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Is there evidence to suggest that nutrients in vitamin capsules are not as readily absorbed as the same nutrients in whole foods?

Is there evidence to suggest that nutrients in vitamin capsules are not as readily absorbed as the same nutrients in whole foods?



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I recently fell ill with a cold, and began to take a vitamin C capsule each day to help my immune system. When I noticed no change in my condition, I began to incorporate an abundance of citrus into my diet instead of taking the capsules. When I ate the citrus my condition began to improve markedly.

The ingredients listed by the vitamin manufacturer are:

  • Ascorbic Cellulose Gel
  • Hydroxypropyl Cellulose
  • Croscarmellose Sodium
  • Stearic Acid
  • Magnesium Stearate
  • Silicon Dioxide

Not excluding the possibility of coincidence, I was was intrigued. Has evidence been published to suggest that nutrients in whole foods like vitamin C in citrus fruits are more readily utilized in the body than nutrients in vitamin capsules?


Vitamin C bioavailability

According to the review Synthetic or Food-Derived Vitamin C-Are They Equally Bioavailable? (Nutrients, 2013), the bioavailability of vitamin C from foods and supplements is similar:

… all steady state comparative bioavailability studies in humans have shown no differences between synthetic and natural vitamin C, regardless of the subject population, study design or intervention used.

and, according to Institute of Medicine (in the US):

The type of food consumed has not been shown to have a significant effect on absorption of either intrinsic or supplemental vitamin C.

Vitamin C supplements as prevention for common cold

Vitamin C supplements, even in doses 200+ mg/day (more than 3 x recommended dietary allowance - RDA) do not likely help in common cold:

This review is restricted to placebo‐controlled trials testing 0.2 g per day or more of vitamin C. Twenty‐nine trial comparisons involving 11,306 participants contributed to the meta‐analysis on the risk ratio (RR) of developing a cold whilst taking prophylactic vitamin C. The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine prophylaxis is not justified. Vitamin C could be useful for people exposed to brief periods of severe physical exercise. (Cochrane, 2007)

To get 200+ mg vitamin C from citruses, you would need to eat at least 3 oranges or 7 lemons.

Considering the above evidence, the improvement of cold symptoms was likely a natural process.

Bioavailability of other nutrients from foods/supplements

There is no general rule to say that nutrients from foods or supplements are absorbed better or worse; it can depend on a specific food and a specific supplement formulation.

Iron:

In our in vitro model, naturally iron-rich mineral waters and synthetic liquid iron formulations have equivalent or better bioavailability compared with ferrous iron sulphate tablets. (European Journal of Nutrition)

Iron-fortified foods:

Bioavailability of fortification iron varies widely with the iron compound used (56), and foods sensitive to color and flavor changes are usually fortified with water-insoluble iron compounds of low bioavailability. Iron compounds recommended for food fortification by the World Health Organization (WHO) (56) include ferrous sulfate, ferrous fumarate, ferric pyrophosphate, and electrolytic iron powder. Many cereal foods, however, are fortified with low-cost elemental iron powders, which are not recommended by WHO (57) and these have even lower bioavailability (AJCN, 2010).

Magnesium:

The results of serum and urine analysis indicated that Mg bioavailability was comparable for mineral waters with different mineralization levels, bread, and a dietary supplement. (Tandofline, 2017)

Mg supplements comparison:

Studies on the bioavailability of different magnesium salts consistently demonstrate that organic salts of magnesium (e.g., Mg citrate) have a higher bioavailability than inorganic salts (e.g., Mg oxide) (Nutrients, 2019)

Potassium:

The bioavailability of potassium is as high from potatoes as from potassium gluconate supplements. (AJCN, 2016)

In conclusion, even if most studies mentioned in this answer suggest that nutrients from foods and supplements are equally bioavailable, you need to check specific supplement formulations, for example, iron from many fortified foods and magnesium oxide can have poor bioavailability. Anyway, the studies show that most people with normal blood nutrient levels do not need dietary supplements (Int J. Prev. Med., 2012 ; Annals of Internal Medicine, 2014).


The answer probably varies for different nutrients. An informal article by ConsumerLab.com indicates that many vitamins are better absorbed from natural sources, but a few are actually more readily absorbed from supplements.

Looking at Vitamin C specifically, a 2013 review article by Carr and Vissers concluded as follows (emphasis mine):

Overall, a majority of animal studies have shown differences in the comparative bioavailability of synthetic versus food-derived vitamin C, or vitamin C in the presence of isolated bioflavonoids, although the results varied depending on the animal model, study design and body compartments measured. In contrast, all steady state comparative bioavailability studies in humans have shown no differences between synthetic and natural vitamin C, regardless of the subject population, study design or intervention used. Some pharmacokinetic studies in humans have shown transient and small comparative differences between synthetic and natural vitamin C, although these differences are likely to have minimal physiological impact.

In other words, with vitamin C natural and synthetic sources appear to be equally bioavailable for humans. The authors do note that "Although synthetic and food-derived vitamin C appear to be equally bioavailable in humans, ingesting vitamin C as part of a whole food is considered preferable because of the concomitant consumption of numerous other macro- and micronutrients and phytochemicals, which will confer additional health benefits."

References:

  • Carr, Anitra C.; Vissers, Margreet C. M. (2013). "Synthetic or food-derived vitamin C-Are they equally bioavailable?". Nutrients 11 (5). pp. 4284-4304. doi:10.3390/nu5114284. PMC 3847730.

This is not a coincidence. Food-sourced vitamins are prized because of being in bio-available form, soluble and absorbable. The only way to make a vitamin more absorbable is to deliver it elementally, with no digestion required at all.

The best absorption rates are through sublingual administration of elemental sprays, no additives,no fillers, nothing except what your body needs for maintenance and repairs. There is a 2011 review of research here:

http://www.ijplsjournal.com/issues%20PDF%20files/nov2011/10.pdf


Sunlight and Vitamin D: They’re Not the Same Thing

ARTICLE SUMMARY
• Sulfate synthesis in the skin captures the sun’s energy. Adequate sunlight exposure to both the skin and the eyes is vital to our long-term health.
• Among other functions, sulfate supports blood vessel health, the body’s electrical supply and the delivery system for important molecules such as cholesterol, vitamin D, dopamine and melatonin.
• Evidence indicates that sunlight protects against cancer, heart disease, hypertension and bone fractures.
• The benefits of sunlight exposure are about much more than vitamin D.
• Many studies show that vitamin D supplementation cannot reproduce sunlight’s health benefits. Moreover, excessive vitamin D supplementation can aggravate systemic sulfate deficiency, which will drive calcium buildup in the arteries.
• Both sunscreen and glyphosate interfere with synthesis and production of melanin—the body’s natural mechanism of sun protection. Aluminum in sunscreen disrupts sulfate synthesis. These disruptions may explain why melanoma prevalence has steadily risen in tandem with the increased use of higher sun-protection-factor sunscreens over the past two decades.

We have been brainwashed into believing that the sun is toxic, whereas in fact it is life-giving. I am a great fan of sunlight exposure to both the skin and the eyes. The sun has been a resource for Planet Earth since the beginning of time, and biological organisms evolved with a constant supply of energy they could count on every day with the rising sun. Plants use the energy of sunlight to convert inorganic carbon into organic matter, with the help of chlorophyll. Why would animals ignore such an obvious energy source? Just as plants need sun­light to grow, sunlight plays an essential role in energizing animals, including humans.

I believe that the mechanism with which we safely exploit the sun’s energy is through the oxidation of sulfur to sulfate, with the help of choles­terol. This reaction takes place in the skin—catalyzed by sunlight—and it is vital to our long-term health.

PROTECTIVE SUNLIGHT

People who live in places with little sun have statistically higher risk for many chronic conditions, including multiple sclerosis, diabe­tes, cardiovascular disease, autism, Alzheimer’s disease and age-related macular degeneration. 1 On the other hand, a great deal of epidemio­logical evidence suggests that sunlight exposure protects from many different types of cancer. Ultraviolet (UV) radiation is recommended in treating different skin conditions, including pso­riasis, eczema, jaundice and acne. Sunlight may also be beneficial in healing various autoim­mune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and thyroiditis.

Yet chances are that your dermatologist has told you to “stay out of the sun and take a vitamin D supplement every day.” For some, this has seemed like good advice because we have been taught to believe that the sun causes skin cancer and that the only reason to get out in the sunlight at all is to boost vitamin D levels through its UV-stimulated synthesis in the skin. Driven by the belief that the benefits of sunlight exposure are mainly due to vitamin D synthesis, the natural conclusion is that vitamin D supple­ments would achieve the same goal.

The story is not that simple, however. When placebo-controlled studies are conducted on vi­tamin D supplementation, they usually produce disappointing results. I believe the reason is that sunlight exposure is about a whole lot more than vitamin D synthesis in the skin. In a paper published in 2016, Richard Weller wrote: “A substantial body of evidence shows that sunlight has health benefits and that these are independent of vitamin D and thus cannot be reproduced by oral supplementation.” 2

THE ROLE OF SULFATE

Those who are familiar with my research know that I believe that keratinocyte cells in the skin, endothelial cells lining the walls of surface veins and red blood cells are able to exploit the energy in sunlight by oxidizing hydrogen sulfide to make sulfate. 3 In the skin, the sulfate is conjugated with both vitamin D and cholesterol, and this makes these otherwise water-insoluble sulfate molecules water-soluble. This greatly facilitates their transport in the blood, because they no longer have to be enclosed inside lipid particles like high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Sunlight exposure thus produces cholesterol sulfate as well as vitamin D sulfate, and it is the cholesterol sulfate that offers many of the benefits that are seen epidemiologically in sunny places. In fact, I believe that systemic sulfate deficiency is a key driver behind many chronic diseases that are on the rise in indus­trialized nations.

The sulfate that is produced in response to sunlight also supplies sulfate to the glycocalyx, the mesh of extracellular matrix glycoproteins that line the walls of all blood vessels. Red blood cells hand off cholesterol sulfate to the endothelial cells as they traverse the capillaries, and both the cholesterol and the sulfate are of vital importance to the endothelial cell’s health. The endothelial cells also can incorporate the sulfate they synthesize themselves directly into the glycocalyx.

Sulfate in the glycocalyx helps to maintain the structured water in the exclusion zone, a layer of gelled water that coats the surface of all the blood vessels. Not only does the gel protect the blood vessel wall from oxidative and glycation damage, but it also provides a slick surface for frictionless traversal of the capillary by the red blood cells. And perhaps most importantly, it carries a negative charge, creating a battery that is likely the main source of electricity for the body. Light—and most es­pecially infrared light—causes the exclusion zone water layer to expand dramatically, by as much as a factor of four. 4 The electricity held in the battery grows in direct correspondence. Professor Gerald Pollack from the University of Washington in Seattle has popularized much of this story in his book, Cells, Gels and the Engines of Life. 5

SUNSCREEN USE AND MELANOMA—BOTH RISING

Most Americans rely heavily on sunscreen if they are outside for an extended period. Mothers well-trained by conventional messaging slather sunscreen on their children every few hours during a day at the beach, believing that this will keep their children safe from skin cancer, with no down side. Americans strongly believe that they are protecting themselves from skin cancer through this practice, but, in fact they may be increasing their risk of skin cancer. Sunscreen interferes with the body’s natural mechanisms of sun protection, which have been perfected over hundreds of millions of years of life’s evolution on earth.

Given the quantity of advertising urging us to use sunscreen, people probably assume that there is plenty of evidence that sunscreen protects from skin cancer. If this is true, then it is hard to explain why melanoma prevalence has been steadily rising in tandem with the increased use of higher and higher sun-protection-factor (SPF) sunscreens over the past two decades. A study published in 2009, which analyzed almost three hundred million person-years of data over more than a ten-year period, concluded that the rate of skin melanoma increased by 3.1 percent per year from 1992 to 2004 in the United States. 6 A population-based study published in 2019—involving twelve thousand four hundred sixty-two cases of head and neck melanoma in the U.S. and Canada from 1995 to 2014—found that this type of cancer had increased by 51 percent over the two decades, with males aged fifteen to thirty-nine years being the population group most strongly affected. 7 Meanwhile, the market value of sun protection products increased from $940 million in 2006 to $1.6 billion in 2016.

As far back as 1996, researchers published a paper that investigated whether sunscreen protects from skin cancer. The authors wrote: “Our results support the hypothesis that sunscreens do not protect against melanoma, probably because of their ability to delay or avoid sunburn episodes, which may allow prolonged exposure to unfiltered ultraviolet radiation.” 8 In other words, sunscreen gives you the illusion that you are safe because you don’t feel the pain or experience the skin redness that naturally happens when your body is letting you know it’s time to get out of the sun. Your skin is getting damaged by too much UV radiation, but the signal that would stop the exposure is missing.

MORE PROBLEMS WITH SUNSCREEN

Worse than this, in my opinion, is that sunscreen disrupts the body’s natural mechanism of sun protection: melanin synthesis. Melanin is produced in response to sunlight exposure. Sun­screen protection lasts only while the sunscreen is topically present melanin, on the other hand, builds up over time and eventually produces a healthy tan with protection that can last for weeks or even months. The smart way to protect yourself from the potential damage of UV rays is to develop a tan slowly during the spring while the sun is not so intense—this arms you with a defense against the intense summer sun that would otherwise be dangerous. As melanin’s powerful antioxidant effects protect you from the UV rays, you can still enjoy the many health benefits of visible light and infrared light, far beyond what you would get from a vitamin D supplement.

Sunscreens contain toxic ingredients that cause damage to the skin in ways that might re­sult in sustained disruption of sulfate synthesis. 9 Particularly disturbing is the aluminum that is added to emulsify the zinc oxide and titanium dioxide additives (the active ingredients). Alu­minum is known to suppress cytochrome P450 enzymes (CYP enzymes). The enzyme that I propose as crucial for sulfate synthesis—en­dothelial nitric oxide synthase (eNOS)—is an orphan CYP enzyme.

I believe that glyphosate, the active ingre­dient in the pervasive herbicide Roundup, also disrupts eNOS. It is known to suppress CYP enzymes in the liver in rat studies. Worse than this, glyphosate interferes with the shikimate pathway in the gut microbes, which is essential for producing the aromatic amino acids. 10 One of these, tyrosine, is a precursor to melanin. Thus, glyphosate likely induces melanin deficiency, which prevents you from developing a healthy tan and, therefore, interferes with natural protec­tive mechanisms against UV damage.

MELANOMA, SUN EXPOSURE AND VITAMIN D

Instinctively, most people who are diag­nosed with skin melanoma make special efforts to avoid the sun following their diagnosis— which is probably a very bad idea. Remarkably, increased sun exposure, more frequent sunburns and solar elastosis (evidence of photo-aging in the skin) were all associated with improved survival statistics in a study of five hundred twenty-eight patients diagnosed with cutaneous melanoma. 11

It has seemed logical to many that the benefit of increased sun exposure must be due to the rise in vitamin D levels induced by sun exposure. Indeed, vitamin D deficiency at the time of diagnosis is associated with a worse prognosis in melanoma. 12 Patients with stage IV melanoma had a twofold worse prognosis if they suffered from vitamin D deficiency at diagnosis. Furthermore, those who began with vitamin D deficiency and whose vitamin D levels either fell or increased by no more than twenty ng/mL had a hazard ratio of 4.68 (meaning a higher risk) compared to patients who were not deficient initially and whose vitamin D increased by more than twenty ng/mL over time.

However, a large placebo-controlled study involving over thirty-six thousand postmeno­pausal women compared women who were supplemented with four hundred IU of vitamin D3 and one thousand mg of elemental calcium— every day for seven years—with controls given a placebo. 13 Rates of skin melanoma and non-melanoma skin cancer were monitored over the seven-year period. There was no difference in rates of either benign or malignant cancers between the two groups. This strongly suggests that vitamin D is not the reason for the improved melanoma survival with sun exposure.

MELANIN, INFRARED LIGHT AND SKIN CANCER

Melanin is able to transform 99.9 percent of absorbed sunlight into heat, and this greatly reduces the skin cancer risk. It also enhances the amount of infrared you can receive from the sun.

A fascinating 2017 study experimented with a novel idea to protect mice from skin cancer. 14 It involved a new technique to treat melanoma skin cancer using a transdermal skin patch, infrared light and melanin. Melanoma tumor cells pro­duce high amounts of melanin. The researchers created a skin patch from ruptured melanoma cells, which they applied to the skin of mice (as a source of melanin). They compared three groups of mice: the controls, mice with only the patch and mice with the patch plus infrared light exposure. When the researchers subsequently injected viable melanoma cells into all three groups to induce skin cancer, 100 percent of the control group succumbed to melanoma cancer within a two-month period. Among the mice with the skin patch, only 13 percent survived. Remarkably, mice who received both the infrared light and the patch were all still living after two months, and 87 percent had no tumors. One wonders what would have happened with only infrared and no patch!

