Key2Health Nutrition Center

Key Compounding Pharmacy is your source for professional nutritional supplements. We offer a vast array of quality pharmaceutical grade products from industry leaders such as those shown below.

Key2Health Nutrition Center

These companies provide quality products that cannot be found in any retail store. Come by our pharmacy or give us a call and let our experienced nutritional team assist you in locating the product you are searching for. We ship products nationwide via FedEx.

Key2Health Nutrition Center

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Key2Health Nutrition Center

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Key Compounding Pharmacy is your source for professional nutritional supplements. We offer a vast array of quality pharmaceutical grade products from industry leaders.

What Our Customers Are Saying!

Don’t just take it from us, let our customers do the talking!

” I have been a customer at Key Compounding  Nutrition center for many years. First started visiting  for  RX pick up when the store was in Des Moines, WA, it was Key Pharmacy. Happy with professional service and great products.”

“I am really happy with the service you provide at Key Compounding Pharmacy. You are always very helpful and when I leave a message you get right back to me. I appreciate all that you do.”

“I also use the over the counter vitamins. Lai is very helpful and knowledgeable.” 

” Key Pharmacy has literally saved my life, starting with Bill Corriston being willing to customize elemental nutrients for me in 2006 (which I am still taking), Debbie Mickel searching far and wide and somehow finding other essential pharmaceuticals for me when they have become very scarce, and everyone else there who has been unfailingly conscientious and courteous. I am greatly indebted to you all!!”

“I am very thankful for key compound pharmacy. It’s a shame that we do not have one here in Oklahoma. I’m feeling sooo much better being on your natural compounded rxs med I thank you very much.”

“Keep up the good customer service. It’s the “BEST”.”

 “Everything was great. Everything was easy. And everything happened better than expected. Thanks!”

Key2Health Natural Detox Skin Care

PCOS and liver detox

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Spring Liver Detox Program

Continuing from last week, Hee Joo Park, RpH and Nina Walsh, ND discussed detox program in-depth. In this podcast, Dr. Nina Walsh brought gentle liver detox protocols from her clinical experience. If you want to try liver detox program, please check your physician...

Spring Detox Guide

Photo Source: Standard Process 21-Day Purification Program According to Eastern Medicine, Spring is the time that stimultes the energy of Liver among five viscera. For that reason, Spring is believed to be the best time for liver detox program to remove the toxins...

Spring Salads and Soup for Your Skin

At whatever point season changes skin responds. On the off-chance that you feel sluggish and drowsy in Spring time, it might be a warning sign that your nutritional status is not all that ideal arousing up from metabolic Winter hibernation. Lack of hydration is the...

Stem cell therapy for your skin

In this edition of Key2Health Podcast, Dr. Nina walked through Cosmetic stem cell therapy. This highly controversial subject has debated and questioned since the products flooded the market,touted as the answer for skin rejuvenation. Plant stem cell peptides with...

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Most of time, you don't have to shell out hard earned cash to take care of your skin via a holistic approach. As a matter of fact, that has been the biggest misconception. If you do your homework, you can find valuable natural remedies everywhere. Just keep in mind...

9 Best Foods for Your Skin Care

We all know that winter brings few more wrinkles. Direct heat from appliances, dry air blown out of the furnace, or bone-chilling wind may all be partners in crime. They all contribute to deprive water molecules on skin matrix. Overall well-being of our skin seriously...

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What is milk, beer and honey in common? Right, those are for the skin rejuvenating cocktails that Cleopatra had delighted in to pampering extravaganza on her skin. As fully understood ancient Egyptian beauty secrets, Cleopatra had enjoyed so much washing, bathing, and...

Holistic skin care

The skin is the first line of protection to underlying tissues from foreign substances, pressure, sun light and microbes. It is a highly sensitive and living organ that is remarkably efficient for its self- repairing mechanism when the immune system is not...

Key2Health Nutrition Special Podcasting

Hee Joo Park, CEO,  Nina Walsh, ND

How do I know if I need a dietary supplement?

Because many products are marketed as dietary supplements, it is important to remember that supplements include vitamins and minerals, as well as herbs, botanicals and other substances.

Some supplements may help ensure that you get adequate amounts of essential nutrients or help promote optimal health and performance if you do not consume a variety of foods, as recommended in the MyPlateexternal link disclaimer and Dietary Guidelines for Americansexternal link disclaimer.

However, dietary supplements are not intended to treat, diagnose, mitigate, prevent, or cure disease. In some cases, dietary supplements may have unwanted effects, especially if taken before surgery or with other dietary supplements or medicines, or if you have certain health conditions.

Do not self diagnose any health condition. Work with your health care provider to determine how best to achieve optimal health and always check with your health care provider before taking a supplement, especially when combining or substituting them with other foods or medicine.

How can I get more information about a particular dietary supplement such as whether it is safe and effective?

Scientific evidence supporting the benefits of some dietary supplements (e.g., vitamins and minerals) is well established for certain health conditions, but others need further study. This is partly due to the way dietary supplements are regulated by the U.S. Food and Drug Administration (FDA).

Research studies in people to prove that a dietary supplement is safe are not required before the supplement is marketed, unlike for drugs. It is the responsibility of dietary supplement manufacturers/distributors to ensure that their products are safe and that their label claims are accurate and truthful. If the FDA finds a supplement to be unsafe once it is on the market, only then can it take action against the manufacturer and/or distributor, such as by issuing a warning or requiring the product to be removed from the marketplace.

The manufacturer does not have to prove that the supplement is effective, unlike for drugs. The manufacturer can say that the product addresses a nutrient deficiency, supports health, or reduces the risk of developing a health problem, if that is true. If the manufacturer does make a claim, it must be followed by the statement “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

Dietary supplements are not intended to treat, diagnose, mitigate, prevent, or cure disease. In some cases, dietary supplements may have unwanted effects, especially if taken before surgery or with other dietary supplements or medicines, or if you have certain health conditions. Whatever your choice, supplements should not replace prescribed medications or the variety of foods important to a healthful diet.

Do not self diagnose any health condition. Work with your health care provider to determine how best to achieve optimal health and always check with your health care provider before taking a supplement, especially when combining or substituting them with other foods or medicine.

In addition to talking with your health care provider about dietary supplements, you can search on-line for information about a particular dietary supplement. It is important to ensure that you obtain information from reliable sources such as:

For tips on evaluating sources of healthcare information on the Internet, please see the following document: How to Evaluate Health Information on the Internet: Questions and Answers.

Where can I find information about the use of dietary supplements for a particular health condition or disease?

Scientific evidence supporting the benefits of some dietary supplements (e.g., vitamins and minerals) is well established for certain health conditions, but others need further study. Whatever your choice, supplements should not replace prescribed medications or the variety of foods important to a healthful diet.

Dietary supplements are not intended to treat, diagnose, mitigate, prevent, or cure disease. In some cases, dietary supplements may have unwanted effects, especially if taken before surgery or with other dietary supplements or medicines, or if you have certain health conditions.

Do not self diagnose any health condition. Work with your health care provider to determine how best to achieve optimal health and always check with your health care provider before taking a supplement, especially when combining or substituting them with other foods or medicine.

In addition to talking with your health care provider about dietary supplements for a particular health condition or disease, you can search on-line for information. It is important to ensure that you obtain information from reliable sources such as:

For tips on evaluating sources of healthcare information on the Internet, please see the following document: How to Evaluate Health Information on the Internet: Questions and Answers.

What is the difference between the RDA and DV for a vitamin or mineral?

Many terms are used when referring to either the amount of a particular nutrient (such as calcium or vitamin D) you should get or the amount in a food or dietary supplement. The two most common are the Recommended Dietary Allowance (RDA) and the Daily Value (DV). These terms can be confusing.

RDAs are recommended daily intakes of a nutrient for healthy people. They tell you how much of that nutrient you should get on average each day. RDAs are developed by the Food and Nutrition Board at the Institute of Medicine of the National Academies. They vary by age, gender and whether a woman is pregnant or breastfeeding; so there are many different RDAs for each nutrient.

DVs, established by the U.S. Food and Drug Administration (FDA), are used on food and dietary supplement labels. For each nutrient, there is one DV for all people ages 4 years and older. Therefore, DVs aren’t recommended intakes, but suggest how much of a nutrient a serving of the food or supplement provides in the context of a total daily diet. DVs often match or exceed the RDAs for most people, but not in all cases.

DVs are presented on food and supplement labels as a percentage. They help you compare one product with another. As an example, the %DV for calcium on a food label might say 20%. This means it has 200 mg (milligrams) of calcium in one serving because the DV for calcium is 1,000 mg/day. If another food has 40% of the DV for calcium, it’s easy to see that it provides much more calcium than the first food.

The FDA has a Web page that lists the DVs for all nutrientsexternal link disclaimer and provides additional details.

Which brand(s) of dietary supplements should I purchase?

There are a number of factors including price, quality and availability that may influence your buying decision. The Office of Dietary Supplements (ODS) does not test, analyze or rate dietary supplements, nor can we recommend certain brands. You may wish to ask your health care provider to make a recommendation.

If you have questions about a specific brand of dietary supplements, you can contact the manufacturer for more information. Ask to speak to someone who can address your questions, some of which may include:

  1. What information does the firm have to substantiate the claims made for the product? Be aware that sometimes firms supply so-called “proof” of their claims by citing undocumented reports from satisfied consumers, or graphs and charts that could be mistaken for well conducted scientific research.
  2. Does the firm have information to share about tests it has conducted on the safety or efficacy of the ingredients in the product?
  3. Does the firm follow good manufacturing practices and have a quality control system in place to determine if the product actually contains what is stated on the label and is free of contaminants?
  4. Has the firm received any adverse events reports from consumers using their products?

In addition, there are a few independent organizations that offer “seals of approval” that may be displayed on certain dietary supplement products. These indicate that the product has passed the organization’s quality tests for things such as potency and contaminants. These “seals of approval” do not mean that the product is safe or effective; they provide assurance that the product was properly manufactured, that it contains the ingredients listed on the label and that it does not contain harmful levels of contaminants.

The following is a list of several organizations offering these programs:

How do I know if the supplement that I purchased contains the ingredients that it claims on the label or if it is contaminated?

You should be aware that the U.S. Food and Drug Administration (FDA) does not analyze the content of dietary supplements. However, FDA has issued Good Manufacturing Practices (GMPs) for dietary supplements, a set of requirements and expectations by which dietary supplements must be manufactured, prepared, and stored to ensure quality. Manufacturers are expected to guarantee the identity, purity, strength, and composition of their dietary supplements. For example, the GMPs aim to prevent the inclusion of the wrong ingredients, the addition of too much or too little of a dietary ingredient, the possibility of contamination (by pesticides, heavy metals such as lead, bacteria, etc.), and the improper packaging and labeling of a product.

Some manufacturers use the term “standardized” to describe efforts to make their products consistent. However, U.S. law does not define standardization. Therefore, the use of this term (or similar terms such as “verified” or “certified”) does not guarantee product quality or consistency.

If you have questions about a specific brand of dietary supplements, you can contact the manufacturer for more information. Ask to speak to someone who can address your questions, some of which may include:

  1. What information does the firm have to substantiate the claims made for the product? Be aware that sometimes firms supply so-called “proof” of their claims by citing undocumented reports from satisfied consumers, or graphs and charts that could be mistaken for well conducted scientific research.
  2. Does the firm have information to share about tests it has conducted on the safety or efficacy of the ingredients in the product?
  3. Does the firm follow good manufacturing practices and have a quality control system in place to determine if the product actually contains what is stated on the label and is free of contaminants?
  4. Has the firm received any adverse events reports from consumers using their products?

In addition, there are a few independent organizations that offer “seals of approval” that may be displayed on certain dietary supplement products. These indicate that the product has passed the organization’s quality tests for things such as potency and contaminants. These “seals of approval” do not mean that the product is safe or effective; they provide assurance that the product was properly manufactured, that it contains the ingredients listed on the label and that it does not contain harmful levels of contaminants.

The following is a list of several organizations offering these programs:

 

With so many dietary supplements to choose from, how can I compare the ingredients and doses in one product with those in another?

The Dietary Supplement Label Database (DSLD) contains label information from thousands of dietary supplement products available in the U.S. marketplace. It can be used to search, for example, for a specific ingredient in a product, a particular supplement manufacturer, text on a label, and a specific health-related claim.

Who is responsible for overseeing the regulation of dietary supplements in the United States?

In the United States, the U.S. Food and Drug Administration (FDA) has regulatory responsibility for dietary supplements. FDA regulates dietary supplements under a different set of regulations than those covering “conventional” foods and drug products (prescription and over-the-counter). Under the Dietary Supplement Health and Education Act of 1994, the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market.

Manufacturers must make sure that product label information is truthful and not misleading. FDA’s post-marketing responsibilities include monitoring safety, e.g. dietary supplement adverse event reporting, and product information, such as labeling, claims, package inserts, and accompanying literature.

For more information, please contact the FDA Center for Food Safety and Applied Nutritionexternal link disclaimer via their Web site or at 1-888-723-3366.

The Federal Trade Commission (FTC) regulates advertising of dietary supplements in national or regional newspapers and magazines; in radio and TV commercials, including infomercials; through direct mail to consumers; or on the Internet. The FTC requires that all information about supplements be truthful and not misleading.

For more information, please contact the FTCexternal link disclaimer via their website.

 Nutrition Related Research and Fact Sheet

What is vitamin A and what does it do?

What is vitamin A and what does it do?

Vitamin A is a fat-soluble vitamin that is naturally present in many foods. Vitamin A is important for normal vision, the immune system, and reproduction. Vitamin A also helps the heart, lungs, kidneys, and other organs work properly.

There are two different types of vitamin A. The first type, preformed vitamin A, is found in meat, poultry, fish, and dairy products. The second type, provitamin A, is found in fruits, vegetables, and other plant-based products. The most common type of provitamin A in foods and dietary supplements is beta-carotene.

How much vitamin A do I need?

The amount of vitamin A you need depends on your age and reproductive status. Recommended intakes for vitamin A for people aged 14 years and older range between 700 and 900 micrograms (mcg) of retinol activity equivalents (RAE) per day. Recommended intakes for women who are nursing range between 1,200 and 1,300 RAE. Lower values are recommended for infants and children younger than 14.

However, the vitamin A content of foods and dietary supplements is given on product labels in international units (IU), not mcg RAE. Converting between IU and mcg RAE is not easy. A varied diet with 900 mcg RAE of vitamin A, for example, provides between 3,000 and 36,000 IU of vitamin A depending on the foods consumed. See our Health Professional Fact Sheet on Vitamin A for more details.

For adults and children aged 4 years and older, the U.S. Food and Drug Administration has established a vitamin A Daily Value (DV) of 5,000 IU from a varied diet of both plant and animal foods. DVs are not recommended intakes; they don’t vary by age and sex, for example. But trying to reach 100% of the DV each day, on average, is useful to help you get enough vitamin A. For more information on DVs, see our Frequently Asked Questions page.

What foods provide vitamin A?

Vitamin A is found naturally in many foods and is added to some foods, such as milk and cereal. You can get recommended amounts of vitamin A by eating a variety of foods, including the following:

  • Beef liver and other organ meats (but these foods are also high in cholesterol, so limit the amount you eat).
  • Some types of fish, such as salmon.
  • Green leafy vegetables and other green, orange, and yellow vegetables, such as broccoli, carrots, and squash.
  • Fruits, including cantaloupe, apricots, and mangos.
  • Dairy products, which are among the major sources of vitamin A for Americans.
  • Fortified breakfast cereals.

What kinds of vitamin A dietary supplements are available?

Vitamin A is available in dietary supplements, usually in the form of retinyl acetate or retinyl palmitate (preformed vitamin A), beta-carotene (provitamin A), or a combination of preformed and provitamin A. Most multivitamin-mineral supplements contain vitamin A. Dietary supplements that contain only vitamin A are also available.

Am I getting enough vitamin A?

Most people in the United States get enough vitamin A from the foods they eat, and vitamin A deficiency is rare. However, certain groups of people are more likely than others to have trouble getting enough vitamin A:

  • Premature infants, who often have low levels of vitamin A in their first year.
  • Infants, young children, pregnant women, and breastfeeding women in developing countries.
  • People with cystic fibrosis.

What happens if I don’t get enough vitamin A?

Vitamin A deficiency is rare in the United States, although it is common in many developing countries. The most common symptom of vitamin A deficiency in young children and pregnant women is an eye condition called xerophthalmia. Xerophthalmia is the inability to see in low light, and it can lead to blindness if it isn’t treated.

What are some effects of vitamin A on health?

Scientists are studying vitamin A to understand how it affects health. Here are some examples of what this research has shown.

Cancer

People who eat a lot of foods containing beta-carotene might have a lower risk of certain kinds of cancer, such as lung cancer or prostate cancer. But studies to date have not shown that vitamin A or beta-carotene supplements can help prevent cancer or lower the chances of dying from this disease. In fact, studies show that smokers who take high doses of beta-carotene supplements have an increased risk of lung cancer.

Age-Related Macular Degeneration

Age-related macular degeneration (AMD), or the loss of central vision as people age, is one of the most common causes of vision loss in older people. Among people with AMD who are at high risk of developing advanced AMD, a supplement containing antioxidants, zinc, and copper with or without beta-carotene has shown promise for slowing down the rate of vision loss.

Measles

When children with vitamin A deficiency (which is rare in North America) get measles, the disease tends to be more severe. In these children, taking supplements with high doses of vitamin A can shorten the fever and diarrhea caused by measles. These supplements can also lower the risk of death in children with measles who live in developing countries where vitamin A deficiency is common.

Can vitamin A be harmful?

Yes, high intakes of some forms of vitamin A can be harmful.

Getting too much preformed vitamin A (usually from supplements or certain medicines) can cause dizziness, nausea, headaches, coma, and even death. High intakes of preformed vitamin A in pregnant women can also cause birth defects in their babies. Women who might be pregnant should not take high doses of vitamin A supplements.

Consuming high amounts of beta-carotene or other forms of provitamin A can turn the skin yellow-orange, but this condition is harmless. High intakes of beta-carotene do not cause birth defects or the other more serious effects caused by getting too much preformed vitamin A.

The upper limits for preformed vitamin A in IU are listed below. These levels do not apply to people who are taking vitamin A for medical reasons under the care of a doctor. Upper limits for beta-carotene and other forms of provitamin A have not been established.

Life Stage Upper Limit
Birth to 12 months 2,000 IU
Children 1–3 years 2,000 IU
Children 4–8 years 3,000 IU
Children 9–13 years 5,667 IU
Teens 14–18 years 9,333 IU
Adults 19 years and older 10,000 IU

Are there any interactions with vitamin A that I should know about?

Yes, vitamin A supplements can interact or interfere with medicines you take. Here are several examples:

  • Orlistat (Alli®, Xenical®), a weight-loss drug, can decrease the absorption of vitamin A, causing low blood levels in some people.
  • Several synthetic forms of vitamin A are used in prescription medicines. Examples are the psoriasis treatment acitretin (Soriatane®) and bexarotene (Targretin®), used to treat the skin effects of T-cell lymphoma. Taking these medicines in combination with a vitamin A supplement can cause dangerously high levels of vitamin A in the blood.

Tell your doctor, pharmacist, and other health care providers about any dietary supplements and medicines you take. They can tell you if those dietary supplements might interact or interfere with your prescription or over-the-counter medicines or if the medicines might interfere with how your body absorbs, uses, or breaks down nutrients.

Vitamin A and healthful eating

People should get most of their nutrients from food, advises the federal government’s Dietary Guidelines for Americans. Foods contain vitamins, minerals, dietary fiber and other substances that benefit health. In some cases, fortified foods and dietary supplements may provide nutrients that otherwise may be consumed in less-than-recommended amounts. For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

Where can I find out more about vitamin A?

Can botanicals be dietary supplements?

What is a botanical?

A botanical is a plant or plant part valued for its medicinal or therapeutic properties, flavor, and/or scent. Herbs are a subset of botanicals. Products made from botanicals that are used to maintain or improve health may be called herbal products, botanical products, or phytomedicines.

In naming botanicals, botanists use a Latin name made up of the genus and species of the plant. Under this system the botanical black cohosh is known as Actaea racemosa L., where “L” stands for Linneaus, who first described the type of plant specimen. In the Office of Dietary Supplements (ODS) fact sheets, we do not include such initials because they do not appear on most products used by consumers.

Can botanicals be dietary supplements?

To be classified as a dietary supplement, a botanical must meet the definition given below. Many botanical preparations meet the definition.

As defined by Congress in the Dietary Supplement Health and Education Act, which became law in 1994, a dietary supplement is a product (other than tobacco) that

  • is intended to supplement the diet;
  • contains one or more dietary ingredients (including vitamins; minerals; herbs or other botanicals; amino acids; and other substances) or their constituents;
  • is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and
  • is labeled on the front panel as being a dietary supplement.

How are botanicals commonly sold and prepared?

Botanicals are sold in many forms: as fresh or dried products; liquid or solid extracts; tablets, capsules, powders; tea bags; and other forms. For example, fresh ginger root is often found in the produce section of food stores; dried ginger root is sold packaged in tea bags, capsules, or tablets; and liquid preparations made from ginger root are also sold. A particular group of chemicals or a single chemical may be isolated from a botanical and sold as a dietary supplement, usually in tablet or capsule form. An example is phytoestrogens from soy products.

Common preparations include teas, decoctions, tinctures, and extracts:

  • A tea, also known as an infusion, is made by adding boiling water to fresh or dried botanicals and steeping them. The tea may be drunk either hot or cold.
  • Some roots, bark, and berries require more forceful treatment to extract their desired ingredients. They are simmered in boiling water for longer periods than teas, making a decoction, which also may be drunk hot or cold.
  • A tincture is made by soaking a botanical in a solution of alcohol and water. Tinctures are sold as liquids and are used for concentrating and preserving a botanical. They are made in different strengths that are expressed as botanical-to-extract ratios (i.e., ratios of the weight of the dried botanical to the volume or weight of the finished product).
  • An extract is made by soaking the botanical in a liquid that removes specific types of chemicals. The liquid can be used as is or evaporated to make a dry extract for use in capsules or tablets.

Are botanical dietary supplements standardized?

Standardization is a process that manufacturers may use to ensure batch-to-batch consistency of their products. In some cases, standardization involves identifying specific chemicals (also known as markers) that can be used to manufacture a consistent product. The standardization process can also provide a measure of quality control.

Dietary supplements are not required to be standardized in the United States. In fact, no legal or regulatory definition exists for standardization in the United States as it applies to botanical dietary supplements. Because of this, the term “standardization” may mean many different things. Some manufacturers use the term standardization incorrectly to refer to uniform manufacturing practices; following a recipe is not sufficient for a product to be called standardized. Therefore, the presence of the word “standardized” on a supplement label does not necessarily indicate product quality.

Ideally, the chemical markers chosen for standardization would also be the constituents that are responsible for a botanical’s effect in the body. In this way, each lot of the product would have a consistent health effect. However, the components responsible for the effects of most botanicals have not been identified or clearly defined. For example, the sennosides in the botanical senna are known to be responsible for the laxative effect of the plant, but many compounds may be responsible for valerian’;s relaxing effect.

Are botanical dietary supplements safe?

Many people believe that products labeled “natural” are safe and good for them. This is not necessarily true because the safety of a botanical depends on many things, such as its chemical makeup, how it works in the body, how it is prepared, and the dose used.

The action of botanicals range from mild to powerful (potent). A botanical with mild action may have subtle effects. Chamomile and peppermint, both mild botanicals, are usually taken as teas to aid digestion and are generally considered safe for self-administration. Some mild botanicals may have to be taken for weeks or months before their full effects are achieved. For example, valerian may be effective as a sleep aid after 14 days of use but it is rarely effective after just one dose. In contrast a powerful botanical produces a fast result. Kava, as one example, is reported to have an immediate and powerful action affecting anxiety and muscle relaxation.

The dose and form of a botanical preparation also play important roles in its safety. Teas, tinctures, and extracts have different strengths. The same amount of a botanical may be contained in a cup of tea, a few teaspoons of tincture, or an even smaller quantity of an extract. Also, different preparations vary in the relative amounts and concentrations of chemical removed from the whole botanical. For example, peppermint tea is generally considered safe to drink but peppermint oil is much more concentrated and can be toxic if used incorrectly. It is important to follow the manufacturer’s suggested directions for using a botanical and not exceed the recommended dose without the advice of a health care provider.

Does a label indicate the quality of a botanical dietary supplement product?

It is difficult to determine the quality of a botanical dietary supplement product from its label. The degree of quality control depends on the manufacturer, the supplier, and others in the production process.

In 2007, the FDA issued Good Manufacturing Practices (GMPs) for dietary supplements, a set of requirements and expectations by which dietary supplements must be manufactured, prepared, and stored to ensure quality. Manufacturers are now expected to guarantee the identity, purity, strength, and composition of their dietary supplements. For example, the GMPs aim to prevent the inclusion of the wrong ingredients, the addition of too much or too little of a dietary ingredient, the possibility of contamination (by pesticides, heavy metals such as lead, bacteria, etc.), and the improper packaging and labeling of a product.

What methods are used to evaluate the health benefits and safety of a botanical dietary supplement?

Like other dietary supplements, botanicals are not required by federal law to be tested for safety and effectiveness before they are marketed, so the amount of scientific evidence available for various botanical ingredients varies widely. Some botanicals have been evaluated in scientific studies. For example, research shows that St. John’s wort may be useful for short-term treatment of mild to moderate depression. Other botanical dietary supplements need more study to determine their value.

Scientists can use several approaches to evaluate botanical dietary supplements for their potential health benefits and risks. They may investigate history of use, conduct laboratory studies using cell or tissue cultures, and experiment with animals. Studies on people (e.g., individual case reports, observational studies, and clinical trials) provide the most direct evidence of a botanical supplement’s effects on health and patterns of use.

What are some additional sources of information on botanical dietary supplements?

Medical libraries are one source of information about botanical dietary supplements. Others include Web-based resources such as PubMed and FDAexternal link disclaimer. For general information about dietary supplements see Dietary Supplements: Background Information from the Office of Dietary Supplements (ODS).

What is thiamin and what does it do?

Introduction

Thiamin (or thiamine) is one of the water-soluble B vitamins. It is also known as vitamin B1. Thiamin is naturally present in some foods, added to some food products, and available as a dietary supplement. This vitamin plays a critical role in energy metabolism and, therefore, in the growth, development, and function of cells [1].

Ingested thiamin from food and dietary supplements is absorbed by the small intestine through active transport at nutritional doses and by passive diffusion at pharmacologic doses [1]. Most dietary thiamin is in phosphorylated forms, and intestinal phosphatases hydrolyze them to free thiamin before the vitamin is absorbed [1]. The remaining dietary thiamin is in free (absorbable) form [1,2]. Humans store thiamin primarily in the liver, but in very small amounts [3]. The vitamin has a short half-life, so people require a continuous supply of it from the diet.

About 80% of the approximately 25–30 mg of thiamin in the adult human body is in the form of thiamin diphosphate (TDP; also known as thiamin pyrophosphate), the main metabolically active form of thiamin. Bacteria in the large intestine also synthesize free thiamin and TDP, but their contribution, if any, to thiamin nutrition is currently unknown [4]. TDP serves as an essential cofactor for five enzymes involved in glucose, amino acid, and lipid metabolism [1,3].

Levels of thiamin in the blood are not reliable indicators of thiamin status. Thiamin status is often measured indirectly by assaying the activity of the transketolase enzyme, which depends on TDP, in erythrocyte hemolysates in the presence and absence of added TDP [3]. The result, known as the “TDP effect,” reflects the extent of unsaturation of transketolase with TDP. The result is typically 0%–15% in healthy people, 15%–25% in those with marginal deficiency, and higher than 25% in people with deficiency. Another commonly used measure of thiamin status is urinary thiamin excretion, which provides data on dietary intakes but not tissue stores [5]. For adults, excretion of less than 100 mcg/day thiamin in urine suggests insufficient thiamin intake, and less than 40 mcg/day indicates an extremely low intake [6].

Recommended Intakes

Intake recommendations for thiamin and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (formerly National Academy of Sciences) [7]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA; intake at this level is assumed to ensure nutritional adequacy.
  • Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current RDAs for thiamin [7]. For infants from birth to 12 months, the FNB established an AI for thiamin that is equivalent to the mean intake of thiamin in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Thiamin [7]
Age Male Female Pregnancy Lactation
Birth to 6 months* 0.2 mg 0.2 mg
7–12 months* 0.3 mg 0.3 mg
1–3 years 0.5 mg 0.5 mg
4–8 years 0.6 mg 0.6 mg
9–13 years 0.9 mg 0.9 mg
14–18 years 1.2 mg 1.0 mg 1.4 mg 1.4 mg
19-50 years 1.2 mg 1.1 mg 1.4 mg 1.4 mg
51+ years 1.2 mg 1.1 mg

*AI

Sources of Thiamin

Food

Food sources of thiamin include whole grains, meat, and fish [2]. Breads, cereals, and infant formulas in the United States and many other countries are fortified with thiamin [2].The most common sources of thiamin in the U.S. diet are cereals and bread [8]. Pork is another major source of the vitamin. Dairy products and most fruits contain little thiamin [3]. About half of the thiamin in the U.S. diet comes from foods that naturally contain thiamin; the remainder comes from foods to which thiamin has been added [9].

Heating foods containing thiamin can reduce their thiamin content. For example, bread has 20%–30% less thiamin than its raw ingredients, and pasteurization reduces thiamin content (which is very small to begin with) in milk by up to 20% [3]. Because thiamin dissolves in water, a significant amount of the vitamin is lost when cooking water is thrown out [3]. Processing also alters thiamin levels in foods; for example, unless white rice is enriched with thiamin, it has one tenth the amount of thiamin in unenriched brown rice [10].

Data on the bioavailability of thiamin from food are very limited [7]. Some studies do show, however, that thiamin absorption increases when intakes are low [1].

Several food sources of thiamin are listed in Table 2.

Table 2: Selected Food Sources of Thiamin [10]
Food Milligrams
(mg) per
serving
Percent
DV*
Breakfast cereals, fortified with 100% of the DV for thiamin, 1 serving 1.5 100
Rice, white, long grain, enriched, parboiled, ½ cup 1.4 73
Egg noodles, enriched, cooked, 1 cup 0.5 33
Pork chop, bone-in, broiled, 3 ounces 0.4 27
Trout, cooked, dry heat, 3 ounces 0.4 27
Black beans, boiled, ½ cup 0.4 27
English muffin, plain, enriched, 1 muffin 0.3 20
Mussels, blue, cooked, moist heat, 3 ounces 0.3 20
Tuna, Bluefin, cooked, dry heat, 3 ounces 0.2 13
Macaroni, whole wheat, cooked, 1 cup 0.2 13
Acorn squash, cubed, baked, ½ cup 0.2 13
Rice, brown, long grain, not enriched, cooked, ½ cup 0.1 7
Bread, whole wheat, 1 slice 0.1 7
Orange juice, prepared from concentrate, 1 cup 0.1 7
Sunflower seeds, toasted, 1 ounce 0.1 7
Beef steak, bottom round, trimmed of fat, braised, 3 ounces 0.1 7
Yogurt, plain, low fat, 1 cup 0.1 7
Oatmeal, regular and quick, unenriched, cooked with water, ½ cup 0.1 7
Corn, yellow, boiled, 1 medium ear 0.1 7
Milk, 2%, 1 cup 0.1 7
Barley, pearled, cooked, 1 cup 0.1 7
Cheddar cheese, 1½ ounces 0 0
Chicken, meat and skin, roasted, 3 ounces 0 0
Apple, sliced, 1 cup 0 0

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for thiamin is 1.5 mg for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer website [10] lists the nutrient content of many foods and provides a comprehensive list of foods containing thiamin arranged by nutrient content and by food name.

Dietary supplements

Thiamin is available in many dietary supplements. Multivitamin/multimineral supplements with thiamin typically provide about 1.5 mg thiamin (100% of the DV) and sometimes more [11]. Supplements containing B-complex vitamins (including thiamin) or thiamin only are also available. The most commonly used forms of thiamin in supplements are thiamin mononitrate and thiamin hydrochloride, which are stable and water soluble [1,11].

Benfotiamine is a synthetic thiamin derivative that is used in some dietary supplements. Benfotiamine is not water soluble and is converted to thiamin in the body [12].

Thiamin Intakes and Status

Most people in the United States consume the recommended amounts of thiamin. An analysis of data from the 2003-2006 National Health and Nutrition Examination Survey showed that only 6% of the U.S. population has a usual intake below the EAR [9].

Among children and teens, the average daily thiamin intake from foods is 1.27 mg for ages 2–5 years, 1.54 mg for ages 6–11 years, and 1.68 mg for ages 12–19 years [13]. In adults aged 20 and older, the average daily thiamin intake from foods is 1.95 mg in men and 1.39 mg in women. The average daily thiamin intake from foods and supplements in children and teens is 1.51 mg for ages 2–5 years, 1.76 mg for ages 6–11 years, and 1.95 mg for ages 12–19 years. In adults aged 20 and older, the average daily thiamin intake from foods and supplements is 4.89 mg in men and 4.90 mg in women.

No current data on rates of thiamin deficiency in the U.S. population are available.

Thiamin Deficiency

In addition to insufficient intakes of thiamin from the diet, the causes of thiamin deficiency include lower absorption or higher excretion rates than normal due, for example, to certain conditions (such as alcohol dependence or HIV/AIDS) or use of some medications [3].

In its early stage, thiamin deficiency can cause weight loss and anorexia, confusion, short-term memory loss, and other mental signs and symptoms; muscle weakness; and cardiovascular symptoms (such as an enlarged heart) [7].

The most common effect of thiamin deficiency is beriberi, which is characterized mainly by peripheral neuropathy and wasting [1-3]. People with this condition have impaired sensory, motor, and reflex functions. In rare cases, beriberi causes congestive heart failure that leads to edema in the lower limbs and, occasionally, death [1,3]. Although beriberi is rare in the United States and other developed countries, people in these countries do occasionally develop the condition [14-17]. Administration of supplemental thiamin, often parenterally, quickly cures beriberi [2,3].

A more common manifestation of thiamin deficiency in the United States is Wernicke-Korsakoff syndrome [2]. This disorder is about 8–10 times more common in people with chronic alcoholism than in the general population, but it can also develop in patients who have severe gastrointestinal disorders, rapidly progressing hematologic malignancies, drug use disorders, or AIDS [2]. In many patients, Wernicke-Korsakoff syndrome has two phases. The first, acute, and life-threatening stage, Wernicke’s encephalopathy, is usually characterized by peripheral neuropathy [3,18]. Without treatment, up to 20% of people with Wernicke’s encephalopathy die; those who survive develop Korsakoff’s psychosis, although some people with Korsakoff’s psychosis have not previously had Wernicke’s encephalopathy [19,20]. Korsakoff’s psychosis, an effect of chronic thiamin deficiency, is associated with severe short-term memory loss, disorientation, and confabulation (confusion between real and imagined memories) [1-3]. At this chronic state of the disorder, parenteral thiamin treatment does not lead to recovery in about one-quarter of patients [21].

The World Health Organization recommends daily oral doses of 10 mg thiamin for a week, followed by 3–5 mg/daily for at least 6 weeks, to treat mild thiamin deficiency [22]. The recommended treatment for severe deficiency consists of 25–30 mg intravenously in infants and 50–100 mg in adults, then 10 mg daily administered intramuscularly for approximately one week, followed by 3–5 mg/day oral thiamin for at least 6 weeks.

Groups at Risk of Thiamin Inadequacy

The following groups are among those most likely to have inadequate thiamin status.

People with alcohol dependence

In highly industrialized countries, chronic alcohol use disorders appear to be the most common cause of thiamin deficiency [1]. Up to 80% of people with chronic alcoholism develop thiamin deficiency because ethanol reduces gastrointestinal absorption of thiamin, thiamin stores in the liver, and thiamin phosphorylation [3,18]. Also, people with alcoholism tend to have inadequate intakes of essential nutrients, including thiamin.

Older adults

Up to 20%–30% of older adults have laboratory indicators that suggest some degree of thiamin deficiency [2,7]. Possible reasons include low dietary intakes, a combination of chronic diseases, concomitant use of multiple medications, and low absorption of thiamin as a natural result of aging [23,24]. Some small studies have found that the risk of deficiency is particularly high in elderly people who reside in an institution [25,26].

People with HIV/AIDS

People with HIV infection have an increased risk of thiamin deficiency and its sequelae, including beriberi and Wernicke-Korsakoff syndrome [1,27]. Autopsies of 380 people with AIDS found that almost 10% had Wernicke’s encephalopathy [28], and some experts believe that thiamin deficiency is underdiagnosed in this population [29]. The association between thiamin deficiency and HIV/AIDS is probably due to malnutrition as a result of the catabolic state associated with AIDS.

People with diabetes

Some small studies have found that thiamin levels in plasma are up to 76% lower in people with type 1 diabetes than in healthy volunteers and 50%–75% lower in people with type 2 diabetes [30,31]. Other studies have shown a higher risk of thiamin deficiency in people with type 1 and/or type 2 diabetes based on tests of erythrocyte transketolase activity [32,33]. These lower thiamin levels might be due to increases in clearance of thiamin by the kidneys. The relevance of these effects to clinical prognosis or outcomes is not known.

People who have undergone bariatric surgery

Bariatric surgery for weight loss is associated with some risks, including severe thiamin deficiency due to malabsorption that can lead to beriberi or Wernicke’s encephalopathy. A 2008 literature review identified 84 cases of Wernicke’s encephalopathy after bariatric surgery (primarily gastric bypass surgery) between 1991 and 2008 [34]. About half of these patients experienced long-lasting neurologic impairments. Micronutrient supplements that include thiamin are almost always recommended for patients following bariatric surgery to avoid deficiencies [35].

Thiamin and Health

This section focuses on four diseases or disorders in which thiamin does or might play a role: Wernicke-Korsakoff syndrome, diabetes, heart failure, and Alzheimer’s disease.

Wernicke-Korsakoff syndrome

Wernicke-Korsakoff syndrome is one of the most severe neuropsychiatric sequelae of alcohol abuse [36]. The authors of a 2013 Cochrane review of thiamin to treat or prevent Wernicke-Korsakoff syndrome found only two studies that met their inclusion criteria, and one of these studies has not been published [36]. These randomized, double-blind, placebo-controlled trials compared 5 mg/day by mouth for 2 weeks or daily intramuscular doses of 5 to 200 mg/day thiamin over 2 consecutive days in a total of 177 people with a history of chronic alcohol use. The Cochrane review authors concluded that the evidence from randomized clinical trials is insufficient to guide health care providers in selecting the appropriate dose, frequency, duration, or route of thiamin supplementation to treat or prevent Wernicke-Korsakoff syndrome in patients with alcohol abuse.

The authors of the European Federation of Neurological Societies guidelines for diagnosing, preventing, and treating Wernicke’s encephalopathy note that even high doses of oral thiamin supplements might not be effective in raising blood thiamin levels or curing Wernicke’s encephalopathy [37]. They recommend 200 mg thiamin, preferably intravenously, three times daily (total of 600 mg/day) until the signs and symptoms stop, along with a balanced diet. In its guidelines for managing Wernicke’s encephalopathy in emergency departments, the Royal College of Physicians in London supports the administration of oral thiamin hydrochloride (100 mg three times a day) in patients with adequate dietary intakes of thiamin and no signs or symptoms of Wernicke’s encephalopathy [38]. However, the authors recommend parenteral thiamin supplementation for patients at high risk, such as those with ataxia, confusion, and a history of chronic alcohol misuse, because oral supplementation is unlikely to produce adequate blood levels.

Diabetes

The proportion of people with type 1 or type 2 diabetes who have poor thiamin status based on erythrocyte transketolase activity ranges from 17% to 79% in studies conducted to date [39]. In a study of 76 consecutive patients with type 1 or type 2 diabetes, for example, 8% had mild thiamin deficiency and 32% had moderate deficiency based on assays of the transketolase enzyme [32].

Some small studies have shown that oral supplementation with 150–300 mg/day thiamin can decrease glucose levels in patients with type 2 diabetes or impaired glucose tolerance [40,41]. However, the authors of these studies did not assess the potential clinical significance of these findings.

A few small randomized studies have assessed the effects of benfotiamine supplements on diabetic neuropathy. Three studies found that, compared to placebo, 120–900 mg/day benfotiamine with or without other B-vitamins decreased the severity of neuropathy symptoms and lowered urinary albumin excretion (a marker of early-stage diabetic nephropathy) [42-44]. However, another study found no effect of 900 mg/day benfotiamine on urinary excretion of albumin or kidney injury molecule-1, a marker of kidney injury [45].

Well-designed studies with larger sample sizes and longer durations are required to determine whether thiamin supplements can reduce glucose levels in patients with diabetes or decrease diabetic compications.

Heart failure

The rates of poor thiamin status in patients with heart failure have ranged in studies from 21% to 98% [46]. Explanations for this association include older age, comorbidities, insufficient dietary intake, treatment with diuretics, and frequent hospitalizations [47].

The authors of one study reported that 33% of 100 patients with chronic heart failure had thiamin deficiency compared to 12% of 50 healthy volunteers [48]. Rates of deficiency were even higher when the investigators excluded those who used thiamin supplements. The different rates of thiamin deficiency in patients with heart failure in these and other studies are probably due to differences in nutrition status, comorbidities, medications and dietary supplements used, and techniques used to measure thiamin status [47].

The authors of a systematic literature review and meta-analysis found two randomized, double-blind, placebo-controlled trials of thiamin supplementation in people with heart failure that met their eligibility criteria [49]. In these trials, thiamin supplements significantly improved net change in left ventricular ejection fraction. The authors did not assess the clinical significance of this finding, however.

More research is needed to determine whether thiamin supplements might benefit people with heart failure, even if they have normal thiamin status.

Alzheimer’s disease

According to animal model studies, thiamin deficiency might play a role in the development of Alzheimer’s disease [50]. For example, thiamin deficiency produces oxidative stress in neurons, death of neurons, loss of memory, plaque formation, and changes in glucose metabolism—all markers of Alzheimer’s disease. Autopsy studies have shown that transketolase and other thiamin-dependent enzymes have decreased activity in the brains of people with Alzheimer’s disease [51,52].

Few studies have assessed the prevalence of thiamin deficiency in people with Alzheimer’s disease. One of these studies found that 13% of 150 patients with cognitive impairment and acute-onset behavioral disturbances were considered thiamin deficient based on plasma levels [23].

The authors of a 2001 Cochrane review assessed three double-blind, randomized trials (including two crossover trials) that compared the effects of 3 g/day oral thiamin to placebo on cognitive function in patients with Alzheimer’s type dementia [53]. The three studies randomly assigned fewer than 20 patients each, and the two crossover studies did not include a washout period [54-56]. The review authors stated that it was not possible to draw any conclusions from these three studies because they were small and the publications describing them did not provide enough detail to combine these data in a meta-analysis.

Larger, well-designed studies are needed to determine whether thiamin supplements are beneficial for Alzheimer’s disease.

Health Risks from Excessive Thiamin

The body excretes excess amounts of thiamin in the urine [2]. Because of the lack of reports of adverse effects from high thiamin intakes (50 mg/day or more) from food or supplements, the FNB did not establish ULs for thiamin [7]. They hypothesize that the apparent lack of toxicity may be explained by the rapid decline in absorption of thiamin at intakes above 5 mg. However, the FNB noted that in spite of the lack of reported adverse events, excessive intakes of thiamin could have adverse effects.

Interactions with Medications

Although thiamin is not known to interact with any medications, certain medications can have an adverse effect on thiamin levels. Some examples are provided below. Individuals taking these and other medications on a regular basis should discuss their thiamin status with their health care providers.

Furosemide

Furosemide (Lasix®) is a loop diuretic used to treat edema and hypertension by increasing urinary output. Research has linked the use of furosemide to decreases in thiamin concentrations, possibly to deficient levels, as a result of urinary thiamin loss [48,57,58]. Whether thiamin supplements are effective for preventing thiamin deficiency in patients taking loop diuretics needs to be determined in clinical studies.

Chemotherapy with Fluorouracil

Fluorouracil (also known as 5-fluorouracil; Adrucil®) is a chemotherapy drug that is commonly used to treat colorectal and other solid cancers. The published literature includes several cases of beriberi or Wernicke’s encephalopathy resulting from treatment with this drug, possibly because the drug might increase thiamin metabolism and block the formation of TDP, the active form of thiamin [59-62]. Thiamin supplements might reverse some of these effects.

Thiamin and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Many whole grains are good sources of thiamin, and yogurt contains thiamin.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Pork, fish, and seafood are good or high sources of thiamin. Beef, beans, and seeds contain thiamin.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

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 This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.
What is riboflavin and what does it do?

Introduction

Riboflavin (also known as vitamin B2) is one of the B vitamins, which are all water soluble. Riboflavin is naturally present in some foods, added to some food products, and available as a dietary supplement. This vitamin is an essential component of two major coenzymes, flavin mononucleotide (FMN; also known as riboflavin-5’-phosphate) and flavin adenine dinucleotide (FAD). These coenzymes play major roles in energy production; cellular function, growth, and development; and metabolism of fats, drugs, and steroids [1-3]. The conversion of the amino acid tryptophan to niacin (sometimes referred to as vitamin B3) requires FAD [3]. Similarly, the conversion of vitamin B6 to the coenzyme pyridoxal 5’-phosphate needs FMN. In addition, riboflavin helps maintain normal levels of homocysteine, an amino acid in the blood [1].

More than 90% of dietary riboflavin is in the form of FAD or FMN; the remaining 10% is comprised of the free form and glycosides or esters [2,3]. Most riboflavin is absorbed in the proximal small intestine [4]. The body absorbs little riboflavin from single doses beyond 27 mg and stores only small amounts of riboflavin in the liver, heart, and kidneys. When excess amounts are consumed, they are either not absorbed or the small amount that is absorbed is excreted in urine [3].

Bacteria in the large intestine produce free riboflavin that can be absorbed by the large intestine in amounts that depend on the diet. More riboflavin is produced after ingestion of vegetable-based than meat-based foods [2].

Riboflavin is yellow and naturally fluorescent when exposed to ultraviolet light [1]. Moreover, ultraviolet and visible light can rapidly inactivate riboflavin and its derivatives. Because of this sensitivity, lengthy light therapy to treat jaundice in newborns or skin disorders can lead to riboflavin deficiency. The risk of riboflavin loss from exposure to light is the reason why milk is not typically stored in glass containers [3,5].

Riboflavin status is not routinely measured in healthy people. A stable and sensitive measure of riboflavin deficiency is the erythrocyte glutathione reductase activity coefficient (EGRAC), which is based on the ratio between this enzyme’s in vitro activity in the presence of FAD to that without added FAD [1,6,7]. The most appropriate EGRAC thresholds for indicating normal or abnormal riboflavin status are uncertain [6]. An EGRAC of 1.2 or less is usually used to indicate adequate riboflavin status, 1.2–1.4 to indicate marginal deficiency, and greater than 1.4 to indicate riboflavin deficiency [1,6]. However, a higher EGRAC does not necessarily correlate with degree of riboflavin deficiency. Furthermore, the EGRAC cannot be used in people with glucose-6-phosphate dehydrogenase deficiency, which is present in about 10% of African Americans [8].

Another widely used measure of riboflavin status is fluorometric measurement of urinary excretion over 24 hours (expressed as total amount of riboflavin excreted or in relation to the amount of creatinine excreted) [2]. Because the body can store only small amounts of riboflavin, urinary excretion reflects dietary intake until tissues are saturated [6]. Total riboflavin excretion in healthy, riboflavin-replete adults is at least 120 mcg/day; a rate of less than 40 mcg/day indicates deficiency [1,6]. This technique is less accurate for reflecting long-term riboflavin status than EGRAC [1,6]. Also, urinary excretion levels can decrease with age and increase with exposure to stress and certain drugs, and the amount excreted strongly reflects recent intake [1].

Recommended Intakes

Intake recommendations for riboflavin and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies [3]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA; intake at this level is assumed to ensure nutritional adequacy.
  • Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current RDAs for riboflavin [3]. For infants from birth to 12 months, the FNB established an AI for riboflavin that is equivalent to the mean intake of riboflavin in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Riboflavin [3]
Age Male Female Pregnancy Lactation
Birth to 6 months* 0.3 mg 0.3 mg
7–12 months* 0.4 mg 0.4 mg
1–3 years 0.5 mg 0.5 mg
4–8 years 0.6 mg 0.6 mg
9–13 years 0.9 mg 0.9 mg
14–18 years 1.3 mg 1.0 mg 1.4 mg 1.6 mg
19-50 years 1.3 mg 1.1 mg 1.4 mg 1.6 mg
51+ years 1.3 mg 1.1 mg

* AI

Sources of Riboflavin

Food

Foods that are particularly rich in riboflavin include eggs, organ meats (kidneys and liver), lean meats, and milk [2,4]. Green vegetables also contain riboflavin. Grains and cereals are fortified with riboflavin in the United States and many other countries [4]. The largest dietary contributors of total riboflavin intake in U.S. men and women are milk and milk drinks, bread and bread products, mixed foods whose main ingredient is meat, ready-to-eat cereals, and mixed foods whose main ingredient is grain [3]. The riboflavin in most foods is in the form of FAD, although the main form in eggs and milk is free riboflavin [9].

About 95% of riboflavin in the form of FAD or FMN from food is bioavailable up to a maximum of about 27 mg of riboflavin per meal or dose [3].The bioavailability of free riboflavin is similar to that of FAD and FMN [9,10]. Because riboflavin is soluble in water, about twice as much riboflavin content is lost in cooking water when foods are boiled as when they are prepared in other ways, such as by steaming or microwaving [11].

Several food sources of riboflavin are listed in Table 2.

Table 2: Selected Food Sources of Riboflavin [12]
Food Milligrams
(mg) per
serving
Percent
DV*
Beef liver, pan fried, 3 ounces 2.9 171
Breakfast cereals, fortified with 100% of the DV for riboflavin, 1 serving 1.7 100
Oats, instant, fortified, cooked with water, 1 cup 1.1 65
Yogurt, plain, fat free, 1 cup 0.6 35
Milk, 2% fat, 1 cup 0.5 29
Beef, tenderloin steak, boneless, trimmed of fat, grilled, 3 ounces 0.4 24
Clams, mixed species, cooked, moist heat, 3 ounces 0.4 24
Mushrooms, portabella, sliced, grilled, ½ cup 0.3 18
Almonds, dry roasted, 1 ounce 0.3 18
Cheese, Swiss, 3 ounces 0.3 18
Rotisserie chicken, breast meat only, 3 ounces 0.2 12
Egg, whole, scrambled, 1 large 0.2 12
Quinoa, cooked, 1 cup 0.2 12
Bagel, plain, enriched, 1 medium (3½”–4” diameter) 0.2 12
Salmon, pink, canned, 3 ounces 0.2 12
Spinach, raw, 1 cup 0.1 6
Apple, with skin, 1 large 0.1 6
Kidney beans, canned, 1 cup 0.1 6
Macaroni, elbow shaped, whole wheat, cooked, 1 cup 0.1 6
Bread, whole wheat, 1 slice 0.1 6
Cod, Atlantic, cooked, dry heat, 3 ounces 0.1 6
Sunflower seeds, toasted, 1 ounce 0.1 6
Tomatoes, crushed, canned, ½ cup 0.1 6
Rice, white, enriched, long grain, cooked, ½ cup 0.1 6
Rice, brown, long grain, cooked, ½ cup 0 0

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for riboflavin is 1.7 mg for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) National Nutrient Database for Standard Referenceexternal link disclaimer website [12] lists the nutrient content of many foods and provides a comprehensive list of foods containing riboflavin arranged by nutrient content and food name.

Dietary supplements

Riboflavin is available in many dietary supplements. Multivitamin/multimineral supplements with riboflavin commonly provide 1.7 mg riboflavin (100% of the DV) [13]. Supplements containing riboflavin only or B-complex vitamins (that include riboflavin) are also available. In most supplements, riboflavin is in the free form, but some supplements have riboflavin 5’-phosphate.

Riboflavin Intakes and Status

Most people in the United States consume the recommended amounts of riboflavin. An analysis of data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) showed that less than 6% of the U.S. population has an intake of riboflavin from foods and supplements below the EAR [14]. An analysis of self-reported data from the 1999–2004 NHANES found that intakes of riboflavin were higher in lacto-ovo vegetarians (2.3 mg/day) than nonvegetarians (2.1 mg/day) [15].

Among children and teens, the average daily riboflavin intake from foods is 1.8 mg for ages 2–5 years, 1.9 mg for ages 6–11, and 2.1 mg for ages 12–19 [16]. In adults, the average daily riboflavin intake from foods is 2.5 mg in men and 1.8 mg in women. The average daily riboflavin intake from foods and supplements in children and teens is 2.1 mg for ages 2–5 years, 2.2 mg for ages 6–11, and 2.3 mg for ages 12–19. In adults aged 20 and older, the average daily riboflavin intake from foods and supplements is 4.5 mg in men and 4.7 mg in women.

Riboflavin Deficiency

Riboflavin deficiency is extremely rare in the United States. In addition to inadequate intake, causes of riboflavin deficiency can include endocrine abnormalities (such as thyroid hormone insufficiency) and some diseases [1]. The signs and symptoms of riboflavin deficiency (also known as ariboflavinosis) include skin disorders, hyperemia (excess blood) and edema of the mouth and throat, angular stomatitis (lesions at the corners of the mouth), cheilosis (swollen, cracked lips), hair loss, reproductive problems, sore throat, itchy and red eyes, and degeneration of the liver and nervous system [1-3,8]. People with riboflavin deficiency typically have deficiencies of other nutrients, so some of these signs and symptoms might reflect these other deficiencies. Severe riboflavin deficiency can impair the metabolism of other nutrients, especially other B vitamins, through diminished levels of flavin coenzymes [3]. Anemia and cataracts can develop if riboflavin deficiency is severe and prolonged [1].

The earlier changes associated with riboflavin deficiency are easily reversed. However, riboflavin supplements rarely reverse later anatomical changes (such as formation of cataracts) [1].

Groups at Risk of Riboflavin Inadequacy

The following groups are among those most likely to have inadequate riboflavin status.

Vegetarian athletes

Exercise produces stress in the metabolic pathways that use riboflavin [17]. The Academy of Nutrition and Dietetics, Dietitians of Canada, and the American College of Sports Medicine state that vegetarian athletes are at risk of riboflavin deficiency because of their increased need for this nutrient and because some vegetarians exclude all animal products (including milk, yogurt, cheese, and eggs), which tend to be good sources of riboflavin, from their diets [18]. These associations recommend that vegetarian athletes consult a sports dietitian to avoid this potential problem.

Pregnant and lactating women and their infants

Pregnant or lactating women who rarely consume meats or dairy products (such as those living in developing countries and some vegetarians in the United States) are at risk of riboflavin deficiency, which can have adverse effects on the health of both mothers and their infants [2]. Riboflavin deficiency during pregnancy, for example, can increase the risk of preeclampsia [19]. The limited evidence on the benefits of riboflavin supplements during pregnancy in both developed and developing countries is mixed [20-22].

Riboflavin intakes during pregnancy have a positive association with infant birth weight and length [23]. Infants of mothers with riboflavin deficiency or low dietary intakes (less than 1.2 mg/day) during pregnancy have a higher risk of deficiency and of certain birth defects (such as outflow tract defects of the heart) [21,24]. However, maternal riboflavin intake has no association with the risk of orofacial clefts in infants [25].

In well-nourished women, riboflavin concentrations in breast milk range from 180 to 800 mcg/L and concentrations of riboflavin in breast milk increase over time [26,27]. In developing countries, in contrast, riboflavin levels in breast milk range from 160 to 220 mcg/L [26].

People who are vegan and/or consume little milk

In people who eat meat and dairy products, these foods contribute a substantial proportion of riboflavin in the diet. For this reason, people who live in developing countries and have limited intakes of meat and dairy products have an increased risk of riboflavin deficiency [28,29]. Vegans and those who consume little milk in developed countries are also at risk of riboflavin inadequacy [30-34].

People with infantile Brown-Vialetto-Van Laere syndrome

Infantile Brown-Vialetto-Van Laere syndrome is a very rare neurological disorder that can begin at any age and is associated with deafness, bulbar palsy (a motor-neuron disease), and respiratory difficulties [35]. The disease is caused by mutations in the SLC52A3 gene, which encodes the intestinal riboflavin transporter. As a result, these patients have riboflavin deficiency. Riboflavin supplementation can be a life-saving treatment in this population.

Riboflavin and Health

This section focuses on two conditions in which riboflavin might play a role: migraine headaches and cancer.

Migraine headaches

Migraine headaches typically produce intense pulsing or throbbing pain in one area of the head [36]. These headaches are sometimes preceded or accompanied by aura (transient focal neurological symptoms before or during the headaches). Mitochondrial dysfunction is thought to play a causal role in some types of migraine [37]. Because riboflavin is required for mitochondrial function, researchers are studying the potential use of riboflavin to prevent or treat migraine headaches [38].

Some, but not all, of the few small studies conducted to date have found evidence of a beneficial effect of riboflavin supplements on migraine headaches in adults and children. In a randomized trial in 55 adults with migraine, 400 mg/day riboflavin reduced the frequency of migraine attacks by two per month compared to placebo [39]. In a retrospective study in 41 children (mean age 13 years) in Italy, 200 or 400 mg/day riboflavin for 3 to 6 months significantly reduced the frequency (from 21.7 ± 13.7 to 13.2 ± 11.8 migraine attacks over a 3-month period) and intensity of migraine headaches during treatment [40]. The beneficial effects lasted throughout the 1.5-year follow-up period after treatment ended. However, two small randomized studies in children found that 50 to 200 mg/day riboflavin did not reduce the number of migraine headaches or headache severity compared to placebo [41,42].

The Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society concluded that riboflavin is probably effective for preventing migraine headaches and recommended offering it for this purpose [43]. The Canadian Headache Society recommends 400 mg/day riboflavin for migraine headache prevention, noting that although the evidence supporting this recommendation is of low quality, there is some evidence for benefit and side effects (such as discolored urine) are minimal [44].

Cancer prevention

Experts have theorized that riboflavin might help prevent the DNA damage caused by many carcinogens by acting as a coenzyme with several different cytochrome P450 enzymes [1]. However, data on the relationship between riboflavin and cancer prevention or treatment are limited and study findings are mixed.

A few large observational studies have produced conflicting results on the relationship between riboflavin intakes and lung cancer risk. A prospective study followed 41,514 current, former, and never smokers in the Melbourne Collaborative Cohort Study for 15 years, on average [45]. The average riboflavin intake among all participants was 2.5 mg/day. The results showed a significant inverse association between dietary riboflavin intake and lung cancer risk in current smokers (fifth versus first quintile) but not former or never smokers. However, another cohort study in 385,747 current, former, and never smokers who were followed for up to 12 years in the European Prospective Investigation into Cancer and Nutrition found no association between riboflavin intakes and colorectal cancer risk in any of the three groups [46]. Moreover, the prospective Canadian National Breast Screening Study showed no association between dietary intakes or serum levels of riboflavin and lung cancer risk in 89,835 women aged 40-59 from the general population over 16.3 years, on average [47].

Observational studies on the relationship between riboflavin intakes and colorectal cancer risk have not yielded conclusive results either. An analysis of data on 88,045 postmenopausal women in the Women’s Health Initiative Observational Study showed that total intakes of riboflavin from both foods and supplements were associated with a lower risk of colorectal cancer [48]. A study that followed 2,349 individuals with cancer and 4,168 individuals without cancer participating in the Netherlands Cohort Study on Diet and Cancer for 13 years found no significant association between riboflavin and proximal colon cancer risk among women [49].

Future studies, including clinical trials, are needed to clarify the relationship between riboflavin intakes and various types of cancer and determine whether riboflavin supplements might reduce cancer risk.

Health Risks from Excessive Riboflavin

Intakes of riboflavin from food that are many times the RDA have no observable toxicity, possibly because riboflavin’s solubility and capacity to be absorbed in the gastrointestinal tract are limited [1,3]. Because adverse effects from high riboflavin intakes from foods or supplements (400 mg/day for at least 3 months) have not been reported, the FNB did not establish ULs for riboflavin [3]. The limited data available on riboflavin’s adverse effects do not mean, however, that high intakes have no adverse effects, and the FNB urges people to be cautious about consuming excessive amounts of riboflavin [3].

Interactions with Medications

Riboflavin is not known to have any clinically relevant interactions with medications.

Riboflavin and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Milk and yogurt are high in riboflavin. Enriched grains are good sources of riboflavin. Quinoa and some fruits and vegetables contain riboflavin.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Beef is rich in riboflavin. Chicken, fish, nuts, and eggs are good sources of riboflavin.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

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  41. Bruijn J, Duivenvoorden H, Passchier J, Locher H, Dijkstra N, Arts WF. Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial. Cephalalgia 2010;30:1426-34. [PubMed abstract]
  42. MacLennan SC, Wade FM, Forrest KM, Ratanayake PD, Fagan E, Antony J. High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child Neurol 2008;23:1300-4. [PubMed abstract]
  43. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1346-53. [PubMed abstract]
  44. Pringsheim T, Davenport W, Mackie G, Worthington I, Aube M, Christie SN, et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 2012;39:S1-59. [PubMed abstract]
  45. Bassett JK, Hodge AM, English DR, Baglietto L, Hopper JL, Giles GG, et al. Dietary intake of B vitamins and methionine and risk of lung cancer. Eur J Clin Nutr 2012;66:182-7. [PubMed abstract]
  46. Johansson M, Relton C, Ueland PM, Vollset SE, Midttun O, Nygard O, et al. Serum B vitamin levels and risk of lung cancer. JAMA 2010;303:2377-85. [PubMed abstract]
  47. Kabat GC, Miller AB, Jain M, Rohan TE. Dietary intake of selected B vitamins in relation to risk of major cancers in women. Br J Cancer 2008;99:816-21. [PubMed abstract]
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This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

What is vitamin B12 and what does it do?

Introduction

Vitamin B12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 exists in several forms and contains the mineral cobalt [1-4], so compounds with vitamin B12 activity are collectively called “cobalamins”. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 that are active in human metabolism [5].

Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis [1-5]. Vitamin B12 functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase catalyzes the conversion of homocysteine to methionine [5,6]. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate [3,5,6], an essential biochemical reaction in fat and protein metabolism. Succinyl-CoA is also required for hemoglobin synthesis.

Vitamin B12, bound to protein in food, is released by the activity of hydrochloric acid and gastric protease in the stomach [5]. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and, thus, does not require this separation step. Free vitamin B12 then combines with intrinsic factor, a glycoprotein secreted by the stomach’s parietal cells, and the resulting complex undergoes absorption within the distal ileum by receptor-mediated endocytosis [5,7]. Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12) [8].

Pernicious anemia is an autoimmune disease that affects the gastric mucosa and results in gastric atrophy. This leads to the destruction of parietal cells, achlorhydria, and failure to produce intrinsic factor, resulting in vitamin B12 malabsorption [3,5,9-11]. If pernicious anemia is left untreated, it causes vitamin B12 deficiency, leading to megaloblastic anemia and neurological disorders, even in the presence of adequate dietary intake of vitamin B12.

Vitamin B12 status is typically assessed via serum or plasma vitamin B12 levels. Values below approximately 170–250 pg/mL (120–180 picomol/L) for adults [5] indicate a vitamin B12 deficiency. However, evidence suggests that serum vitamin B12 concentrations might not accurately reflect intracellular concentrations [6]. An elevated serum homocysteine level (values >13 micromol/L) [12] might also suggest a vitamin B12 deficiency. However, this indicator has poor specificity because it is influenced by other factors, such as low vitamin B6 or folate levels [5]. Elevated methylmalonic acid levels (values >0.4 micromol/L) might be a more reliable indicator of vitamin B12 status because they indicate a metabolic change that is highly specific to vitamin B12 deficiency [5-7,12].

Recommended Intakes

Intake recommendations for vitamin B12 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) [5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender [5], include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects [5].

Table 1 lists the current RDAs for vitamin B12 in micrograms (mcg) [5]. For infants aged 0 to 12 months, the FNB established an AI for vitamin B12 that is equivalent to the mean intake of vitamin B12 in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B12 [5]
Age Male Female Pregnancy Lactation
0–6 months* 0.4 mcg 0.4 mcg
7–12 months* 0.5 mcg 0.5 mcg
1–3 years 0.9 mcg 0.9 mcg
4–8 years 1.2 mcg 1.2 mcg
9–13 years 1.8 mcg 1.8 mcg
14+ years 2.4 mcg 2.4 mcg 2.6 mcg 2.8 mcg

* Adequate Intake

Sources of Vitamin B12

Food

Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, but fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability for vegetarians [5,13-15]. Some nutritional yeast products also contain vitamin B12. Fortified foods vary in formulation, so it is important to read product labels to determine which added nutrients they contain.

Several food sources of vitamin B12 are listed in Table 2.

Table 2: Selected Food Sources of Vitamin B12 [13]

Food Micrograms (mcg)
per serving
Percent DV*
Clams, cooked, 3 ounces 84.1 1,402
Liver, beef, cooked, 3 ounces 70.7 1,178
Breakfast cereals, fortified with 100% of the DV for vitamin B12, 1 serving 6.0 100
Trout, rainbow, wild, cooked, 3 ounces 5.4 90
Salmon, sockeye, cooked, 3 ounces 4.8 80
Trout, rainbow, farmed, cooked, 3 ounces 3.5 58
Tuna fish, light, canned in water, 3 ounces 2.5 42
Cheeseburger, double patty and bun, 1 sandwich 2.1 35
Haddock, cooked, 3 ounces 1.8 30
Breakfast cereals, fortified with 25% of the DV for vitamin B12, 1 serving 1.5 25
Beef, top sirloin, broiled, 3 ounces 1.4 23
Milk, low-fat, 1 cup 1.2 18
Yogurt, fruit, low-fat, 8 ounces 1.1 18
Cheese, Swiss, 1 ounce 0.9 15
Beef taco, 1 soft taco 0.9 15
Ham, cured, roasted, 3 ounces 0.6 10
Egg, whole, hard boiled, 1 large 0.6 10
Chicken, breast meat, roasted, 3 ounces 0.3 5

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers determine the level of various nutrients in a standard serving of food in relation to their approximate requirement for it. The DV for vitamin B12 is 6.0 mcg. However, the FDA does not require food labels to list vitamin B12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer Web site [13]) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B12 arranged by nutrient content and by food name.

Dietary supplements

In dietary supplements, vitamin B12 is usually present as cyanocobalamin [5], a form that the body readily converts to the active forms methylcobalamin and 5-deoxyadenosylcobalamin. Dietary supplements can also contain methylcobalamin and other forms of vitamin B12.

Existing evidence does not suggest any differences among forms with respect to absorption or bioavailability. However the body’s ability to absorb vitamin B12 from dietary supplements is largely limited by the capacity of intrinsic factor. For example, only about 10 mcg of a 500 mcg oral supplement is actually absorbed in healthy people [8].

In addition to oral dietary supplements, vitamin B12 is available in sublingual preparations as tablets or lozenges. These preparations are frequently marketed as having superior bioavailability, although evidence suggests no difference in efficacy between oral and sublingual forms [16,17].

Prescription medications

Vitamin B12, in the form of cyanocobalamin and occasionally hydroxocobalamin, can be administered parenterally as a prescription medication, usually by intramuscular injection [12]. Parenteral administration is typically used to treat vitamin B12 deficiency caused by pernicious anemia and other conditions that result in vitamin B12 malabsorption and severe vitamin B12 deficiency [12].

Vitamin B12 is also available as a prescription medication in a gel formulation applied intranasally, a product marketed as an alternative to vitamin B12 injections that some patients might prefer [18]. This formulation appears to be effective in raising vitamin B12 blood levels [19], although it has not been thoroughly studied in clinical settings.

Vitamin B12 Intakes and Status

Most children and adults in the United States consume recommended amounts of vitamin B12, according to analyses of data from the 1988–1994 National Health and Nutrition Examination Survey (NHANES III) [5,20] and the 1994–1996 Continuing Survey of Food Intakes by Individuals [5]. Data from the 1999–2000 NHANES indicate that the median daily intake of vitamin B12 for the U.S. population is 3.4 mcg [21].

Some people—particularly older adults, those with pernicious anemia, and those with reduced levels of stomach acidity (hypochlorhydria or achlorhydria) or intestinal disorders—have difficulty absorbing vitamin B12 from food and, in some cases, oral supplements [22,23]. As a result, vitamin B12 deficiency is common, affecting between 1.5% and 15% of the general population [24,25]. In many of these cases, the cause of the vitamin B12 deficiency is unknown [8].

Evidence from the Framingham Offspring Study suggests that the prevalence of vitamin B12 deficiency in young adults might be greater than previously assumed [15]. This study found that the percentage of participants in three age groups (26–49 years, 50–64 years, and 65 years and older) with deficient blood levels of vitamin B12 was similar. The study also found that individuals who took a supplement containing vitamin B12 or consumed fortified cereal more than four times per week were much less likely to have a vitamin B12 deficiency.

Individuals who have trouble absorbing vitamin B12 from foods, as well as vegetarians who consume no animal foods, might benefit from vitamin B12-fortified foods, oral vitamin B12 supplements, or vitamin B12 injections [26].

Vitamin B12 Deficiency

Vitamin B12 deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss [1,3,27]. Neurological changes, such as numbness and tingling in the hands and feet, can also occur [5,28]. Additional symptoms of vitamin B12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue [29]. The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage [6]. During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia [30]. Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B12 deficiency.

Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 may also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration [24,25]. Overall, an individual patient’s ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection [8]. In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged [24].

Folic acid and vitamin B12

Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency [3,5] without correcting the neurological damage that also occurs [1,31]. Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency [6,11]. Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults [5].

Groups at Risk of Vitamin B12 Deficiency

The main causes of vitamin B12 deficiency include vitamin B12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency [12]. However, in many cases, the cause of vitamin B12 deficiency is unknown. The following groups are among those most likely to be vitamin B12 deficient.

Older adults

Atrophic gastritis, a condition affecting 10%–30% of older adults, decreases secretion of hydrochloric acid in the stomach, resulting in decreased absorption of vitamin B12 [5,11,32-36]. Decreased hydrochloric acid levels might also increase the growth of normal intestinal bacteria that use vitamin B12, further reducing the amount of vitamin B12 available to the body [37].

Individuals with atrophic gastritis are unable to absorb the vitamin B12 that is naturally present in food. Most, however, can absorb the synthetic vitamin B12 added to fortified foods and dietary supplements. As a result, the IOM recommends that adults older than 50 years obtain most of their vitamin B12 from vitamin supplements or fortified foods [5]. However, some elderly patients with atrophic gastritis require doses much higher than the RDA to avoid subclinical deficiency [38].

Individuals with pernicious anemia

Pernicious anemia, a condition that affects 1%–2% of older adults [11], is characterized by a lack of intrinsic factor. Individuals with pernicious anemia cannot properly absorb vitamin B12 in the gastrointestinal tract [3,5,9,10]. Pernicious anemia is usually treated with intramuscular vitamin B12. However, approximately 1% of oral vitamin B12 can be absorbed passively in the absence of intrinsic factor [11], suggesting that high oral doses of vitamin B12 might also be an effective treatment.

Individuals with gastrointestinal disorders

Individuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores [12,23]. Subtly reduced cognitive function resulting from early vitamin B12 deficiency might be the only initial symptom of these intestinal disorders, followed by megaloblastic anemia and dementia.

Individuals who have had gastrointestinal surgery

Surgical procedures in the gastrointestinal tract, such as weight loss surgery or surgery to remove all or part of the stomach, often result in a loss of cells that secrete hydrochloric acid and intrinsic factor [5,39,40]. This reduces the amount of vitamin B12, particularly food-bound vitamin B12 [41], that the body releases and absorbs. Surgical removal of the distal ileum also can result in the inability to absorb vitamin B12. Individuals undergoing these surgical procedures should be monitored preoperatively and postoperatively for several nutrient deficiencies, including vitamin B12 deficiency [42].

Vegetarians

Strict vegetarians and vegans are at greater risk than lacto-ovo vegetarians and nonvegetarians of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods [5]. Fortified breakfast cereals are one of the few sources of vitamin B12 from plants and can be used as a dietary source of vitamin B12 for strict vegetarians and vegans.

Pregnant and lactating women who follow strict vegetarian diets and their infants

Vitamin B12 crosses the placenta during pregnancy and is present in breast milk. Exclusively breastfed infants of women who consume no animal products may have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency within months of birth [5,43]. Undetected and untreated vitamin B12 deficiency in infants can result in severe and permanent neurological damage.

The American Dietetic Association recommends supplemental vitamin B12 for vegans and lacto-ovo vegetarians during both pregnancy and lactation to ensure that enough vitamin B12 is transferred to the fetus and infant [44]. Pregnant and lactating women who follow strict vegetarian or vegan diets should consult with a pediatrician regarding vitamin B12 supplements for their infants and children [5].

Vitamin B12 and Health

Cardiovascular disease

Cardiovascular disease is the most common cause of death in industrialized countries, such as the United States, and is on the rise in developing countries. Risk factors for cardiovascular disease include elevated low-density lipoprotein (LDL) levels, high blood pressure, low high-density lipoprotein (HDL) levels, obesity, and diabetes [45].

Elevated homocysteine levels have also been identified as an independent risk factor for cardiovascular disease [46-48]. Homocysteine is a sulfur-containing amino acid derived from methionine that is normally present in blood. Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation [46,47,49]. Evidence from retrospective, cross-sectional, and prospective studies links elevated homocysteine levels with coronary heart disease and stroke [46,49-58].

Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to inadequate function of methionine synthase [6]. Results from several randomized controlled trials indicate that combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels in people with vascular disease or diabetes and in young adult women [59-67]. In another study, older men and women who took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels [68].

Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular disease [48,62-67]. In the Women’s Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular disease who took daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid, and 50 mg vitamin B6 for 7.3 years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels [65]. The Heart Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54 years with vascular disease or diabetes, found that daily treatment with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for an average of 5 years reduced homocysteine levels and the risk of stroke but did not reduce the risk of major cardiovascular events [63]. In the Western Norway B Vitamin Intervention Trial, which included 3,096 patients undergoing coronary angiography, daily supplements of 0.4 mg vitamin B12 and 0.8 mg folic acid with or without 40 mg vitamin B6 for 1 year reduced homocysteine levels by 30% but did not affect total mortality or the risk of major cardiovascular events during 38 months of follow-up [66]. The Norwegian Vitamin (NORVIT) trial [62] and the Vitamin Intervention for Stroke Prevention trial had similar results [67].

The American Heart Association has concluded that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk [48].

Dementia and cognitive function

Researchers have long been interested in the potential connection between vitamin B12 deficiency and dementia [47,69]. A deficiency in vitamin B12 causes an accumulation of homocysteine in the blood [6] and might decrease levels of substances needed to metabolize neurotransmitters [70]. Observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer’s disease and dementia [6,47,71]. Low vitamin B12 status has also been positively associated with cognitive decline [72].

Despite evidence that vitamin B12 lowers homocysteine levels and correlations between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent effect on cognition [73-77]. In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older with no or moderate cognitive impairment received 1,000 mcg vitamin B12, 1,000 mcg vitamin B12 plus 400 mcg folic acid, or placebo for 24 weeks [73]. Treatment with vitamin B12 plus folic acid reduced homocysteine concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved cognitive function.

Women at high risk of cardiovascular disease who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study were randomly assigned to receive daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid and 50 mg vitamin B6, or placebo [76]. After a mean of 1.2 years, B-vitamin supplementation did not affect mean cognitive change from baseline compared with placebo. However, in a subset of women with low baseline dietary intake of B vitamins, supplementation significantly slowed the rate of cognitive decline. In a trial conducted by the Alzheimer’s Disease Cooperative Study consortium that included individuals with mild-to-moderate Alzheimer’s disease, daily supplements of 1 mg vitamin B12, 5 mg folic acid, and 25 mg vitamin B6 for 18 months did not slow cognitive decline compared with placebo [77]. Another study found similar results in 142 individuals at risk of dementia who received supplements of 2 mg folic acid and 1 mg vitamin B12 for 12 weeks [75].

The authors of two Cochrane reviews and a systematic review of randomized trials of the effects of B vitamins on cognitive function concluded that insufficient evidence is available to show whether vitamin B12 alone or in combination with vitamin B6 or folic acid has an effect on cognitive function or dementia [78-80]. Additional large clinical trials of vitamin B12 supplementation are needed to assess whether vitamin B12 has a direct effect on cognitive function and dementia [6].

Energy and endurance

Due to its role in energy metabolism, vitamin B12 is frequently promoted as an energy enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit [81].

Health Risks from Excessive Vitamin B12

The IOM did not establish a UL for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the IOM states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals” [5].

Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial) [62,63].

Interactions with Medications

Vitamin B12 has the potential to interact with certain medications. In addition, several types of medications might adversely affect vitamin B12 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B12 status with their healthcare providers.

Chloramphenicol

Chloramphenicol (Chloromycetin®) is a bacteriostatic antibiotic. Limited evidence from case reports indicates that chloramphenicol can interfere with the red blood cell response to supplemental vitamin B12 in some patients [82].

Proton pump inhibitors

Proton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®), are used to treat gastroesophageal reflux disease and peptic ulcer disease. These drugs can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach [83-85]. However, the evidence is conflicting on whether proton pump inhibitor use affects vitamin B12 status [86-89]. As a precaution, health care providers should monitor vitamin B12 status in patients taking proton pump inhibitors for prolonged periods [82].

H2 receptor antagonists

Histamine H2 receptor antagonists, used to treat peptic ulcer disease, include cimetidine (Tagamet®), famotidine (Pepcid®), and ranitidine (Zantac®). These medications can interfere with the absorption of vitamin B12 from food by slowing the release of hydrochloric acid into the stomach. Although H2 receptor antagonists have the potential to cause vitamin B12 deficiency [90], no evidence indicates that they promote vitamin B12 deficiency, even after long-term use [89]. Clinically significant effects may be more likely in patients with inadequate vitamin B12 stores, especially those using H2 receptor antagonists continuously for more than 2 years [90].

Metformin

Metformin, a hypoglycemic agent used to treat diabetes, might reduce the absorption of vitamin B12 [91-93], possibly through alterations in intestinal mobility, increased bacterial overgrowth, or alterations in the calcium-dependent uptake by ileal cells of the vitamin B12-intrinsic factor complex [92,93]. Small studies and case reports suggest that 10%–30% of patients who take metformin have reduced vitamin B12 absorption [92,93]. In a randomized, placebo controlled trial in patients with type 2 diabetes, metformin treatment for 4.3 years significantly decreased vitamin B12 levels by 19% and raised the risk of vitamin B12 deficiency by 7.2% compared with placebo [94]. Some studies suggest that supplemental calcium might help improve the vitamin B12 malabsorption caused by metformin [92,93], but not all researchers agree [95].

Vitamin B12 and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

Fish and red meat are excellent sources of vitamin B12. Poultry and eggs also contain vitamin B12.
  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Milk and milk products are good sources of vitamin B12. Many ready-to-eat breakfast cereals are fortified with vitamin B12.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

References

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What is vitamin B6 and what does it do?

Introduction

Vitamin B6 is a water-soluble vitamin that is naturally present in many foods, added to others, and available as a dietary supplement. It is the generic name for six compounds (vitamers) with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters. Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are the active coenzyme forms of vitamin B6 [1,2]. Substantial proportions of the naturally occurring pyridoxine in fruits, vegetables, and grains exist in glycosylated forms that exhibit reduced bioavailability [3].

Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism [1]. Both PLP and PMP are involved in amino acid metabolism, and PLP is also involved in the metabolism of one-carbon units, carbohydrates, and lipids [3]. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood [3]. Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation [3].

The human body absorbs vitamin B6 in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion [2].

Vitamin B6 concentrations can be measured directly by assessing concentrations of PLP; other vitamers; or total vitamin B6 in plasma, erythrocytes, or urine [1]. Vitamin B6 concentrations can also be measured indirectly by assessing either erythrocyte aminotransferase saturation by PLP or tryptophan metabolites. Plasma PLP is the most common measure of vitamin B6 status.

PLP concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults [3]. However, the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (formerly National Academy of Sciences) used a plasma PLP level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults [1,3].

