{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:35:44Z","timestamp":1790994944855,"version":"4.1.0"},"reference-count":96,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,15]],"date-time":"2020-03-15T00:00:00Z","timestamp":1584230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds. THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system (CNS) diseases. However, they show differences about penetrability and disposition in the brain. The present article is an overview about THC and CBD crossing the blood\u2013brain barrier (BBB) and their brain disposition. Several findings indicate that CBD can modify the deleterious effects on BBB caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction consequent to ischemia. Thus supporting the therapeutic potential of CBD for the treatment of ischemic and inflammatory diseases of CNS. Cannabinoids positive effects on cognitive function could be also considered through the aspect of protection of BBB cerebrovascular structure and function, indicating that they may purchase substantial benefits through the protection of BBB integrity. Delivery of these cannabinoids in the brain following different routes of administration (subcutaneous, oral, and pulmonary) is illustrated and commented. Finally, the potential role of cannabinoids in drug-resistance in the clinical management of neurological or psychiatric diseases such as epilepsy and schizophrenia is discussed on the light of their crossing the BBB.<\/jats:p>","DOI":"10.3390\/pharmaceutics12030265","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T10:01:35Z","timestamp":1584612095000},"page":"265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["Cannabinoids, Blood\u2013Brain Barrier, and Brain Disposition"],"prefix":"10.3390","volume":"12","author":[{"given":"Fabrizio","family":"Calapai","sequence":"first","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7286-5674","authenticated-orcid":false,"given":"Luigi","family":"Cardia","sequence":"additional","affiliation":[{"name":"Anesthesia, Intensive Care and Pain Therapy, A.O.U.G. Martino Messina, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela Elisa","family":"Sorbara","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-7820","authenticated-orcid":false,"given":"Michele","family":"Navarra","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Gangemi","sequence":"additional","affiliation":[{"name":"School and Division of Allergy and Clinical Immunology, Department of Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Calapai","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1292-6284","authenticated-orcid":false,"given":"Carmen","family":"Mannucci","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3389\/fphar.2018.01259","article-title":"Cannabinoids and pain: New insights from old molecules","volume":"9","author":"Srebro","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s40257-018-0410-5","article-title":"Cannabinoids: Potential role in inflammatory and neoplastic skin diseases","volume":"20","author":"Milando","year":"2019","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1039\/C6NP00074F","article-title":"Phytocannabinoids: A unified critical inventory","volume":"33","author":"Hanus","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.pnpbp.2015.07.001","article-title":"Therapeutic potential of cannabis-related drugs","volume":"64","author":"Alexander","year":"2016","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1001\/jama.2015.6358","article-title":"Cannabinoids for medical use: A systematic review and meta-analysis","volume":"313","author":"Whiting","year":"2015","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.neubiorev.2019.09.036","article-title":"How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review","volume":"107","author":"Freeman","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","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":"ref_8","doi-asserted-by":"crossref","first-page":"412","DOI":"10.5740\/jaoacint.18-0208","article-title":"A brief background on cannabis: From plant to medical indications","volume":"102","author":"Klumpers","year":"2019","journal-title":"J. AOAC Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.2174\/092986710790980050","article-title":"Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists","volume":"17","author":"Pertwee","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1016\/j.drudis.2019.05.023","article-title":"Cannabinoid receptors as therapeutic targets for autoimmune diseases: Where do we stand?","volume":"24","author":"Dutra","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2165\/00003088-200342040-00003","article-title":"Pharmacokinetics and pharmacodynamics of cannabinoids","volume":"42","author":"Grotenhermen","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.pharmthera.2018.10.006","article-title":"The neuropsychopharmacology of cannabis: A review of human imaging studies","volume":"195","author":"Bloomfield","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_13","first-page":"149","article-title":"Chemistry, metabolism, and toxicology of cannabis: Clinical implications","volume":"7","author":"Sharma","year":"2012","journal-title":"Iran J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"277","DOI":"10.9740\/mhc.2016.11.277","article-title":"Delta-9-tetrahydrocannabinol and cannabidiol: Separating the chemicals from the \u201cweed,\u201d a pharmacodynamic discussion","volume":"6","author":"Boggs","year":"2016","journal-title":"Ment. Health Clin."