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LE Magazine October 2006

Nutritional Therapies for Managing Homocysteine

By William Davis, MD

“Inadequate blood folate is common among those who do not take multivitamin supplements but unusual among those who do.”

—Godfrey P. Oakley, MD

US Centers for Disease Control and Prevention

Ways to Lower Homocysteine Naturally

The potential benefits of nutritional homocysteine control are great, while the dangers are virtually nonexistent. Based on the weight of accumulated evidence, our clinic advocates lowering homocysteine levels above 7-8 µmol/L using a graded dosing of three B vitamins, up to maximum doses of 5000 mcg of folic acid, 100 mg (occasionally even 500 mg under a doctor’s supervision) of vitamin B6, and up to 1000 mcg of vitamin B12. Our treatment goal is to lower homocysteine to below 7 µmol/L. We also advocate using choline and trimethylglycine (TMG or betaine) from food or nutritional supplements to augment the benefits of B vitamins and to more effectively suppress the after-meal surge in homocysteine that is not fully controlled by vitamins alone.

Your choices for controlling homocysteine include:

• Folic acid. Folic acid is the most important factor in controlling homocysteine. Although the US recommended daily allowance (RDA) for adults is only 400 mcg,47 extensive survey data showed that an extraordinary 88% of US adults have a folic acid intake below the RDA.48 Low folic acid intake by pregnant women carries a particularly dire risk, causing devastating neural tube defects in newborns. Low folic acid intake from diet is a growing problem because of food processing. This prompted the FDA to mandate folic acid fortification in enriched grain products.

Fortification provides an estimated extra 100 mcg of folic acid daily for most adults and does indeed result in modest reductions of about 0.5 µmol/L in homocysteine. Nonetheless, obtaining sufficient quantities of folate (the food form of folic acid) from foods is difficult, and the majority of Americans not taking folic acid supplements have sufficiently low blood levels that allow higher homocysteine levels.49 Keep in mind that folic acid supplements are twice as bioavailable as folate from food.50 For example, 200 mcg of a folic acid supplement (as an individual supplement or added to grains) provides the same active quantity as 400 mcg of naturally occurring folate from food.51 If you do not eat grain products or you have a higher level of homocysteine, specific folic acid supplementation beyond that in your diet will be necessary. A daily folic acid dose of 800 mcg may lower homocysteine by around 25%.52-53 However, some doctors prescribe folic acid doses up to 5000 mcg for highly elevated homocysteine levels.

• Vitamin B12. Vitamin B12 deficiency is common and can contribute to rising homocysteine, particularly in people over 65. In rare cases, replacing folic acid alone can mask a latent B12 deficiency, resulting in nervous system disorders.

As a general rule, vitamin B12 and folic acid should be replaced together to maximize their homocysteine-lowering effects. Absorption of B12 is a little tricky, and in the past, physicians simply injected B12. However, more recent data suggest that a dose of 500-2000 mcg is every bit as good as an injection.54 A recent dose-exploring trial established that even 500 mcg of B12 achieves the same effect in correcting B12 deficiency as injectable forms. If you are not B12 deficient (discuss this with your doctor), then lesser doses are sufficient. Our clinic commonly advises patients to take 250 mcg of B12 along with folic acid, a dose that provides about two thirds of the effectiveness of the higher doses.54

• Vitamin B6. Taken along with folic acid, vitamin B6 is effective in blocking post-meal surges of homocysteine, particularly when methio-nine-rich meats are part of the meal. Low blood levels of B6 are common, especially in people with higher homocysteine levels.55 The precise dose of B6 required for maximum homocysteine lowering has been controversial, with doses of 2–50 mg commonly used in clinical studies. However, Dutch researchers who have extensive experience with homocysteine-lowering therapies routinely use 250 mg of B6 without ill effect.43,56,57

High-dose vitamin B6 (100-500 mg per day) has been used successfully in managing perimenstrual symptoms and carpal tunnel syndrome.58 However, in rare cases, higher doses may cause nervous system dysfunction (peripheral neuropathy).58 Most reported cases of neuropathy associated with vitamin B6 supplementation involved intake of 500 mg or more daily for two years or more.59 Vitamin B6 doses higher than 100 mg should therefore be used only under medical supervision. The vast majority of people obtain substantial homocysteine-lowering effects with 50-100 mg per day, provided folic acid is at optimal levels.

