{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:37:32Z","timestamp":1791859052285,"version":"4.3.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T00:00:00Z","timestamp":1675987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002737","name":"Assessorato Regionale Della Salute, Regione Siciliana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002737","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    <jats:bold>Introduction:<\/jats:bold>\n                    Cannabidiol (CBD) is an active chemical contained in the plant\n                    <jats:italic>Cannabis sativa<\/jats:italic>\n                    . It is a resorcinol-based compound that crosses the blood-brain barrier without causing euphoric effects. CBD has a plethora of pharmacological effects of therapeutic interest. CBD has been authorized in the European Union as an anticonvulsant against serious infantile epileptic syndromes, but its safety profile is still not sufficiently described.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    With the goal of expanding information on the safety of CBD use as an antiepileptic agent beyond the most common side effects known through clinical studies, an analysis of serious case reports on suspected adverse reactions (SARs) to CBD licensed as an anti-epileptic drug found in the EudraVigilance database is reported in this article. EudraVigilance is a system purchased by the European Medicines Agency (EMA) for monitoring the safety of medicinal products marketed in Europe.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    The most frequent serious SARs to CBD in EudraVigilance were epilepsy aggravation, hepatic disorders, lack of efficacy, and somnolence.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Discussion:<\/jats:bold>\n                    Based on our analysis, the following precautions should be adopted for appropriate monitoring of potential adverse effects, more attention towards possible CBD medical use as an antiepileptic: awareness of interactions with other drugs, epilepsy aggravation, and drug effectiveness.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2023.1091978","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T23:43:48Z","timestamp":1675986228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Pharmacovigilance on cannabidiol as an antiepileptic agent"],"prefix":"10.3389","volume":"14","author":[{"given":"Ilaria","family":"Ammendolia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Mannucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Cardia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Calapai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Gangemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Calapai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1684\/epd.2020.1141","article-title":"Epilepsy and cannabidiol: A guide to treatment","volume":"22","author":"Arzimanoglou","year":"2020","journal-title":"Epileptic Disord."},{"key":"B2","doi-asserted-by":"publisher","first-page":"114038","DOI":"10.1016\/j.jpba.2021.114038","article-title":"Corrigendum to \"Therapeutic application of cannabidiol on UVA and UVB irradiated rat skin. A proteomic study\" [J. Pharm. Biomed. Anal. 192 (2021) 1-9\/113656]","volume":"200","author":"Atalay","year":"2021","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B3","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1124\/dmd.120.000350","article-title":"Cytochrome P450-catalyzed metabolism of cannabidiol to the active metabolite 7-hydroxy-cannabidiol","volume":"49","author":"Beers","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"B4","doi-asserted-by":"publisher","first-page":"118277","DOI":"10.1016\/j.molliq.2021.118277","article-title":"Assessment of the free radical scavenging potential of cannabidiol under physiological conditions: Theoretical and experimental investigations","volume":"346","author":"Boulebd","year":"2022","journal-title":"J. Mol. Liq."},{"key":"B5","doi-asserted-by":"publisher","first-page":"989","DOI":"10.3390\/jcm8070989","article-title":"Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol (CBD) use","volume":"8","author":"Brown","year":"2019","journal-title":"J. Clin. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3390\/pharmaceutics12030265","article-title":"Cannabinoids, blood-brain barrier, and brain disposition","volume":"12","author":"Calapai","year":"2020","journal-title":"Pharmaceutics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2509129","DOI":"10.1155\/2019\/2509129","article-title":"Preclinical and clinical evidence supporting use of cannabidiol in psychiatry","volume":"2019","author":"Calapai","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.3390\/cells10051251","article-title":"Regulatory effects of cannabidiol on mitochondrial functions: A review","volume":"10","author":"Chan","year":"2021","journal-title":"Cells"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1038\/s41386-020-0667-2","article-title":"Adverse effects of cannabidiol: A systematic review and meta-analysis of randomized clinical trials","volume":"45","author":"Chesney","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1097\/j.pain.0000000000001386","article-title":"Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain","volume":"160","author":"De Gregorio","year":"2019","journal-title":"Pain"},{"key":"B11","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1111\/epi.12631","article-title":"Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders","volume":"55","author":"Devinsky","year":"2014","journal-title":"Epilepsia"},{"key":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/epi.14628","article-title":"Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial","volume":"60","author":"Devinsky","year":"2019","journal-title":"Epilepsia"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e1204","DOI":"10.1212\/WNL.0000000000005254","article-title":"Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome","volume":"90","author":"Devinsky","year":"2018","journal-title":"Neurology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1056\/NEJMra1010481","article-title":"Sudden, unexpected death in epilepsy","volume":"365","author":"Devinsky","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"8711","DOI":"10.1074\/jbc.M114.618447","article-title":"Fatty acid-binding proteins (FABPs) are intracellular carriers for \u03949-tetrahydrocannabinol (THC) and cannabidiol (CBD)","volume":"290","author":"Elmes","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B17","unstructured":"Epidyolex: EPAR - product information2022"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.3390\/molecules24091694","article-title":"Hepatotoxicity of a cannabidiol-rich cannabis extract in the mouse model","volume":"24","author":"Ewing","year":"2019","journal-title":"Molecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1016\/j.amjmed.2019.05.017","article-title":"Cannabis and cannabinoids: Kinetics and interactions","volume":"132","author":"Foster","year":"2019","journal-title":"Am. J. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1007\/s40262-020-00931-w","article-title":"The interplay between liver first-pass effect and lymphatic absorption of cannabidiol and its implications for cannabidiol oral formulations","volume":"59","author":"Franco","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1097\/00001756-199702100-00014","article-title":"Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra","volume":"8","author":"French","year":"1997","journal-title":"Neuroreport"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1007\/s40263-019-00664-w","article-title":"Potential of cannabinoid receptor ligands as treatment for substance use disorders","volume":"33","author":"Galaj","year":"2019","journal-title":"CNS. Drugs."},{"key":"B23","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/s0387-7604(99)00113-8","article-title":"When antiepileptic drugs aggravate epilepsy","volume":"22","author":"Genton","year":"2000","journal-title":"Brain Dev."},{"key":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","first-page":"7699","DOI":"10.3390\/molecules26247699","article-title":"Applications of cannabis sativa L. In food and its therapeutic potential: From a prohibited drug to a nutritional supplement","volume":"26","author":"Iftikhar","year":"2021","journal-title":"Molecules"},{"key":"B26","doi-asserted-by":"publisher","first-page":"9582","DOI":"10.3390\/ijms22179582","article-title":"Pharmacokinetic drug-drug interactions among antiepileptic drugs, including CBD, drugs used to treat COVID-19 and nutrients","volume":"22","author":"Kara\u017aniewicz-\u0141ada","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1007\/s00210-006-0033-x","article-title":"Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors","volume":"372","author":"Kathmann","year":"2006","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.eplepsyres.2019.03.015","article-title":"Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results","volume":"154","author":"Laux","year":"2019","journal-title":"Epilepsy Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"673","DOI":"10.2147\/NDT.S20173","article-title":"Clobazam as an adjunctive therapy in treating seizures associated with Lennox-Gastaut syndrome","volume":"7","author":"Leahy","year":"2011","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"B30","doi-asserted-by":"publisher","first-page":"5526","DOI":"10.1167\/iovs.08-2196","article-title":"Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor","volume":"49","author":"Liou","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1111\/bcp.13710","article-title":"The pharmacokinetics and the pharmacodynamics of cannabinoids","volume":"84","author":"Lucas","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B32","first-page":"247","article-title":"MedDRA and pharmacovigilance: A complex and little-evaluated tool","volume":"25","year":"2016","journal-title":"Prescrire Int."},{"key":"B33","unstructured":"Introductory guide MedDRA version 25.02022"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1212\/WNL.0b013e318232de76","article-title":"OV-1012 Study Investigators Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome","volume":"77","author":"Ng","year":"2011","journal-title":"Neurology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1111\/epi.17000","article-title":"Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial","volume":"62","author":"Patel","year":"2021","journal-title":"Epilepsia"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1111\/epi.16674","article-title":"Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs","volume":"61","author":"Patsalos","year":"2020","journal-title":"Epilepsia"},{"key":"B37","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1097\/JCP.0000000000001089","article-title":"The potential for pharmacokinetic interactions BetweenCannabis products and conventional medications","volume":"39","author":"Qian","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"106506","DOI":"10.1016\/j.yebeh.2019.106506","article-title":"Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam","volume":"103","author":"Rogawski","year":"2020","journal-title":"Epilepsy Behav."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1007\/s11064-005-6978-1","article-title":"Agonistic properties of cannabidiol at 5-HT1a receptors","volume":"30","author":"Russo","year":"2005","journal-title":"Neurochem. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1159\/000346737","article-title":"Attitudes and opinion about adverse drug events of women living in a city of south Italy","volume":"91","author":"Salvo","year":"2013","journal-title":"Pharmacology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1111\/epi.17036","article-title":"Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial","volume":"62","author":"Scheffer","year":"2021","journal-title":"Epilepsia"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1016\/j.bbrc.2020.10.021","article-title":"Involvement of dopamine receptor in the actions of non-psychoactive phytocannabinoids","volume":"533","author":"Shrader","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B43","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3109\/03602532.2013.849268","article-title":"Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: A systematic review","volume":"46","author":"Stout","year":"2014","journal-title":"Drug Metab. Rev."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1002\/jcph.1412","article-title":"A Phase 1, Open-Label, Parallel-Group, Single-dose trial of the pharmacokinetics and safety of cannabidiol (CBD) in subjects with mild to severe hepatic impairment","volume":"59","author":"Taylor","year":"2019","journal-title":"J. Clin. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.3390\/molecules24193485","article-title":"Preliminary study. Comparison of antioxidant activity of cannabidiol (CBD) and -tocopherol added to refined olive and sunflower oils","volume":"24","author":"Tura","year":"2019","journal-title":"Molecules"},{"key":"B46","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s40272-016-0171-7","article-title":"Pharmacotherapy for Dravet syndrome","volume":"18","author":"Wallace","year":"2016","journal-title":"Paediatr. Drugs"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1111\/epi.17199","article-title":"Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6","volume":"63","author":"Wu","year":"2022","journal-title":"Epilepsia"},{"key":"B48","doi-asserted-by":"publisher","first-page":"16181","DOI":"10.3390\/ijms232416181","article-title":"Advances and challenges of cannabidiol as an anti-seizure strategy: Preclinical evidence","volume":"23","author":"Zavala-Tecuapetla","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1111\/ane.13715","article-title":"Advances in sudden unexpected death in epilepsy","volume":"146","author":"Zhao","year":"2022","journal-title":"Acta Neurol. Scand."},{"key":"B50","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13293-020-00308-5","article-title":"Sex differences in pharmacokinetics predict adverse drug reactions in women","volume":"11","author":"Zucker","year":"2020","journal-title":"Biol. Sex. Differ."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1091978\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T23:43:56Z","timestamp":1675986236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1091978\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,10]]},"references-count":50,"alternative-id":["10.3389\/fphar.2023.1091978"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1091978","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,10]]},"article-number":"1091978"}}