Chemistry and Forms

Fish Oils: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA); cod liver oil; ethyl-omega-3 fatty acids.

Flaxseed and Flaxseed Oil (Linum usitatissimum) : Alpha linolenic acid, alpha-linolenic acid, ALA, type I flaxseed/flaxseed (51%-55% ALA), type II flaxseed/CDC-flaxseed (2%-3% ALA); alashi, brazen, common flax, flachssamen, flax, Graine de Lin, leinsamen, hu-ma-esze, Linaceae, linen flax, lini semen, lino, lino usuale, linseed, linseed oil, lint bells, linum, Linum catharticum, Linum humile seeds, keten, sufulsi, tesi-mosina, winterlien.

Alpha-linolenic acid (ALA): Canola/rapeseed, eichium oil, hemp seed oil, perilla, purslane; fiber.

Related Substances: DHA-45, ethyl-omega-3 fatty acids, Omacor; gamma-linolenic acid (GLA, as in borage, evening primrose, and black currant seeds), hemp seed oil, linoleic acid (LA), n-6 fatty acids, omega-6 fatty acids, omega-6s, omega-9s (from olive and macadamia nuts), vegetable oils.

Note: Omega-6 fatty acids are physiologically and clinically distinct and should not be confused with fatty acids of the omega-3 series.

Physiology and Function

The designation “omega” indicates at which position the first unsaturated (double) bond occurs at the noncarboxyl end of the molecule. Therefore, the first double bond in the omega-3 series is between the third and fourth carbon atoms, for the omega-6 series it is between the sixth and seventh carbon atoms, and for the omega-9 series, between the ninth and tenth carbon atom, from the noncarboxyl end of the molecule. There is no evidence that fatty acids from the omega-3, -6, and -9 series can be interconverted between series in the body.

Omega-3 fatty acids are essential to human physiology, particularly the immune system, circulatory system and central nervous system (CNS), and are obtained through foods and produced endogenously. Fish is the major dietary source of long-chain omega-3 polyunsaturated fatty acids (PUFAs), specifically the 20-carbon eicosapentaenoic acid (EPA) and the 22-carbon docosahexaenoic acid (DHA). Linoleic acid and linolenic acid are also essential fatty acids (EFAs). Alpha-linolenic acid (ALA) is an 18-carbon omega-3 polyunsaturated EFA that can serve as an essential precursor to both EPA and DHA. Humans are capable of synthesizing small amounts of EPA and DHA from ALA, but an as-yet undetermined dietary requirement of DHA and EPA is probable. Conversion of ALA by humans to the more active, longer-chain EPA and DHA is inefficient: less than 5% to 10% for EPA and less than 1% for DHA in men, whereas women can convert up to 9% of ALA to DHA, possibly because of the importance of DHA in fetal and infant nutriture. ¹ Thus, total, ALA requirements may be higher for vegetarians than for nonvegetarians, because vegetarians must rely on conversion of ALA to EPA and DHA. ² Algae-derived DHA supplements may also be an important nutrient source for vegetarians, particularly for men and weaned vegetarian children. EPA may be produced in vivo by beta-oxidation of DHA, although increased availability of algae-derived EPA supplements in the next few years is anticipated. Algae-derived omega-3 fatty acids will undoubtedly become increasingly important for nonvegetarians given the limited capacity of ocean fish stocks to sustain their populations in the face of increasing human demands and habitat destruction.

Linoleic acid, an EFA of the omega-6 series, which occurs naturally in many warm-weather vegetable oils, is the precursor of arachidonic acid (AA), which serves as substrate for inflammatory prostaglandins, thromboxane, and leukotrienes. Extensive research indicates that omega-3 fatty acids modulate inflammation and support healthy function of neural, cardiovascular, joint, and connective tissue. EPA modulates clotting and has a significant anti-inflammatory effect through its impact on prostaglandin metabolism.

The activity of omega-3 fatty acids in modulating immune function involves several important mechanisms. These oils play pivotal roles in the resolution of inflammatory processes through modulation of proinflammatory and prothombotic eicosanoid production (prostaglandins, thromboxane, and leukotrienes derived from AA) and reduction in interleukin-1 (IL-1) and other inflammatory cytokines. They are also directly involved in anti-inflammatory eicosanoid production. The partial replacement of AA with EPA in cell membrane lipids appears to play a key role in the activity and effects of omega-3 fatty acids. EPA acts as a substrate for the synthesis of the PG3 series of prostaglandins and increases production of these prostaglandins and thromboxane A3(TXA3), which produce less inflammation than the PG2 series and TXA2(derived from AA), which they displace. Similarly, EPA acts as the source of series 5 leukotrienes, which have weaker inflammatory effects, while AA acts as the source of the more inflammatory series 4 leukotrienes. TXA3, derived from EPA, is less potent in stimulating platelet aggregation than TXA2, with attendant decrease in thrombotic risk. Furthermore, DHA inhibits the formation of the more inflammatory prostaglandins of the PG2 series, while EPA acts as a substrate for the synthesis of the less inflammatory prostaglandins of the PG3 series.

Fish oils benefit lipid metabolism and cardiovascular function through a variety of mechanisms not fully elucidated. Fish oils, by replacing other membrane fatty acids with omega-3 fats, improve blood flow characteristics, and also decrease platelet aggregation, all of which benefits individuals with atherosclerosis and at risk of clotting off a cerebral or coronary vessel. On the other hand, with individuals at risk for bleeding for other reasons, fish oils may slightly increase that tendency. The activity of EPA and DHA on peroxisome proliferator-activated receptor alpha (PPAR-α) appears to play a role in reducing triglycerides, modulating inflammatory reaction, and optimizing body composition.