Recommended Intakes

Intake recommendations for vitamin B6 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the FNB [1]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current RDAs for vitamin B6 [1]. For infants from birth to 12 months, the FNB established an AI for vitamin B6 that is equivalent to the mean intake of vitamin B6 in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B6 [1]
Age Male Female Pregnancy Lactation
Birth to 6 months 0.1 mg* 0.1 mg*
7–12 months 0.3 mg* 0.3 mg*
1–3 years 0.5 mg 0.5 mg
4–8 years 0.6 mg 0.6 mg
9–13 years 1.0 mg 1.0 mg
14–18 years 1.3 mg 1.2 mg 1.9 mg 2.0 mg
19–50 years 1.3 mg 1.3 mg 1.9 mg 2.0 mg
51+ years 1.7 mg 1.5 mg

* Adequate Intake (AI)

Sources of Vitamin B6

Food

Vitamin B6 is found in a wide variety of foods [1,3,4]. The richest sources of vitamin B6 include fish, beef liver and other organ meats, potatoes and other starchy vegetables, and fruit (other than citrus). In the United States, adults obtain most of their dietary vitamin B6 from fortified cereals, beef, poultry, starchy vegetables, and some non-citrus fruits [1,3,5]. About 75% of vitamin B6 from a mixed diet is bioavailable [1].

The table of selected food sources of vitamin B6 suggests many dietary sources of vitamin B6.

Table 2: Selected Food Sources of Vitamin B6 [4]
Food Milligrams (mg) per serving Percent DV*
Chickpeas, canned, 1 cup 1.1 55
Beef liver, pan fried, 3 ounces 0.9 45
Tuna, yellowfin, fresh, cooked, 3 ounces 0.9 45
Salmon, sockeye, cooked, 3 ounces 0.6 30
Chicken breast, roasted, 3 ounces 0.5 25
Breakfast cereals, fortified with 25% of the DV for vitamin B6 0.5 25
Potatoes, boiled, 1 cup 0.4 20
Turkey, meat only, roasted, 3 ounces 0.4 20
Banana, 1 medium 0.4 20
Marinara (spaghetti) sauce, ready to serve, 1 cup 0.4 20
Ground beef, patty, 85% lean, broiled, 3 ounces 0.3 15
Waffles, plain, ready to heat, toasted, 1 waffle 0.3 15
Bulgur, cooked, 1 cup 0.2 10
Cottage cheese, 1% low-fat, 1 cup 0.2 10
Squash, winter, baked, ½ cup 0.2 10
Rice, white, long-grain, enriched, cooked, 1 cup 0.1 5
Nuts, mixed, dry-roasted, 1 ounce 0.1 5
Raisins, seedless, ½ cup 0.1 5
Onions, chopped, ½ cup 0.1 5
Spinach, frozen, chopped, boiled, ½ cup 0.1 5
Tofu, raw, firm, prepared with calcium sulfate, ½ cup 0.1 5
Watermelon, raw, 1 cup 0.1 5

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B6 is 2 mg for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B6 arranged by nutrient content and by food name.

Dietary supplements

Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone supplement [6]. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP. Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids. Absorption of vitamin B6 from supplements is similar to that from food sources and does not differ substantially among the various forms of supplements [1]. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine [7].

About 28%–36% of the general population uses supplements containing vitamin B6 [8,9]. Adults aged 51 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin B6.

Vitamin B6 Intakes and Status

Most children, adolescents, and adults in the United States consume the recommended amounts of vitamin B6, according to an analysis of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) [9]. The average vitamin B6 intake is about 1.5 mg/day in women and 2 mg/day in men [1].

However, 11% of vitamin B6 supplement users and 24% of people in the United States who do not take supplements containing vitamin B6 have low plasma PLP concentrations (less than 20 nmol/L) [9]. In the 2003–2004 NHANES analysis, plasma PLP concentrations were low even in some groups that took 2.0–2.9 mg/day, which is higher than the current RDA. Among supplement users and nonusers, plasma PLP levels were much lower in women than men, non-Hispanic blacks than non-Hispanic whites, current smokers than never smokers, and people who were underweight than those of normal weight. Teenagers had the lowest vitamin B6 concentrations, followed by adults aged 21–44 years. However, plasma PLP levels in the elderly were not particularly low, even in those who did not use supplements. Based on these data, the authors of this analysis concluded that the current RDAs might not guarantee adequate vitamin B6 status in many population groups [9].

PLP concentrations tend to be low in people with alcohol dependence; those who are obese; and pregnant women, especially those with preeclampsia or eclampsia [1]. They are also low in people with malabsorption syndromes such as celiac disease, Crohn’s disease, and ulcerative colitis [3].

Vitamin B6 Deficiency

Isolated vitamin B6 deficiency is uncommon; inadequate vitamin B6 status is usually associated with low concentrations of other B-complex vitamins, such as vitamin B12 and folic acid [2]. Vitamin B6 deficiency causes biochemical changes that become more obvious as the deficiency progresses [2].

Vitamin B6 deficiency is associated with microcytic anemia, electroencephalographic abnormalities, dermatitis with cheilosis (scaling on the lips and cracks at the corners of the mouth) and glossitis (swollen tongue), depression and confusion, and weakened immune function [1,2]. Individuals with borderline vitamin B6 concentrations or mild deficiency might have no deficiency signs or symptoms for months or even years. In infants, vitamin B6 deficiency causes irritability, abnormally acute hearing, and convulsive seizures [2].

End-stage renal diseases, chronic renal insufficiency, and other kidney diseases can cause vitamin B6 deficiency [3]. In addition, vitamin B6 deficiency can result from malabsorption syndromes, such as celiac disease, Crohn’s disease, and ulcerative colitis. Certain genetic diseases, such as homocystinuria, can also cause vitamin B6 deficiency [2]. Some medications, such as antiepileptic drugs, can lead to deficiency over time.

Groups at Risk of Vitamin B6 Inadequacy

Frank vitamin B6 deficiencies are relatively rare in the United States but some individuals might have marginal vitamin B6 status [2]. The following groups are among those most likely to have inadequate intakes of vitamin B6.

Individuals with Impaired Renal Function

People with poor renal function, including those with end-stage renal disease and chronic renal insufficiency, often have low vitamin B6 concentrations [3]. Plasma PLP concentrations are also low in patients receiving maintenance kidney dialysis or intermittent peritoneal dialysis, as well as those who have undergone a kidney transplant, perhaps due to increased metabolic clearance of PLP [10]. Patients with kidney disease often show clinical symptoms similar to those of people with vitamin B6 deficiency [10].

Individuals with Autoimmune Disorders

People with rheumatoid arthritis often have low vitamin B6 concentrations, and vitamin B6 concentrations tend to decrease with increased disease severity [3]. These low vitamin B6 levels are due to the inflammation caused by the disease and, in turn, increase the inflammation associated with the disease. Although vitamin B6 supplements can normalize vitamin B6 concentrations in patients with rheumatoid arthritis, they do not suppress the production of inflammatory cytokines or decrease levels of inflammatory markers [3,11].

Patients with celiac disease, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, and other malabsorptive autoimmune disorders tend to have low plasma PLP concentrations [3]. The mechanisms for this effect are not known. However, celiac disease is associated with lower pyridoxine absorption, and low PLP concentrations in inflammatory bowel disease could be due to the inflammatory response [3].

People with Alcohol Dependence

Plasma PLP concentrations tend to be very low in people with alcohol dependence [1]. Alcohol produces acetaldehyde, which decreases net PLP formation by cells and competes with PLP in protein binding [1,3]. As a result, the PLP in cells might be more susceptible to hydrolysis by membrane-bound phosphatase. People with alcohol dependence might benefit from pyridoxine supplementation [3].

Vitamin B6 and Health

Cardiovascular Disease

Scientists have hypothesized that certain B vitamins (folic acid, vitamin B12, and vitamin B6) might reduce cardiovascular disease risk by lowering homocysteine levels [1,12]. Therefore, several clinical trials have assessed the safety and efficacy of supplemental doses of B vitamins to reduce heart disease risk. Evaluating the impact of vitamin B6 from many of these trials is challenging because these studies also included folic acid and vitamin B12 supplementation. For example, the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial, which included more than 5,500 adults with known cardiovascular disease, found that supplementation for 5 years with vitamin B6 (50 mg/day), vitamin B12 (1 mg/day), and folic acid (2.5 mg/day) reduced homocysteine levels and decreased stroke risk by about 25%, but the study did not include a separate vitamin B6 group [13].

Moreover, most other large clinical trials have failed to demonstrate that supplemental B vitamins actually reduce the risk of cardiovascular events, even though they lower homocysteine levels. For example, a randomized clinical trial in 5,442 women aged 42 or older found no effect of vitamin B6 supplementation (50 mg/day) in combination with 2.5 mg folic acid and 1 mg vitamin B12 on cardiovascular disease risk [14]. Two large randomized controlled trials, the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, did include a group that received only vitamin B6 supplements (40 mg/day). The combined analysis of data from these two trials showed no benefit of vitamin B6 supplementation, with or without folic acid (0.8 mg/day) plus vitamin B12 (0.4 mg/day), on major cardiovascular events in 6,837 patients with ischemic heart disease [12]. In a trial of adults who had suffered a nondisabling stroke, supplementation with high or low doses of a combination of vitamins B6 and B12 and folic acid for 2 years had no effect on subsequent stroke incidence, cardiovascular events, or risk of death [15].

The research to date provides little evidence that supplemental amounts of vitamin B6, alone or with folic acid and vitamin B12, can help reduce the risk or severity of cardiovascular disease and stroke.

Cancer

Some research has associated low plasma vitamin B6 concentrations with an increased risk of certain kinds of cancer [3]. For example, a meta-analysis of prospective studies found that people with a vitamin B6 intake in the highest quintile had a 20% lower risk of colorectal cancer than those with an intake in the lowest quintile [16].

However, the small number of clinical trials completed to date has not shown that vitamin B6 supplementation can help prevent cancer or reduce its impact on mortality. For example, an analysis of data from two large randomized, double-blind, placebo-controlled trials in Norway found no association between vitamin B6 supplementation and cancer incidence, mortality, or all-cause mortality [17].

Cognitive Function

Poor vitamin B6 status has been hypothesized to play a role in the cognitive decline that some older adults experience [18]. Several studies have demonstrated an association between vitamin B6 and brain function in the elderly. For example, an analysis of data from the Boston Normative Aging Study found associations between higher serum vitamin B6 concentrations and better memory test scores in 70 men aged 54–81 years [19].

However, a systematic review of 14 randomized controlled trials found insufficient evidence of an effect of vitamin B6 supplementation alone or in combination with vitamin B12 and/or folic acid on cognitive function in people with normal cognitive function, dementia, or ischemic vascular disease [18]. According to this review, most of the studies were of low quality and limited applicability. A Cochrane review found no evidence that short-term vitamin B6 supplementation (for 5–12 weeks) improves cognitive function or mood in the two studies that the authors evaluated [20]. The review did find some evidence that daily vitamin B6 supplements (20 mg) can affect biochemical indices of vitamin B6 status in healthy older men, but these changes had no overall impact on cognition.

More evidence is needed to determine whether vitamin B6 supplements might help prevent or treat cognitive decline in elderly people.

Premenstrual Syndrome

Some evidence suggests that vitamin B6 supplements could reduce the symptoms of premenstrual syndrome (PMS), but conclusions are limited due to the poor quality of most studies [21]. A meta-analysis of nine published trials involving almost 1,000 women with PMS found that vitamin B6 is more effective in reducing PMS symptoms than placebo, but most of the studies analyzed were small and several had methodological weaknesses [21]. A more recent double-blind, randomized controlled trial in 94 women found that 80 mg pyridoxine taken daily over the course of three cycles was associated with statistically significant reductions in a broad range of PMS symptoms, including moodiness, irritability, forgetfulness, bloating, and, especially, anxiety [22]. The potential effectiveness of vitamin B6 in alleviating the mood-related symptoms of PMS could be due to its role as a cofactor in neurotransmitter biosynthesis [23]. Although vitamin B6 shows promise for alleviating PMS symptoms, more research is needed before drawing firm conclusions.

Nausea and Vomiting in Pregnancy

About half of all women experience nausea and vomiting in the first few months of pregnancy, and about 50%–80% experience nausea only [24,25]. Although this condition is generally known as “morning sickness,” it often lasts throughout the day. The condition is not life threatening and typically goes away after 12–20 weeks, but its symptoms can disrupt a woman’s social and physical functioning.

Prospective studies on vitamin B6 supplements to treat morning sickness have had mixed results. In two randomized, placebo-controlled trials, 30–75 mg of oral pyridoxine per day significantly decreased nausea in pregnant women who were experiencing nausea [26,27]. The authors of a recent Cochrane review of studies on interventions for nausea and vomiting in pregnancy could not draw firm conclusions on the value of vitamin B6 to control the symptoms of morning sickness [25].

Randomized trials have shown that a combination of vitamin B6 and doxylamine (an antihistamine) is associated with a 70% reduction in nausea and vomiting in pregnant women and lower hospitalization rates for this problem [24,28].

The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 three or four times a day to treat nausea and vomiting in pregnancy [28]. If the patient’s condition does not improve, ACOG recommends adding doxylamine. Before taking a vitamin B6 supplement, pregnant women should consult a physician because doses could approach the UL.

Health Risks from Excessive Vitamin B6

High intakes of vitamin B6 from food sources have not been reported to cause adverse effects [1]. However, chronic administration of 1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements) [7,29-32]. Symptom severity appears to be dose dependent, and the symptoms usually stop if the patient discontinues the pyridoxine supplements as soon as the neurologic symptoms appear. Other effects of excessive vitamin B6 intakes include painful, disfiguring dermatological lesions; photosensitivity; and gastrointestinal symptoms, such as nausea and heartburn [1,2,29].

The scientific literature includes isolated case reports of congenital defects in the infants of women who took pyridoxine supplements during the first half of pregnancy [7]. However, a more recent observational study found no association between pyridoxine supplementation (mean dose 132.3 ± 74 mg/day) in pregnant women starting at 7 weeks gestation and continuing for 9 ± 4.2 weeks and teratogenic effects in the women’s infants [33].

The FNB has established ULs for vitamin B6 that apply to both food and supplement intakes (Table 3) [1]. The FNB noted that although several reports show sensory neuropathy occurring at doses lower than 500 mg/day, studies in patients treated with vitamin B6 (average dose of 200 mg/day) for up to 5 years found no evidence of this effect. Based on limitations in the data on potential harms from long-term use, the FNB halved the dose used in these studies to establish a UL of 100 mg/day for adults. ULs are lower for children and adolescents based on body size. The ULs do not apply to individuals receiving vitamin B6 for medical treatment, but such individuals should be under the care of a physician.

Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin B6 [1]
Age Male Female Pregnancy Lactation
Birth to 6 months Not possible to establish* Not possible to establish*
7–12 months Not possible to establish* Not possible to establish*
1–3 years 30 mg 30 mg
4–8 years 40 mg 40 mg
9–13 years 60 mg 60 mg
14–18 years 80 mg 80 mg 80 mg 80 mg
19+ years 100 mg 100 mg 100 mg 100 mg

*Breast milk, formula, and food should be the only sources of vitamin B6 for infants.

Interactions with Medications

Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B6 status with their health care providers.

Cycloserine

Cycloserine (Seromycin®) is a broad-spectrum antibiotic used to treat tuberculosis. In combination with pyridoxal phosphate, cycloserine increases urinary excretion of pyridoxine [6]. The urinary loss of pyridoxine might exacerbate the seizures and neurotoxicity associated with cycloserine. Pyridoxine supplements can help prevent these adverse effects.

Antiepileptic Medications

Some antiepileptic drugs, including valproic acid (Depakene®, Stavzor®), carbamazepine (Carbatrol®, Epitol®, Tegretol®, and others), and phenytoin (Dilantin®) increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia [34,35]. High homocysteine levels in antiepileptic drug users might increase the risk of epileptic seizures and systemic vascular events, including stroke, and reduce the ability to control seizures in patients with epilepsy. Furthermore, patients typically use antiepileptic drugs for years, increasing their risk of chronic vascular toxicity.

Some research also indicates that pyridoxine supplementation (200 mg/day for 12–120 days) can reduce serum concentrations of phenytoin and phenobarbital, possibly by increasing the drugs’ metabolism [32,36]. Whether lower pyridoxine doses have any effect is not known [6].

Theophylline

Theophylline (Aquaphyllin®, Elixophyllin®, Theolair®, Truxophyllin®, and many others) can prevent or treat shortness of breath, wheezing, and other breathing problems caused by asthma, chronic bronchitis, emphysema, and other lung diseases. Patients treated with theophylline often have low plasma PLP concentrations, which could contribute to the neurological and central nervous system side effects associated with theophylline, including seizures [6,32].

Vitamin B6 and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Many fruits, vegetables, and whole grains are good sources of vitamin B6. Some ready-to-eat breakfast cereals are fortified with vitamin B6.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Fish, beef, and turkey contain high amounts of vitamin B6. Beans and nuts are also sources of vitamin B6.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

References

  1. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Cholineexternal link disclaimer. Washington, DC: National Academy Press; 1998.
  2. McCormick D. Vitamin B6. In: Bowman B, Russell R, eds. Present Knowledge in Nutrition. 9th ed. Washington, DC: International Life Sciences Institute; 2006.
  3. Mackey A, Davis S, Gregory J. Vitamin B6. In: Shils M, Shike M, Ross A, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.
  4. U.S. Department of Agriculture, Agricultural Research Service. 2011. USDA National Nutrient Database for Standard Reference, Release 24. Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/ba/bhnrc/ndlexternal link disclaimer.
  5. Subar AF, Krebs-Smith SM, Cook A, Kahle LL. Dietary sources of nutrients among US adults, 1989 to 1991. J Am Diet Assoc 1998;98:537-47. [PubMed abstract]
  6. Natural Medicines Comprehensive Databaseexternal link disclaimer. Vitamin B6. 2011.
  7. Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I–Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010;23:1323-43. [PubMed abstract]
  8. Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-6. [PubMed abstract]
  9. Morris MS, Picciano MF, Jacques PF, Selhub J. Plasma pyridoxal 5’-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr 2008;87:1446-54. [PubMed abstract]
  10. Merrill AH, Jr., Henderson JM. Diseases associated with defects in vitamin B6 metabolism or utilization. Annu Rev Nutr 1987;7:137-56. [PubMed abstract]
  11. Chiang EP, Selhub J, Bagley PJ, Dallal G, Roubenoff R. Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis. Arthritis Res Ther 2005;7:R1404-11. [PubMed abstract]
  12. Ebbing M, Bonaa KH, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, et al. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med 2010;268:367-82. [PubMed abstract]
  13. Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 2009;40:1365-72. [PubMed abstract]
  14. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008;299:2027-36. [PubMed abstract]
  15. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75. [PubMed abstract]
  16. Larsson SC, Orsini N, Wolk A. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA 2010;303:1077-83. [PubMed abstract]
  17. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119-26. [PubMed abstract]
  18. Balk EM, Raman G, Tatsioni A, Chung M, Lau J, Rosenberg IH. Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med 2007;167:21-30. [PubMed abstract]
  19. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:306-14. [PubMed abstract]
  20. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev 2003:CD004393. [PubMed abstract]
  21. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ 1999;318:1375-81. [PubMed abstract]
  22. Kashanian M, Mazinani R, Jalalmanesh S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet 2007;96:43-4. [PubMed abstract]
  23. Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms. J Am Coll Nutr 2000;19:3-12. [PubMed abstract]
  24. Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med 2010;363:1544-50. [PubMed abstract]
  25. Matthews A, Dowswell T, Haas DM, Doyle M, O’Mathuna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010:CD007575. [PubMed abstract]
  26. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995;173:881-4. [PubMed abstract]
  27. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol 1991;78:33-6. [PubMed abstract]
  28. ACOG (American College of Obstetrics and Gynecology) Practice Bulletin: nausea and vomiting of pregnancy. Obstet Gynecol 2004;103:803-14. [PubMed abstract]
  29. Bendich A, Cohen M. Vitamin B6 safety issues. Ann N Y Acad Sci 1990;585:321-30. [PubMed abstract]
  30. Gdynia HJ, Muller T, Sperfeld AD, Kuhnlein P, Otto M, Kassubek J, et al. Severe sensorimotor neuropathy after intake of highest dosages of vitamin B6. Neuromuscul Disord 2008;18:156-8. [PubMed abstract]
  31. Perry TA, Weerasuriya A, Mouton PR, Holloway HW, Greig NH. Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy. Exp Neurol 2004;190:133-44. [PubMed abstract]
  32. Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr 1999;81:7-20. [PubMed abstract]
  33. Shrim A, Boskovic R, Maltepe C, Navios Y, Garcia-Bournissen F, Koren G. Pregnancy outcome following use of large doses of vitamin B6 in the first trimester. J Obstet Gynaecol 2006;26:749-51. [PubMed abstract]
  34. Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 2006;29:317-26. [PubMed abstract]
  35. Apeland T, Froyland ES, Kristensen O, Strandjord RE, Mansoor MA. Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins. Epilepsy Res 2008;82:1-6. [PubMed abstract]
  36. Hansson O, Sillanpaa M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet 1976;1:256. [PubMed abstract]
  37. U.S. Department of Agriculture, U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2010external link disclaimer. 7th Edition. Washington, DC; 2010.

This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

Coenzyme Q10: What’s the Bottom Line?

What’s the Bottom Line?

How much do we know about CoQ10?

We have some information from high quality studies done in people about the safety and effectiveness of CoQ10 for different conditions.

What do we know about the effectiveness of CoQ10?

CoQ10 supplements may benefit some patients with cardiovascular disorders, but research on other conditions is not conclusive.

What do we know about the safety of CoQ10?

CoQ10 has mild side effects and is generally well tolerated. However, it may make warfarin, an anticoagulant (blood thinner), less effective.

What Is CoQ10 and Why Is It Important?

Coenzyme Q10 (CoQ10) is an antioxidant that is necessary for cells to function properly. It is found in plants, bacteria, animals, and people. Cells use CoQ10 to make the energy they need to grow and stay healthy. CoQ10 can be found in highest amounts in the heart, liver, kidneys, and pancreas. Levels of CoQ10 decrease as you age.

  • A variety of diseases, including some genetic disorders, are associated with low levels of CoQ10.
  • Fish, meats, and whole grains all have small amounts of CoQ10, but not enough to significantly boost the levels in your body.

What the Science Says About the Effectiveness of CoQ10

CoQ10 supplements may benefit some patients with cardiovascular disorders. Researchers have also looked at the effects of CoQ10 for drug-induced muscle weakness, reproductive disorders, cancer, and other diseases. However, results from these studies are limited and not conclusive.

The following information highlights the research status on CoQ10 for the conditions for which it has been studied.

Heart Conditions

  • For patients with heart failure, taking CoQ10 was associated with improved heart function and also feeling better, according to research reviews published in 2007 and 2009. A 2013 meta-analysis also found an association between taking CoQ10 and improved heart function.
  • Taking a combination of nutrients including CoQ10 was associated with quicker recovery after bypass and heart valve surgeries, according to a 2011 randomized controlled trial of 117 patients.
  • For people with high blood pressure, the results of taking CoQ10 supplements have been mixed.
    • Some studies suggest that CoQ10 is associated with blood pressure control, but the findings are limited, a 2009 systematic review showed.
    • CoQ10 does not reduce high blood pressure or heart rate in patients with metabolic syndrome (a group of conditions that put you at risk for heart disease and diabetes), a small, randomized clinical trial reported in 2012.

Muscle Weakness From Statins (Cholesterol-lowering Drugs)

  • A 2010 review described research showing that CoQ10 may help ease the myopathy (muscle weakness) sometimes associated with taking statins. However, the findings are not definite, the review concluded.
  • A 2012 clinical trial of 76 patients who developed muscle pain within 60 days of starting statins found that CoQ10 was no better for pain than a placebo.

Reproductive Disorders

There is evidence that CoQ10 may improve semen quality and sperm count in infertile men, a 2010 review noted. However, it is uncertain whether this improvement affects the likelihood of conception.

Cancer

There is no convincing evidence that CoQ10 prevents or treats cancer, but two large studies from 2010 and 2011 found that women who developed breast cancer were more likely than others to have abnormal CoQ10 levels, either very low or unusually high.

Other Research on CoQ10

Studies have examined CoQ10 for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Down syndrome, diabetes, Huntington’s disease, migraines, Parkinson’s disease, neuromuscular diseases, and age-related changes in cells and genes. The research on CoQ10 for these conditions is limited so we can’t draw conclusions about its effectiveness.

What the Science Says About the Safety and Side Effects of CoQ10

  • Studies have not reported serious side effects related to CoQ10 use.
  • The most common side effects of CoQ10 include insomnia, increased liver enzymes, rashes, nausea, upper abdominal pain, dizziness, sensitivity to light, irritability, headaches, heartburn, and fatigue.
  • CoQ10 should not be used by women who are pregnant or breastfeeding.
  • Statins may lower the levels of CoQ10 in the blood. However, it is unclear what type of health effect this may have on an individual.
  • CoQ10 may make warfarin, an anticoagulant (blood thinner), less effective.

National Institutes of Health (NIH)-Funded Research

NIH is currently sponsoring studies investigating the effects of CoQ10 on mild-to-moderate muscle pain in people who take statins, fertility in older women, and breast cancer treatments.

More To Consider

  • Do not use CoQ10 supplements to replace a healthful diet or conventional medical care, or as a reason to postpone seeing a health care provider about a medical problem.
  • If you’re thinking about using a dietary supplement, first get information on it from reliable sources. Keep in mind that dietary supplements may interact with medications or other supplements and may contain ingredients not listed on the label. Your health care provider can advise you.
  • If you’re pregnant or nursing a child, or if you are considering giving a child a dietary supplement, it is especially important to consult your (or your child’s) health care provider.
  • Look for published research studies on CoQ10 for the health condition that interests you.
  • Tell all your health care providers about any complementary health approaches you use. Give them a full picture of what you do to manage your health. This will help ensure coordinated and safe care.

This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

Chromium: What is it?

Chromium: What is it?

Chromium is a mineral that humans require in trace amounts, although its mechanisms of action in the body and the amounts needed for optimal health are not well defined. It is found primarily in two forms: 1) trivalent (chromium 3+), which is biologically active and found in food, and 2) hexavalent (chromium 6+), a toxic form that results from industrial pollution. This fact sheet focuses exclusively on trivalent (3+) chromium.

Chromium is known to enhance the action of insulin [1-3], a hormone critical to the metabolism and storage of carbohydrate, fat, and protein in the body [4]. In 1957, a compound in brewers’ yeast was found to prevent an age-related decline in the ability of rats to maintain normal levels of sugar (glucose) in their blood [3]. Chromium was identified as the active ingredient in this so-called “glucose tolerance factor” in 1959 [5].

Chromium also appears to be directly involved in carbohydrate, fat, and protein metabolism [1-2,6-11], but more research is needed to determine the full range of its roles in the body. The challenges to meeting this goal include:

  • Defining the types of individuals who respond to chromium supplementation;
  • Evaluating the chromium content of foods and its bioavailability;
  • Determining if a clinically relevant chromium-deficiency state exists in humans due to inadequate dietary intakes; and
  • Developing valid and reliable measures of chromium status [9].

What foods provide chromium?

Chromium is widely distributed in the food supply, but most foods provide only small amounts (less than 2 micrograms [mcg] per serving). Meat and whole-grain products, as well as some fruits, vegetables, and spices are relatively good sources [12]. In contrast, foods high in simple sugars (like sucrose and fructose) are low in chromium [13].

Dietary intakes of chromium cannot be reliably determined because the content of the mineral in foods is substantially affected by agricultural and manufacturing processes and perhaps by contamination with chromium when the foods are analyzed [10,12,14]. Therefore, Table 1, and food-composition databases generally, provide approximate values of chromium in foods that should only serve as a guide.

Table 1: Selected food sources of chromium [12,15-16]
Food Chromium (mcg)
Broccoli, ½ cup 11
Grape juice, 1 cup 8
English muffin, whole wheat, 1 4
Potatoes, mashed, 1 cup 3
Garlic, dried, 1 teaspoon 3
Basil, dried, 1 tablespoon 2
Beef cubes, 3 ounces 2
Orange juice, 1 cup 2
Turkey breast, 3 ounces 2
Whole wheat bread, 2 slices 2
Red wine, 5 ounces 1–13
Apple, unpeeled, 1 medium 1
Banana, 1 medium 1
Green beans, ½ cup 1

What are recommended intakes of chromium?

Recommended chromium intakes are provided in the Dietary Reference Intakes (DRIs) developed by the Institute of Medicine of the National Academy of Sciences [14]. Dietary Reference Intakes is the general term for a set of reference values to plan and assess the nutrient intakes of healthy people. These values include the Recommended Dietary Allowance (RDA) and the Adequate Intake (AI). The RDA is the average daily intake that meets a nutrient requirement of nearly all (97 to 98%) healthy individuals [14]. An AI is established when there is insufficient research to establish an RDA; it is generally set at a level that healthy people typically consume.

In 1989, the National Academy of Sciences established an “estimated safe and adequate daily dietary intake” range for chromium. For adults and adolescents that range was 50 to 200 mcg [17]. In 2001, DRIs for chromium were established. The research base was insufficient to establish RDAs, so AIs were developed based on average intakes of chromium from food as found in several studies [14]. Chromium AIs are provided in Table 2.

Table 2: Adequate Intakes (AIs) for chromium [14]
Age Infants and children
(mcg/day)
Males
(mcg/day)
Females
(mcg/day)
Pregnancy
(mcg/day)
Lactation
(mcg/day)
0 to 6 months 0.2
7 to 12 months 5.5
1 to 3 years 11
4 to 8 years 15
9 to 13 years 25 21
14 to 18 years 35 24 29 44
19 to 50 years 35 25 30 45
>50 years 30 20

mcg = micrograms

Adult women in the United States consume about 23 to 29 mcg of chromium per day from food, which meets their AIs unless they’re pregnant or lactating. In contrast, adult men average 39 to 54 mcg per day, which exceeds their AIs [14].

The average amount of chromium in the breast milk of healthy, well-nourished mothers is 0.24 mcg per quart, so infants exclusively fed breast milk obtain about 0.2 mcg (based on an estimated consumption of 0.82 quarts per day) [14]. Infant formula provides about 0.5 mcg of chromium per quart [18]. No studies have compared how well infants absorb and utilize chromium from human milk and formula [10,14].

What affects chromium levels in the body?

Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed [19-25], and the remainder is excreted in the feces [1,23]. Enhancing the mineral’s absorption are vitamin C (found in fruits and vegetables and their juices) and the B vitamin niacin (found in meats, poultry, fish, and grain products) [26]. Absorbed chromium is stored in the liver, spleen, soft tissue, and bone [27].

The body’s chromium content may be reduced under several conditions. Diets high in simple sugars (comprising more than 35% of calories) can increase chromium excretion in the urine [13]. Infection, acute exercise, pregnancy and lactation, and stressful states (such as physical trauma) increase chromium losses and can lead to deficiency, especially if chromium intakes are already low [28-29].

When can a chromium deficiency occur?

In the 1960s, chromium was found to correct glucose intolerance and insulin resistance in deficient animals, two indicators that the body is failing to properly control blood-sugar levels and which are precursors of type 2 diabetes [1]. However, reports of actual chromium deficiency in humans are rare. Three hospitalized patients who were fed intravenously showed signs of diabetes (including weight loss, neuropathy, and impaired glucose tolerance) until chromium was added to their feeding solution. The chromium, added at doses of 150 to 250 mcg/day for up to two weeks, corrected their diabetes symptoms [7,30-31]. Chromium is now routinely added to intravenous solutions.

Who may need extra chromium?

There are reports of significant age-related decreases in the chromium concentrations of hair, sweat and blood [32], which might suggest that older people are more vulnerable to chromium depletion than younger adults [14]. One cannot be sure, however, as chromium status is difficult to determine [33]. That’s because blood, urine, and hair levels do not necessarily reflect body stores [9,14]. Furthermore, no chromium-specific enzyme or other biochemical marker has been found to reliably assess a person’s chromium status [9,34].

There is considerable interest in the possibility that supplemental chromium may help to treat impaired glucose tolerance and type 2 diabetes, but the research to date is inconclusive. No large, randomized, controlled clinical trials testing this hypothesis have been reported in the United States [14]. Nevertheless, this is an active area of research.

What are some current issues and controversies about chromium?

Chromium has long been of interest for its possible connection to various health conditions. Among the most active areas of chromium research are its use in supplement form to treat diabetes, lower blood lipid levels, promote weight loss, and improve body composition.

Type 2 diabetes and glucose intolerance

In type 2 diabetes, the pancreas is usually producing enough insulin but, for unknown reasons, the body cannot use the insulin effectively. The disease typically occurs, in part, because the cells comprising muscle and other tissues become resistant to insulin’s action, especially among the obese. Insulin permits the entry of glucose into most cells, where this sugar is used for energy, stored in the liver and muscles (as glycogen), and converted to fat when present in excess. Insulin resistance leads to higher than normal levels of glucose in the blood (hyperglycemia).

Chromium deficiency impairs the body’s ability to use glucose to meet its energy needs and raises insulin requirements. It has therefore been suggested that chromium supplements might help to control type 2 diabetes or the glucose and insulin responses in persons at high risk of developing the disease. A review of randomized controlled clinical trials evaluated this hypothesis [35]. This meta-analysis assessed the effects of chromium supplements on three markers of diabetes in the blood: glucose, insulin, and glycated hemoglobin (which provides a measure of long-term glucose levels; also known as hemoglobin A1C). It summarized data from 15 trials on 618 participants, of which 425 were in good health or had impaired glucose tolerance and 193 had type 2 diabetes. Chromium supplementation had no effect on glucose or insulin concentrations in subjects without diabetes nor did it reduce these levels in subjects with diabetes, except in one study. However, that study, conducted in China (in which 155 subjects with diabetes were given either 200 or 1,000 mcg/day of chromium or a placebo) might simply show the benefits of supplementation in a chromium-deficient population.

Overall, the value of chromium supplements for diabetes is inconclusive and controversial [36]. Randomized controlled clinical trials in well-defined, at-risk populations where dietary intakes are known are necessary to determine the effects of chromium on markers of diabetes [35]. The American Diabetes Association states that there is insufficient evidence to support the routine use of chromium to improve glycemic control in people with diabetes [37]. It further notes that there is no clear scientific evidence that vitamin and mineral supplementation benefits people with diabetes who do not have underlying nutritional deficiencies.

Lipid metabolism

The effects of chromium supplementation on blood lipid levels in humans are also inconclusive [1,8,38]. In some studies, 150 to 1,000 mcg/day has decreased total and low-density-lipoprotein (LDL or “bad”) cholesterol and triglyceride levels and increased concentrations of apolipoprotein A (a component of high-density-lipoprotein cholesterol known as HDL or “good” cholesterol) in subjects with atherosclerosis or elevated cholesterol or among those taking a beta-blocker drug [39-41]. These findings are consistent with the results of earlier studies [42-45].

However, chromium supplements have shown no favorable effects on blood lipids in other studies [46-51]. The mixed research findings may be due to difficulties in determining the chromium status of subjects at the start of the trials and the researchers’ failure to control for dietary factors that influence blood lipid levels [9-10].

Body weight and composition

Chromium supplements are sometimes claimed to reduce body fat and increase lean (muscle) mass. Yet a recent review of 24 studies that examined the effects of 200 to 1,000 mcg/day of chromium (in the form of chromium picolinate) on body mass or composition found no significant benefits [11]. Another recent review of randomized, controlled clinical trials did find supplements of chromium picolinate to help with weight loss when compared wtth placebos, but the differences were small and of debatable clinical relevance [52]. In several studies, chromium’s effects on body weight and composition may be called into question because the researchers failed to adequately control for the participants’ food intakes. Furthermore, most studies included only a small number of subjects and were of short duration [36].

For additional information on chromium and body weight, see our health professional fact sheet on Weight Loss.

What are the health risks of too much chromium?

Few serious adverse effects have been linked to high intakes of chromium, so the Institute of Medicine has not established a Tolerable Upper Intake Level (UL) for this mineral [10,14]. A UL is the maximum daily intake of a nutrient that is unlikely to cause adverse health effects. It is one of the values (together with the RDA and AI) that comprise the Dietary Reference Intakes (DRIs) for each nutrient.

Chromium and medication interactions

Certain medications may interact with chromium, especially when taken on a regular basis (see Table 3). Before taking dietary supplements, check with your doctor or other qualified healthcare provider, especially if you take prescription or over-the-counter medications.

Table 3: Interactions between chromium and medications [14,53-55]
Medications Nature of interaction
  • Antacids
  • Corticosteroids
  • H2 blockers (such as cimetidine, famotidine, nizatidine, and rantidine)
  • Proton-pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole)
These medications alter stomach acidity and may impair chromium absorption or enhance excretion
  • Beta-blockers (such as atenolol or propanolol)
  • Corticosteroids
  • Insulin
  • Nicotinic acid
  • Nonsteroidal anti-inflammatory drugs (NSAIDS)
  • Prostaglandin inhibitors (such as ibuprofen, indomethacin, naproxen, piroxicam, and aspirin)
These medications may have their effects enhanced if taken together with chromium or they may increase chromium absorption

Supplemental sources of chromium

Chromium is a widely used supplement. Estimated sales to consumers were $85 million in 2002, representing 5.6% of the total mineral-supplement market [56]. Chromium is sold as a single-ingredient supplement as well as in combination formulas, particularly those marketed for weight loss and performance enhancement. Supplement doses typically range from 50 to 200 mcg.

The safety and efficacy of chromium supplements need more investigation. Please consult with a doctor or other trained healthcare professional before taking any dietary supplements.

Chromium supplements are available as chromium chloride, chromium nicotinate, chromium picolinate, high-chromium yeast, and chromium citrate. Chromium chloride in particular appears to have poor bioavailability [36]. However, given the limited data on chromium absorption in humans, it is not clear which forms are best to take.

Chromium and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Whole grain products and certain fruits and vegetables like broccoli, potatoes, grape juice, and oranges are sources of chromium. Ready-to-eat bran cereals can also be a relatively good source of chromium.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Lean beef, oysters, eggs, and turkey are sources of chromium.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

References

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  2. Mertz W. Chromium in human nutrition: a review. J Nutr 1993;123:626-33.
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  35. Althuis MD, Jordan NE, Ludington EA, Wittes JT. Glucose and insulin responses to dietary chromium supplements: a meta-analysis. Am J Clin Nutr 2002;76:148-55.
  36. Cefalu WT, Hu FB. Role of chromium in human health and in diabetes. Diabetes Care 2004;27:2741-51.
  37. Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, Neumiller JJ, Nwankwo R, Verdi CL, Urbanski P, Yancy WS Jr. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care 2013;36:3821-42. [PubMed abstract]
  38. Offenbacher E, Pi-Sunyer F. Chromium. In: Handbook of Nutritionally Essential Mineral Elements (edited by O’Dell B, Sunde R). Marcel Dekker, New York, 1997, pp. 389-411.
  39. Roeback Jr. JR, Hla KM, Chambless LE, Fletcher RH. Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. A randomized, controlled trial. Ann Intern Med 1991;115:917-24.
  40. Abraham AS, Brooks BA, Eylath U. The effects of chromium supplementation on serum glucose and lipids in patients with and without non-insulin-dependent diabetes. Metabolism 1992;41:768-71.
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  56. Nutrition Business Journal. NBJ’s Supplement Business Report 2003. Penton Media Inc., San Diego, CA, 2003.

This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

Choline and Health

Introduction

Choline is an essential nutrient that is naturally present in some foods and available as a dietary supplement. Choline is a source of methyl groups needed for many steps in metabolism. The body needs choline to synthesize phosphatidylcholine and sphingomyelin, two major phospholipids vital for cell membranes. Therefore, all plant and animal cells need choline to preserve their structural integrity [1,2]. In addition, choline is needed to produce acetylcholine, an important neurotransmitter for memory, mood, muscle control, and other brain and nervous system functions [1-3]. Choline also plays important roles in modulating gene expression, cell membrane signaling, lipid transport and metabolism, and early brain development [1,2].

Humans can produce choline endogenously in the liver, mostly as phosphatidylcholine, but the amount that the body naturally synthesizes is not sufficient to meet human needs [4]. As a result, humans must obtain some choline from the diet. Premenopausal women might need less choline from the diet than children or other adults because estrogen induces the gene that catalyzes the biosynthesis of choline [4]. When a diet is deficient in folate, a B-vitamin that is also a methyl donor, the need for dietary choline rises because choline becomes the primary methyl donor [1].

The most common sources of choline in foods are the fat-soluble phospholipids phosphatidylcholine and sphingomyelin as well as the water-soluble compounds phosphocholine, glycerolphosphocholine, and free choline [1]. When these choline-containing compounds are ingested, pancreatic and mucosal enzymes liberate free choline from about half of the fat-soluble forms and some water-soluble forms [5]. Free choline, phosphocholine, and glycerophosphocholine are absorbed in the small intestine, enter the portal circulation, and are stored in the liver, where they are subsequently phosphorylated and distributed throughout the body to make cell membranes [1-3]. The remaining fat-soluble phospholipids (phosphatidylcholine and sphingomyelin) are absorbed intact, incorporated into chylomicrons, and secreted into the lymphatic circulation, where they are distributed to tissues and other organs, including the brain and placenta [1,6].

