Vitamin B12 and folate deficiencies may be a hidden cause of persistent tiredness and reduced drive in otherwise healthy people, according to new research from Japanese scientists. The study, led by Professor Hiroaki Kanouchi at Osaka Metropolitan University’s Graduate School of Human Life and Ecology, offers the first direct evidence linking low levels of these essential nutrients to exhaustion and motivational deficits in individuals without underlying illness.
The core finding
The investigation focused on a blood marker called homocysteine, an amino acid that rises when the body lacks sufficient vitamin B12 or folate. Among approximately 600 healthy Japanese adults who took part, those with elevated homocysteine readings consistently showed depleted levels of both vitamins, regardless of their sex. When the researchers separated the data by gender and adjusted for factors such as age, sleep patterns, workload and diet, a distinct pattern emerged: men with higher homocysteine were more prone to physical exhaustion, while women with the same marker demonstrated notably reduced motivation.
Professor Kanouchi described the relationship as potentially groundbreaking. “This suggested relationship between vitamin B12, folate, and fatigue in healthy individuals may represent the first report of its kind,” he said. The findings were published in the journal Nutrients.
Study details
The research team recruited healthy Japanese adults and analysed their blood for concentrations of homocysteine, folate and vitamin B12. Participants’ levels of energy and drive were assessed using two established tools: the Chalder Fatigue Scale, a questionnaire developed at King’s College London that measures the severity of tiredness, and a Visual Analog Scale, which captures the subjective experience of fatigue on a continuous line between “not at all tired” and “extremely tired.”
Modern life has seen chronic exhaustion become increasingly common, with mounting professional demands and reduced rest periods often blamed. Yet the Japanese investigators argue that dietary factors deserve greater attention. The findings highlight that even people who consider themselves healthy may be experiencing fatigue rooted in nutritional shortfalls rather than stress or poor sleep alone.
The role of homocysteine
Homocysteine is an amino acid that the body normally converts into methionine with the help of vitamin B12 and folate, which act as essential cofactors in the remethylation pathway. When levels of either vitamin are low, homocysteine accumulates in the blood. Traditionally, elevated homocysteine has been monitored as a risk factor for cardiovascular disease, dementia and bone fractures. Professor Kanouchi noted that those links remain important, but added: “Our findings suggest that attention should also be paid to fatigue and motivation in the future.”
The mechanism by which rising homocysteine could cause tiredness is increasingly understood. The accumulation of this amino acid can trigger oxidative stress, damage the lining of blood vessels and fuel neuroinflammation—processes now thought to directly contribute to the subjective sensation of exhaustion and a loss of drive. The sex-specific effects seen in the study—physical fatigue in men, reduced motivation in women—suggest that the biological response to homocysteine may differ between genders, although further research is needed to clarify why.
Homocysteine is not the only concern. In the UK, an estimated one in ten people are deficient in vitamin B12, with nearly one in three potentially at risk due to their diet alone. Up to one in five over-60s are affected because the stomach produces less acid with age, impairing absorption. Folate deficiency is even more common: one study found it to be almost twice as prevalent as B12 deficiency, with 22% of participants deficient, while another analysis of more than 47,000 blood samples indicated that almost one in eight individuals had low folate levels. Among young adult women aged 21 to 25, 85.5% had folate levels below the threshold recommended to protect against neural tube defects in pregnancy.
Genetic factors also play a role. Up to half of Britons may carry variants of the MTHFR gene that reduce the body’s ability to process vitamin B12 effectively, increasing the likelihood of elevated homocysteine even when dietary intake appears adequate. These figures underscore the scale of the problem in the UK, where many people mistake the symptoms of B12 and folate deficiency for the effects of stress or ageing. Only 23% of Britons surveyed thought they were personally at risk, and just 12% take a daily B12 supplement.
Professor Kanouchi’s advice
The professor’s guidance for maintaining healthy energy levels was clear and practical. “To prevent an increase in homocysteine levels, it is important to avoid deficiencies in vitamin B12 and folate,” he said. “Maintaining a well-balanced diet on a daily basis is essential.”
Dietary sources of vitamin B12 are almost exclusively found in animal products such as meat, fish, eggs and dairy, putting vegans and vegetarians at higher risk. Folate is abundant in leafy green vegetables, legumes and fortified foods such as breakfast cereals. The UK government has announced plans to mandate folic acid fortification in non-wholemeal wheat flour, likely by 2024, in an effort to reduce deficiency rates, particularly among women of reproductive age.
The NHS recommends that anyone experiencing persistent tiredness should consider their diet alongside other factors such as sleep quality, stress and physical activity. The British Dietetic Association advises a healthy, balanced diet with plenty of fruit and vegetables, and notes that supplements may be beneficial for certain groups, including vegans, older adults and those with pernicious anaemia. The Mental Health Foundation also links diet to mood and energy, encouraging regular meals, hydration and a balance of macronutrients.
For the first time, this research provides a clear biological marker—homocysteine—that can help identify individuals whose fatigue may be rooted in nutrient shortfalls rather than lifestyle alone. Professor Kanouchi’s team believes that monitoring homocysteine levels could become a routine part of assessing exhaustion and motivational problems in otherwise healthy people, expanding its role beyond the traditional areas of cardiovascular and cognitive health.