Health Benefits of Fish Oil

Most of my patients have heard me preach about the benefits of fish oils. In fact, many people are surprised to hear that when push comes to shove, I recommend fish oils over a multivitamin. The reason for this recommendation is our extremely low intake of the essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are found in fish. Despite the fact that people today often do not trust the pharmaceutical industry because they have been deceived many times and they believe some medicines only gain popularity due to a constant campaign from companies such as The Marketing Heaven, when it comes to fish oil supplements, their regular intake is highly recommended. The average North American eats fish every 11 days, making our daily EPA and DHA intake equivalent to 130 mg. To consume a dose that will achieve optimal health functioning, however, you should consume fish anywhere between 5-7x/week so that you are getting 800-1000 mg per day. Unfortunately, eating fish this often isn’t considered the wisest dietary choice to make because of recent concerns regarding mercury and other environmental toxins that have crept into our fish supply. Fish 1-2x/week is ideal, with fish oil supplementation on the other days.

Before I begin, I wanted to give you the heads up that I tend to use the terms fish oil and omega 3’s interchangeably since fish oil is the most significant source of dietary omega 3 fatty acids. Thousands of studies have been conducted on the use of omega 3’s for the treatment of various conditions, such as heart disease, high blood fats, rheumatoid arthritis, cancer, alzheimers, depression, etc. Before I get into the clinical benefits of fish oils, I must briefly mention a little physiology to lay the framework for fish oil’s mechanisms of action.

Arachidonic acid, an omega 6, is converted into inflammatory molecules (called prostaglandins and leukotrienes) via certain enzymes (called cyclooxygenase and lipoxygenase). The takeaway from this statement is that too much arachidonic acid increases inflammation! I’m sure you have all heard the expression “you are what you eat”. Well, this is true in that your cell membranes are made up of fats so when you consume increasing levels of omega 3’s, these become incorporated into the cell membrane instead of arachidonic acid. The net effect is reduced inflammation. This is supported by studies that show that fish oil significantly decreases potent inflammatory molecules. It is this anti-inflammatory effect of fish oil that underlies most of the health benefits of these important oils. Certainly there are other mechanisms of action, but I will leave that for another blog post.

If you are interested in having your essential fatty acids measured, come into The Natural Way Health Clinic for a fatty acid blood test. This test measures the primary omega-6’s and omega’s, along with monounsaturated, saturated and trans fats that are present in the red blood cells. Each fatty acid is reported as a percentage of the total fatty acids measured and important fatty acid ratios are presented.

Ok, now I’m going to outline some of the research conducted on fish oils and their benefit in various health conditions. I want to point out that this is only some of the research. There is far too much to summarize in this post (or even 10 posts) so I just wanted to give you a brief summary of some of the key findings.

Cardiovascular Disease
The benefits of fish oil for heart disease have been demonstrated time and time again. Epidemiological studies reveal that diets high in omega 3’s are associated with decreased risk of death due to heart disease, heart attack, and sudden death (Kromhout 1985, Daviglus 1997, Hu 2002, Albert 1998, Albert 2002). Randomized clinical trials also reveal promising results. When patients who recently suffered from a heart attack added 1.8 grams of fish oil into their diet for 1 year, their risk of a cardiac event decreased by 29% while both fatal and nonfatal heart attacks decreased by 48% (Singh 1997). Another study randomized men who had suffered from a heart attack into different groups and those in the group that consumed fatty fish had a 29% reduction in death due to any cause after 2 years compared to those who weren’t instructed to consume fatty fish. Most of the benefits were from a reduction in cardiovascular deaths (Burr 1989). Another trial randomized over 11 000 men who had a heart attack within the previous 3 months into a group consuming 850 mg fish oil per day or a control group. The fish oil group had a 15% reduction in death, nonfatal heart attacks, and stroke after 3.5 years. Most of the benefit came from a 30% reduction in cardiac mortality and a 45% reduction in sudden death (Gruppo Italiano 1999). Based on the mounting evidence in support of fish oils protecting against heart disease, the American Heart Association recommends 1 gram of fish oils per day for those with diagnosed heart disease (Kris-Etherton 2002).

