2. Attention Deficit Hyperactivity Disorder (ADHD)
Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood, affecting about 7% of children and adolescents worldwide
[14][15]. It begins in early childhood and, in most cases, persists into adulthood. Symptoms include hyperactivity, inattention, impulsivity, impaired executive function, and emotional dysregulation, with several comorbidities emerging along the developmental trajectory
[1]. Although ADHD is highly heritable, studies suggest that its etiology is multifactorial, with both genetic and environmental factors reflecting its phenotypic heterogeneity
[1].
Diagnosis of ADHD relies mostly on diagnostic criteria provided by the
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). According to the DSM-5, at least six symptoms of inattention, hyperactivity, or both, before the age of 12 years and in two or more settings, are required for the diagnosis of ADHD
[2]. The symptoms exhibited must interfere with one’s functioning and may be categorized as predominantly inattentive, predominantly hyperactive, or combined. This assessment is based on a comprehensive clinical and psychosocial evaluation, as well as a full developmental and psychiatric history
[16]. Rating scales, though not diagnostic, should also be used to collect supplementary information concerning the symptomatology and its severity in all settings and should be completed by different informants, namely the parents/caregivers, teachers, and/or other relevant adult figures
[16][17]. Examples of validated rating scales widely used are the Conners Comprehensive Behavior Rating Scales, the NICHQ Vanderbilt Assessment Scale, the ADHD-RS-V, the SNAP-IV-26, and the Strengths and Difficulties Questionnaire (SDQ)
[16][17].
Treatment of ADHD currently rests on pharmacotherapeutic interventions with the use of stimulant (methylphenidate and amphetamine formulations) and non-stimulant medications (selective alpha-2 adrenergic agonists: guanfacine, clonidine; and selective norepinephrine reuptake inhibitor: atomoxetine)
[18][19], both of which have proven to effectively reduce ADHD symptomatology in children and adolescents
[19]. These pharmacological approaches, however, have known side effects. Stimulants are associated with short-term adverse effects, such as decreased appetite, weight loss, insomnia, abdominal pain, headaches, and anxiety
[17][19]. They also appear to cause a decrease in growth rate, especially for those on higher and more consistent doses, with no indication of a growth rebound
[20]. As for non-stimulants, atomoxetine is associated with adverse effects, such as headaches, abdominal pain, decreased appetite, and somnolence in children, and adverse effects such as nausea, dry mouth, decreased appetite, and insomnia in adults
[21]. Atomoxetine also seems to cause suicidal thoughts in some children
[22], though an association between atomoxetine and increased risk of suicidality has yet to have been found
[21][23][24]. Liver injuries, though extremely rare, have been connected to treatments with atomoxetine
[24][25]. A link to growth delays has also been found, though it appears to be reversible over time
[19][24][26]. For guanfacine, adverse effects include sedation, somnolence, fatigue, drowsiness, headaches, and upper abdominal pain
[27]. Similarly, for clonidine, adverse effects include fatigue, irritability, pharyngolaryngeal pain, somnolence, headaches, and upper abdominal pain
[28]. Both types of drugs (stimulant and non-stimulant) have effects on heart rate and blood pressure, but the risk of major adverse cardiovascular events is significantly low
[17][19]. Psychosis and mania, though infrequent, have also been reported to occur in those treated with these types of medication
[29].
Besides the aforementioned pharmacological treatments, non-pharmacological interventions, such as psychological therapies and diet, have also been used for the management of ADHD. The psychological therapies include behavioral therapy, cognitive training, and neurofeedback. Of these three, however, only behavioral therapy has shown statistically significant benefits and can be recommended as an evidence-based intervention
[30][31]. In fact, behavioral therapy combined with stimulants appears to be more effective than treatment with stimulants or non-stimulants alone
[30]. Regarding dietary interventions, they mostly focus on dietary supplements with vitamins, minerals, and PUFAs, microbiome-targeted interventions with pre-, pro-, and synbiotic supplementation, and restriction or elimination diets. More recently, studies have focused on dietary patterns with a more holistic approach, as treatment options for ADHD
[6] and the most promising dietetic approaches in ADHD are, in fact, food patterns considered to be healthy (i.e., Mediterranean diet and DASH) and the Few-Foods Diet for children
[13]. Still, the quality of evidence for the impact of non-pharmacological treatments in ADHD is moderately low for the time being, which highlights the need for future high-quality randomized trials
[30][31][32].
