Stress is irrefutably a factor in many illnesses – from headaches to heart disease, immune deficiencies to digestive disorders. A substantial contributor to stress-induced decline in health appears to be Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction and an unregulated production of the stress hormones cortisol & epinephrine, leading to nervous system and later mitochondrial dysfunction. Though it is fundamental for health care practitioners to assess & correct the stressors which may be driving cortisol output, botanical therapies have much to offer in regards to balancing HPA activity, thus improving immunity & insulin sensitivity, maintaining adequate sleeps patterns, and balancing neurotransmitters when necessary. This paper will explore the role of botanical nervines and adaptogens in both the treatment and prevention of stress and adrenal dysregulation and its most common clinical manifestations.
The Physiology of Stress & Adrenal Dysregulation
The prevalence of stress in primary care is high, with an estimated 60–80% of visits having a stress-related component, and 44% of Americans reporting an increase in psychological stress over the past five years.1 Stress can manifest as a major life event (e.g. those often found on a life-stress inventory such as divorce, death of spouse, or major physical health concern), however more common stressors are those operating chronically at low levels (e.g. food allergies, gastrointestinal inflammation, social/professional/financial worries, glycemic dysregulation), both of which can result in profoundly negative clinical outcomes. A substantial contributor to stress-induced decline in health appears to be an increased production of stress hormones (cortisol and epinephrine). All stressors, regardless of origin will result in episodic or chronic elevations in cortisol, and the physiological and psychological consequences of acute and chronic stress can persist well past cessation of the event itself.
The field of psychoneuroendocrinology describes the mechanisms by which stress (as is mediated through the HPA axis) can drastically affect the functioning of the immune, endocrine & nervous systems.2 Within seconds of an acutely stressful event, norepinephrine is released from nerve endings and the adrenal glands release epinephrine and norepinephrine into the bloodstream, resulting in the sympathetic or “fight or flight response”. Within minutes to hours, a much more complex interaction between the nervous (central & enteric), endocrine, and immune systems occur, resulting in an intricate stress adaptation response. In all cases stress will be mediated by multiple systems and levels of cellular organization, with chronic overproduction of cortisol producing increasing levels of inflammatory mediators (e.g. IL-1, IL6, TNF-a). Nonetheless, each person’s individual adaptation to and symptomatic expression of stress will be unique, and thus herbal treatment approaches should be individualized as much as possible to their distinct symptom picture.
|Table 1. Common Clinical Presentation related to HPA Axis Dysfunction
|Central & Enteric Nervous Systems
|Immune & Inflammation
As with inflammation, our goal should not necessarily be to block stress in the body, but to improve its ability to adapt to stress, thus building resilience in the patient to better defend themselves against future potential triggers. However, without adequate management of stress-signaling over time an individual can begin showing signs of “Adrenal fatigue” or what it is more appropriately referred to as “Adrenal dysregulation”, which manifests as a dysfunction in the normal circadian rhythm of cortisol secretion. This rhythm has a natural waveform pattern, with cortisol levels peaking around 9 AM, gradually declining throughout the day, reaching their lowest at midnight, and then slowly rising into the early morning hours. Stress and HPA axis activation exerts a disruptive influence on the normal circadian release of cortisol and can cause changes in several body systems leading to a range of health concerns. Disrupted cortisol rhythms can lead to adrenal insufficiency or exhaustion caused by long-term overstimulation and failure to produce adequate levels of cortisol when needed. Often a patient’s individual symptomatic expression and response to stress can be correlated with either excesses or deficiencies of these pulsatile cortisol patterns, and their treatment goals and options will vary.
Herbal Approach to Stress Management & Adrenal Dysregulation
Alongside fundamental nutrition and lifestyle factors herbal medicine provides a foundational supportive role in the management of stress and its various manifestations. Much like maintaining a healthy diet, many medicinal plants require a long-term treatment approach to properly address long-standing or chronic stressors, adrenal dysregulation, and subsequent endocrine disruption. In most cases medicinal herbs are best suited towards the management of chronic as opposed to acute stressors, however some may be used more for more immediate expressions of sympathetic nervous system activation. Dosing strategies will likely differ depending on the desired treatment outcome, with higher amounts required under acutely stressful circumstances (see Table 3). However, often both long-term and acute herbal approaches can (and often should) be used together.
