Fibrosis

Acetyl-L-Tyrosine (NALT) is the acetylated form of L-tyrosine, the amino acid precursor to adrenal catecholamines (dopamine, norepinephrine, epinephrine). Used in HPA/adrenal axis support formulations to replenish catecholamine precursors depleted during chronic stress. Clinical evidence from tyrosine RCTs supports its role in maintaining cognitive function under acute stress.

Adrenal cortex glandular extract is used in integrative medicine as organotherapy to supply precursor nutrients and cofactors for adrenal steroidogenesis, including cortisol, aldosterone, and DHEA synthesis pathways. A Mayo Clinic Proceedings study found many OTC adrenal support supplements contain cortex tissue and measurable steroid hormones. Used in glandular therapy since the early 20th century.

One of the most extensively studied adaptogens for HPA axis modulation. Multiple RCTs demonstrate that standardized root extract (300–600 mg/day of withanolide-rich extract) significantly reduces serum cortisol, ACTH secretion, and perceived stress over 8–12 weeks. A systematic review found it decreases perceived stress by 30–44% and consistently lowers cortisol in adults with self-reported high stress.

Cordyceps (Cordyceps sinensis/militaris) is an adaptogenic medicinal fungus used in TCM for centuries to combat fatigue, support adrenal function, and enhance stress resilience. Evidence suggests it modulates the HPA axis, supports cortisol regulation, and has been used for exercise-induced adrenal stress and chronic fatigue in integrative medicine protocols.

DHA is a long-chain omega-3 fatty acid concentrated in brain and adrenal tissue with evidence for modulating HPA axis stress reactivity. A 2025 American Journal of Medicine review recommends combined EPA+DHA (1.25–3.0 g/day) for cortisol reduction and stress resilience improvement. NIH documents confirm DHA decreases the magnitude of HPA axis response to stressors.

DHEA is a key adrenal product co-secreted with cortisol via the HPA axis; it acts as a functional counter-regulator of cortisol. The cortisol-to-DHEA ratio is a recognized marker of HPA axis functionality. DHEAS exerts anti-glucocorticoid activity, including protection of the hippocampus from corticosterone effects, and its decline with age reflects adrenopause, a distinct HPA axis aging process.

Eleuthero (Eleutherococcus senticosus, Siberian ginseng) is a well-studied adaptogen first classified by Soviet researchers in the 1940s for HPA axis support, stress resilience, and adrenal function. Clinical and animal studies show it modulates cortisol output, supports the DHEA-to-cortisol ratio, and has been used for elevated cortisol, adrenal deficiency, chronic fatigue, and exercise tolerance.

EPA is an omega-3 fatty acid with clinical evidence for HPA axis modulation. A 2025 American Journal of Medicine review on HPA axis dysfunction recommends EPA+DHA at 1.25–3.0 g/day based on RCT evidence showing reduced cortisol and improved stress resilience over 8–12 weeks. EPA reduces pro-inflammatory cytokine-driven HPA activation.

Panax ginseng is a canonical adaptogen with documented HPA axis-modulating properties. Its ginsenosides modulate the CRH/ACTH/cortisol cascade, suppress adrenal catecholamine release under stress, and normalize glucocorticoid receptor sensitivity. Used in TCM for over 2,000 years, multiple clinical trials confirm its stress-axis and fatigue benefits.

Ginsenosides are the steroidal saponin bioactives of Panax ginseng primarily responsible for HPA axis-modulating and adaptogenic effects. They inhibit ACTH-induced corticosterone production, modulate glucocorticoid receptor activity (via FKBP51), and normalize HPA axis dysregulation in chronic stress and depression models, per PubMed-indexed research.

Glycyrrhetinic acid is the primary active metabolite of glycyrrhizin from licorice root and the more potent inhibitor of 11β-HSD2 responsible for HPA axis cortisol-sparing effects. Human pharmacokinetic studies directly confirm its ability to raise cortisol bioavailability by slowing inactivation.

Glycyrrhizin is the primary triterpene glycoside of licorice root directly responsible for HPA axis effects via potent 11β-HSD2 inhibition, preventing cortisol inactivation. Clinical pharmacokinetic studies confirm its cortisol-sparing mechanism, and it is used in adrenal insufficiency management to increase cortisol bioavailability.

The Terburg et al. (2013) fMRI study found that Zembrin reduced amygdala–hypothalamus coupling, directly implicating the HPA axis pathway in kanna's stress-modulating effects. A Stellenbosch University preclinical study found altered immune/HPA markers under stress with Sceletium treatment. Cell studies also suggest Sceletium extract modulates glucocorticoid production.

L-Theanine, an amino acid from tea, promotes relaxation via GABA, serotonin, and glutamate modulation, indirectly attenuating HPA axis stress reactivity. A 2016 RCT found L-theanine-containing drinks significantly reduced salivary cortisol response to stress, though direct HPA axis cortisol-lowering evidence is mixed across trials.

L-Tyrosine is the amino acid precursor to adrenal catecholamines (dopamine, norepinephrine, epinephrine), supporting both the HPA and sympatho-adrenal medullary stress axes. RCTs in military and stress research show tyrosine supplementation preserves cognitive function under acute stress by maintaining catecholamine biosynthesis when stores are depleted.

Licorice root (Glycyrrhiza glabra) supports the HPA axis through glycyrrhizin-mediated inhibition of 11β-HSD2, which slows conversion of active cortisol to inactive cortisone, prolonging cortisol bioavailability. This mechanism is relevant in low-cortisol states such as adrenal insufficiency. Long used in TCM and Ayurveda for adrenal support and fatigue.

Magnesium modulates HPA axis activity bidirectionally: deficiency enhances HPA reactivity by raising CRH, ACTH, and cortisol, while chronic stress depletes magnesium. The 2025 American Journal of Medicine review identifies magnesium deficiency as impairing adrenal function and recommends 300–400 mg/day supplementation for HPA axis support during stress.

Magnolia bark extract (Magnolia officinalis) contains honokiol and magnolol, which modulate GABA-A receptors and inhibit HPA axis activation, reducing cortisol secretion under stress. It is the primary component of the Relora® formula, which demonstrated significant cortisol reduction in a double-blind RCT in moderately stressed adults.

Omega-3 fatty acids (EPA+DHA from fish or algal oil) are classified as evidence-based supplements for HPA axis dysfunction in a 2025 American Journal of Medicine review. Supplementation at 1.25–3.0 g/day reduces cortisol and improves stress resilience over 8–12 weeks in RCTs, via anti-inflammatory and direct neuroendocrine mechanisms.

Pantethine is the active, biologically reduced form of pantothenic acid (vitamin B5) and a direct precursor to coenzyme A (CoA), which is essential for adrenal steroidogenesis. Used in adrenal/HPA axis support protocols as the more bioavailable and metabolically active form of B5 for supporting cortisol, DHEA, and aldosterone synthesis.

Phellodendron amurense bark is the second component of the Relora® formula for HPA axis and cortisol support. Its berberine content and other alkaloids contribute to cortisol metabolism modulation and stress response regulation. Clinical evidence comes primarily from the Relora® combination RCTs showing significant cortisol reduction in moderately stressed adults.

Phosphatidylserine (PS) has the strongest direct clinical evidence among non-herbal supplements for HPA axis modulation. Multiple RCTs demonstrate it attenuates ACTH and cortisol release during physical and psychological stress. Foundational studies (Monteleone et al., 1990/1992) showed blunted HPA activation with 400–800 mg/day; soy-derived PS at 600 mg/day reduced peak cortisol by 39% in athletes.

DISS (3,6'-disinapoyl sucrose) from P. tenuifolia root modulates the hypothalamic-pituitary-adrenal (HPA) axis in chronic stress rodent models, reducing CORT, ACTH, and CRH and restoring glucocorticoid and mineralocorticoid receptor expression. This represents one of the best-characterized mechanisms of PT in stress-related conditions.

Pregnenolone is the primary adrenal precursor steroid from which all adrenal hormones—cortisol, DHEA, aldosterone, progesterone—are synthesized. Supplementation is used in HPA axis support to replenish the steroidogenic cascade during adrenal insufficiency or chronic stress depletion. Pilot human RCTs show neuroendocrine benefits in aging and PTSD.

Reishi (Ganoderma lucidum) is a classical TCM adaptogen used for over 2,000 years for stress, vitality, and longevity. Its ganoderic acid triterpenoids share structural similarity with steroid hormones and modulate immune-neuroendocrine HPA axis interactions. A human RCT showed benefits for stress-related fatigue (neurasthenia), and it is listed in integrative HPA axis support protocols.

Relora® is a proprietary blend of Magnolia officinalis and Phellodendron amurense bark extracts with clinical trial evidence for HPA axis and cortisol support. A double-blind RCT (Talbott et al., 2013, JISSN) found 500 mg/day for 4 weeks significantly reduced salivary cortisol by 18% and improved mood profiles in moderately stressed adults versus placebo.

Rhodiola rosea is a well-documented adaptogen with clinical evidence for HPA axis regulation, cortisol normalization, and stress-resilience improvement. Active compounds salidroside and rosavins modulate cortisol release and reduce perceived stress and fatigue. Multiple RCTs show meaningful improvements in stress, mood, and functional impairment.

Rosabin is a cinnamyl alcohol glycoside within the rosavin group of Rhodiola rosea, serving as a marker compound alongside rosarin and rosavin in pharmacopeially validated extracts used in HPA axis clinical research. Evidence for HPA modulation is attributed collectively to the rosavin fraction in standardized Rhodiola extracts tested in published RCTs.

Rosarin is one of the rosavin-family cinnamyl glycosides from Rhodiola rosea, constituting part of the ≥3% rosavin fraction specified in pharmacopeial monographs for authentic adaptogenic Rhodiola preparations. Clinical HPA axis and cortisol evidence from RCTs using rosavin-standardized extracts applies collectively to the rosavin group including rosarin.

Salidroside (p-tyrosol glucoside) is one of the principal bioactive compounds of Rhodiola rosea credited with adaptogenic and HPA axis-modulating effects. Preclinical evidence shows it reduces stress-induced corticosterone secretion and hypothalamic CRH receptor expression. Standardized Rhodiola extracts are characterized by salidroside content (≥1%), and clinical RCTs use such extracts.

Sceletium's mesembrine-rich extracts have been shown in vitro and in preclinical models to target adrenal CYP17A1 and other steroidogenic enzymes, reducing glucocorticoid synthesis. Animal data also indicate modulation of HPA-related cytokines and corticosterone under stress. These findings are preclinical; human HPA endpoint trials are underway.

Schisandra was incorporated into official Soviet medical practice in the 1960s as an adaptogen with documented anti-stress and restorative effects. Active compounds influence the HPA axis by suppressing excess cortisol release. A PMC study (Panossian et al.) confirmed schisandra and rhodiola rosea reduce hypothalamic c-Fos expression and HPA-mediated stress markers in rats. Human studies show improved endurance and mental performance in mildly fatigued patients.

Schisandrins are the principal lignans of Schisandra chinensis responsible for its adaptogenic and HPA axis-modulating effects. They suppress cortisol release, reduce stress-induced fatigue, and support hepatic cortisol metabolism. Multiple studies document schisandra's HPA-relevant effects on stress hormones and fatigue markers.

Tongkat Ali has clinical and mechanistic evidence for modulating the HPA axis. A human RCT in healthy young men (600 mg/day, 2 weeks) found testosterone increases with evidence suggesting direct adrenal stimulation within the HPA axis, beyond the HPG axis alone. The Talbott et al. (2013) RCT demonstrated −16% salivary cortisol. Research indicates the HPA axis is a key mediator of Tongkat Ali's adaptogenic effects on stress hormones.

Human clinical data directly demonstrate that MP seed powder reduces elevated serum cortisol in stressed infertile men by 40–49% (P<0.001), consistent with normalization of HPA axis hyperactivation. The mechanism involves L-DOPA-driven dopaminergic inhibition of CRH/ACTH release from the hypothalamus and pituitary. This is the most directly documented human-level action of MP on the HPA axis.

Vitamin B5 (pantothenic acid) is the rate-limiting cofactor for coenzyme A (CoA) biosynthesis, which drives the first step of adrenal steroidogenesis (cholesterol → pregnenolone → cortisol, DHEA, aldosterone). Cited as essential for HPA axis function in the 2025 American Journal of Medicine review and in multiple integrative HPA axis support protocols.

Vitamin B6 (pyridoxine/P-5-P) is an essential cofactor in neurotransmitter biosynthesis pathways (serotonin, dopamine, GABA, norepinephrine) that regulate HPA axis activity. Deficiency impairs adrenal function; it is included in the 2025 American Journal of Medicine's list of key micronutrients for HPA axis support, alongside B5, magnesium, zinc, and vitamin C.

Vitamin C is the most concentrated nutrient in the adrenal cortex, serving as an essential cofactor for cortisol biosynthesis. A human RCT found 500 mg/day significantly reduced cortisol, blood pressure, and subjective stress in participants exposed to psychological stressors. Cited in the 2025 American Journal of Medicine HPA axis review.

The principal steroidal lactone bioactives of Ashwagandha (Withania somnifera), withanolides are the compounds most directly responsible for HPA axis modulation and cortisol attenuation documented in clinical trials. RCTs standardized to withanolide content (≥5%) confirm significant reductions in cortisol, ACTH, and perceived stress. They also influence GABAergic neurotransmission, contributing to anxiolytic effects.

Zinc is required for adrenal steroidogenesis and serves as a cortisol modulator; deficiency is associated with elevated cortisol and HPA axis dysregulation. The 2025 American Journal of Medicine review identifies zinc deficiency as impairing adrenal and neuroendocrine function, and clinical evidence shows supplementation modulates ACTH/cortisol while supporting DHEA production.

Astragalus (Astragalus membranaceus, Huang Qi) is a foundational TCM adaptogen used for over 2,000 years to tonify defensive energy and support vitality under stress. Animal studies document cortisol-normalizing effects under chronic stress, and it is listed as an adaptogen adjunct in HPA axis support protocols. Direct human RCT evidence for cortisol/HPA axis modulation is limited.

Bacopa monnieri (Brahmi) is a classical Ayurvedic adaptogen used for over 3,000 years for stress resilience and cognitive support. Animal evidence shows bacosides reduce stress-induced corticosterone elevation. Listed as an adaptogen for HPA axis support in integrative medicine literature; most human RCTs focus on cognitive outcomes rather than direct cortisol measurement.

Bupleurum falcatum (Chai Hu) is a foundational TCM herb with 2,000+ years of use for harmonizing stress-related conditions consistent with HPA axis dysfunction. Its saikosaponins modulate glucocorticoid receptor sensitivity and protect adrenal tissue in animal models. Listed explicitly in HPA axis ingredient databases and commonly combined with adaptogens in clinical HPA protocols.

Jiaogulan (Gynostemma pentaphyllum), known as 'southern ginseng,' contains gypenosides related to ginsenosides and has adaptogenic properties documented in animal studies, including HPA axis cortisol normalization under chronic stress. Listed in HPA axis support databases and integrative protocols as an adaptogen adjunct. Robust human RCTs measuring cortisol are lacking.

Maca (Lepidium meyenii) is a Peruvian root with centuries of traditional use as an adaptogen for stress, energy, and vitality, commonly included in HPA axis support formulations. Robust clinical trials specifically measuring cortisol or HPA axis markers are limited and inconclusive; evidence is primarily traditional and preliminary.

Pituitary substance is a core component of traditional glandular HPA axis support protocols, reflecting the pituitary's structural role as the central relay between hypothalamic CRH and adrenal cortisol output. Naturopathic practitioners have incorporated it into multi-glandular HPA axis formulas for decades. No clinical trial data support oral supplementation for this purpose.

Preclinical data and mechanistic studies indicate Polygala root modulates the HPA axis by reducing cortisol secretion and promoting GABAergic pathways that dampen the stress response. This is documented as a proposed mechanism for its adaptogenic, anxiolytic, and sedative effects, but human HPA axis studies are absent.

Rehmannia glutinosa (Di Huang) is a foundational TCM herb used for 2,000+ years as a kidney/adrenal tonic, classified in the Caring Sunshine HPA axis ingredient database. Animal studies show it normalizes stress-induced corticosterone elevation. It is commonly combined with other adaptogens in HPA axis support formulas; human RCT evidence specifically for HPA axis markers is limited.

Suma (Pfaffia paniculata), known as 'Brazilian ginseng,' is a South American adaptogen used traditionally for stress, fatigue, and vitality. It is included in integrative HPA axis support formulations and databases. Preclinical evidence suggests adaptogenic, anti-stress, and hormone-modulating properties; robust human RCTs specifically measuring HPA axis markers are lacking.

Whole adrenal glandular extract contains both cortex and medulla fractions, providing precursors for cortisol, DHEA (cortex), and catecholamine (medulla) synthesis pathways. Used in 20th-century organotherapy for adrenal insufficiency and stress-related fatigue. Modern controlled clinical trial evidence is lacking; use is primarily empirical and traditional.