Wednesday, December 23, 2009



Vinpocetine is a derivative of the alkaloid (extracted from Vinca minor) vincamine, and is used in many countries in the treatment and prevention of stroke and vascular dementia. Although there has not been one single mechanism of action agreed upon for vinpocetine, there are many known activities that contribute to its use such as dilating blood vessels, enhancing circulation to the brain, improving oxygen utilization and reducing blood clotting, and inhibition of platelet aggregation. Vinpocetine works on altering the ischemic cascade in several different areas, including ATP depletion, activation of voltage-sensitive sodium and calcium channels, glutamate and free radicals release. The most important of these effects to its neuroprotective activity seems to be the interference of voltage-sensitive sodium channels, and possibly also its strong antioxidant activity (Hadjiev, 2003).

One main Hungarian company markets vinpocetine in Europe as a drug (Cavinton) for improving several types of cerebral insufficiency conditions, and for improving cerebral metabolism. In studies involving vinpocetine’s use in chronic stroke patients, positron emission tomography (PET) scans showed that it improves the brain metabolism and blood flow, especially around the stroke-damaged areas (Szakal et al., 1998; Vas et al., 2002; Gulyas et al., 2002).


There seems to be a good amount of preclinical science and little clincial science to back vinpocetine’s use in cerebrovascular disorders. However, with its low toxicity and side effects, it shows excellent potential for the future use of prevention and treatment of stroke. Its effects on memory on healthy individuals has some merit, but yet needs more clinical backing.

Scientific Support

Cerebrovascular Disease

Hadjiev (2003) reviewed the actions of vinpocetine on the ischemic cascade, and discussed how it may be a new therapeutic approach to treatment and prophylactic neuroprevention in patients with asymtomatic ischemic cerebrovascular disorders (AICVD) and cerebrovascular disease. A subclinical noninvasive diagnosis of AICVD has been recently introduced by the American Heart Association and its treatment was identified as being important in prevention of ischemic stroke and cognitive decline. As a potential treatment to AICVD, the neuroprotective effects of vinpocetine were discussed.

Szapary et al. (2003) examined the high and low dose therapy of vinpocetine on rheological parameters in acute and chronic stroke patients. Vinpocetine is used mainly in a preventative manner, and this study sought to determine if it had value as a treatment for chronic disease. The authors concluded that after parenteral administration with low (30 mg/day) and high (70 mg/day) doses of vinpocetine, the high dose showed significant decreases in hematocrit, the whole blood and plasma viscosity and red blood cell aggregation, indicating a beneficial role in the treatment of chronic cerebrovascular disease.

A pilot clinical study involving the treatment of 30 patients with vinpocetine was conducted in order to determine the safety and feasibility of a full-scale clinical study. Patients were given either dextran alone or dextran in combination with vinpocetine and it was found that the two treatment groups were comparable in their major prognostic variables. However, the National Institute of Health Stroke Scale score was slightly improved in the vinpocetine group at 3 months of follow-up, and no significant side effects were seen. A full-scale clinical study was concluded to be warranted (Feigin et al., 2001).

A systematic review of the literature and researchers in the field (including drug companies) was conducted to determine if therapy with vinpocetine on stroke was effective. Only one trial was found that was of an unconfounded randomized, placebo controlled design. The authors concluded that there were no deaths found, nor drug dependencies, but that there were not enough studies conducted to determine the efficacy of vinpocetine in stroke patients (Bereczki and Fekete, 2000; Bereczki and Fekete, 1999).

As vinpocetine had been used for over 20 years in the treatment of cognitive impairment due to vascular diseases, and there had been many preclinical findings to suggest several important mechanisms of action, no consensus had been reached on its efficacy. Therefore this search was conducted to review the existing literature world-wide to analyze unconfounded double-blind studies pertaining to vinpocetine treatment of vascular dementia, Alzheimer’s dementia and other dementias. The authors concluded that although the preclinical science done on vinpocetine was persuasive and few adverse effects were found, the clinical science was inconclusive and did not support clinical use. The authors called for more clinical work on well-defined types of cognitive impairment. (Szatmari and Whitehouse, 2003).


Twelve healthy females were given vinpocetine in the dosages of 10, 20, or 40 mg for two days or placebo and assessed for psychopharmacological effects in a randomized, double-blind crossover study. Assessment parameters were measured on the third day, and included Critical Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS), and Sternberg Memory Scanning Test. Significant improvements were found in memory as a function of the Sternberg test at the dosage level of 40 mg. The results suggested that vinpocetine has a specific effect on the serial comparison stage of the reaction process (Subhan and Hindmarch, 1985).

