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Nutriceuticals:

Adaptogens

Adaptogens are defined as “substances that increase attention and endurance in fatigue, and reduce stress-induced impairments and disorders related to the neuro-endocrine and immune systems.” In other words,

In other words, adaptogens are non-toxic herbs that help the body adapt to and manage stress, both physical and mental. They help regulate the body’s stress response, potentially suppressing the negative effects of chronic stress by reducing fatigue, improving cognitive function, enhancing mood, and increasing physical endurance. 

 

See also:

See also:

Nutraceuticals

 

 

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Adaptogens

Historically, the supplemental use of adaptogens has not gained much traction in traditional western medicine but rather has been engaged by the naturopathic medicine, complementary and alternative medicine and functional medicine communities. However, in the last 10 years adaptogens have developed growing interest in traditional western medicine and research has begun to shed light on these botanical substances that have had widespread use for literally thousands of years.

 

Introduction – What are Adaptogens?

Adaptogens are natural bioregulators that facilitate adaptation to environmental and psychosocial conditions that are stressful and threaten or cause damage or illness. This adaptation reduces the symptoms and damage from such conditions. Adaptogens lessen the negative impact of stress on the neuro-endocrine and immune systems, increase cognitive performance and reduce fatigue. The Food and Drug Administration (FDA) defines an adaptogen as “a new kind of metabolic regulator that has been proven to help in environmental adaptation and to prevent external harms.”

 

Characteristics of adaptogens:

  1. Increase bodily resistance to physical, chemical and/or biologically noxious agents or factors;
  2. Adaptogens have a normalizing influence and reduce the harm caused by stressed states such as fatigue, infection, and depression;
  3. Adaptogens have positive, excitatory (stimulating) effects on the body;
  4. In contrast to traditional stimulants, the excitatory effects produced by adaptogens must not cause side effects such as insomnia, low protein synthesis, or excessive energy consumption;
  5. Adaptogens do not harm the human body and not disturb body functions at normal levels.

 

Clinical Applications of Adaptogens

Adaptogens offer a wide range of benefits depending on the individual adaptogen and the dosing regimen. Most commonly, adaptogens are used to combat the effects of chronic stress including anxiety, insomnia, mental and physical fatigue, diminished sense of well-being and potential vulnerability to acute and chronic illness. Adaptogens are frequently recommended for use as general tonics in traditional Eastern and Asian medicine.

Adaptogens exert an anti-fatigue effect that increases mental work capacity against a background of stress and fatigue, particularly by increasing tolerance to mental exhaustion and enhanced attention. They reduce stress-induced impairments related to the neuro-endocrine and immune systems.

Because stress is known to impair the immune system, adaptogen’s stabilization of the stress response also supports the assertion that adaptogens improve the immune response during times of high stress. Adaptogens were used prophylactically during COVID-19 to reduce the impact of stress on the immune response and reduce vulnerability to infection.

Stress

Prolonged stress triggers the body’s stress response system which includes the brain and adrenal gland (hypothalamic-pituitary-adrenal (HPA) axis), the part of the stress-system that is believed to play a primary role in the reactions of the body to repeated stress and adaptation.

This concept was based on Hans Selye’s theory of stress and general adaptation syndrome, which has three phases:

    • Stage 1: Alarm
    • Stage 2: Resistance
    • Stage 3: Exhaustion

The initial, short-lived Alarm phase is the body’s normal “fight-or flight” response to danger which is characterized by elevated cortisol and adrenaline levels. The next phase, the Resistance phase, embodies how the body continues to buffer against extended stress exposure, long after the initial fight-or-flight response has resolved. The hormones cortisol and DHEA are released by the adrenals as part of the “resistance” process. However, prolonged stress burdens the hormonal system, creating an imbalance in cortisol and DHEA production which can result in mental and physical fatigue, nervous tension, irritability and poor memory – the features characteristic of stage 3, Exhaustion.

Adaptogens increase the state of non-specific resistance in stress and decrease sensitivity to stressors, which results in stress protection, and prolong the phase of resistance (stimulatory effect). Instead of exhaustion, a higher level of equilibrium (the homeostasis) is attained, “heterostasis.”  Heterostasis refers to “a state of dynamic equilibrium where an organism maintains its internal environment by shifting to new stable states, often in response to stress or external demands.” It contrasts with homeostasis, which maintains a single, relatively stable internal state. In essence, heterostasis is about adapting to change by finding new balances, while homeostasis focuses on resisting change to maintain the status quo.

 

Adaptogens and Sleep

One of the major impacts of stress is the disruption of sleep, including including falling asleep, staying asleep and the quality or restfulness of sleep. One contributing factor that causes sleep-related problems is that stress impairs the normal circadian secretion of the hormone, cortisol. The secretion of cortisol is regulated by the brain and adrenal glands and follows the biological clock and external circadian rhythms.

The normal secretion of cortisol peaks in the morning and then decreases, reaching a minimum value at night. Proper exercise, diet and sleep help maintain stable cortisol levels but excessive stress becomes very disruptive to the normal rhythms of cortisol secretion. Adaptogens help stabilize cortisol levels. The following adaptogens have been shown to facilitate sleep, including the effects of the time zone differences: Ashwagandha, American Ginseng, Schisandra chinensis and Rhodiola rosea.

