A Look into the Surprising Elements of Supplements

   
Posted by Sol on Apr 17, 2014

We recently wrote a pretty simple article for the Guardian in which we covered a few of the more popular supplements.

There was a bit of backlash, and a lot of accusations were made, including the implication that we shill for supplements. Worst of all, our objectivity was questioned.

Examine.com has never (and will never) recommend any supplement brand. We have five editors from diverse backgrounds who all vet the research we publish (a sixth who is a PhD RD will be announced next week). The entire website is a collaborative effort. And we’ve had a singular focus from day one: evidence-based analysis.

So when Tania Browne posted an article on the Guardian questioning our objectivity, we thought it would be prudent to look at her claims of our purported misrepresentation of the evidence:


Examine.com has an overwhelming amount of citations

The Guardian's article links to the relevant sections on examine.com, where there are over 700 PubMed references citing evidence. - Tania Browne

Yes, our fish oil page has 700+ references. It also has almost 22,000 words. It’s a big page, and thus has a lot of citations. This is not a case of citations to prove the point - it’s a case of proving the point with citations.

Unlike most other citation-based websites, we:

  1. Specifically link each claim to a citation. It’s not just a mess of citations at the bottom - they are specifically numbered for a reason.
  2. Link directly to the appropriate pubmed (or journal) link. Most websites just refer to the document name, which adds a very cumbersome step.
  3. Our Human Effect Matrix (HEM) specifically links to the relevant papers for each attribute. Clicking “See all studies” shows every relevant research paper, links to it, includes demographic information given, and has a summary on what the full text found.
We make it as easy as possible to find our citations for any claim we make, both in the HEM and in our Scientific Research section.


Not all studies are equal

So how do you know whether a scientific paper can be trusted? - Tania Browne

Good point. Which is why we specifically label every study listed in the HEM by its trial design: meta-analysis, double blind, other clinical trials that are not double blind (such as cohort studies), and observational studies with no intended intervention.

Still, there is a reason why the same outcome (“health goal” on our site) for one supplement can have multiple meta-analyses - they are not all created equally. For instance, different meta-analyses can have different inclusion criteria, or different statistical methods. We can cite studies - Should meta-analyses trump observational studies? + Systematic Reviews: Meta-analysis and its problems - that explore how meta-studies are not the end-all be-all of scientific research. It is not enough to read the abstract of a meta-study; you must read the full text.

This is why every single paper cited on Examine.com is subjected to rigorous scrutiny by our scientific team.

It is not hard to read a pubmed abstract and come to a conclusion that is contrary to what the authors found. Prudent research requires one to read the full text and not just the abstract.


Glucosamine - do you need it?

We’ll accept blame that our language was not precise enough. You can look at our own glucosamine page to see our more nuanced view. We should have clearly differentiated between knee osteoarthritis (a serious degenerative disease) and other forms of osteoarthritis and less serious joint pain.

For that we accept blame.

With that in mind, let’s look at the actual research findings and the accusations of cherry-picking.

You can see our collation of studies on glucosamine and osteoarthritis here. The single meta-analysis which Tania Browne references is already in our HEM, which we summarized as follows: “A network meta-analysis on glucosamine sulfate found statistically significant pain relief, but deemed that the clinical significance of this pain relief was minimal.”

Except, instead of citing one meta-analysis, we cite six. And our analysis of all of the research (not one meta-analysis but all six of them) finds the following:

There appears to be a small decrease in osteoarthritis symptoms associated with glucosamine (as sulfate, not hydrochloride) which is somewhat unreliable but consistently outperforms placebo on meta-analyses. The magnitude of reduction, however, is somewhat minor but still comparable to acetaminophen (paracetamol). At least three of the meta-analyses also performed funnel plots and found no evidence of publication bias.

And that was our recommendation. Dr. Spencer Nadolsky, dealing with patients who have osteoarthritis, recommends glucosamine instead of acetaminophen. We specifically stated in our recommendation that it is not very potent, that the sulfate version should be used, and that it be used instead of non-steroidal anti-inflammatory drugs (NSAIDs). Glucosamine’s safety profile is well established.

By no means did we mean to imply it was a panacea.

Again - we concur that we should have been more explicit that we were only talking about osteoarthritis, and that instead of saying “it may not be a miracle supplement” we should have stated “it will only provide marginal relief.” We were being pragmatic, but were not clear enough.

In a clinical setting in which a patient is suffering from osteoarthritis, glucosamine is found to be as effective as NSAIDs or paracetamol. This does not mean it is very effective, and it was our mistake in not being clear about that.


Protein

We have written extensively about protein on our website.

The recommended daily amount of protein for 19-50 year olds is 55.5g for men and 45g for women. But according to the British Nutrition Foundation, average protein intake is 88g for men and 64g for women. - Tania Browne

Again, this is where one must look deeper into the evidence instead of just looking at the quick conclusion.

The RDA of protein is based on the minimal protein intake required to ensure no bone or muscle loss. This recommendation is based on a bodyweight and lifestyle that is now outdated due to the obesity epidemic.

Tania Browne commented that Dr. Nadolsky likes to lift weights (how is that relevant?), as if his hobby influences his dietary recommendations. Our suggested protein goals are, in fact, much lower than what most bodybuilders consume. We've summarized all of the research on how much protein you need.

In 2010, a Consumer Reports survey of 15 brands in the US found that some protein drinks were contaminated with heavy metals that could reach harmful levels in the recommended three daily servings. - Tania Browne

Another example of looking at only a subset of the data, not all of the data. Consumer Reports did indeed find contaminants in protein powders. But if you look at other everyday foods, similar amounts of contaminants were found. And here is the FDA’s larger dataset.

