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Worried About Anxiety? What a Body Needs for Prevention and Repair

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This evidence-based primer on anxiety disorders explains the roles of hormones and brain chemicals, drug therapies, and the nutrients & herbs known to help balance brain chemistry for a healthy stress response. It is reproduced with kind permission from the Life Extension Health Concerns and Protocols Library (www.LEF.org). ©1995-2012 Life Extension®. All Rights Reserved. See footnote* for link to all sources.


Worried About Anxiety? What a Body Needs for Prevention and RepairAbout Anxiety [And Natural Therapies to Balance Brain Chemistry]

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 [a cell-damaging amino acid] 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. [Adaptogenics help to increase resistance to stress.]

• Moreover, compounds such as B-vitamins and amino acids can provide the raw materials the body needs to ensure proper neurotransmitter synthesis and signaling.


Anxiety disorders affect about 40 million American adults, or about 18.1% of the U.S. adult population over 18 years of age (Kessler 2010; Bulloch 2011; Roberson-Nay 2011; see footnote* for link to all sources cited in this primer.)

• Nearly 15% of adults will experience an anxiety disorder in their lifetime (Kessler 2010; Bulloch 2011; Roberson-Nay 2011).

• 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 (Kessler 2010; Kessler 2005a; Kessler 2005b).

Also, women are twice as likely as men to suffer from generalized anxiety disorder (Kessler 2010; Kessler 2005a; Kessler 2005b). This last statistic suggests that 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.

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 (Weisberg 2009). 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 (Wyrwich 2011).

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 ten 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 (Kessler 2010). 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 (Roy-Byrne 2005).

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 (Bienvenu 2010; Merlot 2006).

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. Recent research shows OCD affects men and women equally (Kessler 2010).


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 can 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 (Kessler RC et al., 2010). 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 (Machado-de-Sousa 2010; Coelho 2010).

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 (Kessler 2010; Cantor 2009). 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 (Kessler 2010; Cantor 2009).

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 syndrome, 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 (Culpepper 2009; Goodwin 2009; Gureje 2008). 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 (Ringbäck Weitoft 2005).

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 that 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 (Levine 2008), suggesting that 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 (Coppen 2005). Supplementation with homocysteine-lowering B-vitamins was shown to relieve anxiety in 44 women with premenstrual anxiety (De Souza 2000).

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 (Papakostas 2009).

Given the role of healthy methylation in maintaining biochemical balances within the central nervous system, a target blood level of less than 7 – 8 µmol/L of homocysteine helps to ensure proper neurotransmitter metabolism and may balance mood during times of stress, depression and anxiety.  [Note: Deficits in the methylation cycle are a proposed mechanism in the development of ME/CFS/FM, and trials of a nutritional approach to raising glutathione and SAM levels have had promising results, including improved sense of well being.]

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 (Risbrough 2010). 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 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 (Hunot 2007; Tolin 2010) and is effective in treating all anxiety disorders (Hunot 2007; Tolin 2010).

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. [See for example “Disordered Breathing in ME/CFS & Fibromyalgia” by Australian fatigue consultant Blake Graham, and “The Healing Power of Deep Relaxation,” by William Collinge, PhD, a leading ME/CFS/FM self-help expert.] Exposure therapy relies on small, progressive exposures to the frightening trigger, helping people build confidence and control anxiety.

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 act in part by modulating and extending the life of gamma-aminobutyric acid (GABA), an inhibitory (calming) brain neurotransmitter (Durant 2010). 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 (Cloos 2009). 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 benzodiazepenes can also cause significant impairment, a highly undesirable effect.

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 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 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 (Bourin 2002).

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 disorder (Feltner 2011; Greist 2011) as well as helping ease withdrawal symptoms after discontinuation of benzodiazepine therapy (Hadley 2011). This drug often causes dizziness and drowsiness.

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 (e.g., 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 (Cunningham 2009; Parcells 2010; Bloch 2011; Sundermann 2010).

Studies suggest that levels of estrogen and serotonin may be linked, both affecting a positive mood during menstruation in young women (Kikuchi 2010). 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 (Frye 2006). 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 (Saavedra 2006).

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 (Hachul 2008).

Bioidentical Hormone Replacement Therapy (BHRT)

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 (Ruiz 2011).

