Free Shipping on All Orders $75 Or More!

Your Trusted Brand for Over 35 Years

Life Extension Magazine

<< Back to August 2009

Is Homocysteine Making You Sick?

A New Bioactive Form of Folic Acid Can Lower Stubbornly High Homocysteine Levels When Ordinary B-Vitamins Fail

August 2009

By Robert Haas, MS

Homocysteine is a Risk Factor For Cancer

Emerging research suggests that elevated levels of homocysteine may be a risk factor for cancer.39 A number of studies suggest that folate, through its effect on regulating DNA methylation and reducing homocysteine levels, may prevent cancers of the breast, bladder, lung, lymph, and colorectum.40-44

Conflicting evidence with respect to prostate cancer45 raises questions about the efficacy of folate for prostate cancer prevention. Some experts believe that when it comes to taking folate supplements, timing is everything. For example, some have proposed that folate may be beneficial when taken prior to old age because it decreases the likelihood of DNA mutations.

Why Ordinary B Vitamin Supplements May Not Lower Homocysteine

Many people who take B vitamin supplements are unable to sufficiently lower their homocysteine levels low enough to prevent disease.46 One possible reason is that folic acid, the form of the vitamin used in most supplements and enriched foods, is not bioavailable enough to sufficiently increase plasma folate levels in people with certain health problems or genotypes.

Researchers recently found that giving bioactive 5-MTHF to patients with coronary artery disease resulted in a 700% higher plasma folate concentration compared with folic acid. This difference was irrespective of the patient’s genotype.23 Compared with bioactive 5-MTHF, folic acid supplements were relatively ineffective in increasing blood folate concentrations.

Cooking and food processing destroy natural folates. Although red blood cells can retain folate for 40-50 days following discontinuation of supplementation, folic acid is poorly transported to the brain and is rapidly cleared from the central nervous system.1

Even though folic acid-fortified foods are ubiquitous in our food supply, and despite peoples’ best efforts to ensure adequate intake of the vitamin through supplementation, many individuals run the risk of not achieving sufficient plasma folate levels unless they supplement with bioactive folate.

Bioactive Folate: A New Supplement Effective at Lowering Homocysteine

Bioactive folate, or 5-MTHF, is the predominant biologically active form of folate in cells, the blood, peripheral tissues, and particularly the brain.1 Until recently, 5-methyltetrahydrofolate was available only in expensive prescription medicines and medicinal food products. Now, this active form of folate, which provides increased bioavailability together with protection against homocysteine-related health problems, is available as a dietary supplement. Since 5-MTHF is the only form of folate used directly by the body, it doesn’t have to be converted and metabolized to be clinically useful, as does regular folic acid.1

Who Would Benefit From Taking 5-MTHF Supplements?
Please Click Here for Figure 3

Folic acid, as used in ordinary dietary supplements and vitamin-fortified foods, must first be converted to bioactive 5-methyltetrahydrofolate in order to be clinically effective (Figure 3 to the Right). These steps require several enzymes, adequate liver and gastrointestinal function, and sufficient supplies of niacin (B3), pyridoxine (B6), riboflavin (B2), vitamin C, and zinc.1

Another advantage of 5-MTHF is that it is unlikely to mask a vitamin B12 deficiency, a shortcoming of folic acid. Folic acid, when administered as a single agent, may obscure the detection of vitamin B12 deficiency (specifically, folic acid may reverse the hematological manifestations of B12 deficiency, while not addressing the neurological manifestations). Research has shown that bioactive 5-MTHF (5-methyltetrahydrofolate) is less likely than folic acid to mask vitamin B12 deficiency.1

Who Would Benefit From Taking 5-MTHF Supplements?

The low-dose requirements for 5-MTHF make it a relatively inexpensive supplement with superior clinical benefits over folic acid. People who would benefit from taking active folate include:

  • Those who desire to take advantage of 5-MTHF as a part of their anti-aging strategy due to its potency, low cost, and bioavailability.
  • Those with elevated risk factors for cardiovascular disease.
  • Those taking drugs known to interfere with the absorption or metabolism of folate (See sidebar below: “Drugs That Raise Homocysteine Levels.”)
  • People with the gene variant MTHFR C677T.
  • Those who have stubbornly high homocysteine levels despite taking B-complex vitamins.

Individuals with the MTHFR C677T mutation are at higher risk of cardiovascular disease, stroke, pre-eclampsia (high blood pressure in pregnancy), and birth defects that occur during the development of the brain and spinal cord (neural tube defects).

Drugs That Raise Homocysteine Levels

In addition to protein in the diet, a number of prescription drugs and natural compounds can elevate blood levels of homocysteine by interfering with folate absorption or metabolism of homocysteine. These include:1,50,51

  • Azaribine
  • Caffeine
  • Cholestyramine
  • Colestipol
  • Colchicine
  • Fenofibrate
  • Levodopa
  • Metformin
  • Methotrexate
  • Niacin
  • Nitrous oxide
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Pemetrexed
  • Phenytoin
  • Pyrimethamine
  • Sulfasalazine

How Much 5-MTHF Do You Need?

A daily dose of 800-1,000 mcg (0.8 to 1.0 mg) bio-active folate is typically used in research studies to achieve clinically beneficial reduction in elevated plasma homocysteine concentrations. Even doses of 200-400 mcg (0.2 to 0.4 mg) have been shown to achieve this effect.47

A number of drugs and medical food products on the market contain very high amounts (5,000 mcg or 5 mg) of 5-MTHF. Unless specifically prescribed by a physician, food and drug products that contain such high doses are probably not required to normalize homocysteine levels in most people with mild-to-moderate elevations.

