Original paper | Praca oryginalna © Copyright by PTEiDD 2021

redakcja@pediatricendocrinology.pl
Pediatr Endocrinol Diabetes Metab 2021; 27 (1): 12–18 www.pediatricendocrinology.pl
DOI: https://doi.org/10.5114/pedm.2020.101806 www.pteidd.pl

The effect of omega-3 fatty acids supplementation on social and behavioral

disorders of children with autism: a randomized clinical trial
Wpływ suplementacji kwasów tłuszczowych omega-3 na zaburzenia społeczne i behawioralne
u dzieci z autyzmem: badanie kliniczne z randomizacją

1,2
Saeid Doaei, 3Fatemeh Bourbour, 4Zohreh Teymoori, 5Faranak Jafari, 6Naser Kalantari,
7
Saheb Abbas Torki, 3Narges Ashoori, 1Shiva Nemat Gorgani, 8Maryam Gholamalizadeh

1
National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food
Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Research Center of Health and Environment, Guilan University of Medical Sciences, Rasht, Iran
3
Department of Clinical Nutrition and Dietetics, Research Institute Shahid Beheshti University of Medical
Science, Tehran, Iran
4
Roudehen Islamic Azad University, Roudehen, Iran
5
Department of Nursing, Faculty of Nursing and Midwifery, Kermanshah University of Medical Sciences,
Kermanshah, Iran
6
Department of Community Nutrition, School of Nutrition and Food Sciences, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
7
Department of Nutrition, Faculty of Nutrition Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
8
Student Research Committee, Cancer Research Center, Shahid Beheshti University of Medical Sciences,
Tehran, Iran

Abstract
Introduction: Some studies reported that essential fatty acids deficiencies can be related to autism spectrum disorders (ASD) in chil-
dren. This study aimed to investigate the effect of omega-3 on social, verbal, and behavioral activities in ASD children.
Material and methods: A double-blind, randomized clinical trial study was conducted on 54 children with autism, who were as-
signed to the case (n = 28) and control (n = 26) groups. The cases received one capsule of 1000 mg omega-3 daily and the controls
received one capsule of 1000 mg medium chain triglyceride daily as placebo for eight weeks. The Gilliam Autism Rating Scale-second
edition (GARS-2) was used to assess the severity of autism and food frequency questionnaire (FFQ) was used to assess their dietary
intake. All measurements were done at baseline and after the intervention.
Results: After adjusting for age, gender, birth weight, BMI, dietary intake, mother’s age, and mother’s BMI, the intervention group
had significantly improved stereotyped behaviors (p = 0.02), social communication (p = 0.02), and the GARS score (p = 0.001) after
the intervention compared to the control group. No significant change was found in the score of social interaction subscale.
Conclusions: The findings indicate that omega-3 treatment improved autism characteristics including stereotyped behaviors and
social communication. Further studies are needed to confirm these findings and to determine the underlying mechanisms.
Key words:
omega-3, autism, autism spectrum disorders, dietary fat.

12 Maryam Gholamalizadeh Received: 10.05.2020

Cancer Research Center Accepted: 4.09.2020
Conflict of interests: none declared.
Shahid Beheshti University of Medical Sciences
This study was granted by National Nutrition and Food Technology Research Institute,
Jannat, 0021, Tehran, Iran Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical
e-mail: gholamalizadeh@sbmu.ac.ir Sciences, Tehran, Iran (code: 569). Name of the registry: Iranian Registry of Clinical Trials
Trial registration number: IRCT2015122625699N1 Date of registration: 24/1/2016
URL of trial registry record: https://www.irct.ir/trial/21446
Omega-3 supplementation and autism Pediatr Endocrinol Diabetes Metab 2021
Suplementacja omega-3 a autyzm

