The role of nutrition and diet in learning and behaviour of children with symptoms of attention deficit hyperactivity disorder

13 The role of nutrition and diet in learning and behaviour of children with symptoms of attention deficit hyperactivity disorder N. Sinn, University of South Australia, Australia and J. Rucklidge, University of Canterbury, New Zealand

Abstract: Symptoms of hyperactivity, impulsivity and inattention, associated with attention deficit hyperactivity disorder (ADHD), can constitute a chronic, often debilitating psychiatric condition. Despite abundant research, there is no clear consensus on causes and treatments. The most commonly prescribed treatment is stimulant medication; however, there are concerns regarding safety, tolerability and long-term use. We provide an overview of published evidence for nutritional and dietary approaches to addressing ADHD symptoms. Although more research is needed, there is support for a role of food sensitivities with varying support for some nutrients, particularly omega-3 fatty acids, and there may be promise for a multi-ingredient approach. Key words: learning, behaviour, ADHD, children, nutrition, diet, omega-3 fatty acids, additives.

13.1

Overview of attention deficit/hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is the most prevalent childhood disorder, estimated to affect 2–18% of children (Rowland et al., 2002) depending largely on diagnostic criteria used. Core symptoms associated with ADHD are developmentally inappropriate levels of hyperactivity, impulsivity and inattention, with an inattentive subtype (ADD) that does not include hyperactive behaviour. ADHD has a high co-morbidity rate with other mental health problems such as anxiety and mood disorders, including depression, suicidal ideation (Birleson et al., 2000; Root and

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Resnick, 2003) and bipolar disorder (Biederman et al., 1996) and is often particularly associated with anti-social problems such as conduct disorder and oppositional defiant disorder (Crowley et al., 1998; Colledge and Blair, 2001; Root and Resnick, 2003). It is now accepted that ADHD can be a chronic condition across the lifespan (Gittelman et al., 1985) and can lead to anti-social behaviour, substance abuse and borderline personality disorder in late adolescence and adulthood (Biederman, 1997, Ingram et al., 1999; Rey et al., 1995; Fossati et al., 2002). In addition, ADHD is associated with cognitive deficits; it has been estimated that a quarter of these children have a specific learning disability in maths, reading or spelling (Pliszka, 1998). Attention difficulties are associated with delays in general cognitive functioning, weak language skills and poor adjustment in the classroom (Warner-Rogers et al., 2000). The disruptive behaviour, poor self-discipline, distractibility and problems with response inhibition, self-regulation and emotional control that are associated with ADHD can impact adversely on 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. The aetiology of ADHD is complex and is associated with both genetic and environmental factors (Root and Resnick, 2003). Twin studies have provided strong evidence for a genetic component to the disorder which, in combination with other biological factors, is likely to underlie the neurological deficits that are exacerbated over time by environmental influences (Bradley and Golden, 2001). Psychophysiological research has identified neurological abnormalities, particularly in the frontal lobes, in children with ADHD compared with controls (Mann et al., 1992; Riccio et al., 1993). Similarly, a number of studies have identified reduced blood flow to the frontal lobes in children with ADHD (Bradley and Golden, 2001). This is consistent with hypotheses that symptoms of ADHD are related to abnormalities in frontal lobe systems that are thought to be regulated by neurotransmitters noradrenaline and dopamine (Biederman, 1997). The high co-morbidity of ADHD with a variety of other psychopathologies suggests that these mental health problems share similar underlying neurological mechanisms. This notion is supported by the fact that children with ADHD often have family histories of neurodevelopmental and psychiatric disorders (Richardson, 2003). Biological influences that have been associated with ADHD, via their impact on brain development and neurological functioning, include exposure to lead, mercury and pesticides and prenatal exposure to tobacco (Braun et al., 2006; Curtis and Patel, 2008).

13.1.1 Treatment Stimulant medications, such as methylphenidate (Ritalin®), pemoline (Cylert®) and dextroamphetamine (Dexedrine®), with or without cognitive-behavioural therapy, are the most common and most studied © Woodhead Publishing Limited, 2011

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treatments for childhood ADHD (MTA Cooperative Group, 1999; AntaiOtong, 2008). Response rates vary from 30 % to 70 % for these types of interventions (Adler et al., 2005; Antai-Otong, 2008). Additionally, many trials exclude patients with co-occurring disorders, so even less is known about medication treatment in these individuals. These limitations make it difficult to establish who would benefit from drug treatment given that trial participants are often quite different from those seen in the community. Side-effects associated with pharmacological treatments for ADHD can also be concerning, for instance cardiovascular risks associated with methylphenidate (Wilens et al., 2005; Antai-Otong, 2008) and suicide attempts (FDA warning on Strattera/atomoxetine). A recent long-term follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) study (MTA Cooperative Group, 2004), a 14-month randomised controlled trial (RCT), found that children in their pre-teens who had been medicated with methylphenidate had stunted growth (Swanson et al., 2007) as well as increased risk of juvenile delinquency and possibly substance abuse (Molina et al., 2007) compared with those who had been, and remained, unmedicated.

13.1.2 Alternative treatments Complementary and alternative methods (CAM) of treating ADHD are often sought by families wanting treatments with fewer side-effects or remedies they consider ‘safer’ than medication (Sinha and Efron, 2005). The term ‘alternative and complimentary’ is misleading given the essentiality of nutrients as building blocks of our bodies and brains, and indeed for life itself. It is important, however, for clinicians to ask patients and their families whether they are using any supplements, given that these can influence medication treatment. Bussing et al. (2002) found in a sample of 822 families that 12 % of children diagnosed with ADHD used CAM, and 7 % of parents who suspected ADHD in their child used them. Other studies confirm the high rate of CAM use with children and lack of disclosure to medical practitioners (Chan, 2002; Bussing et al., 2003). Stubberfield and colleagues (1999) found that 65 % of their sample of children with ADHD was using some form of alternative therapy. Although there are data showing that children are not receiving the recommended daily allowances of nutrients (Munoz et al., 1997), it appears that the negative trials on megavitamins (doses 100 times the recommended daily intake) in the 1970s that found that these doses were no better than a placebo (e.g., Arnold et al., 1978) may have resulted in a loss of scientific interest on multi-ingredient nutritional approaches for the treatment of ADHD given the dearth of studies performed over the next two decades. Although there is much research on medication, there has been very little on nutrient interventions. The lack of funds available for that type of study may also have contributed to the lack of research (Baime, 2002). The lack of scientific data makes treatment decisions difficult for families, who may © Woodhead Publishing Limited, 2011

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then resort to trial and error. What is more concerning, families often do not inform their medical practitioners of alternative treatments being used, placing children at unnecessary risk from potential interactions between conventional treatments and alternatives (Bussing et al., 2003; Sinha and Efron, 2005). While families are trying many alternative treatments for ADHD, including regulation of diet, biofeedback and massage, this review focuses specifically on nutrient and dietary approaches (see also Rucklidge et al., 20091; Sinn, 20082). Despite poor methodologies in some studies, we attempt to be inclusive given the overall dearth of studies conducted in the area. However, it is cautioned that cross-comparisons cannot be done given that doubleblind, randomised, placebo-controlled trials have a different methodological rigour compared with open-labelled trials. Therefore, following a brief overview of nutrition in brain development and function, this chapter will review the current state of evidence for the role of single nutrients, botanicals, multi-ingredient approaches and food intolerances in ADHD.

13.2 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 (Lecours et al., 2001). Effects of some nutrient deficiencies on development have become widely well-known and accepted; for instance perinatal deficiencies in iodine, now considered the world’s most preventable cause of mental retardation (Hetzel, 2000), folate (Lumley et al., 2001), related to spinabifida, and iron-related anaemia (Lozoff et al., 2006). Severe deficiencies in omega-3 polyunsaturated fatty acids (n-3 PUFA), particularly docosahexaenoic acid (DHA), can result in profound mental retardation associated with peroxisomal disorders (Martinez, 1996; Uauy et al., 1996). A long-term impact of famine on cognitive and behavioural development was demonstrated by a longitudinal follow-up of children who had been malnourished compared to a healthy comparison group from the same classroom after controlling for confounders such as socioeconomic status (Galler and Barrett, 2001) 1

Reproduced from Expert Rev. Neurother]apeutics 9(4), 461–476 (2009) with permission of Expert Reviews Ltd. 2 Reproduced from Nutr Rev 66(10), 558–568 (2008) with permission of International Life Sciences Institute (ILSI).

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Less extreme effects of sub-optimal nutrient levels on brain development and ongoing function are not as well recognised. Given the essentiality of an intricate interplay of macro- and micronutrients for optimal brain function, this could result in cognitive and behavioural 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, increasing by 50 % and 51 %, respectively, in response to cerebral activity (Haller, 2005). 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 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 (Haller, 2005) and n-3 PUFA (Sinn and Howe, 2008). Neurotransmitters such as serotonin and dopamine are also an integral component of the brain’s communication system; various nutrients are required for monoamine metabolic pathways and act as essential co-factors for the enzymes involved in neurotransmitter synthesis (Haller, 2005).

13.3 Nutrients and ADHD 13.3.1 Pyridoxine (vitamin B6) Pyridoxine is essential for neurotransmitter synthesis and normal brain development. Only one study has investigated its effect on hyperactivity, and apparently has not been replicated or extended. Coleman et al. (1979) conducted a small 21-week double-blind cross-over RCT comparing low/ high dose of pyridoxine (10 and 15 mg/kg) with low/high dose of methylphenidate with placebo in six hyperactive children: non-significant trends suggested that pyridoxine and methylphenidate were more effective than placebo in suppressing symptoms of hyperkinesis. Although the evidence does not support therapeutic benefit from pyridoxine supplementation alone, it has not been adequately tested.

13.3.2 Zinc As well as 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 co-factor 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 co-factor for δ6 desaturase, which in turn

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is involved in essential fatty acid conversion pathways (Arnold and DiSilvestro, 2005). A number of researchers have reported that zinc deficiencies can lead to cognitive impairment and slowed information processing (Toren et al., 1996; Yorbik et al., 2008). A comprehensive review on the role of zinc in brain function and in ADHD includes nine published studies around the world that report lower zinc levels in children with ADHD as well as correlations between lower zinc levels and severity of symptoms (Arnold and DiSilvestro, 2005). 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 metabolic wastage of zinc under chemical stress. Behavioural and emotional symptoms also deteriorated in hyperactive children in association with changes in zinc levels (Ward et al., 1990). Two clinical zinc supplementation trials have been conducted in children with ADHD and one trial investigated the effect more broadly on ADHD symptoms in a sample of low socioeconomic status (SES). All zinc trials have been conducted in the Middle East. One controlled study found significant improvements in hyperactivity, impulsivity and socialisation scores, but not inattention, after 12 weeks of supplementation with 150 mg zinc per day in children with ADHD compared with controls. It should be noted that this is a particularly high dose of zinc, and there was a high dropout rate in the study (52.9 % and 50.5 % in the zinc and placebo groups, respectively), although not significantly different between active and placebo groups (Bilici et al., 2004). Most of the dropouts were due to protocol violation and adverse events. The other study allocated 44 children who were diagnosed with ADHD to methylphenidate along with either 55 mg zinc sulfate or placebo over six weeks to investigate adjunctive benefits of zinc. Scores on parent and teacher rating scales improved in both groups, and these improvements were significantly greater in the zinc group (Akhondzadeh et al., 2004). The third double-blind RCT investigated the effect of 15 mg/day of elemental zinc syrup as compared with a placebo group receiving the syrup without the zinc (Uckardes et al., 2009). The trial was 10 weeks and the sample consisted of 252 third grade students (218 finished the trial) in a low SES primary school in Turkey. Based on Conners’ Parent and Teacher Rating Scales as measures of outcome, there were significant changes in both groups on parent-rated symptoms of inattention and hyperactivity; however, the prevalence of children with clinically significant scores for attention and hyperactivity only decreased significantly in the zinc-supplemented group. There were no changes in teacher ratings. Overall, the differences between the two groups were small to negligible.

