Life Extension

What is Stress?

Stress generally occurs when external stimuli disturb the dynamic balance of the body’s physiological processes. A specialized signaling network called the HPA axis coordinates the body’s stress response. 

Acute stress helps prime the body to respond to immediate, transient threats. Intermittent mild stress, such as exercise, is healthy and promotes positive adaptive changes. Chronic stress, however, causes maladaptive responses and dysregulated HPA axis function. It can contribute to many health problems by disrupting the circadian rhythm, promoting inflammation, altering the microbiome, and causing epigenetic changes.

Natural interventions such as adaptogens, L-theanine, B vitamins, and omega-3 fatty acids may help relieve stress and restore normal HPA axis function.

How Can I Determine If Stress is Affecting My Health?

  • Blood tests (including cortisol, dehydroepiandrosterone [DHEA], salivary alpha-[a] amylase, and immunoglobulin A [IgA])
  • Heart rate variability

What Dietary and Lifestyle Changes Can Help Relieve Stress?

  • Cognitive-behavioral therapy
  • Meditation and mindfulness
  • Exercise
  • Maintain good sleep hygiene, sufficient sleep duration, and consistent sleep patterns
  • Maintain sex hormone balance
  • Eat more fruits and vegetables
  • Eat breakfast regularly
  • Minimize caffeine and alcohol intake

Can Medications Help Relieve Stress?

Most cases of stress can be managed with dietary and lifestyle interventions. However, in more severe cases when stress is contributing to other conditions such as anxiety or insomnia, medications may be appropriate for short-term use to temporarily address the stress-related condition(s). It is important to understand that medications do not eliminate stress or the causes of stress, but simply provide temporary relief from some of the symptoms caused by stress.

  • Antidepressants and anti-anxiety medications such as selective serotonin reuptake inhibitors (SSRIs) (eg, Prozac and Zoloft)
  • Beta-blockers (eg, propranolol)
  • Sedatives such as benzodiazepines (eg, Valium and Klonopin)
  • Hydrocortisone

What Natural Interventions May Help Relieve Stress?

  • B vitamins. B vitamin deficiencies are linked with multiple neuropsychiatric disorders. Supplementation with B vitamins has been shown to relieve stress and support normal HPA axis function.
  • Vitamin C. Low intake and circulating levels of vitamin C are correlated with symptoms of depression and anxiety. Increasing vitamin C levels via supplementation has been shown to reduce symptoms.
  • Omega-3 fatty acids. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil, may help prevent and treat stress, anxiety, and depression.
  • L-theanine. L-theanine, an amino acid found in tea, has been shown to reduce perceived stress and physiological markers of the stress response.
  • Bioactive milk peptides. Peptides found in milk, such as a-lactalbumin and casein, may support healthy neurological function, improve mood, and promote sleep.
  • Probiotics and prebiotics. Probiotics and prebiotics can improve the balance of gut bacteria and have a positive impact on stress response. Probiotics may lower stress reactivity and anxiety, and improve mood, memory, and cognition.
  • Adaptogens. Adaptogenic herbs help support homeostasis in the body and can be used to relieve fatigue, improve cognitive function and mood, and support the immune system.
    • Magnolia and phellodendron. This herbal combination has been found to reduce stress and stress-related weight gain.
    • Holy basil. A number of clinical and preclinical studies have demonstrated holy basil’s ability to improve mood and cognition.
    • Ashwagandha. Ashwagandha has been shown to relieve stress, improve stress-related eating behaviors, and promote weight loss.
    • Lemon balm. Lemon balm has been found to improve mood and cognition and relieve symptoms of anxiety and insomnia.
    • Other adaptogens that may help relieve stress include bacopa, saffron, ginseng, rhodiola, cordyceps, and others.
  • Other natural interventions may help relieve stress, including phosphatidylserine, L-tryptophan, melatonin, and dehydroepiandrosterone (DHEA).

Over the course of evolutionary time, the human body has become reliant on the acute stress response to overcome short-term adversity. But human physiology is simply not adapted to the relatively modern phenomenon of unrelenting low-level stress. Consequently, we now face an epidemic of health problems to which chronic stress is a contributing factor.1,2

A key feature of chronic stress is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a network of signaling centers in the brain and body that modulates our physiological response to stress. Normal activation of the HPA axis is necessary for healthy adaptive responses to stressors, but chronic activation leads to a maladaptive stress response marked by changes in the release and activity of the stress hormone, cortisol, which contributes to stress-related illness.2,3 Interactions between the HPA axis and the central nervous system, immune system, and gut microbiome contribute the wide-ranging effects of stress on overall health.4,5

The good news is that making healthy lifestyle decisions and adhering to a healthy diet can enhance resistance to the detrimental effects of chronic stress.4-6 In this protocol, you will learn how chronic stress causes health problems and how you can improve your ability to cope with stress and fortify yourself against the negative health effects of our stressful modern world.

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:

The Fight or Flight Response

Stress generally occurs when external stimuli disturb the dynamic balance of the body’s physiological processes.7 The stress, or “fight or flight,” response begins in the brain, where the perception of a threat triggers the release of corticotropin releasing hormone (CRH) from the region called the hypothalamus. This stimulates the anterior pituitary, a gland that sits just under the hypothalamus, to increase release of adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then acts on the adrenal cortex, raising production and release of cortisol and the less active glucocorticoid, corticosterone, as well as another adrenal hormone called dehydroepiandrosterone, or DHEA.8

Stress Response System

The signaling network between the nervous system and adrenal glands is called the hypothalamic-pituitary-adrenal (HPA) axis and is regulated in part by a negative feedback mechanism, through which rising blood levels of cortisol inhibit release of both CRH and ACTH.3,9

Stress also directly engages sympathetic nervous system signaling in the brain region called the locus coeruleus. Catecholamine neurohormones (epinephrine and norepinephrine, also known as adrenaline and noradrenaline) released by the adrenal medulla and sympathetic nerve endings have physiologic effects intended to help the body respond and adapt to stressful circumstances. Although it tends to work in concert with the HPA axis, the sympathetic nervous system also functions independently to activate the stress response.3,9

Acute Stress

As mediators of the stress response, cortisol and catecholamines have profound effects throughout the body (see Table 1). When acutely elevated, they help prepare the body to escape danger. For example, cardiac output increases to support stronger blood flow; blood sugar levels increase to meet higher energy demands; pupils dilate to allow for greater visual input; alertness and cognition are enhanced; and digestive and reproductive functions are inhibited due to their not being essential in the short term.9

Table 1: Hidden Causes of Acute Stress

Physiological Stressor

Acute Adaptive Stress Response

Low blood glucose level10,11

Catecholamines stimulate breakdown of carbohydrate stores and conversion of protein and fat into glucose

Cortisol inhibits glucose use by non-central nervous system tissue

Low blood pressure3,12

Catecholamines stimulate constriction of blood vessels

Cortisol increases sodium and water retention in the kidneys

Low oxygen saturation3,13,14

Catecholamines stimulate the respiratory center of the brain to increase breathing, increase heart rate and contraction strength, and selectively constrict blood vessels

Oxidative stress15

Catecholamines and cortisol alter cell metabolism to restore reductive-oxidative balance

Inflammatory cytokines1,16

Catecholamines and cortisol modulate immune activities

Chronic Stress

The acute stress response can lead to positive adaptive effects, but when the HPA axis and locus coeruleus are chronically activated, their effects become maladaptive: the response to a chronic or repeated stress may become dull, yet, at the same time, sensitivity to new stressors may be enhanced.12,17 A dysregulated stress response results in altered patterns of cortisol and catecholamine production and/or receptor response to them.3,9 Chronic stress may even alter brain structure.18 In addition, impairment of the HPA axis due to chronic stress appears to suppress DHEA production and release, even under acutely stressful circumstances.8,19 This is important because DHEA opposes some of the actions of cortisol: it protects nerves and stimulates development of neuronal connections, has immune-regulating effects that oppose and balance those of cortisol, and may prevent cortisol-induced metabolic disturbances.8 The exact nature of the response to chronic stress depends on individual characteristics such as personality traits, gender and age, life experiences, and genetic and epigenetic factors.3

The Stress Burden of Social Isolation and Loneliness

In January 2018, the British government announced the establishment of a Ministry of Loneliness. The decision was based on a 2017 report finding that 9 million Britons often or always feel lonely and the growing recognition that social isolation and loneliness take a toll on physical and mental health.20,21

The evidence for links between loneliness, a form of psychological stress, and poor health is particularly strong for cardiovascular disease and mental health problems.20-23 In older adults in particular, loneliness has been linked to increased cognitive decline and dementia, health care use, nursing home admissions, and mortality.21 A recent review of the research noted the health effects of loneliness may be mediated by altered HPA axis and sympathetic nervous system reactivity to stress. Like the stress response itself, the reaction to social isolation appears to vary among individuals.24

Prolonged stress is associated with many chronic disorders and diseases affecting all of the body’s organ systems, and as life’s stressors take their toll on the psyche and body, chronic illness itself becomes a source of stress. The two-way relationship between stress and disease creates a downward spiral in mental and physical health that can become difficult to overcome.2

Stress and the Circadian Rhythm

The HPA axis is closely regulated by circadian signaling in the brain. This circadian signaling is affected by day and night (light and dark) cycles, patterns of eating times, and most likely other factors yet to be discovered. Normally, cortisol levels peak shortly after waking in the morning and are lowest around bedtime. By acting on receptors throughout the body, cortisol imposes diurnal (two-phase; day-night) rhythms to other physiological functions.17,25

Numerous studies have shown that disruption of the circadian clock, such as due to shift work, sleep apnea, and other sleep disorders, is associated with health problems including cardiovascular disease, type 2 diabetes, obesity, and an array of age-related diseases.26,27 Circadian disturbances may even correlate with reduced lifespan.28 Chronic stress appears to impair circadian control of the HPA axis, which can result in either excess evening levels or blunted morning levels of cortisol.29 These dysfunctional patterns of cortisol release may be an underlying factor in the negative physical and mental health consequences of chronic stress and circadian rhythm disruption.30

Stress and Inflammation

One important way that chronic stress affects long-term health is through dysregulated inflammatory signaling. Although cortisol is best known for its immunosuppressive action, its effects on immunity are complex, stimulating some aspects of immunity and inhibiting others.1,25 A phenomenon known as glucocorticoid resistance, in which tissues and cells become less responsive to cortisol, occurs following long-term elevation of cortisol levels due to chronic stress.31,32

Chronic stress-induced immune dysfunction results in reduced immune protection against infections and cancer, as well as inflammatory conditions, such as allergic and autoimmune disorders, and conditions related to low-level systemic inflammation like heart disease and diabetes.1,33 Once inflammation is initiated, it perpetuates the stress response through the actions of cytokines (small signaling proteins of the immune system) on the hypothalamus, pituitary, and adrenal cortex.25,34

Stress and the Microbiome

Chronic stress may impact health through interactions with the gut microbiome—the trillions of microorganisms that reside in the intestines. Through its relationship with nervous system signaling, often referred to as the “gut-microbiota-brain axis,” and its ability to regulate the immune system, a healthy microbiome appears to be essential for modulating stress responsiveness and preventing overstimulation of the HPA axis. Conditions associated with chronic stress have been shown to alter the composition of the gut microbial community. Microbial imbalances, in turn, can cause intestinal and systemic inflammation and abnormal neurological signaling that can trigger HPA activation.35-38

The Epigenetics of Stress

Exposure to stress early in life can alter stress responsiveness and resilience throughout life. Part of this is likely due to effects of stress on brain and adrenal gland development; another important element is epigenetics. Epigenetics refers to environmentally induced modifications to gene expression patterns (as opposed to changes in gene sequence) or factors that control how genes are used to direct protein synthesis in cells. These modifications are lasting, but can be reversed by future circumstances.39

The epigenetic changes induced by prenatal and early life stress result in hyperresponsiveness of the HPA axis and increased risk of neuropsychiatric problems in adulthood, such as depression, anxiety, and post-traumatic stress disorder.39-41 Emerging research has shown that stress-induced epigenetic changes can also occur in adulthood, affecting HPA axis responsiveness and increasing vulnerability to stress-related health problems.42 In addition, because the epigenome is passed on to offspring by both parents, exposure to intense or unremitting stress has implications for resilience and health that may span multiple generations.41,43,44

Hormesis—The Benefits of Intermittent Mild Stress

While chronic stress has toxic effects that can ultimately shorten lifespan, short-term exposure to stress can promote development of adaptive strategies, supporting health and longevity. The process of developing coping mechanisms in response to minor stressors as a means of building resilience against greater stress has been called hormesis. Another way of expressing the concept of hormesis is the common phrase, “What doesn’t kill you makes you stronger.”45,46

Exercise is an example of a hormetic stressor: it causes stress by increasing body temperature, mechanical demands, nutrient and oxygen demands, and free radical production.46 The cellular responses to the stress induced by regular moderate exercise can lead to resiliency reflected in a broad spectrum of health benefits and longer life. On the other hand, extreme exercise, such as bouts lasting 18–24 hours without interruption, exhausts the body’s ability to adapt, can harm health, and may shorten lifespan.45,46 Moderate calorie restriction also confers hormetic benefits: adapting to lower energy availability involves changes in metabolic, immune, and neuroendocrine function that are associated with healthy aging and may extend life.47,48

Chronic stress can exert considerable body-wide health effects. It can contribute to the onset or worsening of many types of ailments. The following discussion highlights some of the more common conditions to which chronic stress often contributes.

Cardiovascular Disease

One of the most widely recognized health effects of chronic stress is heart disease. Through the effects of cortisol and catecholamines, and by disrupting circadian rhythms through sleep disturbance, chronic stress has been shown to impair nervous system regulation of cardiac function,49 and can cause high blood pressure, arrhythmia, and vascular inflammation leading to atherosclerosis and blood clots.50 Prolonged stress at home and at work has been clearly linked to increased risk of coronary artery disease and cardiac events including heart attack and stroke.12,51 A recent meta-analysis highlights the influence of work stress on heart disease risk: after analyzing data from more than 740,000 men and women, researchers found that people who work 55 or more hours per week have a 12% increased risk of coronary artery disease and a 21% increased risk of stroke compared with those who work less.52

Acute stress can also pose a threat to the heart. Studies have noted the incidence of heart attack increases following acutely stressful events such as earthquakes and World Cup soccer championships.53 Takotsubo cardiomyopathy, a sudden weakening of the heart muscle that mimics the symptoms of heart attack or angina and is potentially fatal, is another example of the danger of acute stress to the heart. Also known as stress cardiomyopathy, broken heart syndrome, and apical ballooning syndrome, Takotsubo cardiomyopathy typically occurs a few hours after a severe physical or emotional trauma and is most common in postmenopausal women.54,55

Psychiatric and Neurological Disorders

Persistently high cortisol levels, a marker of chronic stress, can trigger changes to neuronal structure and reduce brain plasticity (the ability to make new neuronal connections).56 Chronic stress is closely associated with several common neuropsychiatric disorders, including depression, anxiety, dementia, and Alzheimer disease.

Inflammation in the brain triggered by stress-related signaling appears to underlie a number of these illnesses.57 In Alzheimer disease, stress-related immune dysfunction appears to weaken the brain’s ability to clear amyloid-beta, a protein involved in Alzheimer disease development and progression.58,59 Early life, repetitive, or chronic stress may also reduce the activity of nerve growth factors, especially brain-derived neurotrophic factor (BDNF), involved in formation of new nerve connections.60-62 Low levels of BDNF are associated with mood disorders as well as learning and memory deficits.62 Furthermore, these stress-related changes may be encoded epigenetically, altering nerve system plasticity and function in lasting ways.63

Cancer

A growing body of evidence suggests that the neurohormones of the stress response can promote the initiation and progression of cancer.64,65 Furthermore, chronic stress may be associated with behaviors, such as smoking, substance abuse, overeating, and decreased physical activity, that increase the risks of certain cancers.66,67 Coping with a cancer diagnosis, symptoms, and treatment is inherently extremely stressful for some individuals,68,69 yet a high burden of stress may negatively impact response to cancer treatment and prognosis.64,70,71

The mechanism by which stress influences cancer is likely to be multifaceted, but the cornerstone may be immune dysregulation, marked by decreased immune surveillance and systemic inflammation. HPA axis dysregulation suppresses immune defenses against cancer, and chronic systemic inflammation creates conditions that support cancer initiation, progression, and metastasis.72,73 Inflammation may stem from other stress-induced sequelae, including weight gain and metabolic disturbance, disruption of the gut microbiome, and epigenetic alterations72; in turn, inflammation can contribute to these processes.74 In addition, stress may affect cancer development by desynchronizing circadian regulation of biological activities.29,75

Metabolic Disturbance: Why Does Stress Make it Hard to Lose Weight?

One of the most important functions of the stress response is to ensure that adequate energy is available to cope with stressful circumstances. During episodes of acute stress, appetite is suppressed to reserve attention for fight or flight, and extra energy in the form of glucose is freed from stored fats and carbohydrates. Under conditions of chronic stress, however, appetite is typically up-regulated and cravings for high-sugar, high-fat, high-calorie foods can intensify as a result of long-term hyperstimulation of the HPA axis and its complex interactions with appetite-regulating neurohormones such as ghrelin and leptin. For reasons that are not entirely clear, an increased appetite as a reaction to chronic stress is more pronounced in women than men.10,76

To make matters worse, chronic stress and HPA axis dysregulation are associated with insulin resistance and type 2 diabetes , as well as fat tissue growth and obesity.77,78 In one study, salivary cortisol tests showed disturbances in the diurnal rhythm of cortisol release were correlated with body mass index (BMI) and waist circumference, a measure of visceral fat and one of the cardiovascular risk factors in metabolic syndrome.79 These metabolic consequences of long-term stress then promote widespread inflammatory signaling that damages blood vessels and increases cardiovascular risk.80,81 Systemic inflammation also affects the nervous system, contributing to mood and cognitive disorders, and creates a vicious cycle of increased HPA axis activation.10,82

Although widely believed that chronic stress can lead to weakened thyroid function, there is little evidence as of the date of this writing to support this notion. In one study, hair cortisol levels were higher in adults with overt hypothyroidism than in healthy adults, and were correlated with higher body weight and BMI; however, in participants with subclinical hypothyroidism, a condition characterized by normal to slightly abnormal lab values and possibly symptoms of hypothyroidism, hair cortisol levels were not significantly different from those of healthy participants.83 Findings from preliminary studies indicate stress may contribute to the onset of autoimmune hypothyroidism; however, a review of these studies was unable to confirm the connection.84 On the other hand, evidence from animal studies suggest hypothyroidism may trigger HPA axis dysregulation and, when chronic, reduce adrenal output.85,86

Additional Health Conditions Stress Can Worsen

Virtually any health condition can be negatively affected by stress. In addition to those already discussed, the following are some of the disorders and diseases that stress may impact:

  • Asthma87
  • Atopic dermatitis88
  • Autoimmune diseases89
  • Chronic fatigue syndrome90
  • Upper and lower respiratory infections91
  • Infertility92
  • Irritable bowel syndrome93
  • Migraine94
  • Pain disorders95,96
  • Sexual dysfunction97

People experiencing high levels of stress and its health effects will undoubtedly fare better by reducing their exposure to high-stress circumstances. For many people, however, stress at home or on the job can seem unavoidable. In such cases, a healthy diet, exercise, and stress management practices can have a strong positive impact on normalizing the stress response and preventing stress-related illness.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) refers to a group of patient-centered techniques focused on changing thought patterns associated with emotional distress and harmful behaviors. A large body of clinical studies show CBT is an effective strategy for managing general stress and relieving anxiety.155 In one recent clinical trial, 100 subjects suffering from chronic stress were assigned to participate in a 12-week internet-based CBT intervention or be placed on a waitlist. After six months, measures of perceived stress and stress-related symptoms were lower in those who received the intervention.156 CBT was found in another study to be similarly effective to mindfulness-based stress reduction (described below) in reducing stress and burnout in parents of children with chronic conditions.157

A recent research review showed CBT is moderately effective for treating stress- and anxiety-related psychological disorders.158 CBT has also been recommended as a treatment strategy for stress-mediated chronic pain.159,160 In a study in 46 women with fibromyalgia (a chronic pain condition), a six-month CBT intervention led to improved sense of control over life and increased coping behaviors, and decreased measures of depression, exhaustion, and stress behaviors; these benefits were maintained and enhanced one year after initiation of the intervention.161

Some stress-affected people may be more likely to benefit than others: researchers have noted that factors such as working night shifts, high burnout scores, and elevated inflammatory marker levels may reduce the efficacy of CBT.162

Meditation and Mindfulness

Meditation helps regulate the stress response, reduce chronic inflammation, and maintain a healthy gut microbiome, and numerous studies indicate its potential benefits in treatment and prevention of diverse health disorders.4 Studies in veterans with post-traumatic stress disorder have shown practicing meditation not only improves patterns of cortisol release but also triggers epigenetic changes that might also contribute to its positive impacts on the stress response.163,164

A review of 45 studies found that meditation lowers cortisol output, blood pressure, heart rate, triglycerides, and inflammatory marker levels, indicating its potential for protecting cardiovascular health.165 The American Heart Association issued a statement in 2017 recognizing meditation’s possible role, alongside smoking cessation and treatment of high blood pressure and high cholesterol, in reducing the risk of heart disease.166

Mindfulness-based stress reduction is a structured program that incorporates meditation, body awareness, and gentle yoga, with an emphasis on awareness of the present moment. The benefits of mindfulness-based stress reduction on various psychological and physical health outcomes have been widely reported.6 For example, reviews of studies on healthcare providers and other types of workers have shown that mindfulness-based interventions can increase well-being and reduce anxiety, depression, and burnout, and may improve work performance.167-170 In a controlled trial in overweight and obese women, a four-month mindfulness program led to reductions in stress-related eating behaviors and prevented weight gain.171 Mindfulness programs are usually conducted in person, but the effectiveness of online mindfulness-based stress reduction programs is gaining interest, with positive effects being reported in recent clinical trials.172-174

Exercise

For many people, stress reduces the desire and motivation to engage in physical activity, yet exercise can improve stress resilience175 and has been shown to reduce symptoms in people with anxiety and stress-related disorders.176

Exercise appears to stimulate anti-inflammatory and anti-stress reactions in the body.177 Engaging in regular exercise improves the body’s ability to adapt to stress and has been correlated with better recovery from illness and surgery.175 Exercise is associated with better sleep,178 less anxiety and depression,179,180 and lower stress reactivity in the nervous and cardiovascular systems.181 A review of the research concluded that approximately 50 minutes per day of moderate intensity exercise is associated with the greatest mental health benefits compared with lower or higher doses; however, sedentary hours erode some of physical activity’s positive mental health effects.182 Clinical evidence also suggests strength training may improve anxiety, depression, and sleep.183,184

Exercise may mitigate stress-related eating behaviors: a number of trials have indicated that even 15-minute bouts of brisk walking can reduce stress-eating in the short term.161 In addition, regular exercise can help prevent or reverse the metabolic, inflammatory, and neurological consequences of chronic stress,66,185,186 and numerous studies support the current World Health Organization recommendation to engage in at least 150 minutes per week of moderate-intensity physical activity as an effective means of reducing death from all causes.187

Activity tracking tools may be useful and effective in incorporating exercise into a stress management protocol.188,189 In a recent preliminary study, 35 sedentary overweight participants were enrolled in a 12-week walking program in which they used pedometers to count the number of steps taken each day. The 30 participants who successfully achieved the goal of 10,000 steps per day not only lost weight and decreased their waist circumference, they also had lower scores on tests of anxiety, depression, fatigue, confusion, anger, and overall mood distress than at the beginning of the study.190 In another trial, increasing physical activity by using a step-counting activity tracker plus a goal setting intervention reduced depressive symptoms in female participants.191

The Stress-relieving Nature of Pets

Researchers have long been interested in the relationships between humans and their companion animals and the effects of such relationships on health. In general, findings suggest pet ownership is associated with less depression and loneliness, better social interaction, and reduced anxiety and stress.192

Several studies have noted that pet owners have lower blood pressure, cholesterol, and triglyceride levels, and are less likely to suffer fatal cardiac events (heart attack and stroke) compared with non-pet owners.193-195 While some of these benefits may be due in part to increased physical activity associated with dog ownership, cat owners too have a lower risk of cardiovascular death, leading researchers to propose that having pets may also impact cardiovascular health by improving mood and reducing stress reactivity.195-197

Studies of dog-assisted interventions suggest even the presence of an unfamiliar dog may lower stress during inherently stressful circumstances, such as during dental procedures.198 In a laboratory setting, the presence of an unfamiliar dog mitigated stress-induced increases in cortisol and heart rate more than the presence of a friend.199 In another study, participants with pets had lower baseline blood pressure and heart rate, and lower cardiovascular reactivity to physical and mental stress tests, than participants without pets. In addition, the presence of their pet during stress testing reduced stress reactivity even further, while the presence of a friend had no effect and presence of their spouse increased stress reactivity.200

Maintain Sex Hormone Balance

The physiologic stress response is strongly influenced by sex hormones (testosterone, estrogen, and progesterone), and gender-related differences in reactions to stress have been widely documented. Although the relationship is complex, stress-induced activation of the HPA axis, in general, is stronger in women than men. Evidence from animal research suggests this may be due to opposite effects of testosterone and estrogen on HPA axis sensitivity: estrogen increases HPA axis responsiveness while testosterone decreases it.201,202 In addition, progesterone appears to suppress sensitivity of the HPA axis and downregulate anxiety.203,204 Furthermore, while acute stress appears to increase progesterone production,204 chronic stress inhibits release of all sex hormones.202 Higher progesterone levels in the second half of the menstrual cycle have been associated with lower levels of premenstrual aggression, irritability, and fatigue in another study.205

In postmenopausal women, whose estrogen and progesterone levels are naturally low, hormone therapy has been shown to affect regulation of the stress response and may enhance some aspects of cognitive function during stress. In one study, 15 sedentary postmenopausal women who had used long-term hormone replacement therapy were compared with 15 similar women who had never used hormone therapy. Those who had never used hormone therapy were found to have abnormal diurnal salivary a-amylase patterns, while hormone therapy users had normal a-amylase patterns. In addition, hormone therapy non-users had less of a rise in salivary a-amylase concentration in response to exercise than hormone therapy users. This suggests that long-term hormone therapy may help maintain normal tone of the sympathetic nervous system.206 On the other hand, another trial found that postmenopausal women using estradiol therapy had a reduced cortisol response and less reduction in working memory after exposure to physical stress compared with women receiving placebo.207

In a preliminary study in 94 postmenopausal women under chronic stress due to caring for a family member with dementia, hormone therapy was correlated with better psychosocial function: those using hormone therapy reported less hostility and fewer negative interactions with members of their support teams than those not using hormone therapy; the greatest benefit was seen in those using both estradiol and progesterone.208

Progesterone therapy alone can help perimenopausal women with symptoms including hot flashes, breast pain, and sleep problems.209,210 Because these symptoms may be a source of stress, progesterone therapy may have anti-stress benefits in peri- and postmenopausal women. Furthermore, animal research suggests progesterone may protect the brain from harmful stress-induced inflammation.211

Taken together, these findings suggest that maintaining balanced sex hormone levels throughout life may be important for regulating stress responsiveness and promoting resilience. Men and women with possible hormone imbalances should review Life Extension’s Male Hormone Restoration , and Female Hormone Restoration protocols.

Stress is well known to trigger changes in eating behaviors, often increasing appetite for unhealthy “comfort” foods like those high in sugar and fat.212 One reason may be that stress alters levels of appetite-regulating hormones, ghrelin and leptin, producing more hunger signaling.213 Although not everyone eats more in response to stress (about 40% of individuals eat more, 40% eat less, and 20% eat the same number of calories when under stress), a stress-induced rise in preference for high-sugar foods has been consistently observed and may be partly due to a dampening effect of sugar on the stress response.214-217 Compounding the problem, stress appears to increase susceptibility to diet-related metabolic disturbances like abdominal obesity and insulin resistance.218

Countering stress-related appetite changes and food cravings is challenging; however, eating a healthy diet may be even more important during times of stress. Healthy eating habits can help ensure adequate intake of vitamins, minerals, protein, complex carbohydrates, anti-inflammatory fats, fiber, and phytochemicals needed to combat the negative health effects of chronic stress and interrupt the cycle of stress and stress-related behaviors.219,220

Eat More Fruits and Vegetables

Increasing fruit and vegetable intake can help combat stress. A study in young adults showed that increasing fruit and vegetable intake by two servings per day for two weeks resulted in enhanced psychological well-being, vitality, flourishing, and motivation.221 A Mediterranean-style diet, which emphasizes olive oil, whole grains, fruits, vegetables, fish, and nuts and seeds, may improve the stress response and has been associated with better regulation of HPA axis activity. This dietary pattern may also mitigate the effects of stress by reducing systemic inflammation and the risk of many chronic health problems.222-224

Eat Breakfast Regularly

Eating breakfast may help build stress resilience. Compared to breakfast skipping, habitual breakfast eating was associated with lower levels of perceived stress, better cognitive function, and fewer job injuries and accidents in a study that included more than 800 nurses.225 In another study in 65 female participants, habitual breakfast skippers had blunted diurnal cortisol variation, increased overall cortisol output, and higher blood pressure compared with habitual breakfast eaters, suggesting a morning meal may be important for maintaining normal circadian regulation of the HPA axis.226

Minimize Caffeine and Alcohol Intake

Caffeine may seem attractive to those affected by stress-related fatigue, but its effects may aggravate symptoms such as anxiety and poor sleep in susceptible people.227,228 Caffeine stimulates the sympathetic nervous system, and in this way may activate the stress response.229 Even with daily consumption, its intake can raise cortisol levels and has been found to increase the cortisol response to mental stress230,231 and prolong the effects of physical stress on heart rate and blood pressure.232 In one study, habitual coffee drinking was associated with greater increases in heart rate and vascular inflammation in response to mental stress.233 On the other hand, drinking coffee appears to promote healthy metabolism and may protect against type 2 diabetes, liver cancer, and cognitive decline.234 While sensitive individuals may fare better eliminating caffeine during times of stress, moderate intake may be reasonable for others.227

Alcohol is often used as a relaxant during times of stress235,236; however, excessive intake raises cortisol levels and long-term use leads to dysregulated HPA axis signaling and disrupts the normal function of the stress response.237-239 Individuals experiencing stress-related insomnia frequently turn to alcohol as a form of self-medication, but because alcohol erodes sleep quality and quantity, it may actually exacerbate sleep difficulties.240 In addition, because people experiencing intense life stress or with a history of early life stress are more vulnerable to developing problematic drinking habits,239,241 it is especially important to avoid stress-related alcohol use.

A variety of natural, integrative interventions have been shown to help balance HPA axis function and counteract the detrimental effects of chronic stress.

Multivitamins and B-Complex Vitamins

Deficiencies of B vitamins are associated with neuropsychiatric disorders such as depression, Alzheimer disease, schizophrenia, and other types of psychosis and dementia, and adequate amounts of all B vitamins are needed for healthy nervous system function.242,243

The ability of multivitamins to reduce perceived stress and fatigue has been demonstrated in a number of trials.244-248 In one randomized controlled trial in 60 working adults, those receiving a high-dose B complex daily for 12 weeks reported lower levels of stress, confusion, and depressed mood compared with those receiving placebo.249 A review of the research concluded that multivitamins, and B complex supplements in particular, can be effective for lowering perceived stress, reducing mild psychiatric symptoms, and improving everyday mood in healthy individuals.250

B vitamins may also support normal HPA axis function. In a placebo-controlled trial with 138 subjects, 16 weeks of supplementation with a multivitamin containing B vitamins increased the cortisol awakening response. The cortisol awakening response, which occurs about 30 minutes after waking and generally results in the highest cortisol level of the day, is considered a marker of healthy HPA axis tone and has been associated with lower distress levels during the rest of the day.251 Another randomized controlled crossover trial examined the effect of one week of treatment with a multivitamin supplement in 240 Chinese military personnel who underwent intense physical stress. The multivitamin was associated with better recovery of normal HPA axis function and improvements in psychological symptoms.252

Vitamin C (Ascorbic Acid)

The adrenal glands have the highest concentration of vitamin C in the body.253 In addition to its well-known function as a free radical scavenger, vitamin C is a cofactor in the synthesis of catecholamines—neurohormones involved in the stress response—and may help modulate central nervous system activities.253-255 Levels of vitamin C in the blood and white blood cells drop quickly during times of stress or infection,256 and symptoms of depression and anxiety have been correlated with low intake and low circulating levels of vitamin C.254

In a controlled clinical trial, patients with stress-induced anxiety and depression had lower levels of vitamin C, as well as vitamins E and A, than healthy subjects, and the addition of these nutrients (1,000 mg per day vitamin C, 800 mg per day vitamin E, and 600 mg per day vitamin A) to antidepressant therapy led to greater reductions in symptoms of anxiety and depression compared with antidepressant therapy alone.257 Another controlled trial found that supplementing with 500 mg per day of vitamin C reduced anxiety levels and lowered average heart rate in healthy high school students.258 In addition, a review of research indicated high doses of vitamin C may reduce anxiety and mitigate stress-related increases in blood pressure.259

Omega-3 Fatty Acids

Omega-3 fatty acids (primarily EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid] from fish oil) may help prevent and treat stress, anxiety, and depression.260-262 Low blood levels of EPA and DHA have been correlated with several biological indicators of stress: elevated markers of inflammation, dysregulated nervous system signaling, and HPA axis hyper-reactivity.263,264 Conversely, omega-6 fatty acids, mainly obtained through eating animal fats and processed vegetable oils, promote inflammation and can thereby induce stress signaling and contribute to stress-related illnesses.261

In a randomized controlled trial in participants with high triglyceride levels, taking 3,400 mg of combined EPA and DHA for eight weeks increased heart rate variability, indicating lower stress-related nervous system signaling; however, a lower dose of 850 mg per day had no effect.265 Another controlled trial found that three weeks of treatment with 60 mg EPA and 252 mg DHA per day improved perceived stress and anxiety and reduced cortisol levels in alcoholic subjects in a residential treatment program.266 Evidence from trials in patients with depression suggest omega-3 fatty acids can correct HPA hyperactivity, mitigate symptoms, and may improve responsiveness to antidepressant therapy.264,267

L-theanine

L-theanine is an amino acid found in tea that has demonstrated anti-stress effects. Numerous studies have found that tea and theanine reduce perceived stress and physiologic markers of the stress response, including blood pressure, heart rate, cortisol levels, and patterns of brain activity.268 In one trial that included 20 pharmacy students, taking 200 mg theanine twice daily for one week decreased morning salivary a-amylase levels more than placebo.269 Its short-term effect was confirmed in another randomized controlled trial in 36 healthy participants between 18 and 40 years old: a single 200 mg dose of theanine decreased subjective stress one hour after administration and the cortisol response to a cognitive stressor three hours after administration. In addition, in a subset of participants whose scores on a test of tendency to experience anxiety were high, theanine increased brain wave activity associated with relaxation.270 Theanine has also been shown to counter the stress-inducing effects of caffeine and enhance focused attention,271 and a two-month clinical trial noted that theanine, in combination with a vitamin/mineral/herbal supplement, lowered perceived stress scores and improved cognitive function in elderly subjects.272

Phosphatidylserine

The phospholipid phosphatidylserine is found in cell membranes and helps facilitate healthy cellular communication. It modulates the tissue response to inflammation and can reduce oxidative stress.273 Several studies have shown that phosphatidylserine can balance HPA axis signaling and may limit the negative consequences of over-activation of the adrenal glands.

In a trial in 75 healthy male volunteers, taking a supplement providing 400 mg each of phosphatidylserine and its precursor phosphatidic acid for 42 days diminished the HPA axis response to acute stress in a subset of men reporting high levels of chronic stress.274 In other clinical research, this same combination was noted to dampen the stress response to mental stress,275 and 300 mg per day of phosphatidylserine alone reduced perceived stress and improved mood in healthy young adults prone to negative emotions like anxiety, worry, and fear.276 Phosphatidylserine has also been found to lower cortisol levels overall and reduce the cortisol response to acute exercise in men, an effect that may help to prevent the harmful outcomes of overtraining, such as decreased performance, injury, immune suppression, and deterioration of psychological well-being.277

L-tryptophan

L-tryptophan is an amino acid precursor to the neurotransmitter serotonin. Serotonin has a complex relationship with the stress response.278 Stress-induced inflammation appears to cause excessive breakdown of tryptophan, which may decrease serotonin production and increase risk of depression279; in addition, tryptophan depletion has been shown to increase stress sensitivity.280 Studies in healthy adults suggest tryptophan supplementation, ranging from 800 to 2,800 mg per day, may reduce the cortisol response to stress, mitigate stress-related negative moods, and prevent stress eating in some individuals.281-283 In a randomized controlled trial, a tryptophan-rich hydrolyzed protein supplement increased positive mood and lowered cortisol release in response to acute stress.284

Bioactive Milk Peptides

Upon ingestion, milk proteins are broken down into peptides (shortened amino acid chains) by enzymes. Some of the resulting peptides can be absorbed intact and exert biological activities.285 For example, a-lactalbumin is a bioactive milk peptide that has a high tryptophan content and has been found to support healthy neurological function, improve mood, and promote sleep.286 An enzyme-treated form of the milk protein, casein, has also demonstrated anti-stress and relaxing properties in animal studies, and appears to work by increasing signaling via receptors for GABA—a neurotransmitter that generally inhibits nervous system activity.287-289

One randomized, controlled, crossover trial included 63 women with stress-related symptoms such as anxiety, sleep problems, and fatigue. Thirty days of treatment with 150 mg per day of a-S1 casein hydrolysate (a form of bioactive milk peptides) was more effective than placebo at relieving symptoms.290 In healthy volunteers, a 200 mg dose of a-S1 casein hydrolysate was found to mitigate increases in blood pressure, heart rate, and cortisol release induced by experimental stress.291

Probiotics and Prebiotics

The gut microbiome, nervous system, and HPA axis are closely connected. Probiotics and prebiotics (indigestible dietary carbohydrates that support the growth of beneficial bacterial colonies) can improve the balance of gut bacteria, and a growing body of evidence points to their potential to have a positive impact on the stress response.35,37,260 Research indicating probiotics may lower stress reactivity and anxiety, and improve mood, memory, and cognition have led some researchers to call probiotics with these effects psychobiotics.292

Fermented milk products made with Lactobacillus casei strain Shirota have been found in several trials to suppress cortisol elevations in response to stress and reduce stress-related health concerns such as depressed or anxious mood, digestive upset, and cold symptoms in healthy medical students.293-295 In a randomized controlled trial, 10 days of supplementation with 10 billion colony forming units (CFUs) of L. plantarum 299v per day decreased salivary cortisol levels in students facing an upcoming exam.296 In other controlled trials, taking a combination of L. helveticus R0052 and Bifidobacterium longum R0175, at a dose of 3 billion CFUs per day, for 30 days lowered scores on scales of perceived stress as well as urinary cortisol levels in healthy volunteers,297 and supplementing with 1 billion CFUs per day of B. longum 1714 for four weeks suppressed the cortisol rise and subjective anxiety associated with an acute stressor.298

Prebiotics are also demonstrating positive effects in clinical research: in a trial in 45 healthy adults, taking 5.5 grams of a prebiotic supplement containing galacto-oligosaccharides for three weeks resulted in lower early-morning cortisol levels and more balanced processing of positive and negative emotional stimuli.299

Melatonin

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 plays a central role in circadian regulation of body systems, including the HPA axis.300 Stress can reduce melatonin levels and destabilize the body’s biological rhythms.301 Chronic disruption of the brain’s internal clock, such as through shift-work or insomnia, harms mental and physical health.302,303

Melatonin supplementation can improve sleep quantity and quality and help restore normal circadian processes,304,305 which may lead to reduced stress and prevention of stress-related deterioration of health.306 In one study, 2 mg of melatonin taken in the evening for six months improved sleep and increased DHEA-S levels in a group of elderly female volunteers.307

Dehydroepiandrosterone (DHEA)

DHEA is an adrenal hormone that, like cortisol, is secreted in response to acute stress, but chronic stress has been associated with low levels.8 The effect of stress on DHEA may be one of the factors linking stress to poor health and accelerated aging.121 Low DHEA-S levels have been correlated with conditions such as osteoporosis, cognitive decline and dementia, cardiovascular disease, mood disorders, and sexual dysfunction.123 Findings from preclinical and clinical research suggest DHEA replacement therapy may have a role in protecting aging bone and vasculature and may help in the treatment of depression and sexual disorders.122,123

In a randomized, placebo-controlled, crossover trial that enrolled 13 men and 17 women between ages 40 and 70 years, treatment with 50 mg DHEA daily for six months led to significant improvements in physical and psychological well-being. Subjects in this study reported a better ability to handle stress, improved mood, and being generally relaxed.308 In a different study, 24 healthy young men took high-dose DHEA (150 mg twice daily) for seven days. Subjects reported improved mood, and DHEA treatment led to reduced levels of cortisol on evening measures.309

Supplemental doses of DHEA typically range from 10–25 mg daily for women and 25–75 mg daily for men, but should be based on DHEA-S blood levels. More information is available in Life Extension’s DHEA Restoration Therapy protocol.

Adaptogens

Adaptogenic herbs have multi-faceted beneficial effects that support the body’s intrinsic resilience to stressful conditions. They work by regulating biological networks in ways that support homeostasis. For example, adaptogens can raise energy levels, yet also support sound sleep. Some typical reasons adaptogens are used include to relieve fatigue, improve cognitive function and mood, and support the immune system.310-312

Magnolia and phellodendron. Magnolia (Magnolia officinalis) is an important plant in traditional Chinese herbal medicine. Its active constituents, magnolol and honokiol, have been found in preclinical and clinical trials to have a variety of beneficial effects, including stress reduction.313 In rodents exposed to chronic stress, both magnolol and honokiol, as well as their combination, have been found to normalize serotonin and HPA axis activity, increase levels of a brain growth factor (brain-derived neurotrophic factor, or BDNF), reduce neuroinflammation and brain oxidative stress, and prevent behaviors indicative of depression.314-317

A combination of magnolia and phellodendron ( Phellodendron amurense) has also been studied for anti-stress effects. In one controlled clinical trial, 56 healthy subjects with moderate stress levels received either a supplement providing 250 mg of magnolia plus phellodendron or placebo twice daily for four weeks. Participants underwent three (morning, noon, and night) salivary cortisol tests and answered mood questionnaires at the beginning and end of the trial. Those receiving the supplement had lower total cortisol exposure and better mood scores than those receiving placebo.318

The same combination supplement was studied for its effect on stress-induced appetite and weight gain. In one controlled trial, magnolia plus phellodendron, at a dose of 250 mg three times daily for six weeks, reduced weight gain compared with placebo in overweight but otherwise healthy premenopausal women who reported stress eating and above-average levels of anxiety.319 In another similarly designed trial, magnolia plus phellodendron reduced temporary anxiety, but did not affect longstanding depression or anxiety, appetite, sleep, or levels of salivary cortisol and amylase.320

Holy basil. Holy basil (Ocimum sanctum, also known as tulsi basil) is an adaptogenic herb from the Ayurvedic tradition. In Hindu spirituality, holy basil is considered a sacred plant and an incarnation of the goddess, Tulsi.321 A number of clinical and preclinical studies have demonstrated holy basil’s anti-stress potential by providing evidence that it improves mood and cognition, normalizes metabolism, regulates immune function, reduces oxidative stress, and prevents toxic damage in various tissues by supporting detoxification.321,322

In a randomized controlled trial with 40 participants, 300 mg of holy basil extract per day for 30 days resulted in reduced anxiety symptoms and improved cognitive test scores compared with placebo.323 Findings from another randomized controlled trial, in which 150 participants received 1,200 mg holy basil per day or placebo, indicated that holy basil lowered stress-related symptoms such as anxiety, fatigue, sleep difficulties, and sexual dysfunction.324 A pilot trial in which 35 patients with anxiety were treated with 500 mg holy basil twice daily found that treatment led to reductions in symptoms of anxiety, stress, and depression.325

Ashwagandha. Ashwagandha (Withania somnifera) is another important herb in the Ayurvedic herbal pharmacy, in which it is used as a general tonic and aphrodisiac.326 Numerous preclinical studies show ashwagandha prevents oxidative damage, supports normal mitochondrial activity, modulates central nervous system signaling, and contributes to immune regulation, suggesting it may be useful in the treatment of chronic stress-related, inflammatory, metabolic, cardiovascular, and neurodegenerative disorders.327-329

Several clinical trials further indicate that ashwagandha is effective for relieving stress and anxiety.330 For example, in a trial with 64 participants, 300 mg ashwagandha extract twice daily was more effective for reducing perceived stress scores and lowering blood cortisol levels than placebo after 60 days of treatment.331 Another trial noted the possible beneficial effects of ashwagandha on weight management in people with chronic stress. Fifty-two chronically stressed participants received either 300 mg ashwagandha twice daily or placebo for eight weeks; those receiving ashwagandha had greater reductions in perceived stress and serum cortisol levels, more improvements in food cravings and eating behaviors, and greater weight loss than those receiving placebo.332

