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Nutritional insufficiencies of omega-3 highly unsaturated fatty acids (HUFAs) may have adverse effects on brain development and neurodevelopmental outcomes. A recent meta-analysis reported a small to modest effect size for the efficacy of omega-3 in youth. Several controlled trials of omega-3 HUFAs combined with micronutrients show sizable reductions in aggressive, antisocial, and violent behavior in youth and young adult prisoners. Studies of HUFAs in youth, however, remain lacking. As the evidence base for omega-3 HUFAs as potential psychiatric treatment develops, dietary adjustments to increase omega-3 and reduce omega-6 HUFA consumption are sensible recommendations based on general health considerations.
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Omega-3 Fatty Acid and
Nutrient Deficits in
Adverse Neurodevelopment and
Childhood Behaviors
Rachel V. Gow, PhD
b
, Joseph R. Hibbeln, MD
a,
*
Funding Sources: Intramural Research Program, National Institute of Alcohol Abuse and
Alcoholism (NIAAA) and Barlean’s Organic Oils, LLC.
a
Section of Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics,
National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers
Lane, Room 3N-01, Rockville, MD 20892, USA;
b
Section of Nutritional Neurosciences, Laboratory
of Membrane Biochemistry and Biophysics, National Institute of Alcohol Abuse and Alcoholism,
National Institutes of Health, 31 Center Drive, Building 31, Room 1B54, Rockville, MD 20892, USA
* Corresponding author.
E-mail address: jhibbeln@mail.nih.gov
KEYWORDS
Omega-3 fatty acids Eicosapentaenoic acid Docosahexaenoic acid
Arachidonic acid Child neurodevelopment Attention-deficit/hyperactivity disorder
Conduct disorder Learning disorders
KEY POINTS
Omega-3 highly unsaturated fatty acids (HUFAs) are critical for both structure and function
of the brain.
The omega-3 HUFA docosahexaenoic acid (DHA) and the omega-6 HUFA arachidonic
acid (AA) are especially critical for the development of the central nervous system.
Omega-3 and omega-6 fatty acids have distinct roles and require a balance of omega-3/-6
for optimal physical and mental health. An excessive intake of one type of fatty acid may
inhibit the conversion of the other.
EPA-rich formulas are linked to improvements in mood and symptoms of attention-deficit/
hyperactivity disorder (ADHD).
The American Psychiatric Association Task Force on Complementary and Alternative
Medicine recommends that the dietary intake of omega-3 for patients with poor impulse
control, mood disorders, or psychotic disorders should include eicosapentaenoic acid 1
docosahexaenoic acid at a daily dose of approximately 1 gram.
Lower concentrations of omega-3 fatty acids have been present in both plasma and red
blood cells of children and young adults with ADHD in comparison with healthy controls.
Supplementation with omega-3 HUFAs in clinical trials have found some improvement in
learning capacity and behavior in youths who are academically underachieving, have
ADHD-like symptoms, and/or have severe misconduct.
The relationshipbetween nutritional deficiencies,in particularof omega-3 fats,and symptoms
of mental ill-health,warrants closerexamination by clinicians andmental health practitioners.
Child Adolesc Psychiatric Clin N Am 23 (2014) 555–590
http://dx.doi.org/10.1016/j.chc.2014.02.002 childpsych.theclinics.com
1056-4993/14/$ – see front matter Published by Elsevier Inc.
INTRODUCTION
Anyone who has observed children knows that their behavior changes dramatically
when they are hungry. However, an important consideration is that children today
may be consuming adequate or excessive calories, but their brains nonetheless can
be starved of vital nutrients critical for optimal brain function, thus increasing the
risk for behavioral disorders and adverse developmental trajectories. Among these
vital nutrients are iodine, folate, B vitamins, iron, zinc, micronutrients, and omega-3
essential fatty acids. The US Department of Agriculture publication Dietary Guidelines
for Americans, 2010
1
addresses both specific nutrients and patterns of healthy eating
for optimization of physical health outcomes. Similarly, this article considers both spe-
cific nutrients and multiple interactive nutrients for optimization of mental health
outcomes.
The primary focus of the article is the effects of deficits in the dietary intake of
omega-3 highly unsaturated fatty acids (HUFAs); the associated potential increase
in risk for attention-deficit/hyperactivity disorder (ADHD) and similar behavioral disor-
ders; and the hypothesis that omega-3 HUFAs have some treatment efficacy. Deficits
in omega-3 HUFAs in depressive and aggressive disorders are also especially relevant
to children; however, the main body of observational data and treatment studies
has been conducted in adults. The proposition that nutritional insufficiencies in early
development may have residual behavioral and cognitive deficits merits critical
consideration.
Abbreviations
AA Arachidonic Acid
ADHD Attention Deficit Hyperactivity Disorder
ALA a-Linolenic Acid
ALSPAC Avon Longitudinal Study of Parents and Children
CDRS Childhood Depression Rating Scale
CESD Center for Epidemiologic Studies Depression Scale
CGI Clinical Global Impression
CPRS Conners Parents’ Rating Scale
CTRS-L Conners’ Teacher Rating Scale
DHA Docosahexaenoic Acid
EPA Eicosapentaenoic Acid
ERP Event-Related Potential
FDA Food Drug Administration
fMRI Functional Magnetic Resonance Imaging
GLA Gamma-Linolenic Acid
GRAS Generally Recognized as Safe
HUFA Highly Unsaturated Fatty Acids
LA Linoleic Acid
LPC Late Positive Component
NAFLD Non-Alcoholic Fatty Liver Disease
NIAAA National Institute on Alcohol Abuse and Alcoholism
PCBs Polychlorinated Biphenyls
PUFA Polyunsaturated Fatty Acid
RA Reaction Time
RCT Randomized Clinical Trial
SAMe S-adenosyl-L-methionine
SMD Standard Mean Difference
Gow & Hibbeln
556
The first part of this article introduces the reader to nutritional requirements for
optimal brain development and the impacts of nutritional inadequacy during preg-
nancy on adverse long-term developmental outcomes. Next, basic science issues
related to neurologic function and essential fatty acid metabolism underlying these
findings are addressed in the context of the dramatic differences between current
dietary patterns and those during hominid evolution. Finally, observational and treat-
ment studies are assessed for the plausibility of the efficacy of nutritional treatments
for psychiatric disorders in children and adolescents.
ESSENTIAL NUTRIENTS AND THE RISK OF DEFICIENCIES
The peak vulnerability to harm from nutritional deficiencies occurs during pregnancy,
when the central nervous system is first developing. The quality of the maternal diet is
particularly dependent on the intake of micronutrients (such as vitamins A and B,
choline, and folate), trace elements (such as iodine, iron, zinc, and copper), and
HUFAs, especially docosahexaenoic acid (DHA) and the omega-6 HUFA arachidonic
acid (AA). These nutrients are especially critical during the fetal and early postnatal
stage, when most areas of the brain are undergoing their most rapid development.
It is well established that nutritional deficiencies (and excesses) may affect the infant
brain and alter subsequent development and behavior permanently.
2–4
For example,
the link between iodine deficiency and mental retardation is widely documented. In
developing countries, approximately 38 million children are born at risk of iodine-
associated mental retardation every year.
5
Deficiencies in iodine and iron (ie, anemia)
during infancy have been linked to a range of suboptimal developmental outcomes,
including:
1. Abnormal neuronal development
6
2. Disruptions in regulatory processes, such as the sleep-wake cycle
7
3. Suboptimal performance in global measurements of cognition, motor skills, and
social-emotional behavior
8–12
4. Mental retardation and cognitive deficits associated with reductions in learning
capacity and productivity
6
In animal models of nutritional deficiencies, a similar pattern of cognitive, motor, and
behavioral changes is observed, along with alterations in dopaminergic function and
lower dopamine levels in the cerebrospinal fluid in comparison with controls.
13
Iron
deficiency also affects other neurotransmitters and other neuronal processes,
including metabolism in hippocampus and striatum, myelination, dendritogenesis,
and both gene and protein profiles.
14–16
HUFAs, including the omega-3 DHA, are simi-
larly proposed to play a critical role during sensitive periods of neurodevelopment dur-
ing early childhood, and also in the regulation of cognitive function throughout the life
span.
17,18
The beneficial effects of eicosapentaenoic acid (EPA) and DHA for cardio-
vascular diseases and stroke are well established, but their potential for preventing
mild cognitive dysfunction and reducing the risk for Alzheimer disease require further
evaluation in large, long-term clinical trials.
19
THE LIPID SUBSTANCE OF THE BRAIN
About 50% to 60% of the dry weight of an adult brain is composed of lipid, and at least
35% of the lipid content is made up of HUFAs. Given the high brain content of HUFAs,
it is remarkable that these fatty acids are dietarily essential. HUFAs cannot be synthe-
sized de novo, but must be either ingested directly from dietary sources or metabo-
lized from essential polyunsaturated fatty acid (PUFA) precursors.
20–22
These fatty
Omega-3 Fatty Acids and Neurodevelopment 557
acids are highly specialized, with very specific metabolic functions and unique bio-
physical properties.
The biosynthetic pathways (see Fig. 1) and metabolic interactions among the
omega-3 and omega-6 series of fatty acids are complex. The parent compounds
for the large number of HUFAs are 2 PUFAs: a-linolenic acid (ALA) is the precursor
for the omega-3 fatty acids, and linoleic acid (LA) is the precursor for the omega-6 fatty
acids.
23
These 2 precursor nutrients are the only fatty acids that are definitely essen-
tial, in the sense that the human body has no way to synthesize them and they must be
ingested in the diet. Until the 1950s, ALA and LA were collectively known as vitamin F.
LA, the omega-6 precursor, is the most abundant PUFA in the Western diet. In addi-
tion to its role in the brain, the omega-6 series is vital for mammalian reproduction.
24
LA is primarily sourced from practically every commercially manufactured food in the
market place; in particular, it is sourced from soybean oil (the most frequently
consumed oil), corn oil, and sunflower oil.
25
Typical dietary intake of omega-6 PUFAs
in Western diets are excessive, and thought to be in the region of 12 to 17 g daily.
26
LA
is a metabolic precursor to g-linolenic acid (GLA) and AA,
26
having been converted by
an elongase and 2 desaturase enzymes. AA is particularly abundant in the lipids of in-
ner cell membranes, is important in the vasculature,
24
and plays a crucial role in the
production of eicosanoids. Although AA can be synthesized from LA, the main dietary
sources of AA are red meat and dairy products including eggs.
27
The omega-3 precursor ALA is metabolized into EPA and DHA, which are consid-
ered the 2 major omega-3 fatty acids. ALA is readily available in vegetable sources
(especially green leafy vegetables, plants, vegetable oils, and nuts and seeds such
as flax and canola). The richest direct source of EPA and DHA is marine fish (such
as mackerel, salmon, herring, and sardine) and seafood.
