Posts Tagged CBD

[Abstract + References] Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

References

  1. 1.
    Russo EB. Cannabis and epilepsy: an ancient treatment returns to the fore. Epilepsy Behav. 2017;70(Pt B):292–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Friedman D, Sirven JI. Historical perspective on the medical use of cannabis for epilepsy: ancient times to the 1980s. Epilepsy Behav. 2017;70(Pt B):298–301.CrossRefPubMedGoogle Scholar
  3. 3.
    O’Shaughnessy WB. On the preparations of the Indian hemp, or Gunjah (Cannabis indica): their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov Med J Retrosp Med Sci. 1843;5:363–9.PubMedCentralGoogle Scholar
  4. 4.
    Gowers W. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881.Google Scholar
  5. 5.
    Reynolds JR. On some of the therapeutical uses of Indian hemp. Arch Med. 1868;2:154–60.Google Scholar
  6. 6.
    McMeens RR. Cannabis indica in convulsions. West Lancet 1856:327–31.Google Scholar
  7. 7.
    Carlini EA, Leite JR, Tannhauser M, Berardi AC. Letter: Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol. 1973;25(8):664–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Consroe P, Wolkin A. Cannabidiol–antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977;201(1):26–32.PubMedGoogle Scholar
  9. 9.
    Izquierdo I, Orsingher OA, Berardi AC. Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Psychopharmacologia. 1973;28(1):95–102.CrossRefPubMedGoogle Scholar
  10. 10.
    Karler R, Cely W, Turkanis SA. The anticonvulsant activity of cannabidiol and cannabinol. Life Sci. 1973;13(11):1527–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Leite JR, Carlini EA, Lander N, Mechoulam R. Anticonvulsant effects of the (−) and (+)isomers of cannabidiol and their dimethylheptyl homologs. Pharmacology. 1982;24(3):141–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last? J Epilepsy Res. 2017;7(2):61–76.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Epidiolex. Full Prescribing Information. https://www.epidiolex.com/sites/default/files/EPIDIOLEX_Full_Prescribing_Information.pdf. Accessed 30 Jan 2019.
  15. 15.
    GWPharmaceuticals. Press release: GW Pharmaceuticals reports positive Phase 3 pivotal trial results for EPIDIOLEX (cannabidiol) oral solution in patients with seizures associated with tuberous sclerosis complex. Carlsbad, USA, May 6, 2019 http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-reports-positive-phase-3-pivotal-trial. Accessed 25 June 2019.
  16. 16.
    Consroe P, Benedito MA, Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol. 1982;83(3–4):293–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Klein BD, Jacobson CA, Metcalf CS, Smith MD, Wilcox KS, Hampson AJ, et al. Evaluation of cannabidiol in animal seizure models by the Epilepsy Therapy Screening Program (ETSP). Neurochem Res. 2017;42(7):1939–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Patra PH, Barker-Haliski M, White HS, Whalley BJ, Glyn S, Sandhu H, et al. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models. Epilepsia. 2019;60(2):303–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332(2):569–77.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Karler R, Turkanis SA. Cannabis and epilepsy. Adv Biosci. 1978;22–23:619–41.PubMedGoogle Scholar
  21. 21.
    Karler R, Turkanis SA. The cannabinoids as potential antiepileptics. J Clin Pharmacol. 1981;21(S1):437S–48S.CrossRefPubMedGoogle Scholar
  22. 22.
    Gobira PH, Vilela LR, Goncalves BD, Santos RP, de Oliveira AC, Vieira LB, et al. Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: possible role of the mTOR pathway and reduction in glutamate release. Neurotoxicology. 2015;50:116–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Do Val-da Silva RA, Peixoto-Santos JE, Kandratavicius L, De Ross JB, Esteves I, De Martinis BS, et al. Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy. Front Pharmacol. 2017;8:131.Google Scholar
  24. 24.
    Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Chiu P, Olsen DM, Borys HK, Karler R, Turkanis SA. The influence of cannabidiol and delta 9-tetrahydrocannabinol on cobalt epilepsy in rats. Epilepsia. 1979;20(4):365–75.CrossRefPubMedGoogle Scholar
  26. 26.
    Turkanis SA, Smiley KA, Borys HK, Olsen DM, Karler R. An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia. 1979;20(4):351–63.CrossRefPubMedGoogle Scholar
  27. 27.
    Rosenberg EC, Patra PH, Whalley BJ. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav. 2017;70(Pt B):319–27.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA. 2017;114(42):11229–34.CrossRefPubMedGoogle Scholar
  29. 29.
    Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Tomson T, et al. Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development. Epilepsia. 2018;59(10):1842-66.Google Scholar
  30. 30.
    Reddy DS, Golub VM. The pharmacological basis of cannabis therapy for epilepsy. J Pharmacol Exp Ther. 2016;357(1):45–55.CrossRefPubMedGoogle Scholar
  31. 31.
    Katona I. Cannabis and endocannabinoid signaling in epilepsy. Handb Exp Pharmacol. 2015;231:285–316.CrossRefPubMedGoogle Scholar
  32. 32.
    Blair RE, Deshpande LS, DeLorenzo RJ. Cannabinoids: is there a potential treatment role in epilepsy? Expert Opin Pharmacother. 2015;16(13):1911–4.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Di Marzo V, De Petrocellis L, Bisogno T. The biosynthesis, fate and pharmacological properties of endocannabinoids. Handb Exp Pharmacol. 2005;168:147–85.CrossRefGoogle Scholar
  34. 34.
    Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol. 2019;18(5):504–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Lupica CRHY, Devinsky O, Hoffman AF. Cannabinoids as hippocampal network administrators. Neuropharmacology. 2017;124:25–37.CrossRefPubMedGoogle Scholar
  36. 36.
    Soltesz I, Alger BE, Kano M, Lee SH, Lovinger DM, Ohno-Shosaku T, et al. Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nat Rev Neurosci. 2015;16(5):264–77.CrossRefPubMedGoogle Scholar
  37. 37.
    Ledgerwood CJ, Greenwood SM, Brett RR, Pratt JA, Bushell TJ. Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways. Br J Pharmacol. 2011;162(1):286–94.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hofmann ME, Frazier CJ. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Exp Neurol. 2013;244:43–50.CrossRefPubMedGoogle Scholar
  39. 39.
