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Cannabinoids in treatment-resistant epilepsy: A review

Published:February 08, 2017DOI:https://doi.org/10.1016/j.yebeh.2016.11.012

      Highlights

      • Review of cannabidiol in open-label studies and randomized control trials
      • Safety and efficacy findings support use in treatment-resistant epilepsy.
      • More research needed into medical marijuana and its derivatives

      Abstract

      Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).
      The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100 mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day.
      This article is part of a Special Issue titled "Cannabinoids and Epilepsy".

      Keywords

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      References

        • Kwan P.
        • Arzimanoglou A.
        • Berg A.T.
        • Brodie M.J.
        • Hauser W.A.
        • Mathern J.
        • et al.
        Definition of drug resistant epilepsy: consensus proposal by the ad hock task force of the ILAE commission on therapeutic strategies.
        Epilepsia. June 2010; 51: 1069-1077
        • Sharma S.
        • Dixit V.
        Epilepsy – a comprehensive review.
        Int J Pharma Res. Rev. Dec 2013; 2: 61-80
        • Milby A.H.
        • Halpern C.H.
        • Baltuch G.H.
        Vagus nerve stimulation in the treatment of refractory epilepsy.
        Neurother. Apr 2009; 6: 228-237
        • Kwan P.
        • Brodie M.J.
        Early identification of refractory epilepsy.
        New Eng J Med. 2000; 342: 314-319
        • Sillanpaa M.
        • Shinnar S.
        SUDEP and other causes of mortality in childhood-onset epilepsy.
        Epilepsy Behav. Aug 2013; 28: 249-255
        • Racoosin J.A.
        • Feeney J.
        • Burkhart G.
        • Boehm G.
        Mortality in antiepileptic drug development programs.
        Neurology. Feb 27, 2001; 56: 514-519
        • Sillanpaa M.
        • Shinnar S.
        Long-term mortality in childhood-onset epilepsy.
        N Engl J Med. 2010; 363: 2522-2529
        • Ryvlin P.
        • Cucherat M.
        • Rheims S.
        Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta analysis of placebo-controlled randomised trials.
        Lancet Neurol. Nov 2011; 10: 961-968
        • Faught E.
        • Duh M.S.
        • Weiner J.R.
        • Guerin A.
        • Cunnington M.C.
        Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM study.
        Neurology. 2008; 71: 1572-1578
        • Friis M.L.
        • Lund M.
        Stress convulsions.
        Arch Neurol. 1974; 31: 155-159
        • Gordon E.
        • Devinsky O.
        Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy.
        Epilepsia. Oct 29, 2001; 42: 1266-1272
        • Devinsky O.
        Cognitive and behavioral effects of antiepileptic drugs.
        Epilepsia. 1995; 36: S46-S65
        • Shumely S.
        • Sisodiya S.M.
        • Gunning W.B.
        • Sander J.W.
        • Thijs R.D.
        Mortality in Dravet syndrome: a review.
        Epilepsy Behav. Nov 2016; 64: 69-74
        • Arzimanoglou A.
        • Resnick T.
        All children who experience epileptic falls do not necessarily have Lennox–Gastaut syndrome… but many do.
        Epileptic Disord. 2011; 13: S3-S13
        • Kramer U.
        • Chi C.-S.
        • Lin K.-L.
        • Specchio N.
        • Mustafa S.
        • Olson H.
