Other Nutrients

The Food and Nutrition Board of the US Institute of Medicine has set an Adequate Intake level for choline, essential fatty acids (linoleic acid and α-linolenic acid), and total fiber. Select a nutrient from the list for more information.



  • Choline is a vitamin-like essential nutrient and a methyl donor involved in many physiological processes, including normal metabolism and transport of lipids, methylation reactions, and neurotransmitter synthesis. (More information)
  • Choline deficiency causes muscle damage and abnormal deposition of fat in the liver, which results in a condition called nonalcoholic fatty liver disease. Genetic predispositions and gender can influence individual variation in choline requirements and thus the susceptibility to choline deficiency-induced fatty liver disease. (More information)
  • The recommended adequate intake (AI) of choline is set at 425 milligrams (mg)/day for women and 550 mg/day for men. (More information)
  • Choline is involved in the regulation of homocysteine concentration in the blood through its metabolite betaine. There is currently no convincing evidence that high choline intakes could benefit cardiovascular health through lowering blood homocysteine. Besides, elevated blood concentrations of trimethylamine N-oxide (TMAO), generated from choline, may increase the risk of cardiovascular events. (More information)
  • The need for choline is probably increased during pregnancy. Case-control studies examining the relationship between maternal choline status and risk of neural tube defects (NTDs) have given inconsistent results. It is not yet known whether periconceptual choline supplementation could confer protection against NTDs. (More information)
  • Animal studies have shown that choline is essential for optimal brain development and influences cognitive function in later life. However, in humans, there is not enough evidence to assert that choline supplementation during pregnancy improves offspring’s cognitive performance or that it helps prevent cognitive decline in older people. (More information)
  • Recent intervention studies have found that supplementation with citicoline (a choline derivative) may be useful to limit neurologic damage in stroke patients and improve retinal function in some glaucoma patients. It remains unclear whether citicoline could be used in the treatment of dementias and in head trauma patients. (More information) 
  • De novo choline synthesis in humans is not sufficient to meet their metabolic needs. Good dietary sources of choline include eggs, meat, poultry, fish, cruciferous vegetables, peanuts, and dairy products. (More information)
  • Excessive consumption of choline (≥7,500 mg) has been associated with blood pressure lowering, sweating, fishy body odor, and gastrointestinal side effects. The tolerable upper intake level (UL) for adults is 3,500 mg/day. (More information)

Although choline is not by strict definition a vitamin, it is an essential nutrient. Despite the fact that humans can synthesize it in small amounts, choline must be consumed in the diet to maintain health. The majority of the body's choline is found in specialized fat molecules known as phospholipids, the most common of which is called phosphatidylcholine (1).


Choline and compounds derived from choline (i.e., metabolites) serve a number of vital biological functions (Figure 1) (1).

Figure 1. Chemical structures of choline and its derivatives, acetylcholine, betaine (trimethylglycine), glycerophosphorylcholine, phosphatidylcholine, and sphingomyelin.

Structural integrity of cell membranes

Choline is used in the synthesis of certain phospholipids (phosphatidylcholine and sphingomyelin) that are essential structural components of cell membranes. Phosphatidylcholine accounts for about 95% of total choline in tissues (2). This phospholipid can be synthesized from dietary choline via the cytidine diphosphocholine (CDP-choline) pathway or through the methylation of another phospholipid, phosphatidylethanolamine (Figure 2) (3). Sphingomyelin is a type of sphingosine-containing phospholipid (sphingolipid) that is synthesized by the transfer of a phosphocholine residue from a phosphatidylcholine to a ceramide (Figure 3). Sphingomyelin is found in cell membranes and in the fatty sheath that envelops myelinated nerve fibers. 

Phosphatidylcholine is synthesized from choline via two pathways. Figure 2a shows the cytidine diphosphocholine (CDP-choline) pathway (enzymes of this pathway include choline kinase, CTP:choline phosphate cytidylyltransferase, and CDP-choline:1,2-diacylglycerol choline phosphotransferase.

Phosphatidylcholine is synthesized from choline via two pathways. Figure 2b shows the methylation of the phospholipid, phosphatidylethanolamine, via the enzyme, phosphatidylethanolamine N-methyltransferase; this reaction requires three molecules of S-adenosylmethionine (SAM).

Figure 3. Synthesis of Sphingomyelin. Sphingomyelin synthase catalyzes the transfer of a phosphocholine headgroup from phosphatidylcholine to ceramide, generating sphingomyelin and 1,2-diacylglycerol.

Cell signaling

The choline-containing phospholipids, phosphatidylcholine and sphingomyelin, are precursors for the intracellular messenger molecules, diacylglycerol and ceramide. Specifically, sphingomyelinases (also known as sphingomyelin phosphodiestarases) catalyze the cleavage of sphingomyelin, generating phosphocholine and ceramide. Diacylglycerol is released by the degradation of phosphatidylcholine by phospholipases. Other choline metabolites known to be cell-signaling molecules include platelet activating factor (PAF) and sphingophosphocholine. 

Nerve impulse transmission

Choline is a precursor for acetylcholine, an important neurotransmitter synthesized by cholinergic neurons and involved in muscle control, circadian rhythm, memory, and many other neuronal functions. Choline acetyltransferase catalyzes the acetylation of choline to acetylcholine, and acetylcholine esterase hydrolyzes acetylcholine to choline and acetate (4). CDP-choline administration was also found to stimulate the synthesis and release of a family of neurotransmitters derived from tyrosine (i.e., the catecholamines, including noradrenaline, adrenaline, and dopamine) (5). Of note, non-neuronal cells of various tissues and organ systems also synthesize and release acetylcholine, which then binds and stimulates cholinergic receptors on target cells (reviewed in 6).

Lipid (fat) transport and metabolism

Fat and cholesterol consumed in the diet are transported to the liver by lipoproteins called chylomicrons. In the liver, fat and cholesterol are packaged into lipoproteins called very-low-density lipoproteins (VLDL) for transport in the bloodstream to extrahepatic tissues. Phosphatidylcholine synthesis by the phosphatidylethanolamine N-methyltransferase (PEMT) pathway is required for VLDL assembly and secretion from the liver (7, 8). Without adequate phosphatidylcholine, fat and cholesterol accumulate in the liver (see Deficiency). 

Major source of methyl groups

Choline may be oxidized in the liver and kidney to form a metabolite called betaine via a two-step enzymatic reaction. In the mitochondrial inner membrane, flavin adenine dinucleotide (FAD)-dependent choline oxidase catalyzes the conversion of choline to betaine aldehyde, which is then converted to betaine by betaine aldehyde dehydrogenase in either the mitochondrial matrix or the cytosol (2). Betaine is a source of up to 60% of the methyl (CH3) groups required for the methylation of homocysteine (9). Betaine homocysteine methyltransferase (BHMT) uses betaine as a methyl donor to convert homocysteine to methionine in one-carbon metabolism (Figure 4). The ubiquitous vitamin B12-dependent methionine synthase (MS) enzyme also catalyzes the re-methylation of homocysteine, using the folate derivative, 5-methyltetrahydrofolate, as a methyl donor (see Nutrient interactions). Elevated concentrations of homocysteine in the blood have been associated with increased risk of cardiovascular disease (10).

Figure 4. Homocysteine Metabolism. (a) Homocysteine is methylated to form the essential amino acid methionine in two pathways. The reaction of homocysteine remethylation catalyzed by the vitamin B12-dependent methionine synthase captures a methyl group from the folate-dependent, one-carbon pool (5-methyltetrahydrofolate). A second pathway requires a choline derivative, betaine (N,N,N-trimethylglycine), as a methyl donor for the methylation of homocysteine catalyzed by betaine homocysteine methyltransferase (BHMT). The catabolic pathway of homocysteine, known as the transsulfuration pathway, converts homocysteine to the amino acid cysteine via two vitamin B6-dependent enzymes: cystathionine beta synthase catalyzes the condensation of homocysteine with serine to form cystathionine, and cystathionine is then converted to cysteine, alpha-ketobutyrate, and ammonia by cystathionine gamma lyase. (b) Methionine is the precursor of the universal methyl donor, S-adenosylmethionine (SAM). Three SAM molecules are required for the methylation of phosphatidylethanolamine to phosphatidylcholine by phosphatidylethanolamine N-methyltransferase (PEMT). Choline can be generated from phosphatidylcholine via the action of phospholipases. Conversely, choline can be converted to phosphatidylcholine via the cytidine diphospho (CDP)-choline pathway.


The conversion of choline to betaine is irreversible. Betaine is an osmolyte that regulates cell volume and protect cell integrity against osmotic stress (especially in the kidney). Osmotic stress has been associated with a reduced BHMT expression such that the role of betaine in osmoregulation may be temporarily prioritized over its function as a methyl donor (2).



Men and women fed intravenously (IV) with solutions that contained adequate methionine and folate but lacked choline have been found to develop a condition called nonalcoholic fatty liver disease (NAFLD) and signs of liver damage that resolved when choline was provided (11). The occurrence of NAFLD is usually associated with the co-presentation of metabolic disorders, including obesity, dyslipidemia, insulin resistance, and hypertension, in subjects with metabolic syndrome. NAFLD is estimated to progress to a more severe condition called nonalcoholic steatohepatitis (NASH) in about one-third of NAFLD patients, as well as to increase the risk of cirrhosis and liver cancer (12)

Because phosphatidylcholine is required in the synthesis of very-low-density lipoprotein (VLDL) particles (see Function), choline deficiency results in impaired VLDL secretion and accumulation of fat in the liver (steatosis), ultimately leading to liver damage. Because low-density lipoprotein (LDL) particles are formed from VLDL particles, choline-deficient individuals also show reduced blood concentrations of LDL-cholesterol (13). Abnormally elevated biomarkers of organ dysfunction in the blood, including creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase, are corrected upon choline repletion. Choline deficiency-induced organ dysfunction has also been associated with increased DNA damage and apoptosis in circulating lymphocytes (14). In the liver, the accumulation of lipids is thought to impair mitochondrial function, thus reducing fatty acid oxidation and increasing the production of reactive oxygen species (ROS) that trigger lipid peroxidation, DNA damage, and apoptosis. Further, oxidative stress is thought to be responsible for prompting inflammatory processes that can lead to the progression of NAFLD to NASH and cirrhosis (end-stage liver disease) (15)

An intervention study in 57 healthy adults who were fed choline-deficient diets under controlled conditions found that 77% of men, 80% of postmenopausal women, and 44% of premenopausal women developed fatty liver, liver damage, and/or muscle damage (16). These signs of organ dysfunction resolved upon choline reintroduction in the diet. Because estrogen stimulates the endogenous synthesis of phosphatidylcholine via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, premenopausal women may be less likely to develop signs of choline deficiency in response to a low-choline diet compared to postmenopausal women (17, 18). Further, a notable single nucleotide polymorphism (SNP; rs12325817) of the PEMT gene, which may affect the expression and/or activity of the PEMT enzyme, is thought to increase the susceptibility to choline deficiency-induced organ dysfunction (17). Additional genetic polymorphisms occurring in choline and one-carbon metabolic pathways may alter the dietary requirement for choline and thus increase the likelihood of developing signs of deficiency when choline intake is inadequate (19-21). The composition of one’s intestinal microbiota has been recently identified as another potential predictor of susceptibility to choline deficiency-induced NAFLD (22). Of note, intestinal microbiota-dependent metabolism of dietary phosphatidylcholine might also be involved in the pathogenesis of cardiovascular disease (see Safety) (23, 24).  

See Disease Prevention for more information on fatty liver diseases.

Nutrient interactions

Together with several B-vitamins (i.e., folate, vitamin B12, vitamin B6, and riboflavin), choline is required for the metabolism of nucleic acids and amino acids, and for the generation of the universal methyl group donor, S-adenosylmethionine (SAM) (see Figure 4 above). SAM is synthesized from the essential amino acid, methionine. Three molecules of SAM are required for the methylation reaction that converts phosphatidylethanolamine into phosphatidylcholine (see Figure 2 above). Once SAM donates a methyl group it becomes S-adenosylhomocysteine (SAH), which is then metabolized to homocysteine. Homocysteine can be converted back to methionine in a reaction catalyzed by vitamin B12-dependent methionine synthase, which requires 5-methyltetrahydrofolate (5-meTHF) as a methyl donor. Alternately, betaine (a metabolite of choline) is used as the methyl donor for the methylation of homocysteine to methionine by the enzyme, betaine-homocysteine methyltransferase (BHMT) (1). Homocysteine can also be metabolized to cysteine via the vitamin B6-dependent transsulfuration pathway (see Figure 4 above). 

Thus, the human requirement for choline is especially influenced by the relationship between choline and other methyl group donors such as folate and S-adenosylmethionine. A low intake of folate leads to an increased demand for choline-derived metabolite, betaine. Moreover, the de novo synthesis of phosphatidylcholine is not sufficient to maintain adequate choline nutritional status when dietary intakes of folate and choline are low (25). Conversely, the demand for folate is increased when dietary supply for choline is limited (26)

The Adequate Intake (AI)

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established a dietary reference intake (DRI) for choline (27). The FNB felt the existing scientific evidence was insufficient to calculate an RDA for choline, so they set an Adequate Intake (AI; Table 1). The main criterion for establishing the AI for choline was the prevention of liver damage. Yet, common polymorphisms in genes involved in choline or folate metabolism alter one’s susceptibility to choline deficiency and thus may affect dietary requirements for choline (see Deficiency) (17, 19).

Table 1. Adequate Intake (AI) for Choline
Life Stage Age Males
Infants 0-6 months 125 125
Infants 7-12 months 150 150
Children 1-3 years 200 200
Children 4-8 years 250 250
Children 9-13 years 375 375
Adolescents 14-18 years 550 400
Adults 19 years and older 550 425
Pregnancy all ages - 450
Breast-feeding all ages - 550

Disease Prevention

Cardiovascular disease

Choline and homocysteine

A large body of research indicates that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular disease (CVD) (10). The most common cause of a myocardial infarction or a stroke is the rupture of atherosclerotic plaques in arterial walls causing blood clot formation (thrombogenesis). High homocysteine concentrations may promote the development of atherosclerosis (atherogenesis) and thrombogenesis via mechanisms involving oxidative stress and endothelial dysfunction, inflammation, abnormal blood coagulation, and disordered lipid metabolism (reviewed in 28). 

Once formed from dietary methionine, homocysteine can be catabolized to cysteine via the transsulfuration pathway or re-methylated to methionine (see Figure 4 above). Folate and choline are involved in alternate pathways that catalyze the re-methylation of homocysteine (see Nutrient interactions). Specifically, choline is the precursor of betaine, which provides a methyl group for the conversion of homocysteine to methionine via the enzyme, betaine-homocysteine methyltransferase (BHMT). While the amount of homocysteine in the blood is regulated by several nutrients, including folate and choline, conditions that cause damage to the liver like nonalcoholic steatohepatitis (NASH) may also affect homocysteine metabolism (29)

Dietary intakes of choline and betaine and CVD

Because both folate- and choline-dependent metabolic pathways catalyze the re-methylation of homocysteine, dietary intakes of both nutrients need to be considered when the association between homocysteine concentrations and cardiovascular disease is assessed. Yet, despite its relevance, the relationship of betaine and choline to homocysteine metabolism has been only lightly investigated in humans, essentially because the choline content of foods could not be accurately measured until recently. In preliminary intervention studies, pharmacologic doses of betaine (1,500 to 6,000 mg/day) were found to reduce blood homocysteine concentrations in a small number of volunteers with normal-to-mildly elevated homocysteine concentrations (30-33). Yet, in a cross-sectional analysis of a large cohort of 16,165 women (ages, 49-79 years), lower betaine doses in the range of dietary intakes were not found to be correlated with homocysteine concentrations (34). This study also showed that levels of choline intake were inversely associated with homocysteine concentrations in the blood. However, an eight-year follow-up study of the cohort failed to show any difference in cardiovascular risk between women in the upper versus bottom quartile of dietary choline intakes (>329 mg/day vs. ≤266 mg/day) (34). The prospective study of the Atherosclerosis Risk in Communities (ARIC) cohort found that the highest vs. lowest quartile (>486 mg/day vs. <298 mg/day) of total choline intakes from food was not significantly associated with the incidence of coronary artery disease in 14,430 middle-aged participants (35). Also, in a recent analysis of the Health Professionals Follow-up Study (HPFS) that enrolled 44,504 men for a period of 24 years, the risk of peripheral artery disease was positively correlated with homocysteine concentrations but neither with betaine nor choline levels of intake (36).

While further research is indicated, convincing evidence that increased dietary intake of choline or betaine could benefit cardiovascular health through lowering homocysteine concentrations in the blood is presently lacking.

Circulating concentrations of choline and betaine and CVD risk

A 1995 study had found that elevated blood homocysteine concentrations in patients who experienced a vascular occlusion were associated with higher urinary excretion of betaine, rather than with reduced intake of choline or betaine or diminished activity of BHMT (37). In a recent prospective study, high urinary betaine excretion was also associated with increased risk of heart failure in 325 nondiabetic subjects who have been hospitalized for acute coronary syndrome (38). In the same study, both top and bottom quintiles of plasma betaine concentrations were associated with an increased risk of secondary acute myocardial infarction. The findings of another prospective study (the Hordaland Health Study) that followed 7,045 healthy adults (ages, 47-49 years and 71-74 years) suggested that high choline and low betaine plasma concentrations were associated with an unfavorable cardiovascular risk profile (39). Indeed, plasma choline was positively associated with a number of cardiovascular risk factors, such as BMI, percentage body fat, waist circumference, and serum triglycerides, and inversely associated with HDL-cholesterol. On the contrary, plasma betaine was positively correlated to HDL-cholesterol and inversely associated with the above-mentioned risk factors as well as with systolic and diastolic blood pressure. More recent studies now suggest that the blood concentration of trimethylamine N-oxide (TMAO), generated from trimethylamine-containing nutrients like dietary choline, rather than that of choline, might influence the risk of cardiovascular events (see Safety).

It is not yet clear whether concentrations of choline, betaine, and/or TMAO in the blood can predict the risk for cardiovascular disease.