    Goffin K, Van Paesschen W, Van Laere K. In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis. Brain. 2011;134(Pt 4):1033–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Ludanyi A, Eross L, Czirjak S, Vajda J, Halasz P, Watanabe M, et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci. 2008;28(12):2976–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Magloczky Z, Toth K, Karlocai R, Nagy S, Eross L, Czirjak S, et al. Dynamic changes of CB1-receptor expression in hippocampi of epileptic mice and humans. Epilepsia. 2010;51(Suppl 3):115–20.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Romigi A, Bari M, Placidi F, Marciani MG, Malaponti M, Torelli F, et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia. 2010;51(5):768–72.CrossRefPubMedGoogle Scholar
  43. 43.
    Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70(Pt B):313–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Nichol K, Stott C, Jones N, Bazelot M, Whalley BJ. The proposed multimodal mechanism of action of cannabidiol in epilepsy: Modulation of intracellular calcium and adenosine-mediated signaling. [abstract] American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/554059. Accessed 12 Feb 2019.
  45. 45.
    Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–805.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2019;176(10):1455–69.CrossRefPubMedGoogle Scholar
  47. 47.
    Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–23.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845–52.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA. 2006;103(20):7895–900.CrossRefPubMedGoogle Scholar
  50. 50.
    De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479–94.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Gaston TE, Szaflarski JP. Cannabis for the treatment of epilepsy: an update. Curr Neurol Neurosci Rep. 2018;18(11):73.CrossRefPubMedGoogle Scholar
  52. 52.
    Aso E, Fernandez-Duenas V, Lopez-Cano M, Taura J, Watanabe M, Ferrer I, et al. Adenosine A2A-cannabinoid CB1 receptor heteromers in the hippocampus: cannabidiol blunts Δ(9)-tetrahydrocannabinol-induced cognitive impairment. Mol Neurobiol. 2019. [Epub ahead of print].Google Scholar
  53. 53.
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791–802.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hill AJ, Jones NA, Smith I, Hill CL, Williams CM, Stephens GJ, et al. Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett. 2014;566:269–74.CrossRefPubMedGoogle Scholar
  55. 55.
    Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, 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;5(11):1131–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12(4):699–730.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Leo A, Russo E, Elia M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacol Res. 2016;107:85–92.CrossRefPubMedGoogle Scholar
  58. 58.
    McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737–53.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Rong C, Lee Y, Carmona NE, Cha DS, Ragguett RM, Rosenblat JD, et al. Cannabidiol in medical marijuana: research vistas and potential opportunities. Pharmacol Res. 2017;121:213–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Thompson CH, Kearney JA. Cannabidiol mellows out resurgent sodium current. Epilepsy Curr. 2016;16(6):399–401.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Bouron A. Phyto and endocannabinoids exert complex actions on calcium and zinc signaling in mouse cortical neurons. Biochem Pharmacol. 2018;152:244–51.CrossRefPubMedGoogle Scholar
  63. 63.
    Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2019;11:487.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Vilela LR, Lima IV, Kunsch EB, Pinto HPP, de Miranda AS, Vieira ELM, et al. Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Behav. 2017;75:29–35.CrossRefPubMedGoogle Scholar
  65. 65.
    Pandolfo P, Silveirinha V, dos Santos-Rodrigues A, Venance L, Ledent C, Takahashi RN, et al. Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur J Pharmacol. 2011;655(1–3):38–45.CrossRefPubMedGoogle Scholar
  66. 66.
    Ghovanloo MR, Shuart NG, Mezeyova J, Dean RA, Ruben PC, Goodchild SJ. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018;293(43):16546–58.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Watkins AR. Cannabinoid interactions with ion channels and receptors. Channels (Austin). 2019;13(1):162–7.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Millar SA, Stone NL, Yates AS, O’Sullivan SE. A systematic review on the pharmacokinetics of cannabidiol in humans. Front Pharmacol. 2018;9:1365.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32(11):1053–67.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327–60.CrossRefPubMedGoogle Scholar
  71. 71.
    Birnbaum AK, Karanam A, Marino SE, Barkley CM, Remmel RP, Roslawski M, et al. Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia. 2019. [Epub ahead of print].Google Scholar
  72. 72.
    Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5–6):165–70.CrossRefPubMedGoogle Scholar
  73. 73.
    Mazur A, Lichti CF, Prather PL, Zielinska AK, Bratton SM, Gallus-Zawada A, et al. Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metab Dispos. 2009;37(7):1496–504.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Zendulka O, Dovrtelova G, Noskova K, Turjap M, Sulcova A, Hanus L, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206–26.CrossRefPubMedGoogle Scholar
  75. 75.
    Morrison G, Crockett J, Blakey G, Sommerville K. 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. [Epub ahead of print].Google Scholar
  76. 76.
    Whalley BJ, Stott C, Gray RA, N.A. J. The human metabolite of cannabidiol, 7-hydroxy-cannabidiol, but not 7-carboxy-cannabidiol, is anticonvulsant in the maximal electroshock threshold test (MEST) in mouse [abstract]. American Epilepsy Society Annual Meeting, December 1-5, 2017, Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381222. Accessed 09 Feb 2019.
  77. 77.
    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204–11.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Wheless JW, Dlugos D, Miller I, Oh DA, Parikh N, Phillips S, et al. Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. CNS Drugs. 2019;33(6):593–604.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Taylor L, Crockett J, Tayo B, Morrison G. A phase 1, open-label, parallel-group, single-dose trial of the pharmacokinetics and safety of cannabidiol (CBD) in subjects with mild to severe hepatic impairment. J Clin Pharmacol. 2019. [Epub ahead of print].Google Scholar