3. Dietary Patterns
Dietary pattern analysis provides a more comprehensive understanding of the diet and nutrient interactions than looking at an isolated food or nutrient
[33]. Changes in society have led to a global nutritional transition that affects dietary and eating patterns, with families having less time for food preparation and for eating together
[34]. Diets began to shift towards increased reliance upon processed foods, increased take-away foods, edible oils, and sugar-sweetened beverages, and all these changes have had negative effects on the health of many populations around the world
[34].
The relationship between dietary patterns and ADHD has yielded inconclusive results, with some studies showing that a healthy eating pattern could significantly decrease the risk of ADHD
[35] and others showing no significant effect
[36]. A recent systematic review and meta-analysis showed that, in fact, the type of diet ingested influences the risk of ADHD
[6]. The authors demonstrated that a healthy dietary pattern with consumption of fruits and vegetables, fish, and high in PUFAs and micronutrients such as magnesium, zinc, and phytochemicals seems to decrease the risk of ADHD by 37% (OR: 0.63; 95% CI: 0.41–0.96). On the other hand, both the Western-type and the junk food dietary patterns, very characteristically consumed by children, increase the risk of ADHD. The Western pattern, rich in red and processed meats, refined cereal grains, soft drinks, and hydrogenated fats, was shown to increase the risk of ADHD by 92% (OR: 1.92; 95% CI: 1.13–3.26;
p: 0.016) while the junk food pattern, characterized by a high consumption of processed foods, with high amounts of artificial food coloring (AFC) and sugar, was found to increase the risk by 51% (OR: 1.51; 95% CI: 1.06–2.16;
p: 0.024). Indeed, the daily consumption of AFC has quadrupled in the last 50 years
[37], and studies have shown they can affect the brain without crossing the blood–brain barrier
[37][38]. In a double-blind, placebo-controlled crossover challenge with 225 mg AFC disguised in chocolate cookies or placebo chocolate cookies for 3 days each week, with testing on the third day each week, the authors found that AFC exposure may affect brainwave activity and ADHD symptoms in college students with ADHD
[38]. However, a 2004 systematic review and meta-analysis showed that the overall effect size of AFCs on hyperactivity is 0.283 (95% CI, 0.079–0.488), falling to 0.210 (95% CI, 0.007–0.414) when the smallest and lowest quality trials were excluded
[39].
Another systematic review
[5] distinguished only two dietary patterns (healthy and unhealthy), and found that the healthy pattern had a protective effect (OR: 0.65; 95% CI: 044–0.97), while the unhealthy pattern increased the risk of ADHD by 41% (OR: 1.41; 95% CI: 1.15–1.74), even after stratifying studies by design (cohort, case-control, or cross-sectional), geographic area (Europe or Asia/Oceania), and sample size (
n ≥ 1000 or
n < 1000). On the other hand, the authors found that children with ADHD show less adherence to healthy eating patterns than children without this disorder. Ríos-Hernández et al.
[7], in a case-control study with a total of 120 children (60 newly diagnosed with ADHD and 60 controls), also found that lower adherence to a Mediterranean diet was associated with ADHD diagnosis (OR: 7.07; 95% CI: 2.65–18.84) in a Spanish population. Although these cross-sectional associations do not establish causality, the authors raise the question of whether low adherence to a Mediterranean diet might play a role in ADHD development.
In Ma’anshan city in China, Yan et al.
[40] did a cross-sectional survey, in a large sample of 14,912 children aged 3–6 years old, and assessed their usual dietary intake through a semi-quantitative food frequency questionnaire and ADHD symptoms based on the 10-item Chinese version of the Conners Abbreviated Symptom Questionnaire. The authors found five different dietary patterns and concluded that the “Processed” (OR = 1.56, 95% CI: 1.31–1.86) and “Snack” (OR = 1.76, 95% CI: 1.49–2.07) dietary patterns were significantly and positively associated with ADHD symptoms, while the “Vegetarian” (OR = 0.67, 95% CI: 0.56–0.79) pattern was negatively correlated with ADHD symptoms.
In conclusion, dietary patterns seem to play a potential role in the risk of ADHD, as patterns described as “Junk-food”, “Processed”, “Snack”, “Sweet”, and “Western-like” are the ones most positively associated with this pathology
[5][6][8], whereas healthy eating patterns, such as the Mediterranean diet, are inversely associated with ADHD
[7][9]. These data support the idea that not only specific nutrients or chemical food compounds but the whole diet should be considered in ADHD.
