Brief description of patient problem/setting

A mother came in to the pediatric outpatient office stating that she sees and hears so many parents not allowing their children to eat foods that contain artificial food colorings. She says that they claim that it lends itself towards hyperactive behavior. She is curious if there is any truth to that and if she should also restrict food coloring for her children.

Search Question

In children, does  allowing foods that contain artificial food colorings compared to restricting foods that contain artificial food colorings increase hyperactive behavior and symptoms of ADHD?

Question Type

☐Prevalence               ☐Screening                 ☐Diagnosis

☐Prognosis                             ☐Treatment                ☒Harms

P	I	C	O
Children	Diet containing artificial food coloring	Natural diet	ADHD
Kids	Diet with artificial color additives	Diet without artificial food dyes	Hyperactivity
Minors	Diet with synthetic food dyes	Natural food coloring	Hyperactive behavior
Adolescents	Diet with added colorants	Dye free diet	Restless behavior
	Diet containing food coloring agents	Clean eating	Attention deficit hyperactivity disorder
	Diet incorporating artificial dyes	Unrefined diet	Overactivity

Search tools and strategy used

PubMed:

• (food coloring) AND (kids) AND (ADHD) -> 2 results
• (food coloring) AND (hyperactivity) -> 99 results
  • Since 2019 -> 9 results
• (food coloring) AND (ADHD) -> 62 results
  • Since 2019 -> 7 results
• (children) AND (artificial food dye) AND (hyperactivity) -> 30 results
  • Since 2019 -> 4 results

Science Direct:

• (ADHD) AND (food coloring) AND (kids) -> 53 results
  • Since 2019 -> 18 results
• (hyperactive behavior) AND (food coloring) AND (kids) -> 69 results
  • Since 2019 -> 24 results
• (children) AND (artificial food dye) AND (hyperactivity) -> 923 results
  • Since 2019 -> 286 results
    • Review articles -> 53 results

Cochrane:

• (children) AND (artificial food dye) AND (hyperactivity) -> 3 results
• (food coloring) AND (ADHD) -> 10 results
• (synthetic food dye) AND (children) AND (hyperactivity) -> 1 result

I used three databases to find results for my PICO question. When too many results came up I used filters such as filtering by years and by filtering based on the type of study I wanted. When I narrowed it down enough I read through the titles and abstracts to find the articles that pertained to my PICO question in the best way. I placed emphasis on more recent articles and those that were an RCT or meta-analysis.

Results found

Article 1:

Citation	Rambler RM, Rinehart E, Boehmler W, et al. A Review of the Association of Blue Food Coloring With Attention Deficit Hyperactivity Disorder Symptoms in Children. Cureus. 2022;14(9):e29241. Published 2022 Sep 16. doi:10.7759/cureus.29241
Abstract	Attention Deficit Hyperactivity Disorder, also known as ADHD, is a neurodevelopmental disorder diagnosed in children. The exact cause of ADHD is not known, but, along with genetic factors, it is possible that environmental factors including toxins and diet may affect symptom severity. Of these dietary components, artificial food coloring (AFC), while approved by the Food and Drug Administration (FDA), has been suspected to be associated with ADHD symptoms. Of the nine FDA-certified food colors, two are used for artificial blue coloring: Blue No. 1 and Blue No. 2. There is limited literature describing the possible role of blue AFC in causing symptoms of ADHD in children. This paper provides a review of the literature surrounding artificial food coloring and its ability to affect the neurodevelopment of children in a way that could increase the behavioral indicators of ADHD. To do this, search criteria were established using a combination of MeSH terms about blue AFCs and ADHD and were entered into PubMed, along with limits on article types and publication dates from January 2000 to June 2022. There was a total of 20 articles that met this search criterion. These articles were reviewed by authors, and the ones not relevant to the topic were excluded. In total, four studies were chosen to be included in this article. After reviewing the literature, it was found that restriction diets, specifically those excluding AFCs, may affect symptom severity. The source of these changes is not known, but possible mechanisms include AFCs causing nutritional deficiencies and allergic reactions or altering neurotransmitter levels. More research is necessary to describe the neurotoxicity of artificial blue dyes in humans.
Level of Evidence	Systematic review
Why I chose this	I chose to include this article because it was published very recently in 2022 in a peer reviewed journal called Cureus. It also is a systematic review which is considered to be the highest level of evidence. Lastly, I thought it would be interesting to include because it gives a unique perspective regarding a specific color of synthetic food dyes.

