The entourage illusion?

The "entourage effect" has been a popular theory in cannabis for decades, but some researchers are not convinced

Flat vector icon illustration of cannabis entourage effect

There is a theory in the world of cannabis called the “entourage effect” that says the whole of the plant is greater than the sum of its parts (Weed Between the Lines, “All About Those Terpenes,” May 27, 2021). According to the theory, different cannabinoids and terpenes all have specific qualities, that, when combined, inhibit or activate specific endocannabinoid receptors in our brains producing strain specific effects for users and patients seeking a specific kind of relief. It’s why full spectrum flower highs are more nuanced than the high from straight THC isolates. It’s why different strains can be used to achieve different effects.

As of now, only a few studies exist to support the idea. But scientists are beginning to find contradicting evidence. One company, called Juva Life, even thinks it may have pinpointed the root cause of this supposed effect—which it argues, has nothing to do with cannabinoids or terpenes at all. 

The entourage theory was first espoused in 1998 by Israeli researchers Raphael Mechoulam and Shimon Ben-Shabat, who described it as “whole-plant synergy.” They argued that the body’s endocannabinoid system responds better to whole plant cannabis extracts, and that the effect “may represent a novel route for molecular regulation of endogenous cannabinoid activity.”

That research focused on two esters (chemical compounds derived from acids) known as 2-Lino-Gl and 2-Palm-Gl, neither of which actually bind to cannabinoid receptors in the brain. However, those two esters do affect how strongly a third, 2-Ara-Gl, binds to cannabinoid receptors CB1 and CB2, producing specific effects for specific cannabinoids.  

“Investigations of the effect of the active component in the presence of its ‘entourage’ compounds may lead to observations of effects closer to those in Nature than investigations with the active component only.” The conclusion of that study, published in the European Journal of Pharmacology, reads. 

Which is to say: The medicinal value of cannabis is greater as a full spectrum natural plant or extract than it is as a limited THC isolate. That’s in line with observations from a 2018 study in Biochemical Pharmacology on breast cancer tissue that showed improved outcomes when extracts included minor cannabinoids, compared to pure THC isolate. 

More recent studies disagree, though. A 2020 paper published in Frontiers in Pharmacology, directly contradicts those findings from 1998. The researchers designed their experiment to look more directly at the relationship between terpenes and endocannabinoid “receptor-mediated activity.” They wanted to know if terpenes such as myrcene, α- and β-pinene, β-caryophyllene, and limonene actually affect how the CB1 and CB2 endocannabinoid receptors receive cannabinoids. 

That study asserts that “no data were produced to support the hypothesis that any of the five terpenes tested (either alone or in mixtures) have direct interactions with CB1 or CB2.”

It concludes, “This study adds to the evidence that the putative entourage effect cannot be explained by direct effects at CB1 or CB2.”

So, if it isn’t the combination of terpenes and cannabinoids interacting to affect endo-cannabinoid receptors and creating the unique effects offered by full-spectrum cannabis, what is

The California-based R&D cannabis company Juva Life thinks it might have found the answer. And it’s making moves to capitalize on it. 

“We have now identified two non-cannabinoid compounds that may begin to explain the clinical benefits of cannabis through an anti-inflammatory mode of action,” the company’s founder and CEO, Doug Chloupek, explains. “While the current industry focus centers on cannabinoids, our strategy breaks from this school of thought.” 

Instead, he says, they focused on unappreciated non-cannabinoids with therapeutic potential. Two of which seemed to show a lot of promise.

They named the novel non-cannabinoid compounds JUVA-019 and JUVA-041 (which they also promptly filed patents for). According to Chloupek, those compounds, which are only present in full-spectrum cannabis products, are what’s truly responsible for cannabis’ anti-inflammatory properties—they are the foundation of cannabis’ medicinal value and the root cause of the entourage effect, according to Juva Life. Because, Chloupek explains, JUVA-019 and JUVA-041 inhibit inflammation selectively and with increased potency to provide varying effects. 

“While the clinical utility of cannabis has been ascribed to a small number of cannabinoid compounds, our platform has revealed that non-cannabinoid compounds possess potent anti-inflammatory properties seen in approved biologics,” Chloupek says. 

Chloupek clarifies that he still believes the entourage effect is a real thing—he just thinks it’s misunderstood. Neither he nor his scientists believe that cannabinoids and terpenes are the main factors behind it. And if Juva Life can prove that its proprietary non-cannabinoid compounds are, it could have huge implications for the pharmaceutical industry. Juva Life could essentially bottle the power of cannabis and the entourage effect in tablet form to sell all over the world. 

For now, though, the jury remains out on the entourage effect. While it seems obvious that it is a real phenomenon, the science doesn’t yet agree on the mechanisms behind it or to what extent it makes a difference. And until the federal prohibition of cannabis comes to an end, definitively answering these lingering questions is going to remain a challenge.

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