  80. 80.
    Stott C, White L, Wright S, Wilbraham D, Guy G. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;2(1):236.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Sativex. Orosomucosal Spray, Summary of Product Characteristics, 28 August 2018 revision. https://www.medicines.org.uk/emc/product/602/smpc#DOCREVISION. Accessed 11 Feb 2019.
  82. 82.
    Arellano AL, Papaseit E, Romaguera A, Torrens M, Farre M. Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines. CNS Neurol Disord Drug Targets. 2017;16(5):554–66.CrossRefPubMedGoogle Scholar
  83. 83.
    Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86–95.CrossRefPubMedGoogle Scholar
  85. 85.
    Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos. 2011;39(11):2049–56.CrossRefPubMedGoogle Scholar
  86. 86.
    Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 2011;88(15–16):730–6.CrossRefPubMedGoogle Scholar
  87. 87.
    Morrison G, Taylor L, Crockett J, Critchley D, Tayo B. A Phase 1 investigation into the potential effects of cannabidiol on CYP3A4-mediated drug-drug interactions in healthy volunteers [abstract]. American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/500033. Accessed 09 Feb 2019.
  88. 88.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888–97.CrossRefPubMedGoogle Scholar
  89. 89.
    Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med. 2015;373(11):1048–58.CrossRefPubMedGoogle Scholar
  90. 90.
    Friedman D, Cilio MR, Tilton N, Sullivan J, Hedlund J, Rosenberg E, et al. The effect of epidiolex (cannabidiol) on serum levels of concomitant anti-epileptic drugs in children and young adults with treatment-resistant epilepsy in an expanded access program [abstract]. American Epilepsy Society 2014 annual meeting. Seattle, WA, December 5–9, 2014. https://www.aesnet.org/annual_meeting/abstract_search#/sortDate_na_dt/DESC/0/epidiolex/?Year=2014. Accessed 09 Feb 2019.
  91. 91.
    Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586–92.CrossRefPubMedGoogle Scholar
  92. 92.
    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–51.CrossRefPubMedGoogle Scholar
  93. 93.
    Giraud C, Treluyer JM, Rey E, Chiron C, Vincent J, Pons G, et al. In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos. 2006;34(4):608–11.CrossRefPubMedGoogle Scholar
  94. 94.
    Diacomit. Summary of Product Characteristics, revised 8 January 2014, European Medicines Agency. https://www.ema.europa.eu/en/documents/product-information/diacomit-epar-product-information_en.pdf. Accessed 06 Mar 2019.
  95. 95.
    Klotz KA, Hirsch M, Heers M, Schulze-Bonhage A, Jacobs J. Effects of cannabidiol on brivaracetam plasma levels. Epilepsia. 2019;60(7):e74–7.CrossRefPubMedGoogle Scholar
  96. 96.
    Tayo B, Ben-Menachem E, Gunning B, Arenas Cabrera CM, Crockett J, Taylor L, et al. Exploration of the potential for plasma protein binding displacement and drug–drug interactions of valproate in combination with cannabidiol [abstract]. American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/540271. Accessed 09 Feb 2019.
  97. 97.
    Grayson L, Vines B, Nichol K, Szaflarski JP. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2018;9:10–1.CrossRefPubMedGoogle Scholar
  98. 98.
    Al Saabi A, Allorge D, Sauvage FL, Tournel G, Gaulier JM, Marquet P, et al. Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse. Drug Metab Dispos. 2013;41(3):568–74.CrossRefPubMedGoogle Scholar
  99. 99.
    Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19–27.CrossRefPubMedGoogle Scholar
  100. 100.
    Niesink RJ, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry. 2013;4:130.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC. Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of Δ9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci. 1998;63(1):1–6.CrossRefGoogle Scholar
  102. 102.
    Todd SM, Arnold JC. Neural correlates of interactions between cannabidiol and Δ(9)-tetrahydrocannabinol in mice: implications for medical cannabis. Br J Pharmacol. 2016;173(1):53–65.CrossRefPubMedGoogle Scholar
  103. 103.
    Todd SM, Zhou C, Clarke DJ, Chohan TW, Bahceci D, Arnold JC. Interactions between cannabidiol and Δ(9)-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur Neuropsychopharmacol. 2017;27(2):132–45.CrossRefPubMedGoogle Scholar
  104. 104.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–20.CrossRefPubMedGoogle Scholar
  105. 105.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270–8.CrossRefPubMedGoogle Scholar
  106. 106.
    Ahn Y, Drummond-Main C, Kiroski I, Rho JM. Cannabidiol impairs mitochondrial function independent of CB1 and GPR55 receptors [abstract]. American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/500201. Accessed 10 Feb 2019.
  107. 107.
    Ahn Y, Drummond-Main C, Yee NC, Kim DY, Rho JM. Effects of cannabidiol on mitochondrial bioenergetics and homeostasis [abstract]. American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344542. Accessed 10 Feb 2019.
  108. 108.
    Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89(7):741–53.CrossRefPubMedGoogle Scholar
  109. 109.
    McCoy B, Wang L, Zak M, Al-Mehmadi S, Kabir N, Alhadid K, et al. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome. Ann Clin Transl Neurol. 2018;5(9):1077–88.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617–24.CrossRefPubMedGoogle Scholar
  111. 111.
    Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge–Weber syndrome. Pediatr Neurol. 2017;71(18–23):e2.Google Scholar
  112. 112.
    Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, et al. Cannabidiol as a potential treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32(1):35–40.CrossRefPubMedGoogle Scholar
  113. 113.
    Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol. 2015;52(5):544–7.CrossRefPubMedGoogle Scholar
  114. 114.
    Dale T, Downs J, Olson H, Bergin AM, Smith S, Leonard H. Cannabis for refractory epilepsy in children: a review focusing on CDKL5 Deficiency Disorder. Epilepsy Res. 2019;151:31–9.CrossRefPubMedGoogle Scholar
  115. 115.
    Devinsky O, Verducci C, Thiele EA, Laux LC, Patel AD, Filloux F, 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;86:131–7.CrossRefPubMedGoogle Scholar
