Life Extension

Although the human body is relatively adept at managing acute physical and/ or psychological stressors, chronic psychological stress can produce a variety of adverse effects.

Chronic unremitting stress can increase our risk of suffering from a barrage of anxiety- and pressure-related diseases ranging from high blood pressure and dementia to depression. Chronic stress also increases our risk for some types of cancer (Thaker 2007; Jacobs 2000; Saul 2005; McEwen 1998; Liu 2010; Eiland 2010). According to reports by the American Academy of Family Practice and the Russian Department of Family Care, nearly two-thirds of doctor’s office visits are related to stress (Mechanic 1978; Servan-Schreiber 2000; Saleeby 2006).

Regrettably, while chronic stress produces significant adverse health effects, conventional medicine often relies upon psychoactive drugs to mask stressed patients’ symptoms. At the same time, mainstream stress management strategies often fail to address biochemical abnormalities, such as imbalanced adrenal hormone levels, that contribute to the detrimental health effects of chronic stress (Strous 2003; Wolkowitz 1997, 1999).

At the core of chronic stress is deregulation of the hypothalamic-pituitary-adrenal (HPA) axis, an interconnected network of physiologic command terminals that governs the production of stress hormones like cortisol and catecholamines like epinephrine and norepinephrine. Chronic stress leads to desynchronization of the HPA axis and subsequent imbalances in stress hormone levels, a critical feature of stress-related illness.

Upon reading this Life Extension protocol, you will appreciate the dangers of chronic stress, understand how it contributes to various diseases, and know how you can optimize your stress response by combining healthy lifestyle habits with scientifically studied natural therapies.

The Deadly Consequences of Chronic Stress

The consequences of chronic stress can be devastating. A chilling example is stress cardiomyopathy, a spontaneous weakening of the heart that predisposes victims to arrhythmia and even sudden cardiac death. While the mechanism is not clearly understood, it is thought that chronic stress-induced elevations in epinephrine (adrenaline) over-stimulate the cardiac muscle, altering its function and causing atrial remodeling (Sakihara 2007; Korlakunta 2005).

Another striking example is a condition the Japanese refer to as Karoshi (death from overworking); this condition was recognized in post-World War II Japan. Overworked and severely emotionally and physically stressed Japanese high level executives suffered strokes and heart attacks at alarming rates at relatively young ages. Researchers discovered that the death of these otherwise healthy men was due to chronic, unremitting stress. Government estimates in 1990 put the number of men dying each year from Karoshi at over 10,000 (Kondo 2010; Saleeby 2006).

Prolonged stress has been linked with elevated circulating markers of inflammation, and increased intima media thickness, a measure of atherosclerosis progression (Gouin 2011; Roepke 2011). Chronic stress considerably increases the risk of anxiety and depression by causing structural and functional changes in the brain as well (McEwen 2004; Liu 2010). Moreover, those who do not properly manage and adapt to chronic stress are more likely to be overweight and develop sexual dysfunction (Kyrou 2008).

TABLE 1: Health Risks Associated with Chronic Stress

Stressor Health Outcome Increased Risk
Sleep Disturbances (Nilsson 2001) Early Death from All Causes 170%
Occupational Injuries 38% (Men)
Perceived Stress (Nielsen 2008) Early Death from All Causes 32%
Death from Respiratory Disease 79%
Death from Heart Attacks 159%
Death from External Causes 207%
Suicide 491%
Adverse Childhood Experiences (Brown 2009) Death by Age 65 140%
Stress at Work (Heraclides 2009; Laszlo 2010; Heraclides 2011) Risk of Type 2 Diabetes in Women 100%
Death from Heart Attack 181%
Early Death from All Causes 65%
Not Enough Reward for Effort at Work (Salavecz 2010) Poor Self-Rated Healt Up to 280%
Divorce (Matthews 2002) Total and Cardiovascular Death 37% (Men)
Major Negative Life Events (Kruk 2011) Breast Cancer 533%

How the Body Responds to Stress

When an individual experiences a stressor, physical or emotional, internal or environmental, the body initiates a complex system of adaptive reactions to help cope with the stress. This reactive response results in the release of glucocorticoids, also known as stress hormones, and catecholamines, which stimulate adaptive changes in a variety of bodily systems.

The “Fight or Flight” Response

Under short-term circumstances, stress-induced changes prioritize functions involved in escaping danger; for example – redirection of blood flow to the muscles from most other body parts, increased blood pressure and blood sugar levels, dilation of pupils, and inhibition of digestion for energy conservation. During this time, fatty acids and glucose (blood sugar) are liberated from storage sites into the bloodstream where they become readily available for utilization by the muscles. This is known as the fight-or-flight response. This reactive and adaptive protection system originates in the brain.

Upon perception of stress, specialized neurons in the paraventricular nucleus of the hypothalamus (a major endocrine-regulating brain region) respond by releasing, among other compounds, corticotrophin releasing hormone (CRH) and vasopressin (VP). Subsequently, these hormones stimulate the release of adrenocorticotropic hormone (ACTH) from the pituitary gland.

After entering circulation and reaching the adrenal glands, ACTH stimulates the production of glucocorticoids and catecholamines, which then act throughout the body to induce the adaptive changes mentioned in the opening paragraph of this section. Cumulatively, this brain-endocrine coordination comprises the hypothalamic-pituitary-adrenal (HPA) axis.

While the fight-or-flight response is undoubtedly necessary to initiate an autonomous response to impending danger in an acute situation (the “rush” you feel when you hear an unexpected loud noise, for example, is the fight-or-flight response in action), it can become devastating when active, even at a low-level, for a protracted period of time (Innes 2007).

We modern humans live in an environment filled with emotional stressors, such as financial worries, and deadline pressures at work or school. All of these modern worries chronically activate the HPA axis in an evolutionarily unnatural way, leading to elevated stress hormone levels, and accompanying physiologic changes, throughout the day.

A few components of the fight-or-flight response are especially damaging to health when the stress response is active over a prolonged timeframe – insulin resistance, and high blood pressure (Lehrke 2008).

The elevation in blood pressure and deteriorating insulin sensitivity contribute, along with several other stress-related physiologic irregularities, to a compromised health state that predisposes chronically stressed individuals to an onslaught of age-related diseases.

Eventually, chronic elevations in glucocorticoid levels damage and destroy neurons in the region of the hypothalamus responsible for regulating CRH release (Siegel 2006). This gives rise to erratic or insufficient HPA axis activation and may lead to the mood disorders, such as depression and anxiety, and fatigue commonly observed in individuals who have been under great stress for a long time.

A Closer Look at Cortisol

Cortisol is, in many ways, a paradoxical hormone. A certain amount of cortisol is necessary for optimal health, but too much or too little can be unhealthy. As mentioned above, during acute episodes of stress, more cortisol is released to help the body cope with physical or psychological stressors (Tomlinson 2004). Its primary functions in the body are:

  • regulation of blood glucose levels by a process called gluconeogenesis in the liver
  • regulation of the immune system;
  • regulation of carbohydrate, protein and lipid metabolism

Essentially, cortisol is regarded as an anti-inflammatory hormone, a blood glucose modulator, an immune-modifier, and an adaptation hormone (Chrousos 2000). Depending on diet, exercise, stress, and time of day, serum levels of cortisol can vary.

During healthy conditions, cortisol levels peak in the early morning hours (usually around 8AM) and dip to their lowest between midnight and 4AM. The complex process of cortisol biosynthesis and release is sensitive to disruption by both internal and external factors (Beishuizen 2001; Tomlinson 2004; Weerth 2003). In the face of chronic psychological stress, for example, the adrenal glands excrete an abnormal amount of cortisol in an abnormal rhythm.

Cortisol, being a catabolic hormone (a hormone that breaks down tissues), when out of balance and unregulated, can have detrimental effects on body composition. Moreover, too much cortisol can suppress the immune system, while too little can lead to autoimmunity and rheumatologic disorders (Chrousos 2000; Wu 2008; Muneer 2011; Sapolsky 2002; Tak 2011).

Cortisol receptors are expressed throughout the body, including in the brain; therefore, derangement of the biosynthesis, metabolism and release of cortisol can disrupt many physiologic systems (Beishuizen 2001; Tomlinson 2004; Weerth 2003).

The Issue of “Adrenal Fatigue”

An alternative medicine term that often finds its way into discussions about stress is “adrenal fatigue”. Although “adrenal fatigue” is not a recognized diagnosis in conventional medicine Life Extension believes that symptoms often attributed to “adrenal fatigue” arise from multifactorial pathological processes involving, among other systems, the HPA axis, and that these conditions must be treated as such.

On the other hand, Addison’s disease, sometimes referred to as “adrenal insufficiency” is a medical condition that can be life threatening. Addison’s disease is typically the result of an autoimmune disorder, but can arise due to genetic abnormalities as well. Consequences of Addison’s disease are much more severe and acute than those induced by stress and the condition should be closely monitored by a qualified healthcare professional. For those who would like more information, Addison’s disease is discussed in our Adrenal Disease protocol.