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It is interesting to note that both zinc and free serum fatty acid levels were found to be lower in a group of 48 children with ADHD compared with 45 controls, and that these levels were strongly correlated in the ADHD group (Bekaroglu et al., 1996). In light of these studies and other nutritional deficiencies in ADHD, a RCT, described later, focused on n-3 PUFA and investigated additive benefits of a multivitamin/mineral (MVM) tablet in conjunction with the PUFA supplement (Sinn and Bryan, 2007). No additional benefits were found with the MVM supplement over and above the PUFA supplement; however, the supplement contained <2 mg zinc, which when compared to the above studies is likely to have provided inconclusive results regarding potentially additive benefits of zinc combined with PUFA. With only three studies investigating zinc supplementation for ADHD, definitive conclusions are not possible, although these initial results suggest more research is warranted. Low zinc could be an effect, a cause, or could simply co-occur with ADHD. For those considering zinc supplementation, it is important to note that excessively high doses can be harmful and that high doses can interfere with copper and iron absorption. For example, at 50–150 mg/day, zinc can cause gastrointestinal problems and headaches and doses of 300 mg/day can suppress immune function (Arnold et al., 2005).

13.3.3 Iron Anaemia is estimated to affect around a quarter of the world’s population and is most prevalent in preschool aged children (47 %; WHO, 2008). Around 50 % of cases are thought to be caused by iron deficiency; other contributors include blood loss, infections and deficiencies in other micronutrients such as vitamins A, B12, folate and riboflavin. Anaemia carries a profound 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 behaviour via its role as a co-factor for tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine synthesis (Black, 2003; Konofal et al., 2004). Iron levels were found to be twice as low in 53 non-anaemic children with ADHD compared to 27 controls with no other evidence of malnutrition; specifically, serum ferritin (a protein that stores iron and releases it in a controlled fashion) 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 (Konofal et al., 2004) as well as sleep disturbance (Cortese et al., 2009). A recent study also found low iron levels in 52

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non-anaemic children with ADHD, and these were correlated with hyperactivity scores on CPRS, although not with a range of cognitive assessments (Oner et al., 2008). It has been suggested that a role of iron in ADHD may be attributed to its neuroprotective effect against lead exposure (Konofal and Cortese, 2007). Iron deficiency is also associated with restless legs syndrome, which has a high co-morbidity with ADHD symptoms and therefore may account for a greater variance of symptoms in this sub-group of children (Konofal et al., 2007). Indeed, a recent study found that children with ADHD who suffered from restless legs had lower iron levels than those without restless legs (Oner et al., 2007). An early uncontrolled pilot study investigated effects of iron supplementation on ADHD symptoms in 14 non-anaemic 7–11 year-old boys. After 30 days of daily supplementation with 5 mg/kg ferrous-calcium citrate (active elemental iron, 0.05 mg/kg daily), blood samples showed increases in serum ferritin levels, and significant decreases were found on parent ratings of symptoms on Conners’ Rating Scales. However, these improvements were not correlated with increased iron levels and no significant improvements were found on teacher ratings. It was concluded that iron supplementation may not be effective in non-iron deficient children and that it should be investigated in iron-deficient children with ADHD (Sever et al., 1997). It is also possible that 30 days may not have been long enough to observe any effects. A case study report outlined effects of iron supplementation on a 3 year-old boy with diagnosed ADHD. This boy did have an iron deficiency and also displayed sleep problems: delayed sleep onset and excessive motility in sleep. Mild improvements in symptoms were reported by parents and teachers after four months of iron supplementation, and marked improvements were reported after eight months. He also showed enhanced quality of sleep (Konofal et al., 2005). These studies were followed up by a double-blind, placebo-controlled study with 23 non-anaemic, iron-deficient children (serum ferritin levels <30 ng/mL) aged 5–8 with ADHD. Following 12 weeks of supplementation with 80 mg ferrous sulfate per day or placebo, symptoms tended to improve in the treatment group on all ADHD scales and were significant on two outcome measures. Seventy-five per cent of children in the treatment group had diagnosed or possible restless leg syndrome and this improved in 12 out of those 14 children following iron supplementation. These improvements were not seen in the placebo group (n = 5) (Konofal et al., 2008). A minority of participants reported gastrointestinal symptoms such as abdominal pain. This study supports indications that children with low iron levels, and suffering both ADHD and restless legs, may be more likely to benefit from iron supplementation. It is not known, however, whether long-term supplementation could induce haemosiderosis, an iron overload disorder.

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13.3.4 Magnesium Sub-optimal magnesium (Mg) levels may impact on brain function via a number of mechanisms including reduced energy metabolism, synaptic nerve cell signalling and cerebral blood flow, and it has been suggested that its suppressive influence on the nervous system helps to regulate nervous and muscular excitability (Kozielec and Starobrat-Hermelin, 1997). 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. Mg levels also correlated highly with a quotient of freedom from distractibility (Kozielec and Starobrat-Hermelin, 1997). In 50 children aged 7–12 years with ADHD, Mg supplementation (200 mg/day) over six months resulted in significant reductions in hyperactivity and improved freedom from distractibility compared with both pre-test scores and a control group of 25 children with ADHD who were not treated with Mg (Starobrat-Hermelin and Kozielec, 1997). Another open study also found lower Mg levels in 30 out of 52 hyperactive children compared with controls, and improvements in symptoms of hyperexcitability following one to six months of supplementation with combined Mg/vitamin B6 (100 mg/day) (Mousain-Bosc et al., 2004). A similar study by the same researchers two 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 two months of Mg/ vitamin B6 supplementation for the 40 children with ADHD, hyperactive symptoms were reduced and school performance improved (Mousain-Bosc et al., 2006). A more recent study investigated the effect of supplementing ADHD children (6–11 years) with Mg–B6 (48 mg of magnesium lactate and 5 mg of pyridoxine HCl) for 30 days as compared with a group of children receiving a multivitamin for 30 days. It was unclear whether the control group had ADHD. Significant changes were noted in the Mg–B6 treated group in anxiety, inattention and hyperactivity and some neurological tests, but not in the control group (Nogovitsina and Levitina, 2007). This work indicates the need for more controlled studies in children with ADHD and magnesium deficiency, and elucidation of individual versus additive benefits of Mg and B6.

13.3.5

Amino acids

Phenylalanine Amino acid precursors have been the subject of clinical interest given that they form the building blocks of some neurotransmitters. For instance,

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phenylalanine is the initial precursor of dopamine. Over 20 years ago (Wood et al., 1985), adults with ADHD were randomised in a two-week doubleblind cross-over study of DL-phenylalanine (50–400 mg three times daily) versus placebo. In the 13 participants who completed the study, mood improved significantly; however, during a subsequent three-month openlabel extension, all improvements were lost. The authors reported that another open-label trial with L-phenylalanine produced no effect. L-tyrosine and tryptophan Tyrosine is an amino acid precursor for catecholamine synthesis and tryptophan is a precursor for indoleamine synthesis. We found two studies on L-tyrosine, both reported more than 20 years ago. Nemzer et al. (1986) conducted a double-blind study comparing L-tyrosine (140 mg/kg), tryptophan (100 mg/kg), dextroamphetamine (5/10 mg) and placebo in 14 ADHD children over a one-week period for each condition. Parent and teacher ratings and measures of attention were obtained at baseline and at the end of each condition. Tyrosine did not differ from placebo on any of the variables measured. However, tryptophan, while not significantly different from placebo on teachers’ ratings, was significantly better on parent ratings, suggesting it could be of benefit for those children with more home-based difficulties. Those on amphetamine improved on all measures compared with placebo. Reimherr et al. (1987) conducted an eight-week open-label trial of L-tyrosine (50–150 mg/kg) in 12 adults with ADHD residual type. Although eight of them showed an initial positive response (within two weeks) with marked to moderate changes, after six weeks they developed tolerance and the authors concluded that L-tyrosine was not effective in the treatment of ADHD. S-adenosyl-methionine (SAM-e) SAM-e is a methyl donor, and therefore plays an important role in many metabolic pathways through the process of methylation; e.g., it participates in the synthesis and catabolism of biogenic amines. Shekim et al. (1990) conducted a four-week open-label trial in eight adults with ADHD, using oral SAM-e titrated up to a maximum of 2400 mg per day. Reduced problems with concentration, restlessness, self-control and impulsivity were reported by 75 % of the participants. Although these researchers indicated that they were planning to conduct an RCT, we were unable to locate such a study. Carnitine Acetyl-L-carnitine is a small water soluble molecule that plays an important role in the metabolism of fatty acids and is biosynthesised from the amino acids lysine and methionine. It binds fatty acids (such as arachidonic acid (AA) and docosahexanoic acid (DHA)) to assist with mitochondrial oxidation, thereby generating metabolic energy, and it can also remove

