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From the Townsend Letter
April 2008


Literature Review & Commentary
by Alan R. Gaby, MD

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Food additives and hyperactivity: Feingold was right
One hundred fifty-three three-year-old children and 144 children aged eight or nine years consumed a diet free of food colorings and sodium benzoate for six weeks. During weeks 2, 4, and 6, they were randomly assigned to receive, in double-blind fashion, a daily drink containing 1) placebo or 2) sodium benzoate plus one of two mixtures of artificial food colors and additives. Mix A contained sunset yellow, carmoisine, tartrazine, and ponceau 4R. Mix B contained sunset yellow, carmoisine, quinoline yellow, and allura red AC. Doses for mixes A and B for three-year-old children were roughly the same as the amount of food coloring in two 56 g bags of sweets. For eight-year-old and nine-year-old children, the dose for mix A was equal to about two bags of sweets per day and for mix B about four bags of sweets per day. In three-year-old children, compared with placebo, Mix A had a significant adverse effect on the main outcome measure (a global hyperactivity score; p < 0.05), whereas Mix B had a nonsignificant adverse effect (p = 0.09). In eight- and nine-year-old children, a significant adverse effect was seen for Mix A (p < 0.03) and Mix B (p = 0.001) when the analysis was restricted to children who consumed at least 85% of the study drinks.

Comment: More then 30 years ago, Dr. Ben Feingold reported that ingestion of artificial colors or large amounts of naturally occurring salicylates was an important contributing factor to hyperactive behavior. Feingold's initial report stimulated a great deal of research, some of which supported his observations, but much of which did not. Most of the negative studies had important flaws. In one study, for example, the effect of a chocolate cookie containing artificial colorings was compared with that of a placebo chocolate cookie. Since many of the children were presumably sensitive to sugar or chocolate, a chocolate cookie was not an appropriate placebo. The results of the present study confirm Feingold's original observations by demonstrating that consumption of artificial colors or sodium benzoate (or both) resulted in increased hyperactivity in three-year-old and eight- and nine-year-old children in the general population.

McCann D, et al. 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. 2007;370:1560-1567.

Omega-3 fatty acids and hyperactivity
Nine children (aged eight to 16 years) with attention deficit hyperactivity disorder (ADHD) received, in open-label fashion, an omega-3 fatty acid supplement for eight weeks. The initial dosage was 30 ml/day, which provided 16.2 g/day of omega-3 fatty acids (10.8 g of eicosapentaenoic acid [EPA] and 5.4 g of docosahexaenoic acid [DHA]). The dosage was adjusted after four weeks based on the ratio of arachidonic acid (AA) to EPA in plasma phospholipids. If the ratio was < 1.0, the dosage was decreased to 15 ml/day. If the ratio was between 1.0 and 1.5, the dosage was decreased to 20 ml/day. After eight weeks, significant improvements were seen in inattention, hyperactivity, oppositional/defiant behavior, and conduct. The mean Clinical Severity of Illness score improved from 4.4 (moderately symptomatic) to 3.3 (mildly symptomatic). There was a significant correlation between the reduction in the AA:EPA ratio and Clinical Severity of Illness score.

Comment: In most previous studies, omega-3 fatty acids were not beneficial for patients with ADHD. The present study, which demonstrated improved behavior in children with ADHD, used substantially higher doses of omega-3 fatty acids than did the earlier studies. Placebo-controlled trials are needed to confirm a beneficial effect of high-dose EPA/DHA in children with ADHD.

Sorgi PJ, et al. Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder. Nutr J. 2007;6:16.

