2021 CMSC Annual Meeting

Nabiximols, a Cannabis-Based Complex Botanical Mixture and MS Spasticity: How Does It Work?


Background: Nabiximols is a complex botanical mixture containing delta-9-tetrahydrocannibinol (THC), cannabidiol (CBD), other plant-derived cannabinoids, and non-cannabinoid constituents. It reduced spasticity in clinical trials of multiple sclerosis (MS) and although not approved in the US, nabiximols is approved as Sativex® in >25 countries for MS spasticity inadequately managed by other anti-spasticity therapies. MS is associated with neuronal hyperexcitability involving diverse mechanisms and molecular targets including the endocannabinoid system (ECS). No causal link between the ECS and MS has been established; however, perturbed ECS is reported in rodent models of MS spasticity. Complex botanical mixtures containing cannabinoids have shown benefit in such models, indicative of their potential in treatment of MS spasticity. The large number of nabiximols’ constituents renders quantitative assessment of the independent or combination effects impossible. However, although effects of nabiximols’ constituents outside the ECS are unknown, nonclinical studies evaluating ECS probes may have predictive validity in understanding elements of nabiximols’ established treatment effects. Objectives: Here we present summary data for cannabinoids in nonclinical models of MS spasticity. Methods: We conducted a literature review of efficacy studies in MS rodent models that used human equivalent therapeutic doses of THC and CBD, similar to those in nabiximols. Results: CB1 receptors are negatively coupled to voltage gated calcium channels, reducing neuronal excitability. CB2 receptor agonism mediates anti-inflammatory effects. CB1- and CB2-selective agonists have been reported to ameliorate motor dysfunction in models of MS spasticity. THC and combinations of cannabinoids, including a nabiximols-like botanical mixture, improved motor dysfunction, relieved spasms, and reduced pain in models of MS spasticity. Conclusions: In nonclinical models, nabiximols-like mixtures decreased neuronal hyperexcitability and modulated the ECS. Although THC may have some therapeutic potential in the treatment of MS spasticity, the complementary pharmacology of CBD and other constituents of nabiximols can yield additional benefit and mitigate THC tolerability. Funding: GW Research Ltd