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The Role of Diet and Nutrition in ADHD: Supplements
By Richard G. Petty, MD, Dr. Petty is Scientific Director, Promedica Research Center, Loganville, GA; Adjunct Professor, Georgia State University, Atlanta, GA. Dr. Petty is a consultant for AstraZeneca Pharmaceuticals and Janssen Pharmaceuticals and serves on the speaker's bureau for AstraZeneca Pharmaceuticals, Janssen Pharmaceuticals, Abbott Pharmaceuticals, and Avanir Pharmaceuticals.
In the first part of this series, the evidence concerning the possible association between food and attention-deficit hyperactivity disorder (ADHD) was presented. This second part will examine the evidence for the safety and efficacy of nutritional supplements in the management of ADHD.
There are three essential principles of brain function that are important in understanding the role of nutritional supplements in psychological or psychiatric illnesses.
First, the brain is exquisitely sensitive to environmental change. In recent years, there has been a change in understanding the genetics of behavior. Genes expressed in the brain do not so much determine mood, behavior, or cognition; instead, they help influence how we respond to the environment.1 This sensitivity to the environment extends to essential nutrients, not only during critical periods of brain development but throughout life.
Second, most clinicians are familiar with the impact of food on our mood, level of arousal, and behavior. What is less well-known is that there is growing evidence that nutrition, particularly in the early years of life, may have a lifelong impact on mood and cognition.2 (A detailed and well-referenced report entitled Feeding Minds was published by the British Mental Health Foundation in January 2006, and was subsequently presented to the British Government. It is available as a free download at http://www.mentalhealth.org.uk/campaigns/food-and-mental-health/). For example, not only are breastfed children less likely to get ADHD later in life, but there is also a correlation between the duration of breastfeeding and the risk of developing ADHD. The effect remains, even when controlled for maternal education or intelligence.3
Third, there is growing evidence that the composition of neuronal cell membranes may play an important role in neurotransmission and neuromodulation. Most neuronal proteins are embedded in phospholipid membranes, and their structure and function are highly dependent on the local phospholipid environment. Virtually all forms of neuronal signal transduction are dependent on the release of chemical mediators from membrane phospholipids.
This has led many to question the catecholamine hypotheses of mental illness and replace them with a phospholipid theory, in which changes in receptor function are secondary to changes in cell membranes.4 This theory also provides a possible link between such disparate observations as the virtually linear relationship between fish consumption and rates of depression, the cognitive decline that accompanies hypertriglyceridemia, and high rates of diabetes mellitus in schizophrenia and bipolar disorder. There already exists some support for the hypothesis: rats with low levels of omega-3 (n-3) polyunsaturated fatty acids in their frontal cortices become hyperactive,5 and children with ADHD have consistently been found to have lower levels of membrane phospholipid precursors in their erythrocyte membranes and in the prefrontal cortex.6 We shall return to those observations in a moment.
Before reviewing the evidence on dietary supplements, it is important for practitioners to be reminded that the FDA regulates supplements under a different set of regulations than conventional foods and drug products. (See http://www.cfsan.fda.gov/~dms/supplmnt.html). Therefore, purity and contents may vary considerably, and that variation may have been a factor in the disparities between different trials.
Amino Acid Supplementation
The idea of using amino acid supplementation is based on reports of low levels of tyrosine, phenylalanine, and tryptophan in ADHD.7
Several open and controlled studies in both adults and children have reported a small short-term benefit from tryptophan (precursor of serotonin), tyrosine (precursor of catecholamines), or phenylalanine (precursor of catecholamines) and S-adenosyl-methionine supplementation.8,9 However, no lasting benefit beyond 2-3 months has been demonstrated; both children and adults develop tolerance, and although amino acid supplementation is still recommended in some books written for the general public, the approach does not seem to be helpful.
