INTRODUCTION - A Solution with Chill Pill
A vast body of literature and research has been focused on attention deficit hyperactivity disorder (ADHD), which is the most prevalent childhood disorder, estimated to affect 2–18% of children1 depending largely on diagnostic criteria. Core symptoms associated with ADHD are developmentally inappropriate levels of hyperactivity, impulsivity, and inattention. ADHD has a high comorbidity rate with other mental health problems such as anxiety and mood disorders, including depression, suicidal ideation,2,3 and bipolar disorder4; it is often particularly associated with antisocial problems such as conduct disorder and oppositional defiant disorder.3,5,6 When combined with these problems, ADHD can lead to antisocial behavior, substance abuse, and borderline personality disorder in late adolescence and adulthood.7–10
In addition, ADHD is associated with cognitive deficits; it has been estimated that a quarter of these children have a specific learning disability in math, reading, or spelling.11 Attention difficulties are associated with delays in general cognitive functioning, weak language skills, and poor adjustment in the classroom.12 The disruptive behavior, poor self-discipline, distractibility, and problems with response inhibition, self-regulation, and emotional control that are associated with ADHD13 can adversely impact families, relationships, social interactions, and children's self-esteem and school performance, presenting substantial personal, social, and economic burden for afflicted children, families, schools, and the broader community.
Prevalence of ADHD appears to be on the rise despite increased prescriptions of pharmaceutical medication, particularly methylphenidate and dextroamphetamine. Many parents are concerned about side effects of these medications, and a recent long-term follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) study14 found that children in their pre-teens who had been medicated with methylphenidate had stunted growth15 as well as increased risk of juvenile behavior and, possibly, substance abuse.16
NUTRITION AND ADHD
Nutrition and the brain
The brain's critical need for adequate nutrition is demonstrated by effects of malnourishment on the developing brain, including reduced DNA synthesis, cell division, myelination, glial cell proliferation, and dendritic branching. The pathological manifestation of malnourishment will depend on the stage of brain development at the time of nutritional insult.23 Effects of some nutrient deficiencies on development have become widely known and accepted; for instance, perinatal deficiencies in iodine – now considered the world's most preventable cause of mental retardation,24 folate – related to spinabifida, and iron-related anemia. Severe deficiencies in omega-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA) can result in profound mental retardation associated with peroxisomal disorders.25,26
Less extreme effects of suboptimal nutrient levels on brain development and ongoing function are not as well recognized.
Given the essentiality of an intricate interplay of macro- and micronutrients for optimal brain function, this could result in cognitive and behavioral problems for which the role of nutrition may be overlooked. Although the brain only accounts for 2–2.7% of body weight, it requires 25% of the body's glucose supply and 19% of the blood supply at rest; these requirements increase by 50% and 51%, respectively, in response to cerebral activity.27 Glucose is required for the brain's metabolic activities and is its primary source of energy. The brain has very limited capacity for storing glucose, hence the essentiality of a continuous and reliable supply of blood. A number of nutrients appear to be involved in maintaining cerebral blood flow and the integrity of the blood-brain barrier, including folic acid, pyridoxine, colabamin, thiamine,27 and omega-3 PUFA.28 Neurotransmitters are also an integral component of the brain's communication system; various nutrients are required for monoamine metabolic pathways and act as essential cofactors for the enzymes involved in neurotransmitter synthesis.27
As well as playing important roles in immune function, growth, development, and reproduction, zinc is required for the developing brain. It plays numerous roles in ongoing brain function via protein binding, enzyme activity, and neurotransmission. As an essential cofactor for over 100 enzymes, zinc is required for the conversion of pyridoxine (B6) to its active form, which is needed to modulate the conversion of tryptophan to serotonin; zinc is involved in the production and modulation of melatonin, which is required for dopamine metabolism and is a cofactor for delta-6 desaturase, which is involved in essential fatty acid conversion pathways.29
A comprehensive review of the role of zinc in brain function and in ADHD is provided by Arnold.29 His review includes reports of nine studies conducted in various parts of the world, which all found lower zinc levels in children with ADHD as well as correlations between lower zinc levels and severity of symptoms. One avenue of zinc depletion in these children may be via reactions to synthetic chemicals found in food additives. Twenty hyperactive males who reacted to the orange food dye tartrazine were challenged in a double-blind, placebo-controlled trial with 50 mg of the food additive. Following the challenge, serum zinc levels decreased and urine levels increased in the hyperactive group compared with controls, suggesting that metabolic wastage of zinc occurs under chemical stress. Behavioral and emotional symptoms also deteriorated in hyperactive children in association with changes in zinc levels.30Iron
