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Omega-3 DHA and EPA for cognition, behavior, and mood: Clinical findings and structural-functional synergies with cell membrane phospholipids

October 2007
Alternative Medicine Review: a Journal of Clinical Therapeutic 12(3):207-27

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PubMed

Authors:

The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are orthomolecular, conditionally essential nutrients that enhance quality of life and lower the risk of premature death. They function exclusively via cell membranes, in which they are anchored by phospholipid molecules. DHA is proven essential to pre- and postnatal brain development, whereas EPA seems more influential on behavior and mood. Both DHA and EPA generate neuroprotective metabolites. In double-blind, randomized, controlled trials, DHA and EPA combinations have been shown to benefit attention deficit/hyperactivity disorder (AD/HD), autism, dyspraxia, dyslexia, and aggression. For the affective disorders, meta-analyses confirm benefits in major depressive disorder (MDD) and bipolar disorder, with promising results in schizophrenia and initial benefit for borderline personality disorder. Accelerated cognitive decline and mild cognitive impairment (MCI) correlate with lowered tissue levels of DHA/EPA, and supplementation has improved cognitive function. Huntington disease has responded to EPA. Omega-3 phospholipid supplements that combine DHA/EPA and phospholipids into the same molecule have shown marked promise in early clinical trials. Phosphatidylserine with DHA/EPA attached (Omega-3 PS) has been shown to alleviate AD/HD symptoms. Krill omega-3 phospholipids, containing mostly phosphatidylcholine (PC) with DHA/EPA attached, markedly outperformed conventional fish oil DHA/EPA triglycerides in double-blind trials for premenstrual syndrome/dysmenorrhea and for normalizing blood lipid profiles. Krill omega-3 phospholipids demonstrated anti-inflammatory activity, lowering C-reactive protein (CRP) levels in a double-blind trial. Utilizing DHA and EPA together with phospholipids and membrane antioxidants to achieve a triple cell membrane synergy may further diversify their currently wide range of clinical applications.

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Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 207

Omega-3 DHA and EPA for

Cognition, Behavior, and Mood:

Clinical Findings and Structural-

Functional Synergies with Cell

Membrane Phospholipids

Parris M. Kidd, PhD

Parris M. Kidd, PhD – Cell biology; University of California, Berkeley; Contributing

Editor, Alternative Medicine Review; health educator; biomedical consultant to

the dietary supplement industry.

Correspondence address: 10379 Wolf Drive, Grass Valley, CA 95949

Email: pk@dockidd.com

Abstract

The omega-3 fatty acids docosahexaenoic acid (DHA) and

eicosapentaenoic acid (EPA) are orthomolecular, conditionally

essential nutrients that enhance quality of life and lower the risk

of premature death. They function exclusively via cell membranes,

in which they are anchored by phospholipid molecules. DHA

is proven essential to pre- and postnatal brain development,

whereas EPA seems more inﬂuential on behavior and mood. Both

DHA and EPA generate neuroprotective metabolites. In double-

blind, randomized, controlled trials, DHA and EPA combinations

have been shown to beneﬁt attention deﬁcit/hyperactivity

disorder (AD/HD), autism, dyspraxia, dyslexia, and aggression.

For the affective disorders, meta-analyses conﬁrm beneﬁts

in major depressive disorder (MDD) and bipolar disorder,

with promising results in schizophrenia and initial beneﬁt for

borderline personality disorder. Accelerated cognitive decline

and mild cognitive impairment (MCI) correlate with lowered

tissue levels of DHA/EPA, and supplementation has improved

cognitive function. Huntington disease has responded to EPA.

Omega-3 phospholipid supplements that combine DHA/EPA

and phospholipids into the same molecule have shown marked

promise in early clinical trials. Phosphatidylserine with DHA/

EPA attached (Omega-3 PS) has been shown to alleviate AD/

HD symptoms. Krill omega-3 phospholipids, containing mostly

phosphatidylcholine (PC) with DHA/EPA attached, markedly

outperformed conventional ﬁsh oil DHA/EPA triglycerides in

double-blind trials for premenstrual syndrome/dysmenorrhea

and for normalizing blood lipid proﬁles. Krill omega-3

phospholipids demonstrated anti-inﬂammatory activity, lowering

C-reactive protein (CRP) levels in a double-blind trial. Utilizing

DHA and EPA together with phospholipids and membrane

antioxidants to achieve a “triple cell membrane synergy” may

further diversify their currently wide range of clinical applications.

(Altern Med Rev 2007;12(3):207-227)

Introduction

e long-chain omega-3 fatty acids doco-

sahexaenoic acid (DHA) and eicosapentaenoic acid

(EPA) are conditionally essential nutrients now es-

tablished to enhance life quality and lower the risk of

premature death. ey are orthomolecules whose func-

tional sites are exclusively cell membranes, wherein they

are structurally and functionally integrated via phos-

pholipid molecules. eir conﬁrmation as eﬃcacious

cardiovascular protectants has spurred research into

their beneﬁts for the human brain. is review focuses

on their clinical roles in cognition, behavior, and mood

and on their potentially synergistic interactions with

the cell membrane phospholipid nutrients.

Adequate dietary availability of DHA and

EPA is fundamental to brain function. DHA/EPA

are important throughout adulthood, as well as during

the brain growth spurts that characterize prenatal and

postnatal development. Dietary supplementation with

DHA and EPA has proven beneﬁcial for many of the

known higher mental functions.

Alternative Medicine Review Volume 12, Number 3 2007

Omega-3s & Brain Function

Page 208

Among the proven brain beneﬁts of DHA/EPA

are the perinatal development of visual and other sensory

functions; perinatal emergence of cognitive function and

maintenance throughout life; behavior management; and

mood control (e.g., the mood swings of bipolar disorder

or symptoms of major depressive disorder (MDD)). e

substantial clinical evidence that supports these applica-

tions is discussed in the sections that follow.

Omega-3s in Childhood Brain

Development

During the last trimester of fetal life and the

ﬁrst two years of childhood, the brain undergoes a pe-

riod of rapid growth – the “brain growth spurt.”

Nu-

trient insuﬃciency during this period can compromise

brain function. DHA is one nutrient absolutely required

for the development of the sensory, perceptual, cogni-

tive, and motor neural systems during the brain growth

spurt.

1,2

EPA’s importance for the brain’s development

in utero is unclear, but colostrum and breast milk con-

tain EPA, albeit in lesser amounts than DHA.

3,4

e fundamental importance of DHA for

brain development is beyond dispute.

e neurons

are continually forming axons and dendritic extensions

with accompanying cell membranes. Growing mem-

brane must be relatively ﬂuid, and DHA is the most

ﬂuidizing element in cell membranes (discussed later

in this review). Even the synapses that are the primary

functional units of brain circuits are made from mem-

branes preferentially enriched in DHA.

e retina, functionally an extension of the

brain, contains rods and cones with the most ﬂuid

membranes of all the body’s cell types; they are also

highly enriched in DHA. Laboratory animals (rodents,

primates) with experimentally induced omega-3 deﬁ-

ciencies show deﬁcits in retinal structure, visual acuity

development, and cognitive performance.

6-8

Perinatal Importance of DHA and EPA

Demand for DHA rises exponentially as the

brain rapidly expands in the third trimester, and con-

tinues after birth as the baby interfaces with environ-

mental stimuli. Infants born prematurely are at special

risk for omega-3 insuﬃciency because they may not

have beneﬁted from a full trimester of the mother’s

lipid stores. Preterm infants have very limited ability to

synthesize DHA from the shorter chain alpha-linolenic

acid (ALA; C18:3).

After birth, omega-3 status depends on the

infant’s innate lipid metabolism and dietary intake of

breast milk or formula. Although DHA and EPA are

prominent ingredients of breast milk, many infant

formulas do not contain these nutrients. Supplement-

ing the mother’s diet with ALA is not a reliable means

for obtaining DHA. In one study, lactating mothers

received 10.7 g/day of ALA from ﬂaxseed oil for four

weeks. Breast milk levels of ALA, EPA, and DPA (do-

cosapentaenoic acid; C22:5 omega-3) increased, but

not that of DHA.

All infants, whether preterm or full term, seem

to require dietary DHA for retinal development and

normal visual function. A meta-analysis evaluated stud-

ies on visual resolution acuity diﬀerences in healthy pre-

term infants, either supplemented or not supplemented

with DHA.

Four prospective trials were included, pro-

viding data from both behavioral acuity tests and visual

evoked potentials. Intake of DHA was correlated with

signiﬁcantly better visual resolution acuity at ages two

months and four months. In another meta-analysis, this

same research group found an advantage of DHA intake

in full-term infants up to four months post-birth.

McCann and Ames published an extensive

review of the evidence that DHA is important for the

development of cognition and other normal brain func-

tions.

eir 258 references included meta-analyses,

randomized controlled trials (RCT) on cognitive and

behavioral performance, studies with rodents and non-

human primates, and breastfeeding studies. Within the

limits imposed by performance testing of infants and

toddlers, they concluded that:

In animals whose brain concentrations Â

of DHA were severely reduced, dietary

supplementation with DHA restored control

performance levels.

Studies with human infants suggest Â

supplementation with DHA in formula or by

boosting maternal levels enhances neuromotor

development.

Application of a wide range of tests yielded a Â

positive association between breastfeeding and infant

mental performance.

Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 209

Although it is diﬃcult to test cognitive perfor-

mance within the ﬁrst year, infants who were fed breast

milk or formulas with DHA were found (within a few

months after birth) to have superior visual acuity com-

pared to those fed less than adequate DHA. is supe-

rior visual function persists through the ﬁrst year after

birth

and perhaps into the seventh year or later.

Treating Developmental Coordination

Disorder/Dyspraxia

e importance of DHA/EPA for overall brain

and motor development after birth is illustrated by dys-

praxia, also known as developmental coordination dis-

order (DCD). DCD/dyspraxia involves speciﬁc impair-

ments of motor function and seriously aﬀects about ﬁve

percent of school-aged children.