Choline status is not routinely measured in healthy people. In healthy adults, the concentration of choline in plasma ranges from 7 to 20 mcmol/L [2]. According to one study, the range is 7–9.3 mcmol/L in fasting adults [7]. Plasma choline levels do not decline below 50% of normal, even in individuals who have not eaten for more than a week [3]. This may be due to the hydrolysis of membrane phospholipids, a source of choline, to maintain plasma choline concentrations above this minimal level, or to endogenous synthesis [2].

Recommended Intakes

Intake recommendations for choline and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) [2]. DRIs is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA; intake at this level is assumed to ensure nutritional adequacy.
  • Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals. It is used to establish an RDA.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Insufficient data were available to establish an EAR for choline, so the FNB established AIs for all ages that are based on the prevention of liver damage as measured by serum alanine aminostransferase levels [2]. The amount of choline that individuals need is influenced by the amount of methionine, betaine, and folate in the diet; gender; pregnancy; lactation; stage of development; ability to produce choline endogenously; and genetic mutations that affect choline needs [1,2,4,5]. Table 1 lists the current AIs for choline [2].

Table 1: Adequate Intakes (AIs) for Choline [2]
Age Male Female Pregnancy Lactation
Birth to 6 months 125 mg/day 125 mg/day
7–12 months 150 mg/day 150 mg/day
1–3 years 200 mg/day 200 mg/day
4–8 years 250 mg/day 250 mg/day
9–13 years 375 mg/day 375 mg/day
14–18 years 550 mg/day 400 mg/day 450 mg/day 550 mg/day
19+ years 550 mg/day 425 mg/day 450 mg/day 550 mg/day

Sources of Choline

Food
Many foods contain choline [4]. The main dietary sources of choline in the United States consist primarily of animal-based products that are particularly rich in choline—meat, poultry, fish, dairy products, and eggs [4,5,8-10]. Cruciferous vegetables and certain beans are also rich in choline, and other dietary sources of choline include nuts, seeds, and whole grains.

About half the dietary choline consumed in the United States is in the form of phosphatidylcholine [8,9]. Many foods also contain lecithin, a substance rich in phosphatidylcholine that is prepared during commercial purification of phospholipids; lecithin is a common food additive used as an emulsifying agent in processed foods, such as gravies, salad dressings, and margarine [1,3]. Choline is also present in breast milk and is added to most commercial infant formulas [3,4]. Precise estimates of the percentage absorption of the different forms of dietary choline in humans are not available [2,3].

Several food sources of choline are listed in Table 2.

Table 2: Selected Food Sources of Choline [11]
Food Milligrams
(mg) per
serving
Percent
DV*
Beef liver, pan fried, 3 ounces 356 65
Egg, hard boiled, 1 large egg 147 27
Beef top round, separable lean only, braised, 3 ounces 117 21
Soybeans, roasted, ½ cup 107 19
Chicken breast, roasted, 3 ounces 72 13
Beef, ground, 93% lean meat, broiled, 3 ounces 72 13
Fish, cod, Atlantic, cooked, dry heat, 3 ounces 71 13
Mushrooms, shiitake, cooked, ½ cup pieces 58 11
Potatoes, red, baked, flesh and skin, 1 large potato 57 10
Wheat germ, toasted, 1 ounce 51 9
Beans, kidney, canned, ½ cup 45 8
Quinoa, cooked, 1 cup 43 8
Milk, 1% fat, 1 cup 43 8
Yogurt, vanilla, nonfat, 1 cup 38 7
Brussels sprouts, boiled, ½ cup 32 6
Broccoli, chopped, boiled, drained, ½ cup 31 6
Cottage cheese, nonfat, 1 cup 26 5
Fish, tuna, white, canned in water, drained in solids, 3 ounces 25 5
Peanuts, dry roasted, ¼ cup 24 4
Cauliflower, 1” pieces, boiled, drained, ½ cup 24 4
Peas, green, boiled, ½ cup 24 4
Sunflower seeds, oil roasted, ¼ cup 19 3
Rice, brown, long-grain, cooked, 1 cup 19 3
Bread, pita, whole wheat, 1 large (6½ inch diameter) 17 3
Cabbage, boiled, ½ cup 15 3
Tangerine (mandarin orange), sections, ½ cup 10 2
Beans, snap, raw, ½ cup 8 1
Kiwifruit, raw, ½ cup sliced 7 1
Carrots, raw, chopped, ½ cup 6 1
Apples, raw, with skin, quartered or chopped, ½ cup 2 0

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 and older [12]. However, the FDA does not require food labels to list choline content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) National Nutrient Database for Standard Referenceexternal link disclaimer website [11] lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by choline contentexternal link disclaimer and by food nameexternal link disclaimer.

Dietary supplements
Choline is available in dietary supplements containing choline only, in combination with B-complex vitamins, and in some multivitamin/multimineral products [13]. Typical amounts of choline in dietary supplements range from 10 mg to 250 mg. The forms of choline in dietary supplements include choline bitartrate, phosphatidylcholine, and lecithin. No studies have compared the relative bioavailability of choline from these different forms.

Choline Intakes and Status

Most people in the United States consume less than the AI for choline. An analysis of data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) found that the average daily choline intake from foods and beverages among children and teens is 256 mg for ages 2–19 [14]. In adults, the average daily choline intake from foods and beverages is 402 mg in men and 278 mg in women. Intakes from supplements contribute a very small amount to total choline intakes.

According to an analysis of 2007–2008 NHANES data, black males of all ages had lower mean choline intakes than their white and Hispanic counterparts, but choline intakes did not differ substantially among females of different races/ethnicities [10].

Choline Deficiency

Choline deficiency can cause muscle damage, liver damage, and nonalcoholic fatty liver disease (NAFLD or hepatosteatosis) [1,2,4,15]. Although most people in the United States consume less than the AI of choline, frank choline deficiency in healthy, nonpregnant individuals is very rare, possibly because of the contribution of choline that the body synthesizes endogenously [1,5].

Groups at Risk of Choline Inadequacy

The following groups are among those most likely to have inadequate choline status.

Pregnant women and their infants
Approximately 90%–95% of pregnant women consume less choline than the AI [16]. Prenatal dietary supplements typically contain little if any choline [17]. The risk of inadequate choline status might be greater in pregnant and lactating women who do not take folic acid supplements, those with low vitamin B12 status, and those with a common variant in methylenetetrahydrofolate dehydrogenase (an enzyme that can affect folate status), all of which reduce the body’s pool of methyl groups needed for metabolism [17-20].

Some evidence indicates that lower plasma or serum choline levels (e.g., serum concentration of 2.77 mmol/L in midpregnancy) are associated with an increased risk of neural tube defects [21,22]. However, other research found no relationship between plasma choline concentrations during pregnancy and neural tube defects in offspring [23].

People with certain genetic alterations
Genes involved in the metabolism of choline, folate, and methionine play a role in the pathways for choline production and use [24,25]. Humans have variations in the DNA sequences for these genes (single nucleotide polymorphisms [SNPs]), and these SNPs can have a strong influence on demands for dietary choline. For example, one common SNP in the PEMT gene reduces endogenous synthesis of choline in women induced by estrogen [26]. The prevalence of SNPs that alter requirements for dietary choline vary by race. In a study of 100 African, Asian, Caucasian, and Mexican Americans, individuals of European ancestry had a higher prevalence of four SNPs that increased the risk of organ dysfunction when these individuals consumed a low-choline diet [27].

Patients requiring total parenteral nutrition
At present, choline is not routinely added to commercial parenteral solutions for infants and adults [28,29]. As a result, adults and infants receiving total parenteral nutrition (TPN) over the long term have low plasma choline concentrations (approximately 5 nmol/ml in adults and 5.7 nmol/ml in infants), which can result in hepatic abnormalities, including NAFLD [30-32]. The American Society for Parenteral and Enteral Nutrition recommends the routine addition of choline to adult and pediatric parenteral nutrition formulations, and calls for the development of a commercially available parenteral product that contains choline [28].

Choline and Health

This section focuses on three conditions in which choline might play a role: cardiovascular and peripheral artery disease, neurological disorders, and NAFLD. Choline is involved in functions that overlap with those of folate and other B vitamins. Many studies do not assess the status of all B vitamins, which can confound results and obscure the true relationship between choline and the observed outcome.

Cardiovascular and peripheral artery disease
Some researchers have suggested that choline might protect cardiovascular health by reducing blood pressure, altering lipid profiles, and reducing levels of plasma homocysteine [3]. Other research suggests that higher dietary choline might increase cardiovascular disease risk because some choline and other dietary ingredients, such as carnitine, are converted to trimethylamine (TMA) by intestinal bacteria. The TMA is then absorbed and converted by the liver into trimethylamine-N-oxide (TMAO), a substance that has been linked to a higher risk of cardiovascular disease [33,34].

Despite the hypothesis that choline might affect heart health, several large observational studies have found no significant associations between choline intakes and cardiovascular or peripheral artery disease risk. An analysis of 72,348 women in the Nurses’ Health Study and 44,504 men in the Health Professionals Follow-up Study showed no association between choline intake and risk of peripheral artery disease in men or women [35]. Similarly, a prospective study in 14,430 middle-aged adults in the Atherosclerosis Risk in Communities Study found that over 14 years, risk of coronary heart disease was not significantly different in the highest choline intake quartile compared to the lowest quartile [36]. Choline intakes also had no association with cardiovascular disease risk in a study of 16,165 women participating in the European Prospective Investigation into Cancer and Nutrition [37].

However, a more recent analysis of data on 80,978 women from the Nurses’ Health Study and 39,434 men from the Health Professionals Follow-Up Study found an increased risk of mortality in those consuming higher levels of choline [33]. The authors suggest that the higher risk might be due to increased production of TMAO, although they did not directly measure TMAO.

Additional research is needed to determine the relationship between choline intakes and cardiovascular and peripheral artery disease as well as the potential risks and benefits of choline supplementation to reduce the risk of these diseases.

Neurological disorders
People with Alzheimer’s disease have lower levels of the enzyme that converts choline into acetylcholine in the brain [38]. In addition, because phosphatidylcholine can serve as a phospholipid precursor, it might help support the structural integrity of neurons and thus might promote cognitive function in elderly adults [8]. Some experts have therefore theorized that consuming higher levels of phosphatidylcholine could reduce the progression of dementia in people with Alzheimer’s disease [38]. However, little research conducted to date supports this hypothesis, as described below.

A few observational studies have shown a link between cognitive performance in adults and both higher choline intakes and plasma concentrations. In one observational study in 2,195 adults aged 70–74 years in Norway, participants with plasma free choline concentrations lower than 8.4 mcmol/L (20th percentile of concentrations in the study population) had poorer sensorimotor speed, perceptual speed, executive function, and global cognition than those with choline concentrations higher than 8.4 mcmol/L [39]. A second study in 1,391 adults aged 36–83 years from the Framingham Offspring study who completed food frequency questionnaires from 1991 to 1995 and again from 1998 to 2001 found that those with higher choline intakes had better verbal memory and visual memory [40]. Furthermore, higher choline intakes during the earlier period were associated with smaller white matter hyperintensity volume (a high volume is a sign of small-vessel disease in the brain).

Some small randomized intervention trials have shown that choline supplements improve cognitive performance in adults [30,41]. However, a 2015 systematic review of 13 studies on the relationship between choline levels and neurological outcomes in adults found that choline supplements did not result in clear improvements in cognition in healthy adults [8]. Similarly, a 2003 Cochrane review of 12 randomized trials in 265 patients with Alzheimer’s disease, 21 with Parkinsonian dementia, and 90 with self-identified memory problems found no clear clinical benefits of lecithin supplementation for treating Alzheimer’s disease or Parkinsonian dementia [38].

Future studies are needed to clarify the relationship between choline intakes and cognitive function and determine whether choline supplements might benefit patients with Alzheimer’s disease or other forms of dementia.

Nonalcoholic fatty liver disease
NAFLD involves the accumulation of lipids in the livers of people who consume less than 20 g/day ethanol and who have no other known causes of steatosis [42,43]. (A single drink [e.g., 12 oz beer, 5 oz wine, or 1.5 oz hard liquor] contains about 12–14 g alcohol.) It is the most common chronic liver disorder, present in up to 65% of overweight individuals and 90% of those with obesity [1]. Although it is often benign, NAFLD can lead to steatohepatitis, fibrosis, cirrhosis, liver failure, and liver cancer [15]. Choline, especially phosphatidylcholine, is essential for transporting lipids from the liver [1]. Therefore, in choline deficiency, fat accumulates in the liver, which can result in NAFLD [44,45]. Although most women of childbearing age are resistant to NAFLD because of their high estrogen levels, at least 40% have a polymorphism that makes them insensitive to activation of the gene by estrogen; adequate consumption of dietary choline is particularly important for this population [46].

Data from a single large observational study support a link between choline deficiency and risk of NAFLD. Specifically, a cross-sectional study of 56,195 Chinese adults aged 40–75 years found an inverse relationship between dietary choline intakes and risk of NAFLD based on 24-hour dietary recall [47]. The risk of NAFLD was 32% lower in women in the highest quintile of choline intake (412 mg/day) compared to the lowest (179 mg/day) and 25% lower in men in the highest (452 mg/day) quintile compared to those in the lowest quintile (199 mg/day). However, choline intake was associated with NAFLD in normal-weight women only and not in those who were overweight or obese. This difference by weight status was not observed in men.

In a cross-sectional study of 664 adults and children from the Nonalcoholic Steatohepatitis Clinical Research Network, postmenopausal women who had nonalcoholic steatohepatitis (an extreme form of NAFLD involving liver inflammation and fibrosis) and a choline intake less than 50% of the AI had more severe fibrosis, but the results showed no relationship between choline intake and degree of liver steatosis [48].

Only limited data are available on the use of choline to treat NAFLD. For example, in a study of 57 adults who consumed a diet that included less than 50 mg choline per 70 kg body weight per day (<10% of the AI) for up to 42 days, 37 of the participants developed liver dysfunction [45]. Liver function returned to normal in 29 participants in this study after they were fed a diet containing 25%–75% of the choline AI and in 8 who consumed an ad libitum diet. A pilot study in 15 adults on TPN found that NAFLD resolved completely in all patients who received their usual TPN regimen with an additional 2 g choline and in none of the patients who received their usual TPN regimen only [49].

Adequate choline intake is needed for proper liver function and to prevent NAFLD, but more research is needed to further clarify the role of choline in preventing or treating NAFLD [50].

Health Risks from Excessive Choline

High intakes of choline are associated with a fishy body odor, vomiting, excessive sweating and salivation, hypotension, and liver toxicity [1,2]. Choline consumption has been shown to increase production of TMAO, a substance that has been linked to a higher risk of cardiovascular disease, in a dose-dependent manner in adults.

The FNB has established ULs for choline from food and supplements based on the amounts of choline that are associated with hypotension and fishy body odor (see Table 3) [2]. The ULs apply to healthy children and adults, but not to those taking high doses of choline under medical supervision. The FNB was unable to establish ULs for infants due to the lack of data on adverse effects in this age group.

Table 3: Tolerable Upper Intake Levels (ULs) for Choline [2]
Age Male Female Pregnancy Lactation
Birth to 6 months*
7–12 months*
1–3 years 1,000 mg 1,000 mg
4–8 years 1,000 mg 1,000 mg
9–13 years 2,000 mg 2,000 mg
14–18 years 3,000 mg 3,000 mg 3,000 mg 3,000 mg
19+ years 3,500 mg 3,500 mg 3,500 mg 3,500 mg

*Not possible to establish; breast milk, formula, and food should be the only sources of choline for infants.

Interactions with Medications

Choline is not known to have any clinically relevant interactions with medications.

Choline and Healthful Diets

The federal government’s 2015–2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlate.external link disclaimer

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

    • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
      Many vegetables, fruits, whole grains, and dairy products contain choline.
    • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
      Fish, beef, poultry, eggs, and some beans and nuts are rich sources of choline.
    • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

References

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Vitamin C and Health

Introduction

Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component [1].

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism [1,2]. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant [3] and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) [4]. Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function [4] and improves the absorption of nonheme iron [5], the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility [1,2,4,6-9].

The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter [4]. Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.

Oral vitamin C produces tissue and plasma concentrations that the body tightly controls. Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1 g/day, absorption falls to less than 50% and absorbed, unmetabolized ascorbic acid is excreted in the urine [4]. Results from pharmacokinetic studies indicate that oral doses of 1.25 g/day ascorbic acid produce mean peak plasma vitamin C concentrations of 135 micromol/L, which are about two times higher than those produced by consuming 200–300 mg/day ascorbic acid from vitamin C-rich foods [10]. Pharmacokinetic modeling predicts that even doses as high as 3 g ascorbic acid taken every 4 hours would produce peak plasma concentrations of only 220 micromol/L [10].

The total body content of vitamin C ranges from 300 mg (at near scurvy) to about 2 g [4]. High levels of vitamin C (millimolar concentrations) are maintained in cells and tissues, and are highest in leukocytes (white blood cells), eyes, adrenal glands, pituitary gland, and brain. Relatively low levels of vitamin C (micromolar concentrations) are found in extracellular fluids, such as plasma, red blood cells, and saliva [4].

Recommended Intakes

Intake recommendations for vitamin C and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) [8]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender [8], include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects [8].

Table 1 lists the current RDAs for vitamin C [8]. The RDAs for vitamin C are based on its known physiological and antioxidant functions in white blood cells and are much higher than the amount required for protection from deficiency [4,8,11]. For infants from birth to 12 months, the FNB established an AI for vitamin C that is equivalent to the mean intake of vitamin C in healthy, breastfed infants.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin C [8]
Age Male Female Pregnancy Lactation
0–6 months 40 mg* 40 mg*
7–12 months 50 mg* 50 mg*
1–3 years 15 mg 15 mg
4–8 years 25 mg 25 mg
9–13 years 45 mg 45 mg
14–18 years 75 mg 65 mg 80 mg 115 mg
19+ years 90 mg 75 mg 85 mg 120 mg
Smokers Individuals who smoke require 35 mg/day
more vitamin C than nonsmokers.

* Adequate Intake (AI)

Sources of Vitamin C

Food

Fruits and vegetables are the best sources of vitamin C (see Table 2) [12]. Citrus fruits, tomatoes and tomato juice, and potatoes are major contributors of vitamin C to the American diet [8]. Other good food sources include red and green peppers, kiwifruit, broccoli, strawberries, Brussels sprouts, and cantaloupe (see Table 2) [8,12]. Although vitamin C is not naturally present in grains, it is added to some fortified breakfast cereals. The vitamin C content of food may be reduced by prolonged storage and by cooking because ascorbic acid is water soluble and is destroyed by heat [6,8]. Steaming or microwaving may lessen cooking losses. Fortunately, many of the best food sources of vitamin C, such as fruits and vegetables, are usually consumed raw. Consuming five varied servings of fruits and vegetables a day can provide more than 200 mg of vitamin C.

Table 2: Selected Food Sources of Vitamin C [12]
Food Milligrams (mg) per serving Percent (%) DV*
Red pepper, sweet, raw, ½ cup 95 158
Orange juice, ¾ cup 93 155
Orange, 1 medium 70 117
Grapefruit juice, ¾ cup 70 117
Kiwifruit, 1 medium 64 107
Green pepper, sweet, raw, ½ cup 60 100
Broccoli, cooked, ½ cup 51 85
Strawberries, fresh, sliced, ½ cup 49 82
Brussels sprouts, cooked, ½ cup 48 80
Grapefruit, ½ medium 39 65
Broccoli, raw, ½ cup 39 65
Tomato juice, ¾ cup 33 55
Cantaloupe, ½ cup 29 48
Cabbage, cooked, ½ cup 28 47
Cauliflower, raw, ½ cup 26 43
Potato, baked, 1 medium 17 28
Tomato, raw, 1 medium 17 28
Spinach, cooked, ½ cup 9 15
Green peas, frozen, cooked, ½ cup 8 13

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin C is 60 mg for adults and children aged 4 and older. The FDA requires all food labels to list the percent DV for vitamin C. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer Web site lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin C arranged by nutrient content and by food name.

Dietary supplements

Supplements typically contain vitamin C in the form of ascorbic acid, which has equivalent bioavailability to that of naturally occurring ascorbic acid in foods, such as orange juice and broccoli [13-15]. Other forms of vitamin C supplements include sodium ascorbate; calcium ascorbate; other mineral ascorbates; ascorbic acid with bioflavonoids; and combination products, such as Ester-C®, which contains calcium ascorbate, dehydroascorbate, calcium threonate, xylonate and lyxonate [16].

A few studies in humans have examined whether bioavailability differs among the various forms of vitamin C. In one study, Ester-C® and ascorbic acid produced the same vitamin C plasma concentrations, but Ester-C® produced significantly higher vitamin C concentrations in leukocytes 24 hours after ingestion [17]. Another study found no differences in plasma vitamin C levels or urinary excretion of vitamin C among three different vitamin C sources: ascorbic acid, Ester-C®, and ascorbic acid with bioflavonoids [16]. These findings, coupled with the relatively low cost of ascorbic acid, led the authors to conclude that simple ascorbic acid is the preferred source of supplemental vitamin C [16].

Vitamin C Intakes and Status

According to the 2001–2002 National Health and Nutrition Examination Survey (NHANES), mean intakes of vitamin C are 105.2 mg/day for adult males and 83.6 mg/day for adult females, meeting the currently established RDA for most nonsmoking adults [18]. Mean intakes for children and adolescents aged 1-18 years range from 75.6 mg/day to 100 mg/day, also meeting the RDA for these age groups [18]. Although the 2001–2002 NHANES analysis did not include data for breastfed infants and toddlers, breastmilk is considered an adequate source of vitamin C [8,13]. Use of vitamin C-containing supplements is also relatively common, adding to the total vitamin C intake from food and beverages. NHANES data from 1999–2000 indicate that approximately 35% of adults take multivitamin supplements (which typically contain vitamin C) and 12% take a separate vitamin C supplement [19]. According to 1999–2002 NHANES data, approximately 29% of children take some form of dietary supplement that contains vitamin C [20].

Vitamin C status is typically assessed by measuring plasma vitamin C levels [4,13]. Other measures, such as leukocyte vitamin C concentration, could be more accurate indicators of tissue vitamin C levels, but they are more difficult to assess and the results are not always reliable [4,9,13].

Vitamin C Deficiency

Acute vitamin C deficiency leads to scurvy [7,8,11]. The timeline for the development of scurvy varies, depending on vitamin C body stores, but signs can appear within 1 month of little or no vitamin C intake (below 10 mg/day) [6,7,21,22]. Initial symptoms can include fatigue (probably the result of impaired carnitine biosynthesis), malaise, and inflammation of the gums [4,11]. As vitamin C deficiency progresses, collagen synthesis becomes impaired and connective tissues become weakened, causing petechiae, ecchymoses, purpura, joint pain, poor wound healing, hyperkeratosis, and corkscrew hairs [1,2,4,6-8]. Additional signs of scurvy include depression as well as swollen, bleeding gums and loosening or loss of teeth due to tissue and capillary fragility [6,8,9]. Iron deficiency anemia can also occur due to increased bleeding and decreased nonheme iron absorption secondary to low vitamin C intake [6,11]. In children, bone disease can be present [6]. Left untreated, scurvy is fatal [6,9].

Until the end of the 18th century, many sailors who ventured on long ocean voyages, with little or no vitamin C intake, contracted or died from scurvy. During the mid-1700s, Sir James Lind, a British Navy surgeon, conducted experiments and determined that eating citrus fruits or juices could cure scurvy, although scientists did not prove that ascorbic acid was the active component until 1932 [23-25].

Today, vitamin C deficiency and scurvy are rare in developed countries [8]. Overt deficiency symptoms occur only if vitamin C intake falls below approximately 10 mg/day for many weeks [5-8,21,22]. Vitamin C deficiency is uncommon in developed countries but can still occur in people with limited food variety.

Groups at Risk of Vitamin C Inadequacy

Vitamin C inadequacy can occur with intakes that fall below the RDA but are above the amount required to prevent overt deficiency (approximately 10 mg/day). The following groups are more likely than others to be at risk of obtaining insufficient amounts of vitamin C.

Smokers and passive “smokers”

Studies consistently show that smokers have lower plasma and leukocyte vitamin C levels than nonsmokers, due in part to increased oxidative stress [8]. For this reason, the IOM concluded that smokers need 35 mg more vitamin C per day than nonsmokers [8]. Exposure to secondhand smoke also decreases vitamin C levels. Although the IOM was unable to establish a specific vitamin C requirement for nonsmokers who are regularly exposed to secondhand smoke, these individuals should ensure that they meet the RDA for vitamin C [4,8].

Infants fed evaporated or boiled milk

Most infants in developed countries are fed breastmilk and/or infant formula, both of which supply adequate amounts of vitamin C [8,13]. For many reasons, feeding infants evaporated or boiled cow’s milk is not recommended. This practice can cause vitamin C deficiency because cow’s milk naturally has very little vitamin C and heat can destroy vitamin C [6,12].

Individuals with limited food variety

Although fruits and vegetables are the best sources of vitamin C, many other foods have small amounts of this nutrient. Thus, through a varied diet, most people should be able to meet the vitamin C RDA or at least obtain enough to prevent scurvy. People who have limited food variety—including some elderly, indigent individuals who prepare their own food; people who abuse alcohol or drugs; food faddists; people with mental illness; and, occasionally, children—might not obtain sufficient vitamin C [4,6-9,11].

People with malabsorption and certain chronic diseases

Some medical conditions can reduce the absorption of vitamin C and/or increase the amount needed by the body. People with severe intestinal malabsorption or cachexia and some cancer patients might be at increased risk of vitamin C inadequacy [26]. Low vitamin C concentrations can also occur in patients with end-stage renal disease on chronic hemodialysis [27].

Vitamin C and Health

Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions. This section focuses on four diseases and disorders in which vitamin C might play a role: cancer (including prevention and treatment), cardiovascular disease, age-related macular degeneration (AMD) and cataracts, and the common cold.

Cancer prevention

Epidemiologic evidence suggests that higher consumption of fruits and vegetables is associated with lower risk of most types of cancer, perhaps, in part, due to their high vitamin C content [1,2]. Vitamin C can limit the formation of carcinogens, such as nitrosamines [2,28], in vivo; modulate immune response [2,4]; and, through its antioxidant function, possibly attenuate oxidative damage that can lead to cancer [1].

Most case-control studies have found an inverse association between dietary vitamin C intake and cancers of the lung, breast, colon or rectum, stomach, oral cavity, larynx or pharynx, and esophagus [2,4]. Plasma concentrations of vitamin C are also lower in people with cancer than controls [2].

However, evidence from prospective cohort studies is inconsistent, possibly due to varying intakes of vitamin C among studies. In a cohort of 82,234 women aged 33–60 years from the Nurses’ Health Study, consumption of an average of 205 mg/day of vitamin C from food (highest quintile of intake) compared with an average of 70 mg/day (lowest quintile of intake) was associated with a 63% lower risk of breast cancer among premenopausal women with a family history of breast cancer [29]. Conversely, Kushi and colleagues did not observe a significantly lower risk of breast cancer among postmenopausal women consuming at least 198 mg/day (highest quintile of intake) of vitamin C from food compared with those consuming less than 87 mg/day (lowest quintile of intake) [30]. A review by Carr and Frei concluded that in the majority of prospective cohort studies not reporting a significantly lower cancer risk, most participants had relatively high vitamin C intakes, with intakes higher than 86 mg/day in the lowest quintiles [2]. Studies reporting significantly lower cancer risk found these associations in individuals with vitamin C intakes of at least 80–110 mg/day, a range associated with close to vitamin C tissue saturation [2,21,31].

Evidence from most randomized clinical trials suggests that vitamin C supplementation, usually in combination with other micronutrients, does not affect cancer risk. In the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study, a randomized, double-blind, placebo-controlled clinical trial,13,017 healthy French adults received antioxidant supplementation with 120 mg ascorbic acid, 30 mg vitamin E, 6 mg beta-carotene, 100 mcg selenium, and 20 mg zinc, or placebo [32]. After a median follow-up time of 7.5 years, antioxidant supplementation lowered total cancer incidence in men, but not in women. In addition, baseline antioxidant status was related to cancer risk in men, but not in women [33]. Supplements of 500 mg/day vitamin C plus 400 IU vitamin E every other day for a mean follow-up period of 8 years failed to reduce the risk of prostate or total cancer compared with placebo in middle-aged and older men participating in the Physicians’ Health Study II [34]. Similar findings were reported in women participating in the Women’s Antioxidant Cardiovascular Study [35]. Compared with placebo, supplementation with vitamin C (500 mg/day) for an average of 9.4 years had no significant effect on total cancer incidence or cancer mortality. In a large intervention trial conducted in Linxian, China, daily supplements of vitamin C (120 mg) plus molybdenum (30 mcg) for 5–6 years did not significantly affect the risk of developing esophageal or gastric cancer [36]. Moreover, during 10 years of follow-up, this supplementation regimen failed to significantly affect total morbidity or mortality from esophageal, gastric, or other cancers [37]. A 2008 review of vitamin C and other antioxidant supplements for the prevention of gastrointestinal cancers found no convincing evidence that vitamin C (or beta-carotene, vitamin A, or vitamin E) prevents gastrointestinal cancers [38]. A similar review by Coulter and colleagues found that vitamin C supplementation, in combination with vitamin E, had no significant effect on death risk due to cancer in healthy individuals [39].

At this time, the evidence is inconsistent on whether dietary vitamin C intake affects cancer risk. Results from most clinical trials suggest that modest vitamin C supplementation alone or with other nutrients offers no benefit in the prevention of cancer.

A substantial limitation in interpreting many of these studies is that investigators did not measure vitamin C concentrations before or after supplementation. Plasma and tissue concentrations of vitamin C are tightly controlled in humans. At daily intakes of 100 mg or higher, cells appear to be saturated and at intakes of at least 200 mg, plasma concentrations increase only marginally [2,10,21,30,36]. If subjects’ vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes [21,22,40,41].

Cancer treatment

During the 1970s, studies by Cameron, Campbell, and Pauling suggested that high-dose vitamin C has beneficial effects on quality of life and survival time in patients with terminal cancer [42,43]. However, some subsequent studies—including a randomized, double-blind, placebo-controlled clinical trial by Moertel and colleagues at the Mayo Clinic [44]—did not support these findings. In the Moertel study, patients with advanced colorectal cancer who received 10 g/day vitamin C fared no better than those receiving a placebo. The authors of a 2003 review assessing the effects of vitamin C in patients with advanced cancer concluded that vitamin C confers no significant mortality benefit [39].

Emerging research suggests that the route of vitamin C administration (intravenous vs. oral) could explain the conflicting findings [1,45,46]. Most intervention trials, including the one conducted by Moertel and colleagues, used only oral administration, whereas Cameron and colleagues used a combination of oral and intravenous (IV) administration. Oral administration of vitamin C, even of very large doses, can raise plasma vitamin C concentrations to a maximum of only 220 micromol/L, whereas IV administration can produce plasma concentrations as high as 26,000 micromol/L [46,47]. Concentrations of this magnitude are selectively cytotoxic to tumor cells in vitro [1,66]. Research in mice suggests that pharmacologic doses of IV vitamin C might show promise in treating otherwise difficult-to-treat tumors [48]. A high concentration of vitamin C may act as a pro-oxidant and generate hydrogen peroxide that has selective toxicity toward cancer cells [48-50]. Based on these findings and a few case reports of patients with advanced cancers who had remarkably long survival times following administration of high-dose IV vitamin C, some researchers support reassessment of the use of high-dose IV vitamin C as a drug to treat cancer [3,46,48,51].

As discussed below, it is uncertain whether supplemental vitamin C and other antioxidants might interact with chemotherapy and/or radiation [52]. Therefore, individuals undergoing these procedures should consult with their oncologist prior to taking vitamin C or other antioxidant supplements, especially in high doses [53].

Cardiovascular disease

Evidence from many epidemiological studies suggests that high intakes of fruits and vegetables are associated with a reduced risk of cardiovascular disease [1,54,55]. This association might be partly attributable to the antioxidant content of these foods because oxidative damage, including oxidative modification of low-density lipoproteins, is a major cause of cardiovascular disease [1,4,55]. In addition to its antioxidant properties, vitamin C has been shown to reduce monocyte adherence to the endothelium, improve endothelium-dependent nitric oxide production and vasodilation, and reduce vascular smooth-muscle-cell apoptosis, which prevents plaque instability in atherosclerosis [2,56].

Results from prospective studies examining associations between vitamin C intake and cardiovascular disease risk are conflicting [55]. In the Nurses’ Health Study, a 16-year prospective study involving 85,118 female nurses, total intake of vitamin C from both dietary and supplemental sources was inversely associated with coronary heart disease risk [57]. However, intake of vitamin C from diet alone showed no significant associations, suggesting that vitamin C supplement users might be at lower risk of coronary heart disease. A much smaller study indicated that postmenopausal women with diabetes who took at least 300 mg/day vitamin C supplements had increased cardiovascular disease mortality [58].

A prospective study in 20,649 British adults found that those in the top quartile of baseline plasma vitamin C concentrations had a 42% lower risk of stroke than those in the bottom quartile [59]. In male physicians participating in the Physicians’ Health Study, use of vitamin C supplements for a mean of 5.5 years was not associated with a significant decrease in total cardiovascular disease mortality or coronary heart disease mortality [60]. A pooled analysis of nine prospective studies that included 293,172 subjects free of coronary heart disease at baseline found that people who took ≥700 mg/day of supplemental vitamin C had a 25% lower risk of coronary heart disease incidence than those who took no supplemental vitamin C [61]. The authors of a 2008 meta-analysis of prospective cohort studies, including 14 studies reporting on vitamin C for a median follow-up of 10 years, concluded that dietary, but not supplemental, intake of vitamin C is inversely associated with coronary heart disease risk [54].

Results from most clinical intervention trials have failed to show a beneficial effect of vitamin C supplementation on the primary or secondary prevention of cardiovascular disease. In the Women’s Antioxidant Cardiovascular Study, a secondary prevention trial involving 8,171 women aged 40 years or older with a history of cardiovascular disease, supplementation with 500 mg/day vitamin C for a mean of 9.4 years showed no overall effect on cardiovascular events [62]. Similarly, vitamin C supplementation (500 mg/day) for a mean follow-up of 8 years had no effect on major cardiovascular events in male physicians enrolled in the Physicians’ Health Study II [63].

Other clinical trials have generally examined the effects on cardiovascular disease of supplements combining vitamin C with other antioxidants, such as vitamin E and beta-carotene, making it more difficult to isolate the potential contribution of vitamin C. The SU.VI.MAX study examined the effects of a combination of vitamin C (120 mg/day), vitamin E (30 mg/day), beta-carotene (6 mg/day), selenium (100 mcg/day), and zinc (20 mg/day) in 13,017 French adults from the general population [32]. After a median follow-up time of 7.5 years, the combined supplements had no effect on ischemic cardiovascular disease in either men or women. In the Women’s Angiographic Vitamin and Estrogen (WAVE) study, involving 423 postmenopausal women with at least one coronary stenosis of 15%–75%, supplements of 500 mg vitamin C plus 400 IU vitamin E twice per day not only provided no cardiovascular benefit, but significantly increased all-cause mortality compared with placebo [64].

The authors of a 2006 meta-analysis of randomized controlled trials concluded that antioxidant supplements (vitamins C and E and beta-carotene or selenium) do not affect the progression of atherosclerosis [65]. Similarly, a systematic review of vitamin C’s effects on the prevention and treatment of cardiovascular disease found that vitamin C did not have favorable effects on cardiovascular disease prevention [66]. Since then, researchers have published follow-up data from the Linxian trial, a population nutrition intervention trial conducted in China [37]. In this trial, daily vitamin C supplements (120 mg) plus molybdenum (30 mcg) for 5–6 years significantly reduced the risk of cerebrovascular deaths by 8% during 10 years of follow-up after the end of the active intervention.

Although the Linxian trial data suggest a possible benefit, overall, the findings from most intervention trials do not provide convincing evidence that vitamin C supplements provide protection against cardiovascular disease or reduce its morbidity or mortality. However, as discussed in the cancer prevention section, clinical trial data for vitamin C are limited by the fact that plasma and tissue concentrations of vitamin C are tightly controlled in humans. If subjects’ vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes [21,22,40,41].

Age-related macular degeneration (AMD) and cataracts

AMD and cataracts are two of the leading causes of vision loss in older individuals. Oxidative stress might contribute to the etiology of both conditions. Thus, researchers have hypothesized that vitamin C and other antioxidants play a role in the development and/or treatment of these diseases.

A population-based cohort study in the Netherlands found that adults aged 55 years or older who had high dietary intakes of vitamin C as well as beta-carotene, zinc, and vitamin E had a reduced risk of AMD [67]. However, most prospective studies do not support these findings [68]. The authors of a 2007 systematic review and meta-analysis of prospective cohort studies and randomized clinical trials concluded that the current evidence does not support a role for vitamin C and other antioxidants, including antioxidant supplements, in the primary prevention of early AMD [69].

Although research has not shown that antioxidants play a role in AMD development, some evidence suggests that they might help slow AMD progression [70]. The Age-Related Eye Disease Study (AREDS), a large, randomized, placebo-controlled clinical trial, evaluated the effect of high doses of selected antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc, and 2 mg copper) on the development of advanced AMD in 3,597 older individuals with varying degrees of AMD [71]. After an average follow-up period of 6.3 years, participants at high risk of developing advanced AMD (i.e., those with intermediate AMD or those with advanced AMD in one eye) who received the antioxidant supplements had a 28% lower risk of progression to advanced AMD than participants who received a placebo. A follow-up AREDS2 study confirmed the value of this and similar supplement formulations in reducing the progression of AMD over a median follow-up period of 5 years [72].

High dietary intakes of vitamin C and higher plasma ascorbate concentrations have been associated with a lower risk of cataract formation in some studies [2,4]. In a 5-year prospective cohort study conducted in Japan, higher dietary vitamin C intake was associated with a reduced risk of developing cataracts in a cohort of more than 30,000 adults aged 45–64 years [73]. Results from two case-control studies indicate that vitamin C intakes greater than 300 mg/day reduce the risk of cataract formation by 70%–75% [2,4]. Use of vitamin C supplements, on the other hand, was associated with a 25% higher risk of age-related cataract extraction among a cohort of 24,593 Swedish women aged 49–83 years [74]. These findings applied to study participants who took relatively high-dose vitamin C supplements (approximately 1,000 mg/day) and not to those who took multivitamins containing substantially less vitamin C (approximately 60 mg/day).

Data from clinical trials are limited. In one study, Chinese adults who took daily supplements of 120 mg vitamin C plus 30 mcg molybdenum for 5 years did not have a significantly lower cataract risk [75]. However, adults aged 65–74 years who received 180 mg vitamin C plus 30 mcg molybdenum combined with other nutrients in a multivitamin/mineral supplement had a 43% significantly lower risk of developing nuclear cataracts than those who received a placebo [75]. In the AREDS study, older individuals who received supplements of 500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene for an average of 6.3 years did not have a significantly lower risk of developing cataracts or of cataract progression than those who received a placebo [76]. The AREDS2 study, which also tested formulations containing 500 mg vitamin C, confirmed these findings [77].

Overall, the currently available evidence does not indicate that vitamin C, taken alone or with other antioxidants, affects the risk of developing AMD, although some evidence indicates that the AREDS formulations might slow AMD progression in people at high risk of developing advanced AMD.

The common cold

In the 1970s Linus Pauling suggested that vitamin C could successfully treat and/or prevent the common cold [78]. Results of subsequent controlled studies have been inconsistent, resulting in confusion and controversy, although public interest in the subject remains high [79,80].

A 2007 Cochrane review examined placebo-controlled trials involving the use of at least 200 mg/day vitamin C taken either continuously as a prophylactic treatment or after the onset of cold symptoms [80]. Prophylactic use of vitamin C did not significantly reduce the risk of developing a cold in the general population. However, in trials involving marathon runners, skiers, and soldiers exposed to extreme physical exercise and/or cold environments, prophylactic use of vitamin C in doses ranging from 250 mg/day to 1 g/day reduced cold incidence by 50%. In the general population, use of prophylactic vitamin C modestly reduced cold duration by 8% in adults and 14% in children. When taken after the onset of cold symptoms, vitamin C did not affect cold duration or symptom severity.

