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Anxiety: Inflammatory Origins and Natural Treatments
The biological causes of anxiety syndromes have historically been poorly understood. However, current research is unveiling a link between anxiety and chronic inflammation – a link that is opening new doors to holistic and nutritional treatments. In this article, we will address what is known about the anxiety-inflammation connection and the specific anti-inflammatory interventions that have been shown to bring relief to patients with this debilitating condition.
Anxiety is a normal emotional response to perceived danger, and most of us experience moments of it on a regular basis. However, when anxiety becomes chronic and leads to a decline in a person’s function or quality of life, it is classified as an anxiety syndrome or disorder.
Individuals with anxiety syndromes experience a wide range of excessive and uncontrollable feelings of nervousness, panic, and fear. These feelings often develop into a number of diverse behaviors and problems, including obsessive-compulsive rituals, irrational fears and phobias, social isolation and avoidance, and, in the case of illness anxiety, repetitive medical appointments and excessive medical testing.
Anxiety syndromes are the most common psychiatric conditions reported in the U.S., affecting more than 40 million adults.[1] They are the third most common cause of mental health burden and disability, behind depression and substance abuse,[2] and are estimated to cost 42 billion dollars a year – almost one-third of the country’s annual mental health expenditure.[3]
As devastating as anxiety can be, few sufferer seek treatment. Those who do usually start with a visit to their medical doctor and, often within just a few minutes of conversation, receive one or more psychiatric medications that have concerning side effects and don’t address root causes. Thus, there is an urgent need to develop more effective treatments.
Conventional treatments
In mainstream psychiatry, the blanket use of pharmaceuticals has become first-line treatment. Anxiety syndromes are clustered together and targeted with drugs commonly known as antidepressants, antipsychotics, beta blockers, hypnotics, and barbiturates, all of which are routinely prescribed with minimal support and without compelling evidence for their efficacy and safety.[4]
Excessive prescription of benzodiazepines (e.g., Xanax and Klonopin) for anxiety has persisted even in the wake of disappointing evidence for their effectiveness[5] and significant concerns about the risk-benefit ratio obtained with their long-term use.[6] Risks include severe withdrawal symptoms, depression and persistent cognitive impairment that continue after drug cessation,[7] rebound anxiety, insomnia, seizures, tremors, headaches, blurred vision, tinnitus, extreme sensitivity to light and noise, feelings of insects crawling on the skin, nightmares, hallucinations, and derealization.
More recently, selective serotonin reuptake inhibitors (SSRIs) such as Paxil and Lexapro have gained popularity due to the perception that they have fewer side effects. However, the evidence does not support this claim. In head-to-head clinical trials, SSRIs were found to have even more adverse events than the benzodiazepines, as well as similar withdrawal symptoms and less effectiveness against anxiety.[8] Yet the most egregious problem with psychiatric medications is that pharmaceutical companies routinely suppress research that suggests their drugs do not work. In a now famous 2008 analysis in the New England Journal of Medicine, researchers discovered that pharmaceutical companies were selectively publishing studies and burying most research that resulted in negative outcomes.[9] They determined that, of the 74 trials on antidepressant drugs completed from 1987 to 2004, only 38 had positive outcomes. Their most startling discovery was that, while 37 of the 38 positive studies were published, just 14 of the 36 negative studies were published (22 remain unpublished to this day),and 11 of those negative studies were later released with a positive spin by the authors. Notably, only two positive studies are required by the FDA for approval of these drugs.
Such manipulation of information both undermines a prescriber’s ability to deliver science-based care and endangers patients’ health. Its cost is the loss of true informed consent, as it prevents physicians from adequately informing patients of the risks and benefits of drugs.
A note about psychological sources of anxiety
It maycome as no surprise that many people develop anxiety as a result of psychological trauma, abuse, or neglect, and this initially may have had little to do with a state of inflammation in the body. However, we now know that psychological stress and trauma on their own can kick-start a roller coaster of chronic inflammation.[10] This may explain why it is so common for patients with anxiety from a past psychological trauma to be at high risk for developing inflammatory conditions, such as cardiovascular disease, bowel disorders, migraine headaches, joint and muscle pain, autoimmune diseases, and even type 2 diabetes and asthma.
In the same vein, it has been shown that psychological interventions such as mindfulness meditation[11] and behavioral therapies[12] lower inflammatory markers and can have profound positive effects on the immune system.[13] This suggests that addressing inflammation with mental retraining as well as physical and nutritional interventions will likely be the most effective treatment for patients, regardless of the initial sources of their conditions.
Inflammatory processes and anxiety
Emerging anxiety research points to specific inflammatory processes that play a part in both causing and exacerbating anxiety symptoms. In this paper, we cover six of the inflammatory states specifically linked to anxiety. These are oxidative stress, unmanaged autoimmune disease, exposure to excitotoxins, nutrient deficiencies and imbalances, excess sugar consumption, and intestinal dysbiosis.
