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Vitamin D Just Got More Complicated

June 10, 2025 by Dr. Steve Chaney

The Hidden Flaws Of Vitamin D Studies

Author: Dr. Stephen Chaney

If I can paraphrase a famous saying, the question is, “To D or not to D.” On the one hand, you are told that vitamin D is a miracle supplement. It cures all your ailments. On the other hand, you are told that vitamin D supplements are worthless. They are a waste of money.

The problem is that vitamin D studies are all over the map. Some have shown beneficial effects of vitamin D supplementation. Others have come up empty. That allows “experts” to cherry pick the studies that support their bias. No wonder you are so confused.

If you have read my books or previous issues of “Health Tips From the Professor”, you know there is no such thing as a perfect clinical study. They all have their flaws. Sometimes the flaws are obvious. But sometimes we never know the flaws. We just know those studies are outliers.

So, let’s delve a little deeper into vitamin D metabolism and the hidden flaws that may have prevented some studies from showing the benefits of vitamin D supplementation. Then we will look at new data suggesting that vitamin D supplementation is more complicated than anyone imagined.

A Vitamin D Primer

Let’s start with a brief review of vitamin D metabolism.

Vitamin D metabolism starts in the skin when 7-dehydrocholesterol (a metabolite of cholesterol) is converted to cholecalciferol (vitamin D3) in a reaction requiring sunlight.

- In this sense, vitamin D3 is a hormone produced by the body. It only became an essential nutrient (vitamin) when Homo sapiens migrated to Northern latitudes and started to spend most of their time indoors.

Vitamin D then travels to the liver where it is converted to 25-hydroxyvitamin D. This is the most abundant form of vitamin D in the blood.

25-hydroxyvitamin D next travels to the kidney where it is converted to 1,25-dihydroxyvitamin D. This is the active form of vitamin D. It is the form that binds to the vitamin D receptor.

Vitamin D was first discovered as an essential nutrient that was needed for adequate bone mineralization. It prevented rickets in children and osteomalacia in adults.

The role of vitamin D in building strong bones is well established.

However, a few decades ago, it was discovered that vitamin D receptors were found in many other tissues including skin, immune system, heart, muscle, brain and nerves, and fat cells. This revolutionized our understanding of vitamin D’s role in the body.

This led to suggestions that vitamin D played a role in immunity and autoimmune diseases, brain function and mood, heart health, muscle and fat metabolism, and much more. Here is where it started to get confusing.

- Some studies showed positive results. They found that vitamin D played an important role in each of these areas, and that vitamin D supplementation was beneficial

- Other studies showed negative results. They found no benefit of vitamin D supplementation.

So, the question arose, “Were the negative studies flawed?” In some cases, the answer was a clear, “Yes”. The flaws were easy to identify. In other cases, no obvious flaw could be discovered.

However, that has changed dramatically in recent years when some “hidden flaws” were discovered that invalidated many of the negative studies. That’s the topic of my next section.

The Hidden Flaws Of Vitamin D Studies

Most previous studies simply measured vitamin D intake:

In dietary studies, vitamin D intake was measured using diet questionnaires.

In supplement studies, vitamin D intake was measured by tracking whether the participants took all the supplement pills they were provided.

It was assumed that a certain dose of vitamin D produced the same blood levels of 1,25-dihydroxyvitamin D in everyone.

Now we know that assumption was flawed. The absorption and conversion of vitamin D to 1,25-dihydroxyvitamin D varies widely from individual to individual.

That means that every vitamin D study that relied on vitamin D intake without measuring its effect on blood 1,25-dihydroxyvitamin D levels is flawed. Their conclusions may or may not be true. Their evidence is unreliable.

I’m willing to give the authors of these studies some grace. They didn’t purposely design a flawed study. At the time they designed their studies we didn’t know about individual variability in the conversion of vitamin D to 1,25-dihydroxyvitamin D.

However, there is another “hidden flaw” I’m less willing to excuse. There have been some recent papers that measured 1,25-dihydroxyvitamin D levels before and after supplementation and have concluded that vitamin D supplementation had no benefit.

