omega^3 dha and epa for cognition, behavior, and mood ... · ing, behavior, and psychosocial...

Alternative Medicine Review Voiume 12, Number3 2007

Omega^3 DHA and EPA forCognition, Behavior, and Mood:Clinical Findings and Structural-Functional Synergies with Cell

Membrane PhospholipidsParrisM.Kidd,PhD

Abstract

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

eicosapentaenoic acid (EPA) are orthomolecuiar. conditionaliy

essential nutrients that enhance quality of iife 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

furtherdiversifytheircurrentlywide range of clinical applications.

(AtternMed Rev 2007 •.12(3):207-221)

IntroductionThe 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 ofpremature death. They are orrhomolecules whose func-tional sites are exclusively cell membranes, wherein theyare structurally and functionally integrated via phos-pholipid molecules. Their confirmation as efficaciouscardiovascular protectants has spurred research intotheir benefits for the human brain. Tliis review focuseson their clinical roles in cognition, behavior, and moodand on their potentially synergistic interactions withthe cell membrane phospholipid nutrients.

Adequate dietiiry ;ivailabiUty of DHA andEPA is fundatnental to brain function. DHA/HPAare important throughout adulthood, as well as duringthe brain growth spurts that characterize prenatal andpostnatal development. Dietary supplementation withDHA and EPA has proven beneficial for many of theknown higher mental functions.

Parris M. Kidd, PhD - Cell biology; University of Califomia, Berkeley; ContributingEditor. Alternative Medicine Review: health educator; biomedical consultant tothe dietary supplement industry.Correspondence address: 10379 Wolf Drive, Grass Valley, CA 95949Email: [email protected]

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Alternative Medicine Review Volume 12, Number 3 2007

Amongthe proven brain benefits of DHA/EPAare the perinatal development of visual and other sensoryfunctions; perinatal emergence of cognitive function andmaintenance throughout lite; behavior management; andmood control (e.g., the mood swings of bipolar disorderor symptoms of major depressive disorder (MDD)). Tliesubstantial clinical evidence that supports these applica-tions is discussed in the sections that follow.

Oniega-3s in Childhood BrainDevelopment

During the last trimester of fetal life and thefirst two years of childhood, the brain undergoes a pe-riod of rapid growth - the "brain growth spurt."' Nu-trient insufficiency during this period can compromisebrain Rmction. DHA is one nutrient absolutely requiredfor the development of the sensory, perceptual, cogni-tive, and motor neural systems during the brain growthspurt.''' EPA's importance for the brain's developmentin utcro is unclear, but colostrum and breast milk con-tain EPA, albeit in lesser amounts than DHA.'*"

The fundamental importance of DHA forbrain development is beyond dispute.' The neuronsare continually forming axons and dendritic extensionswith accompanying cell membranes. Growing mem-brane must be relatively fluid, and DHA is the mostfluidizing element in cell membranes (discussed laterin this review). Even the synapses that are the primaryfunctional units of brain circuits are made from mem-branes preferentially enriched in DHA.^

Ilie retina, functionally an extension of thebrain, contains rods and cones with the most fluidmembranes of all the body's cell types; they are alsohighly enriched in DHA. Laboratory animals (rodents,primates) with experimentally induced omega-3 defi-ciencies show deficits in retinal structure, visual acuitydevelopment, and cognitive performance.^"^

Perinatal Importance of DHA and EPADemand 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 specialrisk for omega-3 insufficiency because rhey may nothave benefited from a full trimester of the mother'sHpid stores. Preterm infants have very limited ability to

synthesize DHA from the shorter chain alpha-linolenicacid (ALA; C18:3).-

After birth, omega-3 status depends on theinfant's innate lipid metabolism and dietary intake ofbreast milk or formula. Although DHA and EPA areprominent ingredients of breast milk, many infantformulas do not contain these nutrients. Supplement-ing the mother's diet with ALA is not a reliable meansfor obtaining DHA. In one study, lactating mothersreceived 10.7 g/day of ALA from flaxseed oil for fourweeks. Breast milk levels of ALA, EPA, and DPA (do-cosapentaenoic acid; C22:5 omega-3) increased, burnot that of DHA.^

All infants, whether preterm or fiill term, seemto require dietary DHA for retinal development andnormal visual fiincdon. A meta-analysis evaluated stud-ies on visual resolution acuity differences in healthy pre-term infants, either supplemented or not supplementedwith DHA.' Four prospective trials were included, pro-viding data from both behavioral acuity tests and visualevoked potentials. Intake of DHA was correlated withsignificantly better visual resolution acuity at ages twomonths and four months. In another meta-analysis, thissame research group found an advantage of DHA intakein fiiU-term infants up to four months post-birth.'"

McCann and Ames published an extensivereview of the evidence that DHA is important for thedevelopment of cognition and other normal brain func-tions.' Tlieir 258 references included meta-analyses,randomized controlled trials (RCT) on cognitive andbehavioral performance, studies with rodents and non-human primates, and breastfeeding studies. Within thelimits imposed by performance testing of infants andtoddlers, they concluded that:

O In animals whose brain concentrationsof DHA were severely reduced, dietarysupplementation with DHA restored controlperformance levels.

O Studies with human infants suggestsupplementation with DHA in formula or byboosting maternal levels enhances neuromotordevelopment.

O Application of a wide range of tests yielded apositive association between breastfeeding and infantmental performance.

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Although it is difficult to test cognitive perfor-mance within the first year, infants who were fed breastmilk or formulas with DHA were found (within a fewmonths after birth) to have superior visual acuity com-pared to those fed less than adequate DHA. Tliis supe-rior visual function persists through the first year afterbirth" and perhaps into the seventh year or later.'^

Treating Developmental CoordinationDisorder/Dyspraxia

The importance of DHA/EPA for overall brainand 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 fivepercent of school-aged children.'^ DCDs core motordeficits are often accompanied by difficulties with learn-ing, behavior, and psychosocial adjustment that ovetlapwith dyslexia and attention deficit/hyperactivity disor-der (AD/HD) and often persist into adulthood.

A double-blind RCT was conducted on 117children ages 5-12, using a mixed omega-3/omega-6supplement versus an olive oil placebo." The supple-ment was 8O'percent fish oil and 20-percent eveningprimrose oil, with a 4:1 omega-3 to omega-6 ratio. Thetotal daily dose provided 174 mg DHA, 558 mg EPA,and 60 mg omega-6 gamma-linolenic acid (GLA), plus9.6 mg d-alpha tocopherol. Although the trial foundno significant improvement in motor skills after threemonths, the researchers did report significant improve-ments in other areas.'' Tlie children who received theomega-3/omega-6 supplement showed three timesthe normal expected gain in reading skills and twicethe normal gain in spelling competency, plus markedimprovement in behavior. The children who receivedthe olive oil placebo were switched to the omega-3/omega-6 supplement after three months and after threemore months showed similar"catch-up gains.

