Nutritional and Dietary
Interventions for Autism Spectrum
Disorder: A Systematic Review

Nila Sathe, MA, MLIS,​a,​b Jeffrey C. Andrews, MD,​b Melissa L. McPheeters, PhD, MPH,​a,​b Zachary E. Warren, PhDc,​d

CONTEXT: Children with autism spectrum disorder (ASD) frequently use special diets orreceive nutritional supplements to treat ASD symptoms.

abstract

OBJECTIVES: Our objective was to evaluate the effectiveness and safety of dietary interventions
or nutritional supplements in ASD.
DATA SOURCES: Databases, including Medline and PsycINFO.

STUDY SELECTION: Two investigators independently screened studies against predetermined

criteria.

DATA EXTRACTION: One investigator extracted data with review by a second investigator.

Investigators independently assessed the risk of bias and strength of evidence (SOE) (ie,confidence in the estimate of effects).

RESULTS: Nineteen randomized controlled trials (RCTs), 4 with a low risk of bias, evaluatedsupplements or variations of the gluten/casein-free diet and other dietary approaches.
Populations, interventions, and outcomes varied. Ω-3 supplementation did not affectchallenging behaviors and was associated with minimal harms (low SOE). Two RCTs ofdifferent digestive enzymes reported mixed effects on symptom severity (insufficient SOE).
Studies of other supplements (methyl B12, levocarnitine) reported some improvements insymptom severity (insufficient SOE). Studies evaluating gluten/casein-free diets reported
some parent-rated improvements in communication and challenging behaviors; however,data were inadequate to make conclusions about the body of evidence (insufficient SOE).
Studies of gluten- or casein-containing challenge foods reported no effects on behavior
or gastrointestinal symptoms with challenge foods (insufficient SOE); 1 RCT reported noeffects of camel’s milk on ASD severity (insufficient SOE). Harms were disparate.
LIMITATIONS: Studies were small and short-term, and there were few fully categorized

populations or concomitant interventions.

CONCLUSIONS: There is little evidence to support the use of nutritional supplements or dietary
therapies for children with ASD.

Departments of aHealth Policy, cPediatrics, and dPsychiatry, Vanderbilt Kennedy Center, and bVanderbilt Evidence-based Practice Center, Institute for Medicine and Public Health, Vanderbilt
University Medical Center, Nashville, Tennessee

Ms Sathe helped to conceptualize and design the review, helped to acquire, analyze, and interpret data, and drafted and helped to revise the initial manuscript;
Drs Andrews, McPheeters, and Warren helped to conceptualize and design the review, helped to acquire, analyze, and interpret data, and helped to draft the initialmanuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

To cite: Sathe N, Andrews JC, McPheeters ML, et al. Nutritional and Dietary Interventions for Autism Spectrum Disorder: A Systematic Review. Pediatrics.
2017;139(6):e20170346

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PEDIATRICS Volume 139, number Downloaded
6, June 2017:e20170346

REVIEW ARTICLE

Autism spectrum disorder (ASD)
is characterized by impairments insocial interaction, communication,and behavior as well as sensory
challenges. Substantial evidence
supports benefits of specificbehavioral, educational, and somepharmacologic interventions forchildren with ASD. However, given
the limits of available treatments
in improving core and associated
ASD symptoms, substantial resource
challenges in accessing evidencebased treatment approaches, andperceptions regarding lessenedrisks of treatment, many families,
if not a majority of families, pursue
dietary and nutritional approaches ascomponents of treatment.‍1–‍‍‍‍‍‍‍ 11‍ Givenlimitations in the existing researchbase, families and providers alike
often struggle to understand thesafety and potential benefit of suchapproaches.

Proponents of the frequently used
gluten/casein-free (GFCF) dietposit varied theories (eg, excess
opioid peptide levels) regarding
why individuals with ASD may havealtered metabolism of gluten or
casein proteins that may negatively
affect behavior.‍12–‍ 14‍ Evidence tosupport specific theories, however,is lacking.‍15,​16 Studies have also
explored differences in nutrient
status in children with and without
ASD and potential correlations with
ASD symptoms as well as the effectsof vitamin supplementation. The
results of these studies have been
inconclusive.‍3,​17‍ –‍‍‍‍‍‍‍‍ 28‍

Despite limited evidence and limited
understanding of the potential
mechanisms underlying variations
in nutrition and metabolism that
may affect behavior, specialized
or restricted diets and nutritional
supplementation are frequently usedtreatments in children with ASD. In
the present review, a component ofan Agency for Healthcare Research
and Quality–commissioned updateof a comparative effectiveness
review of therapies for children with2

