Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies

Exp Neurol. 2023 Jan:359:114237. doi: 10.1016/j.expneurol.2022.114237. Epub 2022 Oct 4.


Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.

Keywords: Anandamide; CBD, Epilepsy; Cannabidiol; Cannabis; Marijuana; Refractory seizure; THC.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Anticonvulsants / pharmacology
  • Anticonvulsants / therapeutic use
  • Cannabidiol* / pharmacology
  • Cannabidiol* / therapeutic use
  • Cannabinoids* / pharmacology
  • Child
  • Drug Resistant Epilepsy* / drug therapy
  • Epilepsies, Myoclonic* / drug therapy
  • Epilepsy* / chemically induced
  • Epilepsy* / drug therapy
  • Humans
  • Lennox Gastaut Syndrome* / drug therapy
  • Seizures / chemically induced
  • Seizures / drug therapy


  • Cannabidiol
  • Anticonvulsants
  • Cannabinoids