CBD both modulated and directly activated glycine receptors in the spinal cord at micromolar concentrations, providing a potential mechanism for its anti-inflammatory and pain-relieving effects.
Read this if you use CBD for pain and want to understand one molecular mechanism behind its effects.
CBD enhanced glycine receptor function at 12-18 micromolar (allosteric modulation)
What the researchers found
Researchers investigated whether CBD interacts with glycine receptors, which are the main inhibitory neurotransmitter receptors in the adult spinal cord and are important for pain processing.
CBD showed a positive allosteric modulating effect on alpha1 and alpha1-beta glycine receptors at low micromolar concentrations (EC50 of 12.3 and 18.1 micromolar). This means CBD enhanced the receptors' response to their natural activator.
At higher concentrations (above 100 micromolar), CBD directly activated the receptors independently (EC50 of 132.4 and 144.3 micromolar).
Since loss of glycinergic inhibition in the spinal cord is a key mechanism in the development of chronic pain following inflammation or nerve injury, CBD's ability to restore or enhance glycine receptor function could explain some of its pain-relieving properties through a non-cannabinoid receptor mechanism.
Why it matters
This study identified a specific non-cannabinoid receptor mechanism for CBD's pain effects. Since glycine receptor dysfunction is implicated in chronic pain development, CBD's ability to enhance glycinergic transmission provides a mechanistic explanation for clinical pain relief.
The numbers in context
Allosteric modulation EC50: alpha1 = 12.3 micromolar, alpha1-beta = 18.1 micromolar. Direct activation EC50: alpha1 = 132.4 micromolar, alpha1-beta = 144.3 micromolar.
How the study worked
Whole-cell patch clamp electrophysiology on cells expressing alpha1 or alpha1-beta glycine receptors. CBD effects were measured as changes in glycine-evoked currents (allosteric modulation) and as direct current induction (direct activation).
What this study cannot tell us
In vitro electrophysiology on expressed receptors may not reflect in vivo conditions. The concentrations needed for direct activation (>100 micromolar) may not be achievable in the spinal cord with typical CBD dosing. Only two receptor subtypes were tested.
How to read the evidence
This is an in vitro electrophysiology study providing preliminary mechanistic evidence. The clinical significance depends on whether therapeutic CBD concentrations reach the relevant levels.
When this study was published
Published in 2009. CBD-glycine receptor interactions have been further characterized in subsequent studies, confirming this as a relevant target.
The bigger picture
This study added glycine receptors to the growing list of non-cannabinoid targets through which CBD exerts pharmacological effects. The glycine receptor mechanism is particularly relevant for understanding CBD's analgesic properties in chronic and inflammatory pain.
Questions still open
- Are spinal glycine receptor concentrations of CBD achievable with therapeutic dosing? Does the allosteric modulation (at lower concentrations) contribute more to pain relief than direct activation?
Common questions
What are glycine receptors?
Is this why CBD helps with pain?
Read the original research
The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.
Pharmacology, 83(4), 217-22
Citation
Ahrens, Jörg; Demir, Reyhan; Leuwer, Martin; de la Roche, Jeanne; Krampfl, Klaus; Foadi, Nilufar; Karst, Matthias; Haeseler, Gertrud. (2009). The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.. Pharmacology, 83(4), 217-22. https://doi.org/10.1159/000201556
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