Cannabidiol (CBD) does not bind to the CB1 and CB2 receptors of the endocannabinoid system (unlike THC). It is not an endocannabinoid-agonist; it exerts antagonism or inverse agonism at these receptor sites. [1,2] Surprisingly, many of the therapeutic benefits of CBD derive from the molecule’s indirect boost of the body’s own endocannabinoid, anandamide.
Arachidonoyl ethanolamide (AEA) was discovered in 1992 and named anandamide afer the Sanskrit word ananda, which means bliss or happiness. Anandamide was the first known natural ligand (endocannabinoid) for the body’s cannabinoid receptors. 
The fatty acid neurotransmitter acts as a direct agonist on CB1 and CB2 receptors and demonstrates effects partially similar to psychotropic exogenous cannabinoids (i.e., THC), albeit much less potent.  Anandamide plays a significant role in physiological homeostasis and protection, with regulatory effects encompassing mood, motivation, pain, inflammation, and neuroprotection. [5-8]
Anandamide is not stored. Instead, it is synthesized on demand in response to increased intracellular calcium. Quick clearance limits the potential of anandamide to activate cannabinoid receptors and elicit therapeutic effects. Fatty acid binding proteins (FABPs), also referred to as anandamide membrane transporters (AMTs), carry anadamide across the cell membrane for uptake. Then the enzyme fatty acid amide hydrolase (FAAH) catalyzes hydrolysis, or chemical breakdown. [7,9-12]
Graph: Larger concentrations of CBD analogues reduce AEA hydrolysis. Source: Bisogno, T., et al. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis
One of the main therapeutic actions of CBD is interfering with both the uptake and hydrolysis of anandamide. This leads to enhanced, sustained levels of the natural neurotransmitter and subsequently, therapeutic effects [1, 7-11]. Uptake may be inhibited due to CBD competing for position on the same transporters (FABPs) as anandamide. The decreased uptake may in turn signal lower production of FAAH [11-13]. Despite the uncertainty regarding molecular mechanisms, it is clear that CBD inhibits the re-uptake and degradation of anandamide.
The implications for health and wellness are beyond the scope of this article. One fascinating recent discovery, published in Journal of Happiness Studies, found that national differences in subjective well-being could actually be connected to FAAH gene mutation. The rs324420 A allele, which lowers FAAH production and therefore increases anandamide, is correlated to national happiness !
Graphic: If anandamide transporters are inhibited, it is not transported for breakdown. Source: Deutsch, D. G. (2016). A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Frontiers in Pharmacology, 7, 370. https://doi.org/10.3389/fphar.2016.00370
- Long, L., et al. (2005). The pharmacological effects of cannabidiol. Drugs of the Future, 30(7), 747-753.
- Pertwee R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British journal of pharmacology, 153(2), 199–215. doi:10.1038/sj.bjp.0707442
- Devane, W. A., et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (New York, N.Y.), 258(5090), 1946–1949.
- Smith, P. B.,et al. (1994). The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. Journal of Pharmacology and Experimental Therapeutics, 270(1), 219 LP – 227. Retrieved from http://jpet.aspetjournals.org/content/270/1/219.abstract
- Clapper, J. R., et al. (2010). Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nature Neuroscience, 13, 1265. Retrieved from https://doi.org/10.1038/nn.2632
- Gobbi, G., et al. (2005). Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18620 LP – 18625. https://doi.org/10.1073/pnas.0509591102
- Maccarrone, M., & Finazzi-Agró, A. (2003). The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death & Differentiation, 10(9), 946–955. https://doi.org/10.1038/sj.cdd.4401284
- Zurier, R. B., & Burstein, S. H. (2016). Cannabinoids, inflammation, and fibrosis. The FASEB Journal, 30(11), 3682–3689. https://doi.org/10.1096/fj.201600646R
- Bisogno, T., et al. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology, 134(4), 845–852. https://doi.org/10.1038/sj.bjp.0704327
- Deutsch, D. G. (2016). A Personal retrospective: Elevating anandamide (AEA) by targeting fatty acid amide hydrolase (FAAH) and the fatty acid binding proteins (FABPs). Frontiers in Pharmacology, 7, 370. https://doi.org/10.3389/fphar.2016.00370
- Elmes, M. W., et al. (2015). Fatty acid-binding proteins (FABPs) are intracellular carriers for Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The Journal of Biological Chemistry, 290(14), 8711–8721. https://doi.org/10.1074/jbc.M114.618447
- Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. (2018). International Journal of Molecular Sciences,19(3), 833. doi:10.3390/ijms19030833
- Lee, J. L., et al. (2017). Cannabidiol regulation of emotion and emotional memory processing: Relevance for treating anxiety-related and substance abuse disorders. British Journal of Pharmacology,174(19), 3242-3256. doi:10.1111/bph.13724
- Minkov, M., & Bond, M. H. (2016). A Genetic component to national differences in happiness. Journal of Happiness Studies,18(2), 321-340. doi:10.1007/s10902-015-9712-y