High Triglycerides
Hypertriglyceridemia, a condition in which triglyceride (a type of blood fat) levels are elevated, is a common disorder in the North America. It is often caused or exacerbated by uncontrolled diabetes mellitus, obesity, and sedentary habits. High triglycerides are a risk factor for coronary artery disease. A review of over 70 trials (Harris 1999) and a systematic review (Balk 2004) have demonstrated the consistent and potent triglyceride lowering effects of fish oil supplementation. One study even demonstrated a 79% reduction in triglycerides with 20 grams of daily fish oil supplementation (Phillipson 1985). Another study showed a 45% reduction in those with severe high triglycerides with 3.4 grams of daily fish oil intake (Harris 1997). Even those taking triglyceride-lowering medication can benefit from fish oil supplementation. Adding 3 grams of fish oil to a statin medication (prevastatin) reduced triglycerides by an additional 33% (Contacos 1993) and another study found that adding 3.4 grams of fish oil to a different statin (simvastatin) showed a reduction by 20 to 30% (Durrington 2001). It appears that there is a dose-dependent lowering of triglycerides with fish oil supplementation, meaning that the higher the dose of fish oil, the greater the reduction of triglycerides. Unfortunately, no significant effects on cholesterol (ie. LDL, HDL or total cholesterol) are seen with fish oil supplementation (Balk 2004).

Rheumatoid Arthritis
Patients with rheumatoid arthritis (RA) benefit from fish oil supplementation according to 2 meta-analyses (Fortin 1995, MacLean 2004). Fish oil supplementation consistently shows symptom improvement and the reduction of nonsteroidal anti-inflammatory drug (NSAID) use. One randomized clinical trial found a significant reduction of NSAID use in subjects receiving 2.8 grams of fish oil compared to a placebo group after 3 months and this effect peaked at 12 months (Lau 1993). Another study showed that fish oil supplementation of 130 mg/kg/day decreased the number of tender joints, duration of morning stiffness, pain, and global arthritis activity versus placebo (Kremer 1995). Although fish oil supplementation may benefit clinical symptoms of RA, it has potential to reduce or even eliminate NSAID use (Kremer 2000) and this is extremely important.

Prostate Cancer
Prostate cancer incidence varies 60-fold globally, which suggests that lifestyle and dietary factors play a role in its cause. Harvard researchers found that a high fish intake does not protect against the initial development of prostate cancer. However, they noted a clear correlation between increased survival and fish intake, particularly from oily fish, with men eating fish 5 or more times weekly having half the risk of dying from prostate cancer when compared to men eating fish less than once a week (Chavarro 2008). A more recent study by Szymanski (2010) found a 63% reduction in prostate cancer-specific mortality in those who consumed fish.

Colon Cancer
Several epidemiological studies have shown that high fat diets are associated with an increased risk of colon cancer while others have shown that diets rich in fish and fish oils are protective against colon cancer. In fact, a strong inverse correlation has been found between recent fish consumption and colon cancer in men (Caygill, 1995). Encouraged by findings such as this, researchers at the Catholic University of Rome set out to determine if fish oil supplementation would inhibit the development of benign polyps (ie. precursors of colon cancer). Their study involved 34 men and 26 women who had just undergone surgery to remove benign polyps from their colon. The patients were divided into 4 groups. Group 1 was supplemented with 1.4 grams of EPA and 1.1 grams of DHA per day, group 2 with 2.7 grams of EPA and 2.4 grams of DHA, group 3 with 4.1 grams of EPA and 3.6 grams of DHA while group 4 received placebo capsules containing mainly olive oil. Overall, patients in the fish oil groups experienced a significant decline in the number of abnormal cells in their colon lining as compared to members of the placebo group. Further analysis showed that the reduction in the number of abnormal cells was limited to patients who had a large number of abnormal cells at the beginning of the trial. A separate 6-month trial involving 15 patients taking 1.4 grams per day of EPA and 1.1 grams per day of DHA also showed a significant drop in the number of abnormal colon lining cells. The researchers concluded that low-dose supplementation with fish oils inhibits the proliferation of abnormal cells in patients at risk for colon cancer and that this effect can be maintained with long- term treatment (Anti 1994).

