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Nutritional Supplementation and JAMA

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Nutritional Supplementation and JAMA

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Editorial Commentary:

In the last few months there has been a disappointing series of nutritional studies published in the Journal of the American Medical Association. JAMA was rabidly opposed to supplementation until 2002, when they published an excellent article that proposed that taking supplements could reduce the risk of chronic disease. [1] That article was right on the money. This recent group of articles challenges those findings, but you will soon find that they were all seriously flawed. Let’s review these clinical trials, and consider how asking the wrong question can yield the wrong answers, and how that process generates negative bias against supplementation.

The first study we will discuss is the:

Physicians’ Health Study II

The first 2 JAMA papers we will review [2, 3] involve the results from the Physicians’ Health Study trial (PHS II). Researchers studied 14,641 male physicians in the United States, aged 50 years or older. They divided them into 4 groups, and gave most of them a placebo, while only 3,656 received both the 400 IU of vitamin E every other day and 500 mg of vitamin C daily. They tracked this group for 8 years.

This trial generated 2 separate articles:

The Heart Disease Report

The first paper [2] concluded that vitamin C and E supplementation did not reduce the risk of major cardiovascular events. However, their selection of candidates was very seriously flawed:

The median age of participants was 64.3 years old [7]
42% already had pre-existing high blood pressure
6% already had pre-existing heart disease
6% already had pre-existing diabetes

The Cancer Report

The second paper [3] used this same flawed cohort to maintain that vitamin C and E supplementation also did not reduce the risk of prostate, or other forms of cancer. The weak points in this study include:

9% already had pre-existing cancers
44% were past or current smokers
All of them were given synthetic supplements

It’s embarrassing to see how much money and time was wasted on such a flawed study design. Why study 64 year olds, many of whom already have the disease under review? Why give them synthetic vitamins? Why give them Vitamin E every other day? The most this study should conclude is that if you wait until you are 64, it may be too late to hope that supplementation may reduce your health risks.

The second large trial we will review is:

Antioxidant and Folic Acid Heart Study

This study was actually one of five “legs” of a much larger clinical trial called the Women’s Health Initiative. The overall study was designed to see whether hormone replacement therapy (HMT), antioxidants, or B vitamins could reduce heart disease or cancer incidence. You may recall that the hormone trial was discontinued in 2002 when it was revealed that HMT had actually increased breast cancer rates by 26%, and heart attack rates by 29%. [9]

Like the PHS II study, this trial led to the publication of 2 different papers [4, 5]. In this trial, researchers gave folic acid, vitamin B6, and vitamin B12 to 5442 female health professionals, aged 42 years or older, over a 7-year period. Interestingly, the group receiving the B vitamins lowered their homocysteine levels by 18%, compared with the placebo group.

The Heart Disease Report

The first published paper reported that taking the 3 B vitamins did not reduce the risk of major cardiovascular events. [4] Although the JAMA paper makes that conclusion, the principal author, Dr. Marian Neuhouser made a rather different statement in a Medscape interview recently [10], when she said that there was “a slightly decreased risk for heart attack (MI) in those who took stress multivitamins — the ones that have high doses of B vitamins, vitamin C, zinc, and selenium — but because there were so few cases in this group, and because there were only 64 MIs among all these women, it’s a little bit hard to draw a firm conclusion, so we didn’t want to draw particular attention to this.”  Unfortunately, the rest of the participants only received 3 of the eight B vitamins.

The problems with this trial were:

The median age of participants was 64 years old [8]
All the participants selected were “high risk”, already having pre-existing cardiovascular disease (CVD) or at least 3 or more major risk factors for CVD. If you were healthy, you could not participate in this trial.

