Homocysteine level and natural ways to lower with vitamins, herbs, and supplements
November 22 2015 by
Ray Sahelian, M.D.

Homocysteine is a derivative of the amino acid methionine. It received a great deal of media attention in 1997 following publication of articles in medical journals indicating that a high homocysteine blood level is a potential risk factor for stroke and heart disease. Kilmer McCully, M.D., a pathologist at the Veterans Affairs Medical Center in Providence, Rhode Island, had been claiming for at least two decades that elevated homocysteine level is as important a risk factor for heart disease as cholesterol, but few in the medical profession paid serious attention to his claim. Dr. McCully appeared to be vindicated with the publication of additional scientific articles in the 1990s, most of which confirmed the dangers of elevated levels. However, recent studies have disputed the role of elevated homocysteine level in cardiovascular disease.

Lowering homocysteine levels
A high blood homocysteine level can be easily lowered by taking supplements of B vitamins, particularly folic acid, B6, and B12 .or by taking betaine. Unfortunately, at this time, having reviewed the positive results and the negative results, no definite statements can be made regarding the benefits of supplementing with B vitamins in regards to stroke and heart disease prevention or treatment.
   So, what's the bottom line? Should you not supplement with B vitamins to lower homocysteine? I still say yes. In addition to lowering homocysteine level in the blood and brain, B vitamins have many benefits including mental health and more energy. But, I don't think high doses are required. One, two, or three times the RDA should be fine. I don't think the B50 or the B100 products, which supply 25 to 50 times the RDA for certain B vitamins, are necessarily beneficial. It may be a good idea to just take a multivitamin supplying one, two, or three times the RDA for all the Bs. 
   Higher amounts of B vitamins, or taking too high a dose of just one or two of the B vitamins may be counterproductive. Unfortunately, as with many simple nutritional questions, such as the role of calcium supplements in osteoporosis, more research will be needed to sort out the real answers.

Cochrane Database Syst Rev. 2013. Homocysteine-lowering interventions for preventing cardiovascular events. This updated Cochrane review found no evidence to suggest that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination should be used for preventing cardiovascular events. Furthermore, there is no evidence suggesting that homocysteine-lowering interventions are associated with an increased risk of cancer.

Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr 2014.

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How to reduce high homocysteine level
Adequate intake of folic acid, B6, and B12 will assure that the blood homocysteine level is kept under control. Considering the possibility that there may be individuals, especially the elderly, who are deficient in B6, folic acid, and B12, an inexpensive and simple way to decrease the rate of damage to the brain from a high homocysteine level would be by supplementing with these vitamins. Keep dosages low.

Danger to the Brain?
In addition to potentially contributing to cardiovascular conditions, homocysteine may be detrimental to the brain since it can act as a toxin to brain cells. Dr. L. Parnetti and colleagues, from Perugia University in Italy published an article discussing its role in cognitive decline. They say, "Homocysteine may represent a metabolic link in the cause of atherosclerotic vascular diseases and old-age dementias. An excessive amount is an independent risk factor for coronary artery disease, peripheral vascular disease, and cerebrovascular disease. Homocysteine is a reliable marker of vitamin B12 deficiency, a common condition in the elderly, which is known to induce neurological deficits including cognitive impairment. A high prevalence of folate deficiency has been reported in geriatric patients suffering from depression and dementia. Both these vitamins occupy a key position in the remethylation and synthesis of S-adenosylmethionine (SAM-e), a major methyl donor in the central nervous system. Therefore, deficiencies in either of these vitamins leads to a decrease in SAM-e and an increase in homocysteine, which can be critical in the aging brain."

