Omega-3 Polyunsaturated Fatty Acids
John C. Umhau and Karl M. Dauphinais
Good health has been linked with healthy diet as far back as the sixth century
b.c. when the clinical effects of a vegetarian diet on a group of Hebrew
captives were documented in the Book of Daniel (Josephus, 1994). In this
chapter, we will discuss diverse effects of an essential component of a healthy
diet, long chain omega-3 polyunsaturated fatty acid (PUFA)(Burr & Burr,
1930). Because modern diets are relatively deficient in this special type of
fat, there is a great potential for improving many aspects of health by adding
it to the diet (Lands, 2003). For example, omega-3 fatty acids, especially
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to
prevent heart attacks and sudden cardiac death in individuals with coronary
artery disease (Albert et al., 2002). Greater omega-3 fat consumption has also
been reported to reduce the risk for dementia (Morris et al., 2003; Tully et al.,
2003), depression (Hibbeln, 1998), high triglycerides (Weber & Raederstorff,
2000), hypertension (Mori, Bao, Burke, Puddey, & Beilin, 1999), arthritis
(Simopoulos, 2002), autoimmune diseases (Adam, 2003; Simopoulos, 2002),
certain cancers (Terry, Rohan, & Wolk, 2003), and preterm delivery (Olsen &
Secher, 2002). This chapter will examine diverse health risks due to omega-3
fatty acid deficiency and the reduction of this risk through the use of dietary
supplements and food sources rich in omega-3 fatty acids, such as seafood.
What Are Omega-3 Polyunsaturated Fatty Acids
and Why Are They Unique?
Fats are not only for storing energy, but they are also important components
of cell membranes, hormones, and signaling molecules. Fats or fatty acids
are long molecules composed of carbon atom chains with a particular ratio of
hydrogen atoms attached. A saturated fat molecule holds a maximum number
of carbon atoms, and is therefore “saturated” with hydrogen atoms. An unsat-
urated fat has one or more double bonds between carbon atoms on the fatty
acid chain. Each double bond takes the place of two hydrogen atoms; thus
∗Tricia H. Umhau, David Herbert, and Joseph Hibbeln provided thoughtful review of
88 John C. Umhau and Karl M. Dauphinais
these carbon chains are not “saturated” with hydrogen. Fat molecules are
monounsaturated if they contain just one double bond and polyunsaturated
if they contain more than one double bond. The number and position of
double bonds in these molecules affect their physical properties and functional
characteristics. The human body can make most fats from any source of
calories consumed. However, there are some types of fats that the body
can not make. These fats include the polyunsaturated omega-6 and omega-3
fatty acids, which are therefore termed “essential”. The terms “omega-3” or
“omega-6” signify that the first double bond in the carbon backbone of the
fatty acid occurs at the third or the sixth carbon–carbon bond, respectively.
Mammals lack the enzymes to introduce double bonds at the omega-6 or
omega-3 position of a long fatty acid molecule, and therefore, these fats
must be obtained from the diet. Humans can interconvert fats in the same
omega family, but omega-6 fats cannot be converted to omega-3 fats. Many
commonly consumed foods of industrialized countries are abundant in omega-
6 fats, particularly linoleic acid (LA) found in soy and corn oils and arachi-
donic acid (AA) found in meat. Because of this, the American diet contains
more than enough of the omega-6 fatty acids, a topic of concern addressed
later in this chapter.
The 20- and 22-carbon long omega-3 fats, EPA and DHA, respectively, are
critical to human health. These omega-3 fats must be obtained directly through
the diet (i.e. from seafood) or manufactured in the body from precursor
omega-3 fats such as the 18-carbon long omega-3 fatty acid, alpha-linolenic
acid (ALNA) found in plant sources such as canola oil, walnuts, or flaxseed.
Conversion of dietary ALNA to EPA is, however, limited, with conversion to
DHA being minimal at best (Brenna, 2002; Pawlosky et al., 2003). The ratio
between the omega-6 fats and the omega-3 fats in the tissue may be critical
because of the ‘competition’ between these two essential fatty acid families
for their entry into the enzymatic pathways, which convert them into bioactive
metabolites. A low dietary ratio of omega-6 to omega-3 PUFAs increases the
conversion of ALNA to EPA and DHA, while a high dietary ratio of omega-6
to omega-3 PUFA will accentuatea diet deficit in ALNA (Brenna, 2002). The
limited conversion of ALNA to longer chain omega-3 fatty acids (EPA and
DHA) establishes the importance of obtaining a diet rich in EPA and DHA
omega-3 directly from the foods we eat. A simple schematic of the essential
fatty acids and their metabolism is shown in Figure 4.1.
The Role of Omega-3 Fatty Acids in the Body
Omega-3 fatty acids have many important roles in the body. Polyunsatu-
rated fatty acids such as omega-3 PUFA help to make up the phospholipids
that are fundamental components of cell membranes. The particular type of
PUFA in the phospholipid influences the biophysical properties of membranes
(Martínez & Mougan, 1998; Niebylski & salem, 1994) and the peculiar
properties of the DHA molecule make it a critical component of nerve and
retinal cells (Anderson, Benolken, Dudley, Landis, & Wheeler, 1974). In the
brain, DHA and the omega-6 PUFA, arachidonic acid (AA), are concentrated
in the synapse where they function in phospholipid-mediated signal trans-
duction (Jones, Toshanari, & Stanley, 1997). DHA is particularly important
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 89
Figure 4.1. Basic enzymatic metabolism and products of the omega-6 and omega-3
for ischemia-reperfusion injuries in the brain as it is metabolized into neuro-
protectin D1, which regulates gene expression that promotes cell survival in
stressed cells (Marcheselli et al., 2003).