However, they failed to mention that the group they were studying already had adequate 1,25-dihydroxyvitamin D levels in their blood prior to supplementation. Under those circumstances there is no reason to expect that vitamin D supplementation will have any significant benefit.

This is an obvious flaw. But I call it a “hidden flaw” because the authors hid it. They didn’t mention it in their abstract or conclusion.

That’s dishonest. Most people just read the abstract and conclusions, and that is the information that is shared in the media. Very few people read the study to see if the abstract and conclusions are accurate.

As if this weren’t complicated enough, our understanding of the effects of vitamin D just got a lot more complicated.

Vitamin D Just Got More Complicated

Two recent reports indicate that predicting who will benefit from vitamin D supplementation may be even more complicated than we thought.

Report #1 suggests that there is significant individual variability in how people respond to blood levels of 1,25-dihydroxyvitamin D. If true, this adds another level of complexity to studies of vitamin D supplementation.

Not only do the studies need to measure the 1,24-dihydroxyvitamin D levels before and after supplementation for everyone in the study.

But they would also need to measure the individual response to 1,25-dihydroxyvitamin D.

This report (C Carlberg and A Haq, Journal of Steroid Biochemistry & Molecular Biology, 175: 12-17, 2018) summarized the results of two clinical studies and used that information to develop what they called the, “Personal Vitamin D Response Index”.

The first study supplemented elderly men (average age = 71) for 5 months during the Finnish winter (when blood 1,25-dihydroxyvitamin D levels are lowest) with 0, 1600 IU, or 3200 IU per day.

The second study supplemented young (average age = 35) men and women with a single high dose of vitamin D (80,000 IU) and followed them for 30 days.

At the beginning and end of each study:

Blood levels of 1,25-dihydroxyvitamim D were measured.

The activity of 24 vitamin D-responsive genes was measured. (These are genes whose activity is controlled by a vitamin D receptor and whose activity was known to respond to vitamin D.)

In addition, more than 100 clinical and biochemical parameters that might be affected by vitamin D levels were measured. Of these, 12 were found to respond to vitamin D supplementation.

The authors of this report combined all 36 vitamin D-responsive biomarkers (24 genes and 12 biochemical parameters) into a single screening panel they called the “personal vitamin D response index” and correlated this index with the change in 25-dihydroxyvitamin D levels for each individual.

They discovered significant individual variability in how the subjects in these studies responded to increases in their 1,25-dihydroxyvitamin D levels. For example:

They were able to divide the study participants into low, mid, and high responders to an increase in 1,25-dihydroxyvitamin D levels.

- In the first study 23.9% were low responders, 50.7% were mid responders, and 25.4% were high responders.

- In the second study 28.6% were low responders, 31.4% were mid responders, and 40% were high responders.

This is a confounding variable for vitamin D studies because the authors of this report estimated:

Low responders might require 1,25-dihydroxyvitamin D blood levels of 75-100 nmol/L to see a benefit of supplementation. Most studies do not attain 1,25-dihydroxyvitamin D levels that high, so low responders would not appear to benefit from supplementation.

High responders may already experience optimal benefits of vitamin D at 1,25-dihydroxyvitamin D levels that are generally considered as inadequate. So, supplementation would offer no apparent benefit for this group either.

Only mid responders might be expected to show a clear benefit from vitamin D supplementation.

The authors concluded, “Individuals can be distinguished into high, mid, and low responders to vitamin D via measuring vitamin D sensitive molecular parameters…Thus, we suggest that the need for vitamin D supplementation depends on the vitamin D status relative to the personal vitamin D response index of an individual rather than on the vitamin D status alone.”

Report #2 (P Maissan and C Carlberg, Nutrients, 17, 1204, 2025)) suggests that the benefits of vitamin D supplementation might vary depending on the time of day the supplement was taken.

This phenomenon is known as circadian rhythm, which describes how time influences physiological and behavioral processes. A little background information is in order.

We have a “biological clock” that is reset every day by sunlight exposure. Hormone levels rise and physiological processes increase and decrease during the day in response to this biological clock.

For the most part, you have no knowledge that this is going on in your body but let me share one example you are probably aware of.

- Some people suffer from “seasonal affective disorder” (SAD). It is a type of depression associated with the winter months, especially in regions with short days and long nights. For these individuals, bright lights that mimic sunlight are often an effective therapy.

Some aspects of circadian rhythm are mediated by the pineal gland which produces melatonin. Others are affected by the hypothalamus.

Since vitamin D synthesis requires sunlight, it makes sense that some vitamin D-responsive genes would also display a circadian rhythm.

This report used the data from the single high-dose vitamin D study described above. They found that:

Of 361 known vitamin D responsive genes, 87 of them show a clear circadian rhythm.

For 14 of these genes, there was significant individual variability in the response to vitamin D supplementation.

- Group 1 (36% of the population) had significantly higher expression of these genes following vitamin D supplementation than Group 2.

The authors concluded, “Overall, our findings emphasize the circadian nature of vitamin D target gene regulation and highlight interindividual variability in the…responses to vitamin D3 supplementation. These insights have important implications for personalized vitamin D3 supplementation strategies, suggesting that optimal dosing regimens may need to consider both circadian biology [the time of day the supplement is taken] and individual responsiveness to vitamin D.”

What Does This Mean For Clinical Studies?

The latest reports explain why vitamin D studies are so confusing – why some studies show benefits of vitamin D supplementation and other studies come up empty. Simply put, it’s because vitamin D metabolism is so complicated. Let me walk you through the complications.

1) There is significant individual variability in the conversion of vitamin D to its active 1,25-dihydroxyvitamin D form.

If vitamin D supplementation does not increase 1,25-dihydroxyvitamin D levels into the adequate range, it is likely that the results will be negative – meaning no benefit of vitamin D supplementation will be observed.

If 1,25-dihydroxyvitamin D levels are already in the adequate range prior to supplementation, the results may also be negative.

Fortunately, it is easy to determine blood levels of 1,25-dihydroxyvitamin D in study participants, and most good vitamin D studies are starting to do that.

But vitamin D metabolism just got more complicated. If recent studies are correct:

2) There may be significant individual variability in the biological response to 1,25-dihydroxyvitamin D.

If someone is a low responder, supplementation at the usual levels of vitamin D is unlikely to result in high enough 1,25-dihydroxyvitamin D levels to give a response.

If someone is a high responder, they will probably have maxed out their response without supplementation, so adding a vitamin D supplement is unlikely to provide any benefit.

Sorting participants in clinical studies into low, mid, and high responders is possible, but not easy. Currently the process of sorting individuals into these categories is based on 26 biomarkers. There is no single biomarker that predicts the vitamin D response level for any individual.

3) There may be a circadian rhythm for some beneficial effects of vitamin D. If this observation is confirmed by future research, the time of day vitamin D supplements should be taken may be important.

What Does This Mean For You?

By this point, you are probably more confused than ever. So, let me sum it up for you.

Many benefits of vitamin D supplementation are unclear. Some studies show benefits. Others come up empty. “Experts” cherry pick studies that support their beliefs.

Vitamin D metabolism is complicated. And each new study appears to introduce a new layer of complexity onto our understanding of how vitamin D works.

Many of the negative vitamin D studies were done before we understood the complexities of vitamin D metabolism or did not take known complexities into account.

But just because many of the negative studies are flawed doesn’t mean all the claims for vitamin D supplementation are true. Every study has its flaws – both positive and negative studies.

So, here is my advice to you.

#1: Be a cautiously optimistic consumer.

If your doctor or some internet guru tells you vitamin D supplementation is worthless, don’t believe them. But also, don’t believe claims for miraculous cures with vitamin D supplements.

We have fairly strong evidence that vitamin D supports healthy bones, a strong immune system, strong muscles, and a healthy brain. If you discover any other benefits of vitamin D supplementation, consider them to be unexpected side benefits.

