The Entourage Effect

Overview

  • The “entourage effect” is a phenomenon where several different compounds work together to produce an outcome that would not be possible on their own
  • The entourage effect may exist in naturally sourced psychedelics such as magic mushrooms due to the synergistic activity of multiple compounds in the botanical ingredient or extract
  • Although popularized in cannabis, a 2020 review of the cannabis literature questioned the validity of the term
  • No review of psychedelics has been conducted and preliminary research shows an entourage effect may be present in magic mushrooms
  • More research is needed to definitively state whether an entourage effect in psychedelics will improve their therapeutic value, although it is clear sub metabolites have the ability to alter experiences

 

Background

Originally coined in 1999 by Raphael Mechoulam (1), the theory of the “entourage effect” describes the complementary effects of multiple compounds outside of the primary active molecule. While Raphael and his chemist colleagues were working with cannabis, they discovered that two compounds, previously thought to serve no purpose, facilitated the binding of the 2-AG molecule with two other cannabinoid receptors. They had uncovered that when two compounds are in relation to one another, one can become more pronounced, while the effect of the other can diminish or even become inactive. Importantly, human receptor sites are not universally identical, therefore it is possible that a combination of natural compounds could have greater efficacy, fewer side effects, and potentially, a shorter onset period compared to a synthetic isolate preparation.

The entourage effect has historically been associated with cannabis, positing that the multiple compounds present in cannabis could produce a cooperative effect, leading to therapeutic potential. The idea has been described as “the sum of all parts that leads to the magic or power of cannabis” (2). For example, the psychoactive component of cannabis, THC, has been found to cause anxiety and paranoia when ingested alone and these unwanted side effects can be diminished with the addition of CBD (3). It is now believed that the concept may apply to naturally sourced psychedelics as well. Typically it has been thought that the psychoactive and therapeutic qualities associated with magic mushrooms are due to psilocybin, however this ignores the potential synergistic effects of other known and unknown metabolites within the mushroom.

 

Psilocybin is made up of many of sub metabolites, many of which could potentially contribute to the therapeutic potential of the compound

 

“When multiple … terpenes act synergistically, it may enhance the therapeutic benefits in the body” (4)

Across the range of plant and fungi species, we have yet to understand the full potential of these secondary compounds within each botanical specimen. They must be studied further as a more thorough understanding could lead to improved therapeutic efficacy.

 

Criticism

A 2020 review of research found no evidence of the entourage effect in most cannabis studies, while other reports claimed mixed results, including the possibility of increased adverse effects (5).

Conclusions from the review include:

  • Literature on the entourage effect is unjustifiably optimistic regardings its benefits and this frequently leads to unfounded marketing claims
  • There is a lack of compelling clinical data
  • The polypharmacy of cannabis may actually be a detriment to the therapeutic effect

 

It is important to note that this review was looking at the potential for the entourage effect specifically in cannabis and that these findings do not include psychedelics. The review primarily stated that the term has been overly-optimistic from a marketing standpoint and that further research was needed. Additionally, previous reviews have presented contrary conclusions, positing that the entourage effect in cannabis serves to reduce anxiety, inflammation and cancer (3).

 

 

The Entourage Effect and Psychedelics

There is evidence that the entourage effect may be present in psychedelics. While psilocybin is often the most abundant psychoactive compound found in magic mushrooms, it is only one of many active components, such as psilocin and baeocystin, which may work synergistically (6).

For example, it has been found that a sub metabolite in magic mushrooms, Aeruginascin, can modify the pharmacological effect of psilocybin, inducing a greater likelihood for a euphoric feeling during an experience (7). One psychedelic start-up suggests that inclusion of this compound in a therapeutic psychedelic mushroom product could eliminate the potential for “bad trips”. Matsushima et al (2009) found that, when compared to pure psilocybin, a psilocybin-containing multiple compound molecule led to reductions in anxiety and obsessive compulsive disorder behaviours in mice (8). Mushroom extracts have been found to be ten times more potent in serotonin behaviour assays than pure psilocybin alone, demonstrating the strong synergistic effect of a multiple compound molecule (9). Although the mechanisms are yet to be fully understood, it is clear from this research that the sub metabolites within mushrooms have the potential to augment the experience and potentially influence the therapeutic effect.

