TryptophanTrp · W

In brief

The molecule

Tryptophan’s side chain is indole, a benzene ring fused to a five-membered ring containing nitrogen. It is the largest of the twenty standard side chains ¹.

It is also the most expensive amino acid to build, with the most complex and energy-consuming synthesis, and the least abundant free amino acid in cells; it is one of the rarest in the proteome ¹.

Where it comes from

Animals cannot make the indole ring, so tryptophan is essential. The adult requirement is 4 mg per kilogram a day ²; a 2026 study in 23 adults over 60 found an average need of 3.9, with no difference between men and women or between people in their sixties and seventies ¹¹.

Tryptophan also counts towards niacin. About 60 mg of dietary tryptophan is generally taken to yield 1 mg of niacin, and a study in Japanese women estimated 67 ⁶; the ratio is not fixed and changes with how much niacin is already present ¹².

EssentialMust come from food. The adult requirement is 4 mg per kilogram a day; a 2026 tracer study in adults over 60 found 3.9 ^2,11.

In the bottle · fermentedMade by fermentation in engineered bacteria through the shikimate pathway ¹³. Fermentation is also how the 1989 disaster happened: one manufacturer changed its bacterial strain and purification, and impurities in its product were linked to eosinophilia–myalgia syndrome ^9,10.

What the body does with it

The kynurenine pathway handles about 95% of tryptophan breakdown and makes NAD⁺, the electron carrier of every cell ⁵. Its first step is the control point: tryptophan 2,3-dioxygenase in the liver, induced by glucocorticoids and regulated by heme, and indoleamine 2,3-dioxygenase in other tissues, induced by interferon-γ ⁵.

Serotonin is made by tryptophan hydroxylase, the rate-limiting enzyme. TPH1 works in the enterochromaffin cells of the gut, which make almost all of the body’s peripheral serotonin; TPH2 works in the raphe neurons of the brain ^3,14. Serotonin does not readily cross the blood–brain barrier, so the gut’s serotonin and the brain’s are separate supplies ³. Peripheral serotonin has a job nobody was looking for, which is deciding how much of an injected drug survives. Intestinal epithelial cells sense microbial stimulation and remotely activate liver Kupffer cells by producing serotonin, and that drives hepatic clearance of delivery systems — lipid nanoparticles, viral vectors and the rest. Transiently suppressing serotonin signaling, by receptor blockade or by dietary intervention, reduced that clearance and improved delivery: more than threefold better effect in chemotherapy and oncolytic virotherapy, and 5- to 15-fold in somatic genome editing and mRNA therapies ¹⁵. The gut's serotonin and the brain's are separate supplies, and the gut's turns out to set the dose of everything else.

In the pineal gland and elsewhere, serotonin is acetylated and then methylated to make melatonin ⁴.

Gut bacteria take a third route, turning tryptophan into indoles. One of them, indole-3-propionic acid, exists in mice only when gut bacteria are present ¹⁶; in people, higher levels go with a more diverse microbiome and a lower risk of developing type 2 diabetes ^17,18. Two 2025 and 2026 papers sharpen that, in opposite directions. The claim that indole-3-propionic acid is microbial was established in mice; in people it has now been done directly — in participants with and without type 2 diabetes given seven days of broad-spectrum antibiotics, it was the ONLY gut-derived metabolite that differed between the groups beforehand (lower in diabetes, with higher levels associated with lower odds of the disease), and antibiotics drove it to near-undetectable in both groups. It also correlated inversely with glycemic variability, and the species it tracked were not the known producers, suggesting the whole community rather than particular taxa set the level ¹⁹. A different indole runs the other way. In a general-population cohort of 13,464 people, higher baseline indole-3-ACETIC acid was associated with a higher risk of future hospital admission for pneumonia (hazard ratio 1.15, 95% CI 1.09 to 1.22); in 158 critically ill patients with severe community-acquired pneumonia it was associated with higher mortality (HR 1.30 per log₂ increase); and in mice, supplementing it worsened lung damage while reducing systemic spread, through the aryl hydrocarbon receptor and more reactive oxygen species from neutrophils ²⁰. The authors' own conclusion is the one to keep: various indoles may have diverging, context-dependent effects. “Gut indoles are good for you” is not a statement this evidence supports.