Geelen (2007) conducted meta-analysis of studies that evaluated the association between fish consumption and colorectal cancer incidence or mortality and found that fish consumption slightly reduced colorectal cancer risk. A more recent randomized, double-blind, placebo-controlled study was conducted on patients with colon polyps and found that treatment with an EPA-containing supplement was associated with a 22% reduction in polyp number and a 30% decrease in polyp diameters. The authors concluded that EPA holds promise as a safe, colorectal cancer chemoprevention agent (West 2010).

Esophageal Cancer
Cancer of the esophagus has a poor prognosis and is increasing in frequency. Esophageal cancer is usually preceded by a condition called Barrett’s esophagus in which the tissue lining the lower esophagus becomes abnormal. There is evidence that the COX-2 enzyme is upregulated in Barrett’s esophagus and esophageal cancer. This COX-2 enzyme increases inflammation. Mehta (2008) conducted a clinical trial in patients with Barrett’s esophagus and found that after 6 months, patients consuming 1.5 grams of EPA per day experienced significantly increased EPA and decreased COX-2 proteins in their esophageal tissue.

Kidney Cancer
An epidemiological Swiss study provides evidence that eating fatty fish is a simple strategy to reduce kidney cancer risk. This study was initiated in the late 1980s and involved 90 000 Swedish women who were questioned about their dietary habits and then followed for more than a decade. Women who consumed at least one portion of fatty fish each week during the study period had a reduced risk of kidney cancer of 74% when compared to those who ate no fatty fish. Eating non-fatty fish (ie. cod, tuna, fresh water fish, shrimp, and lobster) produced no protection (Wolk 2006).

Lung Cancer
Lung cancer is the leading cause of death due to cancer in Canada. It causes approximately 29% of cancer deaths among men and 22% among women. Takezaki (2001) aimed to determine the association between lung cancer and diet by conducting a study on men and women who had been diagnosed with lung cancer. They found that both men and women who ate cooked or raw fish five times a week or more had half the incidence of lung cancer when compared to participants who ate cooked or raw fish less than once a week.

End Stage Cancer
Chemotherapy and other conventional medical treatments have proven ineffective in improving quality of life and survival of patients with end stage cancer. Greek medical researchers have reported that fish oil supplementation may actually increase the survival time for cancer patients with generalized malignancy. Gogos (1998) conducted a study involving 60 patients with generalized solid tumors whereby the patients were divided into two groups with one group receiving 18 grams/day of fish oil and the other group receiving a placebo. Both malnourished and well-nourished patients who received the fish oil supplement survived significantly longer than did patients on placebo. The researchers speculated that fish oils exert their beneficial effect by decreasing the body’s production of a molecule called prostaglandin E2, which is believed to play an important role in the initiation and progression of cancer. They concluded that supplementation with fish oils may offer significant palliative support to cancer patients with end stage metastatic disease.

