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Jennifer Harrison Elder 1 Background: The gluten-free, casein-free (GFCF) diet is heralded by strong anecdotal parental
Consuelo Maun Kreider 2 reports to greatly improve and even “cure” symptoms of autism spectrum disorders (ASDs).
Nancy M Schaefer 3 Yet, to date, little conclusive empirical evidence exists supporting its use.
Mary B de Laosa 4 Objective: The purpose of this paper is to provide an overview of the state of the recent evi-
dence regarding the use of GFCF diet for treatment of individuals with ASD.
1
Department of Family and
Community Health Nursing Science, Methods: Five database providers (PubMed, Web of Knowledge, EBSCO, ProQuest, and
2
Department of Occupational Therapy, WorldCat) were used to search 19 databases, yielding a total of 491 articles that were published
3
Health Science Center Library,
through February 2015. Peer-reviewed articles published between January 2005 and February
4
Department of Psychology, University
of Florida, Gainesville, FL, USA 2015 were included for review if study participants were identified as having ASD and if the
study investigated the effects of the GFCF diet on ASD behaviors or the relationship between
the diet and these behaviors.
Results: Evaluation of search results yielded eleven reviews, seven group experimental studies
including five randomized controlled trials, five case reports, and four group observational studies
published during the last 10 years. These studies represent a marked increase in the number of
Video abstract
reported studies as well as increased scientific rigor in investigation of GFCF diets in ASD.
Conclusion: While strong empirical support for the GFCF diet in ASD is currently lacking,
studies point to the need for identifying subsets of individuals (eg, those with documented
gastrointestinal abnormalities) who may be the best responders to the GFCF diet. Identifying
these subsets is critically needed to enhance rigor in this research area. Until rigorous research
supporting the use of GFCF diet is reported, clinicians should continue to use caution and con-
sider several factors when advising regarding implementation of the GFCF diet for individuals
with ASD.
Keywords: GFCF diet, autism spectrum disorders, review, gluten free, casein free, dietary
intervention
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http://youtu.be/-YDWqy5iyls Introduction
Autism, or the broader category of autism spectrum disorder (ASD), continues to pose
challenges in determining the most efficacious and effective treatment approaches for
managing associated social, communication, behavioral, and developmental symptoms.1
First described in a 1943 case report by Kanner,2 interventional approaches for autism
Correspondence: Jennifer Harrison Elder have been the subject of a vast number of clinical reports and case studies; less common
Department of Family and Community
Health Nursing, University of Florida,
are rigorous intervention trials. Recently, the thinking about ASD has expanded from
PO Box 100187, Gainesville, a solely psychiatric condition to a multisystem inflammatory disorder that includes
FL 32610-0187, USA
Tel 1 352 273 6318
systemic inflammation of the gastrointestinal (GI) tract impacting the brain, immune
Email elderjh@ufl.edu system, and metabolism.3
submit your manuscript | www.dovepress.com Nutrition and Dietary Supplements 2015:7 87–101 87
Dovepress © 2015 Elder et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
http://dx.doi.org/10.2147/NDS.S74718
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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Elder et al Dovepress
One popular treatment for addressing possible systemic casein, GFCF diet, autism, ASD, and Asperger’s syndrome.
inflammation is the gluten-free, casein-free (GFCF) diet, Search efforts yielded a total of 491 articles. Removal of
heralded by strong anecdotal parental reports of greatly duplicates and non-English articles left 290 potential articles,
improved4 and even “cured” symptoms of ASD, such that whose titles (and abstracts when needed) were independently
the child no longer meets criteria for ASD.5 The GFCF diet screened by two members of the research team. Additional
was first identified for use in schizophrenia,6 where a possible screening was conducted for 1) publication date prior to 2005;
genetic defect may contribute to what has been referred to as 2) publication type, such as commentary, letter to the editor,
a “leaky gut”, resulting in an overload of gluten (from wheat) book chapter, or thesis/dissertation; 3) publication in nonpeer
and casein (from dairy). It is posited that this overload causes reviewed periodical; 4) main topics unrelated to gluten- or
high peptide levels, which may produce an opioid-type effect casein-restricted diet; 5) main topics unrelated to ASD;
that manifests in the behavioral symptoms commonly seen 6) non-ASD research participants; and/or 7) non-English
in ASD.7 Others speculate that many individuals with ASD publications. Full texts of the remaining 61 publications
may have undiagnosed gastric conditions and sensitivities were read and sorted by article type (ie, review, experimen-
that are caused or aggravated by the ingestion of casein tal, case, group observational). Review articles focusing on
and gluten. This discomfort, or even severe pain in some GFCF diet in ASD were retained; all remaining articles were
cases, may result in externalizing behaviors (eg, tantrums, read for major focus on use of GFCF diet in ASD. Backward
screaming, and aggression) and inattention to tasks due to searches of references in the eleven included review articles
the distraction because of the pain. yielded one additional published abstract, resulting in the 27
Several systematic reviews8–14 of GFCF studies have publications included in our review. At each step of the article
focused on the few existing intervention studies and reported reduction process, two researchers discussed discrepancies in
inconclusive results.8–14 However, as Kanner2 noted in his their independent evaluations until consensus was reached;
case report, a thorough review must address case studies as when needed, a third member of the research team assisted
well as reports of clinical trials to produce a “full view of with deliberations.
