What Is the Entourage Effect?

It’s the reason why full-spectrum CBD oil is called “full-spectrum”, but what is the Entourage Effect exactly? Luckily it has nothing to do with the HBO series, and is better in every way, even in its current theoretical form. 

Essentially, the Entourage Effect refers to the proposed scientifically and medically meaningful interactions, or synergy, between the molecules produced by the Cannabis sativa plant. 

For example, it is becoming well-known that CBD is a more effective pain killer with THC in the mix. And terpenes found in some cannabis strains affect the way THC and other cannabinoids behave. 

Still, these are just two examples in an unknown sea of possibilities when it comes to the hypothetical Entourage Effect. At any rate, when a cannabis product demonstrates a “full-spectrum”, it simulates the full chemical profile of cannabis to facilitate the Entourage Effect. 

The Endocannabinoid System (ECS) and the Entourage Effect

It can be useful to have a quick primer on the Endocannabinoid System (ECS), the topic of last week’s blog article. The Entourage Effect is complicated and currently still just a theoretical model that attempts to describe why Cannabis is so effective at treating so many issues. And much of this effect occurs because of our ECS.

Legislation Interferes With Research

It isn’t surprising that we are lacking substantial scientific information about the proposed entourage effect. As it is, we are only just learning about the Endocannabinoid System, a body system as important as the circulatory or respiratory system, if not more so. In our article ‘What is the Endocannabinoid System?’ we dig deep into the history of Schedule 1 Classification and why it took so long to discover the ECS.

Why We Know so Little About the Entourage Effect

Because research before widespread legalization was adversely affected by the Schedule 1 classification of THC, studies are needlessly complex. To begin with, out of necessity, pharmaceutical cannabinoid isolates are used as the basis for this research. Consequently, this results in studies describing the Entourage Effect as “the addition of terpenes to cannabinoids”. (Ferber et al, 2020)

Again, if human-centered studies of the plant Cannabis sativa were widely permitted, these redundancies wouldn’t have to exist. In reality, Cannabis sativa produces a complex terpene profile. Therefore, cannabinoids and terpenes are inextricable in the Cannabis plant, unless synthetically separated. 

And this frustrating irony is evidently not lost on the researchers forced into these superfluous conclusions.

Ethan Russo and Chemical Synergy

Indeed, Dr. Ethan B. Russo asks: “Is cannabis merely a crude vehicle for delivery of THC?” (Russo, 2011) Russo is a prolific cannabis researcher who is well-known for conducting major clinical studies on Sativex and Epidiolex (cannabinoid isolate pharmaceuticals).

Still, Russo’s research has contributed meaningful volumes of evidence for this chemical synergy, which was first proposed in the 1990s. 

And in a recent interview with Forbes magazine, he reiterates these findings. Of course, his new company will focus on the type of innovations he advocates for in his numerous published studies. 

What We Do Know about the Entourage Effect

In the 1990s, researchers lead by Mechoulam and Ben-Shabat (Ferber et al, 2020) found several interesting interactions between cannabinoids and accompanying inactive biological products found in Cannabis. Subsequently, this leads to the development of the Entourage Effect hypothesis to help explain the myriad synergistic interactions in the ECS. 

Cannabis Demonstrates the Four Basic Mechanisms of Synergy

Since the ECS wasn’t discovered until the 1990s, most research about its synergistic potential is relatively new. And widespread legalization has necessitated revisiting certain findings with more freedom to allow science to take its course. 

In 2011, Russo highlighted four basic ways that the Entourage Effect might work, based on the potential illustrated by Cannabis sativa and observed repeatedly by research and anecdote. 

In particular, multi-target effects, improved solubility or bioavailability, interactions affecting bacterial resistance, and modulation of adverse effects were observed. (Russo, 2011)

Multi-Target Effects in the ECS

When you vaporize cannabis buds, you inhale cannabinoids, terpenes, flavonoids, and other trace molecules. And as these enter your bloodstream and begin to interact with your ECS, certain molecules can interact with certain sites. For instance, THC has been well-observed interacting at both CB1 and CB2 receptors. It was this interaction that facilitated the discovery of the ECS in the first place. Meanwhile, other molecules present cannot bind to these receptors but will have effects at other meaningful sites.

To demonstrate, an exciting recent discovery in this area pertains to terpenes, which were previously thought to have no meaningful interactions at CB1 (Finlay et al, 2020). New evidence has shown that “terpenes and cannabinoids can produce an additive effect when combined. This study is also the first to identify the CB1 and A2a receptors as terpene targets, and describe the role of these receptors in producing terpene cannabimimetic effects in vivo.” (LaVigne et al, 2021)

The Entourage Effect Modulates Adverse Effects

THC provides welcome effects in many while causing some distress in others. And these are referred to as the “adverse effects” of THC, which earned it the Schedule 1 classification. Of course, these effects have a lot to do with dosage and the mental preparedness of the user for the psychoactive effects. Nonetheless, it turns out that the Cannabis sativa plant produces additional cannabinoids that appear to modulate these “adverse” effects. Indeed, “the ability of CBD to reduce side effects of THC” was observed in studies conducted in 2006 (Russo, 2011). 