With that in mind, the 2010 testing found three positives out of 15 samples, which is not robust enough to serve as conclusive evidence that protein powders are harmful. If we extend this logic, then a past meat recall due to bacterial contamination would be enough to “prove” that meat is harmful. Furthermore, we do not recommend any brands.

Lastly, Consumer Reports looked at three servings per day, something we did not recommend. The author’s wording is basic fearmongering, using a subset of data to make protein look far more dangerous than it actually is.

Furthermore, the NHS warns that excessive protein intake can lead to bone demineralisation and osteoporosis. - Tania Browne

It should be noted that this is from a special report and not an official position statement. The 2011 NHS special report does indeed mention that protein could play a role in bone demineralization, although this contradicts the positions of other organizations like Osteoporosis Canada.

In cases where there is a dispute in positions, we can defer to the studies conducted. We find in epidemiology that low to normal protein intake is predictive of bone loss and higher protein intakes above the RDI are protective relative to lower intakes. This has been observed in other studies as well. Elderly women with a high calcium intake consuming up to 72g of protein a day slowly improved their bone mineral density. In this same study, the group that only took between 16-50g of protein experienced the greatest bone loss.

The studies showing bone loss are essentially non-existent. They were logically extended from initial studies showing increased calcium elimination in the urine with protein intake, and while at this time it seemed logical to assume that protein caused bone loss, the theory just didn’t pan out in interventions. For those who want to read more on this topic, here is a free in-depth review from the American Journal of Clinical Nutrition about the interactions of protein, calcium, and bone health.

More fearmongering with no basis in evidence.

And a recent article in the journal Cell linked high intakes of animal protein to cancer and higher overall mortality in the under 65s. - Tania Browne

We actually analyzed this exact study. And just as we have repeatedly stated, one must read deeper than the abstract.

That very study she linked to only looked at people over the age of 50. It split people into two groups, and found that increased “protein” was beneficial for those older than 65. We state protein in quotation marks because all protein sources were treated equally - be it chicken breast or bacon-wrapped sausages. The NHS also agrees that said study did not find protein intake to be bad.

This ties into an important point - when it comes to epidemiologic studies, it is important that one read the full text and not simply rely on the abstract stating the basic conclusion, and instead focus on the nuances underlying the claim and to which specific demographics the claim can apply to. As someone studying epidemiology, I'm sure the author can agree with that

Protein is an essential macronutrient, and we only recommended protein powder for its convenience. Worries about it having negative effects at the dosage we recommended is unnecessary.


Multivitamins

We will admit that we lost some of our nuance in our recommendation. Our own page on do I need a multivitamin? states the following:

Multivitamins are very useful if you have a poor diet, but they lose much of their benefit if you have a good diet. Many people with good diets take multivitamins unnecessarily. Just supplement the nutrients you need instead.

And that is our entire ethos. Supplementation is done in a targeted manner, and only after your diet is taken into consideration. Identify your deficiencies, and either fix your diet (preferable) or supplement.

In fact, multivitamins might make things worse - Tania Browne

To be blunt, while multivitamins have pretty much no evidence of being beneficial, to say that they “make things worse” is another case of fearmongering.

If we look at only negative effects, excess vitamin E (400 IU) has been associated with an increase in mortality and excess beta-carotene, in smokers, has been associated with an increase in lung cancer. Concerns about multivitamins in a nonsmoker can be negated by simply reducing the vitamin E content. The authors of the meta-analysis that found an increased mortality risk stated that, since most of the studies were done on metabolically unwell people, they are uncertain if the information applies to healthy individuals. Another meta-analysis specifically examining multivitamins finds no impact on mortality.

Multivitamin benefit or detriment is not a clearly agreed upon topic among researchers. Studies within the large meta-analysis include different populations and have widely different results. To say they make things worse is incorrect.


Vitamin D

It has been interesting to see vitamin D go from hype to backlash. The Lancet recently published some studies, and you can see our analysis on their study on vitamin D and osteoporosis prevention. We then summarized vitamin D’s utility in our The Truth about Vitamin D analysis.

Worryingly, Nadolsky also advises 50 micrograms (2,000 IU) of vitamin D per day - Tania Browne

Yes, Dr. Nadolsky did indeed recommend 2,000 IU of vitamin D daily. However, why was this worrying? The lowest dose with any adverse (not toxic) effect that has even been noted was a nonsignificant increase in fat gain at 5,000IU.

2,000IU has never been associated with harm, and at times is associated with significantly more benefit than 800 IU. Higher doses (of 5,000 IU or more) have been associated with varying degrees of harm.

The only evidence the author brought forth was a statement of how our recommendation was apparently “twice the NHS recommended maximum intake of 25 micrograms” and how the recommended intake is 5mcg, which is actually wrong in many countries, as 5mcg is 200 IU (vitamin D3) whereas the RDI tends to fluctuate between 400-800 IU depending on the nation (for example, having been recently increased to 800 IU in Canada). The tolerable upper limit in the US is 4000 IU (100 mcg).

In fact, the Endocrinology Society Guidelines recently bumped up their vitamin D recommendations so that "getting 25(OH)D levels consistently above 30 ng/mL may require at least 1500 to 2000 IU/day of vitamin D. This recommendation was tasked by Dr. Holick, who discovered both 25(OH)D and calcitriol.

In short, “high doses” of vitamin D do cause adverse effects, but 2,000 IU is by no means a high dose. We even have a section on toxicity.

Taking too much vitamin D for a long time can cause calcium build up, damaging the kidneys and even softening bones - Tania Browne
This is true in theory, but only when excess vitamin D is ingested (which as we previously covered, is well above 2000 IU). In short, vitamin D increases calcium utilization and at high doses this occurs in many tissues, which may not actually be beneficial.

Furthermore, vitamin D is thought to have this adverse property because it is in too high a ratio relative to vitamin K. Vitamin K takes calcium out of tissues and reduces calcium buildup in arteries, a reason why the combination of supplements was recommended.

Excess vitamin D can indeed cause harm, but our recommendation of 2000 is not excessive. Any attempt at linking our recommendation to high-dosage vitamin D risks is an illogical leap.

Summary

The real science of dietary supplements shows that very few of us need them and most of us will do just fine by eating a healthy, balanced diet. - Tania Browne

We agree, and we have never claimed otherwise. However, there are situations when the diet is not balanced where supplements can be very helpful.

We also agree that our wording for glucosamine and multivitamins was poor. We should have been more nuanced.

With that said, we take our research very seriously. We are 100% independent and neutral, and we readily admit when we are wrong (have been before, and will be in the future). Yet in the case of our original article for the Guardian, properly looking at the actual evidence clearly validates the assertions we made.

Accusations of chicanery and cherry-picking simply do not hold up when the evidence is looked at in-depth. There is a reason why we have five different editors with advanced degrees in different backgrounds (with a sixth who is a PhD RD being announced next week). If anything, Tania Browne’s article engaged in fearmongering and amateur analysis that was not backed by the full body of evidence.

We focus on the entire body of evidence. Our goal is to objectively summarize the scientific research for supplement and nutrition issues, keeping in mind study quality and methodological issues, and provide consumers with the knowledge needed to make informed decisions.

NOTE: This article was vetted by all of our editors


Posted by Sol on Mar 17, 2014

Whew. It's been a journey.

A few days ago, Examine.com turned 3 years old. In those past 3 years we've:

  • Cited over 30,000 different studies
  • Have had over 5,000,000 people visitors
  • Have delivered over 20,000,000 pageviews
  • Been used as a source of unbiased information across dozens of mainstream magazines, newspapers, and TV shows.

It's been an amazing journey for us, and we're excited to see where the next few years take us!


To Celebrate...

We're discounting our Supplement-Goals Reference Guide.

The guide used to be $39.

For the next 60 hours (from March 17 noon EST until March 19 midnight), it is $29.

From March 19 midnight onwards, it will be $49.

This is your one and only chance to get it at $29. $29 for lifetime access.

Unsure about its value? See what other people have to say (on Facebook).


The Best Independent Supplementation and Nutrition Site - Because of your Support

We want to once again thank everyone for their support over the years, and we look forward to continuing to be the source for independent and unbiased information on supplementation and nutrition! We couldn't do it without your support. *Get the Supplement-Goals Reference Guide Now!


Posted by SpencerNadolsky on Mar 13, 2014

After a long period of research, Vitamin E has been examined and added to the database.

The term ‘vitamin E’ refers to a group of eight molecules, which are divided into two major groups: tocopherols and tocotrienols. Alpha-tocopherol is considered to be the main ‘vitamin-like’ molecule, and is often called Vitamin E, while the other molecules are referred to by their individual names.

Vitamin E has a unique role as a dietary supplement, when it comes to immune support. Alpha-tocopherol (200mg) is able to increase the antibody response to vaccinations. It’s also able to fight age-related immunosuppression in the elderly.

A lot of vitamin E’s benefits come from avoiding a deficiency state. A Vitamin E deficiency is associated with a higher risk of falls and bone fractures in the elderly, but taking more vitamin E than is necessary to correct a deficiency will not provide additional benefits.

Superloading vitamin E (727mg/800 IU or more) is associated with a strong antioxidant effect, which has potential for Alzheimer’s therapy, but this amount of Vitamin E also correlates with an increased risk of prostate cancer and mortality. For this reason, superloading vitamin E is not recommended.

Vitamin E is an important molecule that offers benefits for specific populations, like the elderly. Healthy vitamin E levels are supported through as little as 20-30mg of vitamin E a day. Unlike other vitamins, like vitamin D and vitamin K, a sufficient amount of vitamin E can be attained solely through the diet. Avocados, olives, and almonds are high in vitamin E. Vegetable oils, like palm oil, are a widely distributed source of vitamin E. Sesame seeds in particular are great sources of vitamin E, since they also contain sesamin, which improves vitamin E retention.


Posted by SpencerNadolsky on Mar 6, 2014


Protein is as dangerous as smoking?

A recent study on high protein has been making the media rounds lately, with some news sites using headlines such as “Eating large amounts of meat, cheese may be as deadly as smoking.”

That’s quite the claim. As is our habit, we decided to delve more deeply into the study and its actual findings (we’ve previously covered fish oil and your prostate and the truth about vitamin D).

Note: We’re about to get science-heavy. You can scroll to the bottom for the takeaways. We’ve also summarized important points along the way.


Lets look at the study

The study itself was part epidemiological and part rodent intervention, and can be found here. In assessing the role of IGF-1 in cancer and aging, they took data from a pre-existing survey (NHANES III; one of the largest American-based national surveys of health and nutrition), assessing 6381 adults over the age of 50.

After getting baseline data on protein intake (averaging 16% of caloric intake; 69% of this being animal-based protein), they then divided people into three groups: the highest third (above 20% protein), lowest (below 10% protein), and a middle group (so they could compare the categories).

After dividing everyone into one of these three groups, they looked at the data for these people over the course of the next 18 years to see if mortality or disease in any of the groups differed.

