{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:39:58Z","timestamp":1790203198835,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for the Science, Technology, and Innovation","award":["PE501082200-2023-PROCIENCIA"],"award-info":[{"award-number":["PE501082200-2023-PROCIENCIA"]}]},{"name":"National Agency for the Promotion of Science and Technology, Fund for Scientific and Technical Research","award":["PICT2019-01282"],"award-info":[{"award-number":["PICT2019-01282"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Introduction. In recent years, cannabidiol (CBD) has been used as an adjunct therapy to anti-seizure medications for the control of seizures in patients with drug-resistant epilepsy. In addition to its anticonvulsant effect, CBD also has well-defined anti-inflammatory properties. Since neuroinflammation can trigger various pro-epileptogenic mechanisms, CBD could play an inhibitory role in this process. Epileptogenesis is the process by which epilepsy becomes a chronic disease following a brain injury, and one of its main characteristics is an increased susceptibility to seizures due to a reduced seizure threshold. However, the role of CBD in modulating this susceptibility remains poorly understood. Methodology. We developed an experimental protocol to discretely measure the seizure threshold (DMST) 7 or 14 days after lithium-pilocarpine-induced status epilepticus (SE) through the administration of small intraperitoneal (i.p.) doses of pentylenetetrazol (15 mg\/kg\/every 10 min). Results. Using the DMST, we observed a significant decrease in the seizure threshold after SE associated with a hypersensitivity state characterized by irritability and marked weight loss. A separate cohort of rats was treated with CBD (20 mg\/kg) for 14 days following SE. Conclusions. Treatment with CBD did not improve the seizure threshold; moreover, it worsened the hypersensitivity state and delayed recovery following SE. Our results suggest that orally administered CBD, at a human-equivalent therapeutic and safe dose, does not improve susceptibility to seizure development after SE.<\/jats:p>","DOI":"10.3390\/brainsci16080851","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:30:32Z","timestamp":1786465832000},"page":"851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Subchronic Cannabidiol (CBD) Treatment During the Silent Period Fails to Prevent Increased Seizure Susceptibility Following Lithium-Pilocarpine-Induced Status Epilepticus"],"prefix":"10.3390","volume":"16","author":[{"given":"Claudia Taborda","family":"G\u00f3mez","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agust\u00edn","family":"Jara","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Borda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-6210","authenticated-orcid":false,"given":"Franco","family":"Moscovicz","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6684-0477","authenticated-orcid":false,"given":"Yessenia","family":"Yauri-Huaman","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Neurociencias, Instituto Cient\u00edfico, Facultad de Ciencias de la Salud, Universidad Andina del Cusco, Cusco 08006, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5014-6582","authenticated-orcid":false,"given":"Rodrigo","family":"Caceres-Robles","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Neurociencias, Instituto Cient\u00edfico, Facultad de Ciencias de la Salud, Universidad Andina del Cusco, Cusco 08006, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis F.","family":"Pacheco-Otalora","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Neurociencias, Instituto Cient\u00edfico, Facultad de Ciencias de la Salud, Universidad Andina del Cusco, Cusco 08006, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8979-7631","authenticated-orcid":false,"given":"Alberto","family":"Lazarowski","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4819-2713","authenticated-orcid":false,"given":"Jer\u00f3nimo","family":"Auzmendi","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Farmacol\u00f3gicas, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Ciudad Aut\u00f3noma de Buenos Aires C1113AAA, Argentina"},{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"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":"270","DOI":"10.1016\/S1474-4422(15)00379-8","article-title":"Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial","volume":"15","author":"Devinsky","year":"2016","journal-title":"Lancet 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-Gastaut Syndrome","volume":"378","author":"Devinsky","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_4","unstructured":"Pharmaceuticals, J. (2026, May 20). EPIDIOLEX\u00ae Safely and Effectively. Highlights of Prescribing Informmation, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/210365Orig1s011lbl.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Karazniewicz-Lada, M., Glowka, A.K., Mikulska, A.A., and Glowka, F.K. (2021). Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179582"},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1089\/can.2020.0053","article-title":"In Vitro Screening of Three Commercial Cannabis-Based Products on ATP-Binding Cassette and Solute-Carrier Transporter Function","volume":"7","author":"Anderson","year":"2022","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Auzmendi, J., Palestro, P., Blachman, A., Gavernet, L., Merelli, A., Talevi, A., Calabrese, G.C., Ramos, A.J., and Lazarowski, A. (2020). Cannabidiol (CBD) Inhibited Rhodamine-123 Efflux in Cultured Vascular Endothelial Cells and Astrocytes Under Hypoxic Conditions. Front. Behav. Neurosci., 14.","DOI":"10.3389\/fnbeh.2020.00032"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/sj.bjp.0707467","article-title":"The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids","volume":"152","author":"Holland","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/epi4.12376","article-title":"Is cannabidiol a drug acting on unconventional targets to control drug-resistant epilepsy?","volume":"5","author":"Rocha","year":"2020","journal-title":"Epilepsia Open"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fuentes-Mejia, M., Fallico, M.J., Talevi, A., Gavernet, L., Orozco-Suarez, S.A., and Rocha, L. (2025). Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1644018"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.4155\/fmc.09.93","article-title":"Cannabinoids as novel anti-inflammatory drugs","volume":"1","author":"Nagarkatti","year":"2009","journal-title":"Future Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1089\/can.2018.0073","article-title":"Immune Responses Regulated by Cannabidiol","volume":"5","author":"Nichols","year":"2020","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1096\/fj.201600646R","article-title":"Cannabinoids, inflammation, and fibrosis","volume":"30","author":"Zurier","year":"2016","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aswad, M., Pechkovsky, A., Ghanayiem, N., Hamza, H., and Louria-Hayon, I. (2025). High CBD extract (CBD-X) modulates inflammation and immune cell activity in rheumatoid arthritis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1599109"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gomez, C.T., Lairion, F., Repetto, M., Ettcheto, M., Merelli, A., Lazarowski, A., and Auzmendi, J. (2021). Cannabidiol (CBD) Alters the Functionality of Neutrophils (PMN). Implications in the Refractory Epilepsy Treatment. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030220"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1124\/mol.107.041863","article-title":"Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: Evidence for a site distinct from CB1 and CB2","volume":"73","author":"McHugh","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s00401-021-02348-6","article-title":"Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy","volume":"142","author":"Zimmer","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S109","DOI":"10.3233\/JAD-201074","article-title":"Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases","volume":"82","author":"Merelli","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"a022822","DOI":"10.1101\/cshperspect.a022822","article-title":"Epileptogenesis","volume":"5","author":"Pitkanen","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJM199801013380104","article-title":"A population-based study of seizures after traumatic brain injuries","volume":"338","author":"Annegers","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1002\/ana.410440609","article-title":"Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus","volume":"44","author":"Hesdorffer","year":"1998","journal-title":"Ann. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1161\/STROKEAHA.111.000220","article-title":"Incidence and associations of poststroke epilepsy: The prospective South London Stroke Register","volume":"44","author":"Graham","year":"2013","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.seizure.2012.03.001","article-title":"Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures","volume":"21","author":"Jones","year":"2012","journal-title":"Seizure"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1528-1167.2007.01063.x","article-title":"Epileptogenesis in experimental models","volume":"48","author":"Pitkanen","year":"2007","journal-title":"Epilepsia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"107962","DOI":"10.1016\/j.yebeh.2021.107962","article-title":"Chronic cannabidiol (CBD) administration induces anticonvulsant and antiepileptogenic effects in a genetic model of epilepsy","volume":"119","author":"Leite","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1111\/bph.15181","article-title":"Interactions between cannabidiol and Delta(9) -tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome","volume":"177","author":"Anderson","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/0091-3057(82)90418-X","article-title":"Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats","volume":"16","author":"Colasanti","year":"1982","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_30","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_31","doi-asserted-by":"crossref","unstructured":"Auzmendi, J., Buchholz, B., Salguero, J., Canellas, C., Kelly, J., Men, P., Zubillaga, M., Rossi, A., Merelli, A., and Gelpi, R.J. (2018). Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death. Pharmaceuticals, 11.","DOI":"10.3390\/ph11010021"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/S0022-3565(25)23709-0","article-title":"Kinetics of drug action in disease states. XIV. Effect of infusion rate on pentylenetetrazol concentrations in serum, brain and cerebrospinal fluid of rats at onset of convulsions","volume":"234","author":"Ramzan","year":"1985","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.neuroscience.2012.12.055","article-title":"Are morphologic and functional consequences of status epilepticus in infant rats progressive?","volume":"235","author":"Kubova","year":"2013","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.yebeh.2014.06.010","article-title":"Retigabine calms seizure-induced behavior following status epilepticus","volume":"37","author":"Slomko","year":"2014","journal-title":"Epilepsy Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S1474-4422(03)00265-5","article-title":"Cellular biology of epileptogenesis","volume":"2","author":"Avanzini","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0733-8619(05)70017-7","article-title":"Mechanisms of epileptogenesis","volume":"19","author":"Najm","year":"2001","journal-title":"Neurol. Clin."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jean, G., Carton, J., Haq, K., and Musto, A.E. (2023). The role of dendritic spines in epileptogenesis. Front. Cell Neurosci., 17.","DOI":"10.3389\/fncel.2023.1173694"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107155","DOI":"10.1016\/j.eplepsyres.2023.107155","article-title":"Kindling in humans: Does secondary epileptogenesis occur?","volume":"198","author":"Thompson","year":"2023","journal-title":"Epilepsy Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1176\/jnp.1.4.418","article-title":"The nature and management of aggression in epilepsy","volume":"1","author":"Fenwick","year":"1989","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"147334","DOI":"10.1016\/j.brainres.2021.147334","article-title":"Effects of acute seizures on cell proliferation, synaptic plasticity and long-term behavior in adult zebrafish","volume":"1756","author":"Dalmaz","year":"2021","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jneumeth.2008.04.019","article-title":"The pilocarpine model of temporal lobe epilepsy","volume":"172","author":"Curia","year":"2008","journal-title":"J. Neurosci. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0149-7634(05)80076-4","article-title":"Spontaneous recurrent seizures in rats: An experimental model of partial epilepsy","volume":"14","author":"Leite","year":"1990","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_43","unstructured":"Jara, A., Lazarowski, A., L\u00f3pez, D.E., and Auzmendi, J. (2026, January 16\u201318). Functional, morphological and ethological characterization of a transgenic mice model for the study of epilepsy acquisition. Proceedings of the XIV Congreso Latinoamericano de Epilepsia, Lima, Peru."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1111\/j.1528-1167.2008.01797.x","article-title":"Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models","volume":"50","author":"Blanco","year":"2009","journal-title":"Epilepsia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1111\/j.1460-9568.2012.08143.x","article-title":"Do proconvulsants modify or halt epileptogenesis? Pentylenetetrazole is ineffective in two rat models of temporal lobe epilepsy","volume":"36","author":"Rattka","year":"2012","journal-title":"Eur. J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.yebeh.2016.01.032","article-title":"Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures","volume":"57","author":"Tollner","year":"2016","journal-title":"Epilepsy Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/epi.13345","article-title":"Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats","volume":"57","author":"Drion","year":"2016","journal-title":"Epilepsia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.expneurol.2016.03.015","article-title":"Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain","volume":"280","author":"Hester","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/j.1528-1157.1979.tb04815.x","article-title":"An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats","volume":"20","author":"Turkanis","year":"1979","journal-title":"Epilepsia"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"114240","DOI":"10.1016\/j.expneurol.2022.114240","article-title":"Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures","volume":"359","author":"Reddy","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41582-019-0217-x","article-title":"Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy","volume":"15","author":"Vezzani","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/nn.4338","article-title":"A polarizing question: Do M1 and M2 microglia exist?","volume":"19","author":"Ransohoff","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1098\/rstb.2011.0389","article-title":"Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders","volume":"367","author":"Campos","year":"2012","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s13311-015-0375-5","article-title":"Cannabinoids and Epilepsy","volume":"12","author":"Rosenberg","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1684\/epd.2020.1135","article-title":"The proposed mechanisms of action of CBD in epilepsy","volume":"22","author":"Gray","year":"2020","journal-title":"Epileptic Disord."