     Nutritionists at Tufts University in Boston have also found a connection between B vitamins, homocysteine, and memory. They investigated the relations between blood concentrations of homocysteine and vitamins B-12, B-6 and folate, and scores from a battery of cognitive tests for seventy male subjects, aged 54-81 years. Lower concentrations of vitamin B-12 and folate and higher concentrations of homocysteine were associated with poorer memory. Furthermore, people with low levels of vitamin B12 or folic acid may have a higher risk of developing Alzheimer's disease.
     In older people, higher blood levels of homocysteine are associated with lower mental functioning.
homocysteine, an amino acid that has been tied to heart disease and stroke, can be lowered with folate and vitamins B6 and B12. The latest finding suggests to researchers that B vitamin supplements may help prevent homocysteine related cognitive decline.

S-adenosylhomocysteine, a better test for vascular disease than homocysteine?
Some studies indicate higher blood concentration of S-Adenosylhomocysteine appears to be a more sensitive indicator of vascular disease.

A report in the 2005 issue of the American Journal of Clinical Nutrition, indicates that a high daily dose of choline, supplemented as phosphatidylcholine, lowers fasting as well as postmethionine-loading plasma homocysteine concentrations in healthy men with mildly elevated concentrations. If high homocysteine concentrations indeed cause cardiovascular disease, choline intake may reduce cardiovascular disease risk in humans.

Liver health
High homocysteine level is also associated with higher ALT levels when liver enzyme levels are checked.

Memory loss
A population-based, prospective study of elderly British individuals shows that risk of memory loss increases over time with increasing levels of total blood homocysteine and decreasing folate levels. Homocysteine is an amino acid in the blood. Too much of it ups the risk for coronary heart disease, stroke and fatty deposits in peripheral arteries. High circulating levels of homocysteine, especially with advancing age, have also been associated with cognitive impairment. Homocysteine levels in the blood are strongly influenced by diet and genetics. Folic acid and other B vitamins help break down homocysteine in the body. Annals of Neurology 2005.

Women who have high levels of the amino acid homocysteine in the blood are at increased risk for low bone mineral density (BMD). Using data from a population-based cohort of more than 5,300 middle-aged and elderly men and women, researchers observed that total homocysteine level was inversely related to hip BMD among middle-aged and elderly women, but not among men. Women with high levels were nearly two times more likely to have low BMD compared with women with low levels. Moreover, high homocysteine predicted osteoporosis among women after adjusting for confounding factors such as smoking, physical activity, intake of vitamin D and calcium, and use of estrogen.

Zhonghua Nei Ke Za Zhi. 2015. A prospective study on the association of plasma homocysteine level with stroke in hypertensive patients. Elevated Hcy levels were associated with stroke in hypertensive patients.

Review and Summary
Ray Sahelian, M.D. author of Mind Boosters: A Guide to Natural Supplements That Enhance Your Mind, Memory, and Mood says: Homocysteine, in addition to causing harm to brain cells, may cause hardening of the arteries. Folic acid and B
12 deficiencies are common in the elderly, especially those in nursing homes. Supplementing with folic acid, B6, and B12 seems to be a reasonable approach to lowering the risk from excess homocysteine but there is still not definite proof that taking B vitamins lowers the risk of heart disease or stroke. If you do take B vitamins, keep your dosage to one or two times the RDA. Higher doses may be counterproductive or harmful in some people.

