Essential Oils for Enhancing of Quality of Life in Autism Spectrum Disorder (ASD)
Phase: PHASE2
Conditions: Autism Spectrum Disorder, Quality of Life, Sleep, Anxiety
Sponsor: Jill Hollway

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Essential Oils for Enhancing of Quality of Life in Autism Spectrum Disorder (ASD) 
 
Jill Hollway, PhD, PI 
L. Eugene Arnold, MD, co-PI 
 
INTRODUCTION 
 
Impact and Relevance 
 
Quality of life (QOL) is very often a cause of concern for parents of children with autism 
spectrum disorder (ASD). This concern may develop as parents observe their children struggle to 
adapt to the world around them. Children with ASD may become especially agitated when 
confronted with situations not normally considered challenging for the neurotypical child; and 
parents of children with ASD learn quickly to avoid potentially volatile situations in order to 
maintain their child’s equilibrium. Comorbid anxiety, with prevalence estimates ranging from 
44% to 83% (Johnson et al., 2009; Hollway & Aman, 2011) greatly stresses the ability of the 
family to engage in enrichment activities. Additionally, anxiety in ASD has been found to be a 
strong predictor of sleep disturbance (Hollway, Aman, & Butter, 2013) and irregular and delayed 
sleep may leave the child exhausted, impacting daytime behavior (Meltzer & Mindell, 2006) and 
QOL in children (Hsiao & Nixon, 2007; Wirell, Blackman, Barlow, Mah & Hamiwka, 2005). 
 
Considerably more impairing, the bidirectional nature of sleep disturbance and anxiety 
affects QOL, as anxiety may disturb sleep, and a lack of sleep may lead to increased anxiety 
(Hollway & Aman, 2011). In a report of unpublished data (Hollway, 2012), the investigator 
found that Emotional Functioning on the Pediatric Quality of Life Inventory (PedsQL) was 
associated with sleep disturbance in 1583 children with ASD. Out of 12 possible predictors, 
seven significantly predicted Emotional Functioning [F(7,1482) = 87.643, p <.001]. The results 
indicated that the Children’s Sleep Habits Questionnaire (CSHQ) subscales, Sleep Anxiety, 
Bedtime Resistance, and being a poor sleeper in general, contributed to quality of emotional 
functioning and showed a moderate effect (R2 = .293). This indicated that a moderate proportion 
of the variance found in the PedsQL Emotional Functioning subscale score was explained by the 
model (29.3%) (Cohen, 1988). 
 
Sleep problems cause significant family distress (Hiscock & Wake, 2002; Doo & Wing, 
2006) and clinicians are utilizing behavioral intervention (BI) first for sleep improvement. For 
many, this intervention is sufficient for improving sleep quality and quantity (Andersen et al., 
2008). However, when BI alone is unsuccessful and sleep problems persist, there are few 
alternatives from which parents can choose that do not involve pharmacological agents (e.g., 
melatonin, medication) (Hollway & Aman, 2011a; Hollway & Aman, 2011b).  As an adjunct, an 
essential oil formulation distributed by Young Living Essential Oils may be useful for improving 
quality of life by increasing sleep quantity and equilibrium without the undesirable side effects 
associated with medications. A pilot study of essential oils will help us determine whether 
essential oils are tolerable and effective for improving QOL. This study will provide data to help 
us decide whether continued study is warranted in a much larger multisite study. The proposed 
research will contribute new knowledge that could be useful for clinicians. The purpose of this 
research is to increase the existing knowledge regarding quality of life in children with ASD.  

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Background and Significance 
 
Aromatherapy has been used as a supplement to decrease stress, anxiety, and to help 
induce sleep (Hur, Song, Lee, J. & Lee, M., 2014; Lee, Wu, Tsang, Leung & Cheung, 2011). 
However, there is a paucity of empirical data reflecting its effectiveness for improving quality of 
life in children with sleep disturbances. The data that are available include studies lacking 
systematic rigor that are fraught with methodological problems (Hirokawa & Nishimoto, 2012; 
Hur, Song, Lee, J. & Lee, M., 2014; Lee, Wu, Tsang, Leung & Cheung, 2011; Williams, 2006). 
Studies of late have introduced massage therapy while simultaneously implementing essential 
oils (Cetinkaya, B., Basbakkal, Z.; 2013; Satou, et al. 2012; Williams, 2006). In these studies the 
length of the physical contact during the massage may have influenced the study results and it is 
difficult to tease out whether it was the physical touch during the massage or the aromatherapy 
that was increasing relaxation and sleep. Other studies have used aromatherapy in a variety of 
ways such as the diffusion method, applying the oil directly to a body part (without massaging it 
in), and adding the oil to a cotton ball and attaching it to a piece of clothing (Ndao et al., 2012; 
Nord & Belew, 2009).  In other studies subjects were not randomized (Hirokawa & Nishimoto, 
2012), there was not an adequate placebo (Satou et al., 2013), and the sample sizes were quite 
small (Hirokawa & Nishimoto, 2012; Williams, 2006). Another problem was the subjective 
nature of the data collection (parent or subject self ratings). Not surprisingly the results were 
mixed (Jefarzadeh, Arman & Farahbakhish Pour, 2012; Ndao et al., 2012; O’Flaherty, vanDijk, 
Alertyn & Millar, 2012; Satou et al., 2013; Williams, 2006; Wu, 2014).  Our aim is to 
systematically evaluate in a pilot study the use of Reconnect Essential Oils to determine if it is 
effective for increasing QOL, equanimity, and sleep. We intend to enroll 28 study participants in 
a randomized crossover study of Reconnect Essential Oils and a scented coconut oil comparator. 
Participants will be randomized to two groups. Group 1 will receive Reconnect for the first 3 
months of the study while Group 2 will receive a scented coconut oil comparator. At the end of 
the 3 month period there will be a one month washout and each group will be crossed over to the 
opposite condition.  We will use parent ratings of QOL and objective measures of 
relaxation/sleep (actigraph). 
 