Other developmental brain disorders in chil-dren such as A D / H D and dyslexia overlap with DCD/dyspraxia and are also linked to apparent DHA/EPAdeficits. Many of these children respond to oral supple-mentation of these nutrients, often administered withother nutrients as part ofa comprehensive managementregimen.''"^

Managing Attention Deficit/HyperactivityDisorder

A D / H D is the most common childhood de-velopmental disorder, with prevalence estimates rangingfrom 4-15 percent for school-age children in the UnitedStates and elsewhere (see Richardson, 2006 for a re-cent review ' ). Often A D / H D persists into adulthood.Considerable damage to the individual, family, and so-ciety can be exacerbated by co-morbidity with manyother disorders of behavior, learning, or mood.''' "' AD/H D children consistently exhibit abnormal fatty acidstatus.'*'

Several studies have reported reduced bloodconcentrations of highly unsaturated fatty acids (FAs)in A D / H D children compared to controls (reviewedby Richardson "). Typically, reductions have been foundin DHA and total omega-3 FAs and in the omega-6arachidonic acid (AA)," some of which may persistinto adulthood.'" In one study that included both AD/H D and non-AD/HD boys, low omega-3 levels wereassociated with a range of behavioral and learning prob-lems, irrespective of the clinical diagnosis.'*" Whereaslow blood omega-6 levels tend to correlate with somephysical deficiencies, but not with cognitive or behav-ioral impairments, omega-3 deficiencies correlate withbehavioral problems (conduct disorder, hyperactivity-impulsivity, anxiety, temper tantrums, sleep difficulties)and learning difficulties in children. Thus Richardson,in her insightful review, emphasized,"...omega-3 statusis likely to be more relevant to A D / H D and related be-havioral disorders."''

Clinical evidence from controlled trials, openstudies, and case reports has yielded mixed results fromDHA/EPA supplementation in A D / H D and its co-morbid conditions. In 2001, a double-blind RCT ofomega-3 FAs was conducted on A D / H D children.'^The 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. They received dailyadjunctive treatment of 345 mg pure DHA (from al-gae) or placebo. At the end of the four-month study, nochanges were found on behavioral ratings or measuresof inattention and impulsivity.

Similar negative findings came from a two-month, double-blind RCT of 40 AD/HD-type childrenages 6-12 years in Japan.'" Children were randomized

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ro 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 agreater reduction of aggression in the DHA

A third double-blind RCT was conducted atIndiana's Purdue University on children with primar-ily AD/HD-type difficulties.^^ Fifty children (aver-age age 10 years) were randomized to receive either anomega-3/omega-6 formula from fish oil plus eveningprimrose 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 Their Metabolites

Omega-3 Fatty Acids

alpha-linolenic acid(flax, chia. hemp)

< • • A 6-desaturase

stearidonic acid(black currant oil)

(cofactors - B3. S6, Mg. Zn, Vit C)Enzyme inhibited by alcohol,

trans tats, diabetes.hyperinsuiinism.

eicosatetraenoic acid

elongase(condor - B6)

1 -SeriesProstaglandins &Thromboxanes

eicosapentaenoic acidEPA

(fish, krill)

t l

A 5-desaturase(cotactors - S3, Zn. Vit C}

cyclo-oxygenase-lipoxygenase

docosapentaenoic acidDPA

!i3-Series

Prostaglandins &Thromboxanes,

5-SeriesLeukotrlenes

Omega-6 Fatty Acids

iinoleic acid(sunflower, safflower, corn)

Igamma-linoienic acid

GLA(borage, black currant, evening

primrose)

••}>

dihomo-gamma-iinolenicacid - DHGU\

arachidonic acid(meat, eggs, dairy)

2-SerJesProslaglandins &Thromboxanes,

4-SeriesLeukotrienes

< • •

docosahexaenoic acidDHA

(fish, krill algae)

elongase

docosanoidsoids 1

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Alternative Medicine Review Voiume 12, Number 3 2007

alpha-tocopheryl acetate) or an olive oil placebo for fourmonths. Significant benefits were found for attentionand behavior and on clinical ratings of oppositional de-fiant disorder.

In 2002, Richardson and Puri published ;idouble-blind RCT of 29 United Kingdom childrenwith a primary diagnosis of dyslexia and secondaryAD/HD-rypc symptoms.'^ Half the children receivedan omega-3/omega-6 combination with 480 mg DHAand 96 mg GLA as in the Purdue formula above, butwith EPA higher at 186 mg, AA slightly higher at 42mg, the omega-6 cis-linoleic acid at 864 mg, 60 IU vita-min E as dl-alpha tocopherol, and 8 mg thyme oil. Theother half of the children received an olive oil "placebo"for three months. Tlie omega-3/omega-6 combinationproduced significantly greater benefits than the oliveoil for inattention, anxiety/withdrawal, and disruptivebehavior. The authors noted the olive oil placebo couldhave contributed some benefit and that use ot a trulyinert placebo might have yielded a better overall trialoutcome.

Tlie shorter-chain ALA may not be as effectivefor A D / H D as DHA/EPA plus GLA. Thirty adultswith A D / H D were randomized to supplementationwith a large dose of 60 g/day of flaxseed oil, olive oil,or fish oil.-'' Serum phospholipid fatty acid status wasdetermined at baseline and 12 weeks. Althotigh flax-seed oil supplementation increased ALA levels of bloodphospholipids, levels of EPA, DHA, and other ome-ga-3 fatty acids were not increased; fish oil predictablyincreased EPA, DHA, and total omega-3s.

Thus, it appears a mix of DHA, EPA, andomega-6 fatty acids (GLA and AA) can improve theattention, learning, and behavioral afflictions typicalof AD/HD, as well as co-morbidities such as anxiety/withdrawal, dyslexia, and aggression. There are numer-ous reports of low plasma and/or RBC omega-3 levelsin A D / H D children and adults.'^ Recently, a specificgene polymorphism was discovered that is linked toclinical A D / H D and features suboptimal functioningof fatty acid desaturase enzymes.^^ Figure 1 illustratesthe biosynthesis of the primary omega-3 and -6 fattyacids.

Ameliorating AggressionHamazaki et al performed two double-blind

trials with students clinically diagnosed as aggressive.In the 1996 trial,-*' 41 university students ages 21-30were 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 A A or control capsules of soy oil.The three-month trial was timed to end in the middleof the mental stress of challenging final exams. TheDHA group demonstrated no increase in aggressionduring this stressful time; whereas, the control groupdemonstrated significant increases in aggression againstothers (extra-aggression). The researchers concludedDHA helped prevent extra-aggress ion from increasingat times of mental stress.

In 2005, the same research team conducted athree-month, double-blind trial on aggression involv-ing 166 children ages 9-12 years.^^ The children re-ceived either omega-3 fortified foods that provided 3.6g DHA and 0.84 g EPA per week or control foods withhalf soybean and half rapeseed oil. Physical aggressionas assessed by a hostility-aggression questionnaire in-creased among girls in the control group but not amongthe girls who received omega-3s. Impulsivity was alsosignificantly reduced among the omega-3 girls; no suchdifferences were observed among the boys.