  116. 116.
    Elliott J, DeJean D, Clifford T, Coyle D, Potter BK, Skidmore B, et al. Cannabis-based products for pediatric epilepsy: a systematic review. Epilepsia. 2019;60(1):6–19.CrossRefPubMedGoogle Scholar
  117. 117.
    Pamplona FA, da Silva LR, Coan AC. Potential clinical benefits of CBD-rich cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis. Front Neurol. 2018;9:759.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Pamplona FA, da Silva LR, Coan AC. Corrigendum: Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis. Front Neurol. 2018;9:1050.CrossRefPubMedGoogle Scholar
  119. 119.
    White CM. A review of human studies assessing cannabidiol’s (CBD) therapeutic actions and potential. J Clin Pharmacol. 2019. [Epub ahead of print].Google Scholar
  120. 120.
    FDA. United States of America, 2016. Warning letters and test results for cannabidiol-related products. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm484109.htm. Accessed 17 Feb 2019.
  121. 121.
    Bettiol A, Lombardi N, Crescioli G, Maggini V, Gallo E, Mugelli A, et al. Galenic preparations of therapeutic Cannabis sativa differ in cannabinoids concentration: a quantitative analysis of variability and possible clinical implications. Front Pharmacol. 2019;9:1543.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling accuracy of Cannabidiol extracts sold online. JAMA. 2017;318(17):1708–9.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Carcieri C, Tomasello C, Simiele M, De Nicolo A, Avataneo V, Canzoneri L, et al. Cannabinoids concentration variability in cannabis olive oil galenic preparations. J Pharm Pharmacol. 2018;70(1):143–9.CrossRefPubMedGoogle Scholar
  124. 124.
    Dryburgh LM, Bolan NS, Grof CPL, Galettis P, Schneider J, Lucas CJ, et al. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Br J Clin Pharmacol. 2018;84(11):2468–76.CrossRefPubMedGoogle Scholar
  125. 125.
    Pavlovic R, Nenna G, Calvi L, Panseri S, Borgonovo G, Giupponi L, et al. Quality traits of “Cannabidiol Oils”: Cannabinoids content, terpene fingerprint and oxidation stability of European commercially available preparations. Molecules. 2018;23(5).Google Scholar
  126. 126.
    Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313(24):2491–3.CrossRefPubMedGoogle Scholar
  127. 127.
    Pacifici R, Marchei E, Salvatore F, Guandalini L, Busardo FP, Pichini S. Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometry. Clin Chem Lab Med. 2017;55(10):1555–63.CrossRefPubMedGoogle Scholar
  128. 128.
    Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8):1540–8.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Szaflarski JP, Bebin EM, Cutter G, DeWolfe J, Dure LS, Gaston TE, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018;87:131–6.CrossRefPubMedGoogle Scholar
  130. 130.
    Gaston T, Szaflarski M, Hansen B, Grayson L, Bebin EM, Szaflarski J. Improvement in quality of life ratings after one year of treatment with pharmaceutical formulation of cannabidiol (CBD). Epilepsia. 2017;58:S155.CrossRefGoogle Scholar
  131. 131.
    Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D. Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia. 2017;58(8):e96–100.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–96.CrossRefPubMedGoogle Scholar
  133. 133.
    Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175–85.CrossRefPubMedGoogle Scholar
  134. 134.
    Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften. 1978;65(4):174–9.CrossRefPubMedGoogle Scholar
  135. 135.
    Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Marijuana ‘90 International Conference on Cannabis and Cannabinoids; July 8–11, 1990; Kolympari, Crete (cited by Devinsky et al. 2014).Google Scholar
  136. 136.
    Ames FR, Cridland S. Anticonvulsant effect of cannabidiol. S Afr Med J. 1986;69(1):14.PubMedGoogle Scholar
  137. 137.
    Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014(3):CD009270.Google Scholar
  138. 138.
    Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556–63.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Miller I, Perry MS, Saneto RP, Scheffer I, Gunning B, Sanchez-Carpintero R, et al. Cannabidiol (CBD; 10 and 20 mg/kg/day) significantly reduces convulsive seizure frequency in children and adolescents with Dravet syndrome (DS): results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE2). [abstract]. Annual Meeting of the American Academy of Neurology, Philadelphia, May 4–10, 2019. http://file:///E:/2019-emerging-science-schedule-and-abstracts-with-disclosures.pdf. Accessed 13 May 2019.Google Scholar
  140. 140.
    Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Devinsky O, et al. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia. 2019;60(3):419–28.CrossRefPubMedGoogle Scholar
  141. 141.
    Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019;60(2):294–302.CrossRefPubMedGoogle Scholar
  142. 142.
    Thiele EA, Devinsky O, Checketts D, Knappertz V. Cannabidiol treatment responder analysis in patients with Lennox-Gastaut syndrome on and off clobazam [abstract]. American Epilepsy Society Annual Meeting, New Orleans, LA, November 30–December 4, 2018. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224. Accessed 04 Mar 2019.
  143. 143.
    Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, et al. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Drugs. 2018;78(17):1791–804.CrossRefPubMedGoogle Scholar
  144. 144.
    Sands TT, Rahdari S, Oldham MS, Caminha Nunes E, Tilton N, Cilio MR. Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US. CNS Drugs. 2019;33(1):47–60.CrossRefPubMedGoogle Scholar
  145. 145.
    Babalonis S, Haney M, Malcolm RJ, Lofwall MR, Votaw VR, Sparenborg S, et al. Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers. Drug Alcohol Depend. 2017;172:9–13.CrossRefPubMedGoogle Scholar
  146. 146.
    Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C, et al. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a randomized, double-blind, controlled trial. Epilepsy Behav. 2018;88:162–71.CrossRefPubMedGoogle Scholar
  147. 147.
    Schonhofen P, Bristot IJ, Crippa JA, Hallak JEC, Zuardi AW, Parsons RB, et al. Cannabinoid-based therapies and brain development: potential harmful effect of early modulation of the endocannabinoid system. CNS Drugs. 2018;32(8):697–712.CrossRefPubMedGoogle Scholar

via Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy | SpringerLink

, , , , , , ,

Leave a comment

[Abstract + References] Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Abstract

Background

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

Objective

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

Results

Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

References

  1. 1.
    Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007;68:326–37.CrossRefGoogle Scholar
  2. 2.
    Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Seizure course during pregnancy in catamenial epilepsy. Neurology. 2014;83:339–44.CrossRefGoogle Scholar
  3. 3.
    Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the national general practice study of epilepsy. Lancet. 1995;346:140–4.CrossRefGoogle Scholar
  4. 4.
    Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, et al. Antiepileptic mono-therapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand.  https://doi.org/10.1111/ane.13025 (Epub 2018 Sep 8).
  5. 5.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure. 2015;27:71–4.CrossRefGoogle Scholar
  6. 6.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.CrossRefGoogle Scholar
  7. 7.
    Lattanzi S, Cagnetti C, Foschi N, Lorusso A, Provinciali L, Silvestrini M. Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy. Acta Neurol Scand. 2018;137:29–32.CrossRefGoogle Scholar
  8. 8.
    Lattanzi S, Cagnetti C, Matricardi S, Silvestrini M. Palliative non-resective surgery for drug-resistant epilepsy. Brain Dev. 2018;40:512–3.CrossRefGoogle Scholar
  9. 9.
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.CrossRefGoogle Scholar
  10. 10.
    Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.CrossRefGoogle Scholar
  11. 11.
    GW Pharmaceuticals plc and its U.S. subsidiary Greenwich Biosciences announce FDA approval of EPIDIOLEX® (cannabidiol) oral solution—the first plant-derived cannabinoid prescription medicine. https://www.gwpharm.com/about-us/news/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-biosciences-announce-fda. Accessed Sep 2018.
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.CrossRefGoogle Scholar
  13. 13.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.CrossRefGoogle Scholar
  14. 14.
    Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. Higgins JPT, Green S, editors. The Cochrane Collaboration, 2011. http://handbook-5-1.cochrane.org/. Accessed Jun 2018.
  15. 15.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefGoogle Scholar
  16. 16.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefGoogle Scholar
  17. 17.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86:1344–52.CrossRefGoogle Scholar
  18. 18.
    Lattanzi S, Brigo F, Grillo E, Cagnetti C, Verrotti A, Zaccara G, et al. Adjunctive eslicarbazepine acetate in pediatric patients with focal epilepsy: a systematic review and meta-analysis. CNS Drugs. 2018;32:189–96.CrossRefGoogle Scholar
  19. 19.
    Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta-analysis. J Neurol. 2018;265:733–40.CrossRefGoogle Scholar
  20. 20.
    Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264:1697–704.CrossRefGoogle Scholar
  21. 21.
    Lattanzi S, Brigo F, Cagnetti C, Di Napoli M, Silvestrini M. Patent foramen ovale and cryptogenic stroke or transient ischemic attack: to close or not to close? A systematic review and meta-analysis. Cerebrovasc Dis. 2018;45:193–203.CrossRefGoogle Scholar
  22. 22.
    Lattanzi S, Brigo F, Di Napoli M, Cagnetti C, Corradetti T, Silvestrini M. Endovascular treatment of symptomatic vertebral artery stenosis: a systematic review and meta-analysis. J Neurol Sci. 2018;391:48–53.CrossRefGoogle Scholar
  23. 23.
    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al.; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.CrossRefGoogle Scholar
  24. 24.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al.; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–2020.CrossRefGoogle Scholar
  25. 25.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al.; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888-1897.CrossRefGoogle Scholar
  26. 26.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al.; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox–Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.Google Scholar
  27. 27.
    Lattanzi S, Brigo F, Cagnetti C, Trinka E, Silvestrini M. Efficacy and safety of adjunctive cannabidiol in patients with Lennox–Gastaut syndrome: a systematic review and meta-analysis. CNS Drugs.  https://doi.org/10.1007/s40263-018-0558-9 (Epub 2018 Aug 21).CrossRefGoogle Scholar
  28. 28.
    Morrison G, Sardu M, Rasmussen C, Sommerville K, Roberts C, Blakey GE. Exposure-response analysis of cannabidiol oral solution for the treatment of Lennox–Gastaut syndrome [abstract no. 2.281]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344717. Accessed Jul 2018.
  29. 29.
    FDA. Cannabidiol oral solution. Full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed Jul 2018.
  30. 30.
    Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77:1473–81.CrossRefGoogle Scholar
  31. 31.
    Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70:1950–8.CrossRefGoogle Scholar
  32. 32.
    Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006;21:496–502.CrossRefGoogle Scholar
  33. 33.
    FDA briefing document. Peripheral and central nervous system drugs. Advisory Committee Meeting. April 19, 2018. NDA 210365. Cannabidiol. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm604736.pdf. Accessed Jul 2018.
  34. 34.
    US Department of Health and Human Services. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. 2009. https://www.fda.gov/downloads/Guidances/UCM174090.pdf. Accessed Jul 2018.
  35. 35.
    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.CrossRefGoogle Scholar
  36. 36.
    Thiele EA, Devinsky O, Checketts D, Knappertz V. Cannabidiol (CBD) treatment responders analysis in patients with Lennox–Gastaut syndrome (LGS) on and off clobazam (CLB) [abstract no. 1.436]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224. Accessed Jul 2018.
  37. 37.
    Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.Google Scholar
  38. 38.
    Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of con-trolled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89:741–53.CrossRefGoogle Scholar
  39. 39.
    Rhodes KM, Turner RM, Savović J, Jones HE, Mawdsley D, Higgins JPT. Between-trial heterogeneity in meta-analyses may be partially explained by reported design characteristics. J Clin Epidemiol. 2018;95:45–54.CrossRefGoogle Scholar
  40. 40.
    Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Maintenance of long-term safety and efficacy of cannabidiol (CBD) treatment in Dravet syndrome (DS): results of the open-label extension (OLE) trial (GWPCARE5) [abstract no. 1.289]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/343046. Accessed Jul 2018.
  41. 41.
    Marsh ED, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Checketts D, Nichol K, et al. Maintained safety and efficacy of cannabidiol (CBD) in a long-term open-label trial in patients with Lennox–Gastaut syndrome (LGS) (GWPCARE 5) [abstract no. 2.271]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344387. Accessed Jul 2018.
  42. 42.
    Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al.; CBD EAP study group. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8):1540–8.  https://doi.org/10.1111/epi.14477.CrossRefGoogle Scholar

via Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis | SpringerLink

, , , ,

Leave a comment

[Abstract + References] Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Abstract

Background

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

Objective

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

Results

Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Supplementary material

40265_2018_992_MOESM1_ESM.doc (31 kb)

Supplementary material 1 (DOC 31 kb)