 

Adaptogens and the Neuroendocrine System

One of the most important functions of adaptogens is their ability to help stabilize the internal environment of the human body by modulating the neuroendocrine system. Adaptogens enhance the ability to adapt to external environments and avoid damage. A unique feature of adaptogens is that these substances affect both the neuroendocrine system and the cellular energy system. Adaptogens can increase the rates of oxygen, protein, fat and sugar utilization.

 

Adaptogens and Fatigue

The human organism has a self-regulated cell and organ defense system that can recover normal physiological functions and maintain health in response to stress. Fatigue is a symptom of overload strain and an alarm signal to rest and normalize homeostasis. Fatigue, sometime referred to as weariness, tiredness, and exhaustion, is a common health complaint generally defined as a lack of energy.  However, it can be useful to distinguish different manifestations of fatigue:

    • Physical fatigue is the inability to continue functioning at a level consistent with normal ability
    • Mental fatigue may manifest as decreased attention, reduced ability to concentrate, or somnolence.
    • Brain fatigue  (as distinguished from mental fatigue) is a long-lasting pathological mental/cognitive fatigue related to brain injury. It is characterized by an extreme lack of energy and associated with prolonged mental effort, stress, or neurological conditions, which interferes with an individuals’ ability to perform routine daily activities. It impairs overall well-being, quality of life, and social activities.

 

Over the past decades of technological progress, work has changed from demanding physical effort to demanding mental effort, resulting in increased stress and mental fatigue complaints. During the day, one may face complex tasks by organizing, planning, and managing at work and dealing with household and personal responsibilities, often accompanied by unexpected interruptions that lead to mental fatigue. 

 Mental fatigue occurs when the brain becomes overworked, tired, and exhausted when rest helps but does not cure it. It leads to an aversion to continuing with the present activity, decreased commitment to the tasks, and difficulties in concentration, memory, and overall mental performance.

Stress can magnify fatigue when an individual performs highly cognitive and attention-demanding tasks. Additionally, stress affects brain areas that control working memory, contributing to cognitive overload and impaired learning. It can increase. mental fatigue and introduce a state of anxiety and depression. As such, stress-induced mental fatigue can have a profound and negative impact on the quality of one’s life.

Moreover, mental fatigue is a common symptom that accompanies chronic medical conditions such as depression, fibromyalgia, chronic fatigue syndrome, Alzheimer’s disease, cancer, HIV and multiple sclerosis.

 

Adaptogens and General and Mental Fatigue

Tto date, only a few adaptogenic herbal preparations have been studied in well-conducted randomized, placebo-controlled, double-blind clinical trials to assess anti-fatigue effects and cognitive functions. They include:

    • Rhodiola rosea L. (Arctic root)
    • Eleutherococcus senticosus (Rupr. and Maxim.)
    • Maxim. (eleuthero),
    • Schisandra chinensis Baill. (schisandra)
    • Withania somnifera (L.) Dunal (ashwagandha)
    • Panax ginseng C.A. Mey preparations,

Rhodiola

Referring to Rhodiola studies, numerous clinical trials were conducted in patients who were diagnosed with fatigue syndrome, aging cognitive deficiencies, mild/moderate depression, anxiety, and burnout symptoms, and in healthy subjects who experienced life stress-induced fatigue and 84 reviews only on Rhodiola have been published since 2011 and confirm that Rhodiola preparations exhibit anti-fatigue, antidepressant, and ergogenic activity, shown by an improvement in both physical and mental performance.

 

Adaptogens and Brain Fatigue

The terms brain fatigue and mental fatigue are often used interchangeably, but they are distinctivey different. The term “brain fatigue” is mental or cognitive fatigue or long-lasting pathological mental fatigue after physically recovering from trauma, stroke, infection, brain injury, or inflammation in the central nervous system. Unlike physical fatigue, brain fatigue primarily affects cognitive functions rather than physical stamina, while mental fatigue focuses on the psychological aspect of feeling mentally exhausted. However, they frequently overlap in practice.
Brain fatigue is a pathological and disabling symptom of diminished mental energy related to the consequences of traumatic head injuries, strokes, multiple sclerosis (MS), other diseases that affect the brain and neuropsychiatric conditions including ADHD/ADD and autism,. It is characterized by an extreme lack of energy after moderate mental activity. Extensive fatigue can set in quickly and continuing the activity is impossible. Also typical is a  long-lasting recovery time to regain mental energy. It may be difficult to return to work or participate in social activities. and often one can only remain mentally active for short periods.

While most people recover within months after a mild traumatic brain injury (TBI) or concussion. However, some will suffer from long-term fatigue with reduced quality of life and commonly describe a “stiffness in thinking” and mental energy can suddenly run out. They can be overloaded by the sound of a low-frequency fan. They are typically sensitive to stress and may experience problems with memory. Everyday activities such as working, social conversations, reading, and watching TV may become problematic and completely draining of energy with recovery time disproportionately long.

Symptoms of brain and mental fatigue can overlap but they do have key differences, often reflecting each condition’s physical versus psychological nature:

Symptoms of brain fatigue (physical exhaustion of the brain) include the following:

  • Cognitive slowness: slower reaction times or delayed thinking processes.
  • Mental fog: difficulty processing information or understanding concepts.
  • Headaches or pressure: sensations in the head after cognitive tasks.
  • Memory issues: forgetfulness or inability to recall recent information.
  • Visual disturbances: blurred vision, light sensitivity, or difficulty focusing the eyes.
  • Physical tiredness: feeling physically drained after mental exertion, even without significant physical activity.
  • Coordination problems: in severe cases, mild issues with hand-eye coordination or balance.