Liver diseases

Fatty liver diseases

While a choline-deficient diet results in organ dysfunction and nonalcoholic fatty liver disease (NAFLD) (see Deficiency; 16), it is not known whether suboptimal dietary choline intakes in healthy subjects may contribute to an increased risk for NAFLD. A cross-sectional analysis of two large prospective studies conducted in China – the Shanghai Women’s Health Study and the Shanghai Men’s Health Study – including 56,195 people (ages, 40-75 years), was recently conducted to assess the association between dietary choline intakes and self-reported diagnosis of fatty liver disease (40). The highest versus lowest quintile of choline intake (412 mg/day vs. 179 mg/day) was associated with a 28% lower risk of fatty liver disease in normal-weight women, but no association was found in overweight or obese women or in men. Another cross-sectional study of 664 individuals with NAFLD or nonalcoholic steatohepatitis (NASH) also reported that disease severity was inversely correlated with dietary choline intakes in postmenopausal women, but not in premenopausal women, men, or children (41)

Liver cancer

In animal models, dietary choline deficiency has been associated with an increased incidence of spontaneous liver cancer (hepatocellular carcinoma) and increased sensitivity to carcinogenic chemicals (9). A number of mechanisms have been proposed to contribute to the cancer-promoting effects of choline deficiency: (1) enhanced liver cell regeneration and tissue sensitivity to chemical insults; (2) altered expression of numerous genes regulating cell proliferation, differentiation, DNA repair, and apoptosis due to improper DNA methylation; (3) increased likelihood of DNA damage caused by mitochondrial dysfunction-induced oxidative stress; and (4) activated protein kinase C-mediated cell-signaling cascade, eventually leading to an increase in liver cell apoptosis (2). Yet, it is not known whether choline deficiency can increase the susceptibility to cancer in humans (2).

Neural tube defects

It is known that folate is critical for normal embryonic development, and maternal supplementation with folic acid decreases the incidence of neural tube defects (NTDs) (42). NTDs include various malformations, such as lesions of the brain (e.g., anencephaly, encephalocele) or lesions of the spine (spina bifida), which are devastating and usually incompatible with life (43). These defects occur between the 21st and 28th days after conception, a time when many women do not realize that they are pregnant (44). While the protective effect of folate against NTD is well established, only a few studies have investigated the role of other methyl group donors, including choline and betaine, in the occurrence of NTDs. A case-control study (424 NTD cases and 440 controls) found that women in the highest versus lowest quartile of periconceptual choline intake (>498.46 mg/day vs. ≤290.41 mg/day) had a 51% lower risk of an NTD-affected pregnancy (45). However, more recent studies failed to find an inverse relationship between maternal choline intake and risk of NTDs (46, 47). Another case-control study (80 NTD-affected pregnancy and 409 controls) in US women found that the lowest concentrations of serum choline (<2.49 mmol/L) during mid-pregnancy were associated with a 2.4-fold higher risk of NTDs (48). Finally, a more recent study, including 71 NTD-affected pregnancies, 214 pregnancies with non NTD malformations, 98 normal pregnancies in women with prior NTD-affected pregnancies, and 386 normal pregnancies, found no associations between maternal blood concentrations of choline during pregnancy, choline- and folate-related genetic variants, and risk of NTDs (49). However, it is important to note that circulating choline concentrations do not accurately reflect dietary intake of choline.

More research is needed to determine whether supplemental choline could add to the protective effect currently being achieved by periconceptual folic acid supplementation.

Cognitive health

Neuro-cognitive development

Increased dietary intake of cytidine 5’-diphosphocholine (CDP-choline or citicoline, a precursor of phosphatidylcholine; see Figure 2 above) very early in life can diminish the severity of memory deficits in aged rats (50). Choline supplementation of the mothers of unborn rats, as well as rat pups during the first month of life, led to improved performance in spatial memory tests months after choline supplementation had been discontinued (51). A review by McCann et al. discusses the experimental evidence from rodent studies regarding the availability of choline during prenatal development and cognitive function in the offspring (52)

Because of the importance of DNA methylation in normal brain development, neuronal functions, and cognitive processes (53), methyl donor nutrients like choline are essential for optimal brain functioning. However, clinical evidence to determine whether findings in rodent studies are applicable to humans is currently limited. Recently, the analysis of the Seychelles Child Development Nutrition Cohort study reported a lack of an association between plasma concentrations of choline and its related metabolites and cognitive abilities in 256 five-year-old children. Only plasma betaine concentrations were found to be positively correlated with preschool language test scores (54). Yet, because circulating concentrations of choline are not directly related to dietary choline intakes, the study could not evaluate whether maternal choline intakes influence children’s brain development. 

Project Viva is an ongoing prospective study that has examined the relationship between daily intakes of methyl donor nutrients in 1,210 women during pregnancy and child cognition at three and seven years postpartum. Maternal intake of choline during the first and/or second trimester of pregnancy was not correlated with measures of cognitive performance in children at age 3 years (55). Another report of the study indicated that upper vs. lower quartile of maternal choline intakes during the second trimester of pregnancy (median intakes, 392 mg/day vs. 260 mg/day) was significantly associated with higher visual memory scores in children aged 7 years old (56). Recently, a small randomized, double-blind, placebo-controlled trial in 99 pregnant women (ages, 21-41 years old) evaluated the effect of choline supplementation during pregnancy and lactation on infants’ cognitive function at ages 10 and 12 months (57). The results indicated that maternal choline supplementation (750 mg/day of choline in the form of phosphatidylcholine) from 18 weeks of gestation to 3 months’ postpartum provided no cognitive benefits in children regarding short-term visio-spatial memory, long-term episodic memory, and language and global development. 

Cognitive function in older adults

Cognitive function, including the domains of memory, speed, and executive function, decline gradually with increasing age. The rate of cognitive decline is also influenced by modifiable risk factors like dietary habits. Deficiency in B-vitamins and elevated homocysteine concentrations in the blood have been associated with cognitive impairments in the elderly. Yet, a recent meta-analysis of 11 trials indicated that homocysteine lowering using B-vitamin supplementation fails to limit cognitive decline or improve cognitive performance in older adults (58). The cross-sectional data analysis of a subgroup of 1,391 volunteers (ages, 36-83 years) from the large Framingham Heart Study Offspring cohort has indicated that dietary choline intake was positively associated with specific cognitive functions, namely verbal memory and visual memory (59). Another cross-sectional study of 2,195 individuals (ages, 70-74 years) from the Hordaland Health Study examined cognitive abilities and blood concentrations of various determinants of circulating homocysteine, including choline and betaine (60). Unlike betaine, high vs. low plasma concentrations of free choline (>8.36 mcmol/L vs. ≤8.36 mcmol/L) were found to be significantly associated with a greater performance at cognitive tests assessing sensory motor speed, perceptual speed, executive function, and global cognition. However, in an earlier intervention study that enrolled 235 elderly individuals (mean age, 81 years old) with or without mild vitamin B12 deficiency, baseline concentrations of betaine − but not choline − were found to be positively correlated to test scores evaluating the cognitive domains of construction, sensory motor speed, and executive function (61)

More research is needed to determine the effect of choline on the developing brain and whether choline intakes above the RDA may be useful in the prevention of memory loss or dementia in humans.

Disease Treatment

Cerebrovascular diseases

Cerebrovascular diseases (including stroke and sub-acute ischemic cerebrovascular disease) are the main cause of cognitive impairments in older people. Results from experimental studies have suggested that pharmacological doses of citicoline (CDP-choline) could enhance the metabolism of glucose and the biosynthesis of phospholipids and neurotransmitters, while limiting the degradation of phospholipids in neuronal membranes in models of ischemia and neurodegenerative diseases (reviewed in 62). Many short-term intervention studies in older individuals with vascular diseases have found that therapeutic doses of citicoline given either orally, by intramuscular injection, or by intravenous infusion, resulted in improvements in neuropsychological functions, including cognitive, emotional, and behavioral functions (reviewed in 5).

A six-month, multicenter observational study enrolled 197 stroke subjects (mean age, 81.5 years) with a progressive decline of their mental health and general confusion and/or stupor who were initially administered citicoline for 5 or 10 days (2,000 mg/day, by intravenous infusion) within a four-month period, and then for 21 days (1,000 mg/day, by intramuscular injection), repeated once after a seven-day washout period (63). Citicoline treatment was found to be associated with higher scores on cognitive and functional evaluation scales when compared to baseline measurements. However, only randomized controlled trials would be able to assess whether citicoline is protective against vascular damage and cognitive impairment in elderly adults with complex geriatric symptoms. 

The International Citicoline Trial on acUte Stroke (ICTUS) is a multicenter and double-blind study that assessed the effect of supplementing 2,298 patients with acute ischemic stroke with citicoline (2,000 mg/day) or a placebo for six weeks on several functional and neurologic outcomes and on mortality rate (64). The results showed no difference between treatment groups after a 90-day follow-up period. Only subgroup analyses found significant benefits of citicoline in patients older than 70 years, in those with moderate rather than severe strokes, and in those not treated with recombinant tissue plasminogen activator (rtPA; standard-of-care treatment). An earlier meta-analysis of small randomized, placebo-controlled trials had reported a positive impact of citicoline (1,000 mg/day, administered for 28 days to 12 months) on memory and behavior in subjects with cognitive deficits associated with cerebrovascular disorders (65). The effect of citicoline was also evaluated in a recent multicenter, open-label, controlled trial (IDEALE trial) in Italian elderly adults (ages, 65-94 years) with evidence of vascular lesions on neuroradiology and mild-to-moderate cognitive deficits, as assessed by Mini-Mental State Examination (MMSE; scores ≥21) (66). Three hundred and forty-nine participants received oral citicoline (1,000 mg/day) or no treatment for nine months. MMSE scores in citicoline-treated individuals remained unchanged while they significantly deteriorated in untreated patients such that MMSE scores between groups were found to be significantly different after three and nine months of treatment. No significant effect was reported in measures of functional autonomy, mood, and behavioral disorders. Another recent open-label, randomized, controlled trial evaluated the effect of citicoline (1,000 mg/day for 12 months) in 347 subjects (mean age, 67.2 years) who suffered an acute stroke. The results demonstrated that citicoline significantly limited cognitive impairments in the domains of attention and executive functions and temporal orientation at 6 and 12 months post-stroke in treated compared to untreated patients (67).

Neurodegenerative diseases


Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson’s disease (PD), are characterized by progressive cognitive decline and dementia. Dysfunctions in neurotransmitter signaling, affecting cholinergic and dopaminergic pathways in particular, have been involved in the occurrence of cognitive impairments. Deficits in acetylcholine and abnormal phospholipid metabolism have been reported in postmortem studies of the brains of AD patients (11). For these reasons, inhibitors of (acetyl) cholinesterase (which catalyzes the breakdown of acetylcholine) and large doses of lecithin (phosphatidylcholine) have been used to treat patients with dementia due to AD in hopes of raising the amount of acetylcholine available in the brain. While cholinesterase inhibitors have shown positive effects on cognitive functions and measures of clinical global state (68), a systematic review of randomized controlled trials did not find lecithin to be more beneficial than placebo in the treatment of patients with cognitive impairment, vascular dementia, AD, or mixed dementia (69). Limited data are available to assess whether citicoline (CDP-choline) might improve cognitive performance in subjects with AD (70). No recent trial has investigated the effect of citicoline in PD patients.


Optic neuropathies, including glaucoma, are associated with damage of the optic nerve and loss of visual function. In glaucoma, the progressive deterioration of the optic nerve is caused by loss of a specific neuronal population known as retinal ganglion cells (RGC), such that the condition has been classified as a neurodegenerative disease (71). In a small, double-blind, placebo-controlled study, the effect of citicoline was assessed in 24 subjects affected by open-angle glaucoma and treated with β-blockers. Patients were randomized to follow a therapeutic cycle for a total period of eight years: citicoline (1,000 mg/day, by intramuscular injection) or placebo (β-blockers alone) for a two-month period followed by a four-month washout period (72). Electrophysiological examinations were used to assess the extent of visual dysfunctions, including the simultaneous recordings of Pattern ElectroRetinoGrams (PERG) and Visual Evoked Potentials (VEP). Citicoline was found to enhance retinal function and neural conduction along post-retinal visual pathways, such that responses of the visual cortex to stimuli were significantly improved compared to placebo. 

In a similar pilot trial, citicoline efficacy was assessed in 26 volunteers (mean age, 65.4 years) affected by another type of optic neuropathy known as non-arteritic anterior ischemic optic neuropathy (NAION). Oral citicoline (1,600 mg/day) was given for 60 days followed by 60 days of washout, and the therapeutic cycle was repeated once. Compared to placebo, citicoline was found to improve retinal function and post-retinal neural conduction, evidenced by PERG and VEP measures (73). Oral citicoline (four cycles of 500 mg/day for four months followed by a two-month washout period) was also found to significantly reduce the rate of visual field loss and the level of intraocular pressure in 41 patients with progressive glaucoma (74). Larger randomized controlled trials are needed to establish whether citicoline supplementation could be included in the medical treatment of glaucoma. 

Traumatic brain injury

For decades, pre-clinical and small clinical studies have investigated the effect of citicoline in the management of patients sustaining a traumatic brain injury (TBI). A systematic review of clinical data suggested that citicoline could hasten the resorption of cerebral edema and improve the recovery of consciousness and neurologic disorders in severe TBI cases (classified by Glasgow Coma Scale [GCS] scores of ≤8). Citicoline also appeared to limit memory deficits and the duration and severity of other post-traumatic symptoms (e.g., headache, dizziness, attention disorder) in TBI patients with mild-to-moderate injuries (GCS scores, 9-15) (reviewed in 5). Although citicoline is currently included in TBI therapeutic regimen in 59 countries, only one multicenter, randomized, double-blind, placebo-controlled trial has recently been conducted in the US. The CiticOline Brain Injury Trial (COBRIT) has enrolled 1,213 patients with mild-to-severe TBI and assessed the effect of enteral or oral citicoline (2,000 mg/day, for 90 days) on functional and cognitive outcomes (measured by components of the TBI Clinical Trials Network Care Battery) (75). No significant benefits of citicoline supplementation over placebo were found at 90 days (end of treatment period) and 180 days. A Cochrane review of the effect of citicoline in the treatment of TBI should be available soon (76).


De novo synthesis (biosynthesis)

Humans can synthesize choline moieties in small amounts by converting phosphatidylethanolamine into phosphatidylcholine (see Figure 2 above). Three methylation reactions catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) are required, each using S-adenosylmethionine (SAM) as a methyl group donor. Choline is generated endogenously when the methylation of phosphatidylethanolamine is coupled with the catabolism of newly formed phosphatidylcholine by phospholipases. This is referred to as de novo synthesis of choline. The substitution of choline by serine in the synthesis of phosphatidylserine from phosphatidylcholine by phosphatidylserine synthase-1 also releases choline (4). Because phosphatidylcholine metabolism is a source of endogenous choline, the nutrient was not initially classified as essential (1). Yet, de novo choline synthesis in humans is not sufficient to meet their metabolic needs such that healthy humans fed choline-deficient diets develop fatty liver, liver damage, and/or muscle damage (see Deficiency). 

Food sources

In the US, mean dietary intakes of choline are well below the recommended AI. According to a US national survey, NHANES 2007-2008, mean dietary intakes of choline were approximately 260 mg/day for women and 396 mg/day for men (77). In a 14-year US prospective study, including over 14,000 middle-aged participants, mean daily intakes of choline were 294 mg and 332 mg in women and men, respectively (35). Eggs, liver, and peanuts, are especially rich in choline (27). Major contributors to choline in the American diet are meat, poultry, fish, dairy foods, pasta, rice, and egg-based dishes (77). Spinach, beets, wheat, and shellfish are also good sources of the choline metabolite, betaine (78). Betaine cannot be converted back to choline but can spare some choline requirements for homocysteine remethylation (1). Phosphatidylcholine, which contains about 13% choline by weight, is the main form of choline in dietary products (79). Lecithin extracts, which comprise a mixture of phosphatidylcholine and other phospholipids, are often added during food processing. Lecithins in processed food have been estimated to increase the daily consumption of phosphatidylcholine by about 1.5 mg/kg of body weight for adults (27)

Strict vegetarians, who consume no meat, milk, or eggs, may be at risk for inadequate choline intake. The total choline contents of some choline-containing foods are listed in milligrams (mg) in Table 2. For more information on the nutrient content of specific foods, search the USDA food composition website or the USDA documentation on the choline content of common foods.

Table 2. Some Food Sources of Choline
Food Serving Total Choline (mg)
Beef liver, pan fried 3 ounces* 356
Wheat germ, toasted 1 cup 202
Egg 1 large 147
Beef, trim cut, cooked 3 ounces 97
Scallop, cooked, steamed 3 ounces 94
Salmon, pink, canned 3 ounces 75
Chicken, breast, cooked, roasted 3 ounces 73
Atlantic cod, cooked 3 ounces 71
Shrimp, canned 3 ounces 69
Brussel sprouts, cooked, boiled 1 cup 63
Broccoli, cooked, boiled 1 cup, chopped 63
Milk, skim 8 fluid ounces 38
Peanut butter, smooth 2 tablespoons 20
Milk chocolate 1.5-ounce bar 20
Peanuts 1 ounce 15
*A three-ounce serving of meat or fish is about the size of a deck of cards.


CDP-choline (citicoline) and choline salts, such as choline chloride and choline bitartrate, are available as supplements. Phosphatidylcholine supplements also provide choline; however, choline comprises only about 13% of the weight of phosphatidylcholine (79). Therefore, a supplement containing 4,230 mg (4.23 grams) of phosphatidylcholine would provide 550 mg of choline. Although the term "lecithin" is synonymous with phosphatidylcholine when used in chemistry, commercial lecithins are usually prepared from soybean, sunflower, and rapeseed, and may contain anywhere from 20%-90% of phosphatidylcholine. Egg yolk lecithin is a more unlikely source of lecithin in dietary supplements. Moreover, the nature of phosphatidylcholine-containing fatty acids depends on whether lecithin is produced from vegetable, animal, or microbial sources. In particular, soybean lecithin is richer in polyunsaturated fatty acids than egg yolk lecithin (80).



High doses (10,000 to 16,000 mg/day) of choline have been associated with a fishy body odor, vomiting, salivation, and increased sweating. The fishy body odor results from excessive production and excretion of trimethylamine, a metabolite of choline. In the inherited condition, primary trimethylaminuria (also known as “fish odor syndrome”; see the article on Riboflavin), a defective flavin containing monooxygenase 3 (FMO3) enzyme results in impaired oxidation of trimethylamine in the liver. Disease management includes the use of choline-restricted diets in affected individuals (81).

