Contributor(s): Dr. Benjamin S. Weeks, PhD; Debra Gordon, MS; Dr. Shayna Sandhaus, PhD

1 Overview

Summary and Quick Facts

  • Anxiety disorders affect about 40 million American adults, or about 18.1% of the U.S. adult population over 18 years of age. Nearly 15% of adults will experience an anxiety disorder in their lifetime.
  • Anxiety is a multifaceted disorder and must be addressed as such in order to achieve symptomatic relief. Psychoactive drugs fall short of addressing the underlying causes of anxiety – hormonal and metabolic imbalances that emerge as our bodies attempt to adapt to chronic stress.
  • Clinical studies indicate that nutrients such as omega-3 polyunsaturated fatty acids, magnesium and adaptogenic herbs like rhodiola can synergize with healthy eating habits and stress management techniques to effectively optimize the body’s stress response mechanisms and support healthy neurological communication. Moreover, compounds such as B vitamins and amino acids can provide the raw materials the body needs to ensure proper neurotransmitter synthesis and signaling.

What are Anxiety Disorders?

Anxiety is a normal response to stress that can serve a useful purpose: helping us avoid situations that threaten our sense of security. However, when anxiety occurs inappropriately in response to everyday events, it can become an anxiety disorder. People with anxiety disorders are constantly primed for disaster and may have difficulty coping with regular stressors.

There are different types of anxiety disorders including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and posttraumatic stress disorder (PTSD). The altered neurotransmission present in anxiety disorders may be caused by impaired methylation reactions (disrupting neurotransmitter synthesis and leading to increased homocysteine levels) and hormonal imbalances.

Natural interventions such as S-adenosylmethionine and several amino acids may help optimize the stress response and support healthy neurological communication to relieve symptoms of anxiety.

What are the Risk Factors for Anxiety Disorders?

  • Sex – women are twice as likely to develop an anxiety disorder than men
  • Age – greatest risk of onset is between ages 10 and 25
  • Experiencing a traumatic event can cause PTSD
  • Lack of social connections

Note: People with anxiety disorders are at an increased risk of several medical conditions, such as high blood pressure, cardiac ischemia, and arrhythmia.

What are the Signs and Symptoms of an Anxiety Disorder?

  • Difficulty concentrating
  • Irritability
  • Tense muscles
  • Sleep disturbances
  • Difficulty overcoming worries
  • Symptoms of different kinds of anxiety disorders can vary, and may include panic attacks, compulsive behavior, dread of social interactions, and re-experiencing traumatic events.

What are Conventional Medical Treatments for Anxiety Disorders?

  • Cognitive-behavioral therapy
  • Behavior therapy
  • Drug therapy:
    • Benzodiazepines such as diazepam (Valium), alprazolam (Xanax), and clonazepam (Klonopin)
    • Azapirones such as buspirone (BuSpar)
    • Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) and sertraline (Zoloft)
    • Beta-blockers such as propranolol (Inderal) and atenolol (Tenormin)
    • Pregabalin, an anticonvulsant drug that is also effective in treating anxiety

What are Alternative Treatments for Anxiety Disorders?

  • Bioidentical hormone replacement therapy

What Dietary and Lifestyle Changes May Be Beneficial for Anxiety Disorders?

  • Get enough sleep
  • Exercise regularly
  • Moderate caffeine intake
  • Yoga or Tai Chi
  • Eat a healthy balanced diet – the Mediterranean diet has been shown to reduce mood disorders

What Natural Interventions May Be Beneficial for Anxiety Disorders?

  • Amino acids. L-tryptophan, L-phenylalanine, L-tyrosine, L-lysine, and L-arginine levels have all been linked with symptoms of anxiety. Supplementation may reduce anxiety.
  • B-vitamins. B-vitamins are cofactors in the synthesis of neurotransmitters. Declining levels of B-vitamins can lead to increased homocysteine levels and anxiety—supplementation may help lower homocysteine levels and relieve anxiety.
  • S-adenosylmethionine (SAMe). SAMe is a methyl donor involved in the synthesis of hormones and neurotransmitters. Supplementation improved disposition in depressed patients with HIV/AIDS.
  • Magnesium. Magnesium deficiency has been linked with anxiety disorders. Supplementation may help reduce anxiety.
  • Omega-3 fatty acids. Omega-3 fatty acids have a wide variety of health benefits; they have been shown to improve mood and symptoms of anxiety.
  • Lemon balm. Lemon balm may suppress levels of stress hormones and promote neurogenesis. A combination of lemon balm and valerian was shown to improve symptoms of anxiety.
  • Adaptogenic herbs. Adaptogens such as Rhodiola rosea and ashwagandha have demonstrated anxiety-reducing effects in clinical trials.
  • Probiotics. Probiotics have been shown to improve behaviors and symptoms related to anxiety, stress, and depression.
  • Other natural interventions such as selenium, GABA, N-acetylcysteine, vitamin D, St. John's wort, and ginkgo biloba may help improve symptoms of anxiety.

2 Introduction

As nature intended it, anxiety serves a useful purpose. Characterized by the fear or worry that something bad will happen, normal anxiety occurs occasionally in response to situations that threaten our sense of security. This helps us avoid harm and remember not to put ourselves in the same potentially dangerous situation in the future. Anxiety is a normal stress response that has been conserved throughout human evolution and is evident in all other animals.

However, when anxiety occurs inappropriately in response to normal everyday events, it can become a debilitating condition known as anxiety disorder. Anxiety disorders cause a person to be constantly "primed," or "tense" in expectation of an impending threat to their physical or psychological well-being. Symptoms of anxiety disorders are often chronic, and can include difficulty concentrating, irritability, tense muscles, sleep disturbances, and trouble overcoming worries.