Clinical Experience with AutismThe emergent rationale for employing DHA/

EPA for autistic spectrum disorder (ASD) and otherpervasive developmental disorders (PDD) dates to2001, with case histories provided independently bytwo research groups.^^ Vancassel et al reported lowDHA (measured in plasma phospholipids), 20-per-cent lower-than-normal total omega-3s, and normallevels of omega-6 EAs in ASD children.^' Bradstreetand Kartzinel reported finding omega-3 fatty acid de-ficiencies in nearly 100 percent of ASD cases. ' llienin 2002, Hardy and Hardy claimed that, of 50 childrendiagnosed with PDD, 90 percent were deficient in RBCmembrane DHA/EPA.^' \Airious integrative physiciansworking with ASD and PDD patients have integratedDHA 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.

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aggression, and self-injurious behavior.^^ Interventionwas 1.5 g/day DHA/EPA (700 mg DHA and 840 mgEPA) or placebo. Tlie DHA/EPA was well toleratedand there was a trend toward significant improvementover placebo for hyperactivity. The clinicians reportedthe small number of subjects may have statistically un-dermined the apparent clinical effects of the DHA/EPA.

Support for Adult CognitivePerformance

Tlie brain's reliance on DHA/EPA continuesthroughout adult lite. New research on primates androdents has documented the adult brain cortex under-goes highly active synaptic turnover throughout life.""Iliis finding has helped drive a paradigm shift in un-derstanding brain plasticity. Tlie new paradigm is oneof high brain plasticity and adaptability."*'' It recog-nizes remarkable clinical observations on brain recoverytollowing damage," and relates this to rates ot synap-tic turnover as high as 350 percent per year observedin mammalian brains."'^ The central role tbat DHAplays in perinatal brain development may continue intiie highly dynamic, healthy adult brain.

DHA and EPA Improve CognitivePerformance in Healthy Subjects

DHA and EPA are orthomolecules {moleculesorthodox to the body) as defined by Pauling.''' Thereis evidence that healthy individuals can expect cogni-tive benefit from orthomolecular medicine, includingDHA/EPA.

Fontani et al conducted a double-blind RCTon 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 golive oil as placebo; dietary modificarions were insti-gated via advice from a dietician. Subjects completeda mood questionnaire and took attention tests, andphysiological recordings (electroencephalogram/EEG,electromyogram/EMG) were made at baseline and onday 35. "Ilie DHA/EPA group improved significantlyover placebo on several mood parameters: vigor, anger,anxiety, fatigue, depression, and confusion. Measures ofattention 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 onphysiological measures that correlated with the testfindings. Reaction time was significantly improved, asmeasured by EMG. The EEGs, which are typically hardto interpret, demonstrated the high-frequency beta-2band was significantly reduced and tbe low-fiequencytheta and alpha bands were increased. The researcherstentatively interpreted these changes as consistent withomega-3 support for"direct action...on the central ner-vous system" leading to improved cortical fi.mction.*''They concluded that DHA/EPA supplementation canimprove higher brain fiinctions - sense of wellbeing(vigor), reactivity, attention, cognitive performance, andmood - in young, healtby adults."'

DHA/EPA Intake May Lower DementiaRisk

Spanning at least the past decade, epidemio-logical studies indicate relatively high DHA and EPAintake is linked to lower relative risk of dementia inci-dence Of progression. In 1997, Kalmijn et al reportedon the Rotterdam Study.'' in this longitudinal cobortstudy, 5,386 participants ages 55 or older were screenedfor dementia. Dietary habits were evaluated using asemi-quantitative food frequency questionnaire andthen re-evaluated after 2.1 years. Fish consumptionwas inversely related to dementia incidence (RR=0.4,95% CI=0.2-0.9), and more specifically to the risk ofdeveloping Alzheimer's disease (AD) (RR=0.3, 95%CI=0.1-0.9).

Tliat same year (1997) yielded a report ofthe Zutphen Elderly Study, a smaller study also con-ducted in The Netherlands by Kalmijn's group. ' Iheyevaluated 476 men, ages 69-89 at baseline, performingcognition testing and correlating the data with foodintakes reported in dietary histories. At baseline, highfish 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% CUO.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-3fatty acids was not associated with increased risk for

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dementia.''' By contrast, a later analysis (after five years)of the Zutphen Elderly Study data confirmed the earlierfinding, with consumers offish showing a statistically sig-nificant (p<0.01) decrease in cognitive decline.""' Therewas a linear relationship between DHA/EPA levels andcognitive 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 withmen who consumed an average of only 20 mg/day.

Taken at face value, this finding could suggestthe range of DHA/EPA intakes currently recommend-ed to reduce cardiovascular risk may be sufficient tohelp slow mental decline. The American Heart Associa-tion currently recommends a minimum of 57 mg/dayDHA/EPA for healthy people (a total of 400 mg/weekfrom two fish meals); a minimum of 1,000 mg/day forcardiovascular protection in patients with documentedcoronary 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, 815residents ages 65-94 were evaluated via a self-reportedfood questionnaire and tracked for an average 3.9 years."*A total of 131 participants developed AD. Those whoconsumed a fish meal once weekly had a statisticallysignificant 60-percent decreased risk of Alzheimersdisease, compared with those who rarely or never atefish (RR^O.4, 95% CI=0.2'0.9). Total omega-3 intakeand DHA intake, but not EPA intake alone, were sig-nificantly associated with this lessened Alzheimer risk.This suggests an intake of as little as 30 mg/day DHA/EPA from fish might confer more protection againstcognitive decline than eating no fish at all.

A follow-up of this community study at sixyears found fish consumption (one or more meals perweek) resulted in a 10- to 13-percent slower rate of cog-nitive decline. There was no persuasive evidence for amore specific association with either DHA or EPA.""

In another longitudinal cobort study, serumphosphatidylcholine-DHA (PC-DHA) levels of 1,188elderly Americans (average age 75 years) were analyzedat baseline and 10 years later.'' Those in the lower halfof the distribution of DHA levels at the time the firstsample was taken, but who did not have AD at that time,appeared to have a 67-percent greater risk of developingAD 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, acohort of 899 men and women (median age 76 years),who were free of dementia at baseline, were followed fora mean 9.1 years for development of all-cause dementiaand Alzheimer's disease; the findings were published in2006.''" Ninety-nine new cases ot dementia (including 71of AD) occurred. Baseline and follow-up blood sampleswere tested for fatty acids in the plasma phospholipidfraction. After controlling for other variables, subjectsin the upper quartile of plasma F*C-DH A levels had ap-proximately half the relative risk of developing all-causedementia (RR=0.53, 95% CI=0.29-0.97; p=<0.04)compared to subjects in the three lower quartiles. Theupper quartile (n=488) had a mean DHA intake ot 180mg/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 agecan make an individual more vulnerable to dementia inlater life. Experts agree tbat once accelerated cognitivedecline 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 tested1,613 subjects, ages 45-70, for various cognitive func-tions at baseline and after five years and correlated theresults with habitual food consumption reported on aself-administered food questionnaire.'' Subjects exhib-iring che most impaired cognitive function (lowest 10percent of the group score) also had the lowest intake ofDHA/EPA or fatty fish. Overall cognitive performanceand psychomotor speed were positively correlated withDHA/EPA status. High intakes of cholesterol andsaturated fat were both linked to increased cognitiveimpairment in this middle-aged population.

