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Health Protocols

Homocysteine Reduction

Targeted Natural Strategies


Research studies have documented the homocysteine-lowering effect of the nutraceutical, N-acetyl-cysteine (NAC), which can lead to a highly significant reduction in cardiovascular events, owing to the ability of NAC to lower plasma homocysteine levels and improve endothelial function. Researchers believe that NAC displaces homocysteine from its protein carrier in the blood. This promotes the formation of cysteine and NAC disulfide molecules with high renal clearance, thereby removing homocysteine from plasma.71,72

  • A 2007 study randomized 60 patients with hyperhomocysteinemia and confirmed coronary artery disease to 5 mg folic acid, 600 mg NAC, or placebo daily for eight weeks. Folic acid and NAC supplementation both lowered homocysteine levels and improved endothelial function. Folic acid decreased homocysteine from 21.7 µmol/L to 12.5 µmol/L and NAC decreased homocysteine from 20.9 µmol/L to 15.6 µmol/L. Both treatments improved endothelium-dependent dilation compared to placebo.73
  • In a double-blind crossover design study, Swedish investigators gave NAC supplements to 11 patients with high plasma lipoprotein(a), which is an independent risk factor for cardiovascular disease.74 While investigators observed no significant effect on plasma lipoprotein(a) levels, they did find that plasma levels of homocysteine were significantly reduced during treatment with NAC by an astounding 45%.
  • One study examined the effect of oral NAC supplementation in nine young healthy females and found that the supplement induced a rapid and significant decrease in plasma homocysteine levels and an increase in whole blood concentration of the antioxidant glutathione. Study investigators concluded that NAC might therefore be a highly efficient nutraceutical for reducing blood levels of homocysteine.75

Omega-3 Polyunsaturated Fatty Acids (PUFAs)

A growing body of research on marine lipids, rich in omega-3 polyunsaturated fatty acids (PUFAs), reveals that omega-3 rich fish oil supplementation can reduce elevated homocysteine levels:

  • A 2010 animal model study examined the effect of fish oil rich in omega-3 PUFAs on homocysteine metabolism. Three groups of randomly divided rats were fed olive oil, tuna oil, or salmon oil for eight weeks. The level of plasma homocysteine was significantly decreased only in the group fed tuna oil, rich in omega-3 PUFAs. It is not clear why the salmon oil did not reduce homocysteine as it too is rich in omega-3 PUFAs.76
  • A 2009 randomized double-blind placebo-controlled clinical trial conducted on 81 patients with type 2 diabetes assigned each patient either three capsules of omega-3 fatty acids (3 grams) or a placebo every day for a period of two months. Homocysteine levels in the treatment group declined as much as 3.10 µmol/L; glycolsylated hemoglobin (HbA1C, a measure of long-term sugar levels in the blood) decreased in the treatment group and increased in the control group.77


Supplementing with the amino acid taurine can protect against coronary artery disease by favorably modulating blood levels of homocysteine. Research suggests taurine can block methionine absorption from the diet, thereby reducing available substrate for homocysteine synthesis.78 One animal study found that taurine normalized hyperhomocysteinemia and reduced atherosclerosis by 64% over control animals and reduced endothelial cell apoptosis by 30%.79 Study investigators also observed that taurine supplementation reduced left main coronary artery wall pathology due to a favorable effect on plasma total homocysteine and apoptosis.

A study of 22 healthy middle-aged women (33 to 54 years) found that after taurine supplementation (3 grams per day for four weeks), plasma homocysteine levels exhibited a significant decline, from 8.5 µmol/L to 7.6 µmol/L. The investigators concluded that sufficient taurine supplementation might effectively prevent cardiovascular disease.80

Trimethylglycine (TMG) and Choline

TMG was originally called betaine after its discovery in sugar beets in the 19th century. TMG serves as a methyl donor in a reaction converting homocysteine to methionine. It is commonly used for reducing high homocysteine levels though it has yet to be effectively studied to determine its full cardiovascular benefits through its ability to lower homocysteine.81

A 2009 study examined the effect of betaine (TMG) supplementation on atherosclerotic lesion progression in apolipoprotein E-deficient mice.81 After a 14-week treatment with TMG, analyses revealed that the higher dose of TMG was related to smaller atherosclerotic lesion area. Compared with mice not treated with TMG after 14 weeks, mice receiving 1%, 2%, or 4% TMG had 10.8%, 41%, and 37% smaller lesion areas, respectively. TMG supplementation also reduced aortic expression of the inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), in a dose-dependent way. These data suggest in addition to its homocysteine-lowering action, TMG may also exert its anti-plaque effect by inhibiting aortic inflammatory responses mediated by TNF-α.

