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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Microdosing |
| Keywords | Endocrinology Insulin resistance Type 2 diabetes Pharmacology Metabolic syndrome Leptin Carbohydrate metabolism Skeletal muscle Insulin receptor Diabetes mellitus Glucose uptake |
| Citations | 3 |
| Key points | 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.
Comparable studies
Other preclinical and animal studies on serotonin, 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 | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 4
- Pharmacokinetics and safety of a modified‐release psilocybin formulation: A SAD Phase I trial in normal‐weight and overweight/obese participants British Journal of Clinical Pharmacology September 21, 2026
- Psilocybin, From Ancestral Use to Therapeutic Potential: A Multidimensional Review of Its Pharmacological Basis and Current Perspectives Human Psychopharmacology: Clinical and Experimental September 1, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N -Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure Journal of Medicinal Chemistry January 26, 2026
Cites 15
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Microdosing psychedelics: personality, mental health, and creativity differences in microdosers Psychopharmacology January 2, 2019
- Psychedelic Microdosing: Prevalence and Subjective Effects Journal of Psychoactive Drugs January 23, 2020
- Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities Journal of Psychopharmacology February 28, 2020
and 10 more in the library