The Cancer Report

The second paper [5] used the same flawed cohort to do a statistical analysis for cancer incidence. The weak points in this study include:

No statistics were reported for pre-existing cancers
This paper does not mention the other “leg” that received antioxidants, or the sub-group who took the “stress vitamins” mentioned in the Medscape interview. [10]

Again, we are being told that supplements do not prevent heart disease or cancer, when in fact, what they actually explored was the response of older, sick individuals to taking 3 of the eight B vitamins. That’s like using a “stacked deck” to demonstrate that you can’t win at cards. I refer to this fallacious thinking as the search for The “Silver Bullet”

The major fault in all these reports is that they treat isolated nutrients as though they were experimental drugs. It’s not hard to understand why this flawed approach occurs. Many of these same researchers have a background in running clinical drug trials. As an example: Big Drug Company has just developed an experimental drug to manage heart arrhythmia. To test it, they gather a “cohort” of 200-500 individuals with pre-existing heart arrhythmia, and then give half of them the new drug, and the other half receive placebo.

However, the drug-testing model does not work well with nutrients. Using people who already have heart disease, to see if B vitamins can extinguish it, is ridiculous.  All the long-term trials suggest that it is the deficiencies in those vitamins that contributes to the onset of heart disease.

All the retrospective lifestyle studies of the last 40 years have shown a direct relationship between diet and disease. [11-13] The newest study, just published in the Circulation journal (2-18-09), reviewed 74,886 files from the Nurses’ Health Study, and found that the lowest incidence of heart disease and stroke was in women who’s diets most closely resembled the traditional Mediterranean diet.

That diet contains minimally processed, mostly plant-based foods, with an abundance — not just in terms of quantity, but also in terms of variety — of different plant foods and fish.

The author stated: “Compared with the typical US diet, the Mediterranean-type diet requires a shift toward a more plant-based meal, which means eating less meat and getting more of the day’s protein from plant sources, such as beans and nuts”. [14]

Since the discovery of penicillin by Fleming in 1928, science has succumbed to the siren call of the “silver bullet” approach to disease. A large chunk of the $29 billion budget of the National Institute of Health (the principal sponsor for American research) is devoted to funding single-substance or intervention studies. [15]

The Landmark Study

To date, there is only one retrospective study that has examined the health benefits of taking a full-spectrum of vitamins and minerals over a prolonged period of time. I’m referring to the Landmark Study, which was financed by the Shaklee Corporation. [16] The results from the study clearly demonstrate that longtime use of broad-spectrum nutrients DOES reduce the incidence of vascular disease, heart disease, diabetes, stroke, and cancer.

The primary database the authors used for health comparisons was the National Health and Nutrition Examination Survey (NHANES), a collection of millions of health questionnaires gathered since the 1970s. [17]

In this study, they compared a large group of Shaklee supplement users, who had used a wide variety of supplements for 20+ years, with NHANES groups which had not supplemented, or ones who had used “at least” one multi-vitamin daily.

Lab analysis revealed that the long-term group maintained much higher blood levels of all the essential vitamins and minerals, and they also experienced reduced or normal levels of all the key biomarkers for disease.

Biomarkers refer to the standard blood tests that are used to test for and diagnose disease.

In the 3 groups studied in Landmark, only the long-term users had normal blood homocysteine levels. Homocysteine is a key indicator for vascular disease, and is closely associated with sudden-death heart attack and stroke. [18]

C-reactive Protein (CRP) levels are an indicator of inflammation, and high levels are associated with many disease processes, including heart disease, diabetes, and colon cancer. [19] Unlike the 2 control groups, the long-term group maintained completely normal physiologic levels for CRP.

High levels of triglycerides and low-levels of high-density cholesterol (HDL) are also associated with vascular disease, heart disease, and stroke. [20] Again, the long-term group scored completely normal cholesterol levels while the 2 other groups didn’t. They also maintained completely normal blood pressure levels!

