The HPA Axis: Evidence-Based Adaptogens to Restore Homeostasis

Disruptions to this crucial system drive stress, disturb sleep and feed fatigue; how to help patients reset, recalibrate and restore balance.

Of all the complaints encountered by practitioners, sleep issues, stress and fatigue are perhaps the most prevalent. These (and many other) conditions share a common cause: an imbalance in the hypothalamus-pituitary-adrenal (HPA) axis. Made up of the hypothalamus, the pituitary gland and the adrenal glands, the HPA axis is the body’s command center for regulating stress, and disruptions are linked with a myriad of mental and physical problems. The ability to react to and manage stress effectively depends on a well-functioning HPA axis: here’s what you need to know about its mechanisms of action, consequences of dysfunction and science-backed botanicals shown to restore balance.

 

The HPA axis: mechanisms, malfunctions and ramifications.

The physiological response to stress involves the activation of the HPA axis, a complex system of neuroendocrine pathways and feedback loops designed to modulate stress and maintain homeostasis. In the presence of physical, emotional or psychological stressors, the body responds by releasing corticotropin-releasing hormone (CRH) into the bloodstream. This stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH), which then prompts the adrenal glands to produce cortisol. The rise in cortisol levels feeds back to the hypothalamus and pituitary gland, inhibiting subsequent release of CRH and ACTH. Under normal conditions, the HPA axis returns to homeostasis following acute activation. But disturbances in this tightly regulated system harm multiple aspects of health, associated with a range of physiological and mental disorders.^{1, 2, 3}

Various factors, including certain illnesses and medical conditions, environmental toxins, undiagnosed infections, poor nutrition and uncontrolled inflammation can affect the HPA axis. Prolonged exposure to stress triggers excessive cortisol and throws the HPA axis out of balance. HPA axis dysfunction also impairs the production of melatonin and other hormones, interfering with sleep. Because sleep and stress exist in a bidirectional relationship, sleep loss further impacts the HPA axis, leading to HPA hyperactivity and creating a frustrating cycle of stress, sleep disruptions and ongoing fatigue. Besides disturbing restful sleep, HPA axis dysfunction exacerbates fatigue through other mechanisms, hindering the availability and utilization of energy and influencing neurotransmitter systems involved in regulating mood, motivation and energy levels.^{4, 5}

Over time, continuous overactivation of the HPA axis negatively impacts inflammatory responses, hormones, neurotransmitter production, immune function, metabolism and overall wellness. The result: sleep and mood disturbances, low energy, anxiety, adrenal fatigue and long-term health consequences. A personalized protocol aimed at treating underlying causes can restore energy levels, support restful sleep enhance mood, increase resilience to stress and help your patients regain balance.

Along with a comprehensive medical evaluation and testing to rule out specific conditions, diet and lifestyle modifications are key. Establishing a consistent sleep schedule that includes exposure to early morning light resets circadian rhythms and cortisol secretion patterns, improving alertness and offsetting fatigue after sleep deprivation. Physical exercise—especially yoga—and stress-reduction strategies like relaxation techniques, mindfulness practices and meditation have been shown to regulate the HPA axis and favorably alter cortisol levels.^{6, 7, 8}

And supplement interventions with botanicals shown to modulate the HPA axis can normalize cortisol levels, support the nervous system, soothe stress, encourage restful sleep, ease fatigue and restore homeostasis. Adaptogens in particular are known for their ability to promote a healthy stress response through different mechanisms.

“Adaptogens improve the body’s non-specific response to stress,” says Lise Alschuler, ND, FABNO. “They have a normalizing action, irrespective of the direction of the pathological state. Most adaptogens increase ACTH and cortisol with single, high-dose administration and normalize ACTH and cortisol with longer-term administration and when give prior to stressors. One key mechanism of adaptogens is to restore the intracellular glucocorticoid receptor sensitivity on the hypothalamus and pituitary, thereby reinstating negative feedback.”

 

What the research shows:^{9, 10, 11}

Ashwagandha (Withania somnifera), an adaptogen used for thousands of years in traditional Ayurvedic medicine, is widely recognized for boosting resilience and a balanced response to stress. Current research validates effectiveness in modulating the HPA axis, regulating ACTH release and reducing cortisol. Withanolides, sitoindosides and other compounds in ashwagandha also appear to influence GABAergic neurotransmission and serotonin levels, further contributing to its calming, anxiolytic effects.^{12, 13, 14, 15, 16}