Specific Aims/Hypotheses 
 
 
Our primary aims are to evaluate the feasibility of a larger study and examine preliminary 
data regarding benefit and tolerability of an essential oil formulation distributed by Young 
Living Essential Oils, Lehi, UT., for enhancing QOL in children with ASDs. We will develop 
preliminary data suitable to be submitted in a competitive NIH grant application for a larger 
multisite study. The proposed study will include a 7-month crossover with two 3-month 
conditions and a month washout between, with randomly assigned order. The 2 conditions will 
be a proprietary formula of essential oils and a scented coconut oil comparator. Measures of 
QOL, equanimity, and sleep health will include parent report on valid and reliable rating scales.   
 
Primary Hypotheses 
 
1. We can recruit 28 participants in 2 years with 85% adherence and 85% retention through 
both conditions. 

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2. With essential oils, participants will show significantly improved QOL on the Pediatric 
Quality of Life Inventory compared to the control condition, with a medium effect size. 
3. While receiving essential oils participants will show negligible or no increases in adverse 
events (AEs), including allergic contact dermatitis, immediate contact reactions (contact 
urticaria), and photosensitivity, compared to the control condition.  
 
Secondary Mediational Hypotheses 
 
1. With essential oils, compared to the control condition, participants will show 
significantly improved sleep onset and maintenance on objective and subjective measures 
(actigraphy; parent sleep diaries, and parent and clinician-rated scales) with a medium 
effect size, and this will mediate the improvement in QOL. 
2. With essential oils, compared to the control condition, participants will display greater 
equanimity and improvements in mood and daytime behavior on objective and subjective 
measures (heart rate; parent and clinician rated scale) compared to the control condition 
and this will mediate the improvement in QOL. 
 
Participant Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
Entry criteria are the following: 
i.    Outpatients between 3 and 9 years of age, inclusive;  
ii.   Diagnosis of Autism Spectrum Disorder (ASD) by DSM-V;  
iii.  Total item mean score of  > 1.5 on PedsQL Inventory; 
vi. Care provider who can reliably bring subject to clinic visits and provide trustworthy ratings. 
 
Exclusion Criteria 
Exclusion criteria are the following: 
i. 
Bipolar disorder by Child & Adolescent Symptom Inventory (CASI, Gadow & Sprafkin, 
1997) and clinical interview/history, or major depression accompanied by family history 
of bipolar disorder; 
ii. 
Children with allergies to essential oils; 
iii. 
Children with seizure disorder/epilepsy; 
iv. 
Significant physical illness (e.g., serious cardiovascular, liver, or renal pathology); 
v. 
Medications specifically given for insomnia and exogenous melatonin, which have the 
potential to confound study results, within the previous 2 weeks before baseline; 
vi. 
Anticipated changes of doses of medication or other medical treatments or supplements; 
vii. 
Weight less than 10 kg; 
viii. 
Sleep Disordered Breathing (SDB) as defined by a total score of > 3 on the CSHQ SDB 
subscale and parent report; 
ix. 
Nut allergies; 
x. 
Allergy to vanilla; 
xi. 
A substantial trial of essential oil use within the past 6 months (i.e., consistent use for 6 
weeks). 
  
METHODS 

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Study Design 
 
This study will use a double-blind -controlled crossover design with random assignment 
to order of conditions.  The 2 conditions will be ReconnectTM, a mixture of essential oils 
formulated by Young Living (YL) vs. a fragrant appearance-matched coconut-oil comparator. In 
order to randomize 28 children we anticipate that approximately 36 children will be screened. 
There will 2 conditions in the crossover design.  
 
 
Participants will receive Reconnect or scented coconut oil comparator for 3 months 
following the Baseline visit. At the end of 3 months, participants will be administered all 
endpoint measures for that condition.  Then there will be a 1-month washout prior to the start of 
the second condition. At the end of the second 3-month condition, participants will again be 
administered all endpoint measures for that condition. The endpoint assessment for the 2nd 
condition will be 7 months from original baseline. During the 1st condition participants will be 
evaluated at 2 week intervals for the first month to assess whether the mode of essential oils 
application is tolerable (i.e., inhalation or topical application) and to develop graphs of effect on 
sleep and equanimity over time. During the final 8 weeks of condition one, participants will be 
seen monthly. During the second condition we will have established that the modes of 
application are tolerable and subjects will be evaluated at 3 monthly visits. There will be 10 
visits to the Center including the Screening and Baseline Visits. 
 
Procedures 
 
 All participants must have significant problems with QOL as measured by the PedsQL 
Inventory, with a total item mean score of  > 1.5 (i.e., one standard deviation below the normative 
mean). 
   
At baseline, participants will be randomly assigned to one of two orders of essential oils. 
The oil will be dispensed at the Baseline visit, and will be administered by both massaging the 
oil on the feet and the back of the neck in the morning and by the diffusion method in the 
evening. 
 
 
In this study, clinical responders will be defined as showing a 30% improvement in the 
total score of the PedsQL Inventory.  
 
 
Approximately 50% of children will wear a device known as an actigraph that measures 
activity level and sleep quality. There will be 6 actigraphs and they will be assigned to 
participants as they are made available on a first come first serve basis. There may be some 
participants who are unwilling to wear the actigraph and for those who are tactiley defensive we 
will not require them to do so.  Participants will wear the devices for five consecutive nights, on 
three separate occasions (i.e., between Screening and Baseline, prior to the End Point of the first 
3 month period, and prior to the End Point of the second 3 month period). The small watch-like 
devices worn on the wrist or ankle will collect activity data and measure body temperature while 
the participant sleeps. They will yield the following sleep variables: 1) time in bed, 2) total sleep 
time (from lights out), 3) sleep onset latency, 4) morning waking time, 5) frequency of night 

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wakings, 6) longest sleep period, and 7) sleep efficiency.  This is a reliable method of objective 
data collection for sleep-wake patterns including timing, continuity, and duration of sleep. 
 
 
 In the proposed study, there will be a primary clinician (the physician) and an 
independent evaluator. The physician will discuss possible side effects and make dose or 
administration mode adjustments. The independent evaluator will interview the parents with 
respect to target improvements (QOL) and make DD-CGAS ratings based on all feedback, 
including parent rating scales.  
 
Dosing 
Each participant will utilize both oil delivery methods: diffusion at night and topical application 
in the morning. If a participant is unable to tolerate one of these delivery methods, then both the 
morning and night-time doses can be administered via the same, more tolerable method.  
 