In the 1960s it was found that molecules, which played a key role
in cell signaling and inflammation, were derived from PUFA. These
molecules, called eicosanoids, include leukotrienes, prostaglandins, and
thromboxanes (Bergstrom, Danielsson, & Samuelsson, 1964; Van Dorp,
Beerthuis, Nugteren & Vonkeman, 1964). Eicosanoids derived from the 20-
carbon chain omega-6 fat, AA, are often proinflammatory while eicosanoids
derived from the 20-carbon chain omega-3 fat, EPA, acids often moderate
inflammation (Simopoulos, 2002; Van Epps, 2005). Omega-3 PUFAs can not
only be metabolized into anti-inflammatory eicosanoids (particularly in the
presence of aspirin), but they can compete with and replace omega-6 PUFA as
precursors for the manufacture of inflammation-promoting molecules (Arita
et al., 2005; Bannenberg et al., 2005; Serhan, Arita, Hong, & Gotlinger,
2004; Van Epps, 2005). The relative tissue concentrations of these omega-3
PUFA may be critical as omega-6 and omega-3 fats compete for entry into
the same enzymatic pathways (Flower & Perretti, 2005; Lands, 2003). The
same enzymatic pathways are also acted upon by anti-inflammatory drugs
like ibuprofen, aspirin, and the COX-2 inhibitors. While aspirin blocks the
conversion of AA into proinflammatory molecules, COX-2 inhibitors block
the action of COX-2, an enzyme that promotes the conversion of AA into
proinflammatory prostaglandins. By blocking this effect, COX-2 inhibitors
reduce these proinflammatory prostaglandins and treat rheumatoid arthritis.
However, COX-2 can also convert EPA to the anti-inflammatory eicosanoid,
resolvin E1. When COX-2 inhibitors block this beneficial production of
resolvin E1, the resulting effect may be the serious negative cardiovascular
side effects associated with COX-2 inhibitors (Arita et al., 2005; Bannenberg
et al., 2005; Serhan et al., 2004; Van Epps, 2005).
90 John C. Umhau and Karl M. Dauphinais
Evidence for the Health Benefits of Omega-3 Fatty Acids
Omega-3 fatty acids are critical for pregnant women and their offspring.
Pregnancy causes a decline in maternal DHA levels as DHA is transferred
to the fetus. Maternal DHA levels continue to decline after birth as DHA
is transferred via milk to the newborn. This decline in maternal DHA status
may prove to result in deficient states, impairing maternal health after the
pregnancy. Epidemiological data suggest that lower seafood consumption
and levels of DHA are both associated with an increased risk of postpartum
depression (Hibbeln, 2002). Other data suggest that DHA may have beneficial
effects on pregnancy outcome. Neuronal membranes are highly enriched with
long-chain PUFA, particularly DHA, which is critical for healthy development
of the infant brain (Martínez & Mougan, 1998) and retina (Uauy, Hoffman,
Mena, Llanos, & Birch, 2003). Low consumption of fish has been associated
with preterm labor and low birth weight (Olsen & Secher, 2002) and DHA
supplementation during pregnancy and lactation has been found to augment
children’s IQ (Helland, Smith, Saarem, Saugstad, & Drevon, 2003). DHA
content of human milk varies and this variation is primarily a result of the
mother’s dietary intake. Thus, the low omega-3 diet of American mothers
gives rise to some of the lowest worldwide levels of DHA in human milk
(Hibbeln, 2002). Many researchers believe that pregnant women and women
who are breastfeeding should consider supplementation with fish oil even
though definitive studies have not yet been completed to evaluate the effect of
such supplements. With the data available in 1999, one group of scientists and
clinicians concluded that 300 mg of DHA per day was a reasonable amount
recommended for pregnant women (Simopoulos, Leaf, & Salem, 1999). It is
possible for infant formula to be supplemented with DHA, and beginning in
2002 in the United States, DHA was added to some brands of infant formula.
Omega-3 fatty acids are thought to be important in psychiatric disorders
not only because they are selectively concentrated in the brain, but also
because they affect neurochemical pathways involved in the pathophysi-
ology of psychiatric illnesses (Hibbeln & Salem, 1995). The proposition
that depression and bipolar disorder are linked to a low omega-3 status is
supported by diverse evidence. Many studies report that tissue concentrations
of omega-3 fatty acids are lower among depressed subjects, and this finding is
independent of alcohol abuse (Adams, Lawson, Sanigorski, & Sinclair, 1996;
Edwards, Peet, Shay, & Horrobin, 1998a, 1998b; Maes et al., 1999, 1996;
Peet, Murphy, Shay, & Horrobin, 1998). One large study found that subjects
who consume fish twice or more a week have a lower risk of reporting
depressive symptoms (Tanskanen et al., 2001), while results from double-
blind, placebo-controlled studies show that omega-3 fatty acid supplements,
particularly those higher in EPA than DHA, can reduce depressive symptoms
in participants with mental illness (Frangou, Lewis, & McCrone, 2006; Peet
& Horrobin, 2002; Stoll et al., 1999).
Perhaps the most intriguing health benefit of omega-3 fatty acids for
the population is the possibility for a dramatic reduction in violence
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 91
and aggression. Low blood levels of omega-3 fatty acids have been
found in violent and impulsive offenders (Virkkunen, Horrobin, Jenkins, &
Manku, 1987) and aggressive cocaine addicts (Buydens-Branchey, Branchey,
McMakin, & Hibbeln, 2003). Double-blind, placebo-controlled intervention
trials have demonstrated that omega-3 fatty acids can reduce hostility, an
affective state closely related to anger and aggression (Hamazaki et al., 1996;
Thienprasert et al., 2000; Weidner, Connor, Hollis, & Connor, 1992). Trials
using omega-3s have also reduced aggression in women with borderline
personality disorder (Zanarini & Frankenburg, 2003) and felony level violence
in prisoners (who also received multiple vitamins) (Gesch, Hammond,
Hampson, Eves, & Crowder, 2002). Rates of homicide mortality are twenty
times higher in countries with little seafood consumption compared to those
with the highest consumption (Hibbeln, 2001). The countries with the highest
seafood have an average consumption of EPA + DHA, estimated to be approx-
imately 1000 mg per day. These high levels of consumption contrast with the
United States, which has an estimated daily intake of 180 mg of EPA + DHA
per day. From these data, Hibbeln has estimated that approximately 1000 mg
of EPA + DHA per day (along with a reduction of dietary omega-6 fat) may
be sufficient to significantly decrease the risk of aggressive disorders in the
general US population (Hibbeln, 2001; Hutchins, 2005).
Lower levels of plasma DHA and the DHA metabolite neuroprotectin D1
have been associated with an increased risk of dementia (Conquer, Tierney,
Zecevic, Bettger, & Fisher, 2000; Lukiw et al., 2005; Tully et al., 2003).
