Vitamin B12 and folate deficiencies may be linked to fatigue and decreased motivation.

A study by Japanese scientists on the relationship between blood homocysteine levels, vitamin B12 and folate status, and fatigue and motivation indicators in healthy adults was published in the journal Nutrients. The paper is titled "Associations of Plasma Homocysteine Reflecting Vitamin B12 and Folate Status with Fatigue-Related Outcomes in Healthy Adults."

The authors started from a simple but important idea: fatigue isn't always explained solely by lack of sleep or overwork. For some people, decreased energy and motivation may be due to dietary factors, particularly inadequate intake of water-soluble vitamins involved in metabolism and nervous system function. The focus was on homocysteine, a biomarker that typically increases with vitamin B12 and folate deficiency.

The study measured homocysteine, folate, and vitamin B12 levels in approximately 600 healthy Japanese participants. Fatigue and motivation were assessed using the Chalder Fatigue Scale and a visual analog scale. The primary analysis showed that individuals with higher blood homocysteine levels had lower vitamin B12 and folate levels, regardless of gender.

The main result was different for men and women. In men, higher homocysteine levels were associated with greater physical fatigue, while in women, they were associated with decreased motivation. However, the authors emphasize that this is a cross-sectional analysis, meaning the study shows an association but does not prove that high homocysteine specifically causes fatigue.

Key point	What is known
Magazine	Nutrients
Date of publication	March 17, 2026
Type of study	Cross-sectional analysis
Participants	602 healthy adults
Primary biomarker	Plasma homocysteine
Related nutrients	Vitamin B12 and folate
Fatigue assessment	Chalder Fatigue Scale
Motivation assessment	Visual analogue scale
DOI	10.3390/nu18060941

Why scientists are focusing on homocysteine

Homocysteine is an amino acid formed in the body during methionine metabolism. Normally, it needs to be processed in a timely manner, and for this, the body requires, among other things, folate and vitamin B12. Deficiencies of these vitamins can lead to elevated homocysteine levels.

Until now, high homocysteine levels have been discussed more often in connection with cardiovascular disease, dementia, and fractures. In the new study, the researchers proposed considering it as a possible indicator related to fatigue and motivation. This doesn't mean that homocysteine is a ready-made diagnostic test for fatigue, but it does make it an interesting marker for further research.

Folate and vitamin B12 are involved in one-carbon metabolism, which is important for molecule synthesis, methylation, nervous system function, and overall cellular metabolism. If this metabolism is disrupted, it could theoretically be associated with oxidative stress, altered neural regulation, and a decrease in subjective energy.

It's important not to oversimplify the conclusion. Fatigue is a multifactorial condition. It is influenced by sleep, stress, depression, anxiety, physical activity, anemia, thyroid disease, infections, chronic diseases, medications, and diet. Therefore, homocysteine in this study is not the "main cause of fatigue," but rather one possible biological signal that requires further investigation.

Biological factor	Why is it important?
Homocysteine	Increased in metabolic disorders associated with folate and vitamin B12
Folate	Participates in one-carbon metabolism and the synthesis of important cellular molecules
Vitamin B12	Necessary for hematopoiesis, the nervous system and the processing of homocysteine
Oxidative stress	Considered as a possible mechanism of fatigue
Gender differences	In the study, the association differed between men and women.

How the study was conducted

The analysis included 602 community-dwelling adults. These were healthy participants, not patients diagnosed with chronic fatigue syndrome or severe chronic diseases. This choice was important: the authors wanted to understand whether nutritional biomarkers were associated with daily fatigue and motivation in apparently healthy individuals.

Participants had their blood levels of homocysteine, folate, and vitamin B12 measured. Homocysteine levels were then divided into tertiles for men and women separately, meaning participants of each gender were divided into three groups: those with lower, average, and higher levels of this marker. This approach allowed us to assess the relationship within gender, rather than lumping men and women together.

Fatigue was assessed using the Chalder Fatigue Scale, a scale that includes questions about physical and mental fatigue. Motivation was assessed using a visual analog scale, in which the participant marks their state on an imaginary line. Such methods are widely used in studies of subjective states, although they rely on self-reporting.

In their statistical analysis, the researchers accounted for factors that may influence fatigue: age, sleep duration, workload, dietary habits, lifestyle, and biochemical parameters. This reduces the risk of significant bias but does not completely eliminate the problem of hidden factors, as the study was not an experiment involving vitamin administration or homocysteine lowering.

Element of the methodology	What the authors did
Design	Cross-sectional observational study
Participants	602 healthy adults
Basic analysis	Division of homocysteine into sex-specific tertiles
Fatigue scale	Chalder Fatigue Scale
Motivation scale	Visual analogue scale
Corrections in the analysis	Age, sleep, exercise, nutrition, lifestyle, and biochemical factors
The main goal	Find the connection between homocysteine, vitamin status, fatigue and motivation

What the results showed

The first important result was expected: higher homocysteine tertiles were associated with lower folate and vitamin B12 concentrations in both men and women. This association was statistically significant, with a p < 0.001 level. This confirms that homocysteine levels did indeed reflect vitamin status in the study group.

In men, the lowest homocysteine group was associated with lower physical fatigue on the Chalder Fatigue Scale. In a paired comparison, men in the highest homocysteine group had higher physical fatigue scores compared to the lowest group: the difference was 1.55 points, 95% confidence interval 0.24-2.86, p = 0.022.

The picture was different for women: high homocysteine levels were associated not so much with physical fatigue as with lower motivation. The difference between the highest and lowest homocysteine groups was minus 5.62 points on the visual analog scale, with a 95% confidence interval of minus 10.65 to minus 0.59, p = 0.029.

However, there is an important limitation: when homocysteine was analyzed as a continuous variable, no statistically significant associations were found. This makes the results less robust and means they should be considered a hypothesis rather than a proven clinical rule. The authors themselves write that longitudinal and mechanistic studies are needed to clarify causal relationships.

Result	What was discovered?
Homocysteine and folate	With higher homocysteine, folate levels were lower
Homocysteine and vitamin B12	With higher homocysteine, vitamin B12 levels were lower
Men	High homocysteine has been linked to greater physical fatigue.
Women	High homocysteine has been linked to lower motivation
Continuous homocysteine analysis	No significant associations were found
General interpretation	The results are preliminary and require confirmation.

Why did the results differ between men and women?

One interesting feature of the study was the gender differences. In men, the association was primarily through physical fatigue, while in women, it was through motivation. This may reflect differences in vitamin metabolism, hormonal levels, body composition, lifestyle, subjective assessment of fatigue, or the interaction of several factors.

However, the study doesn't provide a definitive answer as to why this happened. The cross-sectional design captures the condition at a single point in time, so it doesn't reveal dynamics: for example, whether homocysteine levels rise first, followed by fatigue, or whether people with fatigue change their diet and lifestyle in ways that worsen their vitamin status.

A third scenario is also possible: both homocysteine and fatigue are dependent on other factors. For example, insufficient sleep, stress, low physical activity, diet, alcohol consumption, inflammatory processes, or underlying medical conditions can simultaneously affect both biochemical parameters and well-being.

Therefore, the most rigorous conclusion is that the study demonstrates potential differences in the associations between homocysteine levels and fatigue and motivation in men and women, but does not yet explain the mechanism for these differences. To understand causality, studies are needed that follow participants over time or examine whether fatigue and motivation change after correction of folate and vitamin B12 deficiency.

Possible explanation	Why does it require verification?
Differences in vitamin metabolism	Biochemical and longitudinal data are needed
Hormonal factors	The study did not directly test the mechanism.
Different fatigue structures	Men and women may report symptoms differently
Lifestyle and sleep	These factors could influence the relationship
Nutrition	Folate and vitamin B12 deficiencies may reflect an overall dietary imbalance.
Hidden factors	Observational studies do not eliminate them completely

What does this mean for the average person?

The main practical conclusion is not that all people with fatigue urgently need to take vitamin B12 or folic acid. The study did not test vitamin treatments or prove that supplements reduce fatigue. It did show a link between higher homocysteine, lower folate and vitamin B12 levels, and some measures of fatigue or motivation.

