THC, CBD and minor cannabinoid CBDV differently modulate hippocampal neurons firing

Cannabis sativa L. presents a very complex composition that includes several secondary metabolites besides the two main compounds, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Many of these minor cannabinoids are still under investigation and are arousing increasing interest for their biological effects and potential therapeutic roles. Cannabis sativa extracts, either properly purified and enriched with cannabinoids, were tested here on the neuronal activity, by monitoring the spontaneous firing rate and the bursts generation of cultured hippocampal neurons. In particular, we focused on the combined effect of THC, CBD and cannabidivarin (CBDV), a non-psychoactive homologue of CBD whose side chain has two fewer carbon atoms, and their related standard compounds. We found that standard THC, recognised for its psychoactive impact and side effects including anxiety and paranoia, significantly decreased the spontaneous firing discharge of cultured hippocampal neurons, whether applied alone or in combination with standard CBD at comparable concentrations. In contrast, the firing activity did not exhibit any significant alterations when CBD was administered alone. When C. sativa extracts were tested, we found that CBDV was able to reverse the inhibition of the firing discharge caused by the mixture of THC and CBD. Furthermore, when administered alone, CBDV significantly increased the firing discharge of hippocampal neurons. In all tested conditions, the effects exerted by standard compounds or extracts were restored to control conditions after 24 hours from administration. Overall, these data unravel a novel action of CBDV in reverting the detrimental effect exerted by the THC+CBD on neuronal firing activity.