Overall, the evidence to date suggests that regular intakes of vitamin C at doses of at least 200 mg/day do not reduce the incidence of the common cold in the general population, but such intakes might be helpful in people exposed to extreme physical exercise or cold environments and those with marginal vitamin C status, such as the elderly and chronic smokers [80-82]. The use of vitamin C supplements might shorten the duration of the common cold and ameliorate symptom severity in the general population [79,82], possibly due to the anti-histamine effect of high-dose vitamin C [83]. However, taking vitamin C after the onset of cold symptoms does not appear to be beneficial [80].

Health Risks from Excessive Vitamin C

Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes [8]. The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract [4,8].

In postmenopausal women with diabetes who participated in the Iowa Women’s Health Study, supplemental (but not dietary) vitamin C intake (at least 300 mg/day) was significantly associated with an increased risk of cardiovascular disease mortality [58]. The mechanism for this effect, if real, is not clear and this finding is from a subgroup of patients in an epidemiological study. No such association has been observed in any other epidemiological study, so the significance of this finding is uncertain. High vitamin C intakes also have the potential to increase urinary oxalate and uric acid excretion, which could contribute to the formation of kidney stones, especially in individuals with renal disorders [8]. However, studies evaluating the effects on urinary oxalate excretion of vitamin C intakes ranging from 30 mg to 10 g/day have had conflicting results, so it is not clear whether vitamin C actually plays a role in the development of kidney stones [8,84-86]. The best evidence that vitamin C contributes to kidney stone formation is in patients with pre-existing hyperoxaluria [22].

Due to the enhancement of nonheme iron absorption by vitamin C, a theoretical concern is that high vitamin C intakes might cause excess iron absorption. In healthy individuals, this does not appear to be a concern [8]. However, in individuals with hereditary hemochromatosis, chronic consumption of high doses of vitamin C could exacerbate iron overload and result in tissue damage [4,8].

Under certain conditions, vitamin C can act as a pro-oxidant, potentially contributing to oxidative damage [8]. A few studies in vitro have suggested that by acting as a pro-oxidant, supplemental oral vitamin C could cause chromosomal and/or DNA damage and possibly contribute to the development of cancer [8,87,88]. However, other studies have not shown increased oxidative damage or increased cancer risk with high intakes of vitamin C [8,89].

Other reported effects of high intakes of vitamin C include reduced vitamin B12 and copper levels, accelerated metabolism or excretion of ascorbic acid, erosion of dental enamel, and allergic responses [8]. However, at least some of these conclusions were a consequence of assay artifact, and additional studies have not confirmed these observations [8].

The FNB has established ULs for vitamin C that apply to both food and supplement intakes (Table 3) [8]. Long-term intakes of vitamin C above the UL may increase the risk of adverse health effects. The ULs do not apply to individuals receiving vitamin C for medical treatment, but such individuals should be under the care of a physician [8].

Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin C [8]
Age Male Female Pregnancy Lactation
0–12 months Not possible to establish* Not possible to establish*
1–3 years 400 mg 400 mg
4–8 years 650 mg 650 mg
9–13 years 1,200 mg 1,200 mg
14–18 years 1,800 mg 1,800 mg 1,800 mg 1,800 mg
19+ years 2,000 mg 2,000 mg 2,000 mg 2,000 mg

*Formula and food should be the only sources of vitamin C for infants.

Interactions with Medications

Vitamin C supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss their vitamin C intakes with their health care providers.

Chemotherapy and radiation

The safety and efficacy of the use of vitamin C and other antioxidants during cancer treatment is controversial [52,90,91]. Some data indicate that antioxidants might protect tumor cells from the action of radiation therapy and chemotherapeutic agents, such as cyclophosphamide, chlorambucil, carmustine, busulfan, thiotepa, and doxorubicin [53,90,92,93]. At least some of these data have been criticized because of poor study design [51]. Other data suggest that antioxidants might protect normal tissues from chemotherapy- and radiation-induced damage [90,92] and/or enhance the effectiveness of conventional cancer treatment [94]. However, due to the physiologically tight control of vitamin C, it is unclear whether oral vitamin C supplements could alter vitamin C concentrations enough to produce the suggested effects. Individuals undergoing chemotherapy or radiation should consult with their oncologist prior to taking vitamin C or other antioxidant supplements, especially in high doses [53].

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins)

Vitamin C, in combination with other antioxidants, may attenuate the increase in high-density lipoprotein levels resulting from combination niacin–simvastatin (Zocor®) therapy [95,96]. It is not known whether this interaction occurs with other lipid-altering regimens [53]. Health care providers should monitor lipid levels in individuals taking both statins and antioxidant supplements [53].

Vitamin C and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Fruits, particularly citrus fruits, fruit juices, and many vegetables are excellent sources of vitamin C. Some ready-to-eat breakfast cereals are fortified with vitamin C.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

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Ephedra and Ephedrine Alkaloids for Weight Loss and Athletic Performance

This document summarizes the results of an evidence-based review on the efficacy and safety of ephedra and ephedrine alkaloids for weight loss or to enhance athletic performance (power and endurance). The report was prepared by the Southern California Evidence-based Practice Center-RAND (RAND) under contract to the Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services. This work was sponsored by the Office of Dietary Supplements (ODS) and the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health, U.S. Department of Health and Human Services. A summary of this report was published in JAMA and the data described here are drawn from that article [1].

Key points

  • The Chinese botanical ephedra, or ma-huang, is sold as a dietary supplement in the United States. It is a natural source of the alkaloids ephedrine and pseudoephedrine. Some dietary supplement products used for weight loss and to enhance athletic performance contain these alkaloids.
  • Synthetic ephedrine and pseudoephedrine are found in over-the-counter decongestants and cold medicines and are used to treat asthma. Ephedrine is not approved in the United States as a drug for weight loss or to enhance athletic performance.
  • The use of ephedrine, ephedrine plus caffeine, or dietary supplements containing ephedra and botanicals with caffeine is associated with a modest but statistically significant increase in weight loss over a relatively short time (less than or equal to 6 months). No studies have assessed their long-term effects (greater than 6 months).
  • No studies have assessed the effect of dietary supplements containing ephedra and botanicals on athletic performance. The few studies that assessed the effect of ephedrine support a modest effect of ephedrine plus caffeine on very-short-term (1-2 hours after a single dose) athletic performance in a highly selected physically fit population.
  • Results of controlled trials show that the use of synthetic ephedrine, ephedrine plus caffeine, or ephedra plus botanicals containing caffeine is associated with 2-3 times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations compared with placebo.
  • RAND analyzed adverse event reports filed with the U.S. Food and Drug Administration (FDA) and with a manufacturer of ephedra-containing dietary supplements as well as published case reports. Although this analysis raises concerns about the safety of botanical dietary supplements containing ephedra, most of these case reports are not documented sufficiently to support an informed judgment about the relationship between the use of ephedra-containing dietary supplements or ephedrine and the adverse event in question.
  • According to the RAND report, the number of deaths, myocardial infarctions, cerebrovascular accidents, seizures, and serious psychiatric illnesses in young adults is sufficient to warrant further evaluation of the safety of these products in a controlled manner (such as a hypothesis-testing case-control study) to test the possibility that consumption of ephedra or ephedrine causes these serious adverse events.

Introduction to ephedra and ephedrine alkaloids

The Chinese botanical ephedra, or ma-huang, is sold as a dietary supplement in the United States. Ephedra is the common name for three principal species: Ephedra sinica, Ephedra equisentina, and Ephedra intermedia [2]. The active compounds in the plant’s stem (about 1.32% by weight) are the phenylalanine-derived alkaloids ephedrine, pseudoephedrine, phenylpropanolamine (norephedrine), and cathine (norpseudoephedrine) [3,4]. Alkaloid content and composition vary by species and growth conditions [5-7]; total alkaloid content can vary from 0.5% to 2.3%. Ephedrine, the most potent alkaloid, can account for up to 90% of the total alkaloid content and pseudoephedrine can account for up to 27% [3,8,9]. The pharmacologic activity of an ephedra sample depends on its alkaloid composition. North American ephedra species, such as E. nevadensis (known as Mormon tea), contain little or no ephedrine or other alkaloids [10]. Ephedrine is a mixed sympathomimetic agent that enhances the release of norepinephrine from sympathetic neurons and stimulates alpha and beta receptors [11]. Ephedrine stimulates heart rate, thereby increasing cardiac output [11,12]. It causes peripheral constriction resulting in an increase in peripheral resistance that can lead to a sustained rise in blood pressure [13]. It relaxes bronchial smooth muscle [11,12] and is used as a decongestant and for temporary relief of shortness of breath caused by asthma. Ephedrine acts as a stimulant in the central nervous system [11,12]. Of the ephedra alkaloids, ephedrine is the most potent thermogenic agent. It may function as an anorectic by acting on the satiety center in the hypothalamus [14].

Products available for weight loss or athletic enhancement

Ephedrine or products containing combinations of ephedrine and caffeine are not approved in the United States as drugs for weight loss. Botanical dietary supplements for weight loss may include ephedra (a natural source of ephedrine) and other botanicals that are natural sources of caffeine and salicylic acid. In place of ephedra, manufacturers sometimes substitute botanicals that contain sympathomimetic amines, such as country mallow or bitter orange. Botanicals with diuretic or cathartic action are sometimes also included. Although ephedrine is not approved in the United States as a drug for athletic performance, athletes have used over-the-counter stimulants containing ephedrine or its related alkaloids to enhance athletic performance. Products containing ephedra alone or combined with vitamins, minerals, or other botanicals are marketed to increase energy and enhance athletic performance.

Overview of the RAND evidence-based review of ephedra and ephedrine alkaloids

ODS and NCCAM sponsored an evidence-based review by RAND to assess the clinical efficacy and safety of products containing ephedra or synthesized ephedrine alkaloids used for weight loss or to enhance athletic performance. RAND, one of 12 centers participating in the AHRQ Evidence-based Practice Program, prepared a report for AHRQ that was released in March 2003. A technical expert panel that included basic scientists and clinicians with a wide range of expertise provided input for the report. RAND conducted a comprehensive search of published and unpublished sources for controlled clinical trials on ephedra and ephedrine used for weight loss and athletic performance in humans. Each study considered for the review was evaluated according to preestablished criteria. RAND identified 52 controlled clinical trials of synthetic ephedrine or botanical ephedra used for weight loss or athletic performance in humans. Weight-loss studies with at least 8 weeks of follow-up data were reviewed for inclusion in a meta-analysis. Studies of athletic performance used a wide variety of interventions and were not synthesized through meta-analysis. The strongest level of evidence to show that an adverse event was caused by a particular exposure comes from placebo-controlled randomized trials. Data on adverse events associated with the use of ephedrine or ephedra-containing dietary supplements were collected from 52 randomized controlled trials identified in the literature search. The number of events or people (depending on how the study reported the events) was abstracted for each treatment and placebo group. A meta-analysis was conducted on data from 50 trials for subgroups of adverse events, including psychiatric symptoms, autonomic hyperactivity, nausea/vomiting, palpitations, hypertension, and tachycardia. No serious adverse events (death, myocardial infarction, cerebrovascular/stroke events, seizure, or serious psychiatric events) were reported in the clinical trials. However, because participants in clinical trials must meet eligibility criteria, including the absence of specific underlying health risks, they may not represent the general population. Case reports were assessed in this review because the total number of patients in the clinical trials was not sufficient for adequately assessing the possibility of rare outcomes. Although such adverse event reports are not conclusive evidence of a cause-and-effect relationship, they can indicate the potential for such a relationship. The cases came from the published case reports identified in the literature search; case reports from the FDA through September 30, 2001; and case reports from a manufacturer of ephedra-containing dietary supplements. The reports were coded for the type of adverse event; serious adverse events were analyzed further. The goal of the analysis was to identify cases that would be classified medically as idiopathic in etiology (i.e., cause unknown). If use of ephedra or ephedrine-containing products was documented for such cases, then the possibility that ephedra or ephedrine caused the event was considered. Cases were classified as sentinel events if 1) documentation existed that an adverse event meeting the selection criteria occurred, 2) documentation existed that the person having the adverse event took an ephedra-containing supplement within 24 hours before the event (for cases of death, myocardial infarction, stroke, or seizure), and 3) alternative explanations were investigated and excluded with reasonable certainty. If another condition existed that by itself could have caused the adverse event but may have been precipitated by ephedra or ephedrine, it was classified as a possible sentinel event.

Findings

Efficacy of ephedra and ephedrine alkaloids used for weight loss RAND identified 44 controlled trials assessing ephedra and ephedrine alkaloids used in combination with other compounds for weight loss [1]; 20 of these trials met the criteria for inclusion in the meta-analysis. Meta-regressions were used to assess the effect of ephedrine, ephedrine plus caffeine, and ephedra plus herbs containing caffeine. Five pairs of treatment regimens were compared:

  • Ephedrine vs. placebo: 5 studies. Ephedrine was associated with a statistically significant weight loss of 1.3 pounds/month more than was associated with placebo for up to 4 months of use.
  • Ephedrine plus caffeine vs. placebo: 12 studies. Ephedrine plus caffeine was associated with a statistically significant weight loss of 2.2 pounds/month more than was associated with placebo for up to 4 months of use.
  • Ephedrine plus caffeine vs. ephedrine: 3 studies. Ephedrine plus caffeine was associated with a statistically significant weight loss of 0.8 pounds/month more than was associated with ephedrine alone.
  • Ephedrine vs. other active weight loss products: 2 studies. No conclusions could be drawn because of the small sample size in each of these studies.
  • Ephedra plus herbs containing caffeine vs. placebo: 4 studies. Ephedra plus herbs containing caffeine was associated with a statistically significant weight loss of 2.1 pounds/month more than was associated with placebo for up to 4 months of use.

The use of ephedrine, ephedrine plus caffeine, or dietary supplements containing ephedra and herbs with caffeine was associated with a statistically significant increase in weight loss over a relatively short time. Both ephedrine plus caffeine and ephedra plus herbs containing caffeine were somewhat more effective than ephedrine alone in promoting weight loss. Only one study compared ephedra plus other herbs (but without caffeine) with a placebo. The ephedra-containing product was associated with a weight loss of 1.8 pounds/month more than was associated with a placebo for up to 3 months of use. Overall, the effects on weight loss of synthetic ephedrine plus caffeine and ephedra plus herbs containing caffeine were equivalent: weight loss of approximately 2 pounds/month more than was associated with placebo for up to 4 or 6 months of use. No studies assessed the long-term effects on weight loss; the longest published follow-up was 6 months. Efficacy of ephedra and ephedra alkaloids used to enhance athletic performance No studies assessed the effect of dietary supplements containing ephedra with or without herbs containing caffeine on athletic performance. The effects of ephedrine on athletic performance have not been well studied; RAND identified 8 published controlled trials of the effects of synthetic ephedrine on athletic performance, all but 1 of which also included caffeine. These trials were not appropriate for a pooled analysis because they used a wide variety of interventions. A few studies assessed the effect of ephedrine on athletic performance in small samples for short times (1-2 hours after a single dose) and showed a modest effect of ephedrine plus caffeine on very-short-term athletic performance in a highly selected physically fit population. This use does not reflect that of the general population. No studies assessed the sustained use of ephedrine on performance. Safety assessment RAND reviewed adverse events reported in 52 published randomized controlled clinical trials. No serious adverse events (death, myocardial infarction, cerebrovascular/stroke events, seizure, or serious psychiatric events) were reported in the clinical trials. However, evidence from the trials was sufficient to support the conclusion that the use of ephedrine, ephedrine plus caffeine, or ephedra plus caffeine is associated with 2-3 times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations. The contribution of caffeine to these symptoms cannot be determined. RAND also reviewed 71 cases reported in the published medical literature, 1820 case reports provided by FDA, and more than 18,000 consumer complaints reported to a manufacturer of ephedra-containing dietary supplements. Most of the cases were not well documented so decisions could not be made about the potential relationship between the use of ephedra-containing dietary supplements or ephedrine and the adverse event. A total of 65 cases from the published literature, 241 cases from FDA, and 43 cases from a manufacturer of ephedra-containing dietary supplements were included in the adverse event analysis. Sentinel events with prior ephedra consumption included 2 deaths, 3 myocardial infarctions, 9 cerebrovascular/stroke events, 3 seizures, and 5 psychiatric cases. Sentinel events with prior ephedrine consumption included 3 deaths, 2 myocardial infarctions, 2 cerebrovascular/stroke events, 1 seizure, and 3 psychiatric cases. About half of the sentinel events occurred in individuals 30 years of age or younger. An additional 43 cases were identified as possible sentinel events with prior ephedra consumption and an additional 7 cases were identified as possible sentinel events with prior ephedrine consumption.

References

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  9. McKenna DJ, Jones K, Hughes K: Botanical Medicines. The Desk Reference for Major Herbal Supplements, 2nd edition. New York: Haworth Herbal Press, 2002.
  10. Caveney S, Charlet DA, Freitag H, Maier-Stolte M, Starratt AN: New observations on the secondary chemistry of world Ephedra (Ephedraceae). American Journal of Botany 88:1199-1208, 2001. [PubMed abstract]
  11. Hardman JG, Limbird LE, Gilman A, eds.: Goodman and Gilman’s The Pharmacological Basis of Disease. New York: McGraw-Hill, 2001.
  12. Burnham TH, Novak KK, Bell WI, eds.: Ephedrine. In: Drug Facts and Comparisons, 57th edition. St. Louis: Facts and Comparisons, 2003.
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  14. Astrup A, Toubro S, Christensen NJ, Quaade F: Pharmacology of thermogenic drugs. American Journal of Clinical Nutrition 55:246S-248S, 1993. [PubMed abstract]

Disclaimer

This publication is a work of reproduction from Federal government resources  and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

Korean Red Ginseng

In this study, although red ginseng did not improve hyperglycemia, red ginseng improved diabetic hearing impairments observed in type 2 diabetic mice. We suggest that red ginseng efficacy in the auditory function of type 2 diabetic mice may be related to the improved insulin sensitivity of red ginseng and protection efficacy of the nerve from the major ginsenoside of red ginseng.

Ginseng has a long history of use for health enhancement, and there is some evidence from animal studies that it has a beneficial effect on cognitive performance. The purpose of this study was to investigate the effect of Korean red ginseng on cognitive performance in humans. A total of 15 healthy young males with no psychiatric or cognitive problems were selected based on an interview with a board-certified psychiatrist.

In addition, various functions of KRG have been reported, e.g. anti-inflammatory, −coagulating, and -oxidative actions, enhancement of sexual function, and vasodilation. Moreover, some researchers predicted beneficial effects on KRG on women’s health, e.g. targeting postmenopausal symptoms, due to its estrogen like function.

Ginseng cultivated in Korea is classified into three types, depending on how it is processed: fresh ginseng (less than 4 years old), white ginseng (4–6 years old and dried after peeling), and red ginseng (harvested when 6 years old, steamed and dried) [4]. Red ginseng is not skinned before it is steamed or otherwise heated and subsequently dried. In the course of the steaming process, ginseng starch is gelatinized, causing an increase in saponin content. Traditionally red ginseng has been used to restore and enhance normal well-being, and is often referred to as an adaptogenic [5]. One of the therapeutic claims for red ginseng is that it enhances sexual function.

This is the first report to demonstrate the prophylactic function of KRG extract in ameliorating the hyperglycemia of T1D. Immune compartments of diabetic mice were found to be preserved in KRG-treated mice suggesting that Korean red ginseng may benefit T1D patients, not only for its hypoglycemic but also for its immunomodulatory effects.

Because fresh ginseng is easily degraded at room temperature, it needs to be processed to red ginseng by steaming and drying, and accumulating evidence has revealed that red ginseng has higher biological activity and lower side effects compared to fresh or white ginseng [13]. Korean Red Ginseng (KRG) has been known to have various biological activities, including immune enhancement, antioxidant effects, memory enhancement, improvement of menopausal disorder, and induction of metabolic energy.

It has been reported that Korean Red Ginseng has been manufactured for 1,123 years as described in the GoRyeoDoGyeong record. The Korean Red Ginseng manufactured by the traditional preparation method has its own chemical component characteristics. The ginsenoside content of the red ginseng is shown as Rg1: 3.3 mg/g, Re: 2.0 mg/g, Rb1: 5.8 mg/g, Rc:1.7 mg/g, Rb2: 2.3 mg/g, and Rd: 0.4 mg/g, respectively. It is known that Korean ginseng generally consists of the main root and the lateral or fine roots at a ratio of about 75:25. Therefore, the red ginseng extract is prepared by using this same ratio of the main root and lateral or fine roots and processed by the historical traditional medicine prescription.

The swift emergence of new infectious viruses and drug-resistant variants has limited the availability of effective antiviral agents and vaccines. Thus, the development of broad-spectrum antivirals and immunomodulating agents that stimulate host immunity and improve host resilience is essential. Although ginseng itself can exert direct antiviral effects by inhibiting viral attachment, membrane penetration, and replication, the foremost antiviral activities of ginseng are attributed to the enhancement of host immunity.

Large numbers of immune stimulators have recently been discovered, and many studies have scientifically demonstrated their effects on various immune systems. However, excessive immune stimulation results in several side effects, such as the development of immunotoxicity and hypersensitivity. Experimental models are needed to verify immune stimulatory activities that increase host resistance to microbial infection. Here, we investigated whether KRG extract administration efficiently boosts the immune system and protects KRG administered mice against HSV mucosal infection. Since different parts of immune cells regulate HSV, KRG related immune modulation can be either beneficial or detrimental to the host. For example, increased activation of certain TLRs, including TLR2, 3, and 6, induces the innate antiviral pathway [18,19] and acquired HSV specific CD4+ [5,20] and CD8+ T cells [21]. Furthermore, regulatory T cells coordinate early protective immunity to HSV infection, although their exact function is not yet understood. We hypothesized that KRG extract administration would modulate the immune environment and affect genital HSV infectivity.

Our systematic review provided positive evidence of ginseng for sexual function and KRG for sexual arousal and total hot flashes score in menopausal women. However, the results of KRG or ginseng failed to show specific effects on hot flash frequency, hormones, biomarkers, or endometrial thickness. The level of evidence for these findings was low because of unclear risk of bias.

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  • How Much Do We Really Know About Our Favorite Cosmeceutical Ingredients?

    To date, we are unaware of a review that has investigated common cosmeceutical ingredients in order to answer the three specific questions proposed by the father of cosmeceuticals, Dr. Albert Kligman. It is the goal of this review to gather all the published scientific data on five common cosmeceutical ingredients, answer the three major questions about the scientific rationale for their use, and ascertain how much we really know about consumers’ favorite cosmeceutical ingredients.

    Most of the research concerning cosmeceutical retinoid ingredients is based upon the effects of retinoic acid on the skin. Clinical trials concerning retinol and retinaldehyde are scant and lacking in statistical evaluation for significance. There is research substantiating the effects of kinetin in plants and also in-vitro antioxidant effects. However, proof of anti-aging activity remains elusive, and the clinical efficacy of kinetin is based on limited data. Niacinamide is the ingredient investigated that most closely upholds the “Kligman standards” of cosmeceutical-ingredient analysis. With the available scientific evidence on topical niacinamide, clinicians are able to adequately answer questions about permeability, mechanism, and clinical effect. Both green tea and soy have been popularized commercially based on their antioxidant effects, yet there is a paucity of clinical studies concerning their efficacy as topical anti-aging agents. It may be that soy and green tea are better at preventing the signs and symptoms of skin aging than actually reversing them. Since cosmeceutical products are claiming to therapeutically affect the structure and function of the skin, it is rational and necessary to hold them to specified scientific standards that substantiate efficacy claims.

  • Discovering the link between nutrition and skin aging

    Skin has been reported to reflect the general inner-health status and aging. Nutrition and its reflection on skin has always been an interesting topic for scientists and physicians throughout the centuries worldwide. Vitamins, carotenoids, tocopherols, flavonoids and a variety of plant extracts have been reported to possess potent anti-oxidant properties and have been widely used in the skin care industry either as topically applied agents or oral supplements in an attempt to prolong youthful skin appearance. This review will provide an overview of the current literature “linking” nutrition with skin aging.

  • Skin Ageing: Natural Weapons and Strategies

    The fact that the skin is the most visible organ makes us aware of the ageing process every minute. The use of plant extracts and herbs has its origins in ancient times. Chronological and photo-ageing can be easily distinguished clinically, but they share important molecular features. We tried to gather the most interesting evidence based on facts about plants and plant extracts used in antiaging products. Our main idea was to emphasize action mechanisms of these plant/herbal products, that is, their “strategies” in fighting skin ageing. Some of the plant extracts have the ability to scavenge free radicals, to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin. There are some plants that can affect skin elasticity and tightness. Certainly, there is a place for herbal principles in antiaging cosmetics. On the other hand, there is a constant need for more evaluation and more clinical studies in vivo with emphasis on the ingredient concentration of the plant/herbal products, its formulation, safety, and duration of the antiaging effect.

  • Botanicals and Their Bioactive Phytochemicals for Women’s Health

    Botanical dietary supplements are increasingly popular for women’s health, particularly for older women. The specific botanicals women take vary as a function of age. Younger women will use botanicals for urinary tract infections, especially Vaccinium macrocarpon (cranberry), where there is evidence for efficacy. Botanical dietary supplements for premenstrual syndrome (PMS) are less commonly used, and rigorous clinical trials have not been done. Some examples include Vitex agnus-castus (chasteberry), Angelica sinensis (dong quai), Viburnum opulus/prunifolium (cramp bark and black haw), and Zingiber officinale (ginger). Pregnant women have also used ginger for relief from nausea. Natural galactagogues for lactating women include Trigonella foenum-graecum (fenugreek) and Silybum marianum (milk thistle); however, rigorous safety and efficacy studies are lacking. Older women suffering menopausal symptoms are increasingly likely to use botanicals, especially since the Women’s Health Initiative showed an increased risk for breast cancer associated with traditional hormone therapy. Serotonergic mechanisms similar to antidepressants have been proposed for Actaea/Cimicifuga racemosa (black cohosh) and Valeriana officinalis (valerian). Plant extracts with estrogenic activities for menopausal symptom relief include Glycine max (soy), Trifolium pratense (red clover), Pueraria lobata (kudzu), Humulus lupulus (hops), Glycyrrhiza species (licorice), Rheum rhaponticum (rhubarb), Vitex agnus-castus (chasteberry), Linum usitatissimum (flaxseed), Epimedium species (herba Epimedii, horny goat weed), and Medicago sativa (alfalfa). Some of the estrogenic botanicals have also been shown to have protective effects against osteoporosis. Several of these botanicals could have additional breast cancer preventive effects linked to hormonal, chemical, inflammatory, and/or epigenetic pathways. Finally, although botanicals are perceived as natural safe remedies, it is important for women and their healthcare providers to realize that they have not been rigorously tested for potential toxic effects and/or drug/botanical interactions.

  • Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products.

  • Main Benefits and Applicability of Plant Extracts in Skin Care Products

    Natural ingredients have been used for centuries for skin care purposes. Nowadays, they are becoming more prevalent in formulations, due to consumers’ concerns about synthetic ingredients/chemical substances. The main benefits reported for plant extracts, used in skin care, include antioxidant and antimicrobial activities and tyrosinase inhibition effect. In this review, some examples of plants from Portuguese flora, whose extracts have shown good properties for skin care are presented. However, despite the known properties of plant extracts, few studies reported the development of formulations with them. More work in this field can be accomplished to meet consumer demand.
    Main Benefits and Applicability of Plant Extracts in Skin Care Products (PDF Download Available).

  • Trends in aging and skin care: Ayurvedic concepts

    The association between Ayurveda, anti-aging and cosmeceuticals is gaining importance in the beauty, health and wellness sector. Ayurvedic cosmeceuticals date back to the Indus Valley Civilization. Modern research trends mainly revolve around principles of anti-aging activity described in Ayurveda: Vayasthapana (age defying), Varnya (brighten skin-glow), Sandhaniya (cell regeneration), Vranaropana (healing), Tvachya (nurturing), Shothahara (anti-inflammatory), Tvachagnivardhani (strengthening skin metabolism) and Tvagrasayana (retarding aging). Many rasayana plants such as Emblica officinalis (Amla) and Centella asiatica (Gotukola) are extensively used.

  • Anti-Photoaging Effects of Soy Isoflavone Extract (Aglycone and Acetylglucoside Form) from Soybean Cake

    Soy isoflavones, found in soybean and soybean products, have been reported to possess many physiological activities such as antioxidant activity, inhibition of cancer cell proliferation, reduction of cardiovascular risk, prevention of osteoporosis and alleviation of postmenopausal syndrome. In our previous study, soy isoflavone extract ISO-1 (containing 12 soy isoflavones) from soybean cake was demonstrated to prevent skin damage caused by UVB exposure. In this study, soy isoflavone extract from soybean cake was further purified and evaluated for the protective effects on UVB-induced damage.

  • Mushrooms extracts and compounds in cosmetics, cosmeceuticals and nutricosmetics—A reviewThe cosmetic industry is constantly in search of ingredients from natural sources because of their competitive effectiveness and lower toxicity effects. Mushrooms have been an important part of our diet for years and are now finding their way as cosmetic ingredients, either as cosmeceutical or as nutricosmetics. The present review focuses on the most relevant activities of mushroom extracts, as well as on their bioactive compounds, which make them interesting ingredients for cosmetic formulations. Mushroom extracts, as well as their bioactive metabolites, revealed anti-tyrosinase, anti-hyaluronidase, anti-collagenase and anti-elastase activity. Emphasis was also given to their important anti-oxidant, antimicrobial and anti-inflammatory potential, topics largely studied by numerous authors, making them very versatile and multi-functional cosmetic ingredients. Some of the bioactive compounds and the mechanism responsible for the activities ascribed to mushrooms were highlighted. Other activities were identified as needing to be further studied in order to identify the major compounds contributing to the target activity, as well as their mechanisms of action. Based on the above findings, mushroom extracts, as well as their bioac-tive metabolites, constitute important ingredients that can help to combat aging, reduce the severity of inflammatory skin disease and correct hyperpigmentation disorders. These findings and claims must be correctly supported by clinical trials and in vivo studies.
    Mushrooms extracts and compounds in cosmetics, cosmeceuticals and nutricosmetics—A review (PDF Download Available).
  • Practical Uses of Botanicals in Skin Care

    Cosmeceuticals are the fastest growing sector of the cosmetic industry, and the future of antiaging cosmeceuticals in particular is very promising. Botanical extracts that support the health, texture, and integrity of the skin, hair, and nails are widely used in cosmetic formulations. They form the largest category of cosmeceutical additives found in the marketplace today due to the rising consumer interest and demand for natural products. Various plant extracts that formed the basis of medical treatments in ancient civilizations and many traditional cultures are still used today in cleansers, moisturizers, astringents, and many other skin care products. New botanical skin care treatments are emerging, presenting dermatologists and their patients the challenge of understanding the science behind these cosmeceuticals. Thus, dermatologists must have a working knowledge of these botanicals and keep up with how they evolve to provide optimal medical care and answer patient questions. The most popular botanicals commonly incorporated into skin care protocols are discussed.

  • Tolerance of natural baby skin-care products on healthy, full-term infants and toddlers

    The natural baby skin-care products were well tolerated by infants and toddlers when used alone or as part of a skin-care regimen.

  • Skin care: Historical and contemporary views

    Primary prevention, specifically skin care, is an important principle in Islamic theology just as it is emphasized in contemporary medicine. Many skin diseases can be prevented by a proactive approach to skin care, such as proper hygiene and routine inspections, principles that are constantly highlighted in the Islamic literature. Islam promotes primary prevention of disease, including recommendations for skin care practices.

  • Anti-Aging Potential of Phytoextract Loaded-Pharmaceutical Creams for Human Skin Cell Longetivity

    The exposure to ultraviolet radiations (UVR) is the key source of skin sunburn; it may produce harmful entities, reactive oxygen species (ROS), leading to aging. The skin can be treated and protected from the injurious effects of ROS by using various pharmaceutical formulations, such as cream. Cream can be loaded with antioxidants to quench ROS leading to photo-protective effects. Moreover, modern medicines depend on ethnobotanicals for protection or treatment of human diseases. This review article summarizes various in vivo antioxidant studies on herbal creams loaded with phyto-extracts. These formulations may serve as cosmeceuticals to protect skin against injurious effects of UVR. The botanicals studied for dermatologic use in cream form include Acacia nilotica, Benincasa hispida, Calendula officinalis, Camellia sinensis, Camellia sinensis, Nelumbo nucifera, Capparis decidua, Castanea sativa, Coffea arabica, Crocus sativus, Emblica officinalis Gaertn, Foeniculum vulgare, Hippophae rhamnoides, Lithospermum erythrorhizon, Malus domestica, Matricaria chamomilla L., Moringa oleifera, Morus alba, Ocimum basilicum, Oryza sativa, Polygonum minus, Punica granatum, Silybum marianum, Tagetes erecta Linn., Terminalia chebula, Trigonella foenum-graecum, and Vitis vinifera. The observed anti-aging effects of cream formulations could be an outcome of a coordinating action of multiple constituents. Of numerous botanicals, the phenolic acids and flavonoids appear effective against UVR-induced damage; however the evidence-based studies for their anti-aging effects are still needed.

  • Fermenting Red Ginseng Enhances Its Safety and Efficacy as a Novel Skin Care Anti-Aging Ingredient: In Vitro and Animal Study

    FRG offers increased anti-wrinkle efficacy, whitening efficacy, and reduced toxicological potency compared to RG.

  • Advanced Skin Care – A Novel Ingredient:Cupuacu butter

    The skin provides the human body with protection and a major barrier to environmental assault. Caring for skin is sometimes an afterthought. In other words, if something isn’t broken, don’t fix it. However, in the case of the integument, nothing could be further from the truth. Intact skin is paramount to health and well-being. This article will review skin care, specifically, advanced skin care, uncovering novel ingredients, and their importance for prevention and treatment as well as delving into the caring for the skin from the outside in.

Natural Skin Care part 2

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  • Targeting the Redox Balance in Inflammatory Skin Conditions

    Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.

  • Wound-healing properties of nut oil from Pouteria lucuma

    This study aims to evaluate the effect of lucuma (Pouteria lucuma O Kezte) nut oil (LNO) on fibroblasts migration, angiogenesis, inflammation, bacterial and fungal growth, and wound healing.

  • Moisturizers: The Slippery Road

    Moisturizers are an important part of a dermatologist’s armamentarium although little is written and well, a less is truly known about them. There is a cornucopia of projected skin products in the market whose real scientific role is not proven. These products although at times are regarded as mere cosmetics but have a well-known role in many skin disorders. Adequate knowledge about their mechanism of action, dosage, usage, and adverse effects is must for a dermatologist in this era. This article aims to bring forth the ever hidden facts of the much-hyped moisturizers. It is probably the first of its kind covering all aspects of moisturizers ranging from basic science to clinical usage, a subject that receives a short shrift in the current dermatological text.

  • Potential of herbs in skin protection from ultraviolet radiation

    Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A “sclerojuglonic” compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects.

  • Antioxidant, anti-inflammatory, anti-apoptotic, and skin regenerative properties of an Aloe vera-based extract of Nerium oleander leaves (nae-8®)

    The goal for this study was to evaluate the effects of an Aloe vera-based Nerium oleander extract (NAE-8®), compared to an extract of A. vera gel alone (ALOE), and to an aqueous extract of N. oleander (AQ-NOE) in bioassays pertaining to dermatologic potential with respect to antioxidant protection, anti-inflammatory effects, and cytokine profiles in vitro.

Omega-3 Fatty Acids

Introduction

The two major classes of polyunsaturated fatty acids (PUFAs) are the omega-3 and omega-6 fatty acids. Like all fatty acids, PUFAs consist of long chains of carbon atoms with a carboxyl group at one end of the chain and a methyl group at the other. PUFAs are distinguished from saturated and monounsaturated fatty acids by the presence of two or more double bonds between carbons within the fatty acid chain.

Omega-3 fatty acids (omega-3s) have a carbon–carbon double bond located three carbons from the methyl end of the chain. Omega-3s, sometimes referred to as “n-3s,” are present in certain foods such as flaxseed and fish, as well as dietary supplements such as fish oil. Several different omega-3s exist, but the majority of scientific research focuses on three: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA contains 18 carbon atoms, whereas EPA and DHA are considered “long-chain” (LC) omega-3s because EPA contains 20 carbons and DHA contains 22.

PUFAs are frequently designated by their number of carbon atoms and double bonds. ALA, for example, is known as C18:3n-3 because it has 18 carbons and 3 double bonds and is an n-3, or omega-3, fatty acid. Similarly, EPA is known as C20:5n-3 and DHA as C22:6n-3. Omega-6 fatty acids (omega-6s) have a carbon–carbon double bond that is six carbons away from the methyl end of the fatty acid chain. Linoleic acid (C18:2n-6) and arachidonic acid (C20:4n-6) are two of the major omega-6s.

The human body can only form carbon–carbon double bonds after the 9th carbon from the methyl end of a fatty acid [1]. Therefore, ALA and linoleic acid are considered essential fatty acids, meaning that they must be obtained from the diet [2]. ALA can be converted into EPA and then to DHA, but the conversion (which occurs primarily in the liver) is very limited, with reported rates of less than 15% [3]. Therefore, consuming EPA and DHA directly from foods and/or dietary supplements is the only practical way to increase levels of these fatty acids in the body.

ALA is present in plant oils, such as flaxseed, soybean, and canola oils [3]. DHA and EPA are present in fish, fish oils, and krill oils, but they are originally synthesized by microalgae, not by the fish. When fish consume phytoplankton that consumed microalgae, they accumulate the omega-3s in their tissues [3].

After ingestion, dietary lipids are hydrolyzed in the intestinal lumen [1]. The hydrolysis products—monoglycerides and free fatty acids—are then incorporated into bile-salt– containing micelles and absorbed into enterocytes, largely by passive diffusion. The process is efficient, with an absorption rate of about 95%, which is similar to that of other ingested fats [1]. Within intestinal cells, free fatty acids are primarily incorporated into chylomicrons and enter the circulation via the lymphatic system [1,4]. Once in the bloodstream, lipoprotein particles circulate within the body, delivering lipids to various organs for subsequent oxidation, metabolism, or storage in adipose tissue [4,5].

Omega-3s play important roles in the body as components of the phospholipids that form the structures of cell membranes [5]. DHA, in particular, is especially high in the retina, brain, and sperm [3,5,6]. In addition to their structural role in cell membranes, omega-3s (along with omega-6s) provide energy for the body and are used to form eicosanoids. Eicosanoids are signaling molecules that have similar chemical structures to the fatty acids from which they are derived; they have wide-ranging functions in the body’s cardiovascular, pulmonary, immune, and endocrine systems [1,2].

The eicosanoids made from omega-6s are generally more potent mediators of inflammation, vasoconstriction, and platelet aggregation than those made from omega-3s, although there are some exceptions [3,7]. Because both classes of fatty acids compete for the same desaturation enzymes, ALA is a competitive inhibitor of linoleic acid metabolism and vice versa [8]. Similarly, EPA and DHA can compete with arachidonic acid for the synthesis of eicosanoids. Thus, higher concentrations of EPA and DHA than arachidonic acid tip the eicosanoid balance toward less inflammatory activity [9].

Some researchers propose that the relative intakes of omega-6s and omega-3s—the omega-6/omega-3 ratio—may have important implications for the pathogenesis of many chronic diseases, such as cardiovascular disease and cancer [8], but the optimal ratio—if any—has not been defined [10]. Others have concluded that such ratios are too non-specific and are insensitive to individual fatty acid levels [11-13]. Most agree that raising EPA and DHA blood levels is far more important than lowering linoleic acid or arachidonic acid levels.

Currently, most clinicians do not assess omega-3 status, but it can be done by measuring individual omega-3s in plasma or serum phospholipids and expressing them as the percentage of total phospholipid fatty acids by weight [14-16]. Experts have not established normal ranges, but mean values for serum or plasma phospholipid EPA plus DHA among U.S. adults not taking omega-3 supplements are about 3%–4% [14-16]. Plasma and serum fatty acid values, however, can vary substantially based on an individual’s most recent meal, so they do not reflect long-term dietary consumption [3,17].

It is also possible to assess omega-3 status via analysis of erythrocyte fatty acids, a measurement that reflects longer-term intakes over approximately the previous 120 days [18,19]. The “omega-3 index” proposed by Harris and von Schacky reflects the content of EPA plus DHA in erythrocyte membranes expressed as a percentage of total erythrocyte fatty acids [20,21]. This index can be used as a surrogate for assessing tissue levels of EPA plus DHA [16,22,23]. EPA and DHA typically comprise about 3%–5% of erythrocyte fatty acids in Western populations with low fish intakes. In Japan, where fish consumption is high, erythrocyte EPA and DHA levels are about twice those of Western populations [3].