In a prospective study of healthy individuals, eating one fish meal a week
was associated with a 60% decreased risk of developing Alzheimer’s disease
(Morris et al., 2003). Although more randomized, controlled trials are needed,
the data suggest that the consumption of 2.7 or more fish servings per week
or 180 mg or more of DHA per day may be associated with as much as a 50%
decrease in the risk of developing dementia (Hutchins, 2005; Schaefer, 2005).
Inflammatory and Autoimmune Benefits
Proinflammatory signals mediated by metabolites of omega-6 PUFA
(i.e., AA), can be responsible for the inflammation that occurs in diseases such
as rheumatoid arthritis, inflammatory bowel disease, and asthma. Omega-3
PUFA compete for the enzymes, which convert omega-6 PUFA into these
proinflammatory signals, and it may have a profound beneficial impact on
many disease processes. In rheumatoid arthritis, a number of randomized,
placebo-controlled, double-blind studies of fish oil have shown a benefit from
the use of a minimum of 3 g (combined) of EPA + DHA per day over a
period of 12 weeks (Adam, 2003; Calder, 2005; Fortin et al., 1995; Kremer,
2000). There are also a number of promising reports of the use of omega-3
fatty acids in irritable bowel disease and asthma. For example, omega-3 fatty
acids may decrease airway hyper-responsiveness in asthma (Black & Sharpe,
1997; Mickleborough, Ionescu, & Rundell, 2004). At this time, however,
there are insufficient data available to draw firm conclusions regarding the
clinical benefit of omega-3 fatty acids on asthma and bowel disorders (Balk
et al., 2004; MacLean et al., 2004).
92 John C. Umhau and Karl M. Dauphinais
EPA has been suggested to play a protective role in hormone-related cancers,
particularly breast and prostate cancers. In animal experiments, EPA and DHA
have consistently inhibited the proliferation of malignant breast and prostate
cancers; however, epidemiological studies examining the role of omega-3
fats in cancer have not been consistent (Terry et al., 2003). Fish oils can
have a benefit in reversing cancer-related cachexia by decreasing the protein
degradation in cachectic muscle (Tisdale, 2003), suggesting that there may
be a potential place for omega-3 PUFAs in cancer therapy as well as in
prevention (Karmali, 1996).
Some of the strongest evidence for the health benefits of long-chain omega-3
fatty acids comes from research in cardiovascular disease (CVD) (Balk et al.,
2004). In the 1970s, researchers first associated the low rates of heart disease
in Greenland Eskimos with their higher consumption of fatty fish and sea
mammals (Bang, Dyerberg, & Nielsen, 1971). Today, there are numerous
studies including retrospective reviews and prospective randomized clinical
trials, which support fish intake as a preventive measure in CVD, particularly
to prevent sudden death (Albert et al., 2002; GISSI-Prevenzione-Investigators,
1999). In one large study, men who survived myocardial infarctions had 29%
less overall mortality if they increased their fish intake to obtain 500–800 mg
per day of omega-3 fatty acids. A subgroup from this study took 450 mg
of EPA + DHA per day, and had 56% less overall mortality and 62% less
CVD-related death (Burr et al., 1989).
Supplementation of omega-3 fatty acids has been shown to decrease triglyc-
eride levels (Park & Harris, 2003; Weber & Raederstorff, 2000). Triglyceride
reductions of 20% have been documented for intake of 4 g per day of EPA +
DHA, but benefits have been noted with a dose as low as 1 g per day
(Mori et al., 2000; Weber & Raederstorff, 2000). Reasons for this decrease
appear related to both decreased hepatic production and increased clearance
of triglycerides from the body (Nestel et al., 1984; Park & Harris, 2003).
Recent evidence that high levels of triglycerides may be an independent risk
factor for coronary heart disease further emphasizes the potential benefit of
omega-3 PUFAs in these individuals (Eberly, Stamler, & Neaton, 2003).
Research suggests that blood pressure can be reduced by fish oil given in a
dose of 3.7 g per day, while dosages less than 500 mg per day do not show this
effect (Geleijnse, Giltay, Grobbee, Donders, & Kok, 2002). The statistically
significant reduction in systolic blood pressure readings has ranged from 2 to
6 mmHg in hypertensive individuals (Bao, Mori, Burke, Puddey, & Beilin,
1998; Geleijnse et al., 2002; Mori et al., 1999). Greater reductions have been
noted in older, hypertensive individuals and in individuals with concurrent
weight loss (Bao et al., 1998; Geleijnse et al., 2002).
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 93
Historical Human Consumption of Omega-3 Fatty Acids
The modern diet has a very different fat composition compared to that of our
amounts of omega-6 and omega-3 fat (Leaf & Weber, 1987). Today, the addition
of omega-3-rich fish and seafood to the diet can be an expensive luxury, whereas
at one time it was common in the diet (Simopoulos, Leaf, & Salem, 1999). Seed
oilrich in omega-6 fat, particularly soy oil, isa mainstay of today’s food industry.
It is remarkable to note that between 1909 and 2000, the consumption of soy
oil increased a thousand fold, from approximately 0.02 to 20% (expressed as a
percentage of all food calories available) (Hibbeln, Nieminen, & Lands, 2004).
Animals are fattened on omega-6 rich sources of feed and the result is meat that
is higher in omega-6 PUFAs and lower in omega-3 PUFAs. These changes have
resulted in a typical American diet that is now rich in omega-6 fats but depleted
in omega-3. This change in the diet has changed the balance of omega-3 and
omega-6 fats in the tissue, which has resulted in an imbalance of eicosanoid
actions. Because this imbalance is reversible, scientists who study PUFAs are
optimistic that by restoring an appropriate balance of omega-3 to the diet we can
minimize human misery associated with many diseases (Lands, 2003).
Recommendations for the Intake of Omega-3 Fatty Acids
Based on its review of the literature, the FDA concluded that there is suffi-
cient evidence to make a qualified health claim on the label of appropriate
foods containing Omega 3 fatty acids (FDA, 2004a; Hubbard, 2004). It states:
“Supportive but not conclusive research shows that consumption of EPA and
DHA omega-3 fatty acids may reduce the risk of coronary heart disease.” The
Agency for Health Care Research and Quality (AHRQ) has noted that food
sources of the 18-carbon long omega-3 fat, ALNA, may help to reduce deaths
from heart disease, but to a much lesser extent than fish oil (Balk et al., 2004).