These EFAs, particularly DHA, are highly concentrated in the brain's gray matter and retina and play a central role in neurological, cognitive, and behavioral development and function. ^3,4Brain cell membrane fluidity is essential for communication between neurons, and DHA helps maintain cell membrane fluidity as well as replenish brain tissue. Further, DHA supply in pregnancy affects placental expression of fatty acid transport proteins. ⁵ Consequently, infants who fail to receive adequate omega-3 fatty acids from their mothers during pregnancy are at increased risk for developing vision and CNS deficits. ^6-8Furthermore, deficiencies in DHA and EPA during early developmental stages, especially in infants deprived of DHA-rich breast milk, “may lower serotonin levels at critical periods of neurodevelopment and may result in a cascade of suboptimal development of neurotransmitter systems limiting regulation of the limbic system by the frontal cortex.” Subsequently, the resulting deficits may produce residual developmental effects that “may be manifest as dysregulation of sympathetic responses to stress including decreased heart rate variability and hypertension, which in turn have been linked to behavioral dysregulation.” ⁹ The full implications of these developmental perturbations and their significance in healthy function, dysfunction, and disease throughout childhood and adulthood have only begun to be understood. ^8,10-12

NUTRIENT IN CLINICAL PRACTICE

Known or Potential Therapeutic Uses

Omega-3 Fatty Acids

Angina, amyotrophic lateral sclerosis (risk reduction), arthritis, artherosclerosis, asthma, bipolar disorders, breastfeeding support, cancer, cardiovascular disease, cholesterol, chronic obstructive pulmonary disease (COPD), colon cancer, Crohn's disease, cystic fibrosis, depression, diabetes mellitus, dysmenorrhea, eczema, endometriosis, glaucoma, human immunodeficiency virus and acquried immunodeficiency syndrome (HIV/AIDS) support, hyperlipidemia, hypertension, hypertriglyceridemia, immune support, inflammatory bowel disease, mental disorders, migraine, multiple sclerosis, myocardial infarction, neonatal development, nephropathy, neurodegenerative disease, osteoarthritis, osteoporosis, phenylketonuria, photosensitivity, preeclampsia, pregnancy and postpartum support, presurgical and postsurgical support, psoriasis, Raynaud's syndrome, rheumatoid arthritis, sickle cell anemia, sudden cardiac death (risk reduction), systemic lupus erythematosus (SLE), ulcerative colitis.

EPA and DHA (Long Chain Omega-3s)

Acute myocardial infarction, acute respiratory distress syndrome (ARDS), age-related macular degeneration, aggressive behavior, agoraphobia, Alzheimer's disease, angina, anorexia nervosa, anthracycline-induced cardiac toxicity, anticoagulation, antiphospholipid syndrome, anxiety, arthritis, arthrosclerosis, asthma, attention deficit–hyperactivity disorder (ADHD), autoimmune nephritis, Behçet's syndrome, bipolar disorder, borderline personality disorder, breast cancer risk, breastfeeding support, burns, cachexia during chemotherapy, cancer treatment support, cardiovascular disease prevention, chronic fatigue syndrome, chronic obstructive pulmonary disease (COPD), cirrhosis, colorectal cancer risk, Crohn's disease, cystic fibrosis, dementia, depression, dermatomyositis, diabetes mellitus type 1, diabetes mellitus type 2, diabetic nephropathy, diabetic neuropathy, dyslexia, dyslipidemia, dysmenorrhea, dyspraxia, eczema, emphysema, endometriosis, exercise performance enhancement, fibrocystic breasts, gallstones, gingivitis, glaucoma, glomerulonephritis, glycogen storage diseases, gout, hepatorenal syndrome, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, hypoxia, ichthyosis, immune function, immunosuppression, inflammatory bowel disease, leprosy, leukemia, Lyme disease, malaria, male infertility, mastalgia, memory enhancement, menopausal symptoms, menstrual cramps, mental disorders, migraine, multiple sclerosis, myopathy, neck and low back pain, neonatal development, nephrolithiasis, nephropathy, neurodegenerative disease, neuropathy, night vision enhancement, obesity, omega-3 fatty acid deficiency, osteoarthritis, osteoporosis, panic disorder, peripheral vascular disease, phenylketonuria, photodermatitis, photosensitivity, postviral fatigue syndrome, preeclampsia, pregnancy and postpartum support, premature birth prevention, premenstrual syndrome, presurgical and postsurgical support, prostate cancer prevention, psoriasis, Raynaud's phenomenon, Refsum's syndrome, retinitis pigmentosa, Reye's syndrome, rheumatoid arthritis, schizophrenia, seizure disorder, sickle cell anemia, stroke prevention, sudden cardiac death (risk reduction), suicidal tendencies, systemic lupus erythematosus (SLE), tardive dyskinesia, tennis elbow, urolithiasis, ulcerative colitis, vision enhancement.

Alpha-Linolenic Acid (ALA)

Breast cancer, cardiovascular disease, diabetes mellitus, eczema, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, laxative, lupus nephritis, menopause, menstrual breast pain, prostate cancer, psoriasis.

Deficiency Symptoms

Dry scaly skin, hair loss, immune system insufficiency, inflammation, poor wound healing; impaired vision, reduced childhood growth and impaired brain and eye development.

Dietary Sources

Alpha-Linolenic Acid (ALA)

Canola (rapeseed) oil, eggs (from hens fed flaxseed), hemp seed oil, eichium seed oil, flaxseed (linseed), perilla seed, pumpkin seed, purslane, walnuts, wheat germ.

Note: Safflower, sesame, and sunflower, and to a lesser degree soybean, contain ALA but also contain countervailing omega-6 fatty acids in significantly higher amounts.

DHA and EPA

Fish, fish oil; eggs (from hens fed DHA-rich algae); infant formula; margarine and milk fortified with EPA/DHA.

