Cannabis And The Entourage Effect – Truth Beyond The Hype

whole plant cannabis oil in capsule

Whole plant cannabis is better for us, right? The entourage effect tells us so. But how much do we really know about the mysterious synergy in the cannabis plant and does science back up the marketing bravado?

Talk to anyone about medical cannabis and before long you’ll almost certainly find yourself landing on the subject of the entourage effect. It’s a term that’s become embedded in everyday cannabis parlance, and is increasingly treated like scientific fact.

But dig a little deeper and scientific evidence is rather scant. This shouldn’t come as any surprise when one considers how science favors the study of single molecules over the botanical chaos of the cannabis plant.

However, the direct experience of millions of medical cannabis users worldwide suggests that extracts made from the whole cannabis plant deliver superior results when compared with single cannabinoid preparations. This is backed up by patients 1 who have used the synthetic THC drugs Marinol and Nabilone, where many discontinued their use due to the intolerable psychoactive effects and dosing difficulties.

Origin of the Entourage Effect

It might come as a surprise to many to learn that the term entourage effect was originally used to describe a synergy between different elements in the endocannabinoid system – the body’s complex network of receptor sites and neurotransmitters thought to bring homeostasis to the body – and not compounds in the cannabis plant.

Back in 1998, Israeli cannabinoid research pioneer Professor Raphael Mechoulam 2 and his team noticed an interaction between the endogenous cannabinoid 2-AG (a type of cannabis-like chemical made by the body) and two similar molecules, 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2-Palm-Gl)). Alone these non-endocannabinoid esters showed no significant activity, but when teamed with 2-AG, they seemed to potentiate its effect on the body.

Mechoulam summarised: “This effect (‘entourage effect’) may represent a novel route for molecular regulation of endogenous cannabinoid activity.” And with this, the entourage effect phenomena was born.

Entourage Effect Extends to Cannabis

While we now know there to be a direct link between the endocannabinoid system and compounds like THC and CBD in the cannabis plant, at this stage there was no suggestion that the cooperation between endogenous chemicals in the body might be extended to cannabis.

Step in Dr. Ethan Russo and his seminal paper 3, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.” He proposes a unique “herbal synergy” between the lesser studied but potentially biologically active compounds in the cannabis plant, similar to that found in the endocannabinoid system.

Considering the complex and sometimes contradictory nature of the cannabis plant, with its heady mix of over 160 cannabinoids (including 21 newly discovered 4), approximately 200 terpenes (the smelly bits found in all plants), a bunch of flavonoids, and potentially a host of other molecules yet to be discovered, it’s clear the purported health benefits of cannabis do not fit into the single molecule paradigm so painstakingly crafted by the pharmaceutical industry.

And yet, most scientific research into cannabis has indeed followed the pharmaceutical model, using purified versions of THC (Tetrahydrocannabinol) and CBD (Cannabidiol).

cannabis plants growing in field

However, this is not necessarily some big pharma plot to stymie the therapeutic advancement of whole plant cannabis. As Spanish cannabinoid Scientist, Cristina Sanchez, explains in this video, biochemists must study cannabinoids in their purified form in order to understand how they work. She explains how assigning the effects of single compounds would not be possible using whole plant extracts.

Not only that, funding for research into the cannabis plant is notoriously difficult, much in part due to its Schedule 1 status, as well as the lack of any financial incentive for pharmaceutical companies to fund investigations into impossible-to-patent, botanical medicine.

What remains clear is that from the experiences of patients who regularly use whole plant cannabis-based medicines, much remains to be learned about the lesser known cannabinoids, terpenes, and other compounds, and how they interact both individually and collectively, with the human body.

THC and CBD – Better Together

The scientific community are generally a cautious lot, and while apart from Ethan Russo, you’ll be hard pressed to find many willing to publicly proclaim that the entourage effect exists, most will admit that there is some special relationship between the cannabis plant’s two most abundant cannabinoids, THC and CBD.

In a recent article published by Fundación Canna 5, Professor of Biochemistry and Molecular biology Manuel Guzman at the Madrid Complutense University, highlights how thanks to CBD’s dampening of the psychoactive effect, the therapeutic window of THC can be extended, even going so far as to call a THC:CBD combination a “therapeutically improved version of THC”. However, for him, this is no proof of any mysterious synergy within the plant. He goes on, “I believe that it is still not possible to firmly support the existence of an “entourage effect” in cannabis beyond this possible complementary action between THC and CBD, its two main cannabinoids.”

