Persistent fatigue is often blamed on poor sleep, stress, or overwork. New research points to another possible piece of the puzzle: homocysteine, a little-known amino acid that is influenced by how the body processes folate and vitamin B12.
In a study of 602 healthy Japanese adults, higher homocysteine levels were associated with greater physical fatigue in men and lower motivation in women.
Homocysteine is a byproduct created when protein is metabolized. High homocysteine levels are not good, and the body normally recycles it quickly by converting it into other compounds.
The conversion depends partly on folate and vitamins B12 and B6, and when these nutrients are inadequate—or the pathways that use them are disrupted—homocysteine can accumulate in the blood.
“Homocysteine is a risk factor for various diseases and also a source of oxidative stress, which can cause fatigue, so we focused on homocysteine,” Hiroaki Kanouchi, a professor at Osaka Metropolitan University and co-author of the study, told The Epoch Times.
What Homocysteine May Reveal
Homocysteine is at the intersection of several important biological pathways tied to brain and body function, Kara Siedman, a registered dietitian who wasn’t part of the study, told The Epoch Times.
In addition to fatigue, elevated homocysteine may contribute to poor blood vessel health, oxidative stress, inflammation, and changes in connective tissue, all of which could explain its associations with cardiovascular, brain, and bone health, she said.
There is also a direct neurological link: When the body isn’t able to recycle homocysteine well, high levels affect the metabolism of our neurotransmitters. Neurotransmitter metabolism is necessary to synthesize dopamine, serotonin, and norepinephrine, so a shortfall can affect mood, motivation, cognition, and fatigue.
The study did not test this mechanism directly.
Symptoms Differ Between Men and Women
Even in healthy people, Kanouchi and his team found that homocysteine levels may affect energy and drive. Their study, published in Nutrients, analyzed data from 602 healthy Japanese adults with an average age of 44, who underwent blood testing to measure homocysteine, folate, and vitamin B12 levels. Participants also completed questionnaires assessing fatigue and motivation. The research team tracked sleep, work hours, exercise habits, smoking, and diet.
In both men and women, higher homocysteine levels were associated with lower folate and vitamin B12 levels—however, the link to symptoms diverged by gender.
Researchers divided participants into three groups based on homocysteine levels. The third of men with the highest homocysteine levels—17.6 micromoles per liter or more—scored approximately 1.6 points higher on the physical-fatigue scale than men in the lowest third.
Among women, those in the highest third—13.9 micromoles per liter or higher—rated their motivation approximately 5.6 points lower on a 100-point scale than those in the lowest third.
Both differences met the conventional threshold for statistical significance. The authors suggested that men and women may respond differently to elevated homocysteine levels because of hormonal differences. Kanouchi cautioned, however, that causality has not been established and that intervention trials are needed to confirm the relationship.
They also found no strong evidence that folate or vitamin B12 levels alone predicted fatigue or motivation. Homocysteine may therefore offer a functional clue about how the body is using these vitamins, but it is not specific to vitamin deficiency.
B Vitamins Still Matter
Even though the study did not find a direct link between folate (vitamin B9) and vitamin B12 levels and fatigue or motivation, researchers and outside experts agree these water-soluble vitamins are important for maintaining energy levels.
“An insufficiency in water-soluble vitamins may be a risk factor for fatigue,” Kanouchi said, and getting enough of them may help improve fatigue in some people.
Low levels of B vitamins, which many people associate with anemia, can have a range of side effects, Siedman said. “When low, symptoms can go beyond anemia and include fatigue, brain fog, mood changes, neuropathy [numbness and tingling], and elevated homocysteine. This is why folate and B12 are important for whole-body health, not just blood health.”
Folate is commonly found in leafy greens, beans, citrus fruits, and fresh-ground and fortified grains, while vitamin B12 is primarily found in animal products such as meat, fish, eggs, and dairy.
Most adults need about 400 micrograms of folate and 2.4 micrograms of vitamin B12 daily. For context, 1 cup of cooked lentils contains about 350 micrograms of folate. For vitamin B12, a single serving of salmon or tuna can cover a full day’s worth. Eggs and milk provide smaller amounts: about 0.9 micrograms and 0.5 micrograms of vitamin B12, respectively.
Be careful not to overdo the protein. Diets that skew heavily toward animal protein with few fruits and vegetables, such as keto and carnivore diets, may raise homocysteine levels because they supply more methionine but fewer of the nutrients needed to break homocysteine down, Douglas Kalman, a registered dietitian, co-founder of Substantiation Sciences, and clinical associate professor at Nova Southeastern University, told The Epoch Times.
Strict vegetarians and vegans may face a different risk if they don’t supplement or eat fortified foods: insufficient vitamin B12.
What Else Can Raise Homocysteine?
Diet is not the only factor that influences homocysteine levels. Certain medications and health conditions can also affect vitamin status and homocysteine metabolism.
Elevated homocysteine deserves more attention when it appears alongside neurologic symptoms, cardiovascular disease risk, certain medications, or suspected B vitamin deficiency, according to Cara Hoepner, an integrative functional psychiatry and psychopharmacology practitioner.
Long-term use of metformin, commonly prescribed to treat Type 2 diabetes, or acid-suppressing medications may lower vitamin B12 levels, Siedman said, while methotrexate, a drug commonly used for cancer and autoimmune diseases, and some anti-seizure medications can interfere with folate metabolism.
Conditions that impair nutrient absorption—including celiac disease, inflammatory bowel disease, autoimmune gastritis, pernicious anemia, and bariatric or other gastrointestinal surgeries—may also increase risk, Siedman said.
Kidney disease and thyroid dysfunction may contribute to elevated homocysteine independent of diet.
For this reason, a high homocysteine does not necessarily mean that someone simply needs to take in more folate or vitamin B12.
“The main point is that homocysteine is a clue—not a diagnosis—and it should be interpreted in context,” Hoepner told The Epoch Times.
When Fatigue Won’t Go Away
Homocysteine is not typically included in routine blood work. Doctors usually order it only when they suspect an underlying risk or metabolic issue.
If you are concerned about persistent fatigue, you may want to speak with your doctor about whether testing for homocysteine, vitamin B12, or folate levels may be appropriate—particularly if you also have symptoms such as brain fog, low mood, numbness, tingling, or dietary restrictions that could increase the risk of nutritional deficiencies.
“A practical rule is that if basic workup does not explain the symptoms—or if the person has clear risk factors—then checking nutrient status is reasonable,” Hoepner said.
Siedman framed it as one piece of a larger picture.
“The key is not to assume fatigue is ‘just stress’ or ‘just hormones,’ but to recognize that it is often the result of a constellation of factors,” she said. “When symptoms persist or start affecting daily function, targeted lab testing can help identify whether nutritional status is one meaningful piece of the puzzle.”
The experts were unanimous on one point: Homocysteine alone is not a diagnosis. It’s one data point in a broader picture involving diet, metabolic health, medications, and underlying medical conditions. However, the findings add scientific weight to what we intuitively know: Good nutrition—and the metabolic processes it feeds—shapes our lives, giving us energy and motivation.