Fish oils and plant oils are the primary dietary sources of omega-3 fatty acids. The omega-3 fatty acids DHA and EPA are the key constituents in the oil found in cold-water fish. The high concentrations of omega-3 fatty acids in these fish may result from its “antifreeze” property. The richest sources of naturally occurring omega-3 oils include salmon, mackerel, halibut, sardines, and herring. The preparation of fish also influences its physiological and therapeutic actions, with “intake of tuna or other broiled or baked fish being associated with improved cardiac hemodynamics, but fried fish intake being associated with structural abnormalities indicative of systolic dysfunction and potential coronary atherosclerosis.” ¹³ The liver of the cod, halibut, or shark is the primary source of fish liver oil, whereas herring, sardine, salmon, or anchovy flesh usually serves as the source of fish body oil. Other food from the oceans can also provide omega-3 oils. Some marine phytoplankton (microalgae) are good sources of DHA and can be obtained as nutritional products. New Zealand green-lipped mussels (Perna canaliculus) also contain omega-3 fatty acids and have been consumed by the Maori people of the South Pacific for centuries. ¹⁴ EPA/DHA has been added to “fortify” some foods, such as eggs, bread, margarines, and milk. Oil extracted from ocean krill (zooplankton) is also a rich source of EPA and DHA, available as a nutritional supplement, and in which EPA and DHA are uniquely bound in phospholipids, rather than triglycerides as in fish body/liver oils.

Fish liver oil, but not fish body oil, is also rich in vitamins A and D. For example, cod liver oil liquids normally provide concentrations of 750 to 1200 µg (2500-4000 units) vitamin A per 10 mL and 2.5 to 10 µg (100-400 units) vitamin D per 10 mL, although there is significant variability between brands, depending on multiple factors, including region, time of year, and processing. These vitamins are even more concentrated in halibut and shark liver oils. Shark liver oil is also rich in compounds called alkoxyglycerols, which are reputed to have protective effects from radiation therapy. ^15,16Oil from both body and liver of fish also contains some vitamin E.

Although they are readily available in many common foods, the ability to convert omega-3 fatty acids from vegetable sources to EPA within the human body is quite limited. ALA is found in a variety of plant foods, especially canola (rapeseed) oil, flaxseeds, flaxseed oil, pumpkin seeds, pumpkin seed oil, purslane, perilla seed oil, soybeans, soybean oil, walnuts, and walnut oil.

Nutrient Preparations Available

Fish oil products usually contain vitamin E and other antioxidant nutrients to reduce oxidative degradation and rancidity; this inherent problem may also be mitigated by extracting the oxygen from the capsule. Long-term intake of fish oil could theoretically cause a deficiency of vitamin E by increasing oxidative stress on fat-soluble antioxidants. Consequently, many commercial fish oil products contain additional vitamin E, which also acts as an antioxidant to prevent rancidity before ingestion. ¹⁷

Variations on usual fish oil products have been developed for special populations. Fish oil preparations emphasizing DHA and containing no or lesser proportions of EPA are sometimes used with infants (or others) who generally do not need EPA. Enteric-coated, free–fatty acid preparations of purified EPA/DHA derived from fish oil are sometimes preferable for patients with Crohn's disease or other gastrointestinal (GI) conditions because of their reduced tendency to cause digestive distress. Omega-3 fatty acid ethyl esters are a slightly modified form of fish oil approved by the U.S. Food and Drug Administration (FDA) as a prescription treatment for hypertriglyceridemia either as monotherapy or in combination with statins or fibrates. ¹⁸

Both EPA and DHA can be obtained from various algae. DHA-45 is an innovative proprietary source of DHA produced through a multistep fermentation and refining process using a nonpathogenic marine protist. The final product consists of approximately 45% DHA and is intended for use in food, but safety has not been fully established. ¹⁹ Martek produces DHA from cultured microalgae for use in infant formula and DHA products. Several European companies are planning to produce both EPA and DHA from algae, although at the time of this writing, these are not yet commercially available.

Flaxseed, flaxseed oil, and fish oil require refrigeration to maintain their integrity, even though many encapsulated fish oil products are stable at room temperature. Whole flaxseeds need to be consumed within 24 hours of being ground, or their unsaturated fatty acid constituents degrade through oxidation.

Dosage Forms Available

• Fish oil: Capsule, gel cap, oil (liquid, often flavored with citrus or other fruit oils).
• Flaxseed: Oil (liquid), powder, whole seeds.

For fish oil preparations, dosing should be based on the amount of EPA and DHA (omega-3 fatty acids) in a product, not on the total amount of fish oil. Commercial products vary in the amounts and ratios of EPA and DHA. A common amount of omega-3 fatty acids in fish oil capsules is 0.18 g (180 mg) of EPA and 0.12 g (120 mg) of DHA per gram of oil. Five grams of fish oil contains approximately 0.17 to 0.56 g (170-560 mg) of EPA and 0.072 to 0.31 g (72-310 mg) of DHA. Different types of fish contain variable amounts of omega-3 fatty acids; likewise, different types of nuts or oil contain variable amounts of ALA.

Flaxseed can be administered in several forms, as an oil in liquid medium or capsule, ground into powder, or mixed with liquid. See dosage section for further details.

Source Materials for Nutrient Preparations

Fish oil can be derived from a wide variety of fish species, each with different amounts and relative proportions of EPA and DHA. ²⁰ DHA and EPA are also commercially derived from both wild and cultivated algae.

Alpha-linolenic acid (ALA) can be obtained from a variety of nuts and vegetable oils, including canola oil, flaxseed/linseed oil, flaxseeds, olive oil, soybean oil, walnut oil, walnuts (English). ²⁰

Dosage Range

Optimal dosage has not been established. Over-the-counter (OTC) products typically provide 200 to 1500 mg combined EPA/DHA per dose. Clinical trials investigating fish oil therapeutics have often used 3 to 4 g daily (EPA/DHA), but doses of 1 to 2 g may be adequate, depending on the clinical application.

