What is the role of medical cannabis, specifically cannabidiol (CBD), in managing seizures in a patient with a seizure disorder?

Medical Cannabis and Seizures: Role of Cannabidiol in Seizure Management

Cannabidiol (CBD) is an FDA-approved, evidence-based treatment for three specific drug-resistant epilepsy syndromes—Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex—and should be prescribed as pharmaceutical-grade Epidiolex at 5-25 mg/kg/day in divided doses for patients ≥2 years old with these conditions. 1

FDA-Approved Indications and Dosing

The only cannabis-derived medication with regulatory approval for seizures is Epidiolex (purified CBD oral solution), which is specifically indicated for Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. 2, 1

Dosing Protocol

• Initial dose: 5 mg/kg/day divided into two doses 1
• Target dose: 10-20 mg/kg/day based on tolerance 1
• Maximum dose: 25 mg/kg/day in two divided doses 1
• Real-world data demonstrates that slower titration than FDA recommendations is well-tolerated, particularly in children, with higher doses showing safety and efficacy 3

Efficacy Data

CBD demonstrates clinically meaningful seizure reduction in approved indications:

• Median seizure frequency reduction of 37.2-41.9% in Lennox-Gastaut syndrome 1
• 50% responder rate of 37.2% versus 21.2% for placebo (RR 1.76,95% CI 1.07-2.88) 4
• Convulsive seizure reduction in Dravet syndrome with 50% responder rate of 1.69 times placebo (95% CI 1.21-2.36) 5
• Real-world multicenter data shows 36.9% of patients achieve >50% seizure reduction independent of epilepsy subtype 3

Critical Drug Interactions and Monitoring

CBD significantly interacts with multiple antiepileptic medications, requiring dose adjustments and monitoring:

Hepatotoxicity Risk

• Elevated liver enzymes occur in 13% of patients, particularly with concomitant valproate use 6, 1
• No cases of hepatotoxicity reported at total CBD doses <300 mg/day 6
• Monitor liver enzymes at baseline, 1 month, 3 months, then periodically 1
• Transaminase elevations are typically dose-related, reversible, and occur within the first 2 months 6

Specific Drug Interactions

• CBD increases N-desmethylclobazam levels via CYP2C19 inhibition, causing sedation 1
• Interactions documented with rufinamide, zonisamide, topiramate, eslicarbazepine, and warfarin requiring dose adjustment 1

Adverse Effects Profile

Common adverse effects occur in 87.9% of CBD-treated patients versus 72.2% on placebo (RR 1.22,95% CI 1.11-1.33): 4

• Somnolence (most common) 1, 4, 5
• Decreased appetite 1, 4, 5
• Diarrhea 1, 4, 5
• Elevated serum aminotransferases 1, 4, 5

Treatment discontinuation due to adverse effects occurs in 8.9% versus 1.8% on placebo (RR 5.59,95% CI 1.87-16.73), with higher rates at 20 mg/kg/day dosing. 4

Use Beyond Approved Indications

Real-world evidence suggests CBD may have antiseizure effects in other drug-resistant epilepsies, though this remains off-label: 1, 3

• 91.3% of patients in a multicenter study received CBD off-label due to age, epilepsy subtype, or dosing 3
• Efficacy appears independent of epilepsy subtype, with 36.9% achieving >50% seizure reduction across various epilepsy types 3
• Clobazam co-medication was not associated with better outcomes in real-world data 3

Populations Who Should Avoid Cannabis/CBD

Specific populations must avoid all cannabis products:

• Pregnant and breastfeeding women due to potential negative effects on fetal brain development and increased preterm birth risk 2
• Adolescents using recreational cannabis (not pharmaceutical CBD) face risks of neurodevelopmental decline, psychotic disorders, depression, and suicidal ideation 2
• Older adults have increased risk of sedation, confusion, falls, and myocardial ischemia 2

Critical Distinction: Pharmaceutical CBD vs. Recreational Cannabis

The evidence supporting CBD for seizures applies exclusively to pharmaceutical-grade Epidiolex, not to recreational cannabis, CBD oils, or other cannabis products: 1

• The FDA has not approved marijuana for any medical indication, and it remains Schedule I 2
• Recreational cannabis contains variable THC concentrations and lacks standardization 6
• Inhaled cannabis (including CBD) showed potential superior effect in preclinical models but lacks human clinical trial data 7
• Cannabis hyperemesis syndrome can occur with heavy cannabis use (>4 times weekly for >1 year), presenting with cyclical vomiting 6

Practical Implementation Algorithm

For patients with drug-resistant epilepsy:

1. If diagnosis is Dravet syndrome, Lennox-Gastaut syndrome, or Tuberous Sclerosis Complex AND age ≥2 years → Prescribe pharmaceutical Epidiolex 1

2. Baseline assessment:

   • Obtain liver function tests 1
   • Document current antiepileptic medications, especially valproate and clobazam 1
   • Screen for pregnancy in women of childbearing age 2

3. Initiation and titration:

   • Start 5 mg/kg/day divided BID 1
   • Titrate slowly (slower than FDA recommendations is safe, particularly in children) 3
   • Target 10-20 mg/kg/day based on response and tolerability 1
   • Maximum 25 mg/kg/day if needed 1

4. Monitoring:

   • Liver enzymes at 1 month, 3 months, then periodically 1
   • Reduce dose or discontinue if transaminases >3x upper limit of normal 6
   • Assess for sedation, particularly with clobazam co-administration 1

5. For other epilepsy subtypes: CBD remains off-label but real-world data supports consideration in drug-resistant cases, with similar efficacy and safety profiles 3

Common Pitfalls to Avoid

• Do not confuse pharmaceutical Epidiolex with over-the-counter CBD oils or recreational cannabis products—only Epidiolex has proven efficacy and safety data 2, 1
• Do not overlook valproate co-administration as a major risk factor for hepatotoxicity 6, 1
• Do not assume clobazam co-medication is necessary for efficacy—real-world data shows no association 3
• Do not use rapid titration schedules—slower titration improves tolerability, especially in children 3
• Do not prescribe to pregnant or breastfeeding women under any circumstances 2