Anemia from iron deficiency is estimated to affect 20–25% of infants, and many more are thought to suffer iron deficiencies without anemia, putting them at risk for delayed or impaired childhood development. Iron is important for the structure and function of the central nervous system and it plays a number of roles in neurotransmission. Iron deficiency has been associated with poor cognitive development and it has been proposed that iron deficiency may affect cognition and behavior via its role as a co-factor for tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine synthesis.35,36
Iron levels were found to be twice as low in 53 non-anemic children with ADHD compared to 27 controls with no other evidence of malnutrition; specifically, serum ferritin levels were abnormal (<30 ng/mL) in 84% of children with ADHD and 18% of controls (p < 0.001). Furthermore, low serum ferritin levels were correlated with more severe ADHD symptoms measured with Conners' Parent Rating Scales (CPRS), particularly with cognitive problems and hyperactivity.36 A recent study also found low iron levels in 52 non-anemic children with ADHD, and these were correlated with hyperactivity scores on CPRS, although not with a range of cognitive assessments.37 It has been suggested that iron could play a role in ADHD due to its neuroprotective effect against lead exposure.38 Iron deficiency is also associated with restless legs syndrome, which is a common comorbid condition in children with ADHD symptoms, and may, therefore, account for greater variance of symptoms in this subgroup of children.39 Indeed, a recent study found that children with ADHD who suffered from restless legs had lower iron levels than those without restless legs.40Magnesium
Suboptimal magnesium (Mg) levels may impact brain function via a number of mechanisms including reduced energy metabolism, synaptic nerve cell signaling, and cerebral blood flow; it has also been suggested that its suppressive influence on the nervous system helps to regulate nervous and muscular excitability.44 Low Mg levels have been reported in children with ADHD. In 116 children with diagnosed ADHD, 95% were found to have Mg deficiency (77.6% in hair; 33.6% in blood serum), and these occurred significantly more frequently than in a control group. Magnesium levels also correlated highly with a quotient of freedom from distractibility.44 In 50 children aged 7–12 years with ADHD, Mg supplementation (200 mg/day) over 6 months resulted in significant reductions in hyperactivity and improved freedom from distractibility both compared with pre-test scores and with a control group of 25 children with ADHD who were not treated with magnesium.45 Another open study also found lower Mg levels in 30 of 52 hyperactive children compared with controls, and improvements in symptoms of hyperexcitability following 1–6 months of supplementation with combined Mg/vitamin B6 (100 mg/day).46 A similar study by the same researchers 2 years later found lower Mg levels in 40 children with clinical symptoms of ADHD than in 36 healthy controls. Decreased Mg levels were also associated with increased hyperactivity and sleep disturbance and poorer school attention. After 2 months of Mg/vitamin B6 supplementation for the 40 children with ADHD, hyperactive symptoms were reduced and school performance improved.47 This work indicates the need for controlled studies in children with ADHD and magnesium deficiency.
Omega-3 fatty acids
Sixty percent of the dry weight of the brain is composed of fats, and the largest concentration of long-chain omega-3 PUFA docosahexaenoic acid (DHA) in the body is found in the retina, brain, and nervous system.48 There is evidence that DHA is required for nerve cell myelination and is thus critical for neural transmission.49 Importantly, DHA levels in neural membranes vary according to dietary PUFA intake.49,50 DHA precursor eicosapentaenoic acid (EPA) is also believed to have important functions in the brain,51 possibly via its role in synthesis of eicosanoids with anti-inflammatory, anti-thrombotic, and vasodilatory properties. Animal studies have associated omega-3 levels with levels of neurotransmitters dopamine and serotonin;52,53 we have proposed that one of their primary influences on mental health may also be via improved cerebral vascular function.28
In the 1980s, researchers observed signs of fatty acid deficiency in hyperactive children54; thereafter, a number of studies found lower omega-3 PUFA levels in children with ADHD compared with controls.55–59 Randomized controlled trials have found equivocal results, which may be explained by variations in selection criteria, sample size, dosage and nature of the omega-3 PUFA supplement and length of supplementation. One study performed in the United States supplemented 6–12-year-old medicated boys with a “pure” ADHD diagnosis (without comorbidities) with 345 mg of algae-derived DHA per day for 16 weeks and found no significant improvements on outcome measures.60 Another study in the United States gave 50 children aged 6–13 years with ADHD symptoms and skin and thirst problems 480 mg DHA and 80 mg EPA along with 40 mg arachidonic acid (AA; omega-6 PUFA) daily over 4 months. Significant improvements were only found in conduct problems rated by parents and attention problems rated by teachers; importantly, the latter was correlated with increases in erythrocyte DHA levels.61 A study performed in Japan using both DHA and EPA found no significant treatment effects of bread enriched with fish oil (supplying 3600 mg DHA and 700 g EPA per week) on symptoms of ADHD in a 2-month, placebo-controlled, double-blind trial with 40 children aged 6–12 who were mostly drug-free (34/40). The placebo bread contained olive oil.62 Blood samples were not taken, so it is not clear whether this sample had a baseline deficiency in fatty acids. Given that the study was conducted in Japan, a country known to have high fish consumption, it is possible that they did not. It is also possible that 2 months may not have been a sufficient length of time for effects to become observable. Another pilot study in the United Kingdom supplemented 41 non-medicated children aged 8–12 years who had literacy problems (mainly dyslexia) and ADHD symptoms above the population average with 186 mg EPA and 480 mg DHA along with 42 mg AA per day for 12 weeks; the results showed improvements in literacy and in ADHD symptoms evaluated using Conners' Rating Scales.63
