In the US, stroke is the third leading cause of death and a leading cause of serious, long-term disability. Each year, about 700,000 people suffer a stroke. Identifying factors that put a person at risk for stroke and developing prevention strategies is the focus of much medical research. Several studies have found a relationship between elevated homocysteine levels and increased risk of stroke.

Homocysteine is an amino acid, however, unlike other amino acids, it is not a component of a protein. Instead, it is used to produce methionine, another amino acid, which is a component of a protein. Turning homocysteine into methionine requires a number of vitamins—specifically folic acid , vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). If a person’s diet is deficient in any of these three vitamins, levels of homocysteine can build up in the blood.

A study published in the February 4, 2004 issue of the Journal of the American Medical Association looked at whether high doses of vitamins B6 and B12 and folic acid would lower total homocysteine levels and reduce the risk of recurrent stoke as compared with low doses of these vitamins.

About the study

The study included 3,680 adults who had previously suffered a non-disabling stroke. The participants were randomized to receive a low-dose vitamin supplement or a high-dose vitamin supplement once daily. Both supplements contained the reference daily intakes (RDI) recommended by the Food and Drug Administration (FDA) for all other vitamins, but varied in their content of vitamins B6 and B12 and folic acid. The following table provides the different levels of the three vitamins in the supplements and the RDI level.


Low-dose formulation in micrograms (mcg)*

High-dose formulation in milligrams (mg)


Folic acid

20 mcg (0.02 mg)

2.5 mg

400 mcg

Vitamin B6

200 mcg (0.2 mg)

25 mg

1.3 – 1.7 mg

Vitamin B12

6 mcg (0.6 mg)

0.4 mg

2.4 mcg

*1,000 mcg = 1 mg

The study’s participants were followed for up to two years. Researchers measured blood levels of homocysteine throughout the study. The primary outcome of the study was a recurrence of stroke; coronary heart disease (CHD) event and death were measured as secondary outcomes.

The findings

The researchers found that levels of homocysteine in the blood decreased for both groups, but the decrease was greater for the high-dose group. However, there were no significant differences between the two groups in the primary and secondary outcomes measured. For example:

  • 8.1% of the low-dose group as compared to 8.4% of the high-dose group experienced a recurrent stroke;
  • 6.7% of the low-dose group as compared to 6.3% of the high-dose group experienced a CHD event.
  • 6.3% of the low-dose as compared to 5.4% of the high-dose group died.

How does this affect you?

According to these findings, raising homocysteine levels by supplementing with vitamins does not appear to reduce the risk of a recurrent stoke. The authors suggest several reasons to explain why their treatment showed no effect. The participants may have had baseline homocysteine levels that were too low to show a large effect. Also, the sample size may have been too small. In addition, fortification of the nation’s grain with folic acid coincided with the onset of the study; this may have had an impact on homocysteine levels. Lastly, the length of the trial, two years, may have not been long enough to reverse the effects of many years of elevated homocysteine levels. It may take decades of vitamin supplementation in individuals with no history of cardiovascular disease to help prevent stroke and heart attack.

So, should you continue to take those supplements? That remains an open question. The ideal way to attain adequate levels of vitamins is through food, but in today’s fast-paced world it is not always possible to meet your daily nutritional requirements, let alone the high doses of vitamins used in this study. Taking a daily multivitamin may be added insurance that you’re at least meeting your ideal daily intakes. Nevertheless, studies to date remain decidedly mixed on the benefits of vitamins supplementation for most Americans. This study does nothing to clear up the controversy.