What Not to Take With Keppra: Drugs, Herbs & More

Levetiracetam, sold as Keppra, is one of the cleanest seizure medications when it comes to drug interactions. Unlike older antiepileptic drugs, it barely touches the liver’s enzyme system, which means the long lists of clashing medications that come with drugs like phenytoin or carbamazepine mostly don’t apply here. That said, “fewer interactions” is not the same as “no interactions,” and a handful of drugs, supplements, and everyday substances deserve real attention if you’re taking Keppra.

Why Keppra Is Unusually Interaction-Friendly

Most drug interactions happen because two medications compete for the same liver enzymes, or one drug speeds up or slows down how the liver processes the other. Keppra sidesteps this problem almost entirely. About two-thirds of each dose leaves the body unchanged through the kidneys, and the remaining third is broken down by a pathway that doesn’t rely on the cytochrome P450 enzyme system, the set of liver enzymes responsible for the vast majority of drug-drug interactions. Keppra also doesn’t bind much to proteins in the blood, which eliminates another common source of competition between drugs.¹ It doesn’t speed up or slow down liver enzymes, so it won’t alter the levels of most other medications you take alongside it.²

This profile is genuinely unusual among seizure drugs and is one of the main reasons Keppra became so widely prescribed. But “low interaction risk” creates a false sense of security for some patients, who assume they can combine it with anything without a second thought. The interactions that do exist tend to be pharmacodynamic rather than pharmacokinetic. Instead of one drug changing another’s blood levels, both drugs push the brain or body in the same direction at the same time, sometimes amplifying side effects or undermining seizure control.

Methotrexate

One of the better-documented pharmacokinetic interactions involves methotrexate, a drug used in cancer treatment and certain autoimmune conditions like rheumatoid arthritis. Because both Keppra and methotrexate rely heavily on the kidneys for elimination, taking them together can slow the clearance of methotrexate from the body. Delayed methotrexate elimination raises the risk of methotrexate toxicity, which can damage the kidneys, liver, and bone marrow.³ If you’re receiving methotrexate for any reason, your oncologist or rheumatologist and your neurologist need to be aware of the overlap. Close monitoring of methotrexate levels is typically the solution rather than switching medications, but the combination should never fly under the radar.

Caffeine and Seizure Control

This one surprises most people. Caffeine is so embedded in daily life that patients rarely mention it when listing what they take, and clinicians don’t always ask. But animal research has shown that caffeine can reduce Keppra’s protective effect against seizures. In a mouse study testing electroshock seizure thresholds, caffeine weakened levetiracetam’s anticonvulsant effect without changing the drug’s concentration in the brain, meaning the interference was not about absorption or metabolism but about caffeine working against the drug at the level of brain activity itself.⁴

Animal data doesn’t always translate directly to humans, and nobody is running controlled caffeine trials in epilepsy patients for obvious ethical reasons. But the mechanism makes pharmacological sense: caffeine is a stimulant that lowers the seizure threshold, while Keppra is trying to raise it. The two push in opposite directions. This doesn’t mean you need to swear off coffee entirely, but if you’re experiencing breakthrough seizures and you drink large amounts of caffeine, it’s worth discussing with your neurologist. Moderation is a reasonable starting point.

Ginkgo Biloba and Herbs That Lower the Seizure Threshold

Herbal supplements sit in a regulatory blind spot. They don’t undergo the same testing as prescription drugs, and many patients don’t think of them as “medications” when asked about their drug list. For someone on Keppra, the most concerning category is herbs that can lower the seizure threshold, effectively working against the medication.

Ginkgo biloba is probably the best-known example. While the leaf extract commonly sold as a memory supplement is usually the focus, ginkgo nuts contain a potent neurotoxin that is known to induce seizure activity.⁵ The risk is highest with whole ginkgo nut consumption and with products of uncertain standardization, but even standardized leaf extracts have raised concerns among epileptologists. Other herbs that may lower seizure threshold include ephedra (ma huang), evening primrose oil, and high-dose essential oils like eucalyptus and rosemary.

The challenge is that evidence for most herbal interactions is fragmented: isolated case reports, animal studies, and pharmacological reasoning rather than clinical trials. That makes it hard to give you a definitive list of banned supplements. The practical rule is straightforward: tell your neurologist about every supplement you take, including “natural” products, and be especially cautious with anything marketed as a stimulant or neuro-active compound.