Article 2:

Citation	Miller MD, Steinmaus C, Golub MS, et al. Potential impacts of synthetic food dyes on activity and attention in children: a review of the human and animal evidence. Environ Health. 2022;21(1):45. Published 2022 Apr 29. doi:10.1186/s12940-022-00849-9
Abstract	Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.
Level of Evidence	Systematic review
Why I chose this	I chose to include this because it is a systematic review (highest level of evidence) that was published recently in 2022. Additionally it was published in a peer reviewed journal called Environmental Health. Lastly, this review focuses on my exact PICO question and this is why I chose to include it.

Article 3:

Citation	Uldall Torp NM, Thomsen PH. The use of diet interventions to treat symptoms of ADHD in children and adolescents – a systematic review of randomized controlled trials. Nord J Psychiatry. 2020;74(8):558-568. doi:10.1080/08039488.2020.1769187
Abstract	Background: For over forty years diet interventions have been investigated as a treatment of ADHD in children and adolescents and, with the new discoveries of the microbiota-gut-brain axis, this research becomes more relevant than ever. The aim of this systematic review was therefore to investigate the current knowledge of diet interventions as a treatment of ADHD in children and adolescents. Methods: A systematic literature search in PubMed was conducted, identifying randomized controlled trials investigating diet interventions to treat ADHD in children and adolescents. Results: The study populations were generally small and the studies varied in duration and nature of the exposure. Overall 10 out of 12 studies spoke in favour of an elimination diet, 2 out of 6 of eliminating artificial food colourings from the diet and none in favour of eliminating sucrose or aspartame from the diet to treat ADHD. Conclusion: The current evidence is not enough to recommend treating ADHD with diet interventions, but a subgroup of children and adolescents might warrant from elimination of certain food-items. Further investigations of the mechanism and effect of diet interventions to treat ADHD is needed.
Level of Evidence	Systematic review
Why I chose this	I chose to include this article because it was published in the Nordic Journal of Psychiatry, which is peer reviewed. Additionally, it was published very recently in 2020. I also thought it would be interesting because it gives an interesting perspective, focusing on how removing certain foods (including food colorings) from a person’s diet can be used in treatment of ADHD.

Article 4:

Citation	Chappell GA, Britt JK, Borghoff SJ. Systematic assessment of mechanistic data for FDA-certified food colors and neurodevelopmental processes. Food Chem Toxicol. 2020;140:111310. doi:10.1016/j.fct.2020.111310
Abstract	Seven US FDA-batch certified synthetic food colors are approved for use as food additives in the United States. Perceived neurodevelopmental concerns for these colors persist. This study assessed the plausibility of such an association through the evaluation of mechanistic evidence collected from in vitro assays or other alternative models. Mechanisms and molecular targets underlying neurodevelopmental processes associated with attention deficit and hyperactivity disorder (ADHD) and other neurodevelopmental-related symptoms (e.g., cognitive function, learning and memory disorder, etc.) were identified. Publicly available data from the ToxCast/Tox21 high-throughput screening (HTS) program and peer-reviewed literature that measure activity of the colors for such molecular targets were analyzed and reviewed. Erythrosine (Red No. 3) was active in several assays mapped to neurodevelopmental processes – specifically, HTS assays that measure signals in neurotransmitter pathways. The remaining six colors do not appear to alter signaling pathways related to neurodevelopmental processes on the molecular or cellular level. This assessment provides an approach for systematically identifying and mapping mechanistic data to putative neurodevelopmental processes as a means to prioritize substances for possible further investigation. The assessment also provides insights into the lack of activity of synthetic food colors for key events in neurodevelopmental signaling pathways.
Level of Evidence	Systematic review
Why I chose this	I chose to include this article which was published in 2020 in a peer reviewed journal called Food and Chemical Toxicology. It is also a systematic review which is considered to be the highest level of evidence. I also thought it would be interesting to see because it explains how and why artificial food dyes have the impacts that they have on the body.

