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Metabolic psychiatry targeting metabolic dysregulation in mental health

Nature Mental Health (2026)Cite this article

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Abstract

Systemic metabolic abnormalities including insulin resistance, lipid dysregulation, mitochondrial dysfunction and inflammation are highly prevalent in psychiatric illness and may contribute to increased mortality, illness severity and treatment resistance. This Review synthesizes current evidence linking systemic and central metabolic dysfunction with mental health outcomes across disorders. We highlight bidirectional interactions between brain function and metabolic state, and examine how psychotropic medications, stressors and disease mechanisms contribute to metabolic burden. In turn, we discuss how systemic dysfunction may impair brain structure and function. We review emerging metabolism-based interventions used in psychiatry, including pharmacologic agents (metformin, glucagon-like peptide-1 agonists and pioglitazone), lifestyle strategies (intermittent fasting, ketogenic metabolic therapy and exercise) and theoretical models (mitochondrial dysfunction, ‘allostatic load model’ and ‘selfish brain hypothesis’). We summarize the interventions, their observed outcomes, and a ranked assessment of the current level of evidence and class of recommendation. This reflects that some metabolic-based approaches show promising results from clinical studies while other emerging strategies remain too preliminary or inconsistent to draw conclusions, underscoring the need for further trials in humans. We conclude by briefly discussing practical and safety considerations, identifying limitations in the current literature, and propose future directions for building a more integrated model of mental and metabolic health.

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Fig. 1: Interactions between the allostatic load model and selfish brain theory to ensure adequate energy supply.
Fig. 2: The cellular-level impacts of various therapeutics that modulate metabolic functioning of the central nervous system.

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Acknowledgements

We wish to acknowledge P-Squared Philanthropies, Baszucki Brain Research Fund (BBRF), Dharma Fund, and Sobrano Fund for philanthropically supporting our work at Stanford Metabolic Psychiatry. Thank you to BBRF and Stellate Communications for helping support the design of the manuscript figure.

Author information

Authors and Affiliations

  1. Metabolic Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Shebani Sethi & Natalie Rasgon

  2. Deakin University, Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Geelong, Victoria, Australia

    Michael Berk

  3. Orygen, Parkville, Victoria, Australia

    Michael Berk

  4. Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia

    Michael Berk

  5. Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia

    Michael Berk

  6. Department of Psychiatry, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia

    Michael Berk

  7. Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

    Ana Cristina Andreazza

  8. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Ana Cristina Andreazza

  9. Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA

    Lilianne Rivka Mujica-Parodi

  10. Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY, USA

    Lilianne Rivka Mujica-Parodi

  11. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

    Lilianne Rivka Mujica-Parodi

  12. Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Lilianne Rivka Mujica-Parodi

  13. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Lilianne Rivka Mujica-Parodi

  14. Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK

    Iain Campbell

  15. Usher Institute, University of Edinburgh, Edinburgh, UK

    Harry Campbell

  16. Discipline of Mental Health, College of Medicine and Dentistry, James Cook University Clinical School, Douglas, Queensland, Australia

    Calogero Longhitano

  17. Mental Health Service Group, Townsville University Hospital, Douglas, Queensland, Australia

    Calogero Longhitano

  18. Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia

    Calogero Longhitano & Zoltan Sarnyai

  19. Margaret Roderick Centre for Mental Health Research, James Cook University, Townsville, Queensland, Australia

    Calogero Longhitano & Zoltan Sarnyai

  20. Department of Human Sciences, The Ohio State University, Columbus, OH, USA

    Jeff Volek

  21. Departments of Psychiatry and Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada

    Cynthia Victoria Calkin

  22. Mental Health, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

    Judith Ford

  23. Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA

    Judith Ford

  24. Department of Neurosciences and Psychiatry, University of Toledo, Toledo, OH, USA

    Robert McCullumsmith

  25. Neurosciences Institute, Promedica, Toledo, OH, USA

    Robert McCullumsmith

  26. Department of Medicine and Research Centre on Aging, Université de Sherbrooke, Sherbrooke, Quebec, Canada

    Stephen Cunnane

  27. Clinic for Adult Psychiatry, University Psychiatric Clinics, University of Basel, Basel, Switzerland

    Timur Liwinski

  28. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA

    Dominic D’Agostino

  29. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Mark Frye

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Contributions

S.S. and Z.S. developed the concept and drafted the paper. M.B., A.C.A., L.R.M.-P., I.C., H.C., C.L., N.R., J.V., C.V.C., J.F., R.M., S.C., T.L., D.D’A. and M.F. critically revised the paper for important intellectual content.

Corresponding authors

Correspondence to Shebani Sethi or Zoltan Sarnyai.

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Competing interests

S.S. has served as a scientific advisor for Found Health and is a co-founder of Metabolic Psychiatry Labs. Z.S. is chief scientist at Ally Sciences Ltd. M.B. has served as a consultant to AstraZeneca, Otsuka Pharmaceutical, Glaxosmithkline, Janssen Cilag, Lundbeck Merck and Servier. L.R.M.-P. is a cofounder of Neuroblox. S.C. has served as an adviser to Abbott Laboratories, Cargill and holds a patent with Nestle Health Sciences. The other authors declare no competing interests.

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Nature Mental Health thanks Riccardo De Giorgi, Luigi Saccaro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sethi, S., Berk, M., Andreazza, A.C. et al. Metabolic psychiatry targeting metabolic dysregulation in mental health. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00609-5

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