Levetiracetam, commonly sold as Keppra, is one of the most widely prescribed seizure medications, and most people tolerate it well over the long term. But it does carry a distinct set of side effects that can persist or emerge during extended use. The most notable are behavioral and mood changes, with roughly 10% of users experiencing irritability. Beyond mood, long-term use at higher doses has been linked to cognitive effects, a small but real increase in suicidal thinking, and a possible connection to kidney problems in rare cases.
Irritability, Aggression, and “Keppra Rage”
The side effect most associated with levetiracetam is a shift in mood and behavior that patients and caregivers sometimes call “Keppra rage.” This isn’t a formal medical term, but it captures something real. In a systematic review of behavioral side effects across several seizure medications, levetiracetam was associated with irritability in about 9.9% of users, anger in 2.5%, and outright aggressiveness in 2.6%. These effects can appear even in people with no prior psychiatric history.
For most people, these behavioral changes are manageable or mild. But they’re significant enough that between 2.4% and 3.4% of users in clinical studies stopped taking the drug specifically because of aggression or irritability. The doses linked to these effects ranged from 1,000 to about 2,100 mg per day, which covers most standard prescribing ranges.
More serious psychiatric effects, including psychosis and suicidal thoughts, are uncommon but documented. Pooled data from 199 placebo-controlled trials of seizure medications (not just levetiracetam) found that patients taking these drugs had roughly twice the risk of suicidal thinking or behavior compared to those on placebo. In practical terms, that translates to about one additional case for every 530 people treated. The FDA requires a warning about this risk on all seizure medication labels.
Cognitive Effects at Higher Doses
If you’ve been on levetiracetam for a long time and feel like your thinking has slowed down or your memory isn’t as sharp, you’re not imagining it. Research shows that at higher doses, particularly when combined with other seizure medications, levetiracetam is associated with measurable cognitive impairment. The areas most affected are language, attention, and delayed verbal recall, which is your ability to remember spoken information after a delay.
One study found that patients on high doses of levetiracetam were 4.5 times more likely to score below normal on cognitive testing compared to people not taking any seizure medication. This is an important distinction: the cognitive effects appear to be dose-dependent, meaning they’re more pronounced at higher doses and when levetiracetam is part of a multi-drug regimen. People on lower doses as their only seizure medication are less likely to notice these changes.
Bone Health and Metabolism
Many older seizure medications are known to weaken bones over time, which makes this a common concern for anyone on long-term treatment. Levetiracetam appears to be safer in this regard. A meta-analysis of 13 studies covering 612 patients found no significant decrease in bone mineral density at the femoral neck or lumbar spine in people taking levetiracetam.
There is one metabolic change worth noting: levetiracetam was associated with a modest decrease in serum calcium levels. Other bone-related markers, including vitamin D, phosphorus, and parathyroid hormone, were not significantly affected. So while levetiracetam doesn’t appear to carry the same bone-thinning risk as some alternatives, keeping an eye on calcium intake is reasonable during long-term use.
Kidney Function
Levetiracetam is primarily cleared through the kidneys rather than the liver, which is one reason it’s often chosen for people with liver concerns. However, this kidney processing has raised questions about long-term kidney safety. Health Canada conducted a safety review after more than 150 international reports of acute kidney injury were identified in the World Health Organization’s adverse drug reaction database. After reviewing 39 of those cases in depth, the WHO concluded that levetiracetam had possibly caused acute kidney injury in some patients.
Many of those cases involved other contributing factors, such as pre-existing conditions or other medications. The risk appears to be rare, but Health Canada’s review confirmed that a link between levetiracetam and kidney injury could not be ruled out. Liver toxicity, by contrast, is not a well-documented concern with this drug, and routine blood monitoring is generally not required the way it is with some other seizure medications like valproate.
Effects in Children
Parents of children on levetiracetam often worry about whether the drug could affect development over time. The available evidence is somewhat reassuring but limited. In a study comparing infants treated with levetiracetam to those treated with an older seizure medication, there was no significant difference in cognitive, language, or motor development scores on standardized testing. No children in the study had to stop treatment because of side effects, and no concerning changes appeared in blood work.
That said, the behavioral side effects seen in adults also occur in children, and younger patients may have a harder time articulating mood changes. Irritability and behavioral shifts are worth watching for closely, especially in school-age children where these changes can affect social interactions and learning.
Managing Side Effects
Vitamin B6 (pyridoxine) has gained attention as a potential way to reduce levetiracetam’s behavioral side effects. A randomized, double-blind controlled study tested pyridoxine supplementation against placebo in patients experiencing irritability and aggression from levetiracetam. The study found enough promise that this approach is sometimes used in clinical practice, though the optimal dose hasn’t been firmly established.
For cognitive side effects, the most effective strategy is keeping the dose as low as possible while still controlling seizures, and minimizing the number of seizure medications taken simultaneously. If you’re on multiple medications and noticing memory or attention problems, that combination is worth discussing with your neurologist.
Stopping After Long-Term Use
Levetiracetam should not be stopped abruptly. The American Academy of Neurology advises that even people who have been seizure-free for two years (or 1.5 to two years for children) face a risk of seizures returning when they stop their medication. In rare cases, the medication may not work as well if restarted after stopping. Any plan to discontinue levetiracetam should involve a gradual taper supervised by your prescribing doctor, typically over weeks, to minimize the risk of breakthrough seizures.