Is Your Multivitamin Doing More Harm Than Good?

Late in 2011, the Iowa Women’s Health study published a paper saying that taking a multivitamin may in fact be detrimental in older women. Not surprisingly, we received quite a few questions about this from concerned patients. A closer reading of the paper revealed that actually, among the dozens of ingredients in multivitamins, only supplemental iron was strongly associated with a worse outcome. But that is not the first paper to cast aspersions on multivitamins, so I’d like to provide some detail about how I decide on supplement recommendations for my patients (and myself). Multivitamins usually have at least 15 ingredients– and some have closer to 50. Some of those ingredients will have good clinical data behind them–while others are backed with little more than good intentions. Some may appear in their natural forms, as they are found in foods–but sometimes they are in altered forms that are easier to manufacture. There are dozens of manufacturers—-and quality control is so varied that has an entire business devoted to telling you whether the supplements you buy actually contain what is marked on the label! And even if the label is accurate, have the ingredients been shown to absorb well in humans? In short, it is generally a waste of time to try to draw conclusions about “multivitamins” as a group, because there are too many variables. Supplements are a passionate interest of mine. I enjoy reading the studies behind various nutraceuticals and trying to understand which ones are over-hyped, and which ones I should take. If it is worth taking, sometimes only then does the real investigation begin: which company makes the version that is best absorbed–and can they prove it? All of those factors came into play when PhysioAge developed our new Premium Pack, Premium Pack Plus, and NeuroPack. We’re excited about the results, and I hope this post, and the others linked to it, will help you to understand why. Here are five common pitfalls that render most multivitamins more harmful than helpful. Feel free to check the multi in your cabinet against this list:
PITFALL # 1: The wrong kind of vitamin E.
Most multivitamins contain only alpha-tocopherol, and in doses that are far too high. This is probably the most common flaw in multivitamins, and is strongly implicated in worse health outcomes. I’ve already written an extensive review of the dangers of synthetic, high dose Vitamin E, which you can read here: Does Vitamin E Cause Prostate Cancer? PhysioAge’s previous Packs did not have this problem, as we were using mixed tocopherols for our vitamin E. However, the new packs will be improved in that they will also contain a hefty dose of tocotrienols, a type of vitamin E that has excellent data for it’s anti-inflammatory and anti-cancer effects. In addition, tocotrienols have actually been shown—in humans—to not just prevent but actually reverse carotid artery plaques!18,19 When we added tocotrienols, we used 200mg/day: the same dose used in that study. Most multis don’t contain any tocotrienols, and if they do, it is far less than 200mg. If you aren’t using the dose that’s been proven clinically effective, why include it at all?
PITFALL #2: The wrong kind of Folate.
In 1996, the U.S. mandated that enriched flours, breads, pastas and other grain products be fortified with folic acid, the synthetic version of the B vitamin folate. The goal was to help reduce the number of neural tube defects: severe birth defects of the brain and spine. (Neural tube defects include spina bifida, when the skin over the spine fails to close during early fetal development, and anencephaly, when much of the brain never forms.) Some other countries, though, are still debating whether to add folic acid to their grain supply. One concern has been the possibility that folic acid could contribute to breast or colon cancer.1,2 Why would that be? Humans are unable to make their own folate; it is an essential nutrient that is obtained from the diet. Important sources of natural folate are leafy green vegetables, fruits, legumes, liver, eggs, dairy products, and orange juice. There are three forms of folate currently used in dietary supplements: 1) Folic acid, a synthetic chemical compound. Human exposure to this form was non-existent until its chemical synthesis (1943) and use in food fortification (1998) and dietary supplements. Folic acid is the most commonly used form in dietary supplements due to its long shelf-life and low cost. 2) Folinic acid, which is one of the natural forms of folate found in foods. It’s also known as 5-formyl-tetrahydrofolate, leucovorin, or calcium folinate. Folinic acid has been the standard adjunct to anti-cancer drugs such as methotrexate and 5-fluorouracil, but does not usually appear in supplements. 3) More recently, 5-methyltetrahydrofolate (5-MTHF), another natural form of folate, has finally become available for use in dietary supplements. Even taking less than 400 micrograms per day of folic acid from fortified foods or supplements may lead to the appearance of unmetabolized folic acid in the bloodstream. This happens because, unlike the natural folates (e.g., 5-methyltetrahydrofolate and 5-formyltetrahydrofolate), folic acid is not a molecule our body can use. It must be reduced to dihydrofolate and then to tetrahydrofolate first:

Notice the top left corner of the above image: when people take Folic Acid supplements, what they ingest is not biologically active. It gets taken up into the cell and converted to tetrahydrofolate by an enzyme (called dihydrofolate reductase). In some people, that daily intake of folic acid causes that enzyme to get saturated, and it stops working– resulting in unmetabolized folic acid entering the circulation. The health outcomes of chronic exposure to unmetabolized folic acid have not been fully evaluated and there are several studies that seem to indicate potential risks of folic acid intake.[3,4,5,6,7,8] There is a growing body of evidence that seems to suggest a dual role of folates in carcinogenesis: High folate status prevents cancer development in the absence of pre-cancerous lesions, but folic acid supplementation may promote the growth and development of existing pre-cancerous lesions.[1,9,10,11] But aside from that concern, even if we assume that all ingested folate gets converted to tetrahydrofolate (THF), THF still has no biologic activity! You need a second enzyme, called MTHFR (methyl-tetrahydrofolate reductase) to convert it to 5-MTHF, which is what your body really wants. Unfortunately, some people don’t have very active MTHFR enzymes (and the only way to find that out is to do genetic testing). So as you can see, a much better option would be to just ingest 5-MTHF to begin with! Therefore in our new Packs, Folic Acid has been replaced with 5-MTHF. So why doesn't everyone use 5-MTHF instead of folate in their supplements??
Cost is one factor, but more significantly, a pharmaceutical company holds rights to several patents covering the use of 5-MTHF in foods. They have imposed stringent restrictions in the use of 5-MTHF in dietary supplements, such as specifying what formulas and dosages can be used, consequently preventing the general use of 5-MTHF. However, a handful of suppliers have grandfathered permission to use 5-MTHF, and PhysioAge has access to one of those suppiers. We have therefore removed folate from our supplement Packs and replaced it with 5-MTHF.
What's the story with Deplin?
A company now sells L-methylfolate as “Deplin”, claiming it will help combat depression. Deplin is metabolized to 5-MTHF when ingested, so if you feel Deplin works for you, 5-MTHF will do the trick as well.

PITFALL # 3: Beta-carotene and other troublesome carotenoids.
Beta-carotene appears in nearly EVERYONE’s multivitamins (go ahead—check the label on yours), yet there is virtually no proof that it is beneficial, and there is reason to believe it will increase your risk of cancer! Unlike most supplements, beta-carotene has been studied in several large randomized, placebo-controlled clinical trials. The “Beta-Carotene and Retinol Efficacy Trial,” called CARET for short, was stopped early in 1996 because initial results showed that smokers and asbestos workers taking beta-carotene had a 28% increase in lung cancer and a 17% increased risk of death over those taking placebo.12 And in Finland, the Alpha-Tocopherol Beta-Carotene (ATBC) cancer prevention trial evaluated the effects of beta-carotene and/or alpha-tocopherol on more than 29,000 male smokers13 – and there too, after six years the risk of lung cancer in the groups taking beta-carotene increased by 16%! In fact, a 2011 review paper14 looked at six randomized controlled trials, including 40,544 total participants (half in beta-carotene supplement groups, and half in placebo groups). They found that beta-carotene supplements had no preventive effect on either cancer incidence or cancer mortality. (And they noted similar findings whether the trials were for primary prevention or secondary prevention.) Subgroup analyses by various factors revealed that actually beta carotene significantly increased the risk of bladder cancer (RR = 1.52, 95% CI = 1.03-2.24). Also, it marginally increased the overall risk of cancer among current smokers (RR = 1.07, 95% CI = 0.99-1.17).
What about heart disease?
Taking beta carotene doesn’t do much good in preventing cardiovascular disease either. Epidemiologic studies suggest that eating lots of fruits and vegetables (which are high in beta carotene) may decrease cardiovascular disease, so we used to think beta-carotene would do the same thing– but four randomized controlled trials found no evidence that beta-carotene supplements were effective in preventing cardiovascular disease.[12,13,15,16] Based on the results of these randomized controlled trials, the U.S. Preventive Health Services Task Force concluded that there was good evidence that beta-carotene supplements provide no benefit in preventing cardiovascular disease in middle-aged and older adults.
What about other carotenoids?
Beta Carotene is part of a family of molecules called carotenoids—they add bright pigmentation to many vegetables, and are responsible for the amazing bright color of pink flamingos, among other things. Some other carotenoids you may have heard of are lutein and zeaxanthin. If Beta-carotene is a problem, are the others also bad actors? It turns out, unfortunately, that taking lutein and zeaxanthin may also be ill-advised. A study published in 2008 looked at 77,000 people who took supplements, and found that, whether or not they smoked, taking Lutein supplements doubled their risk of lung cancer, and beta carotene tripled it!17 So why do nearly everyone’s multivitamins still contain beta-carotene, and often lutein as well? Well, lutein and zeaxanthin have become popular because they do lower the risk of one type of macular degeneration, which can severely worsen eyesight as you age. But when you look at the big picture, it appears that the benefits may be outweighed by the risks. Therefore at PhysioAge we have decided to completely remove all beta carotene, lutein and zeaxanthin from our new Packs. We will replace it with something called astaxanthin, for which there are numerous human trials supporting its use. But if Astaxanthin is another carotenoid, won’t it just cause the same problems? Actually, no: because of its’ unique molecular structure, astaxanthin is different from other carotenoids, and we are excited to be adding it to our Packs. For the whole story on astaxanthin, see my blog post, Astaxanthin: King of the Carotenoids.