• Trimethylglycine (TMG). Also commonly known as betaine, TMG is a constituent of food. The average American ingests 500–2000 mg of TMG a day. Supplemental TMG reduces homocysteine starting at a dose of 1000 mg a day, up to a maximum 20% reduction at 6000 mg per day, the dose often used in severe homocysteine disorders.60

TMG is the most effective nutritional agent for suppressing the after-meal surge in homocysteine, slashing levels up to 50%.60-62 We commonly use 2000 mg per day as a starting dose for fasting homocysteine levels that do not fully respond to the three B vitamins, using higher doses for the after-meal surge seen with methionine loading. Spinach and wheat germ are two particularly rich food sources of TMG. Be aware that the 6000-mg dose of TMG has been found to raise LDL by around 10%,63 and LDL should therefore be monitored when using this high dose of TMG.

• Choline. Choline is directly converted to TMG in the body. Choline is readily available in various foods and also as a nutritional supplement. Most people ingest 300-1000 mg a day from dietary sources. Choline has recently gained acceptance as an essential nutrient. To avoid deficiency states, the National Academy of Sciences and the US Institute of Medicine recommend a daily intake of 550 mg for men and 425 mg for women. Higher doses are required to obtain the full benefit of lowering homocysteine. Like TMG, choline has modest effects on fasting homocysteine and a larger effect on the after-meal surge of homocysteine.64 A common dose is 2000-4000 mg per day.

• Avoiding methionine-rich foods. Methionine is an amino acid found in food, particularly red meats and dairy products. Although methionine is an essential amino acid, it is also suspected to cause atherosclerotic plaque growth, both directly as well as indirectly by increasing homocysteine levels.65 The US RDA for methionine is 900 mg a day, but the average American takes in a greater quantity of around 2000 mg a day.37 If excess methionine is available in the diet, more homocysteine is produced. This provides the basis for one of the tests for hidden homocysteine excess, the “methionine-loading” test. The after-meal surge in homocysteine is prevented by vitamin B6 availability, along with choline and TMG.

• Fish oil. Along with its other remarkable benefits such as lowering triglycerides, reducing fibrinogen, and stabilizing abnormal heart rhythms, fish oil may lower homocysteine. Homocysteine reductions of 36-48% have been reported,66,67 though practical experience suggests a more modest drop of 1-2 µmol/L can be expected.

• Taurine. This amino acid and byproduct of methionine meta-bolism is emerging as a promising agent for reducing the dangers of homocysteine.68 However, further human data are needed to assess its effects.

• Exercise. In a cardiac rehabilitation program following bypass surgery, angioplasty, or heart attack, 76 participants experienced a modest 12% reduction in homocysteine just by engaging in a modest program of regular exercise. How or why exercise results in such a reduction is unclear, but this is yet another example of how physical activity yields broad health-promoting benefits.69

Foods Naturally Rich In Folate

The US government’s mandate to supplement grain products with folic acid means that, in a practical sense, most folic acid-enriched foods (such as white bread, crackers, and breakfast cereals) are highly processed. Substantial quantities of naturally occurring folate are found in several select foods listed below. Spinach, black beans, and wheat germ are the superstars in folic acid content. While it is difficult to obtain sufficient folic acid every day through diet alone, these foods (along with folic acid supplements) can you help meet your requirements.

Keep in mind that the amount of folic acid taken as a supplement is equal to nearly double the amount of food folate. For example, 400 mcg of folate from broccoli yields the same as 200 mcg of a folic acid supplement.50,58 To avoid confusion, in our list we have converted all units to equivalent quantities of folic acid. It is important to recognize that cooking, canning, and exposing foods for prolonged periods (for example, uncovered in the refrigerator) all sharply diminish the folate content of foods. Recall that the RDA for folic acid is 400 mcg per day. Combining foods rich in folic acid with supplemental folic acid can help you exceed this rock-bottom minimum.

	Folic acid content (mcg)
Avocado: 1 cup, sliced	81
Black beans: 1/2 cup, cooked	128
Broccoli: 1 cup, chopped	55
English walnuts: 1/2 cup, chopped	57
Hazelnuts and filberts: 1/2 cup, whole	65
Orange juice: 6 oz.	54
Romaine lettuce: 1 cup, shredded	64
Spinach: 1 cup, cooked	263
Sunflower seeds: 1/4 cup, raw	82
Wheat germ: 4 tbsp.	128

