COMMENTARY
Free Access
First published: 12 December 2021
Abbreviations
-
- CBD
-
- cannabidiol
-
- CBGA
-
- Cannabigerolic acid
-
- PAM
-
- positive allosteric modulator
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 Lennox-Gastaut 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 anti-epileptic 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 Δ9-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 Δ9-THC (Hill et al., 2012), both of which have well defined anti-seizure effects. This report was unable to distinguish if the effects observed were due to metabolism of CBGA or from a direct effect. Further pharmacological investigation of the effects of CBGA is warranted and should involve identification of its metabolites and characterisation of their biological effects.Consistent with the idea that a metabolite may be involved in the effects of CBGA, the commercially available target screen used by the authors indicated no hits for CBGA. However, follow-up experiments on specific targets implicated in the anti-seizure effects of other cannabinoids indicated direct effects of CBGA. Such effects were consistent with an antagonist effect on GPR55 and/or as positive allosteric modulator (PAM) effect at GABAA receptors. Both putative mechanisms occurred at doses of CBGA for which, despite low bioavailability of this compound, the calculated available concentrations could feasibly have meaningful effects in vivo.It is tempting to speculate that the effects on GABAA receptors and GPR55 identified by Anderson and colleagues may be involved in the in vivo effect of CBGA; demonstrating such roles in future studies would be an important advance in our understanding in the pharmacology of CBGA. For example, the PAM effect of CBGA on GABAA receptors would certainly be consistent with both the anti-convulsant effect in the thermally induced electroshock treatment model and proconvulsant effect in the electroshock procedure. The rationale here is that repeated exposure of GABAA receptors to PAMs has the ability to desensitise GABAA receptors, meaning they can be prone to development of tolerance and eventually even evoke proconvulsant effects. A deeper understanding of whether this is likely to occur in vivo would also have important implications for the potential of CBGA as an anti-seizure drug or as a lead compound for further development.
Taken together, this study by Anderson et al. is an important contribution to our understanding of cannabinoid pharmacology and suggests several avenues of future research which will help increase our understanding of some of the major cannabinoids found in cold-extracted artisanal cannabis products. This study also highlights some of the potential pitfalls of current community use of artisanal cannabis products to treat epilepsy; the exact mix and concentration of cannabinoids present in these products could have profound effects on anti-seizure and proconvulsant potential of these products. However, this study clearly demonstrates that full investigation of the potential of phytocannabinoids including CBGA could still be a potential source of novel and lead compounds for the treatment of drug resistant forms of epilepsy.
NOMENCLATURE OF TARGETS AND LIGANDS
Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander, Christopoulos et al., 2021; Alexander, Mathie et al., 2021).
REFERENCES
