Anxiety and Omega-3 Fatty Acids

Anxiety is one of most the common neurological disorders, but it also is one of the most difficult to understand. Simply stated, anxiety is an apprehension of the future, especially about an upcoming challenging task. This is normal. What is not normal is when the reaction is significantly out of proportion to what might be expected. Over the years, a number of specific terms, such as generalized anxiety disorder, panic disorder, phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and separation anxiety disorder have emerged in an attempt to better categorize general anxiety. Any way you describe anxiety, it is a big problem with nearly 20% of Americans suffering from it, thus making anxiety the largest neurological disorder in the United States (1).

If anxiety is worrying about the future, then it has a fellow traveler, depression. Depression can be viewed as an over-reaction about regret associated with past events. Not surprisingly, almost an equal number of Americans suffer from this condition. This leads to the question: Is there a linkage between the two conditions? I believe the answer is yes and it may be caused by radical changes in the American diet in the past 40 years. These changes have resulted in what I term the Perfect Nutritional Storm (2). The result is an increase in the levels of inflammation throughout the body and particularly in the brain.

The brain is incredibly sensitive to inflammation, not the type you can feel but the type of inflammation that is below the perception of pain. I term this cellular inflammation. What makes this type of inflammation so disruptive is that it causes a breakdown in signaling between cells. What causes cellular inflammation is an increase in the omega-6 fatty acid known as arachidonic acid (AA). From this fatty acid comes a wide range of inflammatory hormones known as eicosanoids that are the usual suspects when it comes to inflammation. This is why anti-inflammatory drugs (aspirin, non-steroid anti-inflammatories, COX-2 inhibitions and corticosteroids) all have a single mode of action—to inhibit the formation of these inflammatory eicosanoids. These drugs, however, can’t cross the blood-brain barrier that isolates the brain from a lot of noxious materials in the blood stream. So when the brain becomes inflamed, its only protection is adequate levels of anti-inflammatory omega-3 fatty acids. But what happens when the levels of omega-3 fatty acids are low in the brain? The answer is increased neuro-inflammation and continual disruption of signaling between nerves.

There are two omega-3 fatty acids in the brain. The first is called docosahexaenoic acid or DHA. This is primarily a structural component for the brain. The other is called eicosapentaenoic acid or EPA. This is the primary anti-inflammatory omega-3 fatty acid for the brain. So if the levels of EPA are low in the blood, they are going to be low in the brain. To further complicate the matter, the lifetime of EPA in the brain is very limited (3,4). This means you have to have a constant supply in the blood stream to keep neuro-inflammation under control.

It is known from work with uni-polar and bi-polar depressed patients, that high-dose fish oil rich in EPA has remarkable benefits (5,6). On the other hand, supplementing the diet with oils rich in DHA have virtually no effects (7).

Since anxiety has a significant co-morbidity with depression, the obvious question becomes is it possible that high levels of EPA can reduce anxiety? The answer appears to be yes (8), according to a study conducted in 2008 using substance abusers. It is known that increased anxiety is one of the primary reasons why substance abusers and alcoholics tend to relapse (9,10). When these patients were given a high dose of EPA (greater than 2 grams of EPA per day), there was a statistically significant reduction in anxiety compared to those receiving a placebo. More importantly, the degree of anxiety reduced was highly correlated to the decrease of the ratio of AA to EPA in the blood (8). In other studies with normal individuals without clinical depression or anxiety, increased intake of EPA improved their ability to handle stress and generated significant improvements in mood (11-13). It may be that depression and anxiety are simply two sides of the same coin of increased cellular inflammation in the brain. Even for “normal” individuals, high dose EPA seems to make them happier and better able to handle stress.

So let’s go back to an earlier question and ask about the dietary changes in the American diet that may be factors in the growing prevalence of both depression and anxiety. As I outline in my book Toxic Fat, it is probably due to a growing imbalance of AA and EPA in our diets (2). What causes AA to increase is a combination of increased consumption of vegetable oils rich in omega-6 fatty acids coupled with an increase in the consumption of refined carbohydrates that generate insulin. When excess omega-6 fatty acids interact with increased insulin, you get a surge of AA production. At the same time, our consumption of fish rich in EPA has decreased. The end result is an increasing AA/EPA ratio in the blood, which means a corresponding increase in the same AA/EPA ratio in the brain creating more cellular inflammation.