23
These 2 omega-3 fatty
acids, EPA and DHA, are associated with many important functions related to neural
activity, such as cell membrane fluidity, neurotransmission, ion channels, enzyme
Fig. 1. Biochemical pathways for the omega-3 and omega-6 fatty acids.
Gow & Hibbeln
558
regulation, gene expression, and myelination.
20,28
DHA alone makes up approximately
30% of the phosphoglycerides in the gray matter of the brain
29,30
and is essential for
optimal neuronal functioning.
31
Within brain tissues, DHA preferentially accumulates in
growth cones, astrocytes, synaptosomes, myelin, and microsomal and mitochondrial
membranes.
32,33
Omega-3 fatty acids mediate a variety of key neurotransmitter func-
tions, including serotonergic responsivity, signal transduction, and phospholipid
turnover.
21,34,35
The eicosanoids, which can be derived from either omega-3 or omega-6 fatty acids,
are a variety of compounds involved in the regulation of blood flow (vasodilatory pros-
tacyclin), halting of blood flow in the case of injury (anti-thrombotic thromboxanes), the
resolution of inflammation (anti-inflammatory prostaglandins), and tissue homeosta-
sis.
24,26
Diets depleted in omega-3 result in reductions of DHA in the brain and a simul-
taneous increase in the turnover of AA to eicosanoids.
36
These effects can be reversed
by adding omega-3 to the diet.
Eicosanoids have varying crucial yet complex functions in the brain, and exercise
control over numerous bodily systems. A growing body of evidence suggests that
inadequate omega-3 fatty acid levels during critical stages of neurogenesis may alter
parameters of cell signaling, including within neurotransmitter systems, resulting in im-
pairments in behavior, learning, and cognition.
37–40
Eicosanoids have been shown to
be involved in long-term potentiation, synaptic plasticity, spatial learning, and sleep
induction; they also reduce neuroinflammation and have neuroprotective properties.
35
EXCESS LINOLEIC ACID AND THE DIETARY BALANCE OF OMEGA-3 AND OMEGA-6
HUFAS
Both omega-3 and omega-6 fatty PUFA precursors are metabolized to their respec-
tive HUFAs by common enzyme pathways, which are influenced by many factors
including diet, oxidative stress, alcohol, smoking, age, and genetic factors.
41–45
These common pathways can be overloaded, leading to a bottleneck in the meta-
bolism of both omega-3 and omega-6 HUFAs.
46,47
The dietary balance of the ratio
of omega-6 to omega-3 PUFAs therefore has important metabolic implications. For
instance, excessive intake of the omega-6 LA, may inhibit the synthesis of the
omega-3 ALA to EPA and DHA, and thereby reduce the availability of EPA and
DHA. An excessive dietary intake of the proinflammatory omega-6 HUFAs may
reduce the synthesis and functioning of anti-inflammatory omega-3 compounds,
leading to a tilt toward inflammatory processes such as cardiovascular disease,
metabolic disorders, immunologic conditions, and cancer.
48,49
Similarly, in the brain,
an excessive intake of omega-6 or an insufficient intake of omega-3 can potentially
increase the risk of depression, speculatively by altering serotonergic and catechol-
aminergic neurotransmission.
39,50–52
The imbalance of omega-3 and 6 fatty acids present in modern diets is a focal point of
much scientific debate. Recent calculations estimate that omega-6 to omega-3 ratios
in dietary intake have risen from about 1:1 to 2:1 to approximately 20:1.
53
It has been
suggested that these ratio increases are predominantly a result of the increased con-
sumption of linoleic-rich soybean oil during the last century.
25
In a randomized clinical
trial in which the intake of LA was selectively increased (N 5221) from approximately
6% to 15 % of dietary energy, increased mortality was observed from both cardiovas-
cular disease (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.03–2.80; P5.04)
compared with controls (n 5237) and coronary heart disease (HR 1.74, 95% CI 1.04–
2.92; P5.04), which are findings consistent with other linoleic-selective trials (see the
Sydney Diet Heart Study updated meta-analysis for more information).
54
Therefore,
Omega-3 Fatty Acids and Neurodevelopment 559
reducing omega-6 LA intake to ensure a good dietary balance of omega-3 and omega-
6 fatty acids may be a key factor in optimal health outcomes.
IMPACT OF INADEQUATE DHA INTAKE ON BRAIN DEVELOPMENT IN ANIMALS
A large body of research has confirmed the essential role of DHA in the development
and function of the brain. The negative impact of inadequate DHA during critical pe-
riods of brain development has been well studied in animals and, to a lesser extent,
in humans. Maternal nutritional deficiencies during neurogenesis and angiogenesis
have long been associated with behavioral impairments in both animal models
55–57
and humans.
39,58,59
It appears that HUFA insufficiency during lactation can lead to
some irreversible changes,
60
presumably because of impaired connectivity.
In animal studies, prenatal and postnatal DHA insufficiency has been associated
with a variety of structural changes, such as delayed neuronal migration, disrupted
dendritic arborization, abnormal neuronal development in the hippocampus,
51
and
abnormalities in timed apoptosis. Neurochemical studies have shown alterations of
several neurotransmission systems, including the dopaminergic and serotonergic sys-
tems.
61
The resulting altered or impaired connectivity may result in permanent distur-
bances.
62
Subsequent functional deficits include cognitive impairments, such as
memory and learning,
55
in addition to deficits in emotional regulation and behavior,
such as depression, anxiety, and aggression, in animal models.
63,64
Repletion of
both omega-3 and omega-6 fatty acids into the diet during lactation in animals re-
stores the composition of brain fatty acid and some parameters of neurotransmitter
function,
60
but only partially.
In humans, DHA insufficiency in utero has been hypothesized to be linked to impaired
magnocellular neurite growth associated with dyslexia.
65
Some studies have also re-
ported findings of abnormal omega-3 HUFA levels in the erythrocytes of children and
young adults with ADHD.
66–73
In addition,a growing body of clinicalresearch has reported
improvements in symptoms of ADHD,
74–76
depression,
77
learning difficulties, and/or
dyslexia
78
following supplementation with omega-3/-6 fatty acids relative to placebo.
There is very little research, however, investigating the potential effects of omega-3
intervention in healthy control children. One functional magnetic resonance imaging
(fMRI) study reported changes in cortical attention networks in healthy boys following
DHA supplementation.
79
A recent randomized placebo-controlled study reported that
DHA supplementation improved both reading and behavior in healthy but underper-
forming schoolchildren,
80
although another clinical trial reported little or no effect of
HUFA intervention compared with placebo on the cognitive ability and behavior of
schoolchildren.
81
A more detailed review of the randomized placebo-controlled clin-
ical trials in this area is provided later in this article.
Omega-3 interventions are more likely to demonstrate benefits among children with
omega-3 deficiencies than among healthy children with omega-3 sufficiency. The col-
lective findings from both animal and human studies has led researchers to postulate
that deficits of omega-3 HUFAs during critical periods of brain development may
increase the risk for neurodevelopmental disorders, such as ADHD, and possibly pre-
dispose toward the later appearance of depressive and aggressive behaviors.
39,82,83
A DIETARY EVOLUTION: UNFORTUNATE CONSEQUENCES OF AGRICULTURAL
DEVELOPMENTS
Crawford and others have argued that the fossil evidence indicates that the lacustrine
(lake and shore) and marine food chains were being extensively exploited during the
period when cerebral expansion took place, suggesting that the transition from the
Gow & Hibbeln
560
archaic to modern humans took place at the land/water interface. At these interfaces,
in regions of hominid evolution, diets consumed from wild foods were lower in satu-
rated fats (range 11–12 in percentage energy [en%]), higher in omega-3 HUFAs
(2.26–17.0 g/d), lower in the omega-6 LA (range 2.3–3.6 en%), and a lower ALA/LA
ratio (range 1.12–1.64 g/d), indicating a lower omega-3/omega-6 ratio than is present
in contemporary diets.
53
The paleolithic diet is a modern dietary regimen that seeks to
mimic the presumed diets of preagricultural hunter-gatherers. Arguably, compared
with modern Western diets consumed today, the paleolithic diets of our ancestors
provided more DHA, which is a known key omega-3 constituent of the brain (and
visual photoreceptor signaling systems). The shore-based theory has provided
considerable evidence for our ancestors settling along the river banks in Africa, with
fish, clams, frogs, and seafood as their stable diet. Stephen Cunnane from the Univer-
sity of Sherbrooke and Kathy Stewart from the Canadian Museum of Nature in Ottawa
have extensively studied fossil material excavated from numerous Homo habilis sites
in eastern Africa, which have revealed a bevy of chewed fish bones, particularly cat-
fish.
84,85
Their theory is that a rich and secure shore-based diet fueled and provided
the essential nutrients to make our brains what they are today. Crawford and col-
leagues
86
have also proposed that the availability of DHA was crucial to permit evolu-
tion of the human brain.
87
DHA is both conserved and irreplaceable in neuronal
signaling, and is involved in the expression of several hundred genes,
88
highlighting
its unique and dominant place in brain evolution and biology in general.
The most dramatic and unfortunate changes from our paleolithic heritage of whole
and unrefined foods are direct consequences of the Agricultural Revolution. Between
the seventeenth and the end of the nineteenth century, and then continuing with a sec-
ond wave after the World War II, new farming and technological changes brought the
advent of mass food production, which has resulted in the problematic “modern
refined diet” consumed today.
48,89–91
Contemporary Western diets also have low
quantities of key micronutrients (minerals, vitamins, and trace elements), amino acids,
antioxidants, fiber, and helpful phytochemicals, and are overloaded with sodium,
refined sugars, and grain products that carry a high glycemic load.
89
Even seemingly healthy parts of the modern Western diet have progressively lost
their nutrient value. In the 1970s, poultry and eggs were the major land-based sources
of protein and omega-3 fatty acids, especially DHA, and poultry was considered a
healthy lean alternative to fatty red meat.
92
However, a laboratory analysis of modern
supermarket chickens revealed that their energy from fat now actually exceeds energy
from protein, and that their omega-6/omega-3 ratio is 9:1 rather than the recommended
2:1 ratio.
93
The loss of omega-3 HUFAs from chicken may result from feeding farm an-
imals with soy-based products that are relatively deficient in omega-3 HUFAs, and the
use of severely cramped bird cages that prevent exercise and reduce mitochondria-
rich muscle mass.
93
This shift toward excessive omega-6 and insufficient omega-3
HUFAs in the human diet is argued to have adverse health consequences.
94
Despite their critical biological role, essential fatty acids cannot be synthesized or
stored by the body for very long periods of time and therefore must be obtained in
the diet, so that these modern dietary changes have significant biological conse-
quences. The recent increase in obesity
95
and diabetes (Word Health Organization
[WHO], 2002) in both children and adults is likely a consequence of both the sedentary
lifestyle and the excessive consumption of energy-dense refined foods rich in salt,
sugar, and fats. Type B malnutrition is now recognized as a new type of malnutrition
directly resulting from multiple micronutrient depletion and very likely deriving from
the globalization of the Western food systems.
