A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function

Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (Na-V) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that Na-V channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of Na-V channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human Na(V)1.1-Na(V)1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the Na(V)1.1-Na(V)1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits Na-V channels revealing half-maximal inhibitory concentration (IC50) values of between 1.6 and 4.2 mu g NP/mL. Purified CBD inhibits Na(V)1.1, Na(V)1.2, Na(V)1.6 and Na(V)1.7 to reveal IC50 values in the micromolar range. The CBD content of the product equates to IC50 values (93-245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit Na-V channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits Na-V channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate Na-V channels.

Automated summary

CBD-dominant nutraceutical product (NP) can strongly inhibit Na-V channels, which may be attributed to the presence of other bioactive compounds such as phytocannabinoids and terpenes.