Effect of Supplementation with Polyunsaturated Fatty Acids and Micronutrients on Learning and Behavior Problems Associated with Child ADHD

Article (PDF Available)inJournal of Developmental & Behavioral Pediatrics 28(2):82-91 · April 2007with1,034 Reads
DOI: 10.1097/01.DBP.0000267558.88457.a5 · Source: PubMed
Various developmental problems including attention-deficit/hyperactivity disorder (ADHD) have been linked to biological deficiencies in polyunsaturated fatty acids (PUFAs). Additionally, there is evidence that symptoms may be reduced with PUFA supplementation. This study investigated effects of supplementation with PUFAs on symptoms typically associated with ADHD. Because nutrients work synergistically, additional effects of micronutrient supplementation were also investigated. A total of 132 Australian children aged 7 to 12 years with scores > or = 2 SD above the population average on the Conners ADHD Index participated in a randomized, placebo-controlled, double-blind intervention over 15 weeks, taking PUFAs alone, PUFAs + micronutrients, or placebo. Due to unreturned questionnaires, data were only available for 104 children. Significant medium to strong positive treatment effects were found on parent ratings of core ADHD symptoms, inattention, hyperactivity/impulsivity, on the Conners Parent Rating Scale (CPRS) in both PUFA treatment groups compared with the placebo group; no additional effects were found with the micronutrients. After a one-way crossover to active supplements in all groups for a further 15 weeks, these results were replicated in the placebo group, and the treatment groups continued to show significant improvements on CPRS core symptoms. No significant effects were found on Conners Teacher Rating Scales. These results add to preliminary findings that ADHD-related problems with inattention, hyperactivity, and impulsivity might respond to treatment with PUFAs and that improvements may continue with supplementation extending to 30 weeks.
Effect of Supplementation with Polyunsaturated Fatty Acids
and Micronutrients on Learning and Behavior Problems
Associated with Child ADHD
Natalie Sinn, PhD*†, Janet Bryan, PhD†
ABSTRACT: Methods: Various developmental problems including attention-deficit/hyperactivity disorder
(ADHD) have been linked to biological deficiencies in polyunsaturated fatty acids (PUFAs). Additionally, there is
evidence that symptoms may be reduced with PUFA supplementation. This study investigated effects of sup-
plementation with PUFAs on symptoms typically associated with ADHD. Because nutrients work synergistically,
additional effects of micronutrient supplementation were also investigated. A total of 132 Australian children
aged 7 to 12 years with scores >2 SD above the population average on the Conners ADHD Index participated in
a randomized, placebo-controlled, double-blind intervention over 15 weeks, taking PUFAs alone, PUFAs
micronutrients, or placebo. Due to unreturned questionnaires, data were only available for 104 children.
Results: Significant medium to strong positive treatment effects were found on parent ratings of core ADHD
symptoms, inattention, hyperactivity/impulsivity, on the Conners Parent Rating Scale (CPRS) in both PUFA
treatment groups compared with the placebo group; no additional effects were found with the micronutrients.
After a one-way crossover to active supplements in all groups for a further 15 weeks, these results were
replicated in the placebo group, and the treatment groups continued to show significant improvements on CPRS
core symptoms. No significant effects were found on Conners Teacher Rating Scales. Conclusion: These results
add to preliminary findings that ADHD-related problems with inattention, hyperactivity, and impulsivity might
respond to treatment with PUFAs and that improvements may continue with supplementation extending to 30
(J Dev Behav Pediatr 28:82–91, 2007) Index terms: attention-deficit/hyperactivity disorder, attention, behavior, polyunsaturated fatty acids, micronutrients.
The aim of this study was to investigate effects of
polyunsaturated fatty acids (PUFAs) and micronutrients
on cognitive and behavioral problems associated with
attention-deficit/hyperactivity disorder (ADHD). ADHD is
one of the most prevalent developmental disorders in
childhood, and finding safe and effective treatments pre-
sents a challenge to both practitioners and parents. More
commonly diagnosed in boys, major symptoms include
poor impulse control, hyperactivity, and/or difficulty in
sustaining attention. Prevalence rates vary, possibly due
to diagnostic inconsistencies, and are estimated at 5% to
10% in Europe,
3% to 7% in the United States,
and 11%
in Australia.
Problems associated with ADHD can adversely affect
school performance, families, relationships, and social
interactions. ADHD is also associated with cognitive def-
icits and specific learning disabilities in math, reading, or
spelling. These children may have poor self-discipline and
low self-esteem, and at least half of children with ADHD
experience comorbidities with psychiatric problems in-
cluding anxiety, mood disorders, and antisocial problems
such as conduct disorder and oppositional defiant disor-
which can later lead to antisocial behavior and
substance abuse. It is believed that two thirds of children
will carry problems associated with ADHD into adult-
There is emerging evidence that ADHD and other neu-
rodevelopmental disorders such as dyspraxia, dyslexia,
and autism, as well as mood disorders, are associated with
deficiencies in omega-3 fatty acids.
Omega-3 (n-3) and
omega-6 (n-6) fatty acids constitute the group of polyun-
saturated fatty acids. PUFAs are essential fatty acids be-
cause they cannot be synthesized by humans and must be
provided via dietary sources. They are key constituents of
all cellular and intracellular membranes or phospholipids,
where they perform vital structural and chemical func-
tions. PUFAs, available in various vegetables, nuts, and
seeds, can be converted to some degree by humans into
long-chain (LC) PUFAs, which can also be derived directly
from the diet via fish oil. However, research indicates that
dietary intake of n-3 fatty acids has been declining in
Western societies,
as well as other micronutrients
that might be required for the metabolism of PUFAs.
See related Commentary on page 139 of this issue.
From *Commonwealth Scientific and Industrial Reasearch Organization Human
Nutrition, Adelaide, South Australia; and †University of South Australia, School of
Psychology, Adelaide, South Australia.
Received May 2006; accepted January 2007.
This study was made possible with the support of the University of South Australia
and CSIRO Human Nutrition. Equazen UK and Novasel Australia supplied fatty acid
supplements and Blackmores Australia supplied multivitamin/mineral tablets.
