In vivo validation of psilacetin as a prodrug yielding modestly lower peripheral psilocin exposure than psilocybin

Psilocybin, a psychedelic compound used in psychotherapy research, is converted in the body to the active metabolite psilocin. Psilacetin (4-AcO-DMT) has long been thought to be an alternative prodrug for psilocin, but direct evidence was lacking. In mice, psilocybin produced 10–25% higher psilocin concentrations than psilacetin at 15 minutes after injection. The half-life of psilocin was about 30 minutes from either prodrug. Overall, psilacetin fumarate yielded about 70% of the psilocin exposure that psilocybin did. These results confirm that psilacetin acts as a psilocin prodrug in vivo and suggest it can be used as a substitute for psilocybin in mechanistic research with mice.

Study at a glance

Abstract

Introduction The use of the psychedelic compound psilocybin in conjunction with psychotherapy has shown promising results in the treatment of psychiatric disorders, though the underlying mechanisms supporting these effects remain unclear. Psilocybin is a Schedule I substance that is dephosphorylated in vivo to form an active metabolite, psilocin. Psilacetin, also known as O-acetylpsilocin or 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), is an unscheduled compound that has long been suggested as an alternative psilocin prodrug, though direct in vivo support for this hypothesis has thus far been lacking. Methods This study employed liquid chromatography–tandem mass spectrometry (LC–MS/MS) to assess the time-course and plasma concentrations of psilocin following the intraperitoneal (IP) administration of psilacetin fumarate or psilocybin to male and female C57Bl6/J mice. Results Direct comparisons of the time courses for psilocin exposure arising from psilocybin and psilacetin found that psilocybin led to 10–25% higher psilocin concentrations than psilacetin at 15-min post-injection. The half-life of psilocin remained approximately 30 min, irrespective of whether it came from psilocybin or psilacetin. Overall, the relative amount of psilocin exposure from psilacetin fumarate was found to be approximately 70% of that from psilocybin. Discussion These findings provide the first direct support for the long-standing assumption in the field that psilacetin functions as a prodrug for psilocin in vivo . In addition, these results indicate that psilacetin fumarate results in lower peripheral psilocin exposure than psilocybin when dosed on an equimolar basis. Thoughtful substitution of psilocybin with psilacetin fumarate appears to be a viable approach for conducting mechanistic psychedelic research in C57Bl6/J mice.