What is the role of Cannabidiol (CBD) in managing seizure disorders?

Antiseizure Effects of Cannabidiol (CBD)

CBD is a highly effective antiseizure medication for refractory epilepsy, demonstrating sustained efficacy across multiple seizure types with 37-49% of patients achieving ≥50% seizure reduction, and is FDA-approved for Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. 1, 2

FDA-Approved Indications and Efficacy

CBD (Epidiolex) is FDA-approved for severe seizures in three specific epilepsy syndromes, with proven efficacy in randomized controlled trials:

• Dravet syndrome: CBD demonstrates significant seizure reduction with an odds ratio of 2.26 (95% CI: 1.38-3.70) compared to placebo 1
• Lennox-Gastaut syndrome: CBD shows the strongest effect with an odds ratio of 2.98 (95% CI: 1.83-4.85) for ≥50% seizure reduction 1
• Tuberous sclerosis complex: CBD achieves an odds ratio of 1.99 (95% CI: 1.06-3.76) for seizure control 1

The pooled analysis across all three syndromes demonstrates CBD is 2.45 times more likely to achieve ≥50% seizure reduction compared to placebo (OR = 2.45,95% CI: 1.81-3.32, p < 0.01) 1

Dosing and Administration

The FDA-approved dosing regimen for CBD is 5-25 mg/kg/day administered twice daily, though real-world evidence supports efficacy up to 50 mg/kg/day:

• Start at 5 mg/kg/day divided into two doses 3
• Titrate every third day by 2.5-5 mg/kg/day increments 3
• Target maintenance dose: 10-20 mg/kg/day (maximum 25 mg/kg/day per FDA label) 3
• Real-world data demonstrates safety and efficacy at doses up to 50 mg/kg/day, particularly in children 4, 5
• Median patient-selected dose in clinical practice is approximately 400 mg per day total 3

Critical dosing consideration: Higher doses are associated with greater seizure control but also increased adverse effects, requiring careful titration 1

Efficacy Beyond FDA-Approved Indications

Real-world evidence demonstrates CBD's antiseizure effects extend beyond the three FDA-approved syndromes:

• A multicenter study of 311 patients (91.3% off-label use) showed 36.9% achieved >50% seizure reduction independent of epilepsy subtype 5
• Another multicenter analysis found 49% achieved ≤25% reduction, 21% reached 51-75% reduction, 20% experienced 76-99% reduction, and 5% achieved near seizure freedom 2
• Median seizure frequency decreased significantly from 30 at baseline to 8 post-treatment (p = 0.000) across various epilepsy etiologies 2
• CBD was particularly effective for epileptic spasms and absence seizures 4

Long-Term Efficacy

CBD maintains its antiseizure efficacy over extended treatment periods without developing tolerance:

• Seizure responder rates remain stable from Year 1 (41.7%) through 60 months of treatment (42.6%) 4
• The seizure response rate shows no significant decline over time (p = 0.12) 4
• Median treatment duration in long-term studies was 45.5 months, demonstrating sustained benefit 4

Safety Profile and Adverse Effects

CBD is generally well-tolerated but carries specific risks that require monitoring:

Common Adverse Effects:

• Diarrhea, somnolence, and sedation are the most frequent side effects 1
• Drowsiness and diarrhea are the primary adverse reactions in long-term use 4
• Overall adverse event rate: 46.9% of patients report some adverse effects 5
• CBD increases odds of any adverse event by 1.81 times compared to placebo (OR = 1.81,95% CI: 1.33-2.46) 1

Serious Adverse Effects:

• Hepatotoxicity is the most concerning risk: CBD causes dose-related, reversible transaminase elevations, typically occurring in the first 2 months 3
• Pooled proportion of elevated liver enzymes: 7% (95% CI: 0.05-0.12) 3
• Drug-induced liver injury occurs in 3% of patients (95% CI: 0.10-0.06) 3
• No cases of hepatotoxicity reported at total CBD doses <300 mg/day 3
• 13% of patients reach three times the upper limit of normal for transaminases 3
• One-third of hepatotoxicity cases resolve spontaneously; remaining cases improve with dose reduction or discontinuation 3

Monitoring Requirements:

• Obtain baseline liver function tests before initiating CBD 3
• Monitor liver enzymes at 1 month, 2 months, and periodically thereafter 3
• Consider CBD as a potential cause in any patient with new or worsening hepatotoxicity 3

Drug Interactions

CBD has significant pharmacokinetic interactions, particularly with clobazam:

• Clobazam co-therapy is associated with greater seizure control but also increased side effects 1
• The combination of CBD with clobazam enhances efficacy but requires careful monitoring for sedation 1, 6
• CBD does not significantly interact with most other antiseizure medications, allowing for safe combination therapy 5
• Most patients can reduce the dose of at least one concomitant antiseizure medication when adding CBD 4

Clinical Pitfalls to Avoid

Key considerations for safe and effective CBD use:

• Do not skip hepatic monitoring: Liver enzyme elevation is dose-dependent and most common in the first 2 months 3
• Avoid rapid titration: Real-world data shows slower titration than FDA-recommended is better tolerated, particularly in treatment-naive patients 5
• Higher doses are safe in children: Pediatric patients tolerate doses up to 50 mg/kg/day better than adults 4, 5
• Comedication with clobazam is not required: Real-world evidence shows comparable efficacy with or without clobazam, contrary to earlier assumptions 5
• One-third of patients discontinue therapy: Most discontinuations occur due to adverse effects or lack of efficacy within the observation period 5

Comparison to Traditional Antiseizure Medications

CBD's efficacy profile is comparable to other antiseizure medications but with distinct advantages:

• CBD demonstrates antiseizure effects independent of epilepsy subtype, unlike many traditional agents 5
• The 37-49% responder rate (≥50% seizure reduction) is comparable to other second-line antiseizure medications 2, 5
• CBD has a more favorable safety profile than traditional agents like phenobarbital or phenytoin, with minimal cardiovascular effects 7, 8
• Unlike benzodiazepines and barbiturates, CBD does not cause significant respiratory depression or profound sedation 3, 8

Mechanisms of Action

CBD's antiseizure effects involve multimodal mechanisms beyond cannabinoid pathways:

• CBD acts through non-cannabinoid pathways, distinguishing it from THC-containing products 6
• Strong anti-inflammatory and neuroprotective activities may contribute to protective effects in epilepsy 6
• The precise antiseizure mechanisms in humans remain incompletely elucidated 6

Role in Treatment Algorithm

CBD should be considered as an adjunctive therapy for refractory epilepsy after failure of 2-3 traditional antiseizure medications:

• CBD is not a first-line agent but demonstrates clear efficacy in drug-resistant epilepsy 6, 2
• For FDA-approved indications (Dravet, Lennox-Gastaut, TSC), CBD should be considered earlier in the treatment algorithm 1, 6
• For other epilepsy subtypes, CBD represents a valuable option when traditional agents fail 2, 5
• CBD allows reduction of other antiseizure medication burden in many patients 4