CBD: an effective therapeutic for seizures?

During the past few years, cannabis has become increasingly accepted from a societal standpoint. Contrary to the overall acceptance of the public, very little funding was gathered to explore therapeutics derived from cannabinoids. The lack of funding may be attributed to psychoactive effects produced by some of the products harvested from the plant such as THC. This has limited the potential benefits that patients may be able to receive due to limited research involving of the isolation of compounds derived from cannabis. Recently, a new isolated compound from hemp, cannabidiol (CBD), looks to have potential benefits but more research still needs to be completed to understand its therapeutic applications.

Figure 1: Minimal energy conformations (A) and 2D structures of CBD and THC (B)(Burstein, 2015).

Cannabis is comprised of two main compounds, which are tetrahydrocannabinol (THC) and CBD. CBD is the main compound of cannabis that has sparked research interest due to its similar structure and nature to THC, without producing the psychoactive high that THC produces (Figure 1). CBD is a cannabinoid, so its chemical targets are the CB1 and CB2 receptors. The CB1 receptor is found on neurons and glial cells, while the CB2 receptor is primarily found throughout the immune system (Volkow, 2015). The difference in structural conformation between CBD and THC allows THC to tightly bind to the CB1 receptor while CBD binds to the CB1 receptor with low affinity. The difference in binding affinities allows CBD to act on other pathways in the brain without eliciting a psychoactive effect (Volkow, 2015). The broad range of CBD’s therapeutic effects include exerting antioxidant, neuroprotectant, anti-tumor, antipsychotic, and anti-anxiety activities. These therapeutic uses have been tested through cell culture and animal models, however, in recent years a new therapeutic benefit of CBD emerged. Emerging research has indicated that CBD may also be used to reduce seizures and act as a mild anti-convulsant and is now an FDA approved therapeutic for treating seizures within genetic diseases.

            Research completed by Patel et al. (2019) emphasized a possible clinical application of CBD. Using the TMEV-induced model of epilepsy, researchers were able to observe the role CBD plays in epileptic seizures. Here, researchers administered two different doses of TMEV to the mice; one group was administered 180 mg/kg and the other group was administered 150 mg/kg and each dose was administered twice a day. These mice were analyzed based on the number and intensity of seizures experienced daily (graded by the Racine scale). When observing the outcomes between the two populations, they observed that the population administered with the 180mg/kg dose of CBD experienced a significant decrease in the frequency and severity of seizures due to TMEV infection. While the population administered with 150 mg/kg of CBD experienced decreased frequency of seizures, they did not experience a significant decrease in the severity of seizures. These results from Patel et al. (2019) suggest that CBD displays promising characteristics as an anti-seizure therapeutic for intractable epilepsies. This evidence of therapeutic success within the TMEV model suggests that further studies should be completed to further investigate the pharmacological effects and mechanisms behind CBD.

            Following the research done by Patel et al., Anderson et al. (2019) explored the pharmacokinetics of CBD and clobazam as a therapeutic to treat Dravet’s syndrome. Dravet’s syndrome, similarly to TMEV, is an intractable childhood epilepsy. The evidence of CBD’s effects as an anti-seizure medication sparked Anderson et al.’s interest to test CBD’s pharmacokinetics as an adjunct with clobazam. Anderson et al. (2019) utilized Scn1a^+/- mice to model the effects of Dravet’s syndrome. Utilizing this mice population, they administered clobazam with various concentrations of CBD, including concentrations that were above and below the anticonvulsant dosage for CBD. Anderson et al. (2019) then subjected the Scn1a^+/- mice to hyperthermia-induced seizure experiments and measured the drug-drug interactions and overall therapeutic efficacy of the treatment. When an anticonvulsant dose of CBD was paired with clobazam, Anderson et al. observed an increased efficacy of clobazam treatment on the mice. CBD acted by extending the half-life, increasing exposure time, and increasing interactions of clobazam and its target, N-CLB. Anderson et al. also discovered a pharmacokinetic mechanism between CBD and clobazam that enhanced inhibitory GABA_A receptor activation, further contributing to its efficacy in treating intractable epilepsy.

Figure 2: U.S. funding of the various cannabis research sectors (https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug)

The studies by Patel et al. and Anderson et al. displayed the therapeutic efficacy and the pharmacological interactions associated with the anti-seizure effects of CBD. Even with strong evidence supporting CBD’s therapeutic benefits, research is still slow to take off due in part, to cannabis being labeled as a Schedule I drug. This labelling has led to funding cannabis research that focuses on harm and abuse of cannabis, rather than the therapeutic benefits (O’Grady, 2021). This skewed distribution of funding has allowed for increased research on why cannabis is a dangerous and abusive substance, rather than the possible benefits of isolated compounds derived from cannabis. This has made introducing cannabis-derived therapeutics challenging, as it is illegal to produce so it is hard to obtain and further isolate its compounds. This negative stigma has been slowly chipped away by public opinion and cultural shifts, which can be observed by 36 states having legalized cannabis and their products for medicinal use. This rapid shifting of cultural norms and values has allowed further CBD and cannabinoid research to take place, allowing for further exploration of the therapeutic benefits that these compounds display. This increase in research has allowed the medical community to realize the therapeutic and clinical benefits of CBD use. The only question to be answered now is: when will society see CBD as a viable therapeutic, rather than simply another recreational substance?

           

By William Lathram, A Master's of Medical Science Student at the University of Kentucky            

References

Anderson, L. L., Absalom, N. L., Abelev, S. V., Low, I. K., Doohan, P. T., Martin, L. J., Chebib, M., McGregor, I. S., & Arnold, J. C. (2019). Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia, 60(11), 2224–2234. https://doi.org/10.1111/epi.16355

Bissell, L. J. L., Balneaves, L. G., Oliffe, J. L., Capler, N. R., & Buxton, J. (2013). Perceptions of cannabis as a stigmatized medicine: A qualitative descriptive study. Harm Reduction Journal, 10(1), 2. https://doi.org/10.1186/1477-7517-10-2

Burstein, S. (2015). Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic & Medicinal Chemistry, 23(7), 1377–1385. https://doi.org/10.1016/j.bmc.2015.01.059

Commissioner, O. of the. (2020, July 31). FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease. U.S. Food and Drug Administration. Retrieved October 27, 2021, from https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare.

O'Grady, C. (2020, August 27). Cannabis research database shows how U.S. funding focuses on harms of the drug. Science. Retrieved October 27, 2021, from https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug.

Patel, D. C., Wallis, G., Fujinami, R. S., Wilcox, K. S., & Smith, M. D. (2019). Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus. Epilepsia Open, 4(3), 431–442. https://doi.org/10.1002/epi4.12351

Volkow, N. D. (2015, June 24). The biology and potential therapeutic effects of cannabidiol. NIDA Archives. Retrieved October 17, 2021, from https://archives.drugabuse.gov/testimonies/2015/biology-potential-therapeutic-effects-cannabidiol.