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

Carol J Milligan; Lyndsey L Anderson; Michael T Bowen; Samuel D Banister; Iain S McGregor; Jonathon C Arnold; Steven Petrou

doi:10.1186/s42238-022-00136-x

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

J Cannabis Res. 2022 Jun 10;4(1):30. doi: 10.1186/s42238-022-00136-x.

Authors

Carol J Milligan¹, Lyndsey L Anderson^{2

3

4}, Michael T Bowen², Samuel D Banister^{2

3

4}, Iain S McGregor^{2

3

4}, Jonathon C Arnold^{2

3

4}, Steven Petrou^{5

6}

Affiliations

¹ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia. carol.milligan@florey.edu.au.
² Brain and Mind Centre, The University of Sydney, Sydney, Australia.
³ Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, Australia.
⁴ Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁵ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁶ Department of Medicine, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Abstract

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_V1.1-Na_V1.8 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_V1.1-Na_V1.7 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 μg NP/mL. Purified CBD inhibits Na_V1.1, Na_V1.2, Na_V1.6 and Na_V1.7 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.

Keywords: Cannabidiol; Entourage effect; Hemp seed oil; Phytocannabinoids; Terpenes; Voltage-gated sodium channels.