Stress is an ambiguous term better understood biologically through the concepts of “allostasis” and “allostatic load,” with the former referring to the active process by which the body responds to daily stressors and maintains homeostasis, and the latter referring to the physiological and behavioral consequences of either too much stress or from inefficient management of allostasis (McEwen, 2007.) In this context, the term “stressed” is analogous with allostasis, while allostatic load is analogous with “stressed out (McEwen, 2005.)”

Allostasis refers to the body’s ability to achieve stability through change, and involves the release of chemical mediators of the stress response, primarily cortisol, sympathetic and parasympathetic hormones and neurotransmitters, cytokines and metabolic hormones. Allostatic load, in contrast, is the wear and tear that results from the sustained release of these mediators due to (a) repeated “hits” from multiple stressors, (b) a lack of adaptation or habituation, (c) prolonged response due to delayed shutdown, and/or (d) inadequate response that leads to compensatory hyperactivity of other mediators (McEwen, 2011.)

Both acute and chronic stress can contribute to disease onset and progression (Cohen S, Janicki-Deverts D, Miller GE, 2007.) Acute stress may play a contributory role in the development of symptoms that are allergic or atopic in nature, vasomotor, gastrointestinal, or psychological. Chronic stress may contribute to the development of several physical, behavioral and/or neuropsychiatric disorders including anxiety, depression, cognitive dysfunction, sleep disorders, cardiovascular disease, obesity, type 2 diabetes mellitus, and osteoporosis, amongst many others (Chrousos GP, 2009.) 

A primary effector of the stress response is the hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of which plays a fundamental role in the development of stress-related pathophysiology (Tsigos C, Chrousos GP, 2002.) Altered HPA axis activity and dysregulation of the adaptive stress response can be divided into two patterns; (1) increased HPA axis activity and stress system hyperarousal, (Jankord R, Herman JP, 2008) and (2) decreased HPA axis activity and stress system hyporarousal (Heim C, Ehlert U, Hellhammer DH, 2000.) These different pathophysiological presentations of chronic stress have been associated with different clinical manifestations (see table 1) (Tsigos C, Kyrou I, Kassi E, et al, 2016.)

Table 1: Examples of Clinical Conditions Associated with Altered HPA Axis Activity

The brain is the central mediating organ of the stress response as it determines what is stressful and directs the physiological and behavioral aspects of stress (McEwen BS, 2017.) Deleterious effects of chronic stress include changes to the structure and function of the brain, in particular atrophy of nerve cells in the hippocampus (involved in learning and memory) and prefrontal cortex (working memory, executive function) and hypertrophy of amygdala (fear response), which, in turn, can contribute to impaired HPA axis regulation and increased vulnerability to chronic stress (McEwen BS, 2004.) A healthy brain is therefore crucial for maintaining resiliency to stress and subsequently safeguarding mental and physical wellbeing (Juster RP, McEwen BS, Lupien SJ, 2010.)

From an integrative, systems biology perspective stress-related disorders can be viewed as the result of an interplay between an individual’s environment, genetic predisposition, neural processing and subsequent dynamic, compensatory, and proactive adjustments in the activities of chemical mediators of the stress response (Goldstein DS, 2013.) Clinical management should therefore focus on improving external coping resources and stress-related physiology, including reducing strain on the body’s adaptive physiological systems and opening windows of opportunity for the brain to repair, adapt, and become more resilient (McEwen BS, 2016.)

Dietary modification and nutritional interventions can be used to support unique clinical and pathophysiological presentations by influencing behavioral and biological aspect of the stress response (Waladkhani AR, Hellhammer J, 2008) (Head KA, Kelly GS, 2009.) Optimization of nutritional status may improve the response of the HPA-axis to stress, with some evidence to support a role for nutritional interventions such as multivitamin and mineral complexes, magnesium, vitamin C (ascorbic acid) and omega-3 polyunsaturated fatty acids (omega-3 PUFA), although research specifically examining the effect of nutrients on HPA-axis function is sparse.

One study found that supplementation with a multivitamin containing B-vitamins in relatively healthy adults resulted in a near-significant trend towards an increased cortisol awakening response over a 16-week period, suggesting an improved adaptive response to stress (Camfield DA, Wetherell MA, Scholey AB, et al, 2013.) Magnesium also appears to influence HPA axis function, with supplementation shown to attenuate elevation in cortisol and increase ACTH secretion in response to physical stress (Dmitrašinović G, Pešić V, Stanić D, Plećaš-Solarović B, Dajak M, Ignjatović S, 2016) (Cinar V, Mogulkoc R, Baltaci AK, Polat Y, 2008.) And in patients with primary insomnia, magnesium supplementation was found to significantly decrease serum cortisol concentration (Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B, 2012.) Treatment with vitamin C has been shown to reduce cortisol reactivity to acute physiological stress, (Brody S, Preut R, Schommer K, Schürmeyer TH, 2002) (Plotnick MD, D’Urzo KA, Gurd BJ, Pyke KE, 2017) and lower basal cortisol levels within 2-weeks (Yeom HH et al, 2008.) Finally, dietary supplementation with omega-3 PUFA has been shown to reduce cortisol in healthy adults, (Delarue J, Matzinger O, Binnert C, Schneiter P, Chioléro R, Tappy L, 2003) patients with major depressive disorder, (Jazayeri S, Keshavarz SA, Tehrani-Doost M, Djalali M, Hosseini M, Amini H, Chamari M, Djazayery A, 2010) and abstinent alcoholics (Barbadoro P, Annino I, Ponzio E, Romanelli RM, D’Errico MM, Prospero E, Minelli A, 2013.)

