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.