Dietary

Adult

No daily requirement for fish oil or EPA and DHA has been established. The adequate intake (AI) for ALA has been established as 1.6 g per day for men and 1.1 g per day for women. AIs represent the least amount needed to deter deficiency but do not take into account disease prevention. A healthy diet should provide at least 5 g total essential fatty acids daily. The dietary intake of omega-3/omega-6 fatty acids of most individuals is typically both low and imbalanced. The average American diet contains approximately 1.6 g omega-3 fatty acids per day, of which only 0.1 to 0.2 g comes from EPA and DHA and approximately 1.4 g (∼90%) from ALA. Moreover, in Western diets, except for specific populations with unusually high fish intake, consumption of omega-6 fatty acids is about 10 to 40 times greater than that of omega-3 fatty acids. This high proportion of omega-6 fatty acid intake results largely from the widespread use of vegetable oils containing linoleic acid, a relatively recent dietary development, historically speaking. Increasing omega-3 fatty acid intake or decreasing intake of omega-6 fatty acids can improve the ratio, as well as health benefits, because omega-6 and omega-3 fatty acids compete for conversion into active metabolites.

The American Heart Association recommends that healthy adults with no history of heart disease eat fish at least twice weekly, preferably broiled or baked, not fried. ²¹ Fatty fish, in particular, are superior sources; these include anchovies, bluefish, carp, catfish, halibut, herring, lake trout, mackerel, pompano, salmon, striped sea bass, tuna (albacore), and whitefish. However, some fish need to be consumed in limited amounts because they contain high levels of mercury and other toxins. Swordfish, king mackerel, shark, and tilefish should be limited to 7 ounces per week (and avoided by pregnant women); tuna and red snapper should be limited to 14 ounces per week; salmon, catfish, mahi mahi, and canned tuna have no established restrictions. Consumption of plant-derived sources of ALA, such as tofu/soybeans, walnuts, flaxseed oil, and canola oil, is also recommended, although some experts have reservations about the euricic acid content of canola oil, which is a potentially problematic, very-long-chain fatty acid. Various national regulatory agencies, as well as the World Health Organization (WHO), recommend a daily dietary intake of 0.3 to 0.5 g EPA plus DHA and 0.8 to 1.1 g ALA (although this latter value is somewhat below the AI established for ALA).

Pregnancy and Nursing

Pregnant and lactating women are often advised to consume sufficient fish oils to provide at least 300 mg DHA daily to promote healthy neural and optical development in the child. Adequate DHA intake during pregnancy has also been associated with a decreased risk for postpartum depression.

Infants and Children

Although widely recognized for its critical role in development, no therapeutic protocols or standards of treatment have been established for the use of fish oils such as DHA by infants or children. An ample supply of DHA and AA enable healthy neurological and retinal development in infancy. Breast milk and brain tissue exhibit the highest naturally occurring concentrations of EPA and DHA in the human body, and breast-fed infants exhibit higher concentrations of erythrocyte DHA and AA than bottle-fed infants, with corresponding increases in visual acuity and developmental tests (vs. bottle-fed counterparts). ^8,22Infant formula is required by law in most developed countries, except the United States, to contain DHA. Formula should contain 0.35% DHA and less than 0.1% EPA.

ALA content in breast milk depends on maternal diet and may be adequate with proper nutrition, but it can vary considerably. Maternal intake of flax oil or fresh-ground seed can be used to increase ALA content in breast milk. Infant formula should contain 1.5% ALA.

A child's fatty acid intake may be enhanced and balanced through addition of freshly ground flaxseeds and flaxseed oil.

Supplemental/Maintenance

The recommendation for fish oil preparations is 3000 to 4000 mg fish oil per day, which is equivalent to approximately two to three servings of fatty fish per week. A single 1000-mg fish oil capsule typically contains 180 mg EPA and 120 mg DHA.

Supplementation is not necessary in children who are breast-fed because breast milk contains adequate amounts, assuming adequate maternal dietary intake. Infants not being breast-fed and other children can benefit from omega-3 fatty acids, but dosage levels have not been established. Exogenous DHA administration can increase levels of DHA in breast milk, and higher breast milk DHA levels increase the DHA in infants’ cell membranes. ^23-25The metabolism of infants appears to have minimal need for EPA.

A typical dose for flaxseed can range from 1 tablespoon two to three times daily to 2 to 4 tablespoons once daily; usually ground and consumed with water; 100 g raw flaxseed provides 22,800 mg ALA.

Flaxseed oil can be dispensed in a liquid form, with a 15-ml tablespoon containing approximately 7 g ALA. A dose of 1 or 2 tablespoons of flaxseed oil daily is appropriate as a general recommendation. Refrigeration is essential to stable storage; integrity is significantly compromised with heating because of rapid oxidation of unsaturated bonds.

Flaxseed oil can also be distributed in a capsule form, with a typical 1000-mg capsule providing 500 mg ALA. Oral consumption of raw flaxseeds in doses up to 50 g daily for up to 4 weeks has been reported. Oral doses of 10 to 60 g daily have been used in several studies for periods of less than 2 weeks. A dose of 50 g flaxseeds is roughly equivalent to 250 g flaxseed flour.

Doses of soluble flaxseed mucilage/fiber as high as 60 to 80 g/kg body weight have been administered in research settings.

Pharmacological/Therapeutic

The appropriate range for an effective dose of omega-3 oils, regardless of the form or source, is under debate. Dosage suggestions in the literature range from 1 to 10 g per day. However, the appropriate dosage varies depending on the pathophysiology in question and the level of health in a given individual. A maximum tolerated dose of 0.3 g/kg/day of fish oil capsules has been proposed; this tolerance is equivalent to 21 1-g capsules daily for a 70-kg (154-lb) patient. ²⁶ Typical dosages of fish oil in therapeutic settings range from 3 to 9 g daily, but this is not the upper limit, and dosages in oncological settings are often 12 to 15 g/day, or more. Subjects in one clinical trial ingested 60 g daily. In essence, matching the dosage used in several major studies would require fish oil adequate to supply about 2 to 3 g EPA (2000-3500 mg) and about 1.0 to 2.5 g DHA (1000-2500 mg) daily. However, much higher doses have been used in some studies. The U.S. FDA classifies intake of up to 3 g/day omega-3 fatty acids from fish as “generally regarded as safe” (GRAS).

