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Name: Levetiracetam
Synonyms: Keppra
Chemical Name: (S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Discontinued)
Company: UCB S.A.
Approved for: Epilepsy and Partial Seizures in U.S., European Union, plus about 20 other countries


Levetiracetam is an atypical anti-convulsant medication and a modulator of the synaptic vesicle protein modulator SV2A. It was developed for the treatment of epilepsy but, as a pyrrolidone acetamide, is chemically unrelated to most other anti-convulsives. Levetiracetam is available as an oral syrup, an intravenous infusion, and immediate- and extended-release tablets. Generic equivalents of these formulations are on the market as well, and the drug is widely used. Its side effects include sleepiness, headache, lack of energy, and others.

This compound's mechanism of action is not fully understood. It does not act on the GABAergic system and is inactive at classic receptor sites linked to epileptic seizures, such as amino-acid-related receptors, adenosine receptors, and ion channels (Sills et al., 1997). Early on, inhibition of calcium signaling or depolarizing currents were proposed as possible mechanisms of action (Margineanu and Wülfert, 1997).

In recent years, Alzheimer’s research has characterized Aβ-induced hyperactivation, aberrant network activity, and nonconvulsive seizure phenotypes in the J20APP23, APP/PS1, and in certain strains of Tg2576 transgenic mouse models of AD amyloidosis (Sep 2007 newsLalonde et al., 2005Minkeviciene et al., 2009Shi et al., 2013). In J20 mice, levetiracetam was reported to quiet epileptiform activity in circuits of the medial temporal lobe network, as well as reverse hyperactivity in behavioral assays and deficits in spatial learning assays (Aug 2012 news). Low doses of the drug reportedly reduce hippocampal hyperactivation and improved memory performance in an aging rat model (Koh et al., 2010). In APP knock-in mice, chronic administration of levetiracetam was reported to reduce levels of Aβ42, the β-carboxyl-terminal fragment bur not full-length APP, reduce plaque burden, and to restore levels of presymptomatic endocytic proteins (Rao and Savas, 2021).

In humans, observational research has linked hippocampal hyperactivity and nonconvulsive seizures to cognitive decline in the early stages of Alzheimer's disease, such as amnestic mild cognitive impairment (aMCI, Dec 2011 newsJuly 2013 news; Vossel et al., 2016). Further studies reported that seizures or subclinical epileptiform brain activity in people with AD coincide with faster loss of cognitive capabilities and more severe disease (Horvath et al., 2021; Voglein et al., 2020).

A proprietary, low-dose formulation of levetiracetam, AGB101, is in a Phase 3 trial evaluating its ability to improve cognition and slow disease progression in people with MCI and AD.


A one-year study of levetiracetam at 500-2,000 mg daily in Alzheimer's patients who had seizures reported improved attention, verbal fluency, and good tolerability for its use in controlling seizures in AD (Cumbo and Ligori, 2010). It is unclear whether these benefits derived from reduced seizures or global cognitive benefits.

Levetiracetam doses of 1,000 mg/day are routinely used in older people with epilepsy. Several studies have examined lower doses to see if they can normalize brain activity and improve cognition in people with mild cognitive impairment or AD. In one single-center, placebo-controlled Phase 2 trial of low-dose levetiracetam, 17 people with aMCI and 17 age-matched controls who received a two-week course of 250 mg daily reportedly reduced hippocampal activity as measured by fMRI and improved performance on a hippocampal memory task. Other tests in a neuropsychological test battery showed no response (May 2012 news).

In 2010–2012, researchers at Johns Hopkins University Medical School conducted a within-subject crossover, dose-finding Phase 2 study of low-dose levetiracetam in people with amnestic mild cognitive impairment (aMCI) and a clinical dementia rating (CDR) of 0.5 at screening; controls had a CDR of zero. The trial compared 125, 250, and 500 mg of levetiracetam per day against placebo for their effect on neuronal activity in the hippocampus and entorhinal cortex, as well as for performance on a memory task performed while in an MRI scanner. The study enrolled 69 aMCI patients and 24 controls, and analyzed data from 54 patients and 17 controls; 15 participants dropped out; seven moved while inside the scanner. At the two lower doses, levetiracetam was reported to have improved performance on the scanning memory task; the highest dose yielded no further improvement. The low doses were also reported to have reduced abnormal hyperactivity in the hippocampal dentate gyrus and CA3 regions, and to have boosted abnormal hypoactivation in the entorhinal cortex, both measured by fMRI. Full results were published in a peer-reviewed journal (for paper and commentary, see Bakker et al., 2015).