Diagnostic Observation Scale (ADOS) and the DSM-IV TR crite-

Introduction ria for a diagnosis of autistic disorder by an expert clinician [17].
Autism spectrum disorders (ASD) are neurological and de-
velopmental disabilities that affect social communication and Inclusion and exclusion criteria
behaviors, psychosocial competence and activities mainly in Inclusion criteria included willingness to participate in the
infants and children. Children with ASD are characteristic by study, diagnosis of autism by a psychiatrist with moderate or
disorder in neuronal connectivity, abnormal synaptic function, severe autism symptoms, age from 5 to 15 years, and referring
and neurotransmitter imbalances [1, 2]. The prevalence of to the Autism Charity Center in Tehran. A drug-free interval of at
autism is higher in boys than girls and occurs in all regions, least 6 weeks was required before baseline assessments were
cultures, and socioeconomic classes [3]. In recent years, ASD conducted. Sixty-four children with ASD were assessed for eligi-
has become highly prevalent and the prevalence of ASD is ap- bility and met inclusion criteria. Sample size was calculated with
proximately 1 percent of the population in the United States [4]. α = 0.95, β = 20%, ratio of unexposed to exposed of 2:1, and
A study in Iran reported that the ASD prevalence in school chil- power of 0.8. The exclusion criteria included the history of infection
dren was 1.9% [5]. Although the causes of autism remained (n = 1), neurological disorders (n = 2), using any kind of medica-
unclear, environmental, genetic, and metabolic factors may play tion (n = 1), history of allergy to fish or nuts (n = 1), consuming
an important role in ASD [6]. Other factors involved in the devel- omega-3 supplementation past 2 months (n = 2), major medi-
opment of autism include immunological, perinatal, neurodevel- cal illness (n = 1) and suffering from diabetes or blood disorders
opmental, biochemical, psychosocial, and familial factors [7]. (n = 1), receiving a psychotropic drug effective on the behavior
The treatment of autistic children needs to enhance their ability (n = 1). The final analysis was performed on fifty-four children with
to integrate into school and make meaningful relationships with ASD who were assigned in the intervention (n = 28) and control
peers [7]. Some studies have reported that haloperidol and re- (n = 26) groups. Parents of children complete a written informed
speridone are effective in the treatment of autism but can cause consent. All participants, parents, and study personnel were
side effects [8]. blinded to group assignment and the randomized sequence list
Initial evidence from clinical studies suggests that nutritional for the entire study, including the data analysis. All measurements
interventions may improve behavioral disorders in ADS [9–12]. were done at baseline and after eight weeks of the intervention
Central nervous system contains poly unsaturated fatty acids
(PUFAs) especially docosa-hexaenoic acid (DHA) and arachi- Anthropometric measurements
donic acid which cannot be synthesized in the human body but Height was measured using a measuring tape fastened to
must be provided by nutrition. PUFAs are essential for normal a wall and without shoes with a nearest 0.5 cm. A bio imped-
brain growth and function [12]. Dietary intake of n-3 polyunsatu- ance analysis scale (BIA) was used to measure body weight
rated fatty acids including eicosa-pentaenoic acid (EPA) and and body mass index (BMI). The extracted data was classified
DHA, which are mainly found in fish and fish oil, may alter the according to World Health Organization z-scores (for height,
risk of adult mental and neurological disorders [13, 14]. weight, and BMI).
Some studies reported that fatty acid imbalances or defi-
ciencies may be involved in childhood neurological disorders Dietary assessment
including attention deficit and hyperactivity disorders (ADHD), A validated 168-item semi-quantitative food frequency ques-
dyslexia, and the spectrum of autism disorders [15, 16]. Given tionnaire (FFQ) was completed through a face to face interview
the increasing prevalence of autism and the lack of studies on of the parents by a trained nutritionist in order to assessment the
the relationship between macronutrient intakes in autistic peo- amount of fatty acids intake and estimation of every day food in-
ple, this study aimed to investigate the relationship between take [18]. All data obtained from FFQ were converted to grams
fatty acid intake and the status of autistic signs such as ste- per day using Iranian household measures reference.
reotyped behavior, social interactions, and social interaction in
children with AS. Assessment of autism
We used a validated form of the Psychometric Properties
of Gilliam Autism Rating Scale (GARS) to assess Autistic Chil-
Material and methods dren [19]. The GARS scale is a standardized instrument for the
Sample characteristics assessment of autism and other severe behavioral disorders and
This study was done in form of a double-blind trial from contains four subscales and each subscale contains 14 items.
March 2018 to January 2019 on 54 children with autism; this The score for each question is between 0 and 3 [19]. The first
means that the patients and researchers were not aware of the subscale is stereotyped behaviors including stereotyped behav-
arms of the study. Participants were randomly selected from Au- iors, motor disorders, and exotic behaviors. The second sub-
tism Charity Center in Tehran, Iran. The allocation to the groups scale is communication, includes items 15 to 28 which describe
was done through web-based randomization using https://www. verbal and nonverbal behaviors that are signs of autism. Social
randomizer.org. Sealed non-transparent envelopes with ran- interaction is the third subscale that includes items 29 to 42.
domized sequences were used to hide the allocation. The diag- The fourth subscale is developmental disorders, which includes
nosis of ASD is done using diagnostic tools such as the Autism items 43 to 56 on childhood developmental status.

