The Effect of High Antioxidant Cacao on Behaviors in Children With Autism Spectrum Disorder
Phase: NA
Conditions: Autism Spectrum Disorder
Sponsor: Loma Linda University

 
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1. 
PROTOCOL INFORMATION  
 
Title: The Effect of High Antioxidant Cacao on Behaviors in Children with Autism 
Spectrum Disorder 
Funding Source: School of Allied Health Professions 
Version Date of Protocol: August 2, 2017 
Phase of Study: September 2017-September 2018 
 
2. 
PRINCIPAL INVESTIGATOR’S INFORMATION 
 
PI: Lee Berk, DrPH, Loma Linda University School of Allied Health Professions,  
 
Name & Address of Research Institution: 
Loma Linda University 
School of Allied Health Professions 
Nichol Hall Room 1605 
Loma Linda, CA 92350 
 
Phone: 909-651-5828 (ext 15828) 
Fax: 909-558-0302 
Email: lberk@llu.edu 
 
3. 
STUDY PERSONNEL 
 
Amy Sadek, MOT, OTR/L, PhD Candidate 
Noha Daher, DrPH, Committee Member 
Kiti Freier Randall, PhD, Committee Member 
Karen Mainess, PhD, Committee Member 
 
4. 
STUDY INFORMATION 
 
The location of the research will take place at each child’s individual school and in 
their home environment. Expected start date is August 2017 and expected end date of 
research is August 2018. This is an experimental repeated measures design.  
 
5. 
INCLUSION / EXCLUSION CRITERIA 
 
Inclusion criteria: children with a diagnosis of Autism Spectrum Disorder, are 
between the ages of 5 and 12, and like 70% dark chocolate.  
 
Exclusion criteria: Food allergies, Caffeine hypersensitivity, Theobromine 
hypersensitivity, History of seizures or epilepsy, Developmental age < 24 months, 
and Diabetics.  
 
 
 
 

 
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6. 
SUBJECT RECRUITMENT & SCREENING 
 
Based on a power analysis, 35 subjects are needed with an expected attrition rate of 
20%. Subjects will include both males and females with an age range between 5 and 
12 years. Study will include subjects from any race or ethnicity that meet eligibility 
criteria. The target study population is school aged children with a diagnosis of 
Autism Spectrum Disorder. Recruitment will be done via flyers at the Inland Empire 
Autism Assessment Center of Excellence, which is an interdisciplinary diagnostic 
center. Upon a formal diagnosis of Autism Spectrum Disorder, the families of those 
children will be offered a flyer to determine if they are interested in participating in 
the study. The contact information of the Principal Investigator and graduate student 
research will be available on the flyer.  
 
7. 
INFORMED CONSENT PROCESS 
 
The informed consent process will be facilitated by the student researcher with the 
parents of the child with a diagnosis of Autism Spectrum Disorder. The informed 
consent process will take place at the child’s elementary school and parents will be 
provided fifteen minutes for decision making and discussion. Due to the subjects’ 
impaired decision making capacity, the parents will provide consent on their behalf. 
Subjects will be selected based on their diagnosis from the Inland Empire Autism 
Assessment Center of Excellence. Medical release forms will be obtained via the 
Inland Empire Autism Assessment Center of Excellence as this center has all baseline 
and demographic data. HIPPA compliance forms will be included with informed 
consent process. Privacy of medical and research records will be secured in a locked 
cabinet in a locked office. 
 
8. 
STUDY DESIGN 
a. Background or rationale for this study. 
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized 
by deficits in behavior, communication, and social skills (American Psychological 
Association, 2013). According to the Center for Disease Control and Prevention 
(CDC), currently 1 in 68 children are identified as having ASD and it is 4.5 times 
more common in males than females (CDC, 2016). The etiology is multifactorial 
as it involves genetics, environment, immunological factors, and oxidative stress 
factors (Damodaran & Arumugam, 2011; Chauhan & Chahuan, 2006). This is of 
particular importance to children as the brain is highly susceptible to oxidative 
stress especially in early childhood development. The reason the brain is 
susceptible to damage by oxidative stress is because it is the organ that requires 
the most oxygen for its normal function, it occupies 2% of our body mass yet uses 
20% of our metabolic oxygen (Damodaran & Arumugam, 2011; Chauhan & 
Chahuan, 2006). Thus, any interruption to its oxygen supply greatly impacts its 
many functions and in the immature nervous system of children protective 
barriers to oxidative damage are not fully formed hence they are more susceptible. 
Antioxidants’ benefits include improvement of cellular structure, counter free 
radical damage, neuroprotective, anti-inflammatory, accumulate in hippocampus 
and cortex, and improve vascular endothelial function (Sokolov, Pavlova, 
Klosterhalfen, & Enck, 2013; Vauzour, Vafeiadou, Rodriguez-Mateos, Rendeiro, 