Oxidative stress
Oxidative stress is a process that occurs when there is an insufficient amount of antioxidants in the body to prevent damage from reactive oxygen species (free radicals). Brain tissue is particularly vulnerable to damage from oxidation because the brain uses around 20 percent of the oxygen we breathe. Without an adequate supply of antioxidants, the fragile fats and lipids that make up the brain can turn “rancid” (undergo lipid peroxidation) and the tissue can become inflamed.
Damage in the brain from oxidative stress is very common and has been linked to several psychiatric syndromes,[14] including schizophrenia, bipolar disorder, ADHD, autism, major depression, and substance abuse disorders. Most recently, anxiety-based syndromes,such as generalized anxiety, panic, and post-traumatic stress disorder (PTSD), have also been linked to oxidative damage. High levels of lipid peroxides are routinely found among those experiencing anxiety[15] and many other psychiatric illnesses.[16]
Although it is not clear in most cases whether anxiety or oxidative stress comes first, the process is likely bidirectional. Anxiety is strongly linked to states of oxidative stress and antioxidant deficiency, and increasing levels of antioxidants reduced symptoms of anxiety in several animal and human trials.[17]To date, the antioxidants shown to be most effective against oxidation-induced anxiety and inflammation are vitamin C, vitamin E (mixed tocopherols), beta-carotene (often wrongly called vitamin A), glutathione, and N-acetyl cysteine (NAC), with NAC showing the most consistent benefits.[18,19,20,21] However, one must be cautious in the use of high levels of antioxidant supplementation, as excessive antioxidant activity may interfere with important biological functions of reactive oxygen species.[16]
Autoimmunity
There is a strong link between autoimmune-induced inflammation and psychiatric symptoms of all kinds. Up to 75 percent of people with systemic lupus erythematosus develop anxiety, depression, or psychosis in the first two years after disease onset.[22] People with celiac disease, an autoimmune condition related to gluten exposure, have a seven times higher risk for anxiety and panic attacks than those without celiac disease.[23] Those with an autoimmune thyroid condition known as Hashimoto’s disease are at increased risk of developing anxiety syndromes, even in the absence of abnormal thyroid function as measured on a standard thyroid panel.[24]
The theory that currently explains how autoimmune conditions develop is based on the notion of “molecular mimicry,” whereby the immune system attacks the body’s tissues when an invading protein appears too similar to endogenous proteins. This invader is typically an undigested food protein, such as gluten, that enters the bloodstream due to increased intestinal permeability, or a leaky gut.”
Treatment of anxiety exacerbated by autoimmune conditions must be individualized. However,it typically involves modulating the immune system to lessen the attack on the tissues as well as managing the inflammation caused by this attack. The compounds most often used include curcumin (from turmeric), vitamins A and D, alpha-lipoic acid (ALA), NAC, selenium (particularly in Hashimoto’s disease and where there is a known deficiency), the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the omega-6 fatty acid gamma linolenic acid(GLA). There are also various traditionally used mushrooms and herbswell known for their immune-modulating properties, which are beyond the scope of this article.
Among the most intriguing substances under consideration to address autoimmune diseases and inflammation are plant sterols, naturally occurring steroid compounds that resemble cholesterol. While the primary research being conducted today on sterols focuses on their ability to lower cholesterol levels in the body, the more important effect is likely their ability to modulate the immune system. A commonly used plant sterol formulation in supplement form, distributed by several brands, is called Moducare. However, immune-modulating supplements are best employed under the care of a knowledgeable healthcare practitioner.
Excitotoxins
Excitotoxins are a group of chemicals, including glutamates, aspartates, and quinolates, that strongly “excite,” or stimulate, cells in the brain. Prolonged excitation is toxic to brain cells and can cause them to die. Excitotoxicity from glutamate exposure from foods has been implicated in various neurodegenerative diseases, such as dementia, amyotrophic lateral sclerosis(ALS, or Lou Gehrig’s disease), and Parkinson’s disease, as well as in migraine headaches.
An increasing amount of research suggests that the glutamatergic system in the brain, which interacts with excitotoxins such as glutamate, may be a potent therapeutic target for anxiety disorders.[25] In animal models, when glutamate receptors are “knocked out,” or blocked, the animals appear to be strongly immune to developing anxiety syndromes and have dampened levels of fear and aversion.[26]
Excitotoxins cause anxiety in two ways. One is through overactivating certain receptors in the brain associated with anxiety. The second is through oxidative stress, and inflammation from the degeneration and death of brain cells.
Low levels of glutamates and aspartates are found naturally in whole foods, such as seaweeds, mushrooms,and cheeses. However, synthetic versions of these excitotoxins are added in highly concentrated amounts to modern processed foods. These include “flavorings” such as monosodium glutamate and artificial sweeteners such as aspartame. Decreasing the amount of excitotoxins in the diet is critical to preserving brain health and reducing symptoms of anxiety.