Cannabidiol (CBD)

CBD products have exploded in popularity, and many people with epilepsy are curious about combining them with their existing medication. There is a pharmaceutical-grade CBD (Epidiolex) approved for certain severe epilepsy syndromes, and its interaction profile with other seizure drugs has been studied in some detail. In an expanded access program combining CBD with multiple antiseizure medications, researchers found that increasing CBD doses led to significant increases in levetiracetam blood levels, an effect that was more pronounced in children than adults.⁶

Higher levetiracetam levels can increase the likelihood of side effects like drowsiness, dizziness, and the irritability Keppra is already known for. If you’re using any CBD product alongside Keppra, your prescriber may need to check drug levels and potentially adjust your Keppra dose. Keep in mind that over-the-counter CBD oils and gummies are far less standardized than pharmaceutical-grade cannabidiol, making the interaction even harder to predict. The dose of CBD you’re actually getting from a dispensary product can vary wildly from what’s on the label.

Alcohol and Sedating Medications

Keppra can cause drowsiness, dizziness, and fatigue on its own. Anything else that depresses the central nervous system will stack on top of those effects. Alcohol is the most obvious example: combining it with Keppra intensifies sedation and impairs coordination and judgment more than either substance alone. Alcohol also independently lowers seizure threshold, particularly during withdrawal or the “rebound” period after heavy drinking. For someone taking a seizure medication, this is a double problem.

The same layering concern applies to prescription sedatives like benzodiazepines (lorazepam, clonazepam), opioid pain medications, sleep aids like zolpidem, and sedating antihistamines like diphenhydramine (Benadryl). None of these typically alter Keppra’s blood levels through liver enzyme competition, but the combined sedation can be enough to impair daily functioning, increase fall risk, or cause respiratory depression when opioids are involved. If you need any of these medications, the combination isn’t necessarily off-limits, but it usually warrants dose adjustments and close monitoring.

Antidepressants

Depression and anxiety are common in people with epilepsy, so co-prescribing seizure medications with antidepressants is routine. Keppra’s clean metabolic profile means it won’t usually alter the blood levels of SSRIs, SNRIs, or other antidepressants through liver enzyme interference. But one antidepressant deserves special caution: bupropion (Wellbutrin). Bupropion is well known to lower the seizure threshold in a dose-dependent manner, and it carries an FDA-recognized seizure risk. Combining it with any seizure medication requires careful clinical judgment, and many neurologists avoid the pairing entirely in patients with poorly controlled epilepsy.

Tricyclic antidepressants (like amitriptyline and nortriptyline) also carry some seizure risk at higher doses, though the effect is less dramatic than with bupropion. The broader point is that pharmacodynamic interactions, where two drugs push the brain in conflicting directions without directly affecting each other’s levels, matter just as much as the pharmacokinetic kind. If you’re starting or adjusting an antidepressant while on Keppra, your providers should be coordinating.

What About Birth Control?

This is one of the genuine bright spots. Several older seizure drugs, particularly carbamazepine, phenytoin, and phenobarbital, are notorious for reducing the effectiveness of hormonal contraceptives by speeding up the liver enzymes that break them down. Keppra does not do this. Research has confirmed that levetiracetam does not interact with combined oral contraceptive pills, progestin-only pills, medroxyprogesterone injections, or levonorgestrel implants, meaning normal-dose contraceptive preparations can be used without adjustment.⁷ If you’re switching from an enzyme-inducing seizure drug to Keppra, you may actually be able to use a wider range of birth control options than before.

Over-the-Counter Pain Relievers and Kidney Health

Because Keppra is cleared primarily through the kidneys, anything that impairs kidney function could theoretically slow its elimination and raise drug levels. Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen can reduce kidney blood flow, particularly with frequent or long-term use, in older adults, or in people who are dehydrated. Occasional use of an NSAID for a headache is unlikely to cause problems in someone with healthy kidneys. But chronic, high-dose NSAID use alongside Keppra is worth flagging with your doctor, especially if you already have any degree of kidney impairment.

Acetaminophen (Tylenol) is metabolized primarily by the liver and doesn’t affect kidney function in the same way, making it a generally safer over-the-counter pain option for people on Keppra, provided you stay within recommended doses. This is one of those practical details that rarely comes up in the prescribing conversation but matters in everyday life.