That being said, THC is the phytocannabinoid-version of our endogenous anandamide (AEA), the molecule responsible for the infamous “Runner’s High”. Indeed, THC has been shown to increase the pain-relieving effects of CBD. So it is important to emphasize that “adverse” is subjective in the case of THC. It has more to do with its problematic Schedule 1 classification than scientific or anecdotal reality.  

Promising Interactions with Terpenes and Terpenoids

Back when we first opened shop, we put together a primer ‘Cannabis 103: A Guide to Terpenes’. Truly, the array of aromas and proven benefits spontaneously produced in cannabis trichome glands as terpenes are astounding. 

Now, research into the Entourage Effect is focusing on terpenes, terpenoids, and their synergistic effects with cannabinoids. To distinguish the two, terpenes are hydrocarbons, meaning they are made up of only carbon and hydrogen atoms. On the other hand, terpenoids are modified terpenes that contain additional elements and functional groups that contain oxygen.

Anti-Depressant And Anti-Anxiety Entourage Effect

Most of the studies testing the Entourage Effect hypothesis have observed “the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids.” (Ferber et al, 2020) Indeed, as more is learned about the ECS, its positive interaction with whole, natural cannabis promises non-addictive treatments for problems like depression, anxiety, PTSD, and insomnia. (Rosner, 2020). Of particular interest are the additional plant-derived chemicals like alkaloids, flavonoids, phenolic acids, lignans, cinnamates, and saponins that have demonstrated anti-anxiety effects in animal studies (Ferber et al, 2020).

Research Methods to Enable Further Discovery

In conclusion, there’s no doubt that over one hundred years of problematic legislation marred the scientific landscape for understanding the Entourage Effect. After all, “functional interactions between two or more biologically active agents are common in pharmacology and toxicology, and there are well-established ways of investigating them.” (Piomelli, 2019) 

Going forward, researchers like Piomelli and Russo have recommendations to improve and accelerate effective clinical research to observe the Entourage Effect. Some methods are beyond the scope of this article’s conclusion. Others are straightforward, emphasizing human-centered research using a combination of vaporized cannabis or oromucosal sprays. fMRI scans paired with drug reaction questionnaires and psychometric testing would form the basis of evaluations (Russo, 2011). Of course, this is an over-simplification. But without a doubt, there are some fascinating developments on the horizon for the Entourage Effect!

References

Alger, Ph.D, B. (2013) “Getting High on the Endocannabinoid System,” PMC US National Library of Medicine, Cerebrum. 2013 Nov-Dec; 2013: 14, [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295/ (Accessed 22 April 2021).

Complex Biotech Discovery Ventures (2020) “Article – Terpenes vs. Terpenoids,” Complex Biotech Discovery Ventures, [online] Available from: https://cbdvl.com/terpenes-vs-terpenoids/ (Accessed 19 May 2021).

Ferber, S. G., Namdar, D., Hen-Shoval, D., Eger, G., Koltai, H., Shoval, G., Shbiro, L. and Weller, A. (2020) “The ‘Entourage Effect’: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders,” Current neuropharmacology, Bentham Science Publishers, [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324885/ (Accessed 11 May 2021).

Finlay, D. B., Sircombe, K. J., Nimick, M., Jones, C. and Glass, M. (2020) “Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors,” Frontiers in Pharmacology, Frontiers Media S.A., [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109307/ (Accessed 11 May 2021).

LaVigne, J. E., Hecksel, R., Keresztes, A. and Streicher, J. M. (2021) “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity,” Scientific Reports, Nature Publishing Group UK, [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050080/ (Accessed 11 May 2021).

Piomelli, D. (2019) “Waiting for the Entourage,” Cannabis and Cannabinoid Research, Mary Ann Liebert, Inc., publishers, [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760171/ (Accessed 11 May 2021).

Rosner, A. (2020) “Ethan Russo’s New Cannabis Company Is All About Innovation,” Forbes, Forbes Magazine, [online] Available from: https://www.forbes.com/sites/abbierosner/2020/04/07/ethan-russos-new-company-looks-from-the-endocannabinoid-system-out/?sh=7b85023a3b0f (Accessed 18 May 2021).

Russo, E. B. (2011) “Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” British Journal of Pharmacology, Blackwell Publishing Ltd, [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/ (Accessed 11 May 2021).

Russo, E. B. (2019) “The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No ‘Strain,” No Gain,” Frontiers in Plant Science, Frontiers Media S.A., [online] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334252/ (Accessed 11 May 2021).