TY - JOUR

T1 - Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice

AU - Fadahunsi, Nicole

AU - Lund, Jens

AU - Breum, Alberte Wollesen

AU - Mathiesen, Cecilie Vad

AU - Larsen, Isabella Beck

AU - Knudsen, Gitte Moos

AU - Klein, Anders Bue

AU - Clemmensen, Christoffer

N1 - © 2022. The Author(s).

PY - 2022

Y1 - 2022

N2 - Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to 'addictive-like' behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism, and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.

AB - Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to 'addictive-like' behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism, and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.

KW - Animals

KW - Energy Metabolism

KW - Feeding Behavior

KW - Hallucinogens/pharmacology

KW - Humans

KW - Mice

KW - Obesity/drug therapy

KW - Psilocybin/pharmacology

KW - Weight Loss

U2 - 10.1038/s41398-022-02103-9

DO - 10.1038/s41398-022-02103-9

M3 - Journal article

C2 - 35953488

VL - 12

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - 330

ER -