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How much to take? This depends on your nutritional needs but generally, B vitamin supplements are formulated to provide much more than you need and this can be a problem for the three B vitamins which can cause toxicity — niacin, folate and B-6. Too much B-12 may also cause problems, including acne. Furthermore, it is now acknowledged that you need less of many B vitamins than believed in the past, but % Daily Value figures on labels don't have to reflect this until the beginning of 2021. In the results table, we show you how products stack up against the latest recommendations (see the numbers in green), as well as which exceed the tolerable limits for niacin, folate, and B-6.
Which product is best? For each B vitamin or B complex, we identify CL's Top Picks. These "picks" were found in testing to be accurately labeled for B vitamins, meet other quality criteria, and, represent excellent value for your money. However, five products (mostly B complexes) failed our tests for providing far less or more ingredient than listed. One of these is a popular B complex that, due to an overage, exceeds the tolerable upper intake level for folate from its synthetic form, folic acid. These five products are listed as "NOT APPROVED" in the results table.
B Vitamins with CL Founder, Dr. Tod Cooperman
Background: B Vitamins:
There are eight B vitamins, generally known as thiamin (B-1), riboflavin (B-2), niacin (B-3), pantothenic acid (B-5), pyridoxine (B-6), biotin (B-7), folate (folic acid, B-9), and cobalamin (B-12). Like most vitamins, B vitamins are essential -- your body needs them but cannot make them; you must get them from your diet or from supplements.
Each B vitamin is associated with a variety of functions, many of which relate to turning food into energy and other needed substances. There are also potential toxicities when getting too much of certain B vitamins. Folate, for example, is important in reducing birth defects of the spinal cord and is, therefore, a critical ingredient in prenatal vitamins. But at a high dosage, folic acid may increase the risk of certain cancers. Niacin, when taken in very high doses, can improve cholesterol levels but can also cause side-effects (such as skin flushing) and liver toxicity.
Combinations of B-6, B-12, and folate have been shown to reduce elevated homocysteine levels -- a risk factor for cardiovascular disease, although studies have not shown this combination to reduce cardiovascular risk itself. A review of 14 studies involving B vitamin supplementation found that reduced levels of homocysteine attributable to B vitamin supplements was associated with a slight (7%) reduction in the risk of stroke. However, there was no reduction in stroke directly associated with the use of B vitamins (Ji, Neurology 2013). Nevertheless, for people who are deficient in vitamin B-9 (folate), supplementing with folate may significantly reduce the risk of stroke (see Folate below).
Memory, Cognition, and Alzheimer's Disease
Certain B vitamins, or combinations, may also help slow declines in memory and cognition when taken long-term (at least 18 months), according to several studies. In a 2-year placebo-controlled study of people aged 70 years or older with mild cognitive impairment, a combination of B vitamins was found to slow cognitive decline, particularly in those who started with elevated levels of plasma homocysteine (over 11.3 micromoles/L) - which can occur with inadequate B-vitamin intake. People in the study were given a daily dose of folic acid (800 mcg), vitamin B-12 (500 mcg), and vitamin B-6 (20 mg) (de Jager, Int J Geriatr Psy 2011). Further analyses of this study found that the beneficial effects of B vitamins were enhanced when people began the study with blood plasma levels of omega-3 fatty acids in the upper range of normal, particularly for DHA. In fact, those with low omega-3 levels did not benefit from B vitamin supplementation. (Oulhaj, J Alz Dis 2016).
In a similar study, this same B vitamin combination reduced the amount of shrinkage in regions of the brain commonly affected by Alzheimer's disease. The benefit was found only among people who started the 2-year study with high homocysteine levels (over 11.06 micromoles/L), but this represented about 50% of the people in the study. Shrinkage was reduced by 8 times compared to the amount of brain shrinkage experienced among those taking placebo (Douaud, PNAS 2013). As with the research noted above by Oulhaj, further analysis of this study also found that higher blood levels of omega-3 fatty acids enhanced the beneficial effect of the B vitamins (Jerneren, Am J Clin Nutr 2015). Not surprisingly, a fish oil study by the same research team found it only helpful to Alzheimer's patients with adequate B vitamin status.
A study in China investigated the effects of folic acid supplementation (400 mcg/day for two years) among 180 older men and women (average age 74) with mild cognitive impairment (MCI). At the end of the study, those who took folic acid had significant improvements in certain measures of cognitive function (vocabulary, comprehension, arithmetic and number recall) and increases in IQ scores compared to those who did not take folic acid. Blood folate levels increased from an average of 7 ng/mL to about 10 ng/mL (Ma, Eur J Nutr 2017). However, it's uncertain whether this cognitive effect would be seen in the U.S., where blood folate levels average 12.2 ng/mL (McDowell NCHS Data Brief 2008) and food is fortified with folate, while there is no fortification in China and folate deficiency is common (> 20% of the population).
Cognitive benefits were seen in a study in Australia that used smaller daily doses of just folic acid (400 mcg) and B-12 (100 mcg -- which is still many times the daily requirement). In that study (Walker, Am J Clin Nutr 2012), adults aged 60 to 74 years with depressive symptoms received the vitamins or placebo in two daily oral doses. Compared to placebo, there were small but significant improvements in short and long-term memory. Improvement was seen after 2 years -- but not after 1 year. The researchers concluded that the vitamin combination is a potentially effective long-term intervention for minimizing cognitive decline. The role of B-12 specifically in minimizing cognitive decline is suggested by a study which, after following several hundred people in their 70's over an eight-year period, found that cognitive decline was faster among those with the lowest blood levels of B-12 (under 257 pmol/L) -- a group representing 40% of those in the study (Morris, J Am Geriatr Soc 2012). Normally, people are not considered B-12 deficient (and at risk for pernicious anemia) until levels go below about 148 pmol/L (200 pg/mL). The study suggests that it may be beneficial to maintain somewhat higher levels of B-12. As noted in the B-12 discussion below, it is already medically recommended that people over age 50 get at least 2.4 mcg of B-12 daily from supplements or foods fortified with B-12.
Similarly, a large placebo-controlled study in Holland of adults 65 and older suggested that blood levels of B-12, particularly in its active form, holo-transcobalamin, may indicate who can most benefit from supplementing with B-vitamins. In this study, all participants had high homocysteine levels (12 to 50 micromol/L) although many were not actually deficient in B-12 (the mean level was 257 pmol/L). After being given folic acid (400 mcg) and B-12 (500 mcg) daily for 2 years, compared to placebo, there was only a possible minor slowing in the decline in cognitive functioning. However, those who started the study with lower levels of holo-transcobalamin (below 64 pmol/L) had more benefit from supplementation in terms of episodic memory performance (i.e., recall and recognition) and information processing speed (van der Zwaluw, Neurology 2014). In this study, both the treated and placebo groups received 600 IU of vitamin D3 daily due to a high percentage of deficiency (44%) in the population.
Two studies in China failed to show a cognitive benefit with B-12 supplementation, although neither study involved corrected B-12 deficiency, as the participants in one study were not deficient in B-12 to start and those in the other study were deficient but did not take enough B-12 to correct their deficiency. In the first study, among older, diabetic adults (average age 75) who had somewhat low but not deficient levels of B-12 (averaging 232 pmol/L), daily supplementation with 1,000 mcg of B-12 (as methylcobalamin) for two years had no effect on cognitive decline as compared to placebo (Kwok, Clin Nutr 2017). In the other study, by the same researchers, giving 238 older adults (average age 77) with mild cognitive decline and elevated homocysteine levels (average 13.9 micromol/L), 500 mcg of vitamin B-12 plus 400 mcg of folic acid daily for two years decreased homocysteine levels (to an average of 9.3 micromol/L) but did not slow cognitive decline compared to placebo. However, among those who took the supplements, average blood levels of B-12 only increased from 86 pmol/L to 124 pmol/L, which still indicates deficiency. Interestingly, those who took aspirin in addition to the supplements had significantly worse clinical dementia ratings at the end of the study than those who did not take aspirin. The researchers noted that a negative effect of aspirin was also observed in another study of B vitamin effects on cognition (Smith, PLOSE One 2010) and speculated that this could be due to possible interference of aspirin with metabolism of folic acid to active folate, although more research is needed to determine if this is the case (Kwok, Clin Nutr 2019).
A 4-year study of adults ages 60 to 68 years in Ireland found that low dietary intake (0.9 — 1.4 mg/day) of vitamin B-6 and low vitamin B-6 blood levels (below 43 nmol/L) were, respectively, associated with 4.2 times and 3.5 times higher rates of cognitive decline. (Note: the recommended intakes of vitamin B-6 are 1.7 mg and 1.5 mg, respectively, for older men and women.) No significant relationships were observed for the other B-vitamins, although none of the participants were deficient in B-12 and only 3% were deficient in folate (Hughes, Nutrients 2017).
In line with the findings above, a study in England among middle-aged adults found that those who reported regularly taking vitamins (i.e., on a daily basis), particularly B vitamins, scored higher on tests of cognitive performance (relating to visuospatial and verbal memory) than those who did not regularly take vitamins (Flitton, Nutr Neurosci 2017).
In summary, if your B-12 levels are somewhat low, taking B-12 (100 to 500 mcg , or more if necessary to correct deficiency) and, possibly, folic acid (400 mcg), each day, may help slow age-related declines in memory and cognition -- particularly when also gettingomega-3 fatty acids, such as from fish. Getting the recommended daily allowance of B-6 (about 1.7 mg), which is easily obtained from foods, is also important. (There is very preliminary evidence that taking aspirin may blunt this effect if one is taking folic acid.)
Breast cancer High blood levels of folate (>24.4 ng/mL) have been associated with an increased risk of breast cancer in women with BRCA1 and BRCA2 gene mutations (Kim, Am J Clin Nutr 2016). Because of this, there has been some concern with how folic acid supplementation may affect breast cancer risk in these women, especially in countries with folic acid food fortification programs, such as the U.S. and Canada. A study among 400 women in Canada with these mutations found that low intakes of folic acid from supplements (8.56 to ≤ 89.29 mcg/day) were associated with a 61% decrease in the risk of breast cancer in women with the BRCA1 gene mutation, but not those with the BRCA2 mutation, compared to no intake of folic acid from supplements; higher intakes of folic acid were associated with a lesser decrease (46%) but this was non-significant. Low intakes of vitamin B12 from supplements (0.02 to ≤ 0.34 mcg/day) were associated with a 52% decrease in risk in women with BRCA1 or BRCA2 gene mutations, while there was no association for higher intakes of B12 nor for any level of intake of vitamin B6. The findings suggest a potential beneficial role for moderate use of folic acid and B12 (Kim, Breast Cancer Res Treat 2019).
Deficiency in B-3 (niacin), B-6, and/or B-12 can cause depression (as well as other symptoms) (Kennedy, Nutrients 2016; NIH 2016). A study in the U.S. found that pregnant women with low-normal blood levels of B12 (190 -300 pg/mL, averaging 249 pg/mL) were 3.82 times more likely to experience depression than those with normal levels (>300 pg/mL — averaging 477 pg/mL) (Peppard, Res Nurs Health 2019). Higher intakes of B-6 and B-12 from supplements are associated with a lower likelihood of depression in older adults (Skarupski, Am J Clin Nutr 2010) and having higher blood levels of B-12 is associated with a higher probability that SSRI medication will help one recover from major depression (Hintikka, BMC Psych 2003).
B-12 injections (1,000 mcg per week) taken with tricyclic antidepressants or SSRIs may improve symptoms of depression in people with low-normal blood levels of vitamin B-12 (190 pg/ml to 300 pg/ml) more than medication alone (Syed, Open Neurol 2013).
Treatment with B-6 was found to help women deficient in B-6 who had depression associated with use of oral contraceptives, but it has generally not helped other people suffering from depression (Williams, Family Practice 2005).
Folate may have a potential role in treating depression when used along with other treatments (Taylor, J Psychopharmacol 2004) For example, a daily dose of 500 mcg of folic acid was shown to increase the effectiveness of the SSRI drug fluoxetine (Prozac) in women (but not men), increasing the recovery rate from depression by 25% compared to treatment with Prozac alone (Coppen, J Affect Disord 2000).