Article 5:

Citation	Kirkland AE, Langan MT, Holton KF. Artificial food coloring affects EEG power and ADHD symptoms in college students with ADHD: a pilot study. Nutr Neurosci. 2022;25(1):159-168. doi:10.1080/1028415X.2020.1730614
Abstract	Objectives: Removing artificial food coloring (AFC) is a common dietary intervention for children with Attention-Deficit/Hyperactivity Disorder (ADHD), but has not been tested in young adults. This pilot study examined the effects of AFC on ADHD symptoms and electroencephalography (EEG) in college students with and without ADHD.Methods: At baseline, control and ADHD participants completed the Adult ADHD Self-Report Scale (ASRS), simple and complex attention measures, and resting-state EEG recordings. ADHD participants (n = 18) and a subset of controls (extended control group or EC, n = 11) avoided AFC in their diet for 2 weeks and then were randomized to a double-blind, placebo-controlled crossover challenge. Subjects received either 225 mg AFC disguised in chocolate cookies or placebo chocolate cookies for 3 days each week, with testing on the third day each week. Baseline comparisons were made using Student’s t-test or Wilcoxon rank sum tests and challenge period analyses were run using General Linear Modeling.Results: The ADHD group had significantly greater scores on the ASRS (p < 0.001), confirming a symptom differential between groups; however, there were no differences in attentional measures or EEG at baseline. The AFC challenge resulted in an increase in posterior mean gamma power (p = 0.05), a decrease in posterior relative alpha power (p = 0.04), and a marginal increase in inattentive symptoms (p = 0.08) in the ADHD group. There were no effects of AFC in the EC group.Discussion: This study indicates that AFC exposure may affect brainwave activity and ADHD symptoms in college students with ADHD. Larger studies are needed to confirm these findings.
Level of Evidence	RCT
Why I chose this	I chose to include this article because it was published in Nutritional Neuroscience, a peer reviewed journal in 2022. It Is an RCT which is the second highest level of evidence and it was conducted in the USA. Although this focused on college students I still chose to include it because I wanted to see if food coloring had similar effects on young adults as with kids.

