Development of cannabidiol as a treatment for severe childhood epilepsies

Abstract

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.

Keywords: Dravet syndrome; cannabidiol; epilepsy.

FIGURE 1

CBD reduces seizure severity in different rat models of chemically induced acute seizure. Intraperitoneal CBD (100 mg·kg⁻¹) caused a significant reduction in seizure severity induced by pentylenetetrazole (80 mg·kg⁻¹ i.p., n = 15; Jones et al., 2010), penicillin 525 IU intracerebroventricular infusion (n = 17–18; Jones et al., 2012), or pilocarpine (380 mg·kg⁻¹ i.p., n = 15; Jones et al., 2010). Intravenous CBD (10 mg·kg⁻¹) caused a significant reduction in seizure severity induced by pilocarpine (380 mg·kg⁻¹ i.v., n = 12–15; Patra et al., 2019). *P < 0.05, nonparametric binomial test

FIGURE 2

CBD affects THC‐stimulated ³⁵S‐GTPγS turnover in cerebellar tissue in a species‐specific manner. CBD (applied at a THC:CBD 1.08:1 ratio) attenuated THC‐stimulated G protein turnover in rat and chicken, but not human, tissue. Note that in human tissue, THC‐stimulated G protein turnover was of generally lower magnitude. *P < 0.05, ANOVA followed by a Tukey's post hoc test on raw data from three separate experiments in triplicate, preparations from multiple brains (data derived from Whalley et al., 2018)