From 1987-1989, the Atherosclerosis Risk inCommunities Study analyzed plasma fatty acids in cho-lesteryl esters and phospholipids in 2,251 residents ofMinneapolis, Minnesota.*** Subjects, average age 57 atbaseline, all had some degree of heart disease.'*^ Thenfrom 1990-1992 and 1996-1998 the participants weretested for word recall, psychomotor speed, and verbal

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fluency. Higher plasma omega-3 FA levels were cor-related with reduced risk for decline in verbal fluency,particularly in bypertensive subjects and subjects withdyslipidemias.

The outcome of this study prompted an edi-torial in the American Journal of Climcal Nutrition.^'^Connor and Connor pointed out that the brains ofAD patients have a lower content of DHA in the graymatter (more active zone), compared with individualswithout Alzheimer's disease at death. They suggest di-etary DHA entering the brain could correct DHA in-sufficiencies in cerebral cortical cell membranes. Theyalso hypothesized dietary EPA could help counterpro-intlammatory processes contributing to neurode-generation. The authors called for more clinical trials ofomega-3 FAs in older adults at risk of cognitive declineand eventual dementia.

Mild cognitive impairment (MCI) is currentlythe condition most predictive for subsequent progres-sion to dementia. MCI features severely impaired mem-ory witbout substantial loss of other cognitive functions.Approximately 10-15 percent of MCI subjects progressto dementia witbin a year of diagnosis."*^ Individualscognitively impaired but not demented tend to have ab-normally low blood levels of DHA and EPA.^"

A research group in Japan included MCIsubjects in their prospective clinical trial on fatty acidtherapy for memory-impaired patients. As background,Kotani et al determined experimental animals (rodents)sbow age-dependent increases in the peroxidativebreakdown products from polyunsaturated fatty acids,notjust of omega-3 DHA but also of omega-6 AA.*"' Ina double-blind trial both these fatty acids were admin-istered to a patient pool that included 21 with MCI, 10with organic brain lesions, and eight with Alzheimer'sdisease. For 90 days, patients received either 240 mg/day DHA and AA (ratio not specified) or a 240 mg/dayolive oil placebo. DHA and AA significantly benefitedthe MCI group compared to placebo on both attentionand memory, while the organic brain-lesion group im-proved on memory alone; the AD group did not showbenefit.^'

Treating Dementia with DHA/EPADespite the fact abnormally low blood phos-

phoIipid-DHA levels are found in patients with AD orother dementias,'" until recently few prospective trialshad been conducted on DHA/EPA for dementia, andoutcomes were inconclusive.

In 2006, a team from Stockholm's KarolinskaUniversity Hospital published a double-blind RCT ofDHA and EPA for !74 patients with mild-to-moder-ate Alzheimer's disease.'^ Patients received either 1.7 gDHA and 0.6 g EPA daily or a placebo for six months,after which all received tbe DHA/EPA supplements forsix more months. After the first six months, decline incognitive function did not differ between groups. How-ever, in a subgroup with less severe cognitive dysfunc-tion (Mini-Mental State Exam score >27 points), asignificantly 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. These findings suggest patients withmild Alzheimer deterioration could benefit from tak-ing a mixed dietary supplement formulation containingboth DHA and EPA.

In 2007, the Karolinska group reported spe-cifically on the neuropsychiatric outcomes of the abovetrial.'' The researchers found no overall treatment effecton neuropsychiatric symptoms, activities of daily living,or caregiver burden. Tliey did find significant improve-ment of agitation in apolipoprotein E4 (APOE4) car-riers and improvement of depression in non-APOE4carriers.

Multiple sclerosis (MS) patients can exhibitdementia as a co-morbid condition, especially as the dis-ease progresses. The etiology of MS and the prospectsfor its integrative management were reviewed in 2001.^''Six decades ago. Swank designed a fat-restricted dietwith similarities to a modern omega-3 enriched diet.Swank developed this innovative diet after noticing tbatcoastal Norwegian residents consuming more fish andless animal fat had lowered risk for MS.^' Beginning in1948, Swank's patients were instructed to restrict ani-mal fat intake and supplement liberally with cod liveroil (5 g/day); margarine and otber hydrogenated oilswere not allowed. Swank also encouraged three fishmeals 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 lowerrate of progression to advanced MS.

In 1988, Swank reviewed 150 of his patientsfollowed for over 35 years.'*' Death rate was 31 percent,compared to the 80-percent predicted for MS patientsnot maintained on a diet. Of patients who commencedthe restricted diet prior to developing disability, 95 per-cent had not progressed after three or more decades ofbeing on the diet.

Other MS researchers published epidemiolog-ical evidence that, between 1949 and 1967, 20 countriesincluding the United States had increased MS mortal-ity risk associated with animal fat intakes and loweredrisk with diets relatively high in fish and vegetables.'^

Huntington Disease: EPA ShowsPromise

Huntington disease (HD) features abnormalmultiplication of a specific DNA sequence on chromo-some 4: cytosine-adenine-guanine (CAG). Healthypeople have just one CAG sequence at this spot; peoplewith HD can have several dozen CAG sequences. Asa rule, the more CAGs the HD patient has, the moresevere their disease. Tlie pathogenesis trom genome tosymptomatology is still poorly understood. On a suspi-cion that certain omega-3 responsive pathways could beinvolved, a team of British researchers have been usingpurified 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 receivedethyl-EPA demonstrated improvement on the orofacialcomponent of the Unified Huntington Disease RatingScale, while the three placebo patients had deteriorated(p<0.03). MRI brain scans revealed the placebo wasassociated with progressive cerebral atrophy and ethyl-EPA was associated with beneficial changes.

Three years later, the group completed a multi-center, double-blind RCT^^ A total of 135 Huntingtonpatients received either 2 g/day ethyl-EPA or placebo.Tlie primary endpoint was the score at 12 months onthe Total Motor Score 4 (TMS-4) subscale. The ethyl-EPA group as a whole failed to show statistically signifi-cant improvement on TMS-4. A subgroup includingpatients with fewer CAG showed significantly betterTMS-4 improvement.*""

The secondary endpoints in this trial suggesteda significantly worse outcome from ethyl-EPA in behav-ioral severity and frequency compared to placebo.''' Thisfinding raises the question of whether a mixture ot HPAand DHA, rather than a purified EPA, might have beenmore effective for this intractable disease.

Established Benefits in AffectiveDisorders

Numerous studies have examined the effects ofDHA/EPA for affective disorders and have found themto be beneficial for mood management. Mood disordersthat apparently respond to DHA/BPA include majordepressive disorder, manic depression (bipolar disor-der), and possibly also schizophrenia, borderline per-sonality disorder (BPD), and anorexia nervosa.