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potentially toxic metabolic intermediates like carboxylic acids. It is suspected of influencing cholinergic and dopaminergic neurochemical pathways, both implicated in ADHD. Humans synthesise about a quarter of their carnitine and then obtain the rest from their diet (Abikoff et al., 2002). Several RCTs of carnitine have been reported in childhood ADHD. Van Oudheusden and Scholte (2002) used a randomised, double-blind, placebocontrolled double cross-over trial with 26 ADHD boys (22 of whom completed the trial). The active ingredient was a maximum of 4 g of carnitine. The trial consisted of three eight-week phases, balanced for order: either carnitine–placebo–carnitine or placebo–carnitine–placebo. Carnitine was well tolerated and associated with significantly better scores on both Conners’ Parent and Teacher Rating Scales. Despite the significant difference, only 54 % of those taking carnitine were considered ‘responders’ based on the Parent Scale and only 50 % based on the Teacher Scale (in contrast to 13 % and 17 % of those on placebo respectively). Overall, carnitine showed promise in this study for improving attention and reducing aggression in boys with ADHD. In contrast, Arnold and colleagues (2007) conducted a 16-week doubleblind multisite placebo-controlled trial with 112 children with ADHD using a soluble strawberry flavoured powder of acetyl-L-carnitine (ALC) in doses ranging from 500–1500 mg b.i.d (an amount up to 25 % less than the Van Oudheusden and Scholte study) or a matching placebo. Although no safety problems were identified, the main analyses revealed no group differences and, indeed, the mean changes on ADHD rating scales by both parents and teachers were small for both groups. In addition to administering lower doses of ALC, this study differed from the previous in that the ALC contained an additive (strawberry flavouring) that may exacerbate ADHD symptoms in some children. However, two interesting secondary findings were noted: superiority of ALC over placebo in those children with the inattentive subtype of ADHD, and an unexplainable geographical effect in that response to the active ingredient varied depending on location of the site. Finally, Torrioli et al. (2008), using a sample of 63 (51 completed) boys with both ADHD and fragile X syndrome, conducted a double-blind, parallel, multicentre comparison of ALC (20–50 mg/kg) with placebo. The children were not taking stimulants during the trial. Although the authors concluded that ALC improved hyperactivity over the one-year period, their reports of statistical analyses directly comparing the placebo and the active ingredient were inconsistently reported. The means on the hyperactivity symptom were lower after 12 months, but only for parent ratings, and it is unclear whether the change is clinically meaningful. Although more clinically significant changes were noted on measures of adaptive behaviour, the conclusions need to be cautiously interpreted. Further, the only data they provided on ADHD symptoms were a global measure of both hyperactivity

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and inattention and it is, therefore, impossible to assess which specific ADHD symptoms improved. In summary, the findings for carnitine are mixed, with two positive trials (but one with some methodological problems) and one negative trial using an ALC supplement containing an additive that may have contributed to the negative outcome. There has been an overall lack of adverse effects reported. Melatonin Although melatonin is not an amino acid, it is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin). It is a hormone produced naturally by the pinealocytes in the pineal gland. Melatonin is not used to directly affect ADHD symptoms, but rather has been used in the treatment of sleep problems common in this population (Cohen-Zion and Ancoli-Israel, 2004). Two randomized placebo-controlled trials have shown that melatonin, while it does not improve ADHD behaviours, does improve initial insomnia and advances circadian rhythms of sleep–wake as well as enhancing total time asleep (Weiss et al., 2006; Van der Heijden et al., 2007).

13.3.6 Polyunsaturated fatty acids (PUFAs) Sixty per cent of the dry weight of the brain is composed of fats, and the largest concentration of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA), docosahexaenoic acid (DHA) in the body is found in the retina, brain and nervous system (Salem et al., 2001). There is evidence that DHA is required for nerve cell myelination and is thus critical for neural transmission (Youdim et al., 2000). Importantly, DHA levels in neural membranes vary according to dietary PUFA intake (Yehuda et al., 2000; Youdim et al., 2000). DHA precursor eicosapentaenoic acid (EPA) is also thought to have important functions in the brain (Hibbeln et al., 2006), possibly via its role in synthesis of eicosanoids with anti-inflammatory, anti-thrombotic and vasodilatory properties. Animal studies have associated lower n-3 levels with lower levels of neurotransmitters dopamine and serotonin and some restoration of neurotransmitter levels with n-3 PUFA supplementation (Chalon et al., 2001; Chalon, 2006); one of their primary influences on mental health may also be via improved cerebral vascular function (Sinn and Howe, 2008). Researchers observed signs of fatty acid deficiency in hyperactive children in the 1980s (Colquhoun and Bunday, 1981), following which a number of studies reported lower n-3 PUFA levels in children with ADHD compared with controls (Mitchell et al., 1983, 1987; Stevens et al., 1995; Burgess et al., 2000; Chen et al., 2004). Randomised controlled trials have found equivocal results, which may be explained by variations in selection criteria, sample size, dosage and nature of the n-3 PUFA supplement and length of supplementation. An American study supplemented 6–12 year-old medi-

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cated boys with a ‘pure’ ADHD diagnosis (without co-morbidities) with 345 mg algae-derived DHA per day for 16 weeks and found no significant improvements on outcome measures (Voigt et al., 2001). However, the children were taking stimulant medication and closer inspection of parent ratings reveals that children’s t-scores (scores standardised by age and gender for comparability) were already in the normal range at baseline, which would have masked the detection of any changes following the DHA supplement. Another American study gave 50 children (43 completed) aged 6–13 with ADHD symptoms and skin and thirst problems 480 mg DHA and 80 mg EPA with 40 mg arachidonic acid (AA; n-6 PUFA) daily over 4 months. Significant improvements were only found on conduct problems rated by parents and attention problems rated by teachers – importantly, the latter improvements were correlated with increases in erythrocyte DHA levels (Stevens et al., 2003). A Japanese study using both DHA and EPA found no significant treatment effects of fish oil-enriched bread (supplying 3600 mg DHA and 700 g EPA per week) on symptoms of ADHD in a two-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 (Hirayama et al., 2004). 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, known to have high fish consumption, it is possible that they did not. It is also possible that two months may not have been a sufficient length of time for effects to become observable. Another pilot study in the UK supplemented 41 unmedicated children aged 8–12 with literacy problems (mainly dyslexia) and ADHD symptoms above the population average with 186 mg EPA and 480 mg DHA with 42 mg AA per day over 12 weeks and reported improvements in ADHD symptoms on Conners’ Rating Scales and literacy (Richardson and Puri, 2002). Since these small trials, two large randomised placebo-controlled, double-blind interventions have been published. The first was conducted in the UK with 117 unmedicated children aged 5–12 with Developmental Coordination Disorder; a third of these children had ADHD symptoms >90th percentile, placing them in the clinical range for a probable diagnosis. On average, these children were functioning a year behind their chronological age on reading and spelling. Following three months of daily supplementation with 552 mg EPA and 168 mg DHA with 60 mg gamma linolenic acid (GLA; n-6 PUFA) from evening primrose oil, children in the treatment group showed significant improvements in core ADHD symptoms 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 (Richardson and Montgomery, 2005). A review of the abovementioned studies was published following the latter trial (Richardson, 2006).

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The next study investigated treatment with the same supplement in 132 unmedicated Australian children aged 7–12 who all had parent-reported ADHD symptoms in the clinical range for a probable diagnosis. This study also investigated additive benefits of a MVM supplement. There were no differences between the PUFA groups with and without the MVM supplement. However, both PUFA groups showed significant improvements compared to placebo in core ADHD symptoms rated by parents on Conners’ Rating Scales over 15 weeks (Sinn and Bryan, 2007). Cognitive assessments found significant improvements in 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 (Sinn et al., 2008). The effect sizes of the UK and Australian studies are similar to those reported in a meta-analysis of stimulant medication trials (Schachter et al., 2001). A Swedish study then investigated the same supplement as the previous two studies in 8–18 year-olds with ADHD over three months (N = 75). They did not find improvements in the treatment group compared with placebo overall; however, when they investigated sub-groups according to comorbidities, those children with the inattentive subtype and co-morbid neurodevelopmental disorders, including learning difficulties, had more than 50 % reduction in symptoms (Johnson et al., 2009). A group in Israel published in the same year a RCT with 7–13 year-old unmedicated children with ADHD (Raz et al., 2009). They reported no treatment effects on parent and teacher questionnaires or a computerised continuous performance task. However, the PUFA supplement contained relatively small amounts of LA (480 mg) and ALA (120 mg), the latter of which is likely to have had minimal conversion to EPA and DHA, and they were only supplemented for seven weeks whereas indications are that at least eight and preferably a minimum of 12 weeks are required to show any improvements overall and with larger doses of long-chain n-3 PUFAs. Interestingly, they did report some improvements in both groups which could be a placebo effect although the placebo contained vitamin C and was therefore not a nonactive compound. These studies were followed up by a recently completed 12-month randomised controlled 3 × 3 cross-over trial that compared EPA-rich and DHA-rich oils (without evening primrose oil) versus a safflower oil placebo. The study focused on children with ADHD and learning difficulties and took erythrocyte (red blood cell) blood samples to try and gain a clearer picture of responders (Sinn et al., 2009; Milte et al., in press). At baseline, higher n-6 PUFA levels predicted poorer literacy (word reading, vocabulary and spelling) and attention, and higher DHA predicted improved word reading after controlling for co-variates (N = 75). When comparing children with learning difficulties (age-scaled literacy scores below age level) and without learning difficulties, DHA was lower in those with learning difficulties after controlling for differences in age and health. Preliminary four

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month parallel results did not find significant differences in outcome measures between groups. However, increased erythrocyte DHA levels were associated with improved parent-rated symptoms and literacy, particularly in the sub-group with learning difficulties. It should be noted that the studies outlined here were not all focusing primarily on children with ADHD (e.g. Durham trial included one third of children with ADHD symptoms). Therefore these findings, taken together with previous studies, indicate that children with learning difficulties as part of a constellation of symptoms associated with developmental disorders, with or without ADHD, may be more likely responders. They may be a different group or their symptoms may occur further along a continuum of developmental problems associated with poor attention. Children’s fish and n-3 PUFA intake is generally poor so parents are advised in any event to ensure that their children consume adequate levels. The International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends 500 mg per day (n-3 PUFAs DHA + EPA) and the safe upper limit for children and adults in Australia is recommended as 3 g per day. It may be that in some children with developmental disorders including ADHD and learning difficulties, low n-3 PUFA levels are contributing to their symptoms. Note that there have been concerns about methylmercury in fish. Well refined, concentrated fish oil preparations contain essentially no methyl mercury and very low levels of organochoride contaminants. For further information on safety of eating fish, refer to the section ‘safety of omega-3 fatty acids’ and references cited by Kris-Etherton and colleagues (2002).

13.4 Botanicals The use of plants as remedies for mental health concerns is not new. For centuries, native peoples around the globe have utilised plants and plant extracts to improve mood, facilitate concentration and alleviate stress (Rohdewald, 2002; Bussmann and Sharon, 2006). Today, the wisdom of traditional healing practices is beginning to be understood in light of scientific knowledge of how certain botanicals may aid in the treatment of health conditions.

