Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine.

OBJECTIVE: To explore effects of zinc supplementation in American children with attention-deficit/hyperactivity disorder (ADHD). Mideastern trials reported significant benefit from 13-40 mg elemental zinc as the sulfate. METHOD: We randomly assigned 52 children aged 6-14 with DSM-IV ADHD to zinc supplementation (15 mg every morning [qAM] or two times per day [b.i.d.] as glycinate, n = 28) or matched placebo (n = 24) for 13 weeks: 8 weeks monotherapy and then 5 weeks with added d-amphetamine (AMPH). AMPH dose was weight-standardized for 2 weeks and then clinically optimized by week 13. Zinc glycinate was chosen as having less gastrointestinal discomfort than sulfate. Hypotheses were that zinc would improve inattention more than placebo by effect size of d > 0.25 at 8 weeks; zinc+AMPH would improve ADHD symptoms more than placebo+AMPH by d > 0.25, and optimal dose of AMPH with zinc would be 20% lower than with placebo. An interim analysis requested by the National Institute of Mental Health resulted in an increased dosage, so that 20 received 15 mg/day qAM and 8 received 30 mg/day (15 mg b.i.d.) RESULTS: Only the third hypothesis was upheld: Optimal mg/kg AMPH dose with b.i.d. zinc was 37% lower than with placebo. Other clinical outcomes were equivocal, sometimes favoring zinc, sometimes placebo, but objective neuropsychological measures mostly favored b.i.d. zinc (d = 0.36-0.7). Safety tests and adverse events were not different between groups. Copper and iron blood indices were not impaired by 8 weeks of 30 mg/day zinc. CONCLUSION: Doses up to 30 mg/day of zinc were safe for at least 8 weeks, but clinical effect was equivocal except for 37% reduction in amphetamine optimal dose with 30 mg/day zinc (not with 15 mg). Possible reasons for difference from mideastern reports include endemic diets, population genetics, relative rate of zinc deficiency, difference in background nutrition, insufficient dosage or absorption, or wrong anion (sulfate may be necessary for reported benefit). Dose may be especially important: All visually impressive advantages over placebo appeared only with 15 mg b.i.d. rather than once a day. Future research should use larger doses than 15 mg/day, provide a basic recommended daily allowance/intake multivitamin/mineral supplement for all to standardize background nutrition, select participants for low zinc, and consider the issue of anion interaction.

Vestibular Stimulation for ADHD: randomized controlled trial of Comprehensive Motion Apparatus.

OBJECTIVE: This research evaluates effects of vestibular stimulation by Comprehensive Motion Apparatus (CMA) in ADHD. METHOD: Children ages 6 to 12 (48 boys, 5 girls) with ADHD were randomized to thrice-weekly 30-min treatments for 12 weeks with CMA, stimulating otoliths and semicircular canals, or a single-blind control of equal duration and intensity, each treatment followed by a 20-min typing tutorial. RESULTS: In intent-to-treat analysis (n = 50), primary outcome improved significantly in both groups (p = .0001, d = 1.09 to 1.30), but treatment difference not significant (p = .7). Control children regressed by follow-up (difference p = .034, d = 0.65), but overall difference was not significant (p = .13, d = .47). No measure showed significant treatment differences at treatment end, but one did at follow-up. Children with IQ-achievement discrepancy > or = 1 SD showed significantly more CMA advantage on three measures. CONCLUSION: This study illustrates the importance of a credible control condition of equal duration and intensity in trials of novel treatments. CMA treatment cannot be recommended for combined-type ADHD without learning disorder.

Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial.

OBJECTIVE: To determine whether acetyl-L-carnitine (ALC), a metabolite necessary for energy metabolism and essential fatty acid anabolism, might help attention-deficit/hyperactivity disorder (ADHD). Trials in Down's syndrome, migraine, and Alzheimer's disease showed benefit for attention. A preliminary trial in ADHD using L-carnitine reported significant benefit. METHOD: A multi-site 16-week pilot study randomized 112 children (83 boys, 29 girls) age 5-12 with systematically diagnosed ADHD to placebo or ALC in weight-based doses from 500 to 1500 mg b.i.d. The 2001 revisions of the Conners' parent and teacher scales (including DSM-IV ADHD symptoms) were administered at baseline, 8, 12, and 16 weeks. Analyses were ANOVA of change from baseline to 16 weeks with treatment, center, and treatment-by-center interaction as independent variables. RESULTS: The primary intent-to-treat analysis, of 9 DSM-IV teacher-rated inattentive symptoms, was not significant. However, secondary analyses were interesting. There was significant (p = 0.02) moderation by subtype: superiority of ALC over placebo in the inattentive type, with an opposite tendency in combined type. There was also a geographic effect (p = 0.047). Side effects were negligible; electrocardiograms, lab work, and physical exam unremarkable. CONCLUSION: ALC appears safe, but with no effect on the overall ADHD population (especially combined type). It deserves further exploration for possible benefit specifically in the inattentive type.

Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to explore the relationship of zinc nutrition to the severity of attention-deficit/hyperactivity disorder (ADHD) symptoms in a middle-class American sample with well-diagnosed ADHD. Previous reports of zinc in ADHD, including two positive clinical trials of supplementation, have come mainly from countries and cultures with different diets and/or socioeconomic realities. METHOD: Children 5-10 years of age with DISC- and clinician-diagnosed ADHD had serum zinc determinations and parent and teacher ratings of ADHD symptoms. Zinc levels were correlated (Pearson's and multiple regression) with ADHD symptom ratings. RESULTS: Forty-eight children (37 boys, 11 girls; 33 combined type, 15 inattentive) had serum zinc levels with a median/mode at the lowest 30% of the laboratory reference range; 44 children also had parent/teacher ratings. Serum magnesium levels were normal. Nutritional intake by a parent-answered food frequency questionnaire was unremarkable. Serum zinc correlated at r = -0.45 (p = 0.004) with parent-teacher-rated inattention, even after controlling for gender, age, income, and diagnostic subtype, but only at r = -0.20 (p = 0.22) with CPT omission errors. In contrast, correlation with parent-teacher-rated hyperactivity-impulsivity was nonsignificant in the opposite direction. CONCLUSION: These findings add to accumulating evidence for a possible role of zinc in ADHD, even for middle-class Americans, and, for the first time, suggest a special relationship to inattentive symptoms. They do not establish either that zinc deficiency causes ADHD nor that ADHD should be treated with zinc. Hypothesis-testing clinical trials are needed.