Nagamine T. Kynurenine pathway dysregulation in attention-deficit hyperactivity disorder: Impact on N-methyl-D-aspartate receptors and phasic dopamine maturation. World J Clin Pediatr 2026; 15(3): 120485 [DOI: 10.5409/wjcp.120485]
Corresponding Author of This Article
Takahiko Nagamine, MD, PhD, Professor Emeritus, Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, 4-13-18 Jiyugaoka, Hofu 7470066, Yamaguchi, Japan. anagamine@yahoo.co.jp
Research Domain of This Article
Psychiatry
Article-Type of This Article
review-article
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World J Clin Pediatr. Sep 9, 2026; 15(3): 120485 Published online Sep 9, 2026. doi: 10.5409/wjcp.120485
Kynurenine pathway dysregulation in attention-deficit hyperactivity disorder: Impact on N-methyl-D-aspartate receptors and phasic dopamine maturation
Takahiko Nagamine
Takahiko Nagamine, Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Hofu 7470066, Yamaguchi, Japan
Author contributions: Nagamine T carried out all aspects of this work.
AI contribution statement: The only AI-related thing I use is Google’s English proofreading.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Corresponding author: Takahiko Nagamine, MD, PhD, Professor Emeritus, Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, 4-13-18 Jiyugaoka, Hofu 7470066, Yamaguchi, Japan. anagamine@yahoo.co.jp
Received: February 27, 2026 Revised: March 13, 2026 Accepted: May 7, 2026 Published online: September 9, 2026 Processing time: 152 Days and 13.3 Hours
Abstract
Recent evidence highlights a significant shift in the kynurenine pathway (KP) toward a neurotoxic profile in medication-naïve children with attention-deficit/hyperactivity disorder (ADHD). This article contextualizes these metabolic alterations – specifically the reduction in kynurenic acid (KYNA) and the elevation of the quinolinic acid (QUIN)/KYNA ratio – as active drivers of neurodevelopmental pathology rather than mere biomarkers. We hypothesize that chronic KP dysregulation disrupts the “N-methyl-D-aspartate-dopamine link”, where KYNA deficiency leads to N-methyl-D-aspartate receptor disinhibition, subsequently interfering with the phasic dopaminergic signaling essential for executive function. Furthermore, the convergence of these metabolic signatures with those found in affective disorders provides a biological rationale for the high rates of depressive comorbidity in ADHD. We discuss the potential for targeting the KP, particularly through kynurenine 3-monooxygenase inhibition, to restore glutamatergic homeostasis. Crucially, we address the role of blood-brain barrier permeability in ADHD as a factor that may exacerbate the impact of peripheral kynurenine metabolites on central nervous system function.
Core Tip: The metabolic imbalance characterized by low kynurenic acid and high quinolinic acid in drug-naïve attention-deficit/hyperactivity disorder patients suggests a systemic failure of neuroprotective mechanisms. This biochemical environment likely disrupts N-methyl-D-aspartate receptor modulation, interfering with the maturation of dopaminergic pathways. The increased permeability of the blood-brain barrier in attention-deficit/hyperactivity disorder may allow these peripheral metabolites to exert a more direct influence on central neurotransmission, making the kynurenine pathway a primary therapeutic target.
