Posted by Andrew Barton on 16th Mar 2021

What Is The Entourage Effect?

People tend to think of medicines and herbs as having an “active ingredient” that is responsible for the effect they experience. The intensity of their experience is attributed to the dose of this particular ingredient that they consumed, and the remaining material is typically thought of as a neutral carrier.

This mindset is reflected in many aspects of daily life, from labeling on over the counter medicines to laws defining sobriety based on the concentration of a particular substance in the bloodstream. The potency of marijuana for instance, is defined based on the concentration of THC found in the material.

While this approach may be valid in some cases, to apply it as a universal rule is not. Rather than the exception, it is the norm for herbs to contain several “active ingredients”. Furthermore, these compounds typically influence each other’s effects. The result is different from the sum of its parts.

Cannabis is a rare example where this phenomenon is blatantly obvious to those who consume it, and the industry has coined the term “Entourage Effect” to describe the phenomenon.

What Is The Entourage Effect?

In cannabis there are countless compounds that contribute to its pharmacological properties, with more being detected and discovered all the time. These substances can be sorted into three broad categories. The most familiar category is the classical cannabinoids (THC, CBD, etc.)1,2,3.

These triterpenoid resins and oils share a metabolic origin in the plant1, and their diverse array of biological properties constitute the primary effects of cannabis. The next category includes all the compounds that make up the essential oil of cannabis (Terpenes, or Terps for short)2,3. Substances in this category include true terpenes, volatile terpenoids, and other volatile flavor and aroma compounds.

Typically thought of as the fraction of cannabis responsible for its flavor and aroma, substances in this category also have powerful pharmacological properties that influence the experience from the more classical cannabinoids. Finally, cannabis contains a vast array of water soluble molecules.

This category includes flavonoids2, alkaloids, polysaccharides, and other polar compounds3. While research into the properties of the aqueous fraction of cannabis is in its infancy, it is undeniable that these compounds play a fundamental role in the medicinal properties of cannabis and its subjective feel when consumed.

Classical cannabinoids tend to affect a few key systems in the body. They interact with cannabinoid receptors (CB1, CB2)1,4,13 both directly and indirectly10,11,13,16, they directly influence the activity and sensitivity of sensory neurons (TRP channel interactions)1,5,13,16, they directly influence gene expression and metabolic processes (PPAR nuclear receptors)1,6,13, they influence neurotransmitter systems both directly and indirectly8,7,13,16, and they alter the activity of a number of key enzymes5,9.

Each cannabinoid has a unique role in all of these systems, and their various combinations can result in remarkably different effects and experiences. For instance, CBD modifies the way other cannabinoids interact with CB1 receptors. CBD slightly changes the shape of the receptor without actually binding to its active site, in a process called negative allosteric modulation10,13,16.

This means that when a CB1 activator like CBN13 binds to the receptor, its effect is reduced. By reducing the intensity of CB1 activation, CBD counteracts some of the sedating and perception-altering qualities of these molecules10. CBD also prolongs the effects of other cannabinoids (both from plants and the body’s own) by preventing their breakdown (Fatty Acid Binding Protein11 and CYP enzyme inhibition9).

cbd chemical

Cannabidiol (CBD)

Another noteworthy interaction between classical cannabinoids is that of CBN and CBG. Both CBN and CBG interact with CB1 receptors13,14,16, but do so with different potencies and in slightly different ways12,16,17. While both cannabinoids can increase appetite by this mechanism, CB1 activation by CBN tends to have a sleep promoting effect14,16 whereas CB1 activation by CBG does not. When combined however, CBG’s ability to suppress adrenaline release (A2 adrenergic agonism)7,13 can improve CBN’s sleep promoting effect.

cannabinol cbn chemical structure cannabigerol chemical structure

Cannabinol (CBN) Cannabigerol (CBG)

A third interesting interaction between cannabinoids involves CBC. While not particularly well studied, very high doses of CBC have been shown to produce similar behaviors in mice as THC17. These changes are not prevented by chemicals that block CB1 receptors, meaning that CBC likely does not produce its effects by directly activating CB113,16,18,19.

However, CBC may intensify and or alter the effect of CB1 active molecules15,16,17. These factors hint that like CBD, CBC may indirectly modify how other molecules interact with CB1 by interacting with an alternative binding site17,18. The difference being that rather than reducing their efficacy, CBC seems to cause a change in shape that increases the sensitivity and/or changes the effect of CB1 receptors to some molecules that activate them16,17, such as CBN. CBC has also been shown to increase the amount of other cannabinoids in the blood that reach the brain, which likely plays an important role in how it interacts with these molecules15.

