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.
Psilocybin, the prodrug of psilocin found in magic mushrooms, shows therapeutic promise for depression and anxiety but produces a psychoactive episode lasting up to 6 hours, which limits clinical use. Researchers engineered a library of 28 novel prodrug derivatives of psilocin by modifying the 4-carbon position of the indole ring. In vitro screening in human serum and cellular fractions identified 15 prodrugs that produced psilocin, notably ester and thiocarbonate-based compounds. Pharmacokinetic studies in mice showed these prodrugs yielded psilocin levels comparable to psilocybin but with reduced overall exposure and no detectable psilocin at 24 hours. Five prodrugs induced head twitch responses approaching or exceeding psilocybin, and two provided long-term anxiety relief in stressed mice. These candidates may shorten the psychedelic experience while retaining therapeutic benefits.