The kynurenine route's destination can be switched by the nervous system, which is new. In oncogene-driven and carcinogen-driven liver cancer in male mice, psychological stress disrupted catecholamine signaling through the β2-adrenergic receptor, which suppressed hepatocyte expression of quinolinate phosphoribosyl transferase — the enzyme that carries kynurenine's carbons on to NAD⁺. Losing it diverted the flux into kynurenic acid, which impaired mitochondria and blunted the effector function of liver CD8 T cells. In human liver tissue, β2-adrenergic receptor and QPRT expression tracked hepatic NAD⁺ and kynurenic acid and the frequency and function of CD8 T cells; and in stressed mice, overexpressing either enzyme or giving nicotinamide restored T cell function and slowed the cancer ²¹. The quiet default route to NAD⁺ has a brain-to-liver switch on it, and chronic stress turns it the wrong way.

How it is made, moved and broken down

In carcinoid syndrome, a tumor turns large amounts of tryptophan into serotonin and so diverts it from NAD; ten of 36 such patients were biochemically niacin-deficient and one had pellagra ²². How often that happens, and how to tell, are both less settled than one study makes them look. A 2026 scoping review of 24 sources finds marked heterogeneity across levels of assessment: urinary 5-HIAA and plasma tryptophan give context on serotonin burden and substrate availability but do NOT define niacin status; biochemical depletion has most often been judged by urinary niacin metabolites, particularly 24-hour N1-methylnicotinamide; functional depletion by whole-blood NAD/NADP indices; and overt pellagra is uncommon and a late, insensitive endpoint. Differing markers and definitions explain most of why the studies cannot be compared, and the authors call their own conclusions hypothesis-generating ²⁶.

Carbon skeleton · glucogenic and ketogenicClassed as both glucogenic and ketogenic, but its more important product is NAD⁺ ⁵.

Where it matters most

Liver

Breaks down most tryptophan, by TDO, into kynurenine and on to NAD⁺ ⁵.

Gut

Enterochromaffin cells make almost all peripheral serotonin; gut bacteria make indoles of their own ^3,27.

Brain

Raphe neurons make serotonin with TPH2, from tryptophan that has competed its way across the blood–brain barrier ^3,24.

Immune cells and inflamed tissue

Interferon-γ induces IDO, which consumes tryptophan locally ^5,23.

Skin

Malassezia furfur, a commensal YEAST, makes tryptophan-derived metabolites that activate the aryl hydrocarbon receptor and maintain the epidermal barrier ²⁸.

When it goes wrong

How it is measured

Tryptophan’s products are measured more often than tryptophan itself. 5-HIAA follows serotonin-secreting tumors ³⁰; the kynurenine-to-tryptophan ratio follows immune activation in research ²³; and niacin status, not tryptophan, is measured when pellagra is suspected ²². What 5-HIAA tracks is narrower than it looks. In 232 patients with neuroendocrine neoplasms, spot urinary 5-HIAA showed no significant association with depression scores, with global health status, with endocrine symptoms or with the DIARRHEA score — and higher 5-HIAA went with LOWER anxiety and fewer gastrointestinal symptoms, the opposite of what the symptom story predicts. Men had roughly twice the 5-HIAA of women and reported fewer symptoms ³⁶. The marker follows the tumor's serotonin output; on this evidence it does not follow how the patient feels.

• 5-HIAA, in urine or bloodThe main breakdown product of serotonin, measured to diagnose and follow serotonin-secreting neuroendocrine tumors ³⁰.In midgut neuroendocrine tumors, the 24-hour urine test discriminated with an area under the curve of 0.80, and plasma 0.72; in one comparison, serum at a 135 nmol/L cut-off had 91% sensitivity against urine ^30,31.Specificity was only about 62% in that comparison, and the test reflects tumor serotonin, not the serotonin of the brain ^3,31.
• Kynurenine-to-tryptophan ratioA blood index of how fast IDO is breaking tryptophan down ²³.Research.Tracks immune activation driven by interferon-γ ²³.Not specific to any one disease; meaningful only alongside other immune markers ²³.
• Plasma tryptophanFree and total tryptophan in plasma; low in Hartnup disorder, where it is lost in the urine ⁸.A single plasma value does not say how much reaches the brain, which depends on the competing amino acids ²⁴.

Food, supplements and the evidence

What is strange about it

In 1989 an epidemic of eosinophilia–myalgia syndrome, with disabling muscle pain and very high eosinophil counts, was traced to tryptophan made by one Japanese company: 29 of 30 cases had taken its product, against 21 of 35 controls ⁹. Contaminants appeared after it changed its bacterial strain and cut the carbon used to purify the product ^9,10; in 2017 one of them, “peak AAA,” was still being structurally identified ³². The contaminant explanation is less settled than this page has treated it. A 2023 review of the episode notes that six components generated during L-tryptophan synthesis have been SPECULATED to induce the syndrome, and that although many in vitro and in vivo studies have assessed the link between impurities and the disease, “no clear and convincing conclusions have been drawn so far” ⁴⁴. Four of that review's six authors are employed by a major manufacturer of L-tryptophan, which is a reason to weigh its framing carefully — and not a reason to ignore the concession, which is a factual statement about what the literature establishes.

Tryptophan supplements vanished from US shelves after the epidemic, and 5-HTP took their place ⁴⁵.

The serotonin theory of depression rests partly on tryptophan depletion studies. Pooled, they lowered mood in drug-free people who had recovered from depression, slightly in those with a family history, and not at all in healthy volunteers ^46,47. The peripheral biochemistry has not held up as neatly. A 2026 synthesis records that recent meta-analyses do show peripheral tryptophan to be lower in depression, but do NOT show a consistent increase in the kynurenine-to-tryptophan ratio, with cerebrospinal fluid findings varying between studies; changes in kynurenine, 3-hydroxykynurenine and quinolinic acid are more apparent in inflammatory SUBGROUPS than in unselected samples; modern evidence for L-tryptophan monotherapy is sparse; and trials of 5-hydroxytryptophan and of microbiota-directed interventions have been mixed. The author proposes the framework for research purposes and says explicitly that it is not for clinical diagnosis or routine supplementation ⁴⁸.

Where it connects

Sources

48 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   Barik S. The uniqueness of tryptophan in biology: properties, metabolism, interactions and localization in proteins.Int J Mol Sci · 2020 · 21(22):8776doi:10.3390/ijms21228776 · PMID 33233627

   Largest amino acid; most costly to make; least abundant.

2. 2
   Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.World Health Organ Tech Rep Ser · 2007 · (935):1–265PMID 18330140

   Tryptophan, 4 mg/kg/day.

3. 3
   Jones LA, Sun EW, Martin AM, Keating DJ. The ever-changing roles of serotonin.Int J Biochem Cell Biol · 2020 · 125:105776doi:10.1016/j.biocel.2020.105776 · PMID 32479926

   TPH1 in gut, TPH2 in brain; peripheral serotonin from enterochromaffin cells.

4. 4
   Tan DX, Hardeland R, Back K, et al. On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species.J Pineal Res · 2016 · 61(1):27–40doi:10.1111/jpi.12336 · PMID 27112772

   The classic pathway, serotonin to N-acetylserotonin to melatonin.

5. 5
   Badawy AA. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.Int J Tryptophan Res · 2017 · 10:1178646917691938doi:10.1177/1178646917691938 · PMID 28469468

   About 95% of tryptophan breakdown; TDO and IDO; NAD⁺.

6. 6
   Fukuwatari T, Ohta M, et al. Conversion ratio of tryptophan to niacin in Japanese women fed a purified diet conforming to the Japanese Dietary Reference Intakes.J Nutr Sci Vitaminol (Tokyo) · 2004 · 50(6):385–391doi:10.3177/jnsv.50.385 · PMID 15895512

   Ten women; about 67 mg tryptophan per mg niacin, against the usual 60.

7. 7
   Prabhu D, Dawe RS, Mponda K. Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra.Photodermatol Photoimmunol Photomed · 2021 · 37(2):99–104doi:10.1111/phpp.12659 · PMID 33471377

   Causes and features of pellagra.

8. 8
   Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.Nat Genet · 2004 · 36(9):999–1002doi:10.1038/ng1405 · PMID 15286787

   The Hartnup gene.

9. 9
   Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use.N Engl J Med · 1990 · 323(6):357–365doi:10.1056/NEJM199008093230601 · PMID 2370887

   29 of 30 cases against 21 of 35 controls used one company’s product.

10. 10
    Mayeno AN, Gleich GJ. Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale.Trends Biotechnol · 1994 · 12(9):346–352doi:10.1016/0167-7799(94)90035-3 · PMID 7765187

    How a manufacturing change introduced the impurities.

11. 11
    Wang Z, Tomlinson C, Pencharz P, et al. Dietary tryptophan requirements in adults aged >60 years is not affected by sex or decades of age.J Nutr · 2026 · 156(11):101827doi:10.1016/j.tjnut.2026.101827 · PMID 42727854

    23 older adults; 3.9 mg/kg/day pooled.

12. 12
    Fukuwatari T, Shibata K. Effect of nicotinamide administration on the tryptophan-nicotinamide pathway in humans.Int J Vitam Nutr Res · 2007 · 77(4):255–262doi:10.1024/0300-9831.77.4.255 · PMID 18271280

    The conversion ratio changes with niacin intake.

13. 13
    Hirasawa T, Satoh Y, Koma D. Production of aromatic amino acids and their derivatives by Escherichia coli and Corynebacterium glutamicum.World J Microbiol Biotechnol · 2025 · 41(2):65doi:10.1007/s11274-025-04264-3 · PMID 39915353

    Fermentation through the shikimate pathway.

14. 14
    Walther DJ, Peter JU, Bashammakh S, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform.Science · 2003 · 299(5603):76doi:10.1126/science.1078197 · PMID 12511643

    The discovery of TPH2.

15. 15
    Wang Q, Chen Z, Zhang G, et al. Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors.Science · 2026 · 391(6791):eadu7686doi:10.1126/science.adu7686 · PMID 41855345

    A gut-liver axis that sets how much of an injected therapy survives the liver. Mice.

16. 16
    Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.Proc Natl Acad Sci U S A · 2009 · 106(10):3698–3703doi:10.1073/pnas.0812874106 · PMID 19234110

    Mice: indole-3-propionic acid depends entirely on gut bacteria.

17. 17
    Menni C, Hernandez MM, Vital M, et al. Circulating levels of the anti-oxidant indoleproprionic acid are associated with higher gut microbiome diversity.Gut Microbes · 2019 · 10(6):688–695doi:10.1080/19490976.2019.1586038 · PMID 31030641

    1,018 women; microbiome explained far more of IPA than diet or genes.

18. 18
    de Mello VD, Paananen J, Lindström J, et al. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study.Sci Rep · 2017 · 7:46337doi:10.1038/srep46337 · PMID 28397877

    Observational; replicated in a Swedish cohort.

19. 19
    Westerbeke FHM, Warmbrunn MV, Rios-Morales M, et al. Plasma indole-3-propionic acid is a gut-derived metabolite and is associated with type 2 diabetes and cardiometabolic outcomes: evidence from a human antibiotic intervention.Gut Microbes · 2026 · 18(1):2736321doi:10.1080/19490976.2026.2736321 · PMID 42799756

    Seven days of broad-spectrum antibiotics as the experiment. The metabolite goes to near-undetectable, which settles where it comes from in people.

20. 20
    Kullberg RFJ, van Linge CCA, Haak BW, et al. Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia.Nat Commun · 2025 · 16(1):8565doi:10.1038/s41467-025-63611-y · PMID 41022731

    13,464 people, 158 critically ill patients and mice, with a conclusion the authors state plainly: different indoles can go in different directions.

21. 21
    Sun R, Jiao D, Yuan W, et al. Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.Nat Metab · 2026 · 8(1):196–214doi:10.1038/s42255-025-01430-7 · PMID 41555012

    Two mouse cancer models plus human liver tissue, with a nervous-system switch on the pathway's destination.

22. 22
    Shah GM, Shah RG, Veillette H, et al. Biochemical assessment of niacin deficiency among carcinoid cancer patients.Am J Gastroenterol · 2005 · 100(10):2307–2314doi:10.1111/j.1572-0241.2005.00268.x · PMID 16181385

    Serotonin is normally a small fraction of tryptophan use; 10 of 36 carcinoid patients niacin-deficient.

23. 23
    Strasser B, Becker K, Fuchs D, Gostner JM. Kynurenine pathway metabolism and immune activation: peripheral measurements in psychiatric and co-morbid conditions.Neuropharmacology · 2017 · 112(Pt B):286–296doi:10.1016/j.neuropharm.2016.02.030 · PMID 26924709

    The kynurenine-to-tryptophan ratio as an IDO index.

24. 24
    Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids.Science · 1972 · 178(4059):414–416doi:10.1126/science.178.4059.414 · PMID 5077329

    Rats: the ratio of tryptophan to competing amino acids sets brain tryptophan.

25. 25
    Scalise M, Galluccio M, Console L, et al. The human SLC7A5 (LAT1): the intriguing histidine/large neutral amino acid transporter and its relevance to human health.Front Chem · 2018 · 6:243doi:10.3389/fchem.2018.00243 · PMID 29988369

    LAT1 at the blood–brain barrier.

26. 26
    Baldini L, Dell'Unto E, Di Pangrazio R, et al. Niacin deficiency in carcinoid syndrome: definitions, biomarkers, and a pragmatic framework for clinical assessment.Nutrition · 2026 · 153:113379doi:10.1016/j.nut.2026.113379 · PMID 42735610

    24 sources, and the honest conclusion that the prevalence and the right marker are both still unsettled.

27. 27
    Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease.Cell Host Microbe · 2018 · 23(6):716–724doi:10.1016/j.chom.2018.05.003 · PMID 29902437

    Serotonin, kynurenine and indole pathways under microbial control.

28. 28
    Gushiken-Ibañez E, Stokmaier M, Barone G, et al. Commensal yeast Malassezia produces tryptophan metabolites to promote tissue homeostasis via the aryl hydrocarbon receptor in mice.Nat Microbiol · 2026 · 11(7):1934–1948doi:10.1038/s41564-026-02382-8 · PMID 42321537

    A fungus rather than a bacterium, with an indole-deficient mutant and a keratinocyte-specific knockout as the controls.

29. 29
    Litaiem N, Sboui K, Zeglaoui F. Pellagra in contemporary clinical practice (2000–2023): a systematic review.Int J Dermatol · 2026 · 65(8):1590–1599doi:10.1111/ijd.70398 · PMID 41876960

    133 studies, 1,212 confirmed cases, with proportions instead of a mnemonic.

30. 30
    de Mestier L, Savagner F, Brixi H, et al. Plasmatic and urinary 5-hydroxyindolacetic acid measurements in patients with midgut neuroendocrine tumors: a GTE study.J Clin Endocrinol Metab · 2021 · 106(4):e1673–e1682doi:10.1210/clinem/dgaa924 · PMID 33382891

    80 tumors, 17 controls; AUROC 0.80 urine, 0.72 plasma.

31. 31
    Ewang-Emukowhate M, Subramaniam K, Lam F, et al. Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.Scand J Clin Lab Invest · 2023 · 83(8):576–581doi:10.1080/00365513.2023.2286645 · PMID 38112030

    135 nmol/L cut-off: sensitivity 91%, specificity 62% against urine.

32. 32
    Klarskov K, Gagnon H, Boudreault PL, et al. Structure determination of disease associated peak AAA from L-tryptophan implicated in the eosinophilia-myalgia syndrome.Toxicol Lett · 2017 · 282:71–80doi:10.1016/j.toxlet.2017.10.012 · PMID 29037509

    The one contaminant statistically linked to cases.

33. 33
    Emslie-Smith AM, Mayeno AN, Nakano S, et al. 1,1′-Ethylidenebis[tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome.Neurology · 1994 · 44(12):2390–2392doi:10.1212/wnl.44.12.2390 · PMID 7991132

    Rats; small animal study.

34. 34
    Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study.Lancet Oncol · 2019 · 20(8):1083–1097doi:10.1016/S1470-2045(19)30274-8 · PMID 31221619

    706 patients; progression-free survival hazard ratio 1.00.

35. 35
    Gontijo I, Camurça M, Kfoury JR. Compensatory pathways in tryptophan metabolism and immune regulation following IDO inhibition.Mol Biol Rep · 2026 · 53(1):12707doi:10.1007/s11033-026-12707-9 · PMID 42730796

    The mechanistic account of why blocking one enzyme in a branching pathway did not work.

36. 36
    Chaudhry R, White BE, Chandrakumaran K, et al. Urine 5-HIAA and quality of life in neuroendocrine neoplasia. Is there an association?Rare Tumors · 2026 · 18:20363613261484137doi:10.1177/20363613261484137 · PMID 42682731

    232 patients analyzed. The marker did not track diarrhea or global health, and ran the wrong way for anxiety.

37. 37
    Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis.Aust N Z J Psychiatry · 2002 · 36(4):488–491doi:10.1046/j.1440-1614.2002.01046.x · PMID 12169147

    Two of 108 trials met quality criteria.

38. 38
    Javelle F, Lampit A, Bloch W, et al. Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis.Nutr Rev · 2020 · 78(1):77–88doi:10.1093/nutrit/nuz039 · PMID 31504850

    13 studies; weak designs, high heterogeneity.

39. 39
    Cheng YC, Huang WL, Chen WY, Huang YC, Kuo PH, Tu YK. Comparative efficacy and tolerability of nutraceuticals for depressive disorder: a systematic review and network meta-analysis.Psychol Med · 2025 · 55:e134doi:10.1017/S0033291725000996 · PMID 40314175

    192 trials, 17,437 patients, 44 nutraceuticals. The size of the effects is itself a reason to be careful.

40. 40
    Chaikali S, Jacobsen J. Serotonin synthesis amplification to augment the therapeutic efficacy of serotonin reuptake inhibitor antidepressants: five decades of clinical evidence.J Clin Psychopharmacol · 2026 · 46(4):462–475doi:10.1097/JCP.0000000000002180 · PMID 41928689

    The second author is affiliated with Evecxia Therapeutics, a company developing a serotonin-precursor product. It is cited here for the concession, which is the strongest thing on the page.

41. 41
    Nguyen HL, Le LT, Nguyen TG, Nguyen QT, Nguyen HV, Le NT. Dietary tryptophan intake density and the risk of cardiovascular diseases: insights from a prospective cohort study.Nutr Metab Cardiovasc Dis · 2025 · 36(3):104468doi:10.1016/j.numecd.2025.104468 · PMID 41478747

    42,146 people in northern Vietnam, a median 11 years of follow-up, and 348 cardiovascular deaths. Food frequency questionnaire, so intake is estimated rather than measured.

42. 42
    Xiu L, Liu Y, Wu P, et al. Tryptophan metabolites and stroke risk after acute myocardial infarction in patients with and without metabolic syndrome: insights from a MACCE-based cohort.Cardiovasc Diabetol · 2026 · 25(1):03138doi:10.1186/s12933-026-03138-8 · PMID 41857600

    3,223 patients after angioplasty, with internal validation in 3,190. The association exists only in the metabolic syndrome half.

43. 43
    Van Keulen HV, Van Keulen GE, Silva JP, Nunes RM, Aguiar AS. Nutritional intervention rich in tryptophan enhances sleep duration and reduces wakefulness during breast cancer treatment.Nutr Neurosci · 2026 · 29(10):1268–1281doi:10.1080/1028415X.2026.2650633 · PMID 42033145

    50 women, six weeks of nightly actigraphy. A split result, reported here as split.

44. 44
    Ko SM, Park JE, Heo IK, Shin YU, Kim YH, Son WC. Safety concerns regarding impurities in L-tryptophan associated with eosinophilia myalgia syndrome.Food Chem Toxicol · 2023 · 179:113946doi:10.1016/j.fct.2023.113946 · PMID 37453474

    Four of the six authors are affiliated with CJ CheilJedang, a major manufacturer of L-tryptophan. Read the reappraisal with that in view; it is cited here for what it concedes, not for what it argues.

45. 45
    Preuss HG, Echard B, Talpur N, et al. Does 5-hydroxytryptophan cause acute and chronic toxic perturbations in rats?Toxicol Mech Methods · 2006 · 16(5):281–286doi:10.1080/15376520500195616 · PMID 20021026

    Tryptophan withdrawn and replaced by 5-HTP on the market; rat toxicity study.

46. 46
    Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies.Mol Psychiatry · 2007 · 12(4):331–359doi:10.1038/sj.mp.4001949 · PMID 17389902

    Tryptophan depletion lowers mood only in vulnerable groups.

47. 47
    Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence.Mol Psychiatry · 2023 · 28(8):3243–3256doi:10.1038/s41380-022-01661-0 · PMID 35854107

    Depletion had no effect in 566 healthy volunteers. Contested.

48. 48
    Kordas B. Dietary tryptophan allocation in depression: serotonin-kynurenine balance, microbial indole pathways, and inflammatory phenotypes.Nutrients · 2026 · 18(16):2716doi:10.3390/nu18162716 · PMID 42654296

    A 2026 synthesis that is careful about which meta-analyses show what, and ends by saying the framework is for research rather than for supplementation.