Effects of a single dose of L-histidine on mental fatigue and vigor in participants with high fatigue levels: a randomized controlled trial.

2026-04-15
Scientific reports 16(1)
- Masatsugu Shimomasuda
- Haruna Fujiyoshi
- Yu Kajiyama
- Mayuka Kanda
- Kenta Kajiwara
- Kenji Nagao
- Akira Abe
- Shigekazu Kurihara
- Hiroyuki Kato
- Hidehiro Nakamura

PubMed: 41986440
DOI: 10.1038/s41598-026-48060-x

Study Design

Type: Randomized Controlled Trial (RCT)
Population: healthy men and women who regularly experienced fatigue and sleep deprivation
Methods: randomized, placebo-controlled, single-dose L-histidine vs placebo, Uchida-Kraepelin Performance test workload
Blinding: Double-blind
Duration: single dose
Funding: Unclear

Rigorous Journal

Mental fatigue is a psychobiological state caused by prolonged periods of demanding cognitive activity that affects many aspects of daily life. Two weeks of L-histidine daily ingestion in humans significantly improves mood states compared with a placebo; however, the effects of a single dose are unknown. We aimed to assess the effects of a single dose of L-histidine on mood states, including fatigue, in healthy men and women who regularly experienced fatigue and sleep deprivation. Participants were randomly assigned to the L-histidine or placebo group. They were provided a workload using the Uchida-Kraepelin Performance test, their mood states before and after the workload were assessed, and performance on mental tasks was measured. In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints. However, in the subgroup with high fatigue levels, the L-histidine group showed significant decreases compared with the placebo group in the changes in fatigue-inertia (FI), confusion-bewilderment (CB), depression-dejection (DD), and total mood disturbance (TMD) T-scores and a significant increase in the change in vigor-activity (VA) T-score (p = 0.022, 0.049, 0.039, 0.036, and 0.023, respectively). Although a single ingestion of L-histidine showed no significant improvements in any of the endpoints compared with the placebo in the prespecified all-participants analysis set, the exploratory findings suggest that it may alleviate negative mood states, including fatigue, confusion, and depression, and may also improve vigor after a workload in humans with high fatigue levels. Clinical Trial Registry number: UMIN000055719.

Research Insights

L-Histidine→Improved Mental Task Performance
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Improved Vigor
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Improved Vigor-Activity
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Confusion and Bewilderment
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Confusion-Bewilderment T-Score
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Depression
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Depression-Dejection T-score
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Fatigue-Inertia
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)
L-Histidine→Reduced Mood Disturbance
In the all participants analysis set, the results did not show superiority of the L-histidine group over the placebo group for all endpoints.
Effect
Neutral
Effect size
Small
Dose
single dose (exact amount not specified in abstract)