SUNLIGHT, VITAMIN D SUPPLEMENTS AND CANCER

In the following sections, I will address evidence that sunlight is protective against four distinct diseases and conditions: cancer, heart disease, hypertension and bone fractures. In each case, studies have shown that vitamin D supplements cannot replace these benefits of sunlight.

As far back as 1980, epidemiological studies showed an inverse geographical relationship between the amount of solar radiation and mortality rates for colon cancer. 15 In the forty years since then, numerous studies have shown that a high serum level of vitamin D is associated with reduced cancer risk for diverse types of cancer. A review paper published in 2018 with one hundred forty references revealed that those with higher serum vitamin D have an improved odds ratio protecting against developing brain, cervical, endometrial, esophageal, ovarian, thyroid and head and neck cancers as well as gastric adenocarcinoma, hepatocellular carcinoma and lymphoma. 16 Moreover, for many types of cancer, those with higher serum vitamin D at the time of cancer diagnosis have statistically improved survival times.

Given all of this evidence for an association between serum vitamin D levels and cancer protection, it seems obvious that vitamin D supple­mentation should be protective against cancer. However, a large placebo-controlled study published in 2019 by more than fifteen authors obtained disappointing results. 17 The study monitored over twenty-five thousand participants over a five-year period, restricting the study population to men over fifty years old and women over fifty-five years old but including participants from various places across the United States. In the group that received vitamin D (two thousand IU per day), supplementation did not lower the incidence of invasive cancer or of cardiovascular events, compared to the placebo group.

SUNLIGHT AND CARDIOVASCULAR DISEASE

Researchers have long been aware that there is a direct relationship, epidemiologically, between cardiovascular disease and latitude. People who live at high latitudes have significantly higher rates of heart disease than those nearer the equator. 18 Furthermore, more people suffer from heart attacks in the winter than in the summer, in both northern and southern latitudes. 19

We have already seen that a large placebo-controlled study did not find any benefit in vitamin D supplementation for heart disease risk. A study based in India is one of very few controlled studies where the researchers compared vitamin D supplementation to sunlight exposure. The study involved one hundred men who had been diagnosed with severe vitamin D deficiency. 20 Half of them were prescribed supplemental vita­min D (one thousand IU/day), and the other half were advised to spend at least twenty minutes out in the sunlight every day at midday. Both groups saw an increase in their serum vitamin D levels, but, remarkably, the two approaches had opposite effects on serum cholesterol. Those exposed to sunlight saw a statistically significant drop in their total cholesterol, and those taking the supplement saw a statistically significant increase.

This makes sense to me because vitamin D supplements are fat-soluble, which means they require the liver to synthesize cholesterol and release LDL particles in order to transport the vitamin D. Sunlight exposure stimulates cholesterol sulfate synthesis in the skin, and the sulfate moiety makes the molecule water-soluble. 3 This means that it can be transported in the blood without being packaged up inside an LDL particle. Because it is both water-soluble and fat-soluble, cholesterol sulfate can easily traverse water-based media to be transferred from the membrane of a cell in the skin to the membrane of an HDL particle or a red blood cell, and it can also easily be transferred to a tissue cell in need of additional cholesterol. Hence, sulfation induced by sunlight promotes efficient delivery of cholesterol to the tissues without the need for LDL carrier particles. These ideas are schematized in Figure 1.

Calcitriol is the 1,25(OH)-D3 that is usually produced by CYP en­zymes in the kidney, and it is the “active form” of vitamin D. Kidney failure can derail this process, and so patients with kidney failure are often given calcitriol as a supplement. However, a study published in 2006 found it counterproductive for young adults with childhood-onset end-stage renal disease to be given calcitriol supplementation, because calcitriol is taken up by cells in the artery wall and leads to increased artery calcification. 21

Basically, vitamin D mobilizes calcium but doesn’t control where calcium goes. I believe that sulfate deficiency in the vasculature drives a conversion of the smooth muscle cells into bone-like cells, and this causes them to actively take up calcium and phosphate. Vitamin D supplements will encourage them to do this faster. Artery calcification is one of the strongest risk factors for cardiovascular disease.

HIGH BLOOD PRESSURE

A 2016 paper aptly titled “Sunlight has car­diovascular benefits independently of vitamin D” argued that sunlight is a therapy option for high blood pressure, an important risk factor for cardiovascular disease. 2 In the paper, a scatter plot showing mean male population blood pres­sure versus central latitude for a large number of countries (reproduced here as Figure 2) dem­onstrated a clear linear relationship. The author argued that the reduction in blood pressure is due to sunlight’s stimulation of the release of nitric oxide from the skin.

Nitric oxide (NO) is a well-known “gaso­transmitter,” a gaseous signaling molecule that has a remarkable ability to induce a relaxation of the artery wall and a resulting drop in blood pressure. Endothelial dysfunction linked to car­diovascular disease is associated with impaired production of NO from arginine by eNOS, and it causes high blood pressure. 22 Researchers have recently become aware that the skin is somehow able to release nitric oxide in response to sunlight exposure. Exactly where the NO comes from is somewhat of a mystery because it has become clear that it is not a result of direct synthesis by eNOS. 23

A clue comes from the fact that glutathione reacts with nitric oxide to produce S-nitrosoglutathione (GSNO), which I believe serves as a temporary storage form of NO. Almost miraculously, visible light (green, blue and purple) can catalyze the release of NO from glutathione. 24 Not only does this cause a relaxation of the blood vessels, but it also frees up glutathione to react with hydrogen sulfide gas to produce sulfate.

As illustrated in Figure 3, glutathione reacts with reduced sulfur to form glutathione persulfide (GSSH), and this can catalyze the oxidation of the extra sulfur atom to sulfur dioxide in the presence of superoxide. eNOS binds to flavins that respond to visible light by releasing electrons that convert oxygen to superoxide. The sulfur dioxide produced by eNOS is then oxidized to sulfate by sulfite oxidase. What this means is that the visible light in sunlight is crucial both for the release of NO from the skin and the synthesis of sulfate in the skin—and both of these results are crucial aspects of the beneficial effects of sunlight exposure.

Note that eNOS is a “moonlighting” enzyme. As described at length in a paper I published with colleagues in 2015, 25 eNOS is able to switch between two synthesized products: nitric oxide and sulfur dioxide, de­pending on electromagnetic signaling that it receives from the circulating red blood cells.

These results might prompt medical professionals to advise people in higher latitudes to take a vitamin D supplement. However, as we by now can guess, a large study on vitamin D supplements and hip fractures gave disappointing results. 26 The study involved women over seventy years old who had at least one self-reported risk factor for hip fracture (low body weight, previous fracture, maternal history of hip fracture, smoker or poor health in general). 27 The intervention involved daily oral supplementation with one thousand mg of calcium and eight hundred IU of vitamin D3. However, to reduce the risk of vitaminosis D, the study excluded women who took calcium supplements, as well as women with a history of bladder or kidney stones, renal failure or hypercalcemia. Despite the near-ideal experimental setup, after a median follow-up period of twenty-five months, there was no significant difference between fractures in the treatment group compared to the control group.

Another three-year study compared three different doses of vitamin D—four hundred IU/day, four thousand IU/day and ten thousand IU/day—specifically looking at bone density. Surprisingly, those on the highest dosage had a statistically significantly worse outcome in terms of bone mineral density. 28 I would argue that systemic sulfate deficiency drives calcium into the arteries, leaching it from the bones— and excessive vitamin D increases the rate at which this happens.

SUNLIGHT AND THE EYES

Sunglass marketing ads have trained us to wear sunglasses whenever we go outside, ostensibly to protect our eyes from damaging UV rays. However, melanin—which gives your eyes their blue, hazel, green or brown color—already protects them from UV rays. In fact, the human eye has evolved to deal naturally with sun exposure through antioxidant protection by melanin, as well as other antioxidant-defense systems based on glutathione and the enzyme superoxide dis­mutase (SOD). I believe it is crucial to get adequate sunlight exposure to the eyes, not just for the sake of eye health but also because critical nuclei in the brain stem make good use of light that enters through the eyes.

THE PINEAL GLAND AND SLEEP DISORDERS

The pineal gland sits behind the eyes, and it can easily receive light that enters through the eyes. It plays an important role in circadian rhythms and promotes restful sleep by synthesizing large amounts of melatonin as the light fades in the evening. The melatonin is conjugated with sulfate and shipped out into the cerebrospinal fluid at night. In a paper published together with Wendy Morley, I have argued that melatonin supplies sulfate to the neurons in the brain at night and that this supports activities during sleep to break down and recycle cellular debris. 29

During the daytime, a sulfotransferase enzyme is sharply upregulated in the pineal gland, and it increases the amount of sulfate in the glycos­aminoglycans (GAGs) in the intercellular spaces of the pineal gland. 30 From this, we can infer that sunlight catalyzes sulfate synthesis in the pineal gland, and, indeed the cells there express eNOS. The sulfate built up by day can be extracted from the matrix and conjugated to melatonin in the evening to maintain the brain’s supply of this critical nutrient.

THE SUBSTANTIA NIGRA AND PARKINSON’S DISEASE

Parkinson’s disease (PD) is a relatively common progressive neu­rological disease manifested as a movement disorder, associated with tremors, stiffness and slowed movement. It is caused by a loss of neurons in the substantia nigra (“black substance”), a dark structure in the midbrain where dopa­mine is synthesized. The dark color is due to substantial production of neuromelanin, a close relative to the skin-tanning agent, melanin. De­pigmentation of the substantia nigra due to loss of neuromelanin is a hallmark feature of PD. 31

Studies that have measured serum vitamin D levels have found significant differences in PD patients versus controls. One study that compared one hundred eighty-six PD patients with non-PD controls revealed that the PD patients had significantly lower bone density as well as significantly lower serum vitamin D levels compared to controls. 32 Another study, based in China, compared two hundred one newly-diagnosed PD patients with one hundred ninety-nine controls and likewise found that low serum vitamin D was linked to Parkinson’s. 33 The Chinese study also used a questionnaire to determine whether the study participants took vitamin D supplements and how much sun exposure they obtained. The frequency of Parkinson’s disease in the group in the highest quartile of sun exposure was only half of the rate for those in the lowest quartile. Interestingly, serum vitamin D levels were highly correlated with degree of sun exposure but not with vita­min D supplementation.

One way in which sun exposure may be beneficial in Parkinson’s is through exposure to the eyes! Bright-light therapy has been shown to benefit PD patients, improving sleep, mood and also motor function. 34 A remarkable study on rats was able to measure the amount of light reaching the mesencephalon (the midbrain, which houses the substantia nigra) when light was shone on the eyes. 35 They observed a sharp peak at around seven hundred ten nanometers, which is in the range of infrared light. It is likely that sunlight stimulates the synthesis of neuromelanin, just as it stimulates the synthesis of melanin in the skin. The neuromelanin then likely protects the dopaminergic neurons from oxidative damage by mopping up free radicals.

Gerald Pollack’s research on structured “exclusion zone” water has shown that infrared light is very effective in growing the exclusion zone size by as much as a factor of four. This will increase the mobilization of electrons (electricity) needed to oxidize oxygen and ultimately form sulfate, assisted by eNOS and sulfite oxidase. The sulfate is of direct benefit to form dopamine sulfate—the water-soluble form of dopamine that is easily transported and delivered to dopamine receptors. This story has parallels to the story regarding cholesterol sulfate in the skin.

Sunlight has been an important source of energy for Planet Earth since its inception. Plants have learned how to use the energy in sunlight to create organic matter, and I believe that animals have exploited sunlight as a source of energy for movement and for cognition.

Sulfate synthesis in the skin is a powerful way to capture the sun’s energy (see Figure 4). Sulfate’s diverse roles in the body are essential for good health, and particularly for maintaining a healthy vasculature, an electrical supply to the body and an efficient delivery system for sulfate-conjugated biologically active molecules—such as cholesterol, vitamin D, dopamine and melatonin. Sunlight also offers natural protection from the harsh summer sun through the production of melanin in the skin. Vitamin D supplements, on the other hand, send the tissues a false signal that cholesterol sulfate is plentiful. Sun exposure is important not just to the skin but also to the eyes, and, perhaps more crucially, to the structures in the brain stem behind the eyes that control circadian rhythms (pineal gland) and movement (substantia nigra).

When I tell people that I worship the sun, they often respond with something like, “Yes, I am aware of all the myriad health benefits of vitamin D.” Then I have to explain that, no, it is not about vitamin D. It is about something vastly more important. Researchers are frustrated be­cause they see that high serum vitamin D is associated with many health benefits, yet when they conduct placebo-controlled studies on vitamin D supplements, they consistently yield discouraging results. And when those diagnosed with skin cancer becomes intent on avoiding the sun, they worsen their prognosis.

Besides sunlight exposure, some foods naturally provide vitamin D and cholesterol sulfate, and these can be very important for people living in northern latitudes. I suspect that eating lots of seal blubber (an excellent source of both vitamin D and cholesterol sulfate) helped the Eskimos get by. Other sources are raw milk and butter from grass-fed cows, organic lard, wild-caught fatty fish like salmon and cod liver oil. However, foods artificially supplemented with vitamin D won’t do the trick because they don’t normally contain cholesterol sulfate. It’s also important to eat only certified organic foods to minimize exposure to glyphosate and toxic chemicals that disrupt the body’s ability to utilize sunlight appropriately.

There are other simple measures you can take. One that I recommend is simply taking a bath with half a cup of Epsom salts and the water temperature set as high as you can comfortably stand. The sulfate in the Epsom salts will pen­etrate your skin, with the heat working syner­gistically to increase exclusion zone water. An infrared sauna is another possibility, although there may be some issues with electromagnetic field (EMF) exposure.

One of the very best things that you can do to maintain good health is to walk barefoot in the water along the ocean shore on a sandy beach on a sunny day. The sand and water assure good grounding, providing the negative charge that is so important to mobilize electrons to fuel the structured water in the exclusion zone lining all the blood vessels. In addition, the ocean air is enriched in hydrogen sulfide gas that can easily penetrate the skin.

If you don’t live near the ocean, walking barefoot in the grass is also beneficial. Even in winter when the sun’s rays are not so intense, the infrared light is still nearly as strong as in the summer. And even in cold weather, winter sun­light shining on your face and hands is health-promoting. Sunlight energizes the electrons in the exclusion zone to induce the synthesis of sulfate from sulfide, which in turn, maintains the exclusion zone in a natural feedback loop. This is the electrical supply to the body, and sunlight is its primary source.

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  9. Plourde E. Sunscreens: the dark side of avoiding the sun. Wise Traditions 201819(4):26-37.
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  25. Seneff S, Davidson RM, Lauritzen A, Samsel A, Wainwright G. A novel hypothesis for atherosclerosis as a cholesterol sulfate deficiency syndrome. Theor Biol Med Model 201512:9.
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  28. Burt LA, Billington EO, Rose MS, et al. Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength: a randomized clinical trial. JAMA 2019322(8):736-45.
  29. Morley WA, Seneff S. Diminished brain resilience syndrome: a modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration. Surg Neurol Int 20145:97.
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This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Spring 2020

About Stephanie Seneff, PhD

Stephanie Seneff, PhD received her Bachelor’s degree in Biology with a minor in Food and Nutrition in 1968 from MIT. She received her Master's and PhD degrees in Electrical Engineering and Computer Science in 1979 and 1985, respectively, also from MIT. Since then, she has been a researcher at MIT, where she is currently a Senior Research Scientist in the Department of Electrical Engineering and Computer Science, and a Principal Investigator in the MIT Computer Science and Artificial Intelligence Laboratory. Throughout her career, Dr. Seneff has conducted research in diverse areas including human auditory modeling, spoken dialogue systems, natural language processing, human language acquisition, information retrieval and summarization, computational biology, and marine mammal socialization. She has published over one hundred fifty refereed articles on these subjects, and has been invited to give keynote speeches at several international conferences. She has also supervised numerous Master's and PhD theses at MIT. She has recently become interested in the effect of drugs and diet on health and nutrition, and she has written several essays on the web articulating her view on these topics. She is the first author of two recently published nutrition-related journal papers, one on the metabolic syndrome and one on Alzheimer's disease. Two papers on theories related to cholesterol sulfate are currently under review. Stephanie will give an all-day workshop on metabolism at Wise Traditions 2011.


