Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms
Martina Colognesi, Daniela Gabbia, Anna Signor, Miles Sarill, Lucia Centofanti, Andrea Rinaldi, Luciano Cascione, Sara Nunziata, Marco Banzato, Andrea Mattarei, Giovanna Finzi, Sonia Sonda, Diana Pendin, Ilaria Zanotto, Stefano Comai, Gianfranco Pasut, Abdullah Alajati, Miriam Saponaro, Loredana Bucciarelli, Maria Elena Lunati, Giulia Guarato, Ilaria Goggi, Stefano la Rosa, Camillo Morano, Rita Clara Paroni, Michele Dei, Giuseppe Daniele, Marco Gentilucci, Marco Pappagallo, Andrea Alimonti, Paolo L. Manfredi, Franco Folli, Sara de Martin
Pharmacological Research December 29, 2025 DOI: 10.1016/j.phrs.2025.108080 via OpenAlex
Summary
AI-generated from the abstractChronic low-dose psilocybin (0.05 mg/kg) reduced body-weight gain, liver steatosis, hyperglycemia, and insulin resistance in mice fed a high-fat/high-fructose diet, without causing central nervous system effects. Multi-omics analyses showed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. The metabolic benefits were independent of the psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver, supporting psilocybin as a potential novel therapeutic for metabolic disorders.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice fed a high-fat/high-fructose diet |
| Intervention | Psilocybin |
| Dose | 0.05 mg/kg |
| Duration | 12 weeks |
| Topics | Psilocybin Serotonin |
| Keywords | Endocrinology Insulin resistance Internal medicine Type 2 diabetes Pharmacology |
| Citations | 3 |
| Key finding | Chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects. |
Abstract
The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.