Neurochemical Insights into the Role of Tryptophan Metabolites and Kynurenine Pathway in Insomnia and its Psychological and Neurological Comorbidities.

Insomnia is a ubiquitous complaint among many people worldwide, significantly impacting cognition, mood, and overall well-being. Despite significant advances made to understand and manage insomnia, shortcomings of its therapeutic interventions are still a concern, as they only provide temporary benefits. Alterations in the immunometabolic fate of tryptophan (TRP) are highly relevant to many neuropsychiatric conditions, including insomnia. TRP is a precursor for synthesizing the neurotransmitter serotonin and many immunoregulatory and neuroactive kynurenines that control energy homeostasis and modulate behavior. Disturbances in TRP metabolic balance, often triggered by neuronal inflammation and immune system activation, lead to dysregulation of the kynurenine pathway (KP). Understanding the neurochemical changes and molecular consequences of KP activation during insomnia and its contribution to other comorbid conditions is yet to be fully investigated. Therefore, this narrative review navigates into the intricate role of TRP metabolism in insomnia and its psychological and neurological comorbidities, particularly cognitive dysfunction, depression, anxiety, stress, traumatic brain injury (TBI), chronic pain, and substance abuse. It also aims to identify potential therapeutic targets within the immune system and TRP metabolism by highlighting current knowledge and inconsistencies. It also explores how alterations in TRP metabolism may contribute to cognitive and affective psychological comorbidities and neurological disorders.