The fresh food you eat is loaded with nutrients necessary for good health, such as magnesium, calcium, and vitamins A and C. But many older adults aren't getting enough nutrients from their diets.

The typical American diet is heavy in nutrient-poor processed foods, refined grains, and added sugars—all linked to inflammation and chronic disease. Yet even if you eat a healthy, well-balanced diet, you may still fall short of needed nutrients. That's a consequence of aging. "As we get older, our ability to absorb nutrients from food decreases. Also, our energy needs aren't the same, and we tend to eat less," explains Dr. Howard Sesso, an epidemiologist at Harvard-affiliated Brigham and Women's Hospital.

Can a supplement make up the difference? "It's a touchy subject, and you need to look at your individual needs first," says Dr. Sesso.

Evidence about supplements

Dietary supplements would seem to be the obvious way to plug gaps in your diet. But taking too much can actually harm you. For example, you can get too much of a particular nutrient without realizing it. "Extra vitamin A supplements can lead to dangerous, toxic levels if taken too frequently," notes Dr. Clifford Lo, an associate professor of nutrition at the Harvard School of Public Health.

The evidence about the benefits of multivitamins is mixed. Dr. Sesso was a lead researcher in one of the largest studies to date on multivitamins, the Physicians' Health Study II, which found that multivitamins were associated with a small reduction in the risk of cancer and cataracts in men, but did not reduce deaths from heart disease. A study published March 1, 2015, in TheJournal of Nutrition found that a multivitamin with minerals lowered the risk of death from heart disease in women, but not in men. However, a review of a number of studies, published in Annals of Internal Medicine in 2013, found that multivitamins showed no benefit in preventing early death. Because the findings from these and many other studies conflict, the U.S. Preventive Services Task Force doesn't support vitamin and mineral supplements to ward off disease.

What you should do

Both Dr. Sesso and Dr. Lo advise that you try to improve your diet before you use supplements. That's because nutrients are most potent when they come from food. "They are accompanied by many nonessential but beneficial nutrients, such as hundreds of carotenoids, flavonoids, minerals, and antioxidants that aren't in most supplements," says Dr. Lo.

Plus, "food tastes better and is often less expensive than adding supplements," says Dr. Sesso. "Work with a dietitian, and try to get a sense of what's missing from your diet and what changes might be considered."

If you are unable to make dietary changes, or if you have a genuine deficiency in a particular nutrient, such as vitamin D, both doctors say that a supplement may be helpful. Just be careful the manufacture of supplements isn't monitored by the government in the way that the manufacture of pharmaceuticals is—so you can't be sure exactly what you're getting.

Bottom line: "Look for a multivitamin with D and B vitamins (especially folate), iron, magnesium, and calcium," says Dr. Sesso, "and go for a well-known brand that's been around for a long time and is likely well tested."

Good food sources of important nutrients

Found in these foods

Lean beef, turkey, tuna, sunflower seeds, spinach and other
leafy greens, eggs

Salmon, tuna, lean beef, vitamin D-fortified milk and yogurt,
fortified orange juice, egg yolk

Liver, oysters, lean beef, chickpeas, beans, lentils, and sesame seeds

Spinach, kale, and other leafy green vegetables unrefined grains
and legumes

Dairy products, fish such as salmon and sardines, and dark, leafy greens.


What is Magnesium?

Magnesium is another of several essential nutrients that your body needs for energy metabolism, which is produced when your body metabolizes fats or carbohydrates. It’s a type of alkali metal, which means that magnesium is very reactive it’s a “free” element and is never found by itself in nature.

Indeed, when exposed to the open air, magnesium tarnishes and can violently react chemically with water, just like other alkali metals including calcium.

Similar to manganese, magnesium is also necessary for bone formation and maintenance, alongside healthy nerve transmission and muscle control. Without magnesium, many bodily functions will simply stop working properly!

In addition to these aspects, your body needs magnesium to transport nutrients like calcium and potassium, to regulate its blood sugar levels, and maintain healthy blood pressure levels.

Magnesium may even play a role in treating depressive symptoms or treatment of migraines. Like manganese, your body can’t produce magnesium by itself, so you have to get it from your diet or from dedicated supplementation.

An adult human body between the ages of 19 and 30 needs 400 or 310 mg of magnesium for males and females, respectively.


3. Magnesium

Do you suffer from leg cramps, fatigue, migraines, sleep issues, anxiety, or high blood pressure? If you have one or more of these symptoms you could be one of many Americans that are deficient in magnesium!

As you age, your body is less capable of absorbing magnesium from food, making magnesium deficiency more common in older adults than younger ones, according to the National Health and Nutrition Examination.

How much magnesium should women take over 50?

Taking a multivitamin with up to 350 mg of magnesium can significantly lower your risk of developing type 2 diabetes, and even lower your blood pressure.

Which magnesium supplement is best for over 50?

Which magnesium supplement should you take? I recommend: Magnesium Glycinate


Parenteral Administration

Drugs given IV enter the systemic circulation directly. However, drugs injected IM or subcutaneously (sc) must cross one or more biologic membranes to reach the systemic circulation. If protein drugs with a molecular mass > 20,000 g/mol are injected IM or sc, movement across capillary membranes is so slow that most absorption occurs via the lymphatic system. In such cases, drug delivery to systemic circulation is slow and often incomplete because of first-pass metabolism (metabolism of a drug before it reaches systemic circulation) by proteolytic enzymes in the lymphatics.

Perfusion (blood flow/gram of tissue) greatly affects capillary absorption of small molecules injected IM or sc. Thus, injection site can affect absorption rate. Absorption after IM or sc injection may be delayed or erratic for salts of poorly soluble bases and acids (eg, parenteral form of phenytoin ) and in patients with poor peripheral perfusion (eg, during hypotension or shock).


Micronutrient Information Center

Vitamin C (L-ascorbic acid) is a potent reducing agent, meaning that it readily donates electrons to recipient molecules (Figure 1). Related to this oxidation-reduction (redox) potential, two major functions of vitamin C are as an antioxidant and as an enzyme cofactor (1).

Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma and tissues. Even in small amounts, vitamin C can protect indispensable molecules in the body, such as proteins, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA), from damage by free radicals and reactive oxygen species (ROS) that are generated during normal metabolism, by active immune cells, and through exposure to toxins and pollutants (e.g., certain chemotherapy drugs and cigarette smoke). Vitamin C also participates in redox recycling of other important antioxidants for example, vitamin C is known to regenerate vitamin E from its oxidized form (see the article on Vitamin E).

The role of vitamin C as a cofactor is also related to its redox potential. By maintaining enzyme-bound metals in their reduced forms, vitamin C assists mixed-function oxidases in the synthesis of several critical biomolecules (1). These enzymes are either monooxygenases or dioxygenases (see Table 1). Symptoms of vitamin C deficiency, such as poor wound healing and lethargy, likely result from the impairment of these vitamin C-dependent enzymatic reactions leading to the insufficient synthesis of collagen, carnitine, and catecholamines (see Deficiency). Moreover, several dioxygenases involved in the regulation of gene expression and the maintenance of genome integrity require vitamin C as a cofactor. Indeed, research has recently uncovered the crucial role played by enzymes, such as the TET dioxygenases and Jumonji domain-containing histone demethylases, in the fate of cells and tissues (see Table 1). These enzymes contribute to the epigenetic regulation of gene expression by catalyzing reactions involved in the demethylation of DNA and histones.

Table 1. Enzymes Requiring Vitamin C as a Cofactor in Mammals (1, 2)
Enzymes* Functions
Monooxygenases
Dopamine β-monooxygenase Norepinephrine (Noradrenaline) biosynthesis
Peptidyl-glycine α-amidating monooxygenase Amidation of peptide hormones
Dioxygenases
3 Prolyl 4-hydroxylase isoenzymes Collagen hydroxylation
3 Prolyl 3-hydroxylase isoenzymes Collagen hydroxylation
3 Lysyl hydroxylase isoenzymes Collagen hydroxylation
4 Hypoxia-inducible factor (HIF) isoenzymes HIF hydroxylation
Trimethyllysine hydroxylase Carnitine biosynthesis
γ-Butyrobetaine hydroxylase Carnitine biosynthesis
4-Hydroxyphenylpyruvate dioxygenase Tyrosine metabolism
Ten-eleven translocation (TET) family of dioxygenases Demethylation of DNA
Jumonji domain-containing histone demethylases Demethylation of histones
*Monooxygenases catalyze the hydroxylation of one substrate, whereas dioxygenases catalyze a reaction that couples the hydroxylation of a specific substrate with the conversion (decarboxylation) of α-ketoglutarate into succinate.

The capacity of vitamin C to influence the methylation status of DNA and histones in mammalian cells supports a role for the vitamin in health and disease beyond what was previously understood, in particular by safeguarding genome integrity (3, 4).

Role in immunity

Vitamin C affects several components of the human immune system in vitro for example, vitamin C has been shown to stimulate both the production (5-9) and function (10, 11) of leukocytes (white blood cells), especially neutrophils, lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (10), chemotaxis (10, 11), and phagocytosis (11). Neutrophils, mononuclear phagocytes, and lymphocytes accumulate vitamin C to high concentrations, which can protect these cell types from oxidative damage (12-14). In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid ("bleach"), and peroxynitrite these reactive oxygen species kill pathogens and, in the process, can damage the leukocytes themselves (15). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from self-inflicted oxidative damage (14). Phagocytic leukocytes also produce and release cytokines, including interferons, which have antiviral activity (16). Vitamin C has been shown to increase interferon production in vitro (17). Additional studies have reported that vitamin C enhances the chemotactic and microbial killing capacities of neutrophils and stimulates the proliferation and differentiation of B- and T-lymphocytes (reviewed in 18).

It is widely thought by the general public that vitamin C boosts immune function, yet human studies published to date are conflicting. Disparate results are likely due to study design issues, often linked to a lack of understanding of vitamin C pharmacokinetics and requirements (19, 20).

Finally, vitamin C increases the bioavailability of iron from foods by enhancing intestinal absorption of non-heme iron (see the article on Iron) (21).

Bioavailability

Depletion-repletion pharmacokinetic experiments demonstrated that plasma vitamin C concentration is tightly controlled by three primary mechanisms: intestinal absorption, tissue transport, and renal reabsorption (22). In response to increasing oral doses of vitamin C, plasma vitamin C concentration rises steeply at intakes between 30 and 100 mg/day. Plasma concentrations of ascorbate reach steady-state at concentrations between 60 and 80 micromoles/L (μmol/L). This is typically observed at doses between 200 to 400 mg/day in healthy young adults, with some degree of individual variation (23, 24).

One hundred percent absorption efficiency is observed when ingesting vitamin C at doses up to 200 mg at a time. Higher doses (>500 mg) result in fractionally less vitamin C being absorbed as the dose increases. Once plasma vitamin C concentrations reach saturation, additional vitamin C is largely excreted in the urine. Notably, intravenous administration of vitamin C bypasses absorptive control in the intestine such that very high concentrations of vitamin C can be achieved in the plasma within a few hours, renal excretion restores vitamin C to baseline plasma concentrations (see Cancer Treatment) (25).

While plasma vitamin C concentration reflects recent dietary intake, leukocyte (white blood cell) vitamin C is thought to be an indicator of body stores. However, leukocyte vitamin C concentration does not accurately reflect vitamin C in several tissues and may specifically underestimate vitamin C uptake into skeletal muscle (26). Yet, plasma concentrations of vitamin C ≥50 μmol/L are sufficient to saturate muscle tissue vitamin C.

There is also some limited evidence suggesting that individuals who carry certain polymorphisms in genes involved in vitamin C transport and detoxification mechanisms may have lower plasma vitamin C concentrations even with high vitamin C intakes (see also Vascular complications of diabetes mellitus) (reviewed in 27).

Due to the pharmacokinetics and tight regulation of plasma vitamin C, supplementation with vitamin C will have variable effects in vitamin C-replete (plasma concentrations near saturation) versus sub-optimal (plasma concentrations <50 μmol/L), marginally deficient (plasma concentrations <23 μmol/L), or severely deficient (plasma concentrations <11 μmol/L) individuals (28). Scientific studies investigating vitamin C efficacy to prevent or treat disease need to assess baseline vitamin C status before embarking on an intervention or statistical analysis (22, 29-31).

For a more detailed discussion on the bioavailability of different forms of vitamin C, see the article, The Bioavailability of Different Forms of Vitamin C.

Deficiency

Severe vitamin C deficiency has been known for many centuries as the potentially fatal disease, scurvy. By the late 1700s, the British navy was aware that scurvy could be cured by eating oranges or lemons, even though vitamin C would not be isolated until the early 1930s. Symptoms of scurvy include subcutaneous bleeding, poor wound closure, and bruising easily, hair and tooth loss, and joint pain and swelling. Such symptoms appear to be related to the weakening of blood vessels, connective tissue, and bone, which all contain collagen. Early symptoms of scurvy like fatigue may result from diminished levels of carnitine, which is needed to derive energy from fat, or from decreased synthesis of the catecholamine norepinephrine (see Function). Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily (32). However, cases have occurred in children and the elderly on very restricted diets (33, 34).

The Recommended Dietary Allowance (RDA)

The recommended dietary allowance (RDA) for vitamin C is based on the amount of vitamin C intake necessary to maintain neutrophil vitamin C concentration with minimal urinary excretion of vitamin C and is proposed to provide sufficient antioxidant protection (Table 2) (35). The recommended intake for smokers is 35 mg/day higher than for nonsmokers, because smokers are under increased oxidative stress from the toxins in cigarette smoke and generally have lower blood concentrations of vitamin C (36).

Table 2. Recommended Dietary Allowance (RDA) for Vitamin C
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 40 (AI) 40 (AI)
Infants 7-12 months 50 (AI) 50 (AI)
Children 1-3 years 15 15
Children 4-8 years 25 25
Children 9-13 years 45 45
Adolescents 14-18 years 75 65
Adults 19 years and older 90 75
Smokers 19 years and older 125 110
Pregnancy 18 years and younger - 80
Pregnancy 19 years and older - 85
Breast-feeding 18 years and younger - 115
Breast-feeding 19 years and older - 120

Disease Prevention

The amount of vitamin C required to help prevent chronic disease is higher than the amount required for prevention of scurvy. Information regarding vitamin C and the prevention of chronic disease is based on both observational prospective cohort studies and randomized controlled trials (29, 37). Prospective cohort studies can examine the incidence of a specific disease in relation to vitamin C intake or body status in a cohort of participants who are followed over time. In contrast, trials are intervention studies that can establish a causal relationship between an exposure and an outcome, e.g., by evaluating the effect of vitamin C supplementation on the incidence of chronic disease in participants randomly assigned to receive either vitamin C or placebo for a given length of time.

Cardiovascular disease

Endothelial dysfunction

Endothelial dysfunction is considered to be an early step in the development of atherosclerosis. Alterations in the structure and function of the vascular endothelium that lines the inner surface of all blood vessels are associated with the loss of normal nitric oxide-mediated endothelium-dependent vasodilation. Endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. The measurement of brachial artery flow-mediated dilation (FMD) is often used as a functional marker of endothelial function FMD values are inversely correlated with the risk of future cardiovascular events (38). A 2014 meta-analysis of 44 randomized controlled trials in subjects with or without chronic diseases summarized the effect of supplemental vitamin C on endothelial function by measuring FMD (19 studies), assessing forearm blood flow (20 studies), or by pulse wave analysis (5 trials) (39). Short-term supplementation with vitamin C was found to reduce endothelial dysfunction in subjects with heart failure, atherosclerosis, or diabetes mellitus, but it had no effect in those with hypertension. Vitamin C also limited endothelial dysfunction that was experimentally induced in healthy volunteers (39). Improved endothelial function was observed with daily vitamin C doses above 500 mg (39).

Hypertension

Hypertension is a major risk factor for cardiovascular disease, including coronary heart disease, stroke, and atrial fibrillation. An analysis that combined data from three, large, independent prospective cohorts, (1) Nurses’ Health Study 1 (NHS1 88,540 women, median age 49 years) (2) Nurses’ Health Study 2 (NHS2 97,315 women, median age 36 years) and (3) Health Professionals Follow-up Study (HPFS 37,375 men, median age 52 years), found no association between the level of vitamin C intake and risk of developing hypertension (40). On the other hand, when plasma vitamin C concentration was measured, cross-sectional studies have consistently indicated an inverse relationship between plasma vitamin C concentration and blood pressure in both men and women (41-43). A 15-year follow-up of about 2,500 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study found that higher plasma vitamin C and a higher diet quality score were independently associated with a reduced risk of developing hypertension (44). Interestingly, there was no relationship between diet score and risk of hypertension in those with the lowest plasma vitamin C, and plasma vitamin C was positively associated with risk of hypertension in those with low diet scores (44).

