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
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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)