Table 1 Characteristics of included studies

Iannone LF et al., 2021

Randomized Open-Label Extension Trial

Mean age: 17.0 ± 13.1

Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day

93

1 year

CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%)

At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group

In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite

Devinsky O et al., 2021

Double-blind RCT

4–10 years

20 mg/kg/CBD and placebo

34

The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods

Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol)

CBD did not affect concomitant AED levels, apart from increased N-CLB (except in patients taking stiripentol)

The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behaviour. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed

Scheffer, Ingrid E., et al., 2021

Open label extension trial

2–18 years

Mean modal dose of 22 mg/kg/day;

330

Median treatment duration was 444 days

84% were on concomitant valproic acid

In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45–74% for convulsive seizures and 49–84% for total seizures. Across all visit windows, ≥ 83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition

Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations > 3 × upper limit of normal

Ian Miller et al., 2020

Double-blind, placebo-controlled, randomised clinical trial

2 to 18 years

Pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo

199

14 weeks

Placebo

Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomised to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI 8.4–46.2%; P = .01) for CBD10 group and 25.7% (95% CI 2.9–43.2%; P = .03) for the CBD20 group

The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium

Jonathan Halford et al., 2019

RCT

Mean age: 9.8 years

Patients received GW’s plant-derived pharmaceutical formulation of highly purified CBD (100 mg/mL) in oral solution

289

72 weeks

Patients were taking a median of three concurrent antiepileptic drugs with 68% taking clobazam, 63% valproate, and 39% stiripentol

Median % reductions from baseline assessed in 12-week intervals were 44%–57% for convulsive and 49–67% for total seizures through 72 weeks. Over 80% of patients/caregivers reported improvements in overall condition

Adverse events (AEs) and serious AEs were reported by 96% and 32% of patients; 7% discontinued due to AEs. Elevated liver transaminases > 3 × upper limit of normal were reported in 9% of patients; none had severe liver injury. Two nontreatment-related deaths were reported

Linda C. Laux et al., 2019

RCT

607 Children and adults with LGS/DS taking stable doses of antiepileptic drugs

Mean age: 12.8

607

96 weeks

Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0–10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1–146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥ 50%, ≥ 75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile

The most common AEs were somnolence (30%) and diarrhea (24%)

Devinsky O et al., 2019

Randomized Open-Label Extension Trial

Mean: 9.8 (4.4)

Pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week period

278

48 weeks

Twenty‐two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥ 3 times the upper limit of normal

In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to week 48 ranged from 38 to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale

Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Seventeen patients (6.4%) discontinued due to AEs

Bláthnaid McCoy et al., 2018

RCT

Mean age: 10.15 years

The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC

20

20 weeks

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). 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%

Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy

Orrin Devisky et al., 2018

Double-blind RCT

4–10 years

CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily

34

4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods

Exposure to CBD and its metabolites was dose-proportional (AUC0–t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol)

The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behaviour. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed

Orrin Devisky et al., 2017

Double-blind RCT

The mean age of the patients was 9.8 years

Cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo

120

14-week treatment period

Placebo

The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, − 22.8 percentage points; 95% confidence interval [CI], − 41.1 to − 5.4; P = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI 0.93 to 4.30; P = 0.08). The frequency of total seizures of all types was significantly reduced with cannabidiol (P = 0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P = 0.08)

Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group