A meta-analysis of 29 small randomized controlled trials of short durations (median duration, 8 weeks) in 1,407 participants (10 to 120 subjects per trial including both normotensive and hypertensive subjects) found that daily supplementation with 60 to 4,000 mg of vitamin C (median dose, 500 mg) reduced systolic blood pressure by 3.84 mm Hg and diastolic blood pressure by 1.48 mm Hg (45). Good quality long-term trials are needed to examine whether the anti-hypertensive effect of vitamin C is sustained over time and eventually results in a reduced risk of cardiovascular events.

It is important for individuals with significantly elevated blood pressure not to rely on vitamin C supplementation alone to reduce their hypertension. They should instead seek or continue treatment with anti-hypertensive medication and make dietary and lifestyle changes in consultation with their health care provider.

Cardiovascular disease risk

Coronary heart disease (CHD) is characterized by the buildup of plaque inside the arteries that supply blood to the heart (atherosclerosis). Over years of buildup and accumulated damage to the coronary arteries, CHD may culminate in a myocardial infarction or heart attack. Many prospective cohort studies have examined the relationship between vitamin C intake from diet and supplements and CHD risk, the results of which have been pooled and analyzed in two separate analyses (46, 47). In 2004, a pooled analysis of nine prospective cohort studies found that supplemental vitamin C intake (≥400 mg/day for a mean of 10 years), but not dietary vitamin C intake, was inversely associated with CHD risk (46). Conversely, a 2008 meta-analysis of 14 cohort studies concluded that dietary, but not supplemental, vitamin C intake was inversely related to CHD risk (47). The most recent large prospective cohort study found an inverse association between dietary vitamin C intake and CHD mortality in Japanese women, but not in men (48). In spite of the variable association depending on source, these analyses indicate an overall inverse association between higher vitamin C intakes and CHD risk.

Limitations inherent to dietary assessment methodology, such as recall bias, measurement error, and residual confounding, may account for some of the inconsistent associations between vitamin C intake and CHD risk. In order to overcome such limitations, some prospective studies measured plasma or serum concentrations of vitamin C as a more reliable index of vitamin C intake and biomarker of body vitamin C status.

The European Investigation into Cancer and Nutrition (EPIC)-Norfolk prospective cohort study investigated the relationship between vitamin C status and incident heart failure in healthy adults (9,187 men and 11,112 women, aged 58.1+/-9.2 years) (49). After a mean follow-up of 12.8 years, plasma vitamin C was inversely associated with incident cases of heart failure. Specifically, plasma vitamin C ranged from approximately 23 to 70 μmol/L in men and 33 to 82 μmol/L in women across this range, every 20 μmol/L increase in plasma vitamin C was associated with a 9% reduction in risk of heart failure. Although a primary source of dietary vitamin C, consumption of fruit and vegetables — assessed by food frequency questionnaire — was not found to be associated with a lower risk of congestive heart failure (49). This highlights the fact that limitations associated with dietary assessment methods such as food frequency questionnaires may be overcome by using biomarkers of nutrient intake (50, 51).

A 2017 review of eight published randomized controlled trials found inconsistent results from seven trials reporting on the effect of vitamin C supplementation on serum cholesterol and triglycerides, established risk factors for cardiovascular disease (52). Only one large trial in more than 14,000 older men participating in the Physicians’ Health Study II (PHS II) reported on cardiovascular outcomes. PHS II found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on major cardiovascular events, total myocardial infarction, or cardiovascular mortality (53). Notably, this study had several limitations (54), including no measurement of vitamin C status and the recruitment of a well-nourished study population.

There is a need for better quality studies to examine the effect of vitamin C on cardiovascular endpoints in participants with elevated risk of cardiovascular disease.

Stroke

A cerebrovascular event, or stroke, can be classified as hemorrhagic or ischemic. Hemorrhagic stroke occurs when a weakened blood vessel ruptures and bleeds into the surrounding brain tissue. Ischemic stroke occurs when an obstruction within a blood vessel blocks blood flow to the brain. Most (

80%) cerebrovascular events in high-income countries are ischemic in nature and associated with atherosclerosis as an underlying condition (55, 56).

With respect to vitamin C and cerebrovascular disease, a prospective cohort study that followed more than 2,000 residents of a rural Japanese community for 20 years found that the risk of stroke in those with the highest serum concentrations of vitamin C was 29% lower than in those with the lowest serum concentrations of vitamin C (57). Similarly, the EPIC-Norfolk study, a 10-year prospective cohort study in 20,649 adults, found that individuals with plasma vitamin C concentrations in the top quartile (25%) had a 42% lower risk of stroke compared to those in the lowest quartile (≥66 μmol/L vs. <41 μmol/L) (58). In both the Japanese (57) and EPIC-Norfolk (58) populations, blood vitamin C concentrations were highly correlated with fruit and vegetable intake. Therefore, as in many studies of vitamin C intake and chronic disease risk, it is difficult to separate the effects of vitamin C from the effects of other components of fruit and vegetables. For example, potassium — found at high levels in bananas, potatoes, and other fruit and vegetables — is known to be important in blood pressure regulation, and elevated blood pressure is a major risk factor for stroke (see the article on Potassium). A 2013 meta-analysis of 17 prospective cohort studies reported a 19% lower risk of stroke with the highest versus lowest dietary vitamin C intakes and a 38% lower risk with the highest versus lowest circulating vitamin C concentrations (59).

A randomized, double-blind, placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study II (PHS II) found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on the incidence of or mortality from any type of stroke (53). Other trials also failed to show any evidence of an effect of vitamin C on the risk of stroke. A meta-analysis of 10 trials that examined antioxidant vitamins, of which five included vitamin C, found no association between any antioxidant vitamin (vitamin C, vitamin E, or β-carotene), administered alone or in combination, and risk of stroke (60).

Cancer

Overall, observational prospective cohort studies have reported no or modest inverse associations between vitamin C intake and the risk of developing a given type of cancer (37, 61-63). Additional detail is provided below for those cancer subtypes with substantial scientific information obtained from prospective cohort studies. Randomized, double-blind, placebo-controlled trials that have tested the effect of vitamin C supplementation (alone or in combination with other antioxidant nutrients) on cancer incidence or mortality have shown no effect (64).

Breast cancer

Two large prospective studies found dietary vitamin C intake to be inversely associated with breast cancer incidence in certain subgroups. In the Nurses' Health Study, premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of vitamin C from food had a 63% lower risk of breast cancer than those who consumed an average of 70 mg/day (65). In the Swedish Mammography Cohort, overweight women who consumed an average of 110 mg/day of vitamin C had a 39% lower risk of breast cancer compared to overweight women who consumed an average of 31 mg/day (66). More recent prospective cohort studies have reported no association between dietary and/or supplemental vitamin C intake and breast cancer (67-69).

Stomach cancer

A number of observational studies have found increased dietary vitamin C intake to be associated with decreased risk of gastric (stomach) cancer, and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic N-nitroso compounds in the stomach (70-72). A nested case-control study in the EPIC study found a 45% lower risk of gastric cancer incidence in individuals in the highest (≥51 μmol/L) versus lowest (<29 μmol/L) quartile of plasma vitamin C concentration no association was observed between dietary vitamin C intake and gastric cancer (73).

Infection with the bacteria, Helicobacter pylori (H. pylori), is known to increase the risk of stomach cancer and is associated with lower vitamin C content of stomach secretions (74, 75). Although two intervention studies failed to show a reduction in stomach cancer incidence with vitamin C supplementation (35), some research suggests that vitamin C supplementation may be a useful addition to standard H. pylori eradication therapy in reducing the risk of gastric cancer (76). Because vitamin C can inactivate urease (an enzyme that facilitates H. pylori survival and colonization of the gastric mucosa at low pH) in vitro, vitamin C may be most effective as a prophylactic agent in those without achlorhydria (77, 78).

Colon cancer

By pooling data from 13 prospective cohort studies comprising 676,141 participants, it was determined that dietary intake of vitamin C was not associated with colon cancer, while total intake of vitamin C (i.e., from food and supplements) was associated with a 19% reduced risk of colon cancer (79). Each of the cohort studies used self-administered food frequency questionnaires at baseline to assess vitamin C intake. Although the analysis adjusted for several lifestyle and known risk factors, the authors noted that other healthy behaviors and/or folate intake may have confounded the association.

Non-Hodgkin lymphoma

A population-based, prospective study, the Iowa Women’s Health Study, collected baseline data on diet and supplement use in 35,159 women (aged 55-69 years) and evaluated the risk of developing non-Hodgkin lymphoma (NHL) over 19 years of follow-up (80). Overall, an inverse association between fruit and vegetable intake and risk of NHL was observed. Additionally, dietary, but not supplemental, intake of vitamin C and other antioxidant nutrients (carotenoids, proanthocyanidins, and manganese) was inversely associated with NHL risk. Another large, multi-center, prospective study — the Women’s Health Initiative — that followed 154,363 postmenopausal women for 11 years found that dietary and supplemental vitamin C intake at baseline was inversely associated with diffuse B-cell lymphoma, a subtype of NHL (81).

Other site-specific cancer types

The Physicians’ Health Study II was a randomized, placebo-controlled trial that examined the effect of vitamin E (400 IU/day), vitamin C (500 mg/day), and a multivitamin supplement on the risk of cancer in 14,641 middle-aged male physicians over 10.3 years (7.6 years of active treatment plus 2.8 years post-treatment follow-up) (82). Supplementation with vitamin C had no effect on the overall risk of cancer or on the risk of prostate, bladder, or pancreatic cancer there was a marginal reduction in colorectal cancer incidence with vitamin C compared to placebo (82).

Type 2 diabetes mellitus

In the National Institutes of Health (NIH)-American Association of Retired Persons (AARP) Diet and Health study that included 232,007 participants, the use of vitamin C supplements for at least seven times a week was associated with a 9% lower risk of developing type 2 diabetes mellitus compared to non-supplement use (83). In a cohort of 21,831 adults followed for 12 years in the EPIC-Norfolk study, high plasma vitamin C was found to be strongly associated with a reduced risk of diabetes (84). Additionally, several cross-sectional studies reported inverse associations between circulating vitamin C concentrations and markers of insulin resistance or glucose intolerance, such as glycated hemoglobin (HbA1c) concentration (50, 85, 86). Yet, short-term randomized controlled studies have found no effect of vitamin C supplementation on fasting glucose, fasting insulin, and HbA1c concentrations in healthy individuals (87). It is not known whether supplemental vitamin C could improve markers of glycemic control in subjects at risk of diabetes.

Adverse pregnancy outcomes

A 2015 meta-analysis of 29 randomized controlled trials found that administration of vitamin C during pregnancy, alone or in combination with a few other supplements, failed to reduce the risks of stillbirth, perinatal death, intrauterine growth restriction, preterm birth, premature rupture of membranes, and preeclampsia (88). Nonetheless, vitamin C supplementation led to a 36% lower risk of placental abruption and to a significant increase in gestational age at birth (88). Another meta-analysis of 40 randomized controlled trials in 276,820 women found no effect of vitamin C, alone or combined with vitamin E or multivitamins, when supplemented during pregnancy (starting prior to 20 weeks’ gestation), on the risks of overall fetal loss, miscarriage, stillbirth, and congenital malformation (89).

Cigarette smoking during pregnancy causes intrauterine growth restriction and preterm birth, among other pregnancy complications (90, 91), and is the primary cause of childhood respiratory illness (92). For some still unclear reasons, smoking has been associated with a lower risk of preeclampsia during pregnancy (93). A secondary analysis of a multicenter, randomized, double-blind, placebo-controlled trial in nearly 10,000 pregnant women found no reduction in the risk of preeclampsia with supplemental vitamin C (1,000 mg/day) and vitamin E (400 IU/day), regardless of women’s smoking status during pregnancy. However, antioxidant supplementation resulted in reduced risks of placental abruption and preterm birth in women who smoked during pregnancy but not in non-smokers (94). Another pilot multicenter trial found better lung function during the first week of life and lower risk of wheezing through one year of age in infants whose smoking mothers were randomized to receive vitamin C (500 mg/day) rather than a placebo during pregnancy (95). The Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function [VCSIP] study is an ongoing trial designed to confirm these preliminary observations using more accurate measurements of pulmonary function in a larger sample of women randomized to receive supplemental vitamin C or placebo (96).

Alzheimer's disease

In the US, Alzheimer’s disease (AD) is the most common form of dementia, affecting 5.5 million individuals 65 years and over (97). Oxidative stress, neuroinflammation, β-amyloid plaque deposition, Tau protein-forming tangles, and neuronal cell death in the brain of subjects affected by AD have been associated with cognitive decline and memory loss. Lower vitamin C concentrations in the cerebrospinal fluid (CSF) and brain extracellular matrix of a mouse model of AD were found to increase oxidative stress and accelerate amyloid deposition and disease progression (98). In another AD mouse model that was lacking the ability to synthesize vitamin C, supplementation with a high versus low dose of vitamin C reduced amyloid deposition in the cortex and hippocampus and limited blood-brain barrier impairments and mitochondrial dysfunction (99).

The majority of large, population-based studies examining the relationship of vitamin C intake or supplementation with AD incidence have reported null results (100). In contrast, observational studies reported lower plasma vitamin C concentrations in AD patients compared to cognitively healthy subjects (101) and found better cognitive function or lower risk of cognitive impairment with higher plasma vitamin C (100).

Few studies have measured vitamin C concentration in the CSF, which more closely reflects the vitamin C status of the brain. Vitamin C is concentrated in the brain through a combination of active transport into brain tissue and retention via the blood-brain barrier (100). Although CSF vitamin C is maintained at concentrations several-fold higher than plasma vitamin C, the precise function of vitamin C in cognitive function and AD etiology is not yet fully understood (102). In a small, longitudinal biomarker study in 32 individuals with probable AD, a higher CSF-to-plasma vitamin C ratio at baseline was associated with a slower rate of cognitive decline at one year of follow-up (103). Impaired blood-brain barrier integrity may affect the brain’s ability to retain vitamin C and thus to maintain a high CSF-to-plasma vitamin C ratio. The significance of the CSF-to-plasma vitamin C ratio in AD progression requires further study.

The effect of vitamin C supplementation, in combination with other antioxidants, on CSF biomarkers and cognitive function has been examined in only a few trials involving AD patients. In a small (n=23), open-label trial, combined supplementation with vitamin C (1,000 mg/day) and vitamin E (400 IU/day) to AD patients taking a cholinesterase inhibitor significantly increased antioxidant levels and decreased lipoprotein oxidation in CSF after one year, but had no effect on the clinical course of AD compared to controls (104). A similar finding was obtained in a double-blind, randomized controlled trial in which combined supplementation with vitamin C (500 mg/day), vitamin E (800 IU/day), and α-lipoic acid (900 mg/day) for 16 weeks reduced lipoprotein oxidation in CSF but elicited no clinical benefit in individuals with mild-to-moderate AD (n=78) (105). In this latter trial, a greater decline in the Mini Mental State Examination (MMSE) score was observed in the supplemented group, however, the significance of this observation remains unclear. A third placebo-controlled trial in mildly cognitively impaired older adults (ages, 60-75 years) found that one-year supplementation with vitamin C (400 mg/day) and vitamin E (300 mg/day) improved antioxidant blood capacity but had no effect on MMSE scores (106).

At this time, avoidance of vitamin C deficiency or insufficiency, rather than supplementation in replete individuals, seems prudent for the promotion of healthy brain aging (101).

Cataracts

The lens of the eye focuses light, producing a clear, sharp image on the retina, a layer of tissue on the inside back wall of the eyeball. Age-related changes to the lens (thickening, loss of flexibility) and oxidative damage contribute to the formation of cataract, i.e., cloudiness or opacity in the lens that interferes with the clear focusing of images on the retina.

In humans, vitamin C concentration is about 15 to 20 times higher in the aqueous humor — fluid that fills the anterior and posterior chambers of the eye — than in plasma, suggesting that the vitamin may be playing an important role in the eye (107). Decreased vitamin C concentrations in the lens of the eye have been associated with increased severity of cataracts (108). A meta-analysis of observational studies found that a reduced risk of age-related cataract with higher dietary vitamin C intakes in case-control studies and with higher circulating vitamin C concentrations in cross-sectional studies. However, no such associations were found in pooled analyses of prospective cohort studies (109). In fact, two prospective cohort studies in Swedish men (110) and women (111) reported that high-dose single nutrient supplements of vitamin C were associated with an increased risk of cataract, especially in those on corticosteroid therapy.

