This meta-analysis shows that supplementation of betaine at 4 to 6 g/d significantly lowers plasma homocysteine concentration in healthy adults by 1.23 μ
mol/L or 11.8% of baseline values. A reduction in plasma homocysteine of 5 μ
mol/L is estimated to reduce the risk of cardiovascular disease by 20% to 30% and stroke by 40% to 60%.22
Based on this current meta-analysis, a person who consumes 4 to 6 g/d of betaine would have a 1.23-μ
mol/L lower plasma homocysteine concentration with an estimated concurrent reduction in cardiovascular disease risk of approximately 5% to 8% and a reduction in stroke risk of approximately 10% to 15%.
The homocysteine-lowering effects of betaine can most likely be ascribed to an increase in betaine-dependent methylation of homocysteine into methionine due to increased betaine availability and enhanced activity of the enzyme BHMT in both the liver and kidney. Betaine supplementation lowers plasma homocysteine levels almost immediately, with maximum results obtained within 4 to 6 weeks.11,15,17,18
It has been shown that betaine doses of 3 and 6 g decreased plasma homocysteine concentrations within 2 hours in healthy adults.17
No serious adverse effects were noted in any of the studies; but it is important to note that, in 2 studies, betaine supplementation significantly increased total serum cholesterol and low-density lipoprotein (LDL) cholesterol, which are both independent risk factors for cardiovascular disease.9,13
However, the changes were small and of minor clinical significance, with increases in both total serum cholesterol and LDL cholesterol of approximately 5 mg/dL. These 2 studies parallel another study that found significant increases in both total serum cholesterol and LDL cholesterol of approximately 10 mg/dL.16
However, in 2 other betaine-supplementation studies, the authors did not find any significant change in total serum cholesterol and LDL cholesterol after betaine supplementation.10,19
No significant changes in high-density lipoprotein cholesterol or triglycerides were noted in any of the studies that reported these values. The mechanism by which betaine might increase total serum cholesterol and LDL cholesterol concentration has been proposed to be the increase in synthesis and export of lipids in very low density lipoprotein from the liver into the circulation.23
Betaine is formed from choline; and so betaine supplementation spares this use of choline so that more is available for phosphatidylcholine biosynthesis in the liver, thereby making more available for very low density lipoprotein formation.
In regard to the risk of developing cardiovascular disease, it is important to point out that the unfavorable effects on serum lipids with betaine supplementation may undo the favorable homocysteine-lowering effects, as a 5- to 10-mg/dL increase in total serum cholesterol can increase the risk of developing cardiovascular disease by 3% to 6%.24
Therefore, in patients with normal plasma homocysteine levels, betaine supplementation may have a negligible effect on cardiovascular health; however, for patients with hyperhomocystinemia, the benefit of a homocysteine-lowering effect outweighs the effect of any modest lipid-related changes.
Many studies to date have shown that dietary supplementation with folic acid lowers plasma homocysteine concentrations in participants with either normal or elevated plasma homocysteine concentrations, with reductions of plasma homocysteine of 10% to 20%.25,26
Therefore, a decrease in plasma homocysteine of 3 μ
mol/L (achievable by daily intake of 800 μ
g folic acid) should reduce the risk of heart disease by 16% and stroke by 24%.22
When comparing betaine vs folic acid, it has been noted that folic acid supplementation lowers plasma homocysteine more than betaine supplementation.27
However, it has also been shown that the association of betaine with plasma homocysteine concentration is more pronounced in participants with low folate serum concentrations.28
Thus, betaine takes over as a methyl donor and sustains methionine synthesis under conditions of impaired folate status. Furthermore, folic acid supplementation has been shown to increase plasma betaine concentration by 15%, which indicates that the 2 remethylation pathways are interconnected.29
Folic acid has no adverse effects on blood lipids; and therefore, folic acid supplementation should remain the preferred homocysteine-lowering treatment in healthy humans.30
However, betaine may enhance homocysteine metabolism when the folic acid response is weak because of genetic polymorphisms such as MTHFR 677C→T. This is a point mutation that leads to an alanine to valine substitution in the enzyme methylenetetrahydrofolate reductase and is associated with approximately 40% higher plasma homocysteine concentration in carriers of the TT genotype compared with those with the CC wild type.31
The allele frequency of the MTHFR 677C→T mutation is 35%, with a homozygous rate of 12%. Betaine supplementation may be a useful adjunct along with folic acid for those 12% of patients who are TT homozygotes for the genetic mutation MTHFR 677C→T. This may be especially true in light of the possibility that patients with this genetic polymorphism are recommended to increase folic acid, but a few studies have shown that too much folic acid may increase the incidence of colorectal cancer.32
The overall purpose of supplementing with betaine is to decrease plasma homocysteine concentrations, which should ultimately lead to a reduction in the incidence of heart disease and stroke. Although no studies to date have concluded that betaine supplementation directly reduces the risk of developing cardiovascular disease and stroke, a recent review concluded that the long-term consumption of betaine may prevent cardiovascular disease mortality.33
More importantly, if homocysteine is elevated in response to a betaine insufficiency, it will not be corrected by folic acid supplementation alone; and this could help to explain why folic acid therapies do not lead to the expected reduction in vascular events.34
Therefore, the elevated homocysteine concentrations in these studies could be an indication of betaine insufficiency; and hence, using folic acid supplementation to lower plasma homocysteine concentrations would not lead to a sufficient decrease in plasma homocysteine to ultimately reduce the incidence of cardiovascular disease. It is important that future studies in this area control for both the betaine and folic acid intakes with respect to their influence on reducing the incidence of cardiovascular disease so that the effects of one can be carefully identified in relation to the other.
One limitation in this meta-analysis is that all 5 studies used participants whose initial plasma homocysteine concentrations before intervention were normal. It has been shown that the extent of the decrease is smaller in healthy volunteers than in patients with hyperhomocystinemia.20
Therefore, future short-term studies must be conducted on patients with hyperhomocystinemia to assess the effects of betaine supplementation on plasma homocysteine, with additional long-term studies to assess the effects of betaine supplementation on reducing cardiovascular disease risk. Other limitations include that only one indexing system was searched and thus it is possible that some studies were not identified, and that only one author performed the selection of the articles included in this study and analysis of the data.