OPINION: 1+1=3? Does the entourage effect theory hold water?

A new study out of Australia investigating the entourage effect theory concludes that terpenes most commonly found in the cannabis plant did not change the effect that THC produces at cannabinoid CB1 and CB2 receptors.

What do the study findings say about the entourage effect, and is it time to shift long-held perceptions?

What is the entourage effect?

The entourage effect is a theory suggesting a mutual synergy of the components of the cannabis plant. First coined by cannabinoid researcher Dr. Ian Russo almost 10 years ago, the theory states that cannabinoids and terpenes found in the cannabis plant work together to produce an effect markedly different from that of pure THC. This is how whole-plant medicine is different from pharmaceutical THC.

The synergy implies that use of the whole plant may exert greater effects than the sum of its parts: 1+1=3. Given how widespread the theory has become, it is somewhat surprising that so little related scientific data exists.

How is cannabis knowledge evolving?

As such, credible research is welcome. With cannabis legalization, though consumer knowledge and understanding of cannabis is expanding, the hope is this growth develops along positive lines. Ideally, this knowledge should be guided by the scientific discoveries about the plant and its interaction with the human body.

Tourist Laura Torgerson, visiting from Arizona, smells cannabis buds at the Green Pearl Organics dispensary on the first day of legal recreational marijuana sales in California, January, 1, 2018 in Desert Hot Springs, California.

Fifty years ago, the general view of cannabis was decidedly less expansive: cannabis was cannabis. No matter how it looked, smelled or made a person feel, most users got some from a friend of a friend and smoked it. At the time not so long ago, the since-rebutted theory of different effects of indica and sativa variants became prominent.

Now, the experienced user and the novice alike are getting to learn about the entourage effect and terpenes—chemicals that, unlike cannabinoids, are also found in many other plants. It is terpenes that contribute to cannabis’ distinct smell, colour and taste. Whether appearing as green, orange or purple and smelling skunky, nutty of lemony, take terpenes away—as happens when cannabis oil is extracted and distilled—and all that distinctiveness is gone.

What is the verdict on entourage effect?

If thinking around the entourage effect was correct, adding terpenes would modify the way THC works at its main action site: the cannabinoid receptors. The aforementioned study from Cannabinoid Therapeutics Lambert Institute in Australia, however, established that six terpenes most common in cannabis—α-pinene, β-pinene, β-caryophyllene, linalool, limonene and β myrcene—made no difference in the effect of THC at the level of cannabinoid receptors researchers know the most about: CB1 and CB2 receptors.

While the findings are somewhat surprising, they do not refute the entourage effect theory. Rather, results point to other under-researched mechanisms of potential interaction.

The synergy may be occurring at a different place. While the most is known about CB1 and CB2 receptors, they are not the only targets where THC and CBD exert their effects.

Another possibility is that minor cannabinoids—while dominant, THC and CBD are but two of the 100-plus cannabinoids—are at the core of the entourage effect. Or maybe 1+1=2 after all, that is, if terpenes act at different molecular targets altogether and produce additive, rather than synergistic, action with cannabinoids. And, if this wasn’t confusing enough, there are also flavonoids—another type of compounds occurring in cannabis and various other plants that may enter the entourage mix, too.

What’s the deal with cannabinoid-terpenoid interactions?

The entourage effect theory covers the potential for both cannabinoid-cannabinoid and cannabinoid-terpenoid interactions. Interaction at the level of THC and CBD—with the latter amplifying desired effects (studies show increased pain relief in animal models) while buffering unwanted effects (decreasing the THC-induced high and anxiety in humans) of the former—is part of the entourage effect and may be why many medical and recreational users are seeking THC/CBD balanced strains.

Scientific evidence for cannabinoid-terpenoid interactions is virtually non-existent, the Australian study states, and is mostly based on extrapolation of pharmaceutical and therapeutic properties of terpenes. For example, the review notes that in studies with laboratory animals, limonene displayed anxiolytic effects, pinene increased gastrointestinal motility, linalool was sedative, anticonvulsant and anxiolytic, and myrcene produced sedation, analgesia and muscle relaxant effects.

Considering the significant interest and general lack of data about terpenes and the entourage effect in general, National Institutes of Health in the U.S. will grant research looking into pain-suppressing properties of minor cannabinoids and terpenes.

The world is slowly opening its arms to cannabis, accelerating the rate of research progress that one day will allow everyone to better understand and harness the full potential of the cannabis plant.

 

Olga Chernoloz, PhD is a specialist in neuropsychopharmacology and founder of Omnica Biotech, which supports the advancement of knowledge in cannabinoid space through an evidence-based approach.