and coordination
- Increases MVA risk by 3 to 7 fold
- Longterm effects from excessive and persistent use
- Cannabinoid Hyperemesis Syndrome
- Psychosis and increased risk of Bipolar Disorder and Schizophrenia
- Suicidality in adults
- History of teenage Marijuana use may increase risk of Suicidality in adults as much as 50%
- Gobbi (2019) Psychiatry 76(4): 426-34 [PubMed]
- Neuropsychological decline in older adults
- Cognitive deficits (IQ decline of 5.5 points) and smaller hippocampal volume by midlife
- Meier (2022) Am J Psychiatry 179(5):362-74 +PMID: 35255711 [PubMed]
- Cardiac Toxicity
- Premature atherosclerosis (e.g. CAD, CVA)
- Increased Acute Coronary Syndrome within first hour of use
- May be related to acutely increased sympathetic tone, Hypertension and Tachycardia
- Arrhythmia association (e.g. Atrial Fibrillation in teens)
- Congestive Heart Failure
- Swaminathan and Mattu in Herbert (2019) EM:Rap 19(8): 7-8
- Rezkalla (2018) Cardiovasc Med S1050-1738(18)30141-5 +PMID:30447899 [PubMed]
- References
XXVI. References
- Moore, Behar, Claudius and Farrah in Herbert (2018) EM:Rap 18(5):11-2
- (2017) Presc Lett 24(9): 51
- (2012) Presc Lett 20(2): 11
- Fontes (2014) Crit Dec Emerg Med 28(1): 14-24
- Mason (2016) EM:Rap 16(8): 5
- Sazegar (2021) Am Fam Physician 104(6): 598-608 [PubMed]