Cannabidiol: metabolism and clinical efficacy in epileptic patients

References

• Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of Cannabidiol. Antioxidants. 2019;9:21. doi: 10.3390/antiox9010021
   Web of Science ®Google Scholar
• Mechoulam R, Shvo Y, Hashish I. The structure of cannabidiol. Tetrahedron. 1963;19(12):2073–2078. doi: 10.1016/0040-4020(63)85022-x
   Google Scholar
• Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21:175–185. doi: 10.1159/000137430
   PubMed Web of Science ®Google Scholar
• Talwar A, Estes E, Aparasu R, et al. Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: a systematic review and meta-analysis. Exp Neurol. 2023;359:114238. doi: 10.1016/j.expneurol.2022.114238
   PubMed Web of Science ®Google Scholar
• Verrotti A, Striano P. Novel therapeutic options for Dravet and Lennox-Gastaut syndrome. Expert Rev Neurother. 2021;21:1191–1194. doi: 10.1080/14737175.2020.1862651
   PubMed Web of Science ®Google Scholar
• Kühne F, Becker LL, Bast T, et al. Real-world data on cannabidiol treatment of various epilepsy subtypes: a retrospective, multicenter study. Epilepsia Open. 2023;8:360–370. doi: 10.1002/epi4.12699
   PubMedGoogle Scholar
• Espinosa-Jovel C, Riveros S, Bolaños-Almeida C, et al. Real-world evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis complex. Seizure. 2023;112:72–76. doi: 10.1016/j.seizure.2023.09.015
   PubMed Web of Science ®Google Scholar
• Marchese F, Vari MS, Balagura G, et al. An open retrospective study of a standardized cannabidiol based-oil in treatment-resistant epilepsy. Cannabis Cannabinoid Res. 2022;7(2):199–206.
   PubMedGoogle Scholar
• Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012 Sep;11(9):792–802. doi: 10.1016/S1474-4422(12)70153-9. Epub 2012 Jul 24. Erratum in: Lancet Neurol. 2012 Sep;11(9):746. PMID: 22832500.
   PubMed Web of Science ®Google Scholar
• Friedman D, Devinsky O, Longo DL. Cannabinoids in the treatment of epilepsy. N Engl J Med. 2015 Sep 10;373(11):1048–58. doi: 10.1056/NEJMra1407304
   PubMed Web of Science ®Google Scholar
• Jones N, Hill T, Stott C, et al. Assessment of the anticonvulsant effects and tolerability of GW Pharmaceuticals’ cannabidiol in the anticonvulsant screening program. AES Abstract #3.034. 2015.
   Google Scholar
• Reddy DS, Mbilinyi RH, Ramakrishnan S. Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures. Exp Neurol. 2023;359:22647. doi: 10.1016/j.expneurol.2022.114240
   Web of Science ®Google Scholar
• Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344–352. doi: 10.1016/j.seizure.2012.03.001
   PubMed Web of Science ®Google Scholar
• Patra PH, Barker-Haliski M, White HS, et al. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models. Epilepsia. 2019;60(2):303–314. doi: 10.1111/epi.14629
   PubMed Web of Science ®Google Scholar
• Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569–77. doi: 10.1124/jpet.109.159145. Epub 2009 Nov 11. PMID: 19906779; PMCID: PMC2819831.
   PubMed Web of Science ®Google Scholar
• FríFríAs-Soria CL, Pérez-Pérez D, Orozco-Suárez S, et al. Cannabidiol modifies the seizure expression and effects of antiseizure drugs in a rat model of recurrent severe seizures. Seizure. 2021 Aug;90:67–73. doi: 10.1016/j.seizure.2021.04.008. Epub 2021 Apr 10. PMID: 33879386.
   PubMed Web of Science ®Google Scholar
• Kaplan JS, Stella N, Catterall WA, et al. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A. 2017 Oct 17;114(42): 11229–11234. Epub 2017 Oct 2. PMID: 28973916; PMCID: PMC5651774. 10.1073/pnas.1711351114.
   PubMed Web of Science ®Google Scholar
• Castillo-Arellano J, Canseco-Alba A, Cutler SJ, et al. The polypharmacological effects of Cannabidiol. Molecules. 2023 Apr 6;28(7):3271. doi: 10.3390/molecules28073271. PMID: 37050032; PMCID: PMC10096752.
   PubMed Web of Science ®Google Scholar
• Demuth DG, Molleman A. Cannabinoid signalling. Life Sci. 2006 Jan 2;78(6):549–63. doi: 10.1016/j.lfs.2005.05.055. Epub 2005 Aug 18. PMID: 16109430.
