Dysregulation of the cannabinoid system in childhood epilepsy: From mechanisms to therapy

Montebello, Gloria and Di Giovanni, Giuseppe 2025. Dysregulation of the cannabinoid system in childhood epilepsy: From mechanisms to therapy. International Journal of Molecular Sciences 26 (13) , 6234. 10.3390/ijms26136234

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Abstract

Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life. The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and immune homeostasis from early life through adolescence and into aging. In pediatric epilepsies, alterations in ECS components, particularly CB1 receptor expression and endocannabinoid levels, reveal disorder-specific vulnerabilities and therapeutic opportunities. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown strong preclinical and clinical efficacy in treating DRE and is approved for Dravet syndrome, Lennox–Gastaut syndrome, and Tuberous Sclerosis Complex. Other ECS-based strategies, such as the use of CB1 receptor-positive allosteric modulators, can selectively enhance endogenous cannabinoid signaling where and when it is active, potentially reducing seizures in conditions like Dravet and absence epilepsy. Similarly, FAAH and MAGL inhibitors may help restore ECS tone without directly activating CB1 receptors. Precision targeting of ECS components based on regional expression and syndrome-specific pathophysiology may optimize seizure control and associated comorbidities. Nonetheless, long-term pediatric use must be approached with caution, given the critical role of the ECS in brain development.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	16 July 2025
Date of Acceptance:	26 June 2025
Last Modified:	16 Jul 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/179861

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