13.4.1 Pinus pinaster bark extract (Pycnogenol®) Anti-oxidants are receiving growing interest for their potential to reduce oxidative stress in the brain, which may contribute to a variety of psychiatric disorders including autism and ADHD (Ng et al., 2008). Pycnogenol is the registered trademark for a potent antioxidant derived from maritime pine bark. It contains concentrated polyphenolic compounds, primarily procyanidins and phenolic acids (for a review of its pharmacology see

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Rohdewald, 2002). Pycnogenol may also increase nitric oxide production and has been reported to improve blood circulation (Fitzpatrick et al., 1998; Nishioka et al., 2007). Therefore it may assist with cerebral blood flow which is also thought to be impaired in ADHD (Bradley and Golden, 2001). Several anecdotal reports indicate successful treatment of ADHD symptoms with Pycnogenol (Greenblatt, 1999; Heimann, 1999). In one case report, parents gave Pycnogenol to their 10 year-old boy with ADHD following unsuccessful response to stimulant medication. They noted significant improvements in target symptoms over two weeks. When they agreed to try him on stimulant medication without the Pycnogenol again, he reportedly became significantly more hyperactive and impulsive and received numerous demerits at school. When Pycnogenol supplementation was reinstated, he again improved within three weeks (Tenenbaum et al., 2002). Only two controlled studies have been conducted. One compared Pycnogenol with methylphenidate and placebo in a three-way cross-over trial with 24 adults aged 24–50 who met the criteria for ADHD. They were all given 1 mg/lb body weight Pycnogenol per day, methylphenidate (increased gradually from 10 mg to 45 mg per day) and placebo for three weeks, each separated by a one week washout. No significant improvements were observed in the methylphenidate or the Pycnogenol groups compared with placebo. It is possible that there wasn’t a treatment effect in this group or alternatively that three weeks was not long enough and/or the sample was too heterogeneous and the sample size too small (Tenenbaum et al., 2002). In the other study, 61 children aged 9–14 with ADHD symptoms [diagnosed as Hyperkinetic Disorder (n = 44), Hyperkinetic Conduct Disorder (n = 11) or ADD (n = 6)] were randomly allocated to receive 1 mg/kg body weight of Pycnogenol or placebo daily for one month and assessed again following an additional month of treatment washout. Significant improvements were observed in the treatment groups after one month on teacher ratings of hyperactivity and inattention, parent ratings of hyperactivity and visual–motoric coordination and concentration. Symptoms tended to relapse following the one month washout (Trebatická et al., 2006). Importantly, biomarkers of oxidative damage decreased in the treatment group compared with placebo, and this was associated with improvement in symptoms (Chovanová et al., 2006; Dvorˇáková et al., 2006, 2007). No significant side-effects have been reported. Further controlled studies are clearly warranted to investigate effects of Pycnogenol /anti-oxidants on ADHD symptoms in children. Note that many fruits, vegetables and nuts/legumes (lacking in many children’s diets) contain a wide variety of anti-oxidants, particularly small red beans, blueberries, red kidney beans, pinto beans, cranberries, artichoke hearts, prunes, raspberries, strawberries, apples, cherries, black plums and pecan nuts (Wu et al., 2004).

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13.4.2 Panax quinquefolium (American ginseng) and Ginkgo biloba Both of these extracts have been shown to increase cerebral dopaminergic activity in animal studies (Itoh et al., 1989; Ramassamy et al., 1992), an area of suspected deficit in people with ADHD (Barkley, 1997). In a four-week open study, 36 children with ADHD were given a product containing ginseng (200 mg) and Ginkgo biloba (50 mg) extracts twice daily (Lyon et al., 2001). Children on medication such as stimulants were included (n = 25) if symptoms of ADHD were poorly controlled in spite of the medication. Five participants reported adverse events during the course of the study but completed anyway. In two cases, the adversity experienced was attributed to the treatment itself: greater emotionality and impulsivity in one and increased hyperactive behaviour in another, though both of these participants reported symptom improvement in other areas. Improvement was defined as a change in individual symptom or global scores of at least five points in the direction of normal range, based on age and gender. To a varying degree (31–47%), improvement was reported in all seven ADHD indices measured at weeks two and four on the Revised Connors Parent Rating Scale (CPRS-R) (L) (Lyon et al., 2001). There are a few limitations to these findings, including: a number of the children who improved were taking stimulant medication as well, so any potential benefit of the botanical supplement must be considered with this in mind, and 3–15 % of the children had a negative outcome, as measured by an increase in T-score on aspects of the CPRS-R (L) by five points (half a standard deviation). Finally, the findings are limited by the uncontrolled nature of an open trial of such short duration. Salehi and colleagues (2010) conducted a double-blind randomised parallel group comparison of Ginkgo biloba (80–120 mg) and methylphenidate (20–30 mg) over a 6 week period. Participants were 50 outpatients with ADHD (6 to 14 years) and outcome measures included the Parent and Teacher ADHD Rating Scales. Although fewer side effects were noted in the Ginkgo biloba group and both groups improved significantly, the group treated with methylphenidate benefited significantly more from the treatment than the Ginkgo biloba treated group. Approximately a third of the Ginkgo biloba group benefited from the treatment compared with 88 % of those in the methylphenidate group. This trial indicates limited benefit of Ginkgo biloba as a treatment for ADHD.

13.4.3 Hypericum perforatum (St John’s wort) One RCT using Hypericum perforatum or St John’s wort for ADHD was found (Weber et al., 2008). St John’s wort has been noted to increase the levels of serotonin, dopamine and noradrenaline in the brain (Muller et al., 1997; Neary and Bu, 1999). Deficiencies in these neurotransmitters, particularly dopamine and noradrenaline, have been implicated in ADHD

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symptoms such as inattention and impulsivity (Kratochvil et al., 2002). Based on this knowledge, a noradrenaline reuptake inhibitor, atomoxetine, has been developed and approved for ADHD treatment in the US (Kratochvil et al., 2002). In an eight-week RCT, 54 children with ADHD were randomised to 300 mg St John’s wort extract standardised to 0.3 % hypericin or a placebo three times daily. Participants were included if scores were >1.5 SDs above age and gender norms on the ADHD Rating Scale-IV and were free of other ADHD medications during the trial. Concurrent use of multivitamins and essential fatty acids was allowed as long as the treatment had been consistent for the previous three months and was expected to remain at the same levels. One participant in the placebo group dropped out due to an adverse event. No significant difference was found in either of the two measures used: the ADHD Rating Scale-IV or the Clinical Global Impression Improvement Scale, indicating that St John’s wort did not improve ADHD symptoms in this study.

13.4.4 Passiflora incarnata Passiflora incarnata is a herb that has been used for the relief of mild symptoms of mental stress and to aid sleep. One study has investigated its use in the treatment of ADHD. In a randomised, double-blind study in 34 children with ADHD (6 and 13 years of age), the efficacy of passion flower tablets was compared with methylphenidate (Akhondzadeh et al., 2005). Seventeen children were treated with passion flower tablets (0.04 mg/kg/ day) for eight weeks. A control group of 17 children received methylphenidate (1 mg/kg/day). Outcome measures included the Parent and Teacher ADHD Rating Scales. Both groups improved significantly over the eightweek trial compared to baseline; there was no statistically significant difference in treatment result between the two groups. Given the small sample size and the lack of a placebo group, these results need to be viewed as preliminary.

13.5 Multi-ingredient formulations Research with multi-ingredient formulae in the treatment of ADHD is relatively rare, despite positive findings for combination therapies in other fields of research such as in the treatment of cognitive deficits, anti-social and disruptive behaviours (Benton, 1992; Schoenthaler and Bier, 2000; Gesch et al., 2002). This may in part be due to earlier studies which found that vitamins, given in ‘mega’ doses (100 times the recommended daily intake) were not effective in the treatment of ADHD (Arnold et al., 1978; Haslam et al., 1984). It has since been suggested that these doses could have

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been toxic, and/or the trials were too short and that the number of trials was too few to draw any specific conclusions about the efficacy of multinutritional approaches in the treatment of ADHD. However, due to these preliminary negative studies, interest in this line of research waned, as demonstrated by the small number of studies published over the following two decades. A number of studies were reported in the individual supplementation section of this review, which added ingredients to the treatment approach initially studied. It is important to consider these in our overall interpretation of the studies and, more generally, in our appreciation of the multinutritional approach to the treatment of ADHD. For example, one of the first reports on PUFA supplementation (Colquhoun and Bunday, 1981) used a combination of ingredients for at least one of their participants (PUFA with zinc, vitamin C, pyridoxine and niacin). Sinn and Bryan (2007) had a third arm in their study on PUFAs which consisted of a multivitamin/ mineral tablet plus fatty acids but found no additive benefit over the PUFAonly arm; however, they acknowledged that the dose may have been too low to reach any conclusions about specific ingredients in the tablet. The majority of studies with PUFA used an oil with added vitamin E to prevent oxidation, although potential antioxidant benefits cannot be discounted; gingko and ginseng were used in combination in Lyon et al.’s open-label trial (2001). A recent trial followed 40 children with clinical symptoms of ADHD over an eight week period during which time they received 6 mg/kg magnesium plus 0.6 mg/kg vitamin B6 (Mousain-Bosc et al., 2006). They were compared to 36 control children not receiving supplementation. Intraerythrocyte magnesium (Erc–Mg) and blood ionised calcium were measured, as well as behaviour. During the supplementation, symptoms of hyperactivity and aggressiveness were significantly reduced and school attention improved. The therapy was then stopped and clinical symptoms returned together with a decrease in Erc–Mg values. Although this ABA (on–off–on) study highlights the therapeutic effect of Mg–B6 supplementation, it was done in children who had low intraerythrocyte Mg values and therefore may not generalise to a larger ADHD population. Further, the children were young (mean age of the sample was 6 years) and the impact of other co-occurring behaviours was not considered. Another three-month open-label trial which combined 200 mg flax oil and an anti-oxidant (25 mg vitamin C twice daily), studied 30 unmedicated children with ADHD and 30 normal controls (Joshi et al., 2006). The controls did not receive any treatment but served as a comparison group for blood work. Fasting venous blood showed that pre-supplementation, children with ADHD had significantly lower red blood cell membrane lipid levels compared with the controls. At post-supplementation, there was a significant increase in n-3 PUFAs EPA and DHA and a decrease in AA (n-6 PUFA) in the children with ADHD. Scores on a parent-rated measure

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of ADHD behaviours showed a significant drop in inattention, impulsivity, hyperactivity, restlessness and self-control. Kaplan and colleagues (2004) conducted an open-label trial with children with a variety of psychiatric disorders, including ADHD, bipolar disorder, anxiety, oppositional behaviours and Asperger’s disorder. Six of the 11 children in the trial had ADHD although one of these dropped out. After 16 weeks of taking a micronutrient supplement (distributed under the name of EMPowerplus3), consisting mainly of minerals, vitamins and amino acids, some of which are given at levels higher than RDA, the children were rated as significantly improved in attention, anxiety, aggression, delinquency and mood. Few adverse effects were reported and those that did occur were mild for all except two who were concurrently taking psychiatric medications. Indeed, Popper (2001) has warned against taking such supplements concurrently with medications due to the hypothesised potentiating effect these combination formulas can have on the medication. The latter trial is limited by observer and placebo/expectancy effects. Pilot data on an open-label trial using EMPowerplus with 14 adults with ADHD and mood instability showed significant improvement in all ADHD symptoms (although problems with inattention were less well controlled than hyperactivity and impulsivity) as well as stabilisation of mood for all patients in the trial (Rucklidge et al., 2011). For those who stayed on the supplement, the changes were sustained and further improved at four months whereas for those who came off it, regression in symptoms typically occurred. Effects were larger than what would be expected for a placebo effect. A case study has shown that these improvements can be sustained to at least a year and that stopping the formula resulted in a return in symptoms (Rucklidge and Harrison, 2010). Side-effects have been mild (gastrointestinal upset or headaches) and transient. More trials, including an RCT, are currently underway with individuals with ADHD to better evaluate the effect this multi-ingredient supplementation approach has on symptoms of ADHD. Harding and colleagues (2003) compared methylphenidate with dietary supplements in the treatment of ADHD symptoms in 20 children over a four-week period. Co-occurring diagnoses and use of other medications served as exclusion criteria. The dietary supplement consisted of many nutrients (taurine, glutathione, α-lipoic acid, garlic extract, glycine, five amino acids, 13 minerals), presumed gastrointestinal and immune support (lactobacillus acidophilus and bifidus, lactoferrin, silymarin), PUFAs and phospholipids, iodine and tyrosine, all the B vitamins and some phytonutrients. Their rationale for such a broad-based approach was that they were attempting to address all the nutritional deficits associated with ADHD. 3

EMPowerplus is distributed by Truehope Nutritional Support. It consists of 36 ingredients: 14 vitamins, 16 minerals, 3 amino acids and 3 antioxidants. A list of the ingredients and their doses can be found on the company’s website, Truehope.com.