   PubMed Web of Science ®Google Scholar
• Howlett AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984 Nov;26(3):532–8. PMID: 6092901.
   PubMed Web of Science ®Google Scholar
• Turner SE, Williams CM, Iversen L, et al. Molecular pharmacology of phytocannabinoids. In: Kinghorn AD, Falk H, Gibbons S Kobayashi J, editors. Progress in the chemistry of organic natural products. Cham Switzerland: Springer Nature, 2017; Vol. 103, p. 61–101.
   Google Scholar
• MacLennan SJ, Reynen PH, Kwan J, et al. Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol. 1998a;124(4):619–622. doi: 10.1038/sj.bjp.0701915
   PubMed Web of Science ®Google Scholar
• Lunn CA, Fine JS, Rojas-Triana A, et al. A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo. J Pharmacol Exp Ther. 2006;316(2):780–788. doi: 10.1124/jpet.105.093500
   PubMed Web of Science ®Google Scholar
• Thomas A, Baillie GL, Phillips AM, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–623. doi: 10.1038/sj.bjp.0707133
   PubMed Web of Science ®Google Scholar
• Laprairie RB, Bagher AM, Kelly MEM, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–4805. doi: 10.1111/bph.13250
   PubMed Web of Science ®Google Scholar
• Tham M, Yilmaz O, Alaverdashvili M, et al. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2019 May;176(10):1455–1469. doi: 10.1111/bph.14440. Epub 2018 Aug 10. PMID: 29981240; PMCID: PMC6487556.
   PubMed Web of Science ®Google Scholar
• Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogs: effect on vanilloid VR1 receptors and the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845–852.
   PubMed Web of Science ®Google Scholar
• De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J Pharmacol. 2011;163(7):1479–1494.
   Google Scholar
• Howlett AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17(14):1382–1393. doi: 10.2174/092986710790980023
   PubMed Web of Science ®Google Scholar
• Joshi N, Onaivi ES. Endocannabinoid system components: overview and tissue distribution. Adv Exp Med Biol. 2019;1162:1–12.
   PubMed Web of Science ®Google Scholar
• Alger BE. Seizing an opportunity for the endocannabinoid system. Basic Sci. 2014;14(5):272–276. doi: 10.5698/1535-7597-14.5.272
   Google Scholar
• Mackie K, Stella N. Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J. 2006 Apr 28;8(2):E298–306. doi: 10.1007/BF02854900. PMID: 16796380; PMCID: PMC3231556.
   PubMed Web of Science ®Google Scholar
• Kano M, Ohno-Shosaku T, Hashimotodani Y, et al. Endocannabinoid-mediated control of the synaptic transmission. Physiol Rev. 2009 Jan;89(1):309–380. doi: 10.1152/physrev.00019.2008. PMID: 19126760. Alger BE, Seizing an opportunity for the endocannabinoid system. Basic Sci 2014;14:272-276.
   PubMed Web of Science ®Google Scholar
• Martínez-Pinilla E, Varani K, Reyes-Resina I, et al. Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Front Pharmacol. 2017 Oct 23;8:744. doi: 10.3389/fphar.2017.00744. PMID: 29109685; PMCID: PMC5660261.
   PubMed Web of Science ®Google Scholar
• Cassano T, Calcagnini S, Pace L, et al. Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Front Neurosci. 2017 Feb 2;11:30. doi: 10.3389/fnins.2017.00030. PMID: 28210207; PMCID: PMC5288380.
   PubMed Web of Science ®Google Scholar
• Xin Q, Xu F, Taylor DH, et al. The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders. Acta Pharm Sin. 2020;41(12):1507–1518. doi: 10.1038/s41401-020-00530-2
   PubMed Web of Science ®Google Scholar
• Sugaya Y, Yamazaki M, Uchigashima M, et al. Crucial roles of the Endocannabinoid 2-arachidonoylglycerol in the suppression of epileptic seizures. Cell Rep. 2016;16(5):1405–1415. doi: 10.1016/j.celrep.2016.06.083
   PubMed Web of Science ®Google Scholar
• Li Y, Kim J. Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus. Neuroscience. 2017;363:11–25. doi: 10.1016/j.neuroscience.2017.08.053
   PubMed Web of Science ®Google Scholar
• Ebrahimi-Ghiri M, Khakpai F The link between cannabinoids and depression. In The neuroscience of depression; Elsevier: Amsterdam (NL), 2021; p. 293–300.