Understanding how herbs work means understanding the wide range of actions they can have in the body, and when managing stress two key complementary action groups to are the Adaptogens and Nervines (Tonics & Relaxants) which are explored in greater detail later in this review. Often these actions can be synchronized to work together alongside each other in a way that will benefit the body on multiple levels. When referring to these actions we are aiming to define the physiological and/or pharmacological effects the herbs will have when introduced to the body, however it’s important to keep in mind that each herb can have numerous actions, a widely variable constituent profile and mechanism of action, safety profile, and several key differences regarding plant energetics and suitability for the patient.
|Table 2. Patterns of Adrenal Dysfunction and Potential Herbal Treatments
|Pattern of HPA Dysfunction
|Common Clinical Presentation
|Treatment Goals & Herbal Options
(Overall elevated cortisol levels)
(Disrupted cortisol rhythm à potential exhaustion)
(Overall low cortisol levels leading to cellular dysfunction)
|Table 3. Herbal Dosing Strategies for Stress Management
|Long–term approach (chronic stress management & prevention):
|Short-term approach (acute stress management & prevention)
Adaptogens are plants that have recently been defined as “a class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and avoid damage from such factors”, essentially increasing adaptability and survival of organisms when undergoing stress.3 Their actions improve the body’s adaptability, increasing our threshold of resistance to the damaging effects of stress (in part through supporting the activity of the adrenal glands), thus helping to prevent some of the more common symptoms of stress, including poor concentration, sleep disturbance, fatigue, decreased immune response, and decreased resistance to infections. Despite their long traditional use, “Adaptogen” is a modern word, coined in the 1960’s to describe their unique qualities and taken from the latin adaptare meaning “to adjust”, referring to their ability to raise nonspecific resistance of the body to stress, so that it is better able to adapt to stressful circumstances. They were defined in 1969 by researchers Brekhman and Dardymov as the following:
- Is nontoxic to the recipient – i.e. must not deplete energy resources or be accompanied by negative side effects (e.g. dependence or withdrawal syndrome)
- Produces a general or nonspecific response in the body.
- Increases the power of resistance of the recipient to a variety of physical, chemical, or biological stressors.
- Has a normalizing influence on physiology – i.e. Increases physical & mental performance without depleting energy resources.4
Various studies have demonstrated the effects adaptogens can have on key mediators of the stress response, stimulating cellular and organismal defense systems, activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides, and enhancing survival against oxidative stress.5 Though as of yet there are unclear precise molecular mechanisms of action they share in common, it appears that adaptogens exert a polyvalent biological activity (i.e. are capable of provoking multiple effects upon the regulation of cellular metabolism and homeostasis), having many molecular targets upon the stress response and adaptation to environmental challenge.6 At their core, adaptogens support allostasis, which is the dynamic process of achieving physiological stability and maintaining internal vitality amid changing conditions. Thus, their normalizing effect can lead to contradictory actions depending on the body’s individual needs.
Gene expression analysis has recently contributed significantly to our understanding of adaptive stress response signaling and molecular mechanisms of action of adaptogenic plants, which appear to affect a large number of genes that play key roles in modulating adaptive homeostasis, indicating their ability to modify genetic expression to prevent stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative–cognitive impairment, metabolic disorders, and cancer (see Table 4). Many of these genes have various functions in cells but a clear majority play important roles in the neuroendocrine immune complex that regulates stress, aging, circulatory, and digestive systems. Adaptogens can thus affect gene expression of neurohormones upstream to the HPA and hypothalamic– pituitary–gonadal axes, which play key roles in the regulation of homeostasis and various physiological functions associated with stress-induced defense response and even reproductive status.7
|Table 4. Potential molecular targets and mediators of adaptive stress response regulated by adaptogens8
Most research appears to suggest a threshold of stress below which adaptogens can increase the stress response and above which they can decrease the stress response. This means they will likely have different effects in each person depending on their individual’s ability to adapt to stress. It is important to point out that their stress-protective effects are not through inhibiting the stress response, but are instead the result of improving the body’s own adaptation or tolerance to stress, often through mild stress-mimicking (hormetic) effects, and normalizing stress-induced elevated levels of cortisol and/or other extra/intracellular mediators of the stress response (e.g. NO, SAPK, NPY and various heat shock proteins).9,10 Adaptogens are modulators, capable of “fine-tuning” stress responses, reducing stress-induced oxidative damage, turning on protective-hormetic response molecules, and normalizing stress-induced elevated levels of cortisol and other mediators of the stress response.11
Though each plant will have its own distinct properties, their effects are achieved primarily through adaptation & alteration of the HPA axis (often by mediating ACTH release which improves the response of the adrenal cortex to stress and can reduce stress-induced damage to body systems), cortisol activity (as cortisol level often dictates the threshold of stress the body can tolerate), the autonomic nervous system (and in some cases neurotransmitter activity), and inflammatory & immune cytokine activity. Phytochemical explanations for how adaptogens work are complex, and explanations on their observed actions are not yet completely understood. What does appear to be clear is that there is no one constituent responsible for their effects, and they serve as an example that plant phytochemicals work better together than apart. Key clinical indications of a selection of adaptogenic herbs are explored in Table 5, and are considered to include indirect and direct corticomimetic activity, inhibition of glucocorticoid degradation, and the inhibition of enzymatic formation and release of inflammation mediators. It’s important when using adaptogens the intention is to support the foundations of a preventative approach to health and well-being rather than offering a quick fix or “band-aid” for maintaining unsustainable stressors or lifestyle factors.