The conventional health care model typically attempts to alleviate anxiety with an array of psychoactive drugs that either mimic or manipulate neurotransmitter signaling. For instance, medications for anxiety might either increase the recycling of existing neurotransmitters or bind directly to neurotransmitter receptors and block or activate them, artificially altering mood. However, psychoactive drugs fall short of addressing the underlying causes of anxiety—hormonal and metabolic imbalances that emerge as our bodies attempt to adapt to chronic stress.

Recognizing and responding to underappreciated risk factors for anxiety disorders, such as elevated homocysteine and sex hormone imbalances, is an important aspect of any treatment regimen. Sadly, mainstream physicians often fail to address these subtleties, an oversight that undoubtedly contributes to the paltry 50% success rate of conventional anxiety treatments.

Anxiety is a multifaceted disorder and must be addressed as such in order to achieve symptomatic relief. Clinical studies indicate that nutrients such as omega-3 polyunsaturated fatty acids, magnesium, and adaptogenic herbs like rhodiola can synergize with healthy eating habits and stress management techniques to effectively optimize the body's stress response mechanisms and support healthy neurological communication. Moreover, compounds such as B-vitamins and amino acids can provide the raw materials the body needs to ensure proper neurotransmitter synthesis and signaling.

3 Prevalence

Anxiety disorders affect about 40 million American adults, or about 18.1% of the U.S. adult population over 18 years of age. Nearly 15% of adults will experience an anxiety disorder in their lifetime.1-3 By comparison, only 14.8 million American adults, or about 6.7% of the U.S. adult population, suffer from major depression. However, depression and anxiety are very much interrelated.

For up to 90% of all cases, anxiety disorders generally develop early in life—before the age of 35 with the greatest risk of onset between ages 10 and 25. Also, women are twice as likely as men to suffer from generalized anxiety disorder.1,4,5 This last statistic suggests an imbalance in female hormone levels during and after menopause, during menstruation, and after pregnancy may be tied to the etiology of anxiety. We will explore this connection in greater detail later in this protocol.

4 Types of Anxiety Disorders

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by worry and tension in the absence of a real provoking environmental factor. A person with GAD is constantly apprehensive, anticipating disaster, and becoming overly concerned about their health, finances and work without cause.

People with GAD are frequently unable to relax and battle insomnia and poor concentration. Other symptoms may include restlessness, fatigue, irritability, muscle tension, high blood pressure, and sleep disturbances. Many people with mild GAD often manage to maintain their careers and function socially. However, severe cases can lead to job failure and avoidance of social situations.

GAD affects almost 6.8 million American adults.6 Physicians diagnose GAD based upon the following criteria—an individual worrying excessively about everyday problems and exhibiting three or more GAD symptoms, on most days, for at least six consecutive months.7

Panic Disorder

Panic disorder is characterized by sudden attacks of fear and the sense of impending doom. A panic attack can cause elevated heart rate, sweating, dizziness, fatigue, shortness of breath, nausea, chest pain, and feelings of being cold and numb. In many cases these physical symptoms exacerbate the panic attack as the person may feel like they are dying or in terrible physical danger.

Panic attacks are often unpredictable and come on suddenly, but can be triggered by exposure to stimuli associated with past trauma, such as driving through an intersection where the person was involved in a major car accident. Panic attacks typically last about 10 minutes. Episodes often appear without warning and with varying frequency. Panic disorder is very disabling, causing people to avoid places or situations that caused attacks before. As a result, people with panic disorder often lose their jobs or change their residence.

Nearly one-third of people with panic disorder will become fearful of leaving their homes and develop agoraphobia, a fear of open spaces.

Panic disorder afflicts about 6 million Americans, and is also twice as common among women as men.1 The clinical definition of panic disorder is when a person experiences recurrent, unexpected panic attacks, at least one of which is followed by one or more of the following: persistent concern about future attacks, worrying about the implications of the attack, and/or a significant change in behavior related to the attacks.8

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is characterized by persistent, upsetting thoughts (obsessions) that can lead to anxiety and the use of ritualistic actions (compulsions) in an attempt to alleviate this anxiety.9,10

A good example is a person obsessed with the presence of bacteria in the environment. In this case, a person with OCD may develop a compulsion to ritualistically and repetitively wash their hands, or engage in some other type of self-cleansing. The person with OCD does not find performing the ritual pleasurable, but it instead provides temporary relief from the anxiety.

While healthy people can demonstrate repetitive behaviors, such as double checking to see if the doors are locked, people with OCD perform rituals so repetitively that their behavior distresses them and can interfere with the performance of everyday tasks.

Approximately 2.2 million American adults suffer with OCD. Eating disorders, other anxiety disorders, and depression commonly accompany OCD. Research shows OCD affects men and women equally.1


Phobias are inexplicable and unjustifiable fears. Phobias may be a fear of certain objects or things. Social phobia, also known as social anxiety disorder, involves excessive self-consciousness and anxiety about everyday social situations. People with social phobia are chronically fearful of embarrassing themselves and being judged by others. They can experience dread weeks before a scheduled encounter or interaction, which may interfere with everyday activities. Physical effects associated with social phobia can include blushing, sweating, nausea, and difficulty speaking.

