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Cannabis and Cannabis Use Disorder

Chapter 466 | just Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 466

Key Clinical Points

  1. Marijuana is defined as containing >0.3% D9THC by dry weight; hemp contains ≤0.3% D9THC.
  2. Cannabis Use Disorder (CUD) is a problematic pattern of cannabis use leading to clinically significant impairment or distress.
  3. Smoked D9THC bioavailability is 10–35%; oral edibles are 5–6% (increased to 200–400% with fatty foods).
  4. Regular cannabis use reduces cannabinoid receptor density in the brain, which recovers within 28 days of abstinence.
  5. EVALI (e-cigarette or vaping product use-associated lung injury) is associated with vitamin E acetate in black-market e-liquids.
  6. Adolescent cannabis use is associated with lower grades, lower IQ, and higher risk of dropping out of school.
  7. No FDA-approved medications currently exist for CUD; treatment relies on tapering and behavioral interventions.
  8. Cannabis withdrawal peaks within 1–3 days of discontinuation and manifests as anxiety, restlessness, insomnia, depression, and reduced appetite.
  9. Prevention interventions targeting the individual, family, and community are effective in reducing adolescent cannabis use.
  10. Maternal marijuana use is associated with lower birth weight and potential fetal growth restriction.

DEFINITION & OVERVIEW

• Marijuana vs. Hemp Definition: Based on Agriculture Improvement Act of 2018 (AIA): • Marijuana: Contains >0.3% D9THC by dry weight. • Hemp: Contains ≤0.3% D9THC by dry weight. • Cannabinoid Varieties: • D8THC: Reported to be milder than D9THC; perceived as legal by some users. • Other Intoxicating Hemp Products (IHPs): Some, such as tetrahydrocannabiphorol, can be considerably more potent (20–30×). • Cannabis Use Disorder (CUD): • Definition: A problematic pattern of cannabis use leading to clinically significant impairment or distress. • Legal Status: • Federal: Marijuana remains federally illegal as of May 2024. • State/Local: 24 states, 3 U.S. territories, and Washington, DC have legalized nonmedicinal (adult) use; 38 states, 4 U.S. territories, and Washington, DC have legalized medicinal use. • Route-Specific Characteristics: • Inhalation (Smoked/Vaped): High bioavailability and rapid onset; linked to increased risk of addiction. • Edibles: Lower bioavailability than inhaled products; slower onset; higher probability of accidental dosing in younger users.

EPIDEMIOLOGY

• General Prevalence: • Over 150 million people worldwide. • 2023 US National Survey: 42 million used marijuana over the last month. • Youth Usage (12–25 years): 10 million consumed marijuana monthly in 2023. • Adolescent Epidemiology: • Risks: Lower grades, lower IQ, and higher risk of dropping out of school. • Brain Impact: Associated with structural/functional changes, including reduced brain connectivity and cortical thickness. • Longitudinal Data: Dose-dependent correlation between use at age 14 and reduced prefrontal cortex thickness at age 19. • Cognitive Impairment: Lower scores on verbal, inhibitory, working memory, and episodic memory tasks. • EVALI: • Associated with vitamin E acetate in black-market e-liquids; cases diminished after the agent was removed.

ETIOLOGY & PATHOPHYSIOLOGY

• Endocannabinoid System (ECS): • D9THC: Primarily a partial agonist of G protein–coupled cannabinoid receptors (CB1R and CB2R). • CB1R Location: Found on excitatory glutamatergic and inhibitory GABA-ergic interneurons and glial cells in regions processing stress, mood, and reward. • Endogenous Ligands: 2-arachidonoylglycerol (2-AG; a full agonist) and anandamide (a partial agonist). • Mechanism of Action: ◦ 2-AG: Modulates synaptic signaling by inhibiting overstimulated synapses. ◦ D9THC Reward: Mediated via glutamatergic/GABAergic activity in the midbrain ventral tegmental area (VTA) → nucleus accumbens (NAc). ◦ D9THC Anxiolysis: Mediated by effects on the amygdala. • Developmental Impact: • Fetal Development: Perturbation of ECS during early development affects neuronal migration and connectivity. • Maternal Use: Associated with lower birth weight, fetal growth restriction, and potentially increased intracranial volumes/blunted visuospatial processing. • Neuroplasticity & Tolerance: • Receptor Density: Regular use reduces cannabinoid receptor density; recovery occurs within 28 days of abstinence. • Tolerance: High-frequency users may show less impairment at a given D9THC plasma concentration compared to occasional users.

CLINICAL FEATURES

• General Effects: • Positive: Enhanced sense of well-being, rewarding sensations, and dampened stress responses. • Negative (High Dose): Anxiety, paranoia, and panic. • Withdrawal Syndrome: • Timing: Peaks within 1–3 days of discontinuation; most symptoms resolve in ~2 weeks. • Symptoms: Anxiety, restlessness, insomnia, depression, and reduced appetite. • Clinical Note: Insomnia may persist longer than 2 weeks and contribute to relapse.

DIFFERENTIAL DIAGNOSIS

• CUD vs. Recreational Use: • Distinction based on the presence of clinically significant impairment or distress. • CUD Indicators: Drug craving, tolerance, withdrawal syndrome, and failure to fulfill role obligations.

DIAGNOSTIC APPROACH

  1. Clinical Assessment (DSM-5): Evaluate for a problematic pattern of cannabis use leading to clinically significant impairment or distress.
  2. Urinalysis: • Detection: Identifies 11-norcarboxy-THC. • Metabolism Pathway: D9THC → 11-hydroxy-THC (pharmacologically active) → 11-norcarboxy-THC (pharmacologically inactive). • Persistence: 11-norcarboxy-THC has a t_{1/2} of 20–35+ hours; detectable for days in occasional users and weeks in frequent users with saturated fat stores.

MANAGEMENT & TREATMENT

  1. Pharmacologic Treatment: • Current Status: No FDA-approved medications currently exist for CUD. • Strategy: Tapering of cannabis use.
  2. Behavioral Interventions: • Primary mode of treatment for CUD.
  3. Prevention Strategies: • Target individual, family, and community levels to reduce adolescent cannabis use.

COMPLICATIONS & PROGNOSIS

• Withdrawal Prognosis: • Anxiety, restlessness, depression, and reduced appetite typically resolve within 2 weeks. • Insomnia: May persist >2 weeks → potential for relapse. • Adolescent Recovery: • Receptor density recovers within 28 days of abstinence. • EVALI Complications: • Linked to vitamin E acetate in e-liquids; risk is associated with specific black-market products.

SPECIAL CONSIDERATIONS

• Pregnancy: • Maternal use associated with lower birth weight and fetal growth restriction. • Adolescents: • Vulnerability: Higher risk of cognitive impairment, lower IQ, and school failure; potential for lasting changes in prefrontal cortex thickness.

KEY PEARLS & CLINICAL TRAPS

• Pharmacokinetics Table 466-1: • Smoked: 10–35% bioavailability; peak plasma at 5–10 min; hysteresis observed. • Vaped: Similar to smoked; rapid onset; easier dose control. • Oral (Standard): 5–6% bioavailability; no hysteresis; first-pass metabolism. • Oral (with Fatty Foods): 200–400% increased bioavailability → bypasses hepatic elimination via lymphatic lacteals → slower effect onset. • Metabolism Pathway: • D9THC → 11-hydroxy-THC (active) → 11-norcarboxy-THC (inactive, used for detection). • Clinical Trap: • Correlation between plasma D9THC levels and impairment is difficult due to tolerance in regular users.