Safety / Dosage

For the use of improving mild to moderate dementia in patients, 5-10 mg, taken 2-3 times daily, is the typical dosage recommendation, however larger dosages have been used clinically for acute treatment. Because vinpocetine is difficult to absorb in large quantities, it is recommended to divide the daily doses as suggested.

Side effects of vinpocetine are rare and transient (with discontinued use) at the recommended dosages. Typically these side effects may include gastrointestinal upset, low blood pressure, dry mouth, insomnia, headaches and heart palpitations. Persons on anti-coagulant therapy should not use vinpocetine, as it may interfere with clotting.

The safety or efficacy of vinpocetine for pregnant or lactating women is undocumented.


1.Bereczki D, Fekete I. Vinpocetine for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000480.

2.Bereczki D, Fekete I. A systematic review of vinpocetine therapy in acute ischaemic stroke. Eur J Clin Pharmacol. 1999 Jul;55(5):349-52.

3.Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV. Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Eur J Neurol. 2001 Jan;8(1):81-5.

4.Gulyas B, Halldin C, Sandell J, Karlsson P, Sovago J, Karpati E, Kiss B, Vas A, Cselenyi Z, Farde L. PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand. 2002 Dec;106(6):325-32.

5.Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz. 2003 May 20;56(5-6):166-72

6.Subhan Z, Hindmarch I. Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol. 1985;28(5):567-71.

7.Szapary L, Horvath B, Alexy T, Marton Z, Kesmarky G, Szots M, Nagy F, Czopf J, Toth K. [Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease] Orv Hetil. 2003 May 18;144(20):973-8.

8.Szakall S, Boros I, Balkay L, Emri M, Fekete I, Kerenyi L, Lehel S, Marian T, Molnar T, Varga J, Galuska L, Tron L, Bereczki D, Csiba L, Gulyas B. Cerebral effects of a single dose of intravenous vinpocetine in chronic stroke patients: a PET study. J Neuroimaging. 1998 Oct;8(4):197-204.

9.Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev. 2003;(1):CD003119.

10.Vas A, Sovago J, Halldin C, Sandell J, Karlsson P, Karpati E, Kiss B, Cselenyi Z, Farde L, Gulyas B. Cerebral uptake and regional distribution of [11C]-vinpocetin after intravenous administration to healthy men: a PET study. Orv Hetil. 2002 Nov 24;143(47):2631-6.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.



As alfalfa has long been a fodder plant used for livestock and horses, much of what has been studied in the scientific literature is based on its use in animals. It has been revered as a food for horses that gives increases strength and speed, and this has contributed to its folkloric use as an herbal supplement for increasing energy, lowering cholesterol, detoxification, arthritis and hot flashes associated with menopause.

Alfalfa truly is a nutritive food, with high levels of protein (up to 50%), B-vitamins, and minerals, and this could go a long way in explaining its claims for energy and reduction of fatigue. Additionally, alfalfa contains saponins which could explain some of its “adaptogenic” reputation, and antioxidants and its alkalizing nature could explain its detoxification claims. Its use in hot flashes and cancer may be explained by its high estrogenic activity.


Alfalfa is still lacking in clinical research to back up its many claims, but as a nutritive food it may add credence to its use in many kinds of wellness formulations. In a recent study on the estrogenic activity of several legumes, alfalfa sprout extract was found to increase cell proliferation above levels found for estradiol, and the authors concluded it to contain phytoestrogens with a high level of activity (Boue et al., 2003).

Scientific Support

Supplementation of alfalfa seeds was clinically tested in patients with hyperlipoproteinemia (HLP) types IIA, IIB, and IV. All patients were given 40 g of alfalfa seeds 3 times daily with meals for 8 weeks. At the end of the 8 week period, there was a 17% lowering of total plasma cholesterol, and an 18% decrease in the low density lipoprotein (LDL) levels in patients with type II HLP. The largest decreases observed were 26% in total cholesterol and 30% in LDL. The authors concluded that the alfalfa seeds may be used to normalize serum cholesterol levels in patients with type II HLP (Molgaard et al., 1987).

Safety / Dosage

Although the dosage used in the clinical study on alfalfa’s use for lowering cholesterol was extremely high (120 grams daily!), typical dosages for alfalfa tend to range from 250-1000 mg 2-3 times daily with meals. In this dosage range, there are no known side effects of alfalfa except a possible mild blood thinning effect.


1.Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. J Agric Food Chem. 2003 Apr 9;51(8):2193-9.

2.Molgaard J, von Schenck H, Olsson AG. Alfalfa seeds lower low density lipoprotein cholesterol and apolipoprotein B concentrations in patients with type II hyperlipoproteinemia. Atherosclerosis. 1987 May;65(1-2):173-9.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.