TABLE 1 Inclusion Criteria
Category
Study population
Publication languages
Admissible evidence(study design andother criteria)

Criteria
Children ages 2–12 y with ASD (mean age + SD is ≤12 y and 11 mo)English only
Admissible designs
RCTs, prospective and retrospective cohort studies with comparison groups,
and non-RCTs
Other criteria
Original research studies published from 2010 to the present
Studies must have relevant population and ≥20 participants with ASD (nonRCTs) or at least 10 total participants (RCTs)
Studies must address ≥1 of the following for ASD:  Outcomes of interest  Treatment modality of interest  Predictors or drivers of treatment outcomes (eg, biomarkers, clinicalchanges)  Maintenance of outcomes across environments or contexts  Sufficiently detailed methods and results to enable data extraction  Reporting of outcome data by target population or intervention

ASD conducted by the Vanderbilt
Evidence-based Practice Center,​‍29
we examine the evidence
specifically for nutritional or dietaryinterventions in children with ASD.
The full comparative effectiveness
review update‍30 and review protocol(PROSPERO registry number:
CRD42016033941) are available atwww.​effectivehealthca​re.​ahrq.​gov.

Methods
Search Strategy and Study Selection
We searched the Medline database
via PubMed, Embase, and the
Cochrane Library from January2010 to September 2016 using
a combination of controlled
vocabulary and key terms related tointerventions for ASD (eg, autism,
ASD, therapy). We note that theoriginal review,​‍31 which the current
report updates, included studies
published from January 2000 to
2011. We also hand-searched thereference lists of included articles
and recent reviews addressing ASD
therapies to identify potentiallyrelevant articles.
We developed inclusion criteria in
consultation with an expert panelof clinicians and researchers (‍Table1). We included comparative study
designs (eg, randomized controlled

trials [RCTs] and prospective or
retrospective cohort studies) andstudies published in English. We
required that eligible RCTs have a
total minimum sample size of 10. We
required a higher minimum sample
size (n = 20) for other comparative
studies because they typically havefewer controls for bias than RCTs.

Data Extraction and Analysis

One investigator extracted data
regarding study design, descriptionsof study populations, intervention
and comparison groups, andbaseline and outcome data using
a standardized form. A second
investigator independently verified
the accuracy of the extraction andmade revisions as needed. Significant
heterogeneity in interventions andoutcomes reported precluded metaanalysis; thus, we synthesized studies
qualitatively.

Assessment of Study Risk of Bias
and Strength of Evidence

Two investigators independently
evaluated the overall methodologic
risk of bias of individual studies
using the ASD-specific assessment
approach developed and used inprevious reviews of interventions
for ASD.‍29,​32,​‍ 33‍ Senior reviewers
resolved discrepancies in risk ofbias assessment, and we used an

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Sathe et alFIGURE 1

Disposition of studies identified for this review. Numbers do not tally because studies could be
excluded for multiple reasons.aapproach described in the full
review‍34 to determine low, moderate,or high risk of bias ratings.
Assessment of the strength ofthe evidence (SOE) reflects theconfidence that we have in thestability of treatment effects in theface of future research. The degreeof confidence that the observed
effect of an intervention is unlikely
to change in additional research,
the SOE, is presented as insufficient,
low, moderate, or high. Assessments
are based on consideration of study
limitations, consistency in the
direction of the effect, directness
in measuring intended outcomes,
precision of effect, and reporting
bias.‍35 We determined the strengthof evidence separately for majorintervention-outcome pairs using aprespecified approach described indetail in the full review.‍34

Results
Our searches (conducted for thebroader systematic review update‍30)
identified 6583 citations, of which
19 RCTs (reported in multiple
publications) met inclusion criteria

and addressed diet or nutritional
therapies (‍Fig 1).‍36–58‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍ Seventeen ofthese studies were published after
the completion of our initial reviewof therapies for children with
ASD,​‍29 and 2 were included in theprevious review.‍49,​50‍ Four RCTs
had low risk of bias,​‍38,​41,​43,​‍ 47‍ 10 had
36,​
37,​
3
9,​
40,​
46,​
49
–51,​
moderate,​‍ ‍‍ ‍ ‍ ‍ 53,​
‍ 56
‍ –‍ 58
‍
42,​
44,​
45,​
48,​
and 5 had high risk. ‍ ‍ ‍ 52,​
‍ 54,​55‍‍Table 2 outlines study characteristics
and risk-of-bias assessments. Study
treatment durations ranged from
7 days to 2 years, and sample sizes
ranged from 12 to 92 (total N = 732).
Follow-up occurred immediately
posttreatment in all studies.