Symptoms of mental fatigue (psychological exhaustion) include the following:

  • Lack of motivation: feeling demotivated to start or continue tasks, even simple ones.
  • Irritability: becoming easily frustrated, annoyed, or emotionally reactive.
  • Difficulty concentrating: struggling to focus on tasks, especially those requiring sus-
  • tained attention.
  • Indecisiveness: making decisions, even about trivial matters, is more demanding.
  • Emotional numbness: feeling emotionally detached, disinterested, or overwhelmed by small things.
  • Sleep disturbances: insomnia or restless sleep due to racing thoughts or stress despite feeling tired.
  • Burnout-like symptoms: feeling mentally and emotionally exhausted, often linked to chronic stress or overload.

 

While brain fatigue is often associated with physical symptoms such as slowed cognitive function, mental fatigue is more likely to be associated with emotional and motivational issues such as irritability, lack of focus, and emotional exhaustion. However, the two can often coexist, especially in high-stress situations.

In most people, brain fatigue improves or resolves when the injury or illness heals, but sometimes it remains for months or even years. Brain fatigue is not related to the severity of the injury/disease and even a mild concussion can have severe and long-lasting consequences. Long-term brain fatigue after a minor head injury occurs in up to 20–25 percent of cases.  Brain fatigue can also be a lingering symptom in some people affected by COVID-19 and can occurs at all ages, including children.

Research suggests neurobiological origins for brain fatigue. including dopamine imbalance, reduced glutamate handling by astrocytes, unspecific signaling of cell networks and reduced energy supply in the brain. Effective recovery of brain and cognitive functions suggests likely requires the development of new neurons (neurogenesis). Neurogenesis activation is associated with the upregulation of genes involved in the proliferation and differentiation of neurons and glial cells.
The results of studies suggest that adaptogens might be helpful in brain fatigue.  However, there is not yet clinical evidence of the efficacy of adaptogens regarding the quality of life in brain fatigue that can provide evidence-based indications for adaptogens to improve the quality of life in brain fatigue.

 

Adaptogens and Adrenal Fatigue

The adrenal glands, often considered the stress glands, provide various responses to physical, biochemical, hormonal, emotional and mental stress. Excessive stress, resulting from a single event or from the accumulation of chronic or repetitive stressors, can result in the adrenals not being able to secrete enough stress hormones to compensate for high levels of stress leads to adrenal fatigue.  Adrenal fatigue occurs where the adrenal glands cannot maintain normal balance (homeostasis), including levels of the three major stress hormones: cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine). Adrenal fatigue is associated with nonspecific symptoms such as body aches, unexplained weight loss, fatigue, nervousness, sleep disturbances and digestive problems.

The following adaptogens support adrenal function by increasing the effectiveness of adrenal gland secretion and stabilizing stress hormone production:

  • Ashwagandha
  • Rhodiola rosea
  • American Ginseng
  • Asian ginseng (Panax)
  • Siberian ginseng
  • Licorice root (Glycyrrhizae radix)

 

Of note, “adrenal fatigue” is a diagnosis supported by alternative medicine clinicians, but isn’t a generally accepted medical diagnosis in traditional western medicine. The traditional medical term is “adrenal insufficiency” (Addison’s disease), referring to inadequate production of one or more of these hormones. The theory behind adrenal fatigue is that the adrenal glands are unable to keep up with the demands of severe or chronic stress and as a result, symptoms develop. Existing blood tests, according to the adrenal fatigue theory, aren’t sensitive enough to detect such a small decline in adrenal function. Adrenal insufficiency, it is argued, can be diagnosed by blood tests and special stimulation tests that show inadequate levels of adrenal hormones. The debate has not been resolved.

The Stimulating Effects of Adaptogens

Some adaptogens are noted for their stimulating effects. Stimulants, defined as drugs that increase the activity of the sympathetic nervous system, can be used to increase alertness and the ability to concentrate on mental tasks. Traditional stimulants such as caffeine, nicotine, amphetamines and cocaine, can with short term use boost endurance and productivity. However, long-term stimulant use can impair mental function and lead to psychotic symptoms. Furthermore, some stimulants are prone to abuse and addiction, have a negative effect on sleep structure and cause rebound hypersomnolence or ‘come down’ effects.

The stimulating adaptogens do not exhibit these negative effects and may actually regulate certain sleep disorders and improve sleep quality. This is because these adaptogens stimulate the nervous system by mechanisms that are totally different from those of traditional stimulants. Adaptogens modulate the response to stressful stimuli and regulate various metabolic elements of the stress system, particularly the SAS.

Depending on the mediators of the stress system involved in the adaptogen-induced stress response, an immediate (single dose effect) or a long term (after multiple administration) stimulating effect may result. While the effectiveness of repeated administration of adaptogens in improving mental performance over various time periods is well documented, research on single dose effects is less well established.

Stimulating adaptogens for single dose use

Single dose use of adaptogens are reported to increase:

      •  Mental working capacity
      •  Physical working capacity
      •  Accuracy of movement

Three of the known plant adaptogens, Rhodiola rosea, Schizandra Berry (Schisandra chinensis) and Siberian Ginseng (Eleutherococcus senticosus), are purported to offer a safe, ‘adaptogen-type’ stimulating effect providing improvements in mental performance and learning efficiency after single dose use. The most activating stimulant is Rhodiola rosea. The stimulating effects of these adaptogens are reported to be apparent within 30 minutes after administration and last for at least 4–6 hours.