   Google Scholar
• Zhang Y, Gao B, Zheng F, et al. The phosphodiesterase 10A inhibitor PF-2545920 enhances hippocampal excitability and seizure activity involving the upregulation of GluA1 and NR2A in post-synaptic densities. Front Mol Neurosci. 2017;10:100. doi: 10.3389/fnmol.2017.00100
   PubMed Web of Science ®Google Scholar
• Laprairie RB, Bagher AM, Denovan-Wright EM. Cannabinoid receptor ligand bias: implications in the central nervous system. Curr Opin Pharmacol. 2017 Feb;32:32–43. doi: 10.1016/j.coph.2016.10.005. Epub 2016 Nov 9. PMID: 27835801.
   PubMed Web of Science ®Google Scholar
• Violin JD, Crombie AL, Soergel DG, et al. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci. 2014 Jul;35(7):308–316. doi: 10.1016/j.tips.2014.04.007. Epub 2014 May 28. Erratum in: Trends Pharmacol Sci. 2014 Sep;35(9):489. PMID: 24878326.
   PubMed Web of Science ®Google Scholar
• Ledgerwood CJ, Greenwood SM, Brett RR, et al. Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways. Br J Pharmacol. 2011 Jan;162(1):286–94.
   PubMed Web of Science ®Google Scholar
• Wallace MJ, Wiley JL, Martin BR, et al. Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur J Pharmacol. 2001 Sep 28;428(1):51–7. doi: 10.1016/S0014-2999(01)01243-2
   PubMed Web of Science ®Google Scholar
• Hill TD, Cascio MG, Romano B, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol. 2013 Oct;170(3):679–92.
   PubMed Web of Science ®Google Scholar
• Xing J, Li J. TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. J Neurophysiol. 2007;97(1):503–511. doi: 10.1152/jn.01023.2006
   PubMed Web of Science ®Google Scholar
• Mori F, Ribolsi M, Kusayanagi H, et al. TRPV1 channels regulate cortical excitability in humans. J Neurosci. 2012 Jan 18;32(3):873–9. doi: 10.1523/JNEUROSCI.2531-11.2012
   PubMed Web of Science ®Google Scholar
• Bhaskaran MD, Smith BN. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy exp neurol. Exp Neurol. 2010;223(2):529–536. doi: 10.1016/j.expneurol.2010.01.021
   PubMed Web of Science ®Google Scholar
• Sun FJ, Guo W, Zheng DH, et al. Increased expression of TRPV1 in the cortex and hippocampus from patients with mesial temporal lobe epilepsy. J Mol Neurosci. 2013 Jan;49(1):182–93.
   PubMed Web of Science ®Google Scholar
• Iannotti FA, Hill CL, Leo A, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Nov 19;5(11):1131–41. doi: 10.1021/cn5000524
   PubMed Web of Science ®Google Scholar
• Costa B, Giagnoni G, Franke C, et al. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharm. 2004;143(2):247–250. doi: 10.1038/sj.bjp.0705920
   PubMed Web of Science ®Google Scholar
• Gray RA, Stott CG, Jones NA, et al. Anticonvulsive Properties of Cannabidiol in a Model of Generalized Seizure Are Transient Receptor Potential Vanilloid 1 Dependent. Cannabis Cannabinoid Res. 2020 Jun 5;5(2):145–149. doi: 10.1089/can.2019.0028
   PubMedGoogle Scholar
• Anderson LL, Absalom NL, Abelev SV, et al. Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia. 2019 Nov;60(11):2224–2234. doi: 10.1111/epi.16355. Epub 2019 Oct 17. PMID: 31625159; PMCID: PMC6900043.
   PubMed Web of Science ®Google Scholar
• Watkins AR. Cannabinoid interactions with ion channels and receptors. Channels. 2019;13(1):162–167. doi: 10.1080/19336950.2019.1615824
   PubMed Web of Science ®Google Scholar
• Ghovanloo MR, Shuart NG, Mezeyova J, et al. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2019;293(43):16546–16558. doi: 10.1074/jbc.RA118.004929
   Web of Science ®Google Scholar
• Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem. 2008 Jun 6;283(23):16124–16134. doi: 10.1074/jbc.M707104200. Epub 2008 Apr 7. PMID: 18390906; PMCID: PMC3259625.
   PubMed Web of Science ®Google Scholar
• Ghit A, Assal D, AS A-S, et al. GABAA receptors: structure, function, pharmacology, and related disorders. J Genet Eng Biotechnol. 2021 Aug 21;19(1):123. doi: 10.1186/s43141-021-00224-0. PMID: 34417930; PMCID: PMC8380214.
