Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

Psilocybin's therapeutic benefits for depression and anxiety are limited by the long duration of its psychedelic effects, driven by sustained exposure to its active metabolite psilocin. To address this, researchers synthesized and screened 28 new chemical entities, introducing various cleavable groups at the 4-hydroxy position of the indole core to alter metabolic processing. Several novel prodrugs showed altered pharmacokinetic profiles and reduced pharmacological exposure compared to psilocybin, suggesting they could maintain long-term therapeutic benefits while shortening the psychedelic experience.

Study at a glance

Abstract

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.