Recognizing When Stress is Getting the Best of You

Everyone has an inborn ability to handle stress. However, tolerance is variable as some people can handle only low levels and short durations of stress, while others adapt and can accommodate higher levels stress for more prolonged periods. Dr. Hans Selye, in 1935, devised the term stress as a factor that induced behavioral changes in mammals. He then furthered this notion to include higher level organisms (humans) as being effected by stress in a harmful way (Viner 1999).

According to Dr. Selye, there are three states the body faces when dealing with stress. The first being the alarm state early on in the process, followed by the resistance state where the body attempts to adapt to the added stress (release of cortisol), and finally, after stress overwhelms and weakens the system, the exhaustion state (Kalaitzakis 2011; Tak 2011). These three “states” can be analogously detailed as physiologic mechanisms:

1) Alarm state: adaptation to acute stress; “fight-or-flight” response;

2) Resistance state: emergence of consequences of prolonged stress response activation (i.e. insulin resistance)

3) Exhaustion state: decline in responsiveness and sensitivity of primary relays of the HPA axis (i.e. hypothalamic deterioration / dysfunction leading to erratic / insufficient stress hormone and catecholamine production and subsequent mood disorders and fatigue).

The same imbalances in the HPA axis and stress response mechanisms that contribute to these signs and symptoms also contribute to the deadly sequelae of more serious stress-related illness. Therefore, recognizing that you are experiencing some or all of the following symptoms is an important initial step towards achieving better overall health and mitigating your risk for various diseases.

Signs that You are Suffering the Effects of Chronic Stress May Include:

  1. Excessive fatigue after minimal exertion; feeling “overwhelmed” by relatively trivial problems
  2. Trouble awakening in the morning, even after adequate sleep
  3. Relying on coffee (caffeine) and other “energy” drinks for a pick me up
  4. Perceived energy burst after 6:00 PM
  5. Chronic low blood pressure
  6. Hypersensitivity to cold temperatures
  7. Increased premenstrual symptoms (PMS) symptoms
  8. Depression and/or labile mood swings
  9. Mental “fog” and poor memory
  10. Decreased sex drive
  11. Anxiety
  12. Craving sugar and salty foods
  13. Decreased appetite
  14. Imbalanced immune system
  15. Chronic allergies
  16. Generalized weakness and dizziness upon standing
Some of these symptoms may mimic, or overlap, with dysfunction of the thyroid gland, gonadal (sex) hormones, malnutrition, depression, chronic fatigue states, chronic illness, infections, alcohol and drug abuse, and heavy metal toxicity (Ng 1990; Gagnon 2006). Therefore, it is very important to rule out other possible causes before attributing symptoms to chronic stress alone.


Impaired Stress Response: A Major Cause of Anxiety and Depression

Often, chronic stress is accompanied by mood disorders, particularly anxiety and depression. In fact, depression and anxiety can both be viewed as manifestations of an impaired stress response; the underlying physiology of both is similar.

In fact, the chronic elevation in glucocorticoids caused by chronic stressors in modern society can lead to physical changes in brain structure.

For example, dendrites, the branches of neurons that receive signals from other neurons, are shifted into less functional patterns upon chronic exposure to glucocorticoids. This has been documented in key brain regions associated with mood, short-term memory, and behavioral flexibility (Krugers 2010). Furthermore, glucocorticoids cause receptors for the mood-regulating neurotransmitter serotonin to become less sensitive to activation (van Riel 2003; Karten 1999). Other detrimental effects of chronic stress include both increased susceptibility to neuronal damage and impaired neurogenesis, the process by which new neurons are “born” (Krugers 2010).

Interestingly, emerging research suggests that certain psychoactive drugs, like those used to treat anxiety and depression, may stabilize mood not only by acting upon neurotransmitter levels, but by modulating the action of glucocorticoids receptors within the brain (Anacker 2011). These new findings strongly support the idea that in order to alleviate mood disorders, controlling stress response is an important aspect of treatment. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to efficiently adapt to stress, to increased rates of anxiety and depression (Strohle 2003; Binder 2010).

Chronic Stress and Nutrition

Deficiencies, toxicities and life style habits impact the adrenal gland. Deficiencies in vitamin C and vitamin B5, which are essential co-factors in cortisol production and adrenal health, are two examples (Brandt 2012*; Daugherty 2002). Copper is a mineral that is essential in some bodily enzymatic reactions, but may disrupt adrenal function if levels are too high (Veltman 1986).

Even relative imbalances between minerals can affect cortisol levels. It has been documented that abnormal ratios of copper to zinc cause adrenal cortex disruption (Ng 1990; Gagnon 2006). A well balanced multivitamin can complement a healthy diet to help ensure that vitamin and mineral intake is sufficient to support optimal adrenal function.

The fatty acid content of the diet also contributes considerably to stress response physiology. Relative imbalances of omega-6 fatty acids to omega-3 fatty acids create conditions that favor heightened inflammation and impaired stress response (Kiecolt-Glaser 2010).

For example, a clinical trial examined the effects of parenteral fish oil infusions on the stress response induced by injections of an endotoxin called lipopolysaccharide. The group who received fish oil exhibited a much less severe stress response, with plasma norepinephrine levels remaining sevenfold lower and ACTH levels fourfold lower than the control group (Pluess 2007). Upon examination, it was found that the platelet phospholipid omega-3 content had increased substantially in fish oil group, reflecting a lowered omega-6 to omega-3 ratio, a state less conducive of inflammation.

It is believed that a diet high in omega-3 fatty acids may attenuate the effects of chronic stress by limiting the influence of inflammation on stress physiology (Kiecolt-Glasser 2010).

Since cholesterol is a building block of the cortisol hormone, ingestion in the diet of some saturated fat is important. However, the liver will synthesize cholesterol, if poor dietary ingestion occurs, from acetate (Hellman 1954). Of course, too much cholesterol has its drawbacks as well, so a happy medium must be reached. Both extremes of dietary fat ingestion have ill effects on the human body. Life Extension suggests an optimal total cholesterol level of 160-180 mg/dL.

Lifestyle Strategies for Overcoming Chronic Stress

Dr. Thierry Hertoghe, an internationally noted endocrinologist, advises a few lifestyle modifications that one should adhere to before consideration of natural or pharmacological therapies. Lifestyle modifications alone for some with mild to moderate forms of impaired stress response may ease symptoms (Kalaitzakis 2011; Tak 2011; Head 2009). Dietary supplements and/or hormone therapy can complement lifestyle modification to resolve adrenal dysfunction (Hertoghe 1999).

The obvious recommendation of avoiding stressful situations and occurrences goes without saying. If commuter stress, for example, is affecting your body, moving to a home closer to your workplace or finding a job closer to home is an obvious solution. If working third-shift causes disruption in your cortisol levels or circadian rhythm resulting in disease, then change your work schedule to eliminate this stressor (Wirth 2011). Smoking, and extremely vigorous or protracted bouts of exhaustive exercise impact the adrenals in a negative way as well (Peters 2001; Wu 2008; Siddiqui 2001).

With regard to the diurnal biorhythms of cortisol release, a few things increase cortisol at the inappropriate time. The consumption of alcohol and caffeinated beverages such as tea and coffee before bedtime is not recommended as caffeine can increase serum cortisol levels, which is counterproductive during the evening hours when the normal trough is expected (Ping 2012). Additionally, caffeine and alcohol affect the release of melatonin (melatonin counters some of the negative effects of cortisol), causing a relative reduction in melatonin secretion during the night when a spike is usually seen (Lovallo 2006).

Other therapies such as acupuncture, Traditional Chinese Medicine (TCM), Ayurvedic medicine, massage therapy, relaxation, yoga and even music therapy have shown success in stress management (Hanley 2003; Dixit 1993; Field 2005).

Several published studies suggest that owning a pet is associated with improved physical and psychological health (Barker 2008; Friedmann 2009). For chronically stressed individuals, adopting a dog or cat may help ameliorate some of the symptoms and effects of chronic stress (Allen 2001).

Hormonal Therapy


DHEA, also an adrenal hormone, counters the action of cortisol in many tissues (Buoso 2011). The balance between cortisol and DHEA is generally maintained in youth. However, as we age, DHEA levels decline sharply (Zaluska 2009). The unabated action of cortisol in the presence of declining DHEA levels can contribute to stress-related diseases.

Furthermore, DHEA replacement therapy can restore balance between cortisol and DHEA (Ferrari 2001). DHEA has been shown to reduce the negative impact of elevated levels of cortisol on the brain of dementia and Alzheimer’s disease study subjects (Rasmuson 2002). The heart benefits as well, with a decline in the incidence of coronary artery disease with DHEA supplementation (Barrett-Connor 1986; Feldman 1998; Shufelt 2010). In the context of metabolic syndrome, which is characterized by abdominal obesity, lipid disorders, insulin resistance, and hypertension, DHEA reduces lipid levels, lowers adipose tissue formation and reduces cardiovascular risk (Villareal 2004; Lasco 2001).

