Summary:
Fatigue is a common symptom that affects daily functioning and can impair concentration, decision‑making and workplace performance. It may also reduce the ability to engage in health‑promoting behaviours such as meal preparation and exercise. This study focuses on homocysteine and its role in fatigue, as elevated homocysteine is associated with oxidative stress and neurotransmitter synthesis. These pathways influence dopamine and serotonin production, which are central to motivation and cognitive regulation. Homocysteine levels are shaped by genetics, kidney function and B‑vitamin status, particularly folate and vitamin B12, making it potentially relevant to fatigue. Because homocysteine can disrupt methylation and other processes, it is plausible that higher concentrations may relate to reduced motivation or increased fatigue. However, evidence in this area is limited. This study examined cross‑sectional data from 602 adults, looking at homocysteine levels and fatigue. Higher homocysteine levels were associated with lower folate and vitamin B12 concentrations. In men, lower homocysteine was linked to lower levels of fatigue, while in women, higher homocysteine was associated with reduced motivation. Overall, this study found sex‑specific associations between homocysteine and fatigue‑related outcomes. These findings are exploratory and should be interpreted cautiously, as more research is needed to determine whether homocysteine plays a causal role in fatigue or motivation.
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Abstract:
Background/Objectives: Fatigue and reduced motivation impair daily functioning and quality of life. Homocysteine (Hcy) has been implicated in oxidative stress and one–carbon metabolism, but its relationship with fatigue–related outcomes remains unclear. We explored associations between plasma Hcy and fatigue-related measures in healthy adults. Methods: We analyzed cross–sectional data from 602 community–dwelling adults. Plasma Hcy concentrations were categorized into sex−specific tertiles. Fatigue and motivation were assessed using the Chalder Fatigue Scale and a visual analog scale (VAS). Sex−stratified multivariable linear models adjusted for lifestyle and biochemical covariates were used to examine associations. Sensitivity analyses additionally modeled Hcy as a continuous variable. Results: Higher Hcy tertiles were associated with lower serum folate and vitamin B12 concentrations in both sexes (p < 0.001). In men, the lowest Hcy tertile was associated with lower Chalder physical fatigue scores, whereas in women the highest Hcy tertile was associated with lower VAS motivation scores in multivariable analyses. Pairwise contrasts indicated higher physical fatigue in men in the highest tertile compared with the lowest (T3–T1: 1.55; 95% CI 0.24–2.86; p = 0.022) and lower motivation in women (T3–T1: −5.62; 95% CI −10.65 to −0.59; p = 0.029). However, no significant associations were observed when Hcy was modeled as a continuous variable. Conclusions: In this exploratory cross−sectional analysis, plasma Hcy showed associations with fatigue−related outcomes in sex−stratified analyses. These findings should be interpreted cautiously and considered hypothesis–generating. Longitudinal and mechanistic studies are needed to clarify potential causal relationships.
Article Publication Date: 17/03/2026
DOI: 10.3390/nu18060941