#2: Base your intake of vitamin D on your blood 1,25-dihydroxyvitamin D levels. The NIH says that 1,25-dihydroxyvitamin D levels of:

<30 nmol/L indicate vitamin D deficiency

30 to <50 nmol/L indicate vitamin D insufficiency.

>50 nmol/L are adequate.

>125 nmol/L may be linked to adverse effects.

#3: Because you don’t know whether you are a low, mid, or high responder to 1,25-dihydroxyvitamin D, you may want to shoot for a 1,25-dihydroxyvitamin D level of somewhat greater than 50 nmol/L (the study said that low responders may need as much as 75-100 nmol/L).

Personally, I would aim for no more than 60-80 nmol/L because I would not want to risk vitamin D toxicity. I realize that 125 nmol/L is the lower limit set for toxicity, but I prefer to err on the side of caution.

#4: Be aware that there may be a circadian rhythm to the effectiveness of your vitamin D supplement.

Sunlight is required for synthesis of vitamin D. So, if there is a circadian rhythm to vitamin D effectiveness, vitamin D supplements might be more effective if taken in the morning than at night.

The Bottom Line

Why do so many studies on the benefits of vitamin D supplementation come up empty? Perhaps it’s because many investigators don’t understand the complexities of vitamin D metabolism. For example:

1) There is significant individual variability in the conversion of vitamin D to its active 1,25-dihydroxyvitamin D form.

This has been well characterized, and the best vitamin D studies are starting to incorporate 1,25-dihydroxyvitamin D measurements into their study design.

And recent studies have added to the complexity of vitamin D metabolism. Our understanding of vitamin D just got a lot more complicated. For example, these studies suggest that:

2) There may be significant individual variability in the biological response to 1,25-dihydroxyvitamin D levels.

3) There may be a circadian rhythm for some beneficial effects of vitamin D.

These observations have yet to be incorporated into clinical studies of vitamin D supplementation and may explain why some existing studies have failed to find beneficial effects of vitamin supplementation.

For more details on these studies and what they may mean for you, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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My posts and “Health Tips From the Professor” articles carefully avoid claims about any brand of supplement or manufacturer of supplements. However, I am often asked by representatives of supplement companies if they can share them with their customers.

My answer is, “Yes, as long as you share only the article without any additions or alterations. In particular, you should avoid adding any mention of your company or your company’s products. If you were to do that, you could be making what the FTC and FDA consider a “misleading health claim” that could result in legal action against you and the company you represent.

For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

_______________________________________________________________________

About The Author

Dr. Chaney has a BS in Chemistry from Duke University and a PhD in Biochemistry from UCLA. He is Professor Emeritus from the University of North Carolina where he taught biochemistry and nutrition to medical and dental students for 40 years.

Dr. Chaney won numerous teaching awards at UNC, including the Academy of Educators “Excellence in Teaching Lifetime Achievement Award”.

Dr Chaney also ran an active cancer research program at UNC and published over 100 scientific articles and reviews in peer-reviewed scientific journals. In addition, he authored two chapters on nutrition in one of the leading biochemistry text books for medical students.

Since retiring from the University of North Carolina, he has been writing a weekly health blog called “Health Tips From the Professor”. He has also written two best-selling books, “Slaying the Food Myths” and “Slaying the Supplement Myths”. And most recently he has created an online lifestyle change course, “Create Your Personal Health Zone”. For more information visit https://chaneyhealth.com.

For the past 53 years Dr. Chaney and his wife Suzanne have been helping people improve their health holistically through a combination of good diet, exercise, weight control and appropriate supplementation.

Which Vitamins Reduce Breast Cancer Risk?

May 30, 2023 by Dr. Steve Chaney

How Can You Reduce Your Risk Of Breast Cancer?

Author: Dr. Stephen Chaney

Breast cancer is scary. The good news is that treatment has gotten much better. Breast cancer is no longer a death sentence. But most women would prefer to avoid breast cancer surgery, radiation, and/or chemotherapy if they could.