 

Most Popular and Efficacious Adaptogens

Popularity is based on sales (e.g., U.S. market: Ashwagandha ranked #12 in 2024 herbal sales ) and search trends. Efficacy is rated high/moderate/low based on Random Controlled Trials (RCTs) and systematic reviews for stress/anxiety/sleep/pain (e.g., reductions in cortisol, anxiety).

Ashwagandha (Withania somnifera):

  • Ashwagandha has strong adaptogenic properties with many benefits that include improving stress resilience, supporting immune response, regulating the sleep cycle, supporting healthy thyroid function and protecting against exhaustion of the nervous system. Ashwagandha may also be beneficial in supporting mood regulation and restoring a sense of calmness under stress.
  • Most popular/efficacious for stress/anxiety (high confidence: 64–75% reduction in scores, cortisol 28–44%), sleep (high: improved quality/latency), cognition (moderate: 80% improvement in attention), fatigue (moderate ), and inflammation/oxidative stress (moderate: 15–25% reductions in CRP/MDA ).
  • Ideal for chronic pain due to HPA modulation.

See: Ashwagandha

 

Rhodiola rosea (Arctic Root):

  • Rhodiola has been studied extensively and is widely used in Eastern Europe and Asia to reduce fatigue, regulate mood, improve mental clarity, work performance and the sleep cycle. It increases resistance to a variety of stressors. Rhodiola supports levels of neurotransmitters in the central nervous system such as serotonin, dopamine and norepinephrine. Salidroside, rosavin and triandrin are the constituents in rhodiola that are best studied and the substances which most benefits are attributed to, including Rhodiola’s neuroprotective and stimulating effects.
  • Highly efficacious for fatigue/stamina (high: improves energy, endurance, stress/anxiety (high: reduces fatigue/anxiety , sleep (moderate), and cognitive function (moderate).
  • Synergies with Ashwagandha for stress. Popular for physical performance in pain patients .

See: Rhodiola

 

Bacopa monnieri:

  • Efficacious for cognition (high: improves memory/attention ), anxiety/depression (moderate), and sleep (low-moderate). Less popular for pain but useful for stress-related cognitive decline.
  • Synergies with Ashwagandha for cognition/anxiety .

 

Panax ginseng (Asian Ginseng):

  • There are at least nine species of ginseng, mostly named by their geographical origins, such as Asian ginseng (Panax ginseng), American ginseng (Panax quinquefolium), and Japanese ginseng (Panax japonicus). Panax ginseng, also called Asian or Korean ginseng, has been reported to have diverse physiological effects in multiple systems, including cardiovascular, immune, and neuronal. It has also been used to enhance sex performance. The main active components of Panax ginseng are ginsenosides, which have been shown to have a variety of beneficial effects, including anti-inflammatory, antioxidant, and anti-cancer effects.
  • Efficacious for fatigue/energy (high), cognition (moderate ), and immune modulation (high). Moderate for stress/anxiety . Popular but less efficacy for pain;
  • Synergies with Ashwagandha for energy.

 

Schisandra chinensis:

Schizandra is an adaptogenic botanical that has been used for centuries in China and Russia to help support mental clarity, stress response and emotional wellness. It is believed to improve physical performance in athletes, support learning and memory and may have some protective factors that support brain health.

  • Popular for fatigue/endurance (moderate ), liver support/gut health (moderate ), and stress (moderate ). Efficacious for inflammation .
  • Synergies with Ashwagandha for oxidative stress .

 

Holy Basil (Tulsi, Ocimum sanctum):

  • Efficacious for stress/anxiety (high), sleep (moderate), and inflammation (moderate).
  • Useful for pain-related comorbidities .

 

Siberian Ginseng  (Eleutherococcus senticosus):

Siberian Ginseng, or Eleuthero, is an Asian herb that has been widely used in China for thousands of years as a healing remedy in folk medicine to combat stress and improve stress resilience, support memory and increase work capacity during strenuous aerobic activity. It is different from, and only distantly related to the “true” ginseng species (Panax ginseng and P. quinquefolius) and possesses entirely different, unrelated chemical constituents.

Eleuthero helps stabilize stress hormones, at least in part by inhibiting catechol-O-methyl transferase (COMT), the enzyme that metabolizes the stress hormones adrenaline and noradrenaline. Eleuthero has also been shown to support the immune system. Syringin is one of the most important bioactive compounds found in Eleuthero, with pharmacological properties that include scavenging free radicals, protection against neuronal cell damage, inhibition of apoptosis, anti-diabetic effect, anti-inflammatory potential, anti-pain action and anti-allergic effects

  • Efficacious for fatigue/immunity (moderate), stress (moderate).
  • Synergies with Ginseng for endurance .

 

Licorice root (Glycyrrhiza glabra):

  • Moderate for stress (cortisol modulation ), but caution for hypertension .
  • Synergies with Ashwagandha for HPA balance

 

Cordyceps (Cordyceps sinensis/militaris):

  • Efficacious for energy/fatigue (moderate), immune support (high).
  • Popular for physical performance in pain patients .