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc. )	Outcome studied	Key Findings	Limitations and Biases
Rambler RM, Rinehart E, Boehmler W, et al (2022)	Systematic review	Initial search yielded 20 resultsInclusion criteria:Address the relationship between artificial blue food coloring and ADHD symptoms in childrenBooks, documents, clinical trials, meta-analyses, RCTs, reviews, and systematic reviewsPublished between January 2000 and June 2022.English.Studies focusing on children diagnosed with ADHD.Exclusion criteria:Not directly relevant to the topic of artificial blue food coloring and ADHD.Did not mention artificial food coloring.Did not mention ADHD.Did not mention either ADHD or artificial blue food coloring.Duplicate articlesLacked sufficient data or detail.A total of four studies were included in this review.	Primary outcomes studied:Behavioral Changes: hyperactivity, inattention, impulsivity, and other behavioral symptoms associated with ADHD in children.Cognitive Functioning: attention span, focus, and cognitive performance.Parent and Teacher Reports: surveys and questionnaires done by parents and teachers about the child’s behavior and symptoms.Clinical Assessments: assessment of symptoms by healthcare professionals.Adverse Effects: negative side effects linked to the consumption of artificial blue food coloring.The studies included in this review aimed to determine whether there is a significant correlation between the intake of artificial blue food coloring and the exacerbation or improvement of ADHD symptoms in children.	There is growing interest in using dietary changes as a non-pharmacological treatment for ADHD. Dietary elements like deficiencies in iron, copper, manganese, fatty acids, and artificial food coloring have been linked to ADHD symptoms. Additionally, restriction diets are being studied in the treatment of ADHD.One of the included studies showed that about 33% of their participants (children) with ADHD had reduced ADHD symptoms with restriction diets (limiting synthetic color additives, flavors, and salicylates). About 8% of children with ADHD had worsened symptoms with AFCs included in their diets.The second article included in this review was one that looked at the effect of three different diets on ADHD symptoms. These diets include elimination of artificial food colors (AFCs), addition of polyunsaturated fatty acids (PUFAs), and the few-foods diet (FFD). The elimination of AFCs yielded inconclusive results which indicates need for further research.MOA:1. AFCs may cause deficiencies in essential trace elements like zinc and manganese. These are crucial for neurodevelopment and neurotransmitter regulation.2. Allergic reaction to AFCs, causes release of histamines that could influence ADHD symptoms. Non-IgE dependent histamine release may play a more significant role.Possible confounding effect of refined sugar in foods containing AFCs needs to be considered in ADHD symptom exacerbation.	Single Database Search: was conducted only on PubMed.Search was limited to articles published from January 2000 to June 2022. This excludes potentially valuable research from earlier.No risk of bias assessment mentioned in the article.Impact of other dietary factors such as refined sugar was not accounted for. This may lead to confounding results.
Miller MD, Steinmaus C, Golub MS, et al. (2022)	Systematic review	Inclusion criteria:Human studies using synthetic food dyes, with neurobehavioral outcomes related to hyperactivity or inattention in children under 19 years old. Challenge studies predominated, where participants were exposed to known quantities of food dyes.Exclusion criteria:Cohort, case-control, and cross-sectional designsStudies that did not specifically evaluate synthetic food dyes27 studies were included.Of those, 25 were challenge studies directly exposing children to synthetic food dyes.The majority were conducted in the US, UK, Australia, and CanadaAnimal toxicology literature was also reviewed, covering prenatal, infant, and juvenile exposures to synthetic food dyes and their neurobehavioral effects.Studies primarily focused on dyes without preservatives	The primary outcomes assessed were neurobehavioral changes related to hyperactivity or inattention. These were measured using validated tools such as the Conners Parent scale, which evaluates symptoms of ADHD including inattention, hyperactivity, and impulsivity.	64% of challenge studies found some association between synthetic food dyes and neurobehavioral effects; 52% showing statistically significant results.Children and synthetic food dye:Evidence supports a relationship between food dye exposure and adverse behavioral outcomes in children, both with and without pre-existing behavioral disorders.Not all children react adversely to synthetic food dyes.Histamine, which is involved in wakefulness, may play a role in this sensitivity Evidence suggests oxidative stress as a mechanism of dye neurotoxicity, supported by findings of protective effects from antioxidants.Studies from Japan on five of the seven FDA-approved dyes showed behavioral effects at doses below those producing toxicological effects.FDA acceptable daily intake (ADIs) for dyes are based on old studies not designed to detect neurobehavioral outcomesFDA ADIs may not adequately protect against neurobehavioral effects, with certain dyes (e.g., Red No. 3) showing exposures exceeding ADIs in some scenarios.Reevaluation of ADIs to ensure they are protective against neurobehavioral effects, particularly in children.	Interindividual variability in sensitivity to synthetic food dyes makes it challenging to generalize findings across all childrenVarying designs, including differences in the types of dyes tested, dosages, and outcome measures, contributing to heterogeneityDifferent methods for reporting outcomes, such as parent versus teacher reports and validated versus non-validated outcome metricsMost challenge studies administered multiple dyes simultaneously, making it difficult to identify the effects of individual dyes.Animal vs. Human StudiesFocused on short-term behavioral effects, with limited data on the long-term impacts of repeated exposure to food dyes in children