PITFALL # 4: Iron, or Copper, or both. Iron and Copper are pro-oxidants, essentially the opposite of what we want in our system. It is not surprising that in the Iowa Women’s Health Study, iron supplements were strongly associated with poor outcomes. Iron should only be supplemented when absolutely necessary, for people who are anemic, and should be discontinued as soon as possible. Copper is a bit trickier. There is some debate over how much is needed, and whether other supplements (Zinc? N-acetyl cysteine? Lipoic Acid?) lower copper levels. However, there is also growing concern that copper intake is increasing due to use of copper water pipes, copper contamination in meat, and of course copper in supplements. Some theorize that the increasing prevalence of Alzheimer’s disease is tracking our increased copper intake. PhysioAge did have some copper in it’s prior packs, but after much discussion we decided that it will not appear in the new Packs. I test serum copper levels on my patients when appropriate, and if anyone warrants supplementation, we can easily add that for them.

PITFALL #5: Using a supplement that has good data behind it, but picking a brand that doesn’t absorb well.

This problem is quite prevalent in the supplement industry. It’s a pitfall that doesn’t really make the supplement harmful; it just makes it a waste of your money. There are many supplements that aren’t absorbed well in mammals. When we reviewed the PhysioAge packs for this revision, we found a few ingredients that probably were not absorbing as well as we’d like: Curcumin, Lipoic Acid, and Coenzyme Q10. In all three cases, we have changed suppliers to obtain versions with excellent human pharmacokinetic studies proving superior absorption. Great effort goes into proving to our satisfaction that the ingredients in PhysioAge Packs are actually being absorbed. For more detail on this process, please see my blog post, Curcumin: Not all brands are created equal!

Show me the REFERENCES.

1. Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006 Oct;64(10 Pt 1):468-75.
2. Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1325-9.
3. Solomons NW. Food fortification with folic acid: has the other shoe dropped? Nutr Rev. 2007 Nov;65(11):512-5.
4. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):189-93.
5. Wright AJ, Dainty JR, Finglas PM. 2007. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. British Journal of Nutrition 98:667-675.
6. Lewis CJ, Crane NT, Wilson DB, et al. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr. 1999 Aug;70(2):198-207. 7. Quinlivan EP, Gregory JF 3rd. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr. 2003 Jan;77(1):221-5.
8. Whittaker P, Tufaro PR, Rader JI. Iron and folate in fortified cereals. J Am Coll Nutr. 2001 Jun;20(3):247-54.