Shaywitz BA, Sullivan CM, Anderson GM, Gillespie SM, Sullivan B, Shaywitz SE. Aspartame, behavior, and cognitive function in children with attention deficit disorder. Pediatrics. 1994; 93: 70-75.
Randomized Controlled Trial
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To determine the effects of large doses of aspartame on behavior, cognition and monoamine metabolism in children with attention deficit disorder.
- Children that satisfy criteria for Attention Deficit Disorder (ADD), according to the Diagnostic and Statistical Manual of Mental Disorders (third edition, DSM-III)
- Children not currently taking medication to control ADD.
- Children without ADD
- Children currently taking medication to control ADD.
Description of Study Protocol:
- Recruited children from the Pediatric Neurology Clinic of Yale-New Haven Hospital
- Recruited through local newspaper, advertisements and via physicians and educators.
- Randomized, double-blind, placebo-controlled study.
- Aspartame vs. placebo
- Placebo was microcrystalline cellulose
- Both were identically packaged with double-blind labels.
- 300mg aspartame capsules
- Parents were instructed to give the child the appropriate number of capsules, which resulted in approximately 34mg per kg of body weight every morning before school
- Range of aspartame consumed was 29.2 to 41.9mg per kg of body weight (average was 34.7mg per kg).
- Paired T-tests were performed to identify significant changes under the two treatments
- Statistical significance was set at P<0.05
- Reported P-values were not adjusted for multiplicity of tests. Instead, effects of multiplicity are recognized in the interpretation of the significant tests.
Data Collection Summary:
Timing of Measurements
- Four-week study with two two-week intervention periods, which were identical except for the use of aspartame or placebo
- At the onset of the study, a complete medical history, physical, neurological exam and intelligence and achievement tests were administered
- On the first day of each week, parents received forms for each week of study to document behavioral changes
- On Day Eight, the children consumed standardized aspartame-free, low-catecholamine meals and began a 12-hour baseline urine collection
- On Day Nine:
- The blood was drawn for the amino acid profile, methanol, formate, glucose, complete blood profile with differential and platelet count and liver function tests
- Take aspartame or placebo
- One hour later, blood was drawn and analyzed for serotonin, plasma monoamine metabolites (homovanillic acid), amino acid profile, methanol and formate
- Two hours later, blood was drawn and analyzed for amino acids, methanol and formate
- Three hours later, a post-dose urine test was collected and analyzed for norepinephrine, epinephrine, dopamine, monoamine metabolites, formate and creatinine.
- During the day, the children were administered attentional status tests
- Subjects were sent home with pills for the next seven days.
- Behavior tests
- Conners Behavior Rating Scales (completed by parents and teachers)
- Assesses 10 behaviors such as restlessness, fidgeting, disturbs other children and temper outbursts.
- Multigrade Inventory for Teachers (completed by parents and teachers).
- Conners Behavior Rating Scales (completed by parents and teachers)
- Adverse experiences: Completed each of the four weeks by study personnel and parents
- Subjects Treatment Emergent Symptom Scale (STESS)
- Completed by children and parents.
- Attentional tests: Completed on Days Nine and 23 of inpatient visit
- Matching Familiar Figures Test
- Wisconsin Card Sorting Test
- Children's Checking Task
- Airplane Test.
- Blood samples: Analyzed at Yale-New Haven Hospital Clinical Chemistry Lab
- Hematology (complete blood count and differential)
- Liver function tests
- Determination of glucose concentration
- Determination of urine creatinine.
- Plasma amino acid samples
- Beckman Amino Acid Analyzer
- Plasma phenylalanine
- Large neutral amino acids (isoleucine, leucine, methionine, tryptophan, tyrosine and valine)
- Used to calculate phenylalanine-to-LNAA ratio.
- Plasma and urine methanol and formate content
- Gas chromatography for methanol
- Spetrophotfluorometric for formate.
- Computer-generated random assignment schedule (cross-over design for aspartame and placebo)
- Each capsule contained 300mg aspartame. Parents were instructed to give the appropriate number of capsules that would be equivalent to approximately 34mg per kg of body weight.
- The children maintained an aspartame-free diet for the duration of the intervention
- Computer-generated random assignment schedule (crossover design for aspartame and placebo)
- Each placebo capsule contained 300mg microcystalline cellulose. Parents were instructed to give the appropriate number of capsules that would be equivalent to approxiamately 34mg per kg of body weight.
Description of Actual Data Sample:
- Initial N: N=15
- Attrition (final N): N=15 (11 boys, four girls)
- Age: Five to 13 years
- Ethnicity: Not provided.
Other Relevant Demographics
- 10 not on medications
- One on amitriptyline and methylphenidate; drug free for more than 60 days prior to the study
- Two on methylphenidate; drug free for more than 60 days prior to the study
- One on methylphenidate; drug free for more than seven days prior to the study
- One on desipramine; drug free for more than 60 days prior to the study
- One on methylphenidate; drug free for less than seven days prior to the study
- 14 diagnosed with attention deficit disorder with hyperactivity
- One diagnosed with attention deficit disorder.
- Subjects weighed 18 to 66kg (recall that there is a large range in ages, which potentially explains the range in the body weights).
- Yale University School of Medicine, New Haven, Connecticut.
Summary of Results:
Aspartame (Treatment Group)
Placebo (Control group)
Statistical Significance of Group Difference
Multigrade Inventory for Teachers; Activity
- Attentional tests, which include the children's checking task, airplane test, matching familiar figures and the Wisconsin card-sorting test, were not significantly different between treatments
- No statistically significant differences between the aspartame and placebo treatments for any of the STESS categories (adverse effects). However, adverse experiences reported during the study by three subjects included a mild stomach ache during the first week of aspartame ingestion, mood swings during the first week of placebo administration and headaches during both aspartame and placebo treatment periods.