Could something as simple as supplementation reduce your risk of developing breast cancer? If so, which vitamins should you be taking? Or, put another way, which vitamins reduce breast cancer risk?

If you ask your doctor, they will tell you, “Supplementation is a waste of money. Vitamins don’t reduce your risk of getting cancer.” And they will be correct! That’s because these are the wrong questions.

Let me explain. These are “one size fits all” questions. Studies to answer these questions start with healthy women and asks if vitamin supplementation reduces breast cancer risk for all of them. The answer to that question is, “No”. Multiple studies have confirmed this.

But the truth is more complicated. We should be asking, “Who benefits from vitamin supplementation”, instead of, “Does everyone benefit from supplementation?”

I have summed up this concept with the Venn diagram on the right. Every woman does not need supplementation. But those with poor diet, increased need, genetic predisposition, and/or certain diseases may benefit from supplementation. That is why we should be asking, “Who needs supplementation?”.

Unfortunately, while this concept of individualized treatment has led to dramatic advances for cancer drug development, it has been virtually ignored for studies on supplementation and breast cancer risk.

The current study (H Song et al., Nutrients, 14: 2644, 2022) is an exception. It asks whether obese women who wish to reduce their risk of breast may benefit more from certain micronutrients than women of normal weight.

How Was This Study Done?

The data for this analysis came from the KoGES study. This was a study administered by the Korea Agency for Disease Control and Prevention between 2004 and 2016. It was designed to provide a scientific basis for personalized prevention of chronic diseases in the Korean population.

Of the 211,721 participants enrolled in the original KoGES study, this study included data from 41,593 women who:

Underwent a health examination at 38 health examination centers upon enrollment between 2004 and 2013 and a follow up health examination between 2012 and 2016. The average follow-up period was 4.9 years.

Were cancer-free when they enrolled in the study and developed breast cancer prior to their follow-up health examination.

Had reliable diet data.

Dietary intake was based on a food frequency questionnaire administered during their initial health screening. Dietary intake of 15 micronutrients (calcium, phosphorous, iron, potassium, vitamin A, sodium, vitamin B1, vitamin B2, vitamin B6, niacin, folic acid, vitamin C, vitamin E, zinc, and cholesterol) and 4 macronutrients (energy, protein, fat, and carbohydrate) was determined from the food frequency data and compared to the Korean Dietary Reference Intakes (KDRIs). [Note: The Korean DRIs are slightly different than US standards.]

The women were then divided into two groups based on whether they consumed more or less than the Korean DRIs for each nutrient.

Which Vitamins Reduce Breast Cancer Risk?

There were two major findings from this study.

1) When the investigators grouped all the women in the study together:

- none of the 15 micronutrients and 4 macronutrients analyzed in this study influenced breast cancer risk.

- This confirms most previous studies that have been designed as a “one size fits all” study. So, if your doctor was relying on this kind of study, they were technically correct in saying that vitamin supplements don’t appear to reduce breast cancer risk.

2) But when the investigators separated the women by weight, an interesting dichotomy was observed:

- For obese women (BMI ≥ 25 kg/m²):

- - Vitamin C intake above the recommended Korean DRI (100 mg/day) reduced the risk of breast cancer by 46%.

- - Vitamin B6 intake above the recommended Korean DRI (1.4 mg/day) reduced the risk of breast cancer by 52%.

- For women of normal weight (BMI < 25 kg/m²) neither vitamin C nor vitamin B6 had any effect on breast cancer risk.

The authors concluded, “In obese women, exceeding the recommended daily intake levels of vitamin C and vitamin B6 was associated with a lower risk of breast cancer. However, other micronutrients were not associated with breast cancer risk in these women.” [Note: Supplement use was not included in the diet survey, so above recommended intake of C and B6 was from foods consumed, not from supplements.]

What Does This Study Mean For You?

This study is a perfect example of why we should be asking, “Who benefits from vitamin supplementation”, instead of, “Does everyone benefit from supplementation?”

In terms of the Venn diagram I introduced above, some people consider obesity a disease.

