The Entourage Effect

 

The entourage effect of cannabinoid activity was first described in 1998 when the biological activity of an endogenous cannabinoid (2-Arachidonoyl-glycerol) was increased by related, endogenous non-cannabiols (2-acyl-glycerols), which show no significant activity when used by themselves.1

In understandable English

A compound that can bind to a receptor site is called a ligand.   (A receptor site is a specific place on a receptor protein which is located in the outer membrane of a cell),   When the ligand binds to the receptor, it induces a certain activity to occur inside that cell.  The entourage effect occurs when the reaction inside the cell is changed because some other compound is present around or inside the cell.  

There are several known mechanisms by which the entourage effect occurs including:

  1. The compound binds to a receptor, not on the receptor site, but a different place on the receptor protein called the allosteric site. When it does this, it either increases or decreases the activity induced inside the cell.  Compounds that do this are called positive or negative allosteric ligands, respectively.  Some allosteric ligands bind to the allosteric site but don’t change the activity inside the cell.  These are called neutral allosteric ligands.  They can be significant clinically because they can block the ability of positive or negative allosteric ligands from binding and exerting their effect.2,3  To be an entourage effect and not just an additive effect, the entourage causing compound cannot bind to same receptor site to which the ligand binds. 
  2. The compound can bind to a completely different receptor protein on the surface of the cell and either increases or decreases the activity induced when a ligand binds to the receptor site.  4,5
  3. Some compounds can do both 1 and 2.

It is well established that CBD is an allosteric ligand of the CB1 receptor and modifies the effects of THC when it binds to CB1 in certain cells.3  However, CBD doesn’t do this on all cells, just certain ones.  We do not yet understand this fully.  This is an example of the mystery that still exists in the entourage effect.  However, the entourage effect of cannabinoids is not limited to THC and CBD but many, if not all, the other minor cannabinoids have been shown to have an entourage effect also.6 In addition, terpenes (compounds that cause smell and taste and are abundant in hemp products) have potent entourage effects with cannabinoids.  Even flavonoids (other smaller compounds occurring in hemp) may have some limited entourage effects.

The importance of the entourage effect is illustrated in a study conducted in a mouse model of inflammatory bowel disease (IBD).  In this study, the half the mice were treated with just cannabidiol (CBD) and the other half were treated with a CBD-enriched hemp oil (CBDHO).  The CBD treated mice had improvement in the motility of the bowel after treatment but no improvement in the inflammation of the bowel.  The CBDHO treated mice had the same improvement in motility but they also had complete resolution of the inflammation in the bowel. 7

Bottom line

The entourage effect is very important clinically and the use of CBD-enriched hemp oil that contains both 1) the other minor cannabinoids (usually including low levels of THC) and 2) terpenes is often better than just CBD by itself.8  However, hemp oil is a naturally occurring material and the concentrations of the various cannabinoids and terpenes can vary widely.9  To obtain consistent results using hemp oil, these variations should be minimized.  That’s why it is extremely important for people to obtain their hemp oil from manufacturers that continually test and maintain quality control of the consistency of their product and publish that information. 

 

(On a personal note: This discussion is a prime example of what a wise old medical school professor once said to me, “If you can think it could happen in medicine, it probably does.”)

References:

  1. Ben-Shabat, S, etal. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacology.1998;353(1):23–31
  2. Morales P, etal. Allosteric modulators of the CB1 cannabinoid receptor: a structural update review. Cannabis Canna Res 2016;1(1):22-30.
  3. Straiker A, et al. Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons. Mol Pharmacol.2018 Jul;94(1):743-748
  4. Ho W, etal. Entourage effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharm 2008;155:837-46.
  5. Petrocellis L, etal. Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interaction with both the cannabinoid and vanilloid signaling systems. Fundamental & Clin Pharmacology 2002;16:297-302.
  6. Pagano E, et al. An orally active Cannabis extract with high content in cannabidiol attenuates chemically-induced intestinal inflammation and hypermotility in the mouse. Frontiers Pharmacology 2016;7:341.
  7. Ross R. Tuning the endocannbinoid system: allosteric modulators of the CB1 receptor. Br J Pharm 2007;152:565-66.
  8. Russo E. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharm 2011;163:1344-64.