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) 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 entitle “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 depend 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 (Fernández-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.
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 (Abdali 2010). In another study, St. John’s Wort improved the quality of life and alleviated sleep problems in symptomatic perimenopausal women aged 60 – 65 (Al-Akoum 2009).
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 (Lipovac 2010). 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 (Terzic 2009).
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 (van Die 2009). A metabolite of the isoflavone daidzein from soy has also been shown to reduce anxiety in premenopausal, perimenopausal and postmenopausal women (Ishiwata 2009). In healthy women of reproductive age, a preparation combining magnolia and Philondendron bark has been shown to reduce anxiety, in part by helping control cortisol levels (Kalman 2008).
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 (Lewis 2011).
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 (Xu 2010). Getting enough sleep and exercise, maintaining a healthy body weight, and moderating caffeine consumption on the other hand are recommended for reducing anxiety (Rogers 2010; Carek 2011).
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 (Streeter 2010). Tai Chi and yoga have been shown to reduce anxiety and heart rate after each 20-minute session (Field 2010). In one study, two-months of yoga classes reduced stress symptoms in women with anxiety disorder (Javnbakht 2009).
Music and massage therapy appear to be particularly helpful in reducing anxiety associated with postoperative stress and treatment for cancer (McRee 2003; Deng 2004; Pellino 2005).
Healthy cooking and a nutritious diet are central to controlling anxiety (Lakhan 2008). In a study involving over 10,000 people, following a Mediterranean diet lead to reductions in mood disorders (Sanchez-Villegas 2009). 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.
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:
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 (Hood 2010; Toker 2010; Beacher 2010; Roiser 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, 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. 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). 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 (Shippy 2004).
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 (Sartori 2012).
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 Souza 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. 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).
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; Appleton 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; Trauner 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. 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 (Bystritsky 2008). 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).
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. (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) 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 (Magalhães 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.
Emerging research has revealed an important relationship between the gastrointestinal tract and its billions of resident organisms—often referred to as the microbiome—and the brain. This has been termed the “gut-microbiota-brain axis” (Petra 2015; Foster 2015; Forsythe 2010; Forsythe 2013; Dinan 2012; Cryan 2012). Probiotics are organisms which, when consumed in adequate doses, exert a beneficial effect on health (Sanders 2008). Probiotics, which are able to modulate the gut-brain axis, have been shown in preclinical and clinical trials to ameliorate behaviors and symptoms of anxiety, stress, and depression (Bravo 2011; Gareau 2007; Messaoudi, Lalonde 2011).
Lactobacillus helveticus (L. helveticus) R0052 has been researched, in combination with another proprietary probiotic strain, Bifidobacterium longum (B. longum) R0175, as a probiotic for psychological health (Arseneault-Breard 2012; Messaoudi, Violle 2011; Messaoudi, Lalonde 2011). Rats given a daily dose of a combination of L. helveticus R0052 and B. longum R0175 for two weeks had markedly reduced signs of anxiety compared to those treated with a placebo. In fact, the probiotics reduced anxious behaviors to a similar degree as diazepam (Valium), the prescription anti-anxiety medication (Messaoudi, Lalonde 2011; Calcaterra 2014).
In a double-blind randomized clinical trial, 55 healthy volunteers took a supplement containing three billion colony-forming units (CFUs) of the combination of L. helveticus R0052 and B. longum R0175, or placebo, for 30 days. The probiotic treated group had significantly lower scores on anxiety, anger, and depression symptom scales (Messaoudi, Lalonde 2011). Among a subset of 25 participants considered to have low levels of chronic stress based on low urinary cortisol levels, the combination of L. helveticus R0052 and B. longum R0175 appeared to act as a preventive, suggesting it may be able to protect against stress-related diseases (Messaoudi, Violle 2011).
Role in Neurotransmission and Stress Response
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