Dozens of studies highlight ashwagandha’s efficacy in blunting cortisol and reducing feelings of stress and anxiety. In a recent systematic review, ashwagandha significantly lowered cortisol levels, stress and anxiety in adults with self-reported high anxiety or a diagnosed anxiety disorder. Another review found ashwagandha decreased perceived stress by 30 to 44 percent, and in additional trials, ashwagandha lessened symptoms of generalized anxiety disorder in more than half the participants.^{17, 18, 19, 20}

Some research points to its sedative properties in promoting restful sleep. Clinical trials of participants with insomnia show ashwagandha improves sleep quality and sleep onset latency, compared to placebo. In other studies, participants who took ashwagandha reported greater mental alertness on rising and increased quality of life.^{21, 22, 23}

Rhodiola (Rhodiola rosea), also known as Arctic root, has long been used in traditional medicine to support the nervous system, enhance mood, reduce stress and anxiety, and alleviate fatigue. As an adaptogen, rhodiola boosts resistance to stressors and has a normalizing influence on stress signals, with dual actions of cognitive stimulation and emotional calming.^{24, 25}

Several active compounds in rhodiola appear to be responsible for HPA axis regulation, cortisol balance and adrenal function, and a number of clinical trials document its positive effects  on cortisol and symptoms of stress, anxiety, exhaustion, weakness and fatigue. In studies, participants who received rhodiola supplements reported significant, consistent and steady improvements in stress, mood and quality of life, with some data suggesting reductions in perceived stress and functional impairment in as little as three days.^{26, 27, 28}

Additional research emphasizes the pronounced anti-fatigue benefits of rhodiola, with studies linking rhodiola supplementation with decreased stress-induced burnout, statistically significant reductions in fatigue, and enhanced overall well-being compared to placebo. Rhodiola has also been shown to increase cognitive function, mental performance and motivation.^{29, 30, 31, 32}

By blunting physiological stress responsivity, rhodiola eases anxiety, balances mood and may promote healthy sleep patterns. Studies have linked rhodiola supplementation with greater mood stability and lower situational anxiety, as well as significant reductions in negative mood, anger and depression.^{33, 34}

Holy Basil (Ocimum sanctum), also called Tulsi, is a traditional Ayurvedic adaptogen prized for its array of medicinal properties, and modern research confirms its positive influences on stress, energy levels, anxiety, mood and sleep. As an adaptogen, holy basil is known to interact with the HPA axis and normalize the stress response. Its primary constituents are thought to work through a combination of pharmacological actions, supporting the central nervous system and the adrenals, regulating cortisol and modulating other components of the stress response.^{35, 36, 37, 38}

Research shows holy basil effectively eases stress and associated symptoms, including sleep disturbances and fatigue. In a six-week, randomized, double-blind, placebo-controlled study, holy basil significantly improved general stress scores, with a 39 percent reduction in stress-related issues such as sleep problems and exhaustion, compared to placebo. In another study, eight weeks of supplementation with a holy basil extract decreased measures of stress and improved measures of sleep quality. Holy basil also counters the psychological effects of stress to benefit mood, with studies reporting significant reductions in anxiety and depression after holy basil supplementation.^{39, 40, 41}

Schisandra (Schisandra chinensis) has been used for centuries in traditional Chinese and Russian medicine to treat a range of conditions, including insomnia, fatigue, vitality and mood. Many studies have validated schisandra’s adaptogenic properties and its positive impacts on stress and related symptoms. Active compounds in schisandra are known to influence the HPA axis, suppressing the release of cortisol, mitigating stress and anxiety, and relieving stress-induced fatigue. Its hepatoprotective activities are thought to play a role: schisandra’s ability to support liver function, involved in cortisol metabolism, indirectly contributes to HPA axis balance.^{42, 43, 44}

Research emphasizes its fatigue-alleviating effects, with studies linking schisandra supplementation to improved stamina and endurance, increased mental performance and reduced fatigue. While human trials are lacking, some research reports schisandra’s beneficial influence on sleep, mood and overall well-being.^{45, 46, 47}

A combination of evidence-based adaptogens may have synergistic actions to further support HPA axis balance, alleviate stress and anxiety, minimize fatigue, and enhance sleep and mood.

“A combination of energizing and calming adaptogens, and nourishing nervines, help to integrate the HPA stress system, the nervous system, immune response and the liver,” says Susan Hirsh, MS Herbal Medicine, CNS, Gaia Herbs PRO Formulation Manager. “The result is a formula that is balancing and supportive to meet most people where they need it.”

Research suggests a specific blend of adaptogens is highly effective in modulating HPA axis function and reducing stress-related symptoms. A randomized, placebo-controlled, double-blind study found a multi-herb formula containing ashwagandha, rhodiola rosea, holy basil and schisandra significantly improved stress, sleep, fatigue and anxiety compared to a placebo.

