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Advances in Nutritional Therapy for Attention Deficit Hyperactivity Disorder

July 2005

By Laurie Barclay, MD

Benefits of Essential Fatty Acids

When considering nutritional supplementation in the management of ADHD, omega-3 essential fatty acids may be the best place to start, as they play a key role in the structure and function of membranes enclosing brain cells, as well as in the transmission of impulses between nerve cells.

Long-chain polyunsaturated fatty acids are more fluid and less rigid in structure than saturated fatty acids—such as the hydrogenated shortenings found in commercial baked goods—and therefore help promote healthy brain cell function.39,40 The fatty acid composition of membrane phospholipids in brain cells reflects their intake from supplements or dietary sources such as cold-water fatty fish. The ratio of omega-3 to omega-6 polyunsaturated fatty acids affects transmission in nerve networks controlled by serotonin and catecholamines.39 When present in excess, omega-6 polyunsaturated fatty acids may increase inflammation and neuronal dysfunction, because their breakdown generates pro-inflammatory prostaglandins. 39 These inflammatory prostaglandins are more likely to cause inflammation than are the breakdown products of omega-3 polyunsaturated fatty acids. 39

Some features of ADHD may relate to abnormalities of fatty acid metabolism.41 Several studies have identified abnormal membrane fatty acids in individuals with ADHD.42 Preliminary data suggest that some patients with ADHD have higher rates of oxidative breakdown of omega-3 polyunsaturated fatty acids.42 This observation provides an additional rationale for supplementation with omega-3 essential fatty acids in the management of ADHD.42

Compared to children without ADHD symptoms, those with ADHD are more likely to have low levels of the essential fatty acids arachidonic acid and DHA (docosahexaenoic acid),43 and children with low omega-3 levels have more temper tantrums, learning disabilities, and sleep disturbances than those with high levels.44 Adults with ADHD have similar deficiencies of essential fatty acids relative to controls, with significantly lower levels of total polyunsaturated fatty acids, total omega-6 fatty acids, and DHA.45

In a controlled study of 41 children, aged 8-12 years, who had specific learning difficulties and above-average ADHD ratings, those who were randomly assigned to receive supplementation with highly unsaturated fatty acids for 12 weeks showed significant improvements in behavior and cognitive problems characteristic of ADHD compared to those receiving placebo.46

A preliminary study of 50 children showed some improvements in ADHD-like symptoms (compared to placebo) from four months of treatment with a polyunsaturated fatty acid supplement providing a daily dose of 480 mg of DHA, 80 mg of EPA (eicosapentanoic acid), 40 mg of arachidonic acid, 96 mg of GLA (gamma-linoleic acid), and 24 mg of alpha-tocopherol acetate (vitamin E).47 Areas of improvement included conduct and behavior reported by parents, poor attention as rated by teachers, and rebellious attitudes and acting-out episodes.47

Another four-month study, however, showed no improvement in ADHD symptoms with DHA supplementation (345 mg daily) compared to placebo,48 and a two-month study in which 3600 mg of DHA were administered weekly also produced negative results.49 “Treatment of ADHD with fatty acids deserves further investigation, but careful attention should be paid as to which fatty acid(s) is used,” concluded Japanese investigators who conducted the latter study.49

A prominent investigator in this field, Dr. Alex Richardson of the University Lab of Physiology and Mansfield College in Oxford, UK, recently noted that both omega-3 and omega-6 polyunsaturated fatty acids are crucial to brain development and function, and that modern diets in developed countries often lack sufficient omega-3 polyunsaturated fatty acids.50

“Increasing evidence …indicates that [polyunsaturated fatty acid] deficiencies or imbalances are associated with childhood developmental and psychiatric disorders including ADHD,” he writes. “Preliminary evidence from controlled trials also suggests that dietary supplementation with [polyunsaturated fatty acids] might help in the management of these kinds of childhood behavioral and learning difficulties.”50

Phosphatidylserine is a phospholipid nutrient related to fatty acids. Its structure combines an amino acid component and a fatty acid component. Like essential fatty acids, phosphatidylserine is vital to normal functioning of neurotransmitter systems, brain metabolism, connections between brain cells, and fluidity of the brain cell membrane.51 It may also help lower cortisol levels, which are increased in conditions of chronic stress.52

ADHD, dyslexia, and certain behavioral disorders in children are referred to as “phospholipid disorders.”53 Future research should help clarify phosphatidylserine’s role in the nutritional treatment of ADHD.

Brain Biochemistry Maps Offer Clues

A new technique related to magnetic resonance imaging (MRI) is proton magnetic resonance spectroscopy (1H-MRS), which reveals important information about chemical compounds in different brain areas.