The individual pieces of data they found from dietary analysis were: - A positive correlation between moderate and high protein intakes and diabetes-related mortality, relative to the lowest intake. This persisted, albeit to a lesser degree, when looking at people over the age of 65. - No relation between higher protein intake with all-cause mortality, cancer-related mortality, or cardiovascular mortality overall. A small increase in risk was seen when looking only at people between the ages of 50-65. This risk was reversed for people above the age of 65, where dietary protein had a protective effect against all forms of mortality (excluding diabetes-related).

When investigating IGF-1 levels (this is separate because the sample is now reduced to 2,253) they found:

  • The increases in IGF-1, which correlated with meat intake, predicted overall mortality seen in the 50-65 cohort as well as the 66+ cohort.
  • The protective effects of protein intake in the elderly (66+) persisted if IGF-1 was lower, but higher levels of IGF-1 were not associated with protective effects, although they were not associated with increased mortality either.

The controls in place to reach this conclusion were restricting the age to people over the age of 50 only, and after assessing protein intake, they controlled for overall calories and other macronutrient intake as well as the sources of protein (either animal or plant). Further controls mentioned were age, race/ethnicity, education, sex, disease status, smoking, dietary changes, and attempted weight loss.

NHANES III gets its nutritional data via 24-hour dietary recall.

A quick note on epidemiological studies - they take data after-the-fact and try to make connections. This is not the same as a randomized clinical trial. This is a very important distinction to make, as epidemiological information cannot be used to state that “A causes B.” It is meant to spur further research.

The above bits of data are all that was available from the epidemiological evidence. A separate rodent study was then conducted to attempt to verify causation. It found:

  • When feeding mice either high (18%) or low (4-7%) protein diets for one week prior to tumor implantation (B16 melanoma cells) and throughout the study, it was noted that the majority of mice in both the high (100%) and low (90%) protein groups bore tumors but the size of the tumors in the low protein group was smaller (78% smaller relative to the high protein group).
  • They did find elevated IGF-1 levels in the high protein group and higher levels of its inhibitor protein (IGFBP-1) in the low protein group.
  • When doing the study again in mice highly deficient in growth hormone (due to their genetic composition), tumor growth associated with high protein was decreased (estimate from graph is to around 10-20% of what was seen in normal mice given that dose of protein)
  • When replicating the study with breast cancer cells rather than B16 melanoma, they found similar results.
  • Replacing animal protein (casein) with plant (soy) did not change the results around much, and serum IGF parameters were similar.
  • When investigating weight (not tumor implantation) into older mice and assessing their growth, it was noted that the expected negative effects of high protein were turned positive

There do not appear to be any significant listed conflicts of interest in this study, with the only disclosed affiliation being the corresponding author (one author having equity in L-Nutra; a provider of medical foods). Funding was provided by NIH/NIA which had no role in producing the methodology.


What does this tell us?

First, it should be mentioned that to fully appreciate this study we must view it as two studies. There is an epidemiological study and there is a mouse intervention study; anytime tumor growth is mentioned, it refers to the mouse study, and causation can only be applied to the mouse study. It cannot be applied to the human study (as it is an epidemiological study).

As such, we’ll address each one independently:

Epidemiology study in humans

This study noted a 2 to 4-fold increase in mortality. This may sound large, but is too small to be directly compared with smoking. That range in smoking has been noted in thorough analysis of studies when referring to overall mortality, yet it is still much less than the 20-fold expected increased risk for lung mortality. Not only do repeated studies on a topic refine and lessen the initial estimates (the first estimates are almost always too high, which are lessened with subsequent meta-analysis), but information on smoking controls biochemical confounds that predict mortality. This study did not. A direct comparison between the two, despite having similar risk ratios, is misleading.

No participant was under the age of 50, and people were divided into either 50-65 or 65+.

Beyond that, there do seem to be interesting results. There was an increased risk of diabetes-related death. This is unique, since the other mortalities and overall mortality were only higher in those between the ages of 50 and 65. For those older than 65, it was reduced. Mortality seemed to be associated with IGF-1 concentrations in all cases, and IGF-1 activity seemed to be negatively associated with the protective effects seen in those over 65.

Higher protein seemed to mean higher mortality between the ages of 50-65. Once over 65, it actually reversed (unless you were diabetic)!

In regards to the data collection and controls, it seems quite adequate. 24-hour dietary recollections from NHANES III are acceptable (self-reported dietary recollection will always be flawed to a degree) and this was supported by serum IGF-1 concentrations. It should also be stated that the sample size was reduced to about a third when it pertains to IGF-1 (due to not having measurements in everyone).

Quite a few unanswered questions

Many good controls were in place, but there are a few questions that readers may have that this study cannot address:

  • “Does exercise exert a protective effect?” - this study did not measure exercise.
  • “What about sources of protein?” - this study did not measure anything beyond whether it came from an animal or plant. Chicken breast is not comparable to processed bologna meat.
  • “Do these results apply to persons younger than 50?” - we don’t know
  • “What about eating your veggies and fruits?” - vegetable and fruit servings were not counted, just carbohydrates and fats.
  • “What did they eat in place of protein in the low protein group?” - protein as a percent of caloric intake was assessed, but not levels of carbs or fats (beyond group averages before division into thirds for analysis), so we don’t know if the macronutrient used to replace protein had a protective effect or not.
  • “Fast food versus home cooked?” - not measured.
  • “Could a healthy lifestyle completely circumvent these effects?” - perhaps, but the study never looked into ‘a healthy lifestyle’ beyond macronutrients
  • “What about weight loss?” - the study controlled for ‘attempted weight loss’, so it would be prudent to assume that no significant weight loss occurred in most subjects. Due to this, any questions pertaining to whether weight loss exerted a protective effect (usually does in other studies, if the weight loss occurs in obese persons) cannot be answered by this study
Many questions arise from an epidemiological study, which is common. It is important to remember these that this is a function of how they are run, and thus why they cannot prove causation.