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 (Khonicheva 2008; Aikey 2002). In humans, increases in testosterone levels seen during DHEA therapy have been linked to reduced anxiety (Strous 2005). Laboratory studies indicate that activation of the androgen receptor by testosterone may reduce anxiety through interaction with GABA receptors (Fernandez-Guasti 2005).

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 (Jezova 2008). 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 (Phillips 2010). 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 (Binder 2009; Strous 2005). Life Extension suggests that 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….

Natural Therapies to Balance Brain Chemistry

In general, a healthy diet is abundant in omega-3 fatty acids, organic fresh fruits and vegetables, and 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 [these explanations are followed by a chart summarizing the nutrients/herbs supporting each of the key brain chemicals, plus Life Extension’s review of generally recommended doses, tests & safety caveats]:

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. And 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 (Hood 2010; Toker 2010; Bleacher 2010; Rosier 2008). 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 (Hood 2010; Toker 2010; Feurte 2001).

Vitamin B6, Magnesium, and Vitamin C
These 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 (Lakhan and Vieira 2008). 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 (Ghosh 2010; Smriga 2004). L-lysine binds to a serotonin receptor, acting as a serotonin antagonist by inhibiting serotonin reuptake in the synapse (Smriga 2003). When presented with a stressful situation, supplementation with L-lysine and L-arginine reduced anxiety in human subjects (Jezova 2005; Lakhan 2008; Smriga 2007).

Theanine, an amino acid found in green tea, produces a calming effect on the brain (Weeks 2009; Heese 2009; Rogers 2008). 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 (Kakuda 2011; Cho 2008).

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 (Ritsner 2011).

S-Adenosylmethionine (SAM-e)
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 (Mischoulon 2002). SAM-e 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 (Shippy 2004).


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 (Sartori 2011).

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 (Carroll 2000). Further, supplementation with magnesium and vitamin B6 effectively reduced premenstrual-related anxiety (De Sousa 2000). In a placebo-controlled study, dietary supplementation with magnesium reduced generalized anxiety disorder (GAD) (Hanus 2004). In community-based studies, a small reduction in mood disorders was seen in those with higher magnesium intakes (Jacka 2009).

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 (Slutsky 2010).

Selenium has been shown to reduce anxiety. In double-blind randomized clinical trials, subjects given 100 mg of selenium daily for 5 weeks reported improved mood and less anxiety (Benton 1990; Benton, 1991). The same treatment regimen also reduced post-partum depression (Mokhber, 2011). Selenium supplementation reduces anxiety in elderly hospitalized patients, cancer patients undergoing chemotherapy, and HIV patients receiving Highly Active Antiretroviral Therapy (HAART) (Gosney 2008; Bargellini 2003; Shor-Posner 2003).

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 (Duntas 2010).

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 (Perica 2011; Ross 2009; Appelton 2008).

In one double-blind, placebo-controlled and randomized clinical trial, medical students were given either 2.5g/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 (Kiecolt-Glaser 2011). In a double-blind, placebo-controlled study, omega-3 fatty acid supplementation for 3 months reduced anxiety and anger in substance abusers (Buydens-Branchey 2008). Reduced test anxiety and lower levels of the stress hormone cortisol have also been associated with omega-3 supplementation (Yehuda 2005).

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 (Weeks 2009; Lakhan 2008; Head 2009; Sarris 2009; Chiappedi 2010; Panossian 2010; Sarris 2011; Saeed 2007). Being that the quality, composition, conditions for growth & 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 (Linde 2009; van der Watt 2008; Linde 2008). 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 (Tadros 2009; Ara 2009). 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) (Canning 2010; vanDie 2009). 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 (Mannel 2004).

Ginkgo biloba
Animals given Ginkgo biloba demonstrated reduced anxiety in cognitive tests (Walesiuk 2009; Kuribara 2003). 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 generalized anxiety disorders without side effects (Woelk 2007; Faustino 2010).

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 (Ortiz 1999; Yuan 2004; Khom 2007; Truaner 2008). Valerian root extracts were shown to have anti-anxiety effects in both rats and mice (Benke 2009; Hadjikhani 2009; Hattesohl 2008). Valerian root extracts have also been shown to activate glutamic acid decarboxylase, an enzyme involved in the synthesis of GABA (Awad 2007).

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 (Andreatini 2002; Muller 2006; Bhattacharyya 2007; Kennedy 2006).