Taking large doses of choline in the form of phosphatidylcholine (lecithin) does not generally result in fishy body odor, because its metabolism results in little trimethylamine. A dose of 7,500 mg/day of choline was found to have a slight blood pressure lowering (hypotensive) effect, which could result in dizziness or fainting. Choline magnesium trisalicylate at doses of 3,000 mg/day has resulted in impaired liver function, generalized itching, and ringing of the ears (tinnitus). However, it is likely that these effects were caused by the salicylate, rather than the choline in the preparation (27).

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established the tolerable upper intake level (UL) for choline at 3,500 mg/day for adults (Table 3). This recommendation was based primarily on preventing hypotension (low blood pressure), and secondarily, on preventing the fishy body odor due to increased excretion of trimethylamine. The UL was established for generally healthy people, and the FNB noted that individuals with liver or kidney disease, Parkinson's disease, depression, or inherited trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL (27).

Table 3. Tolerable Upper Intake Level (UL) for Choline
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-8 years 1,000
Children 9-13 years 2,000
Adolescents 14-18 years 3,000
Adults 19 years and older 3,500
*Source of intake should be food and formula only.

Do high choline intakes and/or phosphatidylcholine supplements increase the risk for cardiovascular disease?

Oral supplementation with phosphatidylcholine (250 mg of total choline from food plus 250 mg of supplemental phosphatidylcholine) has been found to result in detectable concentrations of trimethylamine and trimethylamine N-oxide (TMAO) in the blood (23). The intestinal microbiota is directly implicated in the generation of trimethylamine from dietary choline, phosphatidylcholine, and carnitine. Trimethylamine is subsequently converted into TMAO by flavin-containing monooxygenases in the liver. The prospective study that followed 4,007 individuals,with or without cardiovascular disease (CVD) for a three-year period found baseline concentrations of circulating TMAO to be positively correlated with incidence of death, nonfatal myocardial infarction, and stroke − described as major adverse cardiac events (MACE) (23). In the same cohort, MACE risk was found to be about 30% higher in individuals in the highest vs. lowest quartile of choline or betaine plasma concentrations (82). However, depending on gut microbiota composition, the risk of having an adverse cardiovascular event may be lower in individuals with low vs. high circulating TMAO even though choline and/or betaine concentrations in the blood are elevated (82)

Elevated TMAO concentrations have been reported in subjects at increased risk of CVD, such as those with diabetes mellitus (83) or end-stage renal disease (chronic kidney failure) (84), and in patients with cardiac insufficiency (chronic heart failure) (85). Yet, in the latter patients, high plasma concentrations of choline, betaine, and TMAO were not associated with a poorer survival rate after five years of follow-up (85). Finally, supplementation with choline, TMAO, or betaine was found to result in the formation of macrophage-derived foam cells in atherosclerosis-prone mice (24). Foam cells are known to contribute to the development of atherosclerotic lesions (i.e., atherogenesis) by accumulating excessive amounts of lipids within the arterial walls and triggering the secretion of pro-inflammatory cytokines

Further research is needed to understand how the composition of intestinal microbiota influences the metabolic fate of ingested choline. At present, there is no evidence that dietary choline increases the risk of cardiovascular events.

Drug interactions

Methotrexate, a medication used in the treatment of cancer, psoriasis, and rheumatoid arthritis, inhibits the enzyme dihydrofolate reductase and therefore limits the availability of methyl groups donated from folate derivatives. Rats given methotrexate have shown evidence of diminished nutritional status of choline and greater drug adverse reactions due to liver dysfunction (11, 86). Thus, individuals taking methotrexate may have an increased choline requirement. Treatments with a family of lipid-lowering drugs known as fibrates (e.g., fenofibrate, bezofibrate) have been associated with an increased excretion of betaine in the urine and a rise in homocysteine concentration in the blood of patients with diabetes mellitus or metabolic syndrome (87, 88). If the benefits of fibrate therapy are indeed mitigated by fibrate-induced betaine deficiency, the use and safety of supplementing patients with betaine would need to be considered (89).

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary choline required to promote optimum health or prevent chronic diseases in humans. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 550 mg/day for adult men and 425 mg/day for adult women. A varied diet should provide enough choline for most people, but strict vegetarians who consume no milk or eggs may be at risk of inadequate choline intake. 

Older adults (>50 years)

Little is known regarding the amount of dietary choline most likely to promote optimum health or prevent chronic diseases in older adults. At present, there is no evidence to support a different recommended intake of choline from that of younger adults (550 mg/day for men and 425 mg/day for women).

Authors and Reviewers

Originally written in 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2015 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in February 2015 by:
Steven H. Zeisel, M.D., Ph.D.
Professor and Chair of Nutrition
School of Public Health
The University of North Carolina, Chapel Hill

Copyright 2003-2017  Linus Pauling Institute


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Essential Fatty Acids




Omega-6 and omega-3 fatty acids are polyunsaturated fatty acids (PUFA), meaning they contain more than one cis double bond (1). In all omega-6 fatty acids, the first double bond is located between the sixth and seventh carbon atom from the methyl end of the fatty acid (n-6). Similarly, in all omega-3 fatty acids, the first double bond is located between the third and fourth carbon atom counting from the methyl end of the fatty acid (n-3). Scientific abbreviations for fatty acids tell the reader something about their chemical structure. One scientific abbreviation for α-linolenic acid (ALA) is 18:3n-3. The first part (18:3) tells the reader that ALA is an 18-carbon fatty acid with three double bonds, while the second part (n-3) tells the reader that the first double bond is in the n-3 position, which defines it as an omega-3 fatty acid (Figures 1a and 1b). Double bonds introduce kinks in the hydrocarbon chain that influence the structure and physical properties of the fatty acid molecule (Figure 1c).

EFA Figure 1a. The general structure of a fatty acid: CH3 is the methyl or omega end; CHCH2(n) is the hydrocarbon chain; and COOH is the carboxyl end.

Figure 1b. The chemical structure of alpha-linolenic acid (ALA), 18:3n-3. ALA has 18 carbon atoms and 3 double bonds, the first of which is located 3 carbon atoms from the terminal methyl group (i.e., omega end).

Figure 1c. Chemical structures of linoleic acid (18:2n-6), alpha-linolenic acid (18:3n-3), stearidonic acid (18:3n-3), arachidonic acid (20:4n-6), eicosapentaenoic acid (20:5n-3), docosapentaenoic acid (22:5n-3), and docosahexaenoic acid (22:6n-3).

Although humans and other mammals can synthesize saturated fatty acids and some monounsaturated fatty acids from carbon groups in carbohydrates and proteins, they lack the enzymes necessary to insert a cis double bond at the n-6 or the n-3 position of a fatty acid (1). Consequently, omega-6 and omega-3 fatty acids are essential nutrients. The parent fatty acid of the omega-6 series is linoleic acid (LA; 18:2n-6), and the parent fatty acid of the omega-3 series is ALA (Table 1 and Figure 2). Humans can synthesize long-chain (20 carbons or more) omega-6 fatty acids, such as dihomo-γ-linolenic acid (DGLA; 20:3n-6) and arachidonic acid (AA; 20:4n-6), from LA and long-chain omega-3 fatty acids, such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), from ALA (see Metabolism and Bioavailability).

Table 1. Names and Abbreviations of the Omega-6 and Omega-3 Fatty Acids
Omega-6 Fatty Acids Omega-3 Fatty Acids
Linoleic acid LA 18:2n-6 α-Linolenic acid ALA 18:3n-3
γ-Linolenic acid GLA 18:3n-6 Stearadonic acid SDA 18:4n-3
Dihomo-γ-linolenic acid DGLA 20:3n-6 Eicosatetraienoic acid ETA 20:4n-3
Arachidonic acid AA 20:4n-6 Eicosapentaenoic acid EPA 20:5n-3
Adrenic acid   22:4n-6 Docosapentaenoic acid DPA (n-3) 22:5n-3
Tetracosatetraenoic acid   24:4n-6 Tetracosapentaenoic acid   24:5n-3
Tetracosapentaienoic acid   24:5n-6 Tetracosahexaenoic acid   24:6n-3
Docosapentaenoic acid DPA (n-6) 22:5n-6 Docosahexaenoic acid DHA 22:6n-3


Figure 2. Classes of Essential Fatty Acids. Omega-6 (n-6) and omega-3 (n-3) fatty acids comprise the two classes of essential fatty acids (EFA). The parent compounds of each class, linoleic acid (LA) and alpha-linolenic acid (ALA), give rise to longer chain derivatives inside the body. Due to low efficiency of conversion of ALA to the long-chain omega-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), it is recommended to obtain EPA and DHA from additional sources. Dietary sources of linoleic acid include vegetables oils like safflower oil. Dietary sources of ALA include green leafy vegetables; flax and chia seeds; and canola, walnut, and soybean oils. Arachidonic acid is found in meat, poultry, and eggs. Sources of EPA and DHA include oily fish, algae oil, and krill oil.

Metabolism and Bioavailability

Prior to absorption in the small intestine, fatty acids must be hydrolyzed from dietary fats (triglycerides and phospholipids) by pancreatic enzymes (2). Bile salts must also be present in the small intestine to allow for the incorporation of fatty acids and other fat digestion products into mixed micelles. Fat absorption from mixed micelles occurs throughout the small intestine and is 85-95% efficient under normal conditions.

Blood concentrations of fatty acids reflect both dietary intake and biological processes (3). Humans can synthesize longer omega-6 and omega-3 fatty acids from the essential fatty acids LA and ALA, respectively, through a series of desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions (Figure 3(4, 5). LA and ALA compete for the same elongase and desaturase enzymes in the synthesis of longer polyunsaturated fatty acids, such as AA and EPA.

Figure 3. Desaturation and Elongation of Essential Fatty Acids. Humans can synthesize longer omega-6 and omega-3 fatty acids from the essential fatty acids LA and ALA through a series of desaturation (addition of a double bond) and elongation (addition of two carbon atoms) reactions. Delta-6 desaturase (FADS2) is considered the rate-limiting enzyme in this metabolic pathway. Retroconversion of DHA to EPA in peroxisomes occurs at low basal rates and following DHA supplementation.

The capacity to generate DHA from ALA is higher in women than men. Studies of ALA metabolism in healthy young men indicate that approximately 8% of dietary ALA is converted to EPA and 0-4% is converted to DHA (6). In healthy young women, approximately 21% of dietary ALA is converted to EPA and 9% is converted to DHA (7). The better conversion efficiency of young women compared to men appears to be related to the effects of estrogen (8, 9). Although ALA is considered the essential omega-3 fatty acid because it cannot be synthesized by humans, evidence that human conversion of EPA and, particularly, DHA is relatively inefficient suggests that EPA and DHA may be considered conditionally essential nutrients.

In addition to gender differences, genetic variability in enzymes involved in fatty acid metabolism influences one's ability to generate long-chain polyunsaturated fatty acids (LC-PUFA). Two key enzymes in fatty acid metabolism are delta-6 desaturase (FADS2) and delta-5 desaturase (FADS1) (see Figure 3 above) (10). Two common haplotypes (a cluster of polymorphisms) in the FADS genes differ dramatically in their ability to generate LC-PUFA: haplotype D is associated with increased FADS activity (both FADS1 and FADS2) and is more efficient in converting fatty acid precursors (LA and ALA) to LC-PUFA (EPA, GLA, DHA, and AA) (11). These FADS polymorphisms are relatively common in the population and may explain up to 30% of the variability in blood levels of omega-3 and omega-6 fatty acids among individuals (3).

Finally, DHA is retroconverted to EPA at a low basal rate and following supplementation (see Figure 3 above) (12). After supplementing omnivores (n=8) and vegetarians (n=12) for six weeks with an EPA-free preparation of DHA (1.62 g/day), both EPA and DHA levels increased in serum and platelet phospholipids (13). Based on the measured changes, the estimated percent retroconversion of DHA to EPA was 7.4-11.4% (based on serum phospholipid data) and 12.3-13.8% (based on the platelet phospholipid data), with no significant difference between omnivores and vegetarians. Due to this nontrivial retroconversion efficiency, DHA supplementation represents an alternative to fish oil to increase blood and tissue levels of EPA, DPA, and DHA (5) (see Supplements).

Biological Activities

Membrane structure and function

Omega-6 and omega-3 PUFA are important structural components of cell membranes. When incorporated into phospholipids, they affect cell membrane properties, such as fluidity, flexibility, permeability, and the activity of membrane-bound enzymes (14). In addition to endogenous metabolism, dietary consumption of fatty acids can modify the composition and molecular structure of cellular membranes. Thus, increasing omega-3 fatty acid intake increases the omega-3 content of red blood cells, immune cells (15), atherosclerotic plaques (16), cardiac tissue (17), and other cell types throughout the body.

DHA is selectively incorporated into retinal cell membranes and postsynaptic neuronal cell membranes, suggesting it plays important roles in vision and nervous system function.


DHA is found at very high concentrations in the cell membranes of the retina; the retina conserves and recycles DHA even when omega-3 fatty acid intake is low (18). Animal studies indicate that DHA is required for the normal development and function of the retina. Moreover, these studies suggest that there is a critical period during retinal development when inadequate DHA will result in permanent abnormalities in retinal function. Research indicates that DHA plays an important role in the regeneration of the visual pigment rhodopsin, which plays a critical role in the visual transduction system that converts light hitting the retina to visual images in the brain (19).

Nervous system

The phospholipids of the brain’s gray matter contain high proportions of DHA and AA, suggesting they are important to central nervous system function (20). Brain DHA content may be particularly important, since animal studies have shown that depletion of DHA in the brain can result in learning deficits. It is not clear how DHA affects brain function, but changes in DHA content of neuronal cell membranes could alter the function of ion channels or membrane-associated receptors, as well as the availability of neurotransmitters (21).

Synthesis of lipid mediators


Eicosanoids are potent chemical messengers that play critical roles in immune and inflammatory responses. The term 'eicosanoid' encompasses numerous bioactive lipid mediators that are derived from 20-carbon LC-PUFA. Following stimulation by hormones, cytokines, and other stimuli, DGLA, AA, and EPA are released from cell membranes and become substrates for eicosanoid production (Figure 4). Eicosanoid synthesis relies primarily on three families of enzymes: cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome p450 mono-oxygenases (P450s) (22). From 20-carbon lipid precursors, COX enzymes produce prostaglandins, prostacyclins, and thromboxanes (collectively known as prostanoids); LOX produces leukotrienes and hydroxy fatty acids; and P450s produce hydroxyeicosatetraenoic acids ("HETEs") and epoxides (Figure 5).

Figure 4. Cell Membrane Fatty Acids are Used to Make Bioactive Lipid Mediators. The cell membrane serves as a pool of PUFA available for further metabolism to various bioactive lipids. Various environmental signals induce the enzyme phospholipase A2 to cleave fatty acids from the sn2 position of membrane phospholipids. Liberated fatty acids serve as substrates for the production of various bioactive lipid mediators.

Figure 5. Bioactive Lipid Mediators Derived from Omega-6 and Omega-3 Fatty Acids. Dietary intake can alter the fatty acid composition of cell membranes and influence the local production of bioactive lipid mediators. Each PUFA precursor gives rise to a variety of molecules with a range of immune modulating activities: inflammatory (prostanoids, leukotrienes), anti-inflammatory (hydroxyl fatty acids), and pro-resolving (lipoxins [aspirin-dependent], resolvins, hydroxyl fatty acids, protectins, and maresins); isoprostanes (F2, F3, and F4 isoprostanes) are markers of oxidative stress.

Physiological responses to AA-derived eicosanoids differ from responses to EPA-derived eicosanoids. In general, eicosanoids derived from EPA are less potent inducers of inflammation, blood vessel constriction, and coagulation than eicosanoids derived from AA (23). Nonetheless, it is an oversimplification to label all AA-derived eicosanoids as pro-inflammatory. AA-derived prostaglandins induce inflammation but also inhibit pro-inflammatory leukotrienes and cytokines and induce anti-inflammatory lipoxins, thereby modulating the intensity and duration of the inflammatory response via negative feedback (see Figure 5 above) (16).

Pro-resolving mediators

A separate class of PUFA-derived bioactive lipids, specialized pro-resolving mediators (SPMs), has been recently identified (reviewed in 24). These molecules function as local mediators of the resolution phase of inflammation, actively turning off the inflammatory response. SPMs are derived from both omega-6 and omega-3 PUFA (see Figure 5 above) (25). The S-series of SPMs results from the LOX-mediated oxygenation of EPA and DHA, giving rise to S-resolvins, S-protectins, and S-maresins. A second class of SPMs, the R-series, is generated from the aspirin-dependent acetylation of COX-2 and subsequent generation of aspirin-triggered SPMs from AA, EPA, and DHA. It appears that these mediators may explain many of the anti-inflammatory actions of omega-3 fatty acids that have been described (15, 26).


Isoprostanes are prostaglandin-like compounds that are formed by non-enzymatic, free radical-induced oxidation of any PUFA with three or more double bonds (see Figure 5 above) (22). Because they are produced upon exposure to free radicals, isoprostanes are often used as markers for oxidative stress. In contrast to prostanoids, isoprostanes are synthesized from esterified PUFA precursors and remain bound to the membrane phospholipid until cleaved by PLA2 and released into circulation. In addition to being used as markers of oxidative stress, isoprostanes may also function as inflammatory mediators, exerting both pro- and anti-inflammatory effects (22).

Regulation of gene expression

The results of cell culture and animal studies indicate that omega-6 and omega-3 fatty acids can modulate the expression of a number of genes, including those involved with fatty acid metabolism and inflammation (27, 28). Omega-6 and omega-3 fatty acids regulate gene expression by interacting with specific transcription factors, such as peroxisome proliferator-activated receptors (PPARs) (29). In many cases, PUFA act like hydrophobic hormones (e.g., steroid hormones) to control gene expression and bind directly to receptors like PPARs. These ligand-activated receptors then bind to the promoters of genes and function to increase/decrease transcription.