DHEA also has a positive effect on cognitive function and mood (Ferrari 2004; van Broekhoven 2003; Schmidt 2005). DHEA appears to be beneficial in those with glucose intolerance and diabetes, lowering average serum glucose levels and averting the destructive effects of diabetes (Kameda 2005; Dhatariya 2005). There have been reports of cancer risk reduction with DHEA supplementation as well (Ciolino 2003). With regards to age related bone mineral loss, DHEA supplementation has been shown to combat osteoporosis (Villareal 2000).

A great deal of insight into the function of the adrenal glands can be gained through testing blood levels of DHEA and cortisol. Deviations from the natural rhythm of adrenal function can be detected by an AM / PM cortisol test, in which levels of the adrenal hormone are tested early in the morning and early in the evening of the same day. A DHEA sulfate (DHEA-s) blood test can determine if DHEA levels are sufficient.

Supplemental doses of DHEA typically range from 10 – 25 mg daily for women and 25 – 75 mg daily for men, but should always be determined based upon DHEA-s blood tests. Life Extension suggests that in order to counter the negative effects of aberrant cortisol production, DHEA-s blood levels should remain between 350 – 490 µg/dL for men, and 275 – 400 µg/dL for women.


The hormone melatonin, which is released from the small gland at the base of the brain called the pineal gland, is known for its relationship with the sleep cycle. Melatonin has an antagonistic effect on cortisol, and the circadian rise in melatonin levels at night correlates with a drop in cortisol (Presman 2012). Low levels of melatonin can mean inappropriate and undesirable glucocorticoid signaling during the night when it should be at the lowest.

Chronic, late-night stress, whether physical or psychological, can result in an inappropriately elevated night time cortisol level; shift-work is an example of such a stressor (James 2007). This chronic disruption and inappropriate release of cortisol at night may impair the normal circadian corticosteroid output in the morning (Soszynski 1989; Bruls 2000, Pawlikowski 002; Hertoghe 1999).

Melatonin is also a hormone with great penetration into the nucleus of the cells and is one of the most important antioxidant hormones as it protects cellular (mitochondrial and nuclear) DNA from damage (Reiter 2002). Melatonin has been found to affect the levels of cortisol and the balance between DHEA and cortisol in circulation (Soszynski 1989; Bruls 2000; Pawlikowski 2002). Doses differ in individuals but can start as low as 0.3 mg; some may require up to 10 mg daily.

Maintaining Sex Hormone Balance

Imbalances in the sex hormones (testosterone for men, and estrogen and progesterone for women) may exacerbate the detrimental effects of chronic stress. Some experimental data indicates that having low levels of sex hormones impairs the response to cortisol in the brain (Mitsushima 2008). Overtime, this may lead to an over-compensatory increase in stress hormone production by the adrenal glands, which could become damaging.

Likewise, human trials have confirmed that steroid hormones exert considerable influence over the stress response. In a small trial of women who were overcoming cocaine addiction, higher progesterone levels were associated with a blunted stress response to a drug cue (Sinha 2007).

In another clinical trial, menopausal women treated long-term with hormone replacement therapy (HRT) coped with stress better than non-HRT users in an experimental setting (Patacchioli 2006).

The biological actions of the sex hormone progesterone within the brain are calming, and so age-related declines in progesterone levels may predispose women to anxiety. Specifically, some metabolites of progesterone have been shown to function as ligands at the GABA-a receptor subunit, which is inhibitory upon activation (Majewska 1986).

Stressed men and women should review Life Extension’s Male Hormone Restoration, and Female Hormone Restoration protocols.

Nutrients to Counteract the Effects of Stress

B-Complex vitamins

Several members of the B-vitamin family impact varying aspects of stress response physiology. For example, pantothenic acid is necessary for the synthesis of coenzyme A (CoA), which is integral in the production of cholesterol, and in steroid hormone biosynthesis (Tahiliani 1991; Yasuda 2004). Pantothenic deficiency is rather rare, but it can result in adrenal insufficiency (Tarasov 1985; Webster 1998; Anon 1980; Plesofsky-Vig 1994).

Another correlation between B-vitamins was revealed in a clinical trial that found that injecting either ACTH (adrenocorticotropic hormone) or cortisol into healthy subjects for just four days significantly decreased levels of folic acid and B12 (Berg 2006). These findings suggest that not only are B-vitamins important to promote healthy stress response, but stress itself may lower B-vitamin blood levels. Therefore, B-vitamin supplementation may ameliorate the effects of stress from multiple angles.

Vitamin C (Ascorbic Acid)

Another crucial vitamin in adrenal function and maintenance of healthy levels of cortisol and DHEA is vitamin C (Bornstein 2004; Morfin 2002). Deficiencies of this vitamin can have profound effects on adrenal function (Brody 2002; Carroll 2000). The benefits of vitamin C are multiple, acting as an anti-inflammatory and co-factor in soft tissue synthesis and repair (Eipper 1992; Hemila 1996; Evans 2008).

In addition, ultra-marathon runners who were given 1,500 mg vitamin C after a race displayed less dramatic elevations in cortisol and epinephrine levels than is typical after such extreme stress (Peters 2001). Moreover, this same study found that vitamin C was able to suppress inflammation in the runners as well.


Calcium, magnesium, sodium and potassium are all macro elements. A macro element means that they are found in our bodies in greater quantities than other elements or minerals. These four macro elements are important in supporting and maintaining balanced adrenal function (Kobayashi 1996; Carroll 2000). They are important in the formation and release of adrenal hormones.

Manganese, zinc, chromium, and selenium are some of the trace elements that have an impact on the function of the adrenal glands. Research shows that deficiencies in these trace elements can have a negative effect on adrenal function (Golf 1998; Wilborn 2004; Schulz 1998).


L-theanine is an amino acid found exclusively in green tea that has traditionally been used to enhance relaxation and improve concentration and learning ability (Vuong 2011; Wakabayashi 2011; Nathan 2006).

L-theanine is chemically related to the neurotransmitter glutamate, and binds to glutamate receptors in the brain (Cho 2008). Unlike glutamate, however, which can cause a state called excitotoxicity that can destroy nerve cells, L-theanine protects brain cells against excitotoxicity, calming the nerve networks in the brain (Kakuda 2002; Nagasawa 2004; Di 2010).

Animal studies verify the behavioral benefits of these biochemical effects. In in vitro studies, L-theanine reduces electrical activity associated with anxiety (Dimpfel 2007). L-theanine reduces evidence of anxiety and depression in several different animal models of stress (Yin 2011; Heese 2009). In one animal model, L-theanine led to decreases in nearly all frequencies of brainwave activity, indicating a state of calmness and relaxation (Dimpfel 2007). Moreover, L-theanine has been shown to act synergistically with the GABAergic drug midazolam, a relative of Valium® (Heese 2009).

Brain wave studies have shed some light on the mechanism by which L-theanine may appease anxiety. In one study, healthy subjects took a soft drink containing green tea enriched with L-theanine while their brainwave power was measured (Dimpfel 2007). Power was initially reduced in all frequencies and areas during the first hour, indicating relaxation. Later changes indicated both an increase in mental performance and a higher degree of relaxation. In this case, L-theanine seemed to produce desirable increases in attention, accompanied by durable relaxation—that means subjects could concentrate better without being distracted by anxiety.

Another brainwave study demonstrated that L-theanine significantly increased activity in the frequency band associated with relaxation without inducing drowsiness (Nobre 2008). A third trial concluded that L-theanine plays a general role in sustaining attention during a long-term difficult task (Gomez-Ramirez 2009).

Another way to assess stress and anxiety is by measuring vital signs such as heart rate and salivary content of certain proteins that are increased during stress. Japanese researchers did just that with 12 subjects during a mental arithmetic test given as an acute stressor (Kimura 2007). Results showed that the supplement reduced heart rate response to the acute stress task, compared with placebo. In addition, heart rate variability was improved, a sign that the L-theanine was modulating the sympathetic nervous system, or “fight-or-flight” response.

Omega 3-Fatty Acids (Fish Oil)

Research indicates that intake of fish oil or omega 3-fatty acids (n-3 EFA or EFA) can act in an adaptogenic fashion to help ameliorate the effects of stress (Bradbury 2004; Delarue 2003). Omega-3 fatty acids balance the effects of omega-6 metabolism (Warren 1999; Puri 2007; Maes 2005). Fatty acid balance is also critical for glucorcorticoid hormone receptor function (Hirata 1980; Hidalgo 1978; Willis 1981). In recent years omega-3 fatty acids have been documented to be successful in treating those suffering from depression and anxiety disorders, which themselves can be a consequence or an inducer of stress (Logan 2004; Araujo 2010; Silvers 2005).

