CBD Binding

If CBD does not bind directly with CB1 or CB2, how does CBD interact with the endocannabinoid system?

CBD affects cannabinoid receptor binding by increasing the availability of endocannabinoids (endogenous agonists of the receptors to which THC also binds). (Bonaccorso) CBD accomplishes this in multiple ways:

• CBD inhibits fatty acid amide hydrolase (FAAH), the enzyme that breaks down the endocannabinoid anandamide (Bisogno)
• CBD blocks anandamide reuptake by binding to fatty acid binding proteins (Deutsch, Elmes)
  • Anandamide is an endocannabinoid that has affinity for CB1 and CB2 receptors, and an anti-inflammatory process is mediated through anandamide’s activity on CB1 and CB2. (Nichols)
• CBD also decreases MAGL (monoacylglycerol lipase)-mediated hydrolysis of the endocannabinoid 2-AG. (Ligresti, Campos, Bonaccorso)

Bottom line: As a result of CBD’s inhibition of the metabolism of anandamide and 2-AG, more anandamide and more 2-AG are available to bind to the cannabinoid receptors, and the effects of these endocannabinoids are enhanced. Also, there are fewer CB1 receptors available to bind with THC, thereby dampening the psychoactive effects of THC.

References

• Bonaccorso S, Ricciardi A, Zangani C, Chiappini S, Schifano F. Cannabidiol (CBD) use in psychiatric disorders: A systematic review. 2019 Sep; 74:282-298.
• Deutsch DG. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Front Pharmacol 2016 Oct 13; 7:370. doi:10.3389/fphar.2016.00370
• Elmes MW,  Kaczocha M, Berger WT, Leung K, Ralph BP, Wang L, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetra- hydrocannabinol (THC) and cannabidiol (CBD). J.  Chem.2015; 290(14): 8711–8721.
• Nichols JM, Kaplan BLF. Immune responses regulated by cannabidiol. Cannabis Cannabinoid Res 2020(5):12–31.
• Campos AC, Guimarães F.S., Involvement of 5HT1A receptors in the anxiolytic- like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology2008; 199(2):223–230.