Identifying the source of CBD’s antiseizure activity

Cannabidiol, a component of cannabis often referred to as CBD, is the key compound in Epidiolex, a treatment for seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. But its mechanism of action has been mysterious. Researchers in Argentina now report that CBD’s ability to tame seizures may be, in part, because it inhibits the large-conductance voltage- and Ca²⁺- operated K⁺channel, also known as the BK channel (J. Nat. Prod. 2024, DOI: 10.1021/acs.jnatprod.3c01274).

“One of the most interesting things about CBD is that its affinity for the cannabinoid receptor is low,” says the National University of La Plata’s Pedro Martín, who led the research. This characteristic of CBD is distinct from tetrahydrocannabinol (THC)—the psychoactive component of cannabis. Because CBD has a low affinity for canonical cannabinoid receptors, researchers think that CBD acts on other targets, in particular, ion channels in the central nervous system.

Martín’s team thought the BK channel was a likely target for CBD because the BK channel plays a role in neurons’ repolarization. By inhibiting that repolarization, CBD could dampen seizures. The team’s experiments show that CBD can inhibit BK channels in cells at nanomolar concentrations.

“We know that the BK channel is not the only target that can explain CBD’s effect on the central nervous system. There are a lot of papers showing that CBD can modulate other ion channels, but our most interesting finding is that the concentration that we use to inhibit the BK channel is really low,” Martín says, lower than the concentrations that inhibit other ion channels.

Nazzareno D’Avanzo, who studies cannabinoid regulation of ion channels at the University of Montreal, says in an email that Martín’s results are “intriguing because they contribute to a growing body of evidence supporting the therapeutic potential of cannabinoids for several disorders, including epilepsy.” Instead of interacting with cannabinoid receptors, “it is becoming clearer that cannabinoids directly interact with a growing list of ion channels and receptors in the cell membrane that control how neurons fire,” he says.