Epilepsy

What it is

Epilepsy is a chronic neurological disorder defined by recurrent unprovoked seizures. The condition affects an estimated 3.4 million Americans. Most patients respond to anti-seizure medications, but approximately one-third develop treatment-resistant epilepsy that fails two or more first-line drugs.

Dravet syndrome and Lennox-Gastaut syndrome are rare, severe pediatric-onset epilepsies that are notoriously difficult to control and were historically refractory to nearly all available treatments.

Cannabis and cannabis-derived therapies

The 2017 NASEM consensus report classified the evidence for cannabidiol (CBD) in certain epilepsy syndromes as conclusive or substantial (the highest evidence tier in the report). This finding was based on multiple randomized clinical trials demonstrating significant seizure-frequency reductions in patients with Dravet and Lennox-Gastaut syndromes.

In 2018, the FDA approved Epidiolex (a purified plant-derived cannabidiol oral solution) for treating seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Epidiolex is a Schedule V controlled substance and is dispensed by prescription through standard pharmacy channels, distinct from state medical-cannabis programs.

Evidence for cannabis or cannabinoids in adult-onset epilepsy and other seizure disorders remains less robust. Most state medical-cannabis programs include epilepsy or seizure disorders as qualifying conditions for adult patients.

Epidiolex (cannabidiol oral solution)

Epidiolex is the most rigorously studied cannabis-derived therapy in any condition. Pivotal trials:

• Dravet syndrome (GWPCARE1, NEJM 2017): 39% reduction in convulsive seizure frequency vs 13% with placebo (20 mg/kg/day arm).
• Lennox-Gastaut syndrome (GWPCARE3, GWPCARE4, Lancet 2018): 41-44% reduction in drop seizures vs 20-22% with placebo.
• Tuberous sclerosis complex (GWPCARE6, JAMA Neurology 2021): 49% reduction in TSC-associated seizures vs 27% with placebo.

Approved dosing is 5-10 mg/kg/day starting dose, titrated to 10-20 mg/kg/day target. Twice-daily oral administration in a sesame-oil vehicle.

Drug interactions

Epidiolex (CBD) has clinically significant interactions with several anti-seizure medications:

• Clobazam: CBD inhibits CYP2C19; clobazam's active N-desmethylclobazam metabolite levels rise roughly 3-fold, increasing sedation. Clobazam dose reduction is often needed.
• Valproic acid: combined use elevates transaminases more than either alone. Monthly liver-function testing is recommended during the first 6 months.
• Stiripentol, brivaracetam: elevated levels through CBD-mediated CYP450 inhibition.
• Everolimus (TSC patients): CBD elevates serum levels via CYP3A4 inhibition; dose adjustment is required.

Adverse effects

Per FDA labeling: somnolence (32%), decreased appetite (22%), diarrhea (20%), transaminase elevations (16-28% depending on dose and concomitant valproate), fatigue, malaise, rash, insomnia, and infections. Hepatic adverse events are dose-dependent and require monitoring; permanent-discontinuation rate from hepatic events was 1-3% across the pivotal trials.

Plant cannabis vs Epidiolex

State medical-cannabis program flower, oils, and tinctures differ from Epidiolex in important ways:

• Standardization: Epidiolex is precisely dosed (100 mg/mL CBD). State-program products vary in CBD content batch to batch.
• THC content: Epidiolex is essentially THC-free. State-program products vary; some "low-THC" CBD oils approximate Epidiolex, many do not.
• Trial evidence: dosing in pivotal trials was 10-20 mg/kg/day. State-program patients commonly use lower doses with less monitoring.
• Insurance coverage: Epidiolex is covered by Medicaid and most commercial plans for approved indications. State-program cannabis is not covered.
• Federal scheduling: Epidiolex is Schedule V (rescheduled post-approval). State-program cannabis remains Schedule I federally.

For families with a child with Dravet, LGS, or TSC, Epidiolex via standard pharmacy channels is the evidence-based pathway. State medical-cannabis enrollment may be relevant for adjunctive THC-containing products or for non-FDA-approved seizure indications.

Hemp-derived CBD vs Epidiolex

Over-the-counter hemp-derived CBD products (sold without prescription under the federal 2018 Farm Bill) are not equivalent to Epidiolex. Independent testing studies have found wide variability in actual CBD content, occasional THC contamination, and heavy-metal or pesticide residues. Hemp-derived CBD has not been studied at the 10-20 mg/kg/day doses used in Epidiolex trials. Patients with epilepsy should not substitute hemp-derived CBD for Epidiolex or prescribed anti-seizure medications.

Practical guidance

• Patients with Dravet, Lennox-Gastaut, or TSC should discuss Epidiolex with their neurologist as a first-line cannabis-derived option.
• State medical-cannabis enrollment is most relevant for epilepsy patients with conditions outside the Epidiolex indications, for adjunctive sleep or anxiety symptom management, or for cost reasons in jurisdictions where program cannabis is cheaper than Epidiolex out-of-pocket.
• All patients should coordinate cannabis use with their neurologist to monitor for seizure-threshold effects (THC can lower seizure threshold in some patients) and for drug-level interactions.
• Liver-function monitoring is essential for patients on Epidiolex, particularly with concomitant valproate.

Related conditions

The mmjnow seizure-disorders page covers the broader seizure-disorder category. Patients with autism-spectrum-disorder, traumatic-brain-injury, or hiv-aids may have seizures as a secondary feature of their primary condition.