The Alliance For Natural Health

Designed To Fail: A Trial Without Meaning

The following is an analysis of a recent study on vitamins C and E by the scientific team of the Alliance for Natural Health, our international affiliate.

To read the full analysis, Click Here

Contributed by Steve Hickey, Ph.D.; Damien Downing, M.B.B.S.; and Robert Verkerk, Ph.D., Alliance for Natural Health.

It is unfortunate when researchers waste funds on studies that are unlikely to provide useful results. Sesso et al.’s recent study, the Physicians’ Health Study II, of vitamins C and E in heart disease, published in the Journal of the American Medical Association (JAMA), falls into this category.1 A few years ago, Hickey and Roberts described specific ways to design a trial to show the absence of a benefit from these vitamins in heart disease.2 The new study follows these rules intended to illustrate study bias almost to the letter, forcing us to repeat some basic rules of research into nutrition.

Dr. Hilary Roberts, on reading the newly published Sesso et al. study, said, “We intended our advice to show how NOT to perform a trial of vitamin C and E in heart disease. Perhaps someone should explain that to them.”

Natural vs. synthetic vitamin E

One rule was to use the wrong type of vitamin E. Vitamin E is not a single substance, but a range of at least eight substances (tocopherols and tocotrienols).3 The different forms of “vitamin E” have distinct biological properties.4,5 The form of vitamin E used in the Sesso et al. study was synthetic dl-alpha-tocopherol. This is less effective than the natural forms, and is quite different in biological function and antioxidant activity than the predominant form in the diet6 (as found particularly in vegetable oils); using synthetic vitamin E thus minimizes the possibility of finding benefit. Indeed, its use may interfere with the beneficial effects of natural vitamin E by competitively inhibiting or blocking receptor sites for the natural forms.7 The study also ignored the impacts of the all-important four tocotrienol isomers8 found in natural vitamin E.

The other vitamin evaluated in the Physicians’ Health Study II was vitamin C. This form was also synthetic and lacked the common synergists normally associated with good quality vitamin C supplements, namely citrus-derived bioflavonoids, which have been associated with a reduction of heart disease risk factors such as blood triglycerides.9


Another rule was to use too low a dose. The vitamin E dose in the study (400 IU every other day) is insufficient to act as an antioxidant in humans. This study has no relevance to people taking natural tocopherols or tocotrienol supplements at appropriate doses. In other words, the study does not apply to people who supplement with vitamin E.

Similarly, Hickey and Roberts predicted that a dose of up to 500 mg. vitamin C would have minimal or no effect in preventing heart disease. The daily dose of vitamin C used by Sesso et al. (500 mg.) is only half a typical one-gram tablet, of the type popular with supplement users. Dynamic flow levels of vitamin C, which may prevent heart disease, begin at daily intakes above about 3 g. per day, taken in divided doses (this is a minimum level—higher doses may be needed, depending on individual physiological requirements). A dose of 500 mg. will only marginally raise median blood plasma levels above the baseline level of 70 microM/L and thus be ineffective. For those in the study with preexisting heart disease (754 men in a total population of 14,641), the appropriate vitamin C intake is higher still.

Placebo problems

Both the vitamin C and vitamin E supplements were compared with a “placebo,” but the nature of the placebo was not clarified. This is an important omission in a nutritional study, since the placebo could have contained substances, such as magnesium, which have a beneficial nutritional effect in heart disease.

This raises a fundamental problem of applying randomized controlled trials to the field of nutrition; you cannot apply a true control given that all subjects are exposed to food, if not supplements, and any balanced diet contains substantial amounts of nutrients, many of which interact synergistically. In scientific terms, the occurrence of uncontrolled elements of the diet in both the control and treatment groups introduces a confounding element that is likely to interfere with any meaningful biological effects, particularly if the dosages are low, as they indeed were in the Physicians’ Health Study II. In addition to this, given that the study involves physicians, it is likely that the subjects, with their greater knowledge of health issues, would have consumed diets that are more healthy than those of average Americans.

The study also ignores the typical combinatorial effects of supplement usage when coupled with healthier lifestyles. As Michael Pollan asserted in his book In Defense of Food: An Eater’s Manifesto (Penguin, 2008), a regular supplement user will do most things better, including eating healthier diets, taking more exercise, and generally living healthier lifestyles.

Using statistics as a means to an end

The claim that the “vitamin E” was associated with an increased risk of hemorrhagic stroke could also be irrelevant. The study employed numerous statistical tests of subgroups, with a confidence limit set at one in 20 (p<0.05). Repeated testing of subgroups will, by definition, result in apparently significant results due to chance alone (roughly one in every twenty tests). While a confidence limit of one in twenty is appropriate for a single statistical test, it is not suitable for repeated testing of the same data. In this case, the number and nature of the tests was not made clear and the statistical interpretation was inappropriate.


Sesso and his colleagues conclude that the results of their trial “provide no support for the use of these supplements in the prevention of cardiovascular disease in middle-aged and older men.” A more accurate conclusion might have been that the trial provides no evidence that supplementation of low doses of synthetic vitamin C and E, when taken by physicians over fifty years old over a relatively short period of ten years, has the capacity to prevent cardiovascular disease. However, as the study authors themselves concede, the initiation of supplementation may have been too late to significantly affect the etiology of heart disease.

We have also argued that the low doses, inappropriate synthetic forms and absence of other natural nutrients, and synergists in combination, would—quite predictably—not have the ability to prevent heart disease. Sesso et al’s trial was therefore a trial doomed to fail!