the landscape” of what is currently known about the GFCF Review articles, intervention studies, case reports, and
diet. Such comprehensiveness is needed to assist families group observational studies were included if the study par-
and clinical professionals in making informed decisions ticipants were identified as having ASD, and the study investi-
about implementing the GFCF diet and can identify specific gated either the effects of the GFCF diet on ASD behaviors or
directions for future research. the relationship between the diet and behaviors of individuals
The purpose of this paper is to provide an overview of with ASD. All articles included for review were published in
the state of the recent evidence regarding the use of GFCF peer-reviewed, English-language journals between January
diet for treatment of individuals with ASD as needed for 2005 and February 2015. Studies were excluded if they did
directing future research and advancing clinical practice not focus on GFCF diet in ASD. However, because of the
recommendations. As such, we reviewed the scientific lit- paucity of randomized controlled trials (RCTs) reported in
erature published between January 2005 and February 2015 the literature and because of the study’s rigor, we chose to
and have organized our review into four sections: summaries include the one double-blind RCT reported via published
of review articles, group experimental intervention studies abstract15 (no other published abstracts reported on a RCT
including randomized clinical trials, case reports, and group testing GFCF diets in ASD).
observational studies.
Results
Methods Reviews
We began our review with a scoping search of the literature A total of eleven review articles8–14,16–19 from ten research
in order to gain a broad overview of the existing relevant groups were included in this review and are summarized
literature. Table 1 details our search strategies, which were in Table 2. Hereafter, we will refer to these eleven review
constructed by the third author, a research librarian. Nineteen articles as ten reviews because one review article was written
databases from five database providers (PubMed, Web of as an addendum11 of the group’s review that was published
Knowledge, EBSCO, ProQuest, and WorldCat) were searched in the prior year.10 These authors reviewed a RCT reported
via subject headings and keywords, with the latter truncated in 2010 by Whiteley et al,20 which was published shortly
and/or phrase searched to capture various forms of gluten, after the original review was released. Notably, six12–14,17–19
PubMed ((diet OR dietary) AND (restrict OR restricts OR restricted OR restriction OR restrictions OR limit OR limits OR Clinical trial; review; 2/28/15 86
limited OR limitation OR limitations)) AND (“ASD”[tiab] OR “Child Development Disorders, Pervasive”[Mesh] OR evaluation studies; journal
“Asperger Syndrome”[Mesh] OR Asperger[tiab] OR Asperger’[tiab] OR Asperger’s[tiab] OR Aspergers[tiab] OR article; twin study; published
Aspergers’s[tiab] OR autism[tiab] OR autistic[tiab] OR “Autistic Disorder”[Mesh]) in the last 10 years; English
PubMed ((“gluten free” AND “casein free”) OR “GFCF”[tiab] OR “gluten free casein free”) AND (“ASD”[tiab] OR “Child Published in the last 10 years; 2/28/15 42
Development Disorders, Pervasive”[Mesh] OR “Asperger Syndrome”[Mesh] OR Asperger[tiab] OR Asperger’[tiab] English
OR Asperger’s[tiab] OR Aspergers[tiab] OR Aspergers’s[tiab] OR autism[tiab] OR autistic[tiab] OR “Autistic
Disorder”[Mesh] OR “Child Development Disorders, Pervasive”[Mesh]))
Academic Search (DE “Gluten-free diet” OR DE “Casein-free diet” OR (“gluten free diet*” OR “gluten free” OR “casein free diet*” Scholarly (peer-reviewed 3/17/15 43
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OR ASC OR “autism spectrum disorder*” OR Asperger*)
(Continued)
89
GFCF diet in ASD
Table 1 (Continued)
90
Database Search strategy Limits Date Number
Elder et al
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EXPLODE(“Asperger’s syndrome”)) OR ASD OR autis* OR Asperger*)
Dissertations and diet* AND (gluten* OR casein* OR GFC OR GFCF) AND (autis* OR ASD OR Asperger*). Narrowed by Subject: No limits set 3/27/15 5
Theses (ProQuest) biochemistry; genetics; microbiology; cellular biology; food science; medicine; autism; livestock; toxicology; analytical