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With 10 children per group (based on parental choice), both groups showed significant improvement on neurocognitive tests that measure auditory response control, auditory attention, visual attention and visual response control. The nutrient group did as well as the methylphenidate group. Although there were no measures of behavioural change in ADHD symptoms, this study adds to indications that a dietary approach may be preferable to medication as it does not incur side-effects and indeed may be, at least to some extent, rectifying an underlying problem. Patel et al. (2007) reported an open-label pilot observational study with an even more comprehensive approach. Ten children with both autism and ADHD were treated for three to six months with vitamins (A, B-complex), seven minerals, coenzyme Q10, amino acids and peptides, some PUFAs, milk thistle, α-lipoic acid, digestive enzymes and probiotic bacteria. In addition, the parents of these children received instructions on controlling environmental factors (i.e., mites, exposure to pesticides, toxins, cleaners), an organic diet, gastrointestinal support, antigen injection therapy (to address dust mite allergens, moulds, foods and chemicals), chelation therapy and injection one to three times per week with glutathione and methylcobalamin (vitamin B12). They also continued their usual therapies (e.g., speech, occupational therapy). Although significant changes were observed in urinary lead levels, no other heavy metals were significantly different from baseline (although near significant drops (p < 0.1) were noted in cadmium and mercury). The researchers reported that on parental questionnaires, there was an ‘average’ improvement in concentration and attentional problems (range 40–100 % improvement) and an ‘average’ decrease of hyperactivity-related problems (range 0–95 % improvement); however, they did not report the actual tests used to measure behaviour change, how they defined improvement or any statistical tests. Based on the extensive and varied therapies the children received (ranging from psychosocial to supplementation), it is impossible to evaluate the specific effect of the nutritional supplements on behaviour change. Further, the ecological validity of the programme would make it very difficult to replicate. These types of studies raise the possibility that a multimodal treatment can most effectively address all the symptoms associated with this heterogeneous disorder, but the current research has many methodological limitations and requires more extensive investigation. Most scientific methodology alters a single variable at a time, so it is worth briefly considering the justification for multi-nutrient supplementation. Every neurotransmitter goes through many metabolic steps to ensure its synthesis, uptake and breakdown. Every one of those steps requires enzymes, and every enzyme is dependent upon multiple co-enzymes (co-factors). A variety of vitamins and minerals are required as co-factors in most if not all of those steps. Consequently, as discussed elsewhere (Ames et al., 2002; Kaplan et al., 2007), one possible mechanism underlying psychiatric symptoms is inborn metabolic dysfunction associated with

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slowed metabolic activity due to sub-optimal availability of vitamin and mineral co-factors (Ames et al., 2002). Impaired brain metabolic activity associated with other disorders has already been shown to be correctable through nutrient supplementation (Ames et al., 2002). One can thus envision multi-nutrient supplementation as providing sufficient cofactor that even enzymes with drastically reduced activity become so supersaturated that near-normal function is restored (Ames et al., 2002). Other mechanisms have been hypothesised as explanations for the effect of nutrients on brain function, such as improved energy metabolism (Arnold et al., 2007).

13.6 Food intolerance In addition to nutritional influences, there is evidence that many children with ADHD react to certain foods and/or food additives. Suggestions of links between diet and behaviour go back to the 1920s; they became wellknown in the 1970s with the Feingold diet which focused on eliminating naturally occurring salicylates, artificial food colours, artificial flavours and the preservative butylated hydroxytoluene (BHT) (Feingold, 1975). Behavioural reactions to food substances are associated with pharmacological rather than allergic mechanisms, although it is possible that these reactions co-exist (Swaine et al., 1985). Underlying mechanisms for behavioural food reactions are not entirely clear. Increased motor activity was identified in neonatal rats following red food colour ingestion (Shaywitz et al., 1979); other early animal studies linked reactions to the nervous system, e.g. similar hyperactive response was identified to dopamine depletion as well as administration of sulfanilic acid, an azo food dye metabolite, in developing rats (Goldenring et al., 1982); dose-dependent increase in red food colour may increase the release of acetylcholine into neuromuscular synapses; and colours may affect uptake of neurotransmitters (Kaplita and Triggle, 1982). In support of animal studies, EEG readings were reported to normalise in nearly 50 % of children (N = 20) with behaviour disorders after starting an elimination diet (Kittler and Baldwin, 1970). Behavioural food reactions may be attributable to the presence of metals, including lead, mercury and arsenic, in food colourings (FDA, 2007). Feingold reported that more than half of children who adhered to his elimination diet responded favourably, and that many children’s symptoms reached the normal range of behaviour. It has since been discovered, however, that many of the foods in his diet contained salicylates, and that many of these children also react to other food components such as food colouring (Swaine et al., 1985). The complexities of dietary intervention, most notably the large variety of potentially suspect food substances and individual differences in the nature and dosage of the food intolerance,

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resulted in inconsistencies in subsequent research trials. Many of these studies also had interpretational issues (Weiss, 1982) and methodological limitations involving the formulation of the intervention diet and the placebo diet and washout periods between them. A discussion of these complexities and subsequent research is provided by Breakey et al. (2002). Dietary intervention for ADHD and inconsistent findings have generated a great deal of controversy and titles such as ‘Diet and child behaviour problems: fact or fiction?’ (Cormier, 2007). However, despite methodological difficulties of measuring dietary complexities and individual variation, a recent review cited eight controlled studies that found either significant improvement following a ‘few-food’ (oligoantigenic) diet compared with placebo or worsening of symptoms in placebo-controlled challenges of offending substances following an open challenge to identify the substance (Arnold, 1999). A subsequent meta-analysis confirmed a consistently significant effect of oligoantigenic diets on hyperactivity and related symptoms (Benton, 2007). This paper also notes that food intolerances do not appear to be unique or consistent; i.e. there are individual variations to offending foods and children who react to food substances typically react to more than one item. The most common ones that are noted are dairy products, wheat and chocolate. A meta-analysis of 15 double-blind placebo-controlled trials focusing specifically on artificial food colours found that these food additives promoted hyperactive behaviour in hyperactive children (Schab and Trinh, 2004). Following this meta-analysis, a randomised, double-blinded, placebocontrolled cross-over challenge trial with 153 children aged 3 years and 144 children aged 8/9 years from a general population of British children reported significant effects of artificial colours and sodium benzoate preservative on hyperactive behaviour (McCann et al., 2007). It might be noted that the food colourings and preservative (or placebo) were delivered in fruit juice containing salicylates, which could have confounded effects for the more hyperactive children at risk for salicylate sensitivity. It is notable that this study demonstrated hyperactive effects of food colourings on healthy children from a general population, therefore expanding effects of food colourings beyond children with sensitivities. Finally, there has been a great deal of interest in the role of sugar in hyperactive behaviour, largely through anecdotal observations by parents. For information on research in this area refer to Benton (2007).

13.7 Conclusions Research to date indicates a role for nutritional and dietary influences on hyperactivity and concentration/attention problems associated with ADHD in children. There is some support for sub-optimal iron, zinc and

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magnesium levels and improvements with supplementation in children with low levels of these nutrients. There are also indications that supplementation with antioxidant Pycnogenol might assist with symptoms. However, more well-controlled clinical trials are required. The strongest support so far is for contributing influences of n-3 PUFA, behavioural reactions to food colourings and individual reactions to a variety of food substances. 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 behavioural food reactions. There are also suggestions that these children often react to inhaled environmental substances such as petrol fumes, perfumes, fly sprays and felt pens, which requires investigation (Breakey et al., 2002). The multiingredient approaches require more rigorous studies in order to better assess the impact of a broader supplementation approach to the symptoms of ADHD. There are clearly multiple influences on ADHD, including genetic, environmental and psychosocial factors, and it is unlikely that children with symptoms associated with ADHD represent a homogeneous population although there may be a similar underlying biological component that predisposes children to nutritional deficiency or reaction to environmental substances. It is of note that a longitudinal study of children who suffered moderate to severe malnutrition during their first year of life had 60 % frequency of ADHD compared with 15 % in healthy controls from the same classrooms, and these were not accounted for by differences in socioeconomic factors (Galler and Barrett, 2001). It is also possible that a genetic problem with enzyme production or absorption of nutrients may predispose children to nutrient deficiencies and/or excessive oxidation and contribute concurrently to food sensitivities; these may all exacerbate psychosocial factors (e.g., it is easier to parent a child with an easy-going, undemanding personality). These possibilities need to be explored in multidisciplinary, multimodal research models that take all potential factors into consideration in order to provide optimal treatment for these children.

13.8 Implications for the food industry, nutritionists and policy-makers Converging evidence indicates that a healthy diet with adequate nutrient intake is important not only for children’s physical health and development but also brain development and function – and therefore children’s learning and behaviour. There is also evidence now that some children have neurological reactions to certain foods and food additives. Although more research needs to be invested in this critical area of children’s health and

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development, increasing awareness by parents of dietary influences on their children’s mental health, along with adverse effects of prescription medications that do not address underlying causes, implies that expectations from the food industry for safe, healthy, nutritious food are likely to grow. To respond to this demand and to pursue responsible, ethical practices, the food industry would be well-advised to invest in production and marketing of nutritious food free of artificial colourings and additives for children. Production and marketing of whole foods – including most importantly vegetables, fruit, nuts and oily fish – to children and supporting government policies for media, food manufacturers and schools would assist in promoting increased consumption of essential nutrients outlined herein. It is possible that some children have higher requirements for some nutrients, e.g. n-3 PUFAs, which also has implications for food and supplement manufacturers, although this remains to be established. As a society we are all responsible for investing in our future human capital – our children – and therefore need to take a responsible, multifaceted approach to supporting them in optimal growth and development.

