{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:30:33Z","timestamp":1782390633560,"version":"3.54.5"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BPER Banca"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Refractoriness to antiseizure medications is still a major concern in the pharmacotherapy of epilepsy. For this reason, we decided to evaluate the combination of levetiracetam and cannabidiol, administered at a subthreshold dose, to limit the possible adverse effects of this phytocannabinoid. We administered levetiracetam (300 mg\/kg\/day, via osmotic minipumps), cannabidiol (120 mg\/kg\/day, injected once a day subcutaneously), or their combination for one week in epileptic rats. Saline-treated epileptic rats were the control group. Animals were monitored with video electroencephalography the week before and after the treatment. No changes were found in the controls. Levetiracetam did not significantly reduce the total seizure number or the overall seizure duration. Still, the overall number of seizures (p &lt; 0.001, Duncan\u2019s new multiple range test) and their total duration (p &lt; 0.01) increased in the week following treatment withdrawal. Cannabidiol did not change seizures when administered as a single drug. Instead, levetiracetam combined with cannabidiol resulted in a significant reduction in the overall number and duration of seizures (p &lt; 0.05), when comparing values measured during treatment with both pre- and post-treatment values. These findings depended on changes in convulsive seizures, while non-convulsive seizures were stable. These results suggest that cannabidiol determined a remarkable potentiation of levetiracetam antiseizure effects at a subthreshold dose.<\/jats:p>","DOI":"10.3390\/ph17091187","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T03:16:51Z","timestamp":1725938211000},"page":"1187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Subthreshold Cannabidiol Potentiates Levetiracetam in the Kainic Acid Model of Temporal Lobe Epilepsy: A Pilot Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-2948","authenticated-orcid":false,"given":"Chiara","family":"Lucchi","sequence":"first","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Marcucci","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kawther Ameen Muhammed Saeed","family":"Aledresi","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-7315","authenticated-orcid":false,"given":"Giuseppe","family":"Cannazza","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7130-2511","authenticated-orcid":false,"given":"Giuseppe","family":"Biagini","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1056\/NEJMoa1611618","article-title":"Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome","volume":"376","author":"Devinsky","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1001\/jamaneurol.2020.0073","article-title":"Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial","volume":"77","author":"Miller","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1714631","article-title":"Effect of Cannabidiol on Drop Seizures in the Lennox\u2013Gastaut Syndrome","volume":"378","author":"Devinsky","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0140-6736(18)30136-3","article-title":"Cannabidiol in Patients with Seizures Associated with Lennox-Gastaut Syndrome (GWPCARE4): A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial","volume":"391","author":"Thiele","year":"2018","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1001\/jamaneurol.2020.4607","article-title":"Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial","volume":"78","author":"Thiele","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114237","DOI":"10.1016\/j.expneurol.2022.114237","article-title":"Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies","volume":"359","author":"Reddy","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1111\/jvim.16912","article-title":"The Efficacy and Safety of Cannabidiol as Adjunct Treatment for Drug-resistant Idiopathic Epilepsy in 51 Dogs: A Double-blinded Crossover Study","volume":"37","author":"Rozental","year":"2023","journal-title":"J. Vet. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/epi.17496","article-title":"Long-term Efficacy and Safety of Cannabidiol in Patients with Treatment-resistant Epilepsies: Four-year Results from the Expanded Access Program","volume":"64","author":"Szaflarski","year":"2023","journal-title":"Epilepsia"},{"key":"ref_9","first-page":"630853","article-title":"A Review of the Epidemiology of Temporal Lobe Epilepsy","volume":"2012","year":"2012","journal-title":"Epilepsy Res. Treat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1111\/epi.16973","article-title":"Antiseizure Effects of the Cannabinoids in the Amygdala-kindling Model","volume":"62","author":"Fallah","year":"2021","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/epi.14629","article-title":"Cannabidiol Reduces Seizures and Associated Behavioral Comorbidities in a Range of Animal Seizure and Epilepsy Models","volume":"60","author":"Patra","year":"2019","journal-title":"Epilepsia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1111\/epi.16531","article-title":"Evaluation of Subchronic Administration of Antiseizure Drugs in Spontaneously Seizing Rats","volume":"61","author":"Thomson","year":"2020","journal-title":"Epilepsia"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Costa, A.-M., Russo, F., Senn, L., Ibatici, D., Cannazza, G., and Biagini, G. (2022). Antiseizure Effects of Cannabidiol Leading to Increased Peroxisome Proliferator-Activated Receptor Gamma Levels in the Hippocampal CA3 Subfield of Epileptic Rats. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050495"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.eplepsyres.2008.09.003","article-title":"No Major Role of Common SV2A Variation for Predisposition or Levetiracetam Response in Epilepsy","volume":"83","author":"Lynch","year":"2009","journal-title":"Epilepsy Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Costa, A.-M., Lucchi, C., Malko\u00e7, A., Rustichelli, C., and Biagini, G. (2021). Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020127"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0013-4694(72)90177-0","article-title":"Modification of Seizure Activity by Electrical Stimulation: II. Motor Seizure","volume":"32","author":"Racine","year":"1972","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/WCO.0b013e32833735cf","article-title":"Neurosteroids and Epilepsy","volume":"23","author":"Biagini","year":"2010","journal-title":"Curr. Opin. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"L\u00e9vesque, M., Biagini, G., and Avoli, M. (2020). Neurosteroids and Focal Epileptic Disorders. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249391"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1124\/jpet.123.001816","article-title":"Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic","volume":"388","author":"Reddy","year":"2024","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1474-4422(22)00077-1","article-title":"Safety and Efficacy of Ganaxolone in Patients with CDKL5 Deficiency Disorder: Results from the Double-Blind Phase of a Randomised, Placebo-Controlled, Phase 3 Trial","volume":"21","author":"Knight","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/epi.17826","article-title":"Long-term Treatment with Ganaxolone for Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency Disorder: Two-year Open-label Extension Follow-up","volume":"65","author":"Olson","year":"2024","journal-title":"Epilepsia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.phrs.2017.02.022","article-title":"The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors","volume":"119","author":"Bakas","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ruffolo, G., Gaeta, A., Cannata, B., Pinzaglia, C., Aronica, E., Morano, A., Cifelli, P., and Palma, E. (2022). GABAergic Neurotransmission in Human Tissues Is Modulated by Cannabidiol. Life, 12.","DOI":"10.3390\/life12122042"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.yfrne.2014.06.001","article-title":"GABAA Receptor-Acting Neurosteroids: A Role in the Development and Regulation of the Stress Response","volume":"36","author":"Gunn","year":"2015","journal-title":"Front. Neuroendocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Chintala, S.M., Tateiwa, H., Qian, M., Xu, Y., Amtashar, F., Chen, Z., Kirkpatrick, C.C., Bracamontes, J., Germann, A.L., and Akk, G. (2024). Direct Measurements of Neurosteroid Binding to Specific Sites on GABAA Receptors. Br. J. Pharmacol., Online ahead of print.","DOI":"10.1111\/bph.16490"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"114294","DOI":"10.1016\/j.expneurol.2022.114294","article-title":"Isobolographic Analysis of Adjunct Antiseizure Activity of the FDA-Approved Cannabidiol with Neurosteroids and Benzodiazepines in Adult Refractory Focal Onset Epilepsy","volume":"360","author":"Golub","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.seizure.2020.09.010","article-title":"Interaction of cannabidiol with other antiseizure medications: A narrative review","volume":"86","author":"Gilmartin","year":"2021","journal-title":"Seizure"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107733","DOI":"10.1016\/j.neuropharm.2019.107733","article-title":"Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: Pharmacodynamic and pharmacokinetic studies","volume":"158","author":"Wyska","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/epi4.12815","article-title":"Final analysis of potential drug-drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program","volume":"8","author":"Gaston","year":"2023","journal-title":"Epilepsia Open"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1111\/epi.18044","article-title":"Addressing the problems of treatment failure in epilepsy: You cannot fix what you do not understand","volume":"65","author":"Bertram","year":"2024","journal-title":"Epilepsia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"114749","DOI":"10.1016\/j.expneurol.2024.114749","article-title":"Characterization of the intrahippocampal kainic acid model in female mice with a special focus on seizure suppression by antiseizure medications","volume":"376","author":"Widmann","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/cns.12523","article-title":"Differential Effects of Antiepileptic Drugs on Focal Seizures in the Intrahippocampal Kainate Mouse Model of Mesial Temporal Lobe Epilepsy","volume":"22","author":"Duveau","year":"2016","journal-title":"CNS Neurosci. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e78877","DOI":"10.7554\/eLife.78877","article-title":"Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy","volume":"12","author":"Anderson","year":"2023","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neuropharm.2014.11.008","article-title":"Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice","volume":"90","author":"Klein","year":"2015","journal-title":"Neuropharmacology"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/9\/1187\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:52:36Z","timestamp":1760111556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/9\/1187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ph17091187"],"URL":"https:\/\/doi.org\/10.3390\/ph17091187","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]}}}