},{"key":"ref_15","first-page":"102","article-title":"Even high doses of oral cannabidiol do not cause thc-like effects in humans: Comment on merrick et al","volume":"1","author":"Grotenhermen","year":"2016","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.neubiorev.2017.02.006","article-title":"Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments","volume":"75","author":"Renard","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/bph.12944","article-title":"Are cannabidiol and \u0394-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review","volume":"172","author":"McPartland","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5113","DOI":"10.2174\/138161212802884726","article-title":"The yin and yang of cannabis-induced psychosis: The actions of \u0394-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia","volume":"18","author":"Arnold","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1517\/14656566.2015.1032248","article-title":"Drug repurposing and emerging adjunctive treatments for schizophrenia","volume":"16","author":"Bumb","year":"2015","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.schres.2015.01.033","article-title":"A systematic review of the antipsychotic properties of cannabidiol in humans","volume":"162","author":"Iseger","year":"2015","journal-title":"Schizophr. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541","DOI":"10.2174\/1871527316666170413114210","article-title":"Neurological aspects of medical use of cannabidiol","volume":"16","author":"Mannucci","year":"2017","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1111\/epi.13815","article-title":"Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol","volume":"58","author":"Rosenberg","year":"2017","journal-title":"Epilepsia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","article-title":"The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin","volume":"153","author":"Pertwee","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1111\/bph.13250","article-title":"Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor","volume":"172","author":"Laprairie","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1111\/bph.12615","article-title":"Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation","volume":"171","author":"Hassan","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1038\/sj.bjp.0707460","article-title":"The orphan receptor GPR55 is a novel cannabinoid receptor","volume":"152","author":"Ryberg","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.neuropharm.2018.03.001","article-title":"The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling","volume":"135","author":"Campos","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/ptr.5095","article-title":"Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPAR\u03b3 involvement","volume":"28","author":"Scuderi","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbr.2016.04.042","article-title":"Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice","volume":"309","author":"Sonego","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","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 Schmiedebergs Arch. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-3-030-21737-2_8","article-title":"Pharmacology of medical cannabis","volume":"1162","author":"Amin","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2125.2012.04341.x","article-title":"Cannabidiol for neurodegenerative disorders: Important new clinical applications for this phytocannabinoid?","volume":"75","author":"Sagredo","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_35","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), \u0394\u2079-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_36","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fncel.2016.00002","article-title":"A review of the mechanisms of blood-brain barrier permeability by tissue-type plasminogen activator treatment for cerebral ischemia","volume":"10","author":"Suzuki","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nrn3114","article-title":"Neurovascular pathways to neurodegeneration in Alzheimer\u2019s disease and other disorders","volume":"12","author":"Zlokovic","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The blood-brain barrier","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12987-016-0040-3","article-title":"Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles","volume":"13","author":"Hladky","year":"2016","journal-title":"Fluids Barriers CNS"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.devbrainres.2004.05.008","article-title":"Endothelial cell-astrocyte interactions and TGF beta are required for induction of blood-neural barrier properties","volume":"152","author":"Garcia","year":"2004","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00018-015-2050-8","article-title":"Factors controlling permeability of the blood-brain barrier","volume":"73","author":"Almutairi","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s10545-013-9608-0","article-title":"Blood-brain barrier structure and function and the challenges for CNS drug delivery","volume":"36","author":"Abbott","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.phrs.2019.01.009","article-title":"Blood-brain barrier disturbances in diabetes-associated dementia: Therapeutic potential for cannabinoids","volume":"141","author":"Brook","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1007\/s12017-014-8314-x","article-title":"Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier","volume":"16","author":"Vendel","year":"2014","journal-title":"Neuromol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1111\/apha.12250","article-title":"The neurovascular unit\u2014Concept review","volume":"210","author":"Muoio","year":"2014","journal-title":"Acta Physiol. (Oxf.)"