A 2012 review of nine randomized controlled trials found no substantial effect of β-carotene, vitamin C, and vitamin E, administered individually or in combination over 2.1 to 12 years, on the risk of cataracts or cataract surgery (112). Although trials do not currently support the use of high-dose supplementation with vitamin C in cataract prevention, there is a consistent inverse association observed between high daily intake of fruit and/or vegetables (>5 servings/day) and risk of cataract (113).

Gout

Gout, a condition that afflicts more than 4% of US adults (114), is characterized by abnormally high blood concentrations of uric acid (urate) (115). Urate crystals may form in joints, resulting in inflammation and pain, as well as in the kidneys and urinary tract, resulting in kidney stones. The tendency to exhibit elevated blood uric acid concentrations and develop gout is often inherited however, dietary and lifestyle modification may be helpful in both the prevention and treatment of gout (116). In an observational study that included 1,387 men, higher intakes of vitamin C were associated with lower serum concentrations of uric acid (117). In a cross-sectional study conducted in 4,576 African Americans, the odds of having hyperuricemia was associated with dietary intakes high in fructose, low in vitamin C, or with high fructose-to-vitamin C ratios (118). A prospective study that followed a cohort of 46,994 men for 20 years found that total daily vitamin C intake was inversely associated with incidence of gout, with higher intakes being associated with greater risk reductions (119). The results of this study also indicated that supplemental vitamin C may be helpful in the prevention of gout (119).

A 2011 meta-analysis of 13 randomized controlled trials in healthy individuals with elevated serum uric acid revealed that vitamin C supplementation (a median dose of 500 mg/day for a median duration of 30 days) modestly reduced serum uric acid concentrations by 0.35 mg/dL compared to placebo (120). Such a reduction falls within the range of assay variability and is unlikely to be clinically significant (121). An eight-week, open-label, controlled trial randomized 40 subjects with gout to receive either allopurinol (standard-of-care), vitamin C, or both treatments (122). The effect of vitamin C, alone or with allopurinol, decreasing serum uric acid was modest and much less than that of allopurinol alone. The trial did not examine the effect of vitamin C on other outcomes associated with gout (122).

Although observational studies suggested that supplemental vitamin C may be helpful to prevent incident and recurrent gout, this has not been demonstrated by intervention studies undertaken thus far. In addition, there is currently little evidence to support a role for vitamin C in the management of patients with gout (123).

Mortality

Two large prospective cohort studies assessed the relationship between dietary and supplemental vitamin C intakes and mortality. In the Vitamins and Lifestyle Study, 55,543 men and women (ages 50-76 years) were questioned at baseline on their use of dietary supplements during the previous 10 years (124). After five years of follow-up, vitamin C supplement use was associated with a small decreased risk of total mortality, although no association was found with cardiovascular disease- or cancer-specific mortality. In the second prospective cohort study, the Diet, Cancer and Health Study, 55,543 Danish adults (ages 50-64 years) were questioned at baseline about their lifestyle, diet, and supplement use during the previous 12 months (125). No association between dietary or supplemental intake of vitamin C and mortality was found after approximately 14 years of follow-up. In contrast, a 2014 meta-analysis of 10 prospective cohort studies in 17,696 women with breast cancer found a lower risk of total and breast cancer-specific mortality with higher supplemental and dietary vitamin C intakes (126). A 2012 meta-analysis of 29 trials found no effect of oral vitamin C, given alone or in combination with other antioxidants, on all-cause mortality (127).

In parallel to these dietary assessment studies, a strong inverse association between plasma vitamin C and mortality from all-causes, cardiovascular disease, and ischemic heart disease (and cancer in men only) was observed in the EPIC-Norfolk multicenter, prospective cohort study (128). After approximately four years of follow-up in 19,496 men and women (ages 45-79 years), a dose-response relationship was observed such that each 20 μmol/L increase in plasma vitamin C was associated with an estimated 20% risk reduction in all-cause mortality. Similarly, higher serum vitamin C concentrations were associated with decreased risks of cancer-specific and all-cause mortality in 16,008 adults from the US National Health and Nutrition Examination Survey (NHANES) III (1994-1998) (129).

Disease Treatment

Cardiovascular disease

Complications of cardiac procedures and surgeries

Periprocedural myocardial injury: Coronary angioplasty (also called percutaneous transluminal coronary angioplasty) is a nonsurgical procedure for treating obstructive coronary heart disease (CHD), including unstable angina pectoris, acute myocardial infarction, and multivessel CHD. Angioplasty involves temporarily inserting and inflating a tiny balloon into the clogged artery to help restore the blood flow to the heart. Periprocedural myocardial injury that occurs in up to one-third of patients undergoing otherwise uncomplicated angioplasty increases the risk of morbidity and mortality at follow-up.

One randomized, placebo-controlled trial has examined the effect of intravenous vitamin C administered to patients with stable angina undergoing elective coronary angioplasty (130). Administration of a 1-gram (g) vitamin C infusion one hour prior to the angioplasty reduced the concentrations of oxidative stress markers and improved microcirculatory perfusion compared to placebo (130). Another trial randomized 532 patients to receive a 3-g vitamin C infusion or a placebo (saline solution) within six hours prior to coronary angioplasty (131). Vitamin C treatment substantially reduced the incidence of periprocedural myocardial injury, as assessed by a reduction in the concentrations of two markers of myocardial injury, namely creatine kinase and troponin-I (131). A recent randomized controlled trial assessed the effect of vitamin C and vitamin E administration on reperfusion damage in patients who experienced acute myocardial infarction and underwent coronary angioplasty (see below) (132).

Myocardial reperfusion injury: Reperfusion injury refers to tissue damage occurring at the time of blood flow restoration (reperfusion) following transient ischemia. The heart muscle may become oxygen-deprived (ischemic) as the result of myocardial infarction or with aortic clamping during coronary artery bypass graft (CABG) surgery. Increased generation of reactive oxygen species (ROS) when the heart muscle's oxygen supply is restored might be an important contributor to myocardial damage occurring at reperfusion (133). Myocardial reperfusion injury leads to complications, such as reperfusion arrhythmias (see Atrial fibrillation) and myocardial stunning.

Vitamin C is depleted during and following cardiac surgery (134) and this might be due to the direct quenching of ROS, the regeneration of other antioxidants, and/or a massive synthesis of catecholamines (dopamine, epinephrine, norepinephrine) (135). Two randomized controlled trials conducted in the 1990s reported a reduction in reperfusion-induced oxidative stress and myocardial injury with intravenous (136) or oral (137) vitamin C administration prior to CABG surgery (reviewed in 135). A more recent randomized, double-blind, placebo-controlled trial has been designed to examine the effect of vitamin C and vitamin E administration on ischemia-reperfusion damage in 99 patients with acute myocardial infarction undergoing coronary angioplasty (132). Vitamin C infusion (sodium ascorbate: 3.20 mmol/min for 1 hour then 0.96 mmol/min for 2 hours) prior to reperfusion followed by oral supplementation with vitamin C (1 g/day) and vitamin E (400 IU/day) for 84 days effectively prevented a reduction in antioxidant capacity at reperfusion and for the next six to eight hours. The protocol also limited microvascular dysfunction (i.e., improved microcirculatory perfusion) and improved left ventricular ejection fraction at discharge (on day 84) (138, 139). However, no difference in the infarct size between antioxidant vitamin treatment and placebo was seen (138).

Atrial fibrillation: Atrial fibrillation is the most common type of cardiac arrhythmia. It is also a common post-cardiac surgery complication, leading to an increased risk of cardiovascular morbidity (e.g., heart failure, stroke) and mortality. Three meta-analyses of prospective cohort studies and randomized controlled trials have reported an overall reduction in the risk of post-operative atrial fibrillation following administration of primarily oral vitamin C (140-142). In most trials, participants received 2 g of vitamin C prior to undergoing CABG or valve replacement surgery and 1 to 2 g/day for five days post-surgery. Although only a minority of trials delivered vitamin C intravenously, this administration route appeared to be more effective at reducing the risk of atrial fibrillation — presumably due to higher plasma concentrations achieved (140). Of note, a subgroup analysis in one of the meta-analyses showed a reduction of post-operative atrial fibrillation with vitamin C in non US-based trials (10 trials) but no effect of vitamin C in US-based trials (5 trials) (140).

Cerebral ischemia-reperfusion injury

A small randomized controlled trial performed in 60 ischemic stroke patients showed that intravenous vitamin C administration (500 mg/day for 10 days, initiated day 1 post-stroke) had no effect on serum markers of oxidative stress or neurological outcomes compared to placebo (143).

Vascular complications of diabetes mellitus

Cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes mellitus. The role of increased oxidative stress in the occurrence of vascular complications in subjects with diabetes has led to hypothesis that higher intakes of antioxidant nutrients could help lower the risk of CVD in diabetic subjects (144). A 2018 meta-analysis of randomized controlled trials investigating the effect of antioxidant vitamin supplementation in patients with type 2 diabetes found that most improvement in markers of oxidative stress and blood glucose control could be attributed to vitamin E (145). Another meta-analysis of trials found no effect of vitamins E and C, alone or in combination, on measures of β-cell function and insulin resistance (146). Yet, most studies were small and of short duration and thus did not assess the consequence of long-term use of antioxidant vitamins on the risk of vascular complications in diabetic patients. One 12-month randomized placebo-controlled trial in 456 participants with type 2 diabetes treated with metformin examined the effect of vitamin C (500 mg/day) or acetylsalicylic acid (aspirin 100 mg/day) on risk factors for diabetes-related complications such as CVD (147). Both vitamin C and aspirin reduced fasting blood glucose and HbA1c concentrations and improved blood lipid profile in metformin-treated patients. Compared to placebo, both treatments were found to be more likely to limit risk factors contributing to diabetes-related complications, as well as to lower the risk of future cardiovascular events over a 10-year period (estimated using the Framingham risk score) (147).

Of note, it is possible that genetic differences among diabetic patients influence the effect of vitamin C supplementation on cardiovascular risk. In particular, a specific allele of the haptoglobin gene (Hp), namely Hp2, appears to be associated with an increased risk of diabetic vascular complications. Carriers of two copies of the Hp2 allele (Hp2-2) express a Hp protein that has a lower capacity to bind and remove pro-oxidant, free hemoglobin (Hb) from plasma, compared to Hp proteins coded by the Hp1-1 and Hp1-2 genotypes. When the results of the Women’s Antioxidant Vitamin Estrogen (WAVE) trial were reanalyzed based on Hp genotype, antioxidant therapy (1,000 mg/day of vitamin C + 800 IU/day of vitamin E) was associated with improvement of coronary atherosclerosis in diabetic women with Hp1-1 genotype but worsening of coronary atherosclerosis in those carrying the Hp2-2 genotype (148). Results from another study by the same investigators suggested that vitamin C could not prevent the oxidation of high-density lipoprotein (HDL)-cholesterol by glycated Hb-Hp2-2 complexes in vitro nor restore impaired HDL function in diabetic mice carrying the Hp2-2 genotype (149).

Sepsis

Sepsis and septic shock — defined as persistent sepsis-induced low blood pressure — are associated with elevated mortality rates in critically ill patients (150, 151). Because systemic inflammatory responses involve excessive oxidative stress, it has been suggested that providing antioxidant nutrients like vitamin C may improve the outcome of critically ill patients in intensive care units. In addition, hypovitaminosis C is common in critically ill patients, especially in those with septic shock, and persists despite enteral/parenteral nutritional therapy providing recommended amounts of vitamin C (152). Vitamin C requirements are likely to be increased in this population due to the hypermetabolic response driven by the systemic inflammatory reaction (152, 153). Intravenous administration of 50 mg or 200 mg of vitamin C per kg per day for 96 hours to patients with sepsis admitted in intensive care unit was found to correct vitamin C deficiency. Vitamin C also prevented the rise of Sequential Organ Failure Assessment (SOFA) and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores — used to assess severity of illness and risk of mortality — observed in placebo-treated patients (154). Vitamin C infusion also lowered the concentration of markers of inflammation and endothelial injury in patients compared to placebo (154). In another randomized, double-blind, controlled trial in 28 critically ill patients with septic shock, infusion of 25 mg of vitamin C per kg every six hours for 72 hours significantly limited the requirement to vasopressor norepinephrine — decreasing both the dose and duration of treatment — and dramatically improved the 28-day survival rate (155). Similar results have been reported in septic patients given intravenous vitamin C (1.5 g/6 h), hydrocortisone (50 mg/6 h), and thiamin (200 mg/12 h) until hospital discharge. Compared to standard-of-care, this intervention cocktail more than halved the mean duration of vasopressor use (18.3 h versus 54.9 h) and reduced the odds of mortality by nearly 90% (156). Although intravenous vitamin C administration appears to be safe and well tolerated, there is a non-negligible risk of oxalate nephropathy (a rare cause of kidney failure) in these critically ill patients (157).

Cancer

Route of administration

Studies in the 1970s and 1980s conducted by Linus Pauling, Ewan Cameron, and colleagues suggested that large doses of vitamin C (10 g/day infused intravenously for 10 days followed by at least 10 g/day orally indefinitely) were helpful in increasing the survival time and improving the quality of life of terminal cancer patients (158). Controversy surrounding the efficacy of vitamin C in cancer treatment ensued, leading to the recognition that the route of vitamin C administration is critical (22, 159). Compared to orally administered vitamin C, intravenous vitamin C can result in 30 to 70-fold higher plasma vitamin C concentrations (25). Higher plasma concentrations achieved via intravenous vitamin C administration are comparable to those that are toxic to cancer cells in culture. The anticancer mechanism of intravenous vitamin C action is under investigation. It may involve the production of high levels of hydrogen peroxide, selectively toxic to cancer cells (22, 160-162), or the deactivation of hypoxia inducible factor, a prosurvival transcription factor that protects cancer cells from various forms of stress (159, 163, 164). Vitamin C likely also plays a role in the maintenance of genome integrity and in the protection against cellular transformation through regulating DNA and histone demethylating enzymes (see Function) (165).

Safety

Current evidence from controlled clinical trials indicates that intravenous vitamin C is generally safe and well tolerated in cancer patients. Of note, because intravenous administration of 80 g of vitamin C precipitated hemolytic anemia in two subjects with glucose-6-phosphate dehydrogenase deficiency, patients due to receive high-dose vitamin C infusion are systematically screened for this genetic disorder (166). Four phase I clinical trials in patients with advanced cancer found that intravenous administration of vitamin C at doses up to 1.5 g/kg of body weight (equivalent to about 100 g/day for an average weight [70 kg] person) and 70 to 80 g/m 2 was well tolerated and safe in pre-screened patients (167-170). A few observational studies in cancer patients undergoing chemotherapy and/or radiotherapy reported that complementary intravenous vitamin C treatment was associated with a reduction in treatment-associated side effects and an improved quality of life (171). A phase I study in nine patients with metastatic pancreatic cancer showed that millimolar concentrations of plasma vitamin C could be reached safely when administered in conjunction with the cancer chemotherapy drugs, gemcitabine and erlotinib (168).

Sensitivity to vitamin C

Retrospective in vitro colony formation assays revealed that patient leukemic cells displayed variable sensitivity to vitamin C treatment: leukemic cells from seven out of the nine patients who experienced a significant clinical benefit were sensitive to vitamin C in vitro (i.e., "responders") the leukemic cells from the remaining six patients were not sensitive to vitamin C (i.e., "non-responders"). Thus, in vitro vitamin C sensitivity assays may provide predictive value for the clinical response to intravenous vitamin C treatment. The mechanisms underlying differential sensitivity to vitamin C are under investigation. In vitro experiments performed using 11 different cancer cell lines demonstrated that sensitivity to vitamin C correlated with the expression of catalase, an enzyme involved in the decomposition of hydrogen peroxide (172). Approximately one-half of the cell lines tested were resistant to vitamin C cytotoxicity, a response associated with high levels of catalase activity.

Sensitivity to vitamin C may also be determined by the expression of sodium-dependent vitamin C transporter-2 (SVCT-2), which transports vitamin C into cells (173). Higher SVCT-2 levels were associated with enhanced sensitivity to vitamin C in nine different breast cancer cell lines. Moreover, SVCT-2 was significantly expressed in 20 breast cancer tissue samples, but weakly expressed in normal tissues. Finally, mutations in genes coding for vitamin C-dependent TET demethylases, mutations that are common in cancer cells, may also contribute to resistance to vitamin C treatment (165).

