Cannabidiol and the shifting perspective of epilepsy drug discovery

By Dr. Chinta SidharthanReviewed by Benedette Cuffari, M.Sc.Nov 29 2022

In a recent review published in the journal Experimental Neurology, researchers discuss the important clinical and preclinical research conducted during the 20^th century that contributed to considering cannabidiol, whose use has been historically regulated or restricted, as a potential antiseizure medication in the 21^st century.

Study: Cannabidiol reveals a disruptive strategy for 21st century epilepsy drug discovery. Image Credit: joel bubble ben / Shutterstock.com

Background

Research on epilepsy during the early 20^th century led to the discovery of treatments for symptomatic seizures, such as bromide, phenobarbital, and phenytoin. Furthermore, the development of the maximal electroshock test provided an effective platform for testing various antiseizure medications. Nevertheless, treatment-resistant epilepsy remains a significant challenge for nearly 30% of the patients.

Cannabidiol, a phytocannabinoid derived from Cannabis sativa that does not cause withdrawal or euphoria, was approved in 2018 as a treatment for Dravet syndrome (DS), Tuberous Sclerosis Complex (TSC), and Lennox‐Gastaut syndrome (LGS). However, before cannabidiol was approved by the United States Food and Drug Administration (FDA), very few studies had explored its therapeutic potential against epilepsy and seizures due to the regulatory rules and social stigma associated with marijuana derivatives.

Critical research in the late 20^th century on the therapeutic applications of cannabidiol, changing perceptions about medicinal uses of marijuana, as well as social advocacy for medical marijuana use have transformed the trajectory of cannabidiol use in the treatment of epilepsy.

Antiseizure therapeutic targets

Antiseizure medications broadly target the imbalance in the modulation of excitatory and inhibitory pathways in epilepsy. Over the past few decades, researchers have aimed to address this imbalance by examining understudied molecular targets and the attenuation of neuroinflammation.

Molecular targets being explored for the modulation of excitatory and inhibitory pathways include allosteric modulators of presynaptic sites such as neuronal potassium channels and type 2 metabotropic glutamate receptors.

Previous studies have also explored methods to mitigate epilepsy-associated neuroinflammation, including targeting oxygen reactive species, inflammatory cytokines, and abnormal glial activation. Disease modification by reducing neuroinflammation could reduce or stop the pathological cycle of epilepsy and prevent modifications to the blood-brain barrier that further aggravate the inflammatory response.

Orphan diseases, which are conditions affecting less than 200,000 people in the country, present a potentially under-explored resource for preclinical research to identify new antiseizure medications. Funding and other financial incentives provided by the U.S. Congress Rare Disease Act and U.S. Orphan Drug Act in 2002 and 1983, respectively, have supported the development of novel antiseizure medications for special patient populations. To this end, preclinical research orphan disease models contributed to the approval of cannabidiol treatment for DS, LGS, and TSC between 2018 and 2020.

Research on cannabidiol treatment

Early research on the medicinal properties of Δ9-tetrahydrocannabinol (THC) and cannabidiol, despite not being extensive, revealed that cannabidiol had potential anticonvulsant properties without the euphorigenic activity of THC. Furthermore, maximal electroshock test experiments using animal models showed that cannabidiol had potential applications in cortical focal, grand mal, and complex partial seizure types of epilepsy.

However, the anticonvulsant properties of cannabidiol were considered equivalent to those of phenobarbital and phenytoin. This provided insufficient justification for overturning legal regulations during the strict anti-drug policies in the U.S. during the 1980s, thus decelerating the research on cannabidiol for the next three decades.

Evidence from DS mouse models and increasing case reports describing the effects of cannabidiol in controlling seizures in children with catastrophic epilepsies resulted in a change in public and regulatory agency perceptions and restarted the research on the therapeutic potential of cannabidiol.

DS is a pediatric disease characterized by developmental epileptic encephalopathy resulting in spontaneous and recurrent seizures and a high incidence of death. This condition is also resistant to traditional antiseizure medications such as carbamazepine and phenytoin.

The administration of cannabidiol in mouse models of DS showed a marked reduction in spontaneous seizures. This ultimately led to FDA approval of cannabidiol as a treatment for DS in patients aged one and older, as well as confirming the validity of DS mouse models for antiseizure research.

Conclusions

The current review presents a comprehensive summary of the progress and challenges in exploring cannabidiol as a potential anticonvulsant therapy. While social stigma, legal restrictions, and insufficient or lack of conclusive evidence had limited the development of cannabidiol-based therapies, critical research using DS mouse models provided evidence of the spontaneous seizure-alleviating effects of cannabidiol. Furthermore, these studies afforded the impetus to reexplore the disease-modifying properties of cannabidiol.

The approval of cannabidiol as a therapy for DS has shifted the focus of anti-epileptic therapy research in the 21^st century.