DCD’s core motor

deﬁcits are often accompanied by diﬃculties with learn-

ing, behavior, and psychosocial adjustment that overlap

with dyslexia and attention deﬁcit/hyperactivity disor-

der (AD/HD) and often persist into adulthood.

A double-blind RCT was conducted on 117

children ages 5-12, using a mixed omega-3/omega-6

supplement versus an olive oil placebo.

e supple-

ment was 80-percent ﬁsh oil and 20-percent evening

primrose oil, with a 4:1 omega-3 to omega-6 ratio. e

total daily dose provided 174 mg DHA, 558 mg EPA,

and 60 mg omega-6 gamma-linolenic acid (GLA), plus

9.6 mg d-alpha tocopherol. Although the trial found

no signiﬁcant improvement in motor skills after three

months, the researchers did report signiﬁcant improve-

ments in other areas.

e children who received the

omega-3/omega-6 supplement showed three times

the normal expected gain in reading skills and twice

the normal gain in spelling competency, plus marked

improvement in behavior. e children who received

the olive oil placebo were switched to the omega-3/

omega-6 supplement after three months and after three

more months showed similar “catch-up” gains.

Other developmental brain disorders in chil-

dren such as AD/HD and dyslexia overlap with DCD/

dyspraxia and are also linked to apparent DHA/EPA

deﬁcits. Many of these children respond to oral supple-

mentation of these nutrients, often administered with

other nutrients as part of a comprehensive management

regimen.

14,15

Managing Attention Deﬁcit/Hyperactivity

Disorder

AD/HD is the most common childhood de-

velopmental disorder, with prevalence estimates ranging

from 4-15 percent for school-age children in the United

States and elsewhere (see Richardson, 2006 for a re-

cent review

). Often AD/HD persists into adulthood.

Considerable damage to the individual, family, and so-

ciety can be exacerbated by co-morbidity with many

other disorders of behavior, learning, or mood.

14,16

AD/

HD children consistently exhibit abnormal fatty acid

status.

Several studies have reported reduced blood

concentrations of highly unsaturated fatty acids (FAs)

in AD/HD children compared to controls (reviewed

by Richardson

). Typically, reductions have been found

in DHA and total omega-3 FAs and in the omega-6

arachidonic acid (AA),

some of which may persist

into adulthood.

In one study that included both AD/

HD and non-AD/HD boys, low omega-3 levels were

associated with a range of behavioral and learning prob-

lems, irrespective of the clinical diagnosis.

Whereas

low blood omega-6 levels tend to correlate with some

physical deﬁciencies, but not with cognitive or behav-

ioral impairments, omega-3 deﬁciencies correlate with

behavioral problems (conduct disorder, hyperactivity-

impulsivity, anxiety, temper tantrums, sleep diﬃculties)

and learning diﬃculties in children. us Richardson,

in her insightful review, emphasized, “…omega-3 status

is likely to be more relevant to AD/HD and related be-

havioral disorders.”

Clinical evidence from controlled trials, open

studies, and case reports has yielded mixed results from

DHA/EPA supplementation in AD/HD and its co-

morbid conditions. In 2001, a double-blind RCT of

omega-3 FAs was conducted on AD/HD children.

e 63 children ages 6-12 years were said to be receiv-

ing eﬀective and stable treatment with stimulant medi-

cation, so this was an “add-on” study. ey received daily

adjunctive treatment of 345 mg pure DHA (from al-

gae) or placebo. At the end of the four-month study, no

changes were found on behavioral ratings or measures

of inattention and impulsivity.

Similar negative ﬁndings came from a two-

month, double-blind RCT of 40 AD/HD-type children

ages 6-12 years in Japan.

Children were randomized

Alternative Medicine Review Volume 12, Number 3 2007

Omega-3s & Brain Function

Page 210

to receive either omega-3 fortiﬁed foods (providing ap-

proximately 510 mg DHA and 100 mg EPA per day)

or indistinguishable control foods containing olive oil.

Although no diﬀerences emerged on various cogni-

tive tests, combined teacher and parent ratings found a

greater reduction of aggression in the DHA group.

A third double-blind RCT was conducted at

Indiana’s Purdue University on children with primar-

ily AD/HD-type diﬃculties.

Fifty children (aver-

age age 10 years) were randomized to receive either an

omega-3/omega-6 formula from ﬁsh oil plus evening

primrose oil (each daily dose supplying 480 mg DHA,

80 mg EPA, 96 mg GLA, and 40 mg AA, plus 24 mg

Figure 1. Biosynthesis of the Principal Polyunsaturated Fatty Acids and eir Metabolites

Omega-3 Fatty Acids

alpha-linolenic acid

(flax, chia, hemp)

stearidonic acid

(black currant oil)

eicosatetraenoic acid

eicosapentaenoic acid

EPA

(fish, krill)

arachidonic acid

(meat, eggs, dairy)

dihomo-gamma-linolenic

acid – DHGLA

gamma-linolenic acid

GLA

(borage, black currant, evening

primrose)

docosapentaenoic acid

DPA

docosahexaenoic acid

DHA

(fish, krill algae)

linoleic acid

(sunflower, safflower, corn)

Omega-6 Fatty Acids

3-Series

Prostaglandins &

Thromboxanes,

5-Series

Leukotrienes

5-desaturase

(cofactors – B3, Zn, Vit C)

cyclo-oxygenase

5-lipoxygenase

r 6-desaturase

(cofactors – B3, B6, Mg, Zn, Vit C)

Enzyme inhibited by alcohol,

trans fats, diabetes,

hyperinsulinism.

elongase

(cofactor – B6)

2-Series

Prostaglandins &

Thromboxanes,

4-Series

Leukotrienes

1-Series

Prostaglandins &

Thromboxanes

elongase

docosanoids

Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 211

alpha-tocopheryl acetate) or an olive oil placebo for four

months. Signiﬁcant beneﬁts were found for attention

and behavior and on clinical ratings of oppositional de-

ﬁant disorder.

In 2002, Richardson and Puri published a

double-blind RCT of 29 United Kingdom children

with a primary diagnosis of dyslexia and secondary

AD/HD-type symptoms.

Half the children received

an omega-3/omega-6 combination with 480 mg DHA

and 96 mg GLA as in the Purdue formula above, but

with EPA higher at 186 mg, AA slightly higher at 42

mg, the omega-6 cis-linoleic acid at 864 mg, 60 IU vita-

min E as dl-alpha tocopherol, and 8 mg thyme oil. e

other half of the children received an olive oil “placebo”

for three months. e omega-3/omega-6 combination

produced signiﬁcantly greater beneﬁts than the olive

oil for inattention, anxiety/withdrawal, and disruptive

behavior. e authors noted the olive oil placebo could

have contributed some beneﬁt and that use of a truly

inert placebo might have yielded a better overall trial

outcome.

e shorter-chain ALA may not be as eﬀective

for AD/HD as DHA/EPA plus GLA. irty adults

with AD/HD were randomized to supplementation

with a large dose of 60 g/day of ﬂaxseed oil, olive oil,

or ﬁsh oil.

Serum phospholipid fatty acid status was

determined at baseline and 12 weeks. Although ﬂax-

seed oil supplementation increased ALA levels of blood

phospholipids, levels of EPA, DHA, and other ome-

ga-3 fatty acids were not increased; ﬁsh oil predictably

increased EPA, DHA, and total omega-3s.

us, it appears a mix of DHA, EPA, and

omega-6 fatty acids (GLA and AA) can improve the

attention, learning, and behavioral aﬄictions typical

of AD/HD, as well as co-morbidities such as anxiety/

withdrawal, dyslexia, and aggression. ere are numer-

ous reports of low plasma and/or RBC omega-3 levels

in AD/HD children and adults.

Recently, a speciﬁc

gene polymorphism was discovered that is linked to

clinical AD/HD and features suboptimal functioning

of fatty acid desaturase enzymes.

Figure 1 illustrates

the biosynthesis of the primary omega-3 and -6 fatty

acids.

Ameliorating Aggression

Hamazaki et al performed two double-blind

trials with students clinically diagnosed as aggressive.

In the 1996 trial,

41 university students ages 21-30

were randomized to receive a DHA-rich ﬁsh oil pro-

viding 1.48-1.77 g/day DHA, 0.20-0.24 g/day EPA,

and 0.10-0.12 g/day AA or control capsules of soy oil.

e three-month trial was timed to end in the middle

of the mental stress of challenging ﬁnal exams. e

DHA group demonstrated no increase in aggression

during this stressful time; whereas, the control group

demonstrated signiﬁcant increases in aggression against

others (extra-aggression). e researchers concluded

DHA helped prevent extra-aggression from increasing

at times of mental stress.

In 2005, the same research team conducted a

three-month, double-blind trial on aggression involv-

ing 166 children ages 9-12 years.

e children re-

ceived either omega-3 fortiﬁed foods that provided 3.6

g DHA and 0.84 g EPA per week or control foods with

half soybean and half rapeseed oil. Physical aggression

as assessed by a hostility-aggression questionnaire in-

creased among girls in the control group but not among

the girls who received omega-3s. Impulsivity was also

signiﬁcantly reduced among the omega-3 girls; no such

diﬀerences were observed among the boys.

Clinical Experience with Autism

e emergent rationale for employing DHA/

EPA for autistic spectrum disorder (ASD) and other

pervasive developmental disorders (PDD) dates to

2001, with case histories provided independently by

two research groups.

Vancassel et al reported low

DHA (measured in plasma phospholipids), 20-per-

cent lower-than-normal total omega-3s, and normal

levels of omega-6 FAs in ASD children.

Bradstreet

and Kartzinel reported ﬁnding omega-3 fatty acid de-

ﬁciencies in nearly 100 percent of ASD cases.

en

in 2002, Hardy and Hardy claimed that, of 50 children

diagnosed with PDD, 90 percent were deﬁcient in RBC

membrane DHA/EPA.