But whether you consider obesity a disease or not, it does increase the need for many nutrients. So, it is conceivable that extra vitamins C and B6 might provide benefits in obese women that are not seen in non-obese women.

This is, of course, a ground-breaking study. It is the first study of its kind and deserves to be followed by other studies to confirm this observation. Ideally, these studies would test whether the same effect is seen in other population groups and determine the optimal dose of vitamin C and B6 to reduce breast cancer risk.

However, I am not optimistic that these studies will be done. It is easy to get funding for the “do vitamin supplements benefit everyone?” studies that confirm the existing prejudice against vitamin supplementation.

It is much harder to obtain funding for “who benefits from vitamin supplementation?” studies that challenge the existing paradigm. But these are the kind of studies that are needed most.

How Can You Reduce Your Risk Of Breast Cancer?

As I said, this is the first study of its kind, so you could consider the results as preliminary. However, assuming it might be true:

I do not recommend megadoses of vitamins C and B6. The above average intake of C and B6 in this study came from food alone. And we do not have any dose response studies that might define an optimal dose of C and B6.

I do recommend balance. Based on this study, multivitamins should provide enough C and B6 to have a meaningful effect on breast cancer risk. And multivitamins are inexpensive and risk-free.

In addition, there are things you can do that are proven to reduce breast cancer risk. Here is what the American Cancer Society recommends:

Get to and stay at a healthy weight.

Be physically active and avoid time sitting.

Follow a healthy eating plan.

It is best not to drink alcohol.

Think carefully about using hormone replacement therapy.

I provide more detail about each of these recommendations in a recent article in “Health Tips From the Professor”.

The Bottom Line

Most doctors will tell you that supplementation does not reduce your risk of breast cancer. And that opinion is backed up by multiple published clinical studies.

But the problem is that these studies are all asking the wrong question. They are asking, “Does supplementation reduce the risk of breast cancer for all women?”. A better question would be, “Which women benefit from supplementation?”

A recent study asked both of those questions. They looked at the effect of 15 micronutrients on breast cancer risk.

When the investigators grouped all the women in the study together:

- None of the 15 micronutrients influenced breast cancer risk.

2) But when the investigators separated the women by weight, an interesting dichotomy was observed:

- For obese women (BMI ≥ 25 kg/m²):

- - Vitamin C intake above the recommended intake reduced the risk of breast cancer by 46%.

- - Vitamin B6 intake above the recommended intake reduced the risk of breast cancer by 52%.

- For women of normal weight (BMI < 25 kg/m²) neither vitamin C nor vitamin B6 had any effect on breast cancer risk.

For more information on this study, what it means for you, and proven methods for reducing breast cancer risk read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

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For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

Are Clinical Trials Misleading?

May 30, 2017 by Dr. Steve Chaney

Is Most Of What You’ve Been Told About Vitamins Wrong?

Author: Dr. Stephen Chaney

I am a scientist and a professor. I taught medical students for 40 years. I believe in evidence based medicine. Why would I tell you that many of the clinical trials about the impact of individual nutrients on your health are misleading?

Let me start by sharing a story that I used to tell every new graduate student in my lab. The story goes like this: There is this drunk on the sidewalk, on his hands and knees under a lamppost, just groping around. A policeman comes up to him and says, “What are you doing?” The drunk says, “I’m looking for my housekeys.” The policeman gets down on his hands and knees and he looks too, and finally he says, “I can’t find them anywhere. Are you sure you lost them here?” To which the drunk relies, “Nope, I lost them over there, but the light’s better here.”

The point I was trying to make is that we can only do experiments where the light is good. But the questions we sometimes want to ask are over in the corner, where we can’t really shine the light on it directly. It’s often difficult to look in the right place and/or to ask the right questions.

That’s particularly the case with holistic approaches because holistic approaches, by their very nature, are multi-factorial. You have multiple variables that you’re trying to change at one time. For example, you might want to optimize weight, exercise, vitamins, minerals, and essential fatty acids if you’re trying to look at a healthy lifestyle.

