IMPORTANCE Efficacy of cannabidiol has been demonstrated in seizures associated with
Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in
conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).
OBJECTIVE To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol
dosages vs placebo against seizures associated with TSC.
DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized
clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018;
follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in
Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible
patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medicationresistant
epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline
period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking
at least 1 antiepileptic medication.
INTERVENTIONS Patients received oral cannabidiol at 25mg/kg/day (CBD25) or 50
mg/kg/day (CBD50) or a matched placebo for 16 weeks.
MAIN OUTCOMES AND MEASURES The prespecified primary outcomewas the change from
baseline in number of TSC-associated seizures for cannabidiol vs placebo during the
treatment period.
RESULTS Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized.
Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients
[41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201
completing treatment. The percentage reduction from baseline in the type of seizures
considered the primary end point was 48.6%(95%CI, 40.4%-55.8%) for the CBD25 group,
47.5%(95%CI, 39.0%-54.8%) for the CBD50 group, and 26.5%(95%CI, 14.9%-36.5%) for
the placebo group; the percentage reduction from placebo was 30.1% (95%CI, 13.9%-43.3%;
P < .001) for the CBD25 group and 28.5%(95%CI, 11.9%-42.0%; nominal P = .002) for the
CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%];
CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%];
CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with
cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the
placebo group discontinued treatment because of adverse events. Twenty-eight patients
taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.
CONCLUSIONS AND RELEVANCE Cannabidiol significantly reduced TSC-associated seizures
compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the
50-mg/kg/day dosage.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0254476
