Preclinical Anxiolytic- and Antidepressant-like Effects of α,α-Trehalose, a Bioactive Compound Identified in Psilocybe cubensis.

The genus Psilocybe has been characterized by central nervous system (CNS) effects and as a source of therapeutic drugs such as the alkaloids psilocybin and psilocin-secondary metabolites that produce rapid anxiolytic and antidepressant effects in preclinical and clinical studies. Furthermore, these mushrooms also contain bioactive primary metabolites, for example, the interesting case of α,α-trehalose. To explore the effects of this disaccharide, it was isolated and characterized using phytochemical and spectroscopic analyses. Subsequently, its anxiolytic- and antidepressant-like properties were assessed and corroborated by in vivo behavioral studies using experimental models for anxiety (open-field, hole-board, and plus-maze tests) and depression (forced swimming test complemented by a preliminary rota-rod test). Electrocorticographic in situ recordings and nuclear magnetic resonance analysis were also explored. Finally, an in silico docking analysis was performed to determine the involvement of the 5-HT1A serotonin receptor as one of the main targets identified in the CNS activity of Psilocybe species. The evidence shows that α,α-trehalose is one bioactive metabolite that promotes significant anxiolytic- and antidepressant-like activities mediated by early brain changes and involving an indirect participation of 5-HT1A receptors. In conclusion, α,α-trehalose represents a potential natural drug for mental health, such as in the treatment of anxiety, depression, or their comorbidity.