The proposed multimodal mechanism of action of cannabidiol (CBD) in epilepsy: modulation of intracellular calcium and adenosine-mediated signaling (P5.5-007)

Objective: We present preclinical evidence summarizing CBD’s leading mechanisms of action in epilepsy. Background: Although commonly misrepresented, CBD does not act through cannabinoid receptors at physiologically achievable concentrations. CBD has shown anticonvulsant properties in preclinical studies and antiseizure effects in clinical trials of Dravet and Lennox-Gastaut syndromes with a unique molecular target profile, distinct from other antiepileptic drugs. Design/Methods: Preclinical evidence suggests CBD reduces neuronal hyperexcitability through multiple mechanisms, including modulation of intracellular calcium via G protein-coupled receptor 55 (GPR55), extracellular calcium influx via transient receptor potential vanilloid type 1 (TRPV1) channels, and adenosine-mediated signaling. Results: CBD antagonizes GPR55 at excitatory synapses. The inhibition of intracellular calcium release decreases excitatory currents and seizure activity. GPR55-mediated modulation of neurotransmission was potentiated in excitatory neurons and reduced in inhibitory neurons in a chronic epilepsy model. CBD potently blocked GPR55-mediated increase of miniature excitatory postsynaptic current frequency in pyramidal neurons in both healthy and epileptic tissue. CBD did not affect GPR55-mediated increase of excitatory neurotransmission in inhibitory neurons in healthy tissue. CBD’s anticonvulsant properties were attenuated in GPR55 knockout (KO) animals. CBD desensitizes TRPV1 channels. The resultant decrease in extracellular calcium influx decreases neurotransmission. The dose-dependent, CBD-mediated increase in seizure threshold seen in wildtype mice was significantly attenuated in TRPV1 KO mice. Brain CBD concentrations were consistent with those required for TRPV1 activation and desensitization irrespective of genotype. CBD inhibits equilibrative nucleoside transporters (ENT1), reducing adenosine reuptake. The increase in extracellular adenosine reduces hyperexcitability and neurotransmission. CBD inhibited [3H] adenosine uptake into rat cortical synaptosomes at low micromolar concentrations. Conclusions: While the precise mechanisms by which CBD exerts its anticonvulsant properties in humans remain unknown, growing preclinical evidence suggests CBD reduces neuronal hyperexcitability through a unique multimodal mechanism of action. CBD antagonizes GPR55 at excitatory synapses, desensitizes TRPV1 channels, and inhibits adenosine reuptake. Disclosure: Dr. Nichol has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of Greenwich Biosciences Inc.. Dr. Stott has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd. Dr. Stott holds stock and/or stock options in GW Pharmaceuticals . Dr. Jones has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd. Dr. Gray has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd. Dr. Gray has received compensation for serving on the Board of Directors of GW Pharmaceuticals. Dr. Gray has received research support from GW Pharmaceuticals. Dr. Bazelot has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research LTD. Dr. Bazelot holds stock and/or stock options in GW Research LTD., which sponsored research in which Dr. Bazelot was involved as an investigator. Dr. Bazelot holds stock and/or stock options in GW Research LTD. Dr. Whalley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Research Ltd.