In other cases, PUFA regulate the abundance of transcription factors inside the cell's nucleus (30). Two examples include NFκB and SREBP-1. NFκB is a transcription factor involved in regulating the expression of multiple genes involved in inflammation. Omega-3 PUFA suppress NFκB nuclear content, thus inhibiting the production of inflammatory eicosanoids and cytokines. SREBP-1 is a major transcription factor controlling fatty acid synthesis, both de novo lipogenesis and PUFA synthesis. Dietary PUFA can suppress SREBP-1, which decreases the expression of enzymes involved in fatty acid synthesis and PUFA synthesis. In this way, dietary PUFA function as feedback inhibitors of all fatty acid synthesis.


Essential fatty acid deficiency

Clinical signs of essential fatty acid deficiency include a dry scaly rash, decreased growth in infants and children, increased susceptibility to infection, and poor wound healing (31). Omega-3, omega-6, and omega-9 fatty acids compete for the same desaturase enzymes. The desaturase enzymes show preference for the different series of fatty acids in the following order: omega-3 > omega-6 > omega-9. Consequently, synthesis of the omega-9 fatty acid eicosatrienoic acid (20:3n-9, mead acid, or 5,8,11-eicosatrienoic acid) increases only when dietary intakes of omega-3 and omega-6 fatty acids are very low; therefore, mead acid is one marker of essential fatty acid deficiency (32). A plasma eicosatrienoic acid:arachidonic acid (triene:tetraene) ratio greater than 0.2 is generally considered indicative of essential fatty acid deficiency (31, 33). In patients who were given total parenteral nutrition containing fat-free, glucose-amino acid mixtures, biochemical signs of essential fatty acid deficiency developed in as little as 7 to 10 days (34). In these cases, the continuous glucose infusion resulted in high circulating insulin levels, which inhibited the release of essential fatty acids stored in adipose tissue. When glucose-free amino acid solutions were used, parenteral nutrition up to 14 days did not result in biochemical signs of essential fatty acid deficiency. Essential fatty acid deficiency has also been found to occur in patients with chronic fat malabsorption (35) and in patients with cystic fibrosis (36). Recently, it has been proposed that essential fatty acid deficiency may play a role in the pathology of protein-energy malnutrition (32).

Omega-3 fatty acid deficiency

At least one case of isolated omega-3 fatty acid deficiency has been reported. A young girl who received intravenous lipid emulsions with very little ALA developed visual problems and sensory neuropathy; these conditions were resolved when she was administered an emulsion containing more ALA (37). Isolated omega-3 fatty acid deficiency does not result in increased plasma triene:tetraene ratios, and skin atrophy and dermatitis are absent (1). Plasma DHA concentrations decrease when omega-3 fatty acid intake is insufficient, but no accepted plasma omega-3 fatty acid or eicosanoid concentrations indicative of impaired health status have been defined (1). Studies in rodents have revealed significant impairment of n-3 PUFA deficiency on learning and memory (38, 39) prompting research in humans to assess the impact of omega-3 PUFA on cognitive development and cognitive decline (see Visual and neurological development and Alzheimer's disease).

Omega-3 index

The omega-3 index is defined as the amount of EPA plus DHA in red blood cell (RBC) membranes expressed as the percent of total RBC membrane fatty acids (40). The EPA + DHA content of RBCs correlates with that of cardiac muscle cells (41, 42), and several observational studies indicate that a lower omega-3 index is associated with an increased risk of coronary heart disease (CHD) mortality (43). It is therefore proposed that the omega-3 index be used as a biomarker for cardiovascular disease risk, with proposed zones being high risk, <4%; intermediate risk, 4-8%; and low risk, >8% (44).

Supplementation with EPA + DHA from fish oil capsules for approximately five months dose-dependently increased the omega-3 index in 115 healthy, young adults (20-45 years of age), validating the use of the omega-3 index as a biomarker of EPA + DHA intake (45). Before the omega-3 index can be used in routine clinical evaluation, however, clinical reference values in the population must be established (46). Additionally, fatty acid metabolism may be altered in certain disease states, potentially making the omega-3 index less relevant for some cardiovascular conditions (5).

Disease Prevention

Visual and neurological development

The last trimester of pregnancy and first six months of postnatal life are critical periods for the accumulation of DHA in the brain and retina (47). Human milk contains a mixture of saturated fatty acids (~46%), monounsaturated fatty acids (~41%), omega-6 PUFA (~12%), and omega-3 PUFA (~1.3%) (48). Although human milk contains DHA in addition to ALA and EPA, ALA was the only omega-3 fatty acid present in conventional infant formulas until the year 2001.

Infant formulas

Although infants can synthesize DHA from ALA, they generally cannot synthesize enough to prevent declines in plasma and cellular DHA concentrations without additional dietary intake. Therefore, it was proposed that infant formulas be supplemented with enough DHA to bring plasma and cellular DHA levels of formula-fed infants up to those of breast-fed infants (49). Although formulas enriched with DHA raise plasma and red blood cell DHA concentrations in preterm and term infants, the results of randomized controlled trials (RCTs) examining measures of visual acuity and neurological development in infants fed formulas with or without added DHA have been mixed (50, 51). A 2012 meta-analysis of RCTs (12 trials, 1,902 infants) testing LC-PUFA supplemented versus unsupplemented formula, started within one month of birth, found no effect of LC-PUFA supplementation on infant cognition assessed at approximately one year of age (52). A lack of effect was observed regardless of the dose of LC-PUFA or the prematurity status of the infant. With respect to visual acuity, a 2013 meta-analysis of RCTs (19 trials, 1,949 infants) found a beneficial effect of LC-PUFA-supplemented formula, started within one month of birth, on infant visual acuity up to 12 months of age (53). Notably, two different types of visual acuity assessment were evaluated in the meta-analysis. Visual acuity assessed by using the visually evoked potential (VEP) (10 trials, 852 infants) showed a significant positive effect of LC-PUFA supplemented formula at 2, 4, and 12 months of age. When assessed by the behavioral method (BM) (12 trials, 1,095 infants), a significant benefit of LC-PUFA-supplemented formula on visual acuity was found only at the age of two months. No moderating effects of dose or prematurity status were observed.

Maternal supplementation (placental transfer and breast milk)

The effect of maternal omega-3 LC-PUFA supplementation on early childhood cognitive and visual development was evaluated in a 2013 systematic review and meta-analysis (54). Included in this assessment were 11 RCTs (a total of 5,272 participants) that supplemented maternal diet with omega-3 LC-PUFA during pregnancy or during pregnancy and lactation. Visual outcomes (eight trials) could not be evaluated in the meta-analysis due to variability in assessments; overall, four of six trials had null findings and the remaining two trials had very high rates of attrition. Cognitive outcomes (nine trials) included the Developmental Standard Score (DSS; in infants, toddlers, and preschoolers) or Intelligence Quotient (IQ; in children) and other aspects of neurodevelopment, such as language, behavior, and motor function. No differences were found between DHA and control groups for cognition measured with standardized psychometric scales in infants (<12 months), toddlers (12-24 months), and school aged children (5-12 years); preschool children (2-5 years) in the DHA treatment group had a 3.92 point increase in DSS compared to controls. The authors note that many of the trials of LC-PUFA supplementation in pregnancy had methodological weaknesses (e.g., high rates of attrition, small sample sizes, high risk of bias, multiple comparisons) limiting the confidence and interpretation of the pooled results.

Although epidemiological investigations have demonstrated that higher intakes of omega-3 LC-PUFA from fish and seafood during pregnancy are associated with improved developmental outcomes in offspring (54), trial evidence does not conclusively support or refute this relationship. At present, the potential benefits associated with obtaining long-chain omega-3 fatty acids through moderate consumption of fish (e.g., 1-2 servings weekly) during pregnancy and lactation outweigh any risks of contaminant exposure, though fish with high levels of methylmercury should be avoided (55). For information about contaminants in fish and guidelines for fish consumption by women of childbearing age, see Contaminants in fish.

Gestation and pregnancy

The results of randomized controlled trials (RCTs) during pregnancy suggest that omega-3 fatty acid supplementation does not decrease the incidence of gestational diabetes, pregnancy-induced hypertension, or preeclampsia (56-58) but may result in modest increases in length of gestation, especially in women with low omega-3 fatty acid consumption. A 2006 meta-analysis of six randomized controlled trials in women with low-risk pregnancies found that omega-3 PUFA supplementation during pregnancy resulted in an increased length of pregnancy by 1.6 days (59). A 2007 meta-analysis of randomized controlled trials in women with high-risk pregnancies found that supplementation with long-chain PUFA did not affect pregnancy duration or the incidence of premature births but decreased the incidence of early premature births (<34 weeks of gestation; 2 trials, N=291; Relative Risk [RR]: 0.39 (95% CI: 0.18-0.84) (60).

Because maternal dietary intake of LC-PUFA determines the DHA status of the newborn, several expert panels in the US recommend that pregnant and lactating women consume at least 200 mg DHA per day, close to the amount recommended for adults in general (250 mg/day) (47, 61). The European Food and Safety Authority (EFSA) recommends that pregnant and lactating women consume an additional 100-200 mg of preformed DHA on top of the 250 mg/day EPA plus DHA recommended for healthy adults (62).

Cardiovascular disease

Omega-6 fatty acids: linoleic acid

LA is the most abundant dietary PUFA and accounts for approximately 90% of dietary omega-6 PUFA intake (63). Taking into consideration the results from RCTs and observational cohort studies, a 2009 American Heart Association scientific advisory concluded that obtaining at least 5-10% of total caloric intake from omega-6 PUFA is associated with a reduced risk of coronary heart disease (CHD) relative to lower intakes (64, 65). A pooled analysis of 11 cohort studies, encompassing 344,696 individuals followed for 4 to 10 years, found that replacing 5% of energy from saturated fatty acids (SFAs) with PUFA was associated with a 13% lower risk of coronary events (95% CI: 0.77, 0.97) and a 26% lower risk of coronary deaths (95% CI: 0.61, 0.89) (66). A 2012 meta-analysis of seven RCTs corroborated this beneficial effect, with an estimated 10% reduction in CHD risk (RR: 0.90, 95% CI: 0.83-0.97) for each 5% energy increase in PUFA consumption (67).

In controlled feeding trials, replacing dietary SFA with PUFA consistently lowers serum total and LDL cholesterol concentrations (68, 69). In fact, LA has been shown to be the most potent fatty acid for lowering serum total and LDL cholesterol when substituted for dietary SFA (70). The mechanisms by which linoleic acid lowers blood cholesterol include (1) the upregulation of LDL receptor and redistribution of LDL-C from plasma to tissue, (2) increased bile acid production and cholesterol catabolism, and (3) decreased conversion of VLDL to LDL (71).

Although dietary LA lowers blood cholesterol levels, supplementation with concentrated sources of LA may have adverse cardiovascular effects in individuals with preexisting CHD (see Disease Treatment).

Omega-3 fatty acids: α-linolenic acid

Several prospective cohort studies have examined the relationship between dietary ALA intake and cardiovascular disease (CVD). A 2012 meta-analysis of observational studies evaluated the risk of incident CVD related to dietary consumption or biomarkers of ALA (72). The analysis included 27 studies, 251,049 individuals and 15,327 CVD events (fatal coronary heart disease [CHD], nonfatal CHD, total CHD, and stroke). Overall, the pooled analysis found a moderately lower risk of CVD with higher ALA exposure (Relative Risk [RR]: 0.86; 95% CI: 0.77, 0.97).

Unlike LA, the cardioprotective effects of higher ALA intakes do not appear to be related to changes in serum lipid profiles. A meta-analysis of 14 randomized controlled trials concluded that ALA supplementation had no effect on total cholesterol, LDL cholesterol, or triglyceride levels (73). However, several controlled clinical trials have found that increasing ALA intake decreased serum concentrations of C-reactive protein (CRP), a marker of inflammation that is strongly associated with the risk of cardiovascular events, such as MI and stroke (74-76).

Long-chain omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid

Evidence is accumulating that increasing intakes of long-chain omega-3 fatty acids (EPA and DHA) can decrease the risk of cardiovascular disease by (1) preventing arrhythmias that can lead to sudden cardiac death, (2) decreasing the risk of thrombosis (a clot) that can lead to myocardial infarction (MI) or stroke, (3) decreasing serum triglyceride levels, (4) slowing the growth of atherosclerotic plaque, (5) improving vascular endothelial function, (6) lowering blood pressure slightly, and (7) decreasing inflammation (77).

In spite of these possible biological effects, clinical trials have not shown a significant effect of long-chain omega-3 supplementation on major cardiovascular events. A 2006 systematic review and meta-analysis of randomized controlled trials and prospective cohort studies concluded that long-chain omega-3 fatty acids do not significantly reduce the risk of total mortality or cardiovascular events (78). Likewise, a 2012 meta-analysis of secondary prevention trials (20 RCTs, including 68,680 patients) found no significant effect of omega-3 supplements (~1.5 g/day of EPA + DHA for a median of 2 years) on all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke (79). The same lack of effect was observed in a 2012 systematic review and meta-analysis of RCTs investigating the impact of omega-3 supplementation on inflammatory biomarkers in both healthy and ill individuals (80).

Although supplementation trials have not demonstrated a clear clinical benefit of omega-3 supplements, a recent multicenter, prospective, observational cohort study found a strong relationship between plasma phospholipid omega-3 PUFA levels (a biomarker of omega-3 status) and cardiovascular mortality (81). The Cardiovascular Health Study (CHS) related circulating levels of total and individual LC-PUFA (EPA, DPA, and DHA) to risk of total and CVD-specific mortality in 2,692 older (≥65 years) US adults. Higher levels of individual and combined total omega-3 PUFA in plasma phospholipids were associated with lower total mortality (HR for total omega-3: 0.73, 95% CI: 0.61-0.86). Looking more closely at cause-specific mortality, the observed reduction in risk was attributed mainly to fewer arrhythmic cardiac deaths (HR: 0.52, 95% CI: 0.31-0.86) and specifically with higher circulating DHA content (45% lower risk). Only EPA was associated with nonfatal MI (28% lower risk), while DPA was most strongly associated with stroke death (47% lower risk).

Coronary heart disease: A 2012 meta-analysis of 17 cohort studies with 315,812 participants and an average follow-up of 15.9 years calculated the pooled effect of fish consumption on coronary heart disease (CHD) mortality (82). Low (1 serving/week) or moderate fish consumption (2-4 servings/week) had a significant beneficial effect on the prevention of CHD mortality. Specifically, compared with the lowest fish consumption (<1 serving/month or 1-3 servings/month), consumption of 1 serving of fish per week and 2-4 servings/week was associated with a 16% (RR: 0.84, 95% CI: 0.75, 0.95) and 21% (RR: 0.79, 95% CI: 0.67,0.92) lower risk of fatal CHD, respectively.

Overall, among the various CVD outcomes (Figure 6), findings from prospective cohort studies and RCTs consistently indicate that consumption of fish or fish oil significantly reduces CHD mortality, including fatal myocardial infarction and sudden cardiac death (77, 83, 84). There is little evidence that these effects differ by sex, age, or race/ethnicity (77).

Figure 6. Cardiovascular Disease (CVD) Overview. Cardiovascular disease (CVD) is an umbrella term that encompasses all diseases of the heart and blood vessels, including ventricular arrhythmia, congestive heart failure, heart valve problems (stenosis, mitral valve prolapse), atherosclerosis and coronary heart disease (angina, myocardial infarction, cardiac arrhythmia, sudden cardiac death), and cerebrovascular disease (ischemic stroke and hemorrhagic stroke). Physiological risk factors for CVD include hypertension, high blood cholesterol, hypertriglyceridemia, and diabetes. Behavioral risk factors include diet quality, physical activity, adiposity, and smoking status. There is a general consensus that adequate intakes of fish, fish oil, or omega-3 PUFA supplements have favorable effects on cardiovascular outcomes. However, the primary cardioprotective effect of long-chain omega-3 PUFA seems to be on the last step of CHD, arrhythmia. For this reason, sudden cardiac death appears to be the most consistently affected clinical outcome.

Sudden cardiac death: Sudden cardiac death (SCD) is the result of a fatal ventricular arrhythmia, which usually occurs in people with CHD. Studies in cell culture indicate that long-chain omega-3 fatty acids decrease the excitability of cardiac muscle cells (myocytes) by modulating ion channel conductance (85). The results of epidemiological studies suggest that regular fish consumption is inversely associated with the risk of SCD. A 2011 systematic review and meta-analysis of eight prospective cohort studies evaluated the impact of consuming <250 mg versus ≥250 mg omega-3 PUFA per day on various CHD outcomes (86). Consumption of ≥250 mg omega-3 PUFA per day was associated with a significant, 35% reduction in the risk of SCD (RR: 0.65; 95% CI: 0.54, 0.79).

A meta-analysis of nine randomized controlled trials found no significant effect of omega-3 supplements on SCD or ventricular arrhythmias in patients with previous MI compared to those taking placebo (87). Notably, although the pooled analysis reported no significant effect, the included trials reported either a protective effect (six trials) or null effect (three trials), with no harmful outcomes reported.

Stroke: Ischemic strokes are the result of insufficient blood flow to an area of the brain, which may occur when an artery supplying the brain becomes occluded by a clot. Hemorrhagic strokes occur when a blood vessel ruptures and bleeds into the brain. In the United States, 87% of strokes are ischemic strokes (88). A 2012 meta-analysis of 16 prospective studies, encompassing 402,127 individuals for a mean of 12.8 years, found that increased fish intake was associated with a decreased risk of ischemic stroke, but not hemorrhagic stroke (89). According to this analysis, consuming fish even once per week may significantly reduce the risk of ischemic stroke. In a separate dose-response meta-analysis of these prospective studies, a 3-servings/week increase in fish consumption was associated with a 6% decreased risk of total stroke (95% CI: 0.89-0.99) (90). Again, the association remained significant only for ischemic stroke (RR: 0.90, 95% CI: 0.84-0.97).

Although the protective effect of fish intake could be attributed to many things (e.g., the displacement of red meat, a marker of an overall healthier lifestyle and dietary pattern, nutrient interactions (91, 92)), its high content of omega-3 PUFA may be a major contributing factor. A meta-analysis of eight prospective studies that assessed the association between omega-3 PUFA intake on stroke risk found evidence of a nonlinear relationship between LC-PUFA intake and stroke risk, with only moderate intakes of 200-400 mg/day omega-3 PUFA associated with significantly reduced risk of total stroke (93). Additionally, when analyzed by stroke type, the risk for ischemic stoke was lower in the highest versus lowest category of long-chain omega-3 PUFA intake (RR: 0.82, 95% CI: 0.71-0.94).