But, in the 21^st-century, studies generally focus on individual nutrients or individual drugs in an intervention, placebo-controlled trial. This is considered the “Gold Standard” for evidence based medicine. However, it’s very difficult to evaluate holistic approaches with that kind of study.

The Whole Is Greater Than The Parts

One of the examples that I love to use, because it really made an impression on me as a young scientist, occurred at an International Cancer Symposium I attended more than 30 years ago.

I attended a session in which an internationally renowned expert was giving his talk on colon cancer. He said, “I can show you, unequivocally, that colon cancer risk is significantly decreased by a lifestyle that includes a high-fiber diet, a low-fat diet, adequate calcium, adequate B-vitamins, exercise and weight control. But I can’t show you that any one of them, by themselves, is effective.”

The question that came to me as I heard him speak was: “What’s the message that a responsible scientist or responsible health professional should be giving to their patients or the people that they’re advising?” You’ve heard experts saying: “Don’t worry about the fat” “Don’t worry about calcium.” “Don’t worry about B-vitamins.” “Don’t worry about fiber.” “None of them can be shown to decrease the risk of colon cancer.”

Is that the message that we should be giving people? Or should we really be saying what that doctor said many years ago – that a lifestyle that includes all those things significantly decreases the risk of colon cancer?

Are Clinical Trials Misleading?

A recent paper about how to best evaluate the relationships between nutrition and disease (Shao et al, European Journal of Nutrition, DOI: 10.1007/s00394-017-1460-9) caught my attention. This paper, written by a team of 10 international experts, was a summary of key findings from a recent international meeting of the Council for Responsible Nutrition.

The paper started out by reviewing the strengths of clinical studies in which the effect of a single intervention on a health outcome is evaluated in a double-blind, placebo controlled clinical study; something they referred to as a reductionist approach.

A reductionist approach is ideal for evaluating the effect of drug candidates on disease outcomes. That is because:
- Everyone in the study already has the disease.
- The drug is meant to be used by itself.
- It is easy to measure outcomes. The drug either has an effect on the disease, or it doesn’t.

A reductionist approach has also been valuable in defining the role of nutrients in preventing deficiency diseases. That is because, in the words of the authors:
- “A simple cause-effect relationship exists between a particular nutrient and a specific deficiency disease.
- Symptoms of a specific nutrient deficiency can be explained in terms of the role played by the respective nutrient.
- Providing the nutrient in the diet can prevent, and in many cases, reverse, the deficiency disease.”

However, the authors went on to say that the use of the reductionist approach to study effect of nutrients on optimal health or holistic approaches to health often has led to misleading results. They characterized these studies as often “leading down a rabbit hole.”

For example, the authors said: “In an effort to uncover the magic bullet, scientists inappropriately studied nutrients in a drug-like context. Unlike drugs, nutrients do not function in isolation and have beneficial effects on multiple tissues and organ systems.”

The authors concluded by saying that if we want to truly understand the role of nutrients on health outcomes, we need to focus on holistic studies in which the effect of multiple nutrients on multiple health outcomes are evaluated.

Clinical Trials That Have Mislead Us

I realize that the report I just described is conceptual. It’s difficult to wrap your mind around. To better understand how clinical trials employing a reductionist approach can often mislead us, let’s look at some specific examples comparing holistic studies to reductionist studies.

Healthy diets: Healthy diets have a significant impact on health, but it is not possible to show that individual components of those diets are beneficial: In previous issues of “Health Tips From the Professor,” I have discussed the Mediterranean and DASH diets. I have shared studies showing that the Mediterranean diet dramatically reduces the risk of heart disease, diabetes, cognitive decline, and some forms of cancer. However, you would be hard pressed to show that individual components of the Mediterranean diet have a significant impact on these health outcomes.

Similarly, the DASH diet is as effective as drugs at controlling blood pressure (Moore et al, Hypertension, 38: 155-158, 2001 ). Other than sodium restriction, you would also be hard pressed to show that the individual components of the DASH diet exert a significant effect on blood pressure.