The study examined the effect of the formula on HPA axis modulation in healthy participants, and its impact on perceived stress, sleep quality, fatigue, anxiety and mood. After 60 days, in those taking the formula:

• 86.8 percent experienced a clinically relevant reduction in perceived stress, compared to 42.1 percent in the placebo group.
• 52.46 percent showed clinically meaningful improvements in sleep, compared to 24.56 percent in the placebo group, along with statistically significant improvements in subjective sleep quality and sleep latency compared to placebo.
• 21.3 percent reported less fatigue, compared to 8.7 percent of those in the placebo group.
• 36.2 percent reported improvements in anxiety and 32.8 percent experienced relevant improvements in mood, compared to placebo.

 

References

1. Herman JP et al. Brain mechanisms of HPA axis regulation: neurocircuitry and feedback in context Richard Kvetnansky lecture. Stress. 2020 Nov;23(6):617-632.
2. Keller-Wood M. Hypothalamic-Pituitary–Adrenal Axis-Feedback Control. Compr Physiol. 2015 Jul 1;5(3):1161-82.
3. Kinlein SA et al. Dysregulated hypothalamic-pituitary-adrenal axis function contributes to altered endocrine and neurobehavioral responses to acute stress. Front Psychiatry. 2015 Mar 13;6:31.
4. Hirotsu C et al. Interactions between sleep, stress, and metabolism: From physiological to pathological conditions. Sleep Sci. 2015 Nov;8(3):143-52.
5. Stephens MA, Wand G. Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res. 2012;34(4):468-83.
6. Leproult R et al. Transition from dim to bright light in the morning induces an immediate elevation of cortisol levels. J Clin Endocrinol Metab. 2001 Jan;86(1):151-7.
7. R P, Kumar AP et al. Role of yoga in stress management and implications in major depression disorder. J Ayurveda Integr Med. 2023 Sep-Oct;14(5):100767.
8. Rogerson O et al. Effectiveness of stress management interventions to change cortisol levels: a systematic review and meta-analysis. Psychoneuroendocrinology. 2024 Jan;159:106415.
9. Tóth-Mészáros A et al. The effect of adaptogenic plants on stress: A systematic review and meta-analysis. J Funct Foods. 2023; 108: 105695.
10. Todorova V et al. Plant Adaptogens-History and Future Perspectives. Nutrients. 2021 Aug 20;13(8):2861.
11. Panossian AG et al. Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress- and aging-related diseases. Med Res Rev 2021;41:630-703.
12. Wiciński M et al. Can Ashwagandha Benefit the Endocrine System?-A Review. Int J Mol Sci. 2023 Nov 20;24(22):16513.
13. Mikulska P et al. Ashwagandha (Withania somnifera)-Current Research on the Health-Promoting Activities: A Narrative Review. Pharmaceutics. 2023 Mar 24;15(4):1057.
14. Lopresti AL et al. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine (Baltimore). 2019 Sep;98(37):e17186.
15. Majeed M et al. A Standardized Withania somnifera (Linn.) Root Extract with Piperine Alleviates the Symptoms of Anxiety and Depression by Increasing Serotonin Levels: A Double-Blind, Randomized, Placebo-Controlled Study. J Integr Complement Med. 2023 Oct 25.
16. Candelario M et al. Direct evidence for GABAergic activity of Withania somnifera on mammalian ionotropic GABAA and GABAρ J Ethnopharmacol. 2015 Aug 2;171:264-72.
17. Della Porta M et al. Effects of Withania somnifera on Cortisol Levels in Stressed Human Subjects: A Systematic Review. Nutrients. 2023 Dec 5;15(24):5015.
18. Salve J et al. Adaptogenic and Anxiolytic Effects of Ashwagandha Root Extract in Healthy Adults: A Double-blind, Randomized, Placebo-controlled Clinical Study. Cureus. 2019 Dec 25;11(12):e6466.
19. Lopresti AL, Smith SJ. Ashwagandha (Withania somnifera) for the treatment and enhancement of mental and physical conditions: A systematic review of human trials. J Herb Med. 2021;28:100434.
20. Akhgarjand C et al. Does Ashwagandha supplementation have a beneficial effect on the management of anxiety and stress? A systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2022 Nov;36(11):4115-4124.
21. Deshpande A et al. A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults. Sleep Med. 2020 Aug;72:28-36.