Recommended Intakes

Intake recommendations for fatty acids and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board of the Institute of Medicine (IOM) (now called the National Academy of Medicine) [5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA; intake at this level is assumed to ensure nutritional adequacy.
  • Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.
  • Acceptable Macronutrient Distribution Range (AMDR): range of intake for a particular energy source (macronutrient) that is associated with reduced risk of chronic disease while providing intakes of essential nutrients.

When the IOM last reviewed omega-3s, insufficient data were available to establish an EAR, so the IOM established AIs for all ages based on omega-3 intakes in healthy populations [5].

Table 1 lists the current AIs for omega-3s in grams per day. Human milk contains omega-3s as ALA, EPA and DHA, so the IOM established an AI for infants from birth to 12 months that is equivalent to the mean intake of omega-3s in healthy, breastfed infants.

For infants, the AIs apply to total omega-3s. For ages 1 and older, the AIs apply only to ALA because ALA is the only omega-3 that is essential. The IOM did not establish specific intake recommendations for EPA, DHA or other LC omega-3s.

Table 1: Adequate Intakes (AIs) for Omega-3s [5]
Age Male Female Pregnancy Lactation
Birth to 6 months* 0.5 mg 0.5 mg
7–12 months* 0.5 mg 0.5 mg
1–3 years** 0.7 mg 0.7 mg
4–8 years** 0.9 mg 0.9 mg
9–13 years** 1.2 mg 1.0 mg
14–18 years** 1.6 mg 1.1 mg 1.4 mg 1.3 mg
19-50 years** 1.6 mg 1.1 mg 1.4 mg 1.3 mg
51+ years** 1.6 mg 1.1 mg

*As total omega-3s
**As ALA

Sources of Omega-3s

Food
Plant oils that contain ALA include flaxseed (linseed), soybean, and canola oils [2,3]. Chia seeds and black walnuts also contain ALA.

The omega-3 content of fish varies widely. Cold-water fatty fish, such as salmon, mackerel, tuna, herring, and sardines, contain high amounts of LC omega-3s, whereas fish with a lower fat content—such as bass, tilapia and cod—as well as shellfish contain lower levels [3]. The omega-3 content of fish also depends on the composition of the food that the fish consumes [24]. Farmed fish usually have higher levels of EPA and DHA than wild-caught fish, but it depends on the food they are fed [24,25]. An analysis of the fatty acid composition of farm-raised Atlantic salmon from Scotland showed that the EPA and DHA content significantly decreased between 2006 and 2015 due to the replacement of traditional marine ingredients in fish feed with other ingredients [26].

Beef is very low in omega-3s, but beef from grass-fed cows contains somewhat higher levels of omega-3s, mainly as ALA, than that from grain-fed cows [27].

Some foods, such as certain brands of eggs, yogurt, juices, milk, and soy beverages, are fortified with DHA and other omega-3s. Since 2002, manufacturers have added DHA and arachidonic acid (the two most prevalent LC PUFAs in the brain) to most infant formulas available in the United States [28].

Several food sources of ALA, DHA, and/or EPA are listed in Table 2. The U.S. Food and Drug Administration (FDA) has established a Daily Value (DV) of 65 g for total fat but not for omega-3s. Thus, Table 2 presents the amounts of omega-3 fatty acids in grams per serving only and not the percent of the DV.

Table 2: Selected Food Sources of ALA, EPA, and DHA [29]
Food Grams per serving
ALA DHA EPA
Flaxseed oil, 1 tbsp 7.26
Chia seeds, 1 ounce 5.06
Flaxseed, whole, 1 tbsp 2.35
Salmon, Atlantic, farmed cooked, 3 ounces 1.24 0.59
Salmon, Atlantic, wild, cooked, 3 ounces 1.22 0.35
Herring, Atlantic, cooked, 3 ounces* 0.94 0.77
Canola oil, 1 tbsp 1.28
Sardines, canned in tomato sauce, drained, 3 ounces* 0.74 0.45
Mackerel, Atlantic, cooked, 3 ounces* 0.59 0.43
Salmon, pink, canned, drained, 3 ounces* 0.04 0.63 0.28
Soybean oil, 1 tbsp 0.92
Trout, rainbow, wild, cooked, 3 ounces 0.44 0.40
Black walnuts, 1 ounce 0.76
Mayonnaise, 1 tbsp 0.74
Oysters, eastern, wild, cooked, 3 ounces 0.14 0.23 0.30
Sea bass, cooked, 3 ounces* 0.47 0.18
Edamame, frozen, prepared, ½ cup 0.28
Shrimp, cooked, 3 ounces* 0.12 0.12
Refried beans, canned, vegetarian, ½ cup 0.21
Lobster, cooked, 3 ounces* 0.04 0.07 0.10
Tuna, light, canned in water, drained, 3 ounces* 0.17 0.02
Tilapia, cooked, 3 ounces* 0.04 0.11
Scallops, cooked, 3 ounces* 0.09 0.06
Cod, Pacific, cooked, 3 ounces* 0.10 0.04
Tuna, yellowfin, cooked 3 ounces* 0.09 0.01
Kidney beans, canned ½ cup 0.10
Baked beans, canned, vegetarian, ½ cup 0.07
Ground beef, 85% lean, cooked, 3 ounces** 0.04
Bread, whole wheat, 1 slice 0.04
Egg, cooked, 1 egg 0.03
Chicken, breast, roasted, 3 ounces 0.02 0.01
Milk, low-fat (1%), 1 cup 0.01

*Except as noted, the USDA database does not specify whether fish are farmed or wild caught.
**The USDA database does not specify whether beef is grass fed or grain fed.

The U.S. Department of Agriculture’s National Nutrient Database for Standard Referenceexternal link disclaimer website [29] lists the nutrient content of many foods and provides a comprehensive list of foods containing ALA arranged by nutrient content and by food name, foods containing DHA arranged by nutrient content and by food name, and foods containing EPA arranged by nutrient content and by food name.

Dietary Supplements
LC omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil. A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely [30]. Cod liver oil supplements provide vitamin A and vitamin D in addition to LC omega-3s. Although seafood contains varying levels of methyl mercury (a toxic heavy metal) [31], omega-3 supplements have not been found to contain this contaminant because it is removed during processing and purification [32].

Dietary supplements can contain several different forms of omega-3s, including natural triglycerides, free fatty acids, ethyl esters, re-esterified triglycerides, and phospholipids [32-34]. Natural triglycerides are the form that occur naturally in fish oil, whereas ethyl esters are synthesized from natural triglycerides by replacement of the glycerol molecule of the triglyceride with ethanol. Re-esterified triglycerides are formed by the conversion of ethyl esters back to triglycerides. Omega-3s as re-esterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters, but consumption of all forms significantly increases plasma EPA and DHA levels [33,35].

Krill oil contains omega-3s primarily as phospholipids, and limited research suggests that these have somewhat higher bioavailability than the omega-3s in fish oil [34,36,37].

Plant-based sources of omega-3s from algal oil usually provide around 100–300 mg DHA; some contain EPA as well. These supplements typically contain omega-3s in the triglyceride form [32]. According to a small study, the bioavailability of DHA from algal oil is equivalent to that from cooked salmon [38].

Formulations of omega-3 dietary supplements vary widely, so it is important to check product labels to determine the types and amounts of omega-3s in these products. The Dietary Supplement Label Databaseexternal link disclaimer from the National Institutes of Health contains label information from many dietary supplements on the market that contain omega-3s.

Omega-3 Intakes and Status

According to data from the 2011–2012 National Health and Nutrition Examination Survey (NHANES), most children and adults in the United States consume recommended amounts of omega-3s as ALA [39]. Among children and teens aged 2–19 the average daily ALA intake from foods is 1.32 g for females and 1.55 g for males. In adults aged 20 and over, the average daily ALA intake from foods is 1.59 g in females and 2.06 g in males.

Consumption of DHA and EPA from foods contributes a very small amount to total daily omega-3 intakes (about 40 mg in children and teens and about 90 mg in adults) [39]. Use of dietary supplements containing omega-3s also contributes to total omega-3 intakes. Fish oil is one of the most commonly used nonvitamin/nonmineral dietary supplements by U.S. adults and children [40,41]. Data from the 2012 National Health Interview Survey indicate that 7.8% of U.S. adults and 1.1% of U.S. children use supplements containing fish oil, omega-3s, and/or DHA or EPA [40,41]. According to an analysis of 2003–2008 NHANES data, use of these supplements adds about 100 mg to mean daily ALA intakes, 10 mg to mean DHA intakes, and 20 mg to mean EPA intakes in adults [42].

Omega-3 Deficiency

A deficiency of essential fatty acids—either omega-3s or omega-6s—can cause rough, scaly skin and dermatitis [5]. Plasma and tissue concentrations of DHA decrease when an omega-3 fatty acid deficiency is present. However, there are no known cut-off concentrations of DHA or EPA below which functional endpoints, such as those for visual or neural function or for immune response, are impaired.

Groups at Risk of Omega-3 Inadequacy

Evidence that higher LC omega-3 levels are associated with a reduced risk of several chronic diseases, including coronary heart disease, suggests that many Americans could benefit from slightly higher intakes. However, classical essential fatty acid deficiency in healthy individuals in the United States is virtually nonexistent [5]. During periods of dietary-fat restriction or malabsorption accompanied by an energy deficit, the body releases essential fatty acids from adipose-tissue reserves. For this reason, clinical signs of essential–fatty-acid deficiency are usually only found in patients receiving parenteral nutrition that lacks PUFAs. This was documented in case reports during the 1970s and 1980s [5], but all current enteral and parenteral feeding solutions contain adequate levels of PUFAs.

Omega-3s and Health

The potential health benefits of consuming omega-3s are the focus of a great deal of scientific research. By far, the majority of research has focused on EPA and DHA from foods (e.g., fish) and/or dietary supplements (e.g., fish oil) as opposed to ALA from plant-based foods.

Many observational studies link higher intakes of fish and other seafood with improved health outcomes. However, it is difficult to ascertain whether the benefits are due to the omega-3 content of the seafood (which varies among species), other components in the seafood, the substitution of seafood for other less healthful foods, other healthful behaviors, or a combination of these factors. Data from randomized clinical trials are needed to shed light on these questions.

This section focuses on areas of health in which omega-3s might be involved: cardiovascular disease and its risk factors; infant health and neurodevelopment; cancer prevention; Alzheimer’s disease, dementia, and cognitive function; age-related macular degeneration; rheumatoid arthritis; and other conditions.

Cardiovascular disease (CVD) and CVD risk factors
Many studies have assessed the effects of omega-3s—primarily EPA and DHA—on CVD and CVD risk factors, such as high blood pressure and elevated plasma lipids. This interest was spurred by epidemiological research dating back to the 1970s that found low rates of myocardial infarction and other coronary events among Greenland Inuit and other fish-eating populations, such as the Japanese [3]. Results from observational studies have been consistent with these findings, with several systematic reviews and meta-analyses showing that higher consumption of fish and higher dietary or plasma levels of omega-3s are associated with a lower risk of heart failure [43], coronary disease, and fatal coronary heart disease [44]).

Initial clinical research: Early clinical trial data supported the hypothesis that LC omega-3s offer protection from CVD by reducing the heart’s susceptibility to arrhythmias, lowering triglyceride levels, lowering blood pressure, and decreasing platelet aggregation [45,46]. The first trial to point to a benefit of LC omega-3s in the secondary prevention of heart disease was the 1989 Diet and Reinfarction Trial [47]. In this study, 2,033 men under 70 years of age who had survived a myocardial infarction were randomly assigned to receive dietary advice about fat intake, fish intake, and/or dietary fiber intake or to receive no dietary advice. After 2 years, patients who were advised to consume at least two servings a week of “fatty fish” had a 29% reduction in all-cause mortality compared to those who did not receive this advice. The open-label GISSI-Prevenzione trial was designed to confirm these findings using omega-3 supplementation (with or without 300 mg vitamin E as alpha-tocopherol) in 11,324 patients who had survived a recent myocardial infarction [48]. Supplementation with 1 g/day omega-3s (containing 850–882 mg EPA and DHA) for 3.5 years significantly reduced triglyceride levels and the risk of cardiovascular death and death from all causes compared to no treatment. Vitamin E had no effect. A separate analysis of data from the same study showed a significant reduction in rates of sudden cardiac death with omega-3 supplementation but no effect on rates of non-fatal myocardial infarction [49]. The authors noted that the reduction in sudden cardiac death rates suggests that omega-3s have antiarrhythmic and antifibrillatory effects because ventricular fibrillation and other forms of arrhythmia are the most common causes of sudden cardiac death. A 1993 meta-analysis of 31 placebo-controlled trials also found that omega-3s as fish oil modestly reduced systolic and diastolic blood pressure [50]. The authors of a systematic review that included six secondary-prevention and one primary-prevention trial of omega-3 supplementation published between 1966 and July 2005 (including the GISSI- Prevenzione trial) concluded that consumption of LC omega-3s from fish and fish oil supplements reduces rates of all-cause mortality, cardiac death, sudden death, and stroke [45]. They noted that the evidence of benefit is stronger for secondary than for primary prevention.

Results from the Japan EPA Lipid Intervention Study supported the growing body of evidence that LC omega-3s reduce the risk of heart disease [51]. In this study, 18,645 patients with hypercholesterolemia (total cholesterol of at least 251 mg/dL) with or without coronary artery disease received either 1.8 g/day EPA plus a statin or a statin only. After a mean of 4.6 years, patients in the EPA group had 19% fewer major coronary events than those in the control group. The EPA group also experienced a significant reduction in rates of unstable angina and non-fatal coronary events but not in rates of coronary death compared to the control group. A separate analysis of data from this study found that the EPA supplementation did not affect total stroke incidence but did reduce the risk of recurrent stroke by 20% in patients who had previously experienced a stroke [52].

Subsequent clinical research: More recent studies suggest a more complicated picture, especially with respect to omega-3s from supplements as opposed to food. Higher consumption of seafood, such as fatty fish, appears to provide protection from many adverse CVD outcomes. However, many studies have shown that taking omega-3 dietary supplements, such as fish oil supplements, might not provide the same protection. For example, in the Risk and Prevention Study, a randomized clinical trial of over 12,500 participants in Italy with multiple CVD risk factors or atherosclerotic vascular disease, supplementation with 1 g/day omega-3s (including at least 85% EPA/DHA) for a median of 5 years failed to reduce the risk of death from cardiovascular causes or hospitalization for any cardiovascular cause compared to placebo [53]. Similarly, in the ORIGIN trial that included 12,536 patients who had diabetes or a risk of diabetes and who were at high risk of cardiovascular events, supplementation with 1 g/day omega-3s (containing 375 mg DHA and 465 mg EPA) for about 6 years significantly lowered triglyceride levels but had no effect on risk of myocardial infarction, stroke, or death from cardiovascular causes compared to placebo [54]. In the Alpha Omega Trial, low-dose EPA and DHA supplementation (150 mg DHA and 226 mg EPA daily, supplied as a margarine) for 40 months also failed to reduce the rate of major cardiovascular events compared to placebo among 4,837 older men and women who had previously experienced a myocardial infarction and were receiving antihypertensive, antithrombotic, and/or lipid-lowering medications [55]. Finally, a 2014 ancillary study of the Age-Related Eye Disease Study 2 (AREDS2) found that daily supplementation with 350 mg DHA plus 650 mg EPA (in addition to the AREDS vitamin/mineral formula) for about 5 years did not reduce the risk of CVD compared to placebo in elderly participants with AMD [56].

Contrary to many earlier analyses, a 2012 meta-analysis of 14 randomized, double-blind, placebo-controlled trials in patients with a history of CVD found that omega-3 supplementation does not reduce the risk of cardiovascular events overall or of sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke [57]. Similarly, the authors of a 2012 systematic review and meta-analysis that included 12 randomized controlled trials concluded that LC omega-3 supplementation does not reduce the risk of cerebrovascular disease (including stroke, cerebrovascular accident, and transient ischemic attack) in either primary or secondary prevention trials [58]. A 2014 meta-analysis of 27 randomized controlled trials also found that LC- omega-3 supplementation does not significantly lower the risk of coronary disease, including fatal or nonfatal myocardial infarction, coronary heart disease, coronary insufficiency, coronary death, angina, or angiographic coronary stenosis [59].

Possible reasons for conflicting findings: Some researchers suggest that discrepancies between the findings from earlier and more recent clinical trials might be explained, in part, by a rise in background dietary intakes of omega-3s in study populations [17,54,60]. Public-health messages touting the benefits of fish consumption have likely led to higher dietary intakes of LC omega-3s among participants in more recent supplementation studies than in older studies. A threshold effect might exist, above which increased omega-3 intake offers little or no additional cardiovascular benefit. For example, the authors of a review prepared by the Tufts Medical Center Evidence-based Practice Center on the effects of EPA and DHA on mortality concluded that mean intakes of up to 200 mg/day are associated with a reduced risk of cardiac, cardiovascular, or sudden cardiac death, but higher intakes do not reduce risk any further [61].

Increased use of statins and other cardioprotective therapies in more recent trials is another potential reason for the conflicting findings because omega-3s might offer little additional benefit beyond state-of-the-art pharmacotherapy [17,54,55,62-65]. In the GISSI-Prevenzione study conducted in the mid-1990s, for example, only about 5% of participants were taking a cholesterol-lowering drug at baseline [48]. In contrast, in the more recent Risk and Prevention Study and the ORIGIN trial, about 40–50% of the participants were taking a statin [53,54]. A 2011 meta-analysis of 10 randomized controlled trials examining the effects of omega-3s for secondary prevention of CVD found that omega-3s reduced the risk of death from cardiac causes and sudden cardiac death in patients receiving the standard of care prior to 2003, but not in patients who received more aggressive guidelines-adjusted therapy starting in 2007 [63].

Agency for Healthcare Research and Quality (AHRQ) report: In 2016, AHRQ published a review on the effects of omega-3s on CVD and on risk factors and intermediate markers of CVD [66]. This comprehensive report evaluated 61 randomized controlled trials (primarily in people with CVD or at risk of CVD) and 37 observational studies (primarily in healthy people). The authors concluded that higher intakes of LC omega-3s (primarily EPA and DHA from foods such as fish and seafood as well as dietary supplements) lower triglyceride levels and raise high-density lipoprotein levels, but also raise low-density lipoprotein levels. However, LC omega-3s do not affect major adverse cardiovascular events or rates of coronary revascularization, sudden cardiac death, or all-cause death.

The AHRQ authors also determined that higher intakes of LC omega-3s do not affect systolic or diastolic blood pressure, whereas the evidence suggests, with less certainty, that LC omega-3s lower the risk of ischemic stroke but do not affect the risk of hemorrhagic stroke, atrial fibrillation (a type of arrhythmia), or myocardial infarction. Finally, the authors found that LC omega-3s have inconsistent effects on the risk of cardiac death based on the results of five randomized controlled trials [66].

Some of the AHRQ findings conflict with those from other recent systematic reviews and meta-analyses. For example, a 2014 meta-analysis of 70 studies [67] as well as a 2013 systematic review of 17 studies [68] found a small but statistically significant reduction in systolic (2.56 mmHg) and diastolic (1.47 mmHg) blood pressure in participants with hypertension (but not those with normal blood pressure) taking fish oil supplements. In addition, most [61-63,69-74] but not all [75] systematic reviews and meta-analyses published between 2006 and 2014 indicate that omega-3s reduce the risk of cardiac death.

Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include seafood are associated with reduced risk of CVD [76]. In addition, consuming about 8 ounces per week of a variety of seafood that provides about 250 mg per day EPA and DHA is associated with fewer cardiac deaths in both healthy individuals and those with preexisting CVD.

Conclusions about omega-3s and CVD: Overall, research indicates that consuming fish and other types of seafood as part of a balanced diet promotes heart health. Fish oil and other LC omega-3 supplements improve blood lipids and appear to reduce the risk of cardiac death. However, their effects on other cardiovascular endpoints are unclear and might vary based on dietary omega-3 intakes and the use of cardioprotective medications.

The FDA has approved a qualified health claim for conventional foods and dietary supplements that contain EPA and DHA [77]. It states, “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.” The FDA also specifies that the labels of dietary supplements should not recommend a daily intake of EPA and DHA higher than 2 g [77]. For patients who need to lower their triglycerides, the American Heart Association recommends 2–4 g/day of EPA plus DHA under the care of a physician [46,78]. Several prescription omega-3 preparations are also available to treat hypertriglyceridemia [3,35,79].

Scientists hope to gain additional insight on the effects of omega-3s for the prevention of CVD from the VITamin D and OmegA-3 TriaL (VITAL) trial. This clinical trial will examine the effects of EPA (465 mg/day) and DHA (375 mg/day) supplementation with or without 2,000 IU/day vitamin D for 5 years in 25,875 older adults on the primary prevention of cancer and CVD [64]. Results from this clinical trial and others [80,81] will shed more light on possible associations between omega-3s and cardiovascular events as well as blood pressure and atrial fibrillation.

Infant health and neurodevelopment
Numerous studies have examined the effects of maternal seafood and omega-3 intakes on infant birth weight, length of gestation, visual and cognitive development, and other infant health outcomes. High concentrations of DHA are present in the cellular membranes of the brain and retina [5], and DHA is important for fetal growth and development. The accumulation of DHA in the retina is complete by birth, whereas accumulation in the brain continues throughout the first 2 years after birth.

Evidence from observational research: Observational studies indicate that maternal consumption, during pregnancy and breastfeeding, of at least 8 ounces per week of seafood that contains DHA is associated with better infant health outcomes [76]. For example, in a prospective cohort study of 341 mother–child pairs in the United States, maternal fish consumption more than twice per week compared to no weekly consumption was associated with improved visual motor skills in their children at age 3 after adjustment for covariates such as maternal age, education, maternal smoking and alcohol use during pregnancy, paternal education, and fetal growth [82]. In another observational cohort study in the United Kingdom in 11,875 pregnant women who reported seafood intakes ranging from none to more than 340 g (about 12 ounces) per week, lower consumption of seafood during pregnancy was associated with an increased risk of suboptimal communication skills in the offspring at ages 6 and 18 months and suboptimal verbal IQ and prosocial behavior at age 7–8 years [83]. It is not possible to establish causality, however, because all of these studies were observational.

Seafood contains varying levels of methyl mercury [31]. However, results from numerous studies, including a systematic review of the literature on maternal fish intake and subsequent neurodevelopmental outcomes, show that the health benefits of consuming moderate amounts of seafood during the prenatal period outweigh the risks [83-86].

Randomized controlled trials of omega-3 supplementation: Several randomized controlled trials have examined whether supplementation with fish oil, EPA, and/or DHA during pregnancy and early infancy is beneficial for infant health and neurodevelopment.

One of these trials examined the effects of fish oil supplementation in 2,399 pregnant women on the subsequent clinical outcomes and neurodevelopment of their children [87]. Pregnant women received daily supplements of either fish oil (providing 800 mg DHA and 100 mg EPA) or placebo from less than 21 weeks’ gestation until the birth of their child. Compared to the placebo group, children of mothers who received fish oil were heavier at birth and less likely to be born very preterm (less than 34 weeks’ gestation). However, assessments of 726 of the children (all 96 preterm children and 630 randomly selected full-term children) found no differences between groups in mean cognitive composite scores or mean language composite scores at age 18 months. A follow-up study of the children at age 4 years found no differences between groups in general conceptual ability score or other assessments of cognition, language, and executive functioning [88]. Another study found no benefits on visual function at age 7 years when very preterm infants (less than 33 weeks’ gestation) consumed human milk with a higher DHA concentration than normal (lactating mothers took 900 mg/day DHA supplements) for the first months of life until full term [89]. In a clinical trial in 420 healthy full-term infants, those who received either DHA-enriched fish oil (250 mg DHA and 60 mg EPA) or placebo daily from birth to 6 months had similar scores on neurodevelopment assessments at 18 months [90]. However, infants receiving fish oil had significantly better performance on language assessments, indicating some benefit for early communication development.

The authors of a systematic review and meta-analysis of 11 randomized controlled trials concluded that the evidence neither supports nor refutes the benefits of LC omega-3 supplementation during pregnancy for cognitive or visual development in infants [91]. Another systematic review and meta-analysis that included two randomized controlled trials in women with a previous preterm birth found no significant differences in rates of recurrent preterm birth between women who took omega-3 supplements during pregnancy and those who did not [92]. Omega-3 supplementation did, however, increase latency (time from randomization to birth) by about 2 days and mean birth weight by about 103 g.

AHRQ report: In 2016, AHRQ published a review on the effects of omega-3 fatty acids on child and maternal health [93]. This comprehensive report evaluated the findings from 95 randomized controlled trials and 48 prospective longitudinal studies and nested case-control studies. Most studies examined the effects of fish oil supplements or other DHA and EPA combinations in pregnant or breastfeeding women or of infant formula fortified with DHA plus arachidonic acid, an omega-6. The authors concluded that, except for small beneficial effects on infant birth weight and length of gestation, omega-3 supplementation or fortification has no consistent effects on infant health outcomes.

Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that women who are pregnant or breastfeeding should consume 8–12 ounces of seafood per week, choosing from varieties that are higher in EPA and DHA and lower in methyl mercury [76], such as salmon, herring, sardines, and trout. These women should not consume certain types of fish, such as king mackerel, shark, swordfish, and tilefish that are high in methyl mercury, and they should limit the amount of white (albacore) tuna they consume to 6 ounces a week [31]. The American Academy of Pediatrics has similar advice for breastfeeding women, recommending intakes of 200–300 mg DHA per day by consuming one to two servings of fish per week to guarantee a sufficient amount of DHA in breast milk [86].

Most currently available infant formulas in the United States contain DHA and arachidonic acid. However, the authors of a paper published by the American Academy of Family Physicians and of two Cochrane reviews (one on full-term infants and one on preterm infants) have concluded that the evidence is insufficient to recommend the use of infant formulas that are supplemented with these fatty acids [94-96].

Cancer prevention
Researchers have hypothesized that higher intakes of omega-3s from either foods or supplements might reduce the risk of cancer due to their anti-inflammatory effects and potential to inhibit cell growth factors [60]. Results from observational studies however, have been inconsistent and vary by cancer site and other factors, including gender and genetic risk.

For example, some studies have shown associations between higher intakes and/or blood levels of omega-3s and a decreased risk of certain cancers, including breast and colorectal cancers [97,98]. Other studies have found no associations between omega-3s and cancer risk, and some have even found associations in the opposite direction, suggesting that omega-3s might increase the risk of certain cancers such as prostate cancer [14,15,99]. To date, no large-scale clinical trials have examined the effects of omega-3s on the primary prevention of cancer in the general population, although a large clinical trial that addresses this question, the VITAL trial, is currently underway [64].

Breast cancer: Evidence from several observational studies suggests that higher intakes of LC omega-3s are associated with a lower risk of breast cancer, but clinical trials are needed to confirm this finding. In the prospective Singapore Chinese Health Study of 35,298 women aged 45–74 years, those in the top three quartiles of dietary LC omega-3 intake had a 26% lower risk of breast cancer after an average of 5.3 years of follow-up than those in the lowest quartile [100]. Similarly, among 35,016 female participants aged 50–76 years in the Vitamins And Lifestyle cohort, those who reported current use of fish-oil supplements had a 32% lower risk of breast cancer after a mean of 6 years than those who did not take fish oil [101].

According to a systematic review of three case-control studies and five prospective studies published in 2007–2011, evidence is increasing that higher intakes of dietary and supplemental LC omega-3s are associated with a lower risk of breast cancer [102]. Similarly, the authors of a meta-analysis of data from 21 prospective cohort studies concluded that women with the highest dietary intakes and/or tissue levels of LC omega-3s had a 14% lower risk of breast cancer than those with the lowest intakes and tissue levels [97]. These authors also found a dose-response relationship between higher intakes of combined LC omega-3s and reduced breast cancer risk. Intakes of ALA and of fish, however, had no association with differences in breast cancer risk. This finding, which could be due to varying levels of omega-3s in different fish species, warrants further investigation.

Colorectal cancer: Limited evidence from observational studies suggests that greater consumption of fish and LC omega-3s is associated with a reduced risk of colorectal cancer [102].

The authors of a meta-analysis of 19 prospective cohort studies found no significant association between fish intake and risk of colorectal cancer overall. However, a stratified analysis showed that for participants with the highest fish consumption (those who ate fish at least seven times more often per month than those with the lowest fish consumption), the risk of colorectal cancer was 22% lower than that for the lowest fish consumers [103]. Results from a more recent systematic review and meta-analysis of 22 prospective cohort studies and 19 case-control studies indicate that fish consumption is inversely associated with colorectal cancer risk. In this analysis, 21 of the studies distinguished between colon cancer and rectal cancer. The risk of rectal cancer was 21% lower for participants with the highest fish intakes (as much as one serving/day) compared to those with the lowest fish intakes (as little as none), but fish consumption had no significant association with risk of colon cancer alone [98].

Results from the Vitamins And Lifestyle cohort study suggest that associations between fish or LC omega-3 intakes and colorectal cancer risk might vary by such factors as gender and genetic risk. In this study, researchers evaluated associations between colorectal cancer risk and EPA/DHA intakes from fatty fish (salmon and fresh tuna) and fish oil supplements in 68,109 Washington residents aged 50–76 [104]. The amount of fatty fish consumed ranged from none to 0.8 servings per week or more. Overall, EPA and DHA intakes (from either diet or supplements) and fatty fish consumption were not associated with colorectal cancer risk, but associations varied by genetic characteristics (certain inherited genetic mutations are associated with an increased risk of colorectal cancer). For individuals in the lowest two tertiles of genetic risk, higher fatty fish consumption and higher total EPA and DHA intakes were inversely associated with colorectal cancer risk. For individuals in the highest tertile of genetic risk, higher total EPA and DHA intakes were positively associated with colorectal cancer risk. Risk also varied by gender. Among men, use of fish oil supplements reduced colorectal cancer risk by an average of 34% or more depending on the frequency and duration of use, but this effect did not occur among women. Additional research is needed to clarify possible associations between fish and omega-3 intakes and colorectal cancer risk.

Prostate cancer: Several prospective and case-control studies have investigated associations between either blood levels or intakes of omega-3s and risk of low-grade or high-grade prostate cancer. Results from these studies have been inconsistent.

A few case-control and case-cohort studies have found positive associations between blood levels of LC omega-3s and prostate cancer risk (particularly high-grade disease that is more advanced and more likely to spread than low-grade cancer), suggesting that omega-3s might increase  prostate cancer risk. In a nested case-control analysis of men aged 55–84 years participating in the Prostate Cancer Prevention Trial, serum phospholipid levels of DHA were positively associated with risk of high-grade, but not low-grade, prostate cancer [14]. Serum EPA levels, however, were not associated with risk of either grade of the disease.

Similarly, results from a case-cohort study within the Selenium and Vitamin E Cancer Prevention (SELECT) trial showed that men in the highest quartile of plasma phospholipid LC omega-3s had a 44% higher risk of low-grade prostate cancer and a 71% higher risk of high-grade prostate cancer than those in the lowest quartile [15]. An analysis of data from the European Prospective Investigation into Cancer and Nutrition cohort also found a higher prostate cancer risk in men with higher plasma levels of LC omega-3s [105]. Among whites participating in the Multiethnic Cohort Study, higher levels of omega-3s in erythrocyte membranes and higher ratios of omega-3s to omega-6s were both associated with an increased risk of prostate cancer. However, the results showed no associations, even with advanced or high-grade disease, for other ethnic groups or for the population as a whole [106].

Although the findings from the Prostate Cancer Prevention Trial and the SELECT trial suggest that higher LC omega-3 intakes might increase prostate cancer risk, some scientists have questioned the significance of these findings [107]. They have noted, for example, that in the SELECT trial [15], the difference in the omega-3 levels in the men with and without prostate cancer was very small and of questionable physiological significance. Other scientists have pointed out that localized (even high-grade) prostate cancers usually progress slowly and are common on autopsy in men who have died from other causes, suggesting that prostate cancer mortality is a more critical endpoint than prostate cancer incidence [108]. Finally, desaturation enzymes that convert ALA into EPA and DHA can be upregulated in some cancer cells, suggesting the possibility that it was the disease that raised the omega-3 levels, not the omega-3 levels that raised the disease risk [12].

Results from other observational studies using dietary intake data suggest that higher intakes of fish and/or omega-3s reduce prostate cancer risk. Both fish and omega-3 consumption were associated with a lower risk of fatal prostate cancer in a cohort of 293,464 men participating in the NIH-AARP study [109]. In the Health Professionals Follow-up Study, a prospective cohort of over 47,000 men aged 40–75 years, those who consumed fish more than three times per week had a lower risk of metastatic prostate cancer than those who consumed fish less than twice per month [110]. However, men who used fish oil supplements did not have a decreased risk of prostate cancer.

A number of systematic reviews and meta-analyses of prospective studies of the effects of fish intakes, omega-3 intakes, and omega-3 blood levels on prostate cancer risk have had inconsistent findings as well. For example, circulating levels of EPA, but not DHA, were positively associated with prostate cancer risk in a meta-analysis of 5,098 men with prostate cancer and 6,649 men without prostate cancer from seven studies [111]. Another meta-analysis of 12 studies that included 4,516 men with prostate cancer and 5,728 men without prostate cancer found that high serum levels of these LC omega-3s were positively associated with high-grade disease [112]. In other analyses, dietary intakes of LC omega-3s had no effect on prostate cancer risk [113], whereas fish consumption decreased prostate cancer mortality but had no effect on prostate cancer incidence [114]. A 2015 meta-analysis found no significant associations between dietary intakes or blood levels of LC omega-3s and total prostate cancer risk [115]. The authors noted that most dietary-intake studies included in their meta-analysis found inverse associations, whereas biomarker studies of blood levels of these fatty acids found positive associations.

Overall, the evidence to date shows no consistent relationships between prostate cancer risk or mortality and omega-3 intakes or blood levels.

Other cancers: Evidence is limited for a role of omega-3s in the prevention of cancers at other sites. For example, evidence is insufficient to determine whether omega-3s affect the risk of skin cancers, including basal-cell carcinoma, squamous-cell carcinoma, and melanoma [116,117]. Findings from the Australian Ovarian Cancer Study suggest that there is no association between total or individual omega-3 intakes from foods and ovarian cancer risk [118].

Associations between omega-3 intakes and endometrial cancer have been mixed. Some evidence indicates that dietary intakes of EPA and DHA may provide protection from the development of endometrial cancer [119]. Other evidence indicates that they decrease risk in normal-weight women but have no effect or even increase risk in overweight or obese women [120,121].

A systematic review and meta-analysis of 9 prospective cohort and 10 case-control studies did not find an association between fish or LC-omega-3 intakes and risk of pancreatic cancer [122]. Similarly, systematic reviews and meta-analyses have not found significant associations between fish consumption and risk of gastric or esophageal cancers [123,124].

Summary: Overall, data from observational studies show no consistent relationship between omega-3s and overall cancer risk. Although there are some suggestions of reduced risk for breast and possibly colorectal cancers with higher LC omega-3 intakes, randomized clinical trials are needed to confirm these findings.

The VITAL trial will examine the effects of EPA (465 mg/day) and DHA (375 mg/day) supplementation (with and without 2,000 IU/day vitamin D) for 5 years in 25,875 older adults on the primary prevention of cancer and CVD [64]. Results from this clinical trial will shed more light on possible associations between these omega-3s and cancer.

Alzheimer’s disease, dementia, and cognitive function
Some, but not all, observational studies suggest that diets high in LC omega-3s are associated with a reduced risk of cognitive decline, Alzheimer’s disease, and dementia [125,126]. Because DHA is an essential component of cellular membrane phospholipids in the brain, researchers hypothesize that LC omega-3s might protect cognitive function by helping to maintain neuronal function and cell- membrane integrity within the brain [126]. This hypothesis is supported by findings from case-control studies indicating that patients with Alzheimer’s disease have lower serum levels of DHA than cognitively healthy people [127,128]. Lower serum DHA levels are also associated with more cerebral amyloidosis (build-up of protein deposits called amyloids) in healthy older adults, whereas higher DHA is correlated with preservation of brain volume [129].

Several observational studies have examined the effects of fish, EPA, and/or DHA intakes on cognitive function in healthy older adults. In a prospective cohort study involving 210 healthy men aged 70–89, fish consumption was associated with less cognitive decline at follow-up 5 years later [130]. In addition, a dose-response relationship was observed between tertiles of dietary EPA plus DHA intake and subsequent 5-year cognitive decline. Similarly, in the Rotterdam Study, a population-based prospective study of people aged 55 or older who were free from dementia at baseline, higher fish consumption among 5,386 study participants was associated with a 60% lower risk of dementia and a 70% lower risk of Alzheimer’s disease over an average of 2.1 years [131]. Subsequent follow-up 6 years after baseline, however, found no associations between omega-3 intakes and incidence of dementia or Alzheimer’s disease [132]. The authors suggest that the discrepancy might be explained by the short follow-up period in the first analysis and the small number of patients who developed dementia. A higher omega-3 index was associated with a greater hippocampal volume in the Women’s Health Initiative Memory Study [133] and with a larger brain volume and improved cognitive test scores in the Framingham Offspring cohort [134]. A 2016 dose-response meta- analysis of 21 cohort studies found that increased intakes of fish and dietary DHA were both inversely associated with the risks of dementia and Alzheimer’s disease [135]. Specifically, a 100 mg/day incremental increase in DHA intake was associated with a 14% lower risk of dementia and a 37% lower risk of Alzheimer’s disease.

Results from clinical trials, however, suggest that LC omega-3 supplementation does not affect cognitive function in older adults who have no cognitive impairment. In a trial in the United Kingdom, 748 cognitively healthy adults aged 70–79 years received either 500 mg DHA and 200 mg EPA or placebo daily for 24 months [136]. Cognitive function did not differ significantly between the two groups, although cognitive function did not decline in either group. In the AREDS2 study, treatment with 350 mg DHA and 650 mg EPA for 5 years did not have a significant effect on cognitive function in 3,501 older adults (mean age 72.7 years) with AMD [127].

Clinical trial results also suggest that LC omega-3 supplementation does not benefit patients with Alzheimer’s disease, although it might help patients with mild cognitive impairment. For example, daily supplementation with 2 g DHA for 18 months did not slow the rate of cognitive decline compared to placebo in 295 participants (mean age 76 years) with mild to moderate Alzheimer’s disease [137]. In the OmegaAD trial, daily supplementation with 1,700 mg DHA and 600 mg EPA for 6 months in 174 older adults with mild to moderate Alzheimer’s disease also failed to slow down the rate of cognitive decline compared to placebo [138]. However, a subgroup of patients with very mild impairment experienced a significant reduction in the rate of cognitive decline. In a small trial in Malaysia, fish oil supplementation (1,290 mg DHA and 450 mg EPA daily) for 12 months improved memory—particularly short-term, working, and verbal memory—and delayed recall compared to placebo in 35 older adults with mild cognitive impairment [139].

Several systematic reviews and meta-analyses, including a Cochrane review, have assessed the effects of omega-3 supplementation on cognitive function and dementia in healthy older adults and those with Alzheimer’s disease or cognitive impairment [126,140-142]. Overall, the findings indicate that LC omega-3 supplementation does not affect cognitive function in healthy older adults or in people with Alzheimer’s disease compared to placebo. For people with mild cognitive impairment, omega-3s may improve certain aspects of cognitive function, including attention, processing speed, and immediate recall [142]. However, these findings need to be confirmed in additional clinical trials.

Age-Related Macular Degeneration (AMD)
AMD is a major cause of vision loss among older adults. In most cases, severe vision loss is associated with advanced AMD, which consists of either central geographic atrophy (dry AMD, the most common form) or neovascular AMD (wet AMD) [143]. Based on DHA’s presence as a structural lipid in retinal cellular membranes and the beneficial effects of EPA-derived eicosanoids on retinal inflammation, neovascularization, and cell survival, researchers have suggested that these LC omega-3s have cytoprotective effects in the retina that may help prevent the development or progression of AMD [6].

Results from observational studies suggest that people who consume higher amounts of fatty fish and/or dietary LC omega-3s have a lower risk of developing AMD. In the cross-sectional EUREYE study of 2,275 participants aged 65 years or older, those who ate fatty fish at least once per week had a 53% lower risk of neovascular AMD than those who consumed fatty fish less often [144]. Results were similar in a study in 681 elderly male twins [145] and an analysis of 38,022 healthy female health professionals [143]. In the latter study, women in the highest tertiles of dietary DHA plus EPA intake (median of 330 mg/day) had a 38% lower risk of developing AMD during an average of 10 years of follow-up than those in those in the lowest tertile (median intake of 80 mg/day). Higher serum and erythrocyte membrane levels of EPA (but not DHA) have also been associated with a lower risk of neovascular AMD [146].

