Expanding The Entourage Effect: Examining The Role Of Alcohol Esters In Cannabis Sativa

By T.J. Schultz (Mr. GreenBlood) Head Breeder Green Blood Genetics & Gaurav Dubey (MS Biotechnology).

Thanks to the expanding research into Cannabis over the past 20 years, we’ve discovered a vast array of cannabinoids, beyond just THC, that have both recreational and therapeutic effects in humans. Ultimately, it was found that humans have an actual endocannabinoid system to process the phytocannabinoids from Cannabis, as well as the body’s own endogenous cannabinoids.

Furthermore, the various active and inactive components in Cannabis display a complex symphonic phenomenon dubbed the “Entourage Effect,” where the interplay between all these compounds, from cannabinoids and terpenoids, to flavanoids and alcohol esters, work together in pharmacological harmony to exert each strain’s unique effects. This guide will specifically explore the unique role of alcohol esters in Cannabis Sativa, their role in crafting the seemingly endless odors and tastes of different Cannabis cultivars, and their prospective pharmacological role in how they potentially modulate the Entourage Effect.

What Is the Entourage Effect?

The term “Entourage Effect” was coined by Mechoulam, Shabat and colleagues in 1998, in a paper titled, “An Entourage Effect: Inactive Endogenous Fatty Acid Glycerol Esters Enhance 2-arachidonoyl-glycerol Cannabinoid Activity.” The study discusses the increased activity of a given cannabinoid due to its interaction with other compounds that are present (in this case, esters of a fatty acid).1

See also: Viruses Aren't Going Anywhere, But Neither Is Medical Marijuana

Over time, this term has been used to describe the ensemble-like effect between cannabinoids, terpenoids, flavonoids, ketones, esters and other compounds of the Cannabis plant, and how their combined interaction produces unique effects—usually superior to any single cannabinoid administration alone. Fascinatingly enough, the alcohol esters themselves show no pharmacological activity at cannabinoid receptors, and are considered inactive. However, their presence has been shown to boost the efficacy of other cannabinoids, such as 2-AG, in the above study. Of further interest is the fact that the alcohol esters in cannabis mask and modulate certain terpene profiles, resulting in unexpected readouts.

This guide will explore the special role of esters in Cannabis and draw upon the discoveries of Mechoulam to extrapolate their therapeutic significance. 

Using Esters to Break Free of The Old “Indica vs. Sativa” Paradigm

Seeing as how certain terpenes, such as linalool, are being shown to be as powerful as some Schedule II drugs,3 and combining that knowledge with the known benefits that cannabinoids, such as CBD, possess,4 we can now finally add the emerging research of plant alcohol esters to the equation. It is this scientist’s belief that the countless different combinations of these three categories of compounds largely produce the desired effect which both medical and recreational users are seeking from Cannabis. Unfortunately, the complexity that results in how a certain strain of Cannabis affects the user has been greatly simplified, generally by way of two categories: Indica and Sativa.

As recreational Cannabis has become more prevalent across the country, this old paradigm haunts dispensaries and discourse. Indica strains are generally associated with more “depressive” effects, such as couch-lock, sleepiness, and bodily relief, whereas Sativa strains are given “energizing” qualities, like suddenly wanting to clean your house or go outside. However, these qualities aren’t solely limited to the minor genetic variation between Cannabis Sativa and Cannabis Indica; rather, this research aims to dispel this myth by fully understanding the role of these many compounds, including esters, that influence the complexities of Cannabis expression. And further, what role these compounds play in the Entourage Effect, and how a better understanding may yield more efficacious strains, targeting certain medical conditions or desired effects.

Why Does it Smell like Skunk, Despite Entirely Different Terpene Profiles?

