Keppra (levetiracetam) has one of the lowest interaction profiles of any seizure medication, but a handful of substances can still cause problems. Some raise the risk of side effects, others can make seizures more likely, and one prescription drug combination carries a serious safety warning. Here’s what to watch for.
Why Keppra Has Fewer Interactions Than Most Seizure Drugs
Most seizure medications are processed through the liver’s main detoxification system (the cytochrome P450 enzymes), which is the same system that breaks down hundreds of other drugs. That overlap is what creates most drug interactions. Keppra largely bypasses this system. About 66% of each dose leaves the body unchanged through urine, and less than 10% binds to proteins in the blood. This means other medications rarely change how much Keppra is circulating in your body, and Keppra rarely changes how other medications work.
That said, “low interaction potential” is not the same as “zero interactions.” The risks that do exist tend to fall into a few specific categories.
Methotrexate: The Most Serious Known Interaction
Methotrexate, used for certain cancers, rheumatoid arthritis, and severe psoriasis, is the clearest high-risk combination with Keppra. Taking both drugs together can slow the body’s ability to clear methotrexate, leading to dangerously high levels in the blood. Health Canada reviewed 13 international reports of this interaction. Five of those cases confirmed elevated methotrexate levels, and some patients developed kidney damage or acute kidney failure.
Kidney damage is already a known risk of methotrexate on its own, but Keppra appears to make it worse by competing for the same elimination pathway through the kidneys. If you take both, your doctor should be monitoring blood levels of each drug closely. This is not a combination to manage without that oversight.
St. John’s Wort
St. John’s Wort, a popular herbal supplement for mood support, is not recommended with any seizure medication, Keppra included. The UK’s medicines safety agency issued a specific warning after a patient taking Keppra, lamotrigine, and clobazam alongside St. John’s Wort experienced a significant increase in both the frequency and severity of seizures.
What makes this interaction tricky is that St. John’s Wort was previously thought to interact with seizure drugs only through liver enzymes, a pathway Keppra doesn’t rely on. The case evidence suggests the interaction happens through a different, less understood mechanism. Both the UK’s Herbal Medicines Advisory Committee and the Commission on Human Medicines now recommend against combining St. John’s Wort with any antiepileptic drug.
Alcohol
Alcohol isn’t strictly off-limits with Keppra, but it deserves caution. Both Keppra and alcohol affect the central nervous system, so combining them can amplify drowsiness and impair coordination more than either would alone. The NHS advises avoiding alcohol entirely during your first few days on Keppra until you understand how the medication affects you.
Beyond the sedation issue, alcohol and hangovers can independently lower the seizure threshold in people with epilepsy. That makes drinking a double risk: it can worsen Keppra’s side effects while simultaneously making seizures more likely.
Over-the-Counter Cold and Allergy Medications
Simple pain relievers like acetaminophen (Tylenol) and ibuprofen (Advil) are generally fine to take with Keppra. The problems start with multi-symptom cold products, which often bundle several active ingredients together.
- Dextromethorphan (the “DM” in many cough syrups) can raise seizure risk, particularly at higher doses.
- Pseudoephedrine and phenylephrine (common decongestants in products like Sudafed) have also been linked to rare seizure-related side effects.
- Diphenhydramine (Benadryl) and other older antihistamines can lower the seizure threshold and add to the drowsiness Keppra already causes.
The safest approach is to read ingredient labels on combination cold products rather than assuming a single box handles everything safely. Newer, non-drowsy antihistamines like cetirizine (Zyrtec) or loratadine (Claritin) are generally better tolerated, but single-ingredient products let you control exactly what you’re taking.
CBD and Cannabis Products
The relationship between CBD and Keppra is more complicated than most people expect. Research shows that CBD can alter both the blood levels and the effectiveness of Keppra, but the direction of that change isn’t consistent. One mouse study found that CBD actually reduced Keppra’s seizure-preventing effects. A clinical study in children with epilepsy found that CBD increased Keppra blood levels, though this wasn’t seen in adults.
On the other hand, a pilot study in rats with temporal lobe epilepsy found that a low dose of CBD combined with Keppra reduced both the number and duration of seizures more than Keppra alone. The science is genuinely mixed, and the interactions may depend on dosing, age, and the type of epilepsy involved. If you’re using or considering CBD products alongside Keppra, your prescriber needs to know so they can monitor for changes in seizure control or side effects.
Other Seizure Medications
Keppra is frequently prescribed alongside other antiepileptic drugs, and for the most part these combinations are well tolerated. Enzyme-inducing seizure medications like carbamazepine, phenytoin, and phenobarbital can modestly increase how quickly your body clears Keppra, potentially lowering its effectiveness slightly. Your doctor typically accounts for this when setting your dose.
The interactions between seizure medications are primarily about fine-tuning effectiveness rather than creating dangerous combinations. Clinical research on specific pairings in humans remains limited, which is why blood level monitoring is standard when multiple seizure drugs are used together.
Birth Control
Unlike many seizure medications, Keppra does not reduce the effectiveness of hormonal birth control. It’s classified as a non-enzyme-inducing antiepileptic, meaning it doesn’t speed up the breakdown of estrogen or progestin. If you’re on the pill, patch, ring, or other hormonal contraceptive, Keppra won’t interfere with it. This is a genuine advantage over older seizure drugs like carbamazepine, phenytoin, and phenobarbital, all of which can make hormonal birth control unreliable.
Sedatives and Sleep Aids
Keppra’s most common side effects include drowsiness, fatigue, and dizziness, especially when you’re first starting it or increasing your dose. Anything else that causes sedation will stack on top of those effects. This includes prescription sleep medications, benzodiazepines (like lorazepam or diazepam), muscle relaxants, and opioid pain medications. The combination isn’t necessarily prohibited, but it can significantly impair your alertness and coordination, making driving or operating machinery risky. If you need any of these medications, starting at the lowest effective dose and paying close attention to how you feel is the practical approach.