OmegaS Eatty Acids for DepressionAs of mid-2007 (July), the peer-reviewed lit-

erature yielded seven double-blind RCTs of omega-3fatty acids for MDD (summarized in Sontrop andCampbell^' and Nemets et al"). Of these, six reportedclinically significant benefits, including a trial with de-pressed children ages 6-12 years.^'' These trials admit-tedly were heterogeneous in size, design, and rationale,but from them a few trends emerged;

O DHA taken without EPA may not be sufficientto improve major depression.

O EPA taken without DHA sometimes givesbenefit.

O The highest dosage of HPA did not necessarilyyield the most benefit. In one double-blindtrial, Peet and Horrobin^* used a "dose-ranging"design, giving only EPA (as ethyl-EPA) at lg/day, 2g/day, or 4g/day tor 12 weeks, in addition tounchanged medication. Tlic group receiving lg/daydemonstrated the most improvement, with morethan half (53%) achieving a 50-percent reduction onthe Hamilton Depression Rating Scale.

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Maternal postpartum depression (also called"perinatal depression") has been linked to omega-3 FAdeficiency. As reviewed in Freeman,*^ a survey of moth-er's milk in 23 countries determined that lower DHAcontent or lower seafood consumption was associatedwith higher rates of postpartum depression. Freemannoted that pilot trials of supplementation with DHAand EPA have produced mixed results and called forlarger and better-designed trials to resolve this condi-tion that endangers both mother and child.

Promise for Bipolar DisorderBipolar disorder (BD) with its complex spec-

trum of symptoms is likely associated with neural cellmembrane dysfunction, most likely signal transductionabnormalities. A comprehensive 2004 review of integra-tive management of BD examined the extensive data formembrane abnormalities in BD and suggested supple-menting with DHA/EPA as part ot an integrative med-ical regimen.^^ Several case reports suggest flaxseed oilmay trigger manic episodes in BD, a predilection firstreported by Rudin in 1981.''^

To date, tour published double-blind trialson DHA/EPA for BD have been published. The firstwas a 1999 trial that found significantly longer remis-sion of bipolar symptomology trom a high-dose DHAand EPA mixture (9.6 g/day) compared to placebo.^^Three more double-blind trials were published in 2006with differing results. In the largest trial (75 patients),Frangou et al found significant improvement using EPAonly (ethyl-EPA), with 1 g/day working just as well as2 g/day."^ Keck et al found no significant ditferences be-tween placebo and 6 g/day EPA (no DHA) in 61 pa-tients.'''' Marangell et al conducted a small study on 10patients using only DHA and reported only that DHAwas "well tolerated."™

A 2005, open-label trial, using EPA at 1.5-2.0g/day as "add-on" therapy for BD, tound that eight of 10patients improved at least 50 percent on the depressionscale.' riiis finding is in line with Frangou's double-blind trial outcome cited above."" In another open-labeltrial, children ages 6-17 years demonstrated a modestimprovement in mania with intakes of 1.3-4.3 g/dayDHA/EPA for eight weeks." Taken altogether, theexisting trials of DHA and EPA tor bipolar disordersuggest efficacy, especially for the depression phase, with

EPA appearing to be the most efficacious of the two.The levels of seafood intake per capita in vari-

ous countries of the world roughly correlate with tberespective prevalence rates of BD in community sam-ples. ' The greater the seafood consumption per capitain a country, the lower the prevalence of bipolar spec-trum disorders. Countries that consume a lot of fish onaverage (e.g., Iceland, Korea, and Taiwan) have relativelylow incidence, while countries that consume very littlefish (e.g., Germany, Switzerland, and Hungary) have upto seven times the incidence of countries with high fishintake. Noaghiul and Hibbein estimated a'Vulnerabilitythreshold" for BD at seafood consumption below 50pounds of seafood/person/year.'^'

In 2006, participants in the Omega-3 FattyAcids Subcommittee, assembled by the Committeeon Research on Psychiatric Treatments of the Ameri-can Psychiatric Association, published an extensiveassessment of the available data on the clinical use ofomega-3 fatty acids in the prevention and/or treatmentof psychiatric disorders.^'' This report included meta-analyses of RCTs conducted with DHA and/or EPAfor major (unipolar) depression and bipolar depres-sion. These meta-analyses found statistically significantbenefit (p=0.02) from EPA and EPA/DHA. Tlie Sub-committee found less persuasive evidence for benefit inschizophrenia.

Trials in SchizophreniaCurrently, six double-blind RCTs with DHA/

EPA have been conducted, involving 390 patients withschizophrenia or schizoatfective disorder. Four of thesedocumented clinical benefit from 2/g EPA daily torthree months.'"'"'* One trial found high-EPA fish oilperformed better than high-DHA fish oil or placebo/''Another dose-ranging trial of ethyl-EPA found 2 g/dayworked better than 1 g or 4 g daily. Two trials by thesame group examined ethyl-EPA's etfect on tardive dys-kinesia associated with pharmaceutical management ofschizophrenia. 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 tbe lower dose of 2 g/day.'**

A "phospholipid membrane hypothesis ofschizophrenia" emerged in tbe late 1970s, as reviewedin 2000 by Fenton and colleagues.'' This hypothesisencompasses abnormalities of long-chain omega-6 fatty

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acids such as AA, as well as the omega-3 FAs DHAand EPA. Fenton et al list multiple analyses of RBCmembranes (recognized markers for essential fatty acidstatus) that consistently document depletion of AA,DHA, and EPA. Also noted were studies documentingdepletion in plasma, thrombocytes, and post-mortembrain tissue of schizophrenia patients.^^

Elevations of membrane phospholipase A2activity (measured in platelets) have been reported inschizophrenia, consistent with elevated membraneturnover of fatty acids.''^ These findings are reminiscentof the systemic membrane abnormalities observed in bi-polar disorder.''^

Perhaps the most compelling evidence so farof membrane abnormalities in schizophrenia are thefindings from noninvasive nuclear magnetic resonance(NMR) procedures (summarized in Fenton et aP) .These data suggest elevated membrane phospholipidbreakdown products in the brain at an early stage of theillness and reduced levels of membrane phospholipidprecursors. DHA and EPA are first-line nutrients forrepairing damaged membranes and initial RCT out-comes suggest they deserve further study for the schizo-affective spectrum.

Cell membrane dysfunction is just part otan impressive body of evidence that strongly suggestsschizophrenia is related to other affective disordersacross a pathologic continuum. Striking genetic, symp-tomatic, and pathophysiological overlaps suggest thecontinuum to be unipolar (major) depression==>bipolardisorder=>schizoaffective psych osis^^schizoph re nia.'''"Although the degree of benefit or dosing strategy is notyet conclusive, findings that DHA and EPA have pro-duced benefits for major depression, bipolar disorder,and schizophrenia justify their inclusion in a treatmentprotocol for affective disorders.

