Wednesday, April 24, 2019

Understanding the Science of Cannabis: The Entourage Effect


What is the entourage effect?

The Entourage Effect is the synergy between medicinal compounds known as cannabinoids and terpenes that are produced with in the cannabis plant.

The phrase entourage effect was introduced in 1998 by S. Ben-Shabat, and by Raphael Mechoulam, to represent a novel endogenous cannabinoid molecular regulation route.
“An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.” 

The phrase refers to the compounds present in cannabis supposedly working in concert to create “the sum of all the parts that leads to the magic or power of cannabis”, according to Chris Emerson (Chemist, Stanford Post-Doc, Oregon State Ph.D.). Other cannabinoids', terpenoids', and flavonoids' contribution to clinical cannabis effects has been espoused as an “entourage effect”.

In short, and as we will see in more detail below, it is a principle whereby the association between the different compounds present in cannabis can enhance (or mitigate) the effect of each one of them, in many cases improving the results given when administering isolated cannabinoids. A classic example of this is found in the potentiation of the effects of phytocannabinoids when THC and CBD are administered jointly, in which a level of effectiveness is reached that would be impossible by using the two compounds separately, besides avoiding some of the adverse or undesirable effects of THC. For this reason, more and more patients are looking for cannabis strains with a wider range of cannabinoids and terpenes, to ensure this interaction between the various molecules and, therefore, more potent and effective results from a medicinal point of view.


Cannabinoids are chemical compounds found in cannabis plants.

They are a subset of the 80-100 terpene-derived molecules found only in cannabis plants. Thus, all cannabinoids are terpenoids, but not all terpenoids are cannabinoids. They all have similar structures, but have been shown to have very different effects. Cannabinoids, are found in highest concentrations within the trichomes (or resin glands) found predominantly on the female flowers. Most cannabinoids are found in both acid and neutral forms, and majority are prevalent in acids.


Terpenoids are the chemical compounds responsible for a plant’s fragrance.

They are found within the resin glands of the cannabis plants (or trichomes). They interact with cannabinoids, called ‘entourage effect’ which helps define a given strain’s unique quality. Humankind has been infatuated with terpenes for thousands of years, enjoying the aromas and flavors in beer, candy, perfumes, fruits, incense and much more. In addition to the smells and tastes, we have continuously benefited from the diverse array of the medicinal and nutritional aspects found in terpenes. Terpenoids likely make up the single largest family of chemical compounds available, from across the planet, to herbalists and apothecaries alike for use in compounding remedies and medicine.
Entourage effect and cannabinoid-based medicines

More than twenty years ago, in 1985, a medicine based on pure THC, commercially called Marinol and intended to combat the symptoms of chemotherapy, was marketed in the US and made available by medical prescription. However, both doctors and patients soon realised that this drug was much less effective than the combination of several cannabinoids and terpenes which many experienced when consuming the whole cannabis plant. As a result. the research focused on the interaction between primary and secondary compounds based on different proportions, which often, as witnessed by researchers such as Dr. Sanjay Gupta, offered much more promising results than isolated cannabinoids in pure form.


Israeli professor Raphael Mechoulam, the first to isolate THC

Although research is progressing and more and more products with CBD can be found, some with added terpenes extracted from cannabis or other plants (to increase the permeability of tissues and mucous membranes, improving the assimilation of other compounds), thousands of patients globally cannot fully benefit from this effect if they are unable to also use THC, which according to studies appears to be one of the fundamental ingredients for creating this synergy between molecules.

Ethan B. Russo, an eminent American neurologist and passionate student of cannabis, is another of the many researchers who bet on the entourage effect as a way to get the true benefits that cannabis can offer to thousands of patients. According to his studies, the entourage effect can be very useful to treat a large number of ailments, such as pain, inflammation, depression, anxiety, various cases of addiction, epilepsy, cancer or infections caused by fungi or bacteria. Although careful, he also emphasises the following: THC or tetrahydrocannabinol is still essential to achieve the best results, regardless of the combination of compounds concerned. According to Dr. Russo, the administration of CBD together with THC mitigates ostensibly the possible psychotic effects (or anxiety/paranoia) that the THC can cause when administered in isolation.


THC and CBD enter into synergy when jointly administered


Examples of Cannabinoids, terpenes and the entourage effect:

Limonene + pinene + linalool: effective to treat acne and increase the effects of THC

Limonene + linalool: enhance the effects of CBD

Linalool + caryophyllene + myrcene: potentiate the activity of cannabinoids to treat sleep problems

Caryophyllene + myrcene + pinene: suitable for treating addictions

THC + CBD: cannabinol (CBD) would enhance the beneficial effects of THC while reducing adverse effects and modulating its psychoactivity, also contributing its own therapeutic effects.


As can be seen with these few examples, and given the enormous amount of cannabinoids, terpenes and other compounds (ketones, esters, lactones, alcohols, fatty acids, steroids, etc.) found in cannabis, it’s not hard to imagine the huge amount of possible combinations that might be achieved, each with a series of specific and determined effects. Remember that each plant has its own unique profile of cannabinoids, terpenes and other molecules, so the effects of each plant can vary depending on that profile, or chemotype.

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Studies and publications on cannabinoids and terpenes:An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. ShimonBen-Shabat, Ester Fridea, Tzviel Sheskina, Tsippy Tamirib, Man-Hee Rheec, Zvi Vogelc, Tiziana Bisognod, Luciano De Petrocellise, Vincenzo Di Marzod and RaphaelMechoulam

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Ethan B. Russo

A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Ethan B. Russo and Guy, GW

Cannabis is more than simply D9-tetrahydrocannabinol. Ethan B. Russo and John M. McPartland

The entourage effect: Synergistic actions of plant cannabinoids. Juan Sanchez-Ramos

Medicinal cannabis: is delta-9-tetrahydrocannabinol necessary for all its effects? JD Wilkinson, BJ Whalley, D. Baker, G. Pryce, A. Constanti, S. Gibbons, Williamson MS

The Therapeutic Potential of Cannabis and Cannabinoids. Franjo Grotenhermen, Kirsten Müller-Vahl

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