24
Several scientific and governmental
bodies have made dietary recommendations, including the Dietary Guidelines for
Omega-3 Fatty Acids and Neurodevelopment 561
Americans, 2010, to increase intake of fish and seafood during pregnancy to prevent
suboptimal brain development in utero and residual problems in cognitive and visual
development.
1
In view of the prediction by the WHO of a 50% increase in child mental
ill-health by 2020, the promotion of optimal nutrient requirements for the developing
brain warrants examination as a means to reduce the risk of potential developmental
and functional consequences.
INADEQUATE HUFA INTAKE DURING PREGNANCY ON HUMAN DEVELOPMENTAL
OUTCOME
Fish and seafood are the richest sources of omega-3 fats in the human diet, but also
contain multiple nutrients that are beneficial to optimal brain development. Two major
studies of inadequate seafood intake during pregnancy are offered here as examples
to provide an overview of the potential impact of intrauterine nutrient inadequacies on
behavioral and cognitive deficits later in childhood.
The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal
study of health care outcomes with pregnant mothers and their children conducted
at Bristol University in the United Kingdom. In 1991 more than 14,000 mothers were
enrolled during pregnancy, and the developmental and health trajectory of their chil-
dren has been charted ever since.
96
Among the numerous nutritional factors exam-
ined, the effects of the 2004 US Food and Drug Administration (FDA) advisory to
limit seafood intake during pregnancy was directly evaluated to determine whether
eating seafood (ie, exposure to trace methyl mercury) or avoiding seafood (risk of nutri-
tional deficiencies) was associated with greater harm.
97
One purpose of the advisory
was to protect against impaired verbal development. However, detrimental effects
on verbal development were found among children whose mothers consumed less
than 12 oz (340 g) of seafood per week (odds ratio 51.48 for greater risk of low verbal
IQ). Low maternal seafood intake during pregnancy was also associated with subop-
timal outcomes for fine motor skills, communication, prosocial behavior, and social
development scores.
96
A net effects analysis by the WHO
98
and the FDA
99
found
that the nutritional benefits of fish far exceed the toxicologic effects of methyl mercury.
These findings may result in an update of the 2004 FDA advisory on EPA.
97
Another longitudinal study conducted in Australia, known as the Raine Study,
100
fol-
lowed 2868 live births to age 14 years and then assessed the adolescents for dietary
patterns and ADHD diagnosis. Data were available for 1799 adolescents, including
115 with a diagnosis of ADHD. The 2 main dietary patterns were assessed and cate-
gorized as “Healthy” and “Western.” The Western dietary pattern was correlated with
higher intakes of total and saturated fat, salt, and refined sugars, and was inversely
correlated with intake of folate, fiber, and omega-3 fatty acids.
100
By contrast, the
Healthy dietary pattern was positively correlated with fiber, folate, and omega-3 fatty
acid intake, and inversely correlated with the amount of refined sugars and the total
fat/saturated fat ratio.
100
The results showed that an increased likelihood of an
ADHD diagnosis was significantly associated with the Western dietary pattern, after
adjustment for potential confounding variables from pregnancy to adolescence. The
ADHD diagnosis was not associated with the Healthy dietary pattern. Clearly, firm
conclusions cannot be drawn regarding the causal nature of dietary patterns on the
likelihood of ADHD because of the cross-sectional nature of the study design. The ob-
servations may also be bidirectional; that is, the diagnosed ADHD may indicate poorer
food choices, or the Western diet may have promoted the expression of attention def-
icits. However, this study does highlight the necessity for a closer inspection of the role
of dietary patterns in ADHD.
100
Gow & Hibbeln
562
EFFECT OF HUFA SUPPLEMENTATION IN HEALTHY CHILDREN
Early dietary intake of HUFAs, specifically during pregnancy and breastfeeding, have
been associated with subsequent improvements in an array of functions, including vi-
sual acuity at age 12 months,
101,102
problem-solving ability in infants,
103
and alter-
ations in cortical attention networks in schoolchildren.
79
For example, the effects of DHA supplementation on attention networks in the brain
have been examined in 38 healthy boys (ages 8–10 years) using fMRI.
79
Participants
were randomly allocated to receive DHA (n 512, dose: 400 mg or n 514, dose:
1200 mg) or placebo (n 512), although 5 children were lost to follow-up, withdrawal,
or noncompliance. Their cortical brain activity was recorded at baseline and 8 weeks
later. The results found that DHA erythrocyte membrane composition increased by
47% to 70% at 8 weeks in comparison with the placebo group.
79
Both DHA dose
groups had increased activation of the dorsolateral prefrontal cortex and greater re-
ductions in activation in the occipital and cerebral cortex during a sustained attention
task when compared with controls. Decreases in cerebellar activation were larger in
the 1200-mg group than in the 400-mg group.
79
DHA erythrocyte levels were positively
associated with dorsolateral prefrontal cortex activation and negatively associated
with reaction time, which improved (ie, faster reaction) as brain function increased.
This study was the first to demonstrate that dietary intake of DHA changed cortical
attention networks in healthy boys.
Osendarp and colleagues
104
assessed the effects after randomization of a fortified
drink containing either (1) a mix of micronutrient intervention (zinc, iron, vitamins A, B
6
,
B
12
, and C, folate) alone, (2) DHA 88 mg and/or EPA 22 mg daily alone, (3) the micro-
nutrient intervention plus DHA 88 mg and/or EPA 22 mg daily, or (4) placebo. Two
groups of 6- to 10-year-old schoolchildren were enrolled and classified as well nour-
ished (a group in Adelaide, Australia; n 5396) or marginally nourished (a group in
Jakarta, Indonesia; n 5384).
104
A total of 120 children completed the study. The
micronutrient treatment resulted in significant increases in verbal learning and memory
in the Australian group (estimated effect size: 0.23; 95% CI: 0.01–0.46), and a similar
effect was observed among Indonesian girls (estimated effect size: 0.32; 95% CI:
0.01 to 0.64). No effects were found on tests measuring general intelligence or atten-
tion. No effects of DHA 1EPA on the cognitive tests were observed.
104
Overall, the
investigators concluded that micronutrient intervention can have beneficial effects
on cognitive performance, even in well-nourished children. The failure of EPA and
DHA to produce significant effects on cognitive function, especially in marginally nour-
ished schoolchildren, may be accounted for by the very low combined dose of EPA
and DHA in this study (DHA 88 mg and EPA 22 mg daily), compared with daily doses
in the region of 1000 mg used in other supplementation trials.
Together, these 2 early reports on HUFA supplementation in healthy children pro-
vide preliminary evidence that DHA might result in increased activation of the dorso-
lateral prefrontal cortex, thus improving the functioning of cortical attentional
networks, and improving reaction times. Micronutrients, including vitamins and min-
erals, may improve verbal memory and learning in healthy children, but might not
improve attentional functions.
HUFA ABNORMALITIES IN ADHD
In children and adults with ADHD, abnormalities in fatty acid blood profiles have been
reported,
66,69–73
but it is unclear whether the observed irregularities in omega-3 and
omega-6 HUFAs are due to low dietary intakes of HUFAs in ADHD or an abnormality
in HUFA metabolism.
Omega-3 Fatty Acids and Neurodevelopment 563
For example, Stevens and colleagues
68
reported that in 6- to 12-year-old boys with
ADHD, levels of both AA and DHA were significantly lower than in matched controls
(n 543); in addition, approximately 40% (n 553) had excessive thirst and skin prob-
lems, which are classic signs of fatty acid deficiency from the animal literature.
Combining the ADHD and controls and then classifying them into low or high
omega-3 and omega-6 groups, the researchers found that lower omega-6 concentra-
tions were associated with several signs of fatty acid deficiency, such as excessive
thirst, skin problems, frequent urination, rough and dry skin/hair, frequent colds,
and antibiotic use. The group with low omega-3 was also found to have learning
and behavioral difficulties, such as hyperactive-impulsive behavior, anxiety, temper
tantrums, and conduct disorder symptoms.
105
Another study by Antalis and colleagues
66
compared 35 young adult males with
ADHD with healthy controls, and found that the ADHD group had a higher total
omega-6/omega-3 ratio (ie, the sum of total omega-6 over the total of omega-3)
and a 36% higher ratio of AA/EPA in erythrocytes in comparison with the controls.
Erythrocyte levels of AA were also approximately 10% greater in the ADHD group
than in the control group. DHA levels were 53% lower in plasma and 36% lower in
erythrocytes in the ADHD group in comparison with controls. An identical pattern
was also observed for total omega-3 ratio. Plasma ALA levels were greater in the
ADHD group, but all ALA metabolites were lower. Correlational analysis was conduct-
ed to assess the strength of the relationships between behavior and omega-3 fatty
acid levels. The percentage of DHA in the phospholipid fraction of blood correlated
with the ADHD symptoms (inattention r50.47, impulsivity/hyperactivity r50.45,
and Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]
total ADHD scores r50.047). Similar trends were observed for total omega-3 fatty
acid levels in both plasma phospholipids and erythrocytes. These findings suggest
that lower omega-3 levels were associated with greater severity of ADHD-like
symptoms.
Colter and colleagues
73
also assessed 11 adolescents with ADHD and 12 healthy
controls for fatty acid levels and severity of behavioral symptoms. The ADHD group
self-reported more checklist symptoms of fatty acid deficiency. Intake of both total
fat and saturated fat was positively associated with scores of oppositional, problem-
atic, and hyperactive behaviors. Adolescents with ADHD had lower blood concentra-
tions of DHA and total omega-3 (ALA, DHA, EPA, and docosapentaenoic acid) levels,
and higher levels of the omega-6 LA. DHA levels were negatively correlated and total
omega-6 levels were significantly positively correlated with inattention, behavioral
problems, oppositional behavior, restlessness, and total DSM-IV symptoms on Con-
ners Parent Rating Scale (CPRS) scores. The diet records did not reveal any differ-
ences in total omega-3 fatty acid consumption, potentially suggesting that the lower
DHA levels in ADHD may be due to higher oxidative metabolism rather than dietary
intake.
73
Confounding variables in this study were group differences in vitamin and
mineral supplementation (50% of the ADHD group, 25% of the controls) and in gender,
which is relevant because males and females can differ in their metabolism of
PUFAs.
106
Researchers in Taiwan have examined 58 children (aged 4–12 years) with a clinical
diagnosis of ADHD in a comparison with 52 controls. No differences were found in di-
etary patterns of the children with ADHD, except for higher intake of iron and vitamin C.
The ADHD children were found to have lower LA, AA, and DHA fatty acid levels in red
blood cells (and higher iron levels in their blood) compared with controls.
