This study will assess the effectiveness of the ketogenic diet (high-fat, low-carbohydrate,
and moderate protein) in treating autism spectrum disorder (ASD). Three study groups will be
comprised of children (2-21 years of age) based on whether or not they have ASD and receive
the ketogenic diet - ASD/ketogenic diet, ASD/non-ketogenic diet, and non-ASD/non-ketogenic
Recent studies have shown that the ketogenic diet (high-fat, low-carbohydrate, and moderate
protein; induce a shift from the primary metabolism of glucose to ketones) or Modified-Atkins
diet may be effective in treating autism. Research on the Black and Tan BRachyury (BTBR)
T+tf/J mouse strain, characterized by an autism-like behavioral phenotype, has demonstrated
the efficacy of a ketogenic diet in improving autism. Although, modified diets, such as the
Feingold diet, low-sugar diet, or gluten-free diet, have shown behavioral improvements in
patients with Attention Deficit Hyperactivity Disorder (ADHD), the ketogenic diet has not
been studied in autism spectrum disorder (ASD) despite the high incidence of ADHD
comorbidity. The findings from only one prospective, pilot study have been published, which
reported significant behavioral improvement in all 18 autistic subjects after six months
(assessed at intervals of four weeks on the diet and two weeks diet-free) on the ketogenic
diet. Clearly, the ketogenic and other modified diets as promising treatments for ASD have
been understudied. Additional clinical research is necessary to establish the ketogenic diet
as a safe, effective treatment alternative for children with ASD.
This proposed research project will involve an ethnically diverse sample (varied genetic
background and environmental exposure) to assess the efficacy of the ketogenic diet as a
therapeutic intervention, and to understand its beneficial effects in children with ASD. The
investigators anticipate that noteworthy findings will contribute to the sparse literature on
ASD and effective dietary interventions and prompt future research collaborations with
investigators from other medical centers and/or academic institutions. Funding for future
research appears promising considering that ketogenic therapies are also a novel method for
the treatment of a variety of disorders, including other neurodevelopmental disorders,
diabetes, migraine headaches, brain tumors, multiple sclerosis, and obesity.
In addition, the investigators propose to also examine the potential changes in blood
composition and intestinal (gut) microbiome in children with (without) ASD who are treated
(not treated) with the ketogenic diet in light of the effect on their ASD symptomatology. The
relationship between the gastrointestinal tract and the central nervous system has garnered
increasing interest in the research community. The gut-brain interface describes a
bidirectional relationship in which the central nervous system influences the gut and vice
versa. Little is known about the mechanisms behind anecdotal reports of dietary success in
humans, but it is suspected that alterations in gut microflora are involved. Mulle et al.
(2013) postulated that the connection between the gut microbiome and ASD may be either the
direct cause or as indirect consequence of atypical patterns of feeding and nutrition.
Similarly, diet patterns, including the ketogenic diet, impact nutrient availability and thus
indirectly modulate the gut microbiome. Multiple studies have confirmed differences in levels
of gut commensals and overall metabolite profiles in fecal and urinary samples from healthy
children compared to children with ASD, potentially as a result of changes in the microbiome.
In the maternal immune activation mouse model of ASD, Hsiao et al. (2013) reported that
probiotic treatment with B. fragilis could correct behavioral abnormalities and metabolomics
profile typified in ASD and ameliorate ASD-relevant GI barrier deficits in mice. Sandler et
al. (2000) demonstrated that oral vancomycin treatment showed short-term improvements in
children with regressive-onset autism, suggesting that alterations in gut bacteria profile,
in this case with antibiotic therapy, may improve autistic behavior. Studies of the gut
microbiome in children with ASD may elucidate the role of diet and the alterations in
gastrointestinal microbes related to ASD. As a result of these data, novel treatments may be
The specific aims of this study are:
Aim 1. To evaluate the effect of the ketogenic diet on the core symptoms of autism. The
following instruments will be used to measure core autistic symptoms: a) Autism Diagnostic
Observation Schedule - Second Edition (ADOS-2); b) Asperger Syndrome Diagnostic Scale (ASDS);
c) Childhood Autism Rating Scale (CARS-2); d) Gilliam Autism Rating Scale (GARS-3); e) Social
Responsiveness Scale - Second Edition (SRS-2); f) Diagnostic and Statistical Manual IV Text
Revision (DSM-IV-TR) and DSM-V ASD criteria; g) Standardized social & intelligence tests (if
available, administered by child's school); and h) Vanderbilt ADHD Diagnostic Teacher Rating
Scale Forms (Vanderbilt).
Hypothesis: Participants who have ASD/on the ketogenic diet will have significantly lessened
core autistic symptoms than those that have ASD/not on the ketogenic diet, between baseline
to three and six months after the dietary intervention is initiated.
Aim 2. In anticipation of significant changes in core autistic symptomatology, to examine the
effects of the ketogenic diet on the (a) number and dosage of medications used for behavioral
management, (b) number of lab tests ordered for behavioral management, (c) number of
emergency room or hospital visits for behavioral management, and (d) subject/family
satisfaction with the ketogenic diet.
Hypothesis: The number (and/or dosage) of medications, lab tests ordered, and emergency room
or hospital visits for behavioral management will decrease, and participant/family
satisfaction will be high for participants who have ASD/on the ketogenic diet than those who
have ASD/not on the ketogenic diet, between baseline to three and six months after the
dietary intervention is initiated.
Aim 3. To compare differences and/or changes in (a) biochemical profiles as defined from
blood and stool (gut or fecal microbiome) specimen samples and (b) serum and urine ketone
Hypothesis: Participants who have ASD/on the ketogenic diet will have notably different
biochemical profiles and significantly higher serum/urine ketone levels than those who have
ASD/not on the ketogenic diet and typically developing controls on a regular diet, between
baseline to three and six months after the dietary intervention is initiated.
The investigators anticipate that the KD will be effective in treating ASD, and further an
understanding of dietary patterns and gastrointestinal alterations in ASD. Noteworthy
findings will contribute to the sparse literature on the association between dietary
intervention and neurodevelopmental disorders, and assist with obtaining future funding for
higher-level clinical trials involving collaborative research with other medical centers and
academic institutions. These initiatives, the investigators believe, are necessary to
establish the KD as a novel, safe alternative to effectively treat patients with ASD.
- Ages 2-21 years.
- Primary diagnosis of autism spectrum disorder.
- Parent/legal guardian and child able to read or understand English, and able/willing
to provide informed consent/assent.
- Females of childbearing potential must have a negative pregnancy test result and agree
to use a medically acceptable method of contraception throughout the entire study
period and for 30 days after the last dose of study drug - childbearing potential is
defined a girls who are > Tanner stage 2 and urine pregnancy tests are acceptable.
- Known cardiac disorder including arrhythmias or hypertension.
- BMI < 3rd%ile.
- Carnitine deficiency (primary).
- Carnitine palmitoyltransferase (CPT) I or II deficiency.
- Carnitine translocase deficiency.
- Beta-oxidation defects - medium-chain acyl dehydrogenase deficiency (MCAD), long-chain
acyl dehydrogenase deficiency (LCAD), short-chain acyld dehydrogenase deficiency
(SCAD), long-chain 3-hydroxyacyl-coenzyme A (CoA) deficiency, and medium-chain
- Pyruvate carboxylase deficiency.
- Inability to maintain adequate nutrition.
- Patient or caregiver non-compliance.