Since these small trials, the results of two large, randomized, placebo-controlled, double-blind interventions have been published. The first was conducted in the United Kingdom with 117 non-medicated children aged 5–12 years with developmental coordination disorder; a third of these children had ADHD symptoms above the 90th percentile, placing them in the clinical range for a probable ADHD diagnosis. On average, these children were functioning a year behind their chronological age on reading and spelling. Following 3 months of daily supplementation with 552 mg EPA and 168 mg DHA with 60 mg gamma linolenic acid (GLA; omega-6 PUFA), children in the treatment group showed significant improvements in core ADHD symptoms, as rated by teachers on Conners' Rating Scales. The treatment groups also increased their reading age by 9.5 months (compared to 3.3 months in the placebo group) and their spelling age by 6.6 months (compared to 1.2 months in the placebo group).64 A review of the above-mentioned studies was published following the latter trial.65
The next study (conducted by the present author) investigated treatment with the same supplement in 132 non-medicated Australian children aged 7–12 years who all had ADHD symptoms in the clinical range for a probable diagnosis. This study also investigated additive benefits of a multivitamin/mineral (MVM) supplement. There were no differences between the PUFA groups with and without the MVM supplement. However, both of the PUFA groups showed significant improvements compared to placebo in core ADHD symptoms, as rated by parents on Conners' Rating Scales over 15 weeks.34 Cognitive assessments found significant improvements in the children's ability to switch and control their attention, and in their vocabulary. Importantly, the latter improvements mediated parent-reported improvements in inattention, hyperactivity, and impulsivity.66 The effect sizes of the UK and Australian studies are similar to those reported in a meta-analysis of stimulant medication trials.
Our group is currently following up on these studies by comparing EPA-rich and DHA-rich oils, each providing 1 g omega-3 PUFA per day, on ADHD symptoms and literacy in children with ADHD and learning difficulties; the aim is to identify whether this subgroup with learning difficulties may be more likely to respond to omega-3 supplementation. We are also measuring erythrocyte PUFA levels to gain further information regarding baseline levels, likely responders, and the relative importance of EPA and DHA versus sunflower oil (containing omega-6 PUFA).
Research to date indicates that nutrition and diet may have a role in the hyperactivity and concentration/attention problems associated with ADHD in children. In children with suboptimal levels of iron, zinc, and magnesium, there is some support for improvements being achieved with supplementation of these nutrients. There are also indications that supplementation with Pycnogenol might assist with symptoms. However, more well-controlled clinical trials are required. The strongest support so far is for omega-3 PUFA and behavioral reactions to food colorings. Research still needs to determine optimal levels of these nutrients for this group of children and markers of food sensitivity (currently requiring time-intensive dietary challenges) in order to inform clinical practice in the identification of potential deficiencies and/or behavioral food reactions. Suggestions that these children often react to inhaled environmental substances such as petrol fumes, perfumes, fly sprays, and felt pens, also require further investigation.86
There are clearly multiple influences on ADHD, including genetic and environmental (parental, social) factors. Whether these constitute different groups of children or whether there is a common underlying component to some or all of these remains to be determined. A recent study found lower omega-3 PUFA levels in 35 young adults with ADHD than in 112 controls, but levels of iron, zinc, magnesium, or vitamin B6 were not reduced.91 However, since zinc is required for the metabolism of other nutrients, zinc deficiencies may contribute to suboptimal levels of nutrients such as omega-3 PUFA. In addition, a genetic problem with enzyme production or absorption of nutrients may predispose children to nutrient deficiencies and/or excessive oxidation, thus contributing concurrently to food sensitivities. Adverse genetic, environmental, and nutritional conditions may exacerbate psychosocial factors (e.g., it is easier to parent a child with an easygoing, undemanding personality). In order to provide optimal treatment for these children, all of these possibilities need to be explored in multidisciplinary, multimodal, research models that take all potential factors into consideration.
Declaration of interest. NS is the current recipient of an Australian Research Council Fellowship, with contributions by Novasel Australia, for the 3-year project “Cognitive and behavioral benefits of omega-3 fatty acids across the lifespan”.
N Sinn, Nutritional Physiology Research Centre, School of Health Sciences, University of South Australia, GPO Box 2471, Adelaide, South Australia 5001, Australia. E-mail: email@example.com, Phone: +61 8 8302 1757, Fax: +61 8 8302 2178.
Complete article http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1753-4887.2008.00107.x/