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

Abstract

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.

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  • Authors+Show Affiliations

    ,

    The Nisonger Center, Ohio State University , Columbus, Ohio, USA.

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    Source

    MeSH

    Adolescent
    Attention Deficit Disorder with Hyperactivity
    Central Nervous System Stimulants
    Child
    Copper
    Dextroamphetamine
    Dose-Response Relationship, Drug
    Double-Blind Method
    Drug Therapy, Combination
    Female
    Glycine
    Humans
    Iron
    Male
    Neuropsychological Tests
    Pilot Projects

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21309695

    Citation

    Arnold, L Eugene, et al. "Zinc for Attention-deficit/hyperactivity Disorder: Placebo-controlled Double-blind Pilot Trial Alone and Combined With Amphetamine." Journal of Child and Adolescent Psychopharmacology, vol. 21, no. 1, 2011, pp. 1-19.
    Arnold LE, Disilvestro RA, Bozzolo D, et al. Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. J Child Adolesc Psychopharmacol. 2011;21(1):1-19.
    Arnold, L. E., Disilvestro, R. A., Bozzolo, D., Bozzolo, H., Crowl, L., Fernandez, S., ... Joseph, E. (2011). Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), pp. 1-19. doi:10.1089/cap.2010.0073.
    Arnold LE, et al. Zinc for Attention-deficit/hyperactivity Disorder: Placebo-controlled Double-blind Pilot Trial Alone and Combined With Amphetamine. J Child Adolesc Psychopharmacol. 2011;21(1):1-19. PubMed PMID: 21309695.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. AU - Arnold,L Eugene, AU - Disilvestro,Robert A, AU - Bozzolo,Dawn, AU - Bozzolo,Hernan, AU - Crowl,Lindsay, AU - Fernandez,Soledad, AU - Ramadan,Yaser, AU - Thompson,Susan, AU - Mo,Xiaokui, AU - Abdel-Rasoul,Mahmoud, AU - Joseph,Elizabeth, PY - 2011/2/12/entrez PY - 2011/2/12/pubmed PY - 2011/6/11/medline SP - 1 EP - 19 JF - Journal of child and adolescent psychopharmacology JO - J Child Adolesc Psychopharmacol VL - 21 IS - 1 N2 - 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. SN - 1557-8992 UR - https://www.unboundmedicine.com/medline/citation/21309695/full_citation L2 - https://www.liebertpub.com/doi/full/10.1089/cap.2010.0073?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -