The fungivore-deterrence hypothesis, that psilocybin evolved as a chemical defence against arthropod fungivores via 5-HT receptor agonism, has become the working consensus in fungal chemical ecology, despite resting on a phylogenomic pattern of horizontal gene transfer among saprotrophs and remarkably little direct experimental evidence. Recent biochemistry ...
Stable, high-level biosynthesis of complex natural products requires precise control of heterologous pathway expression, yet transcriptional architectures optimized on plasmids often fail when transferred to the chromosome. Here, we present ePathIntegrate, a genome-centric pathway engineering strategy that leverages CRISPR-associated transposases (CASTs) to ...
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis...
Psilocybin is a psychoactive tryptamine produced by a phylogenetically discontinuous yet ecologically diverse subset of fungi. Despite decades of chemical, pharmacological, and ethnobiological research, the evolutionary forces driving the emergence and persistence of this compound remain insufficiently explained. Recent hypotheses proposing that psilocybin e...
Panaeolus sensu lato is a group of hallucinogenic mushrooms commonly found on dung, in pasture areas, grasslands, and forests. Previous studies indicated that the Panaeolus s.l. clade (panaeo-clade) could be ranked as a family ( Galeropsidaceae ), pending further evidence. In this study, based on phylogenomic, multigene phylogenetic, molecular clock, and mor...
Production of the psychoactive compound psilocybin is a defining feature of the genus Psilocybe, commonly referred to as “psychedelic mushrooms”. However, Psilocybe fuscofulva is a striking exception within Psilocybe sensu stricto as it lacks the stereotypical blue bruising characteristic of the genus, and psilocybin has not been detected in the species.To i...
Psilocybin, the psychoactive compound responsible for the hallucinogenic effects of “magic mushrooms,” is synthesized by a biosynthetic gene cluster (BGC) traditionally associated with Psilocybe species. However, psilocybin production has also been identified in multiple genera across the Strophariaceae, Hymenogastraceae, and Galeropsidaceae families. Here, ...
Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces condition...
Abstract For many, cognitive and affective health declines through typical aging. Although cognitive and affective symptoms are often studied in isolation, they share substantial overlap, and arise, in part, from common biological processes. Aging is accompanied by diminished neural plasticity, heightened neuroinflammation, and widespread alterations in the ...
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis...
ABSTRACT Psilocybe is a genus of mushroom-forming fungi with ecological, ethnomycological, and clinical importance due to psilocybin production by most species. We present five genomes that enable deeper discovery and analysis of the psilocybin gene cluster and increase taxonomic resolution within Psilocybe: Psilocybe semilanceata, Psilocybe gandalfiana nom....
The high therapeutic potential of psilocybin, a prodrug of the psychotropic psilocin, holds great promise for the treatment of mental disorders such as therapy-refractory depression, alcohol use disorder and anorexia nervosa. Psilocybin has been designated a 'Breakthrough Therapy' by the US Food and Drug Administration, and therefore a sustainable production...
Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. T...
Magic mushrooms are fungi that produce psilocybin, a compound with breakthrough status for treatment of mental health disorders. Wood-degrading species of Psilocybe, such as P. subaeruginosa and relatives, have high concentrations of psilocybin but are discouraged for clinical production due to a temporary paralytic side effect known as Wood Lover’s Paralysi...
Psilocybe "magic mushrooms" are chemically well understood for their psychotropic tryptamines. However, the diversity of their other specialized metabolites, in particular terpenoids, has largely remained an open question. Yet, knowledge on the natural product background is critical to understand if other compounds modulate the psychotropic pharmacological e...
Psilocybe zapotecorum is a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genom...
Psychoactive mushrooms in the genus Psilocybe have immense cultural value and have been used for centuries in Mesoamerica. Despite a recent surge in interest in these mushrooms due to emerging evidence that psilocybin, the main psychoactive compound, is a promising therapeutic for a variety of mental illnesses, their phylogeny and taxonomy remain substantial...
Psilocybe magic mushrooms are best known for their main natural product, psilocybin, and its dephosphorylated congener, the psychedelic metabolite psilocin. Beyond tryptamines, the secondary metabolome of these fungi is poorly understood. The genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) were browsed to unde...