Ultimately though, this study is good evidence to suggest that IGF-1 is not only playing a role in the aging process and mortality, but that it is also tied into overall protein intake, and this initially harmful effect may eventually turn protective in the elderly. It is a good study if you omit the grandiose claim of meat being as harmful as smoking.

Intervention in mice

This study proves causation in mice, and was used indirectly to support the role of IGF-1 in humans. The study was quite interesting in regards to tumor size (a 78% reduction in size from dietary modification is nothing to scoff at), but there are a few things to address before delving into the study:

  • It was investigating tumor growth, not mortality.
  • All the mice were implanted with tumors, which is totally different than what happened in the epidemiological study where all persons were cancer-free at baseline. This is important since IGF-1 is thought to promote growth of pre-existing tumors, not to cause them
  • Due to investigating tumors exclusively, this data can supplement the cancer-related mortality seen in the epidemiological study but doesn’t provide much evidence for the diabetes-related mortality or other types.
  • Any conclusion in the epidemiological study and the mouse study should be independent from one another, and if using one to support the other it must be clearly stated; the human component of this study do not state that protein accelerates tumor growth.

With that out of the way, this mouse study noted that protein didn’t necessarily have a protective effect (the vast majority of mice, be it on low protein or high protein, experienced tumor implantation and the tumors stayed there) but it suggests an ‘anti-growth’ effect of lower protein intake or, conversely, a pro-growth effect of higher protein intakes. The type of protein did not matter, since soy also augmented tumor growth to a similar degree as casein.

It demonstrated, perhaps via a correlation again, that tumor growth was associated with IGF-1 activity. This makes logical sense. IGF-1 is an anabolic agent to most cells, be they skeletal or tumor cells! While a GH inhibitor was not used, they did use a GH-deficient line which produces less IGF-1 and found significantly less effects of protein on tumor growth suggesting a causal role.

Higher protein means more IGF-1. IGF-1 is an anabolic agent that causes cell-growth, regardless of type. Skeletal tissue (good) or tumor cells (bad), it does not differentiate.

Other considerations for those that want to know more

In regards to dietary protein overall, the general observation of increased mortality has been noted in other epidemiological research in healthy cohorts, although the magnitude of this increased risk is lesser than observed in this study, with a nonsignificant increased risk of 1.02 (95% CI of 0.98-1.07) and elsewhere a conclusion that increasing protein by a decile increased overall mortality risk by 2% (95% CI of -1% to 5%); to clarify, if the CI (confidence interval) crosses the 0 point the data is not seen as statistically significant.

Interestingly, both studies noted that carbohydrates had a protective effect on mortality (specifically cardiovascular mortality), leading to a hypothesis that perhaps increased protein seen in this study is merely a proxy measurement of reduced carbohydrate intake; plausible due to food sources nor carbohydrate intake in the protein groups being measured, but at this time that hypothesis cannot be addressed with the study in question. If true, however, it would pinpoint protein as accidentally being a red herring in the mortality issue.

Finally, nutritional epidemiology such as this is known to have larger effects whenever a study on a new topic (i.e. mortality in otherwise healthy people) is introduced which the magnitude being significantly reduced when subject to future meta-analysis. This refers to the 2 to 4-fold increased risk (hazard ratios) noted in the study though as the 23 to 73-fold risk being compared to smoking was statistically misleading (and noted by the authors as such), and when paired with the previously cited other studies on mortality it should serve to show that the degree of risk suggested by this study may be an overstatement.

In single-study situations, it seems like everything we eat is associated with cancer. One must look at the full body of evidence.


Any evidence that protein is good for diabetics?

It is always important to look at the full body of evidence, not just one paper. To that end, as the paper showed that high protein was potentially an issue for diabetics, the question to ask is:

Are there any studies done that directly look at diabetics and protein-intake?

This leads us to a Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes.

high-protein diets are effective in improving various markers of cardiovascular risk in people with diabetes and should be considered in the overall strategy of diabetes management.

This systematic review and meta-analysis showed that interventions with higher protein diets can actually improve glycemic control and cardiovascular risk in diabetics. This doesn’t prove that higher protein diets decrease mortality in diabetics, it does show discordance between epidemiological and intervention studies. It does remind us to keep an eye on the bigger picture.


Common questions that I need answered

Should I stop eating meat?

Whether you do or not, it shouldn’t be because of this study. If you eat a lot of heavily smoked and processed meat, it may be a smart choice to eat more slow cooked and non-smoked meat

This study was also done on people over 50 years old. In fact, it found higher protein was beneficial for those older than 65 (unless they had diabetes). Unless you fit that bill, don’t be too concerned.
Should I switch to plant based sources of protein?

Not if you don’t want to. Beyond the hype you may have read, the actual data found that they were either equal (in mice) or that was slightly better (epidemiological).

Should I be worried about IGF-1?

IGF-1 causes cell growth. It doesn’t care if it it’s a muscle cell or an organ cell or a cancerous cell. This same scary-sounding hormone is what helps you build more muscle when you lift weights. Eating protein seems to increase IGF-1. If your underlying diet is poor (too much processed meat, not enough exercise), then high protein intake may be an issue.


What should I know?