Data from the Framingham Offspring Study found that intakes of TMG and choline (choline is metabolized to TMG in the body) were inversely related to circulating homocysteine concentrations, particularly among participants with low folate intake or among those who consumed alcoholic beverages.82 Other studies have shown that choline deficiency in mice and humans is associated with increased plasma homocysteine levels after consuming methionine.83 A Finnish study of TMG supplementation showed a daily supplement of 6 grams TMG for 12 weeks reduced blood homocysteine values in healthy subjects by approximately 9%.84

S-Adenosyl-L-Methionine (SAMe)

SAMe (S-adenosyl-L-methionine), biosynthesized from methionine and ATP, functions as a primary methyl group donor in a variety of reactions in the body and is directly involved in homocysteine synthesis and metabolism. Taking supplemental SAMe promotes the conversion of homocysteine to cysteine and glutathione, thus lowering homocysteine levels.85 One study found that taking SAMe supplements increased the activity of 5-MTHF, a major co-factor involved in the metabolism of homocysteine.86

In effect, SAMe acts as a ‘switch’ to control enzymes involved in the remethylation and transsulfuration pathways of homocysteine metabolism.87 Since some of the SAMe’s methyl groups are used in the body’s production of creatine (an energy substrate used primarily by skeletal muscle), it has been suggested that supplementing one’s diet with creatine would free up SAMe’s methyl groups to favorably modulate homocysteine levels.88 One study found that lab animals maintained on creatine-supplemented diets exhibited significantly lower (~25%) plasma homocysteine levels than controls.89 Those who use SAMe should make sure they are taking supplemental folate, B6 and B12 to ensure that SAMe promotes the conversion of homocysteine to beneficial compounds in the body.


Vitamin B2 (riboflavin) has long been known to be a determinant of plasma homocysteine levels in healthy individuals with the 5-MTHFR C677T gene variant that causes hyperhomocysteinemia.90 Homocysteine is highly responsive to riboflavin (riboflavin is required as a co-factor by MTHFR), specifically in individuals with the MTHFR 677 TT genotype.91

A four-week, randomized, placebo-controlled, double-blind trial found that 10 mg/day oral riboflavin supplementation for 28 days lowered plasma homocysteine concentrations in 42 subjects (60 to 94 years) with low riboflavin status.92

B Vitamins

A two-year randomized clinical trial (known as VITACOG) completed in 2010 found that the accelerated rate of brain atrophy in elderly patients suffering from mild cognitive impairment could be significantly slowed by treatment with homocysteine-lowering B vitamins.93

Researchers at Oxford University, UK randomized study participants to receive either placebo or a combination of folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d), and vitamin B6 (20 mg/d) for 24 months. A subset of participants agreed to have cranial MRI scans at the start and finish of the study for the purpose of measuring the change in rate of atrophy of the entire brain.

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. Results showed that the B-vitamin treatment response was related to baseline homocysteine levels: Participants in the B-vitamin treatment group with the highest levels of homocysteine (≥ 13.0 µmol/L) at the start of the trial experienced half the brain shrinkage over two years compared to those participants with the highest homocysteine blood levels at the start of the trial and who received the placebo.

This important study demonstrated that the accelerated rate of brain atrophy seen in approximately 16% of elderly patients suffering from mild cognitive impairment94 could be significantly slowed by simple treatment with folic acid and vitamins B6 and B12.

Ordinary B-Vitamin Supplements and Folate-Rich Foods May Not Be Enough to Lower Homocysteine

Even though folic acid-fortified foods are ubiquitous, and despite peoples’ best efforts to insure adequate intake of the vitamin through supplementation, many individuals run the risk of not obtaining sufficient amounts of folate necessary to achieve healthy blood levels of homocysteine unless they supplement with bioactive folate. Cooking and food processing destroy natural folates.95 Although red blood cells can retain folate for 40‒50 days following discontinuation of supplementation, synthetic folic acid is poorly transported to the brain and is rapidly cleared from the central nervous system.96

Many people who take ordinary B-vitamin supplements are unable to sufficiently lower their homocysteine levels enough to prevent disease.97 Fortunately, there is hope for those with seemingly intractable homocysteine levels. One study found that giving L-methylfolate (5-MTHF; also called active folate) to patients with coronary artery disease resulted in a 700-percent higher plasma concentration of folate-related compounds compared to folic acid. This difference was irrespective of the patient's genotype.27

5- MTHF is the predominant biologically active form of folate in cells,98 the blood,99 and the cerebrospinal fluid.96 Until recently, 5- MTHF was available only in prescription medicines and medicinal food products. Now, this active form of folate, which provides increased protection against homocysteine-related health problems, is available as a dietary supplement. This form of the vitamin is unlikely to mask a vitamin B12 deficiency, a well-known shortcoming of folic acid. Since 5-MTHF is the only form of folate used directly by the body, it does not have to be converted and metabolized to be clinically useful, as does synthetic folic acid.

