L-Ornithine: What do fatigue, stress and sleep studies show in healthy adults?

Why It Matters #

Ornithine is a non-protein amino acid involved in the urea cycle, which helps dispose of nitrogen as urea. This physiological role explains interest in ammonia handling and fatigue. It does not establish that extra ornithine improves everyday function in people with normal nitrogen metabolism.

What Was Studied #

Healthy-adult studies include 400 mg/day for eight weeks in mildly stressed workers and 1,600 mg/day for seven days before a laboratory stress test. Exercise experiments have used larger short-term doses. Clinical L-ornithine L-aspartate treatment in liver disease is a different formulation and population, not direct evidence for routine plain ornithine use.[1][2][3]

What Was Found #

The eight-week trial reported improvements in selected subjective sleep/stress measures and cortisol-related measures. The later acute-stress study did not find a cortisol effect, although some next-day mood/fatigue measures favored ornithine. The results therefore do not consistently confirm one stress-hormone mechanism.[1][2]

A small exercise crossover trial used 2 g/day of ornithine hydrochloride for seven days and 6 g on the test day; subgroup and subjective findings should not be treated as a replicated general performance advantage.[3]

What the Evidence Means #

Subjective fatigue is a relevant experience, but it is distinct from objective sleep architecture, endurance or preserved function over years. Short studies and several questionnaire outcomes increase the need for prespecified endpoints and independent replication.

What We Can Learn #

A 2025 safety review included 22 articles, but 13 did not report adverse-event information. Gastrointestinal symptoms were the main reported problem. Its 12 g/day no-observed-adverse-effect estimate refers to the hydrochloride salt under studied conditions, approximately 9.4 g of ornithine—not a recommended lifelong dose. The longest study used a different ornithine form.[5][6]

What Remains Unknown #

Whether the reported sleep and fatigue changes persist, improve objective function and reproduce outside industry-associated trials remains uncertain. Better studies should separate free ornithine from its salts and combinations and report adverse events systematically, including participants who stop treatment.

Primary Sources and updates

1. Miyake M, Kirisako T, Kokubo T, Miura Y, Morishita K, Okamura H, Tsuda A. (2014). Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutrition journal DOI: 10.1186/1475-2891-13-53Original full text and bibliographic record reviewed.
2. Moriyasu K, Nakajima A, Morita M. (2024). Effects of Oral Ingestion of L-Ornithine on Mental Stress and Fatigue Based on the Trier Social Stress Test in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial. Journal of clinical medicine DOI: 10.3390/jcm13247583Original full text and bibliographic record reviewed.
3. Sugino T, Shirai T, Kajimoto Y, Kajimoto O. (2008). L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism. Nutrition research (New York, N.Y.) DOI: 10.1016/j.nutres.2008.08.008Bibliographic record; not a detailed study appraisal.
4. Fukuda T, Haraguchi A, Takahashi M, Nakaoka T, Fukazawa M, Okubo J, Ozaki M, Kanatome A, Ohya R, Miura Y, Obara K, Shibata S. (2018). A randomized, double-blind and placebo-controlled crossover trial on the effect of l-ornithine ingestion on the human circadian clock. Chronobiology international DOI: 10.1080/07420528.2018.1490315Bibliographic record; not a detailed study appraisal.
5. Yang H, Kuramochi Y, Sato S, Sakai R, Hayamizu K. (2025). Safety assessment of L-ornithine oral intake in healthy subjects: a systematic review. Amino acids DOI: 10.1007/s00726-025-03455-4Primary review methods, relevant results and disclosures checked on 2026-10-24. The review is not an additional trial independent of its included studies.
6. Miura N, Morishita K, Yasuda T, Akiduki S, Matsumoto H. (2023). Subchronic tolerance trials of graded oral supplementation with ornithine hydrochloride or citrulline in healthy adults. Amino acids DOI: 10.1007/s00726-022-03227-4Bibliographic record; not a detailed study appraisal.
7. Nagayama C, Hamada Y, Kamemoto K, Hasumura T, Minegishi Y, Matsui Y, Ota N, Miyashita M. (2025). The effects of acute and chronic oral tea catechins and ornithine supplementation on exercise-induced ammonia accumulation and cycling performance in healthy young men: a randomized, double-blind, cross-over, placebo-controlled trial. European journal of applied physiology DOI: 10.1007/s00421-025-05833-yBibliographic record; not a detailed study appraisal.
8. Kokubo T, Ikeshima E, Kirisako T, Miura Y, Horiuchi M, Tsuda A. (2013). A randomized, double-masked, placebo-controlled crossover trial on the effects of L-ornithine on salivary cortisol and feelings of fatigue of flushers the morning after alcohol consumption. BioPsychoSocial medicine DOI: 10.1186/1751-0759-7-6Bibliographic record; not a detailed study appraisal.
9. Ito N, Seki S, Ueda F. (2018). Effects of Composite Supplement Containing Collagen Peptide and Ornithine on Skin Conditions and Plasma IGF-1 Levels-A Randomized, Double-Blind, Placebo-Controlled Trial. Marine drugs DOI: 10.3390/md16120482Bibliographic record; not a detailed study appraisal.
10. Butterworth RF, Kircheis G, Hilger N, McPhail MJW. (2018). Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of clinical and experimental hepatology DOI: 10.1016/j.jceh.2018.05.004Bibliographic record; not a detailed study appraisal.

First published: 2026-09-27 / Version 1.0. Sources reviewed 2026-09-27. Funding and conflicts are recorded separately; an unverified disclosure is not a declaration of no funding or no conflict.