Address for reprints: Natalie Sinn, Nutritional Physiology Research Center, University
of South Australia, GPO Box 2471, Adelaide SA 5001, Australia, e-mail:
Copyright © 2007 Lippincott Williams & Wilkins
Original Article
82 Polyunsaturated Fatty Acids and ADHD-Related Symptoms Journal of Developmental & Behavioral Pediatrics
Furthermore, in clinical populations, there is evidence
that these people may have genetic difficulties with me-
tabolizing PUFAs
and therefore have higher than nor-
mal PUFA requirements.
LC-PUFAs are highly active and are concentrated in the
brain and nervous system. The most abundant LC-PUFA in
the brain is docosahexaenoic acid (DHA), from the n-3
group, which is particularly concentrated at nerve cell
synapses where it appears to be involved in neural cell
signaling and neurotransmitter processes.
taenoic acid (EPA), a DHA precursor, is also believed to
play important roles in the brain, along with n-6 PUFA,
arachidonic acid (AA), and gamma-linolenic acid (GLA).
Accordingly, deficiencies in essential fatty acids have
been associated with a range of psychiatric problems
including developmental disorders.
Importantly, there
is evidence that supplementation of these essential fatty
acids can alleviate symptoms associated with these con-
The link between hyperactivity and PUFA deficiency
was first proposed by Colquhoun and Bunday.
then, a number of researchers have reported lower PUFA
levels in blood indices of hyperactive children compared
with matched controls.
Five randomized, placebo-
controlled supplementation studies among children dis-
playing ADHD-related symptoms
have produced
inconsistent results. This could be attributable to varia-
tions in sample sizes, exclusion criteria, ratios, and doses
of n-3 and n-6 fatty acids, length of supplementation, and
baseline fatty acid status. A review of these studies is
provided by Richardson.
Two studies have found significant improvements with
PUFA supplementation in children with ADHD-related
symptoms on Conners ADHD Rating Scales
; a pilot
and a placebo-controlled, double-blind trial re-
cently completed in Durham, UK.
The latter study was
conducted with 117 children with developmental coor-
dination disorder. One third of this sample had scores 2
SD above the population mean on the DSM-IV ADHD
symptoms subscale of Conners Teacher Rating Scale
(CTRS). Across the whole sample, significant treatment
effects were observed for teacher ratings of inattention,
hyperactivity, restlessness/impulsivity, anxiety/shyness,
and oppositional behavior in the PUFA treatment group
compared with a placebo group over 3 months. There
were also significant improvements in reading and spell-
ing. Following a one-way crossover to active treatment,
the placebo group demonstrated similar improvements,
while the original treatment group’s mean scores contin-
ued to improve.
Both of these studies used fish oil supplements con-
taining n-3 fatty acids EPA and DHA along with n-6 fatty
acids AA and GLA. This combination has so far had the
most effective outcomes in PUFA research with ADHD
symptoms. The present study aimed to extend this re-
search by investigating the effect of supplementation
with these PUFAs on children with ADHD-related symp-
toms as identified on Conners ADHD Index, which is
recommended for screening children who may qualify for
a clinical diagnosis of ADHD.
This study also aimed to
investigate any additional effects derived from supple-
mentation with micronutrients. All nutrients required by
the body interact with each other in their metabolism and
so supplementation with PUFAs might not
yield maximum benefits if other nutrients are lacking.
Effective PUFA metabolism relies on other nutrients such
as vitamins C, B
, and B
and the minerals zinc and
; and zinc, B
, and vitamin C are involved in
the PUFA role of synthesizing prostaglandins, chemicals
with important biological roles in brain function. Tacconi
et al
add B
, folates, and B
to this list of vitamins
involved in lipid synthesis. Given that many children have
nutritional deficiencies,
and specifically many chil-
dren with ADHD, for instance, are deficient in zinc
this might have an important bearing on the effi-
cacy of nutritional supplementation.
Therefore, this study compared the effect of 15 weeks
of supplementation with PUFAs alone, PUFAs with a com-
mercially available multivitamin/mineral (MVM) supple-
ment that contained the nutrients outlined above, or
placebo on problems with attention and behavior that are
typically associated with (but not necessarily diagnosed
as) ADHD. Furthermore, the additional effects of a further
15 weeks of supplementation with PUFAs and micronu-
trients in all groups were investigated. It was hypothe-
sized that (1) PUFA supplementation (with or without
MVM) would result in improvements in parent and
teacher ratings of attention and behavior on Conners
Parent and Teacher Rating Scales–Long Versions com-
pared with placebo, (2) PUFA MVM supplementation
would show additional improvements over and above
PUFAs alone, and (3) the placebo group would show
significant improvements during phase 2 similar to those
seen in the two active groups in phase 1, and that after an
additional 15 weeks of supplementation, both PUFA
groups would continue to improve.
A total of 201 children in South Australia aged 7 to 12
years were registered by their parents for the study, of
whom 182 attended their first appointment. Of those, 167
children (128 boys, 39 girls) had scores 2 SD above the
general population average (derived from a normative sam-
ple of 8000 children in the United States and Canada) on
Conners ADHD Index.
Thirty-five of this group dropped
out during the first 15 weeks, and subsequently a further 23
dropped out. Therefore, 132 children completed the first
15-week phase of the study, and a total of 109 completed
the 30 weeks, although data were only available for 104 and
87 of these children, respectively, due to unreturned parent
questionnaires as detailed under Results.
Participants were told they could withdraw at any time
without giving a reason. From information volunteered by
parents, however, attrition was mainly due to noncom-
pliance, and some children were prescribed stimulant
medication, which was an exclusion criterion. A
ysis on study compliance revealed that there were no
significant differences in dropout rates between the
1.91, p .75 during the first or second
Vol. 28, No. 2, April 2007 © 2007 Lippincott Williams & Wilkins 83
phase of the study (N 167). There was also no differ-
ence in the age of children who pulled out before or
during the study, F(2,179) 0.99; p .37. However,
comparison of baseline scores on Conners Index, com-
pleted by parents upon registration for the study, found
that children who withdrew either before starting (mean
28.97) or before the end of phase 1 (mean 28.74)
had significantly higher scores than children who com-
pleted phase 1 (mean 26.27) or the whole study (mean
25.65), F(3,195) 3.37, p .02.
Participants scored on average above the 90th percen-
tile for social problems on Conners parent indices and
between the 74th and 90th percentiles on emotional
lability, anxious/shyness, and perfectionism. Table 1
shows participant demographics for each group. There
were no significant differences between the groups on
background variables at baseline except for parent ratings
of health, for which the placebo group had higher scores
than the polyunsaturated fatty acid (PUFA) group.
