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Health Protocols

Stress Management

Natural and Integrative Interventions for Stress Relief

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 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 α-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


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 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, α-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 α-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 α-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


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.


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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