Phosphatidylserine (PS)

The phospholipid phosphatidylserine (PS) is found in cell membranes and is a critical component for healthy cellular communication. Several studies have shown that a diet rich in PS is able to balance the HPA axis and limit the negative consequences of over-activation of the adrenal cortex (Monteleone 1990; Kelly 1999; Benton 2001; Kimura 2006; Hellhammer 2004). Phosphatidylserine also helps attenuate the increase in cortisol levels during periods of intense, acute stress (Fahey 1998).


Emerging research has revealed an important relationship between the gastrointestinal tract and its billions of resident organisms—often referred to as the microbiome—and the brain. This has been termed the “gut-microbiota-brain axis” (Petra 2015; Foster 2015; Forsythe 2010; Forsythe 2013; Dinan 2012; Cryan 2012). Probiotics are organisms which, when consumed in adequate doses, exert a beneficial effect on health (Sanders 2008). Probiotics, which are able to modulate the gut-brain axis, have been shown in preclinical and clinical trials to ameliorate behaviors and symptoms of stress, anxiety, and depression (Bravo 2011; Gareau 2007; Messaoudi, Lalonde 2011).

Lactobacillus helveticus (L. helveticus) R0052 has been researched, in combination with another proprietary probiotic strain, Bifidobacterium longum (B. longum) R0175, as a probiotic for psychological health (Arseneault-Breard 2012; Messaoudi, Violle 2011; Messaoudi, Lalonde 2011). Rats given a daily dose of a combination of L. helveticus R0052 and B. longum R0175 for two weeks had markedly reduced signs of anxiety compared to those treated with a placebo. In fact, the probiotics reduced stress-related behaviors to a similar degree as diazepam (Valium), the prescription anti-anxiety medication (Messaoudi, Lalonde 2011; Calcaterra 2014).

In a double-blind randomized clinical trial, 55 healthy volunteers took a supplement containing three billion colony-forming units (CFUs) of the combination of L. helveticus R0052 and B. longum R0175, or placebo, for 30 days. The probiotic treated group had significantly lower scores on anxiety, anger, and depression symptom scales (Messaoudi, Lalonde 2011). Among a subset of 25 participants considered to have low levels of chronic stress based on low urinary cortisol levels, the combination of L. helveticus R0052 and B. longum R0175 appeared to act as a preventive, suggesting it may be able to protect against stress-related diseases (Messaoudi, Violle 2011).

Herbal Therapies

Licorice (Glycyrrhiza glabra and G. uralensis)

A mainstay in Traditional Chinese Medicine (TCM), licorice extracts may be of benefit for those who have reached the exhaustion stage and are no longer producing sufficient cortisol.

Licorice has the ability to decrease the breakdown or metabolism of hydrocortisone by the liver, thus increasing the amount of cortisol in circulation and reducing the strain on the adrenal glands to produce it (Methlie 2011). The combination of low doses of licorice with supplemental DHEA may help balance the HPA axis (Tarasov 1985).

It is important to understand that licorice may not be ideal for everyone dealing with day-to-day stress. In high doses over prolonged periods licorice may cause electrolyte imbalance (hypokalemia) and elevations in blood pressure, a syndrome called hypermineralocorticoidism (Schambelan 1994). Due to its ability to increase cortisol levels, licorice is best reserved for those individuals who are experiencing fatigue due to chronic stress and also have low cortisol levels.

Sedative Herbs

Sedative herbs such as hops, passionflower, poppy, and valerian can provide calming effects to reduce stress. The herbal lemon balm (Melissa officinalis) has been shown in a number of studies to reduce stress. This is yet another herbal that has shown benefit in reducing negative effects of stress on the body (Kennedy 2004 and 2006; Dimpfel 2004).

In a recent small clinical trial including 20 stressed volunteers, a standardized lemon balm extract (Cyracos®) was shown to significantly combat anxiety symptoms and insomnia (Cases 2011). The extract “reduced anxiety manifestations by 18%, ameliorated anxiety-associated symptoms by 15% and lowered insomnia by 42%.

Adaptogenic Herbs

A class of herbs known as adaptogens are helpful in regulation of the HPA axis. Dr. Nikolai Lazarev, a noted Russian pharmacologist during the cold war era, coined the term “adaptogenic herb” to describe about 25 of the hundreds of medicinal herbs having particular properties (Kelly 2001). These properties are unique to this class of herbs making them important for human health.

To be classified as an adaptogen, herbs must have the following three properties: There can be no toxicity associated with them; they must have a normalizing ability, (i.e. the same dose can raise or lower physiologic properties), and the mechanisms by which the herbs carry out their effects must be due to more than one physiologic or pharmacologic mechanism (Lipnick 1992; Brekhman: 1969; Saleeby 2006). Unlike any other compound, adaptogens condition your body to respond favorably to stress.

Adaptogenic herbs can become an important supplement to support a healthy HPA axis stress response. The list of adaptogenic herbs include about twenty-five known, and of these several have been studied for their affects on the HPA system. Ginseng (Panax ginseng), Eleuthero (Eleutherococcus senticosus), Rhodiola (Rhodiola rosea), Cordyceps (Cordyceps sinensis) and Ashwagandha (Withania somnifera) to name a few. (Gaffney 2001; Saleeby 2006; Panossian 2005; Kelly 2001; Spasov 2000).


The adaptogenic herb Rhodiola (Rhodiola rosea) has demonstrated in a number of studies improvements in both physical endurance and cognitive performance (De Bock 2004; Spasov 2000; Shevtsov 2003). Its ability to reduce fatigue associated with stress is documented in well-designed research papers (Olsson 2009; Spasov 2000; Panossian 2009). The apparent mechanism of action of Rhodiola is related to its ability in assisting neurotransmitter transport in the brain and the blunting of catecholamine release (Stancheva 1987; van Diermen 2009).

A large, phase III placebo-controlled clinical trial was conducted in Sweden in 2009, studying participants aged 20-55 years with a diagnosis of stress-related fatigue (Olsson 2009). Subjects taking the Rhodiola extract had significantly lower cortisol responses to chronic stress than did the placebo recipients—and as a result they had lower scores on scales of burnout and improved performance on cognitive testing.


Ashwagandha, also known as Withania somnifera, is an important Ayurvedic medicinal herb. It has many uses in traditional Indian medicine such as treatments for stress, fatigue, pain, diabetes, GI and rheumatologic disorders (Mishra 2000). Ashwagandha has shown promise in neuroprotection as scientists have discovered that this adaptogenic herb prevents damage to neurons and improves neurological function in the face of stress (Cooley 2009; Tohda 2005; Choudhary 2004). Additionally, data suggests that Ashwagandha may reduce the harmful effects of stress on male reproductive capacity (Ahmad 2010).

A double blind, randomized, placebo-controlled clinical trial assessed the effects of ashwagandha in 130 chronically stressed subjects (Auddy 2008). Over a 60-day period, doses ranging from 125 mg to 500 mg daily of a patented ashwagandha extract (Sensoril®) significantly improved scores on a standardized measurement of stress intensity, and also favorably modulated several biomarkers associated with cardiovascular health, including C-reactive protein and blood pressure. Moreover, at the end of the study period subjects that received 500 mg of ashwagandha daily had cortisol levels nearly 30% lower than subjects who took a placebo, and their DHEA-s levels were significantly higher as well.


Probably the most recognized of the adaptogen herbs in the West is Ginseng (Panax ginseng). There are eleven species of this medicinal herb, P. ginseng being among the most widely studied (Chen 2004; Huang 1999). American Ginseng (Panax quinquefolius) is another species within the Panax genus that shares medicinal properties (Chan 2000). Siberian ginseng (Eleutherococcus senticosus), while not technically a true ginseng botanical, has similar beneficial properties and is closely related to the Panax family of plants (Davydov 2000).

A wealth of studies exist showing stress reducing properties of true ginseng and the other ginseng related herbals (Barton 2010; Ma 2008). For example the isolated polysaccharides from P. ginseng have demonstrated anti-fatigue properties in one recent study (Wang 2010).

American ginseng extract shows a reduction in oxidative endothelial damage due to diabetes (Sen 2011; Amin 2011). Anti-depressive effects and the positive modulation that benefits the HPA axis is outlined in a research paper on protective ginsenosides in Panax and other ginseng plants showing usefulness in the management of chronic stress (Liu 2011; Cao 2011).

Holy basil (Occiumum tenuiflorum)

Increased cortisol and blood glucose levels are common in people with disorders of the adrenal gland (Pozza 2012). Increased blood glucose is also seen in people receiving chronic glucocorticoid treatment (Mcmahon 1988). Ocimum sanctum, or holy basil, is an herb widely grown in India that is known for its ability to control blood sugar (Grover 2002). A study in mice showed that extracts of Ocimum sanctum decreased serum concentrations of both cortisol and glucose. This study suggested that Ocimum sanctum extract could potentially regulate diabetes mellitus that has developed secondary to corticosteroid treatment (Gholap 2004). Compounds isolated from an extract of holy basil leaves were shown to normalize hyperglycemia, plasma cortisol levels, and adrenal hypertrophy in rats (Gupta 2007).