The American Heart Association (AHA) recommends consumption of at least
two servings of fish per week (particularly of fatty fish) along with food sources
high in ALNA, based on the evident benefit from the omega-3 fatty acids. These
guidelines further recommend that participants with documented coronary heart
disease consume approximately1gofEPA+DHAperdayandthat partici-
pants with significantly elevated triglyceride levels take 2–4 g of EPA + DHA
provided as capsules under a physician’s care (Kris-Etherton, Harris, & Appel,
2002). The National Institutes of Health (NIH), the World Health Organization
(WHO), and the United States Department of Agriculture (USDA) each have
made specific recommendations (summarized in Table 4.1) for the dietary
intake of omega-3 fatty acids, particularly for the intake of EPA and DHA.
Potential Risks of Omega-3 Fatty Acids
The FDA has determined that up to3gofEPA+DHA per day should be
considered “Generally Recognized as Safe” (GRAS). While the addition of
various sources of omega-3 fat to the diet is essentially without risk, it is
always wise to examine potential drawbacks of such a recommendation.
Perhaps the most common drawback of taking fish oil supplements occurs with
less refined forms of fish oil, and is related to eructation, fishy aftertaste, or
gastric upset. In an effort to minimize any fishy odor or gastric distress, some
94 John C. Umhau and Karl M. Dauphinais
Table 4.1. Summary of recommendations from key organizations and expert
AHA, 2002 (Kris-Etherton
et al., 2002) Individuals without cardiovascular disease
(CVD) should eat oily fish twice per week
and foods rich in ALNA (walnuts, canola,
soy, and flaxseed)
Individuals with documented CVD should eat
from oily fish (preferable) or supplements
For triglyceride lowering effects, 2–4 g
of omega-3 fatty acids per day as a
supplement under a physician’s care
NIH-supported expert panel,
1999 (Simopoulos et al.,
Recommends 650 mg of EPA + DHA per
day and 2.2 g of ALNA per day for the
Recommends 300 mg DHA per day for
pregnant or lactating females
WHO, 2003 (WHO, 2003) Recommends 1–2 servings of fish per week
(containing 200–500 mg of EPA + DHA
per serving) to prevent heart disease and
USDA Dietary Guidelines,
2005 (DHHS, 2005) Recommends 8 oz per week (two servings)
of fish high in EPA and DHA content to
AHA, American Heart Association; NIH, National Institutes of Health; WHO, World Health
Organization; USDA, United States Department of Agriculture.
experts have advocated taking fish oil at bedtime or keeping fish oil capsules in
the freezer. Swallowing frozen capsules may delay release of the oil until after
it has passed through the stomach, but the gelatin capsules of some formulation
may not withstand freezing. Although the weight of the evidence suggests that
the benefit of eating fish outweighs potential risks, there is a concern regarding
potential contaminants such as mercury and PCBs. Focusing primarily on the
risks from mercury, the FDA advises that children as well as women who are
pregnant or lactating should avoid fish which are high in mercury such as king
mackerel, swordfish, shark, and tilefish. Seafood low in mercury includes
salmon, caned light tuna, trout, Pollock, flounder, herring, catfish, halibut,
cod, shrimp, crab, oysters, clams, and scallops (FDA, 2004b; Kris-Etherton,
2005). Significant contamination is not found in commercially available
fish oil (Consumer Reports, 2003; Foran, Flood & Lewandrowski, 2003;
Melanson, Lewandrowski, Flood, & Lewandrowski, 2005).
Omega-3 PUFAs have some hypothetical risks, which should be considered.
Although there has been concern that omega-3 fatty acids could cause a
problem by increasing the bleeding time, there is no documented case in the
literature of serious bleeding caused by omega-3 fatty acids, and clinical trials,
including trials of coronary artery bypass surgery, have not shown evidence of
increased blood loss due to intake of omega-3s (Simopoulos, 1991). Increases
in LDL cholesterol have been reported in individuals with extremely elevated
triglyceride levels after treatment with omega-3 fatty acids, but the effect was
not seen in individuals with normal or slightly elevated levels of blood lipids
receiving omega-3 fats (Nestel et al., 1984; Weber & Raederstorff, 2000).
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 95
The effect of omega-3 fatty acids on LDL levels has been inconsistent, while
the overall effect of omega-3 fatty acids on CVD has been positive (Balk et al.,
2004; MacLean et al., 2004; Nestel et al., 1984). Although there has been
suggestion that omega-3 fatty acids may increase fasting blood glucose and
insulin resistance in diabetics (Mori et al., 2000), this was not supported by a
meta-analysis, which did however show a beneficial decrease in triglyceride
levels (MacLean et al., 2004). One recent report showed an increased risk of
arrhythmias in participants with implantable cardiac defibrillators. In these
participants, however, it was noted that there was no change in mortality
with the increased firing of the device and increased episodes of ventricular
tachycardia and fibrillation (Raitt et al., 2005). Because of these concerns,
participants with extremely high triglyceride levels, implantable defibrillators,
or who are taking blood-thinning agents should discuss the use of high doses
(over 3 g per day) of omega-3 fatty acids with their doctor.
Sources of Omega-3 Fatty Acids in the Diet
Seafood, fish, and fish oil supplements are important sources of the long-chain
omega-3 PUFAs, EPA, and DHA. The current average daily combined intake
of EPA + DHA in a typical American diet comes from one fish serving every
10 days (i.e., about 150 mg per day) (Kris-Etherton et al., 2000). Consuming
fish 2.5–3 times per week provides approximately 500 mg of EPA + DHA per
day. Good sources of ALNA include canola oil, nuts (especially walnuts),flax,
and green leafy vegetables. The circulating and tissue levels of omega-3 fatty
acids depend on both the recent and long-term dietary consumption of these
fatty acids. A long-standing diet that is high in omega-6 will be reflected
in the composition of adipose tissue and continue to affect the balance of
omega-6 to omega-3 fats throughout the body tissue for many years. Thus,
the recommended daily intake of omega-3 fat should be higher or lower
depending on the dietary history as well as on the current intake of omega-6
fats. For more details on sources of omega-3 and omega-6 fatty acids and
how to generate a balanced dietary intake, a computer software package,
KIM (Keep it Managed), has been developed, which can be downloaded
free from http://ods.od.nih.gov/eicosanoids. Populations at risk for disease
may have an increased requirement for omega-3 fatty acids. For example,
reduced tissue levels of omega-3 fatty acids can result from heavy alcohol
consumption (Pawlosky, Bacher, & Salem, 2001) and may be associated with
folate deficiency (Umhau et al., 2006), obesity, diabetes, and youth (Sands,
Reid, Windsor, & Harris, 2005).