   PubMed Web of Science ®Google Scholar
• Bakas T, van Nieuwenhuijzen PS, Devenish SO, et al. The direct actions of Cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358–370. doi: 10.1016/j.phrs.2017.02.022
   PubMed Web of Science ®Google Scholar
• Chrestia JF, Esandi MDC, Bouzat C. Cannabidiol as a modulator of α7 nicotinic receptors. Cell Mol Life Sci. 2022 Oct 25;79(11):564. doi: 10.1007/s00018-022-04600-y. PMID: 36282426.
   PubMed Web of Science ®Google Scholar
• Mahgoub M, Keun-Hang SY, Sydorenko V, et al. Effects of cannabidiol on the function of α7-nicotinic acetylcholine receptors. Eur J Pharmacol. 2013 Nov 15;720(1–3):310–9. doi: 10.1016/j.ejphar.2013.10.011. Epub 2013 Oct 18. PMID: 24140434.
   PubMed Web of Science ®Google Scholar
• Albuquerque EX, Pereira EFR, Alkondon M, et al. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89:73–120. doi: 10.1152/physrev.00015.2008
   PubMed Web of Science ®Google Scholar
• Corradi J, Bouzat C. Understanding the bases of function and modulation of α7 nicotinic receptors: implications for drug discovery. Mol Pharmacol. 2016 Sep;90(3):288–99. doi: 10.1124/mol.116.104240. Epub 2016 May 9. PMID: 27190210.
   PubMed Web of Science ®Google Scholar
• Sun P, Liu DG, Ye XM. Nicotinic acetylcholine receptor α7 subunit Is an essential regulator of seizure susceptibility. Front Neurol. 2021 Apr 12;12:656752. doi: 10.3389/fneur.2021.656752. PMID: 33912128; PMCID: PMC8072353.
   PubMed Web of Science ®Google Scholar
• Sciaccaluga M, Ruffolo G, Palma E, et al. Traditional and innovative anti-seizure medications targeting key physiopathological mechanisms: focus on neurodevelopment and neurodegeneration. Curr Neuropharmacol. 2023;21(8):1736–1754. doi: 10.2174/1570159X21666230504160948. PMID: 37143270; PMCID: PMC10514539.
   PubMed Web of Science ®Google Scholar
• Shapiro L, Escayg A, Wong JC. Cannabidiol increases seizure resistance and improves behavior in an Scn8a mouse model. Front Pharmacol. 2022;13:815950. doi: 10.3389/fphar.2022.815950
   PubMed Web of Science ®Google Scholar
• Menezes LFS, Sabiá Júnior EF, Tibery DV, et al. Epilepsy-related voltage-gated sodium channelopathies: a review. Front Pharmacol. 2020 Aug 18;11:1276. doi: 10.3389/fphar.2020.01276. PMID: 33013363; PMCID: PMC7461817.
   PubMed Web of Science ®Google Scholar
• Ghovanloo MR, Ruben PC. Cannabidiol and sodium channel pharmacology: general overview, mechanism, and clinical implications. Neuroscientist. 2022 Aug;28(4):318–334. doi: 10.1177/10738584211017009. Epub 2021 May 24. PMID: 34027742; PMCID: PMC9344566.
   PubMed Web of Science ®Google Scholar
• Mason ER, Cummins TR. Differential inhibition of human Nav1.2 resurgent and persistent sodium currents by Cannabidiol and GS967. Int J Mol Sci. 2020;21(7):2454. doi: 10.3390/ijms21072454
   PubMed Web of Science ®Google Scholar
• Ali RM, Al Kury LT, Yang K-H, et al. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes. Cell Calcium. 2015;57(4):290–299. doi: 10.1016/j.ceca.2015.02.001
   PubMed Web of Science ®Google Scholar
• Ryan D, Drysdale AJ, Lafourcade C, et al. Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci. 2009 Feb 18;29(7):2053–63. PMID: 19228959; PMCID: PMC6666323. doi: 10.1523/JNEUROSCI.4212-08.2009.
   PubMed Web of Science ®Google Scholar
• Yu Y, Yang Z, Jin B, et al. Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2. Pharmacol Res. 2020 Nov;161(161):105128. doi: 10.1016/j.phrs.2020.105128. Epub 2020 Aug 15. Erratum in: Pharmacol Res. 2021 Jun;168:105468. PMID: 32805354.
   PubMedGoogle Scholar
• Musella A, De Chiara V, Rossi S, et al. TRPV1 channels facilitate glutamate transmission in the striatum. Mol Cell Neurosci. 2009 Jan;40(1):89–97. doi: 10.1016/j.mcn.2008.09.001. Epub 2008 Sep 30. PMID: 18930149.
   PubMed Web of Science ®Google Scholar
• Ho KW, Ward NJ, Calkins DJ. TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis. 2012;1(1): 1–14. Epub 2012 Apr 1. PMID: 22737633; PMCID: PMC3560445.