        • et al.
        Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome.
        Epilepsia. Aug 2011; 52: 1956-1965
        • de Vries P.J.
        • Whittemore V.H.
        • Leclezio L.
        • Byars A.W.
        • Dunn E.
        • Ess K.C.
        • et al.
        Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND checklist.
        Pediatr Neurol. Jan 2015; 52: 25-35
        • Wirrell E.C.
        Treatment of Dravet syndrome.
        Can J Neurol Sci. 2016; 43: S13-S18
        • Gofshteyn J.S.
        • Wilfong A.
        • Devinsky O.
        • Bluvstein J.
        • Charuta J.
        • et al.
        Cannabidiol as a potential treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the acute and chronic phases.
        J Child Neurol. Sep 2016; 21 ([pii:0883073816669450 Epub ahead of print])
        • Chiron C.
        • Dulac C.
        The pharmacologic treatment of Dravet syndrome.
        Epilepsia. 2011 Apr; 52: 72-75
        • Glauser T.
        • Kluger G.
        • Sachdeo R.
        • Krauss G.
        • Perdomo C.
        • Arroyo S.
        Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome.
        Neurology. 2008; 70: 1950-1958
        • Mudigoudar B.
        • Weatherspoon S.
        • Wheless J.W.
        Emerging antiepileptic drugs for severe pediatric epilepsies.
        Semin Pediatr Neurol. May 2016; 23: 167-179
        • Russo E.B.
        History of cannabis and its preparations in saga, science, and sobriquet.
        Chem Biodivers. 2007; 4: 1614-1648
        • Pereira P.
        The elements of materia medical and therapeutics.
        Lea & Blanchard, Philadelphia, PA1843
        • McMeens R.R.
        Report of the Ohio state medical committee on Cannabis indica.
        1860
        • Gowers W.
        Epilepsy and other chronic convulsive disorders.
        Churchill, London1881
        • Davis J.P.
        • Ramsey H.H.
        Anti-epileptic action of marijuana-active substances.
        Fed Proc, Am Soc Exp Biol. 1949; 8: 284
        • Mechoulam R.
        • Carlini E.A.
        Toward drugs derived from cannabis.
        Naturwissenschaften. 1978; 65: 174-179
        • Cunha J.M.
        • Carlini E.A.
        • Pereira A.E.
        • Ramos O.L.
        • Pimental C.
        • Gagliardi R.
        • et al.
        Chronic administration of cannabidiol to healthy volunteers and epileptic patients.
        Pharmacology. 1980; 21: 175-185
        • Ames F.R.
        • Cridland S.
        Anticonvulsant effect of cannabidiol.
        S Afr Med J. Jan 4, 1986; 69: 14
        • Trembly B.
        • Sherman M.
        Double-blind clinical study of cannabidiol as a secondary anticonvulsant.
        in: Presented at the Marijuana '90 international conference on cannabis and cannabinoids. July 8–11, 1990 ([Kolympari, Crete]. [abstract])
        • 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. Mar 2016; 15: 270-278
        • Porter B.E.
        • Jacobson C.
        Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.
        Epilepsy Behav. 2013; 29: 574-577
        • Maa E.
        • Figi P.
        The case for medical marijuana in epilepsy.
        Epilepsia. 2014; 55: 783-786
        • Gedde M.
        • Maa E.
        Whole cannabis extract of high concentration cannabidiol may calm seizures in highly refractory pediatric epilepsies.
        in: In press at the 67th annual meeting of the American Epilepsy Society. December 6–10, 2013