Perhaps the most promising source of omea-3 fats for the general population
is through fortified foods. There are a number of foods available that have
been enriched by the addition of EPA and DHA. Eggs enriched with omega-3
fats are becoming commonly available in supermarkets and these eggs contain
DHA, which is the result of feeding chickens with flaxseed meal, fish meal,
or marine algae. One company has developed a line of omega-3-fortified fish
products including salmon burgers, franks, and imitation crabmeat. Another
new source is sandwich bread with omega-3s, which is claimed to supply up
to 80 mg of omega-3 fatty acids in two slices of bread. Other foods fortified
96 John C. Umhau and Karl M. Dauphinais
with omega-3s include margarine, peanut butter, chocolate milk, and spaghetti
sauce. In the future, beef, chicken, and even soybeans may be developed with
a higher proportion of omega-3 fats.
Fish Oil Supplements
In the eighteenth century, fish oil (i.e., cod liver oil) was taken for arthritis,
and in the twentieth century, it was taken for respiratory infections, a
use encouraged by controlled industrial studies demonstrating that a daily
teaspoon of cod liver oil prevented colds and reduced absenteeism by half
(Semba, 1999). Although traditionally associated with a fishy taste, modern
manufacturing techniques can produce fish oil which is essentially tasteless.
Capsules are readily available through many retail outlets, and for capsules
containing1gofEPA+DHA, their cost ranged from $22 to $219 per year
or $0.06 to $0.60 per day (Consumer Reports, 2003). A prescription strength
formulation of 4 g of concentrated EPA+DHA is also available, which is
specified for the reduction of high triglyceride levels and is marketed under
the trade name Omacor®. It should be remembered that fish oil, however,
does not provide all of the important nutrients contained in fish, such as
selenium, calcium, iodine, and particularly vitamin D.
Our message is that omega-3 fats can contribute to a longer and healthier life
and that seafood is a healthy food. For those who do not care to eat fish,
omega-3 rich fish oils are a safe and inexpensive alternative to the pharmaceu-
ticals used to treat diseases that fish oil might prevent. We recommend a diet
rich in sources of long-chain omega-3 PUFA with reduced intake of omega-6
fat. Depending on the background diet and tissue levels of omega-6 fat, 1–2 g
of EPA + DHA per day is likely to prevent most omega-3-related pathology in
the Western countries. Sadly, the relatively low fish consumption in the United
States may be further limited by mixed messages, as consumers hear more
about harmful substances in fish than of the important nutrients it contains
(FDA, 2001, 2004b; Lands, 2003; Verbeke, Sioen, Pieniak, Van Camp, &
De Henauw, 2005). Thus, the maximum health benefit of omega-3s for the
population may not be achieved until omega-3 fats are abundant in the food
supply through fortification of appropriate and universally accepted foods.
Adam, O. (2003). Dietary fatty acids and immune reactions in synovial tissue.
European Journal of Medical Research, 8(8), 381–387.
Adams, P. B., Lawson, S., Sanigorski, A., & Sinclair, A. J. (1996). Arachidonic acid
to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms
of depression. Lipids, 31 Suppl, S157–161.
Albert, C. M., Campos, H., Stampfer, M. J., Ridker, P. M., Manson, J. E., Willett, W. C.,
et al. (2002). Blood levels of long-chain n−3 fatty acids and the risk of sudden death.
New England Journal of Medicine, 346(15), 1113–1118.
Anderson, R. E., Benolken, R. M., Dudley, P. A., Landis, D. J., & Wheeler, T. G.
(1974). Polyunsaturated fatty acids of photoreceptor membranes. Experimental Eye
Research, 18(3), 205.
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 97
Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., et al. (2005).
Stereochemical assignment, antiinflammatory properties, and receptor for the
omega-3 lipid mediator resolvin E1. Journal of Experimental Medicine, 201(5),
Balk, E., Chung, M., Lichtenstein, A., Chew, P., Kupelnick, B., Lawrence, A., et al.
(2004). Effects of omega-3 fatty acids on cardiovascular risk factors and interme-
diate markers of cardiovascular disease. Evidence report/technology assessment.
No. 93 (Prepared by Tufts-New England Medical Center Evidence-based Practice
Center under Contract No. 290-02-0022). AHRQ Publication No. 04-E010-2.
Rockville, MD: Agency for Healthcare Research and Quality.
Bang, H. O., Dyerberg, J., & Nielsen, A. (1971). Plasma lipid and lipoprotein pattern
in Greenlandic West-coast Eskimos. The Lancet, 297(7710), 1143.
Bannenberg, G. L., Chiang, N., Ariel, A., Arita, M., Tjonahen, E., Gotlinger, K. H.,
et al. (2005). Molecular circuits of resolution: Formation and actions of resolvins
and protectins. Journal of Immunology, 174(7), 4345–4355.
Bao, D. Q., Mori, T. A., Burke, V., Puddey, I. B., & Beilin, L. J. (1998). Effects
of dietary fish and weight reduction on ambulatory blood pressure in overweight
hypertensives. Hypertension, 32(4), 710–717.
Bergstrom, S., Danielsson, H., & Samuelsson, B. (1964). The enzymatic formation
of prostaglandin E2 from arachidonic acid prostaglandins and related factors 32.
Biochimica et Biophysica Acta (BBA) – General Subjects, 90(1), 207.
Black, P. N., & Sharpe, S. (1997). Dietary fat and asthma: Is there a connection?
European Respiratory Journal, 10(1), 6–12.
Brenna, J. T. (2002). Efficiency of conversion of [alpha]-linolenic acid to long chain
n−3 fatty acids in man. Current Opinion in Clinical Nutrition & Metabolic Care,
Burr, G. O., & Burr, M. M. (1930). On the nature and role of the fatty acids essential
in nutrition. Journal of Biological Chemistry, 86(2), 587–621.