Homocysteine Study in New England Journal of Medicine - Controversy
Supplementation with folic acid and vitamins B-12 and B-6 did not reduce the risk of major cardiovascular events in patients with cardiovascular disease (CVD) according to two reports in the New England Journal of Medicine for April 13, 2006. The Heart Outcomes Prevention Evaluation (HOPE)-2 investigators, led by Dr. Eva Lonn at McMaster University in Hamilton, Ontario, enrolled 5522 patients age 55 and older who had a history of vascular disease or diabetes and other risk factors for atherosclerosis. Subjects were randomly assigned a daily tablet containing 2.5 mg folic acid, 50 mg vitamin B-6 and 1 mg vitamin B-12 or matching placebo. Baseline homocysteine levels were similar in the two groups (12.2 mol/L). After a mean of 5 years of follow-up, levels had declined to 9.7 mol/L in the active treatment group, but had increased to 12.9 mol/L in the placebo group. Despite the changes in homocysteine levels, no major changes were noticed in myocardial infarction and stroke (18.8% in the supplement group and 19.8% in the placebo group). There were also no significant differences in hospitalization for heart failure or revascularization, total ischemic events, or venous thromboembolism. Even among subjects with the highest baseline levels of homocysteine, outcomes were similar between the two groups. The only significant differences were a slightly decreased risk of stroke in the active treatment group and an increased hazard of hospitalization for unstable angina (9.7% versus 7.9%). The investigators note that the confidence intervals were wide and the results were not adjusted for confounders. In the second report, Dr. Kaare Harald Bonaa, from the University of Tromso, and members of the Norwegian Vitamin (NORVIT) trial group conducted a similar prospective study that included 3749 patients ages 30 to 85 years who had had an acute MI. Participants were randomly assigned to one of four groups. They were given 0.8 mg folic acid plus 0.4 mg vitamin B-12 and 40 mg vitamin B6 (combination therapy), 0.8 mg folic acid and 0.4 mg vitamin B-12, 40 mg of vitamin B6 or placebo. Supplements were taken once daily, and outcomes were assessed after an average of 36 months. In the two groups treated with folate and vitamin B-12, total homocysteine levels declined by 27%, while B-6 alone and placebo had no effect. In the combination therapy group, the odds of stroke, MI, or cardiovascular death was increased 22% compared with placebo. Vitamin B-6 was associated with a 17% increase in the risk of MI, and combination therapy increased the risk of nonfatal MI by 30%. N Engl J Med 2006.

Homocysteine Research
Homocysteine lowering and cardiovascular events after acute myocardial infarction.
N Engl J Med. 2006. Institute of Community Medicine, University of Tromso, Tromso, Norway.
We evaluated the efficacy of homocysteine -lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction. The trial included 3749 men and women who had had an acute myocardial infarction within seven days before randomization. Patients were randomly assigned, in a two-by-two factorial design, to receive one of the following four daily treatments: 0.8 mg of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and 0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease. RESULTS: The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary end point (risk ratio. In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk. Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. A harmful effect from combined B vitamin treatment was suggested.
     Dr. Sahelian comments: It's not accurate to say that a "harmful effect from combined B vitamin treatment was suggested." We can just say that in this study the particular dosages of the B vitamins may have caused a harmful effect. It is quite possible that a different combination of B vitamins that are more balanced, or a lower dose of the B6, may have produced different results.

Homocysteine lowering with folic acid and B vitamins in vascular disease.
N Engl J Med. 2006.
We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased in the active-treatment group and increased in the placebo group. As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes. Fewer patients assigned to active treatment than to placebo had a stroke. More patients in the active-treatment group were hospitalized for unstable angina (relative risk. Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease.

Complex multivitamin supplementation improves homocysteine and resistance to LDL-C oxidation.
J Am Coll Nutr. 2003.
We previously reported in an open-label pilot trial that a 24-ingredient multivitamin formula favorably influenced homocysteine concentration and LDL-C oxidation indices following 24 weeks of supplementation. Our current aim was to more thoroughly examine this same formula in a randomized, placebo-controlled, clinical study. We examined 182 participants for selected plasma vitamin concentrations and clinically relevant variables including homocysteine, lipids and LDL-C oxidation indices at baseline and six months. RESULTS: We found no significant differences between groups for any parameter at baseline. Following six months of vitamin supplementation, we observed elevations in plasma concentrations of vitamin B6 (as pyridoxal 5'-phosphate; PLP), vitamin B12, folate, vitamin C, vitamin E and beta-carotene, all of which were significantly greater than respective placebo group changes. Homocysteine decreased in the treatment and placebo group  from baseline to six months, respectively, with reductions in the treatment group being greater than placebo. LDL-C oxidation indices were also improved. We conclude that a multi-ingredient vitamin formula with antioxidant properties has measurable effects on homocysteine and LDL-C oxidation indices.