 

Maca (Lepidium meyenii):

  • Moderate for fatigue/energy (mood improvement), but less for anxiety/sleep .
  • Synergies limited.

Adaptogen Synergies:

(1) Ashwagandha + Rhodiola: for stress/energy (cortisol reduction)

Ashwagandha and Rhodiola together enhance stress resilience, reducing cortisol by about 30% through complementary HPA axis modulation.

(2) Ashwagandha + Bacopa: for cognition/anxiety

Combining Ashwagandha with Bacopa monnieri amplifies cognitive and anxiolytic benefits via shared GABAergic pathways.

(3) Ashwagandha + Ginseng: for fatigue . Evidence is moderate; long-term RCTs needed [web:9, web:15]. Start with low doses; monitor for interactions (e.g., ginseng with blood thinners) .

 

(4) NrF2 Activators (Curcumin, Resveratrol, etc.)

    • Ashwagandha activates Nrf2, increasing SOD and catalase, reducing MDA and ROS by 15–20%.

(5) Popular combinations: Ashwagandha + L-Theanine or Rhodiola + Caffeine enhance benefits.

 

Recommendations: Adaptogens for chronic pain patients:

  • Focus on Ashwagandha as first choice, consider adding Rhodiola, Bacopa, or Ginseng, as they have high/moderate efficacy for stress, anxiety, sleep and cognition.
  • Consider including Schisandra or Holy Basil for inflammation/gut health .

 

The Dose Matters

Dose-Dependent Reversal Effects of Adaptogens

Sometimes adaptogens, can have the therapeutic effects at low doses, but at high doses have no effect. Or, they can exhibit stimulation at low doses, but sedation at higher doses, as in the case of Rhodiola rosea in animal studies. This effect can make animal studies in particular very confusing when interpreting results. This dual action is not well understood but is due to the complexity of the stress system, including multiple “players” involved in stress response on various levels of regulation. The pharmacodynamics of adaptogens is characterized by their interaction with networks of multiple regulators and mediators of adaptive stress response.

Understanding Adaptogens and Their Impact on the Stress Response

An excellent review article, “Stimulating Effect of Adaptogens: An Overview with Particular Reference to their Efficacy following Single Dose Administration” published in 2005 in Phytotherapy Research, provides a comprehensive introduction to the concepts surrounding the benefits and use of adaptogens for therapeutic benefit.

Physiological adaptation is defined as a biochemical change in an organism that results from exposure to certain environmental conditions or stressors and generates a more effective response to them. Such adaptive changes take the the stress system (a function of the neuroendocrine-immune complex) from its normal steady state (homeostasis) to a heightened level of dynamic equilibrium (heterostasis) or to the state of non-specific resistance (SNSR), the state in which one has greater resistance to the disruptive and potentially damaging effects of stress, offering greater potential for survival. Allostasis is the process of achieving stability, or homeostasis, through physiological or behavioral change. This can be carried out by means of alteration in HPA axis hormones, the autonomic nervous system, cytokines, or other systems.

The general adaptation syndrome, or response to stress, has three stages: the alarm response, the point at which the body identifies a stressor; adaptation, in which the body engages defensive countermeasures against the stressor; and exhaustion, where the body begins to run out of defences. Stress can be considered as challenging but not overwhelming (eustress), or as overloading (distress). Stress can result from positive (desirable) or negative (undesirable) events. Eustress can be beneficial but distress can be harmful and contribute to disease. Eustress may raise levels of adrenaline and prostaglandins in the body, which in turn increases the heart rate, respiration and blood pressure and may promote survival.  Long-term stress, however, contributes to heart disease, high blood pressure, strokes and other illnesses.

Early research suggested that a state of non-specific resistance (SNSR) could be achieved either by gradually training the organism to withstand the effect of the stressor or through use of pharmacologically active compounds named ‘adaptogens’ that modify the body’s response to stress.

Repeated use of adaptogens may be stress-protective, in a manner similar to that produced by repeated physical exercise, and lead to prolonged SNSR with increased endurance and stamina under extreme conditions. Repeated doses of adaptogens have been shown to be effective in sports with fatigue reduction and increased endurance in long distance runners with a more rapid recovery from strenuous exercise – even a single dose of an adaptogen may produce a stimulating effect.

The stress-protective effect obtained by multiple administrations of adaptogens is not the result of inhibition of the stress response, but a result of the adaptive changes in the organism as a consequence of the repeated stress-response modifying effect of the drug. In pharmacological terminology, adaptogens are stress-agonists and not stress-antagonists. Adaptogens function mainly by affecting the stress response system, primarily the hypothalamic–pituitary–adrenal (HPA axis), in response to stimulation by external stress.

 

The Physiologic Basis of the Stress Response

The stress response system is complex, primarily consisting of the central nervous system (CNS) which includes the hypothalamus and the pituitary gland, the peripheral nervous system which includes the autonomic nervous system (sympathetic and parasympathetic) and the adrenal glands. In times of stress, the hypothalamus releases corticotropin releasing hormone (CRH – also known as corticotropin-releasing factor (CRF),  a peptide hormone that stimulates the pituitary to release ACTH (adrenocorticotropic hormone), which acts on the adrenal glands to release the steroid hormone cortisol. Cortisol is a steroid hormone that regulates a wide range of processes throughout the body, including metabolism and the immune response. It has a very important role in helping the body respond to stress. 