People with recurrent aphthous stomatitis (canker sores) may have low dietary intake or deficiency in B-12 and/or folate (Kozlack, J Oral Pathol Med 2010; Preeti, J Oral Maxillofac Pathol 2011). A small study suggested that vitamin B-12 supplementation may help to reduce canker sores even in people who are not deficient in B-12. It found that among 52 adults with recurrent canker sores, most of whom were not deficient in B-12 (≥ 184.5 pmol/L), a sublingual tablet providing 1,000 mcg of vitamin B-12 (Solgar) taken once daily before bedtime for six months decreased the number of canker sores, pain levels, and duration of outbreaks compared to placebo; more than 74% of those who took vitamin B-12 were canker sore-free after six months compared to 32% of those who took a placebo (Volkov, J Am Board Fam Med 2009). Deficiency in thiamin, riboflavin, B6 or folate may also predispose some individuals to recurrent canker sores (Akintoye, Dent Clin North Am 2014).
According to preliminary research, benfotiamine -- a derivative of thiamin (B-1) but not itself considered a B vitamin -- may help alleviate neuropathic pain in people with diabetes when taken at a daily dose of 400 mg (two 50 mg tablets four times daily) (Haupt, Int J Clin Pharmacol Ther 2005).
For more information on uses, doses, safety concerns, and food sources for each of the B vitamins, see the ConsumerTips™ section or use the links below.
Energy Drinks & Shots:
Energy drinks and shot-sized drinks have become hugely popular although, in many cases, they don't deliver much real energy (i.e., calories). What they do deliver is stimulation, due to their significant caffeine content (more on that, later). For example, 5-Hour Energy lists among its ingredients an "energy blend" that includes caffeine. The label notes that the amount of caffeine is comparable to that in a cup of "leading premium coffee." In 2014, ConsumerLab.com reported finding the 1.93 fluid ounce bottle to contain 221.2 mg of caffeine. This is about 23% higher than what you would get from a "short" cup (8 fluid ounces) of a premium coffee such as Starbucks, which Starbucks claims to contain 180 mg of caffeine (Starbucks.com). It is generally advisable not to exceed more than 300 mg of caffeine per day to avoid undesirable side effects, such as jitteriness.
Energy drinks also tend to contain B vitamins -- often much more than you need or want. Why the B vitamins? Probably to play on the fact that B vitamins help convert food to energy. However, since few people are deficient in B vitamins, these added vitamins are likely to provide no benefit and may put you at risk for exceeding Upper Tolerable Intake Levels (ULs) for these vitamins — levels above which there is increasing risk of toxicity. These ULs are based on your total daily intake of each vitamin (including other supplements and fortified foods, like breakfast cereals and energy bars). You can find the ULs for B vitamins in the ConsumerTips section.
So, should you use energy drinks and shots, and are they safe? If you need something to help you stay alert, any product with caffeine may help. In fact, some clinical studies with Red Bull, which has less caffeine than many other "energy" products (80 mg per 8.4 oz can), demonstrated improved alertness during simulated driving experiences (Reyner, Physiol Behav 2002). A study in male and female competitive athletes found that a caffeinated energy drink given one hour before a training session increased self-perceived muscle power during exercise by 13% compared to a placebo drink which contained the same ingredients - including taurine, sodium bicarbonate, L-carnitine and maltodextrin - but no caffeine (Salinero, Br J Nutr 2014). Additionally, the caffeinated energy drink increased the frequency of insomnia (31.2% vs. 10.4%), nervousness (13.2% vs. 0%) and activeness (16.9% vs. 3.9%) compared to placebo. The caffeinated energy drink contained an amount of caffeine based on each athlete's weight (3 mg per kilogram, working out to about 200 mg for a 150 lb athlete). The authors attributed the effects to the presence of caffeine, and not the other ingredients in the drink. An earlier study using the same caffeinated energy drink and non-caffeinated placebo found the caffeinated energy drink significantly improved athletic performance during a simulated rugby match (Del Coso, Appl Physiol Nutr Metab 2013).
Consistent with the findings above, a study of male military personnel found that frequent use (2 times or more per day) of energy drinks, as well as use of larger amounts (24 ounces or more per day), was associated with a doubling or tripling in aggressive behaviors as well as reported mental health problems (including sleep problems, depression, anxiety, post-traumatic stress disorder, and alcohol misuse) as compared to little or no use of energy drinks. Interestingly, energy drink use was also associated with fatigue — likely due to poorer sleep (Toblin, Military Med 2018).
The sugars in Red Bull as well as NOS will also provide some quick energy. It's questionable, though, what all the other ingredients in these products bring to the table (van den Eynde, Tijdschr Psychiatr 2008) and there seems to be no good reason to have to deal with possible skin flush and tingling from all the niacin in just over one bottle of 5-hour Energy or a full bottle of Rockstar -- or potential liver injury from higher intakes. (See the Warning about a case of acute hepatitis associated with excessive niacin intake from energy drinks. Also see the Warning about class action lawsuits against Red Bull for more about energy drinks versus other sources of caffeine).
An online survey of over 2,000 adolescents and young adults (ages 12 to 24) in Canada found that 55.4% of those who had ever consumed an energy drink reported having at least one adverse reaction, and 3.1% had sought or considered seeking medical help for an adverse reaction. The most commonly reported reactions were rapid heartbeat (24.7%), difficulty sleeping (24.1%), headache (18.3%), nausea/vomiting/diarrhea (5.1%) and chest pain (3.6%). Additionally, energy drink consumers were almost three times more likely to report an adverse reaction than coffee consumers (Hammond, CMAJ 2018).
New research has also raised concern over large amounts of L-carnitine in some energy drinks. Carnitine intake may potentially contribute to cardiovascular disease in certain people. People who eat red meat (as opposed to vegetarians and vegans) maintain organisms in their gut which digest carnitine to the compound TMA, which is then converted in the liver to the compound TMAO which appears to advance atherosclerosis (hardening of the arteries) by reducing the normal clearing of cholesterol (Koeth, Nature Medicine 2013). Using a supplement with L-carnitine may potentially foster growth of these organisms, increase levels of TMAO, and have negative long-term cardiovascular effects.
If you do choose to use any of these "energy" products, it seems best to limit your daily intake and not consume any with high amounts of caffeine all at once. If you use these, avoid other caffeinated products or stimulants. Furthermore, as noted in a statement from the American College of Sports Medicine, energy drinks should not be consumed by children or adolescents, pregnant or breastfeeding women, or caffeine naive or sensitive individuals or individuals with cardiovascular conditions, and it should not be used for sports hydration (Higgins, Curr Sports Med Rep 2018).
It is also important not to mix energy drinks with alcohol. The caffeine can mask the depressant effects of alcohol and lead to dangerous situations in which one may feel or act alert but be mentally compromised. The Centers for Disease Control and Prevention notes that drinkers who consume alcohol mixed with energy drinks are more likely to binge drink, be taken advantage of sexually, take advantage of someone else sexually, and ride with a driver under the influence of alcohol (CDC Fact Sheet). In addition, it is important to keep energy drinks away from children, as they are more susceptible to the negative effects of caffeine than adults. In fact, 40% of calls to poison centers from late 2010 to 2013 for "energy drink exposure" involved children under age 6, many of whom were experiencing serious side effects such as abnormal heart rhythm or seizure.
Quality Concerns and What CL Tested For:
Previous reviews by ConsumerLab.com have uncovered problems with the B vitamin content of several supplements. Neither the U.S. government nor any agency is responsible for routinely testing B vitamin products or other dietary supplements for their contents or quality.
ConsumerLab.com, as part of its mission to independently evaluate products that affect health, wellness, and nutrition, purchased dietary supplements sold in the U.S. and Canada claiming to contain single B vitamins or B vitamin complexes. These products were tested to see if they contained their claimed amounts of the eight B vitamins. Quantitative analyses for lead, cadmium and arsenic were done for products containing whole herbs and/or more than 250 mg of minerals per daily dose. Products sold as regular tablets or caplets were also tested for their ability to break apart properly for absorption. In addition, products were evaluated to determine if their suggested daily dose exceeded Tolerable Upper Intake Levels (ULs) for B vitamins as established by the National Academies. See How Products were Evaluated for more details about the testing.
What CL Found:
ConsumerLab.com's testing revealed problems with 5 out of 26 B vitamin supplements selected for review. Twenty-one products passed testing, as did 8 products which passed the same tests through ConsumerLab.com's voluntary Quality Certification Program.
Products which failed testing are designated as "Not Approved" in the results table. The reasons for the failures are described below, and these deficiencies were confirmed in a second independent laboratory. The majority of problems were with B-complexes as opposed to "single" vitamin products.
Eniva B-Complex contained only 53.4% of its listed amount of B-12 (6.4 mcg per tablespoon rather than 12 mcg) and 214% of its listed amount of B-6 (6.4 mg instead of its listed 3 mg). While these amounts are not a health risk (they still provide the daily requirement and don't exceed an upper limit for either vitamin) it suggests poor manufacturing.
Nature Made Super B Energy Complex contained 166.9% of its listed amount of folic acid (1,112.8 mcg DFE instead of its listed 667 mcg DFE).
Organika Vitamin B Complex contained 66.9% of its listed amount of thiamin and 56.4% of its listed amount of pantothenic acid. The actual amounts found are still many times the daily requirements, as this is a "mega" vitamin product.
Sugarbearhair Hair Vitamin contained 160.5% of its listed amount of pantothenic acid and 163% of its listed amount of vitamin B-6. This indicates a high overage of those vitamins but does not pose a health risk. Like other hair and nail formulas, the focus of this product is on its very high dose of biotin (5,000 mcg).
New Chapter Perfect Hair, Skin & Nails contained 223.3% of it listed amount of biotin (670 mcg per capsule instead of the listed 300 mcg). This is not a health risk but suggests poor control over manufacturing.
CL's Top Picks: B-Complexes — As shown in the results table below, these products are very different from one another and which is "best" for you depends on which B vitamins you are seeking, their respective amounts, and the forms of these B vitamins. Be aware that many provide extraordinarily high amounts of B vitamins. To help you appreciate this, we have shown in green the percent of the daily adult requirement (i.e., the Daily Value or DV) of each B vitamin provided by each product.
Do you really need such large amounts of each of these B vitamins? In all likelihood, you probably don't unless you know that you're deficient in them. Fortunately, in most cases the large amounts will not cause you to exceed established Upper Tolerable Intake Levels (ULs), with the exceptions being GNC B-Complex Big 100 (over the UL for niacin and vitamin B-6), Nature Made Super B Energy Complex, (over the UL for folate due to containing much more folic acid than listed) and Organika Vitamin B Complex (over the UL for niacin and folate from folic acid).
If you just want to be sure you're getting the Daily Value of each B vitamin and not exceeding upper limits, your best choice among the products tested in this review is Nutrilite Vitamin B Dual-Action, although it is relatively expensive at 33 cents per daily tablet. It provides 125% to 417% of Daily Values for the range of B vitamins. It is our Top Pick among this group of B-complexes. Unfortunately, our Top Pick from our previous Review (in 2017), Kirkland Signature (Costco) B-Complex, is no longer sold. It provided at least 100% of the DV for each B vitamin without exceeding any UL and a tablet cost only 2 cents. This year we tested Kirkland's higher-dose Super B-Complex, which also costs just 2 cents per tablet and was Approved in testing, but provides very high amounts of B vitamins.
Thiamin (B-1) supplements — Only one product was tested, 21st Century B-1 100 mg, which was Approved. It provides 100 mg of thiamin (8,333% of the Daily Value) per tablet costing 2 cents.
Riboflavin (B-2) supplements — It is very hard, if not impossible, to find a riboflavin-only supplement providing just the daily requirement, which is only 1.3 mg for men and 1.1 mg for women. Most products are very high-dose, and the reason is that studies have shown that high-dose (typically 400 mg daily) riboflavin may reduce the frequency of migraine headaches. For such an application, Bio-Tech B2-400 is CL's Top Pick as it provides 400 mg of riboflavin for 18 cents per capsule, making it a much less expensive source of riboflavin than the other Approved product, Douglas Laboratories Riboflavin, which provides less riboflavin (100 mg) at higher cost (21 cents per capsule).