Iron deficiency as a factor in ADHD
Twenty-three non-anemic children (aged five to eight years) with ADHD and a serum ferritin level less than 30 ng/ml (indicating mild iron deficiency) were randomly assigned in a 3:1 ratio to receive 80 mg/day of iron (as ferrous sulfate; n = 18) in a single morning dose or placebo (n = 5) for 12 weeks. The mean score on the ADHD Rating Scale improved significantly (p < 0.01) in the iron group and became nonsignificantly worse in the placebo group. There was a nonsignificant trend toward greater improvement on the Conners' Parent Rating Scale in the iron group compared with the placebo group. The mean Clinical Global Impression-Severity score improved significantly (p < 0.01) in the iron group and did not change in the placebo group. The magnitude of the improvement with iron was said to be comparable to that achievable with stimulant medications. Iron therapy was well-tolerated, with the exception of gastrointestinal side effects (constipation, nausea, abdominal pain) in some patients.

Comment: Iron deficiency can cause a wide range of mood and behavioral abnormalities. In previous studies, a low serum ferritin concentration without anemia was found to be common in children with ADHD, with a prevalence as high as 84% in one study. The results of the present study indicate that iron deficiency is an important contributing factor to ADHD in some children. In order to reduce the incidence of side effects from iron therapy, it should probably be administered in divided doses throughout the day. In addition, iron status should be monitored periodically in patients receiving iron supplements, both to assure that iron deficiency has been corrected and to reduce the possibility of causing iron overload.

Konofal E, et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38:20-26.

Omega-3 fatty acids and autism
Thirteen children (aged five to 17 years) with autistic disorders accompanied by severe tantrums, aggression, or self-injurious behavior were randomly assigned to receive, in double-blind fashion, menhaden oil (providing 840 mg/day of eicosapentaenoic acid and 700 mg/day of docosahexaenoic acid) or placebo for six weeks. The outcome measure was the Aberrant Behavior Checklist (ABC) at six weeks. There was no significant difference in outcome between groups. However, there was a trend in favor of menhaden oil over placebo for the ABC subscales of hyperactivity (p < 0.1) and stereotypy, each with a large effect size.

Comment: Omega-3 fatty acids have been reported to be beneficial for patients with various psychiatric conditions, including unipolar depression, bipolar disorder, postpartum depression, and schizophrenia. In a case report, an 11-year-old male with autism experienced a marked improvement in anxiety after receiving a fish oil supplement (J Clin Psychiatry. 2003;64:848-849). In the present study, clinically significant improvements were seen in hyperactive and stereotypic behavior in autistic children who received fish oil. However, because of the small sample size, the results were not statistically significant. A larger study is needed to confirm these preliminary observations.

Amminger GP, et al. Omega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot study. Biol Psychiatry. 2007;61:551-553.

Zinc prevents infections in elderly people
Fifty healthy volunteers (mean age, 66 years) were randomly assigned to receive, in double-blind fashion, 45 mg/day of zinc (as zinc gluconate) or placebo for 12 months. The proportion of people having one or more infections during the study was significantly lower in the zinc group than in the placebo group (29% vs. 88%; p < 0.001). The proportion of subjects having more than one infection was 0% in the zinc group and 36% in the placebo group.

Comment: Zinc enhances immune function through several different mechanisms. The typical Western diet, with its high proportion of refined and processed foods, contains suboptimal amounts of zinc. The results of the present study indicate that zinc supplementation can reduce the incidence of infections in healthy elderly people. Long-term zinc supplementation should be accompanied by a copper supplement (1-4 mg per day, depending on the zinc dose), to prevent zinc-induced copper deficiency. For a person taking 45-50 mg of supplemental zinc per day, a reasonable dose of supplemental copper would be 2-3 mg per day.

Prasad AS, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007;85:837-844.

Beta-carotene prevents cognitive decline
Participants in the Physicians' Health Study, which began in 1982, were randomly assigned to receive, in double-blind fashion, 50 mg of beta-carotene every other day or placebo for a mean of 18 years. Participants in the Physicians' Health Study II, which was begun in 1998, were also randomly assigned to receive beta-carotene or placebo for a mean of one year until the beta-carotene arm of the study was terminated. Among participants from the Physicians' Health Study (mean treatment duration, 18 years), the mean global score that assessed cognitive function was significantly higher in the beta-carotene group than in the placebo group (p = 0.03). On verbal memory, the beta-carotene group also performed significantly better than the placebo group (p = 0.007). No difference in cognitive function was seen between the beta-carotene and placebo groups among participants in the Physicians' Health Study II (mean treatment duration, one year).