Three strategies for vitamin supplementation are:
The first is not controversial, although there is always a discussion about whether the RDA is correct. People with ADHD are often "picky" eaters; attentional problems often lead them to stay on much the same diet from day-to-day, and mild nutritional deficiencies of both vitamins and some metals are not uncommon. There is no published evidence that addressing these mild deficiencies has any impact on ADHD. However, in terms of general health, it is advisable to recommend a more balanced diet and perhaps a multivitamin and mineral supplement. Recent data on the value of vitamin and mineral supplements in antisocial behavior suggest that further research on vitamin and mineral supplementation would be warranted in ADHD.10
The second strategy — combinations of high doses of vitamins and minerals — has not been found effective in treating hyperactivity in double-blind, placebo-controlled trials of up to six months.11 There have not been any more recent studies of using this approach to help attentional problems.
The third strategy — the use of single vitamins in huge doses to modulate neuronal metabolism — remains largely unexplored despite some encouraging early reports over 20 years ago.12 Very high doses of vitamins can pose problems as well. This approach should not be recommended until further controlled studies evaluate the risks and benefits of such a strategy.
Iron is a coenzyme involved in the synthesis of catecholamines, hence the interest in iron deficiency as a possible cause of a number of neurological and neurocognitive problems. Iron deficiency may be due to poor diet, celiac disease, excessive milk ingestion, infection, gastrointestinal losses or lead toxicity. Even in affluent societies, many menstruating or recently pregnant women are chronically iron deficient. In a study of 57 children with ADHD and 27 healthy volunteers, there was a significant inverse correlation between ferritin levels and scores on a standard ADHD rating scale.13 There is evidence that iron supplementation may help some children,14 but this is another area that is in great need of further research.
Zinc is a cofactor for at least 100 enzymes, many involved in neural metabolism. It is also necessary for fatty acid absorption and for the production of melatonin. Zinc is so important for the normal functioning of the brain that it is plausible that deficiency would adversely affect behavior, and that restoring optimal levels may provide some benefit.
In a study of 44 children diagnosed with ADHD, serum zinc levels had a significant inverse correlation with attention, even controlling for gender, age, income, and diagnostic subtype.15 In a large, randomized, placebo-controlled trial, children given zinc sulfate (150 mg/d) had significantly more improvement in impulsive behavior and socialization; the best response was observed in those children who had low zinc levels to begin with.16 We do not yet know if using mega-doses of zinc will confer any benefit.
Magnesium deficiency can cause a wide spectrum of neurological and psychiatric disturbance and can result from a wide variety of causes, including increased requirement during childhood.
In one study, children with ADHD had low levels of erythrocyte magnesium. An open-label study supplementing them with 100 mg daily of magnesium and vitamin B6 for 3-24 weeks led to reduced symptoms of hyper-excitability (physical aggression, instability, attention to school work, muscle tension, and spasms) after 1-6 months of treatment.17
Essential Fatty Acid Supplementation
Children with lower plasma levels of omega-3 fatty acids have been shown to have significantly more behavioral problems and temper tantrums, as well as problems with learning, sleep, and physical health than do those with high levels.18 In a four-month randomized, controlled trial of 63 children with ADHD, docosahexaenoic acid 345 mg/d was not effective on any symptoms or behaviors.19
A key point in trials of fatty acids is the origin and proportions of each moiety. A recent review echoes the view that the data on fish oils for ADHD in both adults and children are encouraging, though not conclusive.20 It may be that fish oils will be particularly useful for the large numbers of people with ADHD and co-morbid depression. Large doses of fish oil may inhibit platelet aggregation and increase the risk of bleeding; its use should be discontinued at least 48 hours before having surgery. Many people do not like the taste of fish oil, though in capsules that is not normally a problem.
Evening primrose oil is rich in gamma-linolenic acid, and although occasionally recommended as a treatment for ADHD, small randomized, controlled trials have thus far failed to show a benefit.21
Sleep disturbances are very common with ADHD. In addition, melatonin is involved in modulating dopamine function in several regions of the brain, so it has been a natural candidate for the treatment of ADHD. In a recent study involving 105 medication-free children, melatonin helped with sleep problems in children with ADHD, but had no effect on problem behavior, cognitive performance, or quality of life.22 If used, the recommended dosage is 3-6 mg/d given one hour before retiring.
The brain is exquisitely sensitive to nutritional imbalances. This may be especially true of children and adults with ADHD who may naturally tend toward repetitive and familiar diets that may not meet their nutritional needs. As a starting point, clinicians should ensure that all patients maintain an adequate, balanced diet.
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