 

The Hypothalamic–Pituitary–Adrenal (HPA) Axis

Adaptogens function in response to  stress mainly by affecting the HPA axis, which consists of the hypothalamus, the pituitary gland and the adrenal gland. The HPA axis is the primary component of the body’s stress system that responds to repeated stress and contributes to the adaptation to stress. When stimulated by the hypothalamus via homeostatic feedback mechanisms, the pituitary gland secretes ACTH. The release of ACTH regulates levels of the corticosteroid hormone cortisol, which is manufactured and released from the adrenal gland.  The HPA also functions to balance the release of adrenaline from the adrenal gland and corticosteroids and nitric oxide (that modulates many hormones and other physiologically active substances.  The HPA axis modulates the nervous, cardiovascular, immune, gastrointestinal and endocrine systems.

 

The Sympatho-Adrenal–System (SAS)

In addition to chronic stress adaptation, acute stress adaptations are important in situations that require a rapid response to a stressful situation. In these acute cases, the effects are generally associated with another part of the body’s stress system, namely, the Sympatho-Adrenal-System (SAS). The SAS is a physiological connection between the sympathetic nervous system and the adrenal gland which is crucial to the physiological response to stress. The sympathetic nervous system (SNS) and HPA system interact in terms of functions and systematic anatomy. When responding to the external environment, these systems can interact on different levels, for example, catecholamine can stimulate the HPA axis by releasing of CRH, and the hormones produced by the HPA axis can act on the SNS system. This system’s rapid response to a stressor results in increased levels of the catecholamine stress hormones (adrenaline and noradrenaline) and other physiologically active substances (neuropeptides, ATP, nitric oxide and eicosanoids) that have a variety of effects including inflammation, blood pressure regulation, and the immune response.

 

Research has shown that the inhibitory effects and long-term overexpression of cortisol causes stimulatory effects that are adjusted by the sympathetic nervous system (SNS) under stress. The secretion of CRH increases, promoting the secretion of cortisol and adrenocorticotropic hormone.  The SNS provides a fast response mechanism to stress. In addition to adrenaline and noradrenaline, the SNS and the parasympathetic nervous systems also secrete a variety of neuropeptides, ATP and nitric oxide (NO). In addition, other agents including angiotensin, cytokines and arachidonic acid metabolites participate in the stress response. When these adjustments to the HPA axis occur with use of adaptogens, an increase in energy occurs along with a reduction in the feeling of stress,  improvement of mental concentration and facilitation of sleep. These are all considered the primary function of adaptogens.

 Adaptogens and their ability to modify gene expression

Based on recent research published in 2018, adaptogens presumably worked as eustressors (“stress-vaccines”) to activate the cellular adaptive system by inducing the expression of adaptive stress-response signaling pathways (ASRSPs), which then protect cells from damage caused by distress. Adaptogens activate neuroglia cells to modulate adaptive homeostasis by modifying gene expression to prevent stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and cancer.

Many of the genes regulated by adaptogens are closely associated with adaptive stress-response signaling pathways (ASRSPs) related to corticotropin-releasing hormone, melatonin, nitric oxide synthase, neuroinflammation, neuropathic pain, opioids, and renin-angiotensin and many others.

Adaptogens in context of Eastern Medicine:  Ayerveda and Traditional Oriental Medicine

Evaluation of Eastern medical systems including Indian Ayurvedic medicine and traditional Oriental medical systems including Traditional Chinese Medicine (TCM), traditional Japanese medicine (Kampo) and traditional Korean medicine reveals that the tonics they incorporate are often adaptogens.

Indian Ayurvedic Medicine

Ayurveda, the traditional medical system of India, conceptualizes “doshas,” or “functional principles.” It is the combination of the doshas characteristics based on a five-element philosophy that drives mental and physical well-being. When the doshas are out of balance in quality or quantity, well-being is impaired and symptoms occur. Research suggests that some of the diagnoses established in Ayurveda overlap in many ways with western medical diagnoses, particularly related to anxiety and stress. As such, traditional Ayurveda treatment may offer benefit in the management of anxiety and stress. For example, the adaptogen Ashwagandha is commonly used in Ayerveda to treat conditions associated with stress and anxiety.

Traditional Chinese Medicine (TCM)

In traditional Chinese medicine, it is believed that harmony and balance are required for optimal health and the concepts of yin and yang in the balance of Qi (life energy) are used to diagnose and cure disease. In TCM, medicines that can improve deficiency and weakness caused by deficiency of qi are used to treat the syndrome of qi deficiency and are called tonics.

Tonics

Tonics have wide range of applications in TCM and are used under the conditions of low body resistance and weak constitution or when the body is finding it difficult to fight severe diseases. This function of tonics is similar to that of  adaptogens and tonics typically are adaptogens, but not always.  Chinese herbs considered to be both adaptogens and tonics include the following: Panax ginseng, Panax quniquefolius, Eleutherococcus senticosus, Rhodiola rosea  and Schisandra chinensis. According to the terminology used in TCM, the mechanism of action of plant-based adaptogens is to achieve equilibrium in both yin and yang, resulting in great vitality.

See: Traditional Chinese Medicine (TCM)

 

Understanding Energy and Fatigue as Related to Stress

Brain Energy Resources and Utilization in Brain Fatigue

Understanding the biochemistry of brain energy is essential to understanding how the brain functionsat a cellular and molecular level. The brain’s energy metabolism is a very complex  process that involves glucose and alternative fuel sources such as lactate and ketones.