Ancillary Supplements For Use With 5-MTHF

Individuals who wish to bring their elevated blood levels of homocysteine into the ideal range (under 8.0 µmol/L) may want to adopt a folate-boosting supplement protocol in addition to using bioactive folate 5-MTHF. This requires taking several supplements that work in concert to effectively reduce homocysteine and risk of disease. The following supplements can provide additional support:1

  • Riboflavin (vitamin B2): Plasma riboflavin has been shown to independently influence plasma homocysteine levels.48
  • Vitamin B6 (pyridoxine) helps reduce homocysteine levels by catalyzing the conversion of homocysteine to cysteine, which is then converted to the free-radical scavenger, glutathione (Figure 1 on Page 1).
  • Vitamin B12 (cobalamin) is required by the body to convert homocysteine to the amino acid, methionine, through the process of methylation (Figure 1 on Page 1).
  • A study of betaine (trimethylglycine) supplementation showed that a daily supplement of 6 grams betaine for 12 weeks reduced blood homocysteine values in healthy subjects.49


Elevated levels of homocysteine have been linked with a diverse spectrum of health disorders ranging from cardiovascular disease, stroke, and cancer to migraine, dementia, and macular degeneration. Most conventional physicians fail to detect and treat elevated levels of homocysteine in the blood.

Folate is an essential nutrient for maintaining healthy homocysteine levels, yet up to half of Americans have a genetic inability to properly metabolize regular folic acid to its active form. Fortunately, the active form of folate is now available as a dietary supplement called 5-methyltetrahydrofolate, or 5-MTHF. By increasing blood folate levels 700% more effectively than ordinary folic acid, 5-MTHF offers advanced protection against the homocysteine-related disorders that threaten to compromise our longevity and well-being.

If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-800-226-2370.

  1. Altern Med Rev. 2006 Dec;11(4):330-7.
  2. Circulation. 2004 Jun 8;109(22):2766-72.
  3. Am J Pathol. 1969 Jul;56(1):111-28.
  4. Altern Med Rev. 2008 Sep;13(3):216-26.
  5. J Clin Endocrinol Metab. 2009 Apr;94(4):1207-13.
  6. Curr Osteoporos Rep. 2007 Sep;5(3):112-9.
  7. Pharmacogenet Gernomics. 2009 Jun;19(6):422-8.
  8. Am J Ophthalmol. 2007 Feb;143(2):344-46.
  9. Arch Intern Med. 2009 Feb 23;169(4):335-41.
  10. JAMA. 2002 Oct 23;288(16):2015-22.
  11. Cardiology. 2007;107(1):52-6.
  12. Curr Med Chem. 2007;14(3):249-63.
  13. Am J Epidemiol. 2005 Oct 1;162(7):644-53.
  14. Br J Dermatol. 2009 Mar;160(3):622-8.
  15. Nephrol Dial Transplant. 2008 Feb;23(2):645-53.
  16. Diabetes Care. 2000 Apr;23(4):524-8.
  17. Alcohol. 2005 Oct;37(2):73-7.
  18. Acta Obstet Gynecol Scand. 2005 Nov;84(11):1049-54.
  19. Gynecol Endocrinol. 2007 Sep;23(9):505-10.
  20. JAMA. 1995 Nov 15;274(19):1526-33.
  21. Proc Nutr Soc. 2008 May;67(2):232-7.
  23. Br J Pharmacol. 2004 Mar;141(5):825-30.
  24. Br Med Bull. 1999;55(3):669-82.
  25. JAMA. 2006 Jan 25;295(4):383.
  26. Nutr Health. 1998;12(3):147-61.
  27. Circulation. 2006 Mar 14;113(10):1335-43.
  28. Arterioscler Thromb Vasc Biol. 2000 Aug;20(8):1921-5.
  29. Mech Ageing Dev. 2001 Nov;122(16):2013-23.
  30. N Engl J Med. 2002 Feb 14;346(7):476-83.
  31. Atherosclerosis. 2008 Nov 1.
  32. Cephalalgia. 2006 Jun;26(6):731-7.
  33. J Obstet Gynaecol Can. 2007 Dec;29(12):1003-26.
  34. J Nutr. 2006 Nov;136(11):2820-6.
  35. PLoS Med. 2009 May 5;6(5):e1000061.
  36. JAMA. 1989 Nov 24;262(20):2847-52.
  37. BMJ. 2007 Mar 3;334(7591):464.
  38. Pediatrics. 2009 Mar;123(3):917-23.
  39. Clin Chim Acta. 2002 Aug;322(1-2):21-8.
  40. Epidemiology. 2001 Jul;12(4):420-8.
  41. Lancet Oncol. 2008 Apr;9(4):359-66.
  42. Carcinogenesis. 2007 Aug;28(8):1718-25.
  43. Am J Epidemiol. 2008 Feb 1;167(3):287-94.
  44. Ann Ital Chir. 2008 Jul;79(4):261-7.
  45. J Natl Cancer Inst. 2009 Mar 18;101(6):432-5.
  46. Lancet Neurol. 2004 Aug;3(8):493-5.
  47. Curr Atheroscler Rep. 2006 Mar;8(2):100-6.
  48. Clin Chem. 2000 Aug;46(8 Pt 1):1065-71.
  49. Am J Clin Nutr. 2002 Nov;76(5):961-7.
  50. Drugs. 2002;62(4):605-16.
  51. Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. St. Louis, MO: Mosby Elsevier;2008:186-234.