Homocysteine, Mood, and Memory

Homocysteine plays an important role in depression. Poor response to antidepressant medication, dysthymia (a lesser form of depression), and full-fledged depression have all been linked to low folic acid levels, which are often accompanied by high homocysteine levels.71 Other studies suggest that higher homocysteine levels are very prevalent among the depressed, with up to 50% of subjects exhibiting homocysteine levels above 10 µmol/L.72,73

Antidepressant medications may have limited effectiveness in treating depression, which may, however, respond to folic acid. Studies have firmly established that folic acid replacement, resulting in reduced homocysteine blood levels, is an important treatment for depression. In an Italian study, folic acid supplementation yielded improvements in mood similar to those produced by the use of conventional antidepressants.74

Moreover, several studies have shown that response to prescription antidepressants like fluoxetine (Prozac®) is substantially improved by taking as little as 500 mcg of folic acid per day.75,76 Although few psychiatrists have added folic acid to their antidepressant treatment protocols, the data suggest that this simple, inexpensive treatment should be a part of every depressed person’s panel of therapies. Doses of 1000-5000 mcg are most effective, generally along with 25-100 mg of vitamin B6 and 100-500 mcg of vitamin B12.

There is a growing appreciation of the role of folic acid, vitamins B6 and B12, and homocysteine in the cognitive decline associated with aging. It is well established that diminished memory and cognitive function are associated with deficiencies of these B vitamins and higher homocysteine levels.77,78 An MRI study showed that lower folic acid blood levels were associated with markers of neuropathology in the portion of the brain responsible for higher mental function.79

Last year, Italian researchers reported on the relationship between homocysteine, dementia, and Alzheimer’s disease. For four years, the investigators followed a group of 816 dementia-free adults, averaging 74 years of age. During this interval, 112 subjects developed dementia, including 70 who were diagnosed with Alzheimer’s disease. Individuals who had baseline homocysteine values of greater than 15 µmol/L had a twofold greater risk of developing dementia, and their risk of developing Alzheimer’s disease was more than two times higher than in subjects with lower homocysteine values. The scientists concluded that elevated homocysteine is an independent risk factor for developing dementia and Alzheimer’s disease.80

Homocysteine, Bone Density, and Osteoporosis

Homocysteine may play a role in bone density and the risk of osteoporotic fractures, according to emerging findings.81-83

Researchers examined the association between homocysteine concentration and the risk of hip fracture in over 2,000 men and women, aged 59-81, enrolled in the Framingham Study.81 Blood samples from the participants were collected between 1979 and 1982, and were analyzed for homocysteine concentration. The participants were followed through June 1998 for incident hip fracture. Men and women in the highest quartiles of homocysteine concentration experienced a greater risk of hip fracture than those in the lowest quartile—the risk was almost four times higher for men and nearly two times greater for women. The investigators concluded that homocysteine concentration, which can easily be modified with nutritional intervention, is an important risk factor for hip fracture in middle-aged and elderly adults.81

Foods Rich In Choline And Trimethylglycine (Betaine)

Choline and trimethylglycine (TMG) both reduce homocysteine, particularly the surge of homocysteine that occurs after a methionine-rich meal (of meat, for example). Maximum lowering of homocysteine occurs when choline and trimethylglycine are combined with folate-rich foods or folic acid supplements. Below is a list of foods rich in choline or TMG. We confine our list to healthy foods that are rich in these two nutrients and exclude choline- or TMG-rich foods (such as sausage) that are clearly unhealthy for other reasons.

To avoid liver disease from choline deficiency, the US Institute of Medicine recommends a daily choline intake of 550 mg for men and 425 mg for women. The precise dose of choline for lowering homocysteine is not well known, but our clinic has had success with 2000-4000 mg a day. TMG lowers homocysteine starting at a dose of 1000 mg a day, with full effect at 6000 mg per day. As noted previously, high-dose TMG intake may elevate LDL levels, which should be monitored with your doctor’s help.63

	Choline (mg)	Trimethylglycine (mg)
Almonds: 1/2 cup	37
Atlantic cod: 4 oz. filet	95	10
Baked beans: 1 cup, canned	80
Beets: 1 cup, canned and drained	10	466
Broccoli: 2 spears	30
Brussels sprouts: 1 cup, cooked	64
Cauliflower: 1 cup, cooked	48
Chicken: 4 oz. roasted, w/o skin	34
Green peas: 1 cup	44
Hazelnuts or filberts: 1/2 cup	31
Milk: skim, 1 cup	38	4
Oat bran: 1/2 cup, raw	28	15
Orange roughy: 4 oz., cooked	41
Salmon: 4 oz., cooked	74
Spinach: 1 cup, raw 7	180
Spinach: 1 cup, cooked	45	1,161
Sweet potato: 1 medium	15	39
Tilapia: 4 oz.	94	29
Tofu: 1 cup, soft	69
Tomatoes: 1 cup, chopped	12	55
Tomato sauce: 8 oz.	50
Wheat bran: 1/2 cup	37	670
Wheat germ, toasted: 4 tbsp.	38	310
Whole wheat bread: 2 slices	13	101