Another 2012 systematic review and meta-analysis assessed both prospective cohort studies and RCTs that investigated fish consumption or omega-3 supplementation on cerebrovascular disease (any fatal or non-fatal ischemic stroke, hemorrhagic stroke, cerebrovascular accident, or transient ischemic attack) (91). From 26 prospective cohort studies, the pooled relative risk (RR) for cerebrovascular disease for 2-4 versus ≤1 serving of fish per week was 0.94 (95% CI: 0.90-0.98); for >5 servings versus ≤1 serving per week, the RR was 0.88 (95% CI: 0.81-0.96). No significant association was found between long-chain omega-3 biomarkers and risk of cerebrovascular disease. From the 12 RCTs analyzed, 10 of which recruited subjects with preexisting cardiovascular disease at baseline, no significant effect of omega-3 supplementation (mean dose of 1.8 g/day for a mean duration of 3 years) on cerebrovascular disease outcomes was observed. The same lack of effect of omega-3 supplementation on total stroke risk was observed in a second meta-analysis of RCTs (nine trials) (79).

Serum triglycerides: A meta-analysis of 17 prospective studies found hypertriglyceridemia (serum triglycerides >200 mg/dL) to be an independent risk factor for cardiovascular disease (94). Numerous controlled clinical trials have demonstrated that increasing intakes of EPA and DHA significantly lower serum triglyceride concentrations (95). The triglyceride-lowering effects of EPA and DHA increase with dose (96), but clinically meaningful reductions in serum triglyceride concentrations have been demonstrated at doses of 2 g/day of EPA + DHA (97). In its recommendations regarding omega-3 fatty acids and cardiovascular disease (see Intake Recommendations), the American Heart Association indicates that an EPA + DHA supplement may be useful in patients with hypertriglyceridemia (23).

A 2011 meta-analysis of RCTs compared the effect of EPA alone (10 trials), DHA alone (17 trials), or EPA versus DHA (6 trials) on serum lipids (98). Although both EPA and DHA reduce triglyceride levels, they have different effects on LDL and HDL levels. DHA raises LDL and HDL, whereas EPA has no significant effect. Importantly, DHA may increase LDL via increased conversion of VLDL to LDL and by producing larger, more buoyant LDL particles (3).

Summary: omega-3 and omega-6 PUFA and cardiovascular disease prevention

The results of observational studies and randomized controlled trials suggest that replacing dietary SFA with omega-6 and omega-3 PUFA (from both plant and marine sources) lowers LDL cholesterol and decreases cardiovascular disease risk. Additionally, the results of epidemiological studies provide consistent evidence that increasing dietary omega-3 fatty intake is associated with significant reductions in cardiovascular disease risk through mechanisms other than lowering LDL cholesterol. In particular, increasing fish consumption to at least two servings of oily fish per week has been associated with significant reductions in fatal myocardial infarction and sudden cardiac death (77). This amount would provide about 400-500 mg/day of EPA + DHA (23).

Alzheimer's disease

Alzheimer's disease is the most common cause of dementia in older adults. Alzheimer's disease is characterized by the formation of amyloid plaque in the brain and nerve cell degeneration. Disease symptoms, including memory loss and confusion, worsen over time (99). Some epidemiological studies have associated high intake of fish with lower risks of impaired cognitive function (100), dementia (101), and Alzheimer's disease (101, 102). Proposed mechanisms for a protective effect of long-chain omega-3 fatty acids in the brain and vascular system include (1) the mitigation of inflammation, (2) improved cerebral blood flow, and (3) reduced amyloid aggregation (103).

A 2009 systematic review reported on the association between eating fish (as a source of long-chain omega-3 fatty acids) or taking an omega-3 supplement and the risk of cognitive decline or Alzheimer's disease (103). Out of 11 observational studies, three reported a significant benefit of omega-3 fatty acids on cognitive decline; four of eight observational studies reported positive findings on incident Alzheimer's disease or dementia. The four small clinical trials reviewed showed no evidence for prevention or treatment of any form of dementia (103).

DHA, the major omega-3 fatty acid in the brain, appears to be protective against Alzheimer's disease (104). Observational studies have found that lower DHA status is associated with increased risk of Alzheimer's disease (105-107), as well as other types of dementia (106). The relationship between DHA status and cognitive decline may be dependent on apolipoprotein E (APOE) genotype. Of three common APOE alleles (epsilon 2 [ε2], ε3, and ε4), the presence of the APOE ε4 (E4) allele is associated with increased risk and earlier onset of Alzheimer's disease (108). A protective effect of consumption of fatty fish on the risk for dementia and AD may not apply to carriers of the E4 allele (109, 110). EPA + DHA supplementation did not increase plasma levels of these omega-3 PUFA to the same extent in E4 carriers compared to non-carriers (111), and [13C]DHA tracer studies indicate that DHA metabolism differs in E4 carriers, with greater oxidation and lower plasma levels in E4 positive versus negative individuals (112).

Overall, the data favor a role for diets rich in long-chain omega-3 fatty acids in slowing cognitive decline but not for supplementation in the prevention or treatment of any type of dementia. The efficacy of omega-3 supplementation may depend on the underlying pathology of AD (i.e., the involvement of a vascular issue) (103) or the presence of the APOE4 allele (110, 111). Additionally, consistency in outcome measures and diagnostic criteria, and longer duration trials may be necessary to see a consistent effect.

Disease Treatment

Coronary heart disease

Dietary intervention trials

Omega-6 fatty acids (linoleic acid): In a reanalysis of the Sydney Heart Health Study (SHHS), a single-blind, RCT in 458 men (ages 30-59 years) with a recent coronary event, the replacement of dietary saturated fat with omega-6 linoleic acid led to higher rates of death from all-causes, cardiovascular disease, and coronary heart disease (CHD) compared to controls (113). Furthermore, a meta-analysis that included the SHHS and two other secondary prevention trials revealed an increased risk of mortality when saturated fat is replaced with concentrated sources of linoleic acid. There are some important limitations and considerations with the SHHS to keep in mind: (1) LA intake went from 6% to 15% of total energy for the study participants; in US adults, the average intake of LA is approximately 7% of total energy (114); (2) there may have been displacement of monounsaturated fatty acids and other PUFA in addition to saturated fats in the experimental intervention; and (3) the experimental formulation of safflower oil margarine may have provided trans fat. Regardless of these issues, substituting dietary saturated fat with mixed PUFA (both omega-6 and omega-3) rather than linoleic acid alone reduces CVD risk (113) and is recommended for both the primary and secondary prevention of CVD (65, 67).

Omega-3 fatty acids: In the Diet and Reinfarction Trial (DART), total mortality and fatal MI decreased by 29% in male MI survivors advised to increase their weekly intake of oily fish to 200-400 g (7-14 oz)—an amount estimated to provide an additional 500-800 mg/day of long-chain omega-3 fatty acids (EPA + DHA) (115). The Diet and Reinfarction Trial 2 (DART-2) administered similar dietary advice but to a different cohort of high-risk individuals: those with stable angina (116). In this case, advice to eat oily fish or fish oil did not affect all-cause mortality but was associated with an increased risk of sudden cardiac death. This increased risk was confined to the use of fish oil capsules rather than dietary fish intake. Though the results of the DART trials seem to contradict each other, there are important differences that offer explanations, namely the timing of the intervention (shortly after first MI in the first trial) and the stage of CHD (early versus stable) in the study population. These trials suggest that fish oil may reduce mortality during recovery from MI but perhaps not during later stages of the disease.

The Alpha Omega Trial tested if low doses of EPA + DHA (400 mg per day), ALA (2 g per day), or both in margarines reduced the risk of cardiovascular (CV) events among 4,837 patients (78% male; mean age, 69 years) who had a MI in the previous 10 years (117). After 40 months, none of the omega-3 PUFA treatments significantly affected the rate of major CV events compared to placebo. Notably, medication use in the study population was high: antithrombotic agents (97.5%), antihypertensive drugs (89.7%), and statins (85%).

Supplementation trials

In the largest randomized controlled trial of supplemental omega-3 fatty acids to date, the GISSI-Prevenzione Trial, CHD patients who received supplements providing 850 mg/day of EPA + DHA for 3.5 years had a risk of sudden death that was 45% lower than those who did not take supplements; supplement users also experienced a 20% lower risk of death from all causes compared to non-supplement users (118). Interestingly, it took only three months of supplementation to demonstrate a significant decrease in total mortality and four months to demonstrate a significant decrease in sudden death (119).

The results of a meta-analysis that pooled the findings of 29 randomized controlled trials of dietary or supplementary omega-3 fatty acids indicated that omega-3 fatty acids were not associated with a statistically significant reduction in all-cause mortality or risk of restenosis in high-risk cardiovascular patients (120). Heterogeneity in trial size and follow-up time limited the analysis, and the authors note that the probability of benefit from omega-3 fatty acids still remains high for both endpoints.


The results of randomized controlled trials in individuals with documented CHD suggest a beneficial effect of dietary and supplemental omega-3 fatty acids. Based on the results of these trials, the American Heart Association recommends that individuals with documented CHD consume approximately 1 g/day of EPA + DHA, preferably by consumption of oily fish (see Intake Recommendations) (121).

Diabetes mellitus

Cardiovascular disease are the leading causes of death in individuals with diabetes mellitus (DM). The dyslipidemia typically associated with diabetes is characterized by a combination of hypertriglyceridemia (serum triglycerides >200 mg/dL), low HDL-C, and abnormal LDL composition (122).

A 2009 meta-analysis of 23 randomized controlled trials (RCTs), including 1,075 individuals with type 2 diabetes, found that omega-3 fatty acid supplementation (mean dose, 3.5 g/day) lowered serum triglyceride levels by 0.45 mmol/L, lowered VLDL-C by 0.07 mmol/L, but raised LDL-C by 0.11 mmol/L (123). No significant changes in total cholesterol, HDL-C, HbA1c, fasting glucose, fasting insulin, or body weight were observed.

Since 2009, the results of two additional trials of omega-3 supplementation in diabetic patients have been published. The Alpha Omega Trial evaluated the effect of low-dose supplementation with omega-3 fatty acids on ventricular arrhythmias and fatal CHD in stable, post-MI patients (117). While the main analysis found no effect of supplementation, a secondary analysis of 1,014 diabetic participants found that low-dose supplementation of combined omega-3 fatty acids (~400 mg EPA + DHA and 2 g ALA per day in an experimental margarine spread for 40 months) resulted in fewer ventricular arrhythmia-related events (HR 0.16, 95% CI 0.04-0.69) compared to placebo margarine (124). In the ORIGIN trial, 1 g/day of omega-3 fatty acids (465 mg EPA + 375 mg DHA per day for 6 years) had no effect on rates of major vascular events, all-cause mortality, cardiovascular mortality, or death from arrhythmia in 12,536 dysglycemic patients at high risk for cardiovascular events compared to placebo (125). Triglyceride levels were reduced by 14.5 mg/dL (0.16 mmol/L), but no other blood lipids were affected by supplementation. In both of these trials, a high proportion of study participants used cardiovascular medications.


Increasing EPA and DHA intakes may be beneficial to diabetic individuals, especially those with elevated serum triglycerides or with a history of MI (126). There is no compelling evidence that daily EPA + DHA intakes of less than 3 g/day adversely affect long-term glycemic control in diabetics (127-129). The American Diabetes Association recommends that diabetic individuals increase omega-3 fatty acid consumption by consuming two to three 3-oz servings of fish weekly (121).

Inflammatory diseases

Rheumatoid arthritis

A 2012 meta-analysis of 10 randomized controlled trials, involving 270 rheumatoid arthritis (RA) patients, assessed the efficacy of high-dose omega-3 PUFA supplementation on clinical outcomes of RA (130). Omega-3 consumption of ≥2.7 g/day for a minimum of three months reduced nonsteroidal anti-inflammatory drug (NSAID) use but had no significant effect on tender joint count, swollen joint count, morning stiffness, or physical function compared to placebo. On the other hand, a 2012 systematic review, which included 23 trials investigating omega-3 supplementation (mainly as fish oil) in RA patients, concluded that there appears to be a consistent, though modest, benefit of marine-derived omega-3 PUFA (average intake ~3g/day) on some clinical symptoms of RA (131). Thus, high-dose supplementation of long-chain omega-3 PUFA spares the need for anti-inflammatory medications and may reduce joint pain and swelling in some RA patients.

Inflammatory bowel disease

Crohn’s disease: A 2013 systematic review evaluated the efficacy of omega-3 supplementation in Crohn’s disease (CD) patients, considering the evidence base from both short-term (9 to 24 weeks) and long-term (1 year) trials (132). Among five trials that evaluated the efficacy of omega-3 supplementation on CD relapse rates, conflicting outcomes were reported. Most trials were limited by small sample sizes and short duration; up to three years may be necessary to see an effect on CD relapse rates given the natural relapsing-remitting course of the disease. The two largest and most recent trials (EPIC-1 and EPIC-2) showed no significant effect of omega-3 supplementation on symptoms of CD remission compared to placebo (133). Two additional systematic reviews and a meta-analysis reached similar conclusions (134, 135). Three short-term trials showed positive effects of omega-3 supplementation on plasma biochemical parameters (e.g., reduced inflammatory cytokine expression, increased plasma EPA and DHA levels) compared to controls (132). In spite of its impact on biochemical changes in the short-term, however, the ability of omega-3 supplementation to maintain remission or effect clinically meaningful changes in CD is not supported by the current evidence.

Ulcerative colitis: Seven randomized controlled trials of fish oil supplementation in active ulcerative colitis (UC) patients reported significant improvement in at least one outcome measure, such as decreased corticosteroid use, improved disease activity scores, or improved histology scores (135). In inactive UC patients, omega-3 supplementation had no effect on relapse rates compared to placebo in four separate trials (134, 135).

While no serious side effects were reported in any trials of fish oil supplementation for the maintenance or remission of inflammatory bowel disease, diarrhea and upper gastrointestinal symptoms occurred more frequently with omega-3 treatment (134, 135).


Inflammatory eicosanoids (leukotrienes) derived from arachidonic acid (AA; 20:4n-6) are thought to play an important role in the pathology of asthma (28). Since increasing omega-3 fatty acid intake has been found to decrease the formation of AA-derived leukotrienes, a number of clinical trials have examined the effects of long-chain omega-3 fatty acid supplementation on asthma. Although there is some evidence that omega-3 fatty acid supplementation can decrease the production of inflammatory mediators in asthmatic patients (136, 137), evidence that omega-3 fatty acid supplementation decreases the clinical severity of asthma in controlled trials has been inconsistent (138). Three systematic reviews of randomized controlled trials of long-chain omega-3 fatty acid supplementation in asthmatic adults and children found no consistent effects on clinical outcome measures, including pulmonary function tests, asthmatic symptoms, medication use, or bronchial hyperreactivity (139-141).

Immunoglobulin A nephropathy

Immunoglobulin A (IgA) nephropathy is a kidney disorder that results from the deposition of IgA in the glomeruli of the kidney. The cause of IgA nephropathy is not clear, but progressive renal failure may eventually develop in 15-40% of patients (142). Since glomerular IgA deposition results in increased production of inflammatory mediators, omega-3 fatty acid supplementation could potentially modulate the inflammatory response and preserve renal function.

A 2012 meta-analysis assessed the efficacy of omega-3 fatty acid treatment on adult IgA nephropathy (143). Five randomized controlled trials were included in an analysis involving 239 patients (mean age range, 37 to 41 years) who received placebo or supplemental EPA + DHA at doses of 1.4 to 5.1 g/day for 6 to 24 months. Compared with control groups, omega-3 treatment had no significant effect on urine protein excretion or glomerular filtration rate. Only two trials measured changes in serum creatinine, a marker of renal function, and end-stage renal disease; in both trials, omega-3 treatment had a beneficial effect on these two parameters. No adverse events associated with omega-3 treatment were reported in any of the trials.

Neuropsychiatric disorders

Major depression and bipolar disorder

Data from ecologic studies across different countries suggest an inverse association between seafood consumption and national rates of major depression (144) and bipolar disorder (145). Several small studies have found omega-3 fatty acid concentrations to be lower in the plasma (146-148) and adipose tissue (fat) (149) of individuals suffering from depression compared to controls. Although it is not known how omega-3 fatty acid intake affects the incidence of depression, modulation of neuronal signaling pathways and eicosanoid production have been proposed as possible mechanisms (150).

There may be some benefit of omega-3 PUFA supplementation on depressive disorders, but it is difficult to compare studies and draw conclusions due to great heterogeneity among the trials (151, 152). Small sample sizes, lack of standardization of therapeutic doses, type of omega-3 PUFA administered, co-treatment with pharmacological agents, and diagnostic criteria vary among the trials.

A 2012 systematic review of all published RCTs investigated the effect of omega-3 PUFA supplementation on the prevention and treatment of several types of depression and other neuropsychiatric disorders (151). With respect to major depression, a majority of studies reported a positive effect for omega-3 supplements on depressive symptoms, though efficacy is still considered inconclusive given the great variability among trials. A few themes emerged from this review: more trials reported positive effect for omega-3 PUFA supplements as an adjunct to pharmacological treatment; in monotherapy trials, EPA alone was more effective than DHA alone; and in combination trials, positive effects were more likely if an EPA:DHA ratio of >1.5–2.0 was administered.

Unipolar depression and bipolar disorder are considered distinct psychiatric conditions, although major depression occurs in both. As with major depression, the 2012 review of RCTs indicated that omega-3 supplementation may have a positive effect as an adjunct to therapy in patients with bipolar disorder (151).

While there is some promising evidence for the use of omega-3 fatty acids for major depression and bipolar disorder, additional trials that account for dietary omega-3 intake, changes in red blood cell PUFA levels, the ratio of EPA:DHA provided, co-treatment with medications, and of sufficient duration are necessary.