Our lifestyles can also lead to high levels of endogenous excitotoxins in the brain. For example, when we are under stress, our bodies cannot efficiently convert the amino acid tryptophan to the neurotransmitter serotonin, and some of the tryptophan is degraded into an excitotoxin called quinolinic acid. While this is a chemical normally found in the body, high levels lead to neurodegeneration and inflammation.
There are several nutrients that offer protection from inflammatory excitotoxicity, including magnesium, taurine, amma-amino butyric acid (GABA), vitamin B6 (pyridoxal-5-phosphate being the most biologically active form), zinc, EPA, and DHA, as well as herbs such as ginkgo biloba and red clover. However, the best way to avoid anxiety and brain damage from excitotoxins is to refrain from consuming foods to which they are added. Unfortunately, there are few laws that require the labeling of excitotoxic food additives used in many processed and fast foods, and so it is difficult to avoid them without eschewing processed and packaged foods almost entirely.
Nutrient imbalances
The industrial revolution of the past 125 years has radically altered our intake of several macro – and micronutrients, and increasing numbers of researchers and clinicians – including Weston A. Price, DDS – have pointed the finger at these dietary changes to explain the exponential rise of degenerative diseases. While there are numerous ways diet can enhance our health, two general dietary interventions rise above most others in addressing symptoms of inflammation-induced anxiety: reducing intake of sugars and refined carbohydrates, and optimizing intake ratios of traditionally consumed fats. Addressing any nutrient deficiencies, particularly that of zinc, is also extremely important.
Omega-3 fats: Research has revealed that lower intakes of animal-based omega-3 fatty acids and higher intakes of omega-6 fatty acids, primarily from seed and vegetable oils, are linked with inflammation and anxiety. A diet rich in EPA and DHA- medium- and long-chain forms of omega-3 fats – often results in decreased anxiety, normalized levels of the neurotransmitter dopamine, and reduced inflammatory cytokines, immunoregulatory proteins that increase systemic inflammation.[27]
In fact, EPA and DHA may be the most significant fatty acids in anxiety treatment. In one of the first studies on the subject,those with social anxiety disorder had, on average, 36 percent lower levels of EPA and 22 percent lower concentrations of DHA in their cell membranes than did healthy controls.[28]
A 12-week trial found that 2.5 grams per day of an EPA-DHA blend reduced symptoms of anxiety among otherwise healthy medical students by 20 percent.[29] This reduction in anxiety was correlated with a 14 percent decrease in inflammatory markers, including lipopolysaccharides, which will be discussed later. The researchers noted that more important than supplementation with omega-3s was the ratio of omega-3s to omega-6s in the bloodstream. They concluded that participants whose ratios were closer to 1:1 experienced less anxiety, leading one researcher to suggest that patients with anxiety may benefit from increasing intake of omega-3s, lowering intake of omega-6s, or both.
These results open up new therapeutic options in the treatment of some anxiety syndromes. However, results are preliminary and not entirely consistent among all trials. Some small trials have shown no effect or worsening symptoms among some people with depression, PTSD, and obsessive-compulsive disorder (OCD).[30] Nonetheless, there are several variables that may explain the poor results including use of synthetically produced omega-3 fats, co-administration of pharmaceutical drugs during the trials, and lack of baseline blood levels to show whether any of the subjects suffered from an omega-3 fatty acid deficiency.
Zinc: Zinc deficiency is commonly found in many psychiatric syndromes. In a recent study, zinc was found to be deficient in 41 percent of those with a diagnosed psychiatric syndrome versus just 14 percent of healthy controls.[31] Several studies have suggested that when zinc levels are increased to more optimal levels in patients experiencing anxiety, their symptoms can normalize, often within days.[32,33]
Zinc may be the most important trace mineral in addressing inflammation-induced anxiety, as it modulates inflammation from several sources simultaneously. It lowers inflammation from oxidative stress through its antioxidant effects, from autoimmune conditions through its immune-modulating effects, and from the effects of excitotoxicity through its protection of N-methyl-D-aspartate (NMDA) receptors, brain receptors that are activated by glutamate. Zinc also aids in the production of GABA, a neurotransmitter that helps calm the nervous system.[31]
Anxiety researchers have one word of caution on zinc – that its levels must be balanced with copper levels. It has been observed that both low zinc with elevated copper and elevated zinc without adequate copper are correlated with anxiety.[34]
Sugar consumption
The link between excess sugar consumption and chronic inflammation is gaining increasing attention, but the role of blood glucose imbalances in psychiatric disorders is perhaps less well known. Substantial evidence suggests that people with diabetes have a is proportionately high rate of psychiatric syndromes compared to the general population, with depression and anxiety being the most common diagnoses.[35] A systematic review of studies has revealed that 40 percent of individuals with diabetes have elevated levels of anxiety, with 14 percent meeting diagnostic criteria for generalized anxiety disorder compared to just 4 percent in the general population.[36] This risk for diabetes-related anxiety syndromes increases with age and severity of the condition.[37]
The correlation between anxiety and blood glucose imbalances is not directly established in the literature. However, it is well known that, particularly in the case of type 2 diabetes, inflammation stemming from prolonged high blood glucose plays a primary role in disease progression.[38] In this case,the increased risk of anxiety may be due to the increased inflammation rather than simply elevated blood glucose.