Synthetic folic acid, as used in ordinary dietary supplements and vitamin-fortified foods, must first be converted in cells to active L-methylfolate in order to be effective. These steps require several enzymes, adequate liver and gastrointestinal function, and sufficient supplies of niacin (vitamin B3), pyridoxine (B6), riboflavin (B2), vitamin C, and zinc.100

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.
  • People with the gene variant 5-MTHFR C677T.

Individuals with the 5-MTHFR C677T polymorphism are at higher risk of cardiovascular disease, stroke, preeclampsia (high blood pressure in pregnancy), and birth defects that occur during the development of the brain and spinal cord (neural tube defects). The mutation replaces the DNA nucleotide cytosine with thymine at position 677 in the MTHFR gene. (Nucleotides are the building blocks of DNA.) This change in the MTHFR gene produces a form of the enzyme, methylenetetrahydrofolate reductase, which is thermolabile, meaning its activity is reduced at higher temperatures.

A daily dose of 0.8 mg 5-MTHF is typically used in research studies to achieve a clinically beneficial reduction in elevated plasma homocysteine concentrations. In some cases, doses as low as 0.2 mg to 0.4 mg have been shown to achieve this effect.101

Drugs That Raise Homocysteine Levels

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:

  • Caffeine102: Cafcit, Cafergot, Esgic, Excedrin Migraine, Fioricet, Fiorinal, Norgesic, Synalgos-DC
  • Cholestyramine103: Questran, Questran Light, Cholybar
  • Colestipol104: Cholestid
  • Fenofibrate105: Antara, Fenoglide, Lipofen, Lofibra, Tricor, Trilipix
  • Levadopa106: Parcopa, Sinemet, Stalevo
  • Metformin107: ActoPlus Met, Avandamet, Fortamet, Glucophage Glucovance, Glumetza, Janumet, Metaglip, Prandimet, Riomet
  • Methotrexate107: Rheumatrex
  • Niacin107: Advicor, Ocuvite, Cardio CitraNatal Basic, Heplive, Niaspan, Simcor
  • Nitrous oxide108
  • Pemetrexed109: Alimta
  • Phenytoin110: Dilantin, Phenytek
  • Pyrimethamine111: Daraprim, Fansidar
  • Sulfasalazine112: Azulfidine

What You Need To vKnow

  • Elevated blood levels of homocysteine have been linked with a wide range of health disorders including heart disease, stroke, macular degeneration, hearing loss, migraine, brain atrophy, dementia and cancer.
  • A high-protein diet, especially one that includes red meats and dairy products, is also high in methionine, the parent compound of homocysteine. Following such a diet can increase blood levels of homocysteine.
  • Numerous factors, including prescription drug use, smoking, coffee and alcohol consumption, advancing age, genetics, and obesity contribute to elevated homocysteine levels.
  • Many people carry a genetic variation that is linked with elevated homocysteine levels. People carrying this gene variant suffer from an impaired ability to metabolize folic acid to its active form, but may achieve a significant reduction in plasma homocysteine by taking an active folate (5-MTHF) supplement.
  • Vitamin B2, B6, and B12 supplements as well as those containing choline and TMG work together with active folate to maintain homocysteine levels within a healthy range.
  • As humans grow older, homocysteine levels increase substantially. However, although these increased levels are “normal,” they are still associated with higher risk of various health problems.
  • Although some clinical testing laboratories consider homocysteine levels of up to 15.0 µmol/L as normal, Life Extension believes this is too high for optimal health and therefore recommends keeping homocysteine levels < 8 µmol/L.
  • People taking active folate can achieve plasma folate levels 700% higher than by taking an ordinary folic acid27 supplement and may therefore more effectively lower elevated homocysteine levels.

A program of regular exercise may help people recovering from a heart attack, bypass surgery, or angioplasty to modestly reduce homocysteine levels.

For More Information

To learn more about the conditions associated with hyperhomocysteinemia, see the following protocols:

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.