 
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& Spencer, 2008). More specifically, cacao is a natural and potent antioxidant 
with benefits linked to being neuroprotective, improves blood pressure, improves 
lipid peroxidation, improves cognitive response time, enhances gamma frequency, 
increases cerebral blood flow, anti-inflammatory, and flavanols are able to cross 
the blood brain barrier (Cooper, Donovan, Waterhouse, & Williamson, 2008; 
Sokolov, Pavlova, Klosterhalfen, & Enck,  2013; Mastroiacovo et al, 2015; Berk 
et al, 2017; Vauzour, Vafeiadou, Rodriguez-Mateos, Rendeiro, & Spencer, 2008).  
b. Objectives:  
1. To determine if consuming high antioxidant cacao changes the severity of 
Autistic behaviors;  
2. To determine if parents of children with ASD observe behavioral changes 
following cacao consumption through behavioral scales; 
3.  To determine if teachers of children with ASD observe behavioral 
changes following cacao consumption through behavioral scales;  
4. To determine if parents’ stress level changes following the cacao 
consumption intervention through stress scale. 
c. Procedures involved (Research Interventions) 
1. Informed Consent and HIPPA documents 
2. Subject will also be offered a taste testing of the chocolate bar to be used 
in the study as liking the 70% dark chocolate is part of inclusion criteria.  
3. After consent is provided, parent will fill out the Youth & Adolescent 
Food Frequency Questionnaire based on their child’s typical dietary 
habits, an Autism Spectrum Rating Scale, an Aberrant Behavior Checklist, 
and the Parental Stress Index Questionnaire. 
4. Student researcher will prepare doses (3 squares or 6 grams) of the dark 
chocolate for each child in one week increments at a time. The dark 
chocolate will be wrapped in foil to protect against light and kept in a 
sealed Ziploc bag to prevent against oxidation in order to maintain the 
cacao’s integrity.  
5. Student researcher will meet with each parent/family once per week to 
collect any questionnaires and to deliver the dark chocolate doses for the 
subsequent weeks. 
6. Student researcher will meet with teachers at baseline, end of week two, 
and end of week four to collect all questionnaires. 
7. Subject will consume 3 squares of the dark chocolate every four hours 
daily for four weeks during waking hours between 8:00 a.m. and 8:00 p.m. 
8. Student researcher will contact parents and teachers weekly via 
phone/email to follow up on administration of the chocolate. 
9. Parent and primary school teacher will fill out the Autism Spectrum 
Rating Scale and the Aberrant Behavior Checklist at the end of week two 
and at the end of week four.  

