P.0729 Highlights of psychedelic history and current research on psilocybin application for treatment of depression – a comprehensive literature review

Penedos, Sara; Ramos, Caio Freitas; Miguel, María José López; Alves, Márcio José Martins; Paulino, Luciana Campos; Azevedo, Auro Mauro; Magalhães, Marcelo Oliveira; Moreno, L.; Ribeiro, Nuno Filipe da Silva; Fonseca, I.; Franco, Ana Margarida Romão; Madruga, L.; Gamito, A.

doi:10.1016/j.euroneuro.2021.10.797

Cited by 1 publication

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“…For clinical studies using human participants, there is less likelihood of accelerating progress through substitution alone, given the additional regulatory considerations involved. However, there may be other compensatory benefits to the pursuit of psilacetin or other novel psilocin prodrug strategies as alternatives to psilocybin for human research studies, such as the possibility of reduced ethical, legal, and sustainability concerns by avoiding the commercialization of a natural product with a long documented history of sacramental use by indigenous peoples ( 18 , 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

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

Jones,

Wagner,

Hahn

et al. 2024

Front. Psychiatry

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IntroductionThe 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.MethodsThis 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.ResultsDirect 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.DiscussionThese 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.

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Section: Discussionmentioning

confidence: 99%