Exercise and may have complementary biological and behavioral mechanisms for treating .
Evidence
This commentary synthesizes proposed mechanisms from exercise and psychedelic interventions, including BDNF signaling, , glutamate and serotonin pathways, functional connectivity, and behavior change.
Caveat
The proposed combination has not yet been directly tested for efficacy, tolerability, safety, or neurobiology in people with major depressive disorder.
Simplified
Upwards of 50% of people do not respond to the primary treatment modalities for (MDD), which has led to increased attention and use of alternative methods, including exercise and . 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 largely in the cortex (with only modest effects in the hippocampus), while exercise boosts hippocampal neurogenesis; psychedelics increase glutamate release via stimulation of 5-HTreceptors 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. 2A
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