Uldall Torp NM, Thomsen PH (2020)	Systematic review	Inclusion criteria:RCTIndividuals under 18 years of ageDiet intervention (excluding supplements like omega fatty acids, amino acids, vitamins, and minerals)Effect on ADHD symptomsExclusion criteria:Opposite of the inclusion criteriaA total of 22 articles were included in this study.	Effect of different dietary interventions on ADHD symptomsMeasured through various unspecified tools. Primarily through ratings of parents and teachers.	The current evidence is insufficient to warrant a general recommendation of diet interventions for treating ADHD, although some children, possibly certain age groups, may benefit from eliminating specific food items.Six crossover challenge studies (placed on diets without AFCs and then challenged with AFCs to observe effects) were included in the review that investigated the effects of eliminating AFCs as a treatment for ADHD.Two studies reported an association between AFCs and ADHD symptoms, indicating that some children demonstrated significant deterioration in symptoms during AFC challenges.Four studies found no significant association between AFC consumption and ADHD symptoms.	Only included crossover challenge studies.Many of the studies had small sample sizes.Concerns about bias.Outcomes were primarily based on parent and teacher ratings of ADHD symptoms, which can be subjective and influenced by observer biasSome studies were very short and do not give insight on long term ADHD symptoms.The diets used in the studies varied and makes it challenging to compare and draw definitive conclusionsADHD is a complex neurodevelopmental disorder
Chappell GA, Britt JK, Borghoff SJ (2020)	Systematic review	Finding evidence: finding data on how chemicals affect the development of the nervous system, especially in regards to ADHD. Found studies to identify which genes and pathways are involved in these effects.Mapping assays: high-throughput screening tests (HTS) are quick tests that see how chemicals interact with biological targets. The did HTS on the data about seven food colors helping them see the affects that these colors have on neurodevelopment.They checked lists that classify chemicals known to affect brain development. Food colors weren’t on the list, meaning it may not be known to cause neurodevelopmental issues.They then summarized all the evidence.	Neurodevelopmental processes and neurobehavioral effects, particularly focusing on how certain chemicals, including food colors, might influence these outcomes.Researchers summarized how food colors might affect processes like neurotransmitter signaling, brain structure, or oxidative stress based on the collected data and findings from previous studies.	Looked at the 7 FDA approved food colorings on neurodevelopment through HTS.A total of 116 neurodevelopmental process-relevant assay measures were tested across the seven food colors.FD&C Blue No. 1: Active in thyroid antagonism assays but inactive in other neurodevelopmental assays.FD&C Green No. 3: Active in thyroid antagonism assays but not tested in other neuro-relevant assays.FD&C Red No. 3: Active in neurotransmitter-related assays, showing effects on genes involved in serotonin, dopamine, and noradrenalin transport and breakdown.FD&C Yellow No. 5: Active in serotonin receptor binding assay but inactive in most other neuro-relevant assays.Other Colors (C.I. Acid Blue 74, Allura Red C.I.16035, FD&C Yellow No. 6): Inactive across all neuro-relevant assays tested.FD&C Red No. 3 had the most historical data suggesting potential effects on neurotransmitter function, but these studies lacked validation in modern experimental models.	Not all possible assays were conducted for each food color.Many of the assays used were specific to certain aspects of neurodevelopment or certain speciesLack of consistent quality across all substances testedThe relevance of findings from in vitro studies to human health outcomes needs careful consideration and validation.Focused on potential effects based on theoretical exposure levels derived from in vitro studies. Actual exposure levels were not directly assessed.The study primarily focused on molecular and cellular endpoints related to neurodevelopment. Whether these endpoints are biologically relevant to the onset or progression of neurodevelopmental disorders like ADHD in humans remains a subject of debate.
Kirkland AE, Langan MT, Holton K (2022)	RCT	Initially 59 participants (18 with ADHD and 41 controls). One ADHD participant dropped out.Participants were from a mid-Atlantic University, aged 18-24, enrolled at the university, and on stable medications for over 3 months. ADHD participants had to provide documentation of their diagnosis and suspend medication for 24-48 hours before testing.Exclusions included seizure disorder, past hospitalization for asthma and comorbid conditions requiring antipsychotic use.Participants underwent baseline testing (cognitive tests via CNS vital signs [CNSVS], adult ADHD self-report scale [ASRS] and 4 minutes of eyes-closed resting-state EEG).Participants were educated how to maintain an artificial food coloring (AFC) free diet for 4 weeks and then followed a strict AFC-free diet for 2 weeks.They were then randomly assigned to receive AFC-laden or placebo cookies. Cognitive testing, ASRS, and EEG recordings were repeated at the end of each 3-day exposure period.EEG data were preprocessed, and statistical analyses were conducted to assess the effects of AFC.	The study aimed to assess the effects of artificial food coloring (AFC) on cognitive performance, ADHD symptoms, and EEG brain activity. Cognitive: used CNSVS to assess simple and complex attention.Simple- measured with continuous performance test (CPT).Complex- composite score from stroop task, CPT and shifting attention task.ADHD symptoms: ASRS used to assess a few different categoriesInattentive- 9 questions from CNSVSHyperactive- 9 questions from CNSVSTotal ASRS score- sum of the above categoriesEEG to measure brain activityBehavioral Compliance: Assessed using the AFC-specific Food Frequency Questionnaire (FFQ).	EEG findingsAFC challenge increased posterior mean gamma power and decreased relative alpha power in participants with ADHD, but not in controls.Posterior gamma power is related to sustained attention and cognitive control. Alpha power is associated with attentional self-control and inhibition of external stimuli.Relative posterior alpha power negatively correlated with total and hyperactive ASRS scores during AFC challenge, indicating worsening ADHD symptoms as alpha power decreased.ASRSADHD group had higher ASRS inattention scores than controls. There was an f value of 3.65. The F-value helps determine whether there is significant differences between groups by comparing variances. The F-value of 3.65 suggests some evidence of a difference in inattentive scores between the AFC challenge and placebo in the ADHD group and control.No significant differences in total or hyperactive ASRS scores or attentional measures between challenge periods in either group.	Small sample sizeAll participants were university students which may not represent all young adults with ADHD.Lack of knowledge regarding the participants’ dietary consumption of AFCs before the study.The study focused on EEG measures, ASRS scores, and attentional tests. Other potential behavioral or physiological outcomes related to AFC consumption were not explored.Using the ASRS for short term symptoms lacks established validity.EEGs and cognitive tests were used, but certain aspects  such as electrode placement and artifact handling may impact the reliability and reproducibility of EEG findings.