A 2012–2013 study at Beth Israel Deaconess Medical Center, Boston, compared single administration of 2.5 mg/kg and 7.5 mg/kg of levetiracetam to placebo. This trial enrolled 12 patients with mild AD and seizures, and used perfusion MRI to evaluate whether levetiracetam normalized blood flow in the course of controlling seizures. Memory and executive function tests were secondary outcomes. A paper on this study did not report on blood flow; it did report that the higher dose had network effects, specifically changes in coherence of the delta, low-beta, and high-beta bands. Cognition was unchanged (Musaeus et al., 2017). 

In June 2014, a Phase 2a study at the University of California, San Francisco, and the University of Minnesota, Twin Cities, began enrolling 34 people with AD. This 12-week cross-over trial evaluated 125 mg twice-daily levetiracetam for its ability to improve executive function as per the NIH-EXAMINER composite score, reduce the frequency of epileptiform activity, and improve cognitive function and performance on a virtual navigation task. The trial was originally intended only for people with evidence of seizure activity, but that requirement was later dropped to speed recruitment. The study was completed in July 2020, and results are published (Vossel et al., 2021). Levetiracetam treatment did not change the primary outcome, or any secondary measures in the group as a whole. In a subgroup analysis that compared nine participants with epileptiform brain activity to 13 without, the drug improved performance on two secondary outcomes related to executive function and the navigational task in those with clinical or subclinical seizures. Adverse events were mild; no one left the study because of side effects.

An additional Phase 2 study at Beth Israel Deaconess Medical Center began in August 2019, to determine whether levetiracetam normalizes cortical hyperexcitability, brain network function abnormalities, and cognitive dysfunction in 85 people with early AD. Participants must be between 50 and 80 years old, with a positive PET or CSF markers for brain amyloid, and a Clinical Dementia Rating of 0.5–1.0. In a crossover design, patients receive placebo, 250 mg, or 1000 mg levetiracetam daily for four weeks, with a four-week washout between. Primary outcome measures include change in neuropsychological test battery, plus EEG and other measures of cortical excitability and functional connectivity. Healthy controls with CDR=0 will also be evaluated, but receive no treatment. The trial will end in November 2023.

In October 2018, a Phase 2 study at the University of Oxford began enrolling 30 participants with mild to moderate AD and no history of previous seizures to receive levetiracetam 1,000 mg per day for four weeks. Primary outcome is change in accuracy on a computer-based hippocampal-dependent memory test; secondary outcomes include safety, mood, quality of life. Participants will get an EEG before the study to look for patterns that predict who will benefit from the treatment. The protocol for this study, named ILiAD, is published (Sen et al., 2021).

Starting in January 2020, a Phase 2 trial at Walter Reed National Military Medical Center, Bethesda, Maryland, will enroll 65 participants with clinical AD and neuropsychiatric symptoms. Those with detectable epileptiform activity on EEG will receive 500 mg levetiracetam twice a day for one year. The primary outcome is change on the neuropsychiatric inventory; secondary outcomes include change in measures of AD severity, quality of life, and cognitive ability.

Levetiracetam has also been tested in patients with Parkinson's disease. Prompted by preclinical data suggesting that levetiracetam reduces side effects of long-term levodopa therapy in nonhuman primates (Bezard et al., 2004), numerous small clinical trials were conducted in patients with Parkinson's and levodopa-induced dyskinesia. One pilot trial reported longer “on” time without dyskinesia and shorter “off” time with dyskinesia, but subsequent randomized controlled trials produced mixed results. Some studies indicated modest improvement, others did not, and yet others cautioned that PD patients poorly tolerated levetiracetam (see Wolz et al., 2010; Stathis et al., 2011; Wong et al., 2011; Lyons and Pahwa, 2006).