22. Langade D et al. Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallel-group, placebo-controlled study. J Ethnopharmacol 2021;264:113276.
23. Cheah KL et al. Effect of Ashwagandha (Withania somnifera) extract on sleep: A systematic review and meta-analysis. PLoS One 2021;16:e0257843
24. Brown R et al. Rhodiola rosea: A Phytomedicinal overview. HerbalGram. 2002;5:40–52
25. Panossian A et al. Rosenroot (Rhodiola rosea): Traditional use, chemical composition, pharmacology and clinical efficacy. 2010;17:481–493.
26. Ivanova Stojcheva E, Quintela JC. The Effectiveness of Rhodiola rosea L. Preparations in Alleviating Various Aspects of Life-Stress Symptoms and Stress-Induced Conditions-Encouraging Clinical Evidence. Molecules. 2022 Jun 17;27(12):3902.
27. Edwards D et al. Therapeutic effects and safety of Rhodiola rosea extract WS® 1375 in subjects with life-stress symptoms–results of an open-label study. Phytother Res. 2012 Aug;26(8):1220-5.
28. Lekomtseva Y et al. Rhodiola roseain Subjects with Prolonged or Chronic Fatigue Symptoms: Results of an Open-Label Clinical Trial.  Med. Res. 2017;24:46–52.
29. Shevtsov VA et al. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine. 2003 Mar;10(2-3):95-105.
30. Kasper S, Dienel A. Multicenter, open-label, exploratory clinical trial with Rhodiola rosea extract in patients suffering from burnout symptoms. Neuropsychiatr Dis Treat. 2017 Mar 22;13:889-898.
31. Spasov AA et al. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine. 2000 Apr;7(2):85-9.
32. Darbinyan V et al. Rhodiola rosea in stress induced fatigue–a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine. 2000 Oct;7(5):365-71.
33. Cropley M et al. The Effects of Rhodiola rosea Extract on Anxiety, Stress, Cognition and Other Mood Symptoms. Phytother. Res. 2015;29:1934–1939.
34. Bystritsky A et al. A pilot study of Rhodiola rosea(Rhodax) for generalized anxiety disorder (GAD)  Altern. Complement. Med. 2008;14:175–180.
35. Cohen MM. Tulsi – Ocimum sanctum: A herb for all reasons. J Ayurveda Integr Med. 2014 Oct-Dec;5(4):251-9.
36. Jamshidi N, Cohen MM. The Clinical Efficacy and Safety of Tulsi in Humans: A Systematic Review of the Literature. Evid Based Complement Alternat Med. 2017;2017:9217567.
37. Gholap S, Kar A. Hypoglycaemic effects of some plant extracts are possibly mediated through inhibition in corticosteroid concentration. 2004;59:876–8.
38. Lopresti AL et al. A randomized, double-blind, placebo-controlled trial investigating the effects of an Ocimum tenuiflorum (Holy Basil) extract (HolixerTM) on stress, mood, and sleep in adults experiencing stress. Front Nutr. 2022 Sep 2;9:965130.
39. Saxena RC et al. Efficacy of an Extract of Ocimum tenuiflorum (OciBest) in the Management of General Stress: A Double-Blind, Placebo-Controlled Study. Evid Based Complement Alternat Med. 2012;2012:894509.
40. Chatterjee M et al. Evaluation of ethanol leaf extract of Ocimum sanctumin experimental models of anxiety and depression. Pharm Biol. 2011;49:477–83
41. Bhattacharyya D, et al. Controlled programmed trial of Ocimum sanctum leaf on generalized anxiety disorders. Nepal Med Coll J. 2008;10:176–9.
42. Szopa A et al. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Phytochem Rev. 2017;16(2):195-218.
43. Nowak A et al. Potential of Schisandra chinensis (Turcz.) Baill. in Human Health and Nutrition: A Review of Current Knowledge and Therapeutic Perspectives. Nutrients. 2019 Feb 4;11(2):333.
44. Panossian A, Wikman G. Pharmacology of Schisandra chinensis Bail.: an overview of Russian research and uses in medicine. J Ethnopharmacol. 2008 Jul 23;118(2):183-212.
45. Sowndhararajan K et al. An overview of neuroprotective and cognitive enhancement properties of lignans from Schisandra chinensis. Biomed Pharmacother. 2018 Jan;97:958-968.
46. Li N et al. Sedative and hypnotic effects of Schisandrin B through increasing GABA/Glu ratio and upregulating the expression of GABAA in mice and rats. Biomed Pharmacother. 2018 Jul;103:509-516.
47. Zhang C et al. Gomisin N isolated from Schisandra chinensis augments pentobarbital-induced sleep behaviors through the modification of the serotonergic and GABAergic system. Fitoterapia. 2014 Apr 29;96C:123-130.