Feeling tired despite getting seven or eight hours of sleep is common, and nutritional status may be one factor influencing energy metabolism and overall vitality. Vitamin B12 and folate are essential nutrients involved in normal homocysteine metabolism. A recent study by a Japanese research team, published in Nutrients, investigated the associations between plasma homocysteine, vitamin B12 and folate status, and fatigue-related outcomes in 602 healthy adults, including 204 men and 398 women. After adjusting for factors such as age, body weight, sleep, working hours, and exercise habits, the researchers found that higher homocysteine levels were associated with greater physical fatigue in men, while women with higher homocysteine levels showed lower subjective motivation. The study also found that vitamin B12 and folate levels decreased as homocysteine levels increased in both men and women. These findings highlight the potential relationship between vitamin B12, folate, homocysteine metabolism, and fatigue-related outcomes, while emphasizing the importance of interpreting the results cautiously, as the cross-sectional study design demonstrates associations rather than direct cause-and-effect relationships.
We often instinctively assume that as long as we get enough sleep and rest properly, we should naturally feel refreshed and energetic.
Yet for many people, this is not always the case. Even after sleeping for seven or eight hours, the moment the alarm goes off, it can feel as though the bed has completely “locked” us in place, making it difficult to get up. Even after forcing ourselves to start work, we may struggle to stay energetic throughout the day. The brain can feel as though it is covered by a layer of fog, making it difficult to improve productivity. By the time work is finally over, plans for exercise, studying, or reading are often postponed one after another.
So, what can we do?
It may be tempting to blame ourselves, thinking that we have simply become too lazy or that our self-discipline is getting worse.
In fact, this pervasive feeling of fatigue may also be related to insufficient levels of certain key nutrients in the body that are involved in maintaining normal energy metabolism.
A recent study by a Japanese research team, published in Nutrients, found that vitamin B12 and folate deficiency was associated with higher blood homocysteine levels, which were closely associated with fatigue-related outcomes. Men showed significantly greater physical fatigue, while women were more likely to experience a state of reduced motivation or feeling unable to summon the energy to do things.
DOI: 10.3390/nu18060941
Study Design and Participants
The study used a cross-sectional design and included 602 participants with an average age of 44 years, including 204 men and 398 women.
The researchers measured blood levels of homocysteine, vitamin B12, folate, and other indicators in all participants. They also assessed each participant's physical fatigue, mental fatigue, and motivation using tools including the Chalder Fatigue Scale and a Visual Analog Scale.
However, homocysteine levels naturally differ between men and women. Therefore, the researchers decided to analyze the two groups separately.
For the male participants, the researchers divided them into three groups according to their homocysteine levels, from low to high: the T1 group, with levels below 14.6 µmol/L; the T2 group, with levels between 14.6 and 17.6 µmol/L; and the T3 group, with levels above 17.6 µmol/L.
The women were divided in the same way, with cutoff points of 11.5 µmol/L and 13.9 µmol/L for the three groups.
After adjusting for a series of factors that could potentially influence the results, including age, body weight, sleep, working hours, and exercise habits, the researchers found that higher homocysteine levels were associated with greater physical fatigue in men, while women showed significantly lower motivation in daily life and work.
More specifically, men in the T3 group, which had the highest homocysteine levels, had significantly higher “physical fatigue” scores on the Chalder Fatigue Scale than men in the T1 group, which had the lowest homocysteine levels.
In other words, when blood homocysteine levels remain relatively high in men, the feeling of being physically “drained” or exhausted may be significantly greater.
Compared with men in the highest homocysteine tertile, men in the lowest homocysteine tertile had significantly lower scores for physical fatigue on the Chalder Fatigue Scale.
For women, however, the T3 group, which had the highest homocysteine levels, had significantly lower motivation scores on the Visual Analog Scale than the T1 group, which had the lowest levels.
In other words, women with higher homocysteine levels were more likely to experience a decline in enthusiasm and motivation to engage in activities.
Association between high homocysteine levels and decreased subjective motivation in women.
The Relationship Between Homocysteine, Vitamin B12 and Folate
Not only that, the researchers also observed that as homocysteine levels gradually increased, blood levels of vitamin B12 and folate significantly decreased in both men and women.
Taking men as an example, the vitamin B12 concentration was 443 pg/mL in the T1 group, but decreased to 365 pg/mL in the T3 group. Folate levels also decreased from 9.85 ng/mL to 7.25 ng/mL.
From a mechanistic perspective, one of the key functions of vitamin B12 and folate in the body is to act as cofactors in the conversion of homocysteine into methionine. When levels of these two vitamins are insufficient, this metabolic process may be impaired, making it more difficult for homocysteine to be efficiently metabolized and potentially resulting in higher levels in the blood.
Elevated homocysteine levels may, in turn, interfere with the synthesis and metabolism of neurotransmitters such as dopamine and serotonin in the brain.
These two neurotransmitters are closely involved in processes related to energy, motivation, and the drive to take action. Therefore, insufficient vitamin B12 and folate may ultimately be associated with increased fatigue and reduced motivation.
Folate and vitamin B12 may indirectly influence fatigue by regulating homocysteine levels.
Overall Findings
Overall, the study revealed that individuals with relatively high blood homocysteine levels generally had lower levels of vitamin B12 and folate. In addition, men with lower vitamin B12 and folate status showed greater physical fatigue, while women showed a more pronounced reduction in motivation.
It is important to interpret these findings with caution. The study was cross-sectional in design, so it demonstrates associations between homocysteine, vitamin B12, folate, fatigue, and motivation rather than establishing that low vitamin B12 or folate directly causes fatigue or that elevated homocysteine directly causes reduced motivation.
Nevertheless, the findings highlight the potential importance of maintaining adequate vitamin B12 and folate status and normal homocysteine metabolism when considering factors associated with fatigue and reduced motivation.
References
[1] Kanouchi, H.; Yamamoto, A.; Kuwabara, A.; Takenaka, S.; Nishikubo, E.; Nomura, Y.; Naruto, T.; Watanabe, K.; Mizuno, K.; Watanabe, Y. Associations of Plasma Homocysteine Reflecting Vitamin B₁₂ and Folate Status with Fatigue-Related Outcomes in Healthy Adults. Nutrients 2026, 18, 941. DOI: 10.3390/nu18060941.