As it stands, current scientific research is only beginning to understand how cannabinoid pharmacology and genetics contribute to its effects. One question that has been posed—why do certain cultivars smell similar to known smells, yet have none of, or only small amounts of the same terpenes (the active chemical compound responsible for specific smells and physiologic effects)? For example, Kevin Jodrey of Wonderland Farms pondered, “why do the old school Skunk strains, that smell identical to a skunk’s biodefense odor, have a completely different terpene profile when compared to a skunk’s natural smell?”

The answer is plant alcohol esters: “Volatile esters are produced by virtually all soft fruit species during ripening. They play a dual role in the ripe fruit, serving both as ‘biological bribes’ for the attraction of animals and as protectants against pathogens. In some fruits, like apples (Malus domestica), pears (Pyrus communis), and bananas (Musa sapientum), esters are the major components in their characteristic aroma. In other fruits, like strawberry (Fragaria × ananassa), they contribute as notes to the blend of volatiles that constitute the aroma.”2

Given the primal connection between our brainstem and nose, a necessary link to help us track down and discriminate in food choices, it would make sense that plants would produce smells to draw in animals, who could then help disseminate the seeds held within a fruiting body. Due to their very light chemical bonding, esters are extremely volatile, and easily fill the air with their aroma. These esters can act as catalysts that convert or flavor terpenes, hence the resulting similarities, and ever so slight differences, in the smell between a flowering Cannabis plant, burning Cannabis flower, and a skunk’s defense odor. 

An Unfortunate Happenstance: The Lost Genetics of Dank

Many of the Old School strains were so stinky that growers, for fear of getting caught in less forgiving times, stopped cultivating these strains. Many of these “dank” strains, due to their overbearing and obvious odors, have unfortunately been lost—their genetics, which are more monoterpene-derived, more volatile and aromatic, have been subdued, mixed, and weakened.

See also: Cannabis Strain Names Are Meaningless: What Is The Industry Doing About It?

Lacking these esters, it’s becoming more difficult to reproduce older, “louder” varieties of Cannabis. Some companies, however, are trying to find the way back to these strains, with esters and terpenes that are more focused and potent. It is believed that, with a better understanding of these complexities and how they influence the Entourage Effect, terpenes and esters might play a far more vital role than solely THC content or whether the plant is C. Indica or C. Sativa.

Green Blood Genetics: A Midwest Craft Cannabis Brand Doing Things Differently

One craft cannabis brand out of the Midwest—Green Blood Genetics (GBG)—is doing things differently by taking a closer look at the role of esters in Cannabis.

By hunting down the right genetics and undertaking comprehensive cultivation measures, GBG strives to curate optimal Cannabis products to meet the needs and preferences of recreational connoisseurs and medical patients alike. GBG Founder T. J. Schultz says, “Here at GBG, we are combining genetics of the past with present technology to create the ultimate in cannabis products of the future.” As the complexities of Cannabis and our own endocannabinoid system become better understood, growers will hopefully begin to focus more on the lesser known compounds, like esters, to bring back traits that were lost, but not forgotten.

Works Cited

1.         S, B.-S. et al. An Entourage Effect: Inactive Endogenous Fatty Acid Glycerol Esters Enhance 2-arachidonoyl-glycerol Cannabinoid Activity. European journal of pharmacology vol. 353 https://pubmed.ncbi.nlm.nih.gov/9721036/ (1998).

2.         Beekwilder, J. et al. Functional Characterization of Enzymes Forming Volatile Esters from Strawberry and Banana. Plant Physiol. 135, 1865–1878 (2004).

3.         Peana, A. T. et al. (-)-Linalool produces antinociception in two experimental models of pain. Eur. J. Pharmacol. 460, 37–41 (2003).

4.         Commissioner, O. of the. FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms (2020).

5.         Laverty, K. U. et al. A physical and genetic map of Cannabis sativa identifies extensive rearrangements at the THC/CBD acid synthase loci. Genome Res. 29, 146–156 (2019).

Lead image by Ilona Szentivanyi. Copyright: Benzinga.

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