Cannabichromene cbd chemical structure Tetrahydrocannabinol thc chemical structure

Cannabichromene (CBC) Tetrahydrocannabinol (THC)

Cannabinoid interactions are by no means limited to the examples given above. Cannabinoid receptors are special in that they couple to a variety of different proteins, triggering a wide array of intracellular signaling processes20. The “classical” way that cannabinoid receptors function is to couple to inhibitory G proteins that inhibit the enzyme adenylate cyclase, reducing the formation of the intracellular signaling molecule cyclic adenosine monophosphate (cAMP). In this “classical” pathway, cannabinoid receptor activation also activates the mitogen-activated protein kinase (MAPK) pathway and recruits the intracellular protein beta-arrestin.

The net result is reduced and altered cellular activity and reduced sensitivity to further stimulation20. However, under different circumstances activation of the same cannabinoid receptor type by the same molecule can cause the receptor to instead couple to excitatory G proteins that activate adenylate cyclase and increase levels of cAMP, essentially the opposite of the “classical” pathway20.

Furthermore, recent research shows that cannabinoids (both from plants and the body’s own) are selective as to which pieces of the cannabinoid receptor signaling pathways they activate, and to what extent20. This phenomenon is known as protean agonism or ligand bias21, and is the result of multiple “shapes” of an activated receptor that cause the receptor to do different things, in addition to ligands having differing affinities for each shape that the receptor takes on21.

To summarize, every cannabinoid causes a different response in cannabinoid receptors12,13,14,16,17 and binds preferentially to specific sites and active shapes in the receptor17,20. A single cannabinoid can have different effects depending on the biological environment around it, such as; the presence of other receptor ligands13,14,16,20, the cell type and tissue that the receptor is found in4,20, and the presence of allosteric modulators13,16,17,20. Given this fact, it is easy to see how the combination of cannabinoids can produce different effects from a single cannabinoid in isolation.

cb1 signaling cascade

Illustration of a CB1 signaling cascade

Terpenes and other flavor/aroma molecules also profoundly influence the overall effects from any cannabis preparation, and are considered responsible for the difference between “Indica” and “Sativa” strains. “Indica” strains of cannabis tend to have greater concentrations of terpenoids that have sedative effects. Terpinolene is one such molecule.

Terpinolene has a pungent, musky pine-like scent and flavor. This molecule produces sedation23 in a process that seems to involve serotonin receptors (5HT2a)41, resulting in reduced activity in the frontal lobe of the brain associated with wakefulness. A similar effect and mechanism is shared by several other terpenoids such as citral22.

Linalool, another sedative terpenoid, exerts its effects on several systems including GABA24, serotonin25, glutamate26, and various ion channels27. “Sativa” cannabis strains tend to have mildly stimulating and anxiolytic terpenes and terpenoids. A prominent example is that of alpha pinene.

Alpha pinene has a light, bright pine-like scent and flavor. This molecule reduces anxiety by enhancing the activity of GABA33,42. Alpha pinene also inhibits the enzyme acetylcholinesterase28,29, which is responsible for terminating the signal of cholinergic neurons by breaking down the neurotransmitter acetylcholine32.

By increasing the level of available acetylcholine, alpha pinene can improve alertness and working memory31 as well as subjective feelings of energy.

Terpenoids like cineol28,29 and ocimene30 share this property with alpha pinene. Terpenes such as myrcene, which has an earthy/musky scent and flavor, have a more or less neutral effect on the “Indica/Sativa” scale22,34 and are a dominant constituent of most cannabis strains.

Myrcene itself does not have well described pharmacological action, but it has been shown to alter the metabolism of other molecules. Other “neutral” terpenes include Beta Caryophyllene and Humulene.

Terpinolene linalool a-pinene

Terpinolene Linalool a-Pinene

In whole cannabis flower, the entourage effect is extended past the nonpolar fractions of the plant to include aqueous (water soluble) molecules. As is well known in the industry and cannabis culture, consuming plant material results in a different feeling from concentrates.

Some consumers feel that the plant material is stronger or more pleasurable per unit of cannabinoids than concentrates, and visa-versa. Notably, the ability of cannabis to reduce intraocular pressure appears to come from the aqueous fraction36, more so than from cannabinoids or terpenes35.

Among the polar compounds found in cannabis, flavonoids serve as antioxidants and have a diverse array of pharmacological properties39. While they are not typically tested for, examples such as apigenin have been derived from cannabis3. Alkaloids such as cannabisativine3, while uncharacterized pharmacologically, undoubtedly play a role in the effect of the aqueous fraction.

Polysaccharides are a diverse family of compounds composed of various combinations of sugars and other molecules. They play important roles in cell signaling and immune function37,38. This class of molecule is not well studied, and examples have only just begun to be characterized. Some consumers of cannabis claim that the “juice” of the plant is most valuable for conditions such as lupus40, but research into the matter is inconclusive.

cannabisativine apigenin

Cannabisativine Apigenin

In short, cannabis is more than just the sum of its parts. To utilize this plant to its full potential, the entourage effect must be accounted for. Great care goes into cannabis product development, taking advantage of the interplay between various cannabis constituents to provide the perfect entourage effect for a given use.


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