In the AREDS study, a dietary supplement formulation containing 15 mg beta-carotene, 400 IU vitamin E, 500 mg vitamin C, 80 mg zinc, and 2 mg copper reduced the risk of advanced AMD in people with intermediate AMD or advanced AMD in one eye [147]. Data from a nested cohort study within the AREDS population indicated that participants who reported the highest omega-3 intakes were about 30% less likely to develop central geographic atrophy and neovascular AMD than other participants [148].

These findings, combined with other epidemiological evidence, formed the basis for the AREDS2 clinical trial that examined whether adding 350 mg DHA and 650 mg EPA to the AREDS formulation further reduced the risk of progression to advanced AMD [149]. The results showed that EPA and DHA did not provide any additional benefits after a median follow-up of 5 years. These findings are in line with those from a Cochrane review [150] that included the results from AREDS2 and the Nutritional AMD Treatment 2 study [151], a 3-year randomized clinical trial of LC omega-3 supplements (840 mg/day DHA and 270 mg/day EPA) in patients with early age-related maculopathy and neovascular AMD. The Cochrane review authors concluded that LC omega-3 supplementation for up to 5 years in people with AMD does not reduce the risk of progression to advanced AMD or of moderate to severe vision loss.

Rheumatoid arthritis
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Its symptoms include pain, swelling, stiffness, and functional impairments. RA is typically treated with nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs [152,153]. Due to their antiinflammatory effects, some scientists hypothesize that LC omega-3s reduce some of the symptoms of RA and patients’ reliance on NSAIDs and corticosteroids.

Several clinical trials, many conducted in the 1990s, have examined the use of LC omega-3 supplementation in patients with RA. These trials have generally shown that omega-3 supplements reduce patients’ use of antiinflammatory drugs and corticosteroids, but that they do not have consistent effects on painful and/or tender joints, joint swelling, or morning stiffness [9,153-156]. For example, fish oil supplementation significantly reduced NSAID use in a controlled trial in Sweden [157]. In this study, 43 patients with RA received either 10 g/day fish oil (containing 1.8 g EPA and 1.2 g DHA) or placebo along with their usual RA medications. NSAID use decreased in the treatment group at 3 and 6 months, and global arthritic activity assessed by physicians improved relative to placebo at 3 months. However, patient assessments of pain, morning stiffness, and functional capacity did not differ between groups. In a 2013 clinical trial in South Korea, 81 patients with RA received either LC omega-3s (2.1 g EPA and 1.2 g DHA) or a sunflower oil placebo daily for 16 weeks [152]. Patients were allowed to continue taking NSAIDs, glucocorticoids, and/or antirheumatic drugs throughout the study. Compared to placebo, omega-3 supplementation had no significant effects on clinical symptoms of RA, including pain and morning stiffness. In post-hoc analysis, the researchers found that the supplements reduced the amount of NSAIDs needed, but only in patients weighing more than 55 kg. In a similar study in Denmark, 51 patients received either LC omega-3s (2.0 g EPA and 1.2 g DHA from fish oil) or placebo daily for 12 weeks, and they continued taking RA medications [158]. Compared to placebo, morning stiffness, joint tenderness, and visual pain score decreased significantly in the treatment group. However, there were no significant differences between groups in grip strength, daily activity score, or joint swelling. The amounts of NSAIDs, aspirin, and acetaminophen that patients needed did not change in either group.

Reviews and meta-analyses of studies that assessed whether fish oil and LC omega-3s are beneficial for RA have had inconsistent findings [9,153-156]. Some suggest that they do not significantly affect the clinical symptoms of RA but do reduce the amounts of NSAIDs and corticosteroids that patients need [154,155]. Others indicate that LC omega-3s reduce joint swelling and pain, morning stiffness, and number of painful joints in addition to reducing NSAID use [9,153,156]. Some researchers suggest that differences in findings could be due in part to whether patient-determined use of NSAIDs is considered a measure of pain [9].

Findings to date suggest that LC omega-3s may be helpful as an adjunctive treatment to pharmacotherapy for ameliorating the symptoms of RA [9,156]. However, more research is needed to confirm this finding.

Other conditions
The benefits of omega-3 supplementation are being investigated for several other conditions, including depression, inflammatory bowel disease, attention-deficit/hyperactivity disorder (ADHD), childhood allergies, and cystic fibrosis.

Depression: A 2016 meta-analysis of 26 studies found a 17% lower risk of depression with higher fish intake [159]. However, a 2015 Cochrane review of 26 studies found insufficient evidence to determine whether omega-3s (1,000 to 6,600 mg/day EPA, DHA, and/or other omega-3s) are beneficial for major depressive disorder in adults [160]. The authors did find a small-to-modest beneficial effect on depressive symptoms, but they concluded that this effect was not clinically significant.

Inflammatory bowel disease: The authors of a systematic review of 19 randomized controlled trials concluded that the available evidence does not support the use of omega-3 supplements to treat active or inactive inflammatory bowel disease [161]. Similarly, the authors of a Cochrane review concluded that, based on the evidence from two large, high-quality studies, omega-3 supplements are probably not effective for maintaining remission in people who have Crohn’s disease [162].

ADHD: A systematic review and meta-analysis of 10 studies in children with ADHD or related neurodevelopmental disorders, such as developmental coordination disorder, found no improvements with omega-3 supplementation on measures of emotional lability, oppositional behavior, conduct problems, or aggression [163]. However, in subgroup analyses of only the higher-quality studies and those with strict inclusion criteria, omega-3 supplementation (60 to 1,296 mg/day EPA and/or DHA) did significantly improve parent-rated emotional lability and oppositional behavior.

Childhood allergies: A systematic review and meta-analysis of 10 prospective cohort studies and 5 randomized clinical trials on omega-3 intakes during pregnancy and outcomes of childhood allergic disease (eczema, rhino-conjunctivitis, and asthma) found inconsistent results [164]. Although the authors could not draw firm conclusions due to the heterogeneity of the studies and their results, they concluded that the overall findings were “suggestive” of a protective association between higher maternal intakes of LC omega-3s or fish and incidence of allergic disease symptoms in the offspring. The authors of a Cochrane review that included eight LC omega-3 supplementation trials concluded that there is limited evidence to support the use of LC omega-3 supplements by women during pregnancy and/or lactation for reducing the risk of allergic disease in their children [165].

Cystic fibrosis: A Cochrane review of four studies of cystic fibrosis found that omega-3 supplements (300 to 5,400 mg/day EPA and/or DHA) might improve lung function and increase blood levels of essential fatty acids in people with cystic fibrosis [166]. However, the authors concluded that there is not enough evidence to recommend routine use of omega-3 supplements by people with cystic fibrosis.

Summary: The potential benefits of omega-3s for these and other conditions require further study.

Safety of Omega-3s

For most macronutrients, the IOM has established an AMDR that suggests an “acceptable” range of intake. The AMDR for total fat intake, for example, is based on adverse effects from either very low-fat or high-fat diets. The IOM established an AMDR for omega-3s (as ALA) of 0.6 to 1.2% of energy for children and adults aged 1 year and older [5]. The IOM also noted that about 10% of the AMDR can be consumed as EPA and/or DHA.

The IOM did not establish a UL for any omega-3s, although it noted that high doses of DHA and/or EPA (900 mg/day of EPA plus 600 mg/day DHA or more for several weeks) might reduce immune function due to suppression of inflammatory responses. Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation [5]. However, according to the European Food Safety Authority, long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe [167]. It noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation. The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements [168]. Some doses used in clinical trials exceed these levels.

Commonly reported side effects of omega-3 supplements are usually mild. These include unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat [142,162].

Interactions with Medications

Omega-3 dietary supplements, such as fish oil, have the potential to interact with medications. One example is provided below. People taking these and other medications on a regular basis should discuss possible interactions with their health care providers.

Warfarin (Coumadin®) and similar anticoagulants
Fish oil can have antiplatelet effects at high doses, although it appears to be less potent than aspirin [169,170]. Fish oil might prolong clotting times, as indicated by an elevated international normalized ratio (INR), when it is taken with warfarin [171], but most research indicates that doses of 3–6 g/day fish oil do not significantly affect the anticoagulant status of patients taking warfarin [172]. The authors of a 2014 review concluded that omega-3s do not affect the risk of clinically significant bleeding [173], and the FDA-approved package inserts for omega-3 pharmaceuticals state that studies with omega-3s have not produced “clinically significant bleeding episodes” [174]. However, these package inserts also state that patients taking these products with anticoagulants should be monitored periodically for changes in INR.

Omega-3s and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods…Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less than recommended amounts” [76].

With respect to seafood and omega-3s, the Dietary Guidelines for Americans state that:

  • “Strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include seafood are associated with reduced risk of CVD, and moderate evidence indicates that these eating patterns are associated with reduced risk of obesity.”
  • “For the general population, consumption of about 8 ounces per week of a variety of seafood, which provide an average consumption of 250 mg per day of EPA and DHA, is associated with reduced cardiac deaths among individuals with and without preexisting CVD.”
  • “Similarly, consumption by women who are pregnant or breastfeeding of at least 8 ounces per week from seafood choices that are sources of DHA is associated with improved infant health outcomes.”
  • “Women who are pregnant or breastfeeding should consume at least 8 and up to 12 ounces of a variety of seafood per week, from choices that are lower in methyl mercury…Women who are pregnant or breastfeeding and young children should not eat certain types of fish that are high in methyl mercury.”
  • “The recommendation to consume 8 or more ounces per week (less for young children) of seafood is for the total package of nutrients that seafood provides, including its EPA and DHA content. Some seafood choices with higher amounts of EPA and DHA should be included.”
  • “Seafood varieties commonly consumed in the United States that are higher in EPA and DHA and lower in methyl mercury include salmon, anchovies, herring, shad, sardines, Pacific oysters, trout, and Atlantic and Pacific mackerel (not king mackerel, which is high in methyl mercury).”
  • For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

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What is vitamin D and what does it do?

Introduction

Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol [1].

Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts [1,2]. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults [1]. Together with calcium, vitamin D also helps protect older adults from osteoporosis.

Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation [1,3,4]. Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D [1]. Many cells have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)2D.

Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements [1] and has a fairly long circulating half-life of 15 days [5]. 25(OH)D functions as a biomarker of exposure, but it is not clear to what extent 25(OH)D levels also serve as a biomarker of effect (i.e., relating to health status or outcomes) [1]. Serum 25(OH)D levels do not indicate the amount of vitamin D stored in body tissues.

In contrast to 25(OH)D, circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate [5]. Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe [2,6].

There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health, and cut points have not been developed by a scientific consensus process. Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects [1] (Table 1).

Table 1: Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health* [1]
nmol/L** ng/mL* Health status
<30 <12 Associated with vitamin D deficiency, leading to rickets
in infants and children and osteomalacia in adults
30 to <50 12 to <20 Generally considered inadequate for bone and overall health
in healthy individuals
≥50 ≥20 Generally considered adequate for bone and overall health
in healthy individuals
>125 >50 Emerging evidence links potential adverse effects to such
high levels, particularly >150 nmol/L (>60 ng/mL)

* Serum concentrations of 25(OH)D are reported in both nanomoles
per liter (nmol/L) and nanograms per milliliter (ng/mL).
** 1 nmol/L = 0.4 ng/mL

An additional complication in assessing vitamin D status is in the actual measurement of serum 25(OH)D concentrations. Considerable variability exists among the various assays available (the two most common methods being antibody based and liquid chromatography based) and among laboratories that conduct the analyses [1,7,8]. This means that compared with the actual concentration of 25(OH)D in a sample of blood serum, a falsely low or falsely high value may be obtained depending on the assay or laboratory used [9]. A standard reference material for 25(OH)D became available in July 2009 that permits standardization of values across laboratories and may improve method-related variability [1,10].

Reference Intakes

Intake reference values for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences) [1]. DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects [1].

The FNB established an RDA for vitamin D representing a daily intake that is sufficient to maintain bone health and normal calcium metabolism in healthy people. RDAs for vitamin D are listed in both International Units (IUs) and micrograms (mcg); the biological activity of 40 IU is equal to 1 mcg (Table 2). Even though sunlight may be a major source of vitamin D for some, the vitamin D RDAs are set on the basis of minimal sun exposure [1].

Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D [1]
Age Male Female Pregnancy Lactation
0–12 months* 400 IU
(10 mcg)
400 IU
(10 mcg)
1–13 years 600 IU
(15 mcg)
600 IU
(15 mcg)
14–18 years 600 IU
(15 mcg)
600 IU
(15 mcg)
600 IU
(15 mcg)
600 IU
(15 mcg)
19–50 years 600 IU
(15 mcg)
600 IU
(15 mcg)
600 IU
(15 mcg)
600 IU
(15 mcg)
51–70 years 600 IU
(15 mcg)
600 IU
(15 mcg)
>70 years 800 IU
(20 mcg)
800 IU
(20 mcg)

* Adequate Intake (AI)

Sources of Vitamin D

Food

Very few foods in nature contain vitamin D. The flesh of fatty fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources [1,11]. Small amounts of vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of vitamin D3 and its metabolite 25(OH)D3 [12]. Some mushrooms provide vitamin D2 in variable amounts [13,14]. Mushrooms with enhanced levels of vitamin D2 from being exposed to ultraviolet light under controlled conditions are also available.

Fortified foods provide most of the vitamin D in the American diet [1,14]. For example, almost all of the U.S. milk supply is voluntarily fortified with 100 IU/cup [1]. (In Canada, milk is fortified by law with 35–40 IU/100 mL, as is margarine at ≥530 IU/100 g.) In the 1930s, a milk fortification program was implemented in the United States to combat rickets, then a major public health problem [1]. Other dairy products made from milk, such as cheese and ice cream, are generally not fortified. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of orange juice, yogurt, margarine and other food products.

Both the United States and Canada mandate the fortification of infant formula with vitamin D: 40–100 IU/100 kcal in the United States and 40–80 IU/100 kcal in Canada [1].

Several food sources of vitamin D are listed in Table 3.

Table 3: Selected Food Sources of Vitamin D [11]
Food IUs per serving* Percent DV**
Cod liver oil, 1 tablespoon 1,360 340
Swordfish, cooked, 3 ounces 566 142
Salmon (sockeye), cooked, 3 ounces 447 112
Tuna fish, canned in water, drained, 3 ounces 154 39
Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies) 137 34
Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup 115-124 29-31
Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces (more heavily fortified yogurts provide more of the DV) 80 20
Margarine, fortified, 1 tablespoon 60 15
Sardines, canned in oil, drained, 2 sardines 46 12
Liver, beef, cooked, 3 ounces 42 11
Egg, 1 large (vitamin D is found in yolk) 41 10
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV) 40 10
Cheese, Swiss, 1 ounce 6 2

* IUs = International Units.
** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children age 4 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer Web site lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin D arranged by nutrient content and by food name. A growing number of foods are being analyzed for vitamin D content. Simpler and faster methods to measure vitamin D in foods are needed, as are food standard reference materials with certified values for vitamin D to ensure accurate measurements [15].

Animal-based foods can provide some vitamin D in the form of 25(OH)D, which appears to be approximately five times more potent than the parent vitamin in raising serum 25(OH)D concentrations [16]. One study finds that taking into account the serum 25(OH)D content of beef, pork, chicken, turkey, and eggs can increase the estimated levels of vitamin D in the food from two to 18 times, depending upon the food [16]. At the present time, the USDA’s Nutrient Database does not include 25(OH)D when reporting the vitamin D content of foods. Actual vitamin D intakes in the U.S. population may be underestimated for this reason.

Sun exposure

Most people meet at least some of their vitamin D needs through exposure to sunlight [1,2]. Ultraviolet (UV) B radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3 [1]. Season, time of day, length of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis [1]. Perhaps surprisingly, geographic latitude does not consistently predict average serum 25(OH)D levels in a population. Ample opportunities exist to form vitamin D (and store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes [1].

Complete cloud cover reduces UV energy by 50%; shade (including that produced by severe pollution) reduces it by 60% [17]. UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D [18]. Sunscreens with a sun protection factor (SPF) of 8 or more appear to block vitamin D-producing UV rays, although in practice people generally do not apply sufficient amounts, cover all sun-exposed skin, or reapply sunscreen regularly [1,19]. Therefore, skin likely synthesizes some vitamin D even when it is protected by sunscreen as typically applied.

The factors that affect UV radiation exposure and research to date on the amount of sun exposure needed to maintain adequate vitamin D levels make it difficult to provide general guidelines. It has been suggested by some vitamin D researchers, for example, that approximately 5–30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis and that the moderate use of commercial tanning beds that emit 2%–6% UVB radiation is also effective [6,20]. Individuals with limited sun exposure need to include good sources of vitamin D in their diet or take a supplement to achieve recommended levels of intake.

Despite the importance of the sun for vitamin D synthesis, it is prudent to limit exposure of skin to sunlight [19] and UV radiation from tanning beds [21]. UV radiation is a carcinogen responsible for most of the estimated 1.5 million skin cancers and the 8,000 deaths due to metastatic melanoma that occur annually in the United States [19]. Lifetime cumulative UV damage to skin is also largely responsible for some age-associated dryness and other cosmetic changes. The American Academy of Dermatology advises that photoprotective measures be taken, including the use of sunscreen, whenever one is exposed to the sun [22]. Assessment of vitamin D requirements cannot address the level of sun exposure because of these public health concerns about skin cancer, and there are no studies to determine whether UVB-induced synthesis of vitamin D can occur without increased risk of skin cancer [1].

Dietary supplements

In supplements and fortified foods, vitamin D is available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol) that differ chemically only in their side-chain structure. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol [6]. The two forms have traditionally been regarded as equivalent based on their ability to cure rickets and, indeed, most steps involved in the metabolism and actions of vitamin D2 and vitamin D3 are identical. Both forms (as well as vitamin D in foods and from cutaneous synthesis) effectively raise serum 25(OH)D levels [2]. Firm conclusions about any different effects of these two forms of vitamin D cannot be drawn. However, it appears that at nutritional doses vitamins D2 and D3 are equivalent, but at high doses vitamin D2 is less potent.

The American Academy of Pediatrics (AAP) recommends that exclusively and partially breastfed infants receive supplements of 400 IU/day of vitamin D shortly after birth and continue to receive these supplements until they are weaned and consume ≥1,000 mL/day of vitamin D-fortified formula or whole milk [23]. Similarly, all non-breastfed infants ingesting <1,000 mL/day of vitamin D-fortified formula or milk should receive a vitamin D supplement of 400 IU/day [23]. AAP also recommends that older children and adolescents who do not obtain 400 IU/day through vitamin D-fortified milk and foods should take a 400 IU vitamin D supplement daily. However, this latter recommendation (issued November 2008) needs to be reevaluated in light of the Food and Nutrition Board’s vitamin D RDA of 600 IU/day for children and adolescents (issued November 2010 and which previously was an AI of 200 IU/day).

Vitamin D Intakes and Status

The National Health and Nutrition Examination Survey (NHANES), 2005–2006, estimated vitamin D intakes from both food and dietary supplements [4,24]. Average intake levels for males from foods alone ranged from 204 to 288 IU/day depending on life stage group; for females the range was 144 to 276 IU/day. When use of dietary supplements was considered, these mean values were substantially increased (37% of the U.S. population used a dietary supplement containing vitamin D.) The most marked increase was among older women. For women aged 51–70 years, mean intake of vitamin D from foods alone was 156 IU/day, but 404 IU/day with supplements. For women >70 years, the corresponding figures were 180 IU/day to 400 IU/day [1].

Comparing vitamin D intake estimates from foods and dietary supplements to serum 25(OH)D concentrations is problematic. One reason is that comparisons can only be made on group means rather than on data linked to individuals. Another is the fact that sun exposure affects vitamin D status; serum 25(OH)D levels are generally higher than would be predicted on the basis of vitamin D intakes alone [1]. The NHANES 2005–2006 survey found mean 25(OH)D levels exceeding 56 nmol/L (22.4 ng/mL) for all age-gender groups in the U.S. population. (The highest mean was 71.4 nmol/L [28.6 ng/mL] for girls aged 1–3 years, and the lowest mean was 56.5 nmol/L [22.6 ng/mL] for women aged 71 and older. Generally, younger people had higher levels than older people, and males had slightly higher levels than females.) 25(OH)D levels of approximately 50 nmol/L (20 ng/mL) are consistent with an intake of vitamin D from foods and dietary supplements equivalent to the RDA [1].

Over the past 20 years, mean serum 25(OH)D concentrations in the United States have slightly declined among males but not females. This decline is likely due to simultaneous increases in body weight, reduced milk intake, and greater use of sun protection when outside [25].

Vitamin D Deficiency

Nutrient deficiencies are usually the result of dietary inadequacy, impaired absorption and use, increased requirement, or increased excretion. A vitamin D deficiency can occur when usual intake is lower than recommended levels over time, exposure to sunlight is limited, the kidneys cannot convert 25(OH)D to its active form, or absorption of vitamin D from the digestive tract is inadequate. Vitamin D-deficient diets are associated with milk allergy, lactose intolerance, ovo-vegetarianism, and veganism [1].

Rickets and osteomalacia are the classical vitamin D deficiency diseases. In children, vitamin D deficiency causes rickets, a disease characterized by a failure of bone tissue to properly mineralize, resulting in soft bones and skeletal deformities [17]. Rickets was first described in the mid-17th century by British researchers [17,26]. In the late 19th and early 20th centuries, German physicians noted that consuming 1–3 teaspoons/day of cod liver oil could reverse rickets [26]. The fortification of milk with vitamin D beginning in the 1930s has made rickets a rare disease in the United States, although it is still reported periodically, particularly among African American infants and children [3,17,22].

Prolonged exclusive breastfeeding without the AAP-recommended vitamin D supplementation is a significant cause of rickets, particularly in dark-skinned infants breastfed by mothers who are not vitamin D replete [27]. Additional causes of rickets include extensive use of sunscreens and placement of children in daycare programs, where they often have less outdoor activity and sun exposure [17,26]. Rickets is also more prevalent among immigrants from Asia, Africa, and the Middle East, possibly because of genetic differences in vitamin D metabolism and behavioral differences that lead to less sun exposure.

In adults, vitamin D deficiency can lead to osteomalacia, resulting in weak bones [1,5]. Symptoms of bone pain and muscle weakness can indicate inadequate vitamin D levels, but such symptoms can be subtle and go undetected in the initial stages.

Groups at Risk of Vitamin D Inadequacy

Obtaining sufficient vitamin D from natural food sources alone is difficult. For many people, consuming vitamin D-fortified foods and, arguably, being exposed to some sunlight are essential for maintaining a healthy vitamin D status. In some groups, dietary supplements might be required to meet the daily need for vitamin D.

Breastfed infants

Vitamin D requirements cannot ordinarily be met by human milk alone [1,28], which provides <25 IU/L to 78 IU/L [23]. (The vitamin D content of human milk is related to the mother’s vitamin D status, so mothers who supplement with high doses of vitamin D may have correspondingly high levels of this nutrient in their milk [23].) A review of reports of nutritional rickets found that a majority of cases occurred among young, breastfed African Americans [29]. A survey of Canadian pediatricians found the incidence of rickets in their patients to be 2.9 per 100,000; almost all those with rickets had been breast fed [30]. While the sun is a potential source of vitamin D, the AAP advises keeping infants out of direct sunlight and having them wear protective clothing and sunscreen [31]. As noted earlier, the AAP recommends that exclusively and partially breastfed infants be supplemented with 400 IU of vitamin D per day [23], the RDA for this nutrient during infancy.

Older adults

Older adults are at increased risk of developing vitamin D insufficiency in part because, as they age, skin cannot synthesize vitamin D as efficiently, they are likely to spend more time indoors, and they may have inadequate intakes of the vitamin [1]. As many as half of older adults in the United States with hip fractures could have serum 25(OH)D levels <30 nmol/L (<12 ng/mL) [2].

People with limited sun exposure

Homebound individuals, women who wear long robes and head coverings for religious reasons, and people with occupations that limit sun exposure are unlikely to obtain adequate vitamin D from sunlight [32,33]. Because the extent and frequency of use of sunscreen are unknown, the significance of the role that sunscreen may play in reducing vitamin D synthesis is unclear [1]. Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.

People with dark skin

Greater amounts of the pigment melanin in the epidermal layer result in darker skin and reduce the skin’s ability to produce vitamin D from sunlight [1]. Various reports consistently show lower serum 25(OH)D levels in persons identified as black compared with those identified as white. It is not clear that lower levels of 25(OH)D for persons with dark skin have significant health consequences. Those of African American ancestry, for example, have reduced rates of fracture and osteoporosis compared with Caucasians (see section below on osteoporosis). Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.

People with inflammatory bowel disease and other conditions causing fat malabsorption

Because vitamin D is a fat-soluble vitamin, its absorption depends on the gut’s ability to absorb dietary fat. Individuals who have a reduced ability to absorb dietary fat might require vitamin D supplementation [34]. Fat malabsorption is associated with a variety of medical conditions, including some forms of liver disease, cystic fibrosis, celiac disease, and Crohn’s disease, as well as ulcerative colitis when the terminal ileum is inflamed [1,3,34]. In addition, people with some of these conditions might have lower intakes of certain foods, such as dairy products fortified with vitamin D.

People who are obese or who have undergone gastric bypass surgery

A body mass index ≥30 is associated with lower serum 25(OH)D levels compared with non-obese individuals; people who are obese may need larger than usual intakes of vitamin D to achieve 25(OH)D levels comparable to those of normal weight [1]. Obesity does not affect skin’s capacity to synthesize vitamin D, but greater amounts of subcutaneous fat sequester more of the vitamin and alter its release into the circulation. Obese individuals who have undergone gastric bypass surgery may become vitamin D deficient over time without a sufficient intake of this nutrient from food or supplements, since part of the upper small intestine where vitamin D is absorbed is bypassed and vitamin D mobilized into the serum from fat stores may not compensate over time [35,36].

Vitamin D and Health

Optimal serum concentrations of 25(OH)D for bone and general health have not been established; they are likely to vary at each stage of life, depending on the physiological measures selected [1,2,6]. Also, as stated earlier, while serum 25(OH)D functions as a biomarker of exposure to vitamin D (from sun, food, and dietary supplements), the extent to which such levels serve as a biomarker of effect (i.e., health outcomes) is not clearly established [1].

Furthermore, while serum 25(OH)D levels increase in response to increased vitamin D intake, the relationship is non-linear for reasons that are not entirely clear [1]. The increase varies, for example, by baseline serum levels and duration of supplementation. Increasing serum 25(OH)D to >50 nmol/L requires more vitamin D than increasing levels from a baseline <50 nmol/L. There is a steeper rise in serum 25(OH)D when the dose of vitamin D is <1,000 IU/day; a lower, more flattened response is seen at higher daily doses. When the dose is ≥1,000 IU/day, the rise in serum 25(OH)D is approximately 1 nmol/L for each 40 IU of intake. In studies with a dose ≤600 IU/day, the rise is serum 25(OH)D was approximately 2.3 nmol/L for each 40 IU of vitamin D consumed [1].

In 2011, The Endocrine Society issued clinical practice guidelines for vitamin D, stating that the desirable serum concentration of 25(OH)D is >75 nmol/L (>30 ng/ml) to maximize the effect of this vitamin on calcium, bone, and muscle metabolism [37]. It also reported that to consistently raise serum levels of 25(OH)D above 75 nmol/L (30 ng/ml), at least 1,500-2,000 IU/day of supplemental vitamin D might be required in adults, and at least 1,000 IU/day in children and adolescents.

However, the FNB committee that established DRIs for vitamin D extensively reviewed a long list of potential health relationships on which recommendations for vitamin D intake might be based [1]. These health relationships included resistance to chronic diseases (such as cancer and cardiovascular diseases), physiological parameters (such as immune response or levels of parathyroid hormone), and functional measures (such as skeletal health and physical performance and falls). With the exception of measures related to bone health, the health relationships examined were either not supported by adequate evidence to establish cause and effect, or the conflicting nature of the available evidence could not be used to link health benefits to particular levels of intake of vitamin D or serum measures of 25(OH)D with any level of confidence. This overall conclusion was confirmed by a more recent report on vitamin D and calcium from the Agency for Healthcare Research and Quality, which reviewed data from nearly 250 new studies published between 2009 and 2013 [38]. The report concluded that it is still not possible to specify a relationship between vitamin D and health outcomes other than bone health.

Osteoporosis

More than 40 million adults in the United States have or are at risk of developing osteoporosis, a disease characterized by low bone mass and structural deterioration of bone tissue that increases bone fragility and significantly increases the risk of bone fractures [39]. Osteoporosis is most often associated with inadequate calcium intakes, but insufficient vitamin D contributes to osteoporosis by reducing calcium absorption [40]. Although rickets and osteomalacia are extreme examples of the effects of vitamin D deficiency, osteoporosis is an example of a long-term effect of calcium and vitamin D insufficiency. Adequate storage levels of vitamin D maintain bone strength and might help prevent osteoporosis in older adults, non-ambulatory individuals who have difficulty exercising, postmenopausal women, and individuals on chronic steroid therapy [41].

Normal bone is constantly being remodeled. During menopause, the balance between these processes changes, resulting in more bone being resorbed than rebuilt. Hormone therapy with estrogen and progesterone might be able to delay the onset of osteoporosis. Several medical groups and professional societies support the use of HRT as an option for women who are at increased risk of osteoporosis or fractures [42,43,44]. Such women should discuss this matter with their health care providers.

Most supplementation trials of the effects of vitamin D on bone health also include calcium, so it is difficult to isolate the effects of each nutrient. Among postmenopausal women and older men, supplements of both vitamin D and calcium result in small increases in bone mineral density throughout the skeleton. They also help to reduce fractures in institutionalized older populations, although the benefit is inconsistent in community-dwelling individuals [1,2,45]. Vitamin D supplementation alone appears to have no effect on risk reduction for fractures nor does it appear to reduce falls among the elderly [1,2,45]; one widely-cited meta-analysis suggesting a protective benefit of supplemental vitamin D against falls [46] has been severely critiqued [1]. However, a large study of women aged ≥69 years followed for an average of 4.5 years found both lower (<50 nmol/L [<20 ng/mL]) and higher(≥75 nmol/L [≥30 ng/mL]) 25(OH)D levels at baseline to be associated with a greater risk of frailty [47]. Women should consult their healthcare providers about their needs for vitamin D (and calcium) as part of an overall plan to prevent or treat osteoporosis.

Cancer

Laboratory and animal evidence as well as epidemiologic data suggest that vitamin D status could affect cancer risk. Strong biological and mechanistic bases indicate that vitamin D plays a role in the prevention of colon, prostate, and breast cancers. Emerging epidemiologic data suggest that vitamin D may have a protective effect against colon cancer, but the data are not as strong for a protective effect against prostate and breast cancer, and are variable for cancers at other sites [1,48,49]. Studies do not consistently show a protective or no effect, however. One study of Finnish smokers, for example, found that subjects in the highest quintile of baseline vitamin D status had a threefold higher risk of developing pancreatic cancer [50]. A recent review found an increased risk of pancreatic cancer associated with high levels of serum 25(OH)D (≥100 nmol/L or ≥40 ng/mL) [51].

Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy. The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions [52]. However, the Women’s Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years [53]. More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400–1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared with women taking a placebo [54]. The small number of cancers (50) precludes generalizing about a protective effect from either or both nutrients or for cancers at different sites. This caution is supported by an analysis of 16,618 participants in NHANES III (1988–1994), in which total cancer mortality was found to be unrelated to baseline vitamin D status [55]. However, colorectal cancer mortality was inversely related to serum 25(OH)D concentrations. A large observational study with participants from 10 western European countries also found a strong inverse association between prediagnostic 25(OH)D concentrations and risk of colorectal cancer [56].

Further research is needed to determine whether vitamin D inadequacy in particular increases cancer risk, whether greater exposure to the nutrient is protective, and whether some individuals could be at increased risk of cancer because of vitamin D exposure [48,57]. Taken together, however, studies to date do not support a role for vitamin D, with or without calcium, in reducing the risk of cancer [1].

Other conditions

A growing body of research suggests that vitamin D might play some role in the prevention and treatment of type 1 [58] and type 2 diabetes [59], hypertension [60], glucose intolerance [61], multiple sclerosis [62], and other medical conditions [63,64]. However, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive [1]. Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated. One meta-analysis found use of vitamin D supplements to be associated with a statistically significant reduction in overall mortality from any cause [65,66], but a reanalysis of the data found no association [45]. A systematic review of these and other health outcomes related to vitamin D and calcium intakes, both alone and in combination, was published in August 2009 [45].

Health Risks from Excessive Vitamin D

Vitamin D toxicity can cause non-specific symptoms such as anorexia, weight loss, polyuria, and heart arrhythmias. More seriously, it can also raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels, and kidneys [1]. The use of supplements of both calcium (1,000 mg/day) and vitamin D (400 IU) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women’s Health Initiative [67]. A serum 25(OH)D concentration consistently >500 nmol/L (>200 ng/mL) is considered to be potentially toxic [5].

Excessive sun exposure does not result in vitamin D toxicity because the sustained heat on the skin is thought to photodegrade previtamin D3 and vitamin D3 as it is formed [6]. In addition, thermal activation of previtamin D3 in the skin gives rise to various non-vitamin D forms that limit formation of vitamin D3 itself. Some vitamin D3 is also converted to nonactive forms [1]. Intakes of vitamin D from food that are high enough to cause toxicity are very unlikely. Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D.

Long-term intakes above the UL increase the risk of adverse health effects [1] (Table 4). Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies, and clinical trials suggesting that even lower vitamin D intakes and serum 25(OH)D levels might have adverse health effects over time. The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly. The FNB committee cited research which found that vitamin D intakes of 5,000 IU/day achieved serum 25(OH)D concentrations between 100–150 nmol/L (40–60 ng/mL), but no greater. Applying an uncertainty factor of 20% to this intake value gave a UL of 4,000 IU which the FNB applied to children aged 9 and older, with corresponding lower amounts for younger children.

Table 4: Tolerable Upper Intake Levels (ULs) for Vitamin D [1]
Age Male Female Pregnancy Lactation
0–6 months 1,000 IU
(25 mcg)
1,000 IU
(25 mcg)
7–12 months 1,500 IU
(38 mcg)
1,500 IU
(38 mcg)
1–3 years 2,500 IU
(63 mcg)
2,500 IU
(63 mcg)
4–8 years 3,000 IU
(75 mcg)
3,000 IU
(75 mcg)
≥9 years 4,000 IU
(100 mcg)
4,000 IU
(100 mcg)
4,000 IU
(100 mcg)
4,000 IU
(100 mcg)

Interactions with Medications

Vitamin D supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss vitamin D intakes with their healthcare providers.

Steroids

Corticosteroid medications such as prednisone, often prescribed to reduce inflammation, can reduce calcium absorption [68,69,70] and impair vitamin D metabolism. These effects can further contribute to the loss of bone and the development of osteoporosis associated with their long-term use [69,70].

Other medications

Both the weight-loss drug orlistat (brand names Xenical® and alliTM) and the cholesterol-lowering drug cholestyramine (brand names Questran®, LoCholest®, and Prevalite®) can reduce the absorption of vitamin D and other fat-soluble vitamins [71,72]. Both phenobarbital and phenytoin (brand name Dilantin®), used to prevent and control epileptic seizures, increase the hepatic metabolism of vitamin D to inactive compounds and reduce calcium absorption [73].

Vitamin D and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Milk is fortified with vitamin D, as are many ready-to-eat cereals and some brands of yogurt and orange juice. Cheese naturally contains small amounts of vitamin D.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Fatty fish such as salmon, tuna, and mackerel are very good sources of vitamin D. Small amounts of vitamin D are also found in beef liver and egg yolks.
  • Limits saturated and trans fats, added sugars, and sodium.
    Vitamin D is added to some margarines.
  • Stays within your daily calorie needs.

References

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  10. National Institute of Standards and Technology. NIST releases vitamin D standard reference materialexternal link disclaimer, 2009.
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What is vitamin E and what does it do?

Introduction

Vitamin E is found naturally in some foods, added to others, and available as a dietary supplement. “Vitamin E” is the collective name for a group of fat-soluble compounds with distinctive antioxidant activities [1].

Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity [1]. Alpha- (or α-) tocopherol is the only form that is recognized to meet human requirements.

Serum concentrations of vitamin E (alpha-tocopherol) depend on the liver, which takes up the nutrient after the various forms are absorbed from the small intestine. The liver preferentially resecretes only alpha-tocopherol via the hepatic alpha-tocopherol transfer protein [1]; the liver metabolizes and excretes the other vitamin E forms [2]. As a result, blood and cellular concentrations of other forms of vitamin E are lower than those of alpha-tocopherol and have been the subjects of less research [3,4].

Antioxidants protect cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer [5]. Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species (ROS). The body forms ROS endogenously when it converts food to energy, and antioxidants might protect cells from the damaging effects of ROS. The body is also exposed to free radicals from environmental exposures, such as cigarette smoke, air pollution, and ultraviolet radiation from the sun. ROS are part of signaling mechanisms among cells.

Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fat undergoes oxidation. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

In addition to its activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and other metabolic processes [1]. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes [6]. Vitamin-E–replete endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation [6].

Recommended Intakes

Intake recommendations for vitamin E and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences) [6]. DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects [6].

The FNB’s vitamin E recommendations are for alpha-tocopherol alone, the only form maintained in plasma. The FNB based these recommendations primarily on serum levels of the nutrient that provide adequate protection in a test measuring the survival of erythrocytes when exposed to hydrogen peroxide, a free radical [6]. Acknowledging “great uncertainties” in these data, the FNB has called for research to identify other biomarkers for assessing vitamin E requirements.

RDAs for vitamin E are provided in milligrams (mg) and are listed in Table 1. Because insufficient data are available to develop RDAs for infants, AIs were developed based on the amount of vitamin E consumed by healthy breastfed babies.

At present, the vitamin E content of foods and dietary supplements is listed on labels in international units (IUs), a measure of biological activity rather than quantity. Naturally sourced vitamin E is called RRR-alpha-tocopherol (commonly labeled as d-alpha-tocopherol); the synthetically produced form is all rac-alpha-tocopherol (commonly labeled as dl-alpha-tocopherol). Conversion rules are as follows:

  • To convert from mg to IU:1 mg of alpha-tocopherol is equivalent to 1.49 IU of the natural form or 2.22 IU of the synthetic form.
  • To convert from IU to mg:1 IU of the natural form is equivalent to 0.67 mg of alpha-tocopherol.1 IU of the synthetic form is equivalent to 0.45 mg of alpha-tocopherol.

However, for the manufacture and addition of vitamin E to dietary supplements and foods, as well as for labeling the vitamin E content of these products, the U.S. Food and Drug Administration (FDA) mandates that older conversion factors published by the FNB in 1968 be used: 1 IU = 0.67 mg for d-alpha-tocopherol = 0.90 mg for dl-alpha-tocopherol [7]. Under FDA’s new labeling regulations for foods and dietary supplements that take effect by July 26, 2018 (for companies with annual sales of $10 million or more) or July 26, 2019 (for smaller companies), vitamin E will be listed only in mg and not IUs [8].

Table 1 lists the RDAs for alpha-tocopherol in both mg and IU of the natural form; for example, 15 mg x 1.49 IU/mg = 22.4 IU. The corresponding value for synthetic alpha-tocopherol would be 33.3 IU (15 mg x 2.22 IU/mg).

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin E (Alpha-Tocopherol) [6]
Age Males Females Pregnancy Lactation
0–6 months* 4 mg
(6 IU)
4 mg
(6 IU)
7–12 months* 5 mg
(7.5 IU)
5 mg
(7.5 IU)
1–3 years 6 mg
(9 IU)
6 mg
(9 IU)
4–8 years 7 mg
(10.4 IU)
7 mg
(10.4 IU)
9–13 years 11 mg
(16.4 IU)
11 mg
(16.4 IU)
14+ years 15 mg
(22.4 IU)
15 mg
(22.4 IU)
15 mg
(22.4 IU)
19 mg
(28.4 IU)

*Adequate Intake (AI)

Sources of Vitamin E

Food

Numerous foods provide vitamin E. Nuts, seeds, and vegetable oils are among the best sources of alpha-tocopherol, and significant amounts are available in green leafy vegetables and fortified cereals (see Table 2 for a more detailed list) [9]. Most vitamin E in American diets is in the form of gamma-tocopherol from soybean, canola, corn, and other vegetable oils and food products [4].