Comment: Oxidative stress contributes to brain aging. Because beta-carotene is an antioxidant, it has the potential to slow the aging process, thereby slowing the normal decline in cognitive function. The results of the present study indicate that long-term beta-carotene supplementation prevented cognitive decline, but short-term supplementation did not. Smokers should not take beta-carotene supplements, because this compound has been shown to increase the incidence of lung cancer in smokers. It is probably best to obtain beta-carotene mostly from foods (i.e., fruits and vegetables) rather than from supplements, because foods that contain beta-carotene are also rich in many other beneficial nutrients.

Grodstein F, et al. A randomized trial of beta carotene supplementation and cognitive function in men: The Physicians' Health Study II. Arch Intern Med. 2007;167:2184-2190.

Papaya seeds eradicate intestinal parasites
Sixty asymptomatic Nigerian children with evidence of intestinal parasites on stool microscopic examination were randomly assigned to receive 20 ml of an elixir containing air-dried and blended Carica papaya seeds (0.2 g/ml; 4 g of seeds) and honey or honey alone (placebo). Seven days after the treatment, stool examination was negative for parasites in 76.7% of the children receiving active treatment and in 16.7% of those receiving placebo (p < 0.00002). The stool clearance rates for the various types of parasites were 71.4%-100%: A. lumbricoides, 11 of 13; E. histolytica, 5 of 7; N. americanus, 4 of 5; S. stercoralis, 4 of 4; T. trichiura, 3 of 3; G. lamblia, 2 of 2; and T. saginata, 1 of 1. No adverse effects were seen.

Comment: Seeds of the tropical fruit, Carica papaya, have antihelminthic and anti-amoebic activities and have been used in folk medicine to treat helminthiasis. The results of the present study indicate that this treatment can eradicate most of the common intestinal parasites. Further studies should compare the effectiveness of papaya seeds to that of conventional medications used to treat parasites.

Okeniyi JAO, et al. Effectiveness of dried Carica papaya seeds against human intestinal parasitosis: a pilot study. J Med Food. 2007;10:194-196.

D-Pinitol improves glycemic control in diabetics
Twenty patients (mean age, 65.5 years; mean body mass index, 26.3 kg/m2) with type 2 diabetes that was poorly controlled on sulfonylurea, Metformin, and/or insulin therapy received D-pinitol at a dose of 20 mg per kg of body weight per day for 12 weeks, while continuing their usual medication. The mean fasting plasma glucose concentration decreased from 200 mg/dl at baseline to 169 mg/dl after 12 weeks (15.5% decrease; p < 0.05). The mean hemoglobin A1c concentration decreased from 9.8% to 8.3% (15.3% decrease; p < 0.05).

Comment: D-chiro-inositol, a stereoisomer of myo-inositol (commonly known as inositol), is a component of an endogenous phosphoglycan that has been reported to mediate the action of insulin. D-Pinitol (3-O-methyl- D-chiro-inositol) occurs naturally in several foods such as legumes and citrus fruits and has a chemical structure and biochemical actions similar to those of D-chiro-inositol. In addition, D-pinitol is probably converted to D-chiro-inositol in vivo, as demonstrated by a 14-fold increase in the mean serum concentration of D-chiro-inositol after administration of D-pinitol to diabetic patients. The results of the present study confirm an earlier report (Eur J Clin Nutr. 2005;59:456-458) showing that supplementation with D-pinitol improves glycemic control in patients with type 2 diabetes. Since D-pinitol appears to mediate the action of insulin, rather than enhance the binding of insulin to its receptor, D-pinitol's effects on glycemic control might be additive to those of chromium, which is believed to work by facilitating insulin binding to its receptor.

Kim MJ, et al. Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes.
Diabetes Res Clin Pract. 2007;77(Suppl 1):S247-S251.

Alan R. Gaby, MD


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