Reconnect™ Directions: 
To be applied only by a trusted adult or under adult supervision.  
 
Topical: Apply 1 drop to the back of the neck and 1 drop to the feet. Rub in the oil for 30 
seconds to 1 minute. Each bottle has an orifice that allows the oil to be expelled drop by drop. 
Dilution is not required, except for the most sensitive skin. Apply in the morning.  
  
Aromatic Method: Diffuse one diffuser-full (8-12 drops of oil in water) at night. 
1. Home diffuser instructions: Open the water reservoir by lifting the lid. Add room-
temperature water (distilled water is recommended) up to the fill line of the reservoir. Do 
not exceed the fill line.  
2. Add 8-12 drops of Reconnect to the water.  
3. Replace the lid to cover the water reservoir.  
4. Plug in the Home Diffuser and push the power switch to start diffusing.  
5. When water runs out, the diffuser will automatically shut off.  
6. To cycle through the three-mode power settings, press the power switch quickly:  Mode 
1: Green light - Constant diffusion Mode 2: Red light - 30 seconds intermittent diffusion 
Mode 3: Off.  Use constant diffusion (green light, mode 1).  
7. To turn on/off the ambient LED light, press and hold the power switch for approximately 
2 seconds.  
Notice: Due to the mist output of the Home Diffuser, use caution on surfaces that are sensitive to 
water. 
 
Essential Oil  
The type of Young Living essential oil we will be utilizing is Reconnect™. Reconnect™ 
contains the following ingredients: Caprylic/capric triglycerides, Prunus amygdalus dulcis 
(Sweet almond) oil, Boswellia sacra† oil, Citrus aurantium bergamia† peel oil, Commiphora 
myrrha oil, Lavandula angustifolia† oil, Pelargonium graveolens† flower oil, Callitris 
intratropica wood oil, Santalum paniculatum† wood oil, Cananga odorata† flower oil, Cedrus 
atlantica† wood oil, Aniba rosaeodora† wood oil, Melissa officinalis† leaf oil, Picea pungeons† 

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branch/leaf/wood oil, Picea mariana leaf oil, Hyssopus officinalis† leaf oil, Rosa damascena† 
flower oil. The comparison oil is coconut oil with a tiny amount of vanilla, just enough for an 
aroma. Please see Table 2 for a listing of the ingredients, their current common uses, and  
potential side effects.  
Primary Outcome Measure 
 
Pediatric Quality of Life Inventory (PedsQL) (Varni, Burwinkle, & Seid, 2006). The 23-item 
PedsQL Generic Core Scales were designed to measure the core domains of health and their 
impact on the quality of life in children as outlined by the World Health Organization. The four 
Multidimensional Scales are: Physical Functioning, Emotional Functioning, Social Functioning, 
and School Functioning. The summary scores include a Total Scale Score, a Physical Health 
Summary Score, and a Psychosocial Health Summary Score. Response choices are in Likert-
scale format ranging from 0 to 4 (i.e., 0 = Never, 1 = Almost Never, 2 = Sometimes, 3 = Often, 4 
= Almost Always). There are 4 versions of the PedsQL including versions for ages 2-4 years, 5-
7 years, 8-12 years, and 13-18 years.  We will use the age-normed scale for each child that 
matches the age the child is expected to be at the end of the first condition; once selected, the 
same scale will be used throughout that child’s participation. To be enrolled participants will 
have clinically significant problems with quality of life (i.e., total item mean score of > 1.5). 
 
Other Measures for Establishing Study Inclusion Criteria  
 
Autism Diagnostic Observation Schedule (ADOS) (Rutter et al., 2004). The ADOS is an 
investigator-based assessment that places the child in naturalistic social situations demanding 
specific social and communication responses. Behaviors are coded in the areas of social 
communication, social relatedness, play and imagination, and repetitive behaviors. The ADOS 
provides a DSM- based algorithm for the diagnosis of ASD. The ADOS will be administered by 
a research-reliable clinician if it has not already been done by a reliable administrator.  
 
Child and Adolescent Symptom Inventory (CASI) (Gadow & Sprafkin, 2004). We will use the 
CASI to evaluate children ages 3 to 9 years of age for symptoms of common childhood 
psychiatric disorders. The CASI will aid ruling out exclusionary psychiatric disorders. Based on 
DSM-IV diagnostic criteria, this scale assists clinicians by providing useful diagnostic 
information from parents. The inventory offers both criterion-related cut-off scores and norm-
based scores for determining symptom severity (low, moderate, or high, based on parent ratings.  
 
Exploratory Dependent Measures in addition to PedsQL 
 
Developmental Disabilities – Children’s Global Assessment Scale (DD-CGAS) (Wagner et al., 
2007). The DD-CGAS is a reliable instrument for measuring global functioning of children with 
developmental disorders in treatment studies. We will use the DD-CGAS to characterize 
children’s impairment on the following four domains: Self Care, Communication, Social 
Behavior, and School/Academic. In addition, this scale also includes a series of descriptive 
“bands” to characterize global functioning in children with pervasive developmental disorders 
from “extreme and pervasive impairment” through “superior functioning.” 
 
Parent Stress Index (PSI) (Abidin, 1995). The PSI is used to evaluate the degree of stress in the 

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parent-child relationship. The Short Form is composed of 36 items taken from the full length PSI 
and is completed in 10-15 minutes. Child characteristics in the full scale include 
Distractibility/Hyperactivity, Adaptability, Reinforces Parent, Demandingness, Mood, and 
Acceptability. Parent measures include Competence, Isolation, Attachment, Health, Role 
Restriction, Depression, and Spouse. The PSI is used for early identification of dysfunctional 
parent-child interactions, parental stress, and family functioning. It may be used for parents of 
children up to 12 years, but it is primarily intended for parents of children 0-3 years. It yields a 
Total Score and three domain scores. Parents rate each of the 36 items on a 5-point scale (1 = 
strongly disagree, to 5 = strongly agree). The 90th percentile of the Total PSI score represents a 
clinically significant level of parenting stress (i.e., total score of > 260). The PSI will be a 
secondary outcome. 
 