69
Across these studies on HUFA abnormalities in ADHD, ADHD and ADHD behaviors
in youth appear to be characterized by physical symptoms characteristic of essential
Gow & Hibbeln
564
fatty acid deficiency, low levels of DHA and other omega-3 HUFAs, and a high levels of
omega-6 HUFAs. Patients with low DHA levels were associated with more severe
symptoms of inattention and hyperactivity/impulsivity, the hallmark symptoms of
ADHD, and showed more learning problems and symptoms of conduct disorder. Find-
ings on AA and omega-6 levels were more mixed, but there was a suggestion that the
omega-6/omega-3 ratio may be a marker for more ADHD symptoms. However, gener-
alized essential fatty acid deficiencies are unlikely, as these subjects were replete with
omega-6 LA. These studies raise the question of whether omega-3 fatty acid supple-
mentation, even in the face of adequate omega-6 fatty acid levels, might ameliorate
symptoms of ADHD and some associated physical signs of essential fatty acid
insufficiency.
Most supplementation studies have used mixtures of omega-3 HUFAs and omega-
6 GLA, making it difficult to isolate the potential effects of individual fatty acids. Some
of the early research in children with ADHD focused on supplementation with DHA
alone, and showed little or no therapeutic effect.
107,108
Other clinical trials that have
investigated supplementation with evening primrose oil or formulas rich in omega-6
in children with ADHD have also reported little or no effect on ADHD.
109–111
Very
few trials used comparable experimental designs, supplements, doses, or duration
of supplementation, and most studies were not adequately powered, so their nonsig-
nificant findings and wide variations in findings are often difficult to interpret.
Differential Effects of EPA and DHA in the Brain
Little is known about the biological role of EPA in the brain, especially regarding its
impact on cognition and mood. There are some preliminary research studies reporting
differential effects of EPA and DHA in relation to cognitive and emotional
responses.
112,113
Resting-state electroencephalogram
Sumich and colleagues
112
reported differential associations between DHA and EPA
erythrocyte levels and electroencephalogram (EEG) components in children and ado-
lescents with ADHD: DHA levels were associated with more rapid activity (alpha activ-
ity during eyes-open and beta activity during eyes-closed resting states), and EPA
levels were associated with more slow activity (theta activity during both eyes-open
and eyes-closed resting states). No associations were found with omega-6 HUFA
levels. Alpha activity was found to be positively associated with performance for lan-
guage fluency involving semantic memory, whereas theta activity was negatively
associated with verbal memory performance.
112
Emotion-elicited event-related potentials
Gow and colleagues
113
have reported the relationship between erythrocyte HUFA
levels and event-related potential (ERP) responses to the presentation of happy,
sad, and fearful faces during an emotional processing task in a small sample of
adolescent boys with ADHD. The investigators created an ERP cognitive bias para-
digm based on 2 premises: (1) Beck’s theory of depression, which postulated that
individuals with depression gravitate toward negative schema and stimuli; and (2) ev-
idence suggesting that children with ADHD have difficulty correctly identifying the
emotional expression of others, especially in relation to fear and anger.
114
The inves-
tigators therefore hypothesized that EPA (because of its association with regulating
and improving mood) would be positively associated with a bias in the overt P300
response toward facial expressions of happiness relative to fear or sadness. The
happy-fear cognitive bias was calculated by subtracting the midline frontal P300
Omega-3 Fatty Acids and Neurodevelopment 565
amplitudes to fearful faces from those of happy faces (P300
H–F
). A similar calculation
was made for a happy-sad bias (P300
H–S
). The findings showed there was a significant
positive association between EPA levels and a cognitive bias oriented toward overt
expressions of happiness, relative to both sad and fearful faces, as indexed by midline
frontal P3 amplitude. By contrast, DHA levels were associated with the right temporal
N170 response to fear.
Memory-related event-related potentials in healthy fish-eating children
To the best of the authors’ knowledge, only one study has investigated HUFA status
and ERPs in healthy children. Boucher and colleagues
115
examined the prenatal
omega-3 fatty acid intake of the mothers of 154 children in the fish-eating Inuit com-
munity, and compared the cord plasma concentrations to the child’s subsequent
memory functioning evaluated at a mean age of 11.3 years. This prospective longitu-
dinal study used neurophysiologic data (ERPs during a continuous visual recognition
task) and neurobehavioral measures of memory (Wechsler Intelligence Scales for Chil-
dren, 4th edition, and the California Learning Test Children’s Version). Children with
higher prenatal concentrations of DHA (as measured in cord plasma) displayed, at
age 11, a shorter N4 ERP latency deflection and larger late positive component, which
is a positive-directed ERP component derived from EEG recordings that is thought to
be associated with recognition memory processes. Elevated DHA measures were
related with enhanced N4 amplitudes, and positive associations were also observed
between cord DHA and neurobehavioral performance on memory tasks.
Collectively, these 3 EEG studies provide preliminary evidence to suggest that EPA
and DHA may be implicated in different functional roles related to features of cognitive
and affect processing in ADHD.
Milte and colleagues
116
examined 75 children (ages 7–12 years) with symptoms of
ADHD with or without learning difficulties in the context of a larger study. This study
reports data only from the baseline time point (after controlling for covariates). Pearson
correlational analysis examined associations between literacy (word reading, spelling,
and vocabulary) and behavior (using the CPRS), and found that higher DHA (omega-3)
predicted better word reading (P<.001) whereas higher omega-6 predicted poorer
levels of reading, vocabulary, spelling, and attention.
116
Higher levels of total
omega-6 and AA levels at baseline also predicted lower anxiety/shyness after
4 months. In a similar fashion, both increased levels of EPA and total omega-3 were
associated with decreased anxiety/shyness. However, a key limitation of this study
is that the correlation analyses were used with no statistical correction for multiple
testing, so it is possible that these were spurious findings. The findings are provocative
enough to warrant replication, using correction for multiple testing.
INDIVIDUAL HUFA SUPPLEMENTATION TRIALS IN YOUTH WITH ADHD OR ADHD-TYPE
SYMPTOMS
Several dietary supplementation trials with omega-3 and omega-6 fatty acids have re-
ported some improvement in ADHD symptoms, typically using either the parent-rated
or teacher-rated Conners scales and/or the Clinical Global Impression (CGI) scales as
primary outcomes.
74,76,78,117,118
Omega-3/-6 in Relation to Learning, Behavior, and Motor Skills
The Oxford-Durham study (2005) was arguably the landmark study linking omega-3 or
omega-6 supplementation to improvements in behavior and concentration in under-
achieving mainstream schoolchildren.
74
Although not primarily concerned with
ADHD, this examination of ADHD-like symptoms in children was a pivotal study in
Gow & Hibbeln
566
this field. This placebo-controlled, double-blind, randomized clinical trial (RCT) exam-
ined 117 schoolchildren, aged 5 to 12 years, with untreated DSM-IV developmental
coordination disorder (also known as dyspraxia, or informally as clumsiness). Although
none of the children recruited had previously received a clinical diagnosis of ADHD,
cognitive and behavioral ADHD-like symptoms are frequently associated with devel-
opmental coordination disorder, and 31% of the sample at baseline scored 2 standard
deviations above the mean on the DSM-IV total score on the Conners Teacher Rating
Scale (CTRS-L, which assessed each of 59 items of child behavior on a 4-point scale).
The participants were treated with either fish oil (n 560) or placebo (n 557) for
3 months. The daily dose of 6 capsules provided a combination of omega-3 fatty acids
(EPA 558 mg and DHA 174 mg) and omega-6 fatty acid GLA 60 mg, and vitamin E
9.6 mg (in the natural form, a-tocopherol). Placebo treatment consisted of olive-oil
capsules, which were carefully matched to the active treatment in both appearance
and flavor. After 3 months, the placebo group was crossed over to the active supple-
ment, and the active group continued with active treatment, for another 3 months.
74
Outcome variables included learning, literacy (including word reading and spelling),
motor skills, and teacher ratings of behavior linked to ADHD.
Fish-oil supplementation for 3 months did not improve motor skills in these children
with developmental coordination disorder, but fish oil was found to produce significant
improvements in reading, spelling, and ADHD-like symptoms. The mean achievement
scores at baseline for reading and spelling were 1 year below chronologic age in both
fish-oil and placebo groups. Compared with controls, the fish-oil group showed signif-
icant gains in reading age (9.5 13.9 months vs 3.3 6.7 months for placebo, z5
2.87; P<.004), gains in spelling age (6.0 11.4 months vs 1.2 5.0 months for pla-
cebo, z53.36; P<.001), and improved behavior (CTRS-L scores decreased from
75 27 to 58 28; P<.05) over 3 months of treatment. When the placebo group
was crossed over to the active treatment they showed similar improvements, and
the active group continued to improve up to the end of the 6-month trial. Improve-
ments for those children continuing on active treatment between 3 and 6 months
were characterized by a gain in reading age of 13.5 11.9 months and a gain in
spelling age of 6.2 6.8 months. Those children in the active treatment group demon-
strated improvements above their chronologic age (reading age gain 10.9
11.8 months; spelling age gain 5.3 6.9 months). The placebo-to-active crossover
group demonstrated behavioral improvements in teacher ratings (CTRS-L global
scales) at 6 months, comparable with those of the active group after 3 months.
The findings from the Oxford-Durham trial suggest that omega-3/-6 supplementa-
tion may help children with ADHD-like behavioral symptoms and educational diffi-
culties associated with developmental coordination disorder.
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIALS IN
SCHOOLCHILDREN
Other trials have attempted to replicate the findings of the Oxford-Durham study in
either children with symptoms of ADHD or children with actual clinical diagnoses of
ADHD, with less success. For example, in the well-known Adelaide trial, Sinn and
Bryan
76
conducted a randomized, placebo-controlled, double-blind study of 7- to
12-year-olds who did not have a clinical diagnosis of ADHD but were entered into
the study if they scored 2 standard deviations above the mean on the Conners Abbre-
viated ADHD Index.
76
These psychostimulant-free children were randomly allocated
into 1 of 3 groups: (1) an active group (n 541) who were given the same fish-oil sup-
plements used in the Oxford-Durham trial but with an additional multivitamin/mineral
Omega-3 Fatty Acids and Neurodevelopment 567
supplement containing daily recommended amounts; (2) a fish-oil only group (n 536);
and (3) a placebo group (n 527). There were no significant differences between any of
the treatment groups on CTRS scores at either 15 or 30 weeks, but several differences
were observed on the CPRS. Parent ratings at 15 weeks showed mostly moderate
effect sizes in the 2 HUFA groups compared with placebo in 9 of 14 symptom sub-
scales, including DSM-IV inattentive subscale (effect size: 0.61), Conners ADHD Index
(effect size: 0.59), CPRS cognitive problems and inattention (effect size: 0.52), DSM-IV
total (effect size: 0.49), Conners Global Index restless/impulsive (effect size: 0.45),
Oppositional (effect size: 0.43), Conners Global total (effect size: 0.39), DSM-IV hyper-
active/impulsive subscale (effect size: 0.20), and CPRS hyperactivity (effect size:
0.17). The effects on hyperactivity/impulsivity were statistically significant despite
small effect sizes, especially in comparison with the larger effect sizes on cognitive
measures. When the placebo group crossed over to the active fish oil plus micronu-
trient treatment at week 15, parent ratings showed additional significant improve-
ments between weeks 15 and 30 (on 9 of 14 subscales), but once again no
improvement was observed by the teachers. There were no significant differences
in children treated with or without the supplemental micronutrients on parent or
teacher ratings, suggesting that the therapeutic effects on ADHD were due to the
fish oil, and that the vitamin-mineral supplementation did not add to the fish-oil effect.