A 2013 meta-analysis of 18 studies compared the PUFA composition of red blood cell (RBC) membranes in schizophrenic patients to those of normal controls (153). The majority of studies investigated medicated patients, though the authors separated the analysis into three groups of patients at time of measurement in order to account for possible confounding from pharmacologic agents: antipsychotic-medicated, antipsychotic-naïve, and antipsychotic-free. Overall, decreased levels of DPA, DHA, and AA in RBC membranes were associated with the schizophrenic state. Several mechanisms may account for the altered PUFA levels in schizophrenia, such as altered lipid metabolism, increased oxidative stress, or changes in diet consequent to disease-related behavior.

The use of long-chain omega-3 fatty acid supplements to alleviate symptoms of schizophrenia or to mitigate adverse effects of antipsychotic medications has been investigated in a number of clinical trials (154). Overall, there was no effect of fish oil or LC-PUFA supplements on symptoms of schizophrenia. However, given the high safety profile of fish oil supplements and some evidence of a positive effect of EPA supplementation in a subset of trials, some clinicians may consider EPA a useful adjunct to antipsychotic therapy in schizophrenic patients.

Alzheimer's disease and dementia

Some epidemiological studies have associated decreased DHA status with Alzheimer’s disease and other types of dementia (see above). Although results of studies in animal models have been promising (reviewed in 155), the existing clinical trial data do not support a recommendation for DHA supplementation in the treatment of Alzheimer's disease in humans. A randomized controlled trial (RCT) was conducted to determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease (156). Two hundred ninety-five individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination [MMSE] scores, 14-26) received algal DHA supplement (1 g twice daily) or placebo (corn or soy oil) for 18 months. Although DHA supplementation significantly increased levels of DHA in plasma phospholipids and cerebrospinal fluid, it had no effect on the rate of change on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog), the Clinical Dementia Rating (CDR) sum of boxes, or brain atrophy compared to placebo. No adverse effects were associated with DHA treatment in this trial.


Food sources

Omega-6 fatty acids

Linoleic acid: Food sources of LA include vegetable oils, such as soybean, safflower, and corn oil; nuts; seeds; and some vegetables. Dietary surveys in the US indicate that the average adult intake of LA ranges from 17-20 g/day for men and 12-13 g/day for women (63). Some foods that are rich in LA are listed in Table 2.

Table 2. Food Sources of Linoleic Acid (18:2n-6) (157)
Food Serving Linoleic Acid (g)
Safflower oil 1 tablespoon
Sunflower seeds, oil roasted 1 oz
Pine nuts 1 oz
Sunflower oil 1 tablespoon
Corn oil 1 tablespoon
Soybean oil 1 tablespoon
Pecans, oil roasted 1 oz
Brazil nuts 1 oz
Sesame oil 1 tablespoon

Arachidonic acid: Animals, but not plants, can convert LA to AA. Therefore, AA is present in small amounts in meat, poultry, and eggs.

Omega-3 fatty acids

α-Linolenic acid (ALA): Flaxseeds, walnuts, and their oils are among the richest dietary sources of ALA. Canola oil is also an excellent source of ALA. Dietary surveys in the US indicate that average adult intakes for ALA range from 1.8-2.0 g/day for men and from 1.4-1.5 g/day for women (63). Some foods that are rich in ALA are listed in Table 3.

Table 3. Food Sources of α-Linolenic Acid (18:3n-3) (157)
Food Serving α-Linolenic acid (g)
Flaxseed oil 1 tablespoon
Chia seeds, dried 1 oz
Walnuts, English 1 oz
Flaxseeds, ground 1 tablespoon
Walnut oil 1 tablespoon
Canola oil 1 tablespoon
Soybean oil 1 tablespoon
Mustard oil 1 tablespoon
Walnuts, black 1 oz
Tofu, firm ½ cup

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA): Oily fish are the major dietary source of EPA and DHA. Dietary surveys in the US indicate that average adult intakes of EPA range from 0.03-0.06 g/day, and average adult intakes of DHA range from 0.05-0.10 g/day (63). Omega-3 fatty acid-enriched eggs are also available in the US. Some foods that are rich in EPA and DHA are listed in Table 4.

Table 4. Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (97)
Food Serving EPA (g) DHA (g) Amount Providing
1 g of EPA + DHA
Herring, Pacific 3 oz*
1.5 oz
Salmon, chinook 3 oz
2 oz
Sardines, Pacific 3 oz
2.5 oz
Salmon, Atlantic 3 oz
2.5 oz
Oysters, Pacific 3 oz
2.5 oz
Salmon, sockeye 3 oz
3 oz
Trout, rainbow 3 oz
3.5 oz
Tuna, canned, white 3 oz
4 oz
Crab, Dungeness 3 oz
9 oz
Tuna, canned, light 3 oz
12 oz
*A three-ounce serving of fish is about the size of a deck of cards.

Biosynthesis of EPA and DHA

Humans can synthesize AA from LA and EPA and DHA from ALA through a series of desaturation and elongation reactions. EPA and DPA are also obtained from the retroconversion of DHA (see Metabolism and Bioavailability). Due to low conversion efficiency, it is advised to obtain EPA and DHA from additional sources.


Omega-6 fatty acids

Borage seed oil, evening primrose oil, and black currant seed oil are rich in γ-linolenic acid (GLA) and are often marketed as GLA or essential fatty acid (EFA) supplements (158).

Omega-3 fatty acids

Flaxseed oil (also known as flax oil or linseed oil) is available as an ALA supplement. A number of fish oils are marketed as omega-3 fatty acid supplements. The omega-3 fatty acids from natural fish oil are in the triglyceride form, often with only one of three attached fatty acids an omega-3; thus, up to 70% of fatty acids provided may be other types (3). Ethyl esters of EPA and DHA (ethyl-EPA and ethyl-DHA) are concentrated sources of long-chain omega-3 fatty acids that provide more EPA and DHA per gram of oil. Krill oil contains both EPA and DHA and is considered comparable to fish oil as a source of these long-chain PUFA (159). Cod liver oil is also a rich source of EPA and DHA, but some cod liver oil preparations may contain excessive amounts of preformed vitamin A (retinol) (158). DHA supplements derived from algal and fungal sources are also available. Because dietary DHA is retroconverted to EPA and DPA in humans, DHA supplementation represents yet another alternative to fish oil supplements (see Metabolism and Bioavailability).

EPA and DHA content varies in each of these preparations, making it necessary to read product labels in order to determine the EPA and DHA levels provided by a particular supplement. All omega-3 fatty acid supplements are absorbed more efficiently with meals. Dividing one’s daily dose into two or three smaller doses throughout the day will decrease the risk of gastrointestinal side effects (see Safety).

Infant formula

In 2001, the FDA began permitting the addition of DHA and AA to infant formula in the United States (160). Presently, manufacturers are not required to list the amounts of DHA and AA added to infant formula on the label. However, most infant formula manufacturers provide this information. The amounts added to formulas in the US range from 8-17 mg DHA/100 calories (5 fl oz) and from 16-34 mg AA/100 calories. For example, an infant drinking 20 fl oz of DHA-enriched formula daily would receive 32-68 mg/day of DHA and 64-136 mg/day of AA.


Adverse effects

γ-Linolenic acid (18:3n-6)

Supplemental γ-linolenic acid is generally well tolerated, and serious adverse side effects have not been observed at doses up to 2.8 g/day for 12 months (161). High doses of borage seed oil, evening primrose oil, or black currant seed oil may cause gastrointestinal upset, loose stools, or diarrhea (158). Because of case reports that supplementation with evening primrose oil induced seizure activity in people with undiagnosed temporal lobe epilepsy (162), people with a history of seizures or seizure disorder are generally advised to avoid evening primrose oil and other γ-linolenic acid-rich oils (158).

α-Linolenic acid (18:3n-3)

Although flaxseed oil is generally well tolerated, high doses may cause loose stools or diarrhea (163). Allergic and anaphylactic reactions have been reported with flaxseed and flaxseed oil ingestion (164).

Eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)

Serious adverse reactions have not been reported in those using fish oil or other EPA and DHA supplements. The most common adverse effect of fish oil or EPA and DHA supplements is a fishy aftertaste. Belching and heartburn have also been reported. Additionally, high doses may cause nausea and loose stools.

Potential for excessive bleeding: The potential for high omega-3 fatty acid intakes, especially EPA and DHA, to prolong bleeding times has been well studied and may play a role in the cardioprotective effects of omega-3 fatty acids. Although excessively long bleeding times and increased incidence of hemorrhagic stroke have been observed in Greenland Eskimos with very high intakes of EPA + DHA (6.5 g/day), it is not known whether high intakes of EPA and DHA are the only factor responsible for these observations (1). The US FDA has ruled that intakes up to 3 g/day of long-chain omega-3 fatty acids (EPA and DHA) are Generally Recognized As Safe (GRAS) for inclusion in the diet, and available evidence suggests that intakes less than 3 g/day are unlikely to result in clinically significant bleeding (97). Although the Institute of Medicine did not establish a tolerable upper intake level (UL) for omega-3 fatty acids, caution was advised with the use of supplemental EPA and DHA, especially in those who are at increased risk of excessive bleeding (see Drug interactions and Nutrient interactions) (1).

Potential for immune system suppression: Although the suppression of inflammatory responses resulting from increased omega-3 fatty acid intakes may benefit individuals with inflammatory or autoimmune diseases, anti-inflammatory doses of omega-3 fatty acids could decrease the potential of the immune system to destroy pathogens (165). Studies comparing measures of immune cell function outside the body (ex vivo) at baseline and after supplementing people with omega-3 fatty acids, mainly EPA and DHA, have demonstrated immunosuppressive effects at doses as low as 0.9 g/day for EPA and 0.6 g/day for DHA (1). Although it is not clear if these findings translate to impaired immune responses in vivo, caution should be observed when considering omega-3 fatty acid supplementation in individuals with compromised immune systems.

Infant formula

In early studies of DHA-enriched infant formula, EPA- and DHA-rich fish oil was used as a source of DHA. However, some preterm infants receiving fish oil-enriched formula had decreased plasma AA concentrations, which were associated with decreased weight (but not length and head circumference) (166, 167). This effect was attributed to the potential for high concentrations of EPA to interfere with the synthesis of AA, which is essential for normal growth. Consequently, EPA was removed and AA was added to DHA-enriched formula. Currently available infant formulas in the US contain only AA and DHA derived from algal or fungal sources, rather than fish oil. Randomized controlled trials have not found any adverse effects on growth in infants fed formulas enriched with AA and DHA for up to one year (168).

Pregnancy and lactation

The safety of supplemental omega-3 and omega-6 fatty acids, including borage seed oil, evening primrose oil, black currant seed oil, and flaxseed oil, has not been established in pregnant or lactating (breast-feeding) women (158). Studies of fish oil supplementation during pregnancy and lactation have not reported any serious adverse effects (see Contaminants in fish and Contaminants in supplements).

Contaminants in fish

Some species of fish may contain significant levels of methylmercury, polychlorinated biphenyls (PCBs), or other environmental contaminants (55). In general, larger predatory fish, such as swordfish, tend to contain the highest levels of these contaminants. Removing the skin, fat, and internal organs of the fish prior to cooking and allowing the fat to drain from the fish while it cooks will decrease exposure to a number of fat-soluble pollutants, such as PCBs (169). However, methylmercury is found throughout the muscle of fish, so these cooking precautions will not reduce exposure to methylmercury. Organic mercury compounds are toxic and excessive exposure can cause brain and kidney damage. The developing fetus, infants, and young children are especially vulnerable to the toxic effects of mercury on the brain. In order to limit their exposure to methylmercury, the US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) have made the following joint recommendations for women who may become pregnant, pregnant women, breast-feeding women, and parents:

1) Eat 8-12 ounces of a variety of fish a week.

  • That’s 2 or 3 servings of fish a week.
  • For young children, give them 2 or 3 servings of fish a week with the portion right for the child's age and calorie needs.

2) Choose fish lower in mercury.

  • Many of the most commonly eaten fish are lower in mercury.
  • These include salmon, shrimp, pollock, tuna (light canned), tilapia, catfish, and cod.

3) Avoid 4 types of fish: tilefish from the Gulf of Mexico, shark, swordfish, and king mackerel.

  • These 4 types of fish are highest in mercury.
  • Limit white (albacore) tuna to 6 ounces a week.

4) When eating fish you or others have caught from streams, rivers, and lakes, pay attention to fish advisories on those waterbodies.

For more information about the FDA/EPA consumer advisory on methylmercury in fish, see their online brochure. More information about mercury levels in commercial fish and shellfish is available from the FDA.

Contaminants in supplements

Although concerns have been raised regarding the potential for omega-3 fatty acid supplements derived from fish oil to contain methylmercury, PCBs, and dioxins, several independent laboratory analyses in the US have found commercially available omega-3 fatty acid supplements to be free of methylmercury, PCBs, and dioxins (170). The absence of methylmercury in omega-3 fatty acid supplements can be explained by the fact that mercury accumulates in the muscle, rather than the fat of fish (97). In general, fish body oils contain lower levels of PCBs and other fat-soluble contaminants than fish liver oils. Additionally, fish oils that have been more highly refined and deodorized also contain lower levels of PCBs (171). Pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds, are found in various parts of the borage plant. People who take borage oil supplements should use products that are certified free of pyrrolizidine alkaloids (158).

Drug interactions

γ-Linolenic acid supplements, such as evening primrose oil or borage seed oil, may increase the risk of seizures in people on phenothiazines, such as chlorpromazine (162). High doses of black currant seed oil, borage seed oil, evening primrose oil, flaxseed oil, and fish oil may inhibit platelet aggregation; therefore, these supplements should be used with caution in people on anticoagulant medications. In particular, people taking fish oil or long-chain omega-3 fatty acid (EPA and DHA) supplements in combination with anticoagulant drugs, including aspirin, clopidogrel (Plavix), dalteparin (Fragmin), dipyridamole (Persantine), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and warfarin (Coumadin), should have their coagulation status monitored using a standardized prothrombin time assay (INR). One small study found that 3 g/day or 6 g/day of fish oil did not affect INR values in 10 patients on warfarin over a four-week period (172). However, a case report described an individual who required a reduction of her warfarin dose when she doubled her fish oil dose from 1 g/day to 2 g/day (173).

Nutrient interactions

Vitamin E

Outside the body, PUFA become rancid (oxidized) more easily than SFA. Fat-soluble antioxidants, such as vitamin E, play an important role in preventing the oxidation of PUFA. Inside the body, results of animal studies and limited data in humans suggest that the amount of vitamin E required to prevent lipid peroxidation increases with the amount of PUFA consumed (174). One widely used recommendation for vitamin E intake is 0.6 mg of α-tocopherol per gram of dietary PUFA. This recommendation was based on a small study in men and the ratio of α-tocopherol to LA in the US diet and has not been verified in more comprehensive studies. Although EPA and DHA are easily oxidized outside the body, it is presently unclear whether EPA and DHA are more susceptible to oxidative damage within the body (175). High vitamin E intakes have not been found to decrease biomarkers of oxidative damage when EPA and DHA intakes are increased (176, 177), but some experts believe that an increase in PUFA intake, particularly omega-3 PUFA intake, should be accompanied by an increase in vitamin E intake (1).

Intake Recommendations

US Institute of Medicine

The Food and Nutrition Board of the US Institute of Medicine has established adequate intake (AI) levels for omega-6 and omega-3 fatty acids (Tables 5 and 6) (1).

Table 5. Adequate Intake (AI) for Omega-6 Fatty Acids (1)
Life Stage Age Source Males (g/day) Females (g/day)
Infants 0-6 months Omega-6 PUFA* 4.4 4.4
Infants 7-12 months Omega-6 PUFA* 4.6 4.6
Children 1-3 years LA# 7 7
Children 4-8 years LA 10 10
Children 9-13 years LA 12 10
Adolescents 14-18 years LA 16 11
Adults 19-50 years LA 17 12
Adults 51 years and older LA 14 11
Pregnancy all ages LA - 13
Breast-feeding all ages LA - 13
*The various omega-6 polyunsaturated fatty acids (PUFA) present in human milk can contribute to the AI for infants. # LA, linoleic acid
Table 6. Adequate Intake (AI) for Omega-3 Fatty Acids (1)
Life Stage Age Source Males (g/day) Females (g/day)
Infants 0-6 months ALA, EPA, DHA*
Infants 7-12 months ALA, EPA, DHA
Children 1-3 years ALA
Children 4-8 years ALA
Children 9-13 years ALA
Adolescents 14-18 years ALA
Adults 19 years and older ALA
Pregnancy all ages ALA
Breast-feeding all ages ALA
*All omega-3 polyunsaturated fatty acids present in human milk can contribute to the AI for infants. ALA, α-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

Given the established health benefits of consuming at least two servings of oily fish per week, providing approximately 400-500 mg EPA + DHA, some researchers have proposed that the US Institute of Medicine establish a dietary reference intake (DRI) for EPA + DHA (23). For now, there is no DRI for EPA and DHA specifically.

International recommendations

Upon request of the European Commission, the European Food Safety Authority (EFSA) proposed adequate intakes (AI) for the essential fatty acids LA and ALA, as well as the long-chain omega-3 fatty acids EPA and DHA (62). EFSA recommends an LA intake of 4% of total energy and an ALA intake of 0.5% of total energy; an AI of 250 mg/day is recommended for EPA plus DHA.

The World Health Organization recommends an acceptable macronutrient distribution range (AMDR) for omega-6 fatty acid intake of 6-11% of energy and for omega-3 fatty acid intake of 0.5-2% of energy (178). Their AMDR for EPA plus DHA is 0.250-2 g/day (the upper limit applying to the secondary prevention of CHD).

The International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends for healthy adults an LA intake of 2% energy, ALA intake of 0.7% energy, and a minimum of 500 mg/day of EPA plus DHA for cardiovascular health (179).

American Heart Association recommendation

The American Heart Association recommends that people without documented CHD eat a variety of fish (preferably oily) at least twice weekly (121). Two servings of oily fish provide approximately 500 mg of EPA plus DHA. Pregnant women and children should avoid fish that typically have higher levels of methylmercury (see Contaminants in fish). People with documented CHD are advised to consume approximately 1 g/day of EPA + DHA preferably from oily fish, or to consider EPA + DHA supplements in consultation with a physician. Patients who need to lower serum triglycerides may take 2-4 g/day of EPA + DHA supplements under a physician's care.

