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
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).
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).
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 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%.”
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).
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