Inclusion/Exclusion Criteria
Children were included in the study if they were be-
tween the ages of 7 and 12 years and had scores 2SD
above the general population average (above the 90th
percentile) on Conners abbreviated ADHD Index,
which assesses problems with hyperactivity, impulsivity,
and attentional/cognitive problems. They were excluded
if they were taking any form of stimulant medication and
if they had taken any form of omega-3 supplementation in
the previous 3 months.
Children were recruited via media releases, newspaper
advertisements, and school newsletters advertising for
children aged 7 to 12 years with attention-deficit/hyper-
activity disorder (ADHD)–related learning and behavioral
difficulties (but not necessarily diagnosed). Parents were
given the 12-item Conners ADHD Index
upon registra-
tion to determine their child’s eligibility for the study. As
children were registered for the study, they were catego-
rized according to their age and gender and then within
each age/gender category randomly allocated in sequen-
tial order to one of three experimental conditions. Upon
commencement of the study, parents were required to
complete a background questionnaire and Conners Par-
ent Rating Scale–Long Version (CPRS-L) at baseline (week
0) and the CPRS-L at weeks 15 and 30. School principals
and teachers were contacted about those children taking
part to seek permission for the teachers to complete the
teacher questionnaires. Teachers were given the Conners
Teachers Rating Scale–Long Version (CTRS-L) to com-
plete at weeks 0, 15, and 30. Children’s height and weight
were taken at weeks 0, 15, and 30 to calculate their body
mass index, which was converted into age- and gender-
appropriate percentiles.
They were also given a range of
individual cognitive assessments at 0, 15, and 30 weeks
(to be reported in a separate publication) at the Common-
wealth Scientific and Industrial Research Organisation
(CSIRO) Human Nutrition, which included tests that
were used as an IQ estimate in the present study. At
baseline, parents were given supplements or placebo,
depending on the group to which children were allo-
cated, with appropriate instructions. It was not possible
to obtain a placebo tablet for the multivitamins/minerals,
so boxes were independently packed and sealed to main-
tain the double-blind status for the first phase of the
study. At week 15, all participants were given long-chain
(LC)–PUFA and micronutrient supplements. To monitor
compliance, parents were asked to return all unused
capsules, and children were given calendars along with
stickers to record each time they took the capsules. The
study was approved by the Human Research Ethics Com-
mittees of the CSIRO and University of South Australia,
and the South Australian Department of Education and
Children’s Services and Catholic Education Centre.
The LC-PUFA capsules used for the study were eye q
each containing 400 mg fish oil and 100 mg evening prim-
rose oil with active ingredients eicosapentaenoic acid (EPA)
(93 mg), docosahexaenoic acid (DHA) (29 mg), gamma-
Table 1. Means, standard deviations, and differences between groups on demographic variables at baseline for phase 1 data (weeks 1–15), N 104
(n 41)
(n 36)
(n 27)
Mean SD Mean SD Mean SD F
Age, yr 9.20 1.72 9.44 1.90 9.67 1.90 0.55
BMI percentile 49.6 29.5 64.3 30.1 59.4 30.7 2.39
Health 4.12 0.84 3.81 0.99 4.37 0.56 3.57
IQ estimate 96.4 20.6 92.1 18.2 93.3 17.1 0.51
age 40.3 6.51 41.3 6.13 38.5 10.1 1.10
PC years education 14.0 2.54 13.5 2.25 14.2 6.16 0.34
PC education level 3.76 1.18 3.61 1.05 3.44 1.16 0.62
PC occupation
49.9 14.1 51.5 14.3 51.7 14.3 0.18
Participant gender 29 M, 12 F 29 M, 7 F 19 M, 8 F
PUFAs, polyunsaturated fatty acids; MVM, multivitamin/mineral; BMI, body mass index; PC, primary caregiver.
p .05. IQ estimate taken from Wechsler Intelli-
gence Scale for Children dyad: Vocabulary and Block Design.
Occupation rated on Daniel’s
prestige scale (12 high, 69 low).
84 Polyunsaturated Fatty Acids and ADHD-Related Symptoms Journal of Developmental & Behavioral Pediatrics
linolenic acid (GLA) (10 mg), and vitamin E (1.8 mg). Pla-
cebo capsules contained palm oil. Children were required to
take six active or six placebo capsules per day. The multi-
vitamin/mineral (MVM) supplement were fruit-flavored
chewable tablets. The tablets contained active ingredients:
vitamin A 175 IU, thiamine nitrate 700
g, vitamin B
mg; vitamin B
1.3 mg, nicotinamide 12 mg, vitamin C 60
mg, vitamin D
100 IU, vitamin B
g, vitaminE6IU,
biotin 50
g, vitamin B
2.7 mg, folic acid 100
g, calcium
hydrogen phosphate anhydrous 33.9 mg, ferrous fumarate
7.5 mg, magnesium oxide 8.32 mg, manganese sulfate 77
g, zinc oxide 1.25 mg, copper gluconate 178.6
g, and
potassium iodide 118
g. Those in the LC-PUFAs MVM
group and all children from 15 weeks onward were required
to take one tablet per day.
Conners Rating Scales
The Conners Rating Scales–Revised (CRSs-R)
are de-
signed separately for parents (CPRS) and teachers (CTRS).
They assess parent and teacher ratings of ADHD symp-
toms, including an index that is aligned with the DSM-IV
criteria for ADHD, as well as subscales for co-occurring
problems. Each item is measured ona0to4scale (0
not true at all; 4 very much true). Subscales measuring
core ADHD factors are Cognitive Problems/Inattention,
Hyperactivity, ADHD Index, Conners Global Restless/Im-
pulsive Index, and DSM-IV symptoms inattentive, hyper-
active-impulsive. The remaining subscales assess the fol-
lowing problems: oppositional behavior, anxious/shy,
perfectionism, social problems, psychosomatic, and Con-
ners Global Emotional Lability Index. Internal reliability
coefficients reported in Conners manual
range from .73
to .94 for CPRS and .77 to .96 for CTRS subscales. In the
current study, internal reliability coefficients for all ques-
tionnaires returned at baseline ranged from .76 to .92 on
the CPRS and from .72 to .94 on the CTRS.
Background questionnaires
These included questions about the child’s age, gen-
der, and health (from 1, poor, to 5, excellent). Questions
about children’s primary caregivers included age, number
of years of formal education, highest level of education
attained (from 1, primary school, to 6, postgraduate de-
gree) and occupation (coded according to Daniel’s
tige ratings: 12 high, 69 low).
IQ estimate
An IQ estimate was included as a potential covariate
because parent- and teacher-reported problems with cog-
nition/inattention was an outcome measure and IQ is
typically lower in children with attention problems. IQ
was estimated with the Block Design and Vocabulary
subtests of the Wechsler Intelligence Scale for Children,
version 3 (WISC-III), which were included in the cogni-
tive assessments. This dyad is recommended by Sattler
as a valid estimate of Full Scale IQ.
The study employed a randomized, placebo-controlled
design providing within- and between-group comparisons,
constituting 30 weeks’ participation for each child with a
one-way crossover at 15 weeks. During weeks 0 to 15
(phase 1), participants were given PUFA capsules with an
MVM tablet, PUFA capsules alone, or placebo oil capsules.
At 15 weeks, all children were given PUFAs MVM for
weeks 16 to 30 (phase 2). The first phase of the study was
double blind; phase 2 was single blind in that the research-
ers knew that all children were receiving active treatment
after 15 weeks. Dependent variables included parent and
teacher ratings of ADHD-related problems with attention
and behavior. Background measures including an IQ esti-
mate were examined as potential covariates. Parent ratings
of children’s health were used as a covariate in CPRS anal-
yses involving the placebo group because this group dif-
fered significantly from the PUFA group on this variable
(Table 1). Mixed design 2 2 analyses of covariance were
performed to test hypotheses 1 and 2, testing for treatment
x condition interactions from baseline to week 15, first
between both PUFA groups (combined) and the placebo
group and then between the PUFA MVM and PUFA
groups. Within-group analyses of variance were used to test
both parts of hypothesis 3, that the placebo group would
show significant improvements following their switch to
active treatment from weeks 16 to 30 and that the PUFA
groups would continue to improve with extended supple-
mentation from weeks 16 to 30.
Data Preparation and Analysis
Data were analyzed using SPSS 11.5.0. Missing data
were replaced with that variable’s mean
; on Conners
scales, cases with three or more missing responses on any
one subscale were deleted from the data set. Parents
returned 131 questionnaires at both baseline and week
15. Of these, two cases were deleted due to low compli-
ance (fewer than 200 capsules during phase 1), and a
further 27 deleted due to missing data. Therefore, there
were 104 cases available for phase 1 analysis (0–15
weeks). For those who completed the whole trial, 111
questionnaires were returned for all three time points. Of
those, 24 were deleted due to missing data, leaving 87
cases available for all three times of measurement. Outli-
ers falling 3.29 SD from the mean were brought along-
side the next closest score, and then the distributions for
all measures showed no significant departures from nor-
mality. Bonferroni adjustments were not applied to anal-
yses because many of the CRS-R items overlap in multiple
Furthermore, although multiple analyses
were performed, predicted outcomes based on previous
research have practical significance.
For these reasons,
an alpha level of p .01 was applied to all analyses.
Of the cases with available data, 88% to 95% had data on
compliance, and the average number of capsules taken per
day overall was 5.33 of the stipulated daily dose of six. There
were no significant differences between the groups on num-
ber of capsules taken for phase 1 (F[2,94] 2.90, p .06)
or the whole study (F[2,84] 0.06, p .94).
Conners Parent Rating Scales
Phase 1: weeks 0 to 15
Repeated-measures analyses of covariance (ANCOVAs),
with health as a covariate, were used to test the hypothesis
Vol. 28, No. 2, April 2007 © 2007 Lippincott Williams & Wilkins 85
that the two polyunsaturated fatty acid (PUFA) groups com-
bined would show significant improvements in parent rat-
ings of outcome measures compared with placebo after 15
weeks of supplementation (N 104). Means and SDs for
health and Conners Parent Rating Scales (CPRSs) at weeks 0
and 15 are given in Table 2, along with ANCOVA results that
report treatment condition interactions. There were sig-
nificant improvements in the PUFA treatment groups (com-
bined) compared with placebo after the first 15 weeks on
the following CPRS scores: Cognitive Problems/Inattention,
Conners ADHD Index, Conners Global Index: Restless-Im-
pulsive, both DSM-IV symptoms subscales Inattentive and
Hyperactive-Impulsive, and Oppositional Behavior. Effect
sizes are reported as the standardized mean difference (Co-
hen’s d). Significant treatment effects range in magnitude
from medium to large.
To test the hypothesis that there would be additional
improvements with the PUFAs MVM treatment over
and above the PUFA treatment alone,2x2analyses of
variance (ANOVAs) were performed to investigate treat-
ment x condition interactions from baseline to week 15
in the PUFA and PUFA MVM groups. There were no
additional treatment effects in the PUFA MVM group
compared with the PUFAs alone group.
Phase 2: Treatment Crossover, Weeks 16 to 30
Table 3 shows means and SDs at weeks 0, 15, and 30
on the Conners parent questionnaires returned for par-
ticipants who completed the full 30-week trial (n 87).
