Adrenal / HPA Support
1. Root Cause Overview
The hypothalamic-pituitary-adrenal (HPA) axis regulates the body's stress response through cortisol and DHEA. Chronic psychological, physiological, or inflammatory stress leads to HPA axis dysregulation — characterised by abnormal cortisol patterns (high, low, or flat diurnal rhythm) and reduced DHEA-S. This is often termed 'adrenal fatigue' in functional medicine, though the more precise term is HPA axis dysregulation. It manifests as fatigue, sleep disruption, immune suppression, mood disorders, and metabolic dysfunction. True Addison's disease (adrenal insufficiency) is a separate medical condition.
2. Common Signs & Symptoms
- Profound fatigue, especially in the morning
- Energy crashes in the afternoon (2–4 PM)
- Difficulty waking; unrefreshing sleep
- Salt cravings
- Dizziness on standing (orthostatic hypotension)
- Mood instability: anxiety, irritability, depression
- Reduced stress tolerance
- Recurrent infections (immune suppression)
- Low libido
- Abnormal cortisol pattern on DUTCH or salivary testing
3. Labs to Consider
AM cortisol when clinically indicated, thyroid panel, CBC/CMP, ferritin/B12/vitamin D, glucose/insulin.
Choose the lab option based on what you want to assess within this root cause.
DUTCH Plus
Precision Analytical
4. Clinical Priorities
Assess for the full range of factors that may be contributing to HPA-axis dysregulation, including psychological stress, chronic illness, pain, inflammation, circadian disruption, sleep deprivation, overtraining, stimulants, and blood sugar instability. DUTCH or salivary cortisol testing can help characterise the pattern before supplementing. Prioritise sleep, nervous-system regulation, and metabolic stability, with adaptogens used as adjuncts rather than replacements for lifestyle work.
Where to Start: Top 2 Supplements
The most clinically validated adaptogen for HPA axis dysregulation. RCT evidence shows 27.9% reduction in serum cortisol, significant improvement in stress, anxiety, and sleep quality. KSM-66 is the most studied, standardised root extract. First-line adaptogen for elevated cortisol pattern.
The only supplement with RCT evidence specifically showing normalisation of HPA axis hyper-responsivity. Blunts the cortisol and ACTH response to acute stress. Particularly valuable for patients with high cortisol reactivity, cognitive fatigue, and burnout. Synergistic with ashwagandha.
5. Diet Strategy
Stabilise blood sugar as the primary dietary intervention: eat protein and healthy fat at every meal, avoid skipping meals, eliminate refined sugars and alcohol. Ensure adequate salt intake (unrefined sea salt) if low cortisol/aldosterone pattern. Emphasise nutrient-dense foods rich in B5 (pantothenic acid — avocado, eggs, organ meats), vitamin C (citrus, peppers, kiwi), and magnesium. Reduce caffeine — it stimulates cortisol secretion and worsens HPA dysregulation.
6. Lifestyle Strategy
Sleep is the single most important intervention — prioritise 8–9 hours with consistent sleep/wake times. Implement active stress management: mindfulness, yoga, tai chi, nature exposure. Avoid overtraining — intense exercise without adequate recovery elevates cortisol. Gentle movement (walking, swimming, yoga) is preferred during recovery. Reduce screen time and blue light exposure after 8 PM. Social support and meaningful activity are powerful HPA regulators.
7. Supplement Strategy
Full supplement list below. See Section 4 (Clinical Priorities) for the recommended Top 2 starting supplements. Add additional supplements based on lab results and clinical response at 4–6 week reassessment.
| Supplement | Dosage | Indication | Evidence | Key Results | Example |
|---|---|---|---|---|---|
| Ashwagandha (Withania somnifera, KSM-66®) [1] Mild GI upset; avoid in pregnancy; caution with thyroid medications (may increase T4) | 300–600 mg/day (standardised root extract) | Cortisol reduction; HPA axis modulation; stress and anxiety reduction | Randomised, double-blind, placebo-controlled trial (60 days) | Significant reduction in serum cortisol (27.9%); improved stress, anxiety, and sleep quality scores | Jarrow Formulas Ashwagandha KSM-66 |
| Rhodiola Rosea [2] Mild agitation or insomnia if taken late in the day; avoid in bipolar disorder | 200–600 mg/day (standardised to 3% rosavins, 1% salidroside) | Adaptogen; cognitive fatigue; HPA axis modulation; burnout | RCT (28 days) | Significantly improved cognitive function, mental fatigue, and burnout symptoms; reduced cortisol response to stress | Gaia Herbs Rhodiola Rosea |
| Phosphatidylserine [3] Generally well tolerated; mild GI upset | 400 mg/day | Normalises HPA axis hyper-responsivity; blunts cortisol response to acute stress | RCT (6 weeks) | Normalised the hyper-responsivity of the HPA axis to acute stressor; reduced cortisol and ACTH response | Jarrow Formulas PS100 |
| Omega-3 Fatty Acids (EPA + DHA) [4] Fish burp; anticoagulant interaction at high doses | 2.5 g/day | Cortisol reduction; HPA axis modulation; anti-inflammatory support | RCT (4 months) | Significantly reduced cortisol levels and adrenal activation in response to mental stress | Thorne Research Omega Superb |
| Vitamin C (Ascorbic Acid) [5] Loose stools at high doses; kidney stone risk with megadosing | 500–1,000 mg BID | Adrenal cortex support; cortisol synthesis cofactor; antioxidant protection of adrenal glands | RCT (7 days) | Reduced cortisol levels and subjective stress response; faster cortisol recovery post-stress | Pure Encapsulations Vitamin C |
| Licorice Root Extract (for low cortisol pattern only) [6] Hypertension, hypokalaemia, oedema with prolonged use — limit to 4–6 weeks; contraindicated in hypertension | 250–300 mg TID (standardised to 20% glycyrrhizic acid) | Low cortisol/adrenal insufficiency pattern; cortisol half-life extension; aldosterone support | Review article and clinical evidence | Inhibits 11β-HSD2 enzyme, extending cortisol half-life; useful in low cortisol/aldosterone patterns | Integrative Therapeutics Licorice Root |
8. Safety Notes
Do not use licorice root in patients with hypertension, hypokalaemia, or cardiovascular disease. Ashwagandha may increase thyroid hormone levels — monitor in patients on thyroid medication. True adrenal insufficiency (Addison's disease) requires medical management with corticosteroids — do not attempt to treat with supplements alone. Always confirm cortisol pattern with objective testing before initiating adrenal support protocols.
9. Citations & References
- [1]Ashwagandha (Withania somnifera, KSM-66®)Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 2012;34(3):255–262.View source
- [2]Rhodiola RoseaOlsson EMG, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract SHR-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75(2):105–112.View source
- [3]PhosphatidylserineHellhammer J, Fries E, Buss C, et al. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress. 2004;7(2):119–126.View source
- [4]Omega-3 Fatty Acids (EPA + DHA)Delarue J, Matzinger O, Binnert C, Schneiter P, Chioléro R, Tappy L. Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab. 2003;29(3):289–295.View source
- [5]Vitamin C (Ascorbic Acid)Peters EM, Anderson R, Nieman DC, Fickl H, Jogessar V. Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running. Int J Sports Med. 2001;22(7):537–543.View source
- [6]Licorice Root Extract (for low cortisol pattern only)Armanini D, Fiore C, Mattarello MJ, Bielenberg J, Palermo M. History of the endocrine effects of licorice. Exp Clin Endocrinol Diabetes. 2002;110(6):257–261.View source
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