© Copyright by PTEiDD 2021 13

Pediatr Endocrinol Diabetes Metab 2020 Doaei S., Bourbour F., Teymoori Z., Jafari F., Kalantari N., Torki S.A., Ashoori N.,
Gorgani S.N., Gholamalizadeh M.

Intervention ANOVA for repeated measures was used to identify the signifi-
This study was a randomized double blind placebo-con- cant differences between two groups and between before and
trolled clinical trial. Eligible subjects were randomly divided into after intervention to eliminate the effects of confounders.
two groups. Group (1) received one capsule 1 gram per day
containing omega-3 Long Chain (180 mg EPA + 120 mg DHA) Ethics Statement
(Zahravi Company, Iran) and Group (2) received one capsule The study was approved by the Ethics Committee of the
1 gram per day containing medium chain triglyceride as placebo National Nutrition and Food Technology Research Institute,
for eight weeks. For follow-up and monitoring, participants were Tehran, Iran (reference number: Ir.sbmu.nnftri.rec. 054569, Ap-
contacted by telephone every week after randomization. The proval date: 2014-09-23, 1393/07/01).
children were assessed at week eight for anthropometric as-
sessments, the severity of autism assessment after intervention.
Results
Statistical analysis A total of 54 children were included in the analysis, of which
The comparison of qualitative variables between two 28 were assigned to the intervention group and 26 were as-
groups was performed using chi-square test. Paired and inde- signed to the control group (Fig. 1).
pendent t-test were used to detect any significant differences No significant differences were found between the groups
within and between two groups. Wilcoxon and Mann-Whitney at the baseline, except for sex (Table I). There were also no sig-
nonparametric tests were applied to detect any significant dif- nificant differences observed in anthropometric characteristics
ferences within and between two groups respectively for vari- (children’s and mother’s height, weight, BMI and children’s birth
ables that were not normally distributed. A value of p < 0.05 weight) between the groups at the baseline (Table I). Dietary
was considered to be statistically significant. A mixed-model intake of saturated fatty acids (SFAs; p = 0.04) and mono un-

Enrollment Assessed for eligibility (n = 64)

Excluded (n = 10)
• History of infection (n = 1)
• Neurological disorders (n = 2),
• Using any kind of medication (n = 1)
• History of allergy to fish or nuts (n = 1)
• Consuming omega-3 supplementation past 2
months (n = 2)
• Major medical illness (n = 1)
• Suffering from diabetes or blood disorders (n = 2)

Randomized (n = 54)

Allocation

Allocated to intervention (n = 28) Allocated to control (n = 26)

1 capsule 1 gram per day containing omega-3 long 1 capsule 1 gram per day containing medium chain
chain (EPA & DHA) triglyceride as placebo for

8 weeks follow-up

Lost to follow-up (n = 0) Lost to follow-up (n = 0)

Analysis

Analysed (n = 28 ) Analysed (n = 26)