 

The Entourage Effect and Natural Compounds

When mushrooms are grown and extracted naturally, the sub metabolites stay within the extract, unlike synthetic versions which are purely psilocybin. However, typical magic mushrooms contain only 0.2-1.8 % psilocybin by dry weight, meaning many other compounds exist in the biomass (10). For example, another tryptamine compound found in magic mushrooms, Baeocystin, has been shown to induce a gentle hallucinogenic effect. Additionally, beta-carbolines have been recently discovered in magic mushrooms and these compounds are potent inhibitors of the enzyme that breaks down psilocin inside the body (11). This augmentation could lead to an increased intensity and duration of a psychedelic experience.

These additional sub metabolites in the magic mushroom molecules serve to augment the psychedelic experience and quite possibly the therapeutic potential as well. This is noteworthy as many psychedelic companies are creating synthetic variants that are purely psilocybin, thus potentially limiting the full potential of the natural product.

To date, most studies have used pure psilocybin rather than extracts from the full magic mushrooms. Additionally, most psychedelic companies are creating synthetic versions of pure psilocybin for eventual medical and recreational use. This is due to the fact that a majority of the companies in the psychedelic space lack the infrastructure and expertise to extract from magic mushrooms in a cost effective, stable, and safe manner and so rely on synthetic versions. Additionally, in a medical psychedelic model that relies on patenting products, single-compound molecules could be perceived to be more convenient and profitable for pharmaceutical companies. However, due to only consisting of a single compound, this creates the possibility that any additional therapeutic potential through the entourage effect is failing to be captured in these studies and products.

 

Filament Health View

At Filament Health, we are enthusiastic about the potential of the entourage effect and verifying its existence through our natural extraction efforts. There are hundreds of potentially beneficial compounds that are currently unexplored due to the industry’s focus on synthetic psychedelics. While we have no guarantees that we will prove the entourage effect, we strongly believe that natural extracts provide the best avenue to progress our understanding in this area.

“We have barely scratched the surface of understanding the potential, perhaps necessary potential, of these secondary compounds. I wholeheartedly believe they must be studied further rather than disregarded out of hand”.

Ben Lightburn, CEO of Filament Health

 

Conclusion

Numerous studies have indicated the entourage effect takes place with cannabis and other natural products. Although more research is needed, the effect may present improved therapeutic potential for multi-compound natural products versus single compound molecules. Moving forward, natural-focused companies in the psychedelic industry, like Filament Health, will look to uncover additional benefits from the entourage effect and multi-compound molecules in psychedelic medicines. Identifying and utilizing improvements over current treatments will be imperative in addressing the current mental health crisis.

 

References

  1. Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, et al. (July 1998). “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity”. European Journal of Pharmacology. 353 (1): 23–31. doi:10.1016/s0014-2999(98)00392-6. PMID 9721036.
  2. Chen A (20 April 2017). “Some of the Parts: Is Marijuana’s “Entourage Effect” Scientifically Valid?”. Scientific American. Retrieved 2017-12-31.
  3. Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology, 163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
  4. Honest Hemp. (2022). What is Cannabidiol (CBD)?. Honest Hemp. https://honesthemp.co.uk/pages/what-is-cbd
  5. Cogan PS (August 2020). “The ‘entourage effect’ or ‘hodge-podge hashish’: the questionable rebranding, marketing, and expectations of cannabis polypharmacy”. Expert Review of Clinical Pharmacology. 13 (8): 835–845. doi:10.1080/17512433.2020.1721281. PMID 32116073. S2CID 211726166.
  6. Gartz J. Extraction and analysis of indole derivatives from fungal biomass. Journal of Basic Microbiology. 1994;34(1):17-22. doi:10.1002/jobm.3620340104
  7. Gartz J. Analysis of aeruginascin in fruit bodies of the mushroom Inocybe aeruginascens. International Journal of Crude Drug Research. 1989;27(3):141-144. doi:10.3109/13880208909053954
  8. Matsushima Y, Shirota O, Kikura-Hanajiri R, Goda Y, Eguchi F. Effects of Psilocybe argentipes on Marble-Burying Behavior in Mice. Bioscience, Biotechnology, and Biochemistry. 2009;73(8):1866-1868. doi:10.1271/bbb.90095
  9. Zhuk O, Jasicka-Misiak I, Poliwoda A, et al. Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice. Toxins. 2015;7(4):1018-1029. doi:10.3390/toxins7041018
  10. Why the Entourage Effect Matters (July 23, 2020). Wholecelium. https://www.wholecelium.com/articles/psychedelic-studies/why-the-entourage-effect-matters/
  11. Bauer, B. (March 15, 2019). The Entourage Effect in Magic Mushrooms. Psychedelic Science Review. https://psychedelicreview.com/the-entourage-effect-in-magic-mushrooms/