Efficacy

Current evidence of the efficacy of intravenous vitamin C in cancer patients is limited to observational studies, uncontrolled interventions, and case reports (174, 175). There is a need for larger, longer-duration phase II clinical trials that test the efficacy of intravenous vitamin C in disease progression and overall survival (176).

Common cold

The work of Linus Pauling stimulated public interest in the use of doses greater than 1 g/day of vitamin C to prevent the common cold (177). In the past 40 years, numerous placebo-controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A 2013 meta-analysis of 53 placebo-controlled trials evaluated the effect of vitamin C supplementation on the incidence, duration, or severity of the common cold when taken as a continuous daily supplement (43 trials) or as therapy upon onset of cold symptoms (10 trials) (178). Regarding the incidence of colds, a difference was observed between two groups of participants. Regular supplementation with vitamin C (0.25 to 2 g/day) did not reduce the incidence of colds in the general population (23 trials) however, in participants undergoing heavy physical stress (e.g., marathon runners, skiers, or soldiers in subarctic conditions), vitamin C supplementation halved the incidence of colds (5 trials). A benefit of regular vitamin C supplementation was also seen in the duration of colds, with a greater benefit in children than in adults: The pooled effect of vitamin C supplementation was a 14% reduction in cold duration in children and an 8% reduction in adults. Finally, no significant effect of vitamin C supplementation (1-8 g/day) was observed in therapeutic trials in which vitamin C was administered after cold symptoms occurred.

In addition, a 2013 systematic review by the same investigators identified only two small randomized, double-blind, placebo-controlled trials that examined the effect of vitamin C on the incidence of respiratory infection-induced asthma (179). One trial found that vitamin C supplementation (1 g/day) for 14 weeks reduced the risk of asthma attacks precipitated by respiratory infection. The other trial randomized subjects diagnosed with infection-related asthma to receive 5 g/day of vitamin C or a placebo for one week a lower proportion of participants was found to present with bronchial hypersensitivity to histamine — which characterizes chronic asthma — in the vitamin C group compared to the control group (reviewed in 179). These observations need to be confirmed in larger, well-designed trials.

Asthma

A 2013 systematic review identified 11 randomized controlled studies that evaluated the effect of vitamin C on asthma (eight trials) or exercise-induced bronchoconstriction (three trials) (180). Exercise-induced bronchoconstriction is a transient narrowing of the airways that occurs after exercise and is indicated by a ≥10% decline in Forced Expiratory Volume in 1 second (FEV1). In the three trials that included a total of 40 participants with exercise-induced bronchoconstriction, vitamin C administration before exercise (a 0.5-g dose on two subsequent days in one trial, a single dose of 2 g in the second trial, and 1.5 g daily for two weeks in the third trial) significantly reduced the exercise-induced decline in FEV1. Among the five out of eight trials in asthmatic subjects that reported on FEV1 outcomes, none found a difference between vitamin C supplementation and placebo (180).

Lead toxicity

Although the use of lead paint and leaded gasoline has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in urban areas. Abnormal growth and development have been observed in infants of women exposed to lead during pregnancy, while children who are chronically exposed to lead are more likely to develop learning disabilities, behavioral problems, and to have a low IQ. In adults, lead toxicity may result in kidney damage, high blood pressure, and anemia.

Several cross-sectional studies have reported an inverse association between vitamin C status and blood lead concentration. For instance, in a study of 747 older men, blood lead concentration was significantly higher in those who reported total dietary vitamin C intakes averaging less than 109 mg/day compared to those with higher vitamin C intakes (181). A much larger study of 19,578 people, including 4,214 children from 6 to 16 years of age, found higher serum vitamin C concentrations to be associated with significantly lower blood lead concentrations (182). A US national survey of more than 10,000 adults found that blood lead concentrations were inversely related to serum vitamin C concentrations (183).

Cigarette smoking or second-hand exposure to cigarette smoke contributes to increased blood lead concentration and a state of chronic low-level lead exposure. An intervention trial in 75 adult male smokers found that supplementation with 1,000 mg/day of vitamin C resulted in significantly lower blood lead concentration over a four-week treatment period compared to placebo (184). A lower dose of 200 mg/day did not significantly affect blood lead concentration, although serum vitamin C concentrations were not different from those in the group who took 1,000 mg/day.

The mechanism(s) by which vitamin C reduces blood lead concentration is not known, yet it has been proposed that vitamin C could inhibit intestinal absorption (184) or enhance urinary excretion of lead (185).

Sources

Unlike plants and most animals, humans have lost the ability to synthesize vitamin C endogenously and therefore have an essential dietary requirement for this vitamin (see The Recommended Dietary Allowance). Results from 7,277 participants in the US National Health and Nutrition Examination Survey (NHANES) 2003-2004 indicated that an estimated 7.1% of individuals ages ≥6 years were deficient in vitamin C — based on serum vitamin C concentrations <11.4 μmol/L (36). The national study identified smokers and those of lower socioeconomic status to both be at higher risk for vitamin C deficiency (36).

Food sources

As shown in Table 3, different fruit and vegetables vary in their vitamin C content, but five servings (2½ cup-equivalents) of a variety of fruit and vegetables should average out to about 150 to 200 mg of vitamin C, especially if vitamin C-rich fruits are consumed. If you wish to check foods for their vitamin C content, search USDA's FoodData Central.

Table 3. Some Food Sources of Vitamin C
Food Serving Vitamin C (mg)
Kiwifruit, Zespri SunGold 1 fruit (81 g) 131
Grapefruit juice, pink, raw ¾ cup (6 ounces) 94
Orange juice, raw ¾ cup (6 ounces) 93
Strawberries 1 cup, whole 85
Grapefruit juice, white, raw ¾ cup (6 ounces) 70
Kiwifruit 1 fruit (74 g) 69
Orange 1 medium 65
Sweet red pepper, raw ½ cup, chopped 59
Broccoli, cooked ½ cup 51
Grapefruit, raw ½ medium 44
Brussel sprouts, cooked ½ cup 37
Potato, white, flesh and skin 1 medium, baked 22
Tomato, red, ripe, raw 1 medium 17
Banana, raw 1 medium 10
Apple, raw 1 medium 8
Spinach, raw 1 cup 8

Supplements

Vitamin C (L-ascorbic acid) is available in many forms, but there is little scientific evidence that any one form is better absorbed or more effective than another. Most experimental and clinical research uses ascorbic acid or its sodium salt, called sodium ascorbate. Natural and synthetic L-ascorbic acid are chemically identical and there are no known differences regarding biological activities or bioavailability (186).

Mineral ascorbates

Mineral salts of vitamin C are considered less acidic than vitamin C and therefore are considered "buffered." Some people find them less irritating to the gastrointestinal tract than ascorbic acid. Sodium ascorbate and calcium ascorbate are the most common forms, although a number of other mineral ascorbates are available. Sodium ascorbate provides 111 mg of sodium (889 mg of ascorbic acid) per 1,000 mg of sodium ascorbate, and calcium ascorbate generally provides 90 to 110 mg of calcium (890-910 mg of ascorbic acid) per 1,000 mg of calcium ascorbate.

Vitamin C with flavonoids

Flavonoids are a class of water-soluble plant pigments that are often found in vitamin C-rich fruit and vegetables, especially citrus fruit and berries (see the article on Flavonoids). There is little evidence that the flavonoids in most commercial preparations increase the bioavailability or efficacy of vitamin C (187). Some, yet not all, studies in animal models such as vitamin C-deficient guinea pigs or genetically scorbutic rats found an increased uptake of vitamin C in peripheral circulation and specific organs in the presence of flavonoids. However, studies conducted in humans found no differences in bioavailability of vitamin C from flavonoid-rich whole fruit or fruit juice and synthetic vitamin C (reviewed in 186).

Vitamin C and metabolites

One supplement, Ester-C ® , contains mainly calcium ascorbate and includes small amounts of the vitamin C metabolites, dehydroascorbic acid (oxidized ascorbic acid), calcium threonate, and trace amounts of xylonate and lyxonate. Although these metabolites are purported to increase the bioavailability of vitamin C, the only published study in humans addressing this issue found no difference between Ester-C ® and commercially available vitamin C tablets with respect to the absorption and urinary excretion of vitamin C (187). Ester-C ® should not be confused with ascorbyl palmitate, which is also marketed as "vitamin C ester" (see below).

Ascorbyl palmitate

Ascorbyl palmitate is a vitamin C ester (i.e., ascorbic acid linked to a fatty acid). In this case, vitamin C is esterified to the saturated fatty acid, palmitic acid, resulting in a fat-soluble form of vitamin C. Ascorbyl palmitate has been added to a number of skin creams due to interest in its antioxidant properties, as well as its importance in collagen synthesis (see the separate article, Vitamin C and Skin Health) (188). Although ascorbyl palmitate is also available as an oral supplement, most of it is likely hydrolyzed to ascorbic acid and palmitic acid in the digestive tract before it is absorbed (189). Ascorbyl palmitate is marketed as "vitamin C ester," which should not be confused with Ester-C ® (see above).

Other formulations of vitamin C

One small placebo-controlled, cross-over trial in 11 men showed that the oral administration of 4 g of vitamin C resulted in a greater vitamin C concentration in plasma over a four-hour period when vitamin C was encapsulated in liposomes compared to unencapsulated vitamin C (190). Although liposomal encapsulation could increase vitamin C bioavailability, plasma vitamin C concentrations were much lower than those achieved with intravenous vitamin C administration (190).

For a more detailed review of scientific research on the bioavailability of different forms of vitamin C, see The Bioavailability of Different Forms of Vitamin C.

Safety

Toxicity

A number of possible adverse health effects of very large doses of vitamin C have been identified, mainly based on in vitro experiments or isolated case reports, and include genetic mutations, birth defects, cancer, atherosclerosis, kidney stones, "rebound scurvy," increased oxidative stress, excess iron absorption, vitamin B12 deficiency, and erosion of dental enamel. However, none of these alleged adverse health effects have been confirmed in subsequent studies, and there is no reliable scientific evidence that doses of vitamin C up to 10 g/day in adults are toxic or detrimental to health. The concern of kidney stone formation with vitamin C supplementation is discussed below.

With the latest RDA published in 2000, a tolerable upper intake level (UL) for vitamin C was set for the first time (Table 4). A UL of 2 g (2,000 mg) daily was recommended in order to prevent generally healthy adults from experiencing diarrhea and gastrointestinal disturbances (35). Such symptoms are not generally serious, especially if they resolve with temporary discontinuation of vitamin C supplementation.

Table 4. Tolerable Upper Intake Level (UL) for Vitamin C
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 400
Children 4-8 years 650
Children 9-13 years 1,200
Adolescents 14-18 years 1,800
Adults 19 years and older 2,000
*Source of intake should be from foods or formula only.

Kidney stones

Because oxalate is a metabolite of vitamin C, there is some concern that high vitamin C intake could increase the risk of calcium oxalate kidney stones. Some (24, 191, 192), but not all (193-195), studies have reported that supplemental vitamin C increases urinary oxalate concentrations. Whether any increase in oxalate levels would translate to an elevation in risk for kidney stones has been examined in several epidemiological studies. Two large prospective cohort studies, one following 45,251 men for six years and the other following 85,557 women for 14 years, reported that consumption of ≥1,500 mg of vitamin C daily did not increase the risk of kidney stone formation compared to those consuming <250 mg daily (196, 197). On the other hand, two other large prospective studies reported that a high intake of vitamin C was associated with an increased risk of kidney stone formation in men (198, 199). Specifically, the Health Professionals Follow-Up Study collected data on dietary and supplemental vitamin C intake every four years in 45,619 male health professionals (ages 40-75 years) (198). After 14 years of follow-up, it was found that men who consumed ≥1,000 mg/day of vitamin C had a 41% higher risk of kidney stones compared to men consuming <90 mg of vitamin C daily. In the Cohort of Swedish Men study, self-reported use of single-nutrient vitamin C supplements (taken seven or more times per week) at baseline was associated with a two-fold higher risk of incident kidney stones among 48,840 men (ages 45-79 years) followed for 11 years (199). Despite conflicting results, it may be prudent for individuals predisposed to oxalate kidney stone formation to avoid high-dose vitamin C supplementation.

Drug interactions

Overall, evidence suggesting specific drugs can lower blood vitamin C concentrations in humans is limited. Dihydropyridine calcium channel blockers (e.g., nicardipine, nifedipine) can inhibit vitamin C uptake by intestinal cells in vitro. However, a reduction in blood vitamin C concentrations with these drugs has not been reported in humans (200). Aspirin can impair vitamin C status if taken frequently (201).

Conversely, there are case reports suggesting that supplemental vitamin C may lower blood concentrations of some medications, such as fluphenazine (the antipsychotic drug, Prolixin) and indinavir (the antiretroviral drug, Crixivan) (200). There is some evidence, though controversial, that vitamin C interacts with anticoagulant medications like warfarin (Coumadin). Large doses of vitamin C may block the action of warfarin and thus lower its effectiveness. Individuals on anticoagulants should limit their vitamin C intake to <1 g/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy (200). In addition, vitamin C may bind aluminum in the gut and increase the absorption of aluminum-containing compounds (e.g., aluminum-containing antacids, aluminum-containing phosphate binders). People with impaired kidney function may be at risk for aluminum toxicity when supplemental vitamin C is taken at the same time as these compounds (200, 201). Finally, supplemental vitamin C may increase blood estrogen concentrations in women using oral contraceptives or hormone replacement therapy (200).

The potential effect of antioxidants during chemotherapy is not well understood, yet only likely to be an issue if a specific chemotherapeutic agent acts through an oxidative mechanism, which is uncommon (171). It is not clear whether vitamin C given parenterally could diminish or increase the efficacy of chemotherapy drugs — in particular, akylating agents (e.g., cyclophosphamide, busulfan), antitumor antibiotics (e.g., doxorubicin, bleomycin), and arsenic trioxide. Patients are advised to discuss with their oncologist before using vitamin C supplements (200, 201).

Because high doses of vitamin C have also been found to interfere with the interpretation of certain laboratory tests (e.g., serum bilirubin, serum creatinine, and the stool guaiac assay for occult blood), it is important to inform one's health care provider of any recent supplement use.

Antioxidant supplements and HMG-CoA reductase inhibitors (statins)

A three-year randomized controlled trial in 160 patients with documented coronary heart disease and low blood HDL concentrations found that a combination of simvastatin (Zocor) and niacin increased HDL concentration, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke (202). Surprisingly, when an antioxidant combination (1,000 mg vitamin C, 800 IU vitamin E, 100 mg selenium, and 25 mg β-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of vitamin C cannot be determined. In contrast, a much larger trial in more than 20,000 men and women with coronary heart disease or diabetes mellitus found that simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene daily) did not diminish the cardioprotective effects of simvastatin therapy over a five-year period (203). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering drugs, such as HMG-CoA reductase inhibitors (statins).

Does vitamin C promote oxidative damage under physiological conditions?

Vitamin C is known to function as a highly effective antioxidant in living organisms. However, in test tube experiments, vitamin C can interact with some free metal ions and lead to the generation of potentially damaging free radicals. Although free metal ions are not generally found under physiological conditions, the idea that high doses of vitamin C might be able to promote oxidative damage in vivo has received a great deal of attention. Widespread publicity has been given to a few studies suggesting a pro-oxidant effect of vitamin C (204, 205), but these studies turned out to be either flawed or of no physiological relevance. A comprehensive review of the literature found no credible scientific evidence that supplemental vitamin C promotes oxidative damage under physiological conditions or in humans (206).

Linus Pauling Institute Recommendation

Combined evidence from metabolic, pharmacokinetic, and observational studies, and from randomized controlled trials supports consuming sufficient vitamin C to achieve plasma concentrations of at least 60 μmol/L. While most generally healthy young adults can achieve these plasma concentrations with daily vitamin C intake of at least 200 mg/day, some individuals may have a lower vitamin C absorptive capacity than what is currently documented. Thus, the Linus Pauling Institute recommends a vitamin C intake of 400 mg daily for adults to ensure replete tissue concentrations (29) — an amount substantially higher than the RDA yet with minimal risk of side effects.

This recommendation can be met through food if the diet includes at least several servings of vitamin C-rich fruit and vegetables (e.g., citrus fruit, kiwifruit, peppers see Food sources) as part of the daily recommended fruit and vegetable intake (see article on Fruit and Vegetables). Most multivitamin supplements provide at least 60 mg of vitamin C.