Borderline Personality DisorderBorderline personality disorder may also

respond to omega-3 supplementation. In a double-blind, placebo-controlled trial, 30 female subjectswith moderately severe BPD received 1 g/day EPAonly (as ethyl-EPA) or a placebo for two months.Those taking ethyl-EPA experienced significantly di-minished aggression and less severe depression.^"

Figure 2. Cell Membrane Schematic, Demonstrating the Intrinsic Structural Synergy ofits Fatty Acids, Phospholipids, and Antioxidants ("Triple Cell Membrane Synergy")

Phospholipids

Fatty acids

Antioxidants

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Alternative Medicine Review Voiume 12, Number 3 2007

DHA/EPA Support Cell Membranes,the Pacemakers of Metabolism

What are some of the mechanisms involved inrhe diverse therapeutic applications of omega-3 fattyacids? DHA and EPA literally feed cell memhranes,the dynamic structures that manage the vast majorityof life processes. Almost all the pivotal life processes oc-cur in, on, or attached to membranes.'"*' Membranes areliterally the pacemakers ot metabolism - a high meta-bolic rate correlates with high membrane unsaturationamong vertebrate species."^ Increasing unsaturation en-ables improved fluidity and more versatile cooperationbetween the"sea" of lipids in the membrane and the pro-teins immersed in this medium. Within the membrane-as-pace maker, the polyunsaturated fatty acid contentaffects fluidity to enable the myriad membrane-boundenzymes, receptors, transporters, and other catalyticmolecules.

Within the membrane bilayer, DHA and EPAare attached to the larger pliospholipid 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 tattyacids in the membrane bilayer - saturates, monoun-saturates (omega-9s), and polyunsaturates (omega-6s,minor omega-3s) - and membrane fluidity is a net out-come ot all the electron densities. Carbon-carbon doublebonds have high electron density and impart fluidity tothe membrane. Tliis property renders DHA (six doublebonds) and EPA (five double bonds) the most highlyfluidizing of the major membrane fatty acids."'

As a rule, the more tluid a membrane the moreefficient its biochemical performance.**" In general, ex-perts agree the advanced human cell is only as efficientas its membrane system.*'"" Tliis life principle suggeststhat having adequate levels of DHA and EPA in mem-brane systems is crucial to the survival, growth, renewal,and myriad functions ot human cells.

Relative Functional Significance of DHA,EPA, and ALA

Tlie DHA and EPA content of cell mem-branes reflects ongoing dietary intakes. As dietary in-takes change the membrane profile changes. Withinthe membrane, micro-distributions of the fatty acids

attached to phospholipids are continually being finetuned by enzymes (acyltransferases) that remove themfrom the tails of certain phospholipids and relocatethem toothers."*

Probably due to their highly fluidizing proper-ties, DHA and EPA are found in highest concentrationsin the most dynamic membranes (e.g., retina, brain, andspermatozoa). Beyond conferring membrane fluid-ity, DHA and EPA are orthomolecules that contributeto the homeostatic regulation of tissue performance,renewal, and regeneration. On the other hand, ALA isnot found in high concentrations in cell membranes.

DHA and EPA can provide a degree of bio-chemical backup for each other. Although EPA may notbe readily torward-converted to DHA, DHA is readilyback-converted to EPA.^ The limitations imposed bythe poor conversion of ALA to either EPA or DHA,and by the sluggish conversion of EPA to DHA, sug-gest that intake of pretormed DHA is needed to assureadequate supply to the brain, cardiovascular system, andother organ systems.

DHA/EPA Influence InflammatoryBalance

Eicosanoids are by definition metabolites offatty acids. Healthy, non-inflammatory eicosanoid bal-ance is maintained throughout the body by way ot a ho-meostatic balance between omega-3 and omega-6 fattyacids in cell membranes. Eicosanoid balance then exertsa "downstream" balancing influence on cytokines (smallprotein messenger molecules). Ot the omega-3 FAs, theshorter chain ALA is rarely found in cell membranesand has no identitiable metabolites that might contrib-ute to homeostatic balance. Both DHA and EPA, onthe other hand, are precursors of metabolite messengermolecules that have wide ranging physiological effi cts.

In the context of the modern human lifestyleand diet, the eicosanoid metabolites ot HPA are crucialto provide anti-inflammatory etFects by balancing thepotentially pro-inflammatory eicosanoid metabolitesof the omega-6 AA. It is important to stress that AAmetabolites are not inherently dangerous to health, norare they"bad" fatty acids. Rather, the organism requiresAA for systemic homeostasis, and at higher dietary lev-els than omega-3 FAs. Untortunately, modern dietary

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patterns de-emphasize omega-3 intakes while over-em-phasizing intakes of omega-6s and other fatty acids lessimportant to homeostasis and total health.

The relatively"bad" factor in this scenario is thechronically unbalanced state of the standard Americandiet (SAD). The 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-brty ac-ids, produced through hydrogenation and unnatural tocell membranes; or (3) a large imbalance of omega-6 toomeg3-3 FA intake, due to consumption of meats raisedin feedlots rather than grass fed on the open range (meatfrom grass-fed cows has higher levels of omega-3 FAs).As a consequence, individuals who subsist on the SADare at heightened risk for pro-inflammatory events thatfoster degenerative disease.

Simopoulos concluded from anthropological,epidemiological, and molecular-level studies that hu-mans evolved on a diet witb a ratio of omega-6:omega-3FAs close to 1:1; whereas, in today's Western diets theratio ranges from 15:1-17;1.'*^ Simopoulos is part of agrowing chorus against the SAD, asserting a prepon-derance of dietary omega-6 FAs predisposes tissues toinflammation and subsequent pathology.

In addition to such "acquired" dietary imbal-ances that lessen omega-3 intakes, the healthy humanorganism has limited capacity to elaborate the long-chain DHA and EPA from shorter-chain precursors.Metabolic biochemists have calculated that five percentor less of dierary ALA is converted to EPA, and lessth:in 0.5 percent of dietary ALA makes it to DHA.'*'One approach to bypassing this problem could be tomarkedly increase the dietary intake of ALA. However,a study with Iactating women found that high dietaryALA (10.7 g/day tbr four weeks) did not raise DHAlevels in breast milk or

Docosanoids: Protective DHA MetabolitesDHA in the membrane is a source of metabo-

lites with a novel stereospecificity unHke that of theknown eicosanoids. Aptly christened docosanoids, theyare chemical messengers with potent anti-inflammatoryand other protective actions.'*'' The three known classesof docosanoids - docosatrienes, resolvins, and protec-tins - are produced mainly from controlled oxidativebreakdown of DHA within (or possibly adjacent to)

the membrane. Of the protectins, neuroprotectin D l(NPDl) is generated during stroke and counteractspro-inflammatory gene expression that normally resultsfrom ischemic damage. Tliis messenger substance alsocounteracts potential oxidative damage to DNA in theretinal pigment epithelium cells.'"''^

Current research is focused on another classof docosanoid messengers, the resolvins. As theirname implies, these molecules help resolve (terminate)ongoing inflammatory cascades.'''" Inflammation thatterminates on a timely basis is homeostatic - and de-sirable. However, metabolic insults and imbalances canoften prolong inflammation and trigger pathology. Thephysiological resolution of a well-orchestrated inflam-matory response is essential to maintain homeostasis,and resolvins appear to be involved in this process.

The broader scientific literature on DHA con-firms it is essential tor normal neurological develop-ment, maintenance ot learning and memory, and brainplasticity. DHA in neuronal membranes enhancessynaptic membrane fluidity and function, regulatesgene expression, mediates cell signaling, and enhancesthe electrical basis for memory formation.""' hi labora-tory rats subjected to traumatic brain injury, prior di-etary supplementation of DHA enhances recovery andboosts brain production of brain derived neurotrophicfactor (BDNF), a major brain growth factor."'' Tliis ar-ray of protective and homeostatic activities, workingin harmony with EPA, helps explain the wide range ofwhole-body benefits achieved by both.

Orthomolecular Synergy of CellMembrane Nutrients

DHA and EPA have an obvious and predict-able synergy with other cell membrane nutrients, spe-cifically phospholipids and antioxidants. Depending onthe requirements of the tissue in question, the phos-pholipids pbosphatidylserine (PS), phosphatidyletha-nolaminc (PE), and PC can carry substantial amountsof DHA in their"tair positions, especially tail position2. These phospholipid "parent molecules" also anchorEPA within the membrane.*"

Healthy cells have a complement of antioxi-dants within their membranes that help protect themfrom destruction by intrinsic oxidants (obligatorily gen-erated during routine metabolism) or extrinsic oxidants

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imposed by lifestyle or the environment.*" Membraneantioxidants are structurally intermingled with fatty ac-ids and function as a protective "first line of defense.""'In rhe presence ot antioxidants, tatty adds with themost unsaturated bonds, namely DHA and EPA, areprotected against oxidative ("tree radical') destruction.Tlius, within the dynamic membrane milieu, DHAand BPA exist in homeostatic synergy with both theirparent phospholipids and the antioxidants dispersed inthe membrane lipid bilayer, providing "triple cell mem-brane synergy." Ihus, in addition to protective antioxi-dants, supplements that deliver DHA and EPA boundto phospholipids - such as omega-3s bound to phos-phatidylserine and krill oil that contains omega-3 FAsboimd to phospholipids - provide the building blocksfor healthy cell membranes.

Omega-3 Phosphatidylserine (Omega-3PS)

Phosphatidylserine is an important brain nu-trient. At least 25 RCTs (reviewed in a recent book"* ),conducted over more tban two decades, have establishedPS is beneficial tor declining memory, learning, othercognitive functions, and mood and stress management.PS supports brain energetics and, at the tissue level,supports the receptors tor many chemical transmittersystems. Neuron cell membranes, which are especiallyrich in PS, contain DHA in a proportion of the PSmolecules (Figure 3).

Omega'3 PS Benefits AD/HDVaisman et al reported on a double-blind trial

with omega-3 PS for AD/HD.'^' They recruited 60children (3:1 ratio of boys:girls) with AD/HD-likesymptoms (average age nine years). The children wererandomized to three groups: (1) canoU oil (controls),(2) fish oil (providing 250 mg DHA/EPA daily), and(3) an omega-3/PS combination (providing 300 mg PSand 250 mg DHA/EPA daily). No stimulant medica-tions or other dietary supplements were administeredduring rhe trial period (80-100 days; average 91 days).Ihe group receiving omega-3 PS had the highest pro-

portion of children whose symptoms improved.TTie children's sustained visual attention and

discrimination were assessed using the Test of Variablesof Attention (TOVA). Hie TOVA A D / H D Index "z"

score improved over controls for both the omega-3 PSand the fish oil groups, but significantly more in the PSgroup (p<0.001). This indicates that omcga-PS im-proved attention performance (and more dramaticallythan fish oil) compared to the control group. The ome-ga-3 PS group also manifested a significantly bigher ra-tio of symptom clearance than the control group, with11/18 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 ditferent trom controls.Omega-3 PS ameliorated the inattention symptoms ofA D / H D to a greater degree than equivalent amountsof DHA/EPA from other dietary sources.

Figure 3. Schematic of Omega-3Phosphatidylserine (Omega-3PS)

SERINE

PHOSPHATE

GLYCEROL

ao

t

0

9o

HA a

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Aiternative Medicine Review Volume 12, Number 3 2007

Figure 4* Schematic ofOmega-3 PC Present in KrillPreparations

( CHOUNE )

( PHOSPHATE )

( GLYCEROL;

19o

t

Omega-3 Phospholipids from KrillKrill, 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 andis a traditional food for humans. Tlie Antarctic krill(Euphausia superha) live in the most frigid seas. Tlieircell membranes carry a high complement of DHA andEPA that render them highly fluid in order to fiinctionin ambient temperatures well below the freezing point.

Unlike typical fish oil supplements that carry al-most no phospholipids, much of tbe DHA/EPA in krilloil is linked to phospholipids, particularly phosphatidyl-choline (Figure 4) and in lesser amounts to phosphati-dylethanolamine. The remaining DHA and EPA arein triglyceride form. The krill-phospholipid molecularfraction also includes the potent membrane antioxidantastaxanthin.

Krill omega-3 preparations have been tested inthree double-blind trials - for premenstrual syndrome(PMS) mood management/dysmenorrhea, blood lipidmanagement, and modulation of inflammatory symp-toms and blood markers linked to arthritis. In two trialsthe krill complex was directly compared to fish oil.

Krill for PMS and DysmenorrheaPMS and dysmenorrhea are thought to affect

90 percent of reproductive-age women. Abnormal fattyacid metabolism has been implicated (reviewed in Sam-palis et aF) . A double-blind RCT was conducted witha krill omega-3 supplement (NKO®) on 70 healthyvolunteers sutFering trom PMS/dysmenorrhea.'*" Onegroup received a krill oil supplement while the othergroup received an equivalent amount ot DHA and EPAas 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). Tlie fish oil groupconsumed 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 thetirst 30 days, then for just 10 days per month duringthe succeeding two months (beginning eight days priorto expected menstruation). The women tracked mentaland physical symptoms on a questionnaire developed bythe 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 significantimprovements in breast tenderness, feelings of inad-equacy, stress, irritability, depression, joint discomforr,and bloating. Tlie krill group also reported more im-proved alertness, energy, and wellbeing. By conclusionof the study, the krill group consumed significantly few-er analgesic medications during the 10 perimenstrualdays than the fish oil group. Unlike the krill group, 64percent in the fish oil group complained of unpleasant

Krill Supports Circulatory HealthCirculatory health is fundamental to brain

health. Blood lipid abnormalities (elevated LDL andtotal cholesterol, reduced HDL, and high triglycerides)

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contribute not only to morbidity and mortality associ-ated with cardiovascular disease, but aiso to cognitivedecline. In a double-blind trial, krill oil was comparedro Hsh oil (18% EPA/12% DHA) in men and womenwith hyperlipidemia (total cholesterol above 194 mg/dL; trigiycerides 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 received3 g/day fish oil, and a fourth group received placebo.At its lowest dosage (1-1.5 g/day), krill oil significantlylowered total and LDL cholesterol and elevated HDLcholesterol, compared to baseline and to the fish oil andplacebo groups. At 2 g/day, krill also significantly low-ered serum triglycerides in addition to cholesterol, whilethe highest krill intake (3 g/day) did not produce ad-ditional benefit over 2 g/day. The fish oil lowered cho-lesterol only marginally and failed to lower triglyceridesbelow baseline values.