Repeated-measures one-way ANOVAs were conducted
on the placebo group, comparing their scores at weeks
15 and 30 to test whether there were significant improve-
ments in scores following their switch to active PUFA
capsules (Table 3). After switching to active PUFAs, this
group showed significant improvements on Cognitive
Problems/Inattention, Hyperactivity, ADHD Index, Con-
ners Global Index: Restless-Impulsive, and both DSM-IV
Table 2. Adjusted Means, Standard Deviations, and Mixed Design ANCOVA Results Showing Treatment Condition Interactions Between PUFAS
and Placebo Groups at Baseline and 15 Weeks (N 104) on the Conners Parent Rating Scales
Variable/Subscale Group
Baseline 15 Weeks 2 2 ANCOVAs
Mean SD Mean SD F(1,102)
Effect Size
Cognitive Problems/Inattention PUFAs 24.91 6.42 20.89 7.30
Placebo 25.30 7.05 24.51 6.68 10.06** .52
Hyperactivity PUFAs 13.82 6.69 10.67 6.42
Placebo 13.19 6.21 11.74 5.93 4.21* .17
ADHD Index PUFAs 26.43 5.98 21.53 7.22
Placebo 26.99 5.78 25.29 5.27 9.09** .59
Global: Restless/Impulsive PUFAs 13.54 4.64 10.81 4.66
Placebo 13.33 3.11 12.63 3.31 7.88** .45
Global: Emotional Lability PUFAs 3.97 2.54 3.09 2.42
Placebo 3.63 2.68 3.44 2.42 2.70 .14
Global: Total PUFAs 17.50 6.45 13.92 6.06
Placebo 16.96 4.65 16.07 4.86 8.37** .39
DSM-IV Inattentive PUFAs 20.05 4.82 16.10 5.97
Placebo 19.85 5.29 19.26 4.25 11.24** .61
DSM-IV Hyperactive/Impulsive PUFAs 15.37 6.50 12.19 6.44
Placebo 14.33 5.16 13.40 5.49 7.68** .20
DSM-IV Total PUFAs 35.41 9.56 28.31 10.77
Placebo 34.23 7.75 32.68 6.67 12.91** .49
Oppositional PUFAs 15.74 7.38 12.45 6.94
Placebo 15.92 7.40 15.66 8.10 8.06** .43
Anxious/Shy PUFAs 6.50 4.71 4.96 4.12
Placebo 6.29 4.59 5.09 4.32 0.89 .03
Perfectionism PUFAs 5.36 4.55 4.35 4.34
Placebo 4.89 4.26 4.64 3.61 1.76 .07
Social Problems PUFAs 5.09 3.99 4.43 3.81
Placebo 5.11 4.04 5.33 4.13 2.12 .23
Psychosomatic PUFAs 4.21 3.64 3.20 3.04
Placebo 4.26 3.70 4.33 3.26 3.68 .36
ANCOVA, analysis of covariance; PUFAs, polyunsaturated fatty acids. Groups: PUFA and PUFA multivitamin/mineral, n 77; placebo, n 27.
F values represent
interaction effects between group condition and time. Health was a covariate (the placebo group differed significantly from the PUFA group on baseline health rat-
ings). There were no significant interaction effects between group condition and time for the covariate.
Effect size calculated as Cohen’s d.*p .05; **p .01.
86 Polyunsaturated Fatty Acids and ADHD-Related Symptoms Journal of Developmental & Behavioral Pediatrics
symptoms subscales Inattentive and Hyperactive-Impul-
sive, as well as on the Perfectionism and Social Problems
The same analyses were performed on the active PUFA
groups to assess whether their scores continued to im-
prove significantly following an additional 15 weeks of
supplementation. Both PUFA groups showed continued
improvement on Cognitive Problems/Inattention, ADHD
Index, Conners Global Index: Restless-Impulsive, both
DSM-IV symptoms subscales Inattentive and Hyperactive-
Impulsive and on the Hyperactivity subscale.
Conners Teacher Rating Scales
As with parent ratings, repeated-measures ANOVAs
were performed with the Conners Teacher Rating Scales
data to test the hypotheses that the PUFA groups would
show significant improvements in teacher ratings of out-
come measures compared with placebo after 15 weeks of
supplementation. No significant results were found. Sim-
ilarly, repeated-measures ANOVAs revealed no significant
effects of teacher ratings in the placebo group following
their switch to active treatment after 15 weeks.
This study tested the effect of polyunsaturated fatty
acid (PUFA) supplementation on parent and teacher rat-
ings of attention and behavior in a sample of South Aus-
tralian children with problems with hyperactivity, impul-
sivity, and inattention as rated by parents on Conners
abbreviated ADHD Index. Supplementation with PUFAs
Table 3. Conners Parent Rating Scale Means and Standard Deviations at 0, 15, and 30 Weeks (n 87) plus One-Way RM ANOVA Results for
PUFAs Groups from Weeks 16 to 30 Following 15 Weeks of Continued PUFAs (n 65) and Placebo Group from Weeks 16 to 30 Following Switch
to Active PUFAs (n 22)
Subscale Group
Baseline 15 Weeks 30 Weeks
16–30 Weeks
Mean SD Mean SD Mean SD F(1,26)
Problems/Inattention PUFAs 25.26 6.41 21.04 7.62 18.50 8.74 17.78** .31
Placebo 24.86 7.08 24.49 6.78 18.64 7.52 26.95** .82
Hyperactivity PUFAs 14.28 6.45 11.07 6.18 9.71 6.04 9.45** .22
Placebo 13.32 5.93 12.45 5.29 9.80 5.82 9.48** .48
ADHD Index PUFAs 26.68 6.19 21.90 7.44 18.88 8.37 19.74** .38
Placebo 26.67 6.26 25.76 5.17 19.53 6.77 35.47** 1.03
Global: Restless/Impulsive PUFAs 13.82 4.61 11.22 4.49 9.84 4.69 15.40** .30
Placebo 13.18 3.07 12.95 2.77 10.50 4.11 14.54** .70
Global: Emotional Lability PUFAs 4.13 2.48 3.22 2.44 2.89 2.17 2.38 .14
Placebo 3.18 2.54 3.09 2.41 2.77 2.25 1.15 .14
Global: Total PUFAs 17.95 6.38 14.45 5.84 12.72 6.10 13.73** .29
Placebo 16.36 4.42 16.05 4.50 13.27 5.59 11.54** .55
DSM Inattentive PUFAs 20.34 4.94 16.28 6.22 14.38 7.13 13.13** .28
Placebo 19.50 5.60 19.41 4.53 14.41 5.37 40.67** 1.00
DSM Hyperactive/Impulsive PUFAs 15.87 6.26 12.71 6.13 11.15 6.24 10.86** .25
Placebo 14.77 5.15 14.54 4.71 11.93 5.76 9.60** .50
DSM Total PUFAs 36.19 9.71 29.01 10.86 25.54 11.87 14.65** .31
Placebo 34.33 8.55 33.97 6.12 26.37 9.69 33.89** .94
Oppositional PUFAs 15.99 7.40 12.79 7.08 11.70 6.73 3.78 .16
Placebo 14.81 7.42 15.05 8.32 12.81 7.17 6.78* .29
Anxious/Shy PUFAs 6.84 4.77 5.26 4.24 4.76 4.16 1.98 .12
Placebo 5.49 4.27 4.66 4.52 3.45 3.94 7.23* .29
Perfectionism PUFAs 5.74 4.61 4.78 4.44 4.13 4.09 5.88* .15
Placebo 4.64 4.50 4.47 3.59 2.95 3.43 9.04** .43
Social Problems PUFAs 5.38 4.14 4.65 3.98 4.52 3.93 0.15 .03
Placebo 5.27 4.37 5.95 4.34 4.19 3.90 17.41** .43
Psychosomatic PUFAs 4.58 3.74 3.48 3.18 3.08 3.23 1.88 .12
Placebo 3.64 3.46 3.77 2.89 2.59 3.11 5.24* .39
PUFAs, polyunsaturated fatty acids; RM ANOVA, repeated-measures analysis of variance. Groups: PUFAs MVM (multivitamin/mineral), n 36; PUFAs, n 29; pla-
cebo, n 22. PUFAs MVM group continued on PUFAs MVM from weeks 16 to 30; PUFAs and placebo groups had treatment crossover to PUFAs MVM from
weeks 16 to 30.