Ω-3 Fatty Acid Supplementation

Little evidence supports theeffectiveness of Ω-3 supplementation
to improve core or associated
ASD symptoms. Three RCTs of
Ω-3s versus placebo (low‍41 andmoderate‍39,​40‍ risk of bias) reported
no significant group differences
on most measures of challenging
behavior, communication, language,
and adaptive behavior.‍39–41‍ One
study reported significantly
improved scores in the placebogroup compared with the Ω-3 groupin externalizing behaviors after 6
months of treatment,​‍39 and anotherreported a significant improvementin parent ratings of stereotypy andlethargy in children receiving Ω-3
supplements compared with thosereceiving placebo; teacher ratings
were not significantly different.‍40
Another RCT (moderate risk ofbias) of dietary docosahexanoic
acid (DHA) supplementation versus
placebo reported improvementin parent-rated social skills inchildren receiving placebo versus
those receiving docosahexanoic
acid, whereas teachers rated
communication as more improved in
the treatment group compared withplacebo.‍37 Scores on other measures
did not differ significantly between
groups. Supplemental Table 3 reports
outcome data for all studies.

Digestive Enzyme Supplementation

Evidence is inadequate to assess
the effects of short-term digestive
enzyme supplements. Two RCTs
(moderate risk of bias) addressed
digestive enzyme supplements
compared with placebo: 1 evaluateda proteolytic enzyme supplement(Peptizyde)‍49 and the other adigestive enzyme supplement(Neo-Digestin)‍36; both supplements
contained papain and pepsin or
peptidase. The Peptizyde RCTreported no significant differences inmeasures of behavior, sleep quality,or gastrointestinal symptoms,
and no significant differences inadverse effects.‍49 In a 3-month trialof Neo-Digestin versus placebo,
symptom severity scores improved
significantly in the treatment groupcompared with placebo.‍36

Other Supplements

Two RCTs (low‍38 and moderate‍58
risk of bias) addressed methyl
B12 supplementation. ClinicalGlobal Impression (CGI) scores
improved significantly in the
methyl B12 group in 1 RCT (effectsize = 0.84, P = .005), but studies

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3

TABLE 2 Overview of Studies (k = 19)
Characteristic

Ω-3 Fatty Acids

Digestive
Enzymes

Other Supplements

GFCF Diets

Other Dietary
Intervention

Total

0
1
1
2

0
0
2
0

0
1
2
1

0
0
2
2

3
1
0
1

3
3
7
6

2

0

0

0

1

3

1
3
3
2
0

0
1
0
1
2

0
4
2
1
1

1
3
1
2
0

0
2
3
2
3

2
13
9
8
6

0
2
4

0
0
2

0
1
4

1
1
1

0
1
1

1
5
12

0
0
1
3

1
1
0
0

1
0
0
3

0
0
2
2

2
0
1
2

4
1
4
10

1
3
0
167

0
2
0
135

1
2
1
136

0
2
2
82

2
1
2
212

4
10
5
732

Treatment duration<1–4 wk
5–8 wk
9–12 wk≥13 wka
Primary outcomes addressed
Attention/attention-deficit/hyperactivity
disorder symptoms
Adaptive behavior
ASD symptom severity
Challenging behaviors
Communication
Medical symptoms (eg, sleep,
gastrointestinal)
Neurocognitive skills
Social skills
Harms
Region of study conduct
Asia or Africa
Australia
EuropeNorth America
Risk of bias
Low
Moderate
High
Total N participantsa Two studies were >52 weeks’ duration.‍44,​‍45,​‍54,​‍55

reported few other significant
group differences in measures of
behavior or communication.‍58 Two
RCTs of levocarnitine (moderate‍51
and high42 risk of bias) reported
improvements in symptom severityin the levocarnitine group comparedwith placebo, but scores on otherbehavioral measures or adverse
effects did not differ between
groups.‍42 In the second RCT,
symptom severity did not differ
between groups after 6 months oftreatment.‍51

GFCF Diets

Data to assess the effects of GFCF
diets are limited because dietary
approaches and outcome measuresvaried among studies as did control
diets and monitoring of adherence
to GFCF diets. Four RCTs (in multiple
publications) compared GFCF dietsto either an unaltered diet‍44,​45,​‍ 54‍ –‍ 57‍
or a low-sugar diet (total N acrossstudies = 82).‍53 One RCT (moderate
4risk of bias) reported no significant
differences between groups on
measures of development or
behavior, although the control group
improved significantly from baseline
on visual reception, withdrawal,
aggression, and attention subscales(P values < .05) Another crossover
RCT (moderate risk of bias) similarly
reported no statistically significant
differences between groups on
measures of symptom severity or
language, although parents of 7of the 15 children participating inthe study reported improvements‍ In a retrospective
in language.‍56,​57
analysis of videotapes recorded
during the study period, investigators
found no significant groupdifferences in verbal communication
between children in the diet orcontrol groups or between children
whose parents reported language
improvements after the study period
and those whose parents did not.