Niacin (B-3) supplements — Be aware that the recommended doses of all the niacin-only products and some of the B complex products exceeded the established Tolerable Upper Intake Level (UL) for adults for niacin, above which there is increased risk of side effects (skin flushing and tingling) with regular use. The adult UL for niacin is 35 mg per day. Doses much higher than the ULs are used medically to improve cholesterol levels. However, high doses of niacin can cause dangerous liver inflammation. For this reason, regular lab tests and the supervision of a healthcare professional are strongly advised before taking niacin at doses above the ULs.
Also note that the forms of niacin vary in their use and side effects: nicotinic acid in high doses can lower cholesterol levels but can cause flushing of the skin; niacinamide does not cause flushing (and, for this reason, is given a higher UL in Europe of 500 mg to 900 mg) but does not improve cholesterol levels; and inositol hexanicotinate may provide the best of both worlds in that it may reduce cholesterol levels and cause less flushing — it has been used at high doses to prevent attacks of Raynaud's disease. Another form of niacin, nicotinamide riboside (sold as Niagen or Basis) has been promoted for having anti-aging benefits as well as a cholesterol-lowering effect, without causing skin flushing. However, the evidence for these uses appears to be very preliminary. (See the ConsumerTips section on Niacin for more information about forms of niacin.)
The lowest cost per milligram of niacin from an Approved product is NOW Niacinamide (just 5 cents per capsule providing 500 mg of niacin) and it is CL's Top Pick. If you prefer a delayed-release niacin to reduce the risk of flushing, Slo-Niacin provides 500 mg of niacin from nicotinic acid for 10 cents per tablet (note that the dose was recently reduced from 750 mg). If you want an inositol form of niacin, BulkSupplements.com Flush-Free Niacin provides 500 mg of niacin from inositol nicotinate for 9 cents per ¼ teaspoon of powder (and, in 2017 we tested and Approved Member's Mark (Sam's Club) Niacin -- which is still available, providing 400 mg of niacin from inositol hexanicotinate for 5 cents per capsule). By far the most expensive way to get niacin is Elysium Basis, which provides 250 mg of niacin from nicotinamide riboside from a 2-capsule serving costing $2.00. Elysium Basis, which also includes 50 mg of pterostilbene per serving, is promoted to "Support energy, endurance and recovery time by restoring your NAD+ levels." As noted below, a clinical study of this formulation showed it to increase NAD+ levels and slightly lower diastolic blood pressure, but it also slightly increased LDL "bad" cholesterol levels.
Pantothenic acid (B-5) supplements — This is not a popular category, as deficiency is rare. Our Top Pick for pantothenic acid is Jarrow Formulas Pantothenic Acid B5. Each capsule (8 cents) provides a massive dose of 500 mg, which is 10,000% of the daily requirement (5 mg). The other tested product, Nature's Way Pantothenic Acid, provides the same dose but in two capsules and at higher cost (21 cents). There is no established upper limit for pantothenic acid. Both products contain a small amount of calcium due to the chemical form used -- calcium pantothenate. (See ConsumerTips for Pantothenic Acid).
B-6 Supplements — The supplements which were Approved provided 50 mg to 100 mg of B-6, which is far higher than the daily requirement of about 1.3 mg to 1.7 mg. Our Top Pick, PipingRock.com Vitamin B-6 100 mg provided B-6 at the lowest cost and is just 2 cents per capsule. Bluebonnet Vitamin B6 50 mg cost 10 cents per capsule providing half the dose — 50 mg. Be aware that the dose in PipingRock.com is right at the UL for B-6 (100 mg) and far exceeds the European limit of just 25 mg; either product should only be used if you are known to be deficient in B-6.
Biotin (B-7) supplements — Each of the products contains far more than the daily requirement for biotin (30 mcg) but is likely safe, as there is no UL for biotin. The lowest cost for obtaining biotin is from Spring Valley [Walmart] Biotin 10,000 mcg (7 cents for 10,000 mcg from one softgel). It is our Top Pick if you need a very high dose of biotin. Similar to it is Nature's Bounty Biotin 10,000 mcg (9 cents for 10,000 mcg per capsule). If you are deficient in biotin (which is uncommon), these products are good choices.
However, the popular reason for taking a biotin supplement is the belief that it will improve hair and nails. This stems from 1) the fact that a symptom of biotin deficiency is hair loss -- although taking biotin if you are not deficient won't help your hair, and 2) a small study that showed an increase in nail thickness and a reduced tendency for nails to split when taking 2,500 mcg of biotin twice daily (see ConsumerTips for biotin). If you want to take biotin for these reasons, our Top Pick is NutraBlast Hair Skin & Nails, as it provides 2,500 mcg of biotin per gummy (13 cents) — a bit more expensive than the other Approved products, but the right dose. A less expensive option is Nature's Life Biotin 2,500 mcg -- Hair, Skin and Nails Formula, which we tested in 2017; each 10-cent capsule provided 2,500 mcg of biotin. A popular product for hair and nails is Sugarbearhair Hair Vitamins, which provides 2,500 mcg of biotin per gummy, but it failed our testing for other B vitamins (as discussed above) and it costs 50 cents per gummy. [Note: High doses of biotin (5,000 mcg or more per day) may interfere with certain laboratory tests, so be sure to inform your physician before undergoing tests if you take high doses].
Folate (B-9) supplements — While few people in the U.S. need folate supplementation (due to the fortification of grain products), the daily requirement is 400 mcg of dietary folate equivalents (DFEs), as found in our two Top Picks — Finest Nutrition [Walgreens] Folic Acid (just 2 cents per tablet) and, for those who prefer the methylfolate form of folate, Carlson Methyl Folate (12 cents per capsule). (See ConsumerTips for Folate.) As discussed in more detail below, the synthetic form of folate known as methylfolate (or L-5-methyltetrahydrofolate) may offer modest advantages in certain situations over folic acid, the more common synthetic form, as well as over natural folate itself.
Women capable of becoming pregnant are advised to get 600 mcg DFE of folate daily from folic acid or other synthetic form of folate from a supplement.
The way in which folate is labeled on supplements is changing to reflect the fact that synthetic forms of folate, like folic acid and methylfolate, are better absorbed (about 70% better) than folate which occurs naturally in foods. Labels are changing to list amounts in terms of dietary (i.e., natural) folate equivalents or DFEs. With the new labeling, 400 mcg of folic acid will be labeled as 667 DFE. Since the adult daily requirement is 400 mcg of natural folate, or 400 mcg DFE, you really only need 235 mcg of folic acid (or methylfolate) to achieve this. So, keep in mind that labels using the older method of labeling (i.e., without DFEs) may mislead you to consume more folate than you need. Also, be aware that the upper tolerable limit for folate (UL) applies only to folate from supplements and fortified-foods and remains based on the actual microgram amounts of that folate and not their DFEs (Dietary Folate Equivalents). Consequently, a product that contains 800 mcg of folic acid will not exceed the adult UL of 1,000 mcg of folate, even though, nutritionally, it provides about 1,360 mcg DFE.
B-12 supplements — All of these products are designed to provide far more than the daily requirement of B-12 (2.4 mcg) -- in fact, when selecting products to test, we could not find any marketed supplements (other than B-complexes) which provide only the daily requirement for B-12. Most products provide hundreds or, more often, thousands, of micrograms of B-12. Although there is no established upper limit (UL) for B-12, these very high amounts are really only appropriate if you are deficient in B-12 (in which case you'll want at least 500 mcg to 1,000 mcg per day). There is increasing evidence that routine use of high doses of vitamin B-12 carries some risk.
If you are just trying to increase your intake of B-12, our Top Pick is Mason Natural B12 50 mcg which was Approved in our testing and is the lowest-dose B-12 product we could find (50 mcg per tablet -- which is still a high dose relative to the daily requirement, for 15 cents). Another option for getting a smaller (but still more than adequate) daily dose of vitamin B-12 is Pure Encapsulations B12 Liquid, but, instead of taking the suggested serving size of 1 dropper (1 ml; providing 1,000 mcg of B-12), take just one drop. There are about 28 drops per dropper and a single drop provides approximately 36 mcg of B-12 -- still 15 times the daily requirement. This would be an easier way to get a low dose than breaking up one of the pills, and it is easy to add the single drop to a drink -- avoiding having to swallow a pill. In addition, the cost is 2 cents per drop — so you can get a year's worth for just $7. Furthermore, it is sweetened with stevia and glycerin, not sugar alcohols, and the B-12 is in the form of methylcobalamin -- in case you want to avoid cyanocobalamin (some people are concerned about the cyanide component of the cyanocobalamin form of B-12, but there is little scientific rationale for this concern). Although the little bottle is relatively expensive ($17.10), it will last two years at this rate!
B-12 is commonly sold as quick-dissolving tablets, sublingual tablets, and spray but know that B-12 will get absorbed just as well as from a tablet, as shown in a clinical trial (Sharabi, Br J Clin Pharmacol 2003). Be aware that, to taste good, these special formulations often include sugar substitutes (such as mannitol, sorbitol, and/or sucralose -- you can check the ingredients in each product in the last column of the Results table) and, in some people, these can cause gas, bloating, and diarrhea. These side-effects are more likely if taking multiple units. For example, ConsumerLab.com received a report (on 1/19/17) of a consumer experiencing such symptoms the morning after taking two 500 mcg dissolvable tablets of B-12 which listed mannitol as well as sucralose as ingredients.
Benfotiamine supplements — This ingredient is not a vitamin but a derivative of thiamin (B-1) that can increase levels of thiamin in the body (see ConsumerTips, Thiamin). Only one product was tested, Doctor's Best Benfotiamine, which was Approved. It provides 300 mg of benfotiamine per capsule for 38 cents.
Pantethine supplements — This ingredient is not a vitamin. It is chemically related to pantothenic acid (B-5) but has different effects in the body. It may help slightly lower levels of triglycerides and LDL "bad" cholesterol. Only one product was tested, NutriCology Pantethine, which was Approved. It provides 660 mg of pantethine per 2 capsules for 99 cents.
Test Results by Product:
Listed below are the test results for 34 products containing one or more B vitamins or B vitamin derivative. Products are listed alphabetically within their respective category. ConsumerLab.com selected 26 of the products. Eight products (each indicated with CL flask icon) were tested at the request of their manufacturers/distributors through CL's Quality Certification Program and are included for having passed testing.
Shown for each product are the labeled amounts of the various B vitamins per pill. Products that are at or exceed recommendations on tolerable upper levels (ULs) for certain ingredients are indicated with a "UL" symbol. Prices paid for each product and the costs per daily serving are shown in the third to last column. Listed in the second to last column are other notable ingredients and features, and the last column shows a full listing of labeled ingredients.
ConsumerTips™: on Buying and Using:
Be sure that you are getting enough B vitamins to meet basic nutrient requirements and avoid deficiencies. Check the recommended intakes listed below for each. These values, known as Dietary Reference Intakes (DRIs), are established by the National Academies. One type of DRI is a Recommended Dietary Allowance (RDA) -- the average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all healthy individuals in a particular life stage and gender. Another type of DRI is an Adequate Intake (AI), which is similar to an RDA but is more of an approximation used when there is not sufficient information to develop an RDA.
Don't base your requirements on DV values on labels — they may be wrong!: As required by the FDA, dietary supplement labels or packages must show the percent of the Daily Value for certain vitamins and minerals that they contain. However, the DVs, which were set in 1968, were not updated to reflect the latest Recommended Dietary Allowances (RDAs) or Adequate Intakes (AIs) until 2016 and supplement labels do not have to reflect this change until 2020 for large manufacturers and 2021 for smaller manufacturers. The old DVs tend to be higher than the recommended intakes for most B vitamins, as shown in the table below. For a quick reference chart of current RDAs and AIs for B vitamins and other nutrients go to www.ConsumerLab.com/RDAs. That table includes specific values by life stage and gender. You will also find that information in the B-vitamin specific information further below in this report.
As discussed earlier in the What CL Found section, the change that is of most concern relates to folate, as the labels still in use can mislead people into taking far more folate than is recommended - which can put them at risk.
Comparison of Established DV (Daily Value) and DRI (Dietary Reference Intake) Values for B Vitamins
If you are buying B vitamins to treat a specific medical condition, such as treating high cholesterol with niacin or correcting B vitamin deficiency, you will generally need more than the recommended intakes. Look at each vitamin for suggested doses for treating specific conditions.
In either case, be aware that you can get "too much" of some vitamins. A Tolerable Upper Intake Level (UL) is the highest level of daily intake of a nutrient that is likely to pose no risk of adverse health effects for most people. As intakes increase above the UL, the risk of adverse effects may increase. Like the RDAs and AIs, the ULs vary according to age, and gender. Individuals are advised not to regularly exceed the UL, unless medically recommended and supervised. Be aware that products are not required to provide information indicating whether their ingredients may exceed ULs for the individuals for whom they are intended. As discovered by ConsumerLab.com, many do exceed these ULs. Most products list the amount of each ingredient in the Supplement Facts panel on the side label, so check it along with the Suggested Use to determine how much of each ingredient you'll be getting daily. The information provided below can help you determine whether such amounts are appropriate. Keep in mind that 1,000 mcg (micrograms) is the same as 1 mg (milligram), and 1,000 mg equals 1 gram.
MTHFR gene mutation and B vitamin metabolism
MTHFR gene mutation is a genetic change that affects an enzyme involved in breaking down the amino acid homocysteine and converting folate and folic acid into its active form, L-methylfolate. Roughly 33% of Americans carry one copy of a common MTHFR gene mutation (C677T). People who carry two C677T mutations, which is about 11% of Americans, have a 16% higher chance of developing coronary heart disease compared to people without these mutations and have elevated levels of homocysteine in their blood (homocysteinemia) or urine (homocystinuria) (NIH Genetic and Rare Disease Information Center). MTHFR gene mutations are also associated with an increased risk of other conditions, but a cause-and-effect relationship has not been established (Liew, Eur J Med Genet 2015; Gilbody, Am J Epidemiol 2007).
Currently there are no treatments to remove adverse risks associated with MTHFR gene mutations. However, elevated levels of homocysteine can also occur if there is a lack of folate or B vitamins. Homocysteine levels also tend to rise with age, smoking, and use of certain drugs (such as carbamazepine, methotrexate, and phenytoin).
It is important to ensure that people with and without MTHFR gene mutations receive adequate amounts of naturally occurring folate, choline, and B vitamins (B12, B6, and riboflavin) to mitigate nutritional risks. If adequate nutrition cannot be attained through diet alone, supplementation with folate (e.g., L-5-methylfolate or folinic acid) and B vitamins is considered.
People with C677T mutations may be more likely to have a deficiency in vitamin B-12 (Zittan, Am J Physiol Heart Circ Physiol 2007). Taking vitamin B2 (riboflavin) may also be helpful for people with C677T mutation who also have high blood pressure -- and there is a 27-87% increased risk of hypertension associated with the C677T mutation (McNulty, Mol Aspects Med 2017). A 16-week, placebo-controlled study among such people in Ireland showed that taking 10 mg per day of riboflavin lowered elevated daytime systolic blood pressures (125 mmHg and over) by almost 4 mmHg (Hughes, Proc Nutr Soc 2018). However, according to the American College of Medical Genetics and Genomics there is currently "no evidence that specific treatments reduce risks associated with hyperhomocysteinemia or MTHFR genotype status." (Hickey, Genet Med 2013). (See the sections on Folate, Vitamin B-12 and Riboflavin below for more information).
Supplements containing more than one B vitamin are widely sold. However, two common reasons for buying these complexes are not well supported by scientific evidence:
- Reduction of cardiovascular risk -- Some of the interest in B complexes comes from studies showing the combination of B-6, B-12, and folate can reduce elevated levels of homocysteine -- a risk factor for cardiovascular disease. Unfortunately, trials have failed to show that this combination reduces cardiovascular risk itself, leading the American Heart Association to conclude that the available evidence "is inadequate to recommend folate and other B vitamin supplements as a means to reduce cardiovascular disease risk." (AHA Recommendations — Circulation 2006)
- Increased energy -- B vitamins, such B-12 and folate, are involved in the metabolism of food to create energy. However, if you are not deficient in B vitamins and already get an adequate amount of the B vitamins in your diet, supplementing with additional amounts of B vitamins is not known to improve performance (Lukaski, Nutrition 2004). Nevertheless, many supplements such as "shot-sized" drinks remain touted as energy boosters; the real boost would appear to come from the often unspecified amounts of caffeine added to many of these products. (See the Energy Drinks and Shots section for more information)
Be cautious of mega-doses:
Many B vitamins and complexes provide amounts of vitamins that far exceed recommended daily intakes and can cause toxicity (as with niacin, folate and B-6, in particular) or have been associated the occurrence of adverse events. For details, see the "Upper Limit" section for each B vitamin listed below. Sometimes, these effects are compounded when excessive amounts of more than one B vitamin are taken.
An analysis of studies following over 36,000 Swedish men and women for an average of 11 years found that the use of high-dose B vitamin supplements (i.e., providing at least 10 times recommended daily requirements) was associated with increased risk of age-related cataracts. The greatest increase (88%) in risk was among middle-aged (younger than age 60) men and women using B-complexes or single B supplements (such as B-6 or folic acid) estimated to provide an average of 25 times the recommended daily intakes. Smaller increases in risk were found when doses were not quite as high and among older people — possibly because of reduced absorption with increasing age (Selin, Br J Nutr 2017).
Use of vitamin B-6 and B-12 from individual supplements, not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men, but not women, in a large U.S. study. However, this seems to have been driven by male smokers using the highest doses of B-6 (> 20 mg/day) and/or B-12 (> 55 mcg/day), who were nearly 3 to 4 times more likely to develop lung cancer than male smokers who did not use these vitamins (Brasky, J Clin Oncol 2017).
The B Vitamins:
Thiamin hydrochloride (Thiamine) (B-1) assists the nervous system. It is found in large enough amounts in yeast, peas, beans, and grains that if these foods are regularly included in the diet, supplementation is normally not necessary. Thiamin deficiency, however, can occur in people taking strong diuretics (loop diuretics) for congestive heart failure, and this deficiency itself can adversely affect heart function. Thiamin deficiency is also common in people who abuse alcohol. Thiamin is also found in supplements as thiamin mononitrate. A small study found that 6% of people suffering from POTS (postural tachycardia syndrome — associated with headache and dizziness upon standing) were mildly deficient in B-1 and supplementing with 100 mg of B-1 daily appeared to significantly improve all symptoms in one of four such patients within two weeks. This improvement persisted with continued supplementation. (Three of these patients were also deficient in vitamin D.) (Blitshteyn, Neuro Res 2017).
Recommended Intake: The RDA is 0.5 mg for children 1 to 3, 0.6 mg for those 4 to 8, and 0.9 mg for those 9 to 13. For males 14 years and older the RDA is 1.2 mg. For females 14 to 18 the RDA is 1.0 mg, and it increases to 1.1 mg for those 19 and older. However, the RDA for pregnant or lactating women is 1.4 mg. For use to counter the effects of diuretics, a dose of 100 mg twice daily has been used. Upper Limit: No UL has been established for thiamin. This appears to be a non-toxic supplement.
See the Encyclopedia article on Thiamin for more information about clinical use.
Benfotiamine is a derivative of thiamin (B-1) that has been shown to significantly increase blood and tissue levels of thiamin compared to thiamin hydrochloride and thiamin mononitrate (Bitsch, Ann Nutr Metab 1991; Xie, J Clin Pharamacol 2014). It is commonly promoted to prevent or slow the progression of complications due to diabetes, such as diabetic nerve pain and vascular disease, although this is supported mainly by preliminary animal and in-vitro studies and some small studies in people (Pacal, World J Diabetes 2014). One small, randomized, placebo-controlled double-blind clinical study found that a daily dose of 200 mg benfotiamine (two 50 mg tablets four times daily) for 3 weeks significantly improved neuropathy scores and reduced pain in type 1 and type 2 diabetes patients with polyneuropathy (Haupt, Int J Clin Pharmacol Ther 2005). In people with kidney disease associated with type 2 diabetes, taking 900 mg/ day of benfotiamine for 3 months significantly improved thiamin status but did not improve measures of kidney functioning (Alkhalaf, Diabetes Care 2010). There is no recommended intake or UL established for benfotiamine, but oral daily doses used in clinical studies tend to range from 200 — 800 mg. There are no reports of toxicity.
Riboflavin (B-2) maintains vision and skin. Although found in beef (2.9 mg per 3 oz serving), enriched wheat flour (about 0.5 mg per cup), fortified breakfast cereals (0.4 to 2.5 mg per cup), dairy foods (0.4 mg per cup of milk or yogurt) and certain vegetables (see full USDA list), some supplementation may be needed in children and the elderly. Individuals with a certain genetic type (known as MTHFR 677TT, which affects about 10% of people worldwide and a greater percentage in Northern China (20%) and in Mexico (32%), are predisposed to high blood pressure which may be reduced with low-dose riboflavin supplementation (Wilson, Am J Clin Nutr 2012). A small, placebo-controlled study in people with this genetic type showed that 1.6 mg of riboflavin daily for 16 weeks reduced systolic and diastolic blood pressures by approximately 9.2 mm Hg and 6.0 mm Hg, respectively. Interestingly, these individuals were also taking prescription antihypertensive medication but many had not achieved acceptable blood pressure levels until the riboflavin supplement was also taken. Several studies suggest that very high-dose riboflavin may help reduce the frequency of migraine headaches (Thompson, J Clin Pharm Ther 2017). [Note: It is difficult to find a low-dose riboflavin supplement on the market (most provide a high dose of 100 mg) and none are included in this Review. Food sources remain a good option for most people.] Recommended Intake: The RDA is 0.5 mg for children 1 to 3, 0.6 mg for those 4 to 8, and 0.9 mg for those 9 to 13. For males 14 years and older the RDA is 1.3 mg. For females 14 to 18 the RDA is 1.0 mg, and it increases to 1.1 mg for those 19 and older. However, the RDA for pregnant women is 1.4 mg and for lactating women it is 1.6 mg. Much higher amounts (400 mg per day) have been suggested in the prevention of migraines (Schoenen, Cephalalgia 1994). Upper Limit: No UL has been established for riboflavin.
See the Encyclopedia article on Riboflavin for more information about clinical use.
Niacin (Nicotinic Acid) (B-3) helps release energy from carbohydrates, enhance DNA repair, and prevents pellagra — a disease caused by long-term niacin or tryptophan deficiency, characterized by delusions, diarrhea, and scaly skin sores. Niacin deficiency may also cause a loss of taste (Schiffman, Eur J Clin Nutr 2000). Niacin is available in the diet from enriched white flour as well as peanuts, fish and meat.
When taken in very high doses, it can help improve cholesterol levels -- lowering LDL ("bad") cholesterol, raising HDL ("good") cholesterol, and lowering elevated triglycerides. However, studies show that if you already take a statin drug, adding high-dose niacin does not appear to provide additional benefit and may carry serious risks. For example, one study found that adding high dose niacin to statin drug treatment in people with heart and vascular disease did not reduce the risk of cardiovascular events (including heart attacks and stroke) despite improving HDL and triglyceride levels (NIH News, May 26, 2011 and Boden, NEJM 2011). Patients in the study were given 1,500 to 2,000 mg per day of extended-release nicotinic acid as Niaspan, a prescription drug. The study was stopped early when there was no improvement in outcomes after 32 months of treatment and a small increase in ischemic stroke was noted among those taking Niaspan compared to those taking placebo. Similarly, in a 4-year study using 2,000 mg of extended-release niacin given daily along with an anti-flushing drug (laropiprant) to patients already taking statins, the addition of niacin provided no worthwhile benefit and was associated with a significant increase in disturbances in diabetes control (3.7 percentage points higher than in those not receiving niacin) as well as smaller, but significant, increases in infections, new onset diabetes, problems of the gastrointestinal and musculoskeletal systems, bleeding, and skin problems (Landray, NEJM 2014). Based on this evidence, high-dose niacin would also not be recommended for use with red yeast rice, which naturally contains statin compounds. However, for patients who cannot tolerate statin drugs, high dose niacin currently remains a viable stand-alone treatment without increasing the risk of ischemic strokes (Maningat, NEJM 2011) and some physicians believe that niacin in conjunction with statins may be helpful to certain patients -- so consult your physician. Be aware that approximately 0.67% of people treated with very high dose niacin to lower cholesterol develop niacin maculopathy, which impairs vision.