L-Arginine is a substance that is produced in the body that plays an essential role in the nitric oxide pathway, a pathway involved in the cascade reactions that are responsible for vasodilation. Due to this function, arginine supplements are associated with cardiovascular health, especially in conditions where the nitric oxide pathway may be working insufficiently. For example, there is evidence that in the development of arteriosclerosis, people with high cholesterol have an endothelium that has the reduced ability to produce nitric oxide, and therefore the arteries can not dilate effectively. This leads to the consequence of blood cells having the ability to attach to the inner vessels and cause blockages. L-Arginine has also been shown to stimulate lymphocyte production, and it has therefore been studied in diets of surgery patients.

During the nitric oxide pathway, the nitric oxide synthase enzyme catalyzes the oxidation of arginine to citrulline and nitric oxide (NO). NO production in turn causes vasodilation, and is involved in the overall regulation of overall vasoresistance. Since arginine is produced by our bodies it has been classified as a nonessential nutrient for supplementation, however, recently the amount of arginine produced by the body has been found to be insufficient for maintaining health.


Due to the popularity of dietary supplements for sexual function improvement and the known action of arginine on the NO pathway, numerous supplements now include arginine in combination with other herbs for sexual dysfunction and performance. However, few studies have confirmed the benefits of these combinations nor the action of the single components.

Scientific Support

Cardiovascular Health

A meta-analysis of the use of L-arginine in the enteral/oral diets of stressed patients was conducted to reduce the confusion of whether or not the diets were immune enhancing and beneficial. Although the review found these L-arginine “immune-enhancing” diets to be beneficial, the author contended that nothing proved that this effect was not confounded by other bioactive components, including omega-3 fatty acids, RNAs, and antioxidant vitamins. The author also pointed out that the L-arginine supplemented enteral/oral diets could have a harmful effect in hemodynamically unstable patients, and in patients with multiple organ failure (Cynober, 2003).

A medical food called the Heart Bar is now sold that looks just like the numerous other sports and protein bars. The heart bar is intended to act as a food that nutritionally supports cardiovascular health with its major active constituent being arginine. Its use is substantiated by numerous peer reviewed clinical studies, and it is regulated specially as a “medical food” by the FDA. In one study (a randomized, double-blind, placebo-controlled, crossover trial), thirty-six stable angina outpatients were tested for the electrocardiographic, vascular and clinical effects of the Heart Bar. This medical food was found to improve vascular function, exercise capacity and aspects of quality of life in patients with stable angine (Maxwell et al., 2002).

L-Arginine was clinically studied in a single-blind, controlled, crossover dietary intervention study for its effect on certain cardiovascular parameters, especially blood pressure. Six subjects were given isocaloric diets for one week, with constant measures of sodium in each diet (approx. 180 mmol/day). Three diets were given in random order to each participant: a) control, b) L-arginine enriched by natural foods, and c) L-arginine supplemented orally (same as control diet otherwise). Both arginine-rich diets (b and c) resulted in a blood pressure decrease. The diet b ( but not diet c) resulted in lower total serum cholesterol and triglyceride levels and higher HDL cholesterol. The diet c, and to a lesser extent diet b, resulted in higher creatine clearance (slight) and a fall in fasting glucose. The authors concluded an increase of L-arginine in the diet to lower blood pressure and affect kidney function and carbohydrate metabolism (Siani et al, 2000).

Fujita et al. (2000) clinically tested the ability of L-arginine to affect coronary perfusion abnormality during exercise. Twelve patients with angina pectoris and normal coronary arteries underwent exercise thallium-201 scintigraphy both with intravenous L-arginine or without (control). The administration of L-arginine was found to prolong exercise time and improve the severity score. In 7 of the 12 patients, the TI-201 redistribution disappeared after L-arginine administration, and the percentage of serum L-citrulline increased, and percentage of epicardial coronary diameter in response to acetylcholine compared to the other patients who did not show a change in TI-201 redistribution. The authors concluded that exogenous L-arginine was able to improve myocardial perfusion during exercise in this subset of patients.

High Blood Pressure

In order to determine whether or not a deficient L-arginine-nitric oxide system is active in cortisol-induced hypertension, the effect of L-arginine uptake was studied. Eight healty men were included in the study, and hydrocortisone acetate (50 mg) was given orally every six hours for 24 hous after a 5-day fixed salt diet. L-Arginine levels were not found to be affected by cortisol treatment, and therefore, there was no correlation between cortisol induced hypertension and the L-arginine transport system (Chin-Dusting et al., 2003).