 
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10. Parent will fill out the Parental Stress Index Questionnaire at the end of 
week four.  
d. Concise review of literature that supports the rationale, objectives, and 
methodology of the proposed study.  
Autism Spectrum Disorder involves oxidative stress in the pathophysiology and 
previous literature has shown that level of oxidative stress markers positively 
correlated with severity of behavioral symptoms (Damodaran & Arumugam, 
2011). Antioxidants, such as cacao, have shown to have great health and 
neurocognitive benefits on the adult population. In the ASD population, five 
studies have been conducted looking at an antioxidant intervention on behavior 
change. Researchers examined use of high antioxidant vitamin C providing 
8g/70kg/day for 30 weeks and found a reduction in symptom severity (Dolske, 
Spollen, McKay, Lancashire, & Tolbert, 1993). It appears this is the first study of 
its kind to look at antioxidants potential benefit to children with ASD. In a 2013 
study, children between the ages of three and a half and 16 were randomly 
assigned to one of the two groups to receive N-Acetylcysteine (NAC) (1200 
mg/day)+risperidone or placebo+risperidone. Results showed a significant 
improvement in irritability in the NAC group on the Aberrant Behavior Checklist 
(Ghanizadeh & Moghimi-Sarani, 2013). More recently, in a 2015 study, 
researchers examined children between four and 12 years of age with a diagnosis 
of Autism Spectrum Disorder. One group received risperidone plus NAC and the 
control group received risperidone plus placebo (Nikoo, Radnia, Farokhnia, 
Mohammadi, & Akhondzadeh, 2015). The dose of NAC ranged from 600 to 900 
mg/day. Results showed a significant improvement in both irritability and 
hyperactivity/noncompliance subscales on the Aberrant Behavior Checklist 
(Nikoo, Radnia, Farokhnia, Mohammadi, & Akhondzadeh, 2015). The most 
common adverse effects in the NAC+risperidone group were constipation, 
increased appetite, fatigue, nervousness, and daytime drowsiness(Nikoo, Radnia, 
Farokhnia, Mohammadi, & Akhondzadeh, 2015; Ghanizadeh & Moghimi-Sarani, 
2013). 
Lastly, a 2015 pilot study also assessed NAC in children with ASD between ages 
three and 12 (Hardan et al, 2015). Subjects were randomized to NAC were 
initiated at 900mg/daily for four weeks, then 900mg/twice daily for four weeks 
and 900mg/three times daily for four weeks (Hardan et al, 2015). Follow-up data 
revealed that the NAC group showed significant improvements on the Aberrant 
Behavior Checklist irritability subscale compared to the control group (Hardan et 
al, 2015). Also, stereotypy behaviors improved on the repetitive behavior scale 
and social cognition improved on one of the subtests on the social responsiveness 
scale (Hardan et al, 2015). These five studies are key in showing some of the 
reproducible evidence of potential therapeutic effects of antioxidant interventions 
in children with ASD. To date no study has analyzed the potential effects of high 
antioxidant cacao as an intervention for behavior change in the ASD population. 
 
 
 
 

 
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9. 
DATA COLLECTION 
 
Data collection procedures include psychometric assessments of common behaviors 
found in children with Autism Spectrum Disorder. They will be completed by child’s 
parent and primary teacher. The Youth & Adolescent Food Frequency Questionnaire 
will be administered to parent at baseline to determine their child’s typical dietary 
habits. The Aberrant Behavior Checklist and Autism Spectrum Rating Scale will be 
administered to parent and primary teacher at baseline, end of week two, and end of 
week four to measure behavior change. The Parental Stress Index will be 
administered to the parent at baseline and end of week four to determine if caregiver 
stress changed over the course of the intervention. All assessment tools are self-report 
measures using ordinal data. Demographic data will also be obtained from the Inland 
Empire Autism Assessment Center of Excellence. Further, the purpose of collecting 
medical chart information is to gather demographic data on whether the child has 
received any therapeutic interventions and if so, type of therapy and length of time.  
Age, medications, years in school, developmental factors and milestones, medical 
history, and social history will also be collected. These demographic data would be 
used in data analysis to determine the influence or associations of these variables on 
study outcomes.  
 
See attached appendices of: Aberrant Behavior Checklist, Autism Spectrum Rating 
Scale (short form), Parental Stress Index (short form), Youth & Adolescent Food 
Frequency Questionnaire, and Demographic Data. Short forms are provided to give 
the nature of the questions and the long forms are in the process of being ordered. 
 
10. 
LABELING & STORAGE OF DATA & SPECIMENS 
 
Informed consents and HIPPA documents will be stored in a locked cabinet in a 
locked office. Any electronic research records of behavioral scales, stress scales, and 
any other research information will be stored on a secured and password protected 
computer. All hard copies of research records of behavioral scales, stress scales, and 
any other research information will be kept in a locked cabinet in a locked office. 
Data will be secured in a locked cabinet for a period of three years. 
 
11. 
DATA ANALYSIS 
 
Research analysis plan will include non-parametric statistics. For the pre-test and 
post-test analysis of the Parental Stress Index scale Friedman’s test will be used. For 
all other repeated measures such as the Aberrant Behavior Checklist and the Autism 
Spectrum Rating Scale the Wilcoxon Signed Rank Test will be used.  
 
12. 
RISK AND INJURY 
 
Risks may include a breach of confidentiality and parent or teacher may feel 
uncomfortable answering questions. 
 
13. 
BENEFIT(S) 
 
Although you may not personally benefit from this study, your participation may help 
clinicians and teachers when working with children with a diagnosis of Autism 

 
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Spectrum Disorder. Results of the study can provide insights to practitioners and 
teachers while working with children with Autism Spectrum Disorder. 
 
14. 
COMPENSATION 
 
Families who complete the study in full will receive a $50 gift card at the end of the 
study for completing it in full. 
 
15. 
CONFIDENTIALITY 
 
All records and research materials that identify you will be held confidential. Any 
published document resulting from this study will not disclose your identity without 
your permission. Information identifying you will only be available to the study 
personnel. All data will be secured in a locked cabinet in a locked office.  
 
 
16. 
LITERATURE REVIEW 
 
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is characterized 
by deficits in social skills, communication skills, functional impairments across multiple settings, 
repetitive and restrictive behaviors, as well as hyper or hypo responsiveness to sensory stimuli in 
the environment (American Psychiatric Association, 2013). According to the Center for Disease 
Control and Prevention, 1 in 68 children were labeled as having ASD (CDC, 2016). Further, it is 
four and a half times more common in males than females (CDC, 2016). Although the etiology 
of ASD remains elusive, there are genetic, environmental, immunological, and oxidative stress 
influences that are related to the pathogenesis of the disorder (Damodaran & Arumugam, 2011).  
Oxidative stress is the excess accumulation of free radicals in the body. Oxidative stress 
has been linked to a variety of diseases including cancer, cardiovascular disease, neurological 
diseases, pulmonary disease, rheumatoid arthritis, nephropathy, as well as ocular disease (Pham-
Huy & Pham-Huy, 2008). Oxidative stress has also been under study as part of the 
pathophysiology of ASD and is linked to neuropsychiatric disorders such as schizophrenia, 
major depressive disorder, anxiety, panic disorder, and obsessive compulsive disorders 
(Damodaran & Arumugam, 2011). The human body offers mechanisms to counter the effects of 
free radicals, that lead to oxidative stress, by producing antioxidants. Antioxidants can be 

 
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produced naturally by the body or can be ingested through dietary nutrients. Examples of dietary 
antioxidants include Vitamin E, Vitamin C, Beta-carotene, Lycopene, Selenium, Omega-3 fatty 
acids, Omega-6 fatty acids, and Flavonoids (Pham-Huy & Pham-Huy, 2008). Flavanoids have a 
potent antioxidant content and are derived from foods such as cocoa, green tea, grapes, apples, 
ginkgo biloba, berries, among other foods (Pham-Huy & Pham-Huy, 2008).  
Research suggests that children with ASD tend to have greater markers of oxidative 
stress compared to their age matched controls or their non-Autistic siblings (Ming et al, 2005). 
Oxidative stress can be due to mitochondrial impairment, environmental factors, metabolic 
issues, and genetic predisposition (Ming et al, 2005). In turn, oxidative stress can lead to a 
cascade of events such as inflammation, damage to cell membranes, autoimmunity, methylation 
damage, cell death, and neurological impairments (Goldani, Downs, Widjaja, Lawton, & 
Hendren, 2014). The brain is an organ highly susceptible to oxidative stress which is of 
particular importance in early child development (Chauhan & Chauhan, 2006). Oxidative stress 
can be identified through markers of antioxidant enzymes, lipid peroxidation, and protein 
oxidation which are all higher in children with autism compared to their healthy peers 
(Damodaran & Arumugam, 201; Ming et al, 2005). 
Researchers observed a significant increase in oxidative stress markers in children with 
ASD compared to matched controls and the level of antioxidants excreted in urine samples were 
significantly lower in children with ASD compared to matched controls (Damodaran & 
Arumugam, 2011). Further, the level of severity of autistic behaviors were positively correlated 
with oxidative stress markers and antioxidant levels revealed a negative correlation with autistic 
behaviors (Damodaran & Arumugam, 2011). Ming et al (2005) measured urinary excretion of 8-
iisoprostane and 8-hydroxy-2-deoxyguanosine in children with ASD and matched controls and 
found children with ASD had increased levels of lipid peroxidation. Elevated blood samples of 
glutathione, glutathione peroxidase, methionine, oxidized glutathione, and cysteine have also 

 
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been found in children with ASD (Goldani, Downs, Widjaja, Lawton, & Hendren, 2014). 
Further, the severity of ASD was correlated with a lower level of antioxidants (Goldani, Downs, 
Widjaja, Lawton, & Hendren, 2014). 
Oxidative stress biomarkers are particularly noteworthy as they have the potential to be 
modulated by means of non-pharmacological interventions, such as nutritional interventions. 
Cocoa is a food rich in flavonoids and their sub group flavanols. These are both associated with 
improved cognitive processing, alertness, and processing speed (Crichton, Elias, & Alkerwi, 
2016). Further benefits of cocoa include increased cerebral blood flow, improved cardiovascular 
activity, improved insulin resistance, improved blood pressure, and improved endothelial 
function (Crichton, Elias, & Alkerwi, 2016). 
Current behavioral interventions that are utilized for children with ASD include 
behavioral therapists, speech and language pathologists, occupational therapists, and  
pharmacological interventions. Behavioral therapists work with ASD children on language skills, 
daily living skills, and social functioning, however, it should be noted that this type of therapy 
uses a Skinner approach with rote discrete trials in a one on one setting and is typically 
recommended at 40 hours per week for years on end (Peters-Scheffer, Didden, Korzilius, & 
Sturmey, 2011; Virués-Ortega, 2010). Speech and Language Pathologists also work with 
children with ASD to target social communication skills, request making, speech production, and 
reciprocal interaction (American Speech-Language-Hearing Association, 2006). Occupational 
therapists target sensory processing skills as well as motor skills (Case-Smith & Arbesman, 
2008). In terms of pharmacology, there is no approximately 1/3 of the ASD population take 
Selective Serotonin Reuptake Inhibitor drugs because their behavioral characteristics are similar 
to other serotonin related disorders. There are only two Food & Drug Administration (FDA) 
approved drugs for ASD are Abilify and Risperidone (LeClerc & Easley, 2015). Risperidone is a 
second-generation antipsychotic that has helped children with ASD improve number of tantrums, 

 
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aggressive and self-injurious behaviors and Abilify is a psychotropic drug that was designed to 
treat irritability in children with ASD (LeClerc & Easley, 2015). However, as with any drug they 
come with adverse effects including increased appetite, weight gain, dizziness, drooling, 
drowsiness, fatigue, vomiting, nasopharyngitis, fever, insomnia, and upper respiratory infections 
(LeClerc & Easley, 2015). 
Many antioxidant rich foods and vitamins have been used in the treatment of disease (Li, 
Chen, Zhang, Wu, Wu, & Liu, 2014). For example, vitamin C and vitamin E are both rich in 
antioxidants and have been used for cardiovascular disease and cancer (Li, Chen, Zhang, Wu, 
Wu, & Liu, 2014). Carotenoids have also been used in diseases that are neurodegenerative, 
inflammatory, or cardiovascular in nature (Li, Chen, Zhang, Wu, Wu, & Liu, 2014). 
Polyphenols, such as those found in cocoa, are known to have the ability to remove free radicals 
from the body and can offer protective properties in disease such as arteriosclerosis, heart 
disease, and alcoholic fatty liver (Li, Chen, Zhang, Wu, Wu, & Liu, 2014). 
To date, research has not examined the potential association between antioxidant rich 
foods, such as cocoa, and ASD behaviors. However, it is expected, based on the literature 
reviewed, that oxidative stress markers, such as free radicals, are elevated in children with ASD 
and thus could be reduced by high antioxidant cacao consumption. Thus, the purpose of the 
study is to provide information on the relationship between eating high antioxidant cocoa relative 
to behavior in children with ASD.  
 
 
 
 
 
 

 
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