13.9 Future trends Although many RCTs on nutritional supplementation have been conducted, far more studies are open-label trials which makes it more difficult to comment on the efficacy of many of the individual supplements being studied. Given the lack of controls generally in this field, products do not have to be rigorously tested, and therefore consumers must be sophisticated when considering these treatments in order to make informed decisions based on variable data. One should be sceptical of a treatment if manufacturers claim the product works for everyone with ADHD or other health problems, uses only case histories or testimonials as proof or cites only studies with no control (comparison) groups. While testing a treatment without a control group is a necessary first step in investigating a new treatment, subsequent studies with appropriate control groups are needed to clearly establish effectiveness and to ensure that any effect found using an open-label method is not simply a result of the powerful placebo effect. Many of the studies meet this first criterion, but far fewer, the second. Mainstream medicine has accepted the notion that pharmaceuticals are the preferred approach to the treatment of ADHD. This review reveals that there is potential benefit from nutritional approaches, but much more research is required. One major issue here is the lack of research funding for effects of nutrition on behaviour compared to the extensive funds provided for pharmaceutical trials. An interesting theme that has emerged is the focus taken by many researchers in studying individual nutrients (with varying success) rather than a broad-spectrum approach investigating

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multi-ingredient formulae. Given that physiological function is best optimised by having all systems in balance, with different vitamin and mineral levels affecting the absorption and effectiveness of each other, one needs to question the efficacy of ingredients that are studied individually. Perhaps the single ingredient approach, although easier to test scientifically, is too narrow. Given the heterogeneous nature of ADHD, it is unlikely that a single universal treatment will be effective. As scientists become better at identifying subtypes of this disorder (Nigg, 2005), identification of treatments specific to ADHD subtypes may become more viable. The success of a treatment is influenced by several factors including an individual’s expectations and response, the side-effects experienced, a person’s preconceived ideas and the burden placed on the patient by the treatment. For these reasons, the availability of a variety of empirically-supported treatment options will be beneficial to patients and their families in the long term.

13.10 Sources of further information and advice A reference list for research referred to in this chapter is provided below. There are many books and online resources which need to be accessed with some discretion; some are listed below – we hope these are helpful however please note that the authors and editor take no responsibility for their content: • Food and Behaviour (FAB) Research: www.fabresearch.org. • They are what you feed them: how food affects your child’s behaviour, mood and learning by Dr Alexandra Richardson (Harper Thorsons, 2010). • Twelve effective ways to help your ADD/ADHD child: drug-free alternatives for attention-deficit disorders by Laura J Stevens (Avery, 2009). • Online ADD/ADHD Newsletter (Laura Stevens): www.youradhdnewsletter.com • Nutrition and ADHD: Omega-3 fatty acids, micronutrients and attention deficit hyperactivity disorder by Natalie Sinn, Janet Bryan and Carlene Wilson (VDM Verlag Dr Müller, 2009). • Feingold Association of the United States website provides a resource for scientific studies on food intolerance: http://www.feingold.org/ research.php. • The Royal Prince Alfred Hospital Allergy Unit also provides information on research into food intolerances and behaviour: http://www. sswahs.nsw.gov.au/rpa/allergy/. • Doris Rapp MD provides an extensive resource for information on children’s allergies to food and environment: www.drrapp.com.

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13.11 References abeywardena m y and head r j (2001) Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovascular Research, 52, 361–371. abikoff h b, jensen p s, arnold l l e, hoza b, hechtman l, pollack s, martin d, alvir j, march j s, hinshaw s, vitiello b, newcorn j, greiner a, cantwell d p, conners c k, elliot g, greenhill l l, kraemer h, pelham w e, jr, severe j b, swanson j m, wells k and wigal t (2002) Observed classroom behavior of children with ADHD: relationship to gender and comorbidity. Journal of Abnormal Child Psychology, 30, 349–359. adler l a, spencer t j, milton d r, moore r j and michelson d (2005) Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attentiondeficit/hyperactivity disorder: an interim analysis. Journal of Clinical Psychiatry, 66, 294–299. akhondzadeh s, mohammadi m-r and khademi m (2004) Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. BMC Psychiatry, 4, available at: http://www.biomedcentral.com/1471-244X/4/9 (accessed February 2011). akhondzadeh s, mohammadi m and momeni f (2005) Passiflora incarnata in the treatment of attention-deficit hyperactivity disorder in children and adolescents. Therapy, 2, 609–614. ames b n, elson-schwab i and silver e (2002) High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. American Journal of Clinical Nutrition, 75, 616–658. antai-otong d (2008) The art of prescribing: pharmacological management of adult ADHD: implications for psychiatric care. Perspectives in Psychiatric Care, 44, 196–201. arnold l e (1999) Treatment alternatives for attention-deficit/hyperactivity disorder (ADHD). Journal of Attention Disorders, 3, 30–48. arnold l e and disilvestro r a (2005) Zinc in attention-deficit/hyperactivity disorder. Journal of Child & Adolescent Psychopharmacology, 15, 619–627. arnold l e, christopher j, huestis r d and smeltzer d j (1978) Megavitamins for minimal brain dysfunction: a placebo-controlled study. JAMA: Journal of the American Medical Association, 240, 2642–2643. arnold e m, goldston d b, walsh a k, reboussin b a, daniel s s, hickman e and al e (2005) Severity of emotional and behavioral problems among poor and typical readers. Journal of Abnormal Child Psychology, 33, 205–217. arnold l e, amato a, bozzolo h, hollway j, cook a, ramadan y, crowl l, zhang d, thompson s, testa g, kliewer v, wigal t, mcburnett k and manos m (2007) Acetyll-carnitine in attention-deficit/hyperactivity disorder: a multi-site, placebocontrolled pilot trial. Journal of Child and Adolescent Psychopharmacology, 17, 791–801. baime m j (2002) Review: St. John’s wort, ginkgo, saw palmetto, and kava may be effective for some conditions. ACP Journal Club, 137, 25. barkley r a (1997) Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychological Bulletin, 121, 65– 94. bekaroglu m, aslan y, gedik y, deger o, mocan h, erduran e and karahan c (1996) Relationships between serum free fatty acids and zinc, and attention deficit hyperactivity disorder: a research note. Journal of Child Psychology and Psychiatry, 37, 225–227. benton d (1992) Vitamin-mineral supplements and intelligence. Proceedings of the Nutrition Society, 51, 295–302.

© Woodhead Publishing Limited, 2011

350

Lifetime nutritional influences on behaviour and psychiatric illness

benton d (2007) The impact of diet on anti-social, violent and criminal behaviour. Neuroscience and Biobehavioural Reviews, 31, 752–774. biederman j (1997) ADHD across the lifecycle. Biological Psychiatry, 42, 146S. biederman j, faraone s, mick e, wozniak j, chen l, ouellette c, marrs a, moore p, garcia j, mennin d and lelon e (1996) Attention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity? Journal of the American Academy of Child and Adolescent Psychiatry, 35, 997–1008. bilici m, yildirim f, kandil s, bekarog lu m, yildirmis s, deger o, ülgen m, yildiran a and aksu h (2004) Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 28, 181–190. birleson p, sawyer m and storm v (2000) The mental health of young people in Australia: child and adolescent component of the national survey – a commentary. Australasian Psychiatry, 8, 358–362. black m m (2003) Micronutrient deficiencies and cognitive functioning. Journal of Nutrition, 133, 3927S–3931S. bradley j d d and golden c j (2001) Biological contributions to the presentation and understanding of attention-deficit/hyperactivity disorder: a review. Clinical Psychology Review, 21, 907–929. braun j m, kahn r s, froelich t, auinger p and lanphear b p (2006) Exposures to environmental toxicants and attention deficit hyperactivity disorder in US children. Environmental Health Perspectives, 114, 1094–1909. breakey j, reilly c and connell h (2002) The role of food additives and chemicals in behavioral, learning, activity, and sleep problems in children, in Branen A L, Davidson P M, Salminen S and Thorngate III J H (eds) Food Additives (2nd edn). New York: Marcel Dekker, 96–110. burgess j r, stevens l j, zhang w and peck l (2000) Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. American Journal of Clinical Nutrition, 71, 327–330. bussing r, zima b t, gary f a and garvan c w (2002) Use of complementary and alternative medicine for symptoms of attention-deficit hyperactivity disorder. Psychiatric Services, 53, 1096–1102. bussing r, zima b t, gary f a and garvan c w (2003) Barriers to detection, helpseeking, and service use for children with ADHD symptoms. Journal of Behavioral Health Services & Research, 30, 176–189. bussmann r w and sharon d (2006) Traditional medicinal plant use in Northern Peru: tracking two thousand years of healing culture. Journal of Ethnobiology and Ethnomedicine, 2, 47. chalon s (2006) Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins, Leukotrienes and Essential Fatty Acids, 75, 259–269. chalon s, vancassel s, zimmer l, guilloteau d and durand g (2001) Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission. Lipids, 36, 937–944. chan e (2002) The role of complementary and alternative medicine in attentiondeficit hyperactivity disorder. Journal of Developmental & Behavioral Pediatrics, 23, S37–S45. chen j-r, hsu s-f, hsu c-d, hwang l-h and yang s-c (2004) Dietary patterns and blood fatty acid composition in children with attention-deficit hyperactivity disorder in Taiwan. Journal of Nutritional Biochemistry, 15, 467– 472. chovanová z, muchová j, sivonˇová m, dvorˇáková m, žitnˇanová i, waczuliková i, trebatická j, škodácˇek i and dˇuracˇková z (2006) Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder. Free Radical Research, 40, 1003–1010.

