Catching Up With the Psychedelic Entourage Effect-Part 1: How We Got Here

The entourage effect caught PSR’s eye back in early 2019. What are experts saying about the theory now and how are psychedelic research companies approaching it?

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In early 2019, Psychedelic Science Review published an article titled “The Entourage Effect in Magic Mushrooms.” The article summarized three scholarly papers which brought together the first clues that the entourage effect could play a role in the effects of psychedelic mushrooms. One of the studies was conducted decades ago by the famous mushroom researcher Jochen Gartz.1 He hinted at the entourage effect in his data analysis from reports on accidental mushroom ingestion. Some of the mushrooms contained the compound aeruginascin, while others did not. Gartz observed that,

Aeruginascin seems to modify the pharmacological action of psilocybin to give an always euphoric mood during the ingestion of mushrooms.

Further investigation by researchers has yielded additional evidence suggesting there may be a synergistic relationship between the compounds in magic mushrooms and other organisms.

Finding More Active Compounds

In 1968, researchers Albert Leung and AG Paul isolated the compounds baeocystin and norbaeocystin from the magic mushroom Psilocybe baeocystis.2 Since then, scientists have discovered other active compounds in magic mushrooms beside the more familiar psilocybin and its active metabolite psilocin. For example, in 2017, Claudius Lenz et al. first identified the compound norpsilocin in Psilocybe cubensis.3 A study by Sherwood et al. in 2020 found that norpsilocin was not only active at the serotonin 5-HT2A receptor but was more potent than psilocin using a calcium flux assay.4

In November 2019, Blei et al. reported that they had discovered compounds called ß-carbolines in four Psilocybe species.5 ß-carbolines are naturally occurring alkaloids more commonly known for their presence in the psychotropic beverage ayahuasca. Several ß-carbolines inhibit monoamine oxidase enzymes (MAOs). Without co-administering ß-carbolines, MAOs would break down the DMT (dimethyltryptamine) in the ayahuasca too rapidly for it to produce significant biological effects for the user. Blei et al. summarized the case for ß-carbolines participating in an analogous entourage effect in magic mushrooms, explaining,

We conclude that Psilocybe mushrooms produce an ayahuasca-like and potentially similarly synergistic set of metabolites that may impact upon onset and duration of their effects.

What the Mushroom Experts Are Saying

In a recent interview, psychedelic mushroom expert Paul Stamets told Joe Rogan that the “wave of the future” is making standardized formulations that include multiple psilocybin analogs, not just psilocybin. This is because combining multiple psilocybin analogs provides what Stamets calls “an entourage or symphony effect” that is not present with single active ingredients.

In April 2020, the iconic researcher, documentarian, writer, and psychonaut Hamilton Morris commented to Psychedelic Science Review in an email about the entourage effect in toad secretions. Specifically, we asked him about differences in effects between whole toad secretions versus pure 5-MeO-DMT. Morris said, “The differences are widely reported in the psychedelic community, but are not based on anything approaching a controlled double-blind experiment with a large number of subjects, which would be required to meaningfully establish a difference between the two materials.”

Speaking again about toad secretions, Morris told Joe Rogan in his podcast,

…maybe there’s a little bit of that sort of entourage effect that you get with almost any plant that has a variety of different alkaloids.

So, there are some conflicting opinions about the entourage effect among at least two magic mushroom experts.

What the Pharmacologists Are Saying

Psychedelic Science Review reached out to psychedelic researchers Dr. David Nichols and Dr. Alexander Sherwood for their comments on the state of the entourage effect hypothesis in psychedelic compounds. Regarding magic mushrooms, Dr. Nichols told us,

I do not believe there is an entourage effect for mushrooms. The other two major tryptamines in mushrooms, baeocystin and norbaeocystin, have recently been synthesized and tested and they are not active.[4] Pure synthetic psilocybin seems to represent the essential effect of the whole mushroom. I believe any entourage effect would be very subtle, if any.

When asked about a synergy between the compounds in toad secretions (venom), he noted,

…when the dried toad venom is smoked, the peptides are destroyed by the heat. It is possible that there are other volatile compounds in the toxin, but I have not seen evidence that they contribute to the effect.

For comparison purposes, Dr. Nichols pointed out how research into cannabis compounds is at a more advanced stage than other psychedelics. “Cannabis contains hundreds of compounds, most of which have not been tested. ∆9-THC is the main psychoactive component in cannabis, but it also contains ∆8-THC, cannabidiol, and a variety of terpenes and cannabinoids. It is possible that the overall effect of ingesting cannabis is a combination of its components, or an entourage effect.”

To Dr. Nichols’s point, research is indicating that there is a synergy between some of the cannabinoids found in the Cannabis plant.6,7

Dr. Alexander Sherwood told Psychedelic Science Review, “I am excited to see that there are groups actively working to elucidate this interesting and complex phenomenon.” He offered these additional thoughts,

At this time, I have not seen strong evidence to support the idea [the entourage effect] one way or another. It is tempting to make an analogy between the effects produced by mixtures of lipophilic phytocannabinoids in cannabis and the various alkaloids in psychedelic mushrooms, peyote, or toad secretions, but none are directly comparable.

Looking ahead, Dr. Sherwood added,

The important thing to do now is design good experiments to test the entourage effect hypothesis systematically with representative mixtures of natural products.

He continued, “Discovering that a compound such as norpsilocin is an agonist at the 5-HT2A receptor is a very small piece of the puzzle. Understanding the absorption, distribution, metabolism, and excretion characteristics of the individual components in the mixture is equally, if not more, important to consider.”

There are two conclusions one can glean from this expertise provided by Drs. Nichols and Sherwood. First, there is significant skepticism among psychedelic pharmacologists about the existence of the entourage effect in psychedelic compounds (aside from cannabis). This makes sense due to the lack of proper scientific studies.

Second, it would be helpful for researchers to work toward developing a better understanding of the complete chemical composition of naturally occurring psychedelic sources like magic mushrooms (or toad secretions, ayahuasca, Salvia divinorum, etc.). This requires first identifying all the compounds they contain and understanding their chemistry and pharmacology. Then, studies can be designed to help understand how two or more of the molecules may work together to produce the entourage effect.

Examining the Work of Psychedelic Research Companies

Understandably, many experts remain unconvinced that there is a synergistic relationship between psychedelic compounds except when it comes to Cannabis. But how are commercial psychedelic research companies approaching the entourage effect? Are they treating it as an untapped opportunity or a red herring?

Over the coming weeks, this article series will review several companies that appear to be actively studying the entourage effect in their research efforts. We will summarize what they’re working on and discuss what it could mean for the future of psychedelic research. Keeping an eye on where these companies are heading and the research strategies they are using is a critical part of staying up to date with psychedelic science.

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Jospeh Claussen
7 months ago

Thank you for your work!