Cannabidiol pharmacological effects are mediated through G protein coupled receptors, cannabinoid type I (CB1) and cannabinoid type II (CB2), which are highly expressed in the hippocampus and other parts of the central nervous system. When activated, CB1 receptors inhibit synaptic transmission through action on voltage-gated calcium and potassium channels, which are known to modulate epileptiform and seizure activity. CB2 receptors are primarily expressed in the immune system and have limited expression in the central nervous system. The effects of CBD are CB2 receptor independent.
Studies have demonstrated that CBD has a low affinity for the CB1 receptors, but even at low concentrations, CBD decreases G-protein activity. CB1 receptors are expressed on many glutamatergic synapses that have been implicated in seizure threshold modulation. CBD may act at CB1 receptors to inhibit glutamate release. Studies have shown changes in the expression of CB1 receptors during epileptogenesis and after recurrent seizures. CB1 receptor expression is upregulated at GABAergic synapses and shown to be downregulated at glutamatergic synapses in epilepsy, contributing to lowering seizure thresholds.
Other targets for CBD include transient receptor potential (TRP) channels that are involved with the modulation of intracellular calcium. Cannabinoids are highly lipophilic, allowing access to intracellular sites of action, resulting in increases in calcium in a variety of cell types including hippocampal neurons. CBD actions on calcium homeostasis may provide a basis for CBD neuroprotective properties.