© Woodhead Publishing Limited, 2011

The role of nutrition and diet in learning and behaviour

351

cohen-zion m and ancoli-israel s (2004) Sleep in children with attention-deficit hyperactivity disorder (ADHD): a review of naturalistic and stimulant intervention studies. Sleep Medical Review, 8, 379–402. coleman m, steinberg g, tippett j, bhagavan h n, coursin d b, gross m, lewis c and deveau l (1979) A preliminary study of the effect of pyridoxine administration in a subgroup of hyperkinetic children: a double-blind crossover comparison with methylphenidate. Biological Psychiatry, 14, 741–751. colledge e & blair r j r (2001) The relationship in children between the inattention and impulsivity components of attention deficit and hyperactivity disorder and psychopathic tendencies. Personality and Individual Differences, 30, 1175–1187. colquhoun i and bunday s (1981) A lack of essential fatty acids as a possible cause of hyperactivity in children. Medical Hypotheses, 7, 673–679. cormier e (2007) Diet and child behavior problems: fact or fiction? Pediatric Nursing, 33, 138–143. cortese s, konofal e, bernardina b d, mouren m-c and lecendreux m (2009) Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder. European Child & Adolescent Psychiatry, 18, 393–399. crowley t j, mikulich s k, macdonald m, young s e and zerbe g o (1998) Substancedependent, conduct-disordered adolescent males: severity of diagnosis predicts 2-year outcome. Drug and Alcohol Dependence, 49, 225–237. curtis l t and patel k (2008) Nutritional and environmental approaches to preventing and treating autism and attention deficit hyperactivity disorder (ADHD): a review. The Journal of Alternative and Complementary Medicine, 14, 79– 85. dvorˇáková m, sivonˇová m, trebatická j, škodácˇek i, waczuliková i, muchová j and duracková z (2006) The effect of polyphenolic extract from pine bark, Pycnogenol®, on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD). Redox Report, 11, 163–172. dvorˇáková m, ježová d, blažícˇek p, trebatická j, škodácˇek i, šuba j, waczulíková i, rohdewald p and cˇuracˇková z (2007) Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (Pycnogenol). Nutritional Neuroscience, 10, 151–157. fda (2007) Food Ingredients and Packaging. Silver Spring, MD: US Food & Drug Administration. feingold b f (1975) Why is Your Child Hyperactive? New York: Random House. fitzpatrick d f, bing b and rohdewald p (1998) Endothelium-dependent vascular effects of pycnogenol. Journal of Cardiovascular Pharmacology, 32, 509–515. fossati a, novella l, donati d, donini m and maffei c (2002) History of childhood attention deficit/hyperactivity disorder symptoms and borderline personality disorder: a controlled study. Comprehensive Psychiatry, 43, 369–377. galler j r and barrett r l (2001) Children and famine: long-term impact on development. Ambulatory Child Health, 7, 85–95. gesch b, hammond s, hampson s, eves a and crowder m j (2002) Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. British Journal of Psychiatry, 181, 22–28. gittelman r, mannuzza s, shenker r and bonagura n (1985) Hyperactive boys almost grown up: I. Psychiatric status. Archives of General Psychiatry, 42, 937–947. goldenring j r, batter d k and shaywitz b a (1982) Sulfanilic acid: behavioural change related to azo food dyes in developing rats. Neurobehavioral Toxicology and Teratology, 4, 43–49. greenblatt j (1999) Nutritional supplements in ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 38, 1209–1210.

© Woodhead Publishing Limited, 2011

352

Lifetime nutritional influences on behaviour and psychiatric illness

haller j (2005) Vitamins and brain function, in Lieberman H R, Kanarek R B and Prasad C (eds), Nutritional Neuroscience. Boca Raton, FL: Taylor & Francis Group, 207–233. harding k l, judah r d and gant c (2003) Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Alternative Medicine Review: A Journal of Clinical Therapeutics, 8, 319–330. haslam r h a, dalby j t and rademaker a w (1984) Effects of megavitamin therapy on children with attention deficit disorders. Pediatrics, 74, 103–111. heimann s w (1999) Pycnogenol for ADHD? Journal of the American Academy of Child & Adolescent Psychiatry, 38, 357–358. hetzel b s (2000) Iodine and neuropsychological development. Journal of Nutrition, 130, 493S–495S. hibbeln j, ferguson t a and blasbalg t l (2006) Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation. International Review of Psychiatry, 18, 107–118. hirayama s, hamazaki t and terasawa k (2004) Effect of docosahexaenoic acidcontaining food administration on symptoms of attention-deficit/hyperactivity disorder – a placebo-controlled double-blind study. European Journal of Clinical Nutrition, 58, 467–473. ingram s, hechtman l and morgenstern g (1999) Outcome issues in ADHD: adolescent and adult long-term outcome. Mental Retardation and Developmental Disabilities, 5, 243–250. itoh t, zang y f, murai s and saito h (1989) Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice. Planta Medical, 55, 429–433. johnson m, östlund s, fransson g, kadesjö b and gillberg c (2009) Omega-3/ omega-6 fatty acids for attention deficit hyperactivity disorder. Journal of Attention Disorders, 12, 394–401. joshi k, lad s, kale m, patwardhan b, mahadik s p, patni b, chaudhary a, bhave s and pandit a (2006) Supplementation with flax oil and vitamin C improves the outcome of attention deficity hyperactivity disorder (ADHD). Prostaglandins, Leukotrienes and Essential Fatty Acids, 74, 17–21. kaplan b j, fisher j e, crawford s g, field c j and kolb b (2004) Improved mood and behavior during treatment with a mineral-vitamin supplement: an open-label case series of children. Journal of Child and Adolescent Psychopharmacology, 14, 115–122. kaplan b j, crawford s g, field c j and simpson j s (2007) Vitamins, minerals, and mood. Psychological Bulletin, 133, 747–760. kaplita p v and triggle d j (1982) Food dyes: Behavioural and neurochemical actions. Trends in Pharmacological Sciences, 3, 70–71. kittler f j and baldwin d g (1970) The role of allergic factors in the child with minimal brain dysfunction. Annals of Allergy, 28, 203–206. konofal e and cortese s (2007) Lead and neuroprotection by iron in ADHD. Environmental Health Perspectives, 115, A398–A399. konofal e, lecendreux m, arnulf i and mouren m c (2004) Iron deficiency in children with attention-deficit/hyperactivity disorder. Archives of Pediatric & Adolescent Medicine, 158, 1113–1115. konofal e, cortese s, lecendreux m, arnulf i and mouren m c (2005) Effectiveness of iron supplementation in a young child with attention-deficit/hyperactivity disorder. Pediatrics, 116, e732–e734. konofal e, cortese s, marchand m, mouren m c, arnulf i and lecendreux m (2007) Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Medicine, 8, 711–715.

© Woodhead Publishing Limited, 2011

The role of nutrition and diet in learning and behaviour

353

konofal e, lecendreux m, deron j, marchand m, cortese s, zaim m, mouren m c and arnulf i (2008) Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatric Neurology, 38, 20–26. kozielec t and starobrat-hermelin b (1997) Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnesium Research, 10, 143–148. kratochvil c j, heiligenstein j h, dittmann r, spencer t j, biederman j, wernicke j, newcorn j h, casat c, milton d and michelson d (2002) Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 776–784. kris-etherton p, harris w s and appel l j (2002) AHA Scientific Statement: fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation, 106, 2747–2757. lecours a r, mandujano m and romero g (2001) Ontogeny of brain and cognition: relevance to nutrition research. Nutrition Reviews, 59, S7–S11. lozoff b, beard j, connor j, barbara f, georgieff m and schallert t (2006) Longlasting neural and behavioral effects of iron deficiency in infancy. Nutrition Reviews, 64 (5 Pt 2), S34–S43. lumley j, watson l, watson m and bower c (2001) Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Systematic Reviews, CD001056. lyon m r, cline j c, totosy de zepetnek j, jie shan j, pang p and benishin c (2001) Effect of the herbal extract combination Panax quinquefolium and Ginko biloba on attention-deficit hyperactivity disorder: a pilot study. Journal of Psychiatry & Neuroscience, 26, 221–228. mann c a, lubar j f, zimmerman a w, miler c a and muenchen r a (1992) Quantitative analysis of EEG in boys with attention-deficit-hyperactivity disorder: Controlled study with clinical implications. Pediatric Neurology, 8, 30–36. martinez m (1996) Docosahexaenoic acid therapy in docosahexaenoic acid-deficient patients with disorders of peroxisomal biogenesis. Lipids, 31, S145–S152. mccann d, barrett a, cooper a, crumpler d, dalen l, grimshaw k, kitchin e, lok k, porteous l, prince e, sonuga-barke e, warner j o and stevenson j (2007) Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet, 370, 1560–1567. milte c, sinn n, buckley j d, coates a m, young r m and howe p r c (in press) Erythrocyte polyunsaturated fatty acids, cognition and literacy in children with ADHD and learning difficulties. Journal of Child Health Care. mitchell e a, lewis s and cutler d r (1983) Essential fatty acids and maladjusted behaviour in children. Prostaglandins, Leukotrienes and Medicine, 12, 281–287. mitchell e a, aman m g, turbott s h and manku m (1987) Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clinical Pediatrics, 26, 406–411. molina b s g, flory k, hinshaw s p, greiner a r, arnold l e, swanson j m, hechtman l, jensen p s, vitiello b, hoza b, pelham w e, elliott g r, wells k c, abikoff h b, gibbons r d, marcus s, conners c k, epstein j n, greenhill l l, march j s, newcorn j h, severe j b and wigal t (2007) Delinquent behavior and emerging substance use in the MTA at 36 months: prevalence, course, and treatment effects. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 1028–1040. mousain-bosc m, roche m, rapin j and bali j-p (2004) Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. Journal of the American College of Nutrition, 23, 545S–548S.

© Woodhead Publishing Limited, 2011

354

Lifetime nutritional influences on behaviour and psychiatric illness

mousain-bosc m, roche m, polge a, pradal-prat d, rapin j and bali j-p (2006) Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. Magnesium Research, 19, 46–52. mta cooperative group (1999) A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 56, 1073–1086. mta cooperative group (2004) National Institute of Mental Health multimodal treatment study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics, 113, 762–769. muller w e, rolli m, schafer c and hafner u (1997) Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry, 30 Suppl 2, 102–107. munoz k, krebs-smith s, ballard-barbash r and cleveland l (1997) Food intakes of US children and adolescents compared with recommendations. Pediatrics, 100, 323–329. neary j t and bu y (1999) Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res, 816, 358–363. nemzer e d, arnold l e, votolato n a and mcconnell h (1986) Amino acid supplementation as therapy for attention deficit disorder. Journal of the American Academy of Child Psychiatry, 25, 509–513. ng f, berk m, dean o and bush a i (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. The International Journal of Neuropsychopharmacology, 21, 1–26 [Epub ahead of print]. nigg j t (2005) Neuropsychologic theory and findings in attention-deficit/hyperactivity disorder: the state of the field and salient challenges for the coming decade. Biological Psychiatry, 57, 1424–1435. nishioka k, hidaka t, nakamura s, umemura t, jitsuiki d, soga j, goto c, chayama k, yoshizumi m and higashi y (2007) Pycnogenol, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertension Research, 30, 775–780. nogovitsina o r and levitina e v (2007) Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neuroscience and Behavioral Physiology, 37, 199–202. oner p, dirik e b, taner y, caykoylu a and anlar o (2007) Association between low serum ferritin and restless legs syndrome in patients with attention deficit hyperactivity disorder. Tohoku Journal of Experimental Medicine, 213, 269–276. oner o, alkar o y and oner p (2008) Relation of ferritin levels with symptoms ratings and cognitive performance in children with attention deficit-hyperactivity disorder. Pediatrics International, 50, 40–44. patel k and curtis l t (2007) Comprehensive approach to treating autism and attention-deficit hyperactivity disorder: a prepilot study. Journal of Alternative and Complementary Medicine, 13, 1091–1097. pliszka s r (1998) Comorbidity of attention-deficit/hyperactivity disorder with psychiatric disorder: an overview. Journal of Clinical Psychiatry, 59, 50– 58. popper c w (2001) Do vitamins or minerals (apart from lithium) have moodstabilising effects? Journal of Clinical Psychiatry, 62, 933–935. ramassamy c, naudin b, christen y, clostre f and costentin j (1992) Prevention by Ginkgo biloba extract (EGb 761) and trolox C of the decrease in synaptosomal dopamine or serotonin uptake following incubation. Biochemical Pharmacology, 44, 2395–2401. raz r, carasso r l and yehuda s (2009) The influence of short-chain essential fatty acids on children with attention-deficit/hyperactivity disorder: a double-blind