Various integrative physicians

working with ASD and PDD patients have integrated

DHA and EPA into their comprehensive regimens.

A group in Austria conducted a six-week,

double-blind RCT with 13 children, ages 5-17 years,

diagnosed with ASD and displaying severe tantrums,

Alternative Medicine Review Volume 12, Number 3 2007

Omega-3s & Brain Function

Page 212

aggression, and self-injurious behavior.

Intervention

was 1.5 g/day DHA/EPA (700 mg DHA and 840 mg

EPA) or placebo. e DHA/EPA was well tolerated

and there was a trend toward signiﬁcant improvement

over placebo for hyperactivity. e clinicians reported

the small number of subjects may have statistically un-

dermined the apparent clinical eﬀects of the DHA/

EPA.

Support for Adult Cognitive

Performance

e brain’s reliance on DHA/EPA continues

throughout adult life. New research on primates and

rodents has documented the adult brain cortex under-

goes highly active synaptic turnover throughout life.

is ﬁnding has helped drive a paradigm shift in un-

derstanding brain plasticity. e new paradigm is one

of high brain plasticity and adaptability.

33,34

It recog-

nizes remarkable clinical observations on brain recovery

following damage,

and relates this to rates of synap-

tic turnover as high as 350 percent per year observed

in mammalian brains.

33,34

e central role that DHA

plays in perinatal brain development may continue in

the highly dynamic, healthy adult brain.

DHA and EPA Improve Cognitive

Performance in Healthy Subjects

DHA and EPA are orthomolecules (molecules

orthodox to the body) as deﬁned by Pauling.

ere

is evidence that healthy individuals can expect cogni-

tive beneﬁt from orthomolecular medicine, including

DHA/EPA.

Fontani et al conducted a double-blind RCT

on 33 healthy volunteers ages 22-51 (average age 33).

For 35 days, subjects consumed either 4 g ﬁsh oil/day

(providing 800 mg DHA and 1,600 mg EPA) or 4 g

olive oil as placebo; dietary modiﬁcations were insti-

gated via advice from a dietician. Subjects completed

a mood questionnaire and took attention tests, and

physiological recordings (electroencephalogram/EEG,

electromyogram/EMG) were made at baseline and on

day 35. e DHA/EPA group improved signiﬁcantly

over placebo on several mood parameters: vigor, anger,

anxiety, fatigue, depression, and confusion. Measures of

attention and reaction time were also improved. Partici-

pants demonstrated marked improvement in sustained

attention and a signiﬁcant reduction in errors on the at-

tention test.

Signiﬁcant improvements were also found on

physiological measures that correlated with the test

ﬁndings. Reaction time was signiﬁcantly improved, as

measured by EMG. e EEGs, which are typically hard

to interpret, demonstrated the high-frequency beta-2

band was signiﬁcantly reduced and the low-frequency

theta and alpha bands were increased. e researchers

tentatively interpreted these changes as consistent with

omega-3 support for “direct action…on the central ner-

vous system” leading to improved cortical function.

ey concluded that DHA/EPA supplementation can

improve higher brain functions – sense of wellbeing

(vigor), reactivity, attention, cognitive performance, and

mood – in young, healthy adults.

DHA/EPA Intake May Lower Dementia

Risk

Spanning at least the past decade, epidemio-

logical studies indicate relatively high DHA and EPA

intake is linked to lower relative risk of dementia inci-

dence or progression. In 1997, Kalmijn et al reported

on the Rotterdam Study.

In this longitudinal cohort

study, 5,386 participants ages 55 or older were screened

for dementia. Dietary habits were evaluated using a

semi-quantitative food frequency questionnaire and

then re-evaluated after 2.1 years. Fish consumption

was inversely related to dementia incidence (RR=0.4,

95% CI=0.2-0.9), and more speciﬁcally to the risk of

developing Alzheimer’s disease (AD) (RR=0.3, 95%

CI=0.1-0.9).

at same year (1997) yielded a report of

the Zutphen Elderly Study, a smaller study also con-

ducted in e Netherlands by Kalmijn’s group.

ey

evaluated 476 men, ages 69-89 at baseline, performing

cognition testing and correlating the data with food

intakes reported in dietary histories. At baseline, high

ﬁsh consumption was inversely associated with cogni-

tive impairment. After three years, as with the Rotter-

dam study, high ﬁsh consumption was inversely associ-

ated with cognitive decline (RR=0.5, 95% CI=0.2-1.2).

Omega-3 intake did not correlate with either measure.

A later analysis (after six years) of the Rotter-

dam Study data concluded that low intake of omega-3

fatty acids was not associated with increased risk

for

Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 213

dementia.

By contrast, a later analysis (after ﬁve years)

of the Zutphen Elderly Study data conﬁrmed the earlier

ﬁnding, with consumers of ﬁsh showing a statistically sig-

niﬁcant (p<0.01) decrease in cognitive decline.

ere

was a linear relationship between DHA/EPA levels and

cognitive decline – the higher the intake of DHA/EPA,

the lower the rate of cognitive decline. Men who con-

sumed an average of 400 mg ﬁsh omega-3s per day expe-

rienced signiﬁcantly less cognitive decline compared with

men who consumed an average of only 20 mg/day.

Taken at face value, this ﬁnding could suggest

the range of DHA/EPA intakes currently recommend-

ed to reduce cardiovascular risk may be suﬃcient to

help slow mental decline. e American Heart Associa-

tion currently recommends a minimum of 57 mg/day

DHA/EPA for healthy people (a total of 400 mg/week

from two ﬁsh meals); a minimum of 1,000 mg/day for

cardiovascular protection in patients with documented

coronary heart disease; and 2,000-4,000 mg/day for pa-

tients with high triglycerides.

Even modest ﬁsh intake might oﬀer some pro-

tection for the brain. In a Chicago community study, 815

residents ages 65-94 were evaluated via a self-reported

food questionnaire and tracked for an average 3.9 years.

A total of 131 participants developed AD. ose who

consumed a ﬁsh meal once weekly had a statistically

signiﬁcant 60-percent decreased risk of Alzheimer’s

disease, compared with those who rarely or never ate

ﬁsh (RR=0.4, 95% CI=0.2-0.9). Total omega-3 intake

and DHA intake, but not EPA intake alone, were sig-

niﬁcantly associated with this lessened Alzheimer risk.

is suggests an intake of as little as 30 mg/day DHA/

EPA from ﬁsh might confer more protection against

cognitive decline than eating no ﬁsh at all.

A follow-up of this community study at six

years found ﬁsh consumption (one or more meals per

week) resulted in a 10- to 13-percent slower rate of cog-

nitive decline. ere was no persuasive evidence for a

more speciﬁc association with either DHA or EPA.

In another longitudinal cohort study, serum

phosphatidylcholine-DHA (PC-DHA) levels of 1,188

elderly Americans (average age 75 years) were analyzed

at baseline and 10 years later.

ose in the lower half

of the distribution of DHA levels at the time the ﬁrst

sample was taken, but who did not have AD at that time,

appeared to have a 67-percent greater risk of developing

AD within the subsequent 10-year period (p<0.05).

Longitudinal cohort studies can be more objec-

tive when blood or tissue is analyzed for speciﬁc nutri-

ents. As part of the U.S. Framingham Heart Study, a

cohort of 899 men and women (median age 76 years),

who were free of dementia at baseline, were followed for

a mean 9.1 years for development of all-cause dementia

and Alzheimer’s disease; the ﬁndings were published in

2006.

Ninety-nine new cases of dementia (including 71

of AD) occurred. Baseline and follow-up blood samples

were tested for fatty acids in the plasma phospholipid

fraction. After controlling for other variables, subjects

in the upper quartile of plasma PC-DHA levels had ap-

proximately half the relative risk of developing all-cause

dementia (RR=0.53, 95% CI=0.29-0.97; p=<0.04)

compared to subjects in the three lower quartiles. e

upper quartile (n=488) had a mean DHA intake of 180

mg/day and a mean ﬁsh intake of 3.0 servings per week

(p<0.001).

Slowing Cognitive Decline in a Middle-

Aged Population

Accelerated cognitive decline in middle age

can make an individual more vulnerable to dementia in

later life. Experts agree that once accelerated cognitive

decline is reliably identiﬁed, intervention is advisable.

Evidence is accumulating to suggest omega-3 FA deﬁ-

ciency contributes to accelerated cognitive decline.

An epidemiology team led by Kalmijn tested

1,613 subjects, ages 45-70, for various cognitive func-

tions at baseline and after ﬁve years and correlated the

results with habitual food consumption reported on a

self-administered food questionnaire.

Subjects exhib-

iting the most impaired cognitive function (lowest 10

percent of the group score) also had the lowest intake of

DHA/EPA or fatty ﬁsh. Overall cognitive performance

and psychomotor speed were positively correlated with

DHA/EPA status. High intakes of cholesterol and

saturated fat were both linked to increased cognitive

impairment in this middle-aged population.

From 1987-1989, the Atherosclerosis Risk in

Communities Study analyzed plasma fatty acids in cho-

lesteryl esters and phospholipids in 2,251 residents of

Minneapolis, Minnesota.

Subjects, average age 57 at

baseline, all had some degree of heart disease.

en

from 1990-1992 and 1996-1998 the participants were

tested for word recall, psychomotor speed, and verbal

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Omega-3s & Brain Function

Page 214

ﬂuency. Higher plasma omega-3 FA levels were cor-

related with reduced risk for decline in verbal ﬂuency,

particularly in hypertensive subjects and subjects with

dyslipidemias.

e outcome of this study prompted an edi-

torial in the American Journal of Clinical Nutrition.