- The routine blood tests (hematology, liver function and glucose) performed during the two treatment periods did not show any clinically significant differences between the aspartame and placebo treatments
- Plasma concentrations of MHPG, HVA and formate and whole blood serotonin did not differ significantly between aspartame and placebo
- Plasma phenylalanine (P<0.05) and tyrosine were significantly increased at Hours One and Two, following aspartame ingestion, whereas no changes in plasma phenylalanine were observed with placebo ingestion
- Plasma-phenylalanine-to-large-neutral-amino acid ratio was significantly increased following aspartame ingestion (P<0.05).
- Aspartame at greater than 10 times the usual consumption has no significant effect on cognitive status, behavioral or neurochemical indices, measured in a group of children with ADD
- An apparent lack of effect was observed in the presence of a significant increase in plasma phenylalanine and phenylalanine or large neutral amino acids in a population that might be more vulnerable to neurochemical changes.
|University/Hospital:||Yale University School of Medicine|
- The dose used in this study was reported to be 10 times greater than the 90th percentile of "current" aspartame use in the US. Recall that this study was published in 1994 and that the aspartame consumption may be different in 2006.
- Aspartame consumption during this study was only for two weeks. This study only addresses short-term effects of a high dose of aspartame on behavior, not long-term effects.
- This study was funded by the NutraSweet Company.
Quality Criteria Checklist: Primary Research
|1.||Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)||Yes|
|2.||Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?||Yes|
|3.||Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?||Yes|
|4.||Is the intervention or procedure feasible? (NA for some epidemiological studies)||Yes|
|1.||Was the research question clearly stated?||Yes|
|1.1.||Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?||Yes|
|1.2.||Was (were) the outcome(s) [dependent variable(s)] clearly indicated?||Yes|
|1.3.||Were the target population and setting specified?||Yes|
|2.||Was the selection of study subjects/patients free from bias?||No|
|2.1.||Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?||No|
|2.2.||Were criteria applied equally to all study groups?||Yes|
|2.3.||Were health, demographics, and other characteristics of subjects described?||No|
|2.4.||Were the subjects/patients a representative sample of the relevant population?||Yes|
|3.||Were study groups comparable?||Yes|
|3.1.||Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)||Yes|
|3.2.||Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?||Yes|
|3.3.||Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)||Yes|
|3.4.||If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?||N/A|
|3.5.||If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)||N/A|
|3.6.||If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?||Yes|
|4.||Was method of handling withdrawals described?||Yes|
|4.1.||Were follow-up methods described and the same for all groups?||Yes|
|4.2.||Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)||Yes|
|4.3.||Were all enrolled subjects/patients (in the original sample) accounted for?||Yes|
|4.4.||Were reasons for withdrawals similar across groups?||N/A|
|4.5.||If diagnostic test, was decision to perform reference test not dependent on results of test under study?||Yes|
|5.||Was blinding used to prevent introduction of bias?||No|
|5.1.||In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?||Yes|
|5.2.||Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)||No|
|5.3.||In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?||N/A|
|5.4.||In case control study, was case definition explicit and case ascertainment not influenced by exposure status?||N/A|
|5.5.||In diagnostic study, were test results blinded to patient history and other test results?||???|
|6.||Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?||Yes|
|6.1.||In RCT or other intervention trial, were protocols described for all regimens studied?||Yes|
|6.2.||In observational study, were interventions, study settings, and clinicians/provider described?||Yes|
|6.3.||Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?||Yes|
|6.4.||Was the amount of exposure and, if relevant, subject/patient compliance measured?||No|
|6.5.||Were co-interventions (e.g., ancillary treatments, other therapies) described?||N/A|
|6.6.||Were extra or unplanned treatments described?||N/A|
|6.7.||Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?||N/A|
|6.8.||In diagnostic study, were details of test administration and replication sufficient?||No|
|7.||Were outcomes clearly defined and the measurements valid and reliable?||Yes|
|7.1.||Were primary and secondary endpoints described and relevant to the question?||Yes|
|7.2.||Were nutrition measures appropriate to question and outcomes of concern?||Yes|
|7.3.||Was the period of follow-up long enough for important outcome(s) to occur?||???|
|7.4.||Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?||Yes|
|7.5.||Was the measurement of effect at an appropriate level of precision?||Yes|
|7.6.||Were other factors accounted for (measured) that could affect outcomes?||No|
|7.7.||Were the measurements conducted consistently across groups?||Yes|
|8.||Was the statistical analysis appropriate for the study design and type of outcome indicators?||Yes|
|8.1.||Were statistical analyses adequately described and the results reported appropriately?||Yes|
|8.2.||Were correct statistical tests used and assumptions of test not violated?||Yes|
|8.3.||Were statistics reported with levels of significance and/or confidence intervals?||Yes|
|8.4.||Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?||N/A|
|8.5.||Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?||No|
|8.6.||Was clinical significance as well as statistical significance reported?||Yes|
|8.7.||If negative findings, was a power calculation reported to address type 2 error?||No|
|9.||Are conclusions supported by results with biases and limitations taken into consideration?||Yes|
|9.1.||Is there a discussion of findings?||Yes|
|9.2.||Are biases and study limitations identified and discussed?||Yes|
|10.||Is bias due to study's funding or sponsorship unlikely?||No|
|10.1.||Were sources of funding and investigators' affiliations described?||Yes|
|10.2.||Was the study free from apparent conflict of interest?||No|