© Woodhead Publishing Limited, 2011

The role of nutrition and diet in learning and behaviour

355

placebo-controlled study. Journal of Child and Adolescent Psychopharmacology, 19, 167–177. rey j m, morris-yates a, singh m, andrews g and stewart g w (1995) Continuities between psychiatric disorders in adolescents and personality disorders in young adults. American Journal of Psychiatry, 152, 895–900. riccio c a, hynd g w, cohen m j and gonzalez j j (1993) Neurological basis of attention deficit hyperactivity disorder. Exceptional Children, 60, 118–124. richardson a j (2003) Clinical trials of fatty acid supplementation in ADHD, in Glen A I M, Peet M and Horrobin D F (eds), Phospholipid Spectrum Disorders in Psychiatry and Neurology. Carnforth: Marius Press, 529–541. richardson a j (2006) Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. International Review of Psychiatry, 18, 155–172. richardson a j and montgomery p (2005) The Oxford-Durham study: a randomised, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics, 115, 1360–1366. richardson a j and puri b k (2002) A randomised double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Progress in Neuropsychopharmacology & Biological Psychiatry, 26, 233–239. rohdewald p (2002) A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. International Journal of Clinical Pharmacology and Therapeutics, 40, 158–168. root r w i and resnick r j (2003) An update on the diagnosis and treatment of attention-deficit/hyperactivity disorder in children. Professional Psychology: Research and Practice, 34, 34–41. rowland a s, lesesne c a and abramowitz a j (2002) The epidemiology of Attention-Deficit/Hyperactivity Disorder: a public health view. Mental Retardation and Developmental Disabilities Research Reviews, 8, 162–170. rucklidge j j and harrison r (2010) Successful treatment of Bipolar Disorder II and ADHD with a micronutrient formula: A case study. CNS Spectrums, 15, 289–295. rucklidge j j, johnstone j and kaplan b j (2009) Nutrient supplementation approaches in the treatment of ADHD. Expert Review of Neurotherapeutics, 9, 461–476. rucklidge j j, taylor m r and whitehead k a (2011) Effect of micronutrients on behaviour and mood in adults with ADHD: evidence from an 8-week open label trial with natural extension. Journal of Attention Disorders, 15, 79–91. salehi b, imani r, mohammadi m r, fallah j, mohammadi m, ghanizadeh a, tasviechi a a, vossoughi a, rezazadeh s-a and akhondzadeh s (2010) Ginkgo biloba for attention-deficit/hyperactivity disorder in children and adolescents: a double blind, randomized controlled trial. Progress in Neuropsychopharmacology and Biological Psychiatry, 34, 76–80. salem n jr, litman b, kim h-y and gawrisch k (2001) Mechanisms of action of docosahexaenoic acid. Lipids, 36, 945–959. schab d w and trinh n-h t (2004) Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebocontrolled trials. Journal of Developmental and Behavioral Pediatrics, 25, 423–434. schachter h m, bham b, king j, langford s and moher d (2001) How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? Canadian Medical Association Journal, 165, 1475–1488. schoenthaler s j and bier i d (2000) The effect of vitamin-mineral supplementation on juvenile delinquency among American schoolchildren: a randomized,

© Woodhead Publishing Limited, 2011

356

Lifetime nutritional influences on behaviour and psychiatric illness

double-blind placebo-controlled trial. Journal of Alternative and Complementary Medicine, 6, 7–17. sever y, ashkenazi a, tyano s and weizman a (1997) Iron treatment in children with attention deficit hyperactivity disorder: a preliminary report. Neuropsychobiology, 35, 178–180. shaywitz b a, goldenring j r and wool r s (1979) Effects of chronic administration of food colorings on activity levels and cognitive performance in developing rat pups treated with 6-hydroxydopamine. Neurobehavioral Toxicology, 1, 41–47. shekim w o, antun f, hanna g l, mccracken j t et al. (1990) S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: Preliminary results from an open trial. Psychopharmacology Bulletin, 26, 249–253. sinha d and efron d (2005) Complementary and alternative medicine use in children with attention deficit hyperactivity disorder. Journal of Paediatrics and Child Health, 41, 23–26. sinn n (2008) Nutritional and dietary influences on attention deficit hyperactivity disorder. Nutrition Reviews, 66, 558–568. sinn n and bryan j (2007) Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. Journal of Developmental & Behavioral Pediatrics, 28, 82–91. sinn n and howe p r c (2008) Mental health benefits of omega-3 fatty acids may be mediated by improvements in cerebral vascular function. Bioscience Hypotheses, 1, 103–108. sinn n, bryan j and wilson c (2008) Cognitive effects of polyunsaturated fatty acids in children with attention deficit hyperactivity disorder symptoms: A randomised controlled trial. Prostaglandins, Leukotrienes and Essential Fatty Acids, 78, 311–326. sinn n, milte c, coates a m, buckley j d, young r and howe p r c (2007) Childhood behaviour and learning disorders respond to changes in erythrocyte polyunsaturated fatty acid content. Nutrition Society of Australia. Newcastle, NSW: Asia Pacific Journal of Clinical Nutrition. starobrat-hermelin b and kozielec t (1997) The effects of magnesium physiological supplementation on hyperactivity in children with attention deficit hyperactivity disorder (ADHD). Positive response to magnesium oral loading test. Magnesium Research, 10, 149–156. stevens l j, zentall s s, deck j l, abate m l, watkins b a, lipp s r and burgess j r (1995) Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. American Journal of Clinical Nutrition, 62, 761–768. stevens l j, zhang w, peck l, kuczek t, grevstad n, mahon a k, zentall s s, arnold l e and burgess j r (2003) EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids, 38, 1007–1021. swaine a, soutter v, loblay r and truswell a s (1985) Salicylates, oligoantigenic diets, and behaviour. The Lancet, 2, 41–42. swanson j m, elliott g r, greenhill l l, wigal t, eugene a l, vitiello b, hechtman l, epstein j n, pelham w e, abikoff h b, newcorn j h, molina b s g, hinshaw s p, wells k c, hoza b, jensen p s, gibbons r d, hur k, stehli a m p h, davies m m s, march j s, conners c k, caron m and volkow n d (2007) Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 1015–1027. tenenbaum s, paull j c, sparrow e p, dodd d k and green l (2002) An experimental comparison of Pycnogenol® and methylphenidate in adults with attention-deficit/ hyperactivity disorder (ADHD). Journal of Attention Disorders, 6, 49–60. toren p, eldar s, sela b-a, wolmer l et al. (1996) Zinc deficiency in attention-deficit hyperactivity disorder. Biological Psychiatry, 40, 1308–1310.

© Woodhead Publishing Limited, 2011

The role of nutrition and diet in learning and behaviour

357

torrioli m g, vernacotola s, peruzzi l, tabolacci e, mila m, militerni r, musumeci s, ramos f j, frontera m a, sorge g, marzullo e, romeo g, vallee l, veneselli e, cocchi e, garbarino e, moscato u, chiurazzi p, d’iddio s, calvani m and neri g (2008) A double-blind, parallel, multicenter comparison of Lacetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys. American Journal of Medical Genetics. Part A, 146, 803–812. trebatická j, kopasová s, hradecˇná z, cinovsky k, škodácˇek i, šuba j, muchová j, zitnˇanová i, waczuliková i, rohdewald p and dˇuracˇková z (2006) Treatment of ADHD with French maritime pine bark extract, Pycnogenol®. European Child and Adolescent Psychiatry, 15, 329–335. uauy r, peirano p, hoffman d, mena p, birch d and birch e (1996) Role of essential fatty acids in the function of the developing nervous system. Lipids, 31, S167–S176. uckardes y, ozmert e n, unal f and yurdakok k (2009) Effects of zinc supplementation on parent and teacher behavior rating scores in low socioeconomic level Turkish primary school children. Acta Paediatrica, 98, 731–736. van der heijden k b, smits m g, van someren e j w, ridderinkhof k r and gunning w b (2007) Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 233–241. van oudheusden l j and scholte h r (2002) Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 67, 33–38. voigt r g, llorente a m, jensen c l, fraley j k, berretta m c and heird w c (2001) A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. Journal of Pediatrics, 139, 189–196. ward n i, soulsbury k a, zettel v h, colquhoun i d, bunday s and barnes b (1990) The influence of the chemical additive tartrazine on the zinc status of hyperactive children – a double-blind placebo-controlled study. Journal of Nutritional and Environmental Medicine, 1, 51–57. warner-rogers j, taylor a, taylor e and sandberg s (2000) Inattentive behavior in childhood: Epidemiology and implications for development. Journal of Learning Disabilities, 33, 520–536. weber w, stoep a v, mccarty r l, weiss n s, biederman j and mcclellan j (2008) Hypericum perforatum (St John’s Wort) for attention-deficit/hyperactivity disorder in children and adolescents. JAMA, 299, 2633–2641. weiss b (1982) Food additives and environmental chemicals as sources of childhood behavior disorders. Journal of the American Academy of Child Psychiatry, 21, 144–152. weiss m d, wasdell m b, bomben m m, rea k j and freeman r d (2006) Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. Journal of the American Academy of Child & Adolescent Psychiatry, 45, 512–519. wilens t e, hammerness p g, biederman j, kwon a, spencer t j, clark s, scott m, podolski a, ditterline j w, morris m c and moore h (2005) Blood pressure changes associated with medication treatment of adults with attention-deficit/ hyperactivity disorder. Journal of Clinical Psychiatry, 66, 253–259. wood d r, reimherr f w and wender p h (1985) Treatment of attention deficit disorder with DL-phenylalanine. Psychiatry Research, 16, 21–26. who (2008) Worldwide Prevalence of Anaemia 1993–2005. De Benoist B, McLean E, Ines E, Cogswell M (eds). Geneva: World Health Organization.

© Woodhead Publishing Limited, 2011

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Lifetime nutritional influences on behaviour and psychiatric illness

wu x, beecher g r, holden j m, haytowitz d b, gebhardt s e and prior r l (2004) Lipophilic and hydrophilic antioxidant capacities of common foods in the United States. Journal of Agriculture and Food Chemistry, 52, 4026–4037. yehuda s, rabinovitz s and mostofsky d i (2000) Essential fatty acids are mediators of brain biochemistry and cognitive functions. Journal of Neuroscience Research, 56, 565–570. yorbik o, ozdag m f, olgun a, senol m g, bek s and akman s (2008) Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 32, 662–667. youdim k a, martin a and joseph j a (2000) Essential fatty acids and the brain: possible health implications. International Journal of Developmental Neuroscience, 18, 383–399.

© Woodhead Publishing Limited, 2011