        • Press C.A.
        • Knupp K.G.
        • Chapman K.E.
        Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.
        Epilepsy Behav. 2015; 45: 49-52
        • Tzadok M.
        • Uliel-Siboni S.
        • Linder I.
        • Kramer U.
        • Epstein O.
        • Menascu S.
        • et al.
        CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience.
        Seizure. 2016; 35: 41-44
        • Keeler M.H.
        • Reifler C.B.
        Grand mal convulsions subsequent to marijuana use: case report.
        Dis Nerv Syst. 1967; 28: 474-475
        • Consroe P.F.
        • Wood G.C.
        • Buchsbaum H.
        Anticonvulsant nature of marihuana smoking.
        JAMA. 1975; 234: 306-307
        • Ellison J.M.
        • Gelwan E.
        • Ogletree J.
        Complex partial seizure symptoms affected by marijuana abuse.
        J Clin Psychiatry. 1990; 51: 439-440
        • Mortati K.
        • Dworetzky B.
        • Devinsky O.
        Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature.
        Rev Neurol Dis. 2007; 4: 103-106
        • Gross D.W.
        • Hamm J.
        • Ashworth N.L.
        • Quigley D.
        Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center.
        Neurology. 2004; 62: 2095-2097
        • Hamerle M.
        • Ghaeni L.
        • Kowski A.
        • Weissinger F.
        • Holtkamp M.
        Cannabis and other illicit drug use in epilepsy patients.
        Eur J Neurol. 2014; 21: 167-170
        • Hill A.J.
        • Hill T.D.M.
        • Whalley B.J.
        The development of cannabinoid based therapies for epilepsy.
        in: Onaivi E.S. Darmani N.A. Wagner E. Endocannabinoids: molecular, pharmacological, behavioral and clinical features. Bentham Science, 2013: 164-204
        • Zullino D.F.
        • Delessert D.
        • Eap C.B.
        • Preisig M.
        • Baumann P.
        Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine.
        Int Clin Psychopharmacol. May 2002; 17: 141-143
        • Stout S.M.
        • Cimino N.M.
        Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.
        Drug Metab Rev. Feb 2014; 46: 86-95
        • Volkow N.D.
        • Baler R.D.
        • Compton W.M.
        • Weiss S.R.
        Adverse health effects of marijuana use.
        N Engl J Med. 2014; 370: 2219-2227
        • Gupta S.
        WEED.
        in: Gupta S. CNN. 2013 (The documentary is available through several sources at http://www.youtube.com)
        • Devinsky O.
        • Cilio M.R.
        • 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
        • Gloss D.
        • Vickrey B.
        Cannabinoids for epilepsy.
        Cochrane Database Syst Rev. 2014; 3CD009270
        • Friedman D.
        • Devinsky O.
        Cannabinoids in the treatment of epilepsy.
        N Engl J Med. Sep 10, 2015; 373: 1048-1058
        • National Conference of State Legislatures
        State medical marijuana laws.
        ([Accessed October 13, 2016])
        • Choo E.K.
        • Emery S.L.
        Clearing the haze: the complexities and challenges of research on state marijuana laws.
        Ann N Y Acad Sci. 2016; ([xxxx]): 1-18
        • Bill Status for SB174
        The Alabama Legislature website.
        ([Accessed Oct 26, 2016])
      1. CS/CS/SB 1030: Cannabis. The Florida Senate website. https://www.flsenate.gov/Session/Bill/2014/1030/?Tab=BillText. [Accessed Oct 26, 2016].