One RCT (high risk of bias)
reported significant parent-rated
improvements in communication,
resistance to communication, social
isolation, repetitive or challenging
behavior, and overall impairment inchildren on a GFCF diet comparedwith those on a usual diet (P values‍ Children on the GFCF
≤ .007).‍54,​55
diet also improved significantly on
tests of cognitive skills, motor skills,
verbal and social communication,
anxiety, and reaction to changes inenvironment and routine comparedwith control children (P values< .05). Another high risk of bias
RCT with 24-month follow-up ofparticipants reported few differencesin behavioral measures between
children on a GFCF diet and thosewith no dietary restrictions‍44,​45‍ ; ASD
symptoms improved significantly
in participants in the GFCF dietgroup versus the no diet group at
12 months, but were not different
on any measure in a subset ofparticipants followed for 24 months.

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Sathe et alOther Dietary Approaches
One RCT (high risk of bias)
compared a gluten-free diet to ausual diet and reported significant
improvements in gastrointestinal
symptoms (stomachache, bloating,constipation) from baseline in
the gluten-free diet group, but
not in the control group. Diarrhea
did not improve significantly ineither group. Stereotyped behavior
and communication improved
significantly in the gluten-free groupcompared with control children(P values ≤ .005).‍52 Another small
RCT (low risk of bias) comparing
a gluten- and dairy-free diet witha diet including both gluten anddairy reported no significant
group differences in challenging
behavior (hyperactivity, irritability,
inattention).‍47

Two small RCTs (low‍59 andmoderate‍46 risk of bias) evaluatedthe “challenges” of gluten- or caseincontaining foods, but the evidence
is inadequate to determine if shortterm gluten- or casein-containing
foods affect ASD symptoms or
gastrointestinal function. One RCTthat randomized children who weremaintaining GFCF diets to foods
with gluten, gluten and casein, or
placebo foods reported no significant
group differences in measures ofchallenging behaviors or measures of
sleep quality and stool frequency.‍43
Another RCT (moderate risk of bias)
assessing the effects of introducing
gluten/casein-containing foods
versus placebo foods similarly
reported no significant effects ofadded gluten or casein on behavior
or gastrointestinal symptoms.‍46
Finally, a single RCT (high risk ofbias) compared boiled or raw camel’s
milk with cow’s milk and reported nosignificant differences in ASD severity
between groups after 2 weeks oftreatment.48

Harms

Studies that reported harms either
reported no significant difference

between the intervention groupand the control group, or reported 0
harms for each group. Harms weredisparate and the clinical significancewas generally difficult to assess(Supplemental Table 4).

SOE

Ω-3 fatty acid supplementation andplacebo did not affect challenging
behaviors and was associated withminimal harms. Our confidence
in these conclusions is low (lowSOE). Despite the number of RCTs
with low or moderate risk of bias
addressing other supplements, data
were inadequate to make conclusions
about all clinical efficacy and harms
outcomes because only a few small
studies addressed each supplement(insufficient SOE). Similarly, althoughmultiple RCTs evaluated variationsof a GFCF diet, studies addressed
different outcomes and different
approaches to restricted and control
diets; thus, data were inadequate to
make conclusions about the bodyof evidence (insufficient SOE) or
about other dietary interventions(challenge foods, camel’s milk).

Discussion
Despite their widespread reported
use, little evidence supports
the effectiveness of nutritional
supplements or the GFCF diet for
improving ASD symptoms. Harms
reported in studies were generally
considered mild, but the long-term
effects of these therapies are not wellunderstood. Although the conductof studies generally improved fromthose reported in our 2011 review,
evidence remains insufficient formost interventions given the small
sample sizes, lack of longer term
follow-up, and heterogeneous
agents and populations. Few studies
assessed the effect of concomitant
behavioral or other therapies,
although many children with ASD
receive multiple interventions.