Cutting back vegetable oil and refined carbohydrate intake is difficult since they are now the most inexpensive source of calories. Not surprisingly, they are key ingredients for virtually every processed food product. So if changing your diet is too hard, then consider eating more fish to get adequate levels of EPA. Of course, the question is how much fish? If we use a daily intake level of 2 grams of EPA per day that was used the successful trials of using omega-3 fatty acids reduce anxiety, then this would translate into consuming 14 pounds of cod per day. If you prefer a more fatty fish like salmon, then you would only need about 2 pounds per day to get 2 grams of EPA. The Japanese are able to reach that level because they are the largest consumers of fish in the world. These are highly unlikely dietary changes for most Americans. However, it has been demonstrated that following a strict anti-inflammatory diet coupled with purified fish oil supplements can generate an AA/EPA ratio similar to that found in the Japanese population (11).

There is simply no easy way out of this problem created by the Perfect Nutritional Storm, which will only intensify with each succeeding generation due to the insidious effect of cellular inflammation on fetal programming in the womb. Unfortunately for most Americans this will require a dietary change of immense proportions. This probably means that Valium and other anti-anxiety medications are here to stay.

References

  1. Kessler RC, Chiu WT, Demler O, Merikangas KR, and Walters EE. “Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication”. Arch Gen Psychiatry 62:617–627 (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Chen CT, Liu Z, Ouellet M, Calon F, and Bazinet RP. “Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study.” Prostaglandins Leukot Essent Fatty Acids 80:157-163 (2009)
  4. Chen CT, Liu Z, and Bazinet RP. “Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study.” J Neurochem 116:363-373 (2011)
  5. Nemets B, Stahl Z, and Belmaker RH. “Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.” Am J Psychiatry 159:477-479 (2002)
  6. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, and Marangell LB. “Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.” Arch Gen Psychiatry 56:407-412 (1999)
  7. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, and Puryear LJ. “A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.” Am J Psychiatry 160:996-998 (2003)
  8. Buydens-Branchey L, Branchey M, and Hibbeln JR. “Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.” Prog Neuropsychopharmacol Biol Psychiatry 32:568-575 (2008)
  9. Willinger U, Lenzinger E, Hornik K, Fischer G, Schonbeck G, Aschauer HN, and Meszaros K. “Anxiety as a predictor of relapse in detoxified alcohol-dependent patients.” Alcohol and Alcoholism 37:609-612 (2002)
  10. Kushner MG, Abrams K, Thuras P, Hanson KL, Brekke M, and Sletten S. “Follow-up study of anxiety disorder and alcohol dependence in comorbid alcoholism treatment patients.” Alcohol Clin Exp Res 29:1432-1443 (2005)
  11. Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35:499-507 (2005)
  12. Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. “Eur J Clin Invest 35:691-699 (2005)
  13. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, and Glaser R. “Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial.” Brain Behav Immun 25:1725-1734 (2011)

What is Cellular Inflammation?

People (including virtually all physicians) are constantly confused what cellular inflammation is. So I decided to take the opportunity to explain the concept in more detail.

There are two types of inflammation. The first type is classical inflammation, which generates the inflammatory response we associate with pain such as, heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain. Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body.

Definition of Cellular Inflammation

The definition of cellular inflammation is increased activity of the gene transcription factor know as Nuclear Factor-kappaB (NF-κB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system. Although the innate immune system is the most primitive part of our immune response, it has been resistant to study without recent breakthroughs in molecular biology. In fact, the 2011 Nobel Prize in Medicine was awarded for the earliest studies on the innate immune system and its implications in the development of chronic disease.

There are several extracellular events through which NF-κB can be activated by distinct mechanisms. These include microbial invasion recognized by toll-like receptors (TLR), generation of reactive oxygen species (ROS), cellular generation of inflammatory eicosanoids, and interaction with inflammatory cytokines via defined cell surface receptors. We also know that several of these initiating events are modulated by dietary factors. This also means that appropriate use of the diet can either turn on or turn off the activation of NF-κB. This new knowledge is the foundation of anti-inflammatory nutrition (1-3).

Understanding Cellular Inflammation

Although the innate immune system is exceptionally complex, it can be illustrated in a relatively simple diagram as shown below in Figure 1.

Figure 1. Simplified View of the Innate Immune System

Essential fatty acids are the most powerful modulators of NF-κB. In particular, the omega-6 fatty acid arachidonic acid (AA) activates NF-κB, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) does not (4). Recent work suggests that a subgroup of eicosanoids known as leukotrienes that are derived from AA may play a significant factor in NF-κB activation (5,6)

Extracellular inflammatory cytokines can also activate NF-κB by their interaction with specific receptors on the cell surface. The primary cytokine that activates NF-κB is tumor necrosis factor (TNF) (7). Toll-like receptors (TLR) are another starting point for the activation of NF-κB. In particular, TLR-4 is sensitive to dietary saturated fatty acids (8). The binding of saturated fatty acids to TLR-4 can be inhibited by omega-3 fatty acids such as EPA. Finally ROS either induced by ionizing radiation or by excess free radical formation are additional activators of NF-κB (9).

Anti-inflammatory Nutrition To Inhibit Cellular Inflammation

Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB.

The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane thus reducing the formation of leukotrienes that can activate NF-κB. Having the patient follow an anti-inflammatory diet, such as the Zone Diet coupled with the simultaneous lowering omega-6 fatty acid intake are the primary dietary strategies to accomplish this goal (1-3).

Another effective dietary approach (and often easier for the patient to comply with) is the dietary supplementation with adequate levels of high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. These omega-3 fatty acids taken at high enough levels will lower AA levels and increase EPA levels. This change of the AA/EPA ratio in the cell membrane will reduce the likelihood of the formation of inflammatory leukotrienes that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those from EPA are non-inflammatory. The increased intake of omega-3 fatty acids is also a dietary approach that can activate the anti-inflammatory gene transcription factor PPAR-γ (10-12), decrease the formation of ROS (13) and decrease the binding of saturated fatty acids to TLR-4 (14). This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation.

A third dietary approach is the adequate intake of dietary polyphenols. These are compounds that give fruits and vegetables their color. At high levels they are powerful anti-oxidants to reduce the generation of ROS (15). They can also inhibit the activation of NF-κB (16).

Finally, the least effective dietary strategy (but still useful) is the reduction of dietary saturated fat intake. This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane (8,14).

Obviously, the greater the number of these dietary strategies implemented by the patient, the greater the overall effect on reducing cellular inflammation.

Clinical Measurement of Cellular Inflammation

Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane.

As described above, the leukotrienes derived from AA are powerful modulators of NF-κB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-κB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane (17). Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-κB activation.

The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-κB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-κB. As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-κB activation. However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-κB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage.

Summary

I believe the future of medicine lies in the control of cellular inflammation. This is most effectively accomplished by the constant application of anti-inflammatory nutrition. The success of such dietary interventions can be measured clinically by the reduction of the AA/EPA ratio in the blood.

References

  1. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011)
  4. Camandola S, Leonarduzzi G,Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229:643-647 (1996)
  5. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4:e7250 (2009)
  6. Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17:1657-1663 (2009)
  7. Min JK, Kim YM, Kim SW, Kwon MC, Kong YY, Hwang IK, Won MH, Rho J, and Kwon YG. “TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells.” J Immunol 175: 531-540 (2005)
  8. Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010)
  9. Bubici C, Papa S, Dean K, and Franzoso G. “Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.” Oncogene 25: 6731-6748 (2006)
  10. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67: 867-874 (2005)
  11. Kawashima A, Harada T, Imada K, Yano T, and Mizuguchi K. “Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.” Prostaglandins LeukotEssent Fatty Acids 79: 59-65 (2008)
  12. Chambrier C, Bastard JP, Rieusset J, Chevillotte E, Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville M, and Vidal H. “Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.” Obes Res 10: 518-525 (2002)
  13. Mas E, Woodman RJ, Burke V, Puddey IB, Beilin LJ, Durand T, and Mori TA. “The omega-3 fatty acids EPA and DHA decrease plasma F(2)-isoprostanes.” Free Radic Res 44: 983-990 (2010)
  14. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, and Hwang DH. “Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.” J Lipid Res 44: 479-486 (2003)
  15. Crispo JA, Ansell DR, Piche M, Eibl JK, Khaper N, Ross GM, and Tai TC. “Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells.” Can J Physiol Pharmacol 88: 429-438 (2010)
  16. Romier B, Van De Walle J, During A, Larondelle Y, and Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008)
  17. Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185-1194 (2010)