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 (Yoo 2011). Moreover, lemon balm contains compounds that strongly suppress the breakdown of GABA, which may prolong the anti-anxiety effects of the neurotransmitter (Awad 2007).

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 (Kennedy 2006; Ibarra 2010).

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 (Shevtsov 2003). Another similar 10-week study found that a 340 mg daily dose of Rhodiola rosea extract significantly eased symptoms of generalized anxiety disorder (Bystritsky 2008). Animal studies have found that compounds in Rhodiola rosea help ameliorate the anxiety associated with smoking cessation (Mattioli 2011).

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 (Mishra 2000). 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 (Mohan 2011; Kulkarni 2008; Ramanathan 2011).

Ashwagandha has also been shown to reduce anxiety in humans (Andrade 2009; Bhattacharya 2000). In a clinical trial, patients with significant anxiety were divided into two groups, and for twelve weeks were provided either psychotherapy or treated with naturopathic treatment including ashwagandha. The ashwagandha treated group demonstrated a greater reduction in anxiety parameters (Cooley 2009).

Glutamate and 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% 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.

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. (Nemeroff 2003; Kendell 2005; Kugaya 2005). 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) (Bazil 2005; Abdou 2006; Thorne Research, Inc. 2007).

N-Acetyl Cysteine (NAC)
N-Acetyl Cysteine 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 (Berk 2009). Indeed, in at least one small clinical trial, a 6-month supplementation with NAC lead to a complete remission in depressive symptoms in 6 of 7 subjects, while placebo treatment lead to remission in only 2 of 7 (Magalhaes 2011).

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 (Kalueff 2004). There is a considerable association between low vitamin D levels and depression, but the connection with anxiety is less clear (Parker 2011). 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.

SUMMARY CHART: Six Key Brain Chemicals, Their Roles in
Neurotransmission & Stress Response, and Supporting Nutrients

Glutamate, the excitatory chemical
Heightens overall brain activity
Nutritional Support:
NAC, green tea, vitamin D3, magnesium, omega-3s

GABA, the inhibitory chemical
Slows overall brain activity
Nutritional Support:
GABA, L-theanine, vitamin B6, zinc, inositol, herbal therapies

Norepinephrine, the arousal chemical
Raises level of alertness
Nutritional Support:
Tyrosine, L-theanine, NAC, omega3s, inositol

Dopamine, the reward chemical
Focuses attention and enhances pleasure and reward
Nutritional Support:
Tyrosine, L-theanine, B vitamins, omega-3s, St. John’s wort, ginkgo

Serotonin, the soothing chemical
Calms, regulates sleep and appetite, protects against stress
Nutritional Support:
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
Nutritional Support:
DHEA, B vitamins, antioxidants, herbal adaptogens


Life Extension Recommendations (Doses, Tests, Safety Caveats)

Amino Acids (provides raw materials needed to support neurotransmitter synthesis) {Note: not all of these suggested amino acids will be of benefit in every case of anxiety. It is suggested to start at the low end of the dose range and increase or discontinue based upon results}

L-Tryptophan or 5-HTP: 1,000-2,000 mg tryptophan daily, or 50-150 mg 5-HTP daily
L-Tyrosine: 500 – 1,000 mg daily
L-Phenylalanine: 500 – 1,500 mg daily
L-Lysine: 600 – 1,800 mg daily
L-Theanine: 100 – 400 mg daily
L-Arginine: 800 – 2,400 mg daily
GABA: 700 – 2,100 mg daily
N-Acetyl Cysteine: 600 – 1,800 mg daily

Cofactors (supports the enzymes involved in hormone and neurotransmitter synthesis and metabolism)

B-Complex vitamins: Per label instructions
Vitamin C: 1,000 – 2,000 mg daily
Magnesium: 500 – 2,000 mg daily
Selenium: 200 – 400 mcg daily
S-Adenosylmenthionine (SAM-e): 400 – 1,200 mg daily

Fatty Acids (supports neuronal membrane health and proper neuronal-communication)

Fish oil: 2,000 – 4,000 mg daily

Anti-Anxiety Herbals

St. John’s wort: 300 – 600 mg daily
Ginkgo biloba; standardized extract: 120 – 240 mg daily
Valerian; standardized extract: 600 – 1,200 mg daily
Lemon Balm; standardized extract: 300 – 600 mg daily

Adaptogenic herbs (help to increase resistance to stress)