Crohn’s Disease
Crohn’s disease is an inflammatory disease involving intestinal pain, diarrhea, and malabsorption of nutrients. The disease is characterized by periods of active disease interspersed with periods of remission. Elemental diet (ED) therapy is a common treatment for Crohn’s, which involves tube feeding, but as you can imagine, compliance with this diet is poor, resulting in shorter periods of remission. The medications, prednisone and salycylates, are other common conventional treatments but they have only been marginally successful in extending the periods of remission. Tsujikawa (2000) report that adjusting the elemental diet can be effective for those opting for this route of treatment. They replaced one of the three daily enteral meals with a special meal consisting of rice, cooked fish, and soup. This meal was eaten normally and had an omega-3 to omega-6 ratio of only 0.5. The researchers tried out the new diet regimen on 20 patients with Crohn’s disease who had been using ED therapy for over a month. The patients were allowed to eat this new diet for lunch or dinner and continued with the ED regimen for the other 2 meals and the results were very encouraging. Prior to this diet, 9 out of 10 patients experienced a relapse within one year whereas on the new regimen, only 4 out of the 10 had a flare-up within one year, suggesting that the combination of the enteral diet and the new diet is effective in extending the remission periods in Crohn’s disease. Another study investigated the benefits of fish oil supplementation in Crohn’s patients. Belluzzi (1996) randomized half the patients to receive 2.7 grams of omega 3’s daily, while the other half received placebo capsules. The results of the fish oil therapy were spectacular. While 69% of the patients in the control group had a relapse during the one-year study period, only 28% in the fish oil group did. At the end of the one-year period, 59% of the patients in the fish oil group were still in remission as compared to only 26% in the placebo group, suggesting that fish oil is effective at preventing relapses in patients with Crohn’s disease in remission.

Ulcerative Colitis
Ulcerative colitis is a form of inflammatory bowel disease that is accompanied by an increased level of an inflammatory molecule (called leukotriene B4) in the lining of the colon. Fish oils are known to inhibit the synthesis of leukotrienes and it has therefore been postulated that they might be beneficial in the treatment of ulcerative colitis. Researchers at the Mount Sinai School of Medicine conducted a study aimed at testing this hypothesis. Their small pilot study involved 10 patients with mild to moderate ulcerative colitis who had not been helped by conventional medical therapy. The patients were given 2.7 grams of EPA and 1.8 grams of DHA for 2 months. At the end of the 2 months, 7 out of the 10 patients showed marked to moderate improvement and 4 out of 5 patients on prednisone were able to reduce their daily dose by 20 to 66% (Salomon 1990). Another study was conducted a couple of years later involving 11 male patients aged 31 to 74 years who had been diagnosed with ulcerative colitis. The patients were randomized into two groups with one group receiving 2.7 grams of EPA and 1.8 grams of DHA daily, and the other group receiving placebo capsules (olive oil). After 3 months, mean disease severity score for the patients on fish oil declined by 56% as compared to 4% for the placebo group. In addition, 72% of the patients were able to markedly reduce or totally eliminate their use of anti-inflammatory medication and steroids while taking the fish oils (Aslan 1992).

Psoriasis
Psoriasis is a fairly common skin disease characterized by thick, silvery white scales surrounded by a red, inflamed border. Psoriasis is accompanied by high concentrations of arachidonic acid and a high level of inflammatory molecules (such as leukotriene B4) in the plaques. It is well-established that fish oils suppress the formation of these inflammatory mediators. Researchers at the University of Buenos Aires Faculty of Medicine decided to investigate whether topical application of fish oil to skin areas affected by psoriasis would alleviate the symptoms. Their clinical trial involved 25 patients with psoriasis who were randomly assigned to apply either fish oil or liquid paraffin to their psoriatic plaques and leave them covered for 6 hours overnight under an occlusive dressing. The treatment was repeated daily for a 4-week period. Fish oil proved highly effective in reducing scaling (severity of scaling went from an average rating of 2.91 to 0.32 on a scale from 0 to 4), plaque thickness (from a rating of 2.21 to 0.52), and skin redness (from a rating of 2.71 to 0.90). Itching was not relieved by the fish oil treatment. The 4-week liquid paraffin treatment was also effective in reducing skin redness, but was significantly inferior to the fish oil treatment in reducing scaling and had no significant effect on itching or plaque thickness. Both treatments were well accepted by the patients and the researchers concluded that they are both clinically effective with the fish oil treatment being superior to the paraffin treatment (Escobar 1992).