Linus Pauling Institute recommendation

The Linus Pauling Institute recommends that generally healthy adults increase their intake of omega-3 fats by eating fish twice weekly and consuming foods rich in α-linolenic acid, such as walnuts, flaxseeds, and flaxseed or canola oil. If you don't regularly consume fish, consider taking a two-gram fish oil supplement several times a week. If you are prone to bleeding or take anticoagulant drugs, consult your physician.

Authors and Reviewers

Originally written in 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2014 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2014 by:
Donald B. Jump, Ph.D.
Professor, School of Biological and Population Health Sciences
Principal Investigator, Linus Pauling Institute
Oregon State University

The 2014 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2003-2017  Linus Pauling Institute


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  • Dietary fiber is a diverse group of compounds, including lignin and complex carbohydrates, which cannot be digested by human enzymes in the small intestine. (More information)
  • Although each class of fiber is chemically unique, scientists have tried to classify fibers on the basis of their solubility, viscosity, and fermentability in order to better understand their physiological effects. (More information)
  • Viscous fibers, such as those found in oat products and legumes, can lower serum LDL cholesterol levels and normalize blood glucose and insulin responses. (More information)
  • High-fiber intakes promote bowel health by preventing constipation and diverticular disease. (More information)
  • Large prospective cohort studies provide strong and consistent evidence that diets rich in fiber from whole grains, legumes, fruit, and nonstarchy vegetables can reduce the risk of cardiovascular disease and type 2 diabetes. (More information)
  • Although the results of case-control studies suggested that colorectal cancer was more prevalent in people with low-fiber intakes, more recent findings from large prospective cohort studies and four clinical intervention trials do not support an association between fiber intake and the risk of colorectal cancer. (More information)
  • Observational studies on dietary fiber intake and breast cancer incidence have reported inconsistent findings. (More information)
  • Numerous controlled clinical trials in people with type 1 and type 2 diabetes have found that increasing fiber intake improves blood glucose (glycemic) control and serum lipid profiles. (More information)
  • In 2001, the Food and Nutrition Board of the Institute of Medicine established an Adequate Intake (AI) recommendation for total daily fiber intake. For adults who are 50 years of age and younger, the AI recommendation for total fiber intake is 38 g/day for men and 25 g/day for women. For adults over 50 years of age, the recommendation is 30 g/day for men and 21 g/day for women. (More information)


All dietary fibers are resistant to digestion in the small intestine, meaning they arrive at the colon intact (1). Although most fibers are carbohydrates, one important factor that determines their susceptibility to digestion by human enzymes is the conformation of the chemical bonds between sugar molecules (glycosidic bonds). Humans lack digestive enzymes capable of hydrolyzing (breaking apart) most β-glycosidic bonds, which explains why amylose, a glucose polymer with α-1,4 glycosidic bonds, is digestible by human enzymes, while cellulose, a glucose polymer with β-1,4 glycosidic bonds, is indigestible (Figure 1).

Figure 1. Chemical Structures of Amylose (alpha-1,4 glucosidic bonds), Cellulose (beta-1,4 glucosidic bonds), and Beta-Glucans (mixed beta-1,3 and beta-1,4 glucosidic bonds).

Definitions of Fiber

Although nutritional scientists and clinicians generally agree that a healthful diet should include plenty of fiber-rich foods, agreement on the actual definition of fiber has been more difficult to achieve (2-4). In the 1970s, dietary fiber was defined as remnants of plant cells that are resistant to digestion by human enzymes (5). This definition includes a component of some plant cell walls called lignin, as well as indigestible carbohydrates found in plants. However, this definition omits indigestible carbohydrates derived from animal sources (e.g., chitin) and synthetic (e.g., fructooligosaccharides) and digestible carbohydrates that are inaccessible to human digestive enzymes (e.g., resistant starch) (6). These compounds share many of the characteristics of fiber present in plant foods.

Institute of Medicine: dietary, functional, and total fiber

Before establishing intake recommendations for fiber in 2001, a panel of experts convened by the Institute of Medicine developed definitions of fiber that made a distinction between fiber that occurs naturally in plant foods (dietary fiber) and isolated or synthetic fibers that may be added to foods or used as dietary supplements (functional fiber) (4). However, these distinctions are controversial, and there are other classification systems for dietary fiber (see Other classification systems).

Dietary fiber
  • Lignin: Lignin is not a carbohydrate; rather, it is a polyphenolic compound with a complex three-dimensional structure that is found in the cell walls of woody plants and seeds (7).
  • Cellulose: Cellulose is a glucose polymer with β-1,4 glycosidic bonds found in all plant cell walls (see Figure 1 above) (6).
  • β-Glucans: β-Glucans are glucose polymers with a mixture of β-1,4 glycosidic bonds and β-1,3 glycosidic bonds (see Figure 1 above). Oats and barley are particularly rich in β-glucans (7).
  • Hemicelluloses: Hemicelluloses are a diverse group of polysaccharides (sugar polymers) containing six-carbon sugars (hexoses) and five-carbon sugars (pentoses) (6). Like cellulose, hemicelluloses are found in plant cell walls.
  • Pectins: Pectins are viscous polysaccharides that are particularly abundant in fruit and berries (4).
  • Gums: Gums are viscous polysaccharides often found in seeds (4).
  • Inulin and oligofructose: Inulin is a mixture of fructose chains that vary in length and often terminate with a glucose molecule (8). Oligofructose is a mixture of shorter fructose chains that may terminate in glucose or fructose. Inulin and oligofructose occur naturally in plants, such as onions and Jerusalem artichokes.
  • Resistant starch: Naturally occurring resistant starch is sequestered in plant cell walls and is therefore inaccessible to human digestive enzymes (4). Bananas and legumes are sources of naturally occurring resistant starch. Resistant starch may also be formed by food processing or by cooling and reheating.
Functional fiber

According to the Institute of Medicine’s definition, functional fiber "consists of isolated, nondigestible carbohydrates that have beneficial physiological effects in humans (4)." Functional fibers may be nondigestible carbohydrates that have been isolated or extracted from a natural plant or animal source, or they may be manufactured or synthesized. However, designation as a functional fiber by the Institute of Medicine requires the presentation of sufficient evidence of physiological benefit in humans. Fibers identified as potential functional fibers by the Institute of Medicine include:

  • Isolated or extracted forms of the dietary fibers listed above.
  • Psyllium: Psyllium refers to viscous mucilage, which is isolated from the husks of psyllium seeds. The husks are usually isolated from the seeds of Plantago ovata or blond psyllium. Psyllium is also known as ispaghula husk (4).
  • Chitin and chitosan: Chitin is a nondigestible carbohydrate extracted from the exoskeletons of crustaceans, such as crabs and lobsters. It is a long polymer of acetylated glucosamine units linked by β-1,4 glycosidic bonds. Deacetylation of chitin is used to produce chitosan, a nondigestible glucosamine polymer (9).
  • Fructooligosaccharides: Fructooligosaccharides are short, synthetic fructose chains terminating with a glucose unit. They are used as food additives (8).
  • Polydextrose and polyols: Polydextrose and polyols are synthetic polysaccharides used as bulking agents and sugar substitutes in foods (4).
  • Resistant dextrins: Resistant dextrins, also called resistant maltodextrins, are indigestible polysaccharides formed when starch is heated and treated with enzymes. They are used as food additives (4).
Total fiber

Total fiber is defined by the Institute of Medicine as "the sum of dietary fiber and functional fiber (4)."

Other classification systems

Viscous and nonviscous fiber

Some fibers form very viscous solutions or gels in water. This property is linked to the ability of some fibers to slow the emptying of the stomach, delay the absorption of some nutrients in the small intestine, and lower serum cholesterol. Viscous fibers include pectins, β-glucans, some gums (e.g., guar gum), and mucilages (e.g., psyllium). Cellulose, lignin, and some hemicelluloses are nonviscous fibers (6, 7).

Fermentable and nonfermentable fiber

Some fibers are readily fermented by bacteria that normally colonize the colon. In addition to increasing the amount of bacteria in the colon, fermentation results in the formation of short-chain fatty acids (acetate, propionate, and butyrate) and gases (1). Short-chain fatty acids can be absorbed and metabolized to produce energy. Interestingly, the preferred energy source for colonocytes (epithelial cells that line the colon) is butyrate. Pectins, β-glucans, guar gum, inulin, and oligofructose are readily fermented, while cellulose and lignin are resistant to fermentation in the colon (6, 7). Foods that are rich in fermentable fibers include oats and barley, as well as fruit and vegetables. Cereal fibers that are rich in cellulose, such as wheat bran, are relatively resistant to bacterial fermentation (1).

Soluble and insoluble fiber

"Soluble fiber" originated as an analytical term (10). Soluble fibers are dispersible in water, while insoluble fibers are not. Originally, the solubility of fiber was thought to predict its physiological effects. For example, it was thought that soluble fibers were more likely to form viscous gels and were more easily fermented by colonic bacteria. Further research has revealed that solubility does not reliably predict the physiological effects of fiber. However, the terms "soluble" and "insoluble" fiber are still used by many nutrition and health care professionals, as well as the US Food and Drug Administration (FDA) for nutrition labeling. β-Glucans, gums, mucilages (e.g., psyllium), pectins, and some hemicelluloses are soluble fibers, while cellulose, lignin, some pectins, and some hemicelluloses are insoluble fibers (10). Oat products and legumes (dry beans, peas, and lentils) are rich sources of soluble fiber.

Biological Activities

Lowering serum cholesterol

Numerous controlled clinical trials have found that increasing the intake of viscous dietary fibers, particularly from legumes (dry beans, peas, and lentils) (11-13) and oat products (14-19), decreases serum total and LDL cholesterol. Such findings led the FDA to approve health claims like the following on labels of foods containing at least 0.75 g/serving of soluble fiber from whole oats: "Soluble fiber from foods such as oat bran, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease" (20). Supplementation with viscous fibers, such as pectin, guar gum, and psyllium, has also been found to decrease total and LDL cholesterol levels when compared to low-fiber placebos (17, 21-26). Although many of these studies examined relatively high-fiber intakes, a meta-analysis that combined the results of 67 controlled trials found that even a modest 10-g per day increase in viscous fiber intake resulted in reductions in LDL-cholesterol averaging 22 mg/dL (0.57 mmol/L) and reductions in total cholesterol averaging 17 mg/dL (0.45 mmol/L) (17).

Lowering postprandial glycemia (blood sugar)

The addition of viscous dietary fiber (27, 28) and isolated viscous fibers (29-32) to a carbohydrate-containing meal has been found to result in significant improvements in blood glucose and insulin responses in numerous controlled clinical trials (33). Large, rapid increases in blood glucose levels are potent signals to the β-cells of the pancreas to increase insulin secretion. Over time, recurrent elevations in blood glucose and excessive insulin secretion are thought to increase the risk of developing type 2 diabetes mellitus (DM), as well as cardiovascular disease (see Disease Prevention). When the carbohydrate content of two meals is equal, the presence of fiber, particularly viscous fiber, generally results in smaller but more sustained increases in blood glucose and thus significantly lower insulin levels (33).

Softening stool

Increasing intakes of dietary fibers and fiber supplements can prevent or ameliorate constipation by softening and adding bulk to stool and by speeding its passage through the colon (34). Wheat bran and fruit and vegetables are the fiber sources that have been most consistently found to increase stool bulk and shorten transit time (35). Fiber supplements that have been found to be effective in treating constipation include cellulose and psyllium (4). Sufficient fluid intake is also required to maximize the stool-softening effect of increased fiber intake (36). In addition to increasing fiber intake, drinking at least 64 ounces (~2 liters or 2 quarts) of fluid daily is usually recommended to help prevent and treat constipation (37).

Disease Prevention

Observational studies that have identified associations between high-fiber intakes and reductions in chronic disease risk have generally assessed only fiber-rich foods, rather than fiber itself, making it difficult to determine whether observed benefits are related to fiber or other nutrients and phytochemicals commonly found in fiber-rich foods. In contrast, intervention trials often use isolated fibers to determine whether a specific fiber component has beneficial health effects.

Cardiovascular disease

Prospective cohort studies have consistently found that high intakes of fiber-rich foods are associated with significant reductions in coronary heart disease (CHD) risk (38-48) and cardiovascular-related mortality (48-51). A pooled analysis of 10 prospective cohort studies of dietary fiber intake in the US and Europe found that each 10 g/day increase in total dietary fiber intake was associated with a 14% decrease in the risk of coronary events, such as myocardial infarction (MI), and a 24% decrease in deaths from CHD (51). This inverse association between fiber intake and CHD death was particularly high for cereal fiber and fruit fiber. Three large prospective cohort studies (42, 43, 45) found that dietary fiber intakes of approximately 14 g per 1,000 kcal of energy were associated with substantial (16%-33%) decreases in the risk of CHD; these results are the basis for the Institute of Medicine’s Adequate Intake (AI) recommendation for fiber (see Intake Recommendations) (4).

Although the cholesterol-lowering effect of viscous dietary fibers and fiber supplements probably contributes to the cardioprotective effects of dietary fiber (see Lowering serum cholesterol), other mechanisms are likely to play a role. Beneficial effects of fiber consumption on blood glucose and insulin responses may also contribute to observed reductions in CHD risk (52). Low-fiber, high-glycemic load diets are associated with higher serum triglyceride levels and lower HDL cholesterol levels, two risk factors for cardiovascular disease (53, 54). Fiber-rich diets that are rich in certain micronutrients like magnesium and potassium may also help lower blood pressure, another important risk factor for cardiovascular disease. Some observational studies have found inverse associations between dietary fiber intake and blood pressure (55) or hypertension (56). A meta-analysis of 24 randomized, placebo-controlled trials found that dietary fiber supplementation (average of 11.5 g/day) lowered systolic blood pressure (SBP) by 1.13 mm Hg and diastolic blood pressure (DBP) by 1.26 mm Hg (57). Similarly, another meta-analysis of 25 randomized controlled trials found that an increase in dietary fiber (median increase of 10.7 g/day compared to the control group) was associated with a 1.15 mm Hg reduction in SBP and a 1.65 mm Hg reduction in DBP (58). Both analyses reported that the reductions in DBP, but not SBP, were statistically significant. Additionally, recent studies have indicated that higher consumption of dietary fiber may lower levels of C-reactive protein (59, 60), a biomarker of inflammation that is strongly associated with the risk of cardiovascular events, such as MI and stroke (61). Thus, several mechanisms might contribute to the cardioprotective effect of dietary fiber. Although viscous dietary fibers and fiber supplements appear to be most effective in lowering LDL-cholesterol levels, large epidemiological studies provide strong and consistent evidence that diets rich in all fiber from whole grains, legumes, fruit, and nonstarchy vegetables can significantly reduce CHD risk (62).

Type 2 diabetes mellitus

Increasing intakes of refined carbohydrates and decreasing intakes of fiber in the US have paralleled the increasing prevalence of type 2 diabetes mellitus (DM) to near epidemic proportions (63). Numerous prospective cohort studies have found that that diets rich in fiber, particularly cereal fiber from whole grains, are associated with significant reductions in the risk of developing type 2 DM (64-74). Although no intervention trials have evaluated the effect of increasing dietary fiber intake alone on type 2 DM prevention, two important intervention trials found that a combination of lifestyle modifications that included increasing fiber intake decreased the risk of developing type 2 DM in adults with impaired glucose tolerance (75, 76). Although multiple factors, including obesity, inactivity, and genetics, increase the risk of developing type 2 DM, the results of observational studies and intervention trials indicate that fiber-rich diets improve glucose tolerance and decrease the risk of type 2 DM, particularly in high-risk individuals.


Colorectal cancer

The majority of case-control studies conducted prior to 1990 found the incidence of colorectal cancer was lower in people with higher fiber intakes (77, 78). A recent nested case-control study found an inverse association between dietary fiber intake and risk of colorectal cancer when fiber intake was assessed by food diaries but not when assessed by food-frequency questionnaires (79). To date, most prospective cohort studies have not found significant associations between measures of dietary fiber intake and colorectal cancer risk (80-89). A pooled analysis of 13 prospective cohort studies, which analyzed data from 725,628 adults, did not find high dietary fiber intake to be protective against colorectal cancer when other dietary factors were taken into account (90). However, the largest prospective study on diet and cancer to date, which included 519,978 men and women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) project, found that dietary fiber from foods was protective against colon cancer development (91). This EPIC study was not included in the earlier pooled analysis mentioned above that reported no association between dietary fiber intake and colorectal cancer (90).

In addition, four controlled clinical trials have failed to demonstrate a protective effect of fiber consumption on the recurrence of colorectal adenomas (precancerous polyps). The rate of recurrence of colorectal adenomas over a 4-year period was not significantly different between those who consumed about 33 g/day of fiber from a fruit and vegetable-rich, low-fat diet and those in a control group who consumed about 19 g/day of fiber (92). In another trial, there was no significant difference in the rate of colorectal adenoma recurrence over a 3-year period between those supplemented with 13.5 g/day of wheat-bran fiber and those supplemented with 2 g/day of wheat-bran fiber (93). More recently, a 4-year intervention trial found that supplementation with 7.5 g/day of wheat bran had no effect on colorectal adenoma recurrence (94). Surprisingly, in another intervention trial, supplementation with 3.5 g/day of psyllium for three years resulted in a significant increase in adenoma recurrence compared to placebo (95).

The reasons for the discrepancies between the findings of case-control studies with those of most prospective cohort studies and recent intervention trials have generated considerable debate among scientists. Potential reasons for the lack of a protective effect by dietary fiber observed in these studies include the possibility that the type or the amount of fiber consumed by most people in these studies was inadequate to prevent colorectal cancer (4), or that other dietary factors like fat may interact with fiber, influencing its effects on colorectal cancer (1, 96). The methods used to assess fiber intake in observational studies may also contribute to the disparate results (79). Clearly, more research is needed to sort out the complex effects of dietary fiber and fiber supplements on colorectal cancer risk and progression.