Immune Function

L-Arginine was clinically tested in patients with far advanced gastric cancer for its ability to stimulate lymphocyte production, since it had been previously shown to stimulate lymphocyte production in healthy individuals. The patients received a dietary supplement of L-arginine (30 g daily for 7 days), and the lymphocyte counts and T/B cell ratio in the peripheral blood was tested. Although L-arginine did not show any significant side effects (except transient nausea in 1 patient) or impair liver function, it also did not stimulate lymphocyte function. The authors suggested the possibility that the cancer patients had immune systems that were intrinsically defected, and therefore could not be stimulated (Wu et al., 1993).

Li et al. (1993) tested the ability of L-arginine to decrease incidence of sepsis after surgery in patients with obstructive jauntice. Since arginine had been known as a T lymphocyte stimulator, the use of supplementation and the immunological status of patients with obstructive jauntice after surgery was studied. Arginine was found to significantly enhance immune function of patients with obstructive jauntice.

In order to study the immunomodulatory effect of arginine in surgery patients, 30 cancer patients were randomized, and sixteen were given L-arginine (25 g/day) while the other 14 were given isonitrogenous L-glycine (43 g/day) for 7 days after major surgery. Parameters measured were nitrogen balance (daily), and immune parameters before and after surgery on days 1,4 and 7. T-Lymphocyte response was significantly enhanced to concanavalin A in the L-arginine group compared to the glycine group. L-arginine was also found to increase the CD4 phenotype. L-Arginine was found to be beneficial in modulating the immune system in surgery patients. This immune modulating effect was found to be nontoxic and distinct in its mechanism from its moderate effect on nitrogen metabolism (Daly et al., 1988).

Safety / Dosage

The daily requirement of arginine supplementation has been calculated to be approximately 8 grams daily (for a 70-kg person). Supplements in the range of 8-21 grams daily have been used clinically in people with high cholesterol in order to restore the proper functioning of the vasodilatory pathways. Supplements in the range of 9-14 grams daily have been used clinically to increase blood flow to the peripheries and improve conditions of myocardial ischemia and walking pain due to claudication.

The average daily intake of arginine in the American diet has been calculated to be approximately 5 grams daily. In order to increase arginine in the diet, the primary dietary sources of this amino acid are meats and other high protein foods (nuts, eggs).


1.Chin-Dusting JP, Ahlers BA, Kaye DM, Kelly JJ, Whitworth JA. L-arginine transport in humans with cortisol-induced hypertension. Hypertension. 2003 Jun;41(6):1336-40. Epub 2003 Apr 21.

2.Cynober L. Immune-enhancing diets for stressed patients with a special emphasis on arginine content: analysis of the analysis. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):189-93.

3.Daly JM, Reynolds J, Thom A, Kinsley L, Dietrick-Gallagher M, Shou J, Ruggieri B. Immune and metabolic effects of arginine in the surgical patient. Ann Surg. 1988 Oct;208(4):512-23.

4.Fujita H, Yamabe H, Yokoyama M. Effect of L-arginine administration on myocardial thallium-201 perfusion during exercise in patients with angina pectoris and normal coronary angiograms. J Nucl Cardiol. 2000 Mar-Apr;7(2):97-102.

5.Li H, Xiong ST, Zhang SX, Liu SB, Luo Y. Immunological status of patients with obstructive jaundice and immunostimulatory effect of arginine. J Tongji Med Univ. 1993;13(2):111-5.

6.Maxwell AJ, Zapien MP, Pearce GL, MacCallum G, Stone PH. Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol. 2002 Jan 2;39(1):37-45.

7.Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P.Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens. 2000 May;13(5 Pt 1):547-51.

8.Wu CW, Chi CW, Chiu CC, Wu HS, Liu WY, P'eng FK, Wang SR. Can daily dietary arginine supplement affect the function and subpopulation of lymphocytes in patients with advanced gastric cancer? Digestion. 1993;54(2):118-24.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

B-Complex Vitamins


Four B-vitamins are considered here in one monograph because of their related benefits as dietary supplement for promoting cardiovascular health – folic acid, vitamin B6 and vitamin B12 for their effects in reducing homocysteine levels, and niacin for reducing cholesterol levels.

Vitamin B6 (Pyridoxine) is a water-soluble vitamin. It is also known by the names pyridoxine, pyridoxamine, and pyridoxal. Vitamin B6 performs functions as a cofactor for about 70 different enzyme systems – most of which have something to do with amino acid and protein metabolism. Because vitamin B6 is also involved in the synthesis of neurotransmitters in the brain and nerve cells, it is frequently recommended as a nutrient to support mental function (mood) and nerve conduction. Some athletic supplements include vitamin B6 because of its role in the conversion of glycogen to glucose for energy in muscle tissue. Perhaps the best data supporting the value of B6 supplements is in the area of heart health via reduced homocysteine levels. Food sources include poultry, fish, whole grains and bananas.