• Excluded from analysis (give reasons) (n = 0) • Excluded from analysis (give reasons) (n = 0)

Figure 1. Study flowchart

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Omega-3 supplementation and autism Pediatr Endocrinol Diabetes Metab 2021
Suplementacja omega-3 a autyzm

saturated fatty acids (MUFAs; p = 0.01) were different between dietary fat intake, mother’s age, and mother’s BMI. No significant
two groups and compared with the baseline, whereas poly un- change was found in the status of social interaction (Table III).
saturated fatty acids (PUFAs; p = 0.07) and the total fatty acids
intake (p = 0.06) were not significantly different between two
Discussion
groups.
The intervention group had improved GARS score This study reported that after adjusting for age, gender, birth
(p = 0.001), stereotyped behaviors (p = 0.02), and social com- weight, BMI, dietary fat intake, mother’s age, and mother’s BMI,
munication (p = 0.02) after the intervention compared to the the intervention group had improved GARS score (p = 0.001),
control group after adjusting for age, gender, birth weight, BMI, stereotyped behaviors (p = 0.02), and social communication

Table I. Baseline characteristics of the study participants [1, 2]

Variable Group
Intervention group (n = 28) Control group (n = 26) P3
Age 8.1 ±6.7 8.2 ±3.6 0.75
Mother’s age 36.8 ±0.9 38.6 ±6.7 0.23
Sex
Male 19 20 0.00
Female 9 6
Height 132.12 ±8.1 133.16 ±6.3 0.84
Weight 33.14 ±9.1 32.14 ±8.6 0.66
BMI 18.4 ±5.5 17.3 ±7.9 0.65
Birth weight 2942.684 ±2.2 2960.413 ±4.8 0.97
Mother’s height 159.5 ±9 161.5 ±6.7 0.25
Mother’s weight 71.11 ±8.7 69.9 ±3.8 0.39
Mother’s BMI 28.4 ±1.7 26.4 ±6.2 0.19

BMI – body mass index

Table II. Fatty acid intake between two groups

Variable Group
Intervention group (n = 28) Control group (n = 26) p-value
Fat (g/day) 142.62 ±42 109.33 ±66 0.06
Saturated fatty acids (g/day) 48.48 ±13 29.11 ±9.6 0.04
MUFA (g/day) 52.19 ±19 39.12 ±6.6 0.01
PUFA (g/day) 35.16 ±10 27.9 ±10.1 0.07

Data is expressed as mean ±standard deviation for all variables

© Copyright by PTEiDD 2021 15

Pediatr Endocrinol Diabetes Metab 2020 Doaei S., Bourbour F., Teymoori Z., Jafari F., Kalantari N., Torki S.A., Ashoori N.,
Gorgani S.N., Gholamalizadeh M.

Table III. Effect of omega-3 supplementations on autism according to scores of GARS and its subscales using repeated meas-
ures (n = 54; df = 1)

Variable The intervention group (n = 28) The control group (n = 26) Group × time
At baseline After 8 weeks At baseline After 8 weeks F p-value
Stereotyped Behaviors 20.39 ±5.07 19.07 ±5.06 21.73 ±6.59 21.92 ±6.47 5.926 0.02
Social Communication 22.7857 ±5.34 20.50 ±5.09 24.04 ±7.16 24.42 ±6.87 5.44 0.02
Social Interaction 21.03 ±4.25 20.11 ±3.98 22.84 ±4.36 22.61 ±4.08 1.81 0.18
GARS-2 64.21 ±10.51 59.58 ±10.62 68.61 ±12.86 68.96 ±13.24 13.14 0.001

Adjusted for age, gender, birth weight, BMI, dietary fat intake, mother’s age, and mother’s BMI

(p = 0.02) after the intervention compared to the control group. (27 autistic chidren in total) and the mild level of hyperactivity
No significant change was found in the social interaction sub- in both the placebo and omega-3 treatment groups [21]. The
scale. underlying mechanism of the effects of omega-3 on brain and
In line with this study, Amminger et al. investigated the ome- ASD symptoms is not yet understood, but may be associated
ga-3 fatty acid supplementation in autistic children and found with modulation of serotonergic and dopaminergic systems.
that omega-3 treatment reduced hyperactivity and stereo- The DHA or the DHA–ARA ratio could be associated with nor-
typed behavior [20]. Another study also reported that omega-3 adrenergic system [32, 33]. EPA plus DHA supplementation
supplementation for 12 weeks decreased hyperactivity in ASD lowered plasma NE concentrations in normal volunteers even
children [21]. Lyall et al. investigated the association between at the small dose of 762 mg of EPA plus DHA per day. DHA
maternal dietary fat intake before or during pregnancy and ASD may also change the central noradrenergic system that plays
in children. They reported that maternal linoleic acid intake was a key role in modifying impulsive behaviors related to these neu-
significantly associated with the risk of ASD [22]. rotransmitters such as aggression [32, 33]. Moreover, DHA and
Ansary et al. reported that the plasma fatty acid concentra- EPA have key roles in production of membrane phospholipids,
tions were changed in autism patients, especially increased in especially in the central nervous system [34]. The macronutri-
saturated fatty acids except propionic acid and decreased in ents including omega-3 fatty acids are supposed to have neuro-
PUFA [23]. The omega-3 and omega-6 supplementation for protective role in production of the synaptic maintenance [35],
3 months improved language development in children at risk modulation of brain cell signaling, regulation of monoamines
for ASD [24]. A systematic review identified that omega-3 sup- production, and receptor signal transduction pathway [36–38],
plementation improved attention deficiency and hyperactivity in which could explain the role of omega-3 in psychiatric diseases
children with autism [25]. Another study reported that omega-3 such as autism [38–39]. Omega-3 PUFAs and their metabolic
treatment improved reading skills in children with lowest initial products provide a solid foundation because they play a role
reading skills [26]. Omega-3 treatment may also have some in ASD through their role in brain structure and brain function,
influences on improvement of depression and schizophrenia neurotransmission, cell membrane structure, and microbial do-
[27, 28]. Richardson et al. reported that EPA (3 g) or fish oil main organization [40]. DHA is highly enriched in neural and
(10 g/d) improved symptoms in schizophrenia spectrum dis- synaptic membranes, indicating an important role in neuronal
orders, depression, attention deficiency, hyperactivity disorder cell signaling. It is preferentially incorporated into phosphatidyl-
(ADHD), dyslexia, and dyspraxia disorder [29]. Another study ethanolamine and phosphatidylserine in the inner layer of syn-
reported that DHA and omega-3 concentration significantly apse membranes, and its sterile incompatibility with cholesterol
decreased in ASD children [16]. The findings of one placebo- causes either DHA- or cholesterol-rich lipid rafts. DHA also af-
controlled trial reported that omega-3 treatment could improve fects membrane fatty acid chain fluidity, ion permeability, elas-
behavioral measures, reading and spelling capacities and re- ticity, protein function, phase behavior, and fusion [41].
duce impulsivity in DCD (Developmental Coordination Disorder) This study had some limitations. Although the sample size
children [29–31]. These findings suggested that omega-3 treat- was calculated with the power accepted for the study, the re-
ment could be effective for treating aggression and impulsiv- sults should be confirmed in larger studies. Further studies are
ity [29–31]. In contrast with current study, Bent et al. reported needed to increase our understanding of the effect of omega-3
that omega-3 supplementation did not affect hyperactivity in fatty acids supplementation on social and behavioral disorders
children with ASD. This is probably due to small sample size of children with autism.

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Omega-3 supplementation and autism Pediatr Endocrinol Diabetes Metab 2021
Suplementacja omega-3 a autyzm

tion variables in the intervention group compared with the con-

Conclusions trol group. Further studies with larger sample sizes and longer
This study found that omega-3 supplementation improved period of the intervention are needed to clarify the efficacy of
GARS score, stereotyped behaviors, and social communica- omega-3 supplementation on ASD children.

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