However, the doses of micronutrients were somewhat low (at or below recommended
daily allowances), which may have accounted for the negative findings. The investiga-
tors interpreted the parent ratings as more reliable than the teacher ratings for several
reasons, including: (1) a high teacher turnover, (2) classrooms being taught by different
teachers on different days, (3) long vacations and service leaves, and (4) children mov-
ing to different schools during their enrollment in the study.
During the Adelaide trial, Sinn and colleagues
75
also conducted neuropsychological
assessments of cognition in the same sample of children. In the HUFA-treated groups,
significant improvements were observed in the ability to switch and control attention
(as measured by the Creature Counting Task) at 15 weeks when compared with pla-
cebo (effect size: 0.43), and a similar change was seen in the placebo group after
switching to active treatment between 15 and 30 weeks (effect size: 0.93; P<.001).
The observed improvements in cognitive performance were found to mediate the
parent-rated improvements in hyperactivity/impulsivity and attention scores. How-
ever, no significant improvements were noted in any other cognitive test in a large
assessment battery.
In short, the Oxford-Durham study found that fish oil did not improve motor skills in
children with developmental coordination disorder, but did improve reading, spelling,
and ADHD-like symptoms such as inattention, hyperactivity, and oppositional
behavior. The Adelaide trial, which was the replication by Sinn and colleagues in chil-
dren with symptoms of ADHD, confirmed that fish oil improved both inattention and
hyperactivity/impulsivity symptoms, but neuropsychological testing showed only
very limited areas of cognitive improvement.
Johnson and colleagues
118
conducted a randomized, placebo-controlled clinical
trial of 75 youths (8–18 years old, 64 boys) with ADHD (35 with the combined type
and 40 with the inattentive type) to evaluate the efficacy of omega-3/-6 fish-oil supple-
mentation in reducing core symptoms of ADHD, and to establish subtypes of re-
sponders based on a detailed evaluation of symptoms and comorbid problems. The
study used the same formula and dose of fish oil, as well as the 1-way crossover
(the placebo group was crossed over at 3 months into the active group for another
3 months) used in the Oxford-Durham and the Adelaide studies. There were 37 ran-
domized to the active group and 38 to the placebo group. The investigators carried
Gow & Hibbeln
568
out a medical examination including psychiatrists’ assessment of diagnosis and co-
morbidity using DSM-IV criteria. The 2 primary outcome measures were the
investigator-rated ADHD Rating Scale IV—Parent version (which has been validated
as a clinician-rated parent interview to allow evaluation of symptom severity across
different settings in addition to clinician’s overall experience of the patients) and the
CGI severity scales.
118
Overall the findings of this study were negative, with a lack
of statistically significant differences in either of the outcome measures between
active and placebo groups at 3 or 6 months. In a post hoc analysis of the diagnostic
subtypes, a higher number of responders were found in the inattentive subtype group
(P5.03) compared with the ADHD combined type group. The inattentive group was
more likely to have a comorbid developmental disorder (eg, reading and writing disor-
der, learning disability, or autistic traits). None of the responders had comorbid
conduct disorder, oppositional defiant disorder, depression, or anxiety.
118
It is unclear
why the subgroup of children with inattentive-type ADHD benefited from the omega-
3/-6 intervention, but a similar pattern was observed in the Adelaide trial, warranting
closer examination in future clinical trials of this potential finding of improved attention.
Omega-3/-6 Relation to Dyslexia
Richardson and Puri
78
conducted an earlier 12-week randomized, double-blind, pla-
cebo-controlled study of 41 previously undiagnosed children (ages 8–12 years) with
high ADHD symptom ratings (according to DSM-IV criteria) and specific learning dif-
ficulties, including dyslexia.
78
The active treatment group (n 522) received omega-
3 (EPA 186 mg, DHA 480 mg) and omega-6 (GLA 96 mg, cis-LA 864 mg, AA 42 mg)
HUFAs, vitamin E 60 IU, and thyme oil 8 mg; and the placebo group (n 519) received
olive oil. At the end of 12 weeks, the treatment group had significantly lower scores
than the placebo group on inattention (effect size: 0.61) and a global behavioral scale
(effect size: 0.58), but not on other measures. However, given the large number of
measures, very few positive findings, lack of adequate power, and a questionable con-
trol (the olive-oil placebo contained bioactive properties), it is unclear whether any firm
conclusions can be drawn from this study.
Omega-3/-6 Studies Relating to Attention and Behavior
Stevens and colleagues
119
conducted a randomized, double-blind, placebo-
controlled study with omega-3 or omega-6 HUFA supplementation in 50 children
(ages 6–13 years) with either a clinical or suspected diagnosis of ADHD. The parents
completed a fatty acid deficiency questionnaire, and children who were rated as hav-
ing 4 or more symptoms of fatty acid deficiency were recruited for the study. The fatty
acid deficiency questionnaire included thirst, frequent urination, dry hair, dandruff, dry
skin, brittle nails, and follicular keratosis, which parents rated on a scale of 1 to 4; Ste-
vens and colleagues
68
had previously used this questionnaire and found significantly
higher scores (P5.0009) in an ADHD group in comparison with a control group.
The children with both ADHD and fatty acid deficiency symptoms were randomized
to receive either an active treatment (DHA 80 mg, EPA 80 mg, AA 40 mg, GLA
96 mg, and vitamin E 24 mg daily) or placebo (olive oil 6.4 mg) for 4 months. HUFA sup-
plementation resulted in a 50% increase in plasma and erythrocyte levels of EPA, DHA,
and vitamin E. HUFA treatment was significantly better than placebo on only 2 of 16
measures: parent-rated conduct problems (42.7% vs 9.9%, n 547; P5.05) and
teacher-rated attention (14.8% vs 13.4%, n 547; P5.03). There were significant
correlations between higher EPA levels and reduced parent-rated disruptive behavior
scores (r50.38, n 531; P.05) and, similarly, correlations between higher EPA or DHA
levels with reduced teacher-rated disruptive behavior (r50.49, n 524; P.05).
Omega-3 Fatty Acids and Neurodevelopment 569
Oppositional behavior scores also showed significant improvements. Although these
findings were not strong, this study suggests that HUFA supplementation may improve
both attention and behavior in children with ADHD or ADHD-like symptoms.
PHARMACOLOGIC INTERVENTION AND OMEGA-3 HUFAS FOR ADHD
There are few studies comparing omega-3 with standard pharmacologic treatment or
exploring the plausibility of HUFAs as an adjunctive therapy for ADHD. Perera and
colleagues
120
recruited 98 children (ages 6–12 years) whose parents reported that
methylphenidate produced no improvement in either behavior or learning, and
randomly assigned them to receive either an omega-3/-6 combination (fish oil
296 mg, evening primrose oil 181 mg) (n 548) or placebo (n 546) containing sunflower
oil in an identical capsule. The children continued their methylphenidate treatment
(0.7–1.0 mg/kg/d) and home-/school-based behavioral interventions throughout the
6-month study period. Both treatment groups also took unspecified micronutrients
to guard against any other potential deficiencies. HUFA treatment improved parent
ratings of both ADHD behavior symptoms (aggressiveness, fighting, restlessness, inat-
tention, easy anger, impulsiveness waiting for turn, cooperation) and learning
(completing work, academic performance) more than placebo in 5 of 11 measurements
at 3 months and in all 11 measurements at 6 months. However, HUFA treatment did not
improve distractibility scores. The largest significant improvements in behavior were
reported for aggressiveness (effect size: 0.98) and restlessness (effect size: 1.11).
Harding and colleagues
121
recruited 20 children (ages 7–12 years) with a clinical
diagnosis of ADHD and nonrandomly allocated them (by parental choice) to methyl-
phenidate (n 510) or a dietary supplementation (n 510) consisting of essential fatty
acids, vitamins, minerals, amino acids, phospholipids, probiotics, and phytonutrients
for a period of 4 weeks. Mean daily doses of methylphenidate were not reported, and
parent ratings were collected but not reported. A nonstandard continuous perfor-
mance test was used. No differences were found between methylphenidate and the
dietary supplementation, and the investigators inferred that the dietary supplementa-
tion and methylphenidate were equivalent in effectiveness. However, because there
was no placebo group, it is possible that the nonstandard continuous performance
testing was unable to measure any clinical change, even by the methylphenidate.
This small open-label study does not permit any inferences about effectiveness.
META-ANALYSES AND REVIEWS OF CLINICAL EFFICACY OF OMEGA-3 HUFAS IN ADHD
To examine the clinical efficacy of omega-3 and omega-6 interventions in child ADHD,
Bloch and Qawasmi
122
conducted a recent meta-analysis of 10 well-designed trials
involving 699 children. To represent effects sizes, the standard mean difference
(SMD) was chosen as the summary statistic for meta-analysis, and calculated by pool-
ing the standardized mean improvement of each study using RevMan 5 (The Cochrane
Collaboration). The exact methodology was applied for the secondary analysis to test
the effect of omega-3 HUFAs on symptoms of inattention and hyperactivity/impulsivity
independently.
This meta-analysis found that omega-3 supplementation had a small but statistically
and clinically significant effect on the treatment of ADHD (effect size SMD 50.31, 95%
CI 0.16–0.47, z54.04; P.001). The meta-analysis also demonstrated similar effect
sizes of omega-3 supplementation in the treatment of both the inattention (SMD 5
0.29, 95% CI 0.07–0.50, z52.63; P.009) and hyperactivity/impulsivity symptom clus-
ters (SMD 50.23, 95% CI 0.07–0.40, z52.78; P.005). When the different omega-3
fatty acids were considered separately, higher doses of EPA (which collectively ranged
Gow & Hibbeln
570
from 80 to 750 mg daily), in comparison with ALA and DHA, were significantly but
modestly correlated with omega-3 efficacy in the treatment of ADHD (b50.36, 95%
CI 0.01–0.72, t52.30; P5.04, R
2
50.37).
122
Doses of other omega-3 HUFAs such
as DHA and ALA were not significantly related to efficacy (DHA: b50.24, 95% CI
0.54–1.02, t50.70, P5.50; ALA: b51.71, 95% CI 4.62 to 1.19, t51.33, P5
.22). The effect size of 0.2 to 0.3 for omega-3 fatty acid supplementation was modest
in comparison with standard pharmacologic interventions for ADHD: The effect size for
psychostimulants is approximately 0.8 (where 0.2–0.3 is small, 0.3–0.5 is medium, and
0.6–0.8 or more is large).
