{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:49:00Z","timestamp":1782197340041,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ajinomoto Co., Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: L-tyrosine, classified as a dispensable amino acid, is widely consumed as a component of commonly consumed foods and as a dietary supplement. However, 4-week safety data on supplementation with this amino acid remain limited. Methods: The aim of this study was to evaluate the safety and tolerability of L-tyrosine supplementation over a 4-week period and to estimate the no-observed-adverse-effect level (NOAEL). In a randomized, double-blind, placebo-controlled crossover trial, 30 healthy adult men received L-tyrosine at graded daily doses (0, 1, 2, 3, or 4 g\/day). Each participant received four of the five doses in a randomized sequence, with each intervention period separated by a 2-week washout period. The primary endpoints were clinical laboratory parameters, and the secondary endpoint was the incidence of adverse events. Anthropometric and dietary parameters were also assessed. In addition, plasma amino acid concentrations following L-tyrosine supplementation were evaluated as exploratory outcomes. Results: No clinically meaningful or statistically significant dose-related abnormalities were observed in hematological, biochemical, or electrolyte parameters at any dose. Anthropometric and dietary parameters remained unchanged. No serious adverse events occurred, and the incidence of mild-to-moderate adverse events was comparable to that observed with placebo. At the end of each supplementation period and under fasting conditions, plasma L-tyrosine concentrations modestly increased at the highest dose (4 g\/day), whereas concentrations of other amino acids remained unchanged. Conclusions: Four-week supplementation with L-tyrosine at doses up to 4 g\/day was well tolerated in healthy adult men and was not associated with biochemical and clinically relevant adverse effects under the conditions of this study. These findings suggest that 4 g\/day represents the highest tested intake level without observable adverse effects and may serve as the NOAEL under the present 4-week study conditions.<\/jats:p>","DOI":"10.3390\/nu18122020","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"2020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of the Safety and Tolerability of L-Tyrosine Supplementation in Healthy Adult Men: A Randomized Crossover Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-9598","authenticated-orcid":false,"given":"Hideki","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co. Inc., Kawasaki 210-8681, Japan"},{"name":"Bio and Fine Chemicals Division, Ajinomoto Co. Inc., Tokyo 104-8351, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Miura","sequence":"additional","affiliation":[{"name":"Miura Medical Clinic, Osaka 530-0044, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Naito","sequence":"additional","affiliation":[{"name":"Bio and Fine Chemicals Division, Ajinomoto Co. Inc., Tokyo 104-8351, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9380-1725","authenticated-orcid":false,"given":"Rajavel","family":"Elango","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"},{"name":"BC Children\u2019s Hospital Research Institute, BC Children\u2019s Hospital, Vancouver, BC V6H 3N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S258","DOI":"10.1017\/S0007114512002474","article-title":"Gut luminal endogenous protein: Implications for the determination of ileal amino acid digestibility in humans","volume":"108","author":"Moughan","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1549S","DOI":"10.1093\/jn\/137.6.1549S","article-title":"An overview of phenylalanine and tyrosine kinetics in humans","volume":"137","author":"Matthews","year":"2007","journal-title":"J. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/1523-1747.ep12521344","article-title":"Recent advances in the chemistry of melanogenesis in mammals","volume":"75","author":"Prota","year":"1980","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1755-148X.2009.00610.x","article-title":"Current challenges in understanding melanogenesis: Bridging chemistry, biological control, morphology, and function","volume":"22","author":"Simon","year":"2009","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1152\/physrev.00044.2003","article-title":"Melanin pigmentation in mammalian skin and its hormonal regulation","volume":"84","author":"Slominski","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e71801","DOI":"10.1096\/fj.202600673R","article-title":"Substrate for thyroid hormone synthesis: Biochemistry, evolution, and physiology","volume":"40","author":"Young","year":"2026","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/S2213-8587(14)70225-6","article-title":"Iodine deficiency and thyroid disorders","volume":"3","author":"Zimmermann","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1161\/01.HYP.7.1.81","article-title":"Oral load of tyrosine or L-dopa and plasma levels of free and sulfoconjugated catecholamines in healthy men","volume":"7","author":"Cuche","year":"1985","journal-title":"Hypertension"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/0006-2952(77)90057-0","article-title":"Physiological control of brain catechol synthesis by brain tyrosine concentration","volume":"26","author":"Gibson","year":"1977","journal-title":"Biochem. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/BF01247323","article-title":"Plasma tyrosine in normal humans: Effects of oral tyrosine and protein-containing meals","volume":"47","author":"Melamed","year":"1980","journal-title":"J. Neural Transm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jpeds.2014.03.061","article-title":"Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: Effects of tryptophan and tyrosine","volume":"165","author":"Yano","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s10571-018-0632-3","article-title":"Dopamine: Functions, signaling, and association with neurological diseases","volume":"39","author":"Klein","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1093\/brain\/awab111","article-title":"The role of noradrenaline in cognition and cognitive disorders","volume":"144","author":"Holland","year":"2021","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/j.2040-4603.2015.tb00599.x","article-title":"Peripheral and central effects of circulating catecholamines","volume":"5","author":"Tank","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/bjp.2008.164","article-title":"The rush to adrenaline: Drugs in sport acting on the beta-adrenergic system","volume":"154","author":"Davis","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1539S","DOI":"10.1093\/jn\/137.6.1539S","article-title":"Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain","volume":"137","author":"Fernstrom","year":"2007","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jpsychires.2015.08.014","article-title":"Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands\u2014A review","volume":"70","author":"Jongkees","year":"2015","journal-title":"J. Psychiatr. Res."},{"key":"ref_18","unstructured":"Food and Nutrition Board, and Panel on Macronutrients (2005). Tyrosine in Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids, National Academies Press."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Blachier, F. (2026). Relevance and safe utilization of amino acids in supplements for human nutrition: Lessons from clinical and preclinical studies. Nutrients, 18.","DOI":"10.3390\/nu18020296"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1161\/01.HYP.7.4.593","article-title":"Chronic dietary tyrosine supplements do not affect mild essential hypertension","volume":"7","author":"Sole","year":"1985","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/0361-9230(89)90096-8","article-title":"Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans","volume":"22","author":"Banderet","year":"1989","journal-title":"Brain Res. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0140-6736(89)91081-7","article-title":"Treatment of narcolepsy with L-tyrosine: Double-blind placebo-controlled trial","volume":"2","author":"Elwes","year":"1989","journal-title":"Lancet"},{"key":"ref_23","first-page":"313","article-title":"The effects of tyrosine on cognitive performance during extended wakefulness","volume":"66","author":"Neri","year":"1995","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1177\/0883073807309794","article-title":"Dietary L-tyrosine supplementation in nemaline myopathy","volume":"23","author":"Ryan","year":"2007","journal-title":"J. Child Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Colzato, L.S., Jongkees, B.J., Sellaro, R., and Hommel, B. (2013). Working memory reloaded: Tyrosine repletes updating in the N-back task. Front. Behav. Neurosci., 7.","DOI":"10.3389\/fnbeh.2013.00200"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e259303","DOI":"10.1136\/bcr-2023-259303","article-title":"L-tyrosine for treatment of an infant with nemaline rod myopathy","volume":"17","author":"Dalal","year":"2024","journal-title":"BMJ Case Rep. CP"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1007\/s00726-021-03054-z","article-title":"Tolerable amounts of amino acids for human supplementation: Summary and lessons from published peer-reviewed studies","volume":"53","author":"Blachier","year":"2021","journal-title":"Amino Acids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.fct.2015.11.017","article-title":"13-week repeated dose toxicity study of L-tyrosine in rats by daily oral administration","volume":"87","author":"Shibui","year":"2016","journal-title":"Food Chem. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00726-022-03227-4","article-title":"Subchronic tolerance trials of graded oral supplementation with ornithine hydrochloride or citrulline in healthy adults","volume":"55","author":"Miura","year":"2023","journal-title":"Amino Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s00726-025-03461-6","article-title":"Evaluation of safe utilization of L-threonine for supplementation in healthy adults: A randomized double-blind controlled trial","volume":"57","author":"Matsumoto","year":"2025","journal-title":"Amino Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/2193-1801-3-35","article-title":"Bolus ingestion of individual branched-chain amino acids alters plasma amino acid profiles in young healthy men","volume":"3","author":"Matsumoto","year":"2014","journal-title":"SpringerPlus"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Miura, N., Matsumoto, H., Cynober, L., Stover, P.J., Elango, R., Kadowaki, M., Bier, D.M., and Smriga, M. (2021). Subchronic tolerance trials of graded oral supplementation with phenylalanine or serine in healthy adults. Nutrients, 13.","DOI":"10.3390\/nu13061976"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"Faul","year":"2007","journal-title":"Behav. Res. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hippisley-Cox, J., Fielding, K., and Pringle, M. (1998). Depression as a risk factor for ischemic heart disease in men: Population-based case-control study. BMJ, 316.","DOI":"10.1136\/bmj.316.7146.1714"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Japanese Society of Nephrology (2024). Essential points from evidence-based clinical practice guideline for chronic kidney disease 2023. Clin. Exp. Nephrol., 28, 473\u2013495.","DOI":"10.1007\/s10157-024-02497-4"},{"key":"ref_36","unstructured":"National Cancer Institute (2024, September 01). Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, 2017, Available online: https:\/\/dctd.cancer.gov\/research\/ctep-trials\/for-sites\/adverse-events\/ctcae-v5-5x7.pdf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.2188\/jea.13.1sup_23","article-title":"Food and nutrient intakes assessed with dietary records for the validation study of a self-administered food frequency questionnaire in JPHC Study Cohort I","volume":"13","author":"Sasaki","year":"2003","journal-title":"J. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1017\/S1368980011000504","article-title":"Comparison of relative validity of food group intakes estimated by comprehensive and brief-type self-administered diet history questionnaires against 16 d dietary records in Japanese adults","volume":"14","author":"Kobayashi","year":"2011","journal-title":"Public Health Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/S0140-6736(25)00672-5","article-title":"CONSORT 2025 statement: Updated guideline for reporting randomised trials","volume":"405","author":"Hopewell","year":"2025","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0024-3205(79)90294-7","article-title":"Elevation of plasma tyrosine after a single oral dose of L-tyrosine","volume":"25","author":"Glaeser","year":"1979","journal-title":"Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1093\/ajcn\/nqaa210","article-title":"Tolerance to graded dosages of histidine supplementation in healthy human adults","volume":"112","author":"Gheller","year":"2020","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"675","DOI":"10.3945\/ajcn.117.152520","article-title":"Tolerance to increased supplemented dietary intakes of methionine in healthy older adults","volume":"106","author":"Deutz","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1007\/s00726-018-2594-7","article-title":"Safety of dietary supplementation with arginine in adult humans","volume":"50","author":"McNeal","year":"2018","journal-title":"Amino Acids"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14930","DOI":"10.1073\/pnas.94.26.14930","article-title":"Slow and fast dietary proteins differently modulate postprandial protein accretion","volume":"94","author":"Boirie","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.3945\/jn.115.211615","article-title":"Jejunal casein feeding is followed by more rapid protein digestion and amino acid absorption when compared with gastric feeding in healthy young men","volume":"145","author":"Luttikhold","year":"2015","journal-title":"J. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/ggi.13239","article-title":"Current protein and amino acid intakes among Japanese people: Analysis of the 2012 National Health and Nutrition Survey","volume":"18","author":"Takimoto","year":"2018","journal-title":"Geriatr. Gerontol. Int."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/2020\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:27:34Z","timestamp":1782196054000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18122020"],"URL":"https:\/\/doi.org\/10.3390\/nu18122020","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]}}}