Implications of the effects of cannabigerolic acid on our understanding of the potential of phytocannabinoids in anti‐seizure treatment

Before widespread prohibition, cannabis and cannabis products had been used in the treatment of epilepsy and seizures with evidence for use stretching back millennia. In recent years, there has been growing evidence that cannabis products have anti-seizure properties, with particular interest on the nonpsychoactive components of cannabis such as cannabidiol (CBD). Indeed, a highly purified form of CBD (Epidiolex/Epidyolex) received regulatory approval for the treatment of the severe childhood forms of epilepsy Dravet and LennoxGastaut Syndromes in the USA and EU (Williams & Stephens, 2020). However, it is clear that many more of the >140 phytocannabinoids have the potential to have anti-seizure effects (reviewed in dos Santos et al., 2015). Many patients, particularly including those with intractable childhood epilepsies, continue to use both commercially available and cold-extracted/minimally processed ‘artisanal’ cannabis-derived products for treatment; a variety of reasons underly this, including cost, lack of availability of licenced medicines and personal preferences. Due to this widespread community use of artisanal cannabis products to treat epilepsy, this study by Anderson and colleagues provides timely further information on the anti-seizure potential of some major cannabinoids often found in high concentrations in these products (Anderson et al., 2021). The study by Anderson and colleagues focussed on seven cannabinoids in a mouse model of Dravet syndrome, namely, the Scn1a mouse model which has been widely used to study the potential of anti-seizure drugs for this severe form of epilepsy. Cannabigerolic acid (CBGA) was the most potent of the cannabinoids studied in preventing hyperthermia-induced seizures in this model. This finding is of particular interest as the dose required indicates that CBGA may actually be more potent at this effect than CBD, although there was no direct comparison in this study. Anderson and colleagues also show that CBGA has the ability to improve the anti-convulsant effect of clobazam when used as an adjunct therapy. This raises the possibility that cannabinoids such as CBGA may have synergistic effects with current ‘gold standard’ treatments for this form of epilepsy; however, due to the nonsigmoidal concentration response curve of CBGA, isobolographic analysis to demonstrate this was not possible. This potentiation by CBGA mirrors the effect of CBD to potentiate the effect of clobazam (Anderson et al., 2019); of note, CBD is normally used clinically as an adjunct treatment to clobazam, as reviewed in Williams and Stephens (2020). Thus, this study provides further evidence of the potential of CBGA as a therapeutic option in epilepsy. Another key insight from the current study by Anderson et al. was that the effects of the cannabinoids were only ascertained after seizures had been induced, and epilepsy was established in the Dravet model. This mimics the use of these cannabinoids and other antiepileptic drugs as taken in humans, that is, treatment only commences after epilepsy is established. This again strengthens the rationale for cannabinoids found in artisanal cannabis products having therapeutic potential in humans. Whilst the study demonstrates new insights into the potential of cannabinoids like CBGA in therapy for epilepsy, it also provides a note of caution: CBGA also had proconvulsant properties in the spontaneous seizures in Dravet mice and the 6-Hz electroshock model of seizure (although CBGA did increase the anti-seizure effect of clobazam in the former). These findings link to the conflicting data using extracts of cannabis when compared with purified cannabinoids such as CBD, as well as the confounding mixed anti-seizure and proconvulsant effects seen with other cannabinoids such as Δ-THC. It also demonstrates that whilst there is potential, further research is required into the pharmacological mechanisms of action of cannabinoids such as CBGA found in cold-extracted artisanal products. Whilst the cannabinoids studied primarily had anti-convulsive properties, it is likely that these acidic compounds will act as precursor molecules and be metabolised in vivo; indeed, CBGA is a precursor molecule for both CBD and Δ-THC (Hill et al., 2012), both of which Abbreviations: CBD, cannabidiol; CBGA, Cannabigerolic acid; PAM, positive allosteric modulator. Received: 11 October 2021 Accepted: 27 October 2021