   PubMedGoogle Scholar
• Martínez-Aguirre C, Márquez LA, Santiago-Castañeda CL, et al. Cannabidiol modifies the glutamate over-release in brain tissue of patients and rats with epilepsy: a Pilot study. Biomedicines. 2023 Dec 7;11(12):3237. doi: 10.3390/biomedicines11123237. PMID: 38137458; PMCID: PMC10741033.
   PubMed Web of Science ®Google Scholar
• Lasoń W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol Rep. 2013;65(4):787–801. doi: 10.1016/S1734-1140(13)71060-0
   PubMed Web of Science ®Google Scholar
• Gray RA, Whalley BJ. The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord. 2020 Jan 1;22(S1):10–15. doi: 10.1684/epd.2020.1135. PMID: 32053110.
   PubMedGoogle Scholar
• Rosenberg E, Bazelot M, Chamberland S, et al. Cannabidiol (CBD) exerts anti-epileptic actions by targeting the LPI-GPR55 signaling system potentiated by seizures. Abstr. 2018;3(52). American Epilepsy Society.
   Google Scholar
• Seelig A. P-Glycoprotein: one mechanism, many tasks and the consequences for pharmacotherapy of cancers. Front Oncol. 2020 Oct 26;10:576559. doi: 10.3389/fonc.2020.576559. PMID: 33194688; PMCID: PMC7649427.
   PubMed Web of Science ®Google Scholar
• Li Y, Yuan H, Yang K, et al. The structure and functions of P-glycoprotein. Curr Med Chem. 2010;17(8):786–800. doi: 10.2174/092986710790514507. PMID: 20088754.
   PubMed Web of Science ®Google Scholar
• Zhang C, Kwan P, Zuo Z, et al. The transport of antiepileptic drugs by P-glycoprotein. Adv Drug Deliv Rev. 2012 Jul;64(10):930–42. doi: 10.1016/j.addr.2011.12.003. Epub 2011 Dec 16. PMID: 22197850.
   PubMed Web of Science ®Google Scholar
• Tishler DM, Weinberg KI, Hinton DR, et al. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia. 1995 Jan;36(1):1–6. doi: 10.1111/j.1528-1157.1995.tb01657.x. PMID: 8001500.
   PubMed Web of Science ®Google Scholar
• Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther. 2006 May;317(2):850–7. doi: 10.1124/jpet.105.098541. Epub 2006 Jan 26. PMID: 16439618.
   PubMed Web of Science ®Google Scholar
• Melas PA, Scherma M, Fratta W, et al. Cannabidiol as a potential treatment for anxiety and mood disorders: molecular targets and epigenetic insights from preclinical research. Int J Mol Sci. 2021 Feb 13;22(4):1863. PMID: 33668469; PMCID: PMC7917759. 10.3390/ijms22041863.
   PubMed Web of Science ®Google Scholar
• Pastrana-Trejo JC, Duarte-Aké F, Us-Camas R, et al. Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in cerebral cortex, hypothalamus and Pons of Rats after a systemic administration of Cannabidiol: a preliminary study. Cent Nerv Syst Agents Med Chem. 2021;21(2):142–147. doi: 10.2174/1871524920666200924114524. PMID: 32972354.
   PubMedGoogle Scholar
• Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791–802. doi: 10.1111/epi.12631. Epub 2014 May 22. PMID: 24854329; PMCID: PMC4707667.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270–278. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. Erratum in: Lancet Neurol. 2016 Apr;15(4):352. PMID: 26724101.
   PubMed Web of Science ®Google Scholar
• Szaflarski JP, Bebin EM, Cutter G, et al. UAB CBD program. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018 Oct;87:131–136. doi: 10.1016/j.yebeh.2018.07.020. Epub 2018 Aug 9. PMID: 30100226.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017 May 25;376(21):2011–2020. doi: 10.1056/NEJMoa1611618. PMID: 28538134.
   PubMed Web of Science ®Google Scholar
• Cohen K, Weizman A, Weinstein A. Positive and negative effects of cannabis and cannabinoids on health. Clin Pharmacol Ther. 2019 May;105(5):1139–1147. doi: 10.1002/cpt.1381. Epub 2019 Mar 12. PMID: 30703255.
   PubMed Web of Science ®Google Scholar
• Ramaekers JG, Kauert G, Theunissen EL, et al. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol. 2009 May;23(3):266–77. doi: 10.1177/0269881108092393. Epub 2008 Aug 21. PMID: 18719045.