Vitamin B12 (Cobalamin) is a water-soluble B vitamin. B12 is also known as cobalamin because it contains cobalt. The form of B12 most commonly used in dietary supplements is called cyanocobalamin. B12 is only produced by bacteria, so it is only found in food products of animal origin and in some fermented vegetable products such as tempeh and miso (fermented soybeans). B12 functions in a wide variety of metabolic processes, many of which are involved in transferring methyl groups between amino acids. B12 works closely with another B vitamin, folic acid, in reactions involved with DNA synthesis, blood cell formation, nervous system maintenance and heart health. B12 is also involved in the metabolism of proteins, fats, and carbohydrates, as it is needed to produce succinyl CoA, an intermediary in the Krebs cycle that generates ATP for cellular energy. Like B6, vitamin B12 has been shown to reduce elevated homocysteine levels and thus can be considered a valuable supplement for promoting heart health.

Folic acid is a B vitamin that plays an important role DNA and RNA synthesis, production of red blood cells and maintenance of the nervous system. Fruits and vegtables are the best dietary source (folic acid derives its name from “foliage”), especially for dark leafy greens, oranges and orange juice, beans and peas. Folic acid is known to reduce the risk of neural tube defects in developing fetuses and the FDA requires folate-enrichment of refined cereal grains to increase the population intake of folic acid for this purpose. At these fortification levels of folic acid intake, homocysteine is partially normalized, but further increases in dietary intake, wheteher form foods or supplements provides an additional significant reduction in homocysteine levels.

Niacin is a water-soluble B vitamin – and the common name for two very different compounds: nicotinic acid and niacinamide. Like all B-vitamins, niacin plays a role in many aspects of energy metabolism and nervous system function. One of the most common uses for supplemental niacin is cholesterol regulation (used at very high doses – see below). Rich dietary sources of niacin include many high-protein foods such as meat, chicken, tuna and other fatty fish, peanuts, pork and milk. The nicotinic acid form of niacin is effective, when used at high levels, for reducing cholesterol and triglyceride levels as well as enhancing circulation.


The dosage levels that have been associated with cardioprotective effects (reduced homocysteine and cholesterol levels) of these B-vitamins generally fall within the ranges of 2-12.5mg/day for B6, 50-800mcg/day for B12, 400-1000mcg/day for folate (though much higher milligram levels are also effective) for control of homocysteine levels, and 250-2000mg/day of niacin (a very high level that should be monitored by a physician) for cholesterol and triglyceride reduction.

Vitamins B6 and B12 are found in high concentrations inmost protein-rich foods. Because folic acid is destroyed during cooking, levels are typically highest in raw or lightly steamed vegetables. The chemical form of folic acid found in foods, mono-glutamic acid (conjugated), however, is less well absorbed (40-60% less) compared to the synthetic form, poly-glutamic acid (unconjugated), found in dietary supplements. This suggests that supplemental forms of folic acid may even be warranted in high risk individuals in addition to a well-balanced intake of fruits and vegetables.

Like the other B-vitamins covered here, niacin is very inexpensive – so its effectiveness in reducing cholesterol levels may be an affordable solution to reducing a known risk factor for cardiovascular disease. When monitored properly, niacin therapy can be almost as effective as the popular (and expensive) “statin” drugs for lowering cholesterol and triglyceride levels. It is important to note that, despite the fact that niacin is a B-vitamin, such high-dose niacin therapy should really be considered “drug” therapy and not “nutritional” therapy.

Scientific Support

Although various “structure/function” rationales could be assigned to the value of supplementation with B6/B12/Folate, the clearest and most dramatic effects of these nutrients is in the area of reducing hyperhomocysteinemia (and niacin in reducing hypercholesterolemia) for prevention of heart disease. As such, although some of these related “structure/function” claims will be mentioned, the focus of this summary will be confined to the strongest data set – that being reduction of heart disease risk.

Vitamin B6, like most of the B-vitamins, is involved as a cofactor in a wide variety of enzyme systems. As such, "structure/function" claims can be made for virtually any health condition. For example, because B6 is needed in the conversion of the amino acid tryptophan into niacin, a common B6 claim relates to “healthy cholesterol levels” (because niacin can help lower cholesterol in some people). Because B6 also plays a role in prostaglandin synthesis, claims are often made for B6 in regulating blood pressure, heart function and pain levels (each of which is partially regulated by prostaglandins). Vitamin B6 needs are increased in those individuals consuming a high protein diet as well as in women taking oral contraceptives. Vitamin B6 supplements (in conjunction with folic acid) have been shown to have a significant effect in reducing plasma levels of homocysteine (an amino acid metabolite linked to increased risk of atherosclerosis) – see further discussion below.