F values represent within group changes from weeks 16 to 30.
Effect size calculated as Cohen’s d.*p .05; **p .01.
Vol. 28, No. 2, April 2007 © 2007 Lippincott Williams & Wilkins 87
over 15 weeks resulted in significant improvements com-
pared with placebo in parent ratings of core attention-
deficit/hyperactivity disorder (ADHD)–related behavioral
and cognitive difficulties, namely inattention, hyperactiv-
ity, and impulsivity, with medium to large effect sizes,
and also in ratings of oppositional behavior. Following a
one-way crossover to active treatment for a further 15
weeks, the placebo group showed significant improve-
ments comparable with the active groups during the first
15 weeks, with the exception of oppositional behavior
but with significant improvements also shown on sub-
scales measuring coexisting problems of social problems
and perfectionism. The PUFA groups continued to dem-
onstrate significant improvements in attention, impulsiv-
ity, and hyperactivity following an additional 15 weeks of
supplementation. Overall, 30% to 40% of children over 15
weeks and 40% to 50% of children over 30 weeks had
improvements of 1 SD in scores.
However, there were no significant treatment effects
on the Conners Teacher Rating Scales. This may mean
that the teacher rating scales were unable to detect treat-
ment effects in this study. Research on parent ratings of
developmental problems, including cognitive ability, has
found a high degree of accuracy in identifying children
with ADHD. In some cases, parent ratings were more
accurate in identifying cognitive problems than were psy-
chometric assessments, with 81% accuracy.
It has also
been reported that parent and teacher rating scales are
the most efficient method for assessing ADHD compared
with other diagnostic methods. Indeed, both are pre-
ferred for clinical purposes.
However, how well these
correlate with each other is unclear. A comparison of
parent and teacher ratings of behavior in a normal pop-
ulation of children found no significant differences be-
tween them except on externalizing behavior/social
skills, possibly because teachers have more opportunity
to observe children in a social setting.
In a clinical
population, however, it was found that teachers showed
significantly less agreement with parent and youth ratings
than expected.
These researchers reported that the
significant variability that is often found in responses by
different raters can be accounted for by various demo-
graphic and psychological factors. All in all, variability in
responses may be attributed to a number of rater charac-
teristics and environmental factors and are also likely to
be influenced by the context of the research involved.
The parent ratings in the present trial are similar to those
obtained recently using the same PUFA supplement on
teacher ratings of children in Durham.
In the latter
study, the local education authority and teachers were
actively involved in the project and in administering the
supplements to the children each day at school. Con-
versely, in the current study, the parents were actively
involved in bringing their children in for assessments and
administering the supplements. In the present study,
there were also multiple incidences of teacher sharing
(i.e., two teachers taking the same class on different
days), long-service leave/holidays, and children moving
schools or changing teachers. Validity of ratings might
also have been affected by large class sizes of 30 children
per class. Therefore, all things considered, and although
this discrepancy should be considered when interpreting
these results, it is likely that the parent ratings have
greater validity in the current study.
Contrary to hypotheses, there was no benefit derived
from a multivitamin/mineral supplement over and above
the PUFAs. Although they were set at recommended daily
doses for children, it is possible that greater quantities are
required in clinical populations.
For instance, in a re-
cently published randomized, double-blind, placebo-con-
trolled study,
supplementation with 150 mg zinc per
day reduced symptoms of hyperactivity, impulsivity, and
poor social skills in a group of children with ADHD. In
contrast, the supplement used in the current study pro-
vided a daily dose of less than 2 mg zinc. It must be noted
that high doses of zinc can be toxic or cause gastrointes-
tinal side effects, and caution has been advised as the
above trial experienced a 60% dropout rate
there was no notable difference in dropout rates between
placebo and active zinc treatment). It is possible that the
safe or optimal dose level is dependent on individual
requirements and/or level of deficiency.
This possibility
remains to be explored in an ADHD population.
Correlations have previously been observed between
PUFA deficiency in red blood cells and learning and be-
havioral problems, not only in boys with ADHD, but also
in controls. Furthermore, although the children recruited
for this study met the criteria for a possible clinical diag-
nosis according to Conners Parent Rating Scales,
did not necessarily all have a formal diagnosis. Other
studies reviewed in this paper also found biochemical
PUFA deficiencies in children with hyperactivity and
learning problems that had not necessarily been diag-
nosed as ADHD and linear relationships have been found
between the degree of PUFA deficiency and the severity
of mental health outcomes.
It is possible therefore
that symptoms associated with ADHD may fall on a con-
tinuum rather than into a fixed diagnostic category. The
biochemical approach to treating behavioral problems as
applied in this study could have an advantage of treating
symptoms without some of the issues and limitations
inherent in diagnosis.
This possibility is important to
consider because children with these developmental
problems do not all necessarily have PUFA deficiencies
and those who do might benefit from supplementation
without necessarily reaching the cutoff for a formal diag-
nosis. Therefore, further exploration is warranted via
correlational analyses between PUFA status, degree of
attention and behavioral problems, and degree of im-
provement through supplementation.