Bloch and Qawasmi
122
raised a critical point regarding adequate power and sample
size, noting that to have sufficient power (b580%, 2-tailed a50.05) to detect a sig-
nificant benefit (effect size of 0.31), clinical trials of omega-3 intervention compared
with a placebo would need a sample size of approximately 330 children. Therefore,
the actual sample sizes in the clinical trials to date are considerably underpowered
and are likely to account for the inconsistent findings in the literature to date. Taking
into consideration the relatively mild side-effect profile, the investigators concluded
that it may be reasonable to use omega-3 fatty acid supplementation to augment
traditional pharmacologic interventions or to treat youth whose families decline other
psychopharmacologic options, despite the evidence of only moderate efficacy.
122
In summary, these clinical studies have been criticized by reviewers, such as the
Cochrane Collaboration, as both inconsistent and fragmentary.
123
This article has
reviewed several randomized, placebo-controlled, double-blind trials, and open-label
or pilot studies, of omega-3 supplementation in child literature. The authors recognize
the wide variation in design and methodological issues, as well as a range of formula-
tions, doses, and durations of supplementation: All of these factors have implications
for interpretation and replication. Some improvements in behavior, concentration,
and literacy have been reported following supplementation with HUFA in various pop-
ulations, including underachieving mainstream schoolchildren with developmental co-
ordination disorder and associated ADHD-like symptoms,
74
community samples of
children with ADHD symptoms,
75,76
and youth with verified clinical diagnoses of
ADHD.
120
The neurophysiologic and imaging research on HUFAs in children is
extremely limited,
77,105–107
with only 2 studies on ADHD. Some evidence suggests
abnormal erythrocyte fatty acid levels in children and young adults with ADHD.
66,69–73
To the best of the authors’ knowledge, there are no published HUFA supplementation
trials in adults with ADHD. Despite several reports of HUFA benefits for symptoms of
ADHD in children, 5 trials have found little or no effect.
107–111
The recent meta-
analysis by Bloch and Qawasmi,
122
which found some efficacy of EPA in improving
ADHD symptoms in children,highlighted the valid point that available studies have small
sample sizes and lack the statistical power to demonstrate a substantive effect size.
Future recommendations include carefully designed clinical trials with longer sup-
plementation periods (ie, 6 months or more) and adequate sample sizes conducted
in both children and adults with ADHD. Sensitive measures, such as event-related
potentials combined with fMRI (owing to their temporal and spatial precision, respec-
tively) may be better suited to capture changes in cortical function.
HUFAS AND YOUTH WITH AGGRESSIVE OR CONDUCT-DISORDERED RELATED
BEHAVIORS
In addition to the putative role of HUFAs in ADHD, there is accumulating evidence that
omega-3 HUFA and other micronutrient (vitamins and minerals) deficits may also be
linked to antisocial and aggressive behaviors.
124–128
Given the comorbidity of conduct
Omega-3 Fatty Acids and Neurodevelopment 571
disorder in ADHD and the overrepresentation of ADHD in incarcerated adults,
129
the
use of HUFAs for treating aggressive and delinquent behaviors deserves serious
examination.
In a recent clinical study, Gow and colleagues
130
recruited a sample of 29 male ado-
lescents (ages 12–16 years) with ADHD, and found a significant association between low
EPA levels and high scores of callous-unemotional traits (r50.597, P5.009), as
assessed by the Inventory of Callous-Unemotional Traits.
131,132
The ADHD group also
showed correlations between highcallous-unemotional scores and oppositional behav-
iors (CPRS subscale: r50.464, P5.011) and low total omega-3 levels (r50.498, P5
.027). Though not quite statistically significant, the ADHD group also showed a trend to-
ward a correlation between low DHA levels and high callous-unemotional scores (r5
0.436, P5.054) and a trend toward an association of low total omega-3 levels and
antisocial behaviors (measured by theAntisocial Process Screening Device). This study
suggests a link between low levels of EPA and high callous-unemotional behavior
related to conduct disorder in male children with ADHD. Callous-unemotional personal-
ity traits are known to represent a distinct developmental vulnerability to persistent anti-
social behavior.
133,134
Further research is needed to investigate whether early
intervention with EPA may benefit youth with callous-unemotional traits, and help pre-
vent the subsequent emergence of conduct disorder.
HUFAs and Young Adult Prisoners
Gesch and colleagues
124
conducted a randomized, double-blind, placebo-controlled
trial on the effects of combined supplementation of HUFAs and micronutrients in a pop-
ulation of 231 young adult prisoners (ages 18 years) treated for a minimum of 2 weeks
(mean duration 142 days). The nutrient supplementation consisted of LA 1260 mg, GLA
160 mg, EPA 80 mg, DHA 44 mg daily, and a broad spectrum of vitamins and minerals
at recommended daily levels. The results revealed that nutrient supplementation
(N 5172) at routine low daily doses produced a marked reduction (35%–37% vs
7%–10% in the placebo group) in antisocial behavior and violent offenses for the active
group in comparison with baseline. This landmark study demonstrated that a nutrient
supplement combining HUFAs and micronutrients can have a pronounced effect on
the problem behaviors in a prison population of young adults (18 years). This study
is instructional in showing that nutritional supplementation can affect major antisocial
and aggressive behaviors, but does not isolate the role of HUFAs in producing this
benefit. The findings of Gesch and colleagues
124
were later replicated and confirmed
in a randomized controlled trial in the Netherlands of 221 young adult prisoners
(mean age 21.0, range 18–25 years) who received comparable nutritional supplemen-
tation (N 5115) over a period of 1 to 3 months.
135
This study produced similar findings
of a nearly 30% reduction in major behavioral and conduct incidents.
135
The efficacy of nutritional supplementation, especially the combination of HUFAs
with vitamins and minerals at routine doses, in producing relatively rapid reductions
in major misconduct has now been shown in these 2 large randomized, double-
blind, placebo-controlled studies in young adult prisoners. Future studies of HUFA
and micronutrient supplementation in prison populations could assess for comorbid
ADHD and mood disorders, and thus determine whether HUFAs produce a direct ef-
fect on conduct and aggression or whether the observed HUFA effects are mediated
by improvements in ADHD or mood. These findings highlight the critical importance of
nutrition and the potentially powerful impact that simple dietary interventions involving
HUFAs (and micronutrients) can have in improving antisocial and major misbehavior in
young adult prisoners. However, more clinical research is needed in youth with ADHD
and/or comorbid conduct disorder to establish whether HUFAs with or without
Gow & Hibbeln
572
micronutrients may be a safe and effective intervention in youth at risk for the devel-
opment of more serious delinquent, violent, and criminal behaviors.
OMEGA-3 HUFA SUPPLEMENTATION TRIALS IN YOUTH AND ADULTS WITH
DEPRESSION
Several lines of evidence in adults support the notion that low omega-3 HUFA deficits
are associated with depression and that omega-3 HUFA supplementation can treat
depression.
77,136,137
Other ecologic studies by the authors’ research group on nega-
tive affect in adult populations are informative, but do not establish causation because
of their correlational nature.
138–140
For example, a cross-national ecologic study re-
ported a highly significant association between low seafood consumption and low
maternal milk DHA composition, with a 50-fold greater risk for postpartum depression
(r50.81, P5.0001).
140
More broadly, in comparing countries with the lowest and
highest consumption of seafood, low omega-3 HUFA intake is associated with a
65-fold higher lifetime risk for depression (r 50.84, P5.0001),
141
a 30-fold higher
risk for bipolar disorder (r50.80, P5.0003),
142
and a 10-fold higher risk for death
from homicide (r50.63, P5.0006).
143
Dietary Intake in Youth with Depressive Symptoms
Only one study provides comparable data in youth. A cross-sectional study evaluated
dietary intake data from food-frequency questionnaires among 3067 boys and 3450
girls (ages 12–15 years) in relation to their depression rating scores using the Center
for Epidemiologic Studies Depression Scale.
144
Boys with depressive symptoms
had a lower mean value of EPA, DHA, vitamin B
6
, and folate. It is uncertain why this
was not observed in girls, but possibilities include a greater heterogeneity of contrib-
uting causes to girls’ depressive symptoms or a more efficient endogenous conver-
sion of ALA to EPA among females in comparison with males.
106
For girls, higher
intake of B vitamins was positively associated with EPA and DHA intake. Fewer
depressive symptoms also appeared to be associated with higher dietary intakes of
riboflavin (in girls), folate, pyridoxine (vitamin B
6
), and (in girls) riboflavin (but not with
vitamin B
12
). In girls, but not in boys, higher riboflavin intakes were associated with
fewer depressive symptoms (odds ratio 0.85, 95% CI 0.67–108; Pfor trend 5.03).
In boys and girls, higher folate and pyridoxine (vitamin B
6
) intakes were associated
with lower risk for depressive symptoms. No clear association was seen with vitamin
B
12
intake.
144
These findings suggest that lower EPA and DHA levels are associated
with depressive symptoms in boys but not girls, and that combined vitamins and min-
eral status may be important than HUFAs in preventing depressive symptoms in youth.
In another study, an apparent association between HUFAs and depression scores in
an adolescent population disappeared after adjusting for lifestyle confounders.
145
Omega-3 in Children with Depression
The only randomized, double-blind, placebo-controlled monotherapy study thus far
to investigate omega-3 HUFAs in child depression was conducted by Nemets and
colleagues.
77
These researchers examined omega-3 HUFAs (EPA 400 mg and DHA
200 mg daily) in 20 children (ages 6–12 years) who completed at least a 1-month trial
and were treated for a total of 16 weeks. The findings reported strong statistically sig-
nificant effects of omega-3 fatty acids. By week 8, omega-3 HUFA treatment was su-
perior to placebo (olive oil) on several depression scales: Greater than 50% reductions
in Childhood Depression Rating Scale (CDRS) scores were observed in 7 of 10 children
treated with omega-3 HUFAs and in none of the 10 placebo-treated children (P5.003,
Omega-3 Fatty Acids and Neurodevelopment 573
Fisher exact test); and remission (CDRS score of <29 at the study end point) was
observed in 4 of the omega-3 HUFA-treated children (P>.05). Further research in chil-
dren and adolescents is needed with larger sample sizes to pursue this promising lead.
Omega-3 in Adults with Depression
Studies in adult depression have examined the use of omega-3 HUFAs as monother-
apy or adjunctive therapy.
146–148
In addition, several meta-analyses and review arti-
cles have evaluated the efficacy of omega-3 HUFAs in reducing depressive
symptoms.
148–154
The overall conclusion is that, much as reported in the ADHD liter-
ature, significant heterogeneity is reported in the omega-3 HUFA formulation, depres-
sion severity, experimental design, and study populations in most of these studies.
149
In these studies, only preparations containing more than 50% EPA appear to be
consistently effective.
151,154,155
Another source of heterogeneity in several meta-
analyses may be the inclusion of negative trials of subjects without clinically significant
depression; the severity of depressive symptoms at study entry is a major determinant
of the ability to detect efficacy of any antidepressant treatment.
156
Meta-analyses of
omega-3 HUFA trials that distinguish clinical and nonclinical populations report anti-
depressant effects among those subjects who have significant depressive symp-
toms.