Furthermore, clinical trials in humans have also shown the benefits of holy basil extract for improving immune function, as well as decreasing stress and depression associated with anxiety. Studies in healthy human subjects showed that treatment with 300 mg of holy basil extract for 4 weeks increased antibody levels and cells in the immune system (Mondal 2011). In a clinical trial, 35 subjects with generalized anxiety disorder were treated with 500 mg of holy basil extract twice daily for 60 days. At the end of the study, these subjects showed decreased stress and depression, improved attention, and an increased ability to adapt to changes (Bhattacharyya 2008).


The herb Bacopa monnieri is used in the classical Indian medicinal system of Ayurveda as a tonic for the nervous system and is known to promote mental health (Bhattacharya 1998). It has also been shown to possess anti-anxiety properties. Experiments have shown that rats fed with extracts of Bacopa showed decreased anxiety, which was comparable to that in rats fed lorazepam, a common anti-anxiety drug. The Bacopa-fed rats did not show any adverse effects on physical activity (Bhattacharya 1998). Bacopa possesses adaptogenic properties and evidence shows that it can normalize levels of corticosterone and noradrenaline in rodents exposed to stressful conditions (Sheikh 2007). In a clinical trial on the mental and emotional effects of Bacopa in the elderly, 54 subjects aged 65 years or older were given 300 mg Bacopa or placebo for 12 weeks. Subjects receiving Bacopa showed significantly reduced anxiety and improved cognitive performance (Head 2009). At the time of this writing, a clinical trial is currently underway in Australia to test the effects of Bacopa and another herb, pycnogenol, in reducing cognitive decline with aging. The trial will evaluate the effects of Bacopa supplementation for up to a year on mood, cognition, blood pressure, inflammation, and oxidative stress, among other tests (Stough 2012).


Oxidative stress damages cells and is associated with various health disorders. Cordyceps sinensis is a type of mushroom used in Chinese medicine that has been found to boost the immune system and possesses anti-tumor and antioxidant properties (Li 2003). An experimental study showed that Cordyceps extract stimulated corticosterone production in mice (Leu 2005). Another study found that orally administered Cordyceps extract increased swimming capacity and reduced fatigue in mice (Koh 2003). Also, the weight changes in adrenal glands, which are considered a stress index, were suppressed in rats following a 48-hour stress period (Koh 2003). Furthermore, a polysaccharide isolated from Cordyceps was found to reduce plasma glucose levels in diabetic and hyperglycemic mice (Kiho 1999).

In a clinical trial, Cordyceps powder was provided for 2 weeks to sedentary male subjects who then underwent exhaustive exercise. Exercise tolerance and catecholamine and cortisol levels were compared before and after Cordyceps treatment. Subjects receiving Cordyceps showed improved exercise tolerance, increased levels of epinephrine and norepinephrine, and a slight decrease in cortisol levels. Overall, Cordyceps supplementation appeared to improve energy generation and reduce fatigue (Nagata 2005).


Exposure to chronic stress leads to sustained increases in cortisol levels and deleterious effects on various body systems (Anderson 2008). Schisandra chinensis is traditionally used in East Asia for its anti-stress properties. It was found that Schisandra reduced the levels of corticosterone and glucose and preserved the structure of the adrenal cortex in rats exposed to stress (Sun 2009). Athletes exposed to acute exercise show increased levels of cortisol and nitric oxide (which helps in conducting signals between cells) in the blood and saliva. However, extremely well-trained athletes who are exposed to chronic exercise-related stress do not show such increases. When such subjects are given Schisandra, they start showing increased cortisol and nitric oxide levels, meaning that they further adapted to heavy physical loading. Thus, adaptogens such as Schisandra may increase the ability of the body to respond to stress stimuli (Panossian 2003).


Ahmad MK, Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril. 2010;94(3):989-996.

Allen K et al. Pet ownership, but not ace inhibitor therapy, blunts home blood pressure responses to mental stress. Hypertension. 2001 Oct;38(4):815-20.

Amin KA, Awad EM, Nagy MA. Effects of panax quinquefolium on streptozotocin-induced diabetic rats: role of C-peptide, nitric oxide and oxidative stress. Int J Clin Exp Med. 2011;4(2):136-47.

Anacker C et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011 Jul;16(7):738-50. doi: 10.1038/mp.2011.26. Epub 2011 Apr 12.

Anderson DC. Assessment and nutraceutical management of stress-induced adrenal dysfunction. Integrative Medicine. 2008;7(5):18-25.

Anon., Calcium pantothenate in arthritic conditions. A report from the General Practitioner Research Group. Practitioner 1980;224:208-11.

Arseneault-Breard J, Rondeau I, Gilbert K, Girard SA, Tompkins TA, Godbout R, Rousseau G. Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model. The British journal of nutrition.Jun 2012;107(12):1793-1799.

Auddy B et al. A Standardized Withania Somnifera Extract Significantly Reduces Stress-Related Parameters in Chronically Stressed Humans: A Double-Blind, Randomized, Placebo-controlled Study. 2008; 11(1):50-56.

Barker SB, Wolen AR. The benefits of human-companion animal interaction: a review. J Vet Med Educ. 2008 Winter;35(4):487-95.

Barrett-Connor, E., A Prospective Study of Dehydroepiandrosterone Sulfate, Mortality, and Cardiovascular Disease, N Engl J Med 1986; 315:1519-1524

Barton, DL., Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2010;18 (2): 179–187.

Beishuizen, A., Patterns of corticosteroid--binding globulin and the free cortisol index during sepsic shock and multitrauma. Intensive Care Med, 2001;27:1584-1591.

Benton D., The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci. 2001;4(3):169-178.

Berg AL et al. The effects of adrenocorticotrophic hormone and cortisol on homocysteine and vitamin B concentrations. Clin Chem Lab Med. 2006;44(5):628-31.

Bhattacharya SK, Ghosal S. Anxiolytic activity of a standardized extract of Bacopa monniera: an experimental study. Phytomedicine. 1998;5(2):77–82.

Bhattacharyya D, Sur TK, Jana U, et al. Controlled programmed trial of Ocimum sanctum leaf on generalized anxiety disorders. Nepal Med Coll J. 2008;10(3):176-179.

Binder EB et al. The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry. 2010 Jun;15(6):574-88. Epub 2009 Dec 15.

Bornstein SR. Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr Res. 2004 Nov;30(4):871-875.

Bradbury J., An adaptogenic role for omega-3 fatty acids in stress; a randomised placebo controlled double blind intervention study (pilot). Nutr J. 2004 11: 28.

Brandt. “The Adrenal Medulla”. Available at Accessed 1/6/2012

Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America. Sep 20 2011;108(38):16050-16055.

Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol. 1969a;9:419-30.

Brekhman II., Pharmacological investigation of glycosides from Ginseng and Eleutherococcus.Lloydia. 1969b;32:46-51.

Brody S., A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress.Psychopharmacology (Berl). 2002;159:319-324.

Brown DW, Anda RF, Tiemeier H, et al. Adverse childhood experiences and the risk of premature mortality. Am J Prev Med. 2009 Nov;37(5):389-96.

Bruls E.,Melatonin. I. Physiology of its secretion]. Rev Med Liege. 2000 Aug;55(8):785-92.

Buoso E et al. Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence. Exp Gerontol. 2011 Nov;46(11):877-83. Epub 2011 Jul 27.

Calcaterra NE, Barrow JC. Classics in chemical neuroscience: diazepam (valium). ACS chemical neuroscience.Apr 16 2014;5(4):253-260.

Cao Y, Effects of a Chinese traditional formula Kai Xin San (KXS) on chronic fatigue syndrome mice induced by forced wheel running. J Ethnopharmacol. 2011 Aug 22.

Carroll D. The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2000;150:220-225.

Cases J et al. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med J Nutrition Metab. 2011 Dec;4(3):211-218. Epub 2010 Dec 17.

Chan TWD., Differentiation and Authentication of Panax ginseng, Panax quinquefolius, and Ginseng Products by Using HPCL/MS, Analytical Chemistry, 2000; 72 (10), 2329-2329.

Chen JK., Chinese Medical Herbology and Pharmacology, CA: Art of Medicine Press; 2004.

Cho HS, Kim S, Lee SY, Park JA, Kim SJ, Chun HS. Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology. 2008 Jul;29(4):656-62.

Choudhary MI., Cholinesterase inhibiting withanolides from Withania somnifera. Chem Pharm Bull, 2004;52(11):1358-1361.

Chrousos G., The stress response and immune function: clinical implications., Ann N Y Acad Sci, 2000;917:38-67

Ciolino H., Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo. Int J Cancer 2003;105:321-325

Cooley K, Naturopathic Care for Anxiety: A Randomized Controlled Trial ISRCTN78958974. PLoS ONE 2009; 4(8): e6628.

Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci.2012;13(10):701-712.

Daugherty M et al. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem. 2002 Jun 14;277(24):21431-9. Epub 2002 Mar 28.

Davydov M, Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. Journal of Ethnopharmacology 2000; 72(3): 345–393.

De Bock K, Acute Rhodiola rosea intake can improve endurance exercise performance. Int J Sport Nutr Exerc Metab. 2004;14(3):298-307.

Delarue J., Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab. 2003 Jun;29(3):289-95.

Dhatariya K, Bigelow ML, et al. Effect of DHEA replacement on insulin sensitivity and lipids in hypoadrenal women.Diabetes . 2005 Mar;54(3):765-769.

Di X, Yan J, Zhao Y, et al. L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway. Neuroscience. 2010 Jul 14;168(3):778-86.

Dimpfel W, Kler A, Kriesl E, Lehnfeld R, Keplinger-Dimpfel IK. Source density analysis of the human EEG after ingestion of a drink containing decaffeinated extract of green tea enriched with L-theanine and theogallin. Nutr Neurosci. 2007a Jun-Aug;10(3-4):169-80.

Dimpfel W, Kler A, Kriesl E, Lehnfeld R. Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: I. electrophysiological characterization in the rat hippocampus in-vitro. J Pharm Pharmacol. 2007b Aug;59(8):1131-6.

Dimpfel W., Effects of lozenge containing lavender oil, extracts from hops, lemon balm and oat on electrical brain activity of volunteers. Eur J Med Res. 2004 Sep 29;9(9):423-31.

Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology.Sep 2012;37(9):1369-1378.

Dixit S., Executive fatigue and its management with Mentat. Pharmacopsychoecologia. 1993;6:7-9.

Eiland L et al. Early life stress followed by subsequent adult chronic stresspotentiates anxiety and blunts hippocampal structural remodeling. Hippocampus. 2010 Sep 16. doi: 10.1002/hipo.20862. [Epub ahead of print]

Eipper BA., The biosynthesis of neuropeptides: peptide alpha-amidation. Annu Rev Neurosci(1992). 15: 57–85.

Evans J, Antioxidant supplements to prevent or slow down the progression of AMD: a systematic review and meta-analysis, Eye.2008 Jun; 22(6):751-760.

Fahey TD., The hormonal and perceptive effects of phosphatidylserine administration during two weeks of resistive exercise-induced overtraining. Biol Sport. 1998;15:135-144.

Feldman HA, Johannes CB, et al. Low dehydroepiandrosterone sulfate and heart disease in middle-aged men: cross-sectional results from the Massachusetts Male Aging Study. Ann Epidemiol . 1998 May;8(4):217-228.

Ferrari E, Cravello L, et al. Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates.Eur J Endocrinol . 2001 Apr;144(4):319-29.

Ferrari E., Cognitive and affective disorders in the elderly: a neuroendocrine study. Arch Gerontol Geriatr Suppl . 2004;(9):171-182.

Field, T., Cortisol decreases and serotonin and dopamine increase following massage therapy. The International journal of neuroscience 2005, 115 (10): 1397–1413.

Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cellular and molecular life sciences: CMLS.Jan 2013;70(1):55-69.

Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J. Mood and gut feelings. Brain Behav Immun.Jan 2010;24(1):9-16.

Foster JA, Lyte M, Meyer E, Cryan JF. Gut microbiota and brain function: An evolving field in neuroscience. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP).Oct 4 2015.

Friedmann E, Son H. The human-companion animal bond: how humans benefit. Vet Clin North Am Small Anim Pract. 2009 Mar;39(2):293-326.

Gaffney BT.,The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes. Life Sci.2001;70:431-442.

Gagnon A, Effects of Cu on plasma cortisol and cortisol secretion by adrenocortical cells of rainbow trout (Oncorhynchus mykiss). Aquat Toxicol. 2006 10;78(1):59-65.

Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut.Nov 2007;56(11):1522-1528.

Gholap S and Kar A. Hypoglycaemic effects of some plant extracts are possibly mediated through inhibition in corticosteroid concentration. Pharmazie. 2004;59(11):876-878.

Golf, Sw., On the significance of magnesium in extreme physical stress. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 1998, 12 2 (2suppl): 197–202.

Gomez-Ramirez M, Kelly SP, Montesi JL, Foxe JJ. The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task. Brain Topogr. 2009 Jun;22(1):44-51.

Gouin JP et al. Chronic stress, daily stressors, and circulating inflammatory markers. Health Psychol. 2011 Sep 19. [Epub ahead of print]

Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol. 2002;81(1):81-100.

Gupta P, Yadav DK, Siripurapu KB, et al. Constituents of Ocimum sanctum with antistress activity. J Nat Prod. 2007;70(9):1410-1416.

Hanley J,, Randomised controlled trial of therapeutic massage in the management of stress. Br J Gen Pract. 2003;53:20-25.

Head KA., Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev. 2009;14(2):114-140.

Heese T, Jenkinson J, Love C, et al. Anxiolytic effects of L-theanine--a component of green tea--when combined with midazolam, in the male Sprague-Dawley rat. AANA J. 2009 Dec;77(6):445-9.

Hellhammer, J., Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress (Amsterdam, Netherlands)2004, 7 (2): 119–126.

Hellman, L., Cholesterol synthesis from C14- Acetate in man, J Clin Invest. 1954 33(2): 142-149.

Hemila H. Vitamin C and common cold incidence: a review of studies with subjects under heavy physical stress. Int J Sports Med 1996;17:379-833.

Heraclides A et al. Psychosocial stress at work doubles the risk of type 2 diabetes in middle-aged women: evidence from the Whitehall II study. Diabetes Care. 2009 Dec;32(12):2230-5.

Heraclides AM et al. Work Stress, Obesity and the Risk of Type 2 Diabetes: Gender-Specific Bidirectional Effect in the Whitehall II Study. Obesity (Silver Spring). 2011 May 19.

Hertoghe, T., speech recorded at the American Academy of Anti-Aging Medicine, Las Vegas, NV, 1999.

Hidalgo C., Effect of the lipid environment on protein motion and enzymatic activity of the sacroplasmic reticulum calcium ATPase, J Biol Chem 1978; 253:6879-6887.

Hirata F., Phospholipid methylation and biological signal transmission. Science, 1980;209:1082-1090.

Huang KC. The Pharmacology of Chinese Herbs, 2nd ed. New York: CRC Press; 1999.

Innes KE et al. Chronic stress and insulin resistance-related indices of cardiovascular disease risk, part I: neurophysiological responses and pathological sequelae. Altern Ther Health Med. 2007 Jul-Aug;13(4):46-52.

Jacobs JR et al. Early and chronic stress and their relation to breast cancer. Psychol Med. 2000 May;30(3):669-78.

James FO et al. Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work. Sleep. 2007 Nov;30(11):1427-36.

Kakuda T. Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bull. 2002 Dec;25(12):1513-8.

Kalaitzakis E., Is fatigue related to suppression of hypothalamic-pituitary-adrenal axis activity by bile acids in chronic liver disease?, Med Hypotheses. 2011.

Kameda W, Daimon M, et al. Association of decrease in serum DHEA-S levels with the progression to type 2 diabetes in men of a Japanese population: the Funagata study. Metabolism . 2005 May;54(5):669-676.

Karten YJ et al. Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13456-61.

Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Altern Med Rev. 1999 Aug;4(4):249-65.

Kelly GS. Rhodiola rosea: a possible plant adaptogen. Altern Med Rev. 2001 Jun;6(3):293-302.

Kennedy DO., Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress. Phytother Res. 2006 Feb;20(2):96-102.

Kennedy DO., Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm). Psychosom Med. 2004 Jul;66(4):607-13.

Kiecolt-Glasser JK. Stress, food, and inflammation: psychoneuroimmunology andnutrition at the cutting edge. Psychosom Med. 2010 May;72(4):365-9. Epub 2010 Apr 21.

Kiho T, Ookubo K, Usui S, et al. Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis. Biol Pharm Bull. 1999;22(9):966-970.

Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan;74(1):39-45.

Kimura K., l-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2006;8: 21.

Kobayashi A. Trace element and hormonal responses during flight aptitude test. Aviat Space Environ Med. 1996;67(4):333-337.

Koh JH, Kim KM, Kim JM, et al. Antifatigue and antistress effect of the hot-water fraction from mycelia of Cordyceps sinensis. Biol Pharm Bull. 2003;26(5):691-694.

Kondo N, Oh J. Suicide and karoshi (death from overwork) during the recent economic crisis in Japan: the impacts, mechanisms and political responses. J Epidemiol Community Health. 2010;64(8):649-50.

Korlakunta HL et al. Transient left ventricular apical ballooning: a novel heart syndrome. Int J Cardiol. 2005 Jul 10;102(2):351-3.

