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Abstract We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/mL oral solution). In our cohort, 26 patients had associated epilepsy (26/46 [56%]), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow‐up was 15 mg/kg/day. The median treatment duration was 13 months (range: 1–32 months). CBD reduced the incidence of seizures in seven out of 10 patients (70%) with one seizure‐free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug‐resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.

Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice.Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB−).Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10–12), 14 (10–20), and 15.5 mg/kg/day (10–20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was −41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB– patients.Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.