References

  1. 1.
    Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007;68:326–37.CrossRefGoogle Scholar
  2. 2.
    Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Seizure course during pregnancy in catamenial epilepsy. Neurology. 2014;83:339–44.CrossRefGoogle Scholar
  3. 3.
    Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the national general practice study of epilepsy. Lancet. 1995;346:140–4.CrossRefGoogle Scholar
  4. 4.
    Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, et al. Antiepileptic mono-therapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand.  https://doi.org/10.1111/ane.13025 (Epub 2018 Sep 8).
  5. 5.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure. 2015;27:71–4.CrossRefGoogle Scholar
  6. 6.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.CrossRefGoogle Scholar
  7. 7.
    Lattanzi S, Cagnetti C, Foschi N, Lorusso A, Provinciali L, Silvestrini M. Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy. Acta Neurol Scand. 2018;137:29–32.CrossRefGoogle Scholar
  8. 8.
    Lattanzi S, Cagnetti C, Matricardi S, Silvestrini M. Palliative non-resective surgery for drug-resistant epilepsy. Brain Dev. 2018;40:512–3.CrossRefGoogle Scholar
  9. 9.
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.CrossRefGoogle Scholar
  10. 10.
    Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.CrossRefGoogle Scholar
  11. 11.
    GW Pharmaceuticals plc and its U.S. subsidiary Greenwich Biosciences announce FDA approval of EPIDIOLEX® (cannabidiol) oral solution—the first plant-derived cannabinoid prescription medicine. https://www.gwpharm.com/about-us/news/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-biosciences-announce-fda. Accessed Sep 2018.
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.CrossRefGoogle Scholar
  13. 13.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.CrossRefGoogle Scholar
  14. 14.
    Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. Higgins JPT, Green S, editors. The Cochrane Collaboration, 2011. http://handbook-5-1.cochrane.org/. Accessed Jun 2018.
  15. 15.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefGoogle Scholar
  16. 16.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefGoogle Scholar
  17. 17.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86:1344–52.CrossRefGoogle Scholar
  18. 18.
    Lattanzi S, Brigo F, Grillo E, Cagnetti C, Verrotti A, Zaccara G, et al. Adjunctive eslicarbazepine acetate in pediatric patients with focal epilepsy: a systematic review and meta-analysis. CNS Drugs. 2018;32:189–96.CrossRefGoogle Scholar
  19. 19.
    Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta-analysis. J Neurol. 2018;265:733–40.CrossRefGoogle Scholar
  20. 20.
    Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264:1697–704.CrossRefGoogle Scholar
  21. 21.
    Lattanzi S, Brigo F, Cagnetti C, Di Napoli M, Silvestrini M. Patent foramen ovale and cryptogenic stroke or transient ischemic attack: to close or not to close? A systematic review and meta-analysis. Cerebrovasc Dis. 2018;45:193–203.CrossRefGoogle Scholar
  22. 22.
    Lattanzi S, Brigo F, Di Napoli M, Cagnetti C, Corradetti T, Silvestrini M. Endovascular treatment of symptomatic vertebral artery stenosis: a systematic review and meta-analysis. J Neurol Sci. 2018;391:48–53.CrossRefGoogle Scholar
  23. 23.
    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al.; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.CrossRefGoogle Scholar
  24. 24.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al.; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–2020.CrossRefGoogle Scholar
  25. 25.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al.; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888-1897.CrossRefGoogle Scholar
  26. 26.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al.; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox–Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.Google Scholar
  27. 27.
    Lattanzi S, Brigo F, Cagnetti C, Trinka E, Silvestrini M. Efficacy and safety of adjunctive cannabidiol in patients with Lennox–Gastaut syndrome: a systematic review and meta-analysis. CNS Drugs.  https://doi.org/10.1007/s40263-018-0558-9 (Epub 2018 Aug 21).CrossRefGoogle Scholar
  28. 28.
    Morrison G, Sardu M, Rasmussen C, Sommerville K, Roberts C, Blakey GE. Exposure-response analysis of cannabidiol oral solution for the treatment of Lennox–Gastaut syndrome [abstract no. 2.281]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344717. Accessed Jul 2018.
  29. 29.
    FDA. Cannabidiol oral solution. Full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed Jul 2018.
  30. 30.
    Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77:1473–81.CrossRefGoogle Scholar
  31. 31.
    Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70:1950–8.CrossRefGoogle Scholar
  32. 32.
    Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006;21:496–502.CrossRefGoogle Scholar
  33. 33.
    FDA briefing document. Peripheral and central nervous system drugs. Advisory Committee Meeting. April 19, 2018. NDA 210365. Cannabidiol. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm604736.pdf. Accessed Jul 2018.
  34. 34.
    US Department of Health and Human Services. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. 2009. https://www.fda.gov/downloads/Guidances/UCM174090.pdf. Accessed Jul 2018.
  35. 35.
    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.CrossRefGoogle Scholar
  36. 36.
    Thiele EA, Devinsky O, Checketts D, Knappertz V. Cannabidiol (CBD) treatment responders analysis in patients with Lennox–Gastaut syndrome (LGS) on and off clobazam (CLB) [abstract no. 1.436]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224. Accessed Jul 2018.
  37. 37.
    Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.Google Scholar
  38. 38.
    Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of con-trolled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89:741–53.CrossRefGoogle Scholar
  39. 39.
    Rhodes KM, Turner RM, Savović J, Jones HE, Mawdsley D, Higgins JPT. Between-trial heterogeneity in meta-analyses may be partially explained by reported design characteristics. J Clin Epidemiol. 2018;95:45–54.CrossRefGoogle Scholar
  40. 40.
    Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Maintenance of long-term safety and efficacy of cannabidiol (CBD) treatment in Dravet syndrome (DS): results of the open-label extension (OLE) trial (GWPCARE5) [abstract no. 1.289]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/343046. Accessed Jul 2018.
  41. 41.
    Marsh ED, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Checketts D, Nichol K, et al. Maintained safety and efficacy of cannabidiol (CBD) in a long-term open-label trial in patients with Lennox–Gastaut syndrome (LGS) (GWPCARE 5) [abstract no. 2.271]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344387. Accessed Jul 2018.
  42. 42.
    Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al.; CBD EAP study group. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8):1540–8.  https://doi.org/10.1111/epi.14477.CrossRefGoogle Scholar

via Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis | SpringerLink

, , , ,

Leave a comment

[REVIEW] Epilepsy and Cannabis: A Literature Review – Full Text PDF

Abstract

Epilepsy is considered to be one of the most common non-communicable neurological diseases especially in low to middle-income countries. Approximately one-third of patients with epilepsy have seizures that are resistant to antiepileptic medications. Clinical trials for the treatment of medically refractory epilepsy have mostly focused on new drug treatments, and result in a significant portion of subjects whose seizures remain refractory to medication. The off-label use of cannabis sativa plant in treating seizures is known since ancient times. The active ingredients of this plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the latter considered safer and more effective in treating seizures, and with less adverse psychotropic effects.

Clinical trials prior to two years ago have shown little to no significant effects of cannabis in reducing seizures. These trials seem to be underpowered, with a sample size less than 15. In contrast, more recent studies that have included over 100 participants showed that CBD use resulted in a significant reduction in seizure frequency. Adverse effects of CBD overall appear to be benign, while more concerning adverse effects (e.g., elevated liver enzymes) improve with continued CBD use or dose reduction.

In most of the trials, CBD is used in adjunct with epilepsy medication, therefore it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications. Future trials may evaluate the efficacy of CBD in treating seizures due to specific etiologies (e.g., post-traumatic, post-stroke, idiopathic).[…]

Full Text PDF

, , , , , , ,

Leave a comment

[WEB SITE] Medical Marijuana for Epilepsy: What We Know

Rahul Guha, MD, July 26, 2018

Earlier this year, the Virginia State Legislature voted to expand the medical cannabis oil program in the Commonwealth. I have patients ask me about medical marijuana during every clinic visit. Here are a few talking points that will help guide the discussion with your patients.

Patients usually start the conversation by saying, “I read on my cousin’s Facebook wall that smoking marijuana can treat my epilepsy.”