A modified form of niacin called inositol hexanicotinate (or hexaniacinate) is said to cause less flushing than regular niacin. It may also reduce cholesterol levels. It has been studied particularly as a treatment for intermittent claudication (a kind of leg cramping caused by hardening of the arteries), as well as for Raynaud's disease (another condition that involves arterial blood flow.) One small study found a daily dose of 4 grams of inositol hexanicotinate significantly reduced the number of attacks in people with Raynaud's disease compared to placebo (Sunderland, Clin Rheumatol 1988). (Note: A 400 mg dose of inositol hexanicotinate provides 100 mg of inositol — a compound, which may have some benefit in depression but only much higher doses — thousands of milligrams.) Niacinamide (or nicotinamide) is another form of niacin which does not cause flushing; it does not lower cholesterol. High doses of niacinamide were found to protect mice from memory loss associated with Alzheimer's disease. They were fed an amount equivalent in humans to 2 to 3 grams per day (Green, J Neurosci 2008). However, a study among 31 men and women (average age 79) with mild to moderate Alzheimer's disease found that 1,500 mg twice daily of extended release niacinamide (Endurance Products Company) for six months did not improve cognitive function or functioning in tasks of daily living compared to placebo (Phelan, J Geriatr Med Gerontol 2017).
Another form of niacin, nicotinamide riboside (sold as Niagen and Niacel, and also found in Basis from Elysium Health) has also been promoted to not cause flushing (although this may not always be the case, as noted below), and may lower cholesterol levels in the liver, according to laboratory and animal studies (Lee, J Med Food 2015) -- although cholesterol-lowering has not been shown in clinical studies. Studies in mice have shown it to reduce a main component of amyloid plaque associated with Alzheimer's disease and improve cognitive function (Gong, Neurobiol Aging 2013) and to improve stem cell function (Zhang, Science 2016). Researchers theorize this effect in mice may be due to the fact that nicotinamide riboside is a precursor of nicotinamide adenine dinucleotide (also called NADH or NAD+) — a substance which is needed in the production of energy in the mitochondria of cells. A study by the maker of Niagen, ChromaDex, among 11 healthy men and women showed that a one-time dose of Niagen of 100 mg, 300 mg or 1,000 mg (providing about 42 mg, 126 mg, and 420 mg of niacin) increased NAD+ levels without any serious adverse events, although two people reported flushing at the 300 mg dose and two others reported "feeling hot" at the 1,000 mg dose (Trammell, Nat Commun 2016). A study in which the same doses were given daily for 8 weeks to overweight, but otherwise healthy men and women, showed that whole blood NAD+ levels increased by 22%, 51% and 142%, respectively, within two weeks, and these increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the Niagen and placebo-treated groups, and no elevation of low-density lipoprotein cholesterol ("bad cholesterol") which, as noted further below, has been reported with a combination of nicotinamide riboside and pterostilbene (Conze, Sci Rep, 2019).A study among 24 healthy older men and women (ages 55 to 79) found that 500 mg of Niagen taken twice daily for six weeks significantly increased average blood levels of NAD+ by 60% compared to placebo; flushing was reported in one participant when taking Niagen, and in two participants while taking placebo. Nausea, leg cramps and increased bruising were each reported in one participant while taking Niagen (Martens, Nat Commun 2018). (Supplements typically provide about 250 mg nicotinamide riboside per daily dose.) Although animal and laboratory studies have suggested nicotinamide riboside may help to improve blood sugar control (Lee, J Med Food 2015), a study in Denmark among 40 overweight men with insulin resistance (HOMA-IR ≥ 2.5) found that 1,000 mg of nicotinamide riboside (Niagen) taken twice daily for three months did not decrease fasting blood sugar levels or HbA1c (a measure of blood sugar levels over several months), or improve insulin sensitivity compared to placebo. There were no improvements in body composition (body fat, lean mass or total body mass) compared to placebo. Side effects were generally mild but included itching, excessive sweating, bloating and changes in stool (Dollerup, Am J Clin Nutr 2018).
A study of the effects of a combination of nicotinamide riboside and pterostilbene (Basis, Elysium Health) among 120 older people found that those who took one capsule (providing 250 mg of nicotinamide riboside and 50 mg of pterostilbene — the recommended amount on the product label) or two capsules daily with breakfast for two months had average increases in blood levels of NAD+ of 40% and 55%, respectively. There was a slight but significant increase in LDL ("bad") cholesterol with two capsules and among overweight people taking one capsule. There were no significant changes in total cholesterol, triglyceride levels, or blood pressure -- except for a slight but significant decrease in diastolic blood pressure among those who took 2 capsules per day (Dellinger, NPJ Aging Mech Dis 2017). Six of the 80 people taking Basis reported experiencing nausea, mild fatigue, or moderate abdominal discomfort. [Note: The maker of Niagenclaims that the nicotinamide riboside in Basis is not the same as in Niagen, which has been generally recognized as safe]. There are no long-term studies investigating the safety or efficacy of nicotinamide riboside in people.
There is a theoretical concern that compounds like nicotinamide riboside, as well as NADH, that raise NAD+ levels may promote the growth of existing cancers (Poljsak, J Clin Exp Oncol 2016). In fact, one group of researchers suggested that reducing NAD+ levels may be a promising approach to a cancer treatment (Gujar, PNAS 2016; Wash U Sch Med news 2016). Furthermore, one CL member reported (6/17/2019) that "After one year taking Elysium Basis supplements I experienced a sharp rise in PSA levels from 1.8 to 4.9. After stopping these supplements for one month my PSA returned to 1.9." [Increases in PSA may indicate prostate cancer.] He told us he contacted Elysium Health, but was told they have no data "that point to a correlation or interaction between Basis and PSA levels" although they did acknowledge that "a handful of people" have "reached out to us about positive changes to their PSA levels." Although there is no current evidence of nicotinamide riboside causing or fostering cancer, it would seem prudent to avoid this form of niacin if you have been diagnosed with cancer.
High-dose niacin (500 mg from nicotinamide twice daily) for 12 months appeared to reduce the risk of developing non-melanoma skin cancer (i.e., squamous and basal cell cancer) by 23% in older adults who had a history of these lesions in a placebo-controlled study in Australia (Martin, J Clin Oncol 2005 suppl; abstr 9000). Benefits were evident within 3 months, but no continuing benefit was found 6 months after treatment stopped — i.e., it only helped while being taken (Chen, NEJM 2015). The benefit may be due to enhanced DNA repair and reducing the immunosuppressive effect of UV radiation. Be aware, however, that niacin fortification of food is not mandated in Australia, which is also the country with the highest incidence of skin cancer in the world. Consequently, it is difficult to say if the same level of benefit would be expected in countries such as the U.S. and Canada — both of which require food fortification with niacin (although only at amounts needed to meet RDAs).
In the U.S., researchers found that adults with higher intakes of niacin (from foods and/or supplements) were less likely to develop squamous cell cancer than those with lower intakes. The effect, however, was only significant among women: those with average daily intakes of 20.5 mg of niacin or higher were about 20% less likely (after adjusting for other risk factors) to develop squamous cell cancer during a 16-year period than those with lowest intakes, which averaged 15.8 mg -- just above the RDA for women. The beneficial association may not been detected in men because even those grouped as having the lowest daily intakes still consumed far more niacin (20 mg per day on average) than the RDA for men (16 mg). Higher intakes of niacin were marginally associated with an increase in the risk of basal cell cancer and, among men only, the risk of melanoma (Park, Int J Cancer, 2017).
In short, to help prevent skin cancer, it would seem prudent to get at least the RDA for niacin from your diet and/or supplements, but not necessarily much more.
Recommended Intake: The RDA is 6 mg for children 1 to 3, 8 mg for those 4 to 8, and 12 mg for those 9 to 13. For males 14 years and older the RDA is 16 mg. For females 14 and older the RDA is 14 mg. However, the RDA for pregnant women is 18 mg and for lactating women it is 17 mg. Niacin has documented effects for improving cholesterol profile, but only when taken in doses that are far higher than the RDAs and ULs, ranging from 1,000 mg to 4,000 mg (1 to 4 grams) per day. Liver injury is a real possibility when niacin is used in this way. Be aware that the amount of niacin in inositol hexanicotinate is about 85% of the total compound, i.e., if the front of the bottle says 600 mg inositol hexanicotinate, the product should be expected to have about 500 mg of niacin. Upper Limit:Daily doses over 50 mg per day have been associated with flushing of the skin, including reddening, burning, tingling, itching and pain. Starting with a lower dose and then gradually increasing it may reduce this side effect, as may taking the supplement with food. Slow-release niacin and products made from nicotinamide (or niacinamide) and inositol hexanicotinate are also less likely to cause this reaction. However, at doses at or above 1,500 mg (1.5 grams) of niacin per day, or 3,000 mg (3 grams) of nicotinamide per day, liver toxicity can occur and may be more common among people taking slow-release niacin. For example, a 74-year-old woman who had been taking 500 mg of immediate-release nicotinic acid three times daily at home was switched to 500 mg of extended-release nicotinic acid three times daily for four days during a hospital stay. She developed acute liver failure and died five days after her first dose. It was speculated that the woman's type 2 diabetes and use of steroid medication to treat a skin condition made her more susceptible to liver toxicity from the extended-release niacin (Leung, Hepatol Commun 2018).
Very high doses of niacin used to treat high cholesterol have been reported in approximately 0.67% of patients to cause edema (swelling) of the macula of the eye and decreased vision, a condition known as niacin maculopathy. For example, a 61-year-old man in New York developed severe macular edema and blurry vision after taking 3,000 mg to 6,000 mg of niacin daily for several months to treat high cholesterol. One week after stopping supplementation his vision began to improve, and within two months, the edema completely resolved and his vision returned to normal (Lee, J Vitreoretin Dis 2019).
Progressive declines in platelet counts (thrombocytopenia) (as much as 10% to 20%), as well as decreases in red and white blood cell counts, have been reported in individuals taking long-term, high doses of extended-release niacin (an average of 2,250 mg per day for a year or more), which improves four to five months after stopping supplementation (O'Connell, Am J Hematol 2016). Borderline low platelet and white blood cell counts were also reported by a CL member who took 3,000 mg of "regular" niacin daily for about three years, which returned to normal ranges several weeks after discontinuing the supplement. Due to the risk of thrombocytopenia, high dose and/or extended-release niacin should be used with caution by people who take anticoagulants (Niaspan Prescribing Information).
Elevated liver enzymes may occur without symptoms in up to 20% of people when taking a daily dose of niacin above 500 mg, and two cases of acute hepatitis have been reported in otherwise healthy adults who consumed between 160 mg and 300 mg of niacin daily from energy drinks (Harb, BMJ Case Rep 2016). The UL for niacin applies only to that consumed from supplements and fortified foods (other naturally occurring food sources are not included) and is 10 mg for children 1 to 3, 15 mg for those 4 to 8, 20 mg for those 9 to 13, 30 mg for those 14 to 18, and 35 mg for individuals 19 years and older. Cautions: High-dose niacin may impair glucose control, elevating blood glucose levels; Niacinamide may increase blood levels of anticonvulsant drugs. As niacinamide does not cause skin flushing but may still cause toxicity at very high doses, government agencies in Europe have set higher ULs for niacinamide than established in the U.S. -- 500 mg in the UK and 900 mg in the European Union for adults.
See the Encyclopedia article on Niacin for more information about clinical use.
B-5 (Pantothenic Acid) is involved in the production of energy as well as the synthesis of hormones and neurotransmitters. Deficiency is rare (although seen in alcoholics) and it is found in many foods, with particularly high levels in liver, yeast, and salmon. Recommended Intake: The AI is 2 mg for children 1 to 3, 3 mg for children 4 to 8, and 4 mg for children 9 to 13. For individuals 14 years and older the AI is 5 mg. However, the AI for pregnant women is 6 mg, and for women who breastfeed it is 7 mg. Much higher doses (900 mg per day) of the related substance pantothenate have been used in improving cholesterol profile (especially reducing triglyceride levels) Upper Limit: No UL has been established for pantothenic acid.
See the Encyclopedia article on Pantothenic Acid for more information about clinical use.