It should be noted that this study did not employ an
intent-to-treat analysis because the study was concerned
with treatment efficacy and not with adherence to the
treatment. Therefore, the results focus only on those who
completed the trial. It was found, however, that those
who did not turn up for the first appointment and who
dropped out before completing phase 1 had significantly
higher scores on Conners Index as completed by parents
upon registration for the study than those who completed
phase 1 or the whole study. There are two most probable
88 Polyunsaturated Fatty Acids and ADHD-Related Symptoms Journal of Developmental & Behavioral Pediatrics
explanations for this, according to parent feedback that
was received. First, parents are likely to have put their
children on stimulant medication (an exclusion criterion)
because their behavior became too hard for them to
manage, and second, some of these children were not
compliant. This poses a couple of limitations on the use
of PUFAs as a possible treatment for problems that are
symptomatic of ADHD because in contrast to stimulant
medication, it can take 8 to 12 weeks of supplementation
to notice an improvement in symptoms,
and it might
be more difficult in children with problematic behavior to
elicit compliance in taking up to six capsules per day.
Another implication of children with higher scores drop-
ping out is that the results may be a more conservative
reflection of treatment effects as the children who com-
pleted the study had lower mean scores on the Conners
ADHD Index.
A further limitation to the study was that it was not
possible to take biochemical analyses of nutritional status,
so it is not known whether the children had nutritional
deficiencies. The possibility that supplementation of nu-
trients in combination with each other might provide
greater benefits than isolated nutrients, e.g., zinc and
PUFAs, requires further investigation. Future inspection
of both PUFA and nutrient status at baseline and correla-
tions of supplementation with magnitude of improve-
ment could confirm relationships between nutrients and
PUFAs and deficiency and response. Furthermore, al-
though the study included indirect measures of compli-
ance via returned bottles and calendars, biochemical anal-
yses of PUFA status or independent administration of
supplements (e.g., by teachers as in the Durham trial)
would have provided a more direct and reliable measure
of compliance.
Where treatment effects have been found in research
to date, core ADHD-related symptoms of inattention, hy-
peractivity, and impulsivity seem to respond most consis-
tently to PUFA supplementation. Behavioral problems as-
sociated with ADHD and measured by Conners Rating
Scales such as social problems, anxiety, and perfection-
ism, are less consistent in their response to PUFA treat-
ment. This may be because the children in this sample did
not have significant enough problems in these areas at
baseline, and indeed oppositional behavior, which was
higher in this group at baseline, was more responsive to
PUFA supplementation. Alternatively, it may be that these
types of behaviors are learned as a result of the biological
symptoms. For instance, a child might become anxious
about his/her behavior and the impact that it has on
others or defiant as a result of behavioral consequences or
to cover up difficulties with paying attention in class or
develop social problems as a result of disruptive behavior.
Over time, some of these problems might be naturally
alleviated as other symptoms are reduced; however, be-
havioral interventions might address these comorbid is-
sues more effectively. In any event, ADHD-related prob-
lems have complex etiological influences, and future
researchers should therefore explore the possibility that
some children with ADHD-related problems may derive
increased benefit from combined PUFA/behavioral inter-
ventions. It is also important to note that, although doco-
sahexaenoic acid (DHA) is the most concentrated PUFA
in the brain and at neural synapses, fatty acid research in
mental health to date has had more positive results using
a combination of omega-3 fatty acids eicosapentaenoic
acid (EPA) and DHA than research using DHA alone, and
it has been suggested that EPA is an important PUFA for
mental health outcomes.
The current study and the
Durham trial used a supplement with a high EPA:DHA
ratio and therefore lend further support to this notion. As
noted by Richardson and Montgomery,
however, this
research does not explain the underlying biological mech-
anisms of PUFA; therefore, nutritional/behavioral re-
search requires integration of research from different
fields of specialization.
The present study is the largest PUFA trial to date with
children falling in the clinical ADHD range on Conners
Index. The results support those of other studies that
have found improvements in developmental problems
symptomatic of ADHD with PUFA supplementation.
These results have significant implications for children
with ADHD-related symptoms, parents, and clinicians.
Importantly, core symptoms of hyperactivity, impulsivity,
and inattention improved on average from the upper
clinical range on Conners ADHD Index to mildly clinical
after 30 weeks of supplementation. It is possible that
symptoms may continue to improve over time with con-
tinued supplementation and in combination with psycho-
social therapies to assist children in learning more adap-
tive behaviors.
There has been a great deal of controversy surrounding
the diagnosis and treatment of ADHD and concern regard-
ing the increasing prescription of stimulant medication to
children. As noted by Richardson and Montgomery,
medium effect sizes observed in their study, as also ob-
served in the present trial, are comparable with those
calculated from a meta-analysis of medication trials.
However, there is no known evidence that medication
provides any benefits beyond 4 weeks, whereas in the
present trial, symptoms continued to improve after 15
weeks of supplementation. Importantly, there have been
no reports of adverse effects in fatty acid trials with
children to date. This was not directly assessed in the
current study, but two parents commented that their
children felt a little sick after taking the supplements, and
one boy had nose bleeds (possibly due to the blood-
thinning effect of PUFAs). These effects may not be as
serious as the short-term effects reported from various
stimulant medications, which include weight loss, re-
duced appetite, sleep disturbances, sedation, dulled af-
fect, social withdrawal, irritability, abnormal thinking,
stomachache, and vomiting.
Therefore, PUFA supple-
mentation could provide a safe, healthy option for some
children with ADHD symptoms and particularly the large
subgroup with comorbid symptoms who are more likely
to experience adverse side effects from medication.
Studies comparing the efficacy and safety of medication
and fatty acid supplementation are clearly warranted and
particularly over the longer term given the paucity of
long-term medication trials.
Vol. 28, No. 2, April 2007 © 2007 Lippincott Williams & Wilkins 89
Evidence that a proportion of children with ADHD
symptoms might experience reduced symptoms with nu-
tritional supplementation is therefore important for prac-
titioners to consider as a possible treatment adjunct. Fur-
ther investigation and refinement of research in this area
are required, including optimal doses of PUFAs and mi-
cronutrients, continued treatment effects with extended
supplementation, and the identification of children most
likely to respond to supplementation that includes inves-
tigation of comorbid symptoms and the issue of treating
children with an official diagnosis versus treatment of
symptoms that have not necessarily been diagnosed.