But, with three drug companies supplying the vitamins for the trial, namely BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products (formerly Roche Vitamins), was this perhaps a surer way of protecting the drug companies’ core competence, which is clearly in the field of patented pharmaceuticals, rather than in unpatented synthetic vitamin products?


1 Sesso H.D. Buring J.E. Christen W.G. Kurth T. Belanger C. MacFadyen J. Bubes V. Manson J.E. Glynn R.J. Gaziano J.M. (2008) Vitamins E and C in the Prevention of Cardiovascular Disease in Men, The Physicians’ Health Study II Randomized Controlled Trial, JAMA, 300(18), 2123-2133.

2 Hickey S. Roberts H. (2004) Ascorbate: The Science of Vitamin C, Lulu Press.

3 Sen C.K. Khanna S. Roy S. (2006) Tocotrienols: Vitamin E beyond tocopherols, Life Sci, 78(18), 2088-2098.

4 Jiang Q. Christen S. Shigenaga M.K. Ames B.N. (2001) Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention, Am J Clin Nutr, 74(6), 714-722.

5 Sen C.K. Khanna S. Roy S. Packer L. (2000) Molecular Basis of Vitamin E Action, tocotrienol potently inhibits glutamate-induced pp60c-src kinase activation and death of ht4 neuronal cells, J Biol Chem, 275(17), 13049-13055.

6 Duthie GG, Gonzalez BM, Morrice PC, Arthur JR. (1991) Inhibitory effects of isomers of tocopherol on lipid peroxidation of microsomes from vitamin E-deficient rats. Free Radic Res Commun, 15(1), 35-40.

7 Huang HY, Appel LJ. (2003) Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr, 133(10), 3137-40.

8 Sen CK, Khanna S, Roy S. (2007) Tocotrienols in health and disease: the other half of the natural vitamin E family. Mol Aspects Med, 28(5-6), 692-728. Review.

9 Vinson JA, Jang J. (2001) In vitro and in vivo lipoprotein antioxidant effect of a citrus extract and ascorbic acid on normal and hypercholesterolemic human subjects. J Med Food, 4(4), 187-192.

In Summary, from the Editor

The PHSII study findings published in the November 11 Journal of the American Medical Association referenced nine pooled studies that used 700 mg. of vitamin C, demonstrating a 25 percent reduction in the occurrence of heart disease. The PHSII study itself used 500 mg. a day of vitamin C in the model of a drug study but without a positive control. Why was a dosage lower than that proven in nine previous studies used? Previously published research from Arizona State University from Dr. Carol Johnston mentioned that most Americans get their daily vitamin C from their morning glass of orange juice. We could make a salient case that Americans (including physicians) do not get optimal amounts of vitamin C daily, and 500 mg. may be a far lower dose than their bodies needs. Dr. Linus Pauling’s work spoke of determining your own body’s need for vitamin C. Dr. Pauling’s personal need was 17,000 mg. of vitamin C, which he consumed daily until his passing at age 93.

The conclusion was that vitamin C and vitamin E (400 IU were given daily) did not reduce the occurrence of heart disease in the physicians who consumed these supplements. To many, the results could have been predicted. Nutrients do not “cure” disease in the traditional drug model of suppressing a symptom using a medication or an isolated synthetic active ingredient. Each individual has a unique need for nutrients, and they work synergistically, not by using a single nutrient as a magic bullet. Additionally, lifestyle is always the key factor in the prevention of chronic disease. Diet, exercise, and stress reduction must be included along with dietary supplements. The choice of just vitamin C and vitamin E, ignoring the omega-3 essential fatty acids or other nutrients that have profound heart-function benefits—like potassium, magnesium, coenzyme Q10, d-ribose, l-carnitine, nattokinase, vitamin D, vitamin K2, and aged garlic—seems simplistic and destined to produce a negative outcome. If the doctors continued to eat the processed American diet, remained inactive, continued to be stressed, and perhaps drank too much or ate too much bad fat or too many sweets, why would 500 mg. of vitamin C and 400 IU of vitamin E prevent heart disease or even cancer?

The form of the nutrient in the supplement is now known to be a key factor. As the Wall Street Journal noted in 1996, we may be taking the wrong form of vitamin E. Natural vitamin E, which contains many members of the tocopherol and tocotrienol family, has proven heart benefits. There is much published research, including that done at the Kenneth Jordan Heart Institute, which demonstrates that tocotrienol supplementation reverses plaque within six months. Why would the Harvard researchers use synthetic vitamin E and not a mixed tocopherol vitamin E with tocotrienols?

A presentation on PHSII at the American Association for Cancer Research meeting on November 16 offered similar findings: the daily use of 500 mg. of vitamin C and 400 IU of a synthetic isolate form of vitamin E had no impact on the risk of any type of cancer. However, nutrients like vitamin D, d-indole methane, the glucans from mushrooms, the mixed carotenoids, resveratrol from red grapes and wine, and phytochemcials from pomegranates (just to name a few) have considerable research to back up their use as cancer-fighters—as do other lifestyle changes like exercise.

Millions of Americans lose their lives to heart disease and cancer; millions (if not billions) of dollars are spent in research with failed methodology. PHSII is a prime example of research money that has been badly wasted. The empowering news is that genes can be turned off and turned on preventing even heart disease and cancer. We need to keep hammering home the message of biochemical individuality using the proper forms of nutrients, the message that nutrients are adjuncts to wise lifestyle choices that include diet, exercise, and stress management.

This is a critical time. We must protect the rights of the practitioner to practice and the rights of the consumer to choose. We must support true health freedom, including the free exchange of scientific research not skewed by vested interests.