ADHD
Attention-deficit hyperactivity disorder (ADHD) is a growing problem among adolescents in the western world. Estimates of prevalence vary between 5 and 10% with most victims being boys. The main symptoms of ADHD are cognitive problems (problems with thinking, learning and remembering), hyperactivity, anxiousness, shyness, perfectionism, opposition, social problems, excessive talkativeness, restlessness and noisiness. According to Canadian researchers who performed a meta-analysis of 62 randomized trials of Ritalin, there is no evidence that this drug is effective beyond 4 weeks and there is considerable evidence of its many adverse effects including decreased appetite, insomnia, headaches, stomach aches, drowsiness, anxiety, irritability, and dizziness (Schachter 2001). Therefore, alternative treatments are needed. Considerable evidence has mounted suggesting that ADHD is linked to a fatty acid deficiency and imbalance, specifically a lack of DHA and EPA and an excess of the omega-6 fatty acid, arachidonic acid (AA). Clinicians at the University of Milan decided to explore this issue further and found that supplementation with fish oils is effective in correcting the fatty acid imbalance while helping to improve the symptoms of ADHD. Their study involved 16 adolescents between the ages of 3.5 and 16 years who had been diagnosed with ADHD. The study participants received a fish oil supplement at a dose of 250 mg/day/kg with a ratio of EPA to DHA of 2:1 for 8 weeks. Before supplementation, the average AA:EPA ratio was 41 in the subjects compared to 28 in a group of matched children without ADHD. At the end of the 8-week study period, the ratio in the fish oil group dropped to 4.1. Before supplementation, the average inattention score was 19 and the hyperactivity score was 20 and these values dropped to 13.9 and 15.5, respectively, after supplementation. The researchers speculated that ADHD involves a modification in cell membrane fluidity and architecture caused by an unfavorable AA:EPA ratio, and that fish oil supplementation helps correct this (Germano 2007). Another study involved 6 boys and 3 girls who had been diagnosed with ADHD and were under the care of a psychiatrist. All study participants were instructed to take 2 tablespoons (30 mL) of a liquid concentrate of EPA and DHA supplying a total of 10.8 grams EPA and 5.4 grams of DHA a day. The median AA:EPA ratio 20 at the start of the study and after 8 weeks, it was 1.7. Along with the change in the AA:EPA ratio, a highly significant reduction in ADHD symptoms was observed by both the psychiatrist and parents. Inattention score fell from 18 to 10, hyperactivity score from 11 to 5, oppositional/defiant score from 10 to 5, and conduct disorder score from 5 to 1. The researchers concluded that high-dose EPA+DHA supplementation was effective in reducing the AA:EPA ratio, while markedly reducing the most common symptoms of ADHD (Sorgi 2007).

Menstrual Cramps
Menstrual cramping (or dysmenorrhea) is the most common gynecologic complaint and the leading cause of short-term absenteeism among adolescent schoolgirls. This cramping is believed to be associated with an elevated level of PG2 prostaglandins, which are pro-inflammatory molecules. PG2 prostaglandins are synthesized from the omega-6 fatty acid, arachidonic acid. Researchers at the University of Cincinnati Medical Center reasoned that interventions decreasing the level of these inflammatory molecules would be beneficial in reducing menstrual pain. Since it is known that EPA and DHA compete with arachidonic acid for the enzymes needed to produce these inflammatory molecules, the researchers carried out a clinical trial involving 42 girls between the ages of 15 and 18 years who experienced significant menstrual pain during their periods. The extent of pain was evaluated using the Cox Menstrual Symptom Scale at entry into the study and after 2 months of daily supplementation with a placebo or 1080 mg of EPA and 720 mg of DHA daily. At the end of the study the Cox rating had decreased from an average of 69.9 to an average of 44.0 in the fish oil group and no change was observed in the placebo group. The amount of painkiller (ibuprofen) tablets consumed during the menstrual periods dropped by more than 50% during the fish oil treatment as compared to the placebo treatment (Harel 1996). These results provide compelling evidence that fish oil supplementation has a beneficial effect on menstrual cramps in adolescents.