This study offers compelling proof that long-term supplement use can reduce the incidence of the most serious causes of death and disability. [21]  Finally, it demonstrates that there are no negative side effects to long-term supplement use. This contradicts earlier studies that suggested that beta-carotene was associated with increases in lung cancer. However, all the studies that reported those results used synthetic beta-carotene in the trial.[26]


1. JAMA 2002 (Jun 19); 287 (23): 3127–3129

2. JAMA 2008 (Nov 12); 300 (18): 2123-2133

3. JAMA 2009 (Jan 7); 301 (1): 52-62

4. JAMA 2008 (May 7); 299 (17): 2027-2036

5. JAMA 2008 (Nov 5); 300 (17): 2012-2021

6. Arch Intern Med 2009 (Feb 9); 169 (3):

7. Medscape Family Medicine; 11-24-2008

8. Medscape Family Medicine; 12-12-2006

9. Yale/New Haven Hospital Review; 9-24-2002

10. Medscape’s Heartwire; 2-10-2009

11. National Health and Nutrition Examination Survey

12. Framingham Heart Study Website

13. The Nurses’ Health Study

14. Medscape Medical News; 2-18-2008

15. The NIH Yearly Budget

16. Nutrition Journal 2007 (Oct 24); 6 (30)

17. National Health and Nutrition Examination Survey

18. Nutrition Science News; December 2000

19. C-reactive Protein

20. Alternative Medicine Review 2001 (Dec); 6 (6): 590–600

21. “Mortality Patterns in the United States”

22. Vitamins at Kids Health

23. The FrontRunners website

24. The Carotenoids page

25. The Bioflavonoids Page

26. Alternative Medicine Review 2000 (Dec); 5 (6): 530-545

About the Author:

I was introduced to Chiro.Org in early 1996, where my friend Joe Garolis helped me learn HTML, the "mark-up language" for websites. We have been fortunate that journals like JMPT have given us permission to reproduce some early important articles in Full-Text format. Maintaining the Org website has been, and remains, my favorite hobby.


  1. Dr. Steve July 23, 2009 at 12:35 pm

    I might suggest, Frank, that what they did was ask the RIGHT question that was designed (intentionally or not) to yield the wrong answers! Minor difference I know, but I fully agree with all your analyses you discuss in this very nicely done post. Keep up the great work, my friend!!!

  2. Frank July 23, 2009 at 1:20 pm

    Dr. Steve

    Thanks for your kind comments. I guess the whole article is summed up in this one statement: Using people who already have heart disease, to see if B vitamins can extinguish it, is ridiculous.

    Prevention is the buzzword lately, and the Landmark Study is the only article I have seen (outside of the NHANES database) that speaks to prevention as a serious option.

  3. John July 23, 2009 at 3:31 pm

    I’m curious. What’s the difference between synthetic and natural beyond the fact we think natural “should” be better? Isn’t the active component the very same chemical in both cases?

  4. Frank July 23, 2009 at 5:15 pm

    Hi John

    Great question, even if I don’t have a technical answer for you. I have no idea how chemists determine that something they made out of a testube is *identical* to something produced by a plant, but our bodies seem to know the difference.

  5. Frank November 7, 2010 at 7:07 pm


    While doing research for a previous issue of my nutrition newsletter, which reviewed why Shaklee uses organic crops to create their supplements, [9] I discovered a fascinating article in the June 2009 issue of Functional Ingredients, a trade journal for supplement manufacturers. [10] The author discussed a unique compound called Phytoalexins. The author went on to explain that phytoalexins are a class of compounds produced by plants, in response to bacterial or viral infections, excessive UV light exposure, or parasitic attack. Agricultural scientists refer to this plant-based defense mechanism as Induced Systemic Resistance.

    Phytoalexins are actually a broad class of phenolic compounds produced by plants in response to external attack, and they represent the Plant Kingdom’s inborn immune system. Although some of these compounds are found in low levels in some plants, elevated levels of these miraculous compounds are only found in organic produce. Phytoalexins have been shown to demonstrate powerful antioxidant properties and health-promoting potential. We know that Shaklee only uses naturally grown plants and fruits for their raw materials. Because organic produce contains phytoalexins, Shaklee supplements naturally contain these specialized nutrients that are not present in other manufacturer’s products.