Yes, dietary protein was implicated in mortality. No, it isn’t as harmful as smoking. The number which the comparison was borne from (diabetes-related mortality) does exist in the study and is immediately followed by:

“We underline that our hazard ratios and confidence intervals may be inflated due to our sample size and the extremely low incidence of diabetes mortality in the low protein group. Overall, there were only 21 diabetes deaths among persons without diabetes at baseline, only 1 of which was from the low protein group”

To even suggest that eating protein is as bad as smoking is pure sensationalism.

Human nutrition is a complex topic, and isolating one area can be complicated. Often times, two disparate issues can be combined together incorrectly:

Issue 1: as we explained, IGF-1 is responsible for cell growth, and it does not care what kind of cells it is growing. For those who exercise regularly, IGF-1 is a boon. For those that have poor diet without exercise, it is not.

Issue 2: poor diet is a ubiquitous problem. Processed meats are a staple of poor diets. Processed meats also tend to have protein. The study made no differentiation between different animal sources. As previously stated, chicken breast is not comparable to processed bologna meat.

When you combine Issue 1 and Issue 2 without looking at the bigger picture, one can mistakenly infer that “high protein is bad for you.”

A more accurate headline for this study would have been “High protein for those between 50 years to 65 years old who have poor diet and lifestyle habits may be associated with increased cancer risk.”

Want to know how much protein you should be taking? We looked at the scientific evidence on the recommended intake.


Posted by SpencerNadolsky on Mar 4, 2014

PRL-8-53, a synthetic nootropic compound, has been examined and added to the database. PRL-8-53 is taken for its ability to boost short term memory, though it does not have a lot of evidence for its effects.

PRL-8-53 was created by Nikolaus R. Hansl while he was studying a class of molecules called benzoates. Giving PRL-8-53 to rats showed very promising memory-enhancing effects. In 1978, a human study was conducted. It involved PRL-8-53 supplementation and a subsequent memory test. People that initially scored low on the test benefitted greatly from supplementation, while high performers did not see improvement. PRL-8-53 was compared to nootropics like piracetam, which helps people with poor memory, while having no effect on people with a good memory.

Unfortunately, no additional evidence has been published since that study. Though there is no data to disprove PRL-8-53’s effects, the benefits noted in the lone human study have not been replicated independently.

PRL-8-53 cannot be recommended as a dietary supplement because of the unexplained drop off in research, and because the original studies were funded by the patent holder and have not been replicated.


Posted by SpencerNadolsky on Feb 28, 2014

Today at Examine.com, we bring you a page on Origanum vulgare, also known as oregano.

Oregano is a popular spice and contains an oil component, which can be supplemented for an immune boost.

Research on oregano began in the 1980s. Its potent antioxidant and antibacterial properties lent themselves well to food preservation. Antioxidants are able to prevent the oxidation of fatty acids, which meant oregano could slow down the speed at which meat went bad and fruit browned. The antibacterial properties were also useful, particularly for storing meat.

It was hypothesized that these properties might extend to the human body as well, but there has been little research done on the matter. A single study on people using oil of oregano to ward off an intestinal infection was published in 2000. While the oil appeared to be very effective at eliminating the infection, the study was funded solely by a producer of oregano oil.

Further research is needed to determine if oregano’s effects really do apply to the human body.


Posted by SpencerNadolsky on Feb 25, 2014

The spice Crocus sativus, also known as Saffron, has been added to the Examine.com database. This expensive spice has several surprises up its sleeve, including a set of unique molecules and an ability to combat depression.

Saffron contains a group of molecules called carotenoids that are water soluble, but only in the context of saffron. Normally, carotenoids are fat soluble.

Repeated human trials have concluded that saffron is effective at treating depression, when taken at the standard dose (30mg a day for eight weeks). Its potency is comparable to several prescription drugs.

Research has yet to determine how exactly Saffron achieves this effect. Preliminary evidence suggests it manipulates serotonin signalling, but the exact mechanism has yet to be pinpointed. Prudent supplementation is advised, because saffron can become toxic to the body if used improperly. Doubling the standard dose and time frame (60mg for sixteen weeks) can do damage to the body. Until there is more evidence for saffron’s effects and toxicity, care should be taken during supplementation.


Posted by SpencerNadolsky on Jan 29, 2014

Over the past decade, no supplement has been as recommended as Vitamin D. Unlike its antioxidant cousins, Vitamin C and Vitamin E, vitamin D is something we tend to be deficient in. In fact, many regulatory organizations have started to bump up their recommended daily intake from 400 IU/day to roughly 800 IU/day.

In the past few months, there has been some push back against vitamin D, most notably from The Lancet. They have recently published a plethora of meta-analyses, many of which conclude that vitamin D’s utility is overstated (you can see our analysis of one of their meta-analysis on vitamin D and bone health here). Most of these studies have been interpreted by the media in a very “black or white” manner - either vitamin D is useful, or it is useless.

It should be noted that no compound will be a panacea for everything. Everyone has their own diet, which leads to different deficient vitamins and minerals in the body.

While there are some outlandish associations with vitamin D with weak evidence (an easy one - that vitamin D leads to a testosterone boost), we thought it would be useful to take a step back and look at the big picture.

Vitamin D has been the “hot” supplement for the past decade, which means it inevitably got hyped beyond what it could actually do. We need to stop over-reacting to the latest research, and remember to keep an eye on the big picture.