For clinical trials on levetiracetam in MCI/AD, see

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034

Last Updated: 06 Oct 2021


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News Citations

  1. Epilepsy Drug Calms the Hippocampus, Aids Memory
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?
  3. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
  4. Research Brief: Hippocampal Hyperactivity Tied to Early MCI Atrophy
  5. Epilepsy in Alzheimer’s Can Be Early and Subtle

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)
  2. APP23
  3. APPPS1
  4. Tg2576

Therapeutics Citations

  1. AGB101

Paper Citations

  1. . Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Epilepsy Behav. 2010 Apr;17(4):461-6. PubMed.
  2. . Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688-98. Epub 2015 Feb 21 PubMed.
  3. . Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1065-1076. PubMed.
  4. . Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial. JAMA Neurol. 2021 Nov 1;78(11):1345-1354. PubMed.
  5. . An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study. Trials. 2021 Jul 31;22(1):508. PubMed.
  6. . Levetiracetam improves choreic levodopa-induced dyskinesia in the MPTP-treated macaque. Eur J Pharmacol. 2004 Feb 6;485(1-3):159-64. PubMed.
  7. . Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. J Neural Transm. 2010 Nov;117(11):1279-86. Epub 2010 Aug 29 PubMed.
  8. . Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2011 Feb 1;26(2):264-70. Epub 2010 Dec 13 PubMed.
  9. . A randomized, double-blind, placebo-controlled trial of levetiracetam for dyskinesia in Parkinson's disease. Mov Disord. 2011 Jul;26(8):1552-5. Epub 2011 Apr 29 PubMed.
  10. . Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol. 2006 May-Jun;29(3):148-53. PubMed.
  11. . Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol. 1997 Apr 23;325(1):35-40. PubMed.
  12. . Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus. Br J Pharmacol. 1997 Nov;122(6):1146-50. PubMed.
  13. . Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen. Behav Brain Res. 2005 Feb 10;157(1):91-8. PubMed.
  14. . Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009 Mar 18;29(11):3453-62. PubMed.
  15. . Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice. CNS Neurosci Ther. 2013 Nov;19(11):871-81. PubMed.
  16. . Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. PubMed.
  17. . Levetiracetam Treatment Normalizes Levels of Presynaptic Endocytosis Machinery and Restores Nonamyloidogenic APP Processing in App Knock-in Mice. J Proteome Res. 2021 Jul 2;20(7):3580-3589. Epub 2021 Jun 9 PubMed.
  18. . Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. Epub 2016 Nov 7 PubMed.
  19. . Subclinical epileptiform activity accelerates the progression of Alzheimer's disease: A long-term EEG study. Clin Neurophysiol. 2021 Aug;132(8):1982-1989. Epub 2021 May 8 PubMed.
  20. . Seizures in Alzheimer's disease are highly recurrent and associated with a poor disease course. J Neurol. 2020 Oct;267(10):2941-2948. Epub 2020 Jun 2 PubMed.

External Citations


Further Reading


  1. . Seizures in patients with Alzheimer's disease or vascular dementia: A population-based nested case-control analysis. Epilepsia. 2012 Dec 6; PubMed.
  2. . Levetiracetam: a practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimers Dis Other Demen. 2010 Mar;25(2):149-54. PubMed.
  3. . "Untangling" Alzheimer's disease and epilepsy. Epilepsy Curr. 2012 Sep;12(5):178-83. PubMed.
  4. . Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging. 2003;20(11):791-803. PubMed.
  5. . Effects of levetiracetam, an antiepileptic drug, on memory impairments associated with aging and Alzheimer's disease in mice. Neurobiol Learn Mem. 2013 May;102:7-11. PubMed.
  6. . Advanced Alzheimer's disease is a risk factor for late-onset seizures. Arch Neurol. 1990 Aug;47(8):847-50. PubMed.
  7. . Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur J Neurol. 2007 Oct;14(10):1176-8. PubMed.
  8. . Levetiracetam for agitated Alzheimer's disease patients. Int Psychogeriatr. 2005 Jun;17(2):327-8. PubMed.
  9. . Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2005 Sep;20(9):1205-9. PubMed.
  10. . Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics. 2017 Jul;14(3):662-676. PubMed.
  11. . Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. Neuroreport. 2016 Jun 15;27(9):705-9. PubMed.
  12. . A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. J Alzheimers Dis. 2015;50(1):201-15. PubMed.
  13. . Investigating Neuroprotective Potential of Berberine, Levetiracetam and Their Combination in The Management of Alzheimer's Disease Utilizing Drug Repurposing Strategy. Curr Rev Clin Exp Pharmacol. 2021 Sep 9; PubMed.
  14. . Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer's Disease Model. Cell Rep. 2019 Jun 25;27(13):3741-3751.e4. PubMed.