Supplements That Are Going to Kill You: Individual nutrients can sometimes have adverse effects on your health. Those reports generate a lot of negative press, but the adverse effects usually disappear when those nutrients are consumed along with nutrients that complement their effect on whole body metabolism.

Here are two examples of the negative press that you may have heard about the dangers of supplementation, but what the studies actually showed is that a holistic approach to supplementation was superior to supplementation with individual supplements.

For example, there was something called the Iowa Women’s Health Study that got some negative press in 2011 (Mursu et al, Archives of Internal Medicine, 171:1625-1633, 2011). This is one of those studies that led to headlines saying: “Vitamins can kill you.”

The study did show a slight increase in mortality in people who consumed high-dose vitamin B6 or high-dose folic acid by themselves. But in that same study, people who were taking high-dose B complex containing both B6 and folic acid in balance had no increase in mortality.

Another example is vitamin E and prostate cancer. You probably saw the headlines, which said: “Vitamin E increases the risk of prostate cancer.” Those headlines were based on a study published in the Journal of American Medical Association in 2011 (J Klein et al, Journal of the American Medical Association, 306: 1549-1556, 2011). However, in that same study the people who were taking vitamin E and selenium (two nutrients that work together synergistically) had no increase in cancer risk.

There is a good biochemical rationale for those results. Vitamin E converts some reactive oxygen species to peroxides, which are quite dangerous themselves. Selenium is part of an enzyme that converts peroxides to water. Together, vitamin E and selenium convert reactive oxygen species (free radicals) to something that is completely harmless. By itself, vitamin E does only half the job.

Holistic Approaches to Supplementation: The same appears to be true if you look at holistic approaches to supplementation rather than supplementing with individual nutrients. A study done by Dr. Gladys Block and published in Nutrition Journal in 2007 (Block et al, Nutrition Journal 2007,6:30 doi: 10.1186/1475-2891-6-30) looked at a holistic approach to supplementation for the very first time.

She compared people who were taking multiple supplements, typically a multivitamin, extra antioxidants, extra B vitamins, carotenoids, fish oil and probiotics; people who were taking only a multivitamin; and people who were using no supplements whatsoever over a 20-year period.

The results were dramatic. The holistic supplement users had one-third the prevalence of angina, heart attacks and congestive heart failure and one-quarter the prevalence of diabetes compared to the other two groups. In contrast, reductionist studies looking at the effect of those nutrients individually have generally been inconclusive.

So just like a holistic approach to health, a holistic approach to supplementation appears to be superior to using individual supplements. This is a small study, but it is an example of the kinds of studies that need to be done in the future, if we are to truly understand the role of holistic approaches for optimizing our health.

The Bottom Line

Studies in which the effect of a single intervention on health outcomes is evaluated in a double-blind, placebo-controlled clinical study is considered the “Gold Standard” for evidence based medicine. A recent report has questioned the value of this kind of study in defining the impact of holistic approaches on health outcomes.

The authors concluded that the “Gold Standard” of clinical studies, which they referred to as a reductionist approach:
- Was ideal for evaluating the effect of drugs on preventing or treating diseases.
- Has been well suited for evaluating the role of individual nutrients in preventing deficiency diseases.
- Was not well suited for evaluating the role of holistic approaches on health outcomes.
- Was not well suited for evaluating the role of nutrients for promoting optimal health.
The authors concluded by saying that if we want to truly understand the role of nutrients on health outcomes, we need to focus on holistic studies in which the effect of multiple nutrients on multiple health outcomes are evaluated.
I shared three examples illustrating cases in which holistic approaches were more accurate than reductionist studies:
- Healthy diets have a significant impact on health, but it is not possible to show that that individual components of those diets are beneficial.
- Individual nutrients can sometimes have adverse effects on your health, but the adverse effects disappear when those nutrients are consumed along with nutrients that complement their effect(s) on whole body metabolism.
- A holistic approach to supplementation can have a significant, beneficial effect on health outcomes, but it is difficult to show any benefit from individual nutrients included in that holistic approach to supplementation.

For more details, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.