Connor and Connor pointed out that the brains of

AD patients have a lower content of DHA in the gray

matter (more active zone), compared with individuals

without Alzheimer’s disease at death. ey suggest di-

etary DHA entering the brain could correct DHA in-

suﬃciencies in cerebral cortical cell membranes. ey

also hypothesized dietary EPA could help counter

pro-inﬂammatory processes contributing to neurode-

generation. e authors called for more clinical trials of

omega-3 FAs in older adults at risk of cognitive decline

and eventual dementia.

Mild cognitive impairment (MCI) is currently

the condition most predictive for subsequent progres-

sion to dementia. MCI features severely impaired mem-

ory without substantial loss of other cognitive functions.

Approximately 10-15 percent of MCI subjects progress

to dementia within a year of diagnosis.

Individuals

cognitively impaired but not demented tend to have ab-

normally low blood levels of DHA and EPA.

A research group in Japan included MCI

subjects in their prospective clinical trial on fatty acid

therapy for memory-impaired patients. As background,

Kotani et al determined experimental animals (rodents)

show age-dependent increases in the peroxidative

breakdown products from polyunsaturated fatty acids,

not just of omega-3 DHA but also of omega-6 AA.

a double-blind trial both these fatty acids were admin-

istered to a patient pool that included 21 with MCI, 10

with organic brain lesions, and eight with Alzheimer’s

disease. For 90 days, patients received either 240 mg/

day DHA and AA (ratio not speciﬁed) or a 240 mg/day

olive oil placebo. DHA and AA signiﬁcantly beneﬁted

the MCI group compared to placebo on both attention

and memory, while the organic brain-lesion group im-

proved on memory alone; the AD group did not show

beneﬁt.

Treating Dementia with DHA/EPA

Despite the fact abnormally low blood phos-

pholipid-DHA levels are found in patients with AD or

other dementias,

until recently few prospective trials

had been conducted on DHA/EPA for dementia, and

outcomes were inconclusive.

In 2006, a team from Stockholm’s Karolinska

University Hospital published a double-blind RCT of

DHA and EPA for 174 patients with mild-to-moder-

ate Alzheimer’s disease.

Patients received either 1.7 g

DHA and 0.6 g EPA daily or a placebo for six months,

after which all received the DHA/EPA supplements for

six more months. After the ﬁrst six months, decline in

cognitive function did not diﬀer between groups. How-

ever, in a subgroup with less severe cognitive dysfunc-

tion (Mini-Mental State Exam score >27 points), a

signiﬁcantly slower decline was observed in the DHA/

EPA group. A similar slowing was observed in the pla-

cebo group after crossover to DHA/EPA for the sec-

ond six months. ese ﬁndings suggest patients with

mild Alzheimer deterioration could beneﬁt from tak-

ing a mixed dietary supplement formulation containing

both DHA and EPA.

In 2007, the Karolinska group reported spe-

ciﬁcally on the neuropsychiatric outcomes of the above

trial.

e researchers found no overall treatment eﬀect

on neuropsychiatric symptoms, activities of daily living,

or caregiver burden. ey did ﬁnd signiﬁcant improve-

ment of agitation in apolipoprotein E4 (APOE4) car-

riers and improvement of depression in non-APOE4

carriers.

Multiple sclerosis (MS) patients can exhibit

dementia as a co-morbid condition, especially as the dis-

ease progresses. e etiology of MS and the prospects

for its integrative management were reviewed in 2001.

Six decades ago, Swank designed a fat-restricted diet

with similarities to a modern omega-3 enriched diet.

Swank developed this innovative diet after noticing that

coastal Norwegian residents consuming more ﬁsh and

less animal fat had lowered risk for MS.

Beginning in

1948, Swank’s patients were instructed to restrict ani-

mal fat intake and supplement liberally with cod liver

oil (5 g/day); margarine and other hydrogenated oils

were not allowed. Swank also encouraged three ﬁsh

meals per week, and most patients increased their in-

take of fruits and vegetables. Over the ensuing decades,

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Swank’s patient population experienced a much lower

rate of progression to advanced MS.

In 1988, Swank reviewed 150 of his patients

followed for over 35 years.

Death rate was 31 percent,

compared to the 80-percent predicted for MS patients

not maintained on a diet. Of patients who commenced

the restricted diet prior to developing disability, 95 per-

cent had not progressed after three or more decades of

being on the diet.

Other MS researchers published epidemiolog-

ical evidence that, between 1949 and 1967, 20 countries

including the United States had increased MS mortal-

ity risk associated with animal fat intakes and lowered

risk with diets relatively high in ﬁsh and vegetables.

Huntington Disease: EPA Shows

Promise

Huntington disease (HD) features abnormal

multiplication of a speciﬁc DNA sequence on chromo-

some 4: cytosine-adenine-guanine (CAG). Healthy

people have just one CAG sequence at this spot; people

with HD can have several dozen CAG sequences. As

a rule, the more CAGs the HD patient has, the more

severe their disease. e pathogenesis from genome to

symptomatology is still poorly understood. On a suspi-

cion that certain omega-3 responsive pathways could be

involved, a team of British researchers have been using

puriﬁed EPA in its ethyl ester form (“ethyl-EPA”) as po-

tential therapy for HD.

Puri et al conducted a small RCT with ethyl-

EPA on seven in-patients with advanced (stage III)

HD.

After six months, the four patients who received

ethyl-EPA demonstrated improvement on the orofacial

component of the Uniﬁed Huntington Disease Rating

Scale, while the three placebo patients had deteriorated

(p<0.03). MRI brain scans revealed the placebo was

associated with progressive cerebral atrophy and ethyl-

EPA was associated with beneﬁcial changes.

ree years later, the group completed a multi-

center, double-blind RCT.

A total of 135 Huntington

patients received either 2 g/day ethyl-EPA or placebo.

e primary endpoint was the score at 12 months on

the Total Motor Score 4 (TMS-4) subscale. e ethyl-

EPA group as a whole failed to show statistically signiﬁ-

cant improvement on TMS-4. A subgroup including

patients with fewer CAG showed signiﬁcantly better

TMS-4 improvement.

e secondary endpoints in this trial suggested

a signiﬁcantly worse outcome from ethyl-EPA in behav-

ioral severity and frequency compared to placebo.

is

ﬁnding raises the question of whether a mixture of EPA

and DHA, rather than a puriﬁed EPA, might have been

more eﬀective for this intractable disease.

Established Beneﬁts in Aﬀective

Disorders

Numerous studies have examined the eﬀects of

DHA/EPA for aﬀective disorders and have found them

to be beneﬁcial for mood management. Mood disorders

that apparently respond to DHA/EPA include major

depressive disorder, manic depression (bipolar disor-

der), and possibly also schizophrenia, borderline per-

sonality disorder (BPD), and anorexia nervosa.

Omega-3 Fatty Acids for Depression

As of mid-2007 (July), the peer-reviewed lit-

erature yielded seven double-blind RCTs of omega-3

fatty acids for MDD (summarized in Sontrop and

Campbell

and Nemets et al

). Of these, six reported

clinically signiﬁcant beneﬁts, including a trial with de-

pressed children ages 6-12 years.

ese trials admit-

tedly were heterogeneous in size, design, and rationale,

but from them a few trends emerged:

DHA taken without EPA may not be suﬃcient Â

to improve major depression.

EPA taken without DHA sometimes gives Â

beneﬁt.

e highest dosage of EPA did not necessarily Â

yield the most beneﬁt. In one double-blind

trial, Peet and Horrobin

used a “dose-ranging”

design, giving only EPA (as ethyl-EPA) at 1g/

day, 2g/day, or 4g/day for 12 weeks, in addition to

unchanged medication. e group receiving 1g/day

demonstrated the most improvement, with more

than half (53%) achieving a 50-percent reduction on

the Hamilton Depression Rating Scale.

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Omega-3s & Brain Function

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Maternal postpartum depression (also called

“perinatal depression”) has been linked to omega-3 FA

deﬁciency. As reviewed in Freeman,

a survey of moth-

er’s milk in 23 countries determined that lower DHA

content or lower seafood consumption was associated

with higher rates of postpartum depression. Freeman

noted that pilot trials of supplementation with DHA

and EPA have produced mixed results and called for

larger and better-designed trials to resolve this condi-

tion that endangers both mother and child.

Promise for Bipolar Disorder

Bipolar disorder (BD) with its complex spec-

trum of symptoms is likely associated with neural cell

membrane dysfunction, most likely signal transduction

abnormalities. A comprehensive 2004 review of integra-

tive management of BD examined the extensive data for

membrane abnormalities in BD and suggested supple-

menting with DHA/EPA as part of an integrative med-

ical regimen.

Several case reports suggest ﬂaxseed oil

may trigger manic episodes in BD, a predilection ﬁrst

reported by Rudin in 1981.

To date, four published double-blind trials

on DHA/EPA for BD have been published. e ﬁrst

was a 1999 trial that found signiﬁcantly longer remis-

sion of bipolar symptomology from a high-dose DHA

and EPA mixture (9.6 g/day) compared to placebo.

ree more double-blind trials were published in 2006

with diﬀering results. In the largest trial (75 patients),

Frangou et al found signiﬁcant improvement using EPA

only (ethyl-EPA), with 1 g/day working just as well as

2 g/day.

Keck et al found no signiﬁcant diﬀerences be-

tween placebo and 6 g/day EPA (no DHA) in 61 pa-

tients.

Marangell et al conducted a small study on 10

patients using only DHA and reported only that DHA

was “well tolerated.”

A 2005, open-label trial, using EPA at 1.5-2.0

g/day as “add-on” therapy for BD, found that eight of 10

patients improved at least 50 percent on the depression

scale.

is ﬁnding is in line with Frangou’s double-

blind trial outcome cited above.

In another open-label

trial, children ages 6-17 years demonstrated a modest

improvement in mania with intakes of 1.3-4.3 g/day

DHA/EPA for eight weeks.