Children’s Sleep Habits Questionnaire (CSHQ) (Owens, Spirito, & Mcguinn, 2000). The 
abbreviated CSHQ is a valid measure of sleep problems with good psychometric properties. The 
CSHQ was designed for use in children 3 to 7 years of age. It includes 33 items and is rated 
retrospectively over the previous week by parents to screen for the most common sleep 
problems. The CSHQ incorporates items related to eight key sleep domains. The eight subscales 
include: (1) bedtime resistance (2) sleep onset latency, (3) sleep duration, (4) anxiety around 
sleep, (5) night awakenings, (6) sleep disordered breathing, (7) parasomnias and (8) morning 
waking/daytime sleepiness. A Total Score of 41 or greater on the CSHQ 33 items has been 
reported to be an appropriate clinical cut-off for identifying sleep problems in children.  In a 
recent study of the participants in the Autism Treatment Network 75% of the participants 
analyzed had a CSHQ score of 41 or higher (Hollway, Aman, and Butter, 2013). The 
Abbreviated CSHQ will be used to determine whether a child has a clinically significant sleep 
problem and will be a secondary (mediational) outcome measure of the study. 
 
Parent Sleep Diary (Thomas & Burr, 2009). A parent/caregiver diary documenting overall 
information about participant sleep-wake behavior patterns, will be implemented. Caregivers 
will record “time in bed,” time asleep,” “time awake after sleep onset,” and “number of 
nighttime awakenings.” The diary will be used in conjunction with the CSHQ rating scale to 
collect caregiver estimates of sleep efficiency. These data will be evaluated for their reliability 
when compared to our objective measure of the sleep, the Motion-logger Micro Watch.  The 
sleep diary will be distributed to the caregiver at the end of each visit to be filled in at home 
each morning. 
 
The Autism Anxiety Scale (AAS)(Aman, Scahill, Lecavalier, and Sukodolsky, 2013). Investigators 
from OSU, Emory University, and Children’s Hospital of Philadelphia (CHOP) are engaged in 
developing what will be the definitive instrument for measuring anxiety in children with autism 
spectrum disorders (NIMH grant “Toward outcome measurement of anxiety in youth with autism 
spectrum disorders”).  This project uses the Children and Adolescent Symptom Inventory’s 
(CASI) anxiety items as its nucleus. But investigators have expanded the scale’s content 
following a review of the literature and conducting 6 focus groups with parents of children with 
ASD. In a few months the instrument will be empirically derived and the shape or structure will 
be decided by factor analysis, and the composition will be decided by electrophysiological 
measures. This scale will likely become the standard for use in randomized clinical trials. We are 
fortunate to be allowed to use an early version of this cutting-edge scale. The AAS, in addition to 
the abbreviated CSHQ, will be a secondary (meditational) outcome measure of the study. 

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Aberrant Behavior Checklist (ABC).The ABC is a 58-item parent-report measure with five 
subscales: 1) Irritability (includes agitation, aggression and self-injurious behaviors, 15 items); 2) 
Social Withdrawal (16 items); 3) Stereotypies (7 items); 4) Hyperactivity (16 items); and 5) 
Inappropriate Speech (4 items), (Aman et al., 1985a; Aman et al. 1985b; Aman et al., 1987, 
Brown, Aman, & Havercamp, 2002). Psychometric characteristics of the ABC range from 
satisfactory to very good (Aman et al.,1985b). The ABC has been commonly used in research on 
children with ASD and is highly sensitive. Its parent-rated five subscales will be used to explore 
whether the use of Reconnect Essential Oils is associated with behavior changes during the day. 
We will evaluate the ABC to assess irritability levels and improvement over the course of the 
study. The ABC will be an exploratory outcome measure. 
 
Social Responsiveness Scale (SRS) (Costantino et al., 2003). This 65-item rating scale measures 
the severity of autism spectrum symptoms as they occur in natural social settings.  Completed by 
a parent or teacher in 15 to 20 minutes, the SRS provides a clear picture of a child's social 
impairments, assessing social awareness, social information processing, capacity for reciprocal 
social communication, social anxiety/avoidance, and autistic preoccupations and traits. It is 
appropriate for use with children from 4 to 18 years of age. Sensitive and reliable across a wide 
range of symptom severity, the SRS can be used as a screener in clinical or educational settings, 
an aid to clinical diagnosis, or a measure of response to intervention. SRS scores are particularly 
helpful in identifying Autism, Asperger's Disorder, Pervasive Developmental Disorder Not 
Otherwise Specified (PDD-NOS), and Schizoid Personality Disorder of Childhood. 
 
Short Sensory Profile (SP) (Dunn, 1999). The Short Sensory Profile is a 38-item caregiver 
questionnaire and score sheet designed for use in screening and research protocols. The items on 
the Short Sensory Profile are grouped into three major sections: sensory processing, modulation, 
and behavioral and emotional responses. In a recent report it was found that sensory sensitivities 
were related to sleep difficulties in children with ASD (Hollway, Aman, Butter, 2013). We will 
use the SP to track sensory sensitivities which may be related to avoidance behavior that 
interferes with family QOL, over the course of the study. The SP will be an exploratory measure. 
 
Repetitive Behavior Scale – Revised (RBS-R) (Lam & Aman, 2007). The RBS-R is a 43-item 
self-report questionnaire that is used to measure the breadth of repetitive behavior in children, 
adolescents, and adults with Autism Spectrum Disorders. The RBS-R provides a quantitative, 
continuous measure of the full spectrum of repetitive behaviors. The RBS-R consists of six 
subscales including: Stereotyped Behavior, Self-injurious Behavior, Compulsive Behavior, 
Routine Behavior, Sameness Behavior, and Restricted Behavior that have no overlap of item 
content. This permits differential identification and scoring of discrete varieties of repetitive 
behaviors. Participants are asked to read a list of behaviors and choose a score that best describes 
how much of a problem the behavior has been. Behaviors are rated on a 4-point scale: 0-
Behavior does not occur, 1-Behavior occurs and is a mild problem, 2-Behavior occurs and is a 
moderate problem, 3-Behavior occurs and is a severe problem. We will use the RBS-R to assess 
repetitive behaviors and improvement over the course of the study.  
 
