Introduction
Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are early onset neurodevelopmental disorders that may persist into adulthood. Both ASD and ADHD are umbrella terms that cover heterogeneity of behavioral abnormalities. ADHD is characterized by inattentive, hyperactive and impulsive behavior, whereas the key symptoms of ASD include social deficits, communication deficits and stereotypical behavior [
1]. Despite the differences in the core behavioral symptoms between ASD and ADHD, there are indications for an overlap between the disorders. Indeed, research indicates that these disorders are highly comorbid [
2‐
7]. This overlap could be explained by a shared etiology between ADHD and ASD disorders; for instance, genetic studies have demonstrated common genetic etiology for these disorders [
8,
9]. Although the etiology of ASD and ADHD remains largely unknown, a complex interaction of genetic and environmental factors is thought to contribute to the development of ASD and ADHD [
2,
10,
11].
One of the potential environmental risk factors for neurodevelopmental disorders is diet [
12]. Nutrition has an impact on neurodevelopment, cognition, and behavior, and could therefore play an important role in neurodevelopmental disorders [
13‐
15]. This insight, together with the lack of effective treatments for core ASD symptoms and the concerns about the safety of pharmacological treatments in ADHD [
16], have led to increasing research into the efficacy of nutrition-related interventions as additional or alternative (non-pharmacological) treatments for these disorders. The dietary interventions that have been subjected to clinical trials include various forms of elimination diets and supplementation interventions [
17‐
20]. In this review, we provide an overview of the literature with regard to the most common forms of elimination diets and their efficacy in ADHD and ASD. Furthermore, we discuss the potential mechanisms of elimination diets’ effects in both ADHD and ASD. Finally, we conclude with the practical implications and future directions into the investigation of elimination diets’ efficacy in the treatment of these early onset neurodevelopmental disorders.
Elimination diets in ASD and ADHD
At first, the concept of an elimination diet was introduced to diagnose and treat food allergies [
21]. The main reason for applying an elimination diet is to find out which foods are causing or aggravating physical adverse reactions. Later this link of food with adverse physical adverse reactions has been extended to a connection with neurobehavioral symptoms [
22,
23]. Thus, in this later view, behavioral reactions are seen as possible adverse reactions to food as well. In the domain of psychiatry, it is therefore believed that elimination diets can be used to identify foods that contribute to mental disorders and associated behavioral and cognitive disturbances.
Elimination diets come in different forms and vary in their strictness and food items that are being eliminated. Interestingly, the forms of elimination diets that are being investigated differ between ASD versus ADHD. In ASD, the gluten-free and/or casein-free (GFCF) diet has been mainly investigated, whereas in ADHD, clinical trials examined the effects of food additives exclusion diets and the oligoantigentic diets. These differences in focus between the elimination diets that are applied in the two disorders are due to the different origins of the research in both fields. In the following sections, the origins, rationale, and the general principles of the diets are being described, followed by the degree of evidence with regard to the efficacy. In Table
1, an overview is provided for several characteristics of the respective diets, including the excluded food items, main target group, efficacy, and nutritional elements that would require attention in case of long-term exclusion to avoid deficiencies.
Table 1
Overview of the characteristics of the respective elimination diets
Gluten-free casein-free | Gluten and casein (e.g., products containing wheat, oats, barley, or rye; and milk and dairy products | ASD | No meta-analyses available (recent extensive review by Elder et al. [ 19]) | Results are inconclusive Weak evidence for any positive effects A subset of individuals may respond positively (e.g., those with gastrointestinal abnormalities) | Gluten exclusion: vitamin B, iron, fiber Casein exclusion: calcium, vitamin D, protein Some evidence for suboptimal bone development [ 135] |
Food additives exclusion | Artificial food coloring Artificial flavors Artificial fragrances Preservatives Artificial sweeteners | ADHD | Two recent meta-analyses [ 51, 18] | Small effects Effects may not be specific to ADHD Effects may depend on food sensitivity | No risk for nutritional deficiencies |
Oligoantigenic | Antigenic foods (basic diet may be restricted to a few hypoallergenic foods: turkey, pears, rice, lettuce, water) | ADHD | Two recent meta-analyses [ 51, 18] | Large effects including studies using proximal assessment, but small effects based on probably blinded assessment studies No information on long-term effectiveness | Vitamins, minerals, fiber, proteins No direct evidence for these risk |
Gluten-free diet and/or casein-free diet in ASD
The focus on GFCF diets in ASD originates from the evidence of comorbid gastrointestinal tract problems in patients with ASD [
24‐
26]. The explanation for increased gastrointestinal problems in ASD remains unclear. One explanation is that gastrointestinal tract problems in patients with ASD might be caused by increased intestinal permeability, the so-called leaky gut, which has indeed been demonstrated in children with ASD compared to healthy controls [
27‐
29]. According to the ‘opioid excess theory’, digestion of gluten and casein produces peptides with an opioid activity that can enter the bloodstream when the gut permeability is high [
30,
31]. These neuroactive peptides can in turn bind to opioid receptors and are therefore speculated to affect processes in the central nervous system [
32].
