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

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.

The use of prodrugs as drugs of abuse

“…A structural analogue of psilocybin, 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) has also been detected in the illicit drug market and is understood to be a prodrug as well, although other metabolites might be formed in vivo (Klein et al, 2020;Zhai et al, 2022). Prodrugs of psilocin may present an important therapeutic tool for treatment-resistant anxiety, although there is a concern with the psychedelic effects of the drug (Raithatha et al, 2024).…”

Psilocybin for the treatment of Alzheimer’s disease

“…This strategic modification aims to modulate metabolic processing, resulting in the creation of a novel prodrug of psilocin. Among these active prodrugs, two distinct molecules have demonstrated lasting anxiolytic benefits in chronically stressed mice, as evaluated in the marble-burying psychiatric model ( Raithatha et al, 2023 ).…”