Meta-analysis Barrage

We have addressed the recent meta-analysis to investigate vitamin D and its interactions with bone mineral density, and recently another meta-analysis which had a more encompassing goal was published investigating the role of vitamin D in vascular (heart and stroke related), skeletal (total fractures), and cancer outcomes. While the title seems interesting (and we’ll delve into it shortly), its conclusions are being circulating in some media sources as evidence that vitamin D “confers no health benefits” or that future trials are “unlikely” to support vitamin D supplementation.

The recent meta-analysis appears to be well conducted. They investigated double blind trials with either vitamin D in isolation or the combination with calcium, eliminated confounds such as dairy-enriched vitamin D products or interventions not given to both vitamin D and placebo groups, and eliminated studies with known comorbidities so they could more directly analyze the endpoints they wanted to (vascular, skeletal, and cancer outcomes). The study was funded by the Health Council of New Zealand which had no role in the design or conducting of the study. The study failed to find any interaction between vitamin D supplementation (usually in the range of 400-800 IU), with or without calcium, on any vascular endpoint (myocardial infarction, ischemic heart disease, cardiovascular disease, cerebrovascular disease, or stroke) or on cancer outcomes. No relationship was found even when controlling for baseline vitamin D status.

When investigating skeletal outcomes with regards to fractures (different from the previous meta-analysis covered), overall there was no significant association between supplementation and outcomes regardless of whether calcium was included or not. When investigating further, there was a benefit for reducing hip fracture in institutionalized patients. Community dwelling adults (those not in clinical settings and more likely to be purchasing vitamin D supplements on their own) did not, however, see a benefit to fractures that was deemed clinically significant. Clinical significance in this study was deemed a reduction in risk of 15% or more.

When looking at overall mortality (usually the ultimate end goal of interest), there was uncertainty in the results. When they assessed whether vitamin D could reduce the risk of death by 5% or more, the overall applicable sample size was only 60% of what was deemed statistically optimal; a proper statistical conclusion on mortality, due to this, could not be reached and it was deemed of uncertain status.

The latest The Lancet meta-analysis looked at vitamin D supplementation in the context of vascular, skeletal, and cancer situations.


Take aways from the latest The Lancet study

This recent meta-analysis seemed well conducted and should not be disregarded. The relevant takeaways:

Cardiovascular disease is really not something vitamin D is catered to help treat or solve, and the failure of vitamin D having any benefits is no surprise. While aiming for a 15% reduction in risk may seem like the inefficacy of vitamin D was forced, it was chosen so that the magnitude was large enough to have practical benefits in the real world. Due to statistical reasons and subpar ‘ideal’ sample sizes, whether or not vitamin D reduces mortality by more than 5% cannot be answered with this study.

While a perfect study is pretty much impossible to conduct (hence why the body of evidence is greater than any one study), this one was pretty good. The discussion section does mention what evidence would be required to overturn the results which is always a good discussion to hear, and the reasoning that studies requiring over 50,000 people in sample size to yield a positive result have led to some articles stating that future articles are ‘unlikely to support vitamin D supplementation’ (shortsighted - it should be specifically mentioned for the studied parameters; vascular, skeletal, and cancer outcomes).

That being said, conclusions such as ‘no health effects’ are still much too grand to be associated to this study. This study could not assess everything, and claims that can still be made about vitamin D and its benefits include things such as colorectal cancer risk (this meta-analysis covered all cancer outcomes), multiple sclerosis, actual muscular control in the elderly (although the lack of reduction in fractures could argue against this), mood changes with regards to seasonal affective disorders, and diabetes risk. Some issues, such as the increase in testosterone and overall mortality risk, are still in a grey area.

The study was well-done, but to go from “had no effects on general vascular, skeletal, and cancer health” to “has no health effects” is a stretch (to say the least). It should also be emphasized that it looked at general cases, not specific cases.


So what benefits does vitamin D have?

As we previously cautioned, one must look at the entire body of evidence, not just at the latest research. With that in mind, if you look at our Vitamin D page (more specifically, at our Human Effect Matrix), you will find a plethora of evidence that shows areas that vitamin D has a proven positive effect on. These include:

  • An improvement in muscular control in the elderly.
  • Vitamin D supplementation is strongly associated with a notable decrease in the risk of colorectal cancer, with some possible decreases in risk of other cancers such as breast. The Lancet meta-analysis assessed outcomes for those already diagnosed, and did not look at risk of cancer.
  • Appears to be a significant protective factor for the development of multiple sclerosis.
  • Usage for improving mood pertaining to seasonal affective disorders.
  • Potential (albeit thought to be minor) benefits to glucose control via aiding pancreatic function.

The original RDI of vitamin D, ~400 IU/day, was actually the minimum you need to not get rickets. The above benefits usually come from higher levels of vitamin D in the body, which can be usually obtained with roughly 2000 IU/day. If measuring the blood concentrations of vitamin D, usually you want to be either in the adequate range (50-75nM or 20-30ng/mL) or slightly higher. You do not want to be insufficient (25-50nM or 10-20ng/mL) or outright deficient (less than 25nM or 10ng/mL).

Vitamin D supplementation has a host of positive benefits. One must consider both the full body of research and also look past the quantitative (how long you live) and consider the qualitative (how well you live).


Wrapping it up

Overall, vitamin D is both cheap (roughly 5 cents for a daily dosage of 2000 IU) and safe (is not toxic except at absurdly high levels). While it may not fix everything, it has enough benefits to warrant taking.

Vitamin D is cheap, safe, effective, and most people are in a deficient state. If you do not get enough direct sunlight exposure, supplementation is the prudent choice.

Posted by SpencerNadolsky on Jan 22, 2014

Today at Examine.com, we bring you a page on Chromium, an essential mineral implicated in regulating glucose metabolism and insulin.