B-6 (Pyridoxine hydrochloride, Pyridoxal-5-phosphate, P-5-P) is important in many aspects of metabolism and in maintaining the immune and nervous systems. Symptoms of pyridoxine deficiency may not manifest in people with borderline or mild deficiency, but in more severe deficiency can include seborrheic dermatitis (scaling red patches on the skin), cracks at the corners of the mouth, swollen tongue, loss of taste, microcytic anemia (often diagnosed by low mean corpuscular volume (MCV) in a blood test) weakened immune function, depression, confusion, EEG abnormalities, and seizures (Institute of Medicine (U.S.) 1998; Bromley, Am Fam Physician 2000). Deficiency can also cause nerve damage (as can excessive pyridoxine — see Upper Limit) which begins as numbness, tingling or burning pain in the feet which can progress to the legs and hands, and lead to reduced reflexes, weakness and decreased control of movement (Hammond, Neuro Clin 2013). People with alcohol dependence, impaired kidney function or conditions which cause malabsorption (i.e., celiac disease, Crohn's disease, and ulcerative colitis) are at greater risk of deficiency, and in people with irritable bowel syndrome (IBS) low intake has been associated with more severe IBS symptoms (Ligaarden, Nutr Res 2011). Use of certain medications, including antibiotics cycloserine (Seromycin) and isoniazid (Laniazid), penicillamine (Cuprimine) and antiepileptic drugs, especially enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin or carbamazepine, can cause B-6 deficiency (Merck Manual 2018; Mintzer, Epilepsy Behav 2012).
Pyridoxine hydrochloride is converted in the body to pyridoxal-5-phosphate, the active form of B-6. Most supplements in the U.S. contain the pyridoxine hydrochloride form, although some contain pyridoxal-5-phosphate, or a combination of both forms. Although supplements providing pyridoxal-5-phosphate (also called P-5-P or PLP) provide the "active form" of vitamin B6, this form must still undergo conversion in the intestine in order to be absorbed, so bioavailability may be no better than that of pyridoxine for most people (European Food Safety Authority 2008). People with certain conditions that prevent the body from converting pyridoxine into pyridoxal-5-phosphate (such as pyridoxal 5'-phosphate-dependent epilepsy), however, may be prescribed the pyridoxal-5-phosphate form of B-6. Very preliminary research has found pyridoxal-5-phosphate may be more effective than other forms of vitamin B-6 in slowing kidney damage, neuropathy, and lipid oxidation in animal models of diabetes, however there do not appear to be any studies of these uses in people (Nakamura, J Am Soc Nephrol 2005; Higuchi, J Lipid Res 2006). Pyridoxine in amounts that meet the RDAs is easily available from the diet (e.g., from fortified cereals, meats, starchy vegetables, chickpeas, and non-citrus fruits like bananas -- see NIH Fact Sheet), however mild deficiency is common (10.5% of the U.S. population is deficient according to the CDC), particularly in the elderly and children. A recent study found that people with higher blood levels of vitamin B-6 and methionine (an amino acid) were 50% less likely to develop lung cancer than people with low blood levels of these two nutrients. However, no association was found with the intake of vitamin B-6 -- that is, taking more B-6 was not shown to reduce the risk of lung cancer (Johansson, JAMA 2010).
Recommended Intake: The RDA is 0.5 mg for children 1 to 3, 0.6 mg for those 4 to 8, and 1.0 mg for those 9 to 13. For males 14 to 50 the RDA is 1.3 mg, and for those 51 and older it is 1.7 mg. For females 14 to 18 it is 1.2 mg, for those 19 to 50 it is 1.3 mg, and for those 51 and older it is 1.5 mg. However, the RDA for pregnant women is 1.9 mg and for lactating women it is 2.0 mg. Amounts higher than the RDA but lower than the ULs have been recommended to help reduce the risk of heart disease (5 - 30 mg/day) and reduce the nausea of morning sickness (30 mg/day); some evidence supports these uses. Other proposed uses of pyridoxine such as treating asthma, autism, carpal tunnel syndrome, diabetic neuropathy, tardive dyskinesia and PMS may involve doses higher than the ULs; however, none of these uses has good scientific support.
Upper Limit: The UL for pyridoxine is 30 mg for children 1 to 3, 40 mg for those 4 to 8, 60 mg for those 9 to 13, 80 mg for those 14 to 18, and 100 mg for individuals 19 years and older. All sources of B-6 count toward these upper limits, including that from food sources and multivitamins. The European Food Safety Authority suggests an even lower UL for all forms of vitamin B-6 of 25 mg per day for adults and 5 to 20 mg per day for children depending on their body weight (European Food Safety Authority 2008).
Too much pyridoxine can cause nerve damage and skin lesions. These severe effects are generally seen at doses over 1,000 mg per day, though rare cases have been seen at 200 mg daily and even at doses of 50 mg or less. Symptoms of pyridoxine toxicity (including numbness, tingling and weakness in the arms and legs, and trouble with balance) were reported in a woman consuming large amounts of an energy drink containing 2,000% of the RDA for B-6 (equaling 40 mg) per serving and a B complex supplement. There was no improvement in her symptoms one year after she stopped consuming both products, and it is currently not known whether nerve damage caused by excessive pyridoxine can be reversed (Bacharach, J Clin Neuromuscul Dis 2017). Similarly, a 54-year-old man experienced progressive numbness, nerve damage, and imbalance over several years of taking up to 30 mg per day of supplemental vitamin B-6 and heavy consumption of energy drinks containing high amounts of B-6 (Malek, Acta Neurol Belg 2018).
Some cases of gastrointestinal disturbances such as heartburn, nausea and indigestion, and photosensitivity have been reported at doses between 100 and 200 mg per day (Bendich, Ann N Y Acad Sci 1990).
Some evidence suggests pyridoxal-5-phosphate may not cause the nerve damage or skin lesions associated with excessive doses of pyridoxine, although high doses of pyridoxal-5-phosphate have been reported to cause an increase in seizure frequency and liver damage in infants (Clayton, J Inherit Metab Dis 2006). A study of the effects of different forms of vitamin B-6 on human nerve cells showed the highest toxicity with pyridoxine, the form most commonly in supplements and foods but which is inactive until converted in the body to an active form. The research indicated that pyridoxine inhibits the active form, P-5-P, possibly explaining why high-dose vitamin B-6 supplementation with pyridoxine has sometimes caused the same neurological symptoms seen in B-6 deficiency. The researchers suggested that P-5-P or pyridoxal (an intermediate form also present in foods) may be safer to take than pyridoxine (Vrolijk, Tox in Vitro 2017).
One clinical study found that a daily dose of 25 mg B-6 taken as part of a B-vitamin complex doubled the risk of heart attack, stroke and death in diabetes patients with advanced kidney disease (See Cautions and Concerns section below.)
An analysis of two clinical studies among a total of 6,839 older men and women (average age 62) with cardiovascular disease or history of heart attack found that those who were given 40 mg of vitamin B-6 (as pyridoxine hydrochloride) daily for 1 to 3 years had a 42% increased risk of hip fracture during an 11 year follow-up period compared to those who were given a placebo or other combinations of B vitamins which did not include B-6 (Lopez, J Bone Miner Res 2017). However, as the original studies were not primarily designed to study hip fracture risk, i.e., baseline bone mineral densities were not measured, it is not possible to interpret these results as a cause-and-effect relationship. Although no serious adverse events were reported during the treatment period, the researchers noted that higher daily doses of B-6 have been reported to cause nerve damage, loss of coordination and muscle weakness, which could contribute to the risk of falling. A separate large, long-term study of postmenopausal female nurses in the U.S. also found high daily intakes (from supplements) of B-6 (over 35 mg versus less than 2 mg) or B-12 (30 mcg or more versus less than 5 mcg) to be associated with increases of 29% and 25% in the risk of hip fracture, with a 47% increase with high intakes of both (although there was no increased risk with high B-12 when B-6 intake was low). These intakes are far higher than the recommended dietary allowances but are common in B-6 supplements and some B-complexes (general multivitamins tend to contain less) (Meyer, JAMA Net Open, 2019).
Also be aware that preliminary evidence suggests B-6 could potentially increase the effects of antihypertensive drugs such as diltiazem (Cardizem), amlodipine (Norvasc), and may interfere with some drugs for Parkinson disease. A dose of 200 mg daily B-6 may reduce the effectiveness of the anti-seizure drug phenytoin (Dilantin) (Hansson, Lancet 1976).
See the Encyclopedia article on Vitamin B-6 for more information about clinical use.
Biotin (B-7) is needed for the metabolism of nutrients. Symptoms of deficiency include thinning or loss of hair, loss of hair color, red rash around the eyes, nose, and mouth, depression, listlessness, hallucinations, and tingling in the arms and legs (NIH 2015). However, deficiency is rare under normal circumstances, because biotin can be produced in the gut by bacteria and is also found in organ meats, oatmeal, egg yolk, mushrooms, bananas, peanuts and brewer's yeast. Deficiency might occur with long-term use of antibiotics or anti-seizure medications and, conversely, use of biotin might impair absorption of some anti-seizure medications — so people taking such medications should only use biotin supplements under the supervision of a healthcare professional. A small, but controlled, study among women with brittle nails found that a daily dose of 2,500 mcg of biotin for 6 to 9 months increased nail thickness by 25% and reduced their tendency to split (Columbo, J Am Acad Dermatol 1990). Biotin does not, however, further strengthen healthy nails. A study in Switzerland suggested that biotin deficiency may be common in women complaining of hair loss (Trueb, Int J Trichology 2016); however there are no studies to suggest biotin supplementation improves hair growth or texture in people who are not deficient.
High doses of biotin (e.g. 10 mg or 10,000 mcg or more) which are common in supplements, can cause misleading laboratory results in tests that utilize biotin-based technology to bind to proteins of interest. The FDA has seen an increase in the number of reported adverse events related to biotin interference with lab tests. Unfortunately, there is typically no mention of this potential interference in laboratory reports. Tests for markers of cardiac health, such as troponin can be affected by biotin, and the FDA received a report that a patient taking high levels of biotin died following falsely low troponin test results (FDA 2017). (Although some lab test developers have taken steps to mitigate biotin interference with their tests, others have not. In 2019, the FDA published a list of FDA listed troponin In Vitro Diagnostic Devices that are subject to biotin interference but have not addressed this risk). Biotin supplementation can fully mimic the typical laboratory pattern of Graves' disease (a form of hyperthyroidism) and this can persist for several days after biotin application. This may lead to unnecessary antithyroid treatment and thereby cause unrecognized hypothyroidism that might be deleterious, especially in young children. In addition, biotin treatment can potentially interfere with other streptavidin—biotin immunoassays (Kummer, N Engl J Med 2106). A study in healthy adults without thyroid disease found that a single, 10 mg (10,000 mcg) dose of biotin (which is many times more than the daily requirement of 0.03 mg or 30 mcg, but is found in many B vitamin supplements) decreased levels of TSH (thyroid-stimulating hormone) and altered levels of other thyroid hormones three hours after ingestion. Although TSH levels remained within the normal range and all thyroid hormone levels returned to their pre-supplementation levels after 24 hours, the researchers recommended that in people with laboratory findings indicating hyperthyroidism but without clinical symptoms, possible interference from biotin supplementation should be considered (Biscolla, Thyroid 2017). Even regular daily consumption of 5,000 mcg of biotin (commonly in hair and nail supplements) was reported to cause a 48-year-old woman to undergo extensive and unnecessary diagnostic testing after biotin-based lab assays indicated she had a TSH level on the low end of normal (suggesting subclinical hyperthyroidism) as well as low blood levels of pituitary hormones and elevated blood levels of cortisol and testosterone. Non-biotin based laboratory tests revealed her hormone levels were within normal ranges (Stieglitz, J Endocr Soc 2018).
Additionally, a small study found that 10 mg of biotin taken daily for seven days falsely increased the results of a biotin-based vitamin D blood test (using the Roche Cobas system) by an average of 9.25 ng/mL (Li, JAMA 2017). Roche states there is no risk of interference when less than 60 mcg of biotin is taken daily but advises waiting eight hours if taking a dose of 5 mg to 10 mg and that physicians should consult with the lab if a dose of more than 10 mg of biotin is being taken (Roche Biotin Facts 2017; Roche, Fact Sheet for Physicians 2017).
Recommended Intake: The AI for biotin is 8 mcg for children 1 to 3, 12 mcg for those 4 to 8, and 20 mcg for those 9 to 13. For individuals 14 years to 18, the AI is 25 mcg and for those 19 and older it is 30 mcg. However, the AI increases to 35 mcg for women who are breast-feeding. Upper Limit: No UL has been established for biotin.
See the Encyclopedia article on Biotin for more information about clinical use.
