Physiological profiling of cannabidiol reveals profound inhibition of sensory neurons

Pain. 2024 May 29. doi: 10.1097/j.pain.0000000000003273. Online ahead of print.


Cannabidiol (CBD), the main nonpsychoactive cannabinoid of cannabis, holds promise for nonaddictive treatment of pain. Although preclinical studies have been encouraging, well-controlled human trials have been largely unsuccessful. To investigate this dichotomy and better understand the actions of CBD, we used high-content calcium imaging with automated liquid handling and observed broad inhibition of neuronal activation by a host of ionotropic and metabotropic receptors, including transient receptor potential (Trp) and purinergic receptors, as well as mediators of intracellular calcium cycling. To assess the effect of CBD on overall nociceptor electrical activity, we combined the light-activated ion channel channelrhodposin in TRPV1-positive nociceptors and a red-shifted calcium indicator and found that 1 µM CBD profoundly increased the optical threshold for calcium flux activation. Experiments using traditional whole-cell patch-clamp showed increase of nociceptor activation threshold at submicromolar concentrations, but with unusually slow kinetics, as well as block of voltage-activated currents. To address a more integrated capacity of CBD to influence nociceptor sensitization, a process implicated in multiple pain states, we found that submicromolar concentrations of CBD inhibited sensitization by the chemotherapeutic drug vincristine. Taken together, these results demonstrate that CBD can reduce neuronal activity evoked by a strikingly wide range of stimuli implicated in pain signaling. The extensive effects underscore the need for further studies at substantially lower drug concentrations, which are more likely to reflect physiologically relevant mechanisms. The slow kinetics and block raise biophysical questions regarding the lipophilic properties of CBD and its action on channels and receptors within membranes.