Effects of betaine intake on plasma homocysteine concentrations and consequences for health.
Curr Drug Metab. 2005.
High plasma concentrations of homocysteine may increase risk of cardiovascular disease. Folic acid lowers plasma homocysteine by 25% maximally, because 5-methyltetrahydrofolate is a methyl donor in the remethylation of homocysteine to methionine. Betaine (trimethylglycine) is also a methyl donor in homocysteine remethylation, but effects on homocysteine have been less thoroughly investigated. Betaine in high doses (6 g/d and higher) is used as homocysteine-lowering therapy for people with hyperhomocysteinemia due to inborn errors in the homocysteine metabolism. Betaine intake from foods is estimated at 0.5-2 g/d. Betaine can also be synthesized endogenously from its precursor choline. Studies in healthy volunteers with plasma homocysteine concentrations in the normal range show that betaine supplementation lowers plasma fasting homocysteine dose-dependently to up to 20% for a dose of 6 g/d of betaine. Moreover, betaine acutely reduces the increase in homocysteine after methionine loading by up to 50%, whereas folic acid has no effect. Betaine doses in the range of dietary intake also lower homocysteine. This implies that betaine can be an important food component that attenuates homocysteine rises after meals. If homocysteine plays a causal role in the development of cardiovascular disease, a diet rich in betaine or choline might benefit cardiovascular health through its homocysteine-lowering effects. However betaine and choline may adversely affect serum lipid concentrations, which can of course increase risk of cardiovascular disease. However, whether the potential beneficial health effects of betaine and choline outweigh the possible adverse effects on serum lipids is as yet unclear.

Homocysteine: is it a clinically important cardiovascular risk factor?
Cleve Clin J Med. 2004.
Elevated plasma homocysteine is associated with an increased risk of myocardial infarction, stroke, and venous thromboembolism. Folic acid and other B vitamins lower high homocysteine levels, but whether this therapy confers a clinical benefit has yet to be determined. Until we know the results of ongoing clinical trials of homocysteine lowering therapy, testing for and treating elevated homocysteine is probably justified only in patients with known cardiovascular disease or who are at high risk.

Homocysteine and cognitive function in elderly people.
CMAJ. 2004.
Dementia is highly prevalent among elderly people, and projections show that the number of people affected might triple over the next 50 years, mainly because of a large increase in the oldest-old segment of the population. Because of this and the disease's devastating effects, measures for the prevention and early detection of dementia are crucial. Age and years of education are among the most relevant risk factors for dementia, but in recent years the role of homocysteine has also been investigated. Homocysteine is an amino acid produced in the metabolism of methionine, a process dependent on the B vitamins cobalamin, vitamin B6 and folic acid. There is evidence that increased serum homocysteine levels are associated with declining cognitive function and dementia. We review this evidence in addition to the potential mechanisms through which homocysteine acts on the brain to cause cognitive dysfunction, the metabolism of homocysteine and factors associated with alteration of the normal metabolism.

Homocysteine and the production of collagens, proliferation and apoptosis in human arterial smooth muscle cells.
APMIS. 2004.
Homocysteine is an important and independent risk factor for atherosclerosis. We showed that human aortic smooth muscles in cultures proliferated significantly at a concentration of 25 mumol/L Homocysteine without the presence of serum. There was no effect of Homocysteine on apoptosis. However, collagen types I, III and IV increased significantly in a dose-dependent manner at elevated concentrations of Homocysteine and the amount of type VI collagen was significantly reduced in a dose-dependent manner. Homocysteine induced increased cell replication with an unaffected apoptosis rate. The present observations suggest that Homocysteine may contribute to accelerated progression of atherosclerotic lesions with collagen alterations which transform the injury into fibrotic plaques.

Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women.
Olthof MR. J Nutr. 2003.
High plasma homocysteine is a risk for cardiovascular disease and can be lowered through supplementation with 6 g/d of betaine. However, dietary intake of betaine is approximately 0.5-2 g/d. Therefore, we investigated whether betaine supplementation in the range of dietary intake lowers plasma homocysteine concentrations in healthy adults. Four groups of 19 healthy subjects ingested three doses of betaine or placebo daily for 6 wk. A methionine loading test was performed during run in, on d 1 of betaine supplementation, and after 2 and 6 wk of betaine supplementation. Fasting plasma homocysteine after 6-wk daily intakes of 1.5, 3 and 6 g of betaine was 12% less than in the placebo group, respectively. Furthermore, the increase in plasma homocysteine after methionine loading on the 1st d of betaine supplementation was 16% less than in the placebo group, respectively, and after 6 wk of supplementation was 23% less, respectively. Thus, doses of betaine in the range of dietary intake reduce fasting and postmethionine loading plasma homocysteine concentrations. A betaine-rich diet might therefore lower cardiovascular disease risk.

Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects.
Am J Clin Nutr. 2002.
Betaine (trimethylglycine) is found in several tissues in humans. Betaine is involved in homocysteine metabolism as an alternative methyl donor and is used in the treatment of homocystinuria in humans. In pigs, betaine decreases the amount of adipose tissue. The aim of the study was to examine the effect of betaine supplementation on body weight, body composition, plasma homocysteine concentrations, blood pressure, and serum total and lipoprotein lipids. Forty-two obese, white subjects (14 men, 28 women) treated with a hypoenergetic diet were randomly assigned to a betaine-supplemented group (6 g/d) or a control group given placebo for 12 wk. The intervention period was preceded by a 4-wk run-in period with a euenergetic diet. Body weight, resting energy expenditure, and fat mass decreased significantly in both groups with no significant difference between the groups. Plasma homocysteine concentrations decreased in the betaine group. Diastolic blood pressure decreased without a significant difference between the groups. Serum total and LDL-cholesterol concentrations were higher in the betaine group than in the control group. A hypoenergetic diet with betaine supplementation (6 g daily for 12 wk) decreased the plasma homocysteine concentration but did not affect body composition more than a hypoenergetic diet without betaine supplementation did.

I am wondering if you can tell me what my best course of action might be to lower my homocystine levels. They have bounced around between 10.9 and 15.9 for years, but I am not entirely sure what causes the fluctuation. I cannot seem to get them any lower. I have sarcoidosis, otherwise generally ok. Prescriptions: 10mg prednisone and 10mg benicar (not hct). Supplements - Including a multivitamin, 1000mg methyl b-12, additional 25mg b-6, 1500mg TMG, 2500mg of fish oil, 100mg ALA, curcumin, zyflamend (combo for anti-inflamatory), 100mg co-q10, 1000 mg aged garlic extract, etc.
   A. I prefer not to focus on any particular blood level but to take a comprehensive approach to one's overall health.

Q. I've just purchased some Sam-e for depression as I experience too many side-effects with anti-depressants. I have read that it is wise to take additional B vitamins, particularly B6, B12 and folic acid, when taking Sam-e in order to prevent toxic build-up of homocysteine. Apparently these vitamins assist in the breakdown of homocysteine which is formed when Sam-e breaks down.
     A. We're not totally sure whether extra B vitamins are needed if someone is taking SAM-e. Perhaps it depends on one's diet and biochemistry. It would not hurt to take 1 to 3 times the RDA of the B vitamins.