Burr, M. L., Gilbert, J. F., Holliday, R. M., Elwood, P. C., Fehily, A. M., Rogers, S.,
et al. (1989). Effects of changes in fat, fish, and fibre intakes on death and myocardial
reinfarction: Diet and reinfarction trial (DART). The Lancet, 334(8666), 757.
Buydens-Branchey, L., Branchey, M., McMakin, D. L., & Hibbeln, J. R. (2003).
Polyunsaturated fatty acid status and aggression in cocaine addicts. Drug Alcohol
Depend, 71(3), 319–323.
Calder, P. (2005). Omega-3 fatty acids and inflammation: Impact on heart disease,
irritable bowel syndrome and asthma. Paper presented at the Symposium Highlights –
Omega 3 Fatty Acids: Recommendations for Therapeutics and Prevention,
Conquer, J., Tierney, M., Zecevic, J., Bettger, W. J., & Fisher, R. H. (2000). Fatty
acid analysis of blood plasma of patients with Alzheimer’s disease, other types of
dementia, and cognitive impairment. Lipids, 35, 1305–1312.
Consumer Reports (2003). Omega-3 oil: Fish or pills? Consumer Reports (July),
DHHS (2005, August 19, 2004). Department of Health and Human Services.
Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines
for Americans, 2005. Retrieved December 1, 2005, from http://www.health.gov/
Eberly, L. E., Stamler, J., & Neaton, J. D. (2003). Relation of triglyceride levels,
fasting and nonfasting, to fatal and nonfatal coronary heart disease. Archives of
Internal Medicine, 163(9), 1077–1083.
Edwards, R., Peet, M., Shay, J., & Horrobin, D. (1998a). Depletion of docosa-
hexaenoic acid in red blood cell membranes of depressive patients. Biochemical
Society Transactions, 26(2), S142.
Edwards, R., Peet, M., Shay, J., & Horrobin, D. (1998b). Omega-3 polyunsaturated
fatty acid levels in the diet and in red blood cell membranes of depressed patients.
98 John C. Umhau and Karl M. Dauphinais
Journal of Affective Disorders, 48, 149–155.
FDA (2001). Highlights of FDA food safety efforts: Fruit juice, mercury in fish. FDA
FDA (2004a). FDA news: FDA announces qualified health claims for omega-3 fatty
acids. In FDA (Ed.) (Vol. Sept 8).
FDA (2004b). What you need to know about mercury in fish and shellfish – 2004
EPA and FDA advice for: women who might become pregnant, women who are
pregnant, nursing mothers, young children. Retrieved December 14, 2005, from
Flower, R. J., & Perretti, M. (2005). Controlling inflammation: A fat chance? Journal
of Experimental Medicine, 201(5), 671–674.
Foran, S. E., Flood, J. G., & Lewandrowski, K. B. (2003). Measurement of mercury
levels in concentrated over-the-counter fish oil preparations: Is fish oil healthier
than fish? Archives of Pathology and Laboratory Medicine, 127(12), 1603–1605.
Fortin, P. R., Lew, R. A., Liang, M. H., Wright, E. A., Beckett, L. A., Chalmers, T. C.,
et al. (1995). Validation of a meta-analysis: The effects of fish oil in rheumatoid
arthritis. Journal of Clinical Epidemiology, 48(11), 1379.
Frangou, S., Lewis, M., & McCrone, P. (2006). Efficacy of ethyl-eicosapentaenoic acid
in bipolar depression: Randomised double-blind placebo-controlled study. British
Journal of Psychiatry, 188, 46–50.
Geleijnse, J. M., Giltay, E. J., Grobbee, D. E., Donders, A. R., & Kok, F. J. (2002).
Blood pressure response to fish oil supplementation: Metaregression analysis of
randomized trials. Journal of Hypertension, 20(8), 1493–1499.
Gesch, C. B., Hammond, S. M., Hampson, S. E., Eves, A., & Crowder, M. J. (2002).
Influence of supplementary vitamins, minerals and essential fatty acids on the
antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial.
British Journal of Psychiatry, 181, 22–28.
GISSI-Prevenzione-Investigators (1999). Dietary supplementation with n−3 polyun-
saturated fatty acids and vitamin E after myocardial infarction: Results of the
GISSI-Prevenzione trial. The Lancet, 354(9177), 447.
Hamazaki, T., Sawazaki, S., Itomura, M., Asaoka, E., Nagao, Y., Nishimura, N.,
et al. (1996). The effect of docosahexaenoic acid on aggression in young adults.
A placebo-controlled double-blind study. Journal of Clinical Investigation, 97(4),
Helland, I. B., Smith, L., Saarem, K., Saugstad, O. D., & Drevon, C. A. (2003).
Maternal supplementation with very-long-chain n−3 fatty acids during pregnancy
and lactation augments children’s IQ at 4 years of age. Pediatrics, 111(1), e39-44.
Hibbeln, J. R. (1998). Fish consumption and major depression. The Lancet, 351(9110),
Hibbeln, J. R. (2001). Seafood consumption and homicide mortality. A cross-national
ecological analysis. World Review of Nutrition & Dietetics, 88, 41–46.
Hibbeln, J. R. (2002). Seafood consumption, the DHA content of mothers’ milk and
prevalence rates of postpartum depression: A cross-national, ecological analysis.
Journal of Affective Disorders, 69(1–3), 15–29.
Hibbeln, J. R., Nieminen, L. R., & Lands, W. E. (2004). Increasing homicide rates
and linoleic acid consumption among five Western countries, 1961–2000. Lipids,
Hibbeln, J. R., & Salem, N., Jr. (1995). Dietary polyunsaturated fatty acids and
depression: When cholesterol does not satisfy. American Journal of Clinical
Nutrition, 62(1), 1–9.
Hubbard, W. K. (2004). Letter responding to health claim petition dated June 23, 2003
(Wellness petition): Omega-3 fatty acids and reduced risk of coronary heart disease
(Docket No. 2003Q-0401). In FDA (Ed.). CFSAN/Office of Nutritional Products,
Labeling, and Dietary Supplements.
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 99
Hutchins, H. (2005). Symposium Highlights – Omega-3 Fatty Acids: Recommenda-
tions for Therapeutics and Prevention. Medscape General Medicine, 7(4), 18.
