Attention-deficit/hyperactivity disorder: is it time to reappraise the role of sugar consumption?

Abstract

Attention-deficit/hyperactivity disorder (ADHD) affects nearly 10% of children in the United States, and the prevalence of this disorder has increased steadily over the past decades. The cause of ADHD is unknown, although recent studies suggest that it may be associated with a disruption in dopamine signaling whereby dopamine D2 receptors are reduced in reward-related brain regions. This same pattern of reduced dopamine-mediated signaling is observed in various reward-deficiency syndromes associated with food or drug addiction, as well as in obesity. While genetic mechanisms are likely contributory to cases of ADHD, the marked frequency of the disorder suggests that other factors are involved in the etiology. In this article, we revisit the hypothesis that excessive sugar intake may have an underlying role in ADHD. We review preclinical and clinical data suggesting overlaps among ADHD, sugar and drug addiction, and obesity. Further, we present the hypothesis that the chronic effects of excessive sugar intake may lead to alterations in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD. We recommend further studies to investigate the possible relationship between chronic sugar intake and ADHD.

Figure 1

Midsagittal view of the human brain with dopamine pathways. The light gray lines show the mesolimbic pathway (ventral tegmental area to the prefrontal cortex and nucleus accumbens). The dark gray lines show the nigrostriatal pathway (substantia nigra to the dorsal striatum or caudate/putamen).

Figure 2

Proposed pathway for the development of symptoms associated with ADHD. The ingestion of sugar or other sweeteners results in an acute elevated dopamine release in the striatum associated with reward. This may lead to increasing sugar ingestion, which, over weeks to months, results in a reduction in striatal D₂ receptors. To compensate, increased sugar intake occurs, resulting in dopamine responses that slowly decrease over time. In the periods between sugar ingestion, extracellular dopamine levels may progressively decrease, leading to a low dopamine state. The low dopamine state results in inhibition of frontal cortex control mechanisms, leading to ADHD symptomatology and obesity-prone binge-eating behavior. Abbreviation: ADHD, atention-deficit/hyperactivity disorder.

Figure 3

Differences between glucose and fructose metabolism. Glucose is phosphorylated by glucokinase into glucose-6-phosphate, which is isomerized to fructose-6-phosphate as part of the glycolysis for ATP production in the mitochondria and fat accumulation. Excessive fructose-6-phosphate generation activates GKRP for glucokinase inhibition. Unlike glucose, fructose metabolism is not negatively regulated. Therefore, fructose readily induces intracellular phosphate and ATP depletion during its metabolism by fructokinase. The decrease in intracellular phosphate that occurs during fructose metabolism also results in the stimulation of AMPD, which converts AMP to IMP and uric acid. Abbreviations: AMP, adenosine monophosphate; AMPD, adenosine monophosphate deaminase; ATP, adenosine triphosphate; GKRP, glucokinase regulatory protein; IMP, inosine monophosphate.