About 15 million Americans are affected by social phobias.1 Other anxiety disorders and depression may accompany social phobia. The clinical definition of social phobia is when a persistent fear of social situations causes people to either avoid them or experience them with great anxiety.11,12

Posttraumatic Stress Disorder

Experiencing or witnessing a traumatic or terrifying life event such as a serious accident, violent crime, or natural disaster can precipitate a posttraumatic stress disorder (PTSD). People with PTSD may either relive the event in nightmares or have disturbing recollections of it during waking hours. Ordinary events can trigger flashbacks that may result in a loss of reality, causing the person to believe the event is happening again.

PTSD affects more than 5 million Americans and can occur at any age.1,13 Symptoms associated with PTSD can include an inability to sleep, hypersensitivity to external stimuli, feelings of detachment or numbness, and loss of memory surrounding the traumatic experience.

Physicians diagnosing PTSD consider whether the patient persistently re-experiences the traumatic event through memory, dreams, hallucinations, flashbacks, or physical reactions to internal or external triggers. For a diagnosis of PTSD, symptoms must be present for more than one month, but may occur years after the traumatic event.1,13

5 Risk Factors and Associations

A variety of factors can increase the risk of anxiety disorder. Being female is a risk as it affects twice as many women than men. Age is another factor, with the greatest risk of onset affecting those between the ages of 10 and 25. Research shows children who are shy or likely to be the target of bullies are at a higher risk of developing anxiety disorders later in life. Anxiety disorders also tend to run in families, believed to have both a genetic and learned component. Lack of social connections, traumatic events, and certain medical conditions are also associated with an increased risk of anxiety disorders.

Anxiety can occur independently of or in conjunction with other psychiatric or medical conditions such as depression, chronic fatigue, cardiac disease, or respiratory compromise. Chronic anxiety is associated with a higher risk of illness and death from cerebrovascular and cardiovascular diseases such as hypertension, cardiac ischemia and arrhythmias. Also, chronic anxiety predisposes people to a range of neurological disorders.14-16 People with anxiety disorders are less able to deal with life's occasional blows. Divorce, financial disaster, or other severe stressors may increase their risk of suicidal behavior.17

Homocysteine and the Methylation Cycle

Homocysteine is an intermediary within a metabolic cycle known as methylation. Methylation reactions, relying largely on B-vitamin cofactors (particularly, B6, B12, and folic acid), are critical for the proper synthesis of the neurotransmitters that play an important role in mood regulation.

As B-vitamin levels decline, the methylation cycle becomes impaired-leading to a concurrent increase in homocysteine levels (because it is no longer being recycled efficiently) and a disruption in neurotransmitter synthesis. The close relationship between neurotransmitter synthesis and homocysteine formation has led some researchers to suspect that there is a link between homocysteine and mood. Indeed, studies suggest levels of homocysteine are an effective marker for B-vitamin status, and that changes in homocysteine levels correlate with changes in mood.

Interestingly, homocysteine levels have predicted duration of PTSD,18 suggesting lowering homocysteine levels through supplementation with B-vitamins might reduce symptoms of mood disorders by freeing up metabolic resources involved in neurotransmission. Other studies have clearly tied genetic abnormalities such as a mutation in the folic acid-activating enzyme, MTHFR, to high homocysteine levels (and increased symptoms of mood disorders). This reinforces the notion that homocysteine metabolism is an important target in psychiatric imbalances.19 Supplementation with homocysteine-lowering B-vitamins was shown to relieve anxiety in 44 women with premenstrual anxiety.20

Another compound involved in the methylation cycle is S-adenosylmethionine (SAM-e). SAM-e functions to donate methyl groups into the methylation cycle thereby facilitating the formation of neurotransmitters such as dopamine and serotonin. In clinical trials, SAM-e supplementation has been shown to be as effective as tricyclic antidepressants in treating depressive disorders.21

Given the role of healthy methylation in maintaining biochemical balances within the central nervous system, a target blood level of less than 8 µmol/L of homocysteine helps to ensure proper neurotransmitter metabolism and may balance mood during times of stress, depression and anxiety.

Impaired Stress Response: Anxiety, Depression, and the Hypothalamic-Pituitary-Adrenal Axis

Rarely does an anxiety disorder manifest itself alone. More typically, other mood disorders accompany it, particularly depression. In fact, depression and anxiety can both be viewed as manifestations of impaired stress response, the underlying physiology of which are both very similar.

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

Under short-term circumstances, stress-induced changes prioritize functions involved in escaping danger such as redirection of blood flow to the muscles from most other body parts, dilation of pupils, and inhibition of digestion for energy conservation. During this time, fatty acids and glucose (blood sugar) are liberated from storage sites into the bloodstream where they are readily available for utilization by the muscles. This is known as the fight-or-flight response. This reactive and adaptive protection system originates in the brain. When a threat is perceived by the hypothalamus (a brain region), chemical signals are sent to the pituitary gland (another brain region). The pituitary gland then sends chemical signals to the adrenal glands (endocrine glands atop the kidneys), which in turn releases the stress hormone cortisol. Cortisol then goes on to initiate many of the physiological changes that allow the organism to respond to the impending danger.

The fight-or-flight response is shared among nearly all animals in that the need to escape from imminent danger is paramount for the survival of the species. However, modern humans live in an environment filled with emotional stressors, such as financial worries, deadline pressures at work or school, as well as unnecessary physical stressors such as excessive caloric intake, obesity, and inactivity. All of these modern stressors chronically activate the hypothalamic-pituitary-adrenal axis, leading to adverse health consequences such as increased rates of cardiovascular disease, diabetes, and mood disorders like depression and anxiety.

The relationship between chronic stress, depression, and anxiety is complex and incredibly powerful. The chronic elevations in glucocorticoids (primarily cortisol) caused by excessive stressors in industrialized societies lead to actual physical changes in brain structure.

For example, dendrites, the branches of neurons that receive signals from other neurons, are shifted into less functional patterns upon chronic exposure to glucocorticoids. This has been documented in key brain regions associated with mood, short-term memory, and behavioral flexibility.22 Furthermore, glucocorticoids cause receptors for the mood-regulating neurotransmitter serotonin to become less sensitive to activation.23,24 Other detrimental effects of chronic stress include both increased susceptibility to neuronal damage and impaired neurogenesis, the process by which new neurons are "born."22

Interestingly, emerging research suggests that psychoactive drugs, like those used in anxiety and depression, may stabilize mood not only by acting upon neurotransmitter levels, but by modulating the action of glucocorticoids receptors in the brain itself.25 These new findings strongly support the idea that in order to alleviate mood disorders, controlling stress response is an important aspect of treatment. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to efficiently adapt to stress, to increased rates of anxiety and depression.26,27

6 Diagnosis and Treatment of Anxiety Disorders

Because anxiety and depression may have similar or even overlapping symptoms, diagnosis and treatment of anxiety disorder can be difficult. A person can swing back and forth between anxiety and depression. However, as many of the same neural mechanisms are involved in both, sometimes treatment for one can be effective for the other.

While several screening tests are available to help determine the cause, type, and severity of anxiety, the diagnosis of anxiety disorders remains somewhat subjective and based on observation.28 Once a doctor diagnoses an anxiety disorder, treatment will often integrate several approaches, including but not limited to diet and lifestyle changes, relaxation and massage therapy, psychotherapy, behavioral or cognitive-behavioral therapy, and drug intervention.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy involves modifying thought patterns that influence anxiety and fear. It helps individuals recognize cognitive distortions, exaggerated and irrational thoughts that produce reactions such an anxiety and panic. Special tools then help the person detect distorted thinking and replace distorted thoughts with more accurate ones. Cognitive-behavioral therapy is a first-line treatment and is effective in treating all anxiety disorders.29,30

Behavior Therapy

Behavior therapy uses several techniques such as diaphragmatic breathing exercises and exposure therapy. Diaphragmatic breathing teaches people how to control the physical signs of anxiety by taking slow, deep breaths to help control hyperventilation. Exposure therapy relies on small, progressive exposures to the frightening trigger, helping people build confidence and control anxiety.

Drug Therapy

Drug therapy is often used in combination with psychotherapy to manage the biochemical and physiological abnormalities that produce anxiety, including alterations in the levels of serotonin, norepinephrine, and cortisol (the stress hormone).

Drug therapy can present a number of problems, including poor success rates, side effects, withdrawal symptoms, the development of increased tolerance to the drug, and only acting on a small component of the neurological mechanism involved in anxiety.

Pharmaceutical treatment of anxiety disorders involves manipulating or mimicking the action of neurotransmitters within the brain (typically GABA and serotonin; but sometimes dopamine and norepinephrine). However, these drugs usually do not resolve the over-activation of the hypothalamus-pituitary-adrenal axis that often underlies mood disorders.

Using medications to try to improve brain chemistry can offer relief, at least in the short term. However, medications neither restore normal levels of neurotransmitters, nor promote normal brain function. Instead, they manipulate the brain chemistry to achieve their desired effects.

Over time, the brain can get used to medications, resulting in them losing their effectiveness and requiring either higher doses or different drugs. Stopping them can frequently lead to withdrawal symptoms that feel worse than the original problem.

The following are types of drugs frequently prescribed to treat anxiety disorders:

Benzodiazepines. Benzodiazepines act in part by modulating and extending the life of gamma-aminobutyric acid (GABA), an inhibitory (calming) brain neurotransmitter.31 Benzodiazepines can relieve anxiety symptoms quickly. However, they can become habit forming. Some people develop a tolerance to them, requiring an increased dosage. When benzodiazepines are reduced or removed, some individuals can experience withdrawal symptoms, such as life-threatening seizures, confusion, memory loss, hyperanxiety, and reemergence of the original symptoms.32 Commonly prescribed benzodiazepines include Valium (diazepam), Xanax (alprazolam), Klonopin (clonazepam), and Ativan (lorazepam).

While these drugs are highly effective in calming anxiety, they may also be habit-forming—a factor that dramatically limits their usefulness and possibly their long-term safety. Many benzodiazepines can also cause significant impairment, a highly undesirable effect.

Azapirones. Azapirones do not have the tolerance and dependency issues associated with benzodiazepines. These anti-anxiety drugs are partial serotonin receptor agonists. BuSpar (buspirone) is an azapirone prescribed to treat general anxiety disorder. However, it may take several weeks before the effects of these drugs become apparent. Side effects can include nausea, headaches, and dizziness.

Antidepressants. Antidepressants are sometimes effective for treating anxiety, especially when it occurs in conjunction with depression. Types of antidepressant drugs include selective serotonin reuptake inhibitors (SSRIs) as well as the less common tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). These drugs can have significant side effects. In 2004 the U.S. Food and Drug Administration (FDA) announced that the most popular class of antidepressants, SSRIs, must carry a strong black-box warning advising patients of the dangers of increased suicide among adolescents using SSRIs. Popular SSRIs include Prozac (fluoxetine), Zoloft (sertraline), Luvox (fluvoxamine), Paxil (paroxetine), and Celexa (citalopram).

