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. 2025 Aug;10(4):1111-1119.
doi: 10.1002/epi4.70078. Epub 2025 Jun 21.

Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?

Aglaia Vignoli  1   2 , Giulia Prato  3 , Enrico Alfei  4 , Irene Bagnasco  5 , Alberto Danieli  6 , Massimiliano Celario  7   8 , Jacopo Favaro  9   10 , Sara Matricardi  11 , Francesca Felicia Operto  12 , Alessandro Orsini  13 , Davide Paolo Bernasconi  14   15 , Nicola Pietrafusa  16 , Emilia Ricci  2   17 , Luca Manfredini  18 , Giulia Balletto  3 , Paolo Bonanni  6 , Maria Paola Canevini  2   17 , Valentina De Giorgis  7   8 , Lino Nobili  3 , Stefano Sartori  9   10 , Miriam Nella Savini  17 , Ilaria Viganò  17 , Nicola Specchio  16   19
Affiliations

Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?

Aglaia Vignoli et al. Epilepsia Open. 2025 Aug.

Abstract

Objective: This study aimed to evaluate the efficacy and safety of adjunctive, highly purified Cannabidiol (Epidiolex®) in individuals with drug-resistant epilepsy (DRE) due to genetically determined typical Rett Syndrome (RTT) and CDKL5 Deficiency Disorder (CDD).

Methods: We recruited subjects with genetically confirmed typical RTT and CDD with drug-resistant seizures who received add-on treatment with highly purified Cannabidiol (CBD) through a national collaboration group. CBD treatment was titrated from 5 to 20 mg/kg/day; concurrent antiseizure medications (ASMs) could have been adjusted as clinically indicated.

Results: We enrolled 27 subjects (26 females), carrying a MECP2 genetic variant (14 subjects, 51.9%) or a CDKL5 genetic variant (13 subjects, 48.1%). Median age [IRQ] of individuals was 10.5 [7.9, 18.5] years. The median dose of CBD [IRQ] at last follow-up was 15 [11.12, 18.8] mg/kg/day, in association with a mean of 3 ASMs (range 2-4). The median duration of treatment was 14 [8.5, 20] months. Although not reaching a significant statistical effect, CBD reduced the incidence of seizures with respect to the baseline in 18/27 (66.6%) subjects, with 7 (25.9%) showing a seizure reduction >75%, and 11 (40.7%) >50%. The most relevant adverse events were somnolence seen in 3 subjects, irritability/agitation in 2 subjects, loss of appetite in 2 subjects, and insomnia in 1 individual. Caregivers reported an improvement in attention and reactivity in 12 subjects (44.4%), in sleep quality in 5 subjects (18.5%), and in motor aspects in 3 patients (11.1%).

Significance: CBD resulted effective in reducing seizure frequency in 66.6% of the study sample, regardless of the pathogenic variant; side effects were mild, and caregivers reported an improvement in behavioral and motor features.

Plain language summary: This study explored the use of highly purified Cannabidiol (CBD, Epidiolex®) as an add-on therapy for individuals with drug-resistant epilepsy due to Rett Syndrome (RTT) or CDKL5 Deficiency Disorder (CDD). Twenty-seven participants received CBD alongside their usual ASMs. After a median treatment duration of 14 months, 66.6% experienced fewer seizures, with some showing over 75% reduction. Side effects were generally mild, mainly sleepiness or irritability. Notably, caregivers reported improvements in attention, responsiveness, sleep, and motor function. While results were not statistically significant, they suggest CBD may benefit seizure control and quality of life in RTT and CDD patients.

Keywords: CDKL5 deficiency disorder; Rett syndrome; cannabidiol; drug‐resistant epilepsy.

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Conflict of interest statement

AV has served as a consultant for Anavex, Acadia, and GW Pharmaceuticals and has conducted clinical trials with Newron Pharmaceuticals. NS has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus and Takeda; has received speaker honoraria from Eisai, BioMarin, LivaNova, Sanofi; has served as an investigator for Zogenix, Marinus, BioMarin, UCB, Roche. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Relationship between pathogenic variant and seizure outcome.
FIGURE 2
FIGURE 2
Relationship between seizure outcome and behavioral changes.
See this image and copyright information in PMC

References

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