    The Most Researched Phytoalexins:

    Resveratrol, is firmly tied to the reduced incidence of heart disease (referred to as the “French Paradox”) [11-12] In 1997 it was discovered that resveratrol was associated with the reduced incidence of cancer. [13] In 2003, researchers at Harvard University discovered that resveratrol is a key longevity molecule, due to its ability to turn on the sirtuin gene (Sir2), and later clinical studies demonstrated that resveratrol extended the lifespan of every animal they tested. [14-16] A new study just demonstrated that it also inhibits the growth and spread of Candida albicans. [17]

    Genistein and Daidzein are two other unique phytoalexins. These 2 powerful isoflavones appear to be responsible for most of soy’s reported health benefits. Soy isoflavones function as estrogen agonists, so those who eat diets rich in soy have lower levels of osteoporosis [18] and heart disease. [19] Reduced incidence of breast cancer among soy-users also indicates that these compounds exhibit powerful anti-estrogenic properties. [20] This is wonderful news for peri-menopausal women, who would prefer to avoid hormone replacement therapies.

    Flavonoids are another class of phytoalexins. In 2008 UCLA cancer researchers found that study participants who ate foods containing certain flavonoids seemed to be protected from developing lung cancer, even if they were heavy smokers. Their research indicated that only small amounts of flavonoids are required to achieve reduced risk. [21] Researchers around the world are embracing these natural phenolic compounds for their role in cancer prevention and treatment. [22-23]

    Terpenoids and Carotenoids are another form. These amazing compounds provide a broad spectrum of health benefits, including suppressing the incidence of cancer and heart disease, reduced incidence of macular degeneration and cataracts, enhanced liver detoxification, and even appear to enhance memory. You may learn a lot more about these substances at the Carotenoids Page. [24]

    Another interesting phytoalexin is named Medicarpin. Only found at high levels in organic Alfalfa, this compound has been found to be so effective in treating allergic conditions, asthma, cardiovascular disorders, and inflammation that a pharmaceutical company recently patented a synthetic version of it. This helps to explain why Alfalfa Complex has been a long favorite with Shaklee users for managing respiratory and allergic disorders. [25]


    9. Shaklee Is Better Than Organic
    July 2009 ~ HealthQuest Newsletter
    NOTE: User Name and Password are both shaklee

    10. The ORAC of Organic And The Promise of Phytoalexins
    Functional Ingredients ~ June 2009

    11. Alcohol, Ischemic Heart Disease, And The French Paradox
    Coron Artery Dis 1997 (Oct);8 (10): 645-9

    12. Wine, Alcohol, Platelets, And The French Paradox For Coronary Heart Disease
    Lancet 1992 (Jun 20); 339 (8808): 1523-1526

    13. Cancer Chemopreventive Activity of Resveratrol, A Natural Product Derived From Grapes
    Science 1997 (Jan 10); 275 (5297): 218-20

    14. Therapeutic Potential of Resveratrol: The In Vivo Evidence
    Nature Reviews Drug Discovery 2006 (Jun); 5: 493-506

    15. Resveratrol Improves Health and Survival Of Mice On A High-Calorie Diet
    Nature 2006 (Nov 16); 444 (7117): 337-342 (FULL TEXT)

    16. Resveratrol Prolongs Lifespan and Retards the Onset of Age-related Markers in a Short-lived Vertebrate
    Curr Biol 2006 (Feb 7); 16 (3): 296-300

    17. Resveratrol impaired the morphological transition of Candida albicans under various hyphae-inducing conditions
    J Microbiol Biotechnol. 2010 May;20(5):942-5

    18. Soy and Its Isoflavones: A Review of Their Effects on Bone Density
    Alternative Medicine Review 2002 (Aug); 7 (4): 317–327

    19. Understanding the Cardiovascular Actions of Soy Isoflavones: Potential Novel Targets For Antihypertensive Drug Development
    Cardiovasc Hematol Disord Drug Targets 2008 (Dec); 8 (4): 297-312

    20. The Soy and Cancer Page

    21. Fruits, Vegetables, Teas May Protect Smokers From Lung Cancer
    UCLA Newsletter May 29, 2008

    22. Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention
    Nutr Cancer. 2010; 62 (1): 1-20

    23. New insights on the anticancer properties of dietary polyphenols
    Med Res Rev. 2006 (Nov); 26 (6): 747-66

    24. The Carotenoids Page

    25. Medicarpin Derivatives and Analogs
    Free Patents Online

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