Beta-blockers. Beta-blockers, such as Inderal (propranolol) or Tenormin (atenolol), are used primarily to treat heart conditions. However, they are often prescribed for social phobia to help reduce heart palpitations as well as other physical symptoms of anxiety. Side effects can include sexual dysfunction, slow pulse, drowsiness, fatigue, dry mouth, numbness or tingling of fingers or toes, dizziness, diarrhea, nausea, weakness, and cold hands and feet.33

Pregabalin. Pregabalin is an anticonvulsant drug that is sometimes used to treat anxiety. Its effects become apparent quickly-some studies suggest within one week. Also, it appears to be effective in preventing a relapse of anxiety disorder34,35 as well as helping ease withdrawal symptoms after discontinuation of benzodiazepine therapy.36 This drug often causes dizziness and drowsiness.

7 Anxiety and Hormones

Anxiety disorders affect twice as many women as men. Further, women experience more anxiety when they are pregnant, postpartum, premenstrual and menopausal than at other times in life. This general observation has lead scientists to investigate a hormone-anxiety link.

By now, it is well known that most steroid hormones (eg, pregnenolone, estrogen, progesterone, testosterone, and DHEA) are neurologically active. In fact, large quantities of DHEA, estrogen, progesterone, and testosterone receptors are found in the brain. These hormones affect the brain in a number of ways, including regulation of mood.

A number of studies have linked abnormalities in hormone levels to various anxiety disorders.37-40 Studies suggest that levels of estrogen and serotonin may be linked, both affecting a positive mood during menstruation in young women.41 Likewise, the drop in estrogen during menopause, associated with reduced serotonin production, has a negative impact on mood and cognitive function.

Progesterone also plays a role in anxiety. In an animal study comparing a control group to mice lacking a progesterone receptor, researchers found progesterone decreased anxiety behavior through a mechanism similar to that of benzodiazepines—by acting on GABA receptors.42 Another study found that while a single dose of progesterone given to animals decreased anxiety indicators during stress tests, the abrupt cessation of progesterone therapy increased measures of anxiety.43

In a placebo-controlled trial involving post-menopausal women, hormone replacement therapy using both estrogen and progesterone caused a marked reduction in anxiety, as well as improved sleep quality and better cognitive performance.44

Bioidentical Hormone Replacement Therapy

Bioidentical hormone replacement therapy (BHRT) is an ideal method to restore youthful hormone levels for aging individuals. BHRT involves supplementation (usually) with either transdermal (topical) or oral preparations of hormones obtained from a compounding pharmacy. BHRT differs from conventional synthetic hormone replacement therapy (HRT) in that it relies on the use of natural hormones whose molecular structure exactly matches those of the hormones produced within the human body.

In a clinical trial conducted at the University of Texas, nearly 300 women with an average age of 52 years were treated with bioidentical progesterone and/or estrogen. After six months of BHRT, women aged 40–70 years old experienced dramatic improvements in mood, including a 31% reduction in emotional ability, 37% reduction in irritability, 33% reduction in anxiety, and significant relief from night sweats and hot flashes. Moreover, of the women screened for heart attack or breast cancer an average of 1.9 years after beginning BHRT (21% of the cohort), none of them had either.45

Those who would like to learn more about the benefits of BHRT are encouraged to read the Life Extension Magazine article entitled "Bioidentical Hormones: Why Are They Still Controversial?"

Just as the female brain depends on healthy levels of estrogen and progesterone to function normally, the male brain depends on sufficient testosterone. Low testosterone levels can cause testosterone deficiencies in the brain, thereby impairing brain function-leading to depression and anxiety.

In animal studies, mice with lower levels of testosterone displayed increased anxiety, supporting the idea that testosterone administration reduces anxiety.46,47 In humans, increases in testosterone levels seen during DHEA therapy have been linked to reduced anxiety.48 Laboratory studies indicate that activation of the androgen receptor by testosterone may reduce anxiety through interaction with GABA receptors.49

Normalizing hormone levels can be an integral part of managing anxiety disorders. Of course, it is also important to address the factors that cause hormonal imbalances in the first place. These include blood sugar dysregulation, oxidative stress, inflammation, and other disruptions in metabolic function leading to chronic stress, a condition that frequently results in both hormonal imbalances and anxiety disorders.

In addition to managing hormonal imbalances, it is important to examine the relationship between the stress hormone cortisol and DHEA (a building block for the sex steroid hormones). During times of prolonged stress, a greater proportion of cortisol is made compared to DHEA, with a high cortisol to DHEA ratio being a marker associated with anxiety disorder.50 DHEA counteracts some of the negative impact of cortisol in the body. In a large follow-up study of Vietnam-era U.S. army veterans, the ratio of cortisol to DHEA-sulphate was a strong predictor of all-cause mortality.51 Having higher levels of cortisol and lower levels of DHEA-sulphate were linked with an increased risk of death due to any cause over a 15-year period.

Clinical studies have found DHEA supplementation to be particularly helpful in relieving anxiety in both schizophrenics and females with low hormone levels.48,52 Life Extension suggests males maintain DHEA blood levels of 350–490 µg/dL, while females maintain levels of 275–400 µg/dL.

It is important to note that all the major sex hormones are interrelated. Thus, people with anxiety may benefit from comprehensive hormone testing, and if necessary, a program of bioidentical hormone replacement. Those interested in learning more about hormone replacement therapy should read Life Extension's "Female Hormone Restoration" protocol and/or "Male Hormone Restoration" protocol.

Anti-Anxiety Herbals for Menopause Support

While St. John's wort can be taken by both men and women, it appears to be very effective in easing symptoms associated with women's hormonal fluctuations. Researchers found in a double-blind, randomized, placebo-controlled trial that St. John's wort reduces the duration and severity of hot flashes in premenopausal women.53 In another study, St. John's wort improved the quality of life and alleviated sleep problems in symptomatic perimenopausal women aged 60–65.54

Researchers found in placebo-controlled studies that supplementing with 80 mg of red clover isoflavones per day for 90 days reduced anxiety in postmenopausal women.55 Interestingly, red clover phytoestrogens were shown to lower both total and LDL (bad) cholesterol, triglycerides, and boost HDL (good) cholesterol in 40 postmenopausal women. In this study, there were no reported side effects of the red clover isoflavones.56

Vitex agnus-castus (chaste tree/berry), when taken over a 16-week period in combination with St. John's wort, reduced anxiety associated with premenstrual syndrome and menopause.57 A metabolite of the isoflavone daidzein from soy has also been shown to reduce anxiety in premenopausal, perimenopausal and postmenopausal women.58 In healthy women of reproductive age, a preparation combining magnolia and Philodendron bark has been shown to reduce anxiety, in part by helping control cortisol levels.59

8 Lifestyle Changes

People with anxiety disorders can take a number of steps to reduce their symptoms. For example, programs involving telephone-based exercise interventions have been shown to reduce anxiety in pregnant and postpartum women.60

Smoking, alcohol and caffeine consumption, lack of exercise and an increased body mass index (BMI) can all have a negative impact on the degree to which aging individuals experience anxiety.61 Getting enough sleep and exercise, maintaining a healthy body weight, and moderating caffeine consumption on the other hand are recommended for reducing anxiety.62,63

Recent clinical trials demonstrate the benefit of yoga and tai chi. Most compelling was a study using brain scans showing a significant increase in thalamic GABA activity, which correlated to a better mood after the practice of yoga.64 Tai chi and yoga have been shown to reduce anxiety and heart rate after each 20-minute session.65 In one study, two-months of yoga classes reduced stress symptoms in women with anxiety disorder.66

Music and massage therapy appear to be particularly helpful in reducing anxiety associated with postoperative stress and treatment for cancer.67-69

Healthy cooking and a nutritious diet are central to controlling anxiety.70 In a study involving over 10,000 people, following a Mediterranean diet lead to reductions in mood disorders.71 When it is not always possible to have a well-balanced diet, nutritional supplementation can be an important lifestyle factor in the fight against anxiety.

9 Natural Therapies to Balance Brain Chemistry

In general, a healthy diet is abundant in omega-3 fatty acids, organic fresh fruits and vegetables, filtered water, and devoid of foods high in saturated fats and refined carbohydrates. This dietary pattern resembles the Mediterranean diet.

In addition, the following nutrients may support healthy stress response and help balance brain chemistry naturally.

Amino Acids

When the brain produces a neurotransmitter, it starts with a raw ingredient-usually an amino acid from the diet or another chemical already present in the brain. Enzymes are then used to convert the amino acid into the needed brain chemical. By understanding this process in detail, we can take measures to ensure an ample supply of the raw ingredients and enhance the activity of the enzymes. There are various cofactors that help the enzymes work faster; B-vitamins, for example.

L-tryptophan, L-tyrosine, and L-phenylalanine. Insufficient intakes of L-tryptophan, L-phenylalanine, or L-tyrosine are associated with increased symptoms of anxiety.72-75 Supplementation with L-tryptophan or 5-hydroxytryptophan (5-HTP) has been shown to elevate brain serotonin levels and enhance both mood and one's sense of well-being.72,73,76

Vitamin B6, magnesium, and vitamin C, nutrients already taken by most health-conscious people, are cofactors that facilitate the conversion of tryptophan to serotonin in the brain. As people age they produce more of an enzyme that degrades tryptophan, even if taking tryptophan supplements. Lysine, niacinamide, and anti-inflammatory nutrients such as rosemary have been shown to neutralize the effects of this enzyme and help preserve the synthesis of serotonin from tryptophan.

D,L-phenylalanine and L-tyrosine taken with a carbohydrate-rich meal can increase synthesis of dopamine and norepinephrine.77 There are no reported adverse effects, but high doses should be avoided by pregnant women and individuals taking MAOIs.

L-lysine and L-arginine. An L-lysine deficiency has been shown to increase stress-induced anxiety in humans.78,79 L-lysine binds to a serotonin receptor, acting as a serotonin antagonist by inhibiting serotonin reuptake in the synapse.80 When presented with a stressful situation, supplementation with L-lysine and L-arginine reduced anxiety in human subjects.70,81,82

Theanine. Theanine, an amino acid found in green tea, produces a calming effect on the brain.83-85 Theanine easily crosses the blood-brain barrier. It increases the production of GABA and dopamine and protects the cells of the hippocampus, the seat of learning and memory in the brain from damage.86,87

In an 8-week study involving 60 schizophrenic patients, 400 mg of theanine was added to standard antipsychotic therapy. The addition of theanine significantly reduced anxiety and improved several other measures of mood beyond what was achievable with pharmaceuticals alone.88

S-adenosylmethionine. S-adenosylmethionine (SAM-e) occurs naturally in the body. It is concentrated in the liver and brain and is a major methyl donor in the synthesis of hormones, nucleic acids, proteins, phospholipids, and catecholamine neurotransmitters such as dopamine and serotonin.89 SAMe facilitates glutathione usage and maintains acetylcholine levels, helping to preserve cognitive function while aging and possibly attenuating neurodegeneration.