The idea for the gluten-free diet involves examination of the effects of removing all the food items containing gluten, a mixture of proteins found in wheat, oats, barley, or rye. Thus, all products made with these cereals are excluded from the diet and replaced with special gluten-free version of the common food items. In some cases, the gluten-free diet is combined with a casein-free diet. Casein is a peptide commonly found in milk. Thus, a casein-free diet involves avoiding the intake of milk and dairy products. After a period of elimination, products containing gluten or casein can be reintroduced to test whether it is contributing to the symptoms.
Food additives exclusion diet in ADHD
As discussed above, the elimination diet was originally proposed as a tool for treatment of food allergies [
21]. Feingold, an American pediatrician and allergist, was the first who suggested that allergy to food additives, such as artificial flavors and colors, as well as naturally occurring salicylates could lead to ADHD symptoms [
33]. He based this on observations that aspirin, which contains salicylates, could not only lead to allergic reactions, but also to an increase of hyperkinetic behavior in some patients. This observation has set the stage for the development of various food additives exclusion diets, which typically involves the removal of, for instance, artificial food colors, flavors, fragrances, preservatives, and sweeteners. Sometimes, this diet is part of a broader elimination diet, such as the Feingold diet or Kaiser Permanente diet (
http://feingold.org/), which involves the removal of both natural and artificial salicylates. The intervention usually investigates the effect over periods of a week or longer. Food challenges that include food additives can be used after this period to examine the acute immediate effects of the challenge. The hypothesis is that ADHD could be influenced by either allergenic or pharmacologic mechanisms related to levels of salicylates and salicylates-like substances.
Oligoantigenic diet in ADHD
In oligoantigenic diets, the focus is on eliminating suspected high allergenic food products rather than eliminating artificial colors, flavors, and preservatives specifically. An oligoantigenic diet intervention, also known as a restricted elimination diet or hypoallergenic diet, involves the testin657g of an individually constructed restricted elimination diet. The focus is on eliminating foods that are often found to be highly allergenic, such as cow’s milk, cheese, egg, chocolate, and nuts. Oligoantigenic diets come in different forms and vary in their strictness. The oligoantigenic diet typically involves an elimination phase (usually two to five weeks) in which the specific food items are excluded completely. The food items in the elimination phase could, for instance, consist of only a few hypoallergenic foods such as rice, turkey, lettuce, pears, and water [
34]. If the patient reacts by a substantial decrease of symptoms indicating ‘food sensitivity’, a reintroduction phase, which could take as long as eighteen months, could be applied to find out what specific food items trigger the symptoms. Thus, an elimination diet can be regarded as a ‘diagnostic’ tool for determining whether specific foods cause adverse physical and/or behavioral reactions.
Clinical implications and future research
The GFCF diet might be beneficial for children with ASD and food intolerance/allergy or underlying gastrointestinal disease. However, the evidence for the effectiveness of GFCF diets in children with ASD is weak and thus these diets cannot be generally recommended as a treatment for children with ASD. Yet, a GFCF diet is a commonly applied intervention in children with ASD in practice. Many parents may feel it is better to apply any available treatment when searching for treatment for their child with ASD as therapies for treating core symptoms of ASD are limited. However, using a GFCF diet may not be without harm (e.g., stigmatization, diversion of treatment resources, nutritional deficiency) [
135]. Hence, until there is conclusive evidence for the benefits of GFCF diets for children with ASD, it is the task of health professionals and researchers to communicate with caregivers and inform them about the costs and potential adverse consequences.
Benefits of food additives exclusion diets have been suggested in children diagnosed with ADHD. However, the observed effects are small, which makes food additives exclusion diet not qualified as stand-alone treatment. Nevertheless, given the positive, albeit small effects of this intervention in children with ADHD as well as in children from the general population, and the fact that food additives do not provide any health benefits, it is recommended that children preventatively minimize consumption of processed food products with these ingredients. Moreover, from a public health perspective, food industry might change its policy and lower or even avoid adding unnecessary additives to food.