chemistry; anatomy and physiology; biology; health care management; nursing; occupational therapy; alternative
medicine; parents and parenting; rehabilitation; therapy 247 results, 5 selected as relevant
ERIC (ProQuest) (SU.EXACT.EXPLODE(“Pervasive Developmental Disorders”) OR ASD OR autism* OR Asperger*) AND ((SU. No limits set 3/27/15 23
EXACT.EXPLODE(“Dietetics”) OR diet*) AND (gluten* OR casein* OR GFD OR GFCF))
Christison Systematic review: published trials Authors did not report Authors did not report N7. Inadequate evidence to clearly support
and of gluten and/or casein elimination in ages included in search. years searched. Years of 6 uncontrolled clinical trials. or refute use of GFCF for ASD symptom
Ivany8 children with ASD. Participant ages in included included studies: 1 single-blind RCT. alleviation. Outcome assessments should
studies: 3–22 years. 1990–2002. include measurement of nonverbal cognition.
Elder Narrative overview review. Topics: Authors did not report ages Authors did not report Nnot reported. Great need for additional research exists in
et al16 historical background GFCF diets; GI included in search or review. years searched or years n3 studies regarding effectiveness order to address remaining questions from
abnormalities in ASD; evidence of included studies. of GFCF diet in treatment of ASD. both researchers and families; great needs
informing GFCF effect in ASD. 1 systematic review. exist for patients with ASD and their families.
2 RCTs.
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91
GFCF diet in ASD
92
Elder et al
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Table 2 (Continued)
Study Review type and topic(s) Age of participants Publication years Number and types of studies Author’s conclusions regarding GFCF
included diet in ASD
Dosman Narrative exploratory review. Topics: Authors did not report ages Authors did not report N= not reported. Inconclusive evidence regarding GFCF
et al18 current evidence for potential benefits of included in search or review. years searched or years of n7 testing effect of GFCF diet in diet effectiveness due to methodological
GFCF diet in children with ASD; risks of included studies. treatment of ASD. limitations. Studies suggest existence of a
Abbreviations: AB, 2 phase study where A phase is the baseline phase and B phase is the intervention phase; ASD, autism spectrum disorder; GF, gluten-free only; GFCF, gluten-free, casein-free; EBP, evidence-based practice;
our review period; of these six reviews, five13,14,17–19 reported
on multidimensional considerations (eg, safety, adherence to
evidence-based practice standards, diet allergies), informing
the use of GFCF diets in the treatment of ASD.
Of the ten reviews, two9,12 limited their review to RCTs.
remaining reviews included uncontrolled studies, group
descriptive/observational studies, and case reports in addition
to RCTs. The most rigorous review of the GFCF diet in ASD
is a 2008 Cochrane Review by Millward et al.9 They identified
only two small RCTs (n35), which rendered a meta-analysis
impossible. The authors concluded that despite the evidence
of high use of this diet as well as other complementary and
2 open-label experimental studies.
1 open-label randomized
controlled cohort study.
3 double-blind RCTs.
3 systematic reviews.
randomized trial.
remaining studies allowed study sample age ranges of up to anecdotal reports for some participants on the GFCF diet.
18 years. Additionally, only one study20 tested an intervention Table 3 summarizes the seven group experimental studies
that lasted longer than 3 months. Notably, this was the only included in our review.
study that reported statistically significant improvements in
the GFCF diet group using blinded assessment. No other Case reports
studies using blinded assessment found group differences A total of five case reports5,25–28 were reviewed and are sum-
for the GFCF diet. However, one study4 did note positive marized in Table 4. Of these five cases, one employed a
Mageshwari and Minitha23 Observational description of ASD. N25 enrolled; n=10 descriptive CF diet (group 1),
entire study sample with dietary analysis only, n15 dietary intervention GF diet (group 2),
intervention study of subgroup. analysis; 3–18 years. GFCF diet (group 3);
3 months.