Disruptions in the brain’s energy balance, whether due to age, diet, or disease, can impair brain function and contribute to neurodegenerative conditions. New research demonstrates the potential for targeting energy metabolism to improve brain health and treat neurological disorders.

 

Energy Sources and ATP Generation

Glucose is the primary source of energy for brain functions,  oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components. The human brain needs continuous glucose delivery and consumes about almost 25% of the body’s total energy use. Communication between the brain’s nerve cells (synaptic transmission) needs a constant energy supply; therefore, glucose metabolism is critical for information transfer and processing in the brain.

Under normal physiological conditions, glucose uptake rates into nervous cells are controlled by brain activity.Once in the brain, cells,  glucose is metabolized to produce adenosine triphosphate (ATP),  the most essential chemical energy storage molecule of cellular energy. This process of cellular manufacturing of ATP occurs in the mitochondria, intracellular cellular “energy banks” present in all cells where energy is stored in the form of  these“energy-rich” ATP molecules.

 

How stress significantly affects ATP production in the brain and body

Acute Stress

Depending on its duration and intensity, stress influences ATP production and the role of increased  ATP in the adaptive responses to stress. Acute stress typically triggers an increase in ATP demand to support the “fight-or-flight” response which is regulated by stress hormones such as adrenaline and cortisol, which elevate heart rate, respiration, and blood flow to muscles and the brain.

The brain requires more ATP during acute stress to support heightened alertness, faster processing, and other adaptive responses. In response to acute stress, the body mobilizes glucose for rapid ATP production. This quick energy mobilization boosts ATP generation to meet immediate demands. The increase in ATP demand during acute stress is usually provided by the up-regulation of mitochondrial activity in cells, especially in nerve and muscle cells.

This increase in ATP production serves as a short-term adaptive mechanism that prepares the body to face or escape danger. Essentially, it is a defense response, enabling rapid decision-making and action.

Chronic Stress

During prolonged or chronic stress, the body initially tries to maintain increased ATP production to meet ongoing demands. However, continued. stress can eventually deplete energy stores and impair mitochondrial function. Mitochondrial dysfunction  leads to decreased ATP production over time. This dysfunction is partly due to the increased production of reactive oxygen species (ROS) which is associated with ATP production.  ROS damages mitochondrial components and reduces their ability to produce ATP (oxidation, leading to oxidative stress).

Continued chronic stress and reduced ATP production contribute to feelings of fatigue, reduced cognitive (brain) function, as well as weakened physical function (muscle performance). In the brain, impaired ATP production leads  to memory, learning, and emotional regulation difficulties.

The increased ROS and oxidative stress associated with chronic stress damages cellular components such as lipids, proteins, and DNA, which further compromises ATP production and energy metabolism in the brain and other organs.

With persistent stress, the initial adaptive increase in ATP production becomes unsustainable, leading to a failure of the adaptive response. Mitochondrial biogenesis (the production of new mitochondria) may be hindered under chronic stress, compromising cellular energy reserves.

Combating the impact of chronic stress

Physical fitness, good sleep, and dietary support can enhance mitochondrial health and support ATP production during stress. Importantly, exercise promotes mitochondrial biogenesis and can increase resilience to stress by maintaining a more robust ATP production capacity. Diet support by intake of dietary antioxidants can create resilience to the damages of ROS (remember the anti-inflammatory diet?).  Intermittent fasting can stimulate mitochondrial function and mitochondria biogenesis to enhance ATP production.

In summary, acute stress initially increases ATP production as an adaptive defense response, helping the brain and body mobilize resources and respond effectively. Chronic stress ultimately reduces ATP production due to mitochondrial dysfunction, oxidative damage and depletion of energy stores, which impairs the body’s ability to cope with continued stress. In essence, while an increase in ATP production is an adaptive response to acute stress, prolonged or unmitigated stress leads to a decline in ATP production, compromising cellular function and increasing susceptibility to stress-related diseases.

Overview of Stress-Protective and Anti-Fatigue Effects of Adaptogens

Adaptogens and Adaptive Stress Response

The term adaptogen is primarily associated with the notion of adaptability introduced by George Canguilhem in 1943,  defining adaptability as “the ability of an organism to alter itself or its responses to the changed environment or circumstances.” He also proposed that adaptability includes the ability to learn and improve from experience—repeated mild exposure or low doses of stress can result in the increased resistance of cells and organisms to subsequent stress exposure, resulting in an adaptation that favors survival. In 1957, Lazarev introduced the term “adaptogen” for some chemicals, increasing the so-called “state of nonspecific resistance”

As such, adaptogens promote a time-dependent physiological process of adaptation in response to repeated ingestion of a botanical that triggers intracellular and extracellular activities that enhance adaptive stress response. These activities include adaptive signaling pathways of cellular defense systems (stress system) and the neuroendocrine-immune complex, where the hypothalamic–pituitary–adrenal (HPA) axis provides a rapid response, defense against stress, and adaptation to stress. The key mediators of adaptogens include cortico-releasing hormoneCRH, cortisol,  molecular “chaperones,” monoamines (dopamine; norepinephrine and adrenaline) and melatonin.

Potential indications for use and health claims of adaptogens include stress-induced fatigue, mental and behavioral disorders, infectious diseases, and aging-associated disorders.