Alzheimers
DHA is an absolute requirement for the development of the human central nervous system and the continuous maintenance of brain cell function. DHA is an important part of the plasma membranes of nerve cells and is essential in the maintenance of their fluidity and integrity.

Cognitive decline (memory loss and a decline in awareness and the ability to think, learn and judge) is often part of the aging process and precedes Alzheimer’s disease and dementia. Dutch researchers report that cognitive decline is substantially less among elderly men consuming a diet rich in EPA and DHA. Their study involved 210 men between the ages of 70 and 89 years who completed food frequency questionnaires and were tested with the Mini-Mental State Examination (MMSE) scale at enrolment and 5 years later. After 5 years the MMSE score had declined by 1.2 points among the men who never consumed fish as compared to a decline of only 0.3 points in the fish consumers (a higher MMSE score indicates better cognitive functioning). The researchers also compared the rate of cognitive decline to the calculated daily intake of EPA and DHA. They found that men with an intake of about 400 mg/day actually improved their MMSE score by 0.2 points over the 5-year evaluation period, while men who consumed only about 20 mg/day experienced an average decline of 0.9 points (van Gelder 2007). Another study conducted by researchers at the Rush-Presbyterian-St. Luke’s Medical Center found that participants who consumed fish just once a week had a 60% lower risk of developing Alzheimers than did those who rarely or never ate fish. They also observed that participants whose daily intake of DHA was about 100 mg/day had an incidence of Alzherimers which was 70% lower than those with an intake of 30 mg/day or less (Morris 2003).

Researchers at Tufts University report that a low blood plasma level of DHA also increases the risk of developing Alzheimers. Their study included 899 men and women free of dementia when entering the study. The median age of the participants was 76 years and they were followed up for an average of 9 years. Analysis of blood samples showed that those with high levels of DHA in their blood had a 47% lower risk of developing dementia and a 39% lower risk of developing Alzheimers than did the participants with lower levels. The researchers estimated that the intake of DHA among participants with high plasma levels was about 180 mg/day (Schaefer 2006, Morris 2006). It is important to point out, however, that researchers at the Karolinska Institute report that supplementation with DHA-rich fish oil, while effective at slowing the progression of milder forms of the disease, is not effective in the treatment of moderate existing Alzheimers (Freund-Levi 2006).

Depression
Depression is becoming increasingly prevalent in Western society. Some researchers believe that part of the reason for this can be traced to major dietary changes that have taken place over the past century. During this time there has been a large increase in the intake of saturated fats and omega 6 vegetable oils at the expense of omega 3-rich foods such as fish and wild game. Researchers at the Royal Melbourne Institute of Technology report that the severity of depression is directly associated with the ratio of omega 6: omega 3 fats in the blood (Adams 1996). Another study reported an inverse relationship between the severity of depression and dietary intake of omega 3’s (Edwards 1998). The annual incidence of major depression per 100 people in nine countries was compared with the consumption of fish and a high incidence of depression was found in countries with low fish consumption. New Zealand with an annual fish consumption of only 40 lbs had an annual incidence rate of depression of 5.8% while Korea with a fish consumption of more than 100 lbs/year had an annual incidence rate of only 2.3%. Japan with a fish consumption of almost 150 lbs/year had the lowest incidence of major depression at 0.12% (Hibbeln 1998). Another study found that people who consume fish twice a week or more have a 37% lower risk of being depressed and a 43% lower risk of having thoughts of harming themselves (suicidal tendencies) (Tanskanen 2001). Research also reveals that fish oil supplementation is effective in relieving childhood depression. Nemets (2006) conducted a randomized, placebo-controlled clinical trial involving 20 children (15 boys and 5 girls) between the ages of 8 and 12 years. The study participants were assigned to receive capsules containing either fish oil (providing 400 mg/day of EPA and 200 mg/day of DHA) or a placebo for a total of 16 weeks. After the first 4 weeks of supplementation the researchers noted that the children on fish oil had significantly improved their rating on the Childhood Depression Rating Scale (CDRS) with 7 out of 10 showing an improvement of greater than 50%. None of the children in the placebo group experienced a 50% or better improvement. Four of the 10 children in the fish oil group were classified as being no longer depressed whereas none of the children in the placebo group achieved this goal. Therefore, fish oils may have significant therapeutic benefits in childhood depression.