Folate (Folic Acid, Folacin, Metafolin, Quatrefolic, or B-9) plays an important role in cell division and adequate intake can reduce the risk of heart disease and lessen the risk of developing certain cancers. It also reduces the risk of spina bifida in offspring (a leading cause of childhood paralysis) when consumed by pregnant women. Folate may also reduce the chance of childhood leukemia and other birth defects in offspring. For example, the risks of having a child with autism spectrum disorder (ASD) or severe language delay were, respectively, 39% and 45% lower among mothers in Norway using folic acid supplements (400 mcg/day) around the time of conception (4 weeks before to 8 weeks after the start of pregnancy) than among mothers who did not take a folic acid supplement (Suren, JAMA 2013; Roth JAMA 2011).
Similarly, a study in Israel found that use of a folic acid and/or multivitamin supplement, as compared to non-use, was associated with 61% lower risk of ASD in offspring when taken before pregnancy and a 73% lower risk when taken during pregnancy. The study noted that food in Israel is not fortified with folic acid (it is in the U.S.) (Levine, JAMA Psy 2018). Note: High-dose folic acid during pregnancy is not advisable (see below).
Good sources of folate include dark green leafy vegetables and oranges (see the USDA's list of folate content of various foods). Folic acid, a synthetic folate, is more stable and absorbed about 1.7 times as well as natural folate (and twice as well if taken on an empty stomach). Folate deficiency has decreased since mandatory folic acid fortification of enriched cereal grain products began in 1998. Less than 1% of Americans are now deficient in folate, according the CDC. Sharing folic acid's advantages are two other synthetic compounds, folinic acid and L-5-methyltetrahydrofolate (also referred to as simply "methylfolate"). To be active, the body must first convert folic acid to a reduced form, which is folinic acid, and then add a methyl group, to form methylfolate. Methylfolate is sold either as Metafolin and Quatrefolic, which were accepted as sources of folate by the FDA in 2001 and 2010, respectively. Metafolin and Quatrefolic both contain methylfolate but which is chemically stabilized with calcium (in Metafolin) or glucosamine (in Quatrefolic). They are somewhat more bioavailable than folic acid in short-term use. These forms have been promoted for use by people with common genetic mutations affecting the MTHFR enzyme, however, even people with these mutations appear able to use folic acid, although perhaps with less efficiency (Prinz-Langenohl, BJP 2008). Interestingly, and surprisingly, a 4-week study among 30 adults in Australia, 87% of whom had one or more MTHFR mutations, found that folinic acid was even more effective than an equal amount of methylfolate in raising blood (serum) folate levels: folinic acid increased levels 45% compared to 27% for methylfolate, and these increases were irrespective of MTHFR status. Also surprising was that an equal amount of folic acid raised levels more than the other two during the first half of the study, but, by 4 weeks, levels dropped to slightly below starting levels. Shortcomings in the study, as noted by the authors, are that it did not measure levels of folate actually in cells (such as red blood cells) nor effects on homocysteine levels (Bayes, Adv Integ Med 2019).In a study among 75 women of childbearing age in Malaysia (about 25% of whom had a common MTHFR mutation) with low blood levels of folate (averaging 5.3 ng/mL) who took folate-equivalent doses of either folic acid (1 mg) or Metafolin (1.13 mg — the higher weight is due to calcium in the compound) or placebo daily for three months found that those who took Metafolin had moderately higher average blood (serum) folate levels (23 ng/mL) at the end of the study than those who took folic acid (17.7 ng/mL), although they were equally effective in reducing homocysteine levels (Henderson, J Nutr 2018). Metafolin and Quatrefolic contain a very small amount of D-5-methylfolate, which is not a natural compound and may, hypothetically, reduce the bioavailability of L-5-methylfolate (Willems, Br J Pharmacol 2004).
Recommended Intake: The RDAs for folate are based on intake from regular food sources. If you are relying on supplements or fortified foods (with folic acid or forms of L-5-methylfolate) to reach the RDA, you need only about 60% of the amount listed in the following RDAs: 150 mcg DFE for children 1 to 3, 200 mcg DFE for children 4 to 8, and 300 mcg DFE for children 9 to 13. For individuals 14 years and older the RDA is 400 mcg DFE. However, the RDA for pregnant women is 600 mcg DFE, and for lactating women it is 500 mcg DFE. In view of its importance to developing fetuses during the first few weeks after conception, it is recommended that all women capable of becoming pregnant consume 600 mcg DFE from about 400 mcg of folic acid from supplements or fortified foods in addition to intake of folate from a varied diet. This may be particularly important for women on antiepileptic drugs: Such women are more likely to have children showing autistic traits, but this risk is lower if they are taking folic acid around the time of conception (Bjork, JAMA Neuro 2017). To treat folate deficiency, 250 - 1000 mcg per day is used, although higher amounts (1 to 5 mg) may be appropriate in cases of severe deficiency. A large study in adults being treated for high-blood pressure in China found that adding 800 mcg of folic acid to their anti-hypertensive medication regimen significantly reduced the risk of stroke. Over 4.5 years, 2.7% of those who received folic acid experienced a stroke compared to 3.4% of those who didn't receive folic acid (Huo, JAMA 2015). It should be noted that the study population began the study relatively low in folate (blood levels averaging 8.1 ng/mL) and the observed benefit may only occur among people with low folate levels. In fact, among participants who started the study with the lowest levels of folate (averaging just 5.6 ng/mL) and didn't receive folic acid, 4.6% experienced strokes. Unlike in the U.S., where folic acid is added to grain products (and adult folate levels average 10 to 12 ng/mL), folic acid is not added to grain products in China. Similarly, a study among adults in China with low blood levels of folate (about 5.5 ng/mL) and mild to moderate Alzheimer's disease found that those who took 1,250 mcg of folic acid in addition to their standard medication (donepezil [Aricept]) daily for six months had less inflammation and maintained slightly better cognitive function over the course of the study compared to those who only took the medication (Chen, Mediators Inflamm 2016). Those who took folic acid developed average blood folate levels similar to that U.S. adults (10 to 12 ng/mL, as noted above), so it is not certain that similar supplementation would be beneficial to people with blood folate levels which are already adequate.
Although several small studies suggested that supplementation with a combination folic acid and zinc (both important for sperm production) could improve sperm count and/or quality in men who were not deficient in these nutrients (Wong, Fertil Steril 2002; Azizollahi, J Assist Reprod Genet 2013), a large study in the U.S. found that high dose folic acid (5 mg) and zinc (30 mg elemental zinc) taken daily for six months did not improve sperm count or quality, or increase the rate of live births among men seeking fertility treatment (Schisterman, JAMA 2019). Upper Limit: Prolonged intake of excessive folic acid can cause kidney damage and can complicate the diagnosis of vitamin B-12 deficiency because folic acid supplementation can mask a symptom of vitamin B-12 deficiency known as macrocytosis (which affects red blood cells and is seen in blood tests). A potential benefit of L-5-methylfolate forms over folic acid is that they may not mask vitamin B-12 deficiency. A high folate level in the blood combined with low B-12 has been also associated higher risk of cognitive impairment in older individuals; although, when B-12 levels are normal, high folate levels may be protective against cognitive impairment (Morris, Am J Clin Nutr 2007).Even when B-12 levels are normal, high intake of folate dramatically increases the risk of peripheral neuropathy (often causing reduced sensation in the feet) in elderly people who have a common genetic variant. People with this variant (a change in the TCN2 gene), which is found in about one-quarter of older Americans, are no more likely than others to experience this problem if their daily folate intake is below 800 mcg, but when above 800 mcg (typically due to multivitamin use), the odds of peripheral neuropathy are seven-fold higher compared to those without the variant (Sawaengsri, Am J Clin Nutr 2016).
The UL for folate applies only to that consumed from synthetic forms in supplements and fortified foods and is 300 mcg for children 1 to 3, 400 mcg for those 4 to 8, 600 mcg for those 9 to 13, and 800 mcg for those 14 to 18. For individuals 19 years and older the UL is 1,000 mcg.
While dietary folate may reduce the risk of cancers, most notably colorectal cancer, there is growing concern that too much folic acid from supplementation (including fortified foods) may promote cancer in individuals with pre-cancerous or cancerous tumors (Mason, Nutr Rev 2009). Analysis of results from a large cancer prevention study in the U.S. found a 19% reduction in the risk of colon cancer in people with the highest total folate intake (i.e., combined intake of natural folate and folic acid) compared to those with the lowest intake (Stevens, Gastroenterlolgy 2011). However, folic acid at 1,000 mcg per day (which is equivalent to about 1,700 mcg of folate, so above the UL) from a supplement was associated with a more than doubling of the risk of prostate cancer, although folate from dietary sources (i.e., food) was not found to increase the risk (Figueiredo, J Natl Cancer Inst 2009). A follow-up analysis from this study found that, after discontinuing the folic acid, there was no longer an increased risk of prostate cancer, but among, people with a history of colorectal adenomas (generally benign tumors that have the potential to become cancerous) daily supplementation with 1,000 mcg of folic acid for more than three years seemed to increase the risk of additional precancerous growths (sessile serrated adenomas/polyps) (Passarelli, Am J Clin Nutr 2019). A study in Chile, for example, showed an increase in colorectal cancer after that country began to fortify wheat flour with folic acid and a similar association has been noted in other countries (Hirsch, Eur J Gastroenterol Hepatol 2009).
Although multivitamin supplementation (3 to 5 times a week) in pregnant women is associated with a reduced risk of autism spectrum disorder in children, excessively high blood levels of folate (>59 nmol/L) in pregnant women is associated with an approximate twofold increased risk of ASD according to one observational study (Raghavan, International Meeting for Autism Research 2016). The study also found that for pregnant women who had excessive blood levels of both folate and vitamin B-12, the risk was 17.6 times greater. A study in Spain found that children of mothers who had taken 1,000 mcg or more of folic acid per day during the periconception period of pregnancy (from 3 months before conception to the third month of pregnancy) had lower levels of cognitive development (including verbal memory) when tested at 4 to 5 years of age than children of mothers who had taken lower amounts (400 mcg to 999 mcg). The authors cautioned against use of this high amount of folic acid during pregnancy. Intake of less than 400 mcg of folic acid was also associated with lower scores, while higher intakes of naturally occurring folate from foods was associated higher scores (Valera-Gran, Am J Clin Nutr 2017).
A study in Canada (which, like the U.S., requires folic acid fortification of certain grain-based products -- adding about 100 mcg of folic acid to the average adult daily diet) found that 10-18% of supplement users exceeded the UL for folate and 20-52% had elevated folate levels in their blood cells. The report stressed the need for people to be aware of the potential risks of folate overconsumption. Excluding supplements, average dietary folate intake was about 450 mcg, which meets the adult requirement of 400 mcg, although it was noted that about 40% of women over 70 years obtained less than the requirement -- averaging about 350 mcg (Mudryj, Br J Nutr 2016). Keep in mind that synthetic forms of folate, such as folic acid in supplements and fortified foods, provide about 170% as much absorbable folate as folate naturally found in foods, e.g., if you are short 100 mcg of folate in your diet, you can satisfy that with just 60 mcg of folic acid from a supplement. Unfortunately, most supplement labels don't make this clear and willnot be required to do so until 2021. If a label says "Folic Acid 400 mcg, 100% DV" it actually provides the equivalent of about 667 mcg of natural folate and about 170% of the current DV.
See the Encyclopedia article on Folate for more information about clinical use.