Anti-Inflammatory EffectsC-rcactive protein (CRP) is a systemic inflam-

matory marker and a strong predictor of stroke andcognitive impairment.** In a double-blind RCT, krilloil demonstratedan ti-inflammatoryeffects.' ^ Tlie studyrecruited a total of90 subjects with car-diovascular disease,rheumatoid arthri-tis, or osteoarthri-tis, and high levelsof CRP (>1.0 mg/dL). Subjects re-ceived a low dose of

By day 7, krill had significantly reduced CRP (by 19%;p<0.05) compared to placebo. Tlie CRP reduction wasmore marked at day 30 (30% reduction; p<0.01) com-pared to placebo. Fish oil has tailed to lower CRP in atleast four studies.^

Omega-3 Phospholipids Target theBrain

Much evidence gleaned from animal studies(rodents and primates) indicates fatty acids are morebioavailable when provided in the form of phospho-lipids than as rriglycerides or ethyl esters. In one study,brain fatty acid bioavailability was more than doubledby using phospholipids compared to triglycerides as thedelivery form. This experiment compared tissue depo-sition of a fatty acid (arachidonic acid) in triglycerideform (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 componentof membrane phospholipids, AA is critical for mem-brane function and serves as a precursor for eicosanoidsthat play important roles in cell and tissue regulation.AA is also a precursor for longer-chain adrenic acid

300 mg/day krill oilor placebo and wereassessed at baseline,7, 14, and 30 days.

Figure 5. Tissue Distribution of Radiolabeled Arachidonic Acid Fed toNeonatal Baboons as either Triglycerides (TG-AA) or Phospholipids( P L A A ^

BaboonNewborns:

Tissue22:4 w-6

from20:4 w-6

(% dose perorgan)

0 . 8 -

0 . 6 -

0 . 4 -

0 . 2 -

Liver Brain Lung

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Aiternative Medicine Review Volume 12, Number 3 2007

(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 asingle dose of either TG-AA or PL-AA.'"' After 10 daysthe distribution of radioactivity was analyzed. As shownin Figure 5, the brain accumulated more than twice asmuch radioactivity from PL-AA as from TG-AA. Thisexperiment demonstrated phospholipids improve fattyacid uptake into the primate brain.

ConclusionDHA and EPA are clinically renowned for their

cardiovascular protective properties. A recent systematicreview evaluated rhe effects of fish oil consumption forprimary and secondary prevention ot adverse cardiovas-cular events.^" It concluded that increased consumptionof 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 withonly minor adverse effects. The results of tbis currentreview suggest the brain benefits of DHA and EPA mayeventually prove to be just as impressive as their benefitstor the cardiovascular system.

What is the Correct Intake of DHA/EPAfor Brain Benefits?

Technically, humans can synthesize EPA andDHA from the shorter-chain ALA, but the conversionefficiency is low, even in healthy individuals. Thus flax-seed oil as a source of ALA cannot be assumed to sub-stitute for dietary sources of DHA/EPA. Foods highin omega-3 FAs or supplements with preformed DHAand EPA are required.

In regard to food sources of DHA/EPA, thestandard American diet is unlikely to contribute morethan 50-100 mg/day. Various "functional foods" haveappeared with DHA/EPA added. Omega-3 eggs, forexample, can be a significant source by providing greaterthan 200 mg of "omega-3" per egg. However, it may benecessary to confirm which omega-3 FAs are in the food(e.g., DHA/EPA or ALA). Further caution is advisedto ensure that other ingredients in tbe food are health-ful. For example, one heavily promoted omega-3 spreadcarries trans-fatty acids - a potential toxic counterbal-ance to the omega-3 benefits.

Tlie current knowledge base on DHA/EPA forbrain function does not generate a rational daily intakerecommendation. Hibbeln, from his studies on nationalseafood intakes and affective disorder incidence, sug-gested pregnant women may want to consume a mini-mum 650 mg/day ot DHA and EPA (with a minimum300 mg/day of DHA) to prevent postpartum depres-sion.'*'* Tlie existing recommendations for cardiovascu-lar protection could be taken as a minimum for brainprotection. In North America, the American Heart As-sociation recommends a minimum intake of two fishmeals weekly for primary cardiovascular protection and1,000 mg/day of DHA/EPA for protection against asecond heart attack.

The practicality o( making dietary recommen-dations to eat fish as a primary source of DHA/EPA isthreatened by the fact that suitable fisb are increasinglyexpensive and hard to find.'™ The stocks of wild salmonand other species that are not contaminated with mer-cury or other pollutants are increasingly restricted. Analternative is to take dietary supplements rich in DHA/EPA, including the omega-3 phospholipid complexfrom krill.

While the wild salmon stocks are shrinking,concerns are being voiced about the increasing use ofkrill for aquaculture: salmon farming."" Krill is thoughtto be the largest single biomass on the planet and is alife-sustaining food for diverse marine animals. TheAntarctic stocks (Eitphausia superba) are estimated at50- to 500-million metric tons.'"" The international or-ganization Convention on tbe Conservation of Antarc-tic Marine Living Resources (CCAMLR), part of theAntarctic treaty network, was founded in 1982 primar-ily to protect krill. It has 24 member countries, includ-ing tbe European Union, Norway (a big krill fishingcountry), Russia, and the United States, as well as nineother nonvoting member countries. CCAMLR has set asustainable harvest for krill in the Antarctic of 4.45 mil-lion tons. Although this level has still not been reached,rhe advent of massive krill fishing boats has greatly in-creased rhe capability to harvest Antarctic krill, and theCCAMLR is in the process of tightening its regulatoryframework for krill conservation.

Cultivated microalgae are a good source ofDHA. Although high doses of ALA can increase tissueEPA levels, ALA does nor have the same effect on DHA

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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

foUicular keratosis.'""^ RBC membrane conrent 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 tor coronary hearr

disease.'"^ He suggests adequate sufficiency is likely at-

tained when DHA and EPA exceed eight percent of tbe

roral membrane fatty acids.

Although rhe current clinical literature on

DHA and EPA for brain function is still relatively

small compared ro 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 menral

performance.

The evidence presented in tbis review clear-

ly suggests that rhe timdamental basis for applying

DHA/EPA to human health is their presence in cell

membranes. Tbe 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 QIO.

Implementing this triple cell membrane synergy prom-

ises to bring integrative medicine closer to healing the

dysfunctional brain.

References1. McCann JC, Ames BN. Is docosahexaenoic acid, an

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