Targeting cortisol dysregulation through bioactive compounds: implications for stress, sleep, and mental wellness

Abstract

Stress and sleep disturbances have emerged as significant global health challenges, intricately linked through the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol, the primary stress hormone, serves as a key biomarker of HPA axis activity, influencing metabolism, immune response, and sleep regulation. Chronic elevation of cortisol disrupts circadian rhythm, inhibits melatonin synthesis, and contributes to insomnia, anxiety, and fatigue. Therefore, identifying bioactive compounds capable of modulating cortisol and restoring HPA axis balance offers a natural strategy for improving stress resilience and sleep quality. This review consolidates scientific evidence on several plant-derived and microbial bioactive compounds with cortisol-lowering and sleep-promoting effects. Bioactive compounds that modulate the HPA axis, therefore, represent a multidimensional therapeutic opportunity, acting not only on endocrine regulation but also on neurochemical balance and immune modulation. Integrating these compounds into dietary or nutraceutical interventions could provide a preventive and restorative approach for individuals experiencing chronic stress or sleep disorders. Withania somnifera (ashwagandha) exhibits adaptogenic properties via withanolides that downregulate cortisol and improve sleep onset. Panax ginseng contains ginsenosides that modulate stress hormone release and enhance neural adaptability. Ganoderma lucidum (reishi mushroom) triterpenoids exert anxiolytic and sedative effects, promoting restorative sleep. Centella asiatica triterpenes, including asiaticoside and madecassoside, contribute to cortisol regulation and neuroprotection, improving REM sleep architecture. Matricaria chamomilla flavonoids, notably apigenin, interact with GABAergic receptors and reduce HPA hyperactivation. Emerging evidence also highlights postbiotics, such as those from Limosilactobacillus fermentum PS150 and Bifidobacterium breve BB091109, which influence the gut–brain axis by enhancing neurotransmitter balance, reducing systemic inflammation, and lowering cortisol. 

The novelty of this study lies in presenting an integrated linkage between plant-derived bioactive compounds and postbiotics in the regulation of stress and sleep through modulation of the HPA axis. This framework highlights their potential influence on cortisol dynamics, providing valuable insights for the future development of functional products aimed at stress reduction and the promotion of mental wellness. 

Future research should focus on clinical validation, pharmacokinetic profiling, and formulation optimization to translate these natural agents into evidence-based functional foods and nutraceuticals capable of safely supporting stress regulation and sleep health.

Keyword: Cortisol modulation, Sleep quality, Hypothalamic-pituitary-adrenal (HPA) axis regulation, Adaptogenic bioactive compounds, Gut-brain axis, Neuroendocrine regulation