Older adults (>50 years)

Whether older adults have higher requirements for vitamin C is not yet known with certainty, yet some older populations have been found to have vitamin C intakes considerably below the RDA of 75 and 90 mg/day for women and men, respectively (207). A vitamin C intake of at least 400 mg daily may be particularly important for older adults who are at higher risk for age-related chronic diseases. Pharmacokinetic studies in older adults have not yet been conducted, but there is some evidence suggesting that the efficiency of one of the molecular mechanisms for the cellular uptake of vitamin C declines with age (208). Because maximizing blood concentrations of vitamin C may be important in protecting against oxidative damage to cells and biological molecules, a vitamin C intake of at least 400 mg daily might benefit older adults who are at higher risk for chronic diseases caused, in part, by oxidative damage, such as heart disease, stroke, certain cancers, and cataract.

Authors and Reviewers

Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2013 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2018 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2018 by:
Anitra C. Carr, Ph.D.
Research Associate Professor
Department of Pathology & Biomedical Science
University of Otago
Christchurch, New Zealand

Reviewed in December 2018 by:
Alexander J. Michels, Ph.D.
Research Associate
Linus Pauling Institute
Oregon State University

Copyright 2000-2021 Linus Pauling Institute

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Selenium

Overview

This section contains the following key information:

    is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.
  • The results of epidemiologic studies suggest some complexity in the association between blood levels of selenium and the risk of developing prostate cancer.
  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenterclinical trial, was initiated to examine the effects of selenium and/or vitamin E on the development of prostate cancer.
  • Initial results of SELECT, published in 2009, showed no statistically significant difference in the rate of prostate cancer in men who were randomly assigned to receive the selenium supplements.
  • In 2011, updated results from SELECT showed no significant effects of selenium supplementation on prostate cancer risk, but men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took a placebo.
  • In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer.

General Information and History

Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[1] A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.

Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg.[2] Most dietary selenium occurs as selenocysteine or selenomethionine.[1] Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.[3]

Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.[4] However, at high concentrations, selenium may function as a pro-oxidant.[2]

Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder.[5] Some clinical trials have suggested that high levels of selenium may be associated with diabetes [6] and high cholesterol.[2]

Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.[7] The Nutritional Prevention of Cancer Trial (NPC) was a randomized, placebo-controlled study designed to test the hypothesis that higher selenium levels were associated with lower incidence of skin cancer. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung, colorectal, and prostate cancer were significantly reduced.[8]

There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and SEPP have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[7]

Some companies distribute selenium as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval of such supplements by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of selenium as a treatment or prevention for cancer.

Preclinical/Animal Studies

In vitro studies

Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[9] In a 2011 study, prostate cancer cells were treated with various forms of selenium selenite and methylseleninic acid (MSeA) had the greatest cytotoxic effects.[10]

Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.[11]

Sodium selenite

In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[12]

In a second study, the prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells.[13]

One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite while growth inhibition occurred in PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have adverse effects in hormone-sensitive prostate cancer.[14] However, the relevance of these findings to the clinical setting is unclear. These experiments used selenium concentrations of 1 µg/mL to 10 µg/mL, whereas the average U.S. adult male serum selenium concentrations are about 0.125 µg/mL,[15] and prostate tissue concentrations are about 1.5 µg/g.[16]

Animal studies

A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.[17]

At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite.[18] Another study investigated the effect of age on selenium chemoprevention in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared with selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.[19]

The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse.[20] Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared with treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate differentiation, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection.[21] One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[22]

Human Studies

Epidemiologic studies

The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations.[23] In a prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males.[24] However, in a 2009 study of prostate cancer patients, men with higher plasma selenium levels were at greater risk of being diagnosed with aggressive prostate cancer.[25]

Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, polymorphisms in the selenium-containing enzymes GPX1 and SEP15 genes were found to be associated with prostate cancer risk.[23] Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with single nucleotide polymorphisms (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status.[26] A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer–specific mortality. Among SNPs analyzed, only GPX1 rs3448 was related to overall prostate cancer risk.[27]

A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status.[28] In the Physicians' Health Study, links between SNPs in the SEPP gene (SEPP1) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: rs11959466 was associated with increased risk, and rs13168440 was associated with decreased risk. Tumor SEPP1 mRNA expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer.[29] In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (AA) genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine (V) allele.[25]

An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% confidence interval [CI], 0.73𔂿.91), 1.33-fold (95% CI, 0.77𔃀.30), and 2.60-fold (95% CI, 1.44𔃂.70) increased prostate cancer mortality risk compared with nonusers, respectively (Ptrend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.[30]

Intervention studies

Sixty adult males were randomly assigned to receive either a daily placebo or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen (PSA) at the end of the study.[31]

A meta-analysis published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).[32]

In another study, prostate cancer patients were randomly assigned to receive either combination silymarin (570 mg) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol.[33]

In one study, 140 prostate cancer patients undergoing active surveillance were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of Se-yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[34]

In 2013, results of a phase III randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported. Subjects (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high–Se-yeast (200 µg/d or 400 µg/d). They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[35] In an earlier study, men with HGPIN were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results suggested that selenium supplementation had no effect on prostate cancer risk.[36]

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

On the basis of findings from earlier studies,[8,37] the SELECT, a large multicenter clinical trial, was initiated by the National Institutes of Health in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[38] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico, were randomly assigned to receive vitamin E (alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[38]

Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06) in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[39]

Updated results were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.[40]

A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and Se-yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores.[41] In addition, there were concerns about product consistency with high–Se-yeast.[42] However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[43,44]

Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline but increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (P = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes.[45]

An international collaboration compiled and reanalyzed data from 15 studies that investigated the association between blood and toenail selenium concentrations and prostate cancer risk.[46] In the analysis of 6,497 men with prostate cancer and 8,107 controls, blood selenium level was not associated with the risk of total prostate cancer, but high blood selenium level was associated with a lower risk of aggressive disease. Toenail selenium concentration was inversely associated with risk of total prostate cancer (odds ratio, 0.29 95% CI, 0.22𔂾.40 Ptrend < .001), including both aggressive and nonaggressive disease.

In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of SNPs in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[47]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[34,35] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).[39]

References
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  14. Kandaş NO, Randolph C, Bosland MC: Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 61 (2): 251-64, 2009. [PUBMED Abstract]
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  16. Takata Y, Morris JS, King IB, et al.: Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 69 (15): 1635-42, 2009. [PUBMED Abstract]
  17. Waters DJ, Shen S, Kengeri SS, et al.: Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis. Nutrients 4 (11): 1650-63, 2012. [PUBMED Abstract]
  18. Li GX, Lee HJ, Wang Z, et al.: Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29 (5): 1005-12, 2008. [PUBMED Abstract]
  19. Holmstrom A, Wu RT, Zeng H, et al.: Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice. J Nutr Biochem 23 (9): 1086-91, 2012. [PUBMED Abstract]
  20. Wang L, Bonorden MJ, Li GX, et al.: Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2 (5): 484-95, 2009. [PUBMED Abstract]
  21. Zhang J, Wang L, Anderson LB, et al.: Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3 (8): 994-1006, 2010. [PUBMED Abstract]
  22. Gundimeda U, Schiffman JE, Chhabra D, et al.: Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells. J Biol Chem 283 (50): 34519-31, 2008. [PUBMED Abstract]
  23. Steinbrecher A, Méplan C, Hesketh J, et al.: Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 19 (11): 2958-68, 2010. [PUBMED Abstract]
  24. Muecke R, Klotz T, Giedl J, et al.: Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 48 (3): 452-6, 2009. [PUBMED Abstract]
  25. Chan JM, Oh WK, Xie W, et al.: Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer. J Clin Oncol 27 (22): 3577-83, 2009. [PUBMED Abstract]
  26. Méplan C, Rohrmann S, Steinbrecher A, et al.: Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer. PLoS One 7 (11): e48709, 2012. [PUBMED Abstract]
  27. Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013. [PUBMED Abstract]
  28. Meyer HA, Hollenbach B, Stephan C, et al.: Reduced serum selenoprotein P concentrations in German prostate cancer patients. Cancer Epidemiol Biomarkers Prev 18 (9): 2386-90, 2009. [PUBMED Abstract]
  29. Penney KL, Li H, Mucci LA, et al.: Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival. Prostate 73 (7): 700-5, 2013. [PUBMED Abstract]
  30. Kenfield SA, Van Blarigan EL, DuPre N, et al.: Selenium supplementation and prostate cancer mortality. J Natl Cancer Inst 107 (1): 360, 2015. [PUBMED Abstract]
  31. Zhang W, Joseph E, Hitchcock C, et al.: Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr Res 31 (2): 165-8, 2011. [PUBMED Abstract]
  32. Hurst R, Hooper L, Norat T, et al.: Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 96 (1): 111-22, 2012. [PUBMED Abstract]
  33. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010. [PUBMED Abstract]
  34. Stratton MS, Algotar AM, Ranger-Moore J, et al.: Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer. Cancer Prev Res (Phila) 3 (8): 1035-43, 2010. [PUBMED Abstract]
  35. Algotar AM, Stratton MS, Ahmann FR, et al.: Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer. Prostate 73 (3): 328-35, 2013. [PUBMED Abstract]
  36. Marshall JR, Tangen CM, Sakr WA, et al.: Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila) 4 (11): 1761-9, 2011. [PUBMED Abstract]
  37. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
  38. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PUBMED Abstract]
  39. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [PUBMED Abstract]
  40. Klein EA, Thompson IM, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [PUBMED Abstract]
  41. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [PUBMED Abstract]
  42. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [PUBMED Abstract]
  43. Hatfield DL, Gladyshev VN: The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9 (1): 18-21, 2009. [PUBMED Abstract]
  44. Ohta Y, Kobayashi Y, Konishi S, et al.: Speciation analysis of selenium metabolites in urine and breath by HPLC- and GC-inductively coupled plasma-MS after administration of selenomethionine and methylselenocysteine to rats. Chem Res Toxicol 22 (11): 1795-801, 2009. [PUBMED Abstract]
  45. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [PUBMED Abstract]
  46. Allen NE, Travis RC, Appleby PN, et al.: Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies. J Natl Cancer Inst 108 (11): , 2016. [PUBMED Abstract]
  47. Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-1058, 2016. [PUBMED Abstract]

Overview

This section contains the following key information:

    foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
  • Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.
  • Genistein affects components of multiple growth and proliferation-related pathways in prostate cancercells, including the COX-2/prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.
  • Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
  • Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis. studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
  • Early-phase clinical trials with isoflavones, soy, and soy products for the prevention and treatment of prostate cancer have been limited to relatively short durations of intervention and sample sizes with low statistical power. These studies targeted heterogeneous prostate cancer patient populations (in high-risk, early- and later-stage disease) and varying doses of isoflavones, soy, and soy products, and have not demonstrated evidence of reducing prostate cancer progression.
  • Other trials evaluating the role of isoflavones, soy, or soy products in the management of androgen deprivation therapy (ADT) side effects have found no improvement with isoflavone treatment compared with placebo.
  • Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.

General Information and History

Soybean, a major food source and a medicinal substance, has been used in China for centuries. Soybean was used as one of the early food sources in China.[1,2] Soybean was mentioned in the book titled, The Classic of Poetry (Shijing, 11th𔃅th centuries BCE), with its collection and cultivation. During the Warring States period (475� BCE), soybean became one of five major foods (“five grains”) of the Chinese. The medical use of soybean was also discussed in one of the major Chinese medicine books titled, Inner Canon of the Yellow Emperor (Huangdi Neijing, 400 BCE and 260 BCE), which stated that “five grains are used to nourish and replenish the body." In traditional Chinese medicine, soybean has been used to treat kidney conditions, promote water retention and reduce swelling, and for weakness, dizziness, poor sleep, and night sweats.

Although records of soy use in China date back to the 11th century BCE, it was not until the 18th century that the soy plant reached Europe and the United States. The soybean is an incredibly versatile plant. It can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[3]

Soy foods contain a number of phytochemicals that may have health benefits, but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[4] Other isoflavones found in soy include daidzein and glycitein.[5] Many of these isoflavones are also found in other legumes and plants, such as red clover.

Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours after soy product consumption.[6] Isoflavones are phytoestrogens that bind to estrogen receptors. Prostate tissue is known to express estrogen receptor beta and it has been shown that the isoflavone genistein has greater affinity for estrogen receptor beta than for estrogen receptor alpha.[7]

A link between isoflavones and prostate cancer was first observed in epidemiological studies that demonstrated a lower risk of prostate cancer in populations consuming considerable amounts of dietary soy.[8,9] Subsequent studies evaluating the role of soy in experimental models further showed anticancer properties of soy, specifically relevant to prostate carcinogenesis. These early studies have led to a few clinical trials in humans using soy food products or supplements that targeted men with varying stages of prostate cancer. Although these studies showed modulation of intermediate endpoints or surrogate biomarkers of prostate cancer progression, the results indicating beneficial effects from soy or soy products have been mixed.

Several companies distribute soy as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval of such supplements by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of soy as a treatment for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

Individual isoflavones

A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[10] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin-8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[11] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro. However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[12]

Combinations of isoflavones

Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzein, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggested that products containing a combination of active compounds (e.g., whole foods) may be more effective in preventing cancer than individual compounds.[13] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[14]

At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[15]

Animal studies

Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors epidermal growth factor receptor (EGFR) and insulin like growth factor-1 receptor (IGF-1R) in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[16] In one study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[17]

In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis but no change in primary tumor volume, compared with mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[18]

In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/d or 400 mg genistein/kg body weight/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[19]

Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/d), mixed isoflavones (50 mg/kg body weight/d contained 43% genistein, 21% daidzein, and 2% glycitein), and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[20]

In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[21,22]

Human Studies

Human studies evaluating isoflavones and soy for the prevention and treatment of prostate cancer have included epidemiological studies and early-phase trials. Several phase I-II randomized clinical studies have examined isoflavones and soy product for bioavailability, safety, and effectiveness in prostate cancer prevention or treatment.[23-25] These studies have included a wide range of subject populations, including high-risk men prostate cancer patient populations (localized and later-stage disease) varying doses of isoflavones, soy, and soy products and were limited to relatively short durations of observation or intervention and sample sizes with low statistical power.

Epidemiologic studies

In 2018, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[26] However, these data from population studies must be interpreted with caution as the studies relied on self-reported data obtained using varying forms of dietary data collection instruments with recall bias, in addition to numerous forms of individual or multiple isoflavones, soy supplements, and soy foods. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.

Prevention studies

Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (refer to Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5󈝶 mcg/mL at baseline). The duration of intervention was between 6 months [15] and 1 year [27,28], with varying formulations of isoflavones derived from soy [15,27] and red clover.[28] In a single trial that showed no significant changes in serum PSA after intervention with isoflavones, a reduction in prostate cancer progression at 1 year in a subgroup of men older than 65 years was demonstrated. Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials.

Table 3. Randomized Placebo-controlled Trials of Isoflavones or Soy for Prostate Cancer Prevention a
ReferenceIsoflavone DoseTreatment Groups (Enrolled Treated Placebo or No Treatment Control)Duration of InterventionToxicitiesResultsLevels of Evidence
ALT = alanine transaminase AST = aspartate transaminase PCa = prostate cancer PSA = prostate-specific antigen.
a Men with a negative biopsy and elevated PSA max 10 mcg/mL.
[15]Soy isoflavones (40 mg/d comprising 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg/d) versus placebo 85 43 426 moNo significant adverse effects either in the placebo or supplement groups one subject on placebo experienced severe diarrhea during the trial and dropped out subsequently Decrease in serum PSA (P < .05)1iDii
[28]60 mg/d isoflavone extract from red clover 20 20 None12 moSignificant increase in ALT and AST after 3 mo (P < .001)Decrease in serum PSA (P < .05) 2Dii
[27]60 mg/d isoflavones 158 78 8012 moTwo patients had grade 3 adverse events, one in the isoflavone group suffered iliac artery stenosis and the other in the placebo group suffered ileus other adverse events were mild in severity Decrease in PCa incidence in men older than 65 years with isoflavones (P < .05)1iDi

Treatment of prostate cancer

Clinical trials evaluating isoflavones, soy supplements, and soy products (refer to Table 4 and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.