That said, the first ever approved cannabis-based pharmaceutical drug, Sativex prescribed for the spasticity and pain associated with Multiple Sclerosis, is indeed a 1:1 THC and CBD ratio. A combination of THC and CBD was also used in a groundbreaking study 6 funded by GW Pharma examining the compounds use alongside conventional chemotherapy for patients with Glioblastoma multiforme, an aggressive and extremely difficult to treat type of brain tumor. Not only did a THC:CBD:chemo combo show greater antitumoral effects compared to chemo alone, but a formulation containing more CBD than THC improved patient outcomes most of all.

Breakthrough Study Comes Closer to Shedding Light on the Entourage Effect

‘Cannabis and cancer’ is one of the most exciting areas of cannabinoid research; with THC, CBD, and other lesser-known cannabinoids showing promising antitumoral effects. It’s right and fitting then that a study 7 into cannabis and cancer should come closest to proving the entourage effect. Headed by Professor Cristina Sanchez, again from the Complutense University in Spain, this pioneering investigation set out to compare the antitumoral effects of purified THC and a whole plant cannabis extract in breast cancer cells.

The researchers made sure the whole plant cannabis extract contained the same amount of THC as the purified version, suggesting that any differences in antitumoral action must, therefore, stem from other non-THC compounds.

It’s important to also highlight that the research was only conducted on cell cultures and animal models, and any results cannot be assumed to be the same in humans. That said, what they discovered was the closest any research has come to proving the entourage effect exists.

In all three types of breast cancer, the whole plant extract outperformed the purified THC in terms of reducing tumor growth and limiting the spread of cancer cells. In the in-vitro tests (cell cultures), the team also found the whole plant extract potentiated the antitumoral effects of conventional chemotherapy treatment, although when extended to animal models there was no change in the results.

This left the scientists with the question: what other than THC is killing the cancer cells? As is often the case in scientific research, the best way to start is by ruling out likely suspects. So, the team made a terpene cocktail that reflected the combination found in the whole plant extract and added it to the purified THC. However, in what may be disappointing news to terpene fans out there, this addition did not change the antitumoral effect of THC, thus ruling out terpenes as the likely magic molecules.

They also discovered that the whole plant cannabis extract’s antitumoral effects were due to a completely different mechanism of action. THC reduces cancerous growths by activating the CB2 receptor and provoking reactive oxygen species (ROS), cell damage caused by free radicals. But when Sanchez and her team blocked the CB2 receptor and added a powerful antioxidant to counteract the ROS, the whole plant extract continued to show anti-cancer effects.

That’s not to say that Sanchez et al know just which other compounds in the cannabis extract are responsible for reducing tumors, if it’s due to the entourage effect, or indeed whether the findings would be the same in humans. Let’s hope there’s a follow-up study that goes on to answer these questions.

It seems to me we’ll never know for sure whether the entourage effect actually exists, especially when we still have so little information about the vast majority of compounds in the cannabis plant.

So is the entourage effect anything more than marketing hype? I would say, almost certainly, maybe. Will I be using the term with more caution in the future? Most definitely, yes.


References:

3.
Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology. 2011;163(7):1344-1364. doi:10.1111/j.1476-5381.2011.01238.x
4.
Mudge EM, Murch SJ, Brown PN. Chemometric Analysis of Cannabinoids: Chemotaxonomy and Domestication Syndrome. S. 2018;8(1). doi:10.1038/s41598-018-31120-2
5.
Guzmán M. Cannabis vs. THC: Are they really so different? Fundación CANNA. https://www.fundacion-canna.es/en/cannabis-vs-thc-are-they-really-so-different. Published November 9, 2018. Accessed December 1, 2018.
6.
López-Valero I, Saiz-Ladera C, Torres S, et al. Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide. B. 2018;157:266-274. doi:10.1016/j.bcp.2018.09.007
7.
Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, et al. Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. B. 2018;157:285-293. doi:10.1016/j.bcp.2018.06.025
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