Children (2-12 years)

Daily administration, typically about 1 teaspoon daily of ground flaxseeds or 1 teaspoon of fresh flaxseed oil, is often used in treating children with constipation.

Toxic

In their natural-occurring food contexts, omega-3 fatty acids possess an excellent safety profile and are considered generally nontoxic, particularly with single-dose or short-term application. Omega-3 fatty acids in OTC forms (i.e., free from contaminants) do not exhibit toxic levels in most individuals when used at standard doses. One study involving oncology patients being treated with concomitant fish oils for cachexia proposed a maximum tolerated dose of 21 g/day. ²⁷ No maximum tolerated dose has been established for the general population or patients diagnosed with other conditions. However, the qualified health claim (for prevention of coronary heart disease) allowed for EPA/DHA by the FDA sets a maximum recommended intake of 2 g total EPA and/or DHA and suggests a maximum of 1 g, or about 3 g of usual-strength fish oil.

Contaminants do change the situation for many consumers of fish because methylmercury and other pollutants can represent significant health risks, especially in pregnancy, during breastfeeding, and throughout childhood development. Such contaminants are much less significant in fish oil products than with dietary consumption of fish meat.

Excessive intake of cod liver oil carries a risk of inducing vitamin A excess and thus is generally not considered a preferred source of EPA/DHA for long-term use. However, intakes of more than 1 ounce daily are necessary to provide excessive levels of vitamin A for most products. It would require extremely high intakes of fish liver oils to provide excessive intakes of vitamin D (>10,000 IU/day).

Laboratory Values

No clinical standards for laboratory evaluation of omega-3 fatty acid status have been established.

Fatty Acids, Nonesterified

Circulating nonesterified–fatty acid concentration is an independent factor for cardiac risk, especially sudden death in middle-aged men. ²⁸ Omega-3 fatty acids are “preferentially stored in the Sn-2 position, from which they can be specifically and rapidly released by activated phospholipase A-2.” However, free–fatty acid levels in plasma do not reliably reflect the immediate dietary consumption of fat because they primarily derive from the regulated turnover of lipid stores in adipose tissue by lipolysis and from phospholipids by phospholipases. ²⁹

Fatty Acid Composition of Serum Cholesterol Esters, Free Fatty Acids, Phospholipids, and Triglycerides

Blood levels of long-chain n-3 fatty acids have been used in clinical trials investigating the effects of omega-3 fatty acid intake. ^30,31Such assays are not usually applied in routine clinical settings, although they are incorporated in various risk profile panels used by health care professionals specializing in nutritional therapeutics.

Red Blood Cell Membrane Fatty Acid Composition

Measurement of long-chain omega-3 fatty acids in red blood cell (RBC) membranes is a sensitive indicator of deficiency but remains investigational. This measurement has been used as an indicator of cardiac risk and other related susceptibility. ³¹ Low levels indicate deficiency, but specific reference ranges vary among laboratories.

Serum (or Plasma) Phospholipid

Fatty acid analysis of phospholipid concentration in serum (or plasma) may provide a useful biomarker for assessing nutritional status and EPA/DHA intakes in relation to potential risk. ^32,33Resulting data can then be presented as an “omega-3 fatty acid profile” with both an omega-3 score and a DHA score.

Overview: Fish Oil

Fish oil intake is generally considered to be well tolerated with an excellent safety profile. ^19,34Few clinically significant adverse effects have been reported. Studies investigating the maximum tolerated dose and dose-limiting toxicities of fish oil found GI complaints, mainly nausea, loose stools, or diarrhea, as the predominant adverse effects. In clinical practice, fish-flavored aftertaste and eructations represent the adverse effects most often mentioned by patients using fish oils. Various clinical trials have suggested possible adverse effects from fish oil intake in specific patient populations.

The preeminent issue of toxicity affecting fish oils results not from the nutrients themselves but from damage to the fish and the environment in which they develop. Fish oils are free of intrinsic risks in their native state. However, growing concerns are widely expressed over the effects of pollution, especially the presence of mercury, toxic organochlorines, and polychlorinated biphenyls (PCBs) in seafood and large fish in particular, both directly (for humans, sealife, and the planet) and in effects on fish oil products.

In particular, fish meat may contain methylmercury, pesticides, and heavy metals, and caution is especially warranted in pregnant and lactating women and young children. ³⁴ Methylmercury is known to cause neurological and developmental disorders. ^35,36Fish oils derived from wild fish are generally considered less likely to contain significant amounts of mercury and other heavy metals, although this is ultimately a relative safety factor because these toxic materials have permeated the environment to some degree. Moreover, methylmercury tends to accumulate more readily in fish meat than in fish oil. Consequently, fish oil products have generally been found to be largely free of mercury; a process known as molecular distillation is required for reliable removal of PCBs and other toxic pollutants. Unrefined fish oil preparations may still contain pesticides or other pollutants. Thus, products that are assayed for peroxides and environmental contamination are recommended. Overall, the significant risks associated with fish oil consumption, through dietary and nutraceutical sources, derive from contamination rather than from the nutrients themselves and, in fact, are generally more problematic in fish than in fish oil products.

The loss of biodiversity and destruction of ocean ecosystems constitute the other side of the fish contamination issue. Overfishing, destructive fishing practices, and destruction of habitats all represent huge problems reaching critical proportions. ^37,38Without significant and concerted global efforts to reverse these trends and establish sustainable practices, the availability of fish or omega-3 oils derived from fish may become obsolete and irrelevant. Advocating regular consumption of fish in the diet or products containing omega-3 fatty acids derived from fish on a global basis is unrealistic and inadvisable over the long term. Other technologies, such as those involving use of microalgae cultures, warrant aggressive research and rapid deployment.