This study was made possible with the support of the University of
South Australia and CSIRO Human Nutrition, the generous supply of
eye q
supplements by Equazen (London UK) and Novasel (Queens-
land Australia), and multivitamins and minerals by Blackmores
Australia; Channel 10 News, participants, parents, teachers, and
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© 2007 Lippincott Williams & Wilkins 91
    • "Several randomized placebo-controlled trials with Omega 3 or Omega 3/6 supplements to children with neurodevelopmental disorders [attention deficit hyperactivity disorder (ADHD), developmental coordination disorder (DCD), dyslexia] have reported positive effects on ADHD symptoms (Johnson, O ¨ stlund, Fransson, Kadesjö, & Gillberg, 2009; Johnson et al., 2012; Milte et al., 2012 Milte et al., , 2013 Richardson & Montgomery, 2005; Richardson & Puri, 2002; Sinn & Bryan, 2007 ). Recent reviews and metaanalyses conclude that PUFA supplements appear to have a small but significant effect on ADHD symptoms , but that interpretation of results is clearly limited by the heterogeneity in study designs, participant samples, and supplements used (Bloch & Qawasmi, 2011; Gillies, Sinn, Lad, Leach, & Ross, 2012; Sonuga-Barke et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Previous research has shown positive effects of Omega 3/6 fatty acids in children with inattention and reading difficulties. We aimed to investigate if Omega 3/6 improved reading ability in mainstream schoolchildren. Methods: We performed a 3-month parallel, randomized, double-blind, placebo-controlled trial followed by 3-month active treatment for all subjects. Mainstream schoolchildren aged 9-10 years were randomized 1:1 to receive three Omega 3/6 capsules twice daily or identical placebo. Assessments were made at baseline, 3 months, and 6 months. The primary outcome measure was the Logos test battery for evaluating reading abilities. The trial is registered with ClinicalTrials.gov, number NCT02557477. Results: The study enrolled 154 children (active n = 78; placebo n = 76), of whom 122 completed the first 3 months (active n = 64; placebo n = 58) and 105 completed the whole study (active/active n = 55; placebo/active n = 50). Outcomes were assessed by per protocol (PP) and intention-to-treat (ITT) analyses. Active treatment was superior to placebo at 3 months for improvement in phonologic decoding time (PP active/placebo difference -0.16; 95% CI -0.03, -0.29; effect size (ES) .44; p = .005; and ITT ES .37; p = .036), in visual analysis time (PP active/placebo difference -0.19; 95% CI -0.05, -0.33; ES .49; p = .013; and ITT ES .40; p = .01), and for boys in phonologic decoding time (PP -0.22; 95% CI -0.03, -0.41; ES .62; p = .004). Children with ADHD-RS scores above the median showed treatment benefits in visual analysis time (PP ES .8, p = .009), reading speed per word (PP ES .61, p = .008), and phonologic decoding time per word (PP ES .85, p = .006). Adverse events were rare and mild, mainly stomach pain/diarrhea (active n = 9, placebo n = 2). Conclusions: Compared with placebo, 3 months of Omega 3/6 treatment improved reading ability - specifically the clinically relevant 'phonologic decoding time' and 'visual analysis time' - in mainstream schoolchildren. In particular, children with attention problems showed treatment benefits.
    Article · Aug 2016
    • "Subsequently, a one-way, uncontrolled crossover to active supplement followed for a further three months: similar changes were observed in the placebo-active group, while the original treatment group's scores continued to improve. Sinn and Bryan (2008) on a large sample included 132 children aged 7–12 years with a diagnosis of ADHD [86]. Participants were enrolled in a 15-week double-blind controlled trial and were treated with 93 mg of EPA, 29 mg of DHA and 10 mg of gamma-linolenic acid daily, with or without a micronutrient supplement, and were compared to placebo. "
    [Show abstract] [Hide abstract] ABSTRACT: A new application for omega-3 fatty acids has recently emerged, concerning the treatment of several mental disorders. This indication is supported by data of neurobiological research, as highly unsaturated fatty acids (HUFAs) are highly concentrated in neural phospholipids and are important components of the neuronal cell membrane. They modulate the mechanisms of brain cell signaling, including the dopaminergic and serotonergic pathways. The aim of this review is to provide a complete and updated account of the empirical evidence of the efficacy and safety that are currently available for omega-3 fatty acids in the treatment of psychiatric disorders. The main evidence for the effectiveness of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been obtained in mood disorders, in particular in the treatment of depressive symptoms in unipolar and bipolar depression. There is some evidence to support the use of omega-3 fatty acids in the treatment of conditions characterized by a high level of impulsivity and aggression and borderline personality disorders. In patients with attention deficit hyperactivity disorder, small-to-modest effects of omega-3 HUFAs have been found. The most promising results have been reported by studies using high doses of EPA or the association of omega-3 and omega-6 fatty acids. In schizophrenia, current data are not conclusive and do not allow us either to refuse or support the indication of omega-3 fatty acids. For the remaining psychiatric disturbances, including autism spectrum disorders, anxiety disorders, obsessive-compulsive disorder, eating disorders and substance use disorder, the data are too scarce to draw any conclusion. Concerning tolerability, several studies concluded that omega-3 can be considered safe and well tolerated at doses up to 5 g/day.
    Full-text · Article · Jul 2016
    • "A number of studies in children with ADHD with and without comorbidities have reported improved symptoms with a supplement containing a 3/1 ratio of EPA/DHA (e.g. [58, 59, 60]), leading to conclusions in a meta-analysis that EPA has stronger effects than DHA [61] . However there are a number of methodological considerations that might have contributed to differences between studies, outlined elsewhere [24, 62]. "
    [Show abstract] [Hide abstract] ABSTRACT: There is evidence that children with Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Disorder (ASD) have lower omega-3 polyunsaturated fatty acid (n-3 PUFA) levels compared with controls and conflicting evidence regarding omega-6 (n-6) PUFA levels.This study investigated whether erythrocyte n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower and n-6 PUFA arachidonic acid (AA) higher in children with ADHD, ASD and controls, and whether lower n-3 and higher n-6 PUFAs correlated with poorer scores on the Australian Twin Behaviour Rating Scale (ATBRS; ADHD symptoms) and Test of Variable Attention (TOVA) in children with ADHD, and Childhood Autism Rating Scale (CARS) in children with ASD.Assessments and blood samples of 565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79) were analysed. One-way ANOVAs with Tukey's post-hoc analysis investigated differences in PUFA levels between groups and Pearson's correlations investigated correlations between PUFA levels and ATBRS, TOVA and CARS scores.Children with ADHD and ASD had lower DHA, EPA and AA, higher AA/EPA ratio and lower n-3/n-6 than controls (P
    Full-text · Article · May 2016
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