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Understanding the Entourage Effect
Understanding the controversial theory of how cannabinoids and terpenes commingle to produce effects that are supposedly greater than the proverbial sum of their parts. The term entourage effect, sometimes called "cannabis synergism," describes the synergistic efficacy, or combined effect, of the collection of cannabinoids and terpenes produced by a chemotype (chemovar/cultivar/"strain") of cannabis (from the plant species cannabis sativa).
Technically, this theory remains to be proven by clinical research trials. It states, in simple terms, that the efficacy of a collection of cannabinoids and terpenes is greater than their combined individual influences. The entourage effect embraces the proverb "the whole is greater than the sum of its parts."
The entourage effect is an important theory and biological dynamic because of the simple fact that most consumers ingest (eat) or inhale a complex mix of cannabinoids, terpenes, and flavonoids in broad-spectrum and full-spectrum cannabis and hemp products. Although isolates of a single cannabinoid are available from a variety of companies, this form of consumption is atypical.
While the popular media typically explains cannabinoids and terpenes within the framework of their individual efficacy, this most often has little bearing on the actual health benefits experienced by users in real-world scenarios.
Identified in 1998
Identified and coined in 1998 by Israeli researchers Dr. Raphael Mechoulam (the scientist who isolated tetrahydrocannabinol, or THC, in 1964) and S. Ben-Shabat, the entourage effect theory helps explain many of the nuances and sometimes polarized efficacies of cannabinoids and terpenes in different use case scenarios.
Interestingly, the influence of the entourage effect goes beyond merely which cannabinoids and terpenes are present. In addition, the exact ratios of these molecules determine the precise manner in which they buffer and boost one another. Thus, a 20:1 cannabidiol (CBD) to THC product will deliver a different effect than 3:1 or 1:1 formulations.
Examples of the Entourage Effect
Understanding the Entourage Effect. Examples of the entourage effect include the supposed ability of CBD to curb the negative effects of THC, especially when consumed in potent doses and by inexperienced users. Some researchers believe that CBD is involved in a mechanism in which THC molecules are blocked from binding with CB1 cellular receptors in the brain and central nervous system.
Another example of the entourage effect is the influence of the terpene pinene, which is produced by many plants other than cannabis, including basil, conifer trees, dill, orange peels, and rosemary.
In his 2011 research study entitled "Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects," Dr. Ethan Russo cites research that suggests that a-pinene might help decrease the short-term memory impairment sometimes caused by THC (especially when THC is consumed at high doses).
Russo, an ECS and cannabinoid research pioneer and neurologist who is director of research and development for the International Cannabis and Cannabinoid Institute, believes that a-pinene accomplishes this by preserving the molecule acetylcholine, which is involved in the formation of memories. "[A] main side effect of THC is short-term memory impairment. People [say], 'Uh…what were you saying?' That can be prevented if there's pinene in the cannabis," Russo told Scientific American magazine during a 2017 interview.
Understanding the Entourage Effect. According to the entourage effect theory, the exact mix and specific ratios of cannabinoids and terpenes in a product has significant influence on its efficacy for a disease or condition. Likewise, the consumption avenue employed greatly influences various aspects of efficacy and bioavailability, including onset, peak, and duration.
When the cannabinoid THC is eaten instead of inhaled (smoked or vaporized), it is several times more potent. According to Dr. Jeff Raber, a chemist specializing in cannabinoids and terpenes and CEO of the Werc Shop in Southern California, ingested THC (which is metabolized by the liver) "has five times the activity at the CB1 receptor…as THC itself."
Entourage Effect Research
Understanding the Entourage Effect. The promise and power of a potential entourage effect lies in the ability to formulate cannabis-based products that target specific diseases and
conditions based on the combined synergistic efficacy of the cannabinoids and terpenes present.
As more is learned about the individual cannabinoids and terpenes and their nuanced interaction, researchers—and the companies producing cannabis and hemp products—will gain insight into how to produce more effective formulations for general wellness and specific diseases and conditions (such as seizure disorders or the neurological degradation associated with dementia such as Alzheimer's disease).
A 2021 study entitled "Cannabis Sativa Terpenes are Cannabimimetic and Selectively Enhance Cannabinoid Activity" that was published by the journal Scientific Reports investigated the relationship between cannabinoids, terpenes, and the human endocannabinoid system.
Noted the study's authors, "Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic and could produce an 'entourage effect' whereby they modulate cannabinoids to result in improved outcomes." The researchers noted that the entourage effect "hypothesis is controversial, with limited evidence."
"Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis."
Concluded the study, "Our findings suggest that cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids."
Understanding the Entourage Effect: 2019 Study
A 2019 study conducted by Russo investigated the role of cannabis chemovars, more commonly called "strains" or "cultivars," in the entourage effect and overall efficacy experienced.
The study conducted a meta-analysis of 11 other studies that involved 670 patients. "Those results showed that 71% of patients improved with CBD-predominant cannabis extracts vs. 36% on purified CBD," indicating that the cannabinoids (or other molecules, such as terpenes and flavonoids) may have resulted in the increase in patient improvement.
The Russo study also supported the concept of microdosing, in which users consume relatively small doses of a cannabis product (or individual cannabinoids in an isolate) throughout the day to maintain minimal, but effective, blood levels.
Reported the study, "The mean daily doses were markedly divergent in the groups: 27.1 mg/kg/day for purified CBD vs. only 6.1 mg/kg/day for CBD-rich extracts (a dose only 22.5% of that for CBD alone)." These observations also support the need for consumers and wellness professionals to be especially diligent in terms of determining dosing and the need for "recalibrating" dosing with a planned frequency to compensate or changes in physiology or environment.
The study found that a mix of THC and CBD, as found in full-spectrum cannabis products, was helpful for a variety of diseases and conditions, including mood disorders such as depression and anxiety and common symptoms of thousands of diseases, such as pain and systemic inflammation.
"A mix of THC and CBD, as found in full-spectrum cannabis products, was helpful for a variety of diseases and conditions."
Reported the study, "[a] THC:CBD ratio of 1:39.4...portends to be applicable to treatment of numerous clinical conditions, including pain, inflammation, fibrotic disorders, addiction, anxiety, depression, autoimmune diseases, dermatological conditions, and cancer."
The researchers concluded, "These studies and others provide a firm foundation for cannabis synergy, and support for botanical drug development vs. that of single components."
Understanding the Entourage Effect: 2018 Study
A 2018 study entitled "Appraising the 'Entourage Effect': Antitumor Action of a Pure Cannabinoid Versus a Botanical Drug Preparation in Preclinical Models of Breast Cancer" that was published in the journal Biochemical Pharmacology investigated “the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP)." The investigators chose breast cancer due to the fact that it is the leading cause of death among women.
Concluded the study's researchers, "Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer."
Understanding the Entourage Effect: 2011 Study
Russo's 2011 study, "Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects," that was published in the British Journal of Pharmacology, suggested that several cannabinoids act synergistically with one another to produce beneficial health results. Wrote Russo in the study’s abstract, "the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated."
"Simple combinations of phytocannabinoids and terpenoids may demonstrate synergy as antibiotics."
The study posited the query, "Might it rather display herbal synergy encompassing potentiation of activity by active or inactive components, antagonism (evidenced by the ability of CBD to reduce side effects of THC), summation, pharmacokinetic, and metabolic interactions?"
The study observed, "Simple combinations of phytocannabinoids and terpenoids may demonstrate synergy as antibiotics." The research also suggested that the breeding of "high-terpenoid- and high-phytocannabinoid-specific chemotypes has thus become a rational target that may lead to novel approaches to such disorders as treatment-resistant depression, anxiety, drug dependency, dementia and a panoply of dermatological disorders."
Concluded the study, "A better future via cannabis phytochemistry may be an achievable goal through further research of the entourage effect in this versatile plant that may help it fulfill its promise as a pharmacological treasure trove."
Understanding the Entourage Effect: 1998 Study
A 1998 study entitled "An Entourage Effect: Inactive Endogenous Fatty Acid Glycerol Esters Enhance 2-arachidonoyl-glycerol Cannabinoid Activity" that was published in the European Journal of Pharmacology that was conducted by Raphael Mechoulam's research team at Hebrew University in Israel first coined the term "entourage effect" in the original suggestion of this theory.
"The endocannabinoid 2-AG interacts with both CB1 (located mostly in the brain and central nervous system) and CB2 receptors."
This pinnacle study revealed that the endocannabinoid 2-AG interacts with both CB1 (located mostly in the brain and central nervous system) and CB2 receptors (in the tissues and organs of the immune system) of the ECS.
The study's authors concluded, "These data indicate that the biological activity of 2-Ara-Gl can be increased by related, endogenous 2-acyl-glycerols, which alone show no significant activity in any of the tests employed. This effect ('entourage effect') may represent a novel route for molecular regulation of endogenous cannabinoid activity."
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