Adapted from the USDA Database for the Choline Content of Common Foods, 2004, and Zeisel et al.70

Another study confirmed the relationship between elevated homo-cysteine levels and osteoporotic fractures in older adults. Dutch researchers followed over 2,000 men and women over the age of 55 for five to eight years.82 They determined that an increased level of homocysteine was a strong risk factor for osteoporotic fracture in both men and women. Their research suggests that the risk posed by elevated homocysteine is independent of other factors such as bone mineral density.82

Subsequent research, however, suggests a relationship between homocysteine and bone density. Researchers from Tufts University investigated the relationship between homocysteine, measures of folate and vitamin B12, and bone mineral density in adults aged 55 and older.83 They found that individuals with serum homocysteine levels equal to or above 20 µmol/L had significantly lower bone mineral density than subjects with homocysteine levels below 10 µmol/L, as determined by DEXA hip scans.

The investigators also found a relationship between bone density and methylmalonic acid, which is a measure of tissue vitamin B12 status. Elevated levels of methylmalonic acid, indicating low tissue levels of vitamin B12, were associated with decreased bone mineral density and an increased prevalence of osteoporosis. The researchers concluded that elevated homocysteine and decreased vitamin B12 status were associated with decreased bone mineral density in older adults. In this study, serum and red blood cell folate levels were not related to bone mineral density or osteoporosis.83

In another recent study, the combination of vitamin B12 and folate helped decrease homocysteine levels and prevent hip fractures in individuals who had previously suffered a stroke.84 Elevated homocysteine is a risk factor for both ischemic stroke and osteoporotic fracture in men and women. Over 500 male and female stroke survivors suffering from residual partial paralysis were supplemented with 5000 mcg of folate and 1500 mcg of vitamin B12 or placebo for two years. At baseline, all the patients had high levels of homocysteine and low serum levels of vitamin B12 and folate. At the two-year follow-up, homocysteine levels increased 31% in the placebo group and fell 38% in the B12-folate group. The B12-folate group also experienced a decreased rate of hip fracture compared to the placebo group. The researchers concluded that supplementing with vitamin B12 and folate is safe and effective in reducing hip fracture risk in elderly patients following a stroke.84

Managing elevated homocysteine may thus be an important strategy for preserving bone mineral density, minimizing osteoporosis risk, and preventing bone fractures.81-84

While numerous nutritional remedies may be helpful for reducing homocysteine levels, vitamin B12 may play an especially important role in promoting healthy bone mineral density,83 and the combination of B12 and folate may reduce hip fracture risk following a stroke.84

The mechanism by which homocysteine affects bone density and fracture risk remains unknown, but some investigators speculate that high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thus increasing the risk of osteoporotic fracture.81

Emerging research relates deficient folate and high homocysteine levels with such disparate conditions as complications of pregnancy, inflammatory bowel disease, and some cancers.85-87 Although we await data demonstrating just how supplementation benefits these conditions, the ease of nutritional intervention argues for simply correcting elevated levels of homocysteine, drawing on the compelling knowledge base already established.

Conclusion

Homocysteine is an amino acid that, even at levels previously regarded as normal, exaggerates the adverse effects of other atherosclerotic risk factors and may heighten long-term risk for heart attack, stroke, osteoporosis, depression, blood clot formation, and even cancer.

Fortunately, the nutritional management of elevated homocysteine levels is a relatively straightforward proposition. Despite the government’s well-intended mandate to add folic acid to grain products, most of us are still marginally and sometimes substantially deficient of folic acid. Folic acid supplementation, along with other nutritional strategies to lower homocysteine—using vitamins B6 and B12, choline, and trimethylglycine (TMG)—can provide powerful protection against homocysteine’s ill effects on your life and health.

Dr. William Davis is an author, lecturer, and cardiologist practicing in Milwaukee, WI. He is founder of Track Your Plaque, a heart disease- prevention program that shows how to use the CT scans to control coronary plaque. He can be contacted through www.trackyourplaque.com.

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