Foods, Food Groups, and Nutrients
Within the dietary patterns, at the food level, both Western and junk food patterns contain high amounts of refined grains, processed foods, and sugar, which have been related to ADHD
[8][41]. In a Korean study with 986 school-age children with ADHD and learning disabilities, the authors found that a high intake of sweetened desserts, fried foods, and salt was positively associated with learning, attention, and behavioral problems, whereas a balanced diet, with regular meals, and a high intake of dairy products and vegetables, was negatively associated with these problems
[42].
In fact, Farsad-Naeimi et al.
[43] found that higher consumption of sweetened beverages was associated with 40% greater odds (pooled effect size: 1.22, 95% CI: 1.04–1.42) of ADHD symptoms in children over 7 years old, compared with their lower intake counterparts. However, the authors also found that dietary sugars alone did not increase the risk of developing ADHD symptoms
[43]. This association between sugar intake and ADHD remains conflicting in the literature, with some studies finding positive associations and others finding no significant associations
[41][43][44].
Salvat et al.
[45], in their sample of 100 children with ADHD, found that they ingested less protein, in percentage terms, but a greater amount of simple sugars (
p = 0.007), tea (
p = 0.006), and “ready-to-eat” meals (
p = 0.002) than their control peers. The authors also showed a lower intake of vitamins B1, B2, and C, as well as zinc and calcium, by children with ADHD
[45]. In fact, several studies have shown that children with ADHD have reduced plasma levels of trace elements such as zinc, copper, iron, magnesium, and selenium
[46][47][48][49][50], which are essential for brain development and functioning
[51][52][53]. Iron is an essential cofactor required for several functions, such as neurotransmitter metabolism, particularly dopamine production, which is a core factor in ADHD. Zinc is also an essential trace element, required for cellular functions related to the metabolism of neurotransmitters, melatonin, and prostaglandins. Altered levels of iron and zinc have been related with the aggravation and progression of ADHD
[54].
Vitamins A and D have recently emerged as micronutrients relevant to ADHD, since serum concentrations of 25(OH)D and retinol were linked with this disorder after adjustment for age, Body Mass Index (BMI), season of blood sampling, and sun exposure, and this co-deficiency was associated with symptom severity
[55]. A meta-analysis of five case-control studies found that lower vitamin D status is significantly associated with the likelihood of ADHD (OR: 2.57; 95% CI: 1.09–6.04), and the meta-analysis of prospective studies conducted in 4137 participants indicated that perinatal suboptimal vitamin D concentrations are significantly associated with a higher risk of ADHD in later life (RR: 1.40; 95% CI: 1.09–1.81)
[56].
In addition, PUFAs are crucial for optimal neurotransmitter function, and some studies have confirmed that children and adolescents with ADHD have lower levels of eicosapentaenoic acid (EPA-C20:5), docosahexaenoic acid (DHA-C22:6), and total PUFA series
n-3 in their blood and buccal tissues
[57].
In summary, when looking into a food-based level, sweetened desserts, fried foods, and salt seem to be positively associated with ADHD
[42]. Although the association between sugar intake and ADHD remains conflicting in the literature
[43], it seems reasonable to limit its intake within a healthy eating pattern. Even taking a more microscopic look at a nutrient-based level, children with ADHD have reduced plasma levels of important brain function trace elements, such as zinc, copper, iron, magnesium, and selenium
[46][47][48][49][50]. In addition, vitamins A and D and PUFAs have emerged as nutrients to take into consideration in this disorder
[55][57].
4. Discussion
The findings of the observational studies emphasize a potential role of dietary patterns in ADHD, however, these study designs are unable to establish a causal relationship between diet and ADHD. Moreover, associations between adherence to healthy diets and low prevalence of ADHD do not necessarily imply healthy foods consumed during childhood have a protective effect. The associations between dietary habits and ADHD risk may be caused by other factors that were not recorded. Lifestyle factors (e.g., physical activity, screen time, and sleep) influence dietary patterns and may be important factors in ADHD symptomatology
[58]. Even when statistical adjustment for potential confounding variables was performed, residual confounding was still unavoidable. In addition, the commonly used food frequency questionnaires are known to contain some degree of measurement error
[59]. In many of the included studies in this review, the dietary patterns derived from principal component analysis explained less than 50% of total variance, suggesting the influence of other patterns and factors.
7. Conclusion
Dietary patterns appear to play a significant role in the risk of developing or aggravating ADHD symptoms, with unhealthy patterns being most positively associated with this disorder, and healthy eating patterns being inversely associated with ADHD. Altered levels of nutrients, such as vitamin D, iron, zinc, and PUFAs, have also been associated with the aggravation and progression of ADHD.