   PubMed Web of Science ®Google Scholar
• Murray RM, Quigley H, Quattrone D, et al. Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis. World Psychiatry. 2016 Oct;15(3):195–204. doi: 10.1002/wps.20341. PMID: 27717258; PMCID: PMC5032490.
   PubMed Web of Science ®Google Scholar
• Lev-Ran S, Roerecke M, Le Foll B, et al. The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies. Psychol Med. 2014 Mar;44(4):797–810. doi: 10.1017/S0033291713001438. PMID: 23795762.
   PubMed Web of Science ®Google Scholar
• Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology of cannabinoids. Neurotherapeutics. 2015 Oct;12(4):735–46. doi: 10.1007/s13311-015-0380-8. PMID: 26269228; PMCID: PMC4604177.
   PubMed Web of Science ®Google Scholar
• Smith AM, Fried PA, Hogan MJ, et al. Effects of prenatal marijuana on response inhibition: an fMRI study of young adults. Neurotoxicol Teratol. 2004 Jul;26(4):533–42. doi: 10.1016/j.ntt.2004.04.004. PMID: 15203175.
   PubMed Web of Science ®Google Scholar
• Miller I, Scheffer IE, Gunning B, et al. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: a randomized clinical trial. JAMA Neurol. 2020 May 1;77(5):613–621. doi: 10.1001/jamaneurol.2020.0073
   PubMed Web of Science ®Google Scholar
• Devinsky O, Nabbout R, Miller I, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019 Feb;60(2):294–302. doi: 10.1111/epi.14628. Epub 2018 Dec 23. PMID: 30582156; PMCID: PMC7379690.
   PubMed Web of Science ®Google Scholar
• Scheffer IE, Halford JJ, Miller I, et al. Add-on cannabidiol in patients with Dravet syndrome: results of a long-term open-label extension trial. Epilepsia. 2021 Oct;62(10):2505–2517. doi: 10.1111/epi.17036. Epub 2021 Aug 18. PMID: 34406656.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome. N Engl J Med. 2018 May 17;378(20):1888–1897. doi: 10.1056/NEJMoa1714631. PMID: 29768152.
   PubMed Web of Science ®Google Scholar
• Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with lennox-gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Mar 17;391(10125):1085–1096. Epub 2018 Jan 26. PMID: 29395273. doi: 10.1016/S0140-6736(18)30136-3.
   PubMed Web of Science ®Google Scholar
• Patel AD, Mazurkiewicz-Bełdzińska M, Chin RF, et al. Long-term safety and efficacy of add-on cannabidiol in patients with lennox-gastaut syndrome: results of a long-term open-label extension trial. Epilepsia. 2021 Sep;62(9):2228–2239. doi: 10.1111/epi.17000. Epub 2021 Jul 20. PMID: 34287833.
   PubMed Web of Science ®Google Scholar
• Szaflarski JP, Devinsky O, Lopez M, et al. Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: four-year results from the expanded access program. Epilepsia. 2023 Mar;64(3):619–629. doi: 10.1111/epi.17496. Epub 2023 Jan 10. PMID: 36537757.
   PubMed Web of Science ®Google Scholar
• Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016 Oct;57(10):1617–1624. doi: 10.1111/epi.13499. Epub 2016 Oct 3. PMID: 27696387.
   PubMed Web of Science ®Google Scholar
• Herlopian A, Hess EJ, Barnett J, et al. Cannabidiol in treatment of refractory epileptic spasms: an open-label study. Epilepsy Behav. 2020;106:106988. doi: 10.1016/j.yebeh.2020.106988
   PubMed Web of Science ®Google Scholar
• Thiele EA, Bebin EM, Bhathal H, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. JAMA Neurol. 2021 Mar 1;78(3):285–292. doi: 10.1001/jamaneurol.2020.4607. PMID: 33346789; PMCID: PMC7754080.
   PubMed Web of Science ®Google Scholar
• Wu JY, Cock HR, Devinsky O, et al. 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. Epilepsia. 2022 May;63(5):1189–1199. doi: 10.1111/epi.17199. Epub 2022 Mar 4. PMID: 35175622; PMCID: PMC9314914.
   PubMed Web of Science ®Google Scholar
• Thiele EA, Bebin EM, Filloux F, et al. Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: an open-label extension trial. Epilepsia. 2022 Feb;63(2):426–439. doi: 10.1111/epi.17150. Epub 2021 Dec 27. PMID: 34957550; PMCID: PMC9305454.
   PubMed Web of Science ®Google Scholar
• Patel S, Grinspoon R, Fleming B, et al. The longterm efficacy of cannabidiol in the treatment of refractory epilepsy. Epilepsia. 2021;62(7):1594–1603.
