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
Copyright © 2014 Price-Pottenger Nutrition Foundation, Inc.®
All Rights Reserved Worldwide