Vitamin B6 is often recommended as a treatment for carpal tunnel syndrome (CTS). In the vast majority of cases, CTS is caused by repetitive hand/wrist motions (such as typing), which causes inflammation and nerve compression in a region of the wrist known as the carpal tunnel. CTS is also known to occur in some women during pregnancy, in which case the nerve compression may be related to water retention and swelling, rather than to repetitive motion. B6 is the most frequently recommended dietary supplement in cases of CTS (traditional treatments often include rest, splints, anti-inflammatory medications and surgery). In some cases of CTS, approximately 100-300 mg of vitamin B6 in divided doses has been shown to alleviate symptoms – although these results are not consistent and several studies have found no benefit of vitamin B6 in treating CTS.

Vitamin B12 is an essential cofactor for methylation reactions (including homocysteine metabolism) in the body (many in conjunction with folic acid) – so B12 have involvement in metabolic pathways related to brain function, joint health, and cardiovascular function. Absorption of B12 begins in the stomach, where it must combine with Intrinsic Factor, a compound synthesized by the stomach and required for proper absorption of B12 in the small intestine. An inadequate production of intrinsic factor and hydrochloric acid in the elderly is a common cause of vitamin B12 deficiency. Because B12 is stored in the liver, the symptoms of deficiency develop very slowly, typically not showing up for 5-10 years. Strict vegetarians (vegans), who consume only plant foods, are at the highest risk for developing B12 deficiency and should consider supplements. Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and birth defects such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid (400-800mcg) combined with vitamin B12 (6mcg). The combination of B12 with folic acid is significantly more effective in reducing homocysteine levels than is folic acid alone.

Because folic acid has functions in DNA synthesis and nervous system maintenance, it has been linked to growth and development of the fetus during pregnancy. Clinical evidence clearly shows a beneficial effect of adequate folic acid intake in reducing the risk of brain and spinal cord birth defects. Due to its role in red blood cell formation, homocysteine metabolism and the fact that deficiency of folic acid results in megaloblastic anemia, supplemental levels are often associated with maintenance of energy levels and heart health.

It is abundantly clear that an adequate intake of folic acid is essential during pregnancy. Overwhelming evidence is available to show that women given folic acid supplements during pregnancy have a lower incidence of delivering babies with neural tube birth defects such as spina bifida. Oral contraceptives have been associated with lower folate levels in women who conceived soon after they stop taking the pill. In some cases, former contraceptive users and women who have previously delivered babies with neural tube defects may especially benefit from supplemental levels of folic acid in their diets.

The U.S. Department of Health recommends that pregnant women (and those trying to conceive) should take a daily folic acid supplement of 400mcg (0.4mg). The U.S. Public Health Service recommends that all women of childbearing age consume the same amount of folic acid each day to decrease the risk of having a pregnancy affected by a neural tube defect. Three strategies are available to women to achieve this goal: eat more foods with naturally occurring folic acid (fruits/veggies); eat foods fortified with folic acid (such as breakfast cereals); or use dietary supplements.

Despite the wide-ranging public health benefits of adequate folic acid intake and the widespread public awareness of these benefits, as many as 68-87% of American women of childbearing age still have folic acid intakes below the recommended 400 micrograms per day. Elderly populations are also thought to be at increased risk for folate deficiencies – which may exacerbate their already high risk of heart disease, cancer and neurological impairments. Several recent studies have suggested that folate supplementation should be considered in elderly people, especially those with elevated plasma total homocysteine levels and cardiovascular disease, as well as in those individuals who experience neuropsychiatric disorders. Because of the possibility for high dose folate supplements to mask the symptoms of vitamin B12 (cyanocobalamin) deficiencies (which are also common in the elderly), folic acid supplements should be given in conjunction with B12.

Because niacin is involved in the proper functioning of more than 200 metabolic enzymes, it plays a role in a wide range of bodily processes, including synthesis of hormones and blood cells and the release of energy from fats, carbohydrates and proteins. As a nutrient (vitamin B3) consumed at low doses (20-40mg), there is virtually no difference in overall metabolism between the different chemical forms of niacin. In the mid-1950s, however, it was shown that high doses of niacin (as nicotinic acid) could lower cholesterol levels (although the exact mechanism of action is still not known). The other form of niacin (nicotinamide or niacinamide) does not provide a cholesterol-lowering effect.