Isoflavones
Table 4. Randomized Placebo-controlled Trials of Isoflavones Before Prostatectomy in Men With Localized Prostate Cancer
ReferenceIsoflavone DoseTreatment Groups (Enrolled Treated Placebo or No Treatment Control)Duration of InterventionToxicitiesResultsLevels of Evidence
AR = androgen receptor PSA = prostate-specific antigen.
[29]30 mg/d genistein 54 23 243𔃄 wkClinical adverse events were Grade 1 (mild) two biochemical adverse events recorded, both in the genistein group (one increase in serum lipase, one increase in serum bilirubin) potentially related to study agent Decrease in serum PSA (P < .05), decrease in total cholesterol (P < .01), increase in plasma genistein (P < .001)1iDiii
[30]Soy isoflavone capsules (total isoflavones, 80 mg/d) 86 42 446 wkAll adverse events were Grade 1 (mild) Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared with men receiving placebo were not statistically significant1iDii
[31]Supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones/d versus placebo followed by open-label 53 28 256 mo intervention followed by 6 mo open label (active surveillance)Not evaluatedSignificant increase in serum genistein and daidzein no significant findings regarding serum PSA changes1iDii
[32,33]Isoflavone tablets (60 mg/d) 60 25 284󈝸 wkAdverse events were Grade I and II in both groups, with two events that were identified as Grade III in the treatment arm and determined to be unrelated to agent (constitutional symptoms of fever related to a viral infection) Increase in plasma isoflavones (P < .001) in the isoflavone-treated group versus placebo greater concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) were inversely correlated with changes in serum PSA1iDii
[32,34]Isoflavone capsules 40, 60, or 80 mg 4512 (40 mg), 11 (60 mg) ,10 (80 mg) 1127󈞍 dAdverse events were Grade I-II Increased plasma isoflavones at all doses increased serum total estradiol in the 40 mg (P = .02) isoflavone-treated arm versus placebo increased serum-free testosterone in the 60 mg isoflavone-treated arm (P = .003)1iiDii
[35]Cholecalciferol (vitamin D3) 200,000 IU + genistein (G-2535) 600 mg/d 15 7 821󈞈 dAdverse events occurred in four patients in the placebo group and five patients in the vitamin D + genistein group Increased AR expression (P < .05) no other significant findings1iiDii
Soy protein or whole soy products
Table 5. Randomized Placebo-controlled Trials of Soy Protein or Soy Products Before Prostatectomy in Men With Localized Prostate Cancer
ReferenceIntervention DoseTreatment Groups (Enrolled Treated Placebo or No Treatment Control)Duration of InterventionToxicitiesResultsLevels of Evidence
COX = cyclooxygenase GI = gastrointestinal PSA = prostate-specific antigen.
[36]Soy supplement with 60 mg isoflavone versus placebo supplement 60 29 30 12 wkNine grade I-II GI toxicities in the placebo group and eight from the isoflavone groupNo significant findings1iDii
[37]Soy supplements (three 27.2 mg tablets/d each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo 19 11 8 2 wk before surgeryNot evaluated Higher isoflavone concentration (x6) in tissue than in serum following treatment with the soy supplements1iDiii
[38]Soy isoflavone supplements (total isoflavones, 160 mg/d and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) 33 17 1612 wkNot evaluatedNo significant difference between groups1iDii
[39]Soy (high phytoestrogen), soy and linseed (high phytoestrogen), or wheat (low phytoestrogen) 29 8 (soy), 10 (soy and linseed) 8 (wheat) 8󈝸 wkNot evaluatedReduction in total PSA (P = .02) percentage of change in free/total PSA ratio (P = .01) percentage of change in free androgen index (P = .04) 1iDii
[10]Soy isoflavone supplement (providing isoflavones, 81.6 mg/d) or placebo 25 13 122 wk before surgery (pilot)Not evaluatedDecrease in COX-2 mRNA levels (P < .01) increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with placebo group1iDii

Isoflavones and soy products for biochemical recurrence after treatment

Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [40-43] with one study suggesting modulation of systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of myeloid-derived suppressor cells [43] (refer to Table 6).

Table 6. Clinical Trials of Soy and Soy Products in Men on Active Surveillance or With Biochemical Recurrence After Treatment for Prostate Cancer
ReferenceTrial DesignDoseDuration of InterventionTreatment Group (Enrolled Treated Placebo or No Treatment Control)ToxicitiesResultsLevels of Evidence
GCP = genistein combined polysaccharide GI = gastrointestinal PCa = prostate cancer RCT = randomized controlled trial.
[40] Nonrandomized Soy beverage daily (providing approximately 65󈟆 mg isoflavones)6 mo34 29 NoneAdverse events included minor GI side effectsNo statistically significant findings regarding PSA, PSA-doubling time2C
[41]Open-label Soy milk 3x/d (isoflavones, 141 mg/d)12 mo20 20 NoneToxicity data lacks details GI (loose stools) toxicities were the most common complaint from a small number of men in the GCP group No statistically significant findings regarding serum PSA changes2Dii
[42]RCT Beverage powder containing soy-protein isolate (20 g protein) or calcium caseinate2 y177 87 90All adverse events were grades I-II there were no differences in adverse events between the two groups No significant findings regarding serum PSA changes1iDii
[43]RCTTwo slices of soy bread containing 68 mg/d soy isoflavones or soy bread containing almond powder56 d32 25 NoneSoy and soy-almond breads were without grade 2 or higher toxicitySignificant modulation of multiple plasma cytokines and chemokines1iiDii

Management of androgen deprivation therapy side-effects

ADT is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo.[44,45]

The third randomized placebo-controlled trial assessed changes in PSA level and biomarkers of energy metabolism (e.g., blood glucose level) and inflammation (e.g., blood interleukin-6 level). In this study of men undergoing ADT, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/d total isoflavones, and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[38]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Overall, isoflavones, soy, and soy products were well tolerated in clinical trials of high-risk prostate cancer patients.[28,31,37,41,44,46] The most commonly reported side effects were gastrointestinal symptoms.[31,40,47]

References
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7. Lion’s Mane: A “Smart” Mushroom

Lion’s mane (Hericium erinaceus), also known as yamabushitake, is an edible mushroom native to parts of Asia, North America, and Europe.

It’s been used medicinally and as a culinary delicacy for thousands of years.

Lion’s mane mushroom.

Now it’s sold as a brain supplement.

It’s been said that lion’s mane can impart “nerves of steel and the memory of a lion.”

World-renowned fungi expert Paul Stamets calls it the “first smart mushroom.” (71)

Lion’s mane is a popular nootropic — a substance that improves mental functions such as memory, intelligence, motivation, attention, and concentration while simultaneously making your brain healthier.

Lion’s mane excels at improving cognitive function and treating neurological disorders.

It contains two unique groups of compounds, hericenones and erinacines, that stimulate the formation of nerve growth factor (NGF). (72)

NGF is a protein that is crucial to the growth and maintenance of certain types of neurons.

Lion’s mane can also be helpful for anxiety, depression, Alzheimer’s, and Parkinson’s. (73)

Suggested Lion’s Mane Dosage

Optimal dosages have not yet been established, but a typical dose of lion’s mane extract is 1,000 mg taken three times a day. (74)

In one study, seniors with mild cognitive impairment, which can be a precursor to dementia, experienced significant cognitive improvement taking 3,000 mg of lion’s mane powder daily. (75)

Lion’s mane is available in capsules, powder, liquid tincture, or tea.

You may even find it fresh in Asian or gourmet food stores.

Lion’s Mane Side Effects, Interactions, and Warnings

Lion’s mane is extremely safe.

The only known side effect is itchy skin which is believed to be caused by the increase in nerve growth factor. (76)

Lion’s mane mushroom may not be safe to mix with supplements that affect blood clotting.

Think more clearly, learn faster, and remember more.

Dr. Pat | Be Brain Fit


Summary of Fat-soluble Vitamins

Table 9.10 Fat-Soluble Vitamins

Vitamin Sources Recommended Intake for adults Major functions Deficiency diseases and symptoms Groups at risk of deficiency Toxicity UL
Vitamin A (retinol, retinal, retinoic acid,carotene, beta-carotene) Retinol: beef and chicken liver, skim milk, whole milk, cheddar cheese Carotenoids: pumpkin, carrots, squash, collards, peas 700-900 mcg/day Antioxidant,vision, cell differentiation, reproduction, immune function Xerophthalmia, night blindness, eye infections poor growth, dry skin, impaired immune function People living in poverty (especially infants and children), premature infants, pregnant and lactating women people who consume low-fat or low-protein diets Hypervitaminosis A: Dry, itchy skin, hair loss, liver damage, joint pain, fractures, birth defects, swelling of the brain 3000 mcg/day
Vitamin D Swordfish, salmon, tuna, orange juice (fortified), milk (fortified), sardines, egg, synthesis from sunlight 600-800 IU/day (15-20 mcg/day) Absorption and regulation of calcium and phosphorus, maintenance of bone Rickets in children: abnormal growth, misshapen bones, bowed legs, soft bones osteomalacia in adults Breastfed infants, older adults people with limited sun exposure, people with dark skin Calcium deposits in soft tissues, damage to the heart, blood vessels, and kidneys 4000 IU/day (100 mcg/day)
Vitamin E Sunflower seeds, almonds, hazelnuts,peanuts 15 mg/day Antioxidant, protects cell membranes Broken red blood cells, nerve damage People with poor fat absorption, premature infants Inhibition of vitamin K clotting factors 1000 mcg/day from supplemental sources
Vitamin K Vegetable oils, leafy greens, synthesis by intestinal bacteria 90-120 mcg/day Synthesis of blood clotting proteins and proteins needed for bone health and cell growth Hemorrhage Newborns, people on long term antibiotics Anemia, brain damage ND

Learning Activities

Technology Note: The second edition of the Human Nutrition Open Educational Resource (OER) textbook features interactive learning activities. These activities are available in the web-based textbook and not available in the downloadable versions (EPUB, Digital PDF, Print_PDF, or Open Document).

Learning activities may be used across various mobile devices, however, for the best user experience it is strongly recommended that users complete these activities using a desktop or laptop computer and in Google Chrome.

  1. Sommer A. (2008). Vitamin A Deficiency and Clinical Disease: An Historical Overview. Journal of Nutrition, 138, 1835–39. http://jn.nutrition.org/content/138/10/1835.long. Accessed October 4, 2017. &crarr
  2. Goodman GE, et al. (2004). The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-year Follow-up after Stopping Beta-Carotene and Retinol Supplements. Journal of the National Cancer Institute, 96(23), 1743–50. http://jnci.oxfordjournals.org/content/96/23/1743.long. Accessed October 6, 2017. &crarr
  3. Dietary Supplement Fact Sheet: Vitamin A. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminA-QuickFacts/. Updated September 5, 2012. Accessed October 7, 2017. &crarr
  4. Bischoff-Ferrari, HA, et al. (2005). Fracture Prevention with Vitamin D Supplementation: A Meta-Analysis of Randomized Controlled Trials. Journal of the American Medical Association, 293(18), 2257–64. http://jama.ama-assn.org/content/293/18/2257.long. Accessed October 12, 2017. &crarr
  5. Goodman M, Bostlick RM, Kucuk O, Jones DP. (2011). Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radical Biology & Medicine, 51(5), 1068–84. https://www.ncbi.nlm.nih.gov/pubmed/21683786. Accessed October 5, 2017. &crarr
  6. McGinley C, Shafat A. Donnelly AE. (2009). Does antioxidant vitamin supplementation protect against muscle damage. Sports Medicine, 39(12), 1011–32. https://www.ncbi.nlm.nih.gov/pubmed/19902983. Accessed October 5, 2017. &crarr
  7. Waters DD, et al. (2002). Effects of Hormone Replacement Therapy and Antioxidant Vitamin Supplements on Coronary Atherosclerosis in Postmenopausal Women: A Randomized Controlled Trial. TheJournal of the American Medical Association,288(19), 2432–40. https://jamanetwork.com/journals/jama/fullarticle/195531. Accessed October 5, 2017. &crarr
  8. HOPE and HOPE-TOO Trial Investigators. (2005). Effects of Long-Term Vitamin E Supplementation on Cardiovascular Events and Cancer. The Journal of the American Medical Association, 293, 1338–47. http://jama.ama-assn.org/content/293/11/1338.long., Accessed October 5, 2017. &crarr
  9. Lee IM, et al. (2005). Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer: The Women’s Health Study. The Journal of the American Medical Association,294, 56–65. http://jama.ama-assn.org/content/294/1/56.long. Accessed October 5, 2017. &crarr
  10. Devore EE, et al. (2010). Dietary Antioxidants and Long-Term Risk of Dementia, Archives of Neurology, 67(7), 819–25. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923546/?tool=pubmed. Accessed October 5, 2017. &crarr
  11. Dietary Supplement Fact Sheet: Vitamin E.National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminE-QuickFacts/. Updated October 11, 2011. Accessed October 5, 2017. &crarr

A fat-soluble vitamin that is needed for cell differentiation, reproduction, and vision.

Forms of preformed vitamin A.

Vitamin A in its alcohol form.

Vitamin A in its aldehyde form.

A class of retinoids that can serve as precursors of vitamin A.

A carotenoid that can be cleaved to release two retinol molecules.

A carotenoid that is found in most plant foods like leafy green vegetables, carrots, and squash.

A carotenoid that is found in most plant foods like corn, green peppers, and lemon.

Compounds that inhibit the oxidation of other substances.

A substance that does not dissolve in water. Examples include triglycerides and vitamins A, D, E & K.

The lowest density lipoprotein particles which contain triglycerides, monoglycerides, and small amounts of cholesterol and phospholipids.

A protein that is essential for the transport of vitamin A from the liver to the tissues in need.

A condition due to a deficiency in vitamin A where the eye recovers very slowly from exposure to bright light.

A major antioxidant that prevents damage to important cellular components caused by reactive oxygen species

A highly reactive atom or molecule that causes oxidative damage.

An advanced form of eye lesions resulting from vitamin A deficiency.

Organic compounds that are needed in small amounts in the diet to support and regulate the chemical reactions and processes needed for growth, reproduction, and the maintenance of health.

Essential nutrients that are needed by the body in small amounts. These include vitamins and minerals.

(Recommended Dietary Allowance) The levels of intake of essential nutrients that is based off of scientific knowledge, and it judged by the Food and Nutrition Board to be adequate to meet the known nutrient needs for all healthy people.

(Tolerable Upper Intake Level) The maximum daily nutrient intake levels that are likely to pose health risks to almost all individuals in a given gender and life-stage group.

(Retinol Activity Equivalent) The amount of retinol, alpha-carotene, beta-carotene, or beta-cryptoxanthin that must be consumed to equal 1 mcg of retinol.

Comprised of several types of white blood cells that circulate in the blood and lymph. Jobs are to seek, recruit, attack, and destroy foreign invaders, such as bacteria and viruses.

A fat-soluble vitamin that can be made in the body when there is exposure to sunlight and is needed for the absorption of calcium.

A hormone that acts to increase blood calcium levels and is released from the parathyroid gland.

A disease that is characterized by softening of the bones due to poor calcium deposition within them because of a lack of vitamin D in the body.

A disease that is characterized by defective bone formation that may be due to a vitamin D deficiency or a lack of sunlight exposure.

A disorder affecting the bones that is characterized as a loss in bone mass, increased bone fragility, and increased risk of fractures.

The thickening of artery walls which is caused by the growth of hard deposits containing lipids and other materials.

A hormone secreted by the pancreas in response to elevated blood glucose levels to transport glucose into the muscle or fat cells.

Abnormally high blood pressure.

The organ system that includes the heart and blood vessels that circulates blood throughout the body.

A fat-soluble vitamin that functions as an antioxidant in the body.

The active form of vitamin E in humans.

A water soluble vitamin that is needed for the maintenance of collagen.

Damage resulting from an imbalance between oxidative oxygen molecules and antioxidant defenses.

The deterioration of a portion of the retina that results in loss of visual detail and eventually blindness.

A 6-carbon monosaccharide that is the major carbohydrate used to provide energy in the body.

The deterioration of an individual’s mental state that results in impaired memory, thinking, and judgement.

A disease that results in an irreversible loss of mental function.

A fat-soluble vitamin that is needed for blood clotting.

Chemical groups that bind to enzymes and assist in enzymatic catalysis.

A process where bone is continuously being broken down and reformed for growth and maintenance.

The major structural and supportive connective tissue of the body.

(Adequate Intake) The level of nutrient intake that should be used as a goal when no RDA exists. This value is an approximation of the nutrient intake that sustains health.


Synthetic Vs. Natural Vitamins: Why It Matters & How to Tell the Difference

Heather Dessinger 72 Comments This post contains affiliate links.

Have you ever found yourself standing in front of a store shelf, picking up bottle after bottle of “natural” vitamins and flipping them over to read the label? If the answer is yes, you may already know that many so-called natural vitamins actually use significant amounts of synthetic ingredients in their formulas.

How does that even happen, and does it matter? We’ll dive into those answers today – plus how to spot the synthetic stuff and natural forms to look for – and in a follow-up post I’ll explain what I use and why.