Nutrient Adverse Effects

Eructations, nausea, dyspepsia, reflux, abdominal bloating and discomfort, flatulence, loose stools, diarrhea, and other minor GI complaints represent the most common adverse effects reported in individuals consuming fish oil products at typical levels, appearing in 1.5% to 5% of study subjects; severe diarrhea has been reported on rare occasions with the ingestion of high doses of fish oil supplements. ^39-46GI effects can be minimized if fish oils are taken with meals and if doses are started low and gradually increased; time-release preparations may also mitigate these complications. Such effects are generally considered improbable or inconsequential with dietary consumption of fish.

Caution should be used in regard to the dose of cod liver oil because of high vitamin A and D content. Large doses of vitamin A, particularly with rapid introduction, can be hepatotoxic (>20,000 IU/day combined with other hepatotoxic stress, e.g., chronic acetaminophen or alcohol use). Generally, the potential risk from vitamin D is considered greater in summer than in winter or cloudy climates, but this advisory may change given the emerging knowledge of pervasive vitamin D deficiency and insufficiency, versus previously dominant fears of vitamin D excess and toxicity.

The potential hematological effects of omega-3 fatty acids pose some of the more clinically significant effects in terms of unintended effects and interactions. Omega-3 fatty acids have multiple antithrombotic effects that may exert a bimodal effect (beneficial or adverse) depending on the individual, his or her physiology and medical conditions, and interactive medication effects. In particular, fish oils may decrease platelet aggregation, increase fibrinolysis, prolong bleeding time, and diminish von Willebrand factor, all of which concomitantly decrease thrombotic risk and increase bleeding risk. Daily doses of more than 3 g omega-3 fatty acids (9 g usual-strength fish oil) may increase the risk of bleeding, but there is a paucity of evidence to substantiate concerns of clinically significant bleeding risk at lower doses in most individuals. ^47-49Very high doses of omega-3 fatty acids in the form of fish oil, and at the intake level typical of indigenous Eskimo diet, could theoretically increase the risk of hemorrhagic stroke. ⁵⁰ High-dose intake has also been associated with epistaxis and hematuria, usually in association with other anticlotting agents such as antiplatelet agents, as well as anticoagulants such as warfarin, or heparin. ⁵¹ Notably, in at least one study, hemostatic effects (opposite of increased bleeding risk) observed with dietary fish were not seen with fish oil products. ⁴¹ High levels of long-chain omega-3 fatty acids from marine sources reportedly may increase levels of plasminogen activator inhibitor type 1 (PAI-1), thus inhibiting endogenous fibrinolysis, with the attendant theoretical effect of increasing thrombotic risk. However, after careful assessment of this issue, Hansen et al. ⁵² concluded that, although dietary fat of any type somewhat raises PAI-1 levels, there is no difference between the long-chain omega-3 oils and any other type of fat in this regard.

Fish oil can play an important role in a strategic approach to treatment of individuals with dyslipidemias, hypercholesterolemia, and dermatitis. Dose-dependent elevations in low-density lipoprotein (LDL) levels of 5% to 10% have been observed with increased intake of 1 g or more daily of omega-3 fatty acids, with more substantial elevations in individuals with familial combined hyperlipidemia. ⁵³ However, these LDL-raising effects were not observed in all trials and appear to be transient, and a paradoxical LDL-lowering effect may be seen at high doses (e.g., 32 g fish oil daily). ^41,43,54-57Furthermore, coadministration of pectin or garlic may counteract this possible adverse effect. ^58,59Isolated reports indicate that mild elevations in alanine transaminase (ALT) levels may occur. ⁶⁰ Although fish oils are often used in the treatment of inflammatory skin conditions, skin rashes have been reported on rare occasions. ^54,61

In one rodent study, omega-3 fatty acids were associated with metastatic progression of colon cancer. ⁶² Consequently, concerns have been raised about use of omega-3 fatty acids, through dietary sources or nutraceutical products, in patients with advanced stages of colorectal cancer. The majority of animal studies, however, have indicated an overall anticancer effect of dietary long-chain omega-3 fatty acids.

Adverse Effects Among Specific Populations

Individuals with allergy or hypersensitivity to fish, seafood, or nuts may react to omega-3 fatty acid or ALA products derived from these substances. Checking labeling and avoiding potentially problematic substances are advised.

Hypomania has been reported in patients with bipolar disorder or major depression after use of omega-3 oils. ⁶³ Clinical studies, however, have shown a beneficial effect in both bipolar disorder and depression. ^64-70Rare reports of restlessness and formication (sensation of ants crawling on the skin) suggest the need for vigilance when introducing therapeutic agents in any case involving a psychiatric diagnosis.

Elevations in blood glucose levels have been reported with daily doses of fish oil greater than 3 g for extended periods. The frequency and severity of the potential risk of increased or unstable blood glucose levels appear to be of concern primarily in individuals with diabetes or hypertriglyceridemia, but research has not elucidated a clear and consistent understanding of this observed phenomenon. Addition of vitamin E or regular aerobic exercise (½ hour three times per week) may mitigate this possible potential impairment of glucose tolerance. ^51,71,72

Contraindications

An increased death rate in the fish oil–administered group was observed in a single study involving patients with implanted cardiac defibrillators. ⁷³ In contrast, observations and trials conducted in the United States and Europe indicate that the predominant effect of high omega-3 consumption (e.g., 1000 mg daily from fish oil) is a reduction in risk of sudden cardiac death. ^74,75

Potential effects on female hormones have occasionally led to statements that the use of flaxseed or flaxseed oil during pregnancy and breastfeeding is contraindicated. ⁷⁶ Evidence from clinical trials or qualified case reports is lacking, but animal studies have suggested possible adverse effects.

