"The groundwork of all happiness is health." - Leigh Hunt

Largest diversity study of 'magic mushroom' investigates evolution of psychoactive psilocybin production.

Fungi, colloquially referred to as “magic mushrooms,” have held deep significance within the indigenous cultures of Mesoamerica for hundreds of years. They gained wider world attention as a psychedelic staple within the 60s and 70s. Now, these infamous organisms are on the forefront of the mental health revolution. Psilocybin and psilocin, psychoactive compounds present in nearly all species, have shown promise as treatments for conditions including PTSD, depression, and facilitating end-of-life care.

To use psilocybin as a treatment, scientists need a broad roadmap of the compound's underlying genetics and evolution, information that doesn't exist. Our limited knowledge comes from research on only a fraction of the ~165 known species. Most psilocybin-producing mushrooms haven't been studied since they were first discovered — until now.

A team of researchers led by the University of Utah and the Natural History Museum of Utah (NHMU) has accomplished the most important study of genomic diversity for the genus. Their genomic evaluation of 52 specimens included 39 species that had never been sequenced. .

The authors found that it arose much sooner than previously thought — about 65 million years ago, right across the time that the asteroid that killed the dinosaurs triggered the mass extinction. They demonstrated that psilocybin was first synthesized in mushrooms of the genus 40 to 9 million years ago with 4 to 5 possible horizontal gene transfers to other mushrooms.

Their evaluation revealed two distinct gene orders inside the gene cluster that produces psilocybin. The two gene patterns correspond to an ancient split within the genus, suggesting two independent acquisitions of Psilocybeans in its evolutionary history. This study is the primary to indicate such a robust evolutionary pattern inside the gene sequence that drives the synthesis of psychoactive proteins.

“If psilocybin turns out to be this kind of wonder drug, treatments will need to be developed to improve its efficacy. What if it already exists in nature?” said Bryn Dentinger, curator of mycology at NHMU and senior creator of the study. “There's a wealth of diversity of these compounds out there. To understand where they are and how they're made, we need to do the kind of molecular work to use biodiversity to our advantage.”

All study DNA got here from specimens in museum collections world wide. Twenty-three of the 52 specimens were “type specimens,” the gold standard designating a species against which all other specimens are measured. For example, say you discover a wild mushroom as a particular species of chanterelle — you're betting that the mushroom you picked is similar because the physical material in a museum box. The authors' molecular work on the sort species is a crucial contribution to mycology since it establishes an authoritative foundation for all future work on diversity in taxonomy.

“These types of samples represent hundreds of years of collective effort by scientists to document diversity, before people were even thinking about DNA,” said Alexander Bradshaw, a UK postdoctoral researcher and said the lead creator of the study. “That's the beauty of it — no one has sequenced type specimens at this scale, and now we have to generate molecular and genomic data on the gold standard of types for people to compare.”

The study was published on January 9, 2024 within the journal

A journey through time

Previous studies identified a cluster of 4 primary genes that produce psilocybin based on genomic evaluation of three species. The species were closely related, and all had gene patterns within the psilocybin-producing gene cluster. Extended genomics of 52 samples from this study revealed one other distinct pattern.

“This work represents a major step forward in the understanding of evolutionary relationships because it is the first to include samples from a wide range of species and is based on type specimens,” Virginia Ramírez Cruz, a paleontologist on the Universidad de Guadalajara and said the co-leader. creator of the study.

The authors found that 17 samples had the unique order, while 35 exhibited recent patterns.

“We've shown here that the gene sequence has changed a lot over time, and that provides some new tools for biotechnology. If you change gene expression to produce psilocybin and related compounds, “If you're on the lookout for a approach to do it, you now not should depend on only one set of gene sequences that scientists can have a look at for many alternative properties or functions,” said Dentinger, who's on the University of Utah. Also an Associate Professor of Biology.

The group's dating suggests that an ancient split of the 2 gene cluster patterns occurred around 57 million years ago, which also coincided with a change within the environment. The first psilocybin-producing fungi probably originate as wood-decomposing groups, then migrate to soil after division, some species resembling herbivores to grow on dung. . Climate change in dung beetles has occurred independently at the least twice of their evolutionary history.

What does psilocybin do to mushrooms?

The authors hope that the evolutionary history of psilocybin will make clear essentially the most fundamental query — what does psilocybin do for mushrooms? The gene clusters that produce psilocybin are prone to have some profit, but nobody knows what it's.

Psilocybin's molecular structure mimics that of serotonin and binds strongly to serotonin receptors, particularly 5-HT.2A, a well known receptor that many psychedelic drugs bind to. When a chemical binds to those receptors in mammals and similar insects and arachnids, they produce unnatural and altered behaviors. Some have suggested that this altered mind-set may directly prevent victimization. It can also be possible that psilocybin acts as a laxative or induces vomiting to disperse the spores before they're fully digested. However, psilocybin mushrooms are sometimes found infrequently within the wild, making it unlikely that animals can learn to acknowledge them. An alternative theory is that psilocybin is a chemical defense against insects. However, experimental studies are lacking, and the authors' personal observations confirm that psilocybin-containing mushrooms frequently host healthy, thriving insect larvae.

The authors are preparing experiments to check an alternate theory they call the Gastropod Hypothesis. The timing and declination dates coincide with the KPg boundary, the geological marker of the asteroid that plunged Earth right into a brutal, long winter that killed 80% of all life. Two life forms that flourished throughout the darkness and decay were fungi and terrestrial gastropods. Evidence, including the fossil record, shows that gastropods diversified and proliferated shortly after the asteroid hit, and land slugs are known to be heavy predators of fungi. With molecular dating of the study to around 65 million years ago, it is feasible that psilocybin evolved as a slug deterrent. They hope that their feeding experiments will shed some light on their hypothesis.

In 2020, the authors set a goal of obtaining genome sequences for every kind of specimen. To date, they've sequenced the genomes of 71 type specimens and proceed to collaborate with collections world wide.

“It's inconceivable to overstate the importance of a set to check like this. We stand on the shoulders of giants, who've spent 1000's of man-hours constructing these collections, so I wrote an email about rare specimens. can request access to, lots of which have only been collected once, and will never be collected again,” Bradshaw said.

Other authors who contributed to the study include Guise and Ali Awan of St. Louis. Thomas's NHS Trust, Giuliana Furci of the Fungi Foundation; The research was funded by the National Science Foundation (DEB #2114785) and Fungi Perfecti LLC.