In a groundbreaking new study published in Translational Psychiatry, scientists report compelling findings on the acute and long-term effects of psilocybin, the psychoactive compound in “magic mushrooms,” on energy balance and feeding behavior in mice. This research opens a novel frontier in understanding how psychedelics interact with metabolic processes and appetite regulation, potentially paving the way for innovative treatments targeting metabolic disorders, obesity, and even psychiatric conditions with metabolic components.
Researchers have long been intrigued by the complex interplay between the brain’s serotonergic system—one of the primary targets of psilocybin—and the regulation of feeding and energy homeostasis. Serotonin is well-known not only for its role in mood modulation but also for its pivotal influence over appetite and metabolic rate. Psilocybin, acting as a potent serotonin receptor agonist, especially at the 5-HT2A receptor subtype, triggers a cascade of neural effects, many of which remain underexplored in the context of metabolism. This study fills a crucial gap by systematically characterizing how acute psilocybin administration impacts food intake and energy expenditure, along with mapping persistent long-term outcomes following single and repeated exposures.
The experiment was meticulously designed using murine models to allow fine-grained physiological monitoring alongside behavioral assays. Initially, psilocybin was administered intraperitoneally at doses reflecting psychoactive ranges relative to human consumption. Researchers recorded immediate effects on food consumption, noting a significant suppression of appetite within the first 24 hours. This anorectic effect coincides with activation of central serotonergic circuits that communicate satiety signals, supporting prior hypotheses that psychedelics can acutely curb feeding behavior through neuromodulation.
Crucially, beyond this short-term reduction in eating, the study delved into longitudinal analyses, tracking mice for weeks post-treatment to observe enduring changes. Remarkably, psilocybin-treated animals exhibited sustained alterations in energy balance physiology—manifested as stabilized body weights despite normalized food intake. Metabolic cages revealed enhanced energy expenditure through increased locomotor activity and thermogenesis, suggesting that psilocybin writes a persistent “metabolic tune” that elevates baseline caloric burn. These findings underscore a dual mechanism by which psilocybin may recalibrate energy homeostasis: immediately dampening appetite and subsequently amplifying metabolic rate.
Molecular investigations provided deeper mechanistic insight. Transcriptomic profiling of hypothalamic tissue highlighted significant modulation of genes implicated in appetite regulation, lipid metabolism, and mitochondrial function. Notably, expression of neuropeptides such as pro-opiomelanocortin (POMC), an anorexigenic factor, was upregulated, whereas orexigenic neuropeptides like neuropeptide Y (NPY) were suppressed. Concurrently, markers of mitochondrial biogenesis and oxidative phosphorylation showed increased activity, paralleling enhanced energy expenditure measurements. These data illustrate that psilocybin invokes a broad reprogramming of metabolic gene networks, potentially via epigenetic mechanisms that warrant further exploration.
Behaviorally, treated mice displayed subtle yet significant changes in feeding patterns, with reduced meal frequency but preserved meal size, implying modulation at the level of hunger signaling rather than satiety. This nuanced alteration indicates that psilocybin may rewire neural circuitry governing the motivational aspects of feeding without compromising the ability to consume in response to deprivation. Interestingly, these behavioral changes co-occurred with reduced anxiety-like phenotypes as measured by standard rodent tests, aligning with psilocybin’s established psychoactive anxiolytic effects. Such interplay between mood, anxiety, and feeding behaviors highlights the compound’s potential for integrated neuropsychiatric-metabolic interventions.
The significance of this research extends well beyond rodents. Given psilocybin’s imminent rise in clinical and therapeutic applications for conditions such as depression, PTSD, and addiction, understanding its metabolic side effects and benefits is crucial. Obesity and metabolic syndrome often coexist with psychiatric illnesses, and current treatments rarely address both domains effectively. Psilocybin, by simultaneously modulating mood and metabolism, might represent a paradigm shift in multifaceted treatment strategies.
From a pharmacological perspective, this study revitalizes interest in serotonergic psychedelics not only as psychotherapeutics but also as agents capable of influencing fundamental biological processes like energy homeostasis. The 5-HT2A receptor’s role in regulating cortical plasticity and behavior is well established, but its downstream impact on hypothalamic circuits managing hunger and energy expenditure opens exciting avenues for drug development. Targeted agonists or modulators derived from psilocybin’s molecular scaffold could be engineered to optimize metabolic outcomes while minimizing hallucinogenic effects.
Importantly, the dose-dependent analysis in the study revealed a therapeutic window where metabolic benefits are maximized without overt behavioral disruption. This fine balance between efficacy and psychoactivity will be critical in translating findings into safe clinical protocols for humans. Furthermore, the durability of psilocybin’s effects on energy metabolism, persisting well beyond the clearance of the drug from the body, points toward lasting neural circuit remodeling that could underpin sustained therapeutic advantages.
The research also sheds light on the gut-brain axis, positively demonstrating that central effects of psilocybin may indirectly influence peripheral metabolism. Future studies are anticipated to probe the involvement of gut microbiota, enteroendocrine signals, and vagal nerve pathways in mediating the observed phenotypes. Given the dynamic crosstalk between the microbiome and host metabolism, psilocybin’s capacity to alter gut composition or function could be another layer to its multifaceted physiological actions.
Critically, the authors acknowledge limitations in translating murine data directly to humans but emphasize the robust experimental design, including controlled dosing, multiple behavioral endpoints, and complementary molecular analyses, which strengthen the study’s internal validity. They call for clinical trials evaluating metabolic endpoints in human psilocybin study participants—which could significantly influence dosing strategies for therapeutic use, particularly in populations vulnerable to metabolic dysfunction.
In conclusion, this pioneering study reveals that psilocybin exerts profound acute and long-lasting effects on energy balance and feeding behavior in mice, mediated through serotonergic receptor pathways and complex neuroendocrine gene regulation. It offers a compelling biological rationale for further exploration of psychedelics as modulators of metabolism, potentially heralding innovative treatments for obesity, eating disorders, and metabolic comorbidities of psychiatric diseases. As psychedelics transition to mainstream medicine, integrating metabolic considerations will be vital to harnessing their full therapeutic potential.
By illuminating previously unrecognized roles of psilocybin in fundamental energy physiology, this research sets the stage for a new era of psychedelic science—one that bridges neuroscience, metabolism, and psychiatry, promising holistic intervention strategies that transform patient outcomes. As the field advances, multidisciplinary collaborations will be essential to disentangle the intricate networks influenced by psilocybin, optimize clinical applications, and ensure safety in therapeutic contexts inviting profound neurobiological modulation.
Subject of Research: Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice.
Article Title: Correction: Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice.
Article References:
Fadahunsi, N., Lund, J., Breum, A.W. et al. Correction: Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice. Transl Psychiatry 15, 466 (2025). https://doi.org/10.1038/s41398-025-03729-1
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