        • 2015–2016 Regular Session – HB 1: Haleigh's Hope Act
        Enact. Georgia General Assembly Legislation website.
        ([Accessed Oct 26, 2016])
        • Senate File 2360
        The Iowa Legislature: BillBook website.
        ([Accessed Oct 26, 2016])
        • Senate Bill 1146
        State of Idaho USA Legislature website.
        ([Accessed Oct 26, 2016])
        • SB124:14RS
        Kentucky Legislature website.
        ([Accessed Oct 26, 2016])
        • SB143 by Senator Fred H. Mills, Jr
        Louisiana State Legislature website.
        ([Accessed Oct 26, 2016])
        • House Bill 1231. Mississippi Legislature
        Regular session website.
        ([Accessed Oct 26, 2016])
        • HB 2238
        Missouri House of Representatives website.
        ([Accessed Oct 26, 2016])
        • House Bill 1220/S.L. 2014–53
        NCGA North Carolina General Assembly website.
        ([Accessed Oct 26, 2016])
        • Bill Information for HB 2154
        Oklahoma State Legislature website.
        ([Accessed Oct 26, 2016])
        • A221, R229, S1035 Status Information
        South Carolina General Assembly 120st session.
        ([website]) ([Accessed Oct 26, 2016])
        • SB 2531
        Tennessee General Assembly website.
        ([Accessed Oct 26, 2016])
        • Bill: SB 339
        Texas Legislation Online: history website.
        ([Accessed Oct 26, 2016])
        • H.B. 105 Plant Extract Amendments
        Utah State Legislature website.
        ([Accessed Oct 26, 2016])
        • HB 1445 Cannabidiol oil and THC-A oil
        Possession of marijuana.
        in: Virginia's Legislative Information System. 2015 ([Session website]) ([Accessed Oct 26, 2016])
        • Assembly Bill 726
        Wisconsin State Legislature.
        ([Wisconsin Legislature website]) ([Accessed Oct 26, 2016])
        • 2015 General Session
        63rd Legislature House Bills Index website.
        ([Accessed Oct 26, 2016])
        • Bradford A.C.
        • Bradford W.D.
        Medical marijuana laws reduce prescription medication use in Medicare part D.
        Health Aff. July 2016; 35: 1230-1236
        • Bachuber M.A.
        • Saloner B.
        • Cunningham C.O.
        • Barry C.L.
        Medical cannabis laws and opioid analgesic overdose mortality in the US, 1999–2010.
        JAMA Intern Med. 2014; 174: 1668-1673
        • Geffrey A.L.
        • Pollack S.F.
        • Bruno P.L.
        • Thiele E.A.
        Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
        Epilepsia. 2015; 56: 1246-1251
        • Friedman D.
        • Cilio M.R.
        • 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.
        American Epilepsy Society, Seattle, WA2014
        • Szaflarski J.P.
        • Bebin E.M.
        • Cutter G.
        • DeWolfe J.
        • Dure L.
        • Gaston T.
        • et al.
        Response to pharmaceutical grade cannabidiol in a state-sponsored treatment program.
        in: AES 70th annual meeting abstract: 194427. 2016
        • Szaflarski J.P.
        • Bebin E.
        • Dewolfe J.
        • Dure L.
        • Gaston T.
        • Harsanyi K.
        • et al.
        Seizure response to cannabidiol in a state sponsored open-label program.
        in: AAN 2016 annual meeting abstract: 16-A-3735-AAN. 2016
        • Hess E.J.
        • Moody K.A.
        • Geffrey A.L.
        • Pollack S.F.
        • Skirvin L.A.
        • Bruno P.L.
        • et al.
        Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.
        Epilepsia. Oct 2016; 57: 1617-1624
        • Chu-Shore C.J.
        • Major P.
        • Camposano S.
        • Muzykewicz D.
        • Thiele E.A.
        The natural history of epilepsy in tuberous sclerosis complex.
        Epilepsia. Jul 2010; 51: 1236-1241
        • Gofshteyn J.S.
        • Wilfong A.
        • Devinksy O.
        • Bluvstein J.
        • Charuta J.
        • Ciliberto M.A.
        Cannabidiol as a potential treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the acute and chronic phases.
        J Child Neurol. Sep 21, 2016; ([pii: 0883073816669450. Epub ahead of print])
        • Mikaeloff Y.
        • Jambaque I.
        • Hertz-Pannier L.
        • Zanfirescu A.
        • Adamsbaum C.
        • Ploin P.
        • et al.
        Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis.
        Epilepsy Res. 2001; 69: 67-79
        • Sing R.K.
        • Joshi S.M.
        • Potter D.M.
        • Leber S.M.
        • Carlson M.D.
        • Shellhaas R.A.
        Cognitive outcomes in febrile infection-related epilespy syndrome treated with the ketogenic diet.
        Pediatrics. Nov 2014; 134: e1431-e1435
        • Nabbout R.
        • Mazzuca M.
        • Hubert P.
        • Peudennier S.
        • Allaire C.
        • Flurin V.
        • et al.
        Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
        Epilepsia. 2010; 51: 2033-2037
        • GW Pharmaceutical Announces Positive Phase 3 Pivotal Study Results for Epidiolex®(cannabidiol)
        GW Pharmaceuticals website.
        ([Accessed November 9, 2016])
        • GW Pharmaceutical Announces Positive Phase 3 Pivotal Study Results for Epidiolex®(cannabidiol) in the Treatment of Lennox-Gastaut Syndrome
        GW Pharmaceuticals website.
        ([Accessed November 9, 2016])
        • GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for Epidiolex®(cannabidiol) in the Treatment of Lennox-Gastaut Syndrome
        GW Pharmaceuticals website.
        ([Accessed November 9, 2016])