Jones CR, Toshanari, A., & Stanley, R. (1997). Evidence for the involvement of
docosahexaenoic acid in cholinergic stimulated signal transduction at the synapse.
Neurochemical Research, 22(6), 663–670.
Josephus, F. (1994). Josephus, the essential works (P. Maier, Trans.). Grand Rapids:
Karmali, R. A. (1996). Historical perspective and potential use of n−3 fatty acids in
therapy of cancer cachexia. Nutrition, 12(1 Suppl), S2-4.
Kremer, J. M. (2000). n−3 fatty acid supplements in rheumatoid arthritis. American
Journal of Clinical Nutrition, 71(1 Suppl), 349S–351S.
Kris-Etherton, P. M. (2005). How much omega-3 fatty acid is enough and from when
should it come? Paper presented at the Symposium Highlights – Omega 3 Fatty
Acids: Recommendations for Therapeutics and Prevention, New York.
Kris-Etherton, P. M., Harris, W. S., & Appel, L. J. (2002). Fish consumption, fish oil,
omega-3 fatty acids, and cardiovascular disease. Circulation, 106(21), 2747–2757.
Kris-Etherton, P. M., Taylor, D. S., Yu-Poth, S., Huth, P., Moriarty, K., Fishell, V.,
et al. (2000). Polyunsaturated fatty acids in the food chain in the United States.
American Journal of Clinical Nutrition, 71(1), 179S–188.
Lands, W. E. (2003). Diets could prevent many diseases. Lipids, 38(4), 317–321.
Leaf, A., & Weber, P. C. (1987). A new era for science in nutrition. American Journal
of Clinical Nutrition, 45, 1048–1053.
Lukiw, W. J., Cui, J.-G., Marcheselli, V. L., Bodker, M., Botkjaer, A., Gotlinger, K.,
et al. (2005). A role for docosahexaenoic acid-derived neuroprotectin D1 in neural
cell survival and Alzheimer disease. Journal of Clinical Investigation, 115(10),
MacLean, C., Mojica, W., Morton, S., Pencharz, J., Hasenfeld, G. R., Tu, W.,
et al. (2004). Effects of omega-3 fatty acids on lipids and glycemic control in
type ii diabetes and the metabolic syndrome and on inflammatory bowel disease,
rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteo-
porosis. Evidence report/technology assessment. No. 89. Rockville, MD: Agency
for Healthcare Research and Quality.
Maes, M., Christophe, A., Delanghe, J., Altamura, C., Neels, H., & Meltzer, H. Y.
(1999). Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and
cholesteryl esters of depressed patients. Psychiatry Research, 85(3), 275–291.
Maes, M., Smith, R., Christophe, A., Cosyns, P., Desnyder, R., & Meltzer, H.
(1996). Fatty acid composition in major depression: Decreased omega 3 fractions in
cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl
esters and phospholipids. Journal of Affective Disorders, 38, 35–46.
Marcheselli, V. L., Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., et al.
(2003). Novel docosanoids inhibit brain ischemia–reperfusion-mediated leukocyte
infiltration and pro-inflammatory gene expression. Journal of Biological Chemistry,
Martínez, M., & Mougan, I. (1998). Fatty acid composition of human brain
phospholipids during normal development. Journal of Neurochemistry, 71(6),
Melanson, S. F., Lewandrowski, E. L., Flood, J. G., & Lewandrowski, K. B. (2005).
Measurement of organochlorines in commercial over-the-counter fish oil prepara-
tions: Implications for dietary and therapeutic recommendations for omega-3 fatty
acids and a review of the literature. Archives of Pathology and Laboratory Medicine,
Mickleborough, T. D., Ionescu, A. A., & Rundell, K. W. (2004). Omega-3 fatty acids
and airway hyperresponsiveness in asthma. Journal of Alternative & Complementary
Medicine, 10(6), 1067–1075.
100 John C. Umhau and Karl M. Dauphinais
Mori, T. A., Bao, D. Q., Burke, V., Puddey, I. B., & Beilin, L. J. (1999). Docosa-
hexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and
heart rate in humans. Hypertension, 34(2), 253–260.
Mori, T. A., Burke, V., Puddey, I. B., Watts, G. F., O’Neal, D. N., Best, J. D.,
et al. (2000). Purified eicosapentaenoic and docosahexaenoic acids have differ-
ential effects on serum lipids and lipoproteins, LDL particle size, glucose, and
insulin in mildly hyperlipidemic men. American Journal of Clinical Nutrition, 71(5),
Morris, M. C., Evans, D. A., Bienias, J. L., Tangney, C. C., Bennett, D. A.,
Wilson, R. S., et al. (2003). Consumption of fish and n−3 fatty acids and risk of
incident Alzheimer disease. Archives of Neurology, 60(7), 940–946.
Nestel, P. J., Connor, W. E., Reardon, M. F., Connor, S., Wong, S., & Boston, R.
(1984). Suppression by diets rich in fish oil of very low density lipoprotein
production in man. The Journal of Clinical Investigation, 74(1), 82.
Niebylski, C., & Salem, N. (1994). A calorimetric investigation of a series of mixed-
chain polyunsaturated phosphatidylcholines: effect of sn-2 chain length and degree
of unsaturation. Biophysical Journal, 67(6), 2387–2393.
Olsen, S. F., & Secher, N. J. (2002). Low consumption of seafood in early pregnancy
as a risk factor for preterm delivery: Prospective cohort study. BMJ, 324(7335),
Park, Y., & Harris, W. S. (2003). Omega-3 fatty acid supplementation accelerates
chylomicron triglyceride clearance. Journal of Lipid Research, 44(3), 455–463.
Pawlosky, R. J., Bacher, J., & Salem, N., Jr. (2001). Ethanol consumption alters
electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus
monkeys: Nutritional consequences of a low n−3 fatty acid diet. Alcoholism,
Clinical and Experimental Research, 25(12), 1758–1765.
Pawlosky, R. J., Hibbeln, J. R., Lin, Y., Goodson, S., Riggs, P., Sebring, N., et al.
