Drosophila melanogaster as neuropsychiatric model for the pharmacological characterization of psychoactive mushroom-derived alkaloids

Neuropsychiatric diseases (ND) such as depression, anxiety, post-traumatic stress, and bipolarity represent a substantial long-term challenge for the global health systems due to their rising prevalence, uncertain neuropathology, and lack of effective pharmacological treatments. Moreover, approved neuropsychiatric drugs have proven reduction of sustained tolerability and unpleasant side effects, directly impacting patients’ quality of life. Thus, the implementation of innovative strategies focused on the search of new therapeutic agents are required to improve the success of new drug candidates, advance elucidation of mechanisms of action, and to abate the effectiveness gap. Drosophila melanogaster is one of the most powerful models for neurobiological research due to its versatility, highly genetic homology with humans, and equivalent disease pathways, allowing for high-throughput screenings in drug discovery and development. Herein, psychedelic mushroom extracts and the tryptamine alkaloid psilocybin were investigated to determine the neuropharmacological potential using Drosophila models. Initially, the behavioural effects induced by psilocybin in adults of D. melanogaster were evaluated in a dose-response experiment assessing the locomotory and neuromotor activities. Then, a depression-like state was induced in adult flies using a vibration-stress protocol to assess the antidepressant effects of psilocybin and mushroom extracts after the acute exposition. The effect of psilocybin micro-dosing on inducing changes in the normal or depressive state of Drosophila was evaluated.