Niacin has been studied for its cardiovascular benefits in numerous clinical trials. The primary cardiovascular measures such as cholesterol and triglyceride levels, heart attacks and strokes are all significantly reduced with niacin therapy (sometimes used alone and sometimes used along with other drug therapy). Overall, the use of niacin (nicotinic acid, but not niacinamide) to prevent or treat elevated blood lipids and reduce cardiovascular disease risk is well substantiated (O-Connor et al. 1997). In a large number of clinical trials, nicotinic acid has been shown to consistently lower total and LDL cholesterol by about 15-20% and triglycerides by 10-25%, while increasing levels of HDL cholesterol by 15-25% (O’Connor et al. 1997). The downside is that the amount of niacin needed to lower cholesterol levels also tends to result in “niacin intolerance” in 15-40% of people who try it and the unpleasant side effect of “skin-flushing” (similar to hot flashes) as well as the serious risk of liver damage (see Safety considerations below). Niacin supplements are available in regular and “slow-release” forms. The slow-release forms of nicotinic acid, are intended for prolonged release of niacin during its 6-8 hour transit time in the intestines, but they are also associated with greater toxicity and safe doses are only about half of normal-release forms of niacin (Capuzzi et al. 1998, Guyton et al. 2000, Morgan et al. 1998).

Folate, B6, & B12 are often used in combination therapy to reduce serum levels of homocysteine (an amino acid produced during methionine metabolism). Plasma levels of homocysteine have been recognized in dozens of studies as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis (Righetti et al. 2003) and influences restenosis rate after percutaneous coronary intervention (Schnyder et al. 2002). A 5-micromol/L increase in total homocysteine level is associated with an approximately 70% increase in relative risk of cardiovascular disease in adults (Chait et al. 1999). When folic acid is supplemented alone at 5-15mg/day for 1 year, there is no difference in degree of homocysteine reduction at different levels of folic acid within this range (Righetti et al. 2003), and much lower levels of folic acid (100-600mcg/day for 4 weeks) have resulted in significant reductions in plasma total homocysteine (tHcy) levels in a number of studies (Brouwer et al. 1999, Riddell et al. 2000, Silaste et al. 2003, Venn et al. 2002). Even in the face of folate enrichment of cereal grain products (at 140mcg/100g flour), which would be expected to increase the baseline folic acid intake of the population, dietary supplementation with additional folate (2.5g/day) for 12 weeks has been shown to further increase folic acid status and reduce tHyc levels in CAD patients (Bostom et al. 2002). Even at much lower levels of folic acid supplementation (400mcg/day) when combined with B12 (500mcg/day) and B6 (12.5mg/day) for 3 months, homocysteine levels are reduced by 15% in patients with documented CAD (Lobo et al. 1999). In one study by Malinow and colleagues (1998), 75 men and women with CAD were studied to determine the effect of folate-fortified foods on plasma homocysteine levels. Results showed that cereal fortified with 127mcg folate daily (approximately the level resulting from the FDA’s policy on enrichment of cereal grains) increased plasma folic acid by 31%, but reduced homocysteine by less then 4%. Cereals providing folic acid at 499mcg and 665mcg daily increased plsam folic acid levels by 65% and 106%, respectively and decreased plasma tHyc by 11% and 14%, respectively (Malinow et al. 1998) – suggesting that higher levels of folic acid fortification than currently recommended by the FDA may be needed to control homocysteine level. A similar study by Riddell and colleagues (2000) used fortified breakfast cereal or folic acid supplements to bring total daily folic acid intake to 600mcg/day – finding a 21-24% drop in tHyc that was negatively correlated to serum folate values. The increase in serum folate levels and thus in reductions in tHyc tend to be more dramatic for supplements and fortified foods and more modest for non-enriched folate-containing foods (Riddell et al. 2000, Venn et al. 2002), but dietary interventions to encourage higher intake of folate-rich foods is effective in increasing serum folate by approximately 11-14% and reducing tHyc levels by approximately 10-13% within 5-10 weeks (Chait et al. 1999, Silaste et al. 2003).

Like folic acid, vitamin B12 is an essential cofactor in methionine metabolism and an important coenzyme in various methylation reactions. In folate- and B12-replete subjects, vitamin B6 supplementation (pyridoxine at 1.6mg/day for 12 weeks) has been shown to further reduce plasma tHyc levels by an additional 7.5% (McKinley et al. 2001) and should thus be included in a cocktail of vitamins for reducing elevated plasma homocysteine levels.

Studies of various combinations of Folate, B6 and B12 (FA/B6/B12) therapy for reducing plasma tHyc levels have been nearly unanimous in their support in significantly reducing elevated homocysteine levels while other aspects of cardiovascular risk largely remain unchanged (Hirsch et al. 2002). In patients with established CAD, FA/B6/B12 therapy for 6 months has been shown to significantly reduce homocysteine, as well as reduce the incidence of fatal and non-fatal myocardial infarctions (Schnyder et al. 2002).

