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Kynurenine Pathway, Energy Regulation & Stress Response

The broader picture of mental health, specifically depression, has been correlated with melatonin levels. While low serotonin levels are known to be consistent with clinical depression, low melatonin levels also appear to have a significant connection. Low levels of melatonin may trigger an upregulation in the kynurenine pathway, and kynurenine production, as well as trigger the aryl hydrocarbon receptor (AhR) located on the outer membrane of the mitochondria (1–5). The AhR is responsible for modulating mitochondrial metabolism, melatonergic pathways, acetyl-coenzyme A, and COX-2 prostaglandin. When AhR is triggered, overall endogenous pineal melatonin production is suppressed (1–5).


Melatonin is derived from serotonin using 5-hydroxytryptophan (5-HTP) and tryptophan (1,2). Tryptophan is involved primarily in the melatonin-serotonin pathway and the kynurenic pathway. The melatonin-serotonin pathway accounts for approximately five percent of dietary tryptophan degradation, while the kynurenic pathway accounts for approximately 95 percent of dietary tryptophan degradation (1,3). The kynurenic pathway is an essential process needed to convert tryptophan into nicotinamide adenine dinucleotide (NAD+) for cellular energy. Although the bisecting pathways of tryptophan are involved in separate processes, one pathway is thought to impact the other. Exercise has been found to increase the throughput in the serotonin-melatonin pathway, eventually increasing both serotonin and melatonin levels and impacting mood and cognition (2). Conversely, acute or chronic inflammation and stress have been found to increase the throughput of the kynurenine pathway, leading to an increase in tryptophan’s conversion to kynurenine (1,2). Kynurenine is a byproduct or metabolite produced when tryptophan is converted to niacin. High concentration levels of kynurenine in the brain are present in instances of depression (1,2). Kynurenine is then converted to either kynurenic acid or quinolinic acid. Quinolinic acid is a neurotoxin, while kynurenic acid has neuroprotective properties (1–5).


In addition to the kynurenine pathway, Fila et al. (6) reported that the GI tract is also a major site for tryptophan metabolism. These pathways are interconnected, and when there is dysregulation with one, there is most likely dysregulation with the other. Many neurological disorders feature elements of the kynurenine pathway of tryptophan, specifically the dysregulation of tryptophan metabolism and subsequent melatonin production.



Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: September 22, 2022



1. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, et al. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020;10(9).

2. Ferlazzo N, Andolina G, Cannata A, Costanzo MG, Rizzo V, Currò M, et al. Is melatonin the cornucopia of the 21st century? Vol. 9, Antioxidants. 2020.

3. Maffei ME. 5-hydroxytryptophan (5-htp): Natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Vol. 22, International Journal of Molecular Sciences. 2021.

4. J. Reiter R, C. Manchester L, Tan DX. Neurotoxins: Free Radical Mechanisms and Melatonin Protection. Curr Neuropharmacol. 2010;8(3).

5. Brinkmann V, Ale-Agha N, Haendeler J, Ventura N. The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor. Vol. 10, Frontiers in Physiology. 2020.

6. Fila M, Chojnacki J, Pawlowska E, Szczepanska J, Chojnacki C, Blasiak J. Kynurenine pathway of tryptophan metabolism in migraine and functional gastrointestinal disorders. Vol. 22, International Journal of Molecular Sciences. 2021.

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