153
Given the heterogeneity in design and dose formulation, it is difficult to
determine whether omega-3 fatty acids are effective as monotherapies alone or
only as adjunctive therapies in treating major depression.
Ultimately, monotherapy with omega-3 HUFAs may be attractive for child and
adolescent populations in view of their general health benefits, low side-effect profile,
and reports of efficacy in treatment-resistant depression, but caution should be exer-
cised, as data are insufficient to support a recommendation for treating major depres-
sion in youth.
Omega-3 and Suicide
Several studies in adults suggest that omega-3 HUFAs might have some clinical value
in reducing suicidal thinking and attempts.
157,158
Sublette and colleagues
159,160
demonstrated that low levels of DHA plasma strongly predicted future suicide risk,
and were associated with both hyperfunction of the limbic forebrain and hypofunction
of the parietal and temporal cortex. In a case-control study of 1600 active-duty US
Military personnel, low DHA status was a significant risk factor for suicide death.
158
All US Military personnel in this study had low omega-3 HUFA levels in comparison
with North American, Australian, Mediterranean, Chinese, and other Asian civilian
populations. These military personnel had a significantly higher odds of a suicide
attempt (odds ratio 4.8, 95% CI 1.7–14.3; P<.0003) compared with the highest quar-
tile
161
of the Chinese population. In view of these promising data in adults, a $10
million trial on the efficacy of omega-3 HUFAs (4 g daily) for the prevention of signifi-
cant suicidal behaviors among US Military veterans is currently being conducted at the
Medical College of South Carolina; it is being conducted in collaboration with the Na-
tional Institute on Alcohol Abuse and Alcoholism (NIAAA), and funded by the Defense
Medical Research Program at the US Department of Defense. To the best of the au-
thors’ knowledge, no trials of omega-3 fatty acids in relation to attempted suicide have
yet been conducted in youth.
OMEGA-3 HUFA AND PREVENTION OF PSYCHOSIS IN HIGH-RISK YOUTH
Among the most interesting new developments is the potential for omega-3 HUFA
treatment to prevent adolescents at high risk for psychosis from transitioning to
Gow & Hibbeln
574
schizophrenia. In a study of 81 adolescents at ultra-high risk for psychotic disor-
der,
162
participants were randomized to omega-3 PUFA (1.2 g daily) or placebo for
a 12-week active intervention period, followed by a 40-week monitoring period. At
the end of the 12-month study, transition to a psychotic disorder occurred in only
2 of 41 individuals (4.9%) in the omega-3 group, but in 11 of 40 (27.5%) in the placebo
group (P5.007). For example, the reduction in transition to psychosis was reduced
by 22.6% in that 12-month period (95% CI 4.8–40.4). The omega-3 HUFA intervention
significantly reduced positive symptoms (P5.01), negative symptoms (P5.02), and
general symptoms (P5.01), and improved functioning (P5.002) in comparison with
the placebo group. Changes in intracellular phospholipase A
2
(PLA
2
) activity (key en-
zymes in phospholipid metabolism that release fatty acids from the second carbon
group of glycerol) and erythrocyte membrane fatty acids comparing the omega-3
HUFAs and placebo groups were investigated as a potential mechanism of action.
The levels of membrane omega-3 and omega-6 PUFAs, and PLA
2
(from pre- to post-
treatment) were significantly related to functional improvement, as indicated by
increased Global Assessment of Functioning scores between baseline and the study
end point at 12 weeks. Supplementation with omega-3 PUFA also resulted in a sig-
nificant decrease in PLA
2
activity. This study is the first to demonstrate that a 12-week
intervention trial with omega-3 fatty acids significantly reduced the transition rate
from the prodromal stage to psychosis, and furthermore resulted in significant func-
tional and symptomatic improvements during the entire follow-up period of
12 months.
162
Replication of these findings is currently being attempted in a multina-
tional multisite trial.
CLINICAL RECOMMENDATIONS IN RELATION TO HUFAS
Clinicians can currently be guided by the 2006 treatment recommendations of a sub-
committee of the Committee on Research on Psychiatric Treatments of the American
Psychiatric Association that adults with major depression and other psychiatric ill-
nesses should minimally consume 1 g daily of omega-3 HUFAs or consume seafood
2 to 3 times per week, if only because these patients are at high risk for cardiovascular
and other medical illnesses.
148
In a more recent 2010 report of the Task Force on
Complementary and Alternative Medicine of the American Psychiatric Association,
120
certain alternative treatments for adults with major depressive disorder showed prom-
ising results, such as omega-3 fatty acids, hypericum (St John’s wort), S-adenosyl-L-
methionine (SAMe), folate, acupuncture, mindfulness psychotherapies, light therapy,
and exercise. In relation to omega-3 fatty acids, this review recommended that
more research is necessary to clarify whether EPA is more effective than EPA plus
DHA, optimum doses, and the value of fresh fish intake versus capsules. It also high-
lighted the need for preventive studies and the evaluation of omega-3 as a treatment
intervention in recurrent major depressive disorder both as an adjunct and monother-
apy. The American Psychiatric Association report also highlighted concerns about
confounding variables, such as smoking (which can inhibit absorption of omega-3s
into red blood cells) and methods to control for total omega-3 intake obtained from
the diet in research trials.
120
CAUTIONARY FINDINGS ON OMEGA-3 SUPPLEMENTATION
Not all research is clear-cut, of course, and negative findings can be as important and
insightful as positive outcomes. Several studies that have investigated HUFAs in
behavior, ADHD symptoms, school attendance, and physical aggression in youth
have reported little or no effect of omega-3 supplementation.
107–111
Omega-3 Fatty Acids and Neurodevelopment 575
Hirayama and colleagues
108
conducted a randomized, double-blind, placebo-
controlled study in 40 children (aged 6–12 years) with ADHD who were placed on a
specific diet (fermented soybean milk, steamed bread, and bread rolls) that was forti-
fied with either fish oil (n 520, containing DHA 514 mg daily) or placebo (n 520, olive
oil 1300 mg daily). At baseline and 2 months later, measurements were obtained of
DSM-IV ADHD symptoms (hyperactivity, impulsivity, inattention), aggression (reported
by teachers and parents), visual perception, visual and auditory short-term memory,
visual-motor integration, a continuous performance task measuring sustained atten-
tion, and impatience. After 2 months of treatment, the DHA treatment group did not
improve on any ratings of ADHD-related symptoms in comparison with the olive-oil
group. In fact, the DHA group showed significantly less improvement on commission
errors on the continuous performance test (a marker of impulsivity) and on visual short-
term memory. These negative results highlight several methodological issues:
The selection of fatty acid supplement. Although the dose of DHA was moderate,
previous studies using DHA-rich oils have also been found to be ineffective at
improving cognitive functioning and ADHD-type symptoms. It seems that DHA
alone may not be effective in ameliorating ADHD symptoms. The dose of EPA
(100 mg daily) in the fish-oil group was extremely low and unlikely to have any
noticeable effect.
Choice of placebo. Olive oil is bioactive, with known anti-inflammatory and anti-
oxidant effects, so its use as a control treatment is questionable. There was no
indication of the amount of DHA or EPA that was received by the placebo-
treated group in their fortified diet or olive oil.
Bioavailability of the fatty acids. Arguably the fortification process may have low-
ered the bioavailability of the fatty acids, whereas a direct source of HUFAs
would be more potent.
Short duration of treatment. Without knowing the presupplementation levels of
blood fatty acids, it is difficult to know whether a trial longer than 2 months
was needed to correct a nutrient deficiency.
There is such wide variation of EPA and DHA that researchers would be advised to
measure it in finger-prick blood tests so as to allocate a more appropriate dose.
Itomura and colleagues
163
conducted a randomized, double-blind, placebo-
controlled trial to test whether fish oil could reduce aggression in a normative popu-
lation of 166 schoolchildren (ages 9–12 years). Similarly to the study by Hirayama and
colleagues,
108
the participants were randomized to receive fortified foods with fish oil
(bread, sausage, and spaghetti containing DHA 514 mg plus EPA 120 mg daily) or pla-
cebo (n 583) for 3 months. A self-rated questionnaire did not identify an effect of fish
oil on physical aggression (although physical aggression ratings increased in girls in
the control sample). When aggressive tendencies were assessed by psychological
testing, fish oil had the unexpected effect of appearing to increase aggressive re-
sponses, whereas the controls remained unchanged. When DSM-IV ADHD behav-
ioral impulsivity symptoms were assessed by parents, fish oil appeared to reduce
impulsivity in girls (relative to controls) but not in boys. The findings paint a somewhat
mixed and confusing picture, and suggest a variety of methodological problems,
especially in the assessment instruments, in addition to the questions raised by the
Hirayama study. Furthermore, in this study the investigators mention that a control
sausage contained EPA 40 mg and DHA 80 mg, but clearly control foods should
not have contained any of the active omega-3 intervention at all. Otherwise, this
means that the placebo was not a true placebo, a problem that was not adequately
discussed by the investigators. Furthermore, both groups received the omega-6 LA
Gow & Hibbeln
576
(514–1114 mg daily). The addition of LA in the fish oil group is a major confounder,
because omega-3 and omega-6 compete for incorporation into the red blood cells,
and a higher amount of one would suppress the absorption of the other. In this
case, omega-6 would have likely been the dominant fatty acid in the diet.
Both of these studies are extremely problematic from a methodological point of
view, so it is difficult to know how seriously to accept their somewhat contraintuitive
and inconsistent findings; nevertheless they are mentioned here, mainly for
completeness.
A final study by Hamazaki and colleagues
164
examined the effects of DHA-rich fish
oil on behavior and school attendance in a randomized, double-blind, placebo-
controlled trial in schoolchildren (aged 9–12 years) in Indonesia, who received either
omega-3 supplementation (DHA 650 mg and EPA 100 mg, n 5116) or placebo (soy-
bean oil capsules, n 5117). Omega-3 supplementation did not appear to improve
measures of aggression or impulsivity relative to placebo treatments. However, inter-
estingly school absenteeism appeared to be reduced in the children treated with
DHA-rich fish oil relative to the control group (odds ratio 0.40, 95% CI 0.23–0.71;
P5.002). Although the effects of nutritional supplementation on endemic diseases
might conceivably have been a mediating factor, this particular finding warrants further
exploration because school absenteeism is often linked with depression and anxiety in
Western populations.
Collectively, these studies suggest that DHA-rich formulas show little or no effect in
improving aggressive behaviors, ADHD symptoms, or cognitive performance,
although these studies are particularly problematic from a methodological point of
view. The fortified food studies seemed the least promising, and it is probably prefer-
able to use more directly quantifiable sources of omega-3 fatty acids. Moreover, it may
be speculated that a higher EPA-to-DHA ratio is needed for treating schoolchildren,
consistent with the findings of a recent meta-analysis suggesting that higher EPA is
associated with better clinical efficacy in improving symptoms of ADHD-type
behavior.
