The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type

Neurochem Res. 2022 Sep;47(9):2890-2898. doi: 10.1007/s11064-022-03693-y. Epub 2022 Aug 11.


Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention deficit/hyperactivity disorder (ADHD) symptoms, but the neurochemical mechanism of central fatigue remains hypothetical. The serotonin hypothesis of central fatigue was proposed first, serving as the central dogma for the molecular and neural mechanisms of central fatigue, and underpinning many studies. The tryptophan hypothesis was proposed because tryptophan released into the synaptic cleft of neurons in the brain coincides with and responds sensitively to development of fatigue. Tryptophan is highly bioactive, with brain concentrations of 50 to 200 times that of serotonin. The tryptophan-kynurenic acid-synergy hypothesis posits that central fatigue is not monocausal but a synergistic effect between tryptophan itself and its catabolite kynurenic acid. Central fatigue is associated with mental health problems and is a cause of inattention, thereby warranting scrutiny for its relationship with ADHD. Fatigability in ADHD is mediated by tryptophan, in which abnormal enhancement of the tryptophan-kynurenine-kynurenic acid pathway causes an imbalance in monoamine nervous system function. Notably, noradrenergic neuronal dysfunction is associated with the characteristic inattention of ADHD. Neutral amino acids such as branched-chain amino acids (BCAAs) can assist recovery from attentional and cognitive decline caused by central fatigue. Since they are transported by the same L-amino acid transporter as tryptophan, BCAAs compete with tryptophan to inhibit its brain uptake. Controlling central fatigue this way may improve attentional cognitive performance.

Keywords: ADHD; BCAAs; Central fatigue; Kynurenic acid; Monoamine; Tryptophan.

MeSH terms

  • Amino Acids, Branched-Chain / metabolism
  • Attention Deficit Disorder with Hyperactivity* / metabolism
  • Cognition
  • Humans
  • Kynurenic Acid
  • Quality of Life
  • Serotonin / metabolism
  • Tryptophan / metabolism


  • Amino Acids, Branched-Chain
  • Serotonin
  • Tryptophan
  • Kynurenic Acid