Krugers HJ et al. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment. Front Synaptic Neurosci. 2010 Jul 12;2:24.

Kruk J. Self-reported psychological stress and the risk of breast cancer: A case-control study. Stress. 2011 Aug 29.

Kyrou I et al. Chronic stress, visceral obesity and gonadal dysfunction. Hormones (Athens). 2008 Oct-Dec;7(4):287-93.

Lasco A., Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women.Eur J Endocrinol . 2001 Oct;145(4):457-461.

Laszlo KD et al. Job strain predicts recurrent events after a first acute myocardial infarction: the Stockholm Heart Epidemiology Program. J Intern Med. 2010 Jun;267(6):599-611.

Lehrke M et al. Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress induced insulin resistance in acute inflammatory reactions. Crit Care. 2008;12(6):R157. Epub 2008 Dec 17.

Leu SF, Chien CH, Tseng CY, et al. The in vivo effect of Cordyceps sinensis mycelium on plasma corticosterone level in male mouse. Biol Pharm Bull. 2005;28(9):1722-5.

Li SP, Zhao KJ, Ji ZN, et al. A polysaccharide isolated from Cordyceps sinensis, a traditional Chinese medicine, protects PC12 cells against hydrogen peroxide-induced injury. Life Sci. 2003;73(19):2503-2513.

Lipnick RL, Filov VA. Nikolai Vasilyevich Lazarev, toxicologist and pharmacologist, comes in from the cold. Trends Pharmacol Sci. 1992 Feb;13(2):56-60.

Liu L, Effects of ginsenosides on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor in rats exposed to chronic unpredictable mild stress. Zhongguo Zhong Yao Za Zhi. 2011;36(10):1342-1347.

Liu RT et al. Stress generation in depression: A systematic review of the empirical literature and recommendations for future study. Clin Psychol Rev. 2010 Jul;30(5):582-93. Epub 2010 May 15.

Logan, A. Omega-3 fatty acids and major depression: A primer for the mental health professional. Lipids Health Dis. 2004; 3: 25.

Lovallo WR., Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women. Pharmacol. Biochem. Behav. 2006 83 (3): 441–447.

Ma SW, Benzie IF, Chu TT, et al. Effect of Panax ginseng supplementation on biomarkers of glucose tolerance, antioxidant status and oxidative stress in type 2 diabetic subjects: results of a placebo-controlled human intervention trial. Diabetes Obes Metab. 2008 Nov;10(11):1125-7. Epub 2008 Mar 18.

Maes M,. Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS. Neuro Endocrinol Lett. 2005;26(5): 487-492.

Majewska MD et al. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986 May 23;232(4753):1004-7.

Matthews KA et al. Chronic work stress and marital dissolution increase risk of posttrial mortality in men from the Multiple Risk Factor Intervention Trial. Arch Intern Med. 2002 Feb 11;162(3):309-15.

McEwen BS et al. Protective and damaging effects of stress mediators. N Engl J Med. 1998 Jan 15;338(3):171-9.

McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci. 2004 Dec;1032:1-7.

Mcmahon M, Gerich J, Rizza R. Effects of glucocorticoids on carbohydrate metabolism. Diabetes/Metabolism Reviews. 1988;4(1):17-30.

Mechanic D. Effects of psychological distress on perceptions of physical health and use of medical and psychiatric facilities. J Human Stress 1978; 4:26-32.

Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. The British journal of nutrition.Mar 2011;105(5):755-764.

Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. Jul-Aug 2011;2(4):256-261.

Methlie P et al. Grapefruit juice and licorice increase cortisol availability in patients with Addison's disease. Eur J Endocrinol. 2011 Nov;165(5):761-9. Epub 2011 Sep 6.

Mishra LC, Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev. 2000 Aug;5(4):334-46.

Mitsushima D et al. Gonadal steroid hormones maintain the stress-induced acetylcholine release in the hippocampus: simultaneous measurements of the extracellular acetylcholine and serum corticosterone levels in the same subjects. Endocrinology. 2008 Feb;149(2):802-11. Epub 2007 Oct 25.

Mondal S, Varma S, Bamola VD, et al. Double-blinded randomized controlled trial for immunomodulatory effects of Tulsi (Ocimum sanctum Linn.) leaf extract on healthy volunteers. J Ethnopharmacol. 2011;136(3):452-456.

Monteleone, P., Effects of phosphatidylserine on the neuroendocrine responses to physical stress in humans., Neuroendocrinol. 1990, 52: 243-248.

Morfin R., (ed), DHEA and the Brain; Vol. 1, Taylor & Francis, NY, 2002.

Muneer, M. ADRENAL GLANDS published online, retrieved Aug 20, 2011.

Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S. Possible involvement of group I mGluRs in neuroprotective effect of theanine. Biochem Biophys Res Commun. 2004 Jul 16;320(1):116-22.

Nagata A, Tajima T, Uchida M. Supplemental anti-fatigue effects of Cordyceps sinensis (tochu-kaso) extract powder during three stepwise exercise of human. Jpn J Phys Fitness Sports Med. 2005;55 Suppl.:S145-52.

Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30.

Ng TB., Toxic effect of heavy metals on cells isolated from the rat adrenal and testis. In Vitro Cell Dev Biol. 1990;26(1):24-8.

Nielsen NR et al. Perceived stress and cause-specific mortality among men and women: results from a prospective cohort study. Am J Epidemiol. 2008 Sep 1;168(5):481-91; discussion 92-6.

Nilsson PM et al. Sleep disturbance in association with elevated pulse rate for prediction of mortality--consequences of mental strain? J Intern Med. 2001 Dec;250(6):521-9.

Nobre AC, Rao A, Owen GN. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr. 2008;17 Suppl 1:167-8.

Olsson EM et al. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009 Feb;75(2):105-12.

Panossian A, Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol. 2009 Sep;4(3):198-219.

Panossian A. Adaptogens. Tonic herbs for fatiuge and stress. Altern Complement Ther. 2003;9(6):327-331.

Panossian A., Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration., Phytother Res. 2005;19(10):819-838.

Patacchioli FR et al. Menopause, mild psychological stress and salivary cortisol: influence of long-term hormone replacement therapy (HRT). Maturitas. 2006 Sep 20;55(2):150-5. Epub 2006 Mar 6.

Pawlikowski M., Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Neuroendocrinol Lett. 2002;23 Suppl 1:17-19.

Peters EM, Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running. Int J Sports Med. 2001 (7):537-543.

Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation. Clinical therapeutics.May 1 2015;37(5):984-995.

Ping J et al. Inheritable stimulatory effects of caffeine on steroidogenic acute regulatory protein expression and cortisol production in human adrenocortical cells. Chem Biol Interact. 2012 Jan 5;195(1):68-75. Epub 2011 Nov 12.

Plesofsky-Vig N., Pantothenic acid. In: Shils ME, eds. Modern Nutrition in Health and Disease, 8th ed. Malvern, PA: Lea & Febiger, 1994.

Pluess TT et al. Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects. Intensive Care Med. 2007 May;33(5):789-97. Epub 2007 Mar 22.

Pozza C, Graziadio C, Giannetta E, et al. Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics. J Oncol. 2012;685213.

Presman DM et al. Melatonin inhibits glucocorticoid-dependent GR-TIF2 interaction in newborn hamster kidney (BHK) cells. Mol Cell Endocrinol. 2012 Feb 26;349(2):214-21. Epub 2011 Nov 4.

Puri BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol. 2007;60(2):122-124.

Rasmuson S, Näsman B, Calström K, et el. Increased levels of adrenocortical and gonadal hormones in mild to moderate Alzheimer’s disease. Dement Geriatr Cogn Disord. 2002;13(2):74-9.

Reiter RJ,. Melatonin: an antioxidant in edible plants. Ann N Y Acad Sci. 2002 May;957:341-4.

Rocha Araujo DM., What is the effectiveness of the use of polyunsaturated fatty acid omega-3 in the treatment of depression? Expert Rev Neurother. 2010; 10(7):1117-1129.

Roepke SK et al. Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer's disease caregivers. Stress. 2011 Jul 26. [Epub ahead of print]

Sakihara S et al. Ampulla (Takotsubo) cardiomyopathy caused by secondary adrenal insufficiency in ACTH isolated deficiency. Endocr J. 2007 Aug;54(4):631-6. Epub 2007 Jul 31.

Salavecz G et al. Work stress and health in Western European and post-communist countries: an East-West comparison study. J Epidemiol Community Health. 2010 Jan;64(1):57-62.

Saleeby, Y., Wonder Herbs: A guide to three adaptogens, Xlibris 2006.

Sanders ME. Probiotics: Definition, Sources, Selection, and Uses. Clinical Infectious Diseases.February 1, 2008 2008;46(Supplement 2):S58-S61.

Sapolsky, RM, Endocrinology of the stress-response, Behavioral Endocrinology, 2nd ed. MIT, Press, Cambridge, MA, 2002 pp. 409–450.

Saul AN et al. Chronic stress and susceptibility to skin cancer. J Natl Cancer Inst. 2005 Dec 7;97(23):1760-7.

Schambelan M., Licorice ingestion and blood pressure regulating hormones., Steroids.1994;59(2):127-130.

Schmidt PJ., DHEA monotherapy in midlife-onset and minor depression. Arch Gen Psychiatry. 2005 Feb;62(2):154-162.

Schulz V., Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. 3rd ed. Berlin, Germany: Springer-Verlag; 1998:271, 273.

Sen S, American ginseng (Panax quinquefolius) prevents glucose-induced oxidative stress and associated endothelial abnormalities. Phytomedicine. 2011;18(13):1110-7.

Servan-Schreiber D., Somatizing Patients: Part I. Practical Diagnosis., AAFP, 2000, 2:1073-1080.

Sheikh N, Ahmad A, Siripurapu KB, et al. Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats. J Ethnopharmacol. 2007;111(3):671-676.

Shevtsov VA, A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine. 2003 Mar;10(2-3):95-105.

Shufelt, C., DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health--National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab. 2010 Nov;95(11):4985-4992.

Siddiqui, I., Serum Copper levels in various diseases: A local experience at Aga Khan University Hospital, Karachi, AKUH 2001 Abstract.

Siegel GJ et al. “Basic Neurochemistry; moolecular, cellular, and medical aspects”, 7th Edition. Elsvier Academic Press 2006. Pg 895.

Silvers KM., Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005;72:211-218.

Sinha R et al. Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility. Exp Clin Psychopharmacol. 2007 Oct;15(5):445-52.

Soszynski P., Decreased melatonin concentration in Cushing's syndrome., Horm Metab Res. 1989;21(12):673-674.

Spasov AA., A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine. 2000 Apr;7(2):85-89.

Stancheva SL, Effect of the extract of Rhodiola rosea L. on the content of the brain biogenic monamines. Med Physiol 1987;40:85-87.

Stough CK, Pase MP, Cropley V, et al. A randomized controlled trial investigating the effect of Pycnogenol and Bacopa CDRI08 herbal medicines on cognitive, cardiovascular, and biochemical functioning in cognitively healthy elderly people: the Australian Research Council Longevity Intervention (ARCLI) study protocol (ANZCTR12611000487910). Nutr J. 2012;11:11.

Strohle A et al. Stress responsive neurohormones in depression and anxiety. Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S207-14.

Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003;60:133-141.

Sun LJ, Wang GH, Wu B, et al. [Effects of schisandra on the function of the pituitary-adrenal cortex, gonadal axis and carbohydrate metabolism in rats undergoing experimental chronic psychological stress, navigation and strenuous exercise]. Zhonghua Nan Ke Xue. 2009;15(2):126-129.

Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease. Vitam Horm. 1991;46:165-228.

Tak LM. Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Phychol. 2011;87(2):183-194.

Tak LM., Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol. 2011;87(2):183-194.

Tarasov IuA, Sheibak VM, Moiseenok AG. [Adrenal cortex functional activity in pantothenate deficiency and the administration of the vitamin or its derivatives]. Vopr Pitan. 1985;(4):51-4. [Article in Russian]

Tarasov IuA, Sheibak VM, Moiseenok AG. [Adrenal cortex functional activity in pantothenate deficiency and the administration of the vitamin or its derivatives]. Vopr Pitan. 1985;(4):51-4. [Article in Russian]

Thaker PH et al. The neuroendocrine impact of chronic stress on cancer. Cell Cycle. 2007 Feb 15;6(4):430-3. Epub 2007 Feb 9.

Tohda C, Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005;14(1-2):34-45.

Tomlinson, J., 11ß-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid., Response Endocrine Reviews, 2004, 25: 831-866.

van Broekhoven F., Neurosteroids in depression: a review. Psychopharmacology (Berl) . 2003 Jan;165(2):97-110.

van Diermen D, Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol. 2009;122(2):397-401.

van Riel E et al. Chronic unpredictable stress causes attenuation of serotonin responses in cornu ammonis 1 pyramidal neurons. Neuroscience. 2003;120(3):649-58.

Veltman JC et al. Regulatory effect of copper on rat adrenal cytochrome P-450 and steroid metabolism. Biochem Pharmacol. 1986 Sep 1;35(17):2903-9.

Villareal DT. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA . 2004 Nov 10;292(18):2243-8.

Villareal DT., Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000;53:561-568.

Viner, R., Putting stress in Life: Hans Selye and the making of stress theory., Social Studies of Science, 1999, Vol. 29, No. 3, 391-410.

Vuong QV, Bowyer MC, Roach PD. L-theanine: properties, synthesis and isolation from tea. J Sci Food Agric. 2011a Aug 30;91(11):1931-9.

Vuong QV, Stathopoulos CE, Golding JB, Nguyen MH, Roach PD. Optimum conditions for the water extraction of L-theanine from green tea. J Sep Sci. 2011b Jul 7.

Wakabayashi C, Numakawa T, Ninomiya M, Chiba S, Kunugi H. Behavioral and molecular evidence for psychotropic effects in L: -theanine. Psychopharmacology (Berl). 2011 Aug 23.

Wang J, Anti-fatigue activity of the water-soluble polysaccharides isolated from Panax ginseng. J Ethnopharmacol. 2010; 20;130(2):421-423.

Warren G,. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand. 1999;99(2):112-116.

Webster MJ., Physiological and performance responses to supplementation with thiamin and pantothenic acid derivatives. Eur J Appl Physiol Occup Physiol 1998;77:486-91.

Weerth, C., Development of cortisol circadian rhythm in infancy , Early Human Development, 2003, Vol. 73, Issue 1, Pages 39-52.

Wilborn, D., Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism., Journal of the International Society of Sports Nutrition 2004;1 (2): 12–20.

Willis AL., Nutritional and pharmacologic factors in eicosanoid biology. Nutr Rev 1981; 39:289-301.

Wirth, M., Shiftwork duration and the awakening cortisol response among police officers., Chronobiol Int. 2011 ;28(5):446-57.

Wolkowitz OM, Reus VI, Keebler A, et al. Double-blind treatment of major depression with dehydroepiandosterone. Am J Psychiatry 1999;156:646-649.

Wolkowitz OM, Reus VI, Manfredi F, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry 1997;41:311-318.

Wu, JY., Adrenal insufficiency in prolonged critical illness, Cirt Care. 2008, 12(3): R65.

Yasuda K, Hiraoka M. [Pantothenic acid]. Nihon Rinsho. 2004;62 Suppl 12:198-202. [Article in Japanese]

Yin C, Gou L, Liu Y, et al. Antidepressant-like Effects of L-theanine in the Forced Swim and Tail Suspension Tests in Mice. Phytother Res. 2011 Mar 21.

Zaluska M et al. [Dehydroepiandrosteron (DHEA) in the mechanisms of stress and depression]. Psychiatr Pol. 2009 May-Jun;43(3):263-74.

Maintaining balance in today’s stressful world requires a multimodal approach that encompasses healthy eating habits, getting plenty of exercise, and using innovative natural ingredients to support the body’s natural adaptive abilities. Regular blood testing of DHEA-s, and morning and evening cortisol levels help ensure that stress hormones remain in balance.

Hormonal Therapies

Nutritional Therapies
  • B-Complex vitamin:
    • Thiamine (B1): 75 – 125 mg daily
    • Riboflavin (B2): 50 mg daily
    • Niacin (B3): 50 – 190 mg daily
    • Folate (preferably as L-methylfolate): 400 – 1000 mcg daily
    • Vitamin B12: 300 – 600 mcg daily
    • Biotin: 300 – 3000 mcg daily
    • Pantothenic acid: 100 – 600 mg daily
  • Vitamin C: 1000 – 2000 mg daily
  • Fish oil (with olive polyphenols): 2,000 – 4000 mg daily
  • Phosphatidylserine: 100 – 600 mg daily
  • L-Theanine: 200 – 400 mg daily
  • Calcium: 200 – 1200 mg daily
  • Magnesium: 140 – 500 elemental milligrams of highly-absorbable magnesium
  • Zinc: 30 mg daily
  • Chromium (Crominex™): 500 mcg daily
  • Selenium: 200 mcg daily
  • Manganese: 1 mg daily
  • Comprehensive multivitamin formula: Per label instructions (note: some of the nutrients mentioned in the protocol [i.e. zinc, selenium, manganese, and vitamin C] can be obtained by taking a high quality multivitamin/ mineral supplement).
  • Probiotics (containing a blend of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175): 3 billion CFUs daily
Herbal Therapies Adaptogens

In addition, the following blood testing resources may be helpful:

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You should not stop taking any medication without first consulting your physician.

All Contents Copyright © 1995-2017 Life Extension® All rights reserved.

Life Extension