The study reinforces the simple recommendation: a balanced and varied diet is essential. Folate is typically obtained from green leafy vegetables, legumes, and some other plant foods, while vitamin B12 is primarily obtained from animal products or fortified foods. People with vegan diets, malabsorption, advanced age, or gastrointestinal diseases may be at higher risk of vitamin B12 deficiency.

If fatigue persists for a long time, interferes with work, and is accompanied by drowsiness, weakness, shortness of breath, palpitations, weight loss, depressive symptoms, pain, sleep disturbances, or decreased concentration, it shouldn't be attributed solely to a "vitamin deficiency." In such cases, medical causes should be sought: anemia, thyroid dysfunction, chronic infections, inflammatory diseases, depression, sleep disorders, and other conditions.

A reasonable role for this study is to suggest to physicians and researchers that vitamin status and homocysteine could be part of a broader assessment of fatigue. However, there is currently no evidence to support the use of homocysteine as a standalone diagnostic marker for chronic fatigue or decreased motivation in healthy individuals.

Question	Practical answer
Should everyone have their homocysteine levels tested if they are tired?	No, the study does not make such a recommendation.
Does the study prove that vitamins are beneficial for fatigue?	No, this is not a treatment study.
Can diet be related to fatigue?	Yes, the data supports this hypothesis.
What is important to check if you experience prolonged fatigue?	Sleep, anemia, thyroid, depression, inflammation, chronic disease and nutrition
Is it possible to take high doses of vitamins on your own?	It is better not to do this without indications and medical assessment.
The main benefit of the study	It highlights homocysteine and vitamin status as a promising area for further study.

Limitations of the study

The first limitation is the cross-sectional design. All measurements were taken during the same period, so it's impossible to conclude that high homocysteine levels preceded fatigue or decreased motivation. To test causality, longitudinal studies are needed, where people are followed for months or years.

The second limitation is that the participants were healthy adults from Japan. This is useful for studying early biological relationships, but the results cannot be automatically generalized to patients with chronic fatigue syndrome, myalgic encephalomyelitis, post-COVID syndrome, severe depression, anemia, or significant chronic diseases.

The third limitation is the subjective assessment of fatigue and motivation. While scales are useful and validated, they still depend on a person's perception, current mood, sleep, stress, and daily circumstances. Therefore, it is advisable to supplement such data with objective measures of activity, sleep, cognitive performance, and physiological state.

The fourth limitation is statistical ambiguity. Associations were found when analyzed by tertiles and separately by gender, but did not persist when homocysteine was analyzed as a continuous variable. This makes the conclusions preliminary and requires caution to avoid turning an interesting hypothesis into a premature medical recommendation.

Limitation	Why is this important?
Cross-sectional design	It is impossible to prove causation
Healthy Japanese sample	Results may vary among patients and in other populations.
Self-assessment scales	Fatigue and motivation depend on subjective perception
No intervention	It has not been tested whether vitamin correction helps.
There is no stability in continuous analysis	The statistical signal requires confirmation.
Hidden factors are possible	Sleep, stress, illness and diet could influence the results

The main conclusion

A Nutrients study found that in healthy adults, higher homocysteine levels were associated with lower folate and vitamin B12 levels, as well as with certain measures of fatigue and motivation. In men, the association manifested itself through physical fatigue, while in women, it was through decreased motivation.

The scientific value of this study lies in its broadening understanding of fatigue: in addition to sleep, stress, and exercise, attention should be paid to nutrition, vitamin status, and biochemical markers of metabolism. Homocysteine is particularly interesting as an indicator of possible vitamin B12 and folate deficiency.

But the practical conclusion must be rigorous: this is not proof that vitamins treat fatigue, nor is it a basis for the widespread prescription of supplements. The results should be considered a hypothesis that needs to be tested in longitudinal studies and clinical trials correcting vitamin B12 and folate deficiency.

News source: Hiroaki Kanouchi, Ayaka Yamamoto, Akiko Kuwabara, Shigeo Takenaka, Eiji Nishikubo, Yukihiro Nomura, Takehiro Naruto, Kyosuke Watanabe, Kei Mizuno, Yasuyoshi Watanabe. Associations of Plasma Homocysteine Reflecting Vitamin B12 and Folate Status with Fatigue-Related Outcomes in Healthy Adults. Nutrients 2026;18(6):941. DOI: 10.3390/nu18060941.