A recent animal study suggests a more immediate link between sugar consumption and anxiety symptoms.[39] In this study, normal rats fed a typical Western diet high in sugar and refined carbohydrates developed anxiety-like behaviors in just 18 weeks.
Intestinal dysbiosis
The role of our gut microbiome, the bacteria that live in our digestive tracts, can hardly be overstated when it comes to our mental health. Intriguing research suggests just how sensitive the gut-brain axis can be. Researchers have discovered that even tiny, subclinical bacterial infections in the gut – too minor to activate the immune system – signal changes in the brain within six hours of infection that lead to increased anxiety-like behaviors in mice.[40] Thomas Insel, director of the National Institute of Mental Health, declared that studies on the human microbiome “will be one of the great frontiers of clinical neuroscience in the next decade.”[41]
Dysbiosis (bacterial imbalance) in the gut often results in an overgrowth of gram-negative bacteria, such as Escherichia coli and Salmonella, whose outer membranes contain lipopolysaccharides (LPS), which are potent toxins. LPS easily pass through a permeable intestinal wall and enter the bloodstream, where they have profound stimulatory effects on the immune system, induce brain inflammation, and promote oxidative stress in the nervous system.[42] The link between high blood levels of LPS and anxiety has been confirmed in rodent studies, and they are likely one cause of inflammation-induced anxiety in humans.[43]
Treatment of dysbiosis with probiotic bacteria from supplements and traditionally fermented foods can alleviate anxiety through several mechanisms, including lowering LPS levels and decreasing intestinal permeability. In one recent study, subjects receiving Bifidobacterium longum Lactobaccillus helveticus for 30 days experienced improvement on the Hospital Anxietyand Depression Scale, with a decrease in stress hormones.[44] In another, treatment with L. farciminis reduced levels of LPS as well as stress hormones in experimental rats.[45] In other trials, people with irritable bowel syndrome (IBS), depression, and anxiety improved with administration of Bifidus species bacteria, and subjects with chronic fatigue experienced improvement in anxiety with L. casei.[46]
When we consider the critical role of commensal (colonizing) gut bacteria to our health, using supplements containing soil-based organisms and fulvic acid prebiotics (substances that serve as food for probiotic bacteria) begins to make increasing sense. One such product is Prescript-Assist, which has been studied primarily for irritable bowel disease and contains 29 strains of bacteria.[47] There are several well-studied strains for specific indications, and some of these – found in products such as VSL#3, a high-potency probiotic medical food – have been demonstrated to have anti-inflammatory effects.[48] LPS-induced inflammation also appears to respond well to antioxidants, particularly vitamin E.[49]
Conclusion
Research has recently established that inflammation plays a significant causal and perpetuating role in many anxiety syndromes. Several studies, as well as our clinical observations, have shown that when patients with such syndromes reduce their known causes of inflammation, their conditions often improve. However, more definitive research is necessary to specifically and efficiently identify which patients are likely to benefit most from anti-inflammatory interventions and which interventions are most likely to be effective.
In the meantime, following sound nutritional principles, reducing oxidative stress, balancing the immune system, avoiding excitotoxins, and addressing digestive conditions such as intestinal dysbiosis – as well as working with a knowledgeable psychological professional who can assist with mental retraining – are all reasonable steps to take in healing anxiety.
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About the Authors
Zachary R. Taylor, MA, LPC, is a professional counselor specializing in integrative psychological and nutritional therapies who practices in Charlottesville, VA. He is currently pursuing training in herbal medicine at David Winston’s Center for Herbal Studies. He can be contacted at www.DeerPathHealing.com or followed at @ztaylorwell.
Kelly Brogan, MD, is boarded in psychiatry, psychosomatic medicine, reproductive psychiatry, and integrative holistic medicine, and practices functional medicine. She is the medical director for Fearless Parent, and an advisory board member for GreenMedInfo.com, Fit Pregnancy, Pathways to Family Wellness, NYS Perinatal Association, and Fisher Wallace. She practices in New York City and lectures nationally. Website: www.kellybroganmd.com.
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Published in the Price-Pottenger Journal of Health & Healing
Fall 2014 | Volume 38, Number 3
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