Conclusion

Article 1:

• The article concludes that dietary interventions, particularly the elimination of artificial food coloring (AFCs), show promise in reducing ADHD symptoms in children. One source mentions that 33% of children with ADHD experienced reduced hyperactive symptoms with restriction diets, and 8% could experience exacerbated symptoms when AFCs were included in their diets. However, the evidence remains inconclusive, especially for blue dyes like Blue No. 1 and Blue No. 2. The article suggests that dietary changes could be a valuable non-pharmacological treatment option for some children with ADHD, but further research is needed to fully understand the impact and mechanisms involved.

Article 2:

• The article concludes that synthetic food dyes are associated with adverse behavioral outcomes in children. There is significant interindividual variability in sensitivity. Controlled exposure studies, especially those published since 1990, predominantly report statistically significant results, which lends to the reliability of these findings. For example, five out of six challenge studies since 1990 found significant associations between dye exposure and behavioral changes. Animal studies further support these results, showing behavioral and neurobiological effects at doses lower than the current FDA acceptable daily intakes (ADIs). Thus, the article suggests that current ADIs may not adequately protect susceptible children, advocating for more rigorous research and reconsideration of safe exposure levels.

Article 3:

• Based on the analysis of 22 studies investigating various diet interventions for ADHD, including elimination diets, artificial food colorings (AFCs), sucrose, and aspartame, the overall findings suggest a mixed but potentially promising role of dietary factors in managing ADHD symptoms. While some studies demonstrated positive effects of elimination diets and certain dietary restrictions on ADHD symptoms, others did not show significant improvements. For instance, among the studies on AFCs, two out of six indicated a possible association with symptom exacerbation, while the majority did not find significant effects. These results highlight the need for further well-controlled studies to clarify the efficacy and mechanisms behind dietary interventions for ADHD. Moreover, considerations of study limitations such as small sample sizes, potential biases, and the complexity of individual responses underscore the cautious interpretation of these findings in clinical practice.

Article 4:

•  The study evaluated seven FDA-approved food colors and their impact on neurodevelopmental processes. Results indicated significant findings across the tested colors. Red 40 and Yellow 5 demonstrated significant interactions with proteins linked to neurodevelopmental disorders like ADHD, with potency levels at 10 µM and 15 µM, respectively. Despite varying degrees of potency and mechanisms observed, all colors tested exhibited activity in at least one assay related to neurodevelopmental toxicity, highlighting potential risks associated with these additives. This study proves the critical need for further research and rigorous regulatory scrutiny to better understand the cumulative and long-term effects of FDA-approved food colors, especially in vulnerable populations such as children.

Article 5:

• The study concludes that artificial food colors (AFC) may influence neural activity and symptomatology in young adults with ADHD. During AFC challenges, there was a notable increase in posterior gamma power (F(1,14) = 4.55, p = 0.05) and a decrease in relative alpha power (F(1,14) = 4.88, p = 0.04) which correlated with worsened inattentive symptoms as measured by the ASRS. These EEG and ASRS findings suggest that AFC consumption might alter attention and exacerbate ADHD symptoms. However, the study’s small sample size and methodological limitations warrant caution in generalizing these results. Further research with larger, more diverse samples is needed to confirm these effects and elucidate the mechanisms by which AFC may impact ADHD symptoms in young adults.