Table 2: Selected Food Sources of Vitamin E (Alpha-Tocopherol) [9]
Food Milligrams (mg)
per serving
Percent DV*
Wheat germ oil, 1 tablespoon 20.3 100
Sunflower seeds, dry roasted, 1 ounce 7.4 37
Almonds, dry roasted, 1 ounce 6.8 34
Sunflower oil, 1 tablespoon 5.6 28
Safflower oil, 1 tablespoon 4.6 25
Hazelnuts, dry roasted, 1 ounce 4.3 22
Peanut butter, 2 tablespoons 2.9 15
Peanuts, dry roasted, 1 ounce 2.2 11
Corn oil, 1 tablespoon 1.9 10
Spinach, boiled, ½ cup 1.9 10
Broccoli, chopped, boiled, ½ cup 1.2 6
Soybean oil, 1 tablespoon 1.1 6
Kiwifruit, 1 medium 1.1 6
Mango, sliced, ½ cup 0.7 4
Tomato, raw, 1 medium 0.7 4
Spinach, raw, 1 cup 0.6 3

*DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient content of different foods within the context of a total diet. The DV for vitamin E is 30 IU (approximately 20 mg of natural alpha-tocopherol) for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin E content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer Web site lists the nutrient content of many foods, including, in some cases, the amounts of alpha-, beta-, gamma-, and delta-tocopherol. The USDA also provides a comprehensive list of foods containing vitamin E arranged by nutrient content and by food name.

Dietary supplements

Supplements of vitamin E typically provide only alpha-tocopherol, although “mixed” products containing other tocopherols and even tocotrienols are available. Naturally occurring alpha-tocopherol exists in one stereoisomeric form. In contrast, synthetically produced alpha-tocopherol contains equal amounts of its eight possible stereoisomers; serum and tissues maintain only four of these stereoisomers [6]. A given amount of synthetic alpha-tocopherol (all rac-alpha-tocopherol; commonly labeled as “DL” or “dl”) is therefore only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol; commonly labeled as “D” or “d”). People need approximately 50% more IU of synthetic alpha tocopherol from dietary supplements and fortified foods to obtain the same amount of the nutrient as from the natural form.

Most vitamin-E-only supplements provide ≥100 IU of the nutrient. These amounts are substantially higher than the RDAs. The 1999–2000 National Health and Nutrition Examination Survey (NHANES) found that 11.3% of adults took vitamin E supplements containing at least 400 IU [10].

Alpha-tocopherol in dietary supplements and fortified foods is often esterified to prolong its shelf life while protecting its antioxidant properties. The body hydrolyzes and absorbs these esters (alpha-tocopheryl acetate and succinate) as efficiently as alpha-tocopherol [6].

Vitamin E Intakes and Status

Three national surveys—the 2001–2002 NHANES [11], NHANES III (1988–1994) [11], and the Continuing Survey of Food Intakes by Individuals (1994–1996) [12]—have found that the diets of most Americans provide less than the RDA levels of vitamin E. These intake estimates might be low, however, because the amounts and types of fat added during cooking are often unknown and not accounted for [6].

The FNB suggests that mean intakes of vitamin E among healthy adults are probably higher than the RDA but cautions that low-fat diets might provide insufficient amounts unless people make their food choices carefully by, for example, increasing their intakes of nuts, seeds, fruits, and vegetables [6,11].

Vitamin E Deficiency

Frank vitamin E deficiency is rare and overt deficiency symptoms have not been found in healthy people who obtain little vitamin E from their diets [6]. Premature babies of very low birth weight (<1,500 grams) might be deficient in vitamin E. Vitamin E supplementation in these infants might reduce the risk of some complications, such as those affecting the retina, but they can also increase the risk of infections [13].

Because the digestive tract requires fat to absorb vitamin E, people with fat-malabsorption disorders are more likely to become deficient than people without such disorders. Deficiency symptoms include peripheral neuropathy, ataxia, skeletal myopathy, retinopathy, and impairment of the immune response [6,14]. People with Crohn’s disease, cystic fibrosis, or an inability to secrete bile from the liver into the digestive tract, for example, often pass greasy stools or have chronic diarrhea; as a result, they sometimes require water-soluble forms of vitamin E, such as tocopheryl polyethylene glycol-1000 succinate [1].

Some people with abetalipoproteinemia, a rare inherited disorder resulting in poor absorption of dietary fat, require enormous doses of supplemental vitamin E (approximately 100 mg/kg or 5–10 g/day) [1]. Vitamin E deficiency secondary to abetalipoproteinemia causes such problems as poor transmission of nerve impulses, muscle weakness, and retinal degeneration that leads to blindness [15]. Ataxia and vitamin E deficiency (AVED) is another rare, inherited disorder in which the liver’s alpha-tocopherol transfer protein is defective or absent. People with AVED have such severe vitamin E deficiency that they develop nerve damage and lose the ability to walk unless they take large doses of supplemental vitamin E [16].

Vitamin E and Health

Many claims have been made about vitamin E’s potential to promote health and prevent and treat disease. The mechanisms by which vitamin E might provide this protection include its function as an antioxidant and its roles in anti-inflammatory processes, inhibition of platelet aggregation, and immune enhancement.

A primary barrier to characterizing the roles of vitamin E in health is the lack of validated biomarkers for vitamin E intake and status to help relate intakes to valid predictors of clinical outcomes [6]. This section focuses on four diseases and disorders in which vitamin E might be involved: heart disease, cancer, eye disorders, and cognitive decline.

Coronary heart disease

Evidence that vitamin E could help prevent or delay coronary heart disease (CHD) comes from several sources. In vitro studies have found that the nutrient inhibits oxidation of low-density lipoprotein (LDL) cholesterol, thought to be a crucial initiating step for atherosclerosis [6]. Vitamin E might also help prevent the formation of blood clots that could lead to a heart attack or venous thromboembolism [17].

Several observational studies have associated lower rates of heart disease with higher vitamin E intakes. One study of approximately 90,000 nurses found that the incidence of heart disease was 30% to 40% lower in those with the highest intakes of vitamin E, primarily from supplements [18]. Among a group of 5,133 Finnish men and women followed for a mean of 14 years, higher vitamin E intakes from food were associated with decreased mortality from CHD [19].

However, randomized clinical trials cast doubt on the efficacy of vitamin E supplements to prevent CHD [20]. For example, the Heart Outcomes Prevention Evaluation (HOPE) study, which followed almost 10,000 patients at high risk of heart attack or stroke for 4.5 years [21], found that participants taking 400 IU/day of natural vitamin E experienced no fewer cardiovascular events or hospitalizations for heart failure or chest pain than participants taking a placebo. In the HOPE-TOO followup study, almost 4,000 of the original participants continued to take vitamin E or placebo for an additional 2.5 years [22]. HOPE-TOO found that vitamin E provided no significant protection against heart attacks, strokes, unstable angina, or deaths from cardiovascular disease or other causes after 7 years of treatment. Participants taking vitamin E, however, were 13% more likely to experience, and 21% more likely to be hospitalized for, heart failure, a statistically significant but unexpected finding not reported in other large studies.

The HOPE and HOPE-TOO trials provide compelling evidence that moderately high doses of vitamin E supplements do not reduce the risk of serious cardiovascular events among men and women >50 years of age with established heart disease or diabetes [23]. These findings are supported by evidence from the Women’s Angiographic Vitamin and Estrogen study, in which 423 postmenopausal women with some degree of coronary stenosis took supplements with 400 IU vitamin E (type not specified) and 500 mg vitamin C twice a day or placebo for >4 years [24]. Not only did the supplements provide no cardiovascular benefits, but all-cause mortality was significantly higher in the women taking the supplements.

The latest published clinical trial of vitamin E’s effects on the heart and blood vessels of women included almost 40,000 healthy women ≥45 years of age who were randomly assigned to receive either 600 IU of natural vitamin E on alternate days or placebo and who were followed for an average of 10 years [25]. The investigators found no significant differences in rates of overall cardiovascular events (combined nonfatal heart attacks, strokes, and cardiovascular deaths) or all-cause mortality between the groups. However, the study did find two positive and significant results for women taking vitamin E: they had a 24% reduction in cardiovascular death rates, and those ≥65 years of age had a 26% decrease in nonfatal heart attack and a 49% decrease in cardiovascular death rates.

The most recent published clinical trial of vitamin E and men’s cardiovascular health included almost 15,000 healthy physicians ≥50 years of age who were randomly assigned to receive 400 IU synthetic alpha-tocopherol every other day, 500 mg vitamin C daily, both vitamins, or placebo [26]. During a mean followup period of 8 years, intake of vitamin E (and/or vitamin C) had no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, or cardiovascular morality. Furthermore, use of vitamin E was associated with a significantly increased risk of hemorrhagic stroke.

In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. However, participants in these studies have been largely middle-aged or elderly individuals with demonstrated heart disease or risk factors for heart disease. Some researchers have suggested that understanding the potential utility of vitamin E in preventing CHD might require longer studies in younger participants taking higher doses of the supplement [27]. Further research is needed to determine whether supplemental vitamin E has any protective value for younger, healthier people at no obvious risk of CHD.

Cancer

Antioxidant nutrients like vitamin E protect cell constituents from the damaging effects of free radicals that, if unchecked, might contribute to cancer development [9]. Vitamin E might also block the formation of carcinogenic nitrosamines formed in the stomach from nitrites in foods and protect against cancer by enhancing immune function [28]. Unfortunately, human trials and surveys that have attempted to associate vitamin E intake with cancer incidence have found that vitamin E is not beneficial in most cases.

Both the HOPE-TOO Trial and Women’s Health Study evaluated whether vitamin E supplements might protect people from cancer. HOPE-TOO, which followed men and women ≥55 years of age with heart disease or diabetes for 7 years, found no significant differences in the number of new cancers or cancer deaths between individuals randomly assigned to take 400 IU/day vitamin E or a placebo [22]. In the Women’s Health Study, in which healthy women ≥45 years of age received either 600 IU vitamin E every other day or a placebo for 10 years, the supplement did not reduce the risk of developing any form of cancer [25].

Several studies have examined whether vitamin E intake and/or supplemental vitamin E affects the risk of developing prostate cancer. A prospective cohort study of >29,000 men found no association between dietary or supplemental vitamin E intake and prostate cancer risk [29]. However, among current smokers and men who had quit, vitamin E intakes of more than 400 IU/day were associated with a statistically significant 71% reduction in the risk of advanced prostate cancer. In a clinical trial involving 29,133 male smokers, men randomly assigned to take daily supplements of 50 IU synthetic vitamin E for 5–8 years had 32% fewer prostate cancers compared to subjects who did not take the supplements [30]. Based in part on the promising results of this study, a large randomized clinical trial, called the SELECT trial, began in 2001 to determine whether 7–12 years of daily supplementation with synthetic vitamin E (400 IU, as dl-alpha-tocopheryl acetate), with or without selenium (200 mcg, as L-selenomethionine), reduced the number of new prostate cancers in 35,533 healthy men age 50 and older. The trial was discontinued in October 2008 when an analysis found that the supplements, taken alone or together for about 5.5 years, did not prevent prostate cancer [31]. Results from an additional 1.5 years of follow-up from this trial (during which the subjects no longer received vitamin E or selenium), showed that the men who had taken the vitamin E had a 17 percent increased risk of prostate cancer compared to men only taking placebos, a statistically significant difference [32]. The risk of developing prostate cancer was also slightly increased in subjects taking vitamin E plus selenium or selenium alone, but the differences were not statistically significant. No differences were found among groups in the incidence of lung or colorectal cancers or all cancers combined. Study staff members will continue to monitor participants’ health for up to 5 more years. The National Cancer Institute web site provides additional information on the SELECT trialexternal link disclaimer.

One study of women in Iowa provides evidence that higher intakes of vitamin E from foods and supplements could decrease the risk of colon cancer, especially in women <65 years of age [33]. The overall relative risk for the highest quintile of intake (>35.7 IU/day) compared to the lowest quintile (<5.7 IU/day) was 0.32. However, prospective cohort studies of 87,998 women in the Nurses’ Health Study and 47,344 men in the Health Professionals Follow-up Study failed to replicate these results [34]. Although some research links higher intakes of vitamin E with decreased incidence of breast cancer, an examination of the impact of dietary factors, including vitamin E, on the incidence of postmenopausal breast cancer in >18,000 women found no benefit from the vitamin [35].

The American Cancer Society conducted an epidemiologic study examining the association between use of vitamin C and vitamin E supplements and bladder cancer mortality. Of the almost one million adults followed between 1982 and 1998, adults who took supplemental vitamin E for 10 years or longer had a reduced risk of death from bladder cancer [36]; vitamin C supplementation provided no protection.

Evidence to date is insufficient to support taking vitamin E to prevent cancer. In fact, daily use of large-dose vitamin E supplements (400 IU) may increase the risk of prostate cancer.

Eye disorders

Age-related macular degeneration (AMD) and cataracts are among the most common causes of significant vision loss in older people. Their etiologies are usually unknown, but the cumulative effects of oxidative stress have been postulated to play a role. If so, nutrients with antioxidant functions, such as vitamin E, could be used to prevent or treat these conditions.

Prospective cohort studies have found that people with relatively high dietary intakes of vitamin E (e.g., 30 IU/day) have an approximately 20% lower risk of developing AMD than people with low intakes (e.g., <15 IU/day) [37,38]. However, two randomized controlled trials in which participants took supplements of vitamin E (500 IU/day d-alpha-tocopherol in one study [39] and 111 IU/day dl-alpha-tocopheryl acetate combined with 20 mg/day beta-carotene in the other [40]) or a placebo failed to show a protective effect for vitamin E on AMD. The Age-Related Eye Disease Study (AREDS), a large randomized clinical trial, found that participants at high risk of developing advanced AMD (i.e., those with intermediate AMD or those with advanced AMD in one eye) reduced their risk of developing advanced AMD by 25% by taking a daily supplement containing vitamin E (400 IU dl-alpha-tocopheryl acetate), beta-carotene (15 mg), vitamin C (500 mg), zinc (80 mg), and copper (2 mg) compared to participants taking a placebo over 5 years [41]. A follow-up AREDS2 study confirmed the value of this and similar supplement formulations in reducing the progression of AMD over a median follow-up period of 5 years” [42].

Several observational studies have revealed a potential relationship between vitamin E supplements and the risk of cataract formation. One prospective cohort study found that lens clarity was superior in participants who took vitamin E supplements and those with higher blood levels of the vitamin [43]. In another study, long-term use of vitamin E supplements was associated with slower progression of age-related lens opacification [44]. However, in the AREDS trial, the use of a vitamin E-containing formulation had no apparent effect on the development or progression of cataracts over an average of 6.3 years [45]. The AREDS2 study, which also tested formulations containing 400 IU vitamin E, confirmed these findings” [46].

Overall, the available evidence is inconsistent with respect to whether vitamin E supplements, taken alone or in combination with other antioxidants, can reduce the risk of developing AMD or cataracts. However, the formulations of vitamin E, other antioxidants, zinc, and copper used in AREDS hold promise for slowing the progression of AMD in people at high risk of developing advanced AMD.

Cognitive decline

The brain has a high oxygen consumption rate and abundant polyunsaturated fatty acids in the neuronal cell membranes. Researchers hypothesize that if cumulative free-radical damage to neurons over time contributes to cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, then ingestion of sufficient or supplemental antioxidants (such as vitamin E) might provide some protection [47]. This hypothesis was supported by the results of a clinical trial in 341 patients with Alzheimer’s disease of moderate severity who were randomly assigned to receive a placebo, vitamin E (2,000 IU/day dl-alpha-tocopherol), a monoamine oxidase inhibitor (selegiline), or vitamin E and selegiline [47]. Over 2 years, treatment with vitamin E and selegiline, separately or together, significantly delayed functional deterioration and the need for institutionalization compared to placebo. However, participants taking vitamin E experienced significantly more falls.

Vitamin E consumption from foods or supplements was associated with less cognitive decline over 3 years in a prospective cohort study of elderly, free-living individuals aged 65–102 years [48]. However, a clinical trial in primarily healthy older women who were randomly assigned to receive 600 IU d-alpha-tocopherol every other day or a placebo for ≤4 years found that the supplements provided no apparent cognitive benefits [49]. Another trial in which 769 men and women with mild cognitive impairment were randomly assigned to receive 2,000 IU/day vitamin E (type not specified), a cholinesterase inhibitor (donepezil), or placebo found no significant differences in the progression rate of Alzheimer’s disease between the vitamin E and placebo groups [50]In summary, most research results do not support the use of vitamin E supplements by healthy or mildly impaired individuals to maintain cognitive performance or slow its decline with normal aging [51]. More research is needed to identify the role of vitamin E, if any, in the management of cognitive impairment [52].

Health Risks from Excessive Vitamin E

Research has not found any adverse effects from consuming vitamin E in food [6]. However, high doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol; one trial included Finnish male smokers who consumed 50 mg/day for an average of 6 years [53] and the other trial involved a large group of male physicians in the United States who consumed 400 IU every other day for 8 years [26]. Because the majority of physicians in the latter study were also taking aspirin, this finding could indicate that vitamin E has a tendency to cause bleeding.

The FNB has established ULs for vitamin E based on the potential for hemorrhagic effects (see Table 3). The ULs apply to all forms of supplemental alpha-tocopherol, including the eight stereoisomers present in synthetic vitamin E. Doses of up to 1,000 mg/day (1,500 IU/day of the natural form or 1,100 IU/day of the synthetic form) in adults appear to be safe, although the data are limited and based on small groups of people taking at least 2,000 IU for a few weeks or months. Long-term intakes above the UL increase the risk of adverse health effects [6]. Vitamin E ULs for infants have not been established.

Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin E [6]
Age Male Female Pregnancy Lactation
1–3 years 200 mg
(300 IU)
200 mg
(300 IU)
4–8 years 300 mg
(450 IU)
300 mg
(450 IU)
9–13 years 600 mg
(900 IU)
600 mg
(900 IU)
14–18 years 800 mg
(1,200 IU)
800 mg
(1,200 IU)
800 mg
(1,200 IU)
800 mg
(1,200 IU)
19+ years 1,000 mg
(1,500 IU)
1,000 mg
(1,500 IU)
1,000 mg
(1,500 IU)
1,000 mg
(1,500 IU)

Two meta-analyses of randomized trials have also raised questions about the safety of large doses of vitamin E, including doses lower than the UL. These meta-analyses linked supplementation to small but statistically significant increases in all-cause mortality. One analysis found an increased risk of death at doses of 400 IU/day, although the risk began to increase at 150 IU [54]. In the other analysis of studies of antioxidant supplements for disease prevention, the highest quality trials revealed that vitamin E, administered singly (dose range 10 IU–5,000 IU/day; mean 569 IU) or combined with up to four other antioxidants, significantly increased mortality risk [55].

The implications of these analyses for the potential adverse effects of high-dose vitamin E supplements are unclear [56-59]. Participants in the studies included in these analyses were typically middle-aged or older and had chronic diseases or related risk factors. These participants often consumed other supplements in addition to vitamin E. Some of the studies analyzed took place in developing countries in which nutritional deficiencies are common. A review of the subset of studies in which vitamin E supplements were given to healthy individuals for the primary prevention of chronic disease found no convincing evidence that the supplements increased mortality [60].

However, results from the recently published, large SELECT trial show that vitamin E supplements (400 IU/day) may harm adult men in the general population by increasing their risk of prostate cancer [32]. Follow-up studies are assessing whether the cancer risk was associated with baseline blood levels of vitamin E and selenium prior to supplementation as well as whether changes in one or more genes might increase a man’s risk of developing prostate cancer while taking vitamin E.

Interactions with Medications

Vitamin E supplements have the potential to interact with several types of medications. A few examples are provided below. People taking these and other medications on a regular basis should discuss their vitamin E intakes with their healthcare providers.

Anticoagulant and antiplatelet medications

Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. As a result, taking large doses with anticoagulant or antiplatelet medications, such as warfarin (Coumadin®), can increase the risk of bleeding, especially in conjunction with low vitamin K intake. The amounts of supplemental vitamin E needed to produce clinically significant effects are unknown but probably exceed 400 IU/day [61].

Simvastatin and niacin

Some people take vitamin E supplements with other antioxidants, such as vitamin C, selenium, and beta-carotene. This collection of antioxidant ingredients blunted the rise in high-density lipoprotein (HDL) cholesterol levels, especially levels of HDL2, the most cardioprotective HDL component, among people treated with a combination of simvastatin (brand name Zocor®) and niacin [62,63].

Chemotherapy and radiotherapy

Oncologists generally advise against the use of antioxidant supplements during cancer chemotherapy or radiotherapy because they might reduce the effectiveness of these therapies by inhibiting cellular oxidative damage in cancerous cells [64,65]. Although a systematic review of randomized controlled trials has called this concern into question [66], further research is needed to evaluate the potential risks and benefits of concurrent antioxidant supplementation with conventional therapies for cancer.

Vitamin E and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
    Vitamin E is found in green leafy vegetables, whole grains, fortified cereals, and vegetable oils.
  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
    Nuts are good sources of vitamin E.
  • Limits saturated and trans fats, added sugars, and sodium.
  • Stays within your daily calorie needs.

References

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This publication is a work of reproduction from Federal government resources and is in the public domain. Key Compounding Pharmacy(KCP) has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your primary health care provider. We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by KCP.

What is vitamin K and what does it do?

Introduction

“Vitamin K,” the generic name for a family of compounds with a common chemical structure of 2-methyl-1,4-naphthoquinone, is a fat-soluble vitamin that is naturally present in some foods and is available as a dietary supplement [1]. These compounds include phylloquinone (vitamin K1) and a series of menaquinones (vitamin K2) [2]. Menaquinones have unsaturated isoprenyl side chains and are designated as MK-4 through MK-13, based on the length of their side chain [1,2]. MK-4, MK-7, and MK-9 are the most well-studied menaquinones.

Phylloquinone is present primarily in green leafy vegetables and is the main dietary form of vitamin K [3]. Menaquinones, which are predominantly of bacterial origin, are present in modest amounts in various animal-based and fermented foods [1,4]. Almost all menaquinones, in particular the long-chain menaquinones, are also produced by bacteria in the human gut [5,6]. MK-4 is unique in that it is produced by the body from phylloquinone via a conversion process that does not involve bacterial action [7].

Vitamin K functions as a coenzyme for vitamin K-dependent carboxylase, an enzyme required for the synthesis of proteins involved in hemostasis (blood clotting) and bone metabolism, and other diverse physiological functions [3,5]. Prothrombin (clotting factor II) is a vitamin K-dependent protein in plasma that is directly involved in blood clotting. Warfarin (Coumadin®) and some anticoagulants used primarily in Europe antagonize the activity of vitamin K and, in turn, prothrombin [8]. For this reason, individuals who are taking these anticoagulants need to maintain consistent vitamin K intakes.

Matrix Gla-protein, a vitamin K-dependent protein present in vascular smooth muscle, bone, and cartilage, is the focus of considerable scientific research because it might help reduce abnormal calcification [9]. Osteocalcin is another vitamin K-dependent protein that is present in bone and may be involved in bone mineralization or turnover [5].

Like dietary lipids and other fat-soluble vitamins, ingested vitamin K is incorporated into mixed micelles via the action of bile and pancreatic enzymes, and it is absorbed by enterocytes of the small intestine [10]. From there, vitamin K is incorporated into chylomicrons, secreted into the lymphatic capillaries, transported to the liver, and repackaged into very low-density lipoproteins [2,10]. Vitamin K is present in the liver and other body tissues, including the brain, heart, pancreas, and bone [2,3,11].

In the circulation, vitamin K is carried mainly in lipoproteins [2]. Compared to the other fat-soluble vitamins, very small amounts of vitamin K circulate in the blood. Vitamin K is rapidly metabolized and excreted. Based on phylloquinone measurements, the body retains only about 30% to 40% of an oral physiological dose, while about 20% is excreted in the urine and 40% to 50% in the feces via bile [2,11]. This rapid metabolism accounts for vitamin K’s relatively low blood levels and tissue stores compared to those of the other fat-soluble vitamins [11].

Little is known about the absorption and transport of vitamin K produced by gut bacteria, but research indicates that substantial quantities of long-chain menaquinones are present in the large bowel [7]. Although the amount of vitamin K that the body obtains in this manner is unclear, experts believe that these menaquinones satisfy at least some of the body’s requirement for vitamin K [6,7].

In most cases, vitamin K status is not routinely assessed, except in individuals who take anticoagulants or have bleeding disorders. The only clinically significant indicator of vitamin K status is prothrombin time (the time it takes for blood to clot), and ordinary changes in vitamin K intakes have rarely been shown to alter prothrombin time [5]. In healthy people, fasting concentrations of phylloquinone in plasma have been reported to range from 0.29 to 2.64 nmol/L [12]. However, it is not clear whether this measure can be used to quantitatively assess vitamin K status. People with plasma phylloquinone concentrations slightly below the normal range have no clinical indications of vitamin K deficiency, possibly because plasma phylloquinone concentrations do not measure the contribution of menaquinones from the diet and the large bowel [12]. No data on normal ranges of menaquinones are available [2].

Recommended Intakes

Intake recommendations for vitamin K and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies [3]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA; intake at this level is assumed to ensure nutritional adequacy.
  • Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

Insufficient data were available to establish an EAR for vitamin K, so the FNB established AIs for all ages that are based on vitamin K intakes in healthy population groups [3]. Table 1 lists the current AIs for vitamin K in micrograms (mcg). The AIs for infants are based on the calculated mean vitamin K intake of healthy breastfed infants and the assumption that infants receive prophylactic vitamin K at birth as recommended by American and Canadian pediatric societies [3].

Table 1: Adequate Intakes (AIs) for Vitamin K [3]
Age Male Female Pregnancy Lactation
Birth to 6 months 2.0 mcg 2.0 mcg
7–12 months 2.5 mcg 2.5 mcg
1–3 years 30 mcg 30 mcg
4–8 years 55 mcg 55 mcg
9–13 years 60 mcg 60 mcg
14–18 years 75 mcg 75 mcg 75 mcg 75 mcg
19+ years 120 mcg 90 mcg 90 mcg 90 mcg

Sources of Vitamin K

Food

Food sources of phylloquinone include vegetables, especially green leafy vegetables, vegetable oils, and some fruits. Meat, dairy foods, and eggs contain low levels of phylloquinone but modest amounts of menaquinones [4]. Natto (a traditional Japanese food made from fermented soybeans) has high amounts of menaquinones [1,13]. Other fermented foods, such as cheese, also contain menaquinones. However, the forms and amounts of vitamin K in these foods likely vary depending on the bacterial strains used to make the foods and their fermentation conditions [14]. Animals synthesize MK-4 from menadione (a synthetic form of vitamin K that can be used in poultry and swine feed) [15]. Thus, poultry and pork products contain MK-4 if menadione is added to the animal feed [1,4,14].

The most common sources of vitamin K in the U.S. diet are spinach; broccoli; iceberg lettuce; and fats and oils, particularly soybean and canola oil [5,7]. Few foods are fortified with vitamin K [5]; breakfast cereals are not typically fortified with vitamin K, although some meal replacement shakes and bars are.

Data on the bioavailability of different forms of vitamin K from food are very limited [1]. The absorption rate of phylloquinone in its free form is approximately 80%, but its absorption rate from foods is significantly lower [2]. Phylloquinone in plant foods is tightly bound to chloroplasts, so it is less bioavailable than that from oils or dietary supplements [1]. For example, the body absorbs only 4% to 17% as much phylloquinone from spinach as from a tablet [2]. Consuming vegetables at the same time as some fat improves phylloquinone absorption from the vegetables, but the amount absorbed is still lower than that from oils. Limited research suggests that long-chain MKs may have higher absorption rates than phylloquinone from green vegetables [7].

Several food sources of vitamin K are listed in Table 2. All values in this table are for phylloquinone content, except when otherwise indicated, because food composition data for menaquinones are limited [1].

Table 2: Selected Food Sources of Vitamin K (Phylloquinone, Except as Indicated) [4,13,16]
Food Micrograms
(mcg) per
serving
Percent
DV*
Natto, 3 ounces (as MK-7) 850 1,062
Collards, frozen, boiled, ½ cup 530 662
Turnip greens, frozen, boiled ½ cup 426 532
Spinach, raw, 1 cup 145 181
Kale, raw, 1 cup 113 141
Broccoli, chopped, boiled, ½ cup 110 138
Soybeans, roasted, ½ cup 43 54
Carrot juice, ¾ cup 28 34
Soybean oil, 1 tablespoon 25 31
Edamame, frozen, prepared, ½ cup 21 26
Pumpkin, canned, ½ cup 20 25
Pomegranate juice, ¾ cup 19 24
Okra, raw, ½ cup 16 20
Salad dressing, Caesar, 1 tablespoon 15 19
Pine nuts, dried, 1 ounce 15 19
Blueberries, raw, ½ cup 14 18
Iceberg lettuce, raw, 1 cup 14 18
Chicken, breast, rotisserie, 3 ounces (as MK-4) 13 17
Grapes, ½ cup 11 14
Vegetable juice cocktail, ¾ cup 10 13
Canola oil, 1 tablespoon 10 13
Cashews, dry roasted, 1 ounce 10 13
Carrots, raw, 1 medium 8 10
Olive oil, 1 tablespoon 8 10
Ground beef, broiled, 3 ounces (as MK-4) 6 8
Figs, dried, ¼ cup 6 8
Chicken liver, braised, 3 ounces (as MK-4) 6 8
Ham, roasted or pan-broiled, 3 ounces (as MK-4) 4 5
Cheddar cheese, 1½ ounces (as MK-4) 4 5
Mixed nuts, dry roasted, 1 ounce 4 5
Egg, hard boiled, 1 large (as MK-4) 4 5
Mozzarella cheese, 1½ ounces (as MK-4) 2 3
Milk, 2%, 1 cup (as MK-4) 1 1
Salmon, sockeye, cooked, 3 ounces (as MK-4) 0.3 0
Shrimp, cooked, 3 ounces (as MK-4) 0.3 0

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin K is 80 mcg for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin K content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Databaseexternal link disclaimer website [16] lists the nutrient content of many foods and provides comprehensive lists of foods containing vitamin K (phylloquinone) arranged by nutrient content and by food name, and of foods containing vitamin K (MK-4) arranged by nutrient content and food name.

Dietary supplements

Vitamin K is present in most multivitamin/multimineral supplements, typically at values less than 75% of the DV [17]. It is also available in dietary supplements containing only vitamin K or vitamin K combined with a few other nutrients, frequently calcium, magnesium, and/or vitamin D. These supplements tend to have a wider range of vitamin K doses than multivitamin/mineral supplements, with some providing 4,050 mcg (5,063% of the DV) or another very high amount [17].

Several forms of vitamin K are used in dietary supplements, including vitamin K1 as phylloquinone or phytonadione (a synthetic form of vitamin K1) and vitamin K2 as MK-4 or MK-7 [17]. Few data are available on the relative bioavailability of the various forms of vitamin K supplements. One study found that both phytonadione and MK-7 supplements are well absorbed, but MK-7 has a longer half-life [18].

Menadione, which is sometimes called “vitamin K3,” is another synthetic form of vitamin K. It was shown to damage hepatic cells in laboratory studies conducted during the 1980s and 1990s, so it is no longer used in dietary supplements or fortified foods [3].

Vitamin K Intakes and Status

Most U.S. diets contain an adequate amount of vitamin K [7]. Data from the 2011–2012 National Health and Nutrition Examination Survey (NHANES) show that among children and teens aged 2–19 years, the average daily vitamin K intake from foods is 66 mcg [19]. In adults aged 20 and older, the average daily vitamin K intake from foods is 122 mcg for women and 138 mcg for men. When both foods and supplements are considered, the average daily vitamin K intake increases to 164 mcg for women and 182 mcg for men.

Some analyses of NHANES datasets from 2003–2006 and 2007–2010 raised concerns about average vitamin K intakes because only about one-third of the U.S. population had a vitamin K intake above the AI [20,21]. The significance of these findings is unclear because the AI is only an estimate of need, especially for vitamins (like vitamin K) that are also synthesized endogenously. Moreover, reports of vitamin K deficiency in adults are very rare [3,7]. Finally, food composition databases provide information primarily on phylloquinone; menaquinones—either dietary or from bacterial production in the gut—likely also contribute to vitamin K status [1,6,7].

Vitamin K Deficiency

Vitamin K deficiency is only considered clinically relevant when prothrombin time increases significantly due to a decrease in the prothrombin activity of blood [3,7]. Thus, bleeding and hemorrhage are the classic signs of vitamin K deficiency, although these effects occur only in severe cases. Because vitamin K is required for the carboxylation of osteocalcin in bone, vitamin K deficiency could also reduce bone mineralization and contribute to osteoporosis [22].

Vitamin K deficiency can occur during the first few weeks of infancy due to low placental transfer of phylloquinone, low clotting factor levels, and low vitamin K content of breast milk [7]. Clinically significant vitamin K deficiency in adults is very rare and is usually limited to people with malabsorption disorders or those taking drugs that interfere with vitamin K metabolism [3,7]. In healthy people consuming a varied diet, achieving a vitamin K intake low enough to alter standard clinical measures of blood coagulation is almost impossible [3].

Groups at Risk of Vitamin K Inadequacy

The following groups are among those most likely to have inadequate vitamin K status.

Newborns not treated with vitamin K at birth

Vitamin K transport across the placenta is poor, increasing the risk of vitamin K deficiency in newborn babies [3]. During the first few weeks of life, vitamin K deficiency can cause vitamin K deficiency bleeding (VKDB), a condition formerly known as “classic hemorrhagic disease of the newborn.” VKDB is associated with bleeding in the umbilicus, gastrointestinal tract, skin, nose, or other sites [7,23,24]. VKDB is known as “early VKDB” when it occurs in the first week of life. “Late VKDB” occurs at ages 2–12 weeks, especially in exclusively breastfed infants due to the low vitamin K content of breast milk or in infants with malabsorption problems (such as cholestatic jaundice or cystic fibrosis) [7]. VKDB, especially late VKDB, can also be manifested as sudden intracranial bleeding, which has a high mortality rate [7,24]. To prevent VKDB, the American Academy of Pediatrics recommends the administration of a single, intramuscular dose of 0.5 to 1 milligram (mg) vitamin K1 at birth [23].

People with malabsorption disorders

People with malabsorption syndromes and other gastrointestinal disorders, such as cystic fibrosis, celiac disease, ulcerative colitis, and short bowel syndrome, might not absorb vitamin K properly [3,5,22]. Vitamin K status can also be low in patients who have undergone bariatric surgery, although clinical signs may not be present [25]. These individuals might need monitoring of vitamin K status and, in some cases, vitamin K supplementation.

Vitamin K and Health

This section focuses on two conditions in which vitamin K might play a role: osteoporosis and coronary heart disease.

Osteoporosis

Osteoporosis, a disorder characterized by porous and fragile bones, is a serious public health problem that affects more than 10 million U.S. adults, 80% of whom are women. Consuming adequate amounts of calcium and vitamin D, especially throughout childhood, adolescence, and early adulthood, is important to maximize bone mass and reduce the risk of osteoporosis [26]. The effect of vitamin K intakes and status on bone health and osteoporosis has been a focus of scientific research.

Vitamin K is a cofactor for the gamma-carboxylation of many proteins, including osteocalcin, one of the main proteins in bone [27]. Some research indicates that high serum levels of undercarboxylated osteocalcin are associated with lower bone mineral density [5,27]. Some, but not all, studies also link higher vitamin K intakes with higher bone mineral density and/or lower hip fracture incidence [28-33].

Although vitamin K is involved in the carboxylation of osteocalcin, it is unclear whether supplementation with any form of vitamin K reduces the risk of osteoporosis. In 2006, Cockayne and colleagues conducted a systematic review and meta-analysis of randomized controlled trials that examined the effects of vitamin K supplementation on bone mineral density and bone fracture [34]. Most of the trials were conducted in Japan and involved postmenopausal women; trial duration ranged from 6 to 36 months. Thirteen trials were included in the systematic review, and 12 showed that supplementation with either phytonadione or MK-4 improved bone mineral density. Seven of the 13 trials also had fracture data that were combined in a meta-analysis. All of these trials used MK-4 at either 15 mg/day (1 trial) or 45 mg/day (6 trials). MK-4 supplementation significantly reduced rates of hip fractures, vertebral fractures, and all nonvertebral fractures.

A subsequent clinical trial found that MK-7 supplementation (180 mcg/day for 3 years) improved bone strength and decreased the loss in vertebral height in the lower thoracic region of the vertebrae in postmenopausal women [35]. Other randomized clinical trials since the 2006 review by Cockayne et al. have found that vitamin K supplementation has no effect on bone mineral density in elderly men or women [36,37]. In one of these studies, 381 postmenopausal women received either 1 mg phylloquinone, 45 mg MK-4, or placebo daily for 12 months [37]. All participants also received daily supplements containing 630 mg calcium and 400 IU vitamin D3. At the end of the study, participants receiving either phylloquinone or MK-4 had significantly lower levels of undercarboxylated osteocalcin compared to those receiving placebo. However, there were no significant differences in bone mineral density of the lumbar spine or proximal femur among any of the treatment groups. The authors noted the importance of considering the effect of vitamin D on bone health when comparing the results of vitamin K supplementation studies, especially if both vitamin K and vitamin D (and/or calcium) are administered to the treatment group but not the placebo group [37]. The administration of vitamin D and/or calcium along with vitamin K could partly explain why some studies have found that vitamin K supplementation improves bone health while others have not.

In Japan and other parts of Asia, a pharmacological dose of MK-4 (45 mg) is used as a treatment for osteoporosis [5]. The European Food Safety Authority has approved a health claim for vitamin K, noting that “a cause and effect relationship has been established between the dietary intake of vitamin K and the maintenance of normal bone” [38]. The FDA has not authorized a health claim for vitamin K in the United States.

Coronary heart disease

Vascular calcification is one of the risk factors for coronary heart disease because it reduces aortic and arterial elasticity [39]. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that may play a role in the prevention of vascular calcification [5,40]. Although the full biological function of MGP is unclear, a hypothesis based on animal data suggests that inadequate vitamin K status leads to undercarboxylated MGP, which could increase vascular calcification and the risk of coronary heart disease. These findings might be particularly relevant for patients with chronic kidney disease because their rates of vascular calcification are much higher than those of the general population [9].

In an observational study conducted in the Netherlands in 564 postmenopausal women, dietary menaquinone (but not phylloquinone) intake was inversely associated with coronary calcification [41]. Menaquinone intake was also inversely associated with severe aortic calcification in a prospective, population-based cohort study involving 4,807 men and women aged 55 years and older from the Netherlands [40]. Participants in this study who had dietary menaquinone intakes in the mid tertile (21.6–32.7 mcg/day) and upper tertile (>32.7 mcg/day) also had a 27% and 57% lower risk of coronary heart disease mortality, respectively, than those in the lower tertile of intake (<21.6 mcg/day). Phylloquinone intake had no effect on any outcome.

Despite these data, few trials have investigated the effects of vitamin K supplementation on arterial calcification or coronary heart disease risk. One randomized, double-blind clinical trial examined the effect of phylloquinone supplementation in 388 healthy men and postmenopausal women aged 60–80 years [42]. Participants received either a multivitamin (containing B-vitamins, vitamin C, and vitamin E) plus 500 IU vitamin D3, 600 mg calcium, and 500 mcg phylloquinone daily (treatment) or a multivitamin plus calcium and vitamin D3 only (control) for 3 years. There was no significant difference in coronary artery calcification between the treatment and control groups. However, among the 295 participants who adhered to the supplementation protocol, those in the treatment group had significantly less coronary artery calcification progression than those in the control group. Furthermore, among those with coronary artery calcification at baseline, phylloquinone treatment reduced calcification progression by 6% compared to the control group. Based on these findings, the authors did not make any clinical recommendations, and they called for larger studies in other populations.

At this time, the role of the different forms of vitamin K on arterial calcification and the risk of coronary heart disease is unclear, but it continues to be an active area of research in the general population and in patients with chronic kidney disease [5,9,43].

Health Risks from Excessive Vitamin K

The FNB did not establish ULs for vitamin K because of its low potential for toxicity [3]. In its report, the FNB stated that “no adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals.”

Interactions with Medications

Vitamin K interacts with a few medications. In addition, certain medications can have an adverse effect on vitamin K levels. Some examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin K status with their health care providers.

Warfarin (Coumadin®) and similar anticoagulants

Vitamin K can have a serious and potentially dangerous interaction with anticoagulants such as warfarin (Coumadin®), as well as phenprocoumon, acenocoumarol, and tioclomarol, which are commonly used in some European countries [