Beginning in the late 1990s, medical researchers began to suspect that high levels of homocysteine (a substance produced when the body breaks down the amino acid methionine) may accelerate atherosclerosis, the primary cause of heart attacks, strokes, and intermittent claudication. During a brief period, it was widely proclaimed that homocysteine was an even more important risk factor for heart disease than cholesterol. However, it currently appears that reducing homocysteine provides minimal benefits, if any.
Most of the supporting evidence for a homocysteine–atherosclerosis connection comes from observational studies that found an association between high levels of homocysteine and increased atherosclerosis. Observational studies, however, do not show cause and effect. It is quite possible that unknown underlying factors increase homocysteine levels and also accelerate atherosclerosis, rather than that high homocysteine causes accelerated atherosclerosis. Only intervention trials (studies where people are actually given a treatment) can show whether a treatment is effective.
Several massive studies of this type were initiated in response to the observational data. The results of 5 such trials have now been reported, involving a total of more than 18,000 men and women.20,23-25,49,50 In these studies, high doses of supplementary vitamin B6, vitamin B12, and folate were used to lower homocysteine levels. None of these studies found significant benefit for preventing stroke, heart attack, or heart-related death.
A smaller study failed to find that these same homocysteine-lowering vitamins preserved mental function in people with loss of mental function caused by atherosclerosis in the brain.26 Another study failed to find that lowering homocysteine with B-vitamins can improve mental function in seniors.36 On one of the few positive notes, one substantial trial found that use of these homocysteine-lowering nutrients helped prevent restenosis (recurrent vessel clogging) after angioplasty.27
Besides atherosclerosis, correlations have also been found between high homocysteine levels and numerous other diseases, including Alzheimer’s disease, osteoporosis, complications of pregnancy, deep venous thrombosis, and pulmonary embolism.3-9,28-30 Again, however, most of the supporting evidence for a connection comes from observational studies; the results of double-blind studies are less encouraging. For example, one very substantial double-blind, placebo-controlled study failed to find that reducing homocysteine levels can help prevent recurrent deep venous thrombosis or pulmonary embolism.37 Data gathered in another study also failed to show benefit for preventing these two problems.42 Four double studies failed to find benefit for Alzheimer’s disease or other forms of dementia.26,47,48,51 In addition, double-blind studies of B vitamins for reducing osteoporosis risk have not yet produced convincing evidence of benefit.44-46
On a positive note, a double-blind, placebo-controlled study of 728 Danish seniors with high homocysteine and relatively low folate intake found that use of folate supplements slowed the progression of age-related hearing loss.39 Folate may also improve mental function in seniors with high homocysteine.40
Another study found that in people who had already had a stroke and were partially paralyzed, supplementation with vitamin B 12 and folate reduced the risk of falls leading to hip fractures.21 Participants were elderly Japanese with high levels of homocysteine and low levels of folate and B 12. It is not clear how the treatment produced this benefit: it might have reduced the tendency for recurrent strokes, strengthened bones, improved balance, or produced benefit by some other means. Another study used blood tests to look at effects on bone, and failed to find that reducing homocysteine levels had any effect.41
People with diabetes or inflammatory bowel disease ( Crohn’s disease or ulcerative colitis) and those undergoing kidney dialysis may be at higher than normal risk for elevated homocysteine levels. A simple blood test can determine homocysteine levels. Both conventional and alternative practitioners use the natural substances described in the next section to treat elevated homocysteine.
Principal Proposed Natural Treatments
Three nutrients act together to help the body reduce homocysteine levels: vitamin B6, vitamin B12, and folate.10-15 Many Americans are at least marginally deficient in vitamin B 6.16 Vitamin B 12 deficiency occurs primarily in seniors as well as people who take drugs that suppress stomach acid.17 Folate deficiency is thought to have become fairly uncommon in the US due to the enrichment of grains that began in the late 1990s.18 However, it appears that the dose of folate required to achieve maximum homocysteine reduction is 800 mcg daily, higher than the usual nutritional recommendations.15,31,38
Nonetheless, as noted above, studies utilizing high doses of these vitamins for lowering homocysteine and therefore preventing cardiovascular disease have generally failed to find benefit. For more information on these nutrients, including dosage and safety issues, see the full Vitamin B6, Vitamin B12, and Folate articles.
Other Proposed Natural Treatments
Some people develop extraordinarily high levels of homocysteine due to a genetic defect. The supplement trimethylglycine (TMG) is an FDA-approved treatment for this condition. TMG also seems to be effective for milder forms of high homocysteine.32-33 However, the nutrients mentioned in the previous section are less expensive and probably equally, if not more, effective at lowering homocysteine. Furthermore, TMG might raise cholesterol levels, thereby potentially undoing whatever benefit (if any) that might result from lowering homocysteine.33
References[ + ]
1. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.
2. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204-210.
3. Aubard Y, Darodes N, Cantaloube M. Hyperhomocysteinemia and pregnancy—review of our present understanding and therapeutic implications. Eur J Obstet Gynecol Reprod Biol. 2000;93:157-165.
4. Cattaneo M, Vecchi M, Zighetti ML, et al. High prevalence of hyperhomocysteinemia in patients with inflammatory bowel disease: a pathogenic link with thromboembolic complications? Thromb Haemost. 1998;80:542-545.
5. Clarke R, Smith D, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neruol. 1998;55:1449-1455.
6. Eskes TK. Clotting disorders and placental abruption: homocysteine—a new risk factor. Eur J Obstet Gynecol Reprod Biol. 2001;95:206-212.
7. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet. 2001;109:369-384.
8. Miller JW. Homocysteine, folate deficiency, and Parkinson's disease. Nutr Rev. 2002;60:410-413.
9. Mizrahi EH, Jacobsen DW, Friedland RP. Plasma homocysteine: a new risk factor for Alzheimer's disease? Isr Med Assoc J. 2002;4:187-190.
10. Moghadasian MH, McManus BM, Frohlich JJ. Homocyst(e)ine and coronary artery disease. Arch Intern Med. 1997;157:2299-2308.
11. Ubbink JB, van der Merwe A, Vermaak WJH, et al. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig. 1993;71:993-998.
12. den Heijer M, Brouwer IA, Bos GMJ, et al. Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol. 1998;18:356-361.
13. Ward M, McNulty H, McPartlin J, et al. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM. 1997;90:519-524.
14. Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998;158:862-867.
15. Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695-700.
16. Kant AK, Block G. Dietary vitamin B-6 intake and food sources in the US population: NHANES II, 1976-1980. Am J Clin Nutr. 1990;52:707-716.
17. National Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington DC: National Academy Press; 1998.
18. Cembrowski GS, Zhang MM, Prosser CI, Higgins T. Folate is not what it is cracked up to be. Arch Intern Med. 1999;159:2747-2748.
19. Venn BJ, Mann JI, Williams SM, et al. Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial. Eur J Clin Nutr. 2002;56:748-754.
20. Schwammenthal Y, Tanne D. Homocysteine, B-vitamin supplementation, and stroke prevention: from observational to interventional trials. Lancet Neurol. 2004;3:493-495.
21. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke. JAMA. 2005;293:1082-1088.
22. Olthof MR, Van Vliet T, Boelsma E, et al. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr. 2003;133:4135-4138.
23. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291:565-575.
24. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. New England Journal of Medicine website. Available at: . Accessed March 12, 2006.
25. Bønaa K, Njølstad I, Ueland M, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. New England Journal of Medicine website. Available at: . Accessed March 12, 2006.
26. Stott DJ, Macintosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr. 2005;82:1320-1326.
27. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA. 2002;288:973-979.
28. Sato Y, Honda Y, Iwamoto J, et al. Homocysteine as a predictive factor for hip fracture in stroke patients. Bone. 2005;36:721-726.
29. Sato Y, Iwamoto J, Kanoko T, et al. Homocysteine as a predictive factor for hip fracture in elderly women with Parkinson's disease. Am J Med. 2005;118:1250-1255.
30. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004;350:2042-9.
31. [no authors listed] Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005;82:806-812.
32. Schwab U, Torronen A, Meririnne E, et al. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. J Nutr. 2005;136:34-38.
33. Olthof MR, Vliet TV, Verhoef P, et al. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med. 2005;2:135.
34. Olthof MR, Brink EJ, Katan MB, et al. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr. 2005;82:111-117.
35. Reimann M, Dierkes J, Carlsohn A, et al. Consumption of soy isoflavones does not affect plasma total homocysteine or asymmetric dimethylarginine concentrations in healthy postmenopausal women. J Nutr. 2005;136:100-105.
36. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354: 2764-2772.
37. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism. A randomized, placebo-controlled, double blind trial. Blood. 2006 Sep 7. [Epub ahead of print]
38. Lin PT, Lee BJ, Chang HH, et al. Low-dose folic acid supplementation reduces homocysteine concentration in hyperhomocysteinemic coronary artery disease patients. Nutr Res. 2006;26:460-466.
39. Durga J, Verhoef P, Anteunis LJ, et al. Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial. Ann Intern Med. 2007;146:1-9.
40. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208-216.
41. Green TJ, McMahon JA, Skeaff CM, et al. Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-y randomized controlled trial. Am J Clin Nutr. 2007;85:460-464.
42. Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism. A randomized trial. Ann Intern Med. 2007 Apr 30. [Epub ahead of print]
43. McMahon JA, Skeaff CM, Williams SM, et al. Lowering homocysteine with B vitamins has no effect on blood pressure in older adults. J Nutr. 2007;137:1183-1187.
44. Herrmann M, Umanskaya N, Traber L, et al. The effect of B-vitamins on biochemical bone turnover markers and bone mineral density in osteoporotic patients: a 1-year double blind placebo controlled trial. Clin Chem Lab Med. 2007 Nov 18. [Epub ahead of print]
45. Green TJ, McMahon JA, Skeaff CM, et al. Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-year randomized controlled trial. Am J Clin Nutr. 2007;85:460-464.
46. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA. 2005;293:1082-1088.
47. Sun Y, Lu CJ, Chien KL, et al. Efficacy of multivitamin supplementation containing vitamins b(6) and b(12) and folic Acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in taiwanese patients. Clin Ther. 2007;29:2204-2214
48. van Uffelen JG, Chin A Paw MJ, Hopman-Rock M, et al. The effect of walking and vitamin B supplementation on quality of life in community-dwelling adults with mild cognitive impairment: a randomized, controlled trial. Qual Life Res. 2007 Jul 7. [Epub ahead of print]
49. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027-2036.
50. Ebbing M, Bleie O, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008;300:795-804.
51. Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300:1774-1783.
Last reviewed December 2015 by EBSCO CAM Review Board
Last Updated: 12/15/2015
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