Breast cancer

A number of early case-control studies found significant inverse associations between dietary fiber intake and breast cancer incidence (97-100), but many prospective cohort studies have not found dietary fiber intake to be associated with significant reductions in breast cancer risk (101-108). Three studies have reported a protective association for dietary fiber and breast cancer. A prospective cohort study in the UK found that dietary fiber intake was inversely associated with risk of breast cancer in premenopausal women but not in postmenopausal women (109). Additionally, a prospective cohort study in Sweden found that postmenopausal women with the highest fiber intakes (averaging about 26 g/day) had a risk of breast cancer that was 40% lower than women with the lowest fiber intakes (averaging about 13 g/day) (110). Women with the highest fiber and lowest fat intakes had the very lowest risk of breast cancer. More recently, a prospective study in a cohort of more than 185,000 US postmenopausal women found that those with the highest intakes of dietary fiber (median, 26 g/day) had a 13% lower risk of all forms of breast cancer and a 44% lower risk of hormone receptor-negative tumors (ER-/PR-) compared to those with the lowest intakes of dietary fiber (median, 11 g/day) (111). A 2011 meta-analysis of 10 prospective cohort studies found a modest, 11% lower risk of breast cancer in women with the highest intakes of dietary fiber (112). The results of small, short-term intervention trials in premenopausal and postmenopausal women suggest that low-fat (10%-25% of energy), high-fiber (25-40 g/day) diets could decrease circulating estrogen levels by increasing the excretion of estrogens and by promoting the metabolism of estrogens to less estrogenic forms (113, 114). However, it is not known whether fiber-associated effects on endogenous estrogen levels have a clinically significant impact on breast cancer risk (4). Overall, observational studies examining dietary fiber intake and breast cancer incidence have reported mixed results. In such studies, it is possible that the association may be confounded by consumption of fiber-rich foods, such as fruit and vegetables.

Diverticular disease

Some observational studies have associated high-fiber intakes with a decreased risk of diverticulosis, a relatively common condition that is characterized by the formation of small pouches (diverticula) in the colon (115, 116). However, a recent cross-sectional study of 2,104 adults, found that those with the highest fiber intakes, measured by food frequency questionnaires, had a higher prevalence of diverticula (assessed by colonoscopy) compared to those with the lowest fiber intakes (117). Although most people with diverticulosis experience no symptoms, about 15%-20% may develop pain or inflammation, known as diverticulitis (118). In a large prospective cohort study, men with the highest insoluble fiber intakes (median, 22.7 g/day) had a 37% lower risk of developing symptomatic diverticular disease compared to men with the lowest insoluble fiber intakes (median, 10.1 g/day). The protective effect of dietary fiber against diverticular disease was strongest for cellulose and lignin (119). More research is needed to clarify the association between dietary fiber and diverticular disease.

Weight control

In addition to providing less energy, there is some evidence that higher fiber intakes can help to prevent weight gain or promote weight loss by extending the feeling of fullness after a meal (satiety) (120). Observational studies have found that adults with higher intakes of dietary fiber are leaner (121, 122) and less likely to be obese than adults with low-fiber intakes (123, 124). One large prospective cohort study found that women whose intake of high-fiber foods increased by an average of 9 g/day over a 12-year period were half as likely to experience a major weight gain of at least 55 lb (25 kg) than those whose intake of high-fiber foods decreased by an average of 3 g/day (125). The results of short-term clinical trials examining the effect of increased fiber intake on weight loss have been mixed. Overall, a systematic review of clinical trials conducted prior to 2001 found that increasing fiber intake from foods or supplements by 14 g/day resulted in a 10% decrease in energy intake and weight losses averaging about 4 1b (1.9 kg) over four months (120). However, some more recent clinical trials did not find fiber-rich cereal (126) or fiber supplements (127) enhanced weight loss. A 2011 systematic review of 61 randomized controlled trials examined the effect of different fiber types on body weight (128). This analysis found that dextrins and marine polysaccharides reduced body weight in all of the studies, while chitosan, arabinoxylans, and fructans reduced body weight in at least two-thirds of the studies. Average weight reductions were greatest for the fructans and marine polysaccharides groups (~1.3 kg or 2.8 lb/4 weeks for a 79 kg person in both groups). For all fiber types combined, the average weight reduction was only 0.3 kg (0.7 lb) per 4 weeks for a 79-kg person (128). Although people with higher intakes of fiber-rich foods, particularly whole grains, appear more likely to maintain a healthy body weight, the role of fiber alone in long-term weight control is not yet clear. Effects on body weight might depend on the specific type of dietary fiber.

All-cause mortality

Several prospective cohort studies have found higher intakes of dietary fiber to be associated with a lower risk of mortality from all causes. A recent report from the NIH-AARP Diet and Health Study, which followed 388,122 older adults for an average of nine years, found that men and women in the highest quintiles of dietary fiber intake had a 22% lower risk of mortality when compared to the lowest quintiles of dietary fiber intake (50). Smaller prospective studies have also reported an inverse association between total fiber intake and all-cause mortality (44, 48, 129), and an inverse association between cereal fiber intake and all-cause mortality was found in the Nurses’ Health Study, which included more than 50,000 participants (130). However, no association was found between total fiber intake or soluble fiber intake and mortality from all causes in the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-Up Study—a prospective study that assessed fiber intake by a single, 24-hour dietary recall method (46).

Disease Treatment

Diabetes mellitus

Numerous controlled clinical trials in people who have type 1 or type 2 diabetes mellitus (DM) have found that increasing fiber intake from foods (131, 132) or viscous fiber supplements (133-135) improves markers of glycemic control, particularly postprandial glucose levels and serum lipid profiles. A meta-analysis that combined the results of 23 clinical trials comparing the effects of high-fiber diets (>20 g/1,000 kcal) with those of low-fiber diets (<10 g/1,000 kcal) in diabetic patients found that high-fiber diets lowered postprandial blood glucose concentrations by 13%-21%, serum LDL cholesterol concentrations by 8%-16%, and serum triglyceride concentrations by 8%-13% (136). Based on the evidence from this meta-analysis, the authors recommended a dietary fiber intake of 25-50 g/day (15-25 g/1,000 kcal) for individuals with diabetes, which is consistent with the recommendations of many international diabetes organizations of at least 25-35 g/day (137-139). In general, the results of controlled clinical trials support recommendations that people with diabetes aim for high-fiber intakes by increasing consumption of whole grains, legumes, nuts, fruit, and nonstarchy vegetables. Since there is little evidence from clinical trials that increasing nonviscous fiber alone is beneficial (140), individuals with diabetes should avoid increasing fiber intake exclusively from nonviscous sources, such as wheat bran (136).

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional disorder of the intestines, characterized by episodes of abdominal pain or discomfort associated with a change in bowel movements, such as constipation or diarrhea (141). Although people diagnosed with IBS are often encouraged by health care providers to increase dietary fiber intake, the results of controlled clinical trials of psyllium, methylcellulose, and wheat bran have been mixed (142-144). A systematic review and meta-analysis of 12 randomized controlled trials (RCTs) found a beneficial effect of fiber that was limited to ispaghula husk (psyllium) (143). More recently, a 3-month randomized, placebo-controlled trial in 275 patients with IBS found that supplementation with psyllium (10 g/day) improved symptoms of abdominal pain or discomfort in the first two months of supplementation and also improved symptom severity after three months’ supplementation (145). Compared to placebo, supplementation with insoluble bran fiber (10 g/day) improved abdominal pain or discomfort only after three months’ supplementation and had no effect on symptom severity (145). Additionally, a systematic review of 17 RCTs of fiber supplements in IBS patients found that supplementation with soluble fiber, mainly from psyllium, significantly improved a global measure of IBS symptoms, while supplementation with insoluble fiber, such as corn bran or wheat bran, did not improve IBS symptoms (146). In general, fiber supplements improved constipation in IBS patients, but did not improve IBS-associated abdominal pain. Thus, the results of randomized controlled trials suggest that increasing soluble or viscous fiber intake gradually to 12-30 g/day may be beneficial for patients in whom constipation is the predominant symptom of IBS (147). However, fiber supplements could actually exacerbate symptoms in those whom diarrhea predominates (148). A few clinical trials have found that partially hydrolyzed guar gum (5 g/day), a water-soluble, non-gelling fiber, may improve IBS symptoms in patients with diarrhea and in those with constipation-predominant IBS (149). IBS patients should be advised to increase fiber intake gradually, since increasing intake of viscous, readily fermented fibers could increase gas production and bloating.


Food sources

Dietary fiber intakes in the US average from 16-18 g/day for men and 12-14 g/day for women—well below recommended intake levels (4) (see Intake Recommendations). Good sources of dietary fiber include legumes, nuts, whole grains, bran products, fruit, and nonstarchy vegetables. Legumes, whole grains, and nuts are generally more concentrated sources of fiber than fruit and vegetables. All plant-based foods contain mixtures of soluble and insoluble fiber (10). Oat products and legumes are rich sources of soluble and viscous fiber. Wheat bran and whole grains are rich sources of insoluble and nonviscous fiber. The total fiber content of some fiber-rich foods is presented in Table 1. Some strategies for increasing dietary fiber intake include increasing fruit and nonstarchy vegetable intake, increasing intake of legumes, eating whole-grain cereal or oatmeal for breakfast, substituting whole grains for refined grains, and substituting nuts or popcorn for less healthy snacks. For more information about the fiber content of specific foods, search the USDA National Nutrient Database.

Table 1. Some Food Sources of Dietary Fiber
Food Serving Fiber (g)
Navy beans, cooked from dried ½ cup 9.6
Split peas, cooked from dried ½ cup 8.1
Lentils, cooked from dried ½ cup 7.8
Kidney beans, canned ½ cup 6.8
Refried beans, canned ½ cup 6.1
Cereals and grains
100% (wheat) Bran Cereal ½ cup 12.5
Oats ½ cup 8.3
Bulgur, cooked ½ cup 4.1
Pearled barley, cooked ½ cup 3.0
Oat bran, cooked ½ cup 2.9
Quinoa, cooked ½ cup 2.6
Instant oatmeal, cooked ½ cup 2.0
Rice, long-grained brown, cooked ½ cup 1.8
Artichoke hearts, cooked ½ cup 7.2
Spinach, frozen, cooked ½ cup 3.5
Brussel sprouts, frozen, cooked ½ cup 3.2
Winter squash, cooked 1 cup 2.9
Mushrooms, white, cooked from fresh 1 cup 1.7
Prunes, uncooked ½ cup, pitted 6.2
Guava, fresh ½ cup 4.5
Asian pear 1 small pear 4.4
Raspberries, fresh ½ cup 4.0
Blackberries, fresh ½ cup 3.8
Nuts and Seeds
Almonds 1 ounce (23 kernels) 3.5
Pistachio nuts 1 ounce (49 kernels) 2.9
Pecans 1 ounce (19 halves) 2.7
Peanuts 1 ounce 2.4

Isolated fibers and supplements


β-glucans are viscous, easily fermented, soluble fibers found naturally in oats, barley, mushrooms, yeast, bacteria, and algae (151). β-Glucans extracted from oats, mushrooms, and yeast are available in a variety of nutritional supplements without a prescription.


Pectins are viscous fibers, most often extracted from citrus peels and apple pulp. Pectins are widely used as gelling agents in foods but are also available as dietary supplements without a prescription (9).

Inulins and oligofructose

Inulins and oligofructose, extracted from chicory root or synthesized from sucrose, are used as food additives (8). Isolated inulin is added to replace fat in products like salad dressing, while sweet-tasting oligofructose is added to products like fruit yogurts and desserts. Inulins and oligofructose are highly fermentable fibers that are also classified as prebiotics because of their ability to stimulate the growth of potentially beneficial Bifidobacteria species in the human colon (152). Encouraging the growth of Bifidobacteria could promote intestinal health by suppressing the growth of pathogenic bacteria known to cause diarrhea or by enhancing the immune response (153). Although a number of dietary supplements containing inulins and oligofructose are marketed as prebiotics, the health benefits of prebiotics have not yet been convincingly demonstrated in humans (154, 155).

Guar gum

Guar gum is a viscous, fermentable fiber derived from the Indian cluster bean (4). It is used as a thickener or emulsifier in many food products. Dietary supplements containing guar gum have been marketed as weight-loss aids, but a meta-analysis that combined the results of 11 randomized controlled trials found that guar gum supplements were not effective in reducing body weight (156).


Psyllium, a viscous, soluble fiber isolated from psyllium seed husks, is available without a prescription in laxatives, ready-to-eat cereals, and dietary supplements (9). The FDA has approved health claims like the following on the labels of foods containing at least 1.7 g/serving of soluble fiber from psyllium: "Diets low in saturated fat and cholesterol that include 7 g/day of soluble fiber from psyllium may reduce the risk of heart disease (20)."


Chitosan is an indigestible glucosamine polymer derived from chitin. When administered with food, chitosan decreased fat absorption in animal studies (157). Consequently, chitosan has been marketed as a dietary supplement to promote weight loss and lower cholesterol. Controlled clinical trials in humans have not generally found chitosan supplementation to be more effective than placebo in promoting weight loss (158). While some clinical trials in humans have found chitosan supplementation to result in modest reductions in total and LDL cholesterol levels compared to placebo (159, 160), others found no improvement (161, 162). Chitosan is available as a dietary supplement without a prescription in the US

Note: All fiber supplements should be taken with sufficient fluids. Most clinicians recommend taking fiber supplements with at least 8 ounces (240 ml) of water and consuming a total of at least 64 ounces (~2 liters or 2 quarts) of fluid daily (163, 164).


Adverse effects

Dietary fiber

Some people experience abdominal cramping, bloating, or gas when they abruptly increase their dietary fiber intakes (163, 164). These symptoms can be minimized or avoided by increasing intake of fiber-rich foods gradually and increasing fluid intake to at least 64 oz/day (~2 liters or 2 quarts/day). There have been rare reports of intestinal obstruction related to large intakes of oat bran or wheat bran, usually in people with impaired intestinal motility or difficulty chewing (165-168). The Institute of Medicine has not established a tolerable upper intake level (UL) for dietary or functional fiber (4).

Isolated fibers and fiber supplements

Gastrointestinal symptoms: The following fibers have been found to cause gastrointestinal distress, including abdominal cramping, bloating, gas, and diarrhea: guar gum, inulin and oligofructose, fructooligosaccharides, polydextrose, resistant starch, and psyllium (4). Use of a guar gum-containing supplement for weight loss has been associated with esophageal and small bowel obstruction (169). Additionally, several cases of intestinal obstruction by psyllium have been reported when taken with insufficient fluids or by people with impaired swallowing or gastrointestinal motility (170, 171).

Colorectal adenomas: One randomized controlled trial in patients with a history of colorectal adenomas (precancerous polyps) found that supplementation with 3.5 g/day of psyllium for three years resulted in a significant increase in colorectal adenoma recurrence compared to placebo (see Colorectal cancer) (95).

Allergy and anaphylaxis: Since chitin and chitosan may be isolated from the exoskeletons of crustaceans, such as crabs and lobsters, people with shellfish allergies should avoid taking chitin or chitosan supplements (9). Anaphylaxis has been reported after intravenous (IV) administration of inulin (172), as well as ingestion of margarine containing inulin extracted from chicory (173). Anaphylaxis has also been reported after the ingestion of cereals containing psyllium, and asthma has occasionally been reported in people with occupational exposure to psyllium powder (174).

Drug interactions

Psyllium may reduce the absorption of lithium, carbamazepine (Tegretol), digoxin (Lanoxin), and warfarin (Coumadin) when taken at the same time (9). Guar gum may slow the absorption of digoxin, acetaminophen (Tylenol), and bumetanide (Bumex) and decrease the absorption of metformin (Glucophage), penicillin, and some formulations of glyburide (Glynase) when taken at the same time (175). Pectin may decrease the absorption of lovastatin (Mevacor) when taken at the same time (176). Concomitant administration of kaolin-pectin has been reported to decrease the absorption of clindamycin, tetracyclines, and digoxin, but it is not known whether kaolin or pectin is responsible for the interaction (9). In general, medications should be taken at least one hour before or two hours after fiber supplements.

Nutrient interactions

The addition of cereal fiber to meals has generally been found to decrease the absorption of iron, zinc, calcium, and magnesium in the same meal, but this effect appears to be related to the phytate present in the cereal fiber rather than the fiber itself (177). In general, dietary fiber as part of a balanced diet has not been found to adversely affect the calcium, magnesium, iron, or zinc status of healthy people at recommended intake levels (4). Evidence from animal studies and limited research in humans suggests that inulin and oligofructose may enhance calcium absorption (178, 179). The addition of pectin and guar gum to a meal significantly reduced the absorption of the carotenoids β-carotene, lycopene, and lutein from that meal (180, 181).

Intake Recommendations

The Adequate Intake (AI) for total fiber

In light of consistent evidence from prospective cohort studies that fiber-rich diets are associated with significant reductions in cardiovascular disease risk, the Food and Nutrition Board of the Institute of Medicine established its first recommended intake levels for fiber in 2001 (4). The Adequate Intake (AI) recommendations for total fiber intake are based on the findings of several large prospective cohort studies that dietary fiber intakes of approximately 14 g for every 1,000 calories (kcal) consumed were associated with significant reductions in the risk of coronary heart disease (CHD) (42, 43, 45), as well as type 2 diabetes (66, 67). For adults who are 50 years of age and younger, the AI recommendation for total fiber intake is 38 g/day for men and 25 g/day for women. For adults over 50 years of age, the recommendation is 30 g/day for men and 21 g/day for women. The AI recommendations for males and females of all ages are presented in Table 2 (4).

Table 2. Adequate Intake (AI) for Total Fiber
Life Stage Age Males (g/day) Females (g/day)
Infants  0-6 months   ND* ND
Infants  7-12 months   ND ND
Children  1-3 years   19 19
Children  4-8 years   25 25
Children  9-13 years   31 26
Adolescents  14-18 years   38 26
Adults  19-50 years   38 25
Adults 51 years and older   30 21
Pregnancy  all ages   - 28
Breast-feeding  all ages   - 29
* Not determined

Some suggestions for increasing fiber intake

  • Eat at least five servings of fruit and vegetables daily (see Fruit and Vegetables).
  • Substitute whole grains for refined grains (see Whole Grains).
  • Eat oatmeal, whole-grain cereal, or bran cereal for breakfast.
  • Eat beans, split peas, or lentils at least once weekly (see Legumes).
  • Substitute nuts or popcorn for less healthful snacks like potato chips or candy (see Nuts).


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2012 by:
David M. Klurfeld, Ph.D.
National Program Leader, Human Nutrition
USDA Agricultural Research Service

Copyright 2004-2017  Linus Pauling Institute


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