Lipid lowering therapy with fibrates is known to increase homocysteine levels by up to 40% (Dierkes et al. 2001) – an effect which could counteract the cardioprotective effect of lipid lowering. By combining fenofibrate treatment with daily folic acid (650mcg), B12 (50mcg), and B6 (5mg) for 6 weeks, the increase in homocysteine levels were cut by nearly half, from +47% with no vitamins to only 25% increase with vitamin supplementation (Dierkes et al. 2001). In most hemodialysis patients and patients with end-stage renal disease, levels of B-vitamins are depleted and homocysteine levels are elevated (Dierkes et al. 2001, Henning et al. 2001, Tremblay et al. 2000). In these patients, supplementation with folate, B6, B12 via either an oral or intravenous route is effective in improving B-vitamin status and resulting in a corresponding 30-50% reduction in hyperhomocysteinemia within a period of 4 weeks to 6 months (Dierkes et al. 2001, Henning et al. 2001, Tremblay et al. 2000). Metformin therapy in diabetic patients is also known to reduce serum levels of vitamin B12 and folic acid by 8-17% and increase tHyc levels by nearly 15% (Carlsen et al. 1997), suggesting that homocysteine-lowering therapy with B-vitamin supplements may be beneficial in some diabetic patients.

Safety / Dosage

As water-soluble vitamins, all fo the B-vitamins are generally considered quite safe as dietary supplements. For B6, excessive intakes (2-6 grams acutely or 500mg chronically) are associated with sensory neuropathy (loss of feeling in the extremities) – which may or may not be reversible. The RDA for vitamin B6 is less than 2 milligrams per day – an amount contained in virtually all multi-vitamin supplements. Pregnant and lactating women should not take more than 100mg of vitamin B6 per day.

There are no confirmed reports of toxic side effects associated with vitamin B12 supplements – even at the very high injected doses commonly used to restore cognitive function in elderly subjects suffering from B12 deficiency. Oral intakes as high as 3000mcg are considered non-toxic. The Daily Value for vitamin B12 is 6mcg with a lower RDA set at 2.4mcg.

Extremely high intakes of folic acid (1-5mg/day) have been associated with masking the signs and symptoms of pernicious anemia (vitamin B12 deficiency) and should be avoided. The Daily Value (and RDA) for folic acid is 400 micrograms – an amount that ALL women of childbearing age should consume each day. Like the other B vitamins, dietary needs may be somewhat elevated during times of stress and during pregnancy and lactation. In the elderly, a daily folate supplement of 500mcg may be warranted – although it should not replace the need for a diet rich in fruit and vegetables.

Although the Daily Value for niacin is only 20mg (see RDAs below) and the body can convert the amino acid tryptophan into niacin, a “cholesterol-lowering” dose of niacin (as nicotinic acid, NOT niacinamide or nicotinamide) is typically in the range of 250-2000mg/day. Dosing is usually started at the low-end (250mg/day) with increasing doses of 250mg each week or two until blood lipid levels start to normalize (or side effects develop). Side effects are usually minimized by increasing the dosage slowly to the common therapeutic range of 1000-2000mg/day and should be divided into 2-3 separate doses of no more than 500-750mg per dose. In the high doses of niacin used for controlling cholesterol levels (anything above 100mg/day), nicotinic acid can cause skin flushing and itching of the skin as well as headaches and hypotension. In some cases, the skin flushing and itching side effects can be reduced somewhat by combined use with an aspirin (which also has a beneficial cardiovascular effect via reduced blood clotting). The niacinamide form of niacin does not cause these side effects, but it is not effective in reducing cholesterol levels, so it is seldom taken in such high doses. The slow-release versions of niacin supplements for controlling blood lipids have the potential for causing liver damage (even at “lower” doses of 500mg/day) – so blood tests to monitor for liver damage are recommended and high-dose niacin supplementation should only be undertaken on the advice and guidance by a physician. The inositol hexaniacinate (Niacinol) form of niacin may be less likely to cause liver damage compared to timed-release forms. Anybody with liver disease, including those who consume more than 2 drinks of alcohol daily, should not take high-dose niacin except on specific medical advice. All niacin therapy (at doses exceeding 100mg/day) should be supervised and monitored by a physician.

RDA = Recommended Dietary Allowance / AI = Adequate Intake

UL = Tolerable Upper Limit

tHyc dose = dosage range showing positive effect in reducing total plasma homocysteine levels

NOAEL = No Observed Adverse Effect Level – levels at which the Council for Responsible Nutrition (CRN) has determined no adverse effects are likely to be observed.

LOAEL = Lowest Observed Adverse Effect Level – lowest levels at which CRN has determined that adverse effects are observed.


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EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhDand Kerry Hughes, MS.