These findings generally alignwith conclusions in recent
reviews addressing specific diets
or supplements. One Cochranereview evaluating Ω-3 fatty acids
reported no evidence for effects onsocial interaction, communication,
hyperactivity, or stereotypy.‍27

Another review of GFCF diets
included 32 studies, typically withhigh risk of bias, and noted scarceevidence for GFCF diets, with positiveeffects reported only in lower quality
studies.‍60

Even without a clear evidencebase documenting safety andefficacy, many families of children
with ASD use diet and nutritional
approaches.‍61,​62‍ Parents have cited
better alignment with their personalviews as well as perceived fewer side
effects than conventional medications
as reasons for using “complementaryor alternative” therapies, including
restricted diets and nutritional
supplements.‍5–‍‍ 9‍ Caregivers have also
reported making treatment decisions
about such therapies without aclinician’s input, noting a perceived
unwillingness to consider potential
benefits among clinicians, even in theface of few evidence-based effective
therapies.‍63 These findings continue
to highlight the need for shareddecision-making among providers
and families, including understandingof family motivations for using
specific therapies and discussion ofbalancing potential benefits withpotential risks and resource and time
costs to families.‍64,​

Limitations of the Review Process

We included studies published in
English only and did not include
unpublished data. Although ourpreliminary scan of non-English
publications identified few potential
eligible studies, we recognize thatsome nutritional supplements may
have been studied only in nonWestern countries and will not be
addressed in the current review.
We also included only comparative

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PEDIATRICS Volume 139, number 6, June20175

studies of medical interventions
with at least 10 children with ASD.
Given the heterogeneity in treatment
regimens, outcomes addressed in eachstudy, and patient populations, wewere limited in our ability to metaanalyze findings or identify potential
subgroups that may respond morefavorably to specific treatments.
Finally, we used a nonvalidated tool toassess risk of bias; this tool evaluates
constructs similar to those assessedby organizations such as the Cochrane
Collaboration, with the addition of
ASD-specific domains.

Conclusions
Overall, studies of nutritional
supplements or specialized
diets were typically small andshort-term (<6 months) andprovided little evidence regarding
the potential effects of theseapproaches. Several agents wereaddressed in single studies, which
limit conclusions about theireffects. These findings can help
to inform shared caregiver andclinician decision-making about
therapies for children with ASD.

Acknowledgments
Dr Shanthi Krishnaswami and Ms
Jessica Kimber contributed to the data
extraction. We thank the full researchteam and of the Agency for Healthcare
Research and Quality task order officers
and associate editor for their input.

Abbreviations

ASD: a utism spectrum disorder
CGI: C linical Global Impression
GFCF: g luten/casein-free
RCT: r andomized controlled trial
SOE: s trength of the evidenceThis manuscript was derived from a systematic review conducted by the Vanderbilt Evidence-based Practice Center, “Medical Therapies for Children with Autism
Spectrum Disorder (ASD)—an Update,​” which will be published in full on the Agency for Healthcare Research and Quality Web site.
This project was funded under contract HHSA209201500003I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services.
The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for
Healthcare Research and Quality or the US Department of Health and Human Services. Agency for Healthcare Research and Quality retains a license to display,
reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency’s contract with the author.
DOI: https://​doi.​org/​10.​1542/​peds.​2017-​0346
Accepted for publication Feb 10, 2017
Address correspondence to Zachary E. Warren, PhD, Departments of Pediatrics and Psychiatry, Vanderbilt Kennedy Center, Vanderbilt University Medical Center,
PMB 40, 230 Appleton Pl, Nashville, TN 37203. E-mail: zachary.warren@vanderbilt.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2017 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This project was supported by the Agency for Healthcare Research and Quality (contract HHSA290201500003I).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-0730.

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Sathe et al

Nutritional and Dietary Interventions for Autism Spectrum Disorder: A
Systematic Review
Nila Sathe, Jeffrey C. Andrews, Melissa L. McPheeters and Zachary E. Warren
Pediatrics 2017;139;
DOI: 10.1542/peds.2017-0346 originally published online May 26, 2017;

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Nutritional and Dietary Interventions for Autism Spectrum Disorder: A
Systematic Review
Nila Sathe, Jeffrey C. Andrews, Melissa L. McPheeters and Zachary E. Warren
Pediatrics 2017;139;
DOI: 10.1542/peds.2017-0346 originally published online May 26, 2017;

The online version of this article, along with updated information and services, islocated on the World Wide Web at:
http://pediatrics.aappublications.org/content/139/6/e20170346

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by theAmerican Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:.

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