Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01–100 μM) effects were assessed in vitro using the Mg²⁺-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg²⁺-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 μM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB₁ receptors and displayed no agonist activity in [³⁵S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB₁ receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare.

Background and Purpose: Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ⁹‐tetrahydrocannabinol (THC), variously reported to be pro‐ and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling.Experimental Approach: Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract‐treated rats and treatment‐naïve rat, mouse, chicken, dog and human tissue.Key Results: Prolonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11‐hydroxy‐THC (11‐OH‐THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB₁ receptor)‐mediated signalling. Profiling CB₁ receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract‐induced seizures (rat) than one that did not (dog).Conclusions and Implications: Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis‐induced convulsions from animal models.Linked Articles: This article is part of a themed section on 8^th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc