Epidiolex Drug Interactions: What to Avoid and What to Tell Your Doctor

Because patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex are often on multiple medications, drug interactions with Epidiolex (cannabidiol) are an important clinical consideration. Some interactions can cause serious harm — increased liver toxicity, excessive sedation, or altered drug levels. Here's what you and your healthcare team need to know.

How Does Epidiolex Interact with Other Drugs?

Cannabidiol is metabolized in the liver by enzymes in the cytochrome P450 (CYP) family — specifically CYP3A4 and CYP2C19. It also affects the P-glycoprotein (P-gp) and BCRP drug transporters. Because of this, Epidiolex can both be affected by other drugs and affect the levels of other drugs in the body.

Major Interaction #1: Clobazam (Onfi, Sympazan) — Increased Sedation Risk

Clobazam is one of the most common co-medications in patients on Epidiolex, and this interaction is clinically significant. When Epidiolex and clobazam are taken together, Epidiolex increases the blood levels of N-desmethylclobazam — the active metabolite of clobazam — by approximately 3-fold. This dramatically increases sedation.

What to do: When starting Epidiolex in a patient on clobazam, watch closely for excessive drowsiness, confusion, or difficulty walking. Your neurologist may reduce the clobazam dose to compensate. This interaction is common and manageable, but requires monitoring.

Major Interaction #2: Valproate / Valproic Acid — Increased Liver Toxicity Risk

The combination of Epidiolex and valproate (valproic acid/Depakote) significantly increases the risk of liver enzyme elevations (transaminase elevations). Both drugs are independently associated with liver effects, and together the risk is substantially higher.

In clinical trials for TSC patients taking both valproate and clobazam, 20-25% had ALT elevations greater than 3 times the upper limit of normal. Elevated ammonia levels were also reported in some patients on both Epidiolex and valproate. Regular monitoring of liver function tests is essential for patients on both drugs.

What to do: Your doctor will monitor liver enzymes more closely when these drugs are combined. Signs of liver problems — jaundice, dark urine, upper abdominal pain, unusual fatigue — should be reported to your doctor immediately.

Major Interaction #3: Everolimus (Afinitor) — Increased Everolimus Levels

This interaction is particularly important for TSC patients, who may take everolimus (Afinitor) to treat TSC-associated tumors. Epidiolex significantly inhibits the P-gp transporter and CYP3A4, which increases everolimus blood levels considerably. The prescribing information recommends a lower starting dose of everolimus and appropriate therapeutic drug monitoring when combined with Epidiolex.

What to do: If you have TSC and take both Epidiolex and everolimus, make sure your doctors are coordinating. Your everolimus dose likely needs adjustment. Regular everolimus level monitoring is recommended.

Moderate Interaction: CYP3A4 Inducers — Reduced Epidiolex Efficacy

Strong inducers of CYP3A4 and CYP2C19 enzymes can increase the metabolism of cannabidiol, reducing Epidiolex blood levels and potentially compromising its efficacy. Drugs in this category include:

Carbamazepine (Tegretol) — also contraindicated in Dravet syndrome for other reasons

Rifampin (Rifadin) — an antibiotic used for tuberculosis

Phenytoin (Dilantin) — also contraindicated in Dravet syndrome

St. John's Wort (herbal supplement) — a potent CYP3A4 inducer that can reduce CBD levels

Moderate Interaction: CYP2C19 Substrates — Increased Drug Levels

Epidiolex is an inhibitor of CYP2C19, which means it can increase the levels of other drugs metabolized by this enzyme. Examples include:

Diazepam (Valium) — may need dose reduction if combined with Epidiolex

Stiripentol (Diacomit) — level may increase when combined with Epidiolex

Omeprazole (Prilosec) — a common acid reflux medication that is a CYP2C19 substrate

Alcohol and CNS Depressants: Increased Sedation

Epidiolex causes drowsiness on its own. Combining it with alcohol or other central nervous system depressants (sedatives, sleep aids, opioids, certain antihistamines) significantly increases the risk of dangerous sedation. Avoid alcohol while taking Epidiolex and tell your doctor about all medications — including over-the-counter drugs and supplements.

What to Tell Your Doctor Before Starting Epidiolex

Before starting Epidiolex, give your doctor a complete list of:

All prescription antiseizure medications and doses

Any over-the-counter medications (antihistamines, antacids, pain relievers)

Supplements and vitamins (especially St. John's Wort)

Any other CBD products (including over-the-counter CBD oils)

Any history of liver disease or abnormal liver function tests

For more on Epidiolex side effects and when to call your doctor, see our complete Epidiolex side effects guide. If you're struggling to find your Epidiolex prescription, medfinder can help locate specialty pharmacies near you.