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

One of levetiracetam's key advantages over many other antiepileptic drugs (AEDs) is its relatively clean drug interaction profile. Because it's minimally metabolized by the liver and barely protein-bound, it doesn't compete with most medications for the same metabolic pathways. But "relatively clean" doesn't mean "interaction-free." Here's what you and your doctor need to know.

Why Levetiracetam Has Fewer Interactions Than Most AEDs

Many drugs interact because they compete for the same liver enzymes (especially the cytochrome P450 system) or protein binding sites in the blood. Levetiracetam sidesteps most of this: it's only about 2.5% metabolized by the liver (via hydrolysis, not P450), is less than 10% protein-bound, and is 66% excreted unchanged by the kidneys. This makes it compatible with most medications that AED patients commonly take.

Major Interactions to Avoid

• Opioids (codeine, oxycodone, oxymorphone, hydrocodone): Both levetiracetam and opioids depress the central nervous system. Combining them significantly increases the risk of excessive sedation, respiratory depression, and dangerously slowed breathing. The combination with codeine, oxycodone, and oxymorphone carries an FDA "avoid or use alternative drug" recommendation. If opioids are medically necessary, use the lowest effective dose with close monitoring.
• Alcohol: Alcohol is a CNS depressant. Drinking while taking levetiracetam increases drowsiness, impairs coordination, and lowers seizure threshold. Patients on levetiracetam should avoid or strictly limit alcohol consumption.
• Cannabis: Like alcohol, cannabis (THC) enhances CNS depression when combined with levetiracetam. Additionally, CBD products may have complex interactions with seizure medications. Always tell your neurologist if you use cannabis or CBD products.

Moderate Interactions: Monitor Closely

• Enzyme-inducing AEDs (carbamazepine, phenytoin, primidone, phenobarbital): These drugs induce liver enzymes that process levetiracetam, increasing its clearance by 9–22%. This means levetiracetam levels may be lower when taken alongside these drugs, potentially reducing seizure control. Your neurologist may need to adjust your levetiracetam dose.
• Valproic acid / valproate (Depakote): Valproate decreases the clearance of levetiracetam by about 18.8%, potentially increasing levetiracetam levels. Watch for enhanced CNS depression and side effects when these are used together.
• Orlistat (Alli, Xenical): This weight-loss drug reduces intestinal absorption of levetiracetam, potentially decreasing its blood levels and risking breakthrough seizures. Use with caution and monitor seizure control closely.
• Other CNS depressants (benzodiazepines, sleep aids, muscle relaxants, antihistamines, antipsychotics): Any medication that causes drowsiness will have additive effects with levetiracetam. This includes prescription and over-the-counter options. Discuss all sedating medications with your pharmacist or doctor.

Levetiracetam's Effect on Other Drugs

In most cases, levetiracetam does not significantly affect the levels of other medications in your system. Studies show no significant impact on the levels of carbamazepine, valproic acid, lamotrigine, topiramate, phenytoin, digoxin, warfarin, or oral contraceptives. This is a significant advantage over older AEDs that are potent enzyme inducers or inhibitors.

However, levetiracetam may:

• Decrease levels of dabigatran and rivaroxaban (blood thinners) by an unknown mechanism — monitor anticoagulation closely
• Reduce vitamin B12 (cyanocobalamin) absorption slightly — consider monitoring B12 levels long-term
• Reduce levocarnitine levels slightly — relevant for patients already at risk of carnitine deficiency

Food, Supplement, and Herbal Interactions

Unlike some seizure medications, levetiracetam has no significant interactions with common foods. However:

• Alcohol: Avoid or limit — potentiates CNS depression and lowers seizure threshold.
• CBD oil / cannabidiol: May have unpredictable interactions with levetiracetam and other AEDs. Always disclose CBD use to your neurologist.
• St. John's Wort: Although direct data for levetiracetam is limited, St. John's Wort induces liver enzymes and could theoretically reduce levels of some AEDs. Avoid use without physician guidance.

What to Tell Your Doctor and Pharmacist

Before starting levetiracetam—and at every appointment—tell your healthcare team about:

• All prescription and over-the-counter medications, including pain relievers, sleep aids, and allergy medicines
• All vitamins, supplements, and herbal products
• Alcohol or cannabis use
• Any changes in seizure frequency after adding or removing any medication
• Kidney disease or changes in kidney function (since levetiracetam is renally cleared)

Having trouble finding levetiracetam at your pharmacy? Use medfinder to locate it near you. Also see: Levetiracetam Side Effects: What to Expect and When to Call Your Doctor.