Stress, Mental Health, and Tissue Healing

Chronic psychological stress negatively affects musculoskeletal and tissue healing by disrupting the hypothalamic–pituitary–adrenal (HPA) axis, which regulates hormonal stress responses and maintains immune balance. Stress also activates the sympathetic nervous system (“fight-or-flight”), altering immune function, increasing pro-inflammatory cytokines, and delaying wound healing, bone repair, and overall tissue regeneration [Christian et al., 2006; Makyeyeva et al., 2025; Romana-Souza et al., 2023; Haffner-Luntzer et al., 2019].

Acute vs Chronic Stress Responses

During acute stress, activation of the HPA axis increases cortisol production, which helps limit excessive inflammation, maintain cardiovascular stability, and protect tissues during injury and recovery [Russell & Lightman, 2019; Nicolaides et al., 2015].

However, chronic stress and prolonged elevated cortisol impair tissue healing by:

Inhibiting angiogenesis (formation of new blood vessels)
Reducing collagen synthesis
Suppressing immune function

These mechanisms contribute to delayed repair and prolonged recovery [Miller & Auchus, 2020; Nicolaides et al., 2015].

Stress-Induced Neuroplasticity and Pain

Chronic stress can induce maladaptive neuroplasticity, particularly in the prefrontal cortex and corticolimbic pathways, increasing pain perception and raising the risk of mood disorders. Stress-related neuroinflammation further hinders recovery and contributes to persistent pain [Ren et al., 2025; Algaidi, 2025; Radley et al., 2015; Vachon-Presseau, 2018; Li et al., 2017; Rivat et al., 2010; Koo & Wohleb, 2021; Kokkosis et al., 2024; White et al., 2024].

Psychological Disorders and Wound Healing

Depression and anxiety significantly affect healing outcomes:

Depression is consistently associated with delayed wound repair, higher complication rates, increased infection risk, persistent inflammation, and impaired immune function. Behavioral factors such as reduced self-care and poor adherence to treatment further impede recovery [O’Donovan et al., 2025; Jian et al., 2021; Cole-King & Harding, 2001].
Anxiety may also impair healing, though evidence is less consistent than for depression [O’Donovan et al., 2025; Cole-King & Harding, 2001].

Positive Psychological Interventions

Conversely, positive mood, strong social support, and mindfulness-based stress reduction (MBSR) can enhance tissue healing by lowering stress and reducing pro-inflammatory cytokines, creating a favorable environment for recovery [Broadbent & Koschwanez, 2012; Meesters et al., 2018].

References:

Algaidi, S.A., 2025. Chronic stress-induced neuroplasticity in the prefrontal cortex: structural, functional, and molecular mechanisms from development to aging. Brain Research

Broadbent, E. & Koschwanez, H.E., 2012. The psychology of wound healing. Current Opinion in Psychiatry, 25(2), pp.135–140. https://doi.org/10.1097/YCO.0b013e32834e1424

Christian, L.M., Graham, J.E., Padgett, D.A. et al., 2006. Stress and wound healing. Neuroimmunomodulation, 13(5–6), pp.337–346. https://doi.org/10.1159/000104862

Cole-King, A. & Harding, K.G., 2001. Psychological factors and delayed healing in chronic wounds. Psychosomatic Medicine, 63(2), pp.216–220. https://doi.org/10.1097/00006842-200103000-00004

Haffner-Luntzer, M., Foertsch, S., Fischer, V. et al., 2019. Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling. Proceedings of the National Academy of Sciences, 116(17), pp.8615–8622. https://doi.org/10.1073/pnas.1819218116

Jian, J., Yi-Heng, H., Bang-Hui, Z. et al., 2021. Effects of depression on healing and inflammatory responses of acute wounds in rats.

Koo, J.W. & Wohleb, E.S., 2021. How stress shapes neuroimmune function: implications for the neurobiology of psychiatric disorders. Biological Psychiatry

Kokkosis, A.G., Madeira, M.M., Hage, Z. et al., 2024. Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior. Glia

Li, M.J., Liu, L.Y., Chen, L. et al., 2017. Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala. Pain

Makyeyeva, L., Belenichev, I., Aliyeva, O. et al., 2025. Impact of chronic social stress on molecular markers of skin regeneration during experimental excisional wounding. Frontiers in Immunology, 16, p.1656214. https://doi.org/10.3389/fimmu.2025.1656214

Meesters, A., den Bosch-Meevissen, Y.M.C.I., Weijzen, C.A.H. et al., 2018. The effect of mindfulness-based stress reduction on wound healing: a preliminary study. Journal of Behavioral Medicine, 41(3), pp.385–397. https://doi.org/10.1007/s10865-017-9901-8

Nicolaides, N.C., Kyratzi, E., Lamprokostopoulou, A. et al., 2015. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation, 22(1–2), pp.6–19. https://doi.org/10.1159/000362736

O’Donovan, F., Capobianco, L., Taylor-Bennett, J. & Wells, A., 2025. Relationships between anxiety, depression and wound healing outcomes in adults: a systematic review and meta-analysis. PLoS One, 20(5), p.e0309683. https://doi.org/10.1371/journal.pone.0309683

Radley, J.J., Morilak, D.A., Viau, V. & Campeau, S., 2015. Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes. Neuroscience & Biobehavioral Reviews

Ren, B., Yuan, Q., Cha, S. et al., 2025. Maladaptive neuroplasticity under stress: insights into neuronal and synaptic changes in the prefrontal cortex. Molecular Neurobiology

Romana-Souza, B., Chen, L. & DiPietro, L.A., 2023. Repeated stress-induced crosstalk between the sympathetic nervous system and mast cells contributes to delayed cutaneous wound healing in mice. Journal of Neuroimmunology, 379, p.578104. https://doi.org/10.1016/j.jneuroim.2023.578104

Russell, G. & Lightman, S., 2019. The human stress response. Nature Reviews Endocrinology, 15(9), pp.525–534. https://doi.org/10.1038/s41574-019-0228-0

White, A.G., Elias, E., Orozco, A. et al., 2024. Chronic stress-induced neuroinflammation: relevance of rodent models to human disease. International Journal of Molecular Sciences

​Stress, Mental Health, and Tissue Healing