Role of zinc in the pathogenesis of attention-deficit hyperactivity disorder: implications for research and treatment

CNS Drugs. 2010 Sep;24(9):721-8. doi: 10.2165/11537610-000000000-00000.


The dopamine transporter is regulated by zinc (Zn2+), which directly interacts with the transporter protein as a potent non-competitive blocker of substrate translocation (dopamine transport inward and outward). The fact that dysfunction of the dopamine transporter is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD) is interesting in the context of studies that suggest the involvement of zinc deficiency in patients with ADHD. In this article, we present a hypothesis exploring the causative mechanism of zinc deficiency in ADHD and why zinc might be beneficial as a supplementary medication and/or adjunct to psychostimulants (methylphenidate, amfetamine) in zinc-deficient ADHD patients. The hypothesis is based on published in vitro observations that the human dopamine transporter contains a high-affinity zinc binding site (His-193, His-375, Glu-396) on its extracellular face that modulates transporter function, and in vivo studies suggesting that response to stimulants is reduced in zinc-deficient ADHD patients. It seems likely that zinc supplementation in zinc-deficient ADHD patients improves the binding status of insufficiently occupied zinc binding sites on the dopamine transporter. We propose to test our hypothesis by recruiting zinc-deficient ADHD patients who will undergo positron emission tomography with the 11C-raclopride displacement method to investigate whether zinc increases extracellular dopamine levels.

Publication types

  • Review

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / etiology*
  • Central Nervous System Stimulants / therapeutic use
  • Dietary Supplements*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Drug Therapy, Combination
  • Humans
  • Methylphenidate / therapeutic use
  • Treatment Outcome
  • Zinc / deficiency*
  • Zinc / therapeutic use*


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Methylphenidate
  • Zinc