Precautions and Warnings

Patients being treated for cardiac arrhythmias, particularly with a history of sustained ventricular fibrillation or ventricular tachycardia, require close supervision when introducing fish oil preparations into their therapeutic regimen or significantly altering the dose or form. Complex and often bimodal responses are possible and vary depending on source (fish vs. fish oils), dose, and patient characteristics. For example, although some research indicates that individuals who ate fish had a reduced risk for developing atrial fibrillation, preliminary data suggest that a high level of fish consumption (five or more servings per week) is associated with an increased risk of atrial fibrillation in middle-age men. ⁷⁷ However, fish consumption also protects against ventricular fibrillation and sudden cardiac death and helps to protect the coronary vessels.

Likewise, similar cautions are relevant in patients with hypertension, diabetes, or other cardiovascular disease. Although omega-3 fatty acids may be beneficial for many individuals with these conditions, regular monitoring and close supervision are appropriate when introducing any nutraceutical or pharmacological agent, altering dose or form, or interjecting new medications that might interact with the nutrient or comedications.

Individuals with familial combined hyperlipidemia may exhibit an increased incidence of spontaneous bleeding. ^48,78

Coincident ingestion of fat-soluble vitamins, specifically vitamins A, D, and E, can unintentionally elevate these levels through use of fish oil products. Attention to labels and cumulative dose is important to avoid adverse effects, although frank toxicity caused by supplemental intake at typical doses is unlikely, except in cases of regular use of fish liver oils. These oils are particularly rich in vitamins A and D, the concentrations of which can vary widely between products, depending on source of fish liver and processing of the product.

Strategic Considerations

The physiological, preventive, and therapeutic effects of omega-3 fatty acids are overwhelmingly positive, and most interactions between this nutrient class and conventional pharmaceutical agents are beneficial. Although not quite the panacea predicted by many early enthusiasts, the breadth of research into and possible clinical applications of fish oils (DHA, EPA) and ALA has grown at an astounding pace in the past few decades. These “discoveries” not only point to the fundamental and multifactorial roles that omega-3 fatty acids play in many aspects of human physiology, but also highlight the deficits and imbalances in the human diet in developed societies. Moreover, the manifold mechanisms by which omega-3 fatty acids support and modulate many physiological functions, while introducing few significant adverse effects, make them a particularly appropriate agent for integration with a broad range of pharmaceutical agents, particularly those that treat or increase oxidative damage or inflammation, neuroendocrine or immune dysregulation, or cardiovascular dysfunction. Recommendation of two or more servings of fish rich in omega-3 oils per week has become standard within conventional medicine and governmental policy, but clinical application of the benefits of fish oil and ALA in nutraceutical forms has yet to be integrated into conventional practice guidelines.

Research into the physiology and therapeutics of long-chain omega-3 fatty acids has grown steadily ever since Bang and Dyerberg reported the association between a diet rich in long-chain marine omega-3 fatty acids and reduced incidence of atherosclerotic heart disease in Greenland Eskimos. ^79-81However, the epidemiological associations of dietary fish intake and therapeutic effects (or risks) of omega-3 fatty acids and fish oil in the subsequent decades of literature are often intertwined and mixed without clarity or consistency in analyses and conclusions. ^57,82Most importantly, many key variables need to be taken into account in study design, in presentation of findings, and in dissemination of news. Variables such as proportions of preintervention dietary constituents, differentiation of dietary fish rich in omega-3s versus less oily fish, proportions of EPA and DHA in different preparations, and methods of extraction and purification can significantly alter findings and their clinical implications. However, these factors frequently are inadequately factored into meta-analyses, reviews, and news reports in both professional publications and the lay press.

The role of fish oil in development of the CNS and subsequent neurological and cognitive function is generally accepted. ^83-88In particular, DHA is pivotal through its activity as a major component of the phospholipid layer of neuronal membranes. Its roles in chloride and other ion channel opening at the synapse of neurons, increasing stability of neuronal functioning, influencing multiple gene expressions, modulating GABA responses, promoting dopamine and serotonin neurotransmission, increasing acetylcholine release, inhibiting multiple spikes in epileptiform activity, protecting against oxidative stress, and serving as an overall neuroprotectant, place DHA, and to a lesser extent its shorter-chain sibling EPA, at the center of ongoing and evolving neurocognitive science. ^89-96Surprisingly, however, the medical literature still contains lingering hesitations regarding the universal efficacy of increasing DHA during pregnancy and infant nutrient intake. In these areas the incomplete and sometimes contradictory evidence regarding the preventive properties of fish oil remains a source of controversy and investigation. Further research into the important supportive role of fish oil throughout the life cycle, from embryonic and infant development to preventing dementia in the elderly, continues to emerge, and the only remaining question is the degree to which conventional medicine can integrate this important nutritive strategy.

A broad consensus supports the proposition that fish and marine omega-3 fatty acid intake is associated with improved cardiovascular health. The central role of fish oil in risk reduction, prevention, and treatment of cardiovascular disease derives from broadly accepted functions and activities, including effects on inflammation and oxidation, membrane physiology and lipoprotein metabolism, blood vessel pliability and atherosclerotic plaque formation, platelet reactivity, and blood flow characteristics. Nevertheless, the efficacy and safety of fish oil administration for heart disease in general and patients with particular conditions remain controversial and uncertain, with data and interpretations suggesting a range of responses, from beneficial to potentially dangerous; some commentators interpret these contradictory findings to suggest that fish oil's benefit to individuals with heart disease is slight or nonexistent. ^97-99Consequently, according to various sources, fish and fish oil may reduce the risk, incidence, and severity of atherosclerosis, thrombosis, arrhythmias, atrial fibrillation, coronary heart disease, sudden cardiac death, heart failure, and stroke or may, on the other hand, potentially increase risk of sudden death from myocardial infarction in individuals with stable heart disease. ^97,99-101Nevertheless, in a review of data on the efficacy and safety of different antilipidemic agents and diets on mortality, Studer et al. ¹⁰² found that fish oil is superior to statin therapy for lowering overall cardiac mortality risk. They also found, regarding the fibrate class of antilipidemics (which historically preceded the statins), “any potential reduction in cardiac mortality from fibrates is offset by an increased risk of death from noncardiovascular causes.” ¹⁰²

In addition to nutritive, antioxidant, and inflammatory modulation effects, the known antithrombotic effects of omega-3 fatty acids on platelet aggregation and blood viscosity suggest that administration may be beneficial in conjunction with surgical procedures such as prevention of restenosis after coronary angioplasty (PTCA) or prevention of graft failure after heart bypass surgery. Analyzing electrocardiographic (ECG) data from two prospective trials that included 52 heart transplant recipients, Harris et al. ¹⁰³ found that administration of 1 to 3.4 g omega-3 fatty acid daily for 4 to 6 months reduced heart rates and prolonged QRS duration, even though these patients were presumably devoid of vagal innervation, suggesting that n-3 fatty acids may modify electrophysiological properties of the myocardium itself. Research into such integrative approaches, however, is still emerging and inconclusive, with findings that have been mixed and often less positive than expected. ^46,104-109

The potential small increase in bleeding risk, possibility of elevated LDL cholesterol level, and impact on glycemic control constitute the primary adverse effects consistently appearing in the literature, besides nausea, loose stools, and fishy eructations. These effects, however, are often transient, dose dependent, and preparation related and can usually be corrected by regular exercise and increasing dietary fibers such as pectin, especially within the context of a comprehensive strategy integrating lifestyle changes, improved diet, stress management, conventional medications, and specific nutrient/herb combinations. ^59,72Such synergistic approaches can be personalized and can evolve in response to the initiative and abilities, risks and needs, and susceptibilities and tolerances of the individual patient. As with other intersections of body systems and pathophysiology, individual pharmacogenomic variability, patient participation and compliance, and the therapeutic relationship play highly influential roles in determining risk severity, medication reactions, and therapeutic response. Although issues regarding potential for increased bleeding risk at high doses and possible elevation of LDL cholesterol level or reduced glycemic control will remain cause for concern and monitoring, these adverse effects are not axiomatic, universal, severe, or irremediable.

A review of the scientific and medical literature reveals broad support, with a strong and consistent underlying body of scientific evidence, for regular dietary intake of omega-3 fatty acids in amounts greater than currently in common use, with an accompanying reduction in omega-6 fatty acid intake (predominantly from warm-weather vegetable oils and grains) and a preferred emphasis on dietary fish consumption. The issue of shifting the balance between omega-3 and omega-6 fatty acids remains a central concern in epidemiological, dietary, and therapeutic contexts. The gross preponderance of omega-6 fatty acids in the typical American diet, especially through corn oil, is universally considered problematic in terms of physiological stress, particularly inflammatory thresholds, and as an impediment against the beneficial activities of fish oil and other omega-3 fatty acids. ⁹³ Reducing the excess intake of omega-6 oils and shifting the balance of intake toward omega-3 oils can be beneficial in preventing or treating numerous pathological processes. For example, increasing omega-3 sources and reducing omega-6 intake may benefit several cardiovascular risk parameters. ¹¹⁰ Likewise, animal research indicates that increasing omega-3 fatty acid levels and decreasing omega-6 levels could reduce the risk of prostate cancer through beneficial effects on prostate cell membrane composition, cyclooxygenase-2 (COX-2) activity, and lowering of prostaglandin E2(PGE2) production. ¹¹¹ The Mediterranean diet in particular has become the center of population studies on a broad level and more focused research in terms of particular constituents. In addition to its general emphasis on healthy dietary fats and a significantly higher proportion of omega-3 (vs. omega-6) fatty acids, this dietary approach is rooted in the regional ecosystem and provides a generous supply of whole grains, fresh fruits and vegetables, olive oil (rich in omega-9 fats, which are neutral in the omega-6/omega-3 equation), garlic, and other herbs, with high amounts of protein from fish and seafood and moderate amounts from meat. ¹¹²

Overall, the body of evidence from scientific literature and clinical practice demonstrates the recurring need for a personalized, evolving, comprehensive therapeutic intervention, multidisciplinary in content and integrative in approach, toward the many areas of human physiology and health, as well as pathophysiology and disease that are affected by omega-3 fatty acids. Whether neurological health and cognitive function; inflammatory modulation, free-radical quenching, and immune function; or cardiovascular health and heart disease or stroke, this nutrient class exhibits a diverse range of direct effects and possibilities for therapeutic synergy.

The issue of toxic pollution attributable to humans, particularly methylmercury, dioxins, and PCBs, appears to be the most significant risk and limiting factor associated with dietary intake of omega-3 fatty acids from fish or fish-derived nutraceutical forms. Given the compromised state of oceanic ecologies and systemic damage to sealife, especially fisheries, a global policy of high dietary fish consumption seems unwise and unsustainable, and ultimately may prove irresponsible. Thus, the need arises for increased production and easier access to omega-3 fatty acids from nonfish sources. Shifting to nutraceutical forms of omega-3 intake leads to questions that rarely appear in looking at dietary sources, except among those small populations who consume fish or other sealife sources at high levels, sometimes referred to as “Eskimo” levels. A large and diverse set of well-designed, adequately powered, and long-duration clinical trials will be necessary to answer many of the lingering questions that have arisen from epidemiological and population studies, clinical interventions, and emergent integrative strategies.

This review has considered flaxseed and related plant sources of omega-3 fatty acids, particularly ALA, only in relation to those effects and interactions associated with the fatty acid constituents. Potential preventive, therapeutic, and interactions issues related to the fiber or lignan components, such as proposed laxative or anticancer properties, have not been considered.

In relation to possible interactions involving flaxseed, reasonable application of known pharmacological principles suggests that oral consumption of flaxseed (but not flaxseed oil) may impair absorption of drugs or other nutrients ingested at the same time. Such possible pharmacokinetic effects on bioavailability may be minimized by separating intake by 1 to 2 hours before or 2 to 4 hours after flaxseed ingestion, depending on dose and other variables.

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