Abstract
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.
Disputes & Debates: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.