Pregnancy
Omega 3 fatty acids are extremely important for having a healthy pregnancy. Please refer to my separate blog post where I cover this topic (under the “Pregnancy” section).

References
Adams, Peter B., et al. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids, Vol. 31 (suppl), 1996, pp. S157-S61

Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:23– 8.

Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002;346:1113– 8.

Anti, Marcello, et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology, Vol. 107, December 1994, pp. 1709-18.

Aslan, Alex and Triadafilopoulos, George. Fish oil fatty acid supplementation in active ulcerative colitis: A double-blind, placebo-controlled, crossover study. American Journal of Gastroenterology, Vol. 87, April 1992, pp. 432-37

Balk E, Chung M, Lichtenstein A, et al. Effects of omega-3 fatty acids on cardiovascular risk factors and intermediate markers of cardiovascular disease. Evidence report/technology assessment no. 93. AHRQ publication no. 04-E010-2. Rockville (MD): Agency for Healthcare Research and Quality; 2004.

Belluzzi, Andrea, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. The New England Journal of Medicine, Vol. 334, No. 24, June 13, 1996, pp. 1557-60

Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757– 61.

Caygill, C.P.J. and Hill, M.J. Fish, n-3 fatty acids and human colorectal and breast cancer mortality. European Journal of Cancer Prevention, Vol. 4, 1995, pp. 329-32

Chavarro, JE, et al. A 22-year prospective study of fish intake in relation to prostate cancer incidence and mortality. American Journal of Clinical Nutrition, Vol. 88, 2008, pp. 1297-303

Contacos C, Barter PJ, Sullivan DR. Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Arterioscler Thromb 1993;12:1755– 62.

Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997;336:1046 –53.

Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridemia. Heart. 2001;85:544 – 8.

Edwards, Rhian, et al. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. Journal of Affective Disorders, Vol. 48, 1998, pp. 149-55

Escobar, S.O., et al. Topical fish oil in psoriasis: a controlled and blind study. Clinical and Experimentology Dermatology, Vol. 17, 1992, pp. 159-62.

FDA announces the revised consumer advisory on methylmercury in fish. Rockville (MD): Food and Drug Administration; 2004 [cited 2004 May 13]. Available from: http://www.fda.gov/bbs/topics/news/2004/NEW01038.html

Fortin PR, Lew RA, Liang MH, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995;48:1379 –90.

Geelen A, Schouten JM, Kamphuis C, Stam BE, Burema J, Renkema JM, Bakker EJ, van’t Veer P, Kampman E. Fish consumption, n-3 fatty acids, and colorectal cancer: a meta-analysis of prospective cohort studies. Am J Epidemiol. 2007 Nov 15;166(10):1116-25.

Germano, M, et al. Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD). Nutritional Neuroscience, Vol. 10, February/April 2007, pp. 1-9

Gogos, Charalambos A., et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy. Cancer, Vol. 82, January 15, 1998, pp. 395-402

Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI- Prevenzione trial. Lancet 1999;354:447–55.

Harel, Z, et al. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. American Journal of Obstetrics and Gynecology, Vol. 174, April 1996, pp. 1335-38

Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997;4:385–91.

Harris WS. N-3 fatty acids and human lipoprotein metabolism: an update. Lipids 1999;34S:S257– 8.

Hibbeln, Joseph R. Fish consumption and major depression. The Lancet, Vol. 351, April 18, 1998, p. 1213 (correspondence)

Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287:1815–21.