Swanson, Nolan, and Pelham Version IV Parent Rating Scale (SNAP-IV).  The SNAP-IV ADHD 
and ODD sections include the 18 DSM-IV symptoms of ADHD (9 hyperactive/impulsive items 

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and 9 inattention items) and eight symptoms of ODD (Oppositional Defiant Disorder) on a 0-3 
metric; it can be downloaded from www.adhd.net. We will use the SNAP-IV to assess ADHD 
and ODD symptoms and improvement over the course of the study. 
 
Objective Measure of Sleep 
 
Motionlogger Micro Watch (Ambulatory Monitoring). The Motionlogger Micro Watch includes 
basic sleep estimation with simultaneous environmental data collection. A range of recording 
capabilities exist including four validated sleep algorithms and a suite of circadian rhythm 
analyses. The software package allows for quick easy download of actigraph data. Study 
participants will wear the actigraph on five consecutive nights between the Screen and Baseline 
Visits, between Visit 5 and 6 and again between visits 9 and 10. 
 
Safety Measures 
 
Laboratory Tests. On three separate occasions during the study participants will have blood 
drawn and laboratory tests will be conducted to assess any changes in test values since the 
Screening Visit. Blood and urine will be collected at the Screen Visit, at the Endpoint of the first 
phase (Week 12), and at the Endpoint of the last phase (Week 28). The following tests will be 
run on the blood samples: ALT, AST, total and direct bilirubin, creatinine, CRP, IL-6, and CBC. 
The following tests will be run on the urine samples: standard urinalysis, to evaluate protein, PH, 
glucose, ketones, nitrites, appearance, color, specific gravity, and bacteria. 
Adverse Events (AEs). To minimize the risk, subjects will be systematically monitored. AEs, 
vital signs, including resting BP, will be evaluated at each visit throughout all phases of the 
study. When the treating clinician elicits an AE, it will be documented on a case report form, 
regardless of suspected relationship to the essential oil. For all AEs, the investigator will obtain 
sufficient information to determine the onset, course, and outcome of the AE.  If a subject has 
experienced an AE, the subject may return to the site for an unscheduled visit at the PI’s 
discretion.  If any of these AEs are serious and/or unexpected, the site PI will contact the 
Sponsor and notify the IRB as appropriate.   
   
 
Potential AEs include sun sensitivity due to the Bergamot in the essential oil, possibly 
gynecomastia in pre-pubescent males due to the lavender oil in the essential oil, and skin 
irritation at the application site.  
Sample Characteristics 
 
Demographic Profile.  This will be completed by the parent / caregiver at screening to 
document basic demographic information (parent education, occupation, and marital status). 
 
Cognitive / Developmental Measures.  Depending on the age and functioning level of the child, 
the Stanford-Binet Intelligence Scales; 5th Edition abbreviated battery (Nagle & Bell, 1993) or 
Mullen Scales of Early Learning AGS Edition will be administered (Mullen, 1995). These are 
the two cognitive/developmental measures used in the Autism Treatment Network and our other 
projects.  We will evaluate level of cognitive functioning to characterize our sample. The IQ test 
results will be used to characterize our sample via mean and standard deviation.  
 

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Social Validity 
 
Consumer Satisfaction Questionnaire. The Consumer Satisfaction Questionnaire will be filled in 
by parents at the end of both the first condition and the second. This questionnaire will be used 
to determine parents level of satisfaction with the study conditions and procedures. The 
Consumer Satisfaction Questionnaire (CSQ) speaks to feasibility of a larger study, which is one 
of the study’s aims. 
 
Masking Questionnaire. The Making Questionnaire will be completed by parents and by a study 
clinician at Visit 10 (Week 28). This questionnaire will be used to determine whether parents 
and clinicians can guess the oils that parents received during the first and last 3 months of the 
study and why. This questionnaire will provide information about the efficacy of masking 
essential oils treatments that may be useful for future studies.  
 
Data Analytic Plan 
 
The primary goal of this double-blinded randomized pilot study is to establish the 
feasibility of a full-scale study by evaluating (1) recruitment (retention and adherence), (2) 
safety, (3) and preliminary evaluation of the effect on the clinical outcomes. The primary 
outcome is QOL.  Chief secondary outcomes are CSHQ, AAS and PSI.  Exploratory outcomes 
include DD-CGAS, ABC SRS, RBS and Actigraphy.  
 
 
Data analysis will be primarily comparing Reconnect to the control condition. For drop-
outs, we will do a terminal evaluation and evaluate whether it is related to study oils or 
procedures or to some unrelated issue (e.g., moving away), and report the pattern of drop out. If 
more subjects drop out at a very early stage (week 1 or 2) than expected based on our experience, 
we will consider recruiting additional subjects to insure 28 subjects experiencing both 
conditions.  
 
 
Demographic and recruitment information will be summarized. Frequency tables will be 
used to summarize toxicity and tolerability based on type, severity, and attribution of the adverse 
events during each condition. Clinical outcomes will be plotted and summarized for all subjects 
over time by individual and condition. Data summaries for missing and outlying data will be 
distributed and reviewed. Visual displays will be generated and presented to investigators in 
order to identify any outliers or other problems that could be missed by summary statistics.  The 
categorical outcomes will be tabulated for each condition. The effect sizes of the changes of 
these clinical outcomes after 12 weeks will be estimated, using Cohen’s definition, for each 
condition. Each phase will last for a total of 12 weeks. The effect size of active vs control 
condition will be calculated as the differences of the mean improvements between conditions, 
divided by pooled standard deviation of the improvements from the two groups.  
 
Sample size and Randomization 
 
This randomized crossover pilot study will have 28 subjects randomized into 2 orders of 
condition with a block size of 4 initially, then block size of 2 as the sample size nears 

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completion. Considering up to 15% early drop outs due to reasons not related to essential oils, 
we plan to randomize up to 33 subjects. 
 
With 28 participants in this crossover study and using the participants as their own 
controls we estimate that we will be able to detect statistical significance with an effect size of 
0.8. In addition, we will compare the changes of the clinical outcome variables between 
Reconnect and control conditions by testing the interaction of condition and time based on a 
linear mixed model for repeated measurement, with conventional alpha of 0.05 for the primary 
outcome. In order to protect against Type 2 error in this pilot study, we will not correct for 
multiple tests.  
 