Food, Tube Feeding, and Absorption

Some seizure medications are sensitive to food timing: phenytoin absorption, for example, can be altered by enteral nutrition formulas in tube-fed patients, leading to erratic blood levels and seizure breakthroughs. Keppra doesn’t share this vulnerability. A study testing levetiracetam absorption when mixed with food and enteral nutrition formulas found no significant differences in how much drug reached the bloodstream compared to taking it on an empty stomach.⁸ You can take Keppra with or without meals, and if you receive nutrition through a feeding tube, the drug can be administered through the tube without special hold protocols.

Vitamin B6 and Managing Keppra’s Behavioral Side Effects

Keppra’s most talked-about side effect is irritability, sometimes described as “Keppra rage.” It can show up as mood swings, agitation, aggressive behavior, or a short fuse that feels out of character. This is not technically a drug interaction issue, but it’s relevant because the remedy involves a supplement, and people frequently ask whether adding something to their regimen can help.

Several studies have looked at whether vitamin B6 (pyridoxine) can reduce Keppra-related behavioral side effects. In a case series from the UAE, about two-thirds of patients who started pyridoxine while on levetiracetam showed significant behavioral improvement.⁹ A study in U.S. veterans found more mixed results, with roughly half of patients reporting subjective improvement in irritability after starting B6.¹⁰ In children, a prospective study found pyridoxine to be both safe and effective for controlling levetiracetam-induced behavioral adverse effects.¹¹

The evidence is encouraging but still based on small studies without large randomized trials. Many neurologists will suggest trying B6 before abandoning Keppra entirely, since it’s well tolerated and inexpensive. Typical doses in the studies ranged from about 50 to 200 mg daily, but the right amount for you should come from your prescriber. Very high doses of B6 over long periods can cause nerve problems, so this isn’t a “more is better” situation.

Folic Acid During Pregnancy

Women of childbearing age who take any antiseizure medication face a heightened concern about pregnancy outcomes. For Keppra specifically, the drug is considered one of the lower-risk seizure medications during pregnancy in terms of major birth defects, but there’s an important supplement angle. A large Norwegian study found that children exposed to antiepileptic drugs in utero had a much higher risk of autistic traits if their mothers did not take folic acid supplements during pregnancy. The adjusted odds were roughly six times higher at 18 months and eight times higher at 36 months compared to AED-exposed children whose mothers did supplement with folic acid.¹²

This finding applied across antiepileptic drugs generally, not just levetiracetam. But the takeaway is concrete: if you’re on Keppra and there’s any chance you could become pregnant, folic acid supplementation is not optional. Most epilepsy guidelines already recommend higher-than-standard folic acid doses (often 1 to 5 mg daily rather than the usual 0.4 mg prenatal dose) for women on seizure medication. This is one area where a supplement isn’t just compatible with Keppra but appears to be actively protective.

Drugs That Affect Kidney Function

Since Keppra depends on the kidneys for elimination, any medication or condition that substantially reduces kidney function can cause the drug to accumulate, raising both its effectiveness and its side effects. Beyond NSAIDs, this includes certain antibiotics (aminoglycosides like gentamicin, amphotericin B), some blood pressure medications (ACE inhibitors and ARBs in patients with already compromised kidneys), and contrast dyes used in imaging studies. None of these represent a strict contraindication with Keppra, but if your kidney function drops for any reason, your Keppra dose likely needs to be reduced.

This is particularly relevant for older adults, who often have declining kidney function that hasn’t been formally diagnosed. If you’re over 65 and on Keppra, periodic kidney function checks are standard practice. Dehydration from illness, intense exercise, or simply not drinking enough can also transiently reduce kidney clearance. During a stomach bug or any illness that leaves you unable to keep fluids down, watch for increased drowsiness or dizziness that might signal rising Keppra levels.

Energy Drinks and High-Stimulant Supplements

Energy drinks combine caffeine with other stimulant compounds like guarana (another caffeine source), taurine, and sometimes herbal extracts. Given the animal evidence that caffeine can undermine Keppra’s seizure protection, energy drinks are a concentrated version of that concern. Some products contain the caffeine equivalent of several cups of coffee in a single can, plus additional stimulants whose interactions with seizure medications are essentially unstudied. Pre-workout supplements marketed to athletes fall into the same category: high-stimulant, minimally regulated, and designed to rev up the nervous system, which is exactly what someone on an anti-seizure drug doesn’t want happening unpredictably.

If you rely on caffeine to get through the day (which is common, since Keppra itself causes fatigue), a measured amount of coffee or tea is a more controllable choice than energy drinks or supplements with unclear ingredient lists. Keeping your caffeine intake consistent from day to day also avoids the seizure-threshold fluctuations that come with binging and then withdrawing from caffeine.