Taken altogether, the

existing trials of DHA and EPA for bipolar disorder

suggest eﬃcacy, especially for the depression phase, with

EPA appearing to be the most eﬃcacious of the two.

e levels of seafood intake per capita in vari-

ous countries of the world roughly correlate with the

respective prevalence rates of BD in community sam-

ples.

e greater the seafood consumption per capita

in a country, the lower the prevalence of bipolar spec-

trum disorders. Countries that consume a lot of ﬁsh on

average (e.g., Iceland, Korea, and Taiwan) have relatively

low incidence, while countries that consume very little

ﬁsh (e.g., Germany, Switzerland, and Hungary) have up

to seven times the incidence of countries with high ﬁsh

intake. Noaghiul and Hibbeln estimated a “vulnerability

threshold” for BD at seafood consumption below 50

pounds of seafood/person/year.

In 2006, participants in the Omega-3 Fatty

Acids Subcommittee, assembled by the Committee

on Research on Psychiatric Treatments of the Ameri-

can Psychiatric Association, published an extensive

assessment of the available data on the clinical use of

omega-3 fatty acids in the prevention and/or treatment

of psychiatric disorders.

is report included meta-

analyses of RCTs conducted with DHA and/or EPA

for major (unipolar) depression and bipolar depres-

sion. ese meta-analyses found statistically signiﬁcant

beneﬁt (p=0.02) from EPA and EPA/DHA. e Sub-

committee found less persuasive evidence for beneﬁt in

schizophrenia.

Trials in Schizophrenia

Currently, six double-blind RCTs with DHA/

EPA have been conducted, involving 390 patients with

schizophrenia or schizoaﬀective disorder. Four of these

documented clinical beneﬁt from 2/g EPA daily for

three months.

74-78

One trial found high-EPA ﬁsh oil

performed better than high-DHA ﬁsh oil or placebo.

Another dose-ranging trial of ethyl-EPA found 2 g/day

worked better than 1 g or 4 g daily. Two trials by the

same group examined ethyl-EPA’s eﬀect on tardive dys-

kinesia associated with pharmaceutical management of

schizophrenia. In a 2002 trial, Emsley et al found ben-

eﬁt at 3 g/day,

but a later 2006 trial did not demon-

strate beneﬁt at the lower dose of 2 g/day.

A “phospholipid membrane hypothesis of

schizophrenia” emerged in the late 1970s, as reviewed

in 2000 by Fenton and colleagues.

is hypothesis

encompasses abnormalities of long-chain omega-6 fatty

Alternative Medicine Review Volume 12, Number 3 2007

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Page 217

acids such as AA, as well as the omega-3 FAs DHA

and EPA. Fenton et al list multiple analyses of RBC

membranes (recognized markers for essential fatty acid

status) that consistently document depletion of AA,

DHA, and EPA. Also noted were studies documenting

depletion in plasma, thrombocytes, and post-mortem

brain tissue of schizophrenia patients.

Elevations of membrane phospholipase A2

activity (measured in platelets) have been reported in

schizophrenia, consistent with elevated membrane

turnover of fatty acids.

ese ﬁndings are reminiscent

of the systemic membrane abnormalities observed in bi-

polar disorder.

Perhaps the most compelling evidence so far

of membrane abnormalities in schizophrenia are the

ﬁndings from noninvasive nuclear magnetic resonance

(NMR) procedures (summarized in Fenton et al

ese data suggest elevated membrane phospholipid

breakdown products in the brain at an early stage of

the illness and reduced levels of membrane phospho-

lipid precursors. DHA and EPA are ﬁrst-line nutrients

for repairing damaged membranes and initial RCT

outcomes suggest they deserve further study for the

schizoaﬀective spectrum.

Cell membrane dysfunction is just part of

an impressive body of evidence that strongly suggests

schizophrenia is related to other aﬀective disorders

across a pathologic continuum. Striking genetic, symp-

tomatic, and pathophysiological overlaps suggest the

continuum to be unipolar (major) depression⇒bipolar

disorder⇒schizoaﬀective psychosis⇒schizophrenia.

Although the degree of beneﬁt or dosing strategy is not

yet conclusive, ﬁndings that DHA and EPA have pro-

duced beneﬁts for major depression, bipolar disorder,

and schizophrenia justify their inclusion in a treatment

protocol for aﬀective disorders.

Borderline Personality Disorder

Borderline personality disorder may also

respond to omega-3 supplementation. In a double-

blind, placebo-controlled trial, 30 female subjects

with moderately severe BPD received 1 g/day EPA

only (as ethyl-EPA) or a placebo for two months.

ose taking ethyl-EPA experienced signiﬁcantly di-

minished aggression and less severe depression.

Figure 2. Cell Membrane Schematic, Demonstrating the Intrinsic Structural Synergy of

its Fatty Acids, Phospholipids, and Antioxidants (“Triple Cell Membrane Synergy”)

Phospholipids

Fatty acids

Antioxidants

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Omega-3s & Brain Function

Page 218

DHA/EPA Support Cell Membranes,

the Pacemakers of Metabolism

What are some of the mechanisms involved in

the diverse therapeutic applications of omega-3 fatty

acids? DHA and EPA literally feed cell membranes,

the dynamic structures that manage the vast majority

of life processes. Almost all the pivotal life processes oc-

cur in, on, or attached to membranes.

Membranes are

literally the pacemakers of metabolism – a high meta-

bolic rate correlates with high membrane unsaturation

among vertebrate species.

Increasing unsaturation en-

ables improved ﬂuidity and more versatile cooperation

between the “sea” of lipids in the membrane and the pro-

teins immersed in this medium. Within the membrane-

as-pacemaker, the polyunsaturated fatty acid content

aﬀects ﬂuidity to enable the myriad membrane-bound

enzymes, receptors, transporters, and other catalytic

molecules.

Within the membrane bilayer, DHA and EPA

are attached to the larger phospholipid molecules via es-

ter bonds.

Phospholipids with their attached fatty ac-

ids are the molecular building blocks of the membrane

(Figure 2). DHA and EPA interact with the other fatty

acids in the membrane bilayer – saturates, monoun-

saturates (omega-9s), and polyunsaturates (omega-6s,

minor omega-3s) – and membrane ﬂuidity is a net out-

come of all the electron densities. Carbon-carbon double

bonds have high electron density and impart ﬂuidity to

the membrane. is property renders DHA (six double

bonds) and EPA (ﬁve double bonds) the most highly

ﬂuidizing of the major membrane fatty acids.

As a rule, the more ﬂuid a membrane the more

eﬃcient its biochemical performance.

In general, ex-

perts agree the advanced human cell is only as eﬃcient

as its membrane system.

81,82

is life principle suggests

that having adequate levels of DHA and EPA in mem-

brane systems is crucial to the survival, growth, renewal,

and myriad functions of human cells.

Relative Functional Signiﬁcance of DHA,

EPA, and ALA

e DHA and EPA content of cell mem-

branes reﬂects ongoing dietary intakes. As dietary in-

takes change the membrane proﬁle changes. Within

the membrane, micro-distributions of the fatty acids

attached to phospholipids are continually being ﬁne

tuned by enzymes (acyltransferases) that remove them

from the tails of certain phospholipids and relocate

them to others.

Probably due to their highly ﬂuidizing proper-

ties, DHA and EPA are found in highest concentrations

in the most dynamic membranes (e.g., retina, brain, and

spermatozoa). Beyond conferring membrane ﬂuid-

ity, DHA and EPA are orthomolecules that contribute

to the homeostatic regulation of tissue performance,

renewal, and regeneration. On the other hand, ALA is

not found in high concentrations in cell membranes.

DHA and EPA can provide a degree of bio-

chemical backup for each other. Although EPA may not

be readily forward-converted to DHA, DHA is readily

back-converted to EPA.

e limitations imposed by

the poor conversion of ALA to either EPA or DHA,

and by the sluggish conversion of EPA to DHA, sug-

gest that intake of preformed DHA is needed to assure

adequate supply to the brain, cardiovascular system, and

other organ systems.

DHA/EPA Inﬂuence Inﬂammatory

Balance

Eicosanoids are by deﬁnition metabolites of

fatty acids. Healthy, non-inﬂammatory eicosanoid bal-

ance is maintained throughout the body by way of a ho-

meostatic balance between omega-3 and omega-6 fatty

acids in cell membranes. Eicosanoid balance then exerts

a “downstream” balancing inﬂuence on cytokines (small

protein messenger molecules). Of the omega-3 FAs, the

shorter chain ALA is rarely found in cell membranes

and has no identiﬁable metabolites that might contrib-

ute to homeostatic balance. Both DHA and EPA, on

the other hand, are precursors of metabolite messenger

molecules that have wide ranging physiological eﬀects.

In the context of the modern human lifestyle

and diet, the eicosanoid metabolites of EPA are crucial

to provide anti-inﬂammatory eﬀects by balancing the

potentially pro-inﬂammatory eicosanoid metabolites

of the omega-6 AA. It is important to stress that AA

metabolites are not inherently dangerous to health, nor

are they “bad” fatty acids. Rather, the organism requires

AA for systemic homeostasis, and at higher dietary lev-

els than omega-3 FAs. Unfortunately, modern dietary

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Page 219

patterns de-emphasize omega-3 intakes while over-em-

phasizing intakes of omega-6s and other fatty acids less

important to homeostasis and total health.

e relatively “bad” factor in this scenario is the

chronically unbalanced state of the standard American

diet (SAD). e SAD confronts the consumer with: (1)

an overall lack of natural fatty acids due to the consump-

tion of “low-fat” foods; (2) an overload of trans-fatty ac-

ids, produced through hydrogenation and unnatural to

cell membranes; or (3) a large imbalance of omega-6 to

omega-3 FA intake, due to consumption of meats raised

in feedlots rather than grass fed on the open range (meat

from grass-fed cows has higher levels of omega-3 FAs).

As a consequence, individuals who subsist on the SAD

are at heightened risk for pro-inﬂammatory events that

foster degenerative disease.