Seung et al24 Retrospective/secondary ASD. N13; n13 analyzed; GFCF diet; 6 weeks.
analysis of 1-group prepost data 2–16 years.
from double-blind RCT.4
Nazni et al22 Observational description of ASD. N50 enrolled with descriptive analysis; CF diet (group 1),
entire study sample with dietary n30 dietary intervention analysis; 3 to GF diet (group 2),
intervention study of subgroup. 11 years. GFCF diet (group 3);
2 months.
Hyman et al15 Double-blind RCT. ASD. N21 enrolled; n14 included in GFCF diet with
analysis; 30–54 months. weekly double-blind
snack challenges;
12 weeks.
Whiteley et al20 Two-stage, single-blind RCT PDD (ICD- N72 started the trial; n55 analyzed GFCF diet; 24
using an adaptive design with 10 code F84). after 12 months, n35 analyzed after months (control
interim analysis. 24 months; 4 years to 10 years group received 12
11 months. months intervention
as result of interim
analysis).
Johnson et al21 Parallel 3-group, single-blind RCT. ASD. N unreported; n22 completed study; GFCF diet; 3
3–5 years. months.
quasi-experimental design. Irvin25 utilized a ABAB (2-phase on the GFCF diet as compared to a regular diet. However,
design where A1 is the baseline, B1 is the introduction of the remaining four case reports described positive changes
intervention, A2 is the withdrawal of intervention, and B2 in cognitive, behavioral, and language symptoms of the
is the reintroduction of intervention) reversal design and children with ASD following implementation of the GFCF
measured the frequency of problem behaviors in a controlled diet. Additionally, in these four cases,5,26–28 parents reported
setting while on and off the GFCF diet. No significant reduc- positive results, such as improved language and cognitive
tion in problem behaviors was found while the child was development and satisfaction with the overall changes in their
96
Study Age; Previous/additional Behavioral/developmental Gastrointestinal/ Intervention Behavioral outcome Gastrointestinal
Elder et al
Dovepress
intervention
Irvin25 12-year-old male; GCCF diet for 1 year Extreme self-injury, physical None reported. Single case ABAB quasi- No change in problem None reported.
ASD and prior to initial trial. aggression, property experimental design: behaviors. Behaviors
intellectual destruction, and self-restraint. A11 year GFCF diet, measured during attention,
disability. B112 days regular diet, demand, and play conditions.
A210 days GFCF diet,
B230 months regular diet.
child. Three5,26,27 of the five case reports noted that the GFCF
Abbreviations: ASD, autism spectrum disorder; CAM, complementary and alternative medicines; CHARGE, coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality; GFCF,
improved but did
diet improved the child’s communication skills and cognitive
implementation
gastrointestinal
of GFCF diet,
not resolve.
scores so drastically that the children eventually no longer
symptoms
Following
met the diagnostic criteria for ASD. Most notable among the
five case reports reviewed was the presence of preexisting
GI symptoms in the four cases,5,26–28 reporting improvement
improvement in tantrum
Language improvements
implemented.
Four group observational studies29–32 were reviewed that
contribute evidence informing more nuanced aspects of
Note: ABAB: 2-phase design where A1 is the baseline, B1 is the introduction of intervention, A2 is the withdrawal of intervention, and B2 is the reintroduction of intervention.
future GFCF diet trials; these studies are summarized in
Table 5. An observational study by Patel and Curtis29 incor-
5 years old. Recurrent illness
respond to pharmacological
Parents implemented GFCF
Experienced seizures at
therapy. Therefore, a
(ADHD-IV) scores.
eye contact, lack of social
Escalating tantrums, no
Discussion
Our review of the recent literature on gluten- and/or casein-
stereotypies.
seizure onset at
Dovepress
or potential
responders (n); age
Patel ASD plus ADHD, N10; number Design: open label observational study. Parents, teacher, and physician pre- and Improved behavior, social, motor, and GI
and Asperger syndrome receiving GFCF diet not Description: 3–6 month comprehensive postintervention reports regarding child’s: symptoms; statistically significant reduction of
Curtis29 plus ADHD. reported; age: multidimensional treatment program including: motor capabilities, behavioral capabilities, urinary lead levels; four participants able to
4–10 years. environmental control, organic diet or educational capabilities, ASD and ADHD attend mainstream classes.
in the 12-year span of 1990 and 2002, and the remaining 10 come to light and has not yet been incorporated into the
studies (42%) were published during the 7-year period of published clinical trials included in our review.