Study Time Line 
 
Study Timeline. The time-line for the study appears in Figure 1. The first several months 
will be used to obtain IRB approvals and create Case Report Forms or source documents. The 
next 19 months will be used for participant recruitment, supplementation, and assessment. 
Finally, the last 3 months will involve data analysis and manuscript writing.  
 
Table 3. Study Timeline (24 months) 
 
 
Year 1 
Year 2 
Month 
0-3 
4-6 
6-9 
9-12 
0-3 
3-6 
6-9 
9-12 
Activity 
Preparation 
Recruiting, Assessment, Oil Use 
Completion 
 
(Training on actigraphy ; IRB, Teleforms)  
(Data analysis, manuscript 
writing, progress reports) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

12 
V 1.4 8/3/2016 
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17 
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Table 1. Schedule of Measures for the use of Essential Oils in Children with Autism Spectrum Disorder to improve Quality of life 
 
Screen 
Visit 1 
Wk0 
V2 BL 
Wk2 
V3 
Wk4 
V4 
Wk8 
V5 
Wk12 
V6 
Wk16 
V7 BL (2) 
Wk20 
V8 
Wk24 
V9 
Wk 28 
V10 
 
Actigraphy 
Begin 
Cond 1 
 
 
Actigraphy 
End Cond 1 
Begin WO 
Begin Cond 
2 
 
Actigraphy  
End 
Cond 2 
Laboratory  Analysis 
X 
 
 
 
 
X 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
CASI  
X 
 
 
 
 
 
 
 
 
 
Pediatric Quality of Life 
Inventory 
X 
 
 
 
 
X 
 
 
 
X 
Parent Stress Index 
 
X 
 
 
 
X 
 
 
 
X 
CSHQ/Sleep Interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Autism Anxiety Scale 
(AAS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DD-CGAS 
 
X 
 
 
 
X 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
DSM-V Interview 
X 
 
 
 
 
 
 
 
 
 
ADOS 
X 
 
 
 
 
 
 
 
 
 
IQ Test (SB-5 or MSEL) 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
Vital Signs; Height, 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical/Psychiatric  
History/Medication 
History 
X 
 
 
 
 
 
 
 
 
 
Pre-existing conditions 
X 
X 
 
 
 
 
 
 
 
 
Adverse Events, skin 
exam 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Aberrant Behavior 
Checklist (ABC) 
 
X 
 
 
 
X 
 
 
 
X 
Repetitive Behavior 
Scale-Revised (RBS-R) 
 
X 
 
 
 
X 
 
 
 
X 
Short Sensory Profile 
 
X 
 
 
 
X 
 
 
 
X 
Social Responsiveness 
Scale-2 
 
X 
 
 
 
X 
 
 
 
X 
SNAP-IV 
X 
 
 
 
 
X 
 
 
 
X 
Parent Satisfaction  
 
 
 
 
 
X 
 
 
 
X 
Masking Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Actigraph 
X (T) 
X (D) 
 
 
X (T) 
X (D) 
 
 
X (T) 
X(D) 
Note: Schedule based on 12 weeks in each of 2 conditions with 1-month washout between, with two biweekly then two monthly visits in first condition and four monthly visits in the second condition. 

18 
V 1.4 8/3/2016 
 
Table 2. Ingredients of Reconnect formulation of essential oils, their uses/actions, and potential side effects. 
ReconnectTM 
Ingredient 
Uses 
Safety 
Chemical 
Composition 
Citations 
Prunus 
amygdalus dulcis 
(Sweet Almond) 
oil 
Protects skin's barrier 
function and keeps it 
from drying - used in 
body lotions, face 
creams, and body 
oils; anti-
inflammatory and 
pain relieving 
CIR approved as safe for topical application; 
absorbs slowly through skin; completely 
digested if taken orally; non-irritating and non-
sensitizing in any concentration **Nut/almond 
allergies 
Oleic acid (62-86%), 
Linoleic acid (20-
30%), other fatty 
acids, α-tocopheral, 
arginine, 
phytosterols, 
polyphenols 
Almond oil (prunus amygdalus 
dulcis) – the universal skin oil 
(n.d.). Bio G Cosmetics. Web. 
Boswellia sacra 
oil 
"Frankincense." 
Perfumes and skin 
care; edible. Potential 
anti-depressant. 
Studies suggest it 
may have cancer-
killing properties and 
improve 
osteoarthritis. 
Not CIR or FDA approved, but widely used and 
appears to be well tolerated 
Acid resin (56%), 
gum (similar to gum 
arabica) (30-36%), 3-
acetyl-β-boswellic 
acid, α-boswellic 
acid, incensole 
acetate, phellandrene 
Martin, N. (n.d.). Sacred 
Frankincense Essential Oil - The 
Original Oil Given to Baby Jesus? 
Experience-Essential-Oils.com. 
Web. 
Citrus aurantium 
bergamia peel oil 
Helps with heartburn, 
gas, insomnia, mild 
depression, and upset 
stomach (Martin). 
FDA approved as a Food Additive and generally 
regarded as safe, but not recommended for 
children < 5 years old and can result in skin 
irritation, particularly from frequent usage or 
UV light exposure (Martin). 
α-pinene, myrcene, 
limonene, α-
bergaptene, β-
bisabolene, linalool, 
linalyl acetate, nerol, 
neryl acetate, 
geraniol, geraniol 
acetate and α-
terpineol (Bergamot) 
Bergamot essential oil information 
(2014). Esoteric Oils CC. Web. 
 
Martin, N. (n.d.). The Benefits of 
Bergamot include Easing Stress 
from Mind & Body! Experience-
Essential-Oils.com. Web. 
 
Commiphora 
myrrha oil 
Helps clear colds, 
bronchitis, cough by 
removing mucus; 
used for chapped 
skin, eczema, skin 
ulcers, ringworm, 
skin wounds 
Non-toxic, non-irritating, and non-sensitizing 
α-pinene, cadinene, 
limonene, 
cuminaldehyde, 
eugenol, m-cresol, 
heerabolene, acetic 
acid, formic acid 
Myrrh essential oil information 
(2014). Esoteric Oils CC. Web. 

