A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome

Bláthnaid McCoy, Laura Wang, Maria Zak, Sameer Al-Mehmadi, Nadia Kabir, Kenda Alhadid, Kyla McDonald, Grace Zhang, Rohit Sharma, Robyn Whitney, Katia Sinopoli, O Carter Snead 3rd, Bláthnaid McCoy, Laura Wang, Maria Zak, Sameer Al-Mehmadi, Nadia Kabir, Kenda Alhadid, Kyla McDonald, Grace Zhang, Rohit Sharma, Robyn Whitney, Katia Sinopoli, O Carter Snead 3rd

Abstract

Introduction: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.

Methods: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.

Results: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.

Conclusions: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Figures

Figure 1
Figure 1
Study participant flow chart.
Figure 2
Figure 2
The doses of CBD (A) and THC (B) achieved for all participants during the intervention period. The Boxplots show mean values, with 25th and 75th percentiles. The whiskers denote the minimum and maximum doses.
Figure 3
Figure 3
Change in reported somnolence during intervention period, in 4‐week blocks. Rates of reported somnolence were high, and increased in the first 8 weeks during TIL‐TC150 titration, subsequently dropping during the remaining weeks. There was a reduction in somnolence during the last 4‐week period (weeks 17–20) when compared with the first 8 weeks (r = −0.97).
Figure 4
Figure 4
Percentage change in Seizure frequency. Each bar represents a study participant. Bars represent the percentage change in frequency of motor seizures during the primary end point period (17–20 weeks), compared with the pre‐intervention period (−4–0 weeks) measured by seizure diary. The red line represents the mean percentage change across the entire 20 weeks. Percentage changes for each participant are sorted from highest to lowest values. 2 participants were seizure free during the last 4 weeks.
Figure 5
Figure 5
Mean number of seizure free days in each 4‐week period comparing pre‐intervention (week −4–0) with each 4 week block of intervention period (weeks 1–20). The mean (bar) and standard deviation (tail) are shown below for all 19 participants. *P < 0.05; **P < 0.01

