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Effect of L-Citrulline Supplementation on Endothelial Function and Body Composition in Post-COVID-19 Syndrome: A Randomized Clinical Trial.

  • 2026-05-27
  • Nutrients 18(11)
    • Salgado-Fernández María Fernanda
    • Orea-Tejeda Arturo
    • Sierra-Vargas Martha Patricia
    • González-Islas Dulce
    • Debray-García Yazmín
    • Aztatzi-Aguilar Octavio Gamaliel
    • Galicia-Amor Susana
    • Hernández-López Samantha
    • Renteria-Serralde Getsemani
    • Cruz-Gijón Gabriela
    • Maldonado-Vargas Valeria

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 43
Population
adults aged ≥18 years who recovered from COVID-19 and required hospitalization during acute COVID-19
Methods
open-label randomized controlled clinical trial, L-citrulline group (4 g/day) vs control group
Blinding
Open-label
Duration
three months
  • Rigorous Journal
Background: Post-COVID-19 syndrome is associated with endothelial dysfunction (ED) and various sequelae, particularly in individuals who experienced critical illness during the acute phase, affecting lung function and the musculoskeletal system. L-citrulline, a nonessential amino acid, has been shown to improve endothelial function, systemic inflammation, blood pressure, and physical performance. This study aimed to assess the effects of L-citrulline supplementation on ED and body composition in patients with post-COVID-19 syndrome. Methods: We conducted an open-label randomized controlled clinical trial at the Instituto Nacional de Enfermedades Respiratorias in Mexico City, Mexico, from February 2021 to May 2022. Eligible subjects were adults aged ≥18 years who recovered from COVID-19 and required hospitalization during acute COVID-19. Participants were randomized 1:1 into two groups: (1) the L-citrulline group (4 g/day) and (2) the control group. The intervention lasted three months. Endothelial-related biomarkers, including endothelin-1, sE-selectin, ICAM-1, and VCAM-1, were investigated. Body composition was measured using electrical bioimpedance, and aerobic capacity was assessed with the 6 min walk test (6MWT). Treatment effects were analyzed using two-way repeated-measures ANOVA (group × time). Results: In total, 43 subjects participated in the study. After three months of follow-up, the intervention group showed a decrease in ICAM-1 (-32.59 ng/mg of protein; 95% CI -52.85 to -12.33 vs. -2.31 ng/mg of protein, CI 95%: -21.59 to 16.95, p = 0.034) and an increase in 6MWT (141.2 m; 95% CI: 98.40 to 184 vs. 67.70 m, CI 95%: 30.62 to 104.78, p = 0.011) compared with the control group. No differences in body composition were observed between the groups at follow-up. Conclusions: L-citrulline supplementation for three months decreased ICAM-1 and increased 6MWT.

Research Insights

  • L-Citrulline→Improved 6-minute Walking Distance

    increase in 6MWT (141.2 m; 95% CI: 98.40 to 184 vs. 67.70 m, CI 95%: 30.62 to 104.78, p = 0.011)

    Effect
    Beneficial
    Effect size
    Large
    Dose
    4 g/day
  • L-Citrulline→Improved Body Composition

    No differences in body composition were observed between the groups at follow-up.

    Effect
    Neutral
    Effect size
    Small
    Dose
    4 g/day
  • L-Citrulline→Reduced Endothelin-1 Level

    Endothelial-related biomarkers, including endothelin-1, sE-selectin, ICAM-1, and VCAM-1, were investigated. ... After three months of follow-up, the intervention group showed a decrease in ICAM-1 ... No differences in body composition were observed

    Effect
    Neutral
    Effect size
    Small
    Dose
    4 g/day
  • L-Citrulline→Reduced ICAM-1 Level

    the intervention group showed a decrease in ICAM-1 (-32.59 ng/mg of protein; 95% CI -52.85 to -12.33 vs. -2.31 ng/mg of protein, CI 95%: -21.59 to 16.95, p = 0.034)

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    4 g/day
  • L-Citrulline→Reduced VCAM-1 Level

    Endothelial-related biomarkers, including endothelin-1, sE-selectin, ICAM-1, and VCAM-1, were investigated. ... After three months of follow-up, the intervention group showed a decrease in ICAM-1 ... No differences in body composition were observed

    Effect
    Neutral
    Effect size
    Small
    Dose
    4 g/day
  • L-Citrulline→Reduced sE-Selectin Level

    Endothelial-related biomarkers, including endothelin-1, sE-selectin, ICAM-1, and VCAM-1, were investigated. ... After three months of follow-up, the intervention group showed a decrease in ICAM-1 ... No differences in body composition were observed

    Effect
    Neutral
    Effect size
    Small
    Dose
    4 g/day
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