Q. I've just read about Trimethyglycine on your site. I recently had blood work done and everything was great except my Homocysteine, which was 11.1. I want to lower it to the 6-7 range. I've been researching and found sites with TMG protocols of up to 6 grams along with B6 (100-500 mg), B12 (1000-3000 mcg), and folic acid (800-5000 mcg). My question: Does taking these supplements at these dosages have side effects? Especially the TMG, which is very high? One site mentioned someone who had a Homocysteine number of 18. He took TMG at 6 grams and 500 mg of B6 and lowered it to 4 in 60 days. I'm just curious as to your opinion of these kind of dosages. Your thoughts are appreciated. Your site is very informative.
     A. TMG at high doses can increase body temperature and cause irritability and insomnia. My preference is not to use TMG in a dosage greater than 750 mg daily. Also, massive doses of B vitamins are not required to lower homocysteine. A fraction of the doses mentioned in your email can be effective. Each person is unique in their response, though, and some require less, others more.

Q. Do you think testing for homocysteine blood level is important?
     A. I'm not really sure homocysteine levels need to be checked since taking B vitamins will lower them anyway. We do so many blood tests in this country, and medical expenses are skyrocketing. Why not just take a cheap B vitamin complex? That' s my opinion, another doctor may disagree.

Q. Which supplement, choline or betaine, is more effective at lowering homocysteine levels?
     A. A combination of low doses of B vitamins, one or two times the RDA, would be more effective, along with low doses of betaine or choline, such as 50 mg. Each person is unique, it is difficult to say which will work in a particular person but the important point is to use low dosages.

Q. Are homocysteine and metabolic syndrome X related?
     A. Not directly, but those with poor dietary habits and who do not exercise enough are likely to have high homocysteine and have metabolic syndrome x.

Q. I read your May newsletter on homocysteine and that is disturbing news. Everyione, including Dr Jonahtan Wright is saying that homocysteine causes more heart attacks than high chlosterol. Now I don't know what to think?
     A. Unfortunately, science does not always give us clear answers. It takes a long time, often decades, to find out good answers to even simple nutritional questions.

Q. My letter is actually about your statement on B vitamins (especially in the effort to reduce homocysteine levels) - I was wondering if you had read the H-Factor, where the authors describe clinical studies
where the homocysteine levels were not reduced using B-vitamins because TMG amounts were not included. Could it be that the trials you were referencing did not include the proper amounts of TMG? I did not test for homocysteine levels before starting on the regime (I believe you have to go outside the
US for testing) and I do plan to test in the future, but also feel confident that meanwhile I am reducing it significantly so that when I do test, I should have a very healthy number.
     A. B vitamins lower homocysteine levels, but whether that leads to a change in health is not fully answered at this time. Homocysteine levels can be routinely tested in a doctor's office. TMG can also lower homocysteine levels.

Q. I have a question about Source Naturals Homocysteine Defense. Is there a problem in taking only a few of the B vitamins? I've been under the impression that they should all be taken together.
     A. As a general statement, I think taking one or two times the RDA for all the B vitamins is a good option at this point until we learn more about this complex issue.

Q. I have read about TMG and it states that it helps convert homocystine to methionine. Doesn't methionine all convert back to homocystine? Also, I have read that TMG raises LDL. Is this actually a benefit if it raises LDL but lowers Homocystine?
   A. The whole methionine, homocysteine, TMG, SAM-e, etc. biochemistry is quite complicated, and rather than focusing on the individual biochemical steps that are involved, it is more practical to take a comprehensive approach to reducing heart disease risk factors. TMG is quite potent, and most people don't need more than 100 or 200 mg a day even though tablets come in 750 mg. TMG may lower homocysteine, but if too high doses are used, insomnia can occur or heart rate could increase and thus negate the homocysteine lowering benefits. Much of the benefit or risk of a supplement depends on the dosage.

Do you have an opinion on supplementing hydroxocobalamine, cyanocobalamine or methylcobalamine with Folic acid and Trimethylglycine TMG to help reduce high homocysteine level and to support recovery of nerve damage caused by B12 deficiency? You seem to recommend against it because TMG does the same thing as the other two.
   Without specific research on these nutrients and comparisons, it is difficult to know which one or combination is best and what dosage to use.