(2003). Effects of beef- and fish-based diets on the kinetics of n−3 fatty acid
metabolism in human subjects. American Journal of Clinical Nutrition, 77(3),
Peet, M., & Horrobin, D. F. (2002). A dose-ranging study of the effects of ethyl-
eicosapentaenoate in patients with ongoing depression despite apparently adequate
treatment with standard drugs. Archives of General Psychiatry, 59(10), 913–919.
Peet, M., Murphy, B., Shay, J., & Horrobin, D. (1998). Depletion of omega-3 fatty acid
levels in red blood cell membranes of depressive patients. Biology and Psychiatry,
Raitt, M. H., Connor, W. E., Morris, C., Kron, J., Halperin, B., Chugh, S. S., et al.
(2005). Fish oil supplementation and risk of ventricular tachycardia and ventricular
fibrillation in patients with implantable defibrillators: A randomized controlled trial.
JAMA, 293(23), 2884–2891.
Sands, S. A., Reid, K. J., Windsor, S. L., & Harris, W. S. (2005). The impact of
age, body mass index, and fish intake on the EPA and DHA content of human
erythrocytes. Lipids, 40(April), 343–347.
Schaefer, A. (2005). Omega-3 fatty acids and dementia. Omega-3 fatty acids: Recom-
mendations for therapeutics and prevention symposium.
Semba, R. D. (1999). Vitamin A as “anti-infective” therapy, 1920–1940. Journal of
Nutrition, 129(4), 783–791.
Serhan, C. N., Arita, M., Hong, S., & Gotlinger, K. (2004). Resolvins, docosatrienes,
and neuroprotectins, novel omega-3-derived mediators, and their endogenous
aspirin-triggered epimers. Lipids, 39(11), 1125–1132.
Simopoulos, A. (1999). Genetic variation and evolutionary aspects of diet.
In: A.M. Papas (ed). Antioxidant status, diet, nutrition and health (pp. 65–88).
Boca Raton, FL: CRC Press.
Simopoulos, A. P. (1991). Omega-3 fatty acids in health and disease and in growth
and development. American Journal of Clinical Nutrition, 54(3), 438–463.
Chapter 4 Omega-3 Polyunsaturated Fatty Acids and Health 101
Simopoulos, A. P. (2002). Omega-3 fatty acids in inflammation and autoimmune
diseases. Journal of the American College of Nutrition, 21(6), 495–505.
Simopoulos, A. P., Leaf, A., & Salem, N., Jr. (1999). Workshop on the Essentiality of
and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids. Journal
of the American College of Nutrition, 18(5), 487–489.
Stoll, A. L., Severus, W. E., Freeman, M. P., Rueter, S., Zboyan, H. A., Diamond, E.,
et al. (1999). Omega 3 fatty acids in bipolar disorder: A preliminary double-blind,
placebo controlled trial. Archives of General Psychiatry, 56, 407–412.
Tanskanen, A., Hibbeln, J. R., Tuomilehto, J., Uutela, A., Haukkala, A., Viinamaki, H.,
et al. (2001). Fish consumption and depressive symptoms in the general population
in Finland. Psychiatric Services, 52(4), 529–531.
Terry, P. D., Rohan, T. E., & Wolk, A. (2003). Intakes of fish and marine fatty acids
and the risks of cancers of the breast and prostate and of other hormone-related
cancers: A review of the epidemiologic evidence. American Journal of Clinical
Nutrition, 77(3), 532–543.
Thienprasert, A., Hamazaki, T., Kheovichai, K., Samuhaseneetoo, S., Nagasawa, T., &
Wantanabe, S. (2000). The effect of docosahexaenoic acid on aggression/hostility
in elderly subjects: A placebo-controlled double blind trial (abstract) (pp. 189).
Tsukuba, Japan: 4th Congress of the International Society for the Study of Lipids
and Fatty Acids.
Tisdale, M. J. (2003). Pathogenesis of cancer cachexia. The Journal of Supportive
Oncology, 1(3), 159–168.
Tully, A. M., Roche, H. M., Doyle, R., Fallon, C., Bruce, I., Lawlor, B., et al. (2003).
Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer’s disease:
A case-control study. British Journal of Nutrition, 89(4), 483–489.
Uauy, R., Hoffman, D. R., Mena, P., Llanos, A., & Birch, E. E. (2003). Term
infant studies of DHA and ARA supplementation on neurodevelopment: Results of
randomized controlled trials. The Journal of Pediatrics, 143(4, Supplement 1), 17.
Umhau, J. C., Dauphinais, K. M., Patel, S. H., Nahrwold, D. A., Hibbeln, J. R.,
Rawlings, R. R., et al. (2006). The relationship between folate and docosahexaenoic
acid in men. European Journal of Clinical Nutrition,60(3), 352–357.
Van Dorp, D. A., Beerthuis, R. K., Nugteren, D. H., & Vonkeman, H. (1964). The
biosynthesis of prostaglandins. Biochimica et Biophysica Acta (BBA) – General
Subjects, 90(1), 204.
Van Epps, H. L. (2005). Inflammation control gets fishy. Journal of Experimental
Medicine, 201(5), 662.
Verbeke, W., Sioen, I., Pieniak, Z., Van Camp, J., & De Henauw, S. (2005). Consumer
perception versus scientific evidence about health benefits and safety risks from
fish consumption. Public Health Nutrition, 8(4), 422–429.
Virkkunen, M. E., Horrobin, D. F., Jenkins, D. K., & Manku, M. S. (1987). Plasma
phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent,
and impulsive offenders. Biology and Psychiatry, 22, 1087–1096.
Weber, P., & Raederstorff, D. (2000). Triglyceride-lowering effect of omega-3 LC-
polyunsaturated fatty acids – A review. Nutrition Metabolism & Cardiovascular
Diseases, 10(1), 28–37.
Weidner, G., Connor, S. L., Hollis, J. F., & Connor, W. E. (1992). Improvements
in hostility and depression in relation to dietary change and cholesterol lowering.
Annals of Internal Medicine, 117, 820–823.
WHO (2003). Diet, nutrition and the prevention of chronic diseases: Report of the
joint WHO/FAO expert consultation, Geneva.
Zanarini, M. C., & Frankenburg, F. R. (2003). Omega-3 Fatty acid treatment of women
with borderline personality disorder: A double-blind, placebo-controlled pilot study.
American Journal of Psychiatry, 160(1), 167–169.