Recent studies using 1H-MRS suggest that choline, creatine, glutamate, and other specific compounds may play a role in ADHD. Choline is one of the building blocks of acetylcholine, an important neurotransmitter involved in memory. Glutamate and glutamine are amino acids involved in the production of GABA (gamma-aminobutyric acid), a neurotransmitter that inhibits certain nerve impulses and may affect hyperactivity.

In one study, 1H-MRS analysis showed that children with inherited and structural features linked to poor memory had lower concentrations of creatine-phosphocreatine and choline-containing compounds, whereas creatine and N-acetyl aspartate were associated with good memory, reflecting differences in energy metabolism in the frontal lobes of the brain.54

Paradoxically, however, a 1H-MRS study of ADHD showed a mild increase in the ratio of choline to creatine on one side of the striatum, a deep brain region in which about one quarter of the nerve cells were lost or severely dysfunctional. The investigators concluded that neurotransmission involving acetylcholine was mildly hyperactive.55

In another 1H-MRS study, eight children with ADHD but without learning disabilities had increased glutamate-to-glutamine ratios in both frontal areas, and increased N-acetyl aspartate and choline in the right frontal area, compared to eight controls.56

Investigators from Venezuela found diminished blood levels of the amino acids glutamine and phenylalanine in ADHD patients. They hypothesized that this imbalance could cause alterations in amino acid metabolism and transport to the brain, which might alter central nervous system function. Their findings support the theory that ADHD represents a disorder of the inhibitory neurotransmission system.57

Choline supplementation is theoretically more beneficial for diminished memory and learning than for other ADHD symptoms such as hyperactive, impulsive behavior. Choline has an unpleasant taste, so children may prefer DMAE (dimethylaminoethanol), a supplement that increases brain levels of choline.58 DMAE may speed up production of acetylcholine in the brain, and it has been used in ADHD treatment for reduced attention span, learning and reading problems, hyperactivity, and poor coordination.59,60

Acetyl-L-Carnitine Boosts Brain Energy

Abnormalities in energy production and fatty acid oxidation may underlie behavioral and brain changes in ADHD. Acetyl-L-carnitine helps transport fatty acids into the mitochondria, the energy-producing powerhouses within each cell. This process boosts energy production when the fatty acids are burned, or oxidized, as cellular fuel.61

In a rat model of ADHD, treatment with acetyl-L-carnitine reduced impulsive behavior and increased levels of the neurotransmitter noradrenaline in the medial frontal cortex.62 “[Acetyl-L-carnitine], a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children,” according to Italian investigators.

In a randomized, controlled study, 13 of 24 boys treated with carnitine improved significantly (by 20-65%) in behavior at home and school.63 “Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD,” reported researchers in the Netherlands.

Effects of Vitamins and Minerals

Vitamins and minerals may be helpful in some ADHD patients because they act as cofactors that facilitate the actions of enzymes involved in energy metabolism and neurotransmitter synthesis.9,64 B vitamins are needed to burn carbohydrates as fuel and support neurotransmitter synthesis and nerve-insulating myelin.65 Vitamin B6 supplementation may help boost low levels of serotonin in hyperactive children.66

Zinc is an important cofactor for the production of neurotransmitters and the metabolism of dopamine and fatty acids. Alterations in these biochemicals may play a role in the pathophysiology of ADHD.64 Zinc deficiency in children with ADHD is associated with decreased blood levels of fatty acids.67 The relationship between zinc and fatty acids was demonstrated in a study showing that evening primrose oil, a supplement rich in GLA, improved school behavior in children with ADHD but only in those who were deficient in zinc.64

In a well-controlled, randomized study of 400 children with ADHD, zinc sulfate was statistically superior to placebo in reducing symptoms of hyperactive or impulsive behavior and impaired socialization. Patients most likely to benefit from zinc were older and more overweight, and had low levels of zinc and fatty acids.68

Children with ADHD treated with Ritalin® for six weeks had better behavioral ratings by teachers and parents when they also received zinc sulfate (55 mg/day) compared to children who received Ritalin® and a placebo.69

Magnesium levels in blood plasma and red cells may be low in patients with ADHD. Supplementation with magnesium, alone or in combination with vitamin B6, may reduce hyperactivity.70,71

In a recent study, iron deficiency, which causes abnormalities in dopamine neurotransmission, was present in 84% of 53 children with ADHD.72 Because measures of iron deficiency were correlated with more severe ADHD symptoms, French researchers concluded, “low iron stores contribute to ADHD and . . . ADHD children may benefit from iron supplementation.”