References

    1. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies. Epilepsia 2010;51:1069–1077.
    1. Yakoub M, Dulac O, Jambaqué I, et al. Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev. 1992;14:299–303.
    1. Sakauchi M, Oguni H, Kato I, et al. Retrospective multi‐institutional study of the prevalence of early death in Dravet syndrome. Epilepsia 2011;52:1144–1149.
    1. Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y. A long‐term follow‐up study of Dravet syndrome up to adulthood. Epilepsia 2010;51:1043–1052.
    1. Dravet C. Dravet syndrome history. Dev Med Child Neurol 2011;53:1–6.
    1. Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence from long‐term course and neuropathology. Brain 2011;134(Pt 10):2982–3010.
    1. Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia 2017;58:1807–1816.
    1. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2012;6:CD009270.
    1. Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften 1978;65:174–179.
    1. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 1980;21:175–185.
    1. Ames FR, Cridland S. Anticonvulsant effect of cannabidiol. S Afr Med J 1986;69:14.
    1. Trumbly B, Sherman M. Double‐blind clinical study of cannabidiol as a secondary anticonvulsant. Presented at Marijuana ‘90 International Conference on Cannabis and Cannabinoids, Kolympari (Crete), July 8–11, 1990.
    1. Murphy L, Bartke A. Marijuana/cannabinoids neurobiology and neurophysiology. 1st ed. Boca Raton, Florida: CRC Press, 1992.
    1. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics 2015;12:747–768.
    1. Izquierdo I, Tannhauser M. Letter: the effect of cannabidiol on maximal electroshock seizures in rats. J Pharm Pharmacol 1973;25:916–917.
    1. Chesher GB, Jackson DM. Anticonvulsant effects of cannabinoids in mice: drug interactions within cannabinoids and cannabinoid interactions with phenytoin. Psychopharmacologia 1974;37:255–264.
    1. Chesher GB, Jackson DM, Malor RM. Interaction of delta9‐tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J Pharm Pharmacol 1975;27:608–609.
    1. Karler R, Turkanis SA. Subacute cannabinoid treatment: anticonvulsant activity and withdrawal excitability in mice. Br J Pharmacol 1980;68:479–484.
    1. Turkanis SA, Smiley KA, Borys HK, et al. An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia 1979;20:351–363.
    1. Consroe P, Benedito MA, Leite JR, et al. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol 1982;83(3–4):293–298.
    1. Koppel BS, Brust JCM, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders. Neurology 2014;82:1556–1563.
    1. Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 2005;78:539–548.
    1. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55:791–802.
    1. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol 2013;64:21–47.
    1. Kaur R, Ambwani SR, Singh S. Endocannabinoid system: a multi‐facet therapeutic target. Curr. Clin. Pharmacol. 2016;11:110–117.
    1. Karniol IG, Carlini EA. Pharmacological interaction between cannabidiol and delta 9‐tetrahydrocannabinol. Psychopharmacologia 1973;33:53–70.
    1. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC‐elicited paranoid symptoms and hippocampal‐dependent memory impairment. J. Psychopharmacol. (Oxford) 2013;27:19–27.
    1. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014;55:783–786.
    1. Porter BE, Jacobson C. Report of a parent survey of cannabidiol‐enriched cannabis use in pediatric treatment‐resistant epilepsy. Epilepsy Behav 2013;29:574–577.
    1. Tzadok M, Uliel‐Siboni S, Linder I, et al. CBD‐enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 2016;35:41–44.
    1. Brodie MJ, Ben‐Menachem E. Cannabinoids for epilepsy: what do we know and where do we go? Epilepsia 2018;59:291–296.
    1. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment‐resistant epilepsy: an open‐label interventional trial. Lancet Neurol. 2016;15:270–278.
    1. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug‐resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011–2020.
    1. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox‐Gastaut syndrome (GWPCARE4): a randomised, double‐blind, placebo‐controlled phase 3 trial. Lancet 2018;391(10125):1085–1096.
    1. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose‐ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018;90:e1204–e1211.
    1. Canada H. Authorized Licensed Producers of Cannabis for Medical Purposes ‐ . 2018;[cited 2018 May 2] Available from:
    1. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med 2018;49:12–19.
    1. Cairns DR, Sabaz M, Lawson JA, et al. Development, use and planned use of the QOLCE: the quality of life in childhood epilepsy questionnaire. Quality Life Newsletter 2001;2001:17–18.
    1. Sabaz M, Cairns DR, Lawson JA, et al. Validation of a new quality of life measure for children with epilepsy. Epilepsia 2000;41:765–774.
    1. Sabaz M, Lawson JA, Cairns DR, et al. Validation of the quality of life in childhood epilepsy questionnaire in American epilepsy patients. Epilepsy Behav 2003;4:680–691.
    1. Sparrow S, Balla D, Cicchetti D. Vineland adaptive behavior scales. 2nd ed. Circle Pines, MN: AGS Publ; 2005.
    1. Bloomfield MAP, Ashok AH, Volkow ND, Howes OD. The effects of Δ9‐tetrahydrocannabinol on the dopamine system. Nature 2016;539:369–377.
    1. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug‐drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015;56:1246–1251.
    1. Gaston T, Bebin E, Cutter G, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 2017;58:1586–1592.
    1. Brisbois TD, de Kock IH, Watanabe SM, et al. Delta‐9‐tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double‐blind, placebo‐controlled pilot trial. Ann Oncol 2011;22:2086–2093.
    1. Kirkham TC. Cannabinoids and appetite: food craving and food pleasure. Int. Rev. Psychiatry 2009;21:163–171.
    1. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects. Br J Pharmacol 2011;163:1344–1364.
    1. 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. 2011;10:961–968.
    1. Tomson T, Hirsch LJ, Friedman D, et al. Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials. Epilepsia 2013;54:135–140.
    1. Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res 2016;128:43–47.

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