Simopoulos concluded from anthropological,

epidemiological, and molecular-level studies that hu-

mans evolved on a diet with a ratio of omega-6:omega-3

FAs close to 1:1; whereas, in today’s Western diets the

ratio ranges from 15:1-17:1.

Simopoulos is part of a

growing chorus against the SAD, asserting a prepon-

derance of dietary omega-6 FAs predisposes tissues to

inﬂammation and subsequent pathology.

In addition to such “acquired” dietary imbal-

ances that lessen omega-3 intakes, the healthy human

organism has limited capacity to elaborate the long-

chain DHA and EPA from shorter-chain precursors.

Metabolic biochemists have calculated that ﬁve percent

or less of dietary ALA is converted to EPA, and less

than 0.5 percent of dietary ALA makes it to DHA.

One approach to bypassing this problem could be to

markedly increase the dietary intake of ALA. However,

a study with lactating women found that high dietary

ALA (10.7 g/day for four weeks) did not raise DHA

levels in breast milk or RBCs.

Docosanoids: Protective DHA Metabolites

DHA in the membrane is a source of metabo-

lites with a novel stereospeciﬁcity unlike that of the

known eicosanoids. Aptly christened docosanoids, they

are chemical messengers with potent anti-inﬂammatory

and other protective actions.

e three known classes

of docosanoids – docosatrienes, resolvins, and protec-

tins – are produced mainly from controlled oxidative

breakdown of DHA within (or possibly adjacent to)

the membrane. Of the protectins, neuroprotectin D1

(NPD1) is generated during stroke and counteracts

pro-inﬂammatory gene expression that normally results

from ischemic damage. is messenger substance also

counteracts potential oxidative damage to DNA in the

retinal pigment epithelium cells.

87,88

Current research is focused on another class

of docosanoid messengers, the resolvins. As their

name implies, these molecules help resolve (terminate)

ongoing inﬂammatory cascades.

Inﬂammation that

terminates on a timely basis is homeostatic – and de-

sirable. However, metabolic insults and imbalances can

often prolong inﬂammation and trigger pathology. e

physiological resolution of a well-orchestrated inﬂam-

matory response is essential to maintain homeostasis,

and resolvins appear to be involved in this process.

e broader scientiﬁc literature on DHA con-

ﬁrms it is essential for normal neurological develop-

ment, maintenance of learning and memory, and brain

plasticity. DHA in neuronal membranes enhances

synaptic membrane ﬂuidity and function, regulates

gene expression, mediates cell signaling, and enhances

the electrical basis for memory formation.

In labora-

tory rats subjected to traumatic brain injury, prior di-

etary supplementation of DHA enhances recovery and

boosts brain production of brain derived neurotrophic

factor (BDNF), a major brain growth factor.

is ar-

ray of protective and homeostatic activities, working

in harmony with EPA, helps explain the wide range of

whole-body beneﬁts achieved by both.

Orthomolecular Synergy of Cell

Membrane Nutrients

DHA and EPA have an obvious and predict-

able synergy with other cell membrane nutrients, spe-

ciﬁcally phospholipids and antioxidants. Depending on

the requirements of the tissue in question, the phos-

pholipids phosphatidylserine (PS), phosphatidyletha-

nolamine (PE), and PC can carry substantial amounts

of DHA in their “tail” positions, especially tail position

2. ese phospholipid “parent molecules” also anchor

EPA within the membrane.

Healthy cells have a complement of antioxi-

dants within their membranes that help protect them

from destruction by intrinsic oxidants (obligatorily gen-

erated during routine metabolism) or extrinsic oxidants

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Omega-3s & Brain Function

Page 220

imposed by lifestyle or the environment.

Membrane

antioxidants are structurally intermingled with fatty ac-

ids and function as a protective “ﬁrst line of defense.”

In the presence of antioxidants, fatty acids with the

most unsaturated bonds, namely DHA and EPA, are

protected against oxidative (“free radical”) destruction.

us, within the dynamic membrane milieu, DHA

and EPA exist in homeostatic synergy with both their

parent phospholipids and the antioxidants dispersed in

the membrane lipid bilayer, providing “triple cell mem-

brane synergy.” us, in addition to protective antioxi-

dants, supplements that deliver DHA and EPA bound

to phospholipids – such as omega-3s bound to phos-

phatidylserine and krill oil that contains omega-3 FAs

bound to phospholipids – provide the building blocks

for healthy cell membranes.

Omega-3 Phosphatidylserine (Omega-3

PS)

Phosphatidylserine is an important brain nu-

trient. At least 25 RCTs (reviewed in a recent book

conducted over more than two decades, have established

PS is beneﬁcial for declining memory, learning, other

cognitive functions, and mood and stress management.

PS supports brain energetics and, at the tissue level,

supports the receptors for many chemical transmitter

systems. Neuron cell membranes, which are especially

rich in PS, contain DHA in a proportion of the PS

molecules (Figure 3).

Omega-3 PS Beneﬁts AD/HD

Vaisman et al reported on a double-blind trial

with omega-3 PS for AD/HD.

ey recruited 60

children (3:1 ratio of boys:girls) with AD/HD-like

symptoms (average age nine years). e children were

randomized to three groups: (1) canola oil (controls),

(2) ﬁsh oil (providing 250 mg DHA/EPA daily), and

(3) an omega-3/PS combination (providing 300 mg PS

and 250 mg DHA/EPA daily). No stimulant medica-

tions or other dietary supplements were administered

during the trial period (80-100 days; average 91 days).

e group receiving omega-3 PS had the highest pro-

portion of children whose symptoms improved.

e children’s sustained visual attention and

discrimination were assessed using the Test of Variables

of Attention (TOVA). e TOVA AD/HD Index “z”

score improved over controls for both the omega-3 PS

and the ﬁsh oil groups, but signiﬁcantly more in the PS

group (p<0.001). is indicates that omega-PS im-

proved attention performance (and more dramatically

than ﬁsh oil) compared to the control group. e ome-

ga-3 PS group also manifested a signiﬁcantly higher ra-

tio of symptom clearance than the control group, with

11/18 of the omega-3 PS children becoming asymp-

tomatic versus 3/21 of the control children (p<0.05).

Of the ﬁsh oil group, 7/21 became asymptomatic –

not statistically signiﬁcantly diﬀerent from controls.

Omega-3 PS ameliorated the inattention symptoms of

AD/HD to a greater degree than equivalent amounts

of DHA/EPA from other dietary sources.

Figure 3. Schematic of Omega-3

Phosphatidylserine (Omega-3

PS)

SERINE

PHOSPHATE

GLYCEROL

DHA and EPA

FATTY ACID

1 2

Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 221

Omega-3 Phospholipids from Krill

Krill, small shrimp-like crustaceans, are ubiq-

uitous in the oceans and are some of the planet’s hardi-

est creatures. Krill sustains many marine animals and

is a traditional food for humans. e Antarctic krill

(Euphausia superba) live in the most frigid seas. eir

cell membranes carry a high complement of DHA and

EPA that render them highly ﬂuid in order to function

in ambient temperatures well below the freezing point.

Unlike typical ﬁsh oil supplements that carry al-

most no phospholipids, much of the DHA/EPA in krill

oil is linked to phospholipids, particularly phosphatidyl-

choline (Figure 4) and in lesser amounts to phosphati-

dylethanolamine. e remaining DHA and EPA are

in triglyceride form. e krill-phospholipid molecular

fraction also includes the potent membrane antioxidant

astaxanthin.

Krill omega-3 preparations have been tested in

three double-blind trials – for premenstrual syndrome

(PMS) mood management/dysmenorrhea, blood lipid

management, and modulation of inﬂammatory symp-

toms and blood markers linked to arthritis. In two trials

the krill complex was directly compared to ﬁsh oil.

Krill for PMS and Dysmenorrhea

PMS and dysmenorrhea are thought to aﬀect

90 percent of reproductive-age women. Abnormal fatty

acid metabolism has been implicated (reviewed in Sam-

palis et al

). A double-blind RCT was conducted with

a krill omega-3 supplement (NKO



) on 70 healthy

volunteers suﬀering from PMS/dysmenorrhea.

One

group received a krill oil supplement while the other

group received an equivalent amount of DHA and EPA

as ﬁsh oil.

In the krill group, 36 women consumed 2 g/

day krill oil with meals (providing 800 mg phospho-

lipids and 600 mg omega-3 FAs). e ﬁsh oil group

consumed 2 g/day ﬁsh oil (18:12; 18% EPA/12%

DHA) with meals, providing 600 mg DHA/EPA. Sub-

jects in both groups took supplements every day for the

ﬁrst 30 days, then for just 10 days per month during

the succeeding two months (beginning eight days prior

to expected menstruation). e women tracked mental

and physical symptoms on a questionnaire developed by

the American College of Obstetrics and Gynecology.

Although the ﬁsh oil and krill groups both im-

proved in weight, abdominal discomfort, and swelling,

only the krill group experienced statistically signiﬁcant

improvements in breast tenderness, feelings of inad-

equacy, stress, irritability, depression, joint discomfort,

and bloating. e krill group also reported more im-

proved alertness, energy, and wellbeing. By conclusion

of the study, the krill group consumed signiﬁcantly few-

er analgesic medications during the 10 perimenstrual

days than the ﬁsh oil group. Unlike the krill group, 64

percent in the ﬁsh oil group complained of unpleasant

reﬂux.

Krill Supports Circulatory Health

Circulatory health is fundamental to brain

health. Blood lipid abnormalities (elevated LDL and

total cholesterol, reduced HDL, and high triglycerides)

Figure 4. Schematic of

Omega-3 PC Present in Krill

Preparations

CHOLINE

PHOSPHATE

GLYCEROL

DHA and EPA

FATTY ACID

1 2

Alternative Medicine Review Volume 12, Number 3 2007

Omega-3s & Brain Function

Page 222

contribute not only to morbidity and mortality associ-

ated with cardiovascular disease, but also to cognitive

decline. In a double-blind trial, krill oil was compared

to ﬁsh oil (18% EPA/12% DHA) in men and women

with hyperlipidemia (total cholesterol above 194 mg/

dL; triglycerides above 204 mg/dL).