Chromium is found in plants, specifically grains. It is part of a protein called chromodulin. Chromodulin is responsible for the actions of insulin receptors, and it increases in activity as more chromium ions bind to it.

Supplementation of chromium should be examined through the frame of deficiency. A subclinical deficiency is when the body has lower than normal levels of chromium, but not to the point of a true deficiency. A true deficiency is characterized by inactive chromodulin. Supplementation of chromium is very beneficial during a true deficiency, but it is often touted as useful during a subclinical deficiency as well.

However, if there is no deficiency state, the evidence does not support chromium’s ability to enhance glucose metabolism in the body. Some researchers have observed benefits for insulin sensitivity, glucose, body weight and quality of life in diabetic people, but these effects are very unreliable, both in terms of frequency and magnitude.

Chromium supplementation may also be able to reduce carbohydrate cravings and binge eating patterns, but more research is needed to confirm these effects.


Posted by SpencerNadolsky on Jan 19, 2014

A recently published Lancet article about vitamin D and bone mineral density is making waves in the medical world and on the web. It calls into question whether Vitamin D should be recommended to all community-dwelling adults for osteoporosis prevention.

This meta-analysis sought to investigate the interactions between vitamin D supplementation and bone mineral density (BMD). BMD is a proxy measurement for fracture risk that, while not always accurate, is usually a good indicator of fracture risk. Changing your lifestyle can have an impact on your BMD within the year, whereas to measure risk directly would require much larger sampler sizes and numerous years of tracking.

While bone mineral density (BMD) is not a direct measurement of fracture risk, it is a solid and measurable indicator.

The authors argued that previous meta-analyses on vitamin D and fractures were of low quality due to the available data being of limited statistical power, inappropriate doses, or not in deficient populations.

A new meta-analysis questions whether blanket vitamin D recommendations are suitable for osteoporosis prevention.


Recap

The meta-analysis assessed 19 studies on Vitamin D supplementation which analyzes bone mineral density. The studies invested were studies using vitamin D supplementation of either D2 or D3 form in adults. Age was not limited to older people, and if calcium was taken with Vitamin D then the placebo group must have also received calcium. Thus, some of the studies are just vitamin D, while others are vitamin D + calcium vs placebo + calcium.

The inclusion criteria were a bit vague, and this may have been to broaden the search (and thus include more data). That being said, while permissive inclusion criteria can include more data, they can also add so much data that benefits to one group of people (e.g. the elderly, women, etc.) can be lost because people in other groups are included. For these complications, we look further in the data to when factors are controlled for.

Inclusion criteria are the characteristics of the subjects in the study. Having both young and elderly in this meta-analysis could have influenced the results.

At the outset of the study, the meta-analysis found that at the four areas of the body where bone mineral density was measured, only one (femoral neck) saw a small benefit with supplementation. The other four (hip/trochanter, lumbar, forearm, and total) did not; the confidence intervals (CI values) all crossed the zero point, indicating no statistical benefit.

The authors concluded the study prior to doing any analysis of the cohorts in their data, and as such we cannot use this data to conclude anything about the age groups.


Lets take a closer look

At the outset, a major complication with this study would be how it had a very large and permissive inclusion criteria set to allow many studies to be analyzed yet it did not do further analysis into whether there were commonalities in the studies that showed benefit versus those that don't. The question "did including younger adults cause an apparent benefit in elderly people to be missed" cannot be answered without further statistical analysis. It should be noted that six of the included studies (comprising 871 subjects, about 21% of the total subjects analyzed) had a mean age under 50. This could have influenced the results if we assume the elderly would benefit more from Vitamin D supplementation than youth (which, according to the previous literature, is a very sound hypothesis).

Furthermore, vitamin D levels in serum were quite variable, as at baseline in these studies there seems to be quite a mix of studies with baseline Vitamin D below 30nM (five studies), between 30-50nM (three studies), 50-75nM (eleven studies) and one above 75nM. When looking at Vitamin D concentrations in serum after supplementation, it remains a variable 53-92nM (the range of the averages across the studies).

Penultimately, while perhaps of lesser importance due to standardization in the past suggesting intramuscular and oral supplementation of the following doses are somewhat bioequivalent, there was still a large variability in studies giving daily (thirteen) or weekly/monthly (four) oral supplementation and injections once a year (two studies).

Finally, while the studies in the subject were 92% women, which may simply be something that should be mentioned in the reporting of this study as the actions of vitamin D on bone health are somewhat comparable between men and women (although perhaps a bit more robust in women due to usually more advanced and common osteoporotic symptoms than men).


What should I know?

Overall, there are very limited practical conclusions we can draw from this study.

To start, remember that we need to keep an eye on the prize. While bone mineral density (BMD) is a useful measurement for bone fractures, the ultimate issue we are concerned with is injuries and death from falling, especially in the elderly. Vitamin D supplementation has been shown studies to decrease falls and fractures in the elderly. That's important!

Various studies show that in the elderly, vitamin D supplementation decreases falls and fractures.

The broad inclusion criteria means that in general, we can say that Vitamin D does not help improve BMD. As vitamin D is not generally recommended to alleviate osteoporosis in the general population, it would have been beneficial for the analysis to include a breakdown for a variety of age groups.

The bottom line is that we care most about preventing fractures and subsequent death. The people most at-risk for those are the elderly, and several studies show that vitamin D helps prevent such falls. The Lancet study focused on the entire adult population.

When you factor in the prevalence of vitamin D deficiency, the myriad of other health benefits of vitamin D, its low cost, and how safe it is, it is our opinion that vitamin D supplementation is a safe and intelligent choice.