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).