Elucidating the Phase I metabolism of psilocin in vitro.
Junqi Chen, Ziteng Wang, Ching Yee Yong, Evelyn Mei Ling Goh, Hooi Yan Moy, Eric Chun Yong Chan
Archives of Toxicology March 1, 2025 DOI: 10.1007/s00204-024-03952-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Human enzymes |
| Intervention | psilocin |
| Topics | Psilocybin |
| Keywords | Metabolic pathways Biotransformation Hallucinogens Psychedelic compounds Liver enzymes mono Cytosolic enzyme Monoamine oxidase Phase i metabolism |
| Citations | 3 |
| Key points | MAO-A is the primary enzyme responsible for psilocin's Phase I metabolism, producing the intermediate 4-HIA, and contributes extensively to both hepatic and extrahepatic clearance. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 2
- Liquid chromatography-tandem mass spectrometry-based pharmacokinetic and metabolic analysis of 4-bromo-2,5-dimethoxyphenethylamine and its metabolites in human plasma. Drug Metabolism and Disposition April 28, 2025
- Synthesis and Characterization of Psilocybin Metabolites and Deuterated Analogs ACS Chemical Neuroscience March 3, 2026
Cites 7
- The pharmacology of psilocybin Addiction Biology October 1, 2002
- Hallucinogens and dissociative agents naturally growing in the United States. Pharmacology & Therapeutics May 1, 2004
- Psychedelic drugs—a new era in psychiatry? Dialogues in Clinical Neuroscience June 30, 2019
- Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants Clinical Pharmacology & Therapeutics December 12, 2022
- In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin Frontiers in Pharmacology April 29, 2024
and 2 more in the library