Let’s take a step back and talk about the clinically important compounds in marijuana. The first is tetrahydrocannabinol (THC). It exerts its effect through a pair of G protein-coupled cannabinoid receptors named, conveniently, CB1 and CB2. The effect of THC on synapses produces the typical “high” that allows you to tolerate 11-minute guitar solos and most items on Taco Bell’s late-night menu. Early animal models showed mixed effects of THC on epilepsy and, in some cases, worsening seizures. This is different from cannabidiol (CBD), which interacts with a variety of other receptors. More promising effects reported in early animal models and anecdotal evidence from case reports spurred the movement towards clinical trials measuring the effect of CBD on epilepsy.

Will medical marijuana help my epilepsy?

We don’t know which epilepsy syndromes are most responsive to CBD. We don’t know the long-term effects of CBD or THC in the brains of patients with epilepsy. We have not agreed on the best dosing strategy for these medications. The best evidence for CBD in epilepsy comes from two recently published trials studying the effect of the drug in patients with Lennox-Gastaut syndrome and Dravet syndrome.[1,2] These diseases develop in childhood or infancy due to underlying genetic changes and are resistant to treatment.

In the studies, patients who were taking an average of six other antiepileptic medications received CBD as an add-on therapy to conventional medications. At 3 months’ follow-up, patients who received the CBD experienced a statistically significant decrease in average seizure frequency compared with placebo.

Can I use commercially available CBD?

Unfortunately, many of the products that are available online or over the counter at your local vape shop are not consistent with labeling. Simply put, there’s no guarantee that you are getting what’s advertised. In addition to unknown dosing and concentrations of THC and CBD, there is a possibility of contaminants, such as pesticides or other drugs, in the product. We can only guarantee the safety and efficacy of US Food and Drug Administration (FDA)-approved products.

How will CBD affect my other medications?

CBD is metabolized by the liver and inhibits cytochrome P450 (CYP) isoenzymes. This inhibition leads to increased levels of topiramate, zonisamide, eslicarbazepine, rufinamide, clobazam, and valproic acid.

Is it legal?

The FDA recently approved a CBD formulation, but there is currently no formulation of CBD that can be prescribed with a Drug Enforcement Administration (DEA) license. Under federal law, cannabis is still considered a Schedule I drug. It is only available through clinical trials and rare compassionate-use exceptions. Patients and providers should familiarize themselves with local laws before recommending CBD for the treatment of epilepsy.

 

via Medical Marijuana for Epilepsy: What We Know

 

, , , , ,

Leave a comment

[WEB SITE] Cannabis Oil for Epilepsy – What You Need to Know

Cannabis Oil for Epilepsy – What You Need to KnowCredit: Pixabay

via Cannabis Oil for Epilepsy – What You Need to Know | Technology Networks

, , , , , , ,

1 Comment

[Slideshow] Epilepsy & CBD

H Andre, O Danna, W Emma
… Scharfman and MacLusky, 2006 Page 34. Inhibition – Ledgerwood et al., 2010 ● CBD
is shown to inhibit synaptic transmission in hippocampal slices ○ In many forms of epilepsyseizures originate in the medial temporal lobe, an area that includes the hippocampus …

 

The Epilepsy & CBD Slideshow PDF file

, , ,

Leave a comment

[WEB SITE] Epilepsy Drug With Marijuana-Based Ingredient Could Be Available In The US This Year

 By Allan Adamson Tech Times

A new class of epilepsy drugs based on a marijuana ingredient could be become available in the United States as early as the second half of 2018 pending approval from the Food and Drug Administration.

Epidiolex

GW Pharmaceuticals, the maker of the drug called Epidiolex, announced on Wednesday the promising results of a clinical study of the drug.

A group of 171 individuals were randomly assigned to either receive Epidiolex treatment or placebo. The participants were between 2 and 55 years old with a condition called Lennox-Gastaut syndrome. They were also suffering from seizures existing drugs cannot efficiently control.

The participants on average had tried and discontinued use of six anti-seizure treatments and were experiencing 74 “drop” seizures per month. This particular seizure involves the entire body, head and trunk, and often leads to fall and other injuries.

LGS Patients Taking Epidiolex Sees Significant Reduction Seizures

Results of the study, which was reported in the journal Lancet,  showed that over a period of 14 weeks, 44 percent of the patients taking the drug saw significant reduction in seizures. The rate is significantly higher compared with the 22 percent in the placebo group. More of those who were given the experimental drug also experienced a 50 percent or greater reduction in drop seizures.

“LGS is one of the most difficult types of epilepsy to treat and the majority of patients do not have an adequate response to existing therapies,” said Elizabeth Thiele, from Harvard Medical School. “These results show that Epidiolex may provide clinically meaningful benefits for patients with LGS.”

Epidiolex is based on pure marijuana-derived cannabidiol or CBD. The cannabis compound has been known for its medical benefits sans making people feeling “stoned.”

Adverse Events Linked To Use Of Epidiolex

Adverse events associated with use of the drug include diarrhea, decreased appetite, sleepiness, vomiting, and fever. Once given the go-signal to be marketed in the United States, the drug is intended to be used as a prescription drug to be dispensed by doctors.

“Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial,” investigators wrote in their report.

GW Pharmaceuticals has not yet disclosed the pricing of the drug, but Justin Gover, GW’s chief executive officer, said that the company is already in talks with health insurers about coverage.

via Epilepsy Drug With Marijuana-Based Ingredient Could Be Available In The US This Year : Health : Tech Times

, , , , , , , ,

Leave a comment

[ARTICLE] Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? – Full Text PDF

The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Marijuana and other cannabis products with high content in Δ(9) –tetrahydrocannabinol (THC), utilized primarily for recreational purposes, are generally unsuitable for this indication, primarily because THC is associated with many undesired effects. Compared with THC, cannabidiol (CBD) shows a better defined anticonvulsant profile in animal models and is largely devoid of adverse psychoactive effects and abuse liability. Over the years, this has led to an increasing use of CBD-enriched extracts in seizure disorders, particularly in children. Although improvement in seizure control and other benefits on sleep and behavior have been often reported, interpretation of the data is made difficult by the uncontrolled nature of these observations. Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. In these studies, CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. For the first time, there is now class 1 evidence that adjunctive use of CBD improves seizure control in patients with specific epilepsy syndromes. Based on currently available information, however, it is unclear whether the improved seizure control described in these trials was related to a direct action of CBD, or was mediated by drug interactions with concomitant medications, particularly a marked increased in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Clarification of the relative contribution of CBD to improved seizure outcome requires re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies controlling for the confounding effect of this interaction. (2017;7:61-76) […]

Full Text PDF 

, , , , , , , , ,

Leave a comment

[WEB SITE] Can Cannabis Prevent and Treat Traumatic Brain Injury?