Improving an individual’s nutritional status could therefore be useful clinically for the management of stress-related illness with physiological evidence of HPA-axis dysfunction. Salivary cortisol is a sensitive measure of dynamic HPA axis activity and can be used in a clinical setting (Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM, 2005.) Biochemical assessment of nutritional status may help personalize interventions by identifying people with sub-optimal nutritional intakes and increased physiological requirements. Currently, the evaluation of HPA-axis dysfunction and personalized nutrition are clinically implemented for the management of stress related illness. More research, however, is needed to clarify the potential of this promising approach.



Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B (2012). The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. J Res Med Sci, 17(12):1161-9.

Barbadoro P, Annino I, Ponzio E, Romanelli RM, D’Errico MM, Prospero E,Minelli A (2013). Fish oil supplementation reduces cortisol basal levels and perceived stress: a randomized, placebo-controlled trial in abstinent alcoholics. Mol Nutr Food Res, ;57(6):1110-4.

Brody S, Preut R, Schommer K, Schürmeyer TH (2002). A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology (Berl), 159(3):319-24.

Camfield DA, Wetherell MA, Scholey AB, et al (2013). The effects of multivitamin supplementation on diurnal cortisol secretion and perceived stress. Nutrients, 5(11):4429-50.

Chrousos GP (2009). Stress and disorders of the stress system (July 1, 2009). Nat Rev Endocrinol, 5(7):374-81.

Cinar V, Mogulkoc R, Baltaci AK, Polat Y (2008). Adrenocorticotropic hormone and cortisol levels in athletes and sedentary subjects at rest and exhaustion: effects of magnesium supplementation. Biol Trace Elem Res, (121):215–20.

Cohen S, Janicki-Deverts D, Miller GE (2007). Psychological stress and disease. JAMA. 10;298(14):1685-7.

Delarue J, Matzinger O, Binnert C, Schneiter P, Chioléro R, Tappy L (2003). Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab, 29(3):289-95.

Dmitrašinović G, Pešić V, Stanić D, Plećaš-Solarović B, Dajak M, Ignjatović S (2016). ACTH, Cortisol and IL-6 Levels in Athletes following Magnesium Supplementation. J Med Biochem, 35(4):375-384.

Goldstein DS (2013). Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems. Compr Physiol, 3(4):1569-610.

Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM (2005). Salivary cortisol determined by enzyme immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic–pituitary–adrenal axis activity. Clin Endocrinol (Oxf), 63(3):336-341.

Head KA, Kelly GS (2009). Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev, 14(2):114-40.

Heim C, Ehlert U, Hellhammer DH (2000). The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25(1):1-35.

Jankord R, Herman JP (2008). Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann N Y Acad Sci, 1148:64-73.

Jazayeri S, Keshavarz SA, Tehrani-Doost M, Djalali M, Hosseini M, Amini H, Chamari M, Djazayery A (2010). Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder. Psychiatry Res, 178(1):112-5.

Juster RP, McEwen BS, Lupien SJ (2010). Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev, 35(1):2-16.

McEwen BS (2016). In pursuit of resilience: stress, epigenetics, and brain plasticity. Ann N Y Acad Sci, 1373(1):56-64.

McEwen BS (2017). Neurobiological and Systemic Effects of Chronic Stress. Chronic Stress (Thousand Oaks), 1. doi: 10.1177/2470547017692328.

McEwen BS (2007). Physiology and neurobiology of stress and adaptation: central role of the brain. Physiological Reviews, 87, 3, 873-904.

McEwen BS (2004). Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci, 1032:1-7.

McEwen BS (2005). Stressed or stressed out: what is the difference?. Journal of Psychiatry & Neuroscience : Jpn, 30, 5, 315-8.

McEwen BS, & Gianaros PJ (2011). Stress- and Allostasis-Induced Brain Plasticity. Annual Review of Medicine, 62, 1, 431-445.

Plotnick MD, D’Urzo KA, Gurd BJ, Pyke KE (2017). The influence of vitamin C on the interaction between acute mental stress and endothelial function. Eur J Appl Physiol, 117(8):1657-1668.

Tsigos C, Chrousos GP (2002). Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res, 53(4):865-71.

Tsigos C, Kyrou I, Kassi E, et al (2016). Stress, Endocrine Physiology andPathophysiology. In: De Groot LJ, et al (2000). Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. Available from http://www.ncbi.nlm.nih.gov/books/NBK278995/

Waladkhani AR, Hellhammer J (2008). Dietary modification of brain function: effects on neuroendocrine and psychological determinants of mental health- and stress-related disorders. Adv Clin Chem, 45:99-138.

Yeom HH, et al (2008). Changes In Worker Fatigue After Vitamin C Administration. JOM, 28:205-209.