122
More research is needed to answer these basic questions about dose
and formulation in child populations.
SAFETY AND ADVERSE EFFECTS
Omega-3 supplementation is considered to be a safe intervention by the FDA, which
currently advises that dietary dosage of up to 3 g daily of omega-3 fatty acids from ma-
rine sources are “Generally Recognized as Safe” (GRAS). The European Food Safety
Authority has set a safe upper limit of 5 g daily for total omega-3 fatty acids, including
DHA, EPA, and docosapentaenoic acid. These standards are set for adults, with no
separate designations for children or adolescents.
At present, there is no established procedural system for reporting adverse events
of food supplements, so systematically collected information is not available on a na-
tional scale. Several omega-3 products have been approved by the FDA for marketing
in the United States as medications rather than as food supplements, and the
manufacturing companies have reported mostly minor but some severe side effects.
In addition, there is some information about adverse effects from clinical research tri-
als, some of which use relatively higher omega-3 dosing regimens. Given the lack of
systematic data, the monitoring of adverse effects in research and clinical settings
should receive higher prioritization. Nonetheless, some general observations on
adverse effects can be made (Table 1).
Omega-3 fatty acids can increase the incidence of excessive bleeding, including
gastrointestinal bleeding and even hemorrhagic stroke. For patients who are
Omega-3 Fatty Acids and Neurodevelopment 577
anticipating surgery, it is advisable to ensure that surgeons are aware of when their
patients are consuming HUFAs, because many surgeons will want to discontinue their
use 3 to 7 days before surgery, depending on the type of surgery.
Gastrointestinal effects of omega-3 fatty acids are common, and may include loose
stools, diarrhea, nausea, vomiting, and reduced appetite; some of these adverse ef-
fects may be mitigated by administration with meals or more gradual dose elevation.
Omega-3 HUFAs may have hepatoprotective properties, and have been used to treat
nonalcoholic fatty liver disease; however, there have been reports of increased liver
transaminases (mainly alanine aminotransferase).
Short-term memory loss and headache have been reported, although increasing the
EPA-to-DHA ratio has been reported to be a possible treatment for headache.
165
Chronic treatment with HUFAs can cause vitamin E deficiency, so many clinicians
provide advice about concurrent supplementation with vitamin E, especially at higher
HUFA doses. Moreover, many commercial HUFA products include vitamin E as a pre-
servative to reduce oxidation.
Many patients object to the fishy odor of some products, a result of the vulnerability
of fatty acids to oxidation, which is especially problematic when weak manufacturing
processes are used. High-quality preparations are also recommended to reduce the
risks of exposure to potential contaminants, including mercury, dioxins, and poly-
chlorinated biphenyls, although many products are now manufactured in accordance
with WHO standards, which call for methods to reduce contaminants.
It should be emphasized that most data on the adverse effects of omega-3 HUFAs
are derived from observations on adults, and the side-effect profile might be some-
what different in children and adolescents.
SUMMARY
Western diets can lead to imbalances in HUFA metabolism and alter molecular sub-
strates in the brain. Omega-3 insufficiency and omega-6 excess can have particularly
important effects on brain development, structure, and functioning. Malnutrition and
inadequate nutrient intakes are well-established risk factors for both impaired cogni-
tive development and adverse behavioral outcomes.
The case for nutritional intervention to reduce the burden of ADHD, aggressive and
delinquent behaviors, and, possibly, major depressive disorder in youth is promising,
but the research data at present are mainly suggestive. In adults, omega-3 HUFA
Table 1
Potential adverse effects of omega-3 HUFA supplementation
Common (1%–10%) Dyspepsia, nausea, diarrhea, increased bleeding
Uncommon
(0.1%–1%)
Gastrointestinal symptoms, upper abdominal pain, allergic
hypersensitivity, dizziness, headache, increased low-density
lipoprotein levels, increased alanine aminotransferase levels, mania,
depression
Rare (1/1000 to
1/10,000)
Hyperglycemia, headache, gastrointestinal pain, hepatotoxicity, acne,
pruritic rash, ventricular tachycardia
Very rare
(<1/10,000)
Hypotension, urticaria, nasal dryness, gastrointestinal hemorrhage,
hemorrhagic stroke, increased blood lactate dehydrogenase,
hemolytic anemia
Frequency figures are estimates for the general population, and certain individuals may be espe-
cially vulnerable based on their medical status, concurrent medication usage, and other individual
factors.
Gow & Hibbeln
578
supplementation is an inexpensive and safe adjunctive treatment for reducing symp-
tom severity in mood disorders
146,166
and depression.
147
The role of omega-3 in adults
with ADHD has not yet been investigated, but current research efforts are being under-
taken by the authors’ research team in the Section of Nutritional Neurosciences at the
National Institutes of Health.
In applying the early intervention research to clinical practice, it is notable that
omega-3 HUFAs are considered GRAS by the FDA in doses up to 3 g daily for adults,
with no added specifications concerning children. This designation does not indicate
that higher levels are unsafe, but rather that most cardiovascular and other health ben-
efits are likely to have been achieved by that level of intake.
The American Psychiatric Association has recommended at least 1 g daily of
omega-3 fatty acids, based on likely benefits for patients with certain psychiatric con-
ditions as well as its more general medical benefits, but it has offered no specific rec-
ommendations for youth.
148
International guidelines recommend the consumption of a
minimum of dose of 200 mg of DHA daily for pregnant and lactating women
167
to sup-
port the developing nervous system, but the authors are not aware of similar recom-
mendations for children and adolescents. The Dietary Guidelines for Americans, 2010
recommend consumption of seafood 2 to 3 times per week for children.
1
For children
who refuse to eat fish, dietary supplements, fortified foods, or smoothie drinks may be
more feasible sources to ensure daily recommended allowances.
In selecting a particular formulation of omega-3 fatty acids, clinicians should be
aware that there are marked differences in quality among manufacturers. Total con-
centrations and ratios of omega-3 HUFAs vary widely across commercially available
products (Table 2). In old, spoiled, or poorly manufactured products, oxidized omega
Table 2
Contents and ratios of omega-3 HUFAs vary widely across commercially available products
Total Oils in Capsules/
Serving
Total
Omega-3
HUFA (mg)
EPA
(mg)
DHA
(mg)
%ofEPAin
Total Omega-3
HUFA
No. of Capsules
Needed to Deliver
HUFA at 2 g Daily
Daily
Cost
Unconcentrated fish oil
(1000 mg capsules)
300 120 180 40 7 caps $
Molecularly distilled
(1000 mg capsules)
500 300 200 60 4 caps $$
Highly purified
(1100 mg capsules)
1000 600 400 60 2 caps $$$
Algal oils (625 mg capsules) 500 180 320 36 4 caps $$$
Algal oils (500 mg capsules) 200 0 200 w100 10 caps $$$
Liquid oil (highly
concentrated)
(1 teaspoon 55 mL)
2510 1450 1060 58 3/4 teaspoon $$
Emulsion (highly
concentrated) (15 mL
serving)
1500 910 590 60 20 mL (1.25
tablespoons)
$$$
Sardines, canned in oil
(3.75 oz [106.3 g])
921 435 486 47 2 cans $
Salmon, Atlantic, farmed,
broiled (3 oz [85 g])
1824 586 1238 32 3.3 oz (93.5 g) $$
White tuna, canned (3 oz
[85 g])
733 198 535 27 8 oz (227 g) $
Omega-3 eggs (1 egg, 50 g) 130 5 125 4 15 eggs $
Omega-3 Fatty Acids and Neurodevelopment 579
fatty acid HUFAs smell strongly of adverse fish odors. Fresh preparations have a clean
smell akin to fresh seafood, unless masked by other natural flavors such as lemon,
lime, or strawberry, and are more desirable to consume. Naturally flavored emulsions
or capsules may also be beneficial to children or adults with olfactory neurosensory
issues. In addition, honey placed on broiled salmon (or any fish) may increase the likeli-
hood of consumption by children.
Owing to the small number of well-powered trials in adults and youth, more research
is needed to better determine the optimal ratios and doses of EPA and DHA. Most
studies indicate that symptom improvement in adults with depression and youth
with ADHD symptoms is more likely using preparations containing higher levels of
Box 1
Explanation of modified US Preventive Services Task Force (USPSTF) grading system used in
Tables 3 and 4
Tables 3 and 4use a modified form of the USPSTF system
Each treatment is assigned a grade for “Quality of Evidence” and a grade for “Strength of
Recommendations”
The Quality of Evidence grade is a qualitative ranking of the strength of the published evidence
in the medical literature regarding a treatment:
Good: Consistent benefit in well-conducted studies in different populations
Fair: Data show positive effects, but weak, limited, or indirect evidence
Poor: Cannot show benefit owing to data weakness
The Strength of Recommendations grade provides a qualitative ranking of the clinical
recommendations that can be drawn from findings of the studies:
Insufficient data
Recommend against: Fair evidence of ineffectiveness or harm
Neutral: Fair evidence for, but appears risky
Recommend: Fair evidence of benefit and safety
Recommend strongly: Good evidence of benefit and safety
Adapted from U.S. Preventive Services Task Force Grade Definitions. May 2008. Available at:
http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm. Accessed February 26, 2014.
Table 3
Evidence-based treatment evaluations derived from the medical literature (quality of
evidence/strength of recommendations for each treatment and indication)
EPA Alone DHA Alone Fish Oil
ADHD Good/Recommend Insufficient data Fair/Recommend
Depression Fair/Recommend Poor/Insufficient data Fair/Recommend
Aggression/Defiance Fair/Insufficient data Insufficient data Fair/Recommend
Cognitive parameters Fair/Insufficient data Insufficient data Good/Recommend
Dyspraxia Insufficient data Insufficient data Good/Recommend
Basis for ADHD in youth Multiple RCTs Multiple RCTs Meta-analyses
Levels of evidence based on US Preventive Services Task Force: http://www.uspreventiveservicestask
force.org.
Gow & Hibbeln
580
EPA than DHA. The mechanisms of action of this tentative clinical finding are not well
understood.
Supplementation with omega-3 fatty acids has proved to be safe, easy to use, and
relatively inexpensive and, despite open questions regarding mechanisms of action
in different psychiatric disorders, these treatments have a clear biological rationale.
Preparations that are EPA-rich (as opposed to DHA-rich) appear to be linked to
improvement in symptoms of both affect and cognition. However, more well-
powered studies are needed in youth with ADHD, conduct disorder, and mood dis-
orders before clinical treatment recommendations can be made (Box 1,Tables 3
and 4).
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Table 4
Expert clinical opinion regarding HUFA treatment of ADHD (quality of evidence/Strength of
recommendations for each treatment and indication)
Treatment ADHD Opinion
EPA >60% Good/Recommend Effects are consistent, but not as large as stimulant
medications
DHA >60% Insufficient data Case reports for decreased anxiety and disruptive behaviors
are encouraging
Fish oil Fair/Recommend Effects may be larger for aggression and mood than for
inattention
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