Digging Deeper….

The two major groups of active components found in adaptogens 

(1) Phenolic compounds  which have chemical structures similar to catecholamines, suggesting an effect on the sympathoadrenal system and possibly imply an effect in the early stages of the stress response.

The first group of adaptogens includes Eleutherococcus senticosus, Rhodiola rosea, Schisandra chinensis and Sideritis scardica. The chemical composition of the group of (i) phenolic-rich adaptogens is characterized by a high content of compounds containing four common types of structural fragments (pharmacophores) covalently incorporated into the chemical structures of some active principles of adaptogenic plants, which are structurally similar to catecholamines (epinephrine, dopamine, norepinephrine) and the tyrosine fragment of neuropeptide Y, suggesting that these biased ligands have high affinity and allosterically compete for receptor sites of proteins involved in signaling pathways and cellular responses.

(2) Tetracyclic and pentacyclic triterpenes, such as ginsenosides, withanolides, cucurbitacines, and andrographolides, which structurally resemble the catabolic hormones corticosteroids that inactivate the stress system to protect against overreaction to stressors; and anabolic-androgenic steroids structurally related to testosterone and estrogen androgenic steroid hormones which regulate lipids and sugar metabolism.

This second group contains the substances in extracts of Panax ginseng, Ashwagandha (Withania somnifera), (L.) Dunal, Andrographis paniculata and Bacopa monnieri.

 

Pharmacological Activities of Adaptogens

Stimulating and Tonic Effects on the CNS System

  1. Modulation of the stress response system, including the hypothalamus–hypophysis–adrenal (H.P.A.) axis
  2. Modulation of the endocrine system and metabolic regulation
  3. Regulation of cellular homeostasis and metabolism
  4. Modulation of the immune response
    • • Increased expression of defensin peptides
    • •Increased expression of pathogen pattern recognition proteins, TLRs
    • • Increased expression of interferons
    • • Inhibition of cytokine release
    • • Inhibition of NF-κB
    • • Activation of natural killer cells
    • • Activation of phagocytic cells
    • • Activation of T- and B-lymphocytes
    • Activation of the melatonin signaling pathway

 

Anti-inflammatory activity

  • • Inhibition of NF-κB-mediated signaling
  • • Inhibition of PLA2, arachidonic acid release, and metabolism
  • Inhibition of nitric oxide generation
  • Detoxification and reparation of oxidative stress-induced damages in compromised cells
  • • Activation of NRF2-signaling pathway proteins (KEAP1)
  • • Expression of phases I/II-metabolizing and antioxidant enzymes: glutathione S-transferase (G.S.T.), N.A.D. (P)H quinone oxidoreductase 1 (NQO1), superoxide dismutase (S.O.D.), and heme oxygenase 1 (HO1).
  • • Molecular chaperon (Hsp70)-mediated cytoprotection and repair processes
  • • Activation of melatonin signaling pathway

Barriers to the understanding of adaptogens

There are multiple challenges to the study of the stress response. First, it is difficult to quantify external stressors, especially psychological stressors such as grief. In addition, little is known about the interactions between stressors and the body. Second, the hormones, neurotransmitters, neuro-regulators and cytokines, which are involved in the stress response have been identified, but the specific functions of these agents remain incompletely understood. Furthermore, it has not been determined whether there are different mechanisms of action for different stressors. As a result, it is not possible to differentiate and measure the stress response (including adaptation), making the response stress difficult to quantify.

References:

Note: much of the content of this section is built upon the following publications:

This review discusses Ashwagandha and Rhodiola’s combined effects on cortisol and stress resilience.

  • Cropley M, Banks AP, Boyle J. (2015). The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Mood in a Healthy Population. Journal of Psychopharmacology, 29(11):1214–1222. https://doi.org/10.1177/0269881115597712.

This study provides evidence for Rhodiola’s SAS modulation, suggesting synergy with Ashwagandha’s HPA effects for stress/energy.

New:

  1. Adaptogens in Long-Lasting Brain Fatigue – An Insight from Systems Biology and Network Pharmacology – 2025

Asian Traditional Medicine

  1. Ayurveda and Traditional Chinese Medicine – A Comparative Overview – 2005

Adaptogens – Overviews

  1. Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity – 2010
  2. Relationships Among Classifications of Ayurvedic Medicine Diagnostics for Imbalances and Western Measures of Psychological States – An Exploratory Study – 2019
  3. Stimulating Effect of Adaptogens- An Overview With Particular Reference to Their Efficacy Following Single Dose Administration – 2005
  4. A preliminary review of studies on adaptogens – comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide – 2018
  5. Novel Molecular Mechanisms for the Adaptogenic Effects of Herbal Extracts on Isolated Brain Cells Using Systems Biology – 2018
  6. Adaptogens Exert a Stress-Protective Effect by Modulation of Expression of Molecular Chaperones – 2009
  7. Understanding Adaptogenic Activity- Specificity of the Pharmacological Action of Adaptogens and Other Phytochemicals – 2017′
  8. Adaptogens in Mental and Behavioral Disorders – 2013
  9. Evidence-based Efficacy of Adaptogens in Fatigue, and Molecular Mechanisms Related to Their Stress-Protective Activity – 2009
  10. Chemistry and Pharmacology of Syringin, A Novel Bioglycoside – A Review – 2015

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

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