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Review
. 2024 Nov 10;14(11):611.
doi: 10.3390/metabo14110611.

Impact of Substance Use Disorder on Tryptophan Metabolism Through the Kynurenine Pathway: A Narrative Review

Lindsey Contella  1   2 , Christopher L Farrell  1 , Luigi Boccuto  1 , Alain H Litwin  3   4   5 , Marion L Snyder  2
Affiliations
Review

Impact of Substance Use Disorder on Tryptophan Metabolism Through the Kynurenine Pathway: A Narrative Review

Lindsey Contella et al. Metabolites. .

Abstract

Background/Objectives: Substance use disorder is a crisis impacting many people in the United States. This review aimed to identify the effect addictive substances have on the kynurenine pathway. Tryptophan is an essential amino acid metabolized by the serotonin and kynurenine pathways. The metabolites of these pathways play a role in the biological reward system. Addictive substances have been shown to cause imbalances in the ratios of these metabolites. With current treatment and therapeutic options being suboptimal, identifying biochemical mechanisms that are impacted during the use of addictive substances can provide alternative options for treatment or drug discovery. Methods: A systematic literature search was conducted to identify studies evaluating the relationship between substance use disorder and tryptophan metabolism through the kynurenine pathway. A total of 32 articles meeting eligibility criteria were used to review the relationship between the kynurenine pathway, tryptophan breakdown, and addictive substances. Results: The use of addictive substances dysregulates tryptophan metabolism and kynurenine metabolite concentrations. This imbalance directly affects the dopamine reward system and is thought to promote continued substance use. Conclusions: Further studies are needed to fully evaluate the metabolites of the kynurenine pathway, along with other options for treatment to repair the metabolite imbalance. Several possible therapeutics have been identified; drugs that restore homeostasis, such as Ro 61-8048 and natural products like Tinospora cordifolia or Decaisnea insignis, are promising options for the treatment of substance use disorder.

Keywords: kynurenine pathway; substance use disorder; tryptophan.

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Conflict of interest statement

Lindsey Contella and Marion L. Snyder are employees of Luxor Scientific. The paper reflects the views of the scientists, and not the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Metabolism of TRP by the KP. The KP has two main branches: the neurotoxic pathway and the neuroprotective pathway. The impacts addictive substances have on KP metabolites in the blood are shown in grey boxes: + indicates an increase, − decrease, = no change, and § mixed results. Enzymes involved in the pathway are shown in shaded boxes. Abbreviations: EtOH: alcohol; METH: methamphetamine; TRP: tryptophan hydroxylase; AA: aromatic acid; IDO1: indoleamine 2,3-dioxygenase-1; IDO2: indoleamine 2,3-dioxygenase-2; TDO: tryptophan 2,3-dioxygenase; KATs: kynurenine aminotransferases; KMO: kynurenine 3-monooxygenase; KYNU: kynureninase; NE: Nonenzymatic; HAAO: 3-hydroxy anthranilate 3,4-dioxygenase; AFMID: arylformamidase; ACMSD: α-amino-β-carboxymuconate-ε-semialdehyde-decarboxylase; AADAT: aminoadipate aminotransferase; NAD+: nicotinamide adenine dinucleotide.
Figure 2
Figure 2
Flow diagram depicting selection of literature included in systematic search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
See this image and copyright information in PMC

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