In an 8-week clinical study involving depressed individuals with HIV/AIDS, supplementation with up to 1,600 mg of SAM-e considerably improved disposition on multiple standardized assessments. The effects of treatment with SAM-e became evident in as little as one week.90


Magnesium. Magnesium deficiency has been linked to anxiety disorders in several clinical studies. In fact, when researchers want to study anxiety disorder, they use mice that have been specifically bred to be magnesium deficient. This model is very effective at inducing anxiety.91

Several human trials have supported the link between magnesium deficiency and anxiety. When taken for one month in combination with a multivitamin, zinc and calcium, magnesium dramatically decreased symptoms of distress and anxiety compared to a placebo.92 Further, supplementation with magnesium and vitamin B6 effectively reduced premenstrual-related anxiety.20 In a placebo-controlled study, dietary supplementation with magnesium reduced GAD.93 In community-based studies, a small reduction in mood disorders was seen in those with higher magnesium intakes.94

Groundbreaking research has recently shed light on a new preparation, magnesium threonate, which may overcome a long-standing obstacle in magnesium supplementation—blood-brain barrier permeability.

High magnesium levels in the brain have been linked with superior cognitive function. However, conventional magnesium supplements are not efficient in raising these levels because they do not penetrate the blood-brain barrier. Researchers at the Massachusetts Institute of Technology have shown that magnesium threonate effectively elevates magnesium levels inside the central nervous system. The scientists also discovered that magnesium threonate improves cognitive function significantly better than other forms of magnesium in laboratory animals.95

Selenium.Selenium has been shown to reduce anxiety. In double-blind randomized clinical trials, subjects given 100 mg of selenium daily for five weeks reported improved mood and less anxiety.96,97 The same treatment regimen also reduced post-partum depression.98 Selenium supplementation reduces anxiety in elderly hospitalized patients, cancer patients undergoing chemotherapy, and HIV patients receiving Highly Active Antiretroviral Therapy (HAART).99-101

The role of selenium in supporting positive mood is quite complex. Selenium is a critical component in a variety of important enzymes whose action can significantly impact overall health. For example, the enzymes that help synthesize thyroid hormones. In a selenium deficient state, thyroid hormone synthesis may deteriorate, which can lead to poor mood and many other negative conditions.102

Fatty Acids

Omega-3 fatty acids. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are necessary for proper brain function. The typical Western diet has an overly high ratio of inflammatory omega-6 fatty acids to anti-inflammatory omega-3 fatty acids. Omega-3 fatty acids have been shown to have a variety of health benefits, most recently being improved mood and reduced anxiety.103-105

In one randomized, double-blind, placebo-controlled clinical trial, medical students were given either 2.5 grams/day of omega-3 polyunsaturated fatty acids (PUFAs) or placebo capsules containing the fatty acid profile of a typical American diet. Compared to controls, those students receiving the omega-3 capsules showed a 20% reduction in anxiety.106 In a double-blind placebo-controlled study, omega-3 fatty acid supplementation for three months reduced anxiety and anger in substance abusers.107 Reduced test anxiety and lower levels of the stress hormone cortisol have also been associated with omega-3 supplementation.108

Life Extension suggests that the omega-6 to omega-3 ratio should be kept below 4 to1 for optimal neuro-psychiatric and overall health. More information on testing and optimizing your omega-6 to omega-3 ratio can be found in the Life Extension Magazine article entitled "Optimize Your Omega-3 Status."

Herbs and Botanical Medicine

Botanical herbs have been shown to manage many psychiatric disorders, including anxiety.70,83,109-114 Being that the quality, composition, conditions for growth and extraction processes of herbal products can vary greatly, care should be taken in choosing an herbal remedy.

The following herbs either have anti-anxiety effects or target key molecular sites associated with neurotransmitters in the central nervous system.

St. John's wort (Hypericum perforatum). St. John's wort is an aromatic perennial native to Europe, parts of Asia, North and South America. The majority of controlled studies found it superior to placebo and similarly effective as standard antidepressant drugs.115-117 St. John's wort has been shown to increase brain levels of serotonin in animals, operating through slightly different and more complex pathways than those of prescription SSRIs.118,119 For instance, the combined antioxidant and anti-inflammatory properties of St. John's wort extract contribute to anti-depressant affects through normalization of an overactive HPA axis.

While St. John's wort is known for its anti-depressive affects, two recent studies also suggest that supplementation with this herb can reduce the anxiety associated with premenstrual syndrome (PMS).120,121 St. John's wort is contraindicated for use during pregnancy, lactation, exposure to strong sunlight, and should not be taken concurrently with anti-depressant medication.122

Ginkgo biloba. Animals given ginkgo biloba demonstrated reduced anxiety in cognitive tests.123,124 Several double-blind placebo-controlled studies showed that ginkgo biloba binds to and activates the GABA receptor, and like a benzodiazepine, reduces anxiety in patients with GADs without side effects.125,126

Valerian (Valeriana officiaonalis). This temperate herb has been used for medicinal purposes since the time of Hippocrates. Components of valerian root have been shown in laboratory studies to bind to GABA receptors, increase the release of GABA, and decrease its reuptake.127-130 Valerian root extracts were shown to have anti-anxiety effects in both rats and mice.131-133 Valerian root extracts have also been shown to activate glutamic acid decarboxylase, an enzyme involved in the synthesis of GABA.134

In recent clinical studies, psychiatric rating scales have shown that a daily dose of 400‒900 mg of extracts from valerian root is as effective as diazepam at reducing anxiety.135-138

Lemon balm (Melissa officinalis). Lemon balm is a member of the mint family, sometimes used as a culinary herb and flavoring agent. The plant also has several anxiolytic (anti-anxiety) actions.

In animal studies, extracts from lemon balm have been shown to suppress levels of stress hormones (glucocorticoids) while also promoting the growth of new neurons, a process called neurogenesis.139 Moreover, lemon balm contains compounds that strongly suppress the breakdown of GABA, which may prolong the anti-anxiety effects of the neurotransmitter.134

Lemon balm has been shown to reduce anxious behavior in laboratory animals. In a human clinical trial, it significantly suppressed anxiety when combined with valerian root, another anxiolytic herb.138,140

Rhodiola. Rhodiola rosea is a known adaptogen, an herb that helps improve one's resistance to stress. It has also shown promise in alleviating anxiety disorder. Ten subjects receiving a daily dose of Rhodiola rosea extract for 10 weeks demonstrated significant improvement in symptoms of anxiety. Another similar 10-week study found that a 340 mg daily dose of Rhodiola rosea extract significantly eased symptoms of GAD.141 Animal studies have found that compounds in Rhodiola rosea help ameliorate the anxiety associated with smoking cessation.142

Ashwagandha (Withania somnifera). Ashwagandha, or Indian ginseng, has long been used by Ayurvedic practitioners as a rejuvenating tonic. The herb has anti-inflammatory, antitumor, anti-stress, antioxidant, immunomodulatory, and rejuvenating properties.143 In several studies, rodents treated with extracts of ashwagandha showed reduced anxiety when compared to a control group; and to a similar extent when compared to several benzodiazepine drugs.144-146

Ashwagandha has also been shown to reduce anxiety in humans.147,148 In a clinical trial, patients with significant anxiety were divided into two groups, and for 12 weeks were provided either psychotherapy or treated with naturopathic treatment including ashwagandha. The ashwagandha treated group demonstrated a greater reduction in anxiety parameters.149

GABA. Our bodies are truly elegant in their design. This is especially apparent with brain function. A common element of this design is the brain's binary systems, wherein one chemical activates a process while its partner turns it off again. One example is glutamate and GABA, which together account for over 80 percent of brain activity. Glutamate accelerates brain activity (excitatory), while GABA puts the brakes on (inhibitory). Together, they keep the brain humming along at just the right pace—not too fast, not too slow.

If you have developed anxiety, then the balance of these two chemicals has been thrown off. As a result, the brain's activity level is turned up too high, at least in some areas. The balancing supplements for glutamate and GABA include but are not limited to the amino acids GABA and L-theanine; the antioxidant NAC; vitamins B6 and D; the minerals magnesium and zinc; and omega-3 fatty acids.

GABA, a neurotransmitter made from the amino acid glutamate, can be taken in the form of a dietary supplement. GABA is the chief inhibiting, or calming neurotransmitter in the brain, functioning as a brake on the neural circuitry during stress. Low GABA levels are associated with restlessness, anxiety, insomnia and a poor mood.150-152 Clinical studies have shown that the use of GABA as a dietary supplement relieves stress, anxiety, and increases the production of alpha brain waves (associated with relaxation).153-155

N-acetyl cysteine. N-acetyl cysteine (NAC) shows promise for alleviating mood disorders through a variety of mechanisms. It acts as a precursor to glutathione, a potent cellular antioxidant that may help ease neuronal oxidative stress. Furthermore, in contributing to glutathione synthesis, NAC uses up excess glutamate stores. This might lessen the excitatory transmission triggered by glutamate.156 Indeed, in at least one small clinical trial, a 6-month supplementation with NAC led to a complete remission in depressive symptoms in six of seven subjects, while placebo treatment led to remission in only two of seven subjects.157

Vitamin D. The impact of this hormone-like vitamin on mood disorders is complex. There are receptors for vitamin D throughout the brain, and animal data indicates that lower vitamin D signaling leads to increased anxious behavior.158 There is a considerable association between low vitamin D levels and depression, but the connection with anxiety is less clear.159 Nonetheless, maintaining a vitamin D level between 50–80 ng/mL is suggested for everyone to promote optimal health and protect against the ravages of aging.


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."160-165 Probiotics are organisms which, when consumed in adequate doses, exert a beneficial effect on health.166 Probiotics, which are able to modulate the gut-brain axis, have been shown in preclinical and clinical trials to ameliorate behaviors and symptoms of anxiety, stress, and depression.167-169

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.169-171 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 anxious behaviors to a similar degree as diazepam (Valium), the prescription anti-anxiety medication.169,172

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.169 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.171

Brain Chemical

Role in Neurotransmission and Stress Response

Nutritional Support

Glutamate, the excitatory chemical

Heightens overall brain activity

NAC, green tea, vitamin D3, magnesium, omega-3s

GABA, the inhibitory chemical

Slows overall brain activity

GABA, L-theanine, vitamin B6, zinc, inositol, herbal therapies

Norepinephrine, the arousal chemical

Raises level of alertness

Tyrosine, L-theanine, NAC, omega-3s, inositol

Dopamine, the reward chemical

Focuses attention and enhances pleasure and reward

Tyrosine, L-theanine, B vitamins, omega-3s, St. John's wort, ginkgo

Serotonin, the soothing chemical

Calms, regulates sleep and appetite, protects against stress

Tryptophan/5-HTP, DHEA, folic acid, vitamin B6, vitamin B12, vitamin D, omega-3s, St. John's wort

CRH/cortisol, the stress hormone

Prolonged elevation leads to fat storage, insulin resistance, degenerative brain disorders, memory loss, inflammation

DHEA, B vitamins, antioxidants, herbal adaptogens

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.


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