The combination of exercise and psychedelics for the treatment of major depressive disorder
Nicholas Fabiano, Brendon Stubbs, David W. Lawrence, Joshua D. Rosenblat, Pedro J. Teixeira, Stanley Wong, Carl Zhou, Robin Carhart-Harris
Discover Mental Health March 7, 2026 Peer reviewed DOI: 10.1007/s44192-026-00408-5 via OpenAlex
Summary
Over 50% of individuals with major depressive disorder do not respond to standard treatments, prompting interest in alternative methods like exercise and psychedelics. While both have shown positive effects individually, their combined potential remains unexplored. Exercise and psychedelics may enhance brain function through different mechanisms, such as boosting brain-derived neurotrophic factor (BDNF) and serotonin release. Future studies are needed to investigate the effectiveness and safety of using these two approaches together.
Study at a glance
| Design | commentary |
|---|---|
| Population | individuals with major depressive disorder |
| Key finding | Exercise and psychedelics may work together to improve treatment outcomes for major depressive disorder through complementary biological mechanisms. |
Abstract
Upwards of 50% of people do not respond to the primary treatment modalities for major depressive disorder (MDD), which has led to increased attention and use of alternative methods, including exercise and psychedelics. While interventions using either exercise or psychedelics have demonstrated largely positive results in isolation, their synergistic potential has yet to be explored. As such, this commentary provides an overview of exercise/psychedelics as a treatment for depression and their potential synergy and/or complementarity. From a biological perspective, psychedelics acutely enhance brain-derived neurotrophic factor (BDNF) signalling, while exercise provides sustained BDNF elevation; psychedelics enhance neuroplasticity largely in the cortex (with only modest effects in the hippocampus), while exercise boosts hippocampal neurogenesis; psychedelics increase glutamate release via stimulation of 5-HT2A receptors on pyramidal neurons, while exercise enhances glutamatergic transmission via the endocannabinoid system and reduction of systemic inflammation; both boost serotonin release; and psychedelics temporarily disrupt functional connectivity between the hippocampus and default mode network (DMN), while exercise normalizes this connectivity, which may sustain post-psychedelic gains. Through the lens of psychological and behaviour change, psychedelics appear to facilitate the adoption or maintenance of physical activity habits, increase psychological flexibility, and since exercise is associated with emotional resilience to acute stress, this may allow users to experience deeper immersion and exploration during their psychedelic experience, improving antidepressant outcomes. In summary, exercise and psychedelics have numerous potential complementary mechanisms, therefore, future research is warranted to explore the efficacy, tolerability, safety, and neurobiology of this combination.