Wherefore the magic? The evolutionary role of psilocybin in nature

Research into psychedelic compounds is in resurgence due to the exciting potential for their use in the treatment of psychiatric and mental health disorders. Despite this revival, remarkably little is known about their evolution. One of the most intriguing psychedelic compounds is psilocybin, the compound found in magic mushrooms and used in ritual ceremonies in Central America for generations. Associated with agaricomycete fungi of the genus Psilocybe, psilocybin acts in a similar way to the neurotransmitter serotonin, yet how and why natural selection favoured its biosynthesis remains unclear. Given the resemblance to serotonin, modulation of invertebrate behaviour for defence is a likely explanation, but neither this nor alternative hypotheses have ever been formally tested. Here, we show that Drosophila larvae exposed to extracts from Psilocybe mushrooms exhibit reduced survival, pupation rates, and inhibited locomotion. Adults exposed during development show reduced thorax and wing size, along with increased fluctuating asymmetry, indicating developmental stress. Conversely, mutants lacking 5HT2A receptors showed the same response to Psilocybe extracts as wild-type flies. Furthermore, DNA metabarcoding revealed that while Psilocybe semilanceata demonstrates a distinct invertebrate community compared to most other grassland fungi, it overlapped with the non-psychedelic species Mycena epipterygia. This study provides a crucial first step toward understanding the evolutionary role of psilocybin-producing fungi and provides a grounding for future research into the molecular mechanisms, ecological interactions and evolutionary origins of psychedelic compounds in nature.