MAPS Speakers Discuss Importance Entourage Effect and “Minor” Tryptamines

Scientists at MAPS Webinar Series Discuss the Importance of “Minor” Tryptamines and the Entourage Effect

Recently, several experts in psychedelic medicine have presented at MAPS webinar series hosted by Shannon Smadella. The series draws from a diverse group of speakers, including Mark Haden, Nan Shuni Giron, Nan Shuni Giron, Dr. Dennis McKenna, Paul Stamets, Rick Doblin, Erika Dyck, Zoe Helene, Chris Dyer, Duncan Trussell, Kuauhtli, Dr. Monnica Williams, Dr. Bia Labate, and Wade Davis.  The series covers a broad range of topics, several of which pertain to science and highlight the state of the art as follows:

  • There is a growing appreciation for the importance of the entourage effect provided by consuming psychedelics in their natural form; 
  • But, natural products are not “standardized,” making them unsuitable in contexts where it’s important to administer a precise amount of known ingredients;
  • And, although the scientific community has made significant progress studying some single molecules in natural products, our understanding of the “minor” components is still in the dark ages, presumably due to a lack of reliable compounds.

Growing Recognition of the Entourage Effect

Magic mushrooms contain psilocybin but they are not the same as psilocybin. On the MAPS website, Paul Stamets notes that “Psilocybin is one molecule of several that can cause altered states of consciousness” in magic mushrooms.  In other words, there is a difference between (a) pure psilocybin and (b) the cocktail of active ingredients naturally present in magic mushrooms.  Here, Mr. Stamets notes that “Psilocybin mushrooms have been used for thousands of years” whereas “Psilocybin as a molecule has been used for a few dozen.” Mr. Stamets points out that “the single-molecule medicines available for psychotherapists have failed to show the same level of positive outcome,” indicating that consuming the full spectrum of compounds provided by naturally occurring magic mushrooms may have advantages over “the reductionist view” of using single purified molecules.

Mr. Stamets’s insightful points lead to his ultimate question: “Where and when can the use of the natural form of psilocybin mushrooms be appropriate for psychotherapy and cognitive health?”  On the Joe Rogan Podcast #1385, he suggests an answer: We need standardized formulations that provide multiple magic mushroom active ingredients.

Unmet Need for Standardized Formulations of Multiple Compounds

Given the advantages of consuming natural products, why does the industry appear to be moving towards making compositions with only a single active ingredient, like pure psilocybin?  In a recent interview with Joe Rogan, Mr. Stamets explains, “The problem with natural products is how do you standardize them to the active constituent when you have more than one active constituent, you know, how do you standardize them all?”  Here, Mr. Stamets appears to recognize the benefits of both (1) “standardizing” psychoactive drugs, i.e. using known amounts of known ingredients and also (2) preserving nature’s cocktail of active ingredients.  What would this look like in practice?

One might envision making formulations that include multiple active ingredients from magic mushrooms in standardized precisely dosed amounts. For example, a formulation that includes psilocybin and another magic mushroom active, like baeocystin.  Another example would be formulations that include both psilocybin and aeruginascin. See Gartz, J., Int. J. of Crude Drug Research Volume 27, 1989 – Issue 3, pp. 141-144. (“It seems that the significant amounts of the indole derivative aeruginascin can modify the pharmacological action of psilocybin to give an euphoric mood during psychosis with hallucinations.”) Alternatively, one might envision standardized formulations that exclude psilocybin and provide only the “minor” alkaloids, such as baeocystin, norbaeocystin, norpsilocin, and/or aeruginascin. Many other examples are possible and different combinations of these molecules could have different benefits for different people in different situations.  

The Massive Potential of “Minor” Components

Psilocybin is one promising molecule but it’s just the tip of the iceberg. The cannabis industry has recently learned this lesson: THC was once considered the single active ingredient in cannabis; but now scientists recognize the importance of other molecules like CBD as well as the importance of combining different cannabinoids and terpenes to modulate or optimize the properties of the formulation.  On this topic, the previous week’s speaker at the MAPS webinar, Dr. Dennis McKenna also discussed the importance of some lesser known, “minor” components in psychoactive plants and fungi.

On June 16th, 2020, Dr. Dennis McKenna presented a talk titled “Psychopharmacognosy: Prospects for Discovering Novel Psychedelics in Nature.” Dr. McKenna notes that “most people are familiar with the major natural psychedelics, such as psilocybin mushrooms, Ayahuasca, San Pedro cactus, Peyote, etc. All of these have a rich cultural and historical background, and the pharmacology and chemistry of the active constituents is well understood.” For example, scientists have made considerable progress studying and understanding the pharmacology of psilocybin, which has been touted as “the active constituent” of magic mushrooms.  Dr. McKenna contrasts these advances in single molecule pharmacology with our relatively poor understanding of natural medicinals and the many “minor” compounds that contribute to their pharmacology: “Yet hidden within the vast biodiversity of the planet, undiscovered psychedelics remain poorly investigated, if they are known to science at all.”  

Although both Dr. McKenna and Mr. Stamets recognize the potential importance of “minor” compounds, scientific studies in this area are just beginning to emerge.  For example, it wasn’t until 2017 that Dirk Hoffmiester discovered the compound norpsilocin in magic mushrooms. And it wasn’t until 2020, that Sherwood et al. published a synthetic method for producing norpsilocin and other minor magic mushroom compounds in the laboratory.  In that 2020 paper, the authors explained that “few studies have been conducted to evaluate pharmacological activity of these tryptamines, largely due to lack of availability of the compounds.” In other words, the first step to studying compounds is sourcing the compounds.

By synthesizing norpsilocin, Sherwood’s team was then able to conduct the first pharmacological screening of the compound.  Surprisingly, they found that it is even more potent than psilocin (the active metabolite of psilocybin) at 5-HT2A but strangely does not produce a “head twitch response” characteristic of “tripping” when administered to laboratory animals. Could norpsilocin provide some of the therapeutic benefits of magic mushrooms without the trip?  Based on Paul Stamets’s account of consuming pure baeocystin (a prodrug of norpsilocin), this seems possible: “So, here we found an analog of psilocybin that does not get you high, that’s legal, that reduced anxiety. I think it’s the tip of the proverbial iceberg.” See Joe Rogan Podcast #1385.

Sherwood’s team also synthesized aeruginascin, baeocystin, and norbaeocystin, opening up similar areas of research. Aeruginascin is a particularly interesting compound because it has been implicated in causing temporary paralysis (see Sherwood) and/or heightened euphoria (see Gartz).  Although the mainstream media (e.g., Vice, DoubleBlind) has recently discussed the importance of these phenomena, the pharmacology of aeruginascin has not been scientifically studied.  Notably, aeruginascin’s putative active metabolite (it’s dephosphorylated analog, 4-OH-TMT) has not been synthesized, which could be responsible for the lack of research in this area. Milne et al. observed 4-OH-TMT as a fermentation product of genetically engineered Saccharomyces cerevisiae but they did not isolate the compound or study its pharmacology.


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