Bacopa. Bacopa (Bacopa monnieri) has been used historically in Ayurvedic medicine to support healthy cognitive function.333 A number of animal studies have demonstrated its adaptogenic potential, noting its ability to normalize stress hormone levels and neurotransmitter balance,334 reduce oxidative stress,335 protect against neurodegeneration,336 and prevent or reverse other negative physiologic and behavioral consequences of stress.337-339 Furthermore, in rodent models of chronic stress, bacopa and an active constituent (bacopaside-I) have been found to reduce depressive behavior, normalize HPA axis function, reduce brain oxidative stress, and prevent a drop in BDNF and other changes in the brain environment,340-342 Bacopa has also been found to increase stress resilience and lifespan in another laboratory animal model.343

In a preliminary trial in 17 healthy adults, a standardized extract of bacopa, taken in single doses of 320 mg and 640 mg, improved cognitive performance one to two hours later on multitasking mental tests while also reducing cortisol levels, suggesting that part of its cognitive benefits may be related to stress-reducing effects.344 In a randomized controlled trial in 54 elderly subjects, taking 300 mg per day of bacopa for 12 weeks led to improved cognitive performance, lower depression and anxiety scores, and reduced heart rate compared with placebo.345

Lemon balm. Lemon balm (Melissa officinalis) is a plant in the mint family used in herbal medicine as a relaxing and uplifting nervous system tonic.346,347 Consumed in food or drink, lemon balm was found to generally improve mood and cognitive performance in healthy young adults.348 In healthy subjects exposed to experimental stress, individual doses of lemon balm had acute anti-stress and cognitive-enhancing effects, and increased self-reported calmness and alertness.349

In a pilot trial in 20 stressed volunteers with mild-to-moderate anxiety and insomnia, 15 days of treatment with 300 mg lemon balm extract twice daily led to symptom improvement in 19 (95%) of the participants. In addition, 14 participants had a complete remission of anxiety, 17 had remission of insomnia, and 14 had remission of both anxiety and insomnia.350 In a placebo-controlled clinical trial in 80 patients with stable angina, 3 grams per day of lemon balm for eight weeks reduced anxiety, depression, and stress, and improved sleep.351 In animal research, lemon balm decreased stress-induced symptoms of irritable bowel syndrome.352

Saffron. Saffron (Crocus sativus) is a yellow spice prized for its color and flavor. It also has a long history of use in herbal medicine for its sedative, adaptogenic, and other properties. Several clinical trials have shown that saffron is helpful in treating mild-to-moderate depression.353,354 Saffron and its active constituent crocin have also demonstrated anti-stress and anti-anxiety effects in animal studies, and preclinical evidence suggests it may exert its benefits in part by moderating HPA axis responsiveness.355-358 In addition, crocetin, another active compound from saffron, was found to prevent stress-induced depressive behavior in rats.359

In a randomized controlled trial, subjects without depression but reporting low mood who received treatment with 28 mg per day of saffron extract for four weeks had greater improvement in mood and reductions in symptoms of stress and anxiety than those receiving placebo.360

Ginseng. Ginseng is a common name for a group of similar plants, including Asian ginseng (Panax ginseng), American ginseng (Panax quinquefolius), and Chinese ginseng ( Panax notoginseng). These plants all contain active compounds called ginsenosides. Panax ginseng and its unique ginsenosides have been especially widely studied for their effects on disease prevention and overall well-being.361 This herb has been used for thousands of years to enhance vitality and longevity, and numerous studies show it has a broad range of actions such as immune-modulating, anti-inflammatory, anti-cancer, free radical scavenging, neuroprotective, and cardioprotective.362-365 With regard to stress physiology, a fermented ginseng extract was found to reduce oxidative stress and HPA axis signaling in response to exercise stress.366

Although unrelated to the Panax species of ginseng, Siberian ginseng (Eleutherococcus or Acanthopanax senticosus) is another popular adaptogenic herb. It contains active compounds called eleutherosides and has also demonstrated a range of anti-stress properties.367

Rhodiola. Rhodiola (Rhodiola rosea, also known as roseroot or golden root), is an adaptogenic herb that grows in Arctic regions and is used around the world to enhance physical and mental stamina and relieve stress.368 Rhodiola appears to modulate HPA axis function, reduce oxidative stress, and regulate immune activity.369,370

Pilot trials in patients with chronic fatigue symptoms, burnout, and mild anxiety have found that 400 mg rhodiola extract daily is associated with improvements in measures of energy level, mood, sleep, cognitive function, and general well-being.371-373 Rhodiola has also been found to help patients with stress-induced depression.374 This effect may be due in part to its promotion of new connections in the brain.375

Amla. Amla (Phyllanthus emblica), an adaptogen also known as Indian gooseberry, is used in Ayurvedic medicine to restore strength and good health.376 Some of its active constituents have demonstrated strong oxidative stress-reducing capacity.377 In a preliminary trial in 12 healthy volunteers, 500 mg of a standardized alma extract twice daily for 14 days mitigated acute stress-induced increase in arterial stiffness and decrease in cardiac blood flow.378 Research in animals suggests alma may reduce brain oxidative stress, prevent chronic stress-related damage to testicular tissue, improve stress resilience in general, and lengthen lifespan.379-381

Schisandra. Schisandra (Schisandra chinensis) has been used for centuries in the treatment of depression, anxiety, and insomnia, as well as a wide range of health problems related to fatigue and weakness.382,383 Schisandra and its active constituents have also demonstrated liver-protecting, anti-inflammatory, immunomodulating, anti-proliferative, and cognitive enhancing effects. Schisandra also holds promise as a cardiac and neurological protectant.382-384 Findings from animal research suggest Schisandra may help regulate HPA axis activity and relieve the negative effects of stress.385-387

Cordyceps. Cordyceps (Ophiocordyceps [formerly Cordyceps] sinensis) is a fungal/insect complex used in traditional Chinese medicine to treat fatigue and as a promoter of health, longevity, and physical performance.388,389 Many active compounds from cordyceps have been identified and studies have shown their actions to include anti-inflammation, immune-modulation, and oxidative stress reduction.390 Furthermore, preclinical research suggests it has potential as an anti-aging, anti-fatigue, neuroprotective, and aphrodisiac agent.389 In an animal model of chronic stress, cordyceps supplementation alleviated depression-like behavior induced by unpredictable and repeated mild stress. Furthermore, cordyceps treatment reduced some markers of inflammation and upregulated expression of BDNF.391 Preliminary clinical evidence suggests cordyceps may improve athletic performance and suppress the exercise-induced rise in cortisol release, which may help prevent the harmful effects of overtraining.392

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