19 
V 1.4 8/3/2016 
Lavandula 
angustifolia oil 
Natural antibiotic, 
anti-depressant, 
sedative; promotes 
healing and 
stimulates the 
immune system 
(Worwood 1990); 
Pain relief, antiseptic, 
stress and anxiety 
relief, burns and 
insect bites, 
aromatherapy 
(“Lavender Oil”). 
Topical application can sometimes cause 
irritation; likely safe in food and possible safe in 
medicinal amounts; disrupts hormones in pre-
pubertal boys and can result in gynecomastia 
(abnormal breast growth) (Henley 2007) 
Linalool (51%) and 
linalyl acetate (35%) 
mostly. Other 
components include 
α-pinene, limonene, 
1,8-cineole, cis- and 
trans-ocimene, 3-
octanone, camphor, 
caryophyllene, 
terpinen-4-ol and 
lavendulyl acetate 
(“Lavender Oil”) 
Henley, D.V. (2007) Prepubertal 
Gynecomastia Linked to Lavender 
and Tea Tree Oils. N Engl J Med. 
356(5), 479-485. 
 
"Lavender Oil." Wikipedia. 
Wikimedia Foundation (2014). 
Web. 
 
Worwood, V.A (1990) The 
Fragrant Pharmacy. London: 
Macmillan. 
Pelargonium 
graveolens flower 
oil 
Antidepressant, 
anxiolytic, astringent, 
diuretic 
Generally regarded as safe and approved as a 
food additive by the FDA; non-toxic, non-
irritant and generally non-sensitizing 
α-pinene, myrcene, 
limonene, menthone, 
linalool, geranyl 
acetate, citronellol, 
geraniol and geranyl 
butyrate 
Rose geranium essential oil 
information (2014). Esoteric Oil 
CC. Web. 
 
 
Callitris 
intratropica 
wood oil 
Fragrances; helps 
with arthritis and 
asthma 
No contraindications found; generally regarded 
as safe 
Guaiol, guaienes, 
selinenes, 
guaiazulene, 
eudesmols, 
furnanones 
Rose, Jeanne. 375 Essential Oils 
and Hydrosols. Berkeley, CA: 
Frog, 1999. 51. Blue Cypress 
Essential Oil. AromaWeb. Web. 
Cananga odorata 
flower oil 
Antidepressant, 
aphrodisiac, 
hypotensive, 
sedative; helps with 
oily skin, anxiety, 
tension, and fear 
Non-toxic, non-irritating, and in most cases non-
sensitizing, but sensitivity has been reported and 
headaches and nausea can result from excessive 
use. 
Linalool, geranyl 
acetate, 
caryophyllene, p-
cresyl methyl ether, 
methyl benzoate, 
benzyl acetate, 
benzyl benzoate and 
other sesquiterpenes. 
Ylang-ylang essential oil 
information (2014). Esoteric Oil 
CC. Web. 
Aniba rosaeodora 
wood oil 
Anti-depressant, 
mildly analgesic, 
antiseptic, 
aphrodisiac; helps 
with headaches 
Non-toxic, non-irritating, non-sensitizing; 
generally regarded as safe 
α-pinene, camphene, 
geraniol, neral, 
geranial, myrcene, 
limonene, 1,8-
cineole, linalool, 
benzaldehyde, 
linalool oxides and a-
Rosewood essential oil 
information (2014). Esoteric Oil 
CC. Web. 

20 
V 1.4 8/3/2016 
terpineol 
Picea mariana 
(Spruce) leaf oil 
Helps with arthritis, 
infections, and pain; 
supports the immune 
system 
FDA approved Food Additive and Flavoring 
Agent; non-toxic and generally safe but could 
result in skin irritation 
Pinenes, limonene, 
boryl acetate, 
tricyclene, 
phellandrene, thujone 
Martin, N. (n.d.). Spruce Essential 
Oil offers Support for Muscles and 
the Immune System! Experience-
Essential-Oils.com. Web. 
Hyssopus 
officinalis leaf oil 
Used in cooking; 
medicinally used as a 
cough suppressant 
and expectorant; 
helps with nervous 
exhaustion and grief 
Contains thujone which stimulates the CNS and 
can cause seizures as the oil, even in low doses, 
in children; otherwise non-irritating and non-
sensitizing 
α-pinene, camphene, 
β-pinene, sabinene, 
myrcene, limonene, 
pinocamphone, 
isopinocamphene, γ-
terpineol, 1,8-cineole 
and thujone 
Woolf, A. (1999). Essential Oil 
Poisoning. Clinical 
Toxicology, 37(6), 721-727. 
 
Rosa damascena 
flower oil 
Helps with dry 
skin/eczema, asthma, 
heart arrhythmia, 
high BP; anti-
depressant, sedative, 
laxative, aphrodisiac, 
anxiolytic 
Non-toxic, non-irritating, and non-sensitizing 
300+ compounds, but 
main ones are 
citronellol, phenyl 
ethanol, geraniol, 
nerol, farnesol, 
stearpoten, α-pinene, 
myrcene, limonene, 
menthone, and 
linalool (Rose) 
Woolf, A. (1999). Essential Oil 
Poisoning. Clinical 
Toxicology, 37(6), 721-727. 
 
Rose geranium essential oil 
information (2014). Esoteric Oils 
CC. Web. 
Santalum 
paniculatum 
(Royal Hawaiian 
Sandalwood) 
wood oil 
Perfume, meditation, 
relaxation; Helps 
chapped skin, scars, 
and stretch marks; 
anti-inflammatory, a 
disinfectant, diuretic, 
and anti-depressant; 
said to help with 
insomnia, bug bites, 
headaches, 
depression 
May cause skin irritation and should be diluted. 
100% steam-distilled 
pure Sandalwood oil 
from Hawaiian trees 
(organic compounds 
not specified) 
"Royal Hawaiian Sandalwood 
Essential Oil Santalum 
Paniculatum." Hana Naia 
Aromatherapy. Hana Naia LLC, 
2014. Web. 
Caprylic/capric 
triglycerides 
Ester derived from 
Coconut oil; Good 
solvent and 
emollient, acts as a 
Skin exposure shows very low toxicity and no 
potential for skin/eye irritation/sensitization; 
FDA approved as a food additive and CIR 
approved for cosmetic use 
Derived from 
coconut oil and 
glycerin 
"Caprylic/Capric 
Triglycerides." Truth in Aging. 
Truthinaging.com, 2013. Web.  