   PubMed Web of Science ®Google Scholar
• Wheless J, Bebin EM, Filloux F, et al. Long-term safety and efficacy of add-on cannabidiol (CBD) for treatment of seizures D. Samanta epilepsy & behavior 128 (2022) 108577 10 associated with tuberous sclerosis complex (TSC) in an open-label extension (OLE) trial (GWPCARE6)(1127). AAN Enterprises; 2021.
   Google Scholar
• Weinstock A, Bebin EM, Checketts D, et al. Long-term efficacy and safety of cannabidiol (CBD) in patients with tuberous sclerosis complex (TSC): 4-year results from the expanded access program (EAP) (2405). AAN Enterprises; 2021.
   Google Scholar
• Kaplan EH, Offermann EA, Sievers JW, et al. Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol. 2017 Jun;71:18–23.e2. doi: 10.1016/j.pediatrneurol.2017.02.009. Epub 2017 Feb 22. PMID: 28454984.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Verducci C, Thiele EA, et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and doose syndromes. Epilepsy Behav. 2018 Sep;86:131–137. doi: 10.1016/j.yebeh.2018.05.013. Epub 2018 Jul 11. PMID: 30006259.
   PubMed Web of Science ®Google Scholar
• Dell’Isola GB, Portwood KE, Consing K, et al. Current overview of CDKL-5 deficiency disorder treatment. Pediatr Rep. 2024 Jan 3;16(1):21–25. doi: 10.3390/pediatric16010002. PMID: 38251311; PMCID: PMC10801578.
   PubMedGoogle Scholar
• Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017 Jan;32(1):35–40. doi: 10.1177/0883073816669450. Epub 2016 Sep 29. PMID: 27655472.
   PubMed Web of Science ®Google Scholar
• Riva A, D’Onofrio G, Pisati A, et al. Cannabidiol add-on in glycosylphosphatidylinositol-related drug-resistant epilepsy. Cannabis Cannabinoid Res. 2023 Mar 1. doi: 10.1089/can.2022.0255. Epub ahead of print. PMID: 36862522.
   Google Scholar
• Dell’Isola GB, Vinti V, Fattorusso A, et al. The broad clinical spectrum of epilepsies associated with protocadherin 19 gene mutation. Front Neurol. 2022 Jan 17;12:780053. doi: 10.3389/fneur.2021.780053. PMID: 35111125; PMCID: PMC8801579.
   PubMed Web of Science ®Google Scholar
• Kühne F, Becker LL, Bast T, et al. Real-world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study. Epilepsia Open. 2023 Jun;8(2):360–370. doi: 10.1002/epi4.12699. Epub 2023 Feb 6. PMID: 36693811; PMCID: PMC10235575.
   PubMedGoogle Scholar
• Espinosa-Jovel C, Riveros S, Bolaños-Almeida C, et al. Real-world evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis complex. Seizure. 2023 Nov;112:72–76. doi: 10.1016/j.seizure.2023.09.015. Epub 2023 Sep 17. PMID: 37769547.
   PubMed Web of Science ®Google Scholar
• Vicino W, Muccioli L, Pondrelli F, et al. Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy. Seizure. 2023 Oct;111:39–41. doi: 10.1016/j.seizure.2023.07.009. Epub 2023 Jul 17. PMID: 37506564.
   PubMed Web of Science ®Google Scholar
• Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014 Feb;46(1):86–95. doi: 10.3109/03602532.2013.849268. Epub 2013 Oct 25. PMID: 24160757.
   PubMed Web of Science ®Google Scholar
• Graham M, Martin JH, Lucas CJ, et al. Cannabidiol drug interaction considerations for prescribers and pharmacists. Expert Rev Clin Pharmacol. 2022 Dec;15(12):1383–1397. doi: 10.1080/17512433.2022.2142114. Epub 2022 Nov 9. PMID: 36317739.
   PubMed Web of Science ®Google Scholar
• Gilmartin CGS, Dowd Z, Parker APJ, et al. Interaction of cannabidiol with other antiseizure medications: a narrative review. Seizure. 2021 Mar;86:189–196. doi: 10.1016/j.seizure.2020.09.010. Epub 2020 Oct 3. PMID: 33541771.
   PubMed Web of Science ®Google Scholar
• Geffrey AL, Pollack SF, Bruno PL, et al. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–1251. doi: 10.1111/epi.13060
   PubMed Web of Science ®Google Scholar
• Morrison G, Crockett J, Blakey G, et al. A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin Pharmacol Drug Dev. 2019 Nov;8(8):1009–1031. doi: 10.1002/cpdd.665. Epub 2019 Feb 21. PMID: 30791225; PMCID: PMC6899822.