With regard to oligoantigenic diets, if applied under close supervision, these interventions could be valuable instruments to assess whether ADHD is triggered by food. However, the efficacy of this diet as a treatment for ADHD remains to be investigated as there are no studies yet that have demonstrated long-term beneficial effects of this treatment after consolidating the diet. Our research group is currently conducting a large clinical trial to assess the long-term beneficial effects of an oligoantigenic diet in children with ADHD.
Previous work has shown that only a subset of the children with ADHD responds to an oligoantigenic diet [
34]. However, the characteristics of responders versus non-responders remain to be determined in future work. In the application of an elimination diet, it is important to take the individual differences in treatment response into account. First observations from our ongoing randomized controlled trial (
www.project-trace.nl) suggest that some children might not improve on the primary symptoms, but rather on symptoms that usually accompany the disorder, such as emotion regulation problems (e.g., irritability) and physical symptoms (e.g., intestinal disturbances). These observations might suggest that the effects of an elimination diet are not per se symptom/diagnosis specific and it could be important to monitor changes in different domains that are relevant for the well-being of the child. Furthermore, we have observed large individual differences in terms of time that is needed for any positive effects of the diet to surface during the elimination phase. Some children appear to be ‘fast-responders’, who show a positive reaction after a few days, whereas other children are ‘slow-responders’, who show a positive reaction after a couple of weeks. It remains to be investigated what could explain these individual differences and whether these individual differences are useful indicators for optimizing the individual treatment by reducing the duration of the treatment. Similarly, individual variation during the reintroduction phase is evident, with aggravation of ADHD symptoms in some children after food reintroduction after 5 days, whereas others only respond after 10–14 days. In addition, children with little variation in their normal food habits tend to respond more strongly to the intervention, but also seem to have the most difficulty in adhering to the diet since they dislike many foods that are present in the elimination phase. This may result in the child eating too few different foods during this phase, increasing the risk for non-adherence since the elimination phase is then overly strict. For the feasibility of this intensive treatment, it is also crucial to consider the optimal moment to start the diet. Stressors or life events, such as change of school environment or family structure, illnesses, but also positive events, such as celebrations and holidays, may negatively impact the motivation and feasibility of the successful application of the treatment. The reintroduction phase is the most intensive part of the treatment given its long duration. Close supervision by professionals when applying this diet or any other elimination diet is necessary such that effects of the diet as well as parent–child relationships can be monitored, the diet can be adjusted if needed, and training, support and guidance can be given to prevent the risk of adverse consequences. Apart from stigmatization, diversion of treatment resources, and nutritional deficiency, parent–child interaction problems may also be a risk. For instance, it has occurred that the child seized the opportunity to put pressure on parents to get what he/she desires with the ‘threat’ of not adhering to the diet. Practitioners should inform the caregivers that an elimination diet requires a change of lifestyle, and success will depend largely on the level of control over the child’s diet and behavior, and the resources and organizational capacities within the family. Finally, caregivers should be reminded that the decision to explore the effects of an elimination diet should be weighed against potential adverse consequences.
Future research is necessary to establish the clinical utility of elimination diets in the treatment of children with ADHD and ASD, particularly considering the widespread use of these treatments. Adequately powered, long-term RCTs, including blinded assessment of the primary outcome, should be conducted to determine the effectiveness and cost-effectiveness of elimination diets for children with ADHD and ASD. In these trials, a reintroduction or food challenge phase, preferably double-blind placebo-controlled, should take place after the elimination phase to determine the effects of the eliminated food items thoroughly. It remains to be investigated whether effects of specific foods can be specific for certain disorders or behavioral problems. In addition, many questions pertaining to the feasibility of these treatments remain to be answered. Attrition rates ranging from 0 to 25% have been reported in the literature, but these numbers were mostly based on a range of short-term trials with large heterogeneity in the designs (e.g., in preselection of patients, duration of trial, and nature of controlled challenge phase of the experiment). Thus, long-term clinical trials are particularly important for answering questions related to feasibility. Finally, this work should investigate how biopsychosocial variables may be affected by the treatment and may play a role in the efficacy of the treatment.
New avenues should also include the identification of predictors of treatment response, especially given that elimination diets may only improve the behavior in a (small) subset of the affected children. Future research might also target the microbiome–gut–brain connection as a potential mechanism that underlies the development of neurodevelopment disorders and elimination diets’ effect in reducing symptoms [
126,
136]. A multidisciplinary approach is essential for the investigation of the relation between the microbiome–gut–brain connection and behavioral symptoms of ASD and ADHD, which potentially involves multiple systems, including the metabolic, immune, endocrine, and neural system. The knowledge acquisition pertaining to the mechanism of action could ultimately help inform clinicians about potential markers and targets for preventative and individualized treatment.