2005 through 2012. This observation, in conjunction with
the number of reviews focusing on GFCF in ASD published Summary
in 2012 and 2013 (six of ten included in our review) indi- Despite its lack of empirical validation, there is enough
cates an increased interest in GFCF treatments for ASD over interest in the GFCF diet that the treatment strategy remains
the past 10 years. Researchers’ collective understanding of widely used with individuals with ASD. The GFCF diet serves
the questions at hand has refined to reflect an incomplete as a strong exemplar of science lagging behind in its ability
but multifaceted understanding of gluten- and/or casein- to inform the practices of a community of interest. Some
restricted diets in the treatment of ASD. Some studies point reasons for this paucity of empirical support are discussed
to a child’s age at diet introduction,31 while others suggest in the reviewed literature and include challenges related to
duration of diet20,30 as well as possible food sensitivities and conducting clinical trials that must ensure dietary compli-
allergies10–12,14,18 as potential factors impacting efficacy of ance and experimental blinding in naturalistic, day-to-day
GFCF diet in ASD. Others note physiological abnormalities settings and interactions. In short, well-controlled GFCF
in ASD that may help to elucidate potential responders.33–37 dietary trials are difficult to conduct but remain desperately
These findings are highly significant and similar to our con- needed in order to inform clinical treatment decisions. Fur-
clusions about the state of the science related to the GFCF ther concerted efforts must be made to identify subsets of
intervention in ASD. individuals (eg, those with documented GI abnormalities)
who may be the best GFCF diet “responders”. Finally, until
Limitations such evidence is available, clinicians should advise those
Findings were limited by our specific question investigating wishing to implement the GFCF diet that it is not likely to
the current state of evidence regarding the use of the GFCF be a “miraculous cure” as some claim. As such, clinicians
dietary intervention in ASD. That is, we were seeking infor- should use caution and consider a number of factors, such as
mation about results of the GFCF diet itself and not neces- the individual’s overall nutritional status as well as potential
sarily what patient characteristics might suggest the best added family burden related to cost and time commitments,
responders. As a result, only eight studies included for review when advising regarding implementation of the GFCF diet
contributed evidence as to who may be the best responders for individuals with ASD.
to a GFCF diet for treatment of ASD.10–12,14,18,20,30,31
Acknowledgments
Future direction: targeting subgroups The authors acknowledge Caroline S Mikaiel for assistance
of likely responders with initial data analysis. This work was supported in part
The recent literature indicates a need for future GFCF diet by the National Institutes of Health – National Center for
trials to target likely responders. Case report descriptions of Medical and Rehabilitation Research (NICHD) and the
positive effects in the four (of five) cases included in our study National Institute for Neurological Disorders and Stroke
reporting GI symptoms are consistent with conclusions drawn under grant number K12 HD055929. The content is solely the
from reviews published between January 2005 and February responsibility of the authors and does not necessarily repre-
2015. Specifically, Mulloy et al10,11 and Marí-Bauset et al14 sent the official views of the National Institutes of Health.
recommended consideration of the GFCF diet only when
food allergy and/or sensitivities have been diagnosed. In their Author contributions
reviews of the scientific literature, Dosman et al,18 Hurwitz,12 JHE, CMK, and NMS contributed to the literature search.
and Mari-Bauset et al14 recommended screening for celiac CMK, NMS, and MBD contributed to the data collection.
disease and/or food allergies prior to implementation of the All authors contributed toward data analysis, drafting and
GFCF diet. Conclusions drawn in at least two reviews,13,17 critically revising the paper, gave final approval of the version
analysis of two clinical trials,15,20 and one observational to be published, and agree to be accountable for all aspects
cross-sectional study30 suggest the existence of a subgroup of the work.
of responders to GFCF dietary interventions. Empirically
derived information suggestive of subgroups that may be Disclosure
responsive to GFCF dietary interventions has only recently The authors report no conflicts of interest in this work.
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