In this 90-day trial, two groups of subjects re-

ceived krill at either 1-1.5 g/day or 2-3 g/day (depend-

ing on body mass index (BMI)), another group received

3 g/day ﬁsh oil, and a fourth group received placebo.

At its lowest dosage (1-1.5 g/day), krill oil signiﬁcantly

lowered total and LDL cholesterol and elevated HDL

cholesterol, compared to baseline and to the ﬁsh oil and

placebo groups. At 2 g/day, krill also signiﬁcantly low-

ered serum triglycerides in addition to cholesterol, while

the highest krill intake (3 g/day) did not produce ad-

ditional beneﬁt over 2 g/day. e ﬁsh oil lowered cho-

lesterol only marginally and failed to lower triglycerides

below baseline values.

Anti-Inﬂammatory Eﬀects

C-reactive protein (CRP) is a systemic inﬂam-

matory marker and a strong predictor of stroke and

cognitive impairment.

In a double-blind RCT, krill

oil demonstrated

anti-inflammatory

eﬀects.

e study

recruited a total of

90 subjects with car-

diovascular disease,

rheumatoid arthri-

tis, or osteoarthri-

tis, and high levels

of CRP (>1.0 mg/

dL). Subjects re-

ceived a low dose of

300 mg/day krill oil

or placebo and were

assessed at baseline,

7, 14, and 30 days.

By day 7, krill had signiﬁcantly reduced CRP (by 19%;

p<0.05) compared to placebo. e CRP reduction was

more marked at day 30 (30% reduction; p<0.01) com-

pared to placebo. Fish oil has failed to lower CRP in at

least four studies.

Omega-3 Phospholipids Target the

Brain

Much evidence gleaned from animal studies

(rodents and primates) indicates fatty acids are more

bioavailable when provided in the form of phospho-

lipids than as triglycerides or ethyl esters. In one study,

brain fatty acid bioavailability was more than doubled

by using phospholipids compared to triglycerides as the

delivery form. is experiment compared tissue depo-

sition of a fatty acid (arachidonic acid) in triglyceride

form (as often found in ﬁsh oil) or phospholipid form,

fed to neonatal baboons.

Arachidonic acid is the predominant polyun-

saturated fatty acid in the brain. As a major component

of membrane phospholipids, AA is critical for mem-

brane function and serves as a precursor for eicosanoids

that play important roles in cell and tissue regulation.

AA is also a precursor for longer-chain adrenic acid

Figure 5. Tissue Distribution of Radiolabeled Arachidonic Acid Fed to

Neonatal Baboons as either Triglycerides (TG-AA) or Phospholipids

(PL-AA)

0.8

0.6

0.4

0.2

Liver Brain Lung

Baboon

Newborns:

Tissue

22:4 w-6

from

20:4 w-6

(% dose per

organ)

Alternative Medicine Review Volume 12, Number 3 2007

Review Article

Page 223

(C22:5; omega-6), which is also abundant in the brain.

In the baboon experiment, AA was radioactively la-

beled, then incorporated into triglycerides (TG-AA)

or phospholipids (PL-AA) and fed to the animals as a

single dose of either TG-AA or PL-AA.

After 10 days

the distribution of radioactivity was analyzed. As shown

in Figure 5, the brain accumulated more than twice as

much radioactivity from PL-AA as from TG-AA. is

experiment demonstrated phospholipids improve fatty

acid uptake into the primate brain.

Conclusion

DHA and EPA are clinically renowned for their

cardiovascular protective properties. A recent systematic

review evaluated the eﬀects of ﬁsh oil consumption for

primary and secondary prevention of adverse cardiovas-

cular events.

It concluded that increased consumption

of omega-3 fatty acids from ﬁsh or ﬁsh-oil supplements,

but not from ALA, reduces rates of all-cause mortality,

cardiac and sudden death, and possibly stroke; all with

only minor adverse eﬀects. e results of this current

review suggest the brain beneﬁts of DHA and EPA may

eventually prove to be just as impressive as their beneﬁts

for the cardiovascular system.

What is the Correct Intake of DHA/EPA

for Brain Beneﬁts?

Technically, humans can synthesize EPA and

DHA from the shorter-chain ALA, but the conversion

eﬃciency is low, even in healthy individuals. us ﬂax-

seed oil as a source of ALA cannot be assumed to sub-

stitute for dietary sources of DHA/EPA. Foods high

in omega-3 FAs or supplements with preformed DHA

and EPA are required.

In regard to food sources of DHA/EPA, the

standard American diet is unlikely to contribute more

than 50-100 mg/day. Various “functional foods” have

appeared with DHA/EPA added. Omega-3 eggs, for

example, can be a signiﬁcant source by providing greater

than 200 mg of “omega-3” per egg. However, it may be

necessary to conﬁrm which omega-3 FAs are in the food

(e.g., DHA/EPA or ALA). Further caution is advised

to ensure that other ingredients in the food are health-

ful. For example, one heavily promoted omega-3 spread

carries trans-fatty acids – a potential toxic counterbal-

ance to the omega-3 beneﬁts.

e current knowledge base on DHA/EPA for

brain function does not generate a rational daily intake

recommendation. Hibbeln, from his studies on national

seafood intakes and aﬀective disorder incidence, sug-

gested pregnant women may want to consume a mini-

mum 650 mg/day of DHA and EPA (with a minimum

300 mg/day of DHA) to prevent postpartum depres-

sion.

e existing recommendations for cardiovascu-

lar protection could be taken as a minimum for brain

protection. In North America, the American Heart As-

sociation recommends a minimum intake of two ﬁsh

meals weekly for primary cardiovascular protection and

1,000 mg/day of DHA/EPA for protection against a

second heart attack.

e practicality of making dietary recommen-

dations to eat ﬁsh as a primary source of DHA/EPA is

threatened by the fact that suitable ﬁsh are increasingly

expensive and hard to ﬁnd.

100

e stocks of wild salmon

and other species that are not contaminated with mer-

cury or other pollutants are increasingly restricted. An

alternative is to take dietary supplements rich in DHA/

EPA, including the omega-3 phospholipid complex

from krill.

While the wild salmon stocks are shrinking,

concerns are being voiced about the increasing use of

krill for aquaculture: salmon farming.

101

Krill is thought

to be the largest single biomass on the planet and is a

life-sustaining food for diverse marine animals. e

Antarctic stocks (Euphausia superba) are estimated at

50- to 500-million metric tons.

100

e international or-

ganization Convention on the Conservation of Antarc-

tic Marine Living Resources (CCAMLR), part of the

Antarctic treaty network, was founded in 1982 primar-

ily to protect krill. It has 24 member countries, includ-

ing the European Union, Norway (a big krill ﬁshing

country), Russia, and the United States, as well as nine

other nonvoting member countries. CCAMLR has set a

sustainable harvest for krill in the Antarctic of 4.45 mil-

lion tons. Although this level has still not been reached,

the advent of massive krill ﬁshing boats has greatly in-

creased the capability to harvest Antarctic krill, and the

CCAMLR is in the process of tightening its regulatory

framework for krill conservation.

Cultivated microalgae are a good source of

DHA. Although high doses of ALA can increase tissue

EPA levels, ALA does not have the same eﬀect on DHA

Alternative Medicine Review Volume 12, Number 3 2007

Omega-3s & Brain Function

Page 224

levels,

rendering supplementation necessary. How does

one know whether supplementation is necessary? Phys-

ical signs and symptoms of deﬁciency include excessive

thirst, frequent urination, rough dry hair and skin, and

follicular keratosis.

14,18

RBC membrane content re-

mains the most accepted laboratory measure. Harris

developed an “omega-3 index” (RBC DHA/EPA) as a

marker and perhaps also a risk factor for coronary heart

disease.

102

He suggests adequate suﬃciency is likely at-

tained when DHA and EPA exceed eight percent of the

total membrane fatty acids.

Although the current clinical literature on

DHA and EPA for brain function is still relatively

small compared to the literature on circulatory ben-

eﬁts, the weight of the current evidence strongly sup-

ports the utility of these conditionally essential nutrient

orthomolecules for cognition, behavior, and mood, as

well as for early brain development and overall mental

performance.

e evidence presented in this review clear-

ly suggests that the fundamental basis for applying

DHA/EPA to human health is their presence in cell

membranes. e cell membrane rationale for DHA/

EPA also points to linked supplementation with their

synergistic “parent” phospholipids, such as PS and PC.

A further cell membrane synergy can be achieved by

adding fat-soluble antioxidants, such as astaxanthin

and other carotenoids, vitamin E, and coenzyme Q10.

Implementing this triple cell membrane synergy prom-

ises to bring integrative medicine closer to healing the

dysfunctional brain.

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Investigating the impact of omega-3 fatty acids on oxidative stress and pro-inflammatory cytokine release in iPSC-derived forebrain cortical neurons from ADHD patients

Article

Feb 2025
J PSYCHIATR RES

Fatty acid content and profile of round sardinella (Sardinella aurita), an expanding thermophilic species in the NW Mediterranean

Article

Full-text available

Jun 2024

Over the past few decades, due to sea warming driven by global climate change, the habitat range of round sardinella (Sardinella aurita) has expanded into the north-western Mediterranean Sea. This study evaluates the fatty acid content and fatty acid profile of this small, warm-water pelagic fish caught in this area, specifically the northern Catalan coast. The findings provide important insights into the nutritional status of the species under changing environmental conditions. The study confirms that fatty acid content varies according to the individual specimen’s maturity stages (immature, pre-spawners, and spawners). Pre-spawners showed higher fat levels compared to spawners, whose lipids are allocated to their gonads to enhance the survival of their offspring. While a high content of omega-3 polyunsaturated fatty acids (n-3 PUFAs) was generally found at all stages of maturity, pre-spawners had higher levels of EPA but lower levels of DHA than immature individuals and spawners. Moreover, compared to small pelagic fish more typical of the temperate waters in the region (European anchovy, Engraulis encrasicolus, and European sardine, Sardina pilchardus), round sardinella generally have a higher level of PUFAs, especially DHA. Encouraging consumption of this warm water species could provide significant nutritional benefits while reducing fishing pressure on European sardine and European anchovy, whose populations are currently in a very poor state.

