As hypothesised with cannabis, could the ‘entourage effect’ play a role in the therapeutic effects of psilocybin mushrooms?
Put forward by Dr Ethan Russo in 2011, the entourage effect is a hypothesis that different compounds in cannabis work synergistically to create a therapeutic effect. This is as opposed to compounds such as THC or CBD working in isolation.
However, the hypothesis has been touched on a handful of times in the scientific literature in relation to psychedelic mushrooms.
One instance is the 1989 paper ‘Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe’ by Dr Jochen Gartz, who proposed a synergistic relationship between compounds in the mushrooms.
Another example is a 2015 paper ‘Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice’ by Zhuck et al, who observed the effect of psychedelic mushroom extracts on mice was much stronger than pure psilocybin.
Clinical trials
With a sharp increase in clinical trials and research looking at the therapeutic potential of psilocybin for mental health conditions, more research is needed to understand how mushrooms work to have therapeutic effects.
Currently, the majority of clinical trials and research into psilocybin are using isolated psilocybin. However, much like cannabis, psychoactive mushrooms contain many other compounds that could play a role in the reported therapeutic effects.
Additionally fuelling this theory are the many anecdotal reports that suggest different species of psychoactive mushrooms have their own unique effects.
Mycologist Alan Rockefeller specialises in DNA sequencing and fungi photography and has discovered and named the psychoactive mushroom species Psilocybe allenii, along with co-authoring a 2020 publication characterising five psilocybe species.
Speaking to Psychedelic Health, Rockefeller commented: “No one really knows whether the entourage effect occurs with mushrooms.
“It is difficult to study because the same batch of mushrooms will have different effects in different people, and the same person on different days.”
Challenges with multi-compound research
Often, synthetic psilocybin is used in research because running clinical trials and conducting research on organic, multi-compound medicines can pose a number of challenges.
They often contain hundreds of different compounds – for example, cannabis has over 400 known compounds including THC, CBD, CBG and CBN. Some of the different compounds contained in species of psilocybe mushrooms include psilocybin, psilocin, baeocystin and norbaeocystin.
Having a large volume of different compounds can make identifying which ones are active and what their impact is difficult to measure. To add to this, the concentrations of these compounds can vary depending on factors such as growth conditions and processing techniques.
In this context, the standardisation of multi-compound medicines is a huge challenge, as medicine consistency, reproducibility and dosing all become very difficult. However, these are essential factors when it comes to conducting clinical trials and receiving approval for medicines from regulators.
“There are a dozen different tryptamines that can occur in mushrooms, plus a few beta-carbolines and hundreds of other molecules – so there is probably more than just psilocybin having an effect,” said Rockefeller.
“Studying one compound at a time is hard enough, studying mixtures of hundreds of compounds is much more difficult. Without pure compounds, it is difficult to get repeatable results.
“It is possible that the therapeutic potential is different depending on the different compounds in the mushrooms. It’s also possible that psilocybin is the only thing that matters, and the other compounds are mostly inactive.”
Further challenges with researching multi-compound medicine and understanding the entourage effect in psychoactive mushrooms, is understanding the pharmacokinetics – which is absorption, distribution, metabolism and excretion – and pharmacodynamics – effects on the body.
Then, there is then the challenge of understanding the compounds’ interactions with other drugs.
Challenges with regulations
Cannabis has faced many challenges when it comes to its medical use. While the USA has legalised medical cannabis in most states and more countries across Europe and the rest of the world are embracing medical cannabis, only three cannabis-based medicinal products (CBMPs) have been approved for use in the UK, for example.
These contain isolated cannabinoids extracted from the cannabis plant and do not contain a variety of cannabinoids.
To add to these challenges, in many countries, regulators require rigorous efficacy and safety data of medicines before they can be approved, and frameworks for investigating this are designed for single-compound medicines.
Researching psilocybin is already incredibly expensive due to high licensing costs due to it being place placed in Schedule 1 of the UN Convention on Psychotropic Substances 1971, along with drugs such as raw opium.
Investigating the multiple compounds contained within psilocybin species of mushrooms would add to these costs, as research and trials into multi-compound medicines require significant financial support.
Securing such funding can be a major challenge as investors may perceive higher risks associated with this type of research.
“The different active compounds in mushrooms need to be separated or synthesised, and clinical trials need to be done with the various pure compounds and these compounds in various combinations,” Rockefeller concluded.