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1227\/01.NEU.0000097715.11966.8E","article-title":"Mechanisms of disease: The blood-brain barrier","volume":"54","author":"Neuwelt","year":"2004","journal-title":"Neurosurgery"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s11481-006-9025-3","article-title":"Blood-brain barrier: Structural components and function under physiologic and pathologic conditions","volume":"1","author":"Persidsky","year":"2006","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.nbd.2013.06.016","article-title":"Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: A role for A2A receptors","volume":"59","author":"Mecha","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/bph.13368","article-title":"Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPAR\u03b3 and 5-HT1A receptors","volume":"173","author":"Hind","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1021\/acs.molpharmaceut.8b01252","article-title":"Cannabidiol increases proliferation, migration, tubulogenesis, and integrity of human brain endothelial cells through trpv2 activation","volume":"16","author":"Luo","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1801588","DOI":"10.1002\/smll.201801588","article-title":"Drug delivery to the brain across the blood-brain barrier using nanomaterials","volume":"14","author":"Tsou","year":"2018","journal-title":"Small"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1021\/acs.molpharmaceut.8b01344","article-title":"Cannabidiol enhances the passage of lipid nanocapsules across the blood-brain barrier both in vitro and in vivo","volume":"16","author":"Romero","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/WCO.0b013e32832b3101","article-title":"Pathogenesis of septic encephalopathy","volume":"22","author":"Pytel","year":"2009","journal-title":"Curr. Opin. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1742-2094-8-5","article-title":"Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: An intravital microscopy study","volume":"8","author":"Benito","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","article-title":"Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders","volume":"14","author":"Sweeney","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"H610","DOI":"10.1152\/ajpheart.00236.2007","article-title":"Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption","volume":"293","author":"Rajesh","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1016\/j.jacc.2010.07.033","article-title":"Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy","volume":"56","author":"Rajesh","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1007\/s12035-015-9154-x","article-title":"Minocycline attenuates neonatal germinal-matrix-hemorrhage-induced neuroinflammation and brain edema by activating cannabinoid receptor 2","volume":"53","author":"Tang","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/aps.2016.149","article-title":"Brain cannabinoid receptor 2: Expression, function and modulation","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"S61","DOI":"10.1016\/j.bbi.2011.03.001","article-title":"HIV-1 infection and alcohol abuse: Neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions","volume":"25","author":"Persidsky","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4004","DOI":"10.1523\/JNEUROSCI.4628-11.2012","article-title":"Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions","volume":"32","author":"Ramirez","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1160\/TH05-06-0413","article-title":"Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells","volume":"95","author":"Maccarrone","year":"2006","journal-title":"Thromb. Haemost."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"H785","DOI":"10.1152\/ajpheart.00571.2015","article-title":"Endocannabinoids in cerebrovascular regulation","volume":"310","author":"Ruisanchez","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/nm1561","article-title":"Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells","volume":"13","author":"Maresz","year":"2007","journal-title":"Nat. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0014-5793(98)00851-5","article-title":"The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler\u2019s murine encephalomyelitis virus by a receptor-mediated pathway","volume":"433","author":"Guaza","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1088208","article-title":"CB1 cannabinoid receptors and on-demand defense against excitotoxicity","volume":"302","author":"Marsicano","year":"2003","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/1742-2094-8-102","article-title":"Anandamide inhibits Theiler\u2019s virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB receptors","volume":"8","author":"Mestre","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/B978-0-12-801284-0.00008-7","article-title":"Marijuana use and brain immune mechanisms","volume":"118","author":"Cabral","year":"2014","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1600-0773.1977.tb02120.x","article-title":"Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier","volume":"41","author":"Schou","year":"1977","journal-title":"Acta Pharmacol. Toxicol. (Cph.)"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15A","DOI":"10.1155\/2005\/242516","article-title":"Pharmacokinetics of cannabinoids","volume":"10","author":"McGilveray","year":"2005","journal-title":"Pain Res. Manag."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.taap.2010.04.019","article-title":"Disposition of smoked cannabis with high \u0394-tetrahydrocannabinol content: A kinetic model","volume":"246","author":"Hunault","year":"2010","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/BF00427095","article-title":"Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis","volume":"74","author":"Lindgren","year":"1981","journal-title":"Psychopharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/jat\/16.5.276","article-title":"Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana","volume":"16","author":"Huestis","year":"1992","journal-title":"J. Anal. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2042-7158.1984.tb04376.x","article-title":"Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin","volume":"36","author":"Law","year":"1984","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/230593a0","article-title":"Distribution of marihuana in monkey brain and concomitant behavioural effects","volume":"230","author":"McIsaac","year":"1971","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/hup.369","article-title":"Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa","volume":"17","author":"Nahas","year":"2002","journal-title":"Hum. Psychopharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/hup.258","article-title":"The pharmacokinetics of THC in fat and brain: Resulting functional responses to marihuana smoking","volume":"16","author":"Nahas","year":"2001","journal-title":"Hum. Psychopharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"208S","DOI":"10.1002\/j.1552-4604.1981.tb02597.x","article-title":"The kinetics of cannabinoid distribution and storage with special reference to the brain and testis","volume":"21","author":"Nahas","year":"1981","journal-title":"J. Clin. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/jat\/16.5.283","article-title":"Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of delta-9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)","volume":"16","author":"Huestis","year":"1992","journal-title":"J. Anal. Toxicol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/3-540-26573-2_23","article-title":"Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol","volume":"168","author":"Huestis","year":"2005","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1093\/jat\/34.8.516","article-title":"Disposition of cannabichromene, cannabidiol, and \u0394\u2079-tetrahydrocannabinol and its metabolites in mouse brain following marijuana inhalation determined by high-performance liquid chromatography-tandem mass spectrometry","volume":"34","author":"Poklis","year":"2010","journal-title":"J. Anal. Toxicol."},{"key":"ref_82","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":"Uttl","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1093\/jat\/bkx033","article-title":"Postmortem fluid and tissue concentrations of THC, 11-OH-THC and THC-COOH","volume":"41","author":"Saenz","year":"2017","journal-title":"J. Anal. Toxicol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"484963","DOI":"10.1155\/2015\/484963","article-title":"Bypassing P-glycoprotein drug efflux mechanisms: Possible applications in pharmacoresistant schizophrenia therapy","volume":"2015","author":"Hoosain","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/ane.12778","article-title":"Role of P-glycoprotein inhibitors in children with drug-resistant epilepsy","volume":"136","author":"Elkhayat","year":"2017","journal-title":"Acta Neurol. Scand."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s13346-016-0353-4","article-title":"A novel mechanism governing the transcriptional regulation of ABC transporters in MDR cancer cells","volume":"7","author":"Lu","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.drup.2014.11.002","article-title":"The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade","volume":"18","author":"Kathawala","year":"2015","journal-title":"Drug Resist. Updat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/cpt.64","article-title":"Regulation of ABC transporters at the blood-brain barrier","volume":"97","author":"Miller","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1528-1167.2007.01302.x","article-title":"ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy","volume":"48","author":"Lazarowski","year":"2007","journal-title":"Epilepsia"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrn1728","article-title":"Drug resistance in brain diseases and the role of drug efflux transporters","volume":"6","author":"Potschka","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1369-1600.2008.00096.x","article-title":"Disposition of Delta tetrahydrocannabinol in CF1 mice deficient in mdr1a P-glycoprotein","volume":"13","author":"Benyamina","year":"2008","journal-title":"Addict. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Spiro, A.S., Wong, A., Boucher, A.A., and Arnold, J.C. (2012). Enhanced brain disposition and effects of \u03949-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035937"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1208\/s12248-017-0081-9","article-title":"Functional expression of P-glycoprotein and organic anion transporting polypeptides at the blood-brain barrier: Understanding transport mechanisms for improved cns drug delivery?","volume":"19","author":"Abdullahi","year":"2017","journal-title":"AAPS J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e2081","DOI":"10.7717\/peerj.2081","article-title":"ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice","volume":"4","author":"Brzozowska","year":"2016","journal-title":"PeerJ"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.7717\/peerj.153","article-title":"Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines","volume":"1","author":"Feinshtein","year":"2013","journal-title":"PeerJ"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1124\/dmd.104.001230","article-title":"The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the MDR1A\/1B knockout mouse model","volume":"33","author":"Doran","year":"2005","journal-title":"Drug Metab. Dispos."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/3\/265\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:07:03Z","timestamp":1760173623000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/3\/265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,15]]},"references-count":96,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["pharmaceutics12030265"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12030265","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,15]]}}}