Mushrooms independently evolved different recipes for psilocybin

Different mushrooms used entirely separate enzyme toolkits to make the same mind active molecule, psilocybin, according to a new study. The finding shows that nature can reach the same chemical finish line by taking unrelated starting paths.

When people ingest psilocybin, the body clips a phosphate to form psilocin, which binds the brain’s 5-HT2A receptor and changes signaling that affects perception and mood.

These receptor-level effects are a key reason why scientists are investigating psilocybin, under strict medical supervision, as a possible therapy for depression.

Two paths to psilocybin

The study was led by Dirk Hoffmeister of Friedrich Schiller University Jena and the Leibniz Institute for Natural Product Research and Infection Biology. He noted that psilocybin has a very long history with humans.

The study shows that Psilocybe mushrooms and the fiber cap genus Inocybe both produce psilocybin, but they do so through different reaction sequences and with entirely unrelated enzymes.

Nature managed to create the same active compound twice, using separate evolutionary routes that led to psilocybin in different mushroom groups. This shows that evolution can solve the same problem with entirely different biochemical tools.

The role of enzymes

An enzyme is a protein that speeds up a specific chemical step, and the lineup of steps matters because it sets what intermediates exist inside cells.

In Psilocybe, the pathway starts by removing carbon dioxide from a tryptophan based starter, then adds a hydroxyl at a precise ring position, adds methyl groups, and finally attaches phosphate to finish psilocybin.

In Inocybe corydalina, the order flips, and a different cast of catalysts handles each job with no reaction in common with the Psilocybe route. That branched route also yields baeocystin as a second end product rather than a transient stepping stone.

Why mushrooms make psilocybin

A 2020 study showed that injured Psilocybe mushrooms rapidly turn blue when enzymes unmask psilocin and link it into oligomers.

Those polymers can bind proteins, which suggests a chemical shield that activates only when the tissue is bitten or cut. “Perhaps the molecule is a type of chemical defense mechanism,” said Hoffmeister.

The researchers noted that the ecological role of psilocybin is still uncertain, and its function may differ depending on the habitat and the organisms that interact with the mushrooms.

What it could mean for medicine

In a trial with 233 adults who had treatment-resistant depression, a single 25 mg dose of psilocybin reduced depression scores more than a control dose over 3 weeks.

The higher-dose group showed larger mean improvements, though side effects were common and longer studies are still needed to judge durability and safety.

Those medical results do not depend on which mushroom enzyme set built the molecule, since the drug administered is the same. The new enzymatic options do matter for how future medicines could be produced at scale with better control and lower cost.

How evolution built the toolkit

The two routes are a clear case of convergent evolution, where unrelated solutions arrive at the same trait. The finding complements earlier work that mapped horizontal gene transfer of psilocybin gene clusters among mushroom lineages.

Convergence inside the same order of mushrooms is rare and instructive because it sharpens questions about what ecological pressures select for the trait.

Psilocybe species often grow on wood or dung, while fiber caps live in forests, so the same molecule may solve different problems in different niches.

Future research directions

Multiple enzyme sets give biotechnologists more levers to build psilocybin in yeast, bacteria, or cell free systems that can be tuned, cleaned, and scaled.

Swapping in enzymes that prefer certain intermediates can smooth production, avoid unstable steps, and raise yields without complex chemical synthesis.

Regulators will still require the same safety and quality checks, regardless of the assembly line that makes the molecule. What changes is the manufacturing flexibility, and that could speed careful medical access if ongoing trials support benefit.

Details inside the lab

The Psilocybe route uses one methyltransferase that places two methyl groups in sequence, then a kinase that adds phosphate with broad tolerance for intermediate forms.

Inocybe splits the methylation across two methyltransferases with different preferences and uses a different kinase that strongly favors fully methylated precursors before adding phosphate.

Those preferences steer traffic toward either psilocybin or baeocystin, and the kinetic balance appears tuned so small shifts can change the final mix. That branch design may be the reason why baeocystin occurs as a major end product in some fiber caps.

Psilocybin lessons from mushrooms

Pathways are not recipes that nature follows once, they are strategies that can arise more than one way when biology has reasons to reach a target.

Chemical defense, competition with microbes, or communication with other organisms are all plausible pressures, and the blue reaction after injury gives a concrete clue to test.

The key point is that shared molecules do not guarantee shared histories. Evolution often tinkers with whatever parts are on the shelf and that can lead to different machines that build the same thing.

The study is published in Angewandte Chemie International Edition.

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