Traumatic Brain Injury, or TBI, is a serious condition usually caused by an external blow to the head that can cause severe and often chronic symptoms. These symptoms can be cognitive, behavioral, movement related, speech and visual impairing, mood altering, involve painful headaches, and even cause gastrointestinal issues.

Each year in just the U.S., nearly 52,000 people die from TBI and 80,000 sustain severe disabilities. Compare that to car fatalities (32,675) and homicides (14,196), which combined claim fewer lives. Moreover, 5.3 million people in the U.S. live with TBI-related disabilities, a number comparable to those living with Alzheimer’s disease.

How Cannabis Can Slow Traumatic Brain Injury Damage

Medical marijuana

While effective therapies to treat ongoing TBI symptoms have been difficult to come by, thanks to researchers like Prof. Yosef Sarne of Tel Aviv University, we’ve discovered that cannabis may prevent long-term brain damage by administering THC before or shortly after the injury. In fact, Israel Defense Force (IDF) practitioners administer CBD or low-dose THC as a first-line treatment to IDF soldiers – and even enemy combatants – who suffer brain trauma.

Sarne and his team published their results in 2013, where they demonstrated that administering just a fraction of the amount of THC that would be found in a typical cannabis joint anywhere from one to seven days prior to, or one to three days after an injury, induces the biochemical processes necessary to protect critical brain cells while preserving long-term cognitive function.

Can Cannabis Help People Currently Suffering From TBI?

Brain scan

Given the success found in Israel utilizing cannabis to halt TBI in its tracks, it begs the question: can cannabis help persistent TBI symptoms?

Anecdotally, many patients and their families report success. The daughter of one patient wrote in a Reddit forum:

“My father suffered severe TBI for years. He used to sit around hating his life all day. Once he started using marijuana, he changed a lot. He was able to get off some of his meds, start eating more, go outside, enjoy music, laugh at a movie, sleep at night, less anxiety in the day, less body pain. The list goes on and on.”

We hear many success stories like this, but these are, of course, anecdotal. Thus far, there aren’t any notable clinical trials demonstrating the efficacy of cannabis to treat ongoing symptoms in TBI patients. Unfortunately, even outside of cannabis research, phase II/III clinical trials of potential treatments haven’t demonstrated any consistent improvements in outcomes.

How Does Cannabis Consumption Affect the Brain?

The lack of cannabinoid-focused trials is likely due in part to the federal government’s long-standing position that cannabis is a “substance [with] no currently accepted medical use” and “a high potential for abuse” – a position that has long frustrated scientists who are forced to navigate significant bureaucratic obstacles to conduct high-quality rigorous studies.

Nonetheless, despite the federal government’s position, there is some evidence that at least lends support to speculation that cannabis-derived treatments may be beneficial:

Cannabinoids 101: What Makes Cannabis Medicine?

“Effect of Marijuana Use on Outcomes in Traumatic Brain Injury” (UCLA Medical Center, 2014):

In a three-year retrospective review of 446 separate cases of similarly injured patients, researchers found traumatic brain injury (TBI) patients who had a history of cannabis consumption possessed increased survival rates compared to non-consumers (97.6 percent survived surgery, versus 88.5% of those who didn’t consume cannabis).

“[O]ur data suggest an important link between the presence of a positive THC screen and improved survival after TBI,” the researchers concluded. “With continued research, more information will be uncovered regarding the therapeutic potential of THC, and further therapeutic interventions may be established.”

CTE in Professional Football Players, and the Potential of CBD to Address the Crisis

“Endocannabinoids and Traumatic Brain Injury” (Mechoulam, 2007):

This Israeli study points to research that demonstrates:

“…the [endocannabinoid] system…has the ability to [positively] affect the functional outcome after TBI by a variety of mechanisms.”

How Does Your Endocannabinoid System Impact Your Brain’s Response to Social Interaction?

“The Therapeutic Potential of the Cannabinoids in Neuroprotection” (Grundy RI, 2002):

This review shows that in experimental models:

“…various cannabinoids rescue dying neurons in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury.”

5 Promising Cannabis Studies That Explore How Cannabinoids Interact with the Human Body

Positive results in experimental models don’t always translate to human subjects, hence the desperate need for more research. But, as early research shows promise and we know cannabinoids demonstrate neuroprotective effects in a variety of neurological conditions, there’s no excuse not to prioritize further research.

Further, because TBI is a condition affecting a highly complex, intricate system like the brain, successful strategies will likely involve more than a single “magic bullet.”

CBD Can Be Remarkably Effective for TBI

Patient receiving an MRI

In the meantime, as we continue to learn more about THC and other cannabinoids to treat traumatic brain injury, many physicians believe CBD can be a safe and effective treatment. CBD, a largely non-psychoactive cannabinoid that possesses neuroprotective, anti-inflammatory, and anti-anxiety properties, could be as close to a “magic bullet” as we have right now. In fact, CBD may be more beneficial than THC. Japanese researchers found cannabidiol (CBD) exhibited stronger antioxidative power than THC without creating tolerance to its neuroprotective effect.

Dr. Allan Frankel, of GreenBridge Medical in Santa Monica, California, believes incorporating small amounts of CBD as a daily nutritional supplement is a safe and sensible adjunct to therapy. “I had a patient recently, a 45 year mother who was in a bad car accident. She experienced memory loss, and hadn’t been making any progress. I suggested CBD,” recounts Frankel. “Within four to six weeks, she made significant progress – her cognitive function improved and her memory returned to normal.” Frankel notes that this is just one of many patients he’s had who have experienced successful recoveries.

While clearly there’s lots of promise in the limited research to date and anecdotal reports, we need to continue developing our understanding of cannabinoid neurobiology in order to most effectively exploit the numerous therapeutic properties of cannabis. We can then, hopefully, unleash the full spectrum of potential benefits cannabis may be able to provide and discover innovative new treatments that could quite possibly help the millions of people who continue to suffer.

How Does Cannabis Consumption Affect Neurodegenerative Diseases?

via Can Cannabis Prevent and Treat Traumatic Brain Injury? | Leafly

, , , ,

Leave a comment

%d bloggers like this: