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Multicenter Study
. 2025 Jul;66(7):2253-2267.
doi: 10.1111/epi.18378. Epub 2025 Mar 24.

Expanding the therapeutic role of highly purified cannabidiol in monogenic epilepsies: A multicenter real-world study

Emanuele Cerulli Irelli  1 , Adolfo Mazzeo  1 , Roberto H Caraballo  2 , Marco Perulli  3 , Patrick B Moloney  4 , Javier Peña-Ceballos  5 , Marica Rubino  6 , Katarzyna M Mieszczanek  7 , Andrea Santangelo  8 , Laura Licchetta  9 , Valentina De Giorgis  10   11 , Gabriela Reyes Valenzuela  2 , Susanna Casellato  12 , Elisabetta Cesaroni  13 , Francesca F Operto  14 , Jana Domínguez-Carral  15 , Alia Ramírez-Camacho  15 , Alessandro Ferretti  16 , Giuseppe Santangelo  17 , Angel Aledo-Serrano  18 , Andrea Rüegger  19 , Maria M Mancardi  20 , Giulia Prato  20 , Antonella Riva  21 , Luca Bergonzini  9 , Duccio M Cordelli  9 , Paolo Bonanni  22 , Francesca Bisulli  9   23 , Giancarlo Di Gennaro  24 , Sara Matricardi  25 , Pasquale Striano  20   21 , Norman Delanty  5   26   27 , Carla Marini  13 , Domenica Battaglia  3 , Carlo Di Bonaventura  1 , Georgia Ramantani  19 , Elena Gardella  7   28 ; GENE‐CBD Study Group; Alessandro Orsini  8 , Antonietta Coppola  6
Collaborators, Affiliations
Multicenter Study

Expanding the therapeutic role of highly purified cannabidiol in monogenic epilepsies: A multicenter real-world study

Emanuele Cerulli Irelli et al. Epilepsia. 2025 Jul.

Abstract

Objective: This real-world, retrospective, multicenter study aims to investigate the effectiveness of highly purified cannabidiol (CBD) in a large cohort of patients with epilepsy of genetic etiology due to an identified monogenic cause. Additionally, we examine the potential relationship between specific genetic subgroups and treatment response.

Methods: This study was conducted across 27 epilepsy centers and included patients with monogenic epileptic disorders (pathogenic or likely pathogenic variants) who were treated with highly purified CBD for at least 3 months.

Results: A total of 266 patients (135 females, 50.8%) with monogenic epilepsies were included with a median age at CBD initiation of 12 years (interquartile range [IQR] = 7-19) and a median follow-up duration of 17 months (IQR = 12-24). Overall, 77 different monogenic epilepsies have been included, with the most common genes being SCN1A (32.3%), TSC2 (13.5%), CDKL5, and MECP2 (4.5% each). The mean seizure reduction at the last follow-up was 38.6%, with 47.5% of patients achieving ≥50% seizure reduction and 7.4% achieving seizure freedom. The Clinical Global Impression scale indicated improvement in 65.8% of patients. The general linear mixed model revealed that a shorter maximum duration of seizure freedom before CBD initiation and a higher degree of intellectual disability were independently associated with lower CBD effectiveness. Conversely, no significant differences in seizure outcome were observed across different epilepsy syndromes (Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex epilepsy, and other developmental and epileptic encephalopathy), between approved indications and off-label use, or between concomitant clobazam use or not.

Significance: This study supports CBD as a potential treatment for monogenic epilepsies beyond its licensed indications, demonstrating comparable effectiveness between approved and off-label use and suggesting genetic subgroups with promising treatment responses.

Keywords: CBD; Lennox–Gastaut syndrome; developmental and epileptic encephalopathy; effectiveness; epilepsy; intellectual disability.

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Conflict of interest statement

E.C.I. reports speaking honoraria from Lusofarmaco, outside the submitted work. P.B.M. has served on an advisory board for Angelini Pharma and has received travel expenses from UCB Pharma, outside the submitted work. J.P.‐C. has served as a speaker and has received travel expenses from Angelini Pharma and LivaNova, outside the submitted work. V.D.G. has served on scientific advisory boards for Longboard Pharmaceuticals, has received research grants from Jazz Pharmaceuticals, and has received speaker and consultancy fees from Jazz Pharmaceuticals, Novartis, Nutricia, Vitaflo, and Dr. Schar Kanso, outside the submitted work. J.D.‐C. has received speaker honoraria from Jazz Pharmaceuticals, outside the submitted work. F.B. has served on scientific advisory boards for Angelini Pharma, UCB, Jazz Pharmaceuticals, Ethypharm, and Eisai and has received speaker honoraria from Angelini Pharma and UCB, outside the submitted work. Her research receives support from the Multidisciplinary Transition Model for Patients With Complex Epilepsy (Trans‐Epic) project, supported by Ricerca Corrente. S.M. has served on scientific advisory boards for Zogenix, UCB, and Ethypharm and has received speaker honoraria for Biocodex, Jazz Pharmaceuticals, Eisai, and UCB, outside the submitted work. N.D. has served as a paid advisor and/or speaker for Actiobio Sciences, Angelini Pharma, Bial, Eisai, Jazz Pharmaceuticals, LivaNova, and UNEEG Medical, outside the submitted work. C.D.B. reports personal fees from UCB Pharma, Eisai, Jazz Pharmaceuticals, Angelini Pharma, Lusofarmaco, and Ecupharma, outside the submitted work. G.R. has served on advisory boards or received speaker honoraria paid to her department from Angelini, Bial, Jazz Pharmaceuticals, Neuraxpharm, Neurocrine, and Takeda, outside the submitted work. Her research receives support from the Swiss National Science (SNSF: 208184) and Anna Mueller Grocholski Foundations. The other authors report no disclosures relevant to this article. 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
Distribution of patients by their monogenic epilepsy etiologies. Each bar represents a specific genetic cause, with the corresponding number of patients.
FIGURE 2
FIGURE 2
Antiseizure medications used at the time of cannabidiol prescription. Bars show the distribution of antiseizure medications (ASMs) used at the time of cannabidiol treatment initiation, with the number of patients per ASM indicated. Legend: ACZ: acetazolamide; BDZ: benzodiazepines; BRV: brivaracetam; CLB: clobazam; CNB: cenobamate; ESM: ethosuximide; EVE: everolimus; FEN: fenfluramine; FLB: felbamate; KD: ketogenic diet; LEV: levetiracetam; LTG: lamotrigine; PB: phenobarbital: PER: perampanel; PGB: pregabalin; GBP: gabapentin; RFN: rufinamide; SCB: sodium channel blockers; STM: Sulthiame STP: stiripentol; TPM: topiramate; VGB: vigabatrin VPA: valproic acid; ZNS: zonisamide.
FIGURE 3
FIGURE 3
Response to cannabidiol (CBD) treatment at the last visit stratified by epilepsy syndrome. (A) Mean percentage reduction in seizure frequency from baseline at the last visit. (B) Proportion of patients achieving ≥50% seizure reduction (responder rate). (C) Retention rate, indicating continued CBD use until the last visit. (D) Clinical Global Impression improvement, showing the percentage of patients rated as improved by the treating epileptologist. DEE, developmental and epileptic encephalopathy; DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; PME, progressive myoclonic epilepsy; TSC, tuberous sclerosis complex.
FIGURE 4
FIGURE 4
Side effects over time during cannabidiol treatment. Blue bars represent the proportion of patients reporting each side effect at any time during follow‐up, whereas red bars indicate those experiencing the same side effects at the last visit. FU, follow‐up; GI, gastrointestinal.
See this image and copyright information in PMC

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