Klein-Platat, Carine, et al. Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. American Journal of Clinical Nutrition, Vol. 82, 2005, pp. 1178-84

Kremer JM, Lawrence DA, Petrillo GF, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1995;38:1107–14.

Kremer JM. N-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71:349S–51S.

Kris-Etherton PM, Harris WS, Appel LJ. AHA sci- entific statement: fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747–57.

Kromhout D, Bosschieter EB, de Lezenne CC. The inverse relation between fish consumption and 20- year mortality from coronary heart disease. N Engl J Med 1985;312:1205–9.

Lau CS, Morley KD, Belch JJ. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis—a double blind placebo controlled study. Br J Rheumatol 1993;32:982–9.

MacLean CH, Mojica WA, Morton SC, et al. Effects of omega-3 fatty acids on lipids and glycemic control in type ii diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evidence report/technology assessment no. 89. AHRQ publication no. 04-E012-1. Rockville (MD): Agency for Healthcare Research and Quality; 2004.

Mehta, SP, et al. Effect of n-3 polyunsaturated fatty acids on Barrett’s epithelium in the human lower esophagus. American Journal of Clinical Nutrition, Vol. 87, 2008, pp. 949-56.

Morris, MC, et al. Consumption of fish and n-3 fatty acids and risk of incident of Alzheimer’s disease. Archives of Neurology, Vol. 60, July 2003, pp. 940-46 Friedland, RP. Fish consumption and the risk of Alzheimer disease. Archives of Neurology, Vol. 60, July 2003, pp. 940-46

Morris, Martha Clare. Docosahexaenoic acid and Alzheimer disease. Archives of Neurology, Vol. 63, November 2006, pp. 1527-28 (editorial).

Nakamura K, Karivazono H, Komokata T, Hamada N, Sakata R, Yamada K. Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer. Nutrition. 2005 Jun;21(6):639-49.

Nemets, Hanah, et al. Omega-3 treatment of childhood depression. American Journal of Psychiatry, Vol. 163, June 2006, pp. 1098-1100.

Phillipson BE, Rothrock DW, Connor WE, Harris WS, Illingworth DR. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. NEJM.1985;312:1210 – 6.

Salomon, Peter, et al. Treatment of ulcerative colitis with fish oil n-3-omega fatty acid: an open trial. Journal of Clinical Gastroenterology, Vol. 12, No. 2, 1990, pp. 157-61.

Schachter, HM, et al. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? Canadian Medical Association Journal, Vol. 165, November 27, 2001, pp. 1475-88.

Schaefer, Ernst J., et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease. Archives of Neurology, Vol. 63, November 2006, pp. 1545-50

Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebo- controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival— 4. Cardiovasc Drugs Ther 1997;11:485–91.

Sorgi, PJ, et al. Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder. Nutrition Journal, Vol. 6, 2007, pp. 16-23

Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010 Nov;92(5):1223-33. Epub 2010 Sep 15.

Takezaki, T., et al. Dietary factors and lung cancer risk in Japanese with special reference to fish consumption and adenocarcinomas. British Journal of Cancer, Vol. 84, No. 9, May 4, 2001, pp. 1199- 1206.

Tanskanen, Antti, et al. Fish consumption, depression, and suicidality in a general population. Archives of General Psychiatry, Vol. 58, May 2001, pp. 512-13

Tsujikawa, Tomoyuki, et al. Clinical importance of n-3 fatty acid-rich diet and nutritional education for the maintenance of remission in Crohn’s disease. Journal of Gastroenterology, Vol. 35, 2000, pp. 99-104.

van Gelder, BM, et al. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men. American Journal of Clinical Nutrition, Vol. 85, 2007, pp. 1142-47.

West et al. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010 Jul;59(7):918-25.

Wolk, A et al. Long-term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women. Journal of the American Medical Association, 2006, Vol. 296, No. 11, pp. 1371-6

Dr. Angela MacNeil