Cobalamin (B-12) helps make the genetic material in all cells. Deficiency can cause anemia, irreversible nerve damage, and low sperm count. Symptoms can include loss of taste, fatigue, depression, tingling in the arms and legs, weakness, loss of balance or trouble walking, which could potentially lead to falls (Bromley, Am Fam Physician 2000; Briani, Nutrients 2013; Jansen Ned Tijdschr Geneeskd 2013). A rare case of excessive daytime sleepiness (persistent sleepiness during the day even after adequate or prolonged sleep) associated with B12 deficiency was reported in a 71-year-old man. His sleepiness was completely resolved after six months of supplementation with B12 (2,000 mcg daily), which increased his blood levels of B12 from less than 60 pg/mL to 1,810 pg/mL (Khawaja, J Clin Sleep Med 2019). Occasionally, B12 deficiency can cause hyperpigmentation (darkening) of the skin, as in the case of a 59 year-old man with B12 deficiency likely due to gastritis and resulting in megaloblastic anemia, weakness, and darkened skin on the face, chest, knuckles and around the armpit; these changes resolved after treatment with cobalamin (Garcia-Villa, Rev Clin Esp 2017). Other symptoms can include vitiligo, inflammation in the corners of the mouth, and hair changes (Kannan, Can Fam Phys 2008). B12 deficiency can also cause a low white blood cell count and increase the risk of infection, as occurred in a 19-year-old man in India on a vegetarian diet, who experienced fatigue, shortness of breath, muscle pain, low-grade fever, and a yeast infection of the throat. His symptoms resolved after treatment with anti-fungal medication and B-12 injections (Bhattacharjee, Adv J Emerg Med 2019). Although uncommon, hypotension (low blood pressure) has also been reported due to B12 deficiency, as occurred in a previously healthy 27-year old man from Nepal who was a strict vegetarian. He also developed tingling in his and feet, pallor, pancytopenia (low red and white blood cell counts), severe megaloblastic anemia, and fever, all of which resolved, along with his hypotension, within two weeks of receiving B12 (1,000 mcg daily as cyanocobalamin) initially by intramuscular injection and then from tablets (Yousaf, BMJ Case Rep 2019).B12 deficiency has been misdiagnosed as conditions such progressive multiple sclerosis (Feldman, BMJ Case Rep 2019) and progressive dementia (Silva, BMJ Case Rep 2019) which have been reversed once treated with B12.
Deficiency is defined as blood levels below 200 pg/mL, although older adults may have symptoms at blood levels of 200 — 500 pg/mL (NIH 2014). Higher levels of B-12 intake and in the blood have also been associated with minimizing cognitive decline in older individuals. Vitamin B-12 is found in abundant quantity in meats and is also plentiful in poultry and fish. For vegetarians, fortified cereals, milk and yogurt may provide sufficient B-12. However, unless fortified, plant-based foods are not good sources of B-12. A healthful diet should meet the vitamin B-12 RDAs, but supplementation is often needed for strict vegetarians, alcohol and drug abusers, people recovering from surgery or burns, or those with bowel or pancreatic cancer. According to the CDC, 2% of Americans are deficient in B-12, including 4% of older adults. Deficiency may also occur in people with low stomach acidity, such as older individuals or those taking medications that reduce stomach acid, because stomach acid is necessary to allow absorption of vitamin B-12 from foods. In fact, a large study in adults found that the chance of being B-12 deficient was 65% higher among people taking a proton-pump inhibitor (e.g. Prevacid, Prilosec) and 25% higher among those taking a H2-blocker (e.g., Pepcid, Zantac) than among people not taking these drugs. Furthermore, the risk of B-12 deficiency was 95% higher among people averaging more than 1.5 of these pills daily compared to those averaging less than 0.75 pill. The association was particularly strong among younger adults (under 30), who are otherwise less likely to be deficient in B-12 (Lam, JAMA 2013). Long-term use (several years or more) of the anti-diabetes drug metformin (Glucophage, Glumetza, Riomet) is also associated with an increased risk of B12 deficiency, which may occur in an estimated 30% of individuals who take this drug (Bell, South Med J 2010). It is thought to interfere with B12-intrinsic factor absorption in the lower small intestine (Aroda, J Clin Endocrinol Metab 2016).
The purified vitamin B-12 found in supplements does not require stomach acid for absorption. Consequently, it is advisable for people over 50 years of age as well as those taking acid-blocking medications to meet their RDA by consuming foods fortified with purified vitamin B-12 or by taking a dietary supplement.
The most common form of B-12 in supplements is cyanocobalamin. Although this form includes a cyanide molecule, it is very safe -- even at a very high dose (5,000 mcg), it would provide about a thousand times less cyanide than is toxic, and the cyanide is excreted in the urine (an exception: the ability to excrete cyanide in the urine can be compromised in people with kidney failure and therefore cyanocobalamin is not advisable in such individuals) (Spence Clin Chem Lab Med 2013). B-12 is also available in supplements as methylcobalamin and hydroxocobalamin (also called hydroxycobalamin). A small study found that cyanocobalamin resulted in a more than twofold increase in B12 levels in comparison with hydroxocobalamin in people with low or normal blood levels of vitamin B12 (Greibe, Eur J Nutr 2017), although for people with very rare genetic defects in cobalamin metabolism (typically diagnosed in the first year of life), the hydroxocobalamin form may be better utilized (Obeid, Mol Nutr Food Res 2015). There is no clinical evidence indicating differences in the absorption, bioavailability, or clinical efficacy of cyanocobalamin and methylcobalamin, although cyanocobalamin may be preferable as it is more stable and less expensive (Obeid, Mol Nutr Food Res 2015). Some websites claim methylcobalamin to be superior because it is the "active" form of B-12 (the form utilized in the body). However, it's important to note that all forms are converted into the common intermediate cobalamin which, in turn, transfers into the active forms of B-12 used by the body (methylcobalamin and adenosylcobalamin).
Recommended Intake: The RDA is 0.9 mcg for children 1 to 3, 1.2 mcg for those 4 to 8, and 1.8 mcg for those 9 to 13. For individuals 14 years and older the RDA is 2.4 mcg. However, the RDA for pregnant women is 2.6 mcg and for lactating women it is 2.8 mcg. A dose of 500 mcg given either sublingually or orally has been shown to be equally effective in correcting early B-12 deficiency (suggesting that sublingual B-12 is actually being absorbed in the stomach from swallowed saliva and not in the mouth), although higher doses (1,000 to 5,000 mcg orally) have been used to treat more advanced deficiency (Sharabi, Br J Clin Pharmacol 2003). High doses of vitamin B-12 (about 400 mcg per day) have also been proposed for helping to prevent heart disease. Vitamin B-12 in far higher dosages has also been proposed for the treatment of other conditions including asthma, fatigue, and male infertility, but there is no reliable evidence that it is effective.
Be aware that you cannot actively absorb more than about 1.5 mcg from supplements or foods at a time (i.e., in any 4 to 6 hour period) (Institute of Medicine (US) Food and Nutrition Board 1998). This is because absorption requires "intrinsic factor," a substance produced in the stomach. Only about 1% of B-12 can be absorbed without intrinsic factor simply by passive diffusion (i.e., flooding your gut with B-12, so that a tiny amount leaks into your blood). Consequently, whether you take a dose of 5 mcg or 50 mcg of B-12, only about 1.5 mcg will be absorbed (Abels, J Intern Med 1959), but if you need to significantly boost your B-12 level, you can take a supplement with a high dose, such as 1,000 mcg -- in which case you will absorb 1.5 mcg plus another 10 mcg. It was shown in a 3-month study that giving vegans and vegetarians with marginal B-12 deficiency 50 mcg of sublingual B-12 daily was able to restore adequate B-12 levels. Giving 2,000 mcg of sublingual B-12 weekly (nearly times as much B-12 per week) was no better, and the lower dose was deemed preferable (Del Bo, Clin Nutr 2019). To get the most B-12 from a meal and from a supplement, take them at different times of the day.
Although B-12 injections are a traditional treatment for people with B-12 deficiency, evidence from several clinical studies suggests that treatment with a high oral dose (1,000 mcg daily) can be effective in treating deficiency, even in people lacking intrinsic factor (a common cause of pernicious anemia), and those with compromised absorption due to gastrointestinal disease or bowel resection (Andres, Expert Opin Pharmacother 2010; Kolber, Can Fam Physician 2014). In fact, an analysis of cases in Israel found that blood levels of B-12 actually rose more with use of daily sublingual tablets (1,000 mcg as cyanocobalamin, typically given for 6 months) than with intramuscular injections (1,000 mcg as cyanocobalamin, typically given every other day for 2 weeks and then weekly for 4 weeks) (Bensky, Drug Deliv Transl Res 2019). Oral B-12 supplementation may also be a good option for people taking anticoagulant or antiplatelet medications who may be advised to avoid intramuscular injections. However, due to a lack of research in more severe cases, B-12 injections remain the most appropriate treatment for people with severe, deficiency-related neurological symptoms (Andres, J Blood Med 2012). Upper Limit: No UL has been established for vitamin B-12. This appears to be a very safe ingredient for most people. However, a large study in the Netherlands found that giving 500 mcg of vitamin B-12 (208 times the requirement) and 400 mcg of folic acid (a moderate amount) daily to people age 65 and older for 2 to 3 years was associated with a 77% higher risk of colorectal cancer than in the placebo group (3.4% vs. 2% occurrence, respectively) during the period of study and up to 6 years of follow up. Overall cancer rates were 25% higher in the treated group (13.6% vs. 11.3%, respectively). The researchers noted that most other studies with folate alone have not shown associations with higher cancer risk, but studies with folate and B-12 have (Araghi, Canc Epi Biomark Prev 2018).
Use of B-12 supplements before or during chemotherapy treatment has been associated, respectively, with an 83% and 104% higher risk of poorer disease-free and overall survival rate (Ambrosone, J Clin Oncol 2020).
As noted in Concerns and Cautions below, a B-complex supplement providing 1,000 mcg of B-12 daily was found to increase the risk of heart attack, stroke and death in people with type 1 or type 2 diabetes who had advanced kidney disease. A study in Italy found that malnourished people admitted to hospitals who had elevated B-12 blood levels (>1,000 pg/mL) were twice as likely to die in the hospital as similar patients whose B-12 levels were not elevated. B-12 levels can be affected by disease, but the association in this study was found to be independent of kidney and liver function, inflammation, and degree of weight loss. While this does not prove a cause-and-effect relationship, the researchers cautioned about inappropriate B-12 supplementation (Cappello, Nutrients 2017).
Outbreaks of acne and rosacea have occurred in people taking 20 mcg of B-12 or more per day or intramuscular injection of 1,000 mcg of B-12 (Jansen, J Eur Acad Dermatol Venereol 2001; Sherertz, Cutis 1991). The likely mechanism for this, as demonstrated in a series of experiments, is that oversupply of B-12 in some people causes a common and usually harmless skin bacteria, Propionibacterium acnes, to overproduce an inflammatory protein which leads to pimples on the skin (Kang, Sci Tranl Med 2015). In a report of acne outbreaks in five women (ages 21 to 62) who took either intramuscular or oral B-12, researchers noted that the outbreaks occurred primarily on the face, upper back, chest and shoulder, one week to five months after starting on B-12. The acne completely resolved within three to six weeks after stopping B-12 (Veraldi, J Cosmet Dermatol 2017). Two of the women were noted to have had high blood levels of B-12 (above 1800 pg/mL) at the time of the outbreak.
Unless you have a known deficiency in B-12, it would seem prudent to take no more than the daily requirement (for most adults, 2.4 mcg). Unfortunately, it's hard to get just this amount from a B-12 supplement since most are designed to treat deficiency and contain hundreds of micrograms, although some moderate multivitamins provide this amount or 6 mcg — which had been the requirement until 1998.
To improve taste, some B-12 supplements, such as sublingual, sprays, dissolvable tablets, and occasionally, regular tablets, contain sugar substitutes (such as mannitol, sorbitol, and/or sucralose) which can cause gas, bloating, and diarrhea in some people. You can check for these in the list of ingredients located in the last column of the Results table for each product tested. These side-effects are more likely if taking multiple units. Although rare, there have been reports of possible allergic reaction to vitamin B12 supplementation (Ullah, Cureus 2018 ).
See the Encyclopedia article on Vitamin B-12 for more information about clinical use.
Concerns and Cautions:
Try to avoid taking too much of any B vitamin. Check the ULs listed above and, if you need to take a product with vitamins exceeding the ULs, do so under a physician's supervision and with awareness of potential side effects. For example, a large study of diabetes patients (type 1 and type 2) with advanced nephropathy (kidney disease) given high-dose B vitamins (folic acid - 2,500 mcg, B-6 - 25 mg, and B-12 - 1,000 mcg daily) showed a worsening of kidney function and doubling of the risk of myocardial infarction (MI), stroke, and death in the B-vitamin group compared to the placebo group. The study was designed with the expectation that the vitamins would have the opposite effect because of the ability of B vitamins to lower homocysteine levels, which did decrease. (House, JAMA 2010).
Be aware that certain B vitamins can interact with other drugs and supplements as noted above.
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