   PubMed Web of Science ®Google Scholar
• Rana RR, Rajasekaran K, Knappertz V, et al. Pharmacodynamic synergism contributes to the antiseizure action of cannabidiol and clobazam. Exp Neurol. 2023 Feb;360:114286. doi: 10.1016/j.expneurol.2022.114286. Epub 2022 Nov 25. PMID: 36442674.
   PubMed Web of Science ®Google Scholar
• Bialer M, Perucca E. Does cannabidiol have antiseizure activity independent of its interactions with clobazam? An appraisal of the evidence from randomized controlled trials. Epilepsia. 2020 Jun;61(6):1082–1089. doi: 10.1111/epi.16542. Epub 2020 May 26. PMID: 32452568.
   PubMed Web of Science ®Google Scholar
• Lattanzi S, Trinka E, Striano P, et al. Cannabidiol efficacy and clobazam status: a systematic review and meta-analysis. Epilepsia. 2020 Jun;61(6):1090–1098. doi: 10.1111/epi.16546. Epub 2020 May 26. PMID: 32452532.
   PubMed Web of Science ®Google Scholar
• Gunning B, Mazurkiewicz-Bełdzińska M, Chin RFM, et al. Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials. Acta Neurol Scand. 2021 Feb;143(2):154–163. doi: 10.1111/ane.13351. Epub 2020 Oct 22. PMID: 32969022; PMCID: PMC7821324.
   PubMed Web of Science ®Google Scholar
• Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015 Aug;56(8):1246–1251. doi: 10.1111/epi.13060. Epub 2015 Jun 26. PMID: 26114620.
   PubMed Web of Science ®Google Scholar
• Savage TE, Sourbron J, Bruno PL, et al. Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam. Epilepsy Res. 2020 Feb;160:106263. doi: 10.1016/j.eplepsyres.2019.106263. Epub 2019 Dec 28. PMID: 31923763.
   PubMed Web of Science ®Google Scholar
• Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586–1592.
   PubMed Web of Science ®Google Scholar
• Gaston TE, Bebin EM, Cutter GR, et al. Final analysis of potential drug–drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program. Epilepsia Open. 2023 Aug 18;8(4):1405–1412. doi: 10.1002/epi4.12815. Epub ahead of print. PMID: 37593907.
   PubMedGoogle Scholar
• Socała K, Wyska E, Szafarz M, et al. 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. Neuropharmacology. 2019 Nov 1;158:107733. doi: 10.1016/j.neuropharm.2019.107733. Epub 2019 Aug 1. PMID: 31377197.
   PubMed Web of Science ®Google Scholar
• Gaston TE, Bebin EM, Cutter GR, et al. Drug-drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label expanded access program. Epilepsy Behav. 2019 Sep;98(Pt A):201–206. doi: 10.1016/j.yebeh.2019.07.008. Epub 2019 Aug 2. PMID: 31382177.
   PubMedGoogle Scholar
• Wiemer-Kruel A, Stiller B, Bast T. Cannabidiol interacts significantly with Everolimus-Report of a patient with tuberous sclerosis complex. Neuropediatrics. 2019 Dec;50(6):400–403. doi: 10.1055/s-0039-1695786. Epub 2019 Sep 20. PMID: 31539915.
   PubMed Web of Science ®Google Scholar
• Wray L, Berwaerts J, Critchley D, et al. Pharmacokinetic drug-drug interaction with coadministration of Cannabidiol and everolimus in a phase 1 healthy volunteer trial. Clin Pharmacol Drug Dev. 2023 Sep;12(9):911–919. doi: 10.1002/cpdd.1262. Epub 2023 May 3. PMID: 37132402.
   PubMedGoogle Scholar
• Ebrahimi-Fakhari D, Agricola KD, Tudor C, et al. Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex. Pediatr Neurol. 2020;105:59–61. doi: 10.1016/j.pediatrneurol.2019.11.017
   PubMed Web of Science ®Google Scholar
• Fattorusso A, Matricardi S, Mencaroni E, et al. The pharmacoresistant epilepsy: an overview on existant and new emerging therapies. Front Neurol. 2021 Jun 22;12:674483. doi: 10.3389/fneur.2021.674483. PMID: 34239494; PMCID: PMC8258148.
   PubMed Web of Science ®Google Scholar
• Operto FF, Pastorino GMG, Viggiano A, et al. Epilepsy and cognitive impairment in childhood and adolescence: a mini-review. Curr Neuropharmacol. 2023;21(8):1646–1665. doi: 10.2174/1570159X20666220706102708. PMID: 35794776; PMCID: PMC10514538.
   PubMed Web of Science ®Google Scholar