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00213-011-2415-0","article-title":"Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour","volume":"219","author":"Deiana","year":"2012","journal-title":"Psychopharmacology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1089\/can.2022.0121","article-title":"Pharmacokinetics of Cannabidiol in Sprague-Dawley Rats After Oral and Pulmonary Administration","volume":"8","author":"Schwotzer","year":"2023","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000535726","article-title":"Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects","volume":"7","author":"Zhang","year":"2024","journal-title":"Med. Cannabis Cannabinoids"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Millar, S.A., Stone, N.L., Yates, A.S., and O\u2019Sullivan, S.E. (2018). A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01365"},{"key":"ref_60","first-page":"833","article-title":"Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs","volume":"120","author":"Herdegen","year":"2023","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1590\/1516-4446-2017-0015","article-title":"Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test","volume":"41","author":"Linares","year":"2019","journal-title":"Braz. J. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9561","DOI":"10.1073\/pnas.160105897","article-title":"The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis","volume":"97","author":"Malfait","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"104941","DOI":"10.1016\/j.neubiorev.2022.104941","article-title":"Cannabinoid treatments for anxiety: A systematic review and consideration of the impact of sleep disturbance","volume":"143","author":"Narayan","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.bpsgos.2021.06.014","article-title":"Cannabidiol Produces Distinct U-Shaped Dose-Response Effects on Cocaine-Induced Conditioned Place Preference and Associated Recruitment of Prelimbic Neurons in Male Rats","volume":"2","author":"Nedelescu","year":"2022","journal-title":"Biol. Psychiatry Glob. Open Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e70194","DOI":"10.1111\/bcpt.70194","article-title":"Antiseizure Effects of Cannabidiol in Combination with Cannabigerol in the Maximal Electroshock Seizure Model","volume":"138","author":"Zhou","year":"2026","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_66","first-page":"8820","article-title":"High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect","volume":"8","author":"Mao","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Leigh, N.J., and Goniewicz, M.L. (2020). Acute Effect of Electronic Cigarette-Generated Aerosol From Flavored CBD-Containing Refill Solutions on Human Bronchial Epithelial Cells. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.592321"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"152654","DOI":"10.1016\/j.bbrc.2025.152654","article-title":"The effects of Cannabidiol on podocytes in vitro","volume":"784","author":"Didik","year":"2025","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1007\/s00204-024-03754-x","article-title":"Toxicity of cannabidiol and its metabolites in TM3 mouse Leydig cells: A comparison with primary human Leydig cells","volume":"98","author":"Li","year":"2024","journal-title":"Arch. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"20220362","DOI":"10.1515\/tnsci-2022-0362","article-title":"Optimization of seizure prevention by cannabidiol (CBD)","volume":"16","author":"Bhandari","year":"2025","journal-title":"Transl. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.euroneuro.2017.10.037","article-title":"Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC","volume":"27","author":"Hlozek","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"61","DOI":"10.14581\/jer.17012","article-title":"Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?","volume":"7","author":"Perucca","year":"2017","journal-title":"J. Epilepsy Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1111\/epi.13852","article-title":"Interactions between cannabidiol and commonly used antiepileptic drugs","volume":"58","author":"Gaston","year":"2017","journal-title":"Epilepsia"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1111\/epi.16355","article-title":"Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions","volume":"60","author":"Anderson","year":"2019","journal-title":"Epilepsia"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/8\/851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:38:35Z","timestamp":1786466315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/8\/851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":74,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["brainsci16080851"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16080851","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}