|Table 5. Herbal Adaptogens: *Listed roughly from least to most energizing
|Key Clinical Indications
|Withania somniferum (Ashwagandha)
|Schisandra chinensis (Schisandra)
|Rhodiola rosea (Arctic Rose)
|Glycyrrhiza glabra (Licorice)
|Eleutherococcus senticosus (Eleuthero)
|Panax ginseng (Asian Ginseng)
Nervines are an herbal action group broadly defined as plants that will have a beneficial effect upon the nervous system in some way. They are traditionally used alongside herbal adaptogens as they have similar clinical indications, as well as complementary and often synergistic effects. Though some adaptogens overlap with the nervines, in herbal terminology they are considered to have distinctive effects upon central & peripheral nervous system activity. Like adaptogens, they are ideally used long-term (minimum 1-2 months) when addressing stress and its complications, however some may be used acutely when necessary. To explore nervines properly they are best differentiated into 3 major groupings:
1) Tonics: Support symptoms related to stress & anxiety, and will strengthen & nourish the nervous system when coping with excessive or prolonged periods of tension and/or stress. In some cases, nervine tonics will help restore central & peripheral tissues directly, and/or modulate the action of various neurotransmitters (e.g. GABA, Serotonin) through pharmacological mechanisms. Most are mildly relaxing and used in mood disorders. Note: Adaptogens have much overlap with this action due to their ability to aid the whole of the body and mind to cope with demands made upon it.
|Table 6. Herbal Nervine Tonics
|Key Clinical Indications
|Bacopa monniera (Brahmi)
|Centella asiatica (Gotu kola)
|Hypericum perforatum (St. John’s wort)
|Crocus sativus (Saffron)
2) Relaxants: Address symptoms that accompany pain, insomnia, and anxiety. Often bitter, and having sedative effects which are usually dose-dependent, as in higher doses many of these herbs will act as anxiolytics and help promote a more restful sleep. They are perhaps the closest natural alternative for pharmaceutical tranquilizers, but should always be used in a broad holistic way. They often contain volatile oils or alkaloids with direct parasympathomimetic effects upon the nervous system), and also acting as antispasmodics, analgesics, and hypotensives. When addressing sleep disturbance, they combine especially well alongside calming adaptogens (e.g. Ashwagandha) as the initiation of sleep occurs concurrently with a low HPA activation, and nighttime awakenings are often associated with pulsatile cortisol release or HPA axis hyperactivity which can lead to fragmentation of sleep. Both adaptogens and nervine relaxants can help normalize HPA axis abnormality, and often decrease both CRH & cortisol hyperactivity and associated symptoms.
|Table 7. Herbal Nervine Relaxants (Listed roughly from least to most sedating)
|Key Clinical Indications
|Scutellaria lateriflora (Skullcap)
|Matricaria recutita (Chamomile)
|Piper methysticum (Kava Kava)
|Zizyphus jujube (Jujube)
|Passiflora incarnata (Passionflower)
|Valeriana officinalis (Valerian)
|Anxiolytic (may be due to increased concentrations of GABA in the synaptic cleft, which may decrease CNS activity and binds to benzodiazepine receptors109,110
Sedative for improving symptoms related to sleep disturbance and sleep quality (e.g. in geriatric sleep-disturbed patients, nonelderly chronic insomniacs, and periodic insomniacs).111,112
Antispasmodic with muscle relaxing effect on smooth and skeletal muscle (e.g. dysmenorrhea, neuralgias, intestinal spasm and arrhythmias).113,114
Hot flashes in postmenopausal women.115
3) Stimulants: Cause direct stimulation of the central nervous system, usually contain alkaloids (e.g. caffeine) and are used sparingly if not avoided completely when managing stress and HPA axis dysregulation. They are easily the most popular herbs on the planet for improving energy, focus, and concentration. However, in most cases it would be far more appropriate to stimulate the body’s innate vitality with the help of adaptogens or tonics. A problem with commonly used stimulants (such as tea & coffee) is that they have a number of side effects and can themselves be involved in causing many problems, such as anxiety and tension.
Stress is an unavoidable fact of everyday life and is can result in significant physiological problems, including cardiovascular, gastrointestinal, immunological, endocrine and nervous system disorders. Though herbal medicines are not a to be considered a band-aid for poor diet & lifestyle habits, when used alongside a healthy diet and adequate sleep & exercise botanicals can provide support for the many manifestations of stress-related conditions in both short and long-term treatment strategies though taking a three-pronged approach:
- Support the HPA-axis long-term with Adaptogenic herbs (minimum 3 months), and recognize that though all adpatogens will help modulate the stress response, some will be more/less stimulating and be better suited to the patient’s individual constitution, systems imablannce, and symptom picture. Moreover, dosing & timing of delivery should be adjusted appropriate based on the patient’s changing symptom picture and their symptomatic manifestations of stress.
- Support the Nervous System with Nervine Tonics which often pair well alongside adaptogens and should be used for a minimum of 3 months. Choose specific herbs for their ability to modulate & enhance nerve impulse transmission, improve mood, memory and cognition, and neuropathic pain.