DHA and EPA protect against cognitive impairment induced by chronic sleep deprivation through regulating iron-mitophagy homeostasis

Article

Jan 2025

International Journal of Medicine and Medical Sciences Pathophysiology of spinal cord injury and potential health benefits of omega-3 fatty acid

Article

Full-text available

Nov 2024

Spinal cord injury (SCI), is a life changing threatening neurological condition that completely changes patients' life. It has been shown that early treatment soon after the injury may improve neurological recovery. To date, no therapeutic modalities exist that have shown very positive effect on neurological outcomes. However, recent clinical and preclinical studies have shown little hope for the treatment of SCI. In medical management, recent advances have significantly improved diagnosis, stabilization, survival rate, and well-being of SCI patients, but there has been little progression in the treatment. An important strategy for SCI treatment is to reduce the levels of reactive oxygen species, and oxidative stress. Today, the main focus is on neutraceuticals as they are natural compounds, easy to accommodate and have high antioxidant properties which diminish the toxic effects of oxidative stress responsible for the progression of several pathologies of the nervous system. Omega-3 fatty acids are important polyunsaturated fatty acids (PUFA) with some roles in normal cellular metabolism. They have anti-inflammatory and antioxidant properties, and it has been proven to be beneficial in ameliorating inflammation in different diseases and thus improves neurological outcomes after neuronal injury. PUFA helps in suppressing the Inflammatory and oxidative stress markers responsible for SCI inflammatory events, Leukotriene-5, thromboxane-3 and prostaglandin-3 are derived from essential fatty acids, and are known to be therapeutically important in inflammatory conditions as well as for mental health. Fatty fishes such as salmon, mullet and mackerel are the best sources of EPA and DHA and thus have significant health benefits.

Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain—Study in a Mouse Model of the Disease

Article

Full-text available

Jun 2024
INT J MOL SCI

Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p < 0.0001), and in the bran, decreased 8-isoprostane amounts (p < 0.0001), increased resolvin D1 levels (p < 0.005) and increased quantity of total n-3 PUFAs (p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = −0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = −0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.

Pathophysiology of spinal cord injury and potential health benefits of omega-3 fatty acid

Article

Full-text available

Apr 2024

Nutritional Quality Implications: Exploring the Impact of a Fatty Acid-Rich Diet on Central Nervous System Development

Article

Full-text available

Apr 2024

Given the comprehensive examination of the role of fatty acid-rich diets in central nervous system development in children, this study bridges significant gaps in the understanding of dietary effects on neurodevelopment. It delves into the essential functions of fatty acids in neurodevelopment, including their contributions to neuronal membrane formation, neuroinflammatory modulation, neurogenesis, and synaptic plasticity. Despite the acknowledged importance of these nutrients, this review reveals a lack of comprehensive synthesis in current research, particularly regarding the broader spectrum of fatty acids and their optimal levels throughout childhood. By consolidating the existing knowledge and highlighting critical research gaps, such as the effects of fatty acid metabolism on neurodevelopmental disorders and the need for age-specific dietary guidelines, this study sets a foundation for future studies. This underscores the potential of nutritional strategies to significantly influence neurodevelopmental trajectories, advocating an enriched academic and clinical understanding that can inform dietary recommendations and interventions aimed at optimizing neurological health from infancy.

Behavior problems of the aging cat

Chapter

Jan 2025

Valarie V. Tynes

Green extraction of marine phospholipids from Conger eel by-product using SC-CO 2 : Lipidomic profiles and biological activities

Article

Aug 2024

This paper presents an eco-friendly approach to recovering phospholipids (PLs) from the Conger myriaster head (CMH) via supercritical carbon dioxide (SC–CO2) extraction using ethanol as a cosolvent. The lipidomic profile and biological activities of the extracted PLs were investigated. Purity assessments, PL composition analysis, and fatty acid profiling were performed to characterize the PLs. Biological activity was determined through antioxidant, antimicrobial, antihypertensive, anti-inflammatory, and anticancer evaluations. The results showed that the yields of the SC–CO2 extracted CMH PLs (SCHP) and organic solvent extracted CMH PLs (OCHP) were 3.26% ± 0.20 % (76.18% ± 0.09% purity) and 9.02% ± 0.21% (purity = 18.29% ± 0.04%), respectively. The 31P NMR analysis revealed a diverse PL composition in both extracts, with the SCHP showing higher PC content and selective extraction characteristics. The SCHP exhibited significantly superior antioxidant, antimicrobial, antihypertensive, and anti-dementia activities compared to the OCHP. Both extracts inhibited nitric oxide production in RAW 264.7 cells, suggesting anti-inflammatory activity. Selective anticancer activity was observed, with high toxicity in SK-N-SH cells but no cytotoxicity in RAW 264.7 and HaCaT cells. The findings highlight the potential of SC-CO2 extraction using ethanol to obtain bioactive PLs from marine by-products, with promising applications in the pharmaceutical, cosmetic, and food industries.

Gut Microbiota and Altered Behaviour: Target on Neuroimmune Interplays

Chapter

Apr 2024

There are over 100 trillion microflorae in the human gut which engage in multiple interactions with human health during the whole life span. They influence human physiology, nutrition, metabolism and immunity. There is a two-way connection between the gut and brain known as gut-brain axis through which it influences the physiological, behavioural and cognitive functions of brain. This research focuses on the gut-brain axis, a bidirectional communication pathway between the gut and the brain that impacts brain function through vagus nerve and HPA axis and the metabolites such as neurotransmitters and SCFAs. The disruption in composition and relative abundance of gut microbiota known as dysbiosis leads to pathogenesis of several neurological disorders such as Alzheimer’s disease, Parkinson’s disease and autism. The individuals with neurological disorders presented with altered composition of gut microbes and its metabolites which varies from the normal individuals. This altered behaviour of gut microbes can be influenced or changed by supplementing with a bioactive live microorganisms known as probiotics. This study explores the potential of manipulating gut microbiota through probiotics to improve neurological function and potentially treat these disorders.

Is docosahexaenoic acid, an n−3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals

Article

Aug 2005

This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely to result in altered brain concentrations of the n−3 fatty acid docosahexaenoic acid (DHA) during the perinatal period of “brain growth spurt.” Experimental designs reviewed include observational breastfeeding studies and randomized controlled trials in humans and studies in rodents and nonhuman primates. This review is based on a large number of expert reviews and commentaries and on some 50 recent studies in humans and animals that have not yet been included in published reviews. Expert opinion regarding the strengths and weaknesses of the major experimental systems and uncertainties associated with interpreting results is summarized. On the basis of our reading of this literature, we conclude that evidence from several types of studies, particularly studies in animals, suggests that, within the context of specific experimental designs, changes in brain concentrations of DHA are positively associated with changes in cognitive or behavioral performance. Additional experimental information required to conclude that a causal association exists is discussed, as are uncertainties associated with applying results from specific experimental designs to the question of whether infant formula should be supplemented with DHA.

The role of essential fatty acids in neural development: implications for perinatal nutrition

Article

May 1993

M A Crawford

The brain is 60% structural lipid, which universally uses arachidonic acid (AA; 20:4n−6) and docosahexaenoic acid (DHA; 22:6n−3) for growth, function, and integrity. Both acids are consistent components of human milk. Experimental evidence in animals has demonstrated that the effect of essential fatty acid deficiency during early brain development is deleterious and permanent. The risk of neurodevelopmental disorder is highest in the very-low-birth-weight babies. Babies born of low birth weight or prematurely are most likely to have been born to mothers who were inadequately nourished, and the babies tend to be born with AA and DHA deficits. Because disorders of brain development can be permanent, proper provision should be made to protect the AA and DHA status of both term and preterm infants to ensure optimum conditions for the development of membrane-rich systems such as the brain, nervous, and vascular systems.

Antioxidant adaptation: Its role in Free Radical pathology

Article

Jan 1985

.Omega EPA in bipolar disorder: report of an open-label study

Article

Jul 2005
J CLIN PSYCHIAT

Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.

The Brain that Changes Itself

Book

Dec 2007

Norman Doidge

Grown-up connections: Mice, monkeys remake brain links as adults

Article

Mar 2006
Sci News

Bruce Bower

Omega3 Eicosapentaenoic Acid in Bipolar Depression: Report of a Small Open-Label Study

Article

Jun 2005

Introduction: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. Method: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. Results: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. Limitations: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. Conclusions: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.

Diet and the geographical distribution of multiple sclerosis

Article

Nov 1974

BernardW. Agranoff

Data are presented to suggest that a geographical predisposing factor (G.P.F.) in multiple sclerosis (M.S.) may reflect regional dietary differences, and, further, that this factor is directly related to milk production or consumption. A number of biochemical hypotheses are proposed which would predict a resultant weakened blood-brain barrier or immunological defence, or the production of defective myelin, which would then increase susceptibility to the ætiological agent, possibly a virus. From the standpoint of brain development, two different ideas emerge—one, that differences in the composition of bovine and human milk, particularly during weaning, lead to the G.P.F.; the other, that drinking of milk beyond the normal nursing period is detrimental. More epidemiological studies are needed, with emphasis on diet, especially during periods of rapid brain development. Cow's milk may be an unfortunate substitute for human milk in infancy or a risky food source thereafter, or both. Epidemiological data raise these questions but do not provide ready answers. The milk correlation could be spurious, but at least ideas based on such a correlation pay attention to the most important epidemiological clue in M.S.—namely, the geographical distribution of the disease.