The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms

Am J Psychiatry. 2010 Sep;167(9):1108-15. doi: 10.1176/appi.ajp.2010.09101529. Epub 2010 Jun 15.


Objective: Food additives can exacerbate ADHD symptoms and cause non-immunoglobulin E-dependent histamine release from circulating basophils. However, children vary in the extent to which their ADHD symptoms are exacerbated by the ingestion of food additives. The authors hypothesized that genetic polymorphisms affecting histamine degradation would explain the diversity of responses to additives.

Method: In a double-blind, placebo-controlled crossover trial, challenges involving two food color additive and sodium benzoate (preservative) mixtures in a fruit drink were administered to a general community sample of 3-year-old children (N = 153) and 8/9-year-old children (N = 144). An aggregate ADHD symptom measure (based on teacher and parent blind ratings of behavior, blind direct observation of behavior in the classroom, and--for 8/9-year-old children only--a computerized measure of attention) was the main outcome variable.

Results: The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. There was no evidence that polymorphisms in catecholamine genes COMT Val108Met, ADRA2A C1291G, and DRD4-rs7403703 moderated the effect on ADHD symptoms.

Conclusions: Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Attention Deficit Disorder with Hyperactivity / chemically induced*
  • Attention Deficit Disorder with Hyperactivity / diagnosis
  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Child
  • Diet / adverse effects
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Female
  • Food Additives / adverse effects*
  • Food Additives / pharmacology
  • Food Coloring Agents / adverse effects
  • Food Coloring Agents / pharmacology
  • Histamine / genetics*
  • Histamine / metabolism
  • Histamine N-Methyltransferase / genetics
  • Histamine Release / drug effects
  • Histamine Release / genetics
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Dopamine D4 / drug effects
  • Receptors, Dopamine D4 / genetics


  • DRD4 protein, human
  • Dopamine Plasma Membrane Transport Proteins
  • Food Additives
  • Food Coloring Agents
  • SLC6A3 protein, human
  • Receptors, Dopamine D4
  • Histamine
  • Histamine N-Methyltransferase
  • Dopamine