21 
V 1.4 8/3/2016 
carrier for fat-soluble 
vitamins; used in 
cosmetics: hair 
products, dyes, 
sunscreen, 
deodorants, make-up 
Cedrus atlantica 
(Cedarwood) 
wood oil 
Acne, arthritis, 
coughing, dermatitis, 
bronchitis, stress 
No special precautions indicated 
Atlantone, 
caryophyllene, 
cedrol, cadinene 
"Atlas Cedarwood Essential 
Oil." AromaWeb. AromaWeb, 
LLC, 2014. Web.  
Melissa officinalis 
leaf oil 
Antidepressant, 
sedative, 
antispasmodic, 
hypotensive; helps 
with nausea, 
headaches 
Non-toxic, but could be irritating or sensitizing 
so should be diluted and not used on sensitive 
skin 
Tannins, eugenol, 
terpenes, citronellal, 
octyl benzoate, 
linalool, nerol, etc 
"Melissa Essential Oil (a.k.a. 
Lemon Balm Essential Oil) 
Information." Esoteric Oils. 
Esoteric Oils CC, 2014. Web. 
Picea pungens 
(Idaho blue 
spruce) 
branch/leaf/wood 
oil 
Relax the mind and 
muscles, relieve 
muscle tension, 
cleanse minor skin 
irritations 
FDA approved as a Food Additive, so generally 
safe 
45-55% monoterpenes 
(mostly α-pinene and 
limonene); 3-12% 
sesquiterpenes 
"Idaho Blue Spruce Essential 
Oil." Aromatherapy Living with 
Young Living Essential Oils. 
Young Living Essential Oils, 
2012. Web.  
 
 
 
 
 
 
 
 
Table 3. Ingredients of coconut oil scented with 0.5% vanilla absolute oil, their uses/actions, and potential side effects. 
Scented Coconut Oil 
Ingredient 
Uses 
Safety 
Chemical Composition 
Citations 
Vanilla Absolute Oil 
Found in Madagascar. Used 
primarily as a fragrance.  
 
A solution of 10% vanillin diluted in 
petrolatum resulted in occasional contact 
allergy.  
 
In a study by Hausen, no positive 
reactions to vanillin were found.  
Primary constituents include 
vanillin, vanillic acid, and p-
hydroxybenzaldehyde 
"Certificate of Analysis: Vanilla 
Absolute." Eden Botanicals. Eden 
Botanicals, 2015. Web.   
 
Wöhrl, S., Hemmer, W., Focke, 
M., Götz, M. and Jarisch, R. 
(2001), The significance of 
fragrance mix, balsam of Peru, 

22 
V 1.4 8/3/2016 
colophony and propolis as 
screening tools in the detection of 
fragrance allergy. British Journal 
of Dermatology, 145: 268–273. 
doi: 10.1046/j.1365-
2133.2001.04345.x 
 
Hausen BM. Contact allergy to 
balsam of Peru. II. Patch test 
results in 102 patients with 
selected balsam of Peru 
constituents. Am J Contact 
Dermat. 2001;12(2):93–102. 
[PubMed] 
 
Coconut Oil 
Used as a flavoring in foods. Added 
to some pharmaceuticals and 
cosmetics. Commonly rubbed on 
the skin.  
Populations of people that consume large 
quantities of coconut oil show no adverse 
effects.  
According to the FDA, “There is no 
evidence in the available information on 
coconut oil, peanut oil, and oleic acid 
that demonstrates, or suggests reasonable 
grounds to suspect, a hazard to the public 
as they are now used in paper and cotton 
packaging material for food at levels now 
current or as they might reasonably be 
expected to be used for such purposes in 
the future.” 
Composed of 92% saturated 
fatty oils.   
Thampan, P.K., Glimpses of 
coconut industry in India, Coconut 
Development Board, Cochin 1988. 
 
Krishna, G., Rah, G., Bhatnagar, 
A. S., Kumar, P., & 
Chandrashekar, P. Indian Coconut 
Journal. “Coconut Oil: Chemistry, 
Production and Its Applications - 
A Review.” 2010.  
 
"Select Committee on GRAS 
Substances (SCOGS) Opinion: 
Coconut Oil (packaging)." U.S. 
Food and Drug Administration, 
Apr. 2013. Web. 02 Jan. 2015. 

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Human Subjects considerations 
 
Participants: 
Participants are 28 children age 3-9 with autism spectrum disorder and excessive anxiety and 
sleep disturbance.  Although we are not treating autism, this population is especially prone to 
impaired QOL due to sleep problems and anxiety, and is the population for which OTC essential 
oils are most often used by consumers without adequate test of benefits and safety.  Careful 
evaluation of this practice has been requested by parents of children with autism. 
 
Risks: 
Essential oils themselves are generally regarded as safe and are routinely used by the public.  
One of the purposes of this pilot study is to check whether this assumption is valid.  The main 
known risk/discomfort is from the blood draws, with possible bleeding, bruising, or infection. 
The ratings pose some time/effort burden for parents and the usual confidentiality risks apply.  
Although uncommon, skin irritation with topical administration or breast enlargement in boys is 
a potential side effect of a few ingredients of Reconnect (See Table 2).  
 
Minimization of risk: 
Numbing cream will be offered for blood draws, which will be done by experienced 
phlebotomists.  The usual security for personal health information will be used, with locked files 
accessible only to CITI-trained and HIPAA-trained research staff and password-protected 
electronic data.  Time/effort burden will be partially compensated by payment.  All families will 
be given phone numbers of the PIs and coordinator to reach in the event of some unexpected 
adverse event. Potential skin sensitivity and potential male breast enlargement will be checked 
for at each visit by a physician, who may discontinue the oils or switch mode of administration 
based on clinical judgment.   
  
Ethnic & Sex Composition of sample: 
The sample is expected to reflect the ethnic proportions of central Ohio.  Sex ratio is expected to 
mirror that of the autism population, 4:1 boys.  Both males and females will be included in the 
study.