The entourage effect in magic mushrooms

Psymbiotika Lab is testing a hypothesis that an experience on magic mushrooms is complex beyond psilocin, 5HT2A receptors, set, and setting

Biological systems are complex. Exceptions to rules appear with deeper understanding and biology textbooks are rewritten every few years.

The clinical understanding of magic mushrooms is that psilocin (the ‘active’ version of psilocybin) binds to specific serotonin receptors. The accepted factors that influence a trip are the amount of psilocybin ingested, our mood at the time, and our environment (dose, set, and setting). Clinically, synthetic psilocybin, LSD, and mescaline all have the same psychoactive effect and cannot be distinguished by users, except by duration of experience (determined here).

Psychoactive experiences are subjective and challenging to describe. What new information would we need about magic mushrooms that might change our current understanding about their use and whether multiple factors are at play in a psychedelic experience? Psymbiotika Lab has developed genotypes of mushroom that differ in their ratios of tryptamines to explore the entourage effect in preclinical models and hopes to answer this question.

The tryptamines produced on the way to psilocybin and their de-phosphorylated molecules that agonise serotonin receptors.

Magic mushrooms metabolise tryptophan, an amino acid, into psilocybin through a series of enzymatic reactions (as determined here and here). Psilocin is the only hallucinogenic compound produced by mushrooms, but along the way, at least two other tryptamines (4-hydroxytryptamine and norpsilocin) are produced that bind to serotonin receptors just as well as (if not better than) psilocin (as determined here and here). One of these (norpsilocin) has anti-depressant activity in rats (determined here), however, because there is no psychedelic activity from either compound, they are not considered to impact the experience. Given they are agonists at 5HT2A receptors, the hypothesis to be tested is that they impact the binding of psilocin even if just through competition.

Norpsilocin and 4-hydroxytryptamine are thought to occur in concentrations too low to impact a psilocybin experience. The concentration measured for psilocybin and its analogs depends on the solvent. All tryptamines are measured in alcohols because psilocybin is soluble in alcohol. Changing the solvent to slightly acidic water (similar to stomach acid) increases the concentration of analogs to amounts that are comparable to psilocin.

Psymbiotika Lab hypothesises that our genotypes of magic mushroom that produce different ratios of norpsilocin to psilocin will alter the psychedelic experience. We have bred new genotypes of mushroom using knowledge of the genes that produce psilocybin. These new genotypes are characterised for their tryptamine profile. Stay tuned to see how these different genotypes impact cellular and animal models.

The results are in, naturally derived psilocybin outperforms synthetic psilocybin in terms of longevity of neural plasticity in mice (determined here). Likely, as more researchers compare synthetic psilocybin to extracts from magic mushrooms, other differences will unfold. These differences could stem from the tryptamine profile, or from other compounds produced by mushrooms that help prevent degradation of tryptamines once the mushroom is ingested (determined here). We are providing mushrooms characterised for their tryptamine profile to help researchers further explore the entourage effect and why natural psilocybin has better clinical outcomes than synthetic.