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<p>Psilocin is a well-studied controlled substance with potential psychotherapeutic applications. However, research gaps remain regarding its metabolism. Our objective was to elucidate a comprehensive Phase I metabolic profile of psilocin to support its forensic management and clinical development. We utilized human enzymes from various sources to characterize the Phase I metabolism of psilocin and estimated its hepatic and extrahepatic clearances via in vitro to in vivo extrapolation. We identified 2-(4-hydroxy-1H-indol-3-yl)-acetaldehyde (4-HIA) as the Phase I intermediate metabolite for the first time. Psilocin was metabolized to 4-HIA by monoamine oxidase A (MAO-A), and further metabolized to the terminal metabolite 2-(4-hydroxy-1H-indol-3-yl)-acetic acid (4-HIAA) by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs). MAO-A-mediated hepatic clearance of psilocin (CL<sub>H,MAO-A</sub>) was estimated to be 158.74&#xa0;mL/min, accounting for 80.9% of the total hepatic metabolism of psilocin (CL<sub>H,all</sub>). MAO-A primarily contributed to the Phase I metabolism of psilocin. Total MAO-A-mediated organ clearance (CL<sub>all organs,MAO-A</sub>) was estimated to be 614.81&#xa0;mL/min, with CL<sub>H,MAO-A</sub> accounting for 25.8%, indicating extensive MAO-A-mediated extrahepatic clearance of psilocin. Overall, our study sheds novel insights on Phase I metabolic pathway of psilocin and illuminated the importance of MAO-A-mediated hepatic and extrahepatic clearances of psilocin.</p>

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Elucidating the Phase I metabolism of psilocin in vitro

  • 期刊论文

  • 发表日期：

    2025年1月3日

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  • Junqi Chen,
  • Ziteng Wang,
  • Ching Yee Yong,
  • Evelyn Mei Ling Goh,
  • Hooi Yan Moy,
  • Eric Chun Yong Chan

摘要

Psilocin is a well-studied controlled substance with potential psychotherapeutic applications. However, research gaps remain regarding its metabolism. Our objective was to elucidate a comprehensive Phase I metabolic profile of psilocin to support its forensic management and clinical development. We utilized human enzymes from various sources to characterize the Phase I metabolism of psilocin and estimated its hepatic and extrahepatic clearances via in vitro to in vivo extrapolation. We identified 2-(4-hydroxy-1H-indol-3-yl)-acetaldehyde (4-HIA) as the Phase I intermediate metabolite for the first time. Psilocin was metabolized to 4-HIA by monoamine oxidase A (MAO-A), and further metabolized to the terminal metabolite 2-(4-hydroxy-1H-indol-3-yl)-acetic acid (4-HIAA) by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs). MAO-A-mediated hepatic clearance of psilocin (CLH,MAO-A) was estimated to be 158.74 mL/min, accounting for 80.9% of the total hepatic metabolism of psilocin (CLH,all). MAO-A primarily contributed to the Phase I metabolism of psilocin. Total MAO-A-mediated organ clearance (CLall organs,MAO-A) was estimated to be 614.81 mL/min, with CLH,MAO-A accounting for 25.8%, indicating extensive MAO-A-mediated extrahepatic clearance of psilocin. Overall, our study sheds novel insights on Phase I metabolic pathway of psilocin and illuminated the importance of MAO-A-mediated hepatic and extrahepatic clearances of psilocin.