Ashwagandha; standardized extract: 125 – 250 mg daily
Rhodiola; standardized extract: 250 – 500 mg daily

General and Hormonal Support

Vitamin D: (women and men): 5,000 – 8,000 IU daily (depending on blood test results)
DHEA: (women and men): 15 – 75 mg daily (depending on blood test results)
Soy isoflavones: (typically for women only): 50 – 150 mg daily
Vitex; standardized extract: 20 mg daily

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

Male Panel with Hormone Add-On
Female Panel with Hormone Add-On
Omega Score
Cortisol AM/PM

Caveats (Regarding Safety/Possible Side Effects)

L-Tryptophan or 5-HTP

• Serotonin syndrome is characterized by high levels of serotonin and symptoms such as confusion, sweating, agitation, nausea, involuntary muscle contractions, and a racing heartbeat. Do not take L-tryptophan or 5-HTP if you experience these symptoms. Do not take L-tryptophan or 5-HTP in combination with other agents that increase serotonin levels in the central nervous system without consulting your physician. Agents that increase serotonin levels can include psychiatric medications (e.g. antidepressants, lithium), migraine medications (e.g. sumatriptan), Parkinson’s disease medications (e.g. carbidopa), and dextromethorphan, an over-the-counter cough suppressant. Do not use for the first time before driving or operating heavy machinery; tolerance should be assessed before regular use.


• Cancer patients should avoid taking L-phenylalanine and L-tyrosine. Certain cancers, such as melanoma, depend on these amino acids to fuel their growth.

• Supplemental use of L-phenylalanine and L-tyrosine may raise or normalize blood pressure. Insomnia may occur from over-stimulation if taken too close to bedtime. Individuals with the rare metabolic disorder phenylketonuria should avoid phenylalanine. Those suffering from migraine headaches should avoid L-phenylalanine and L-tyrosine. They form tyramine, a substance that may trigger migraines.


• May cause anxiety, high blood pressure, and headache. Do not use if you have phenylketonuria. Do not use phenylalanine or tyrosine if you have cancer or muscular dystrophy. Because phenylalanine can elevate blood pressure in hypertensives, consult your healthcare practitioner if you have hypertension. Insomnia may occur from overstimulation if taken too close to bedtime.


• If you have diabetes and/or significant kidney or liver disease, please consult with your healthcare practitioner before using this product.


• If taken in high doses, magnesium may have a laxative effect. If this occurs, divide dosing, reduce intake, or discontinue use of product.

S-Adenosylmethionine (SAM-e)

• SAM-e should not be taken by those diagnosed with bipolar disorder.

Fish Oil

• If you are taking anti-coagulant or anti-platelet medications, or have a bleeding disorder, consult your healthcare provider before taking this product.

St. John’s Wort

• Side effects can include insomnia, vivid dreams, restlessness, anxiety, agitation, irritability, gastrointestinal discomfort, fatigue, dry mouth, dizziness, and headache. Do not use if taking digoxin unless under a doctor’s care. When using St. John’s Wort, avoid prolonged sunlight exposure. Concomitant use with oral contraceptives may decrease steroid concentrations, resulting in breakthrough bleeding and irregular menstrual bleeding. Effectiveness of antiretroviral drugs may be reduced.

Ginkgo Biloba

• If you are taking anti-coagulant or anti-platelet medications, or have a bleeding disorder, consult your healthcare provider before taking this product.


• Individuals with manic or bipolar disorder should not use Rhodiola. Take early in the day if Rhodiola extract interferes with your sleep.

• Valerian use may cause sedation. Valerian should not be used for the first time before driving or operating heavy machinery. Talk to your doctor before starting valerian if you are taking any medications.


• Do not use DHEA if you are at risk for or have been diagnosed with any type of hormonal cancer, such as prostate or breast cancer.

Soy Isoflavones

• Persons with estrogen dependent cancers should consult a healthcare professional before beginning a soy regimen.


(Contributing author – Benjamin S Weeks, PhD)

* Sources: All stress management references cited in this article can be found HERE.

Note: This information has not been evaluated by the FDA. It is based on the research and opinion of LifeExtension.org staff unless otherwise specified and is meant for general informational purposes only. It is not intended to prevent, diagnose, treat or cure any condition, illness or disease and should not be used for diagnosis or treatment of any health problem or for prescription of any treatment. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

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