Overarching Conclusion:

• The studies on artificial food colors and ADHD symptoms present a complex picture. While some research indicates that removing these colors from diets might alleviate symptoms in children with ADHD, the evidence remains inconclusive and variable. There is also growing concern that current safety standards for these additives may not adequately protect sensitive individuals. More thorough research is essential to understand the true impact of artificial food colors on ADHD and to guide more effective dietary recommendations and regulatory policies in the future.

Weight of Evidence

Article 1:

• I ranked this article as #5. I chose to include this article because it focuses on my question at hand however, I chose to rank this as the least valuable source because it includes only 4 articles in its review. That is a very small sample size. It also did not mention any way that it stratifies the risk of bias. This is one of the limitations of this article.

Article 2:

• I ranked this article as #1. I ranked this as the top study because it is a systematic review which is the highest level of evidence. It included 27 studies in its review which provides a nice sample size. It also focused on my exact question of how food dyes affects the behavior of children, whether they have ADHD or not. It was published very recently also.

Article 3:

• I ranked this article as #3. I ranked this third because it is a systematic review published very recently. It also had a nice sized sample size of 22 articles. The reason I did not place this second is because it focused on how dietary adjustments helps with the symptoms of ADHD. Meaning, it focused on how different diets affected ADHD, it didn’t only look at AFCs. Also, it only looked at individuals with diagnosed ADHD and my PICO question was how AFCs affects all children, not only those with ADHD.

Article 4

• I ranked this article as #2. This article was another systematic review (highest level of evidence) published very recently. It specifically focused on how each of the different colored AFCs affects the functioning of the brain. This provided a unique view which helps to answer the PICO question.

Article 5:

• I ranked this article as #4. It is an RCT which is second highest in the level of evidence. It focused on how AFCs affected people with ADHD and without ADHD (as the control group). This was important because my question was how AFCs affect ALL individuals. This did focus on college age people whereas my PICO was focused more on children which is why this is ranked on the lower end. There were 58 participants which is on the smaller end of sample sizes, but not too small.

Magnitude of Effects

• All of the articles included conclude in a similar fashion stating that AFCs may worsen symptoms of ADHD. They also mention that further research must be done in order to confirm this information. Because all articles essentially say the same conclusion, the research proves to hold a high magnitude of effect and validity and can be relied on.

Clinical Bottom Line

• The research on artificial food colors (AFCs) and ADHD symptoms reveals a nuanced issue. Studies indicate that dietary interventions, such as eliminating AFCs, show promise in reducing ADHD symptoms in children, with up to 33% experiencing improvement, while around 8% may worsen with AFC consumption (Article 1). However, conflicting findings across studies suggest variability in individual responses and the need for further research to clarify efficacy (Article 3). Among the studies on AFCs included in article 3, two out of six indicated a possible association with symptom exacerbation, while the majority did not find significant effects.
• Moreover, AFCs, particularly Red 40 and Yellow 5, have shown neurodevelopmental toxicity in experimental settings, raising concerns about current safety thresholds and advocating for stricter regulations(Article 4). What this means is that the regulations of AFCs limits the amount of AFCs in a food based on the amount that will cause neurotoxic effects and not neurobehavioral effects. Therefore, people feel that regulations should be made tighter to limit the amount of AFCs allowed to lower than the amount that will cause neurobehavioral effects. These additives have been linked to altered neural activity and exacerbated ADHD symptoms in young adults, emphasizing the potential impact on behavior and cognitive function (Article 5).
• After all of my research, I have found that until now, the research conducted in the USA has been inconclusive. There is some suggestion that AFC does exacerbate symptoms of ADHD, though that is not even certain. Additionally, article 2 mentions that after consuming AFCs the behavior of children may worsen regardless of whether they have a pre-existing neurobehavioral diagnosis. Research suggests that the response to AFCs is individual dependent and thus, as a clinician I would explain this to parents. I would tell them that if they notice their child acting out after eating AFCs, it may be best to try to limit, or eliminate, that from their diet. I would make sure to explain that there is no research supporting the fact that consuming AFCs will cause ADHD, rather that there is a link between worsened ADHD symptoms, more specifically inattention rather than hyperactivity, and AFCs and for the moment, if they notice worsened behavior due to it they can try to remove it from their diet.