Hypothalamic-Pituitary-Adrenal (HPA) axis

The body’s stress response is governed primarily by the Hypothalamic-Pituitary-Adrenal (HPA) axis, which coordinates the mental, emotional and physiological response to acute and chronic stressors. The downstream organs in this axis, the adrenals, are located on top of the kidneys and produce steroid hormones, such as cortisol and aldosterone, as well as catecholamines, including epinephrine and norepinephrine.

Steroid hormones are critical for many functions in the body including growth, metabolism and reproduction, while catecholamines are involved in the body’s fight or flight response. The adrenal glands also play a significant role in the body’s circadian rhythm through cortisol secretion.¹ During acute stress, cortisol is released by the adrenals as a protective mechanism, helping to increase heart rate, enhance glucose production and suppress non-essential functions like digestion and immunity; this is a natural and necessary part of the stress response, allowing the individual to fight or flee from impending danger.

When the immediate threat dissipates, this fight or flight response should transition back to ‘rest and digest,’ allowing cortisol levels to normalize and the parasympathetic nervous system to restore calm and balance. In the modern world, however, many individuals are living in a state of chronic elevated stress, and have lost this ability to move fluidly between fight and flight or rest and digest.

Stress can have numerous root causes- mental and emotional, stemming from socioeconomic status to overwhelm with life situations, to physiological causes, such as living with a chronic disease. The longer an individual lives with stress and dysregulation of the HPA axis, the more susceptible they become to comorbid conditions like cardiovascular disease, immune dysfunction, depression and diabetes.²

Herbal Medicines for Adrenal Support

Herbal medicines have a long history of use in supporting the human stress response, from calming immediate acute stress to building a deeper resilience against the negative effects of long-term stress. Adaptogens are revered for their ability to build this foundational resilience. Initially classified as plants that enhance a state of ‘non-specific’ resistance to stress,³ modern research has helped to elucidate the various mechanisms by which these plants provide protection against the negative impacts of mental, emotional and physiological stress. In both animal and human research, adaptogens have been shown to exhibit neuroprotective, anti-fatigue, immune modulating, antidepressive, anxiolytic, antioxidant, nootropic and CNS modulating activity.⁴ Two of these adaptogenic herbs, licorice root and rehmannia rhizome, have been used for centuries in traditional systems of medicine in the treatment of a variety of disorders stemming from dysfunction within the HPA axis and the long-term ramifications of unmanaged stress.

Licorice

Licorice (Glycyrrhiza glabra) is a plant in the legume or Fabaceae family, native to regions of Asia and Europe. Licorice roots have been used as a medicine and flavoring agent for over 4000 years, recorded in early texts such as the Assyrian Herbal (2000 BC) and Ebers Papyrus (1600 BC).⁵ The ancient Egyptian, Chinese and Greek civilizations used the root in the treatment of various diseases, including colds, coughs, chills, skin diseases, wounds and stomach disorders. Hippocrates recommended the use of the herb for treating dropsy (edema), while Dioscorides is believed to be the first to describe its use in treating stomach and intestinal ulcers.⁵

Licorice (Glycyrrhiza glabra) is a plant in the legume or Fabaceae family, native to regions of Asia and Europe. Licorice roots have been used as a medicine and flavoring agent for over 4000 years, recorded in early texts such as the Assyrian Herbal (2000 BC) and Ebers Papyrus (1600 BC).⁵ The ancient Egyptian, Chinese and Greek civilizations used the root in the treatment of various diseases, including colds, coughs, chills, skin diseases, wounds and stomach disorders. Hippocrates recommended the use of the herb for treating dropsy (edema), while Dioscorides is believed to be the first to describe its use in treating stomach and intestinal ulcers.⁵

In Traditional Chinese Medicine (TCM) the root is used as a Qi tonic, indicated in the treatment of debility and weakness, as well as building resilience to and treating viral infections and other immune system dysfunctions. Similarly, in traditional Western herbal medicine, licorice is classified as an adaptogenic plant, and used as an adrenal tonic to help improve resilience against the negative physical, mental and emotional impacts of acute or chronic stress. Licorice exerts its adaptogenic effects through several mechanisms, primarily involving the modulation of steroid hormone production and immune response.

The key bioactive constituent in licorice is the triterpene saponin glycyrrhizin, one of the compounds responsible for the sweet taste associated with licorice root. Steroidal saponins, found in many adaptogenic plants, have been shown to promote neuroplasticity/neurogenesis, restore neurotransmitter function, enhance key neuroprotective compounds like BDNF, and exert a protective effect over the HPA-axis.^6,7 Glycyrrhizin has been shown to inhibit 11β-hydroxysteroid dehydrogenase (11β-HSD), the enzyme responsible for inactivating cortisol. Inhibiting 11β-HSD supports maintaining or elevating cortisol levels, a key reason for the historical use of licorice in the treatment of Addison’s Disease.^8,9  Human studies show that while licorice can raise cortisol in patients with Addison’s disease, it can lower cortisol in others.¹⁰ This modulating rather than overtly stimulating or suppressing effect exemplifies the definition of an adaptogen – an herb that can help support individual response to stressors through hormone regulation, adrenal response and improving nervous system tone.

Licorice is considered a Safety Class 2B, 2D herb by the American Herbal Products Association (AHPA). It is not for use in pregnancy except under the supervision of a qualified healthcare practitioner, and not for use in persons with hypertension, liver disorders, edema, severe kidney insufficiency, low blood potassium, heart disease with edema, or congestive heart failure. It is not considered appropriate for prolonged use or in high doses except under the supervision of a qualified healthcare practitioner.¹¹

Rehmannia

The uncured root of rehmannia (Rehmannia glutinosa), known in TCM as ‘dihuang,’ has been used in traditional medicine for centuries to nourish the yin, or the body’s restorative qualities – the ability to rest, find stillness and experience calm.  In TCM, rehmannia was used in the treatment of febrile diseases, skin eruptions, nosebleed, to prolong life, and improve cognitive function.¹² As an herb that cools heat and restores the bodily fluids, rehmannia is particularly indicated in cases of autoimmune diseases and other chronic, inflammatory disorders. Like licorice, rehmannia is known as an adaptogen in Western herbal medicine, and is used in the management of both acute and chronic stress.

The uncured root of rehmannia (Rehmannia glutinosa), known in TCM as ‘dihuang,’ has been used in traditional medicine for centuries to nourish the yin, or the body’s restorative qualities- the ability to rest, find stillness and experience calm.  In TCM, rehmannia was used in the treatment of febrile diseases, skin eruptions, nosebleed, to prolong life, and improve cognitive function.¹² As an herb that cools heat and restores the bodily fluids, rehmannia is particularly indicated in cases of autoimmune diseases and other chronic, inflammatory disorders. Like licorice, rehmannia is known as an adaptogen in Western herbal medicine, and is used in the management of both acute and chronic stress.

Much of the modern research exploring the mechanisms of action for rehmannia highlight the impact of the root on improving response to physiological stressors and immune response. In an animal model of adrenal depletion, administering rehmannia root prevented or reduced structural changes to the pituitary and adrenal cortex,¹³ suggesting that rehmannia root protects the pituitary and adrenals on a physical level during times of acute stress.

Preclinical research has also demonstrated that rehmannia extracts were effective in nerve damage recovery, memory enhancement, and cognitive function.¹⁴

The strong immunomodulating properties of rehmannia make the root a key botanical for individuals who experience immune challenges during times of stress- such as autoimmune flares triggered by mental or emotional stress- or those who live with the physiological stress of chronic immune disorders. Preclinical research has shown that rehmannia root is effective in mitigating inflammation and symptoms associated with atopic dermatitis and allergic dermatitis,^15,16 and downregulating key markers associated with autoimmune disorders, including IL-2, IFN-γ, IL-6, IL-10, and TNF-α.¹⁷

Clinical Takeaways

Licorice and rehmannia are a powerful herbal combination for strengthening the ability to stay well during times of elevated stress so that one’s mental, emotional and physical resources do not become as depleted. Together, these herbs are indicated for the person who needs to metaphorically slow life down in order to find wellness – the person who tends towards hyperirritability and agitation followed by depleting fatigue when faced with stress, or who, during times of stress, seems susceptible to every infection circulating in their community. As immunomodulating herbs, licorice and rehmannia can support individuals living with a variety of chronic diseases through both tempering the stress response and helping to mitigate inflammation and immune dysregulation associated with chronic disease.

Rehmannia and licorice, along with many other adaptogens, offer the support and ability to walk through the most challenging times in life with a little more ease and health. When working with plants to address acute and chronic stress, it’s important to remember that the goal isn’t to eliminate the stressors- for many, that is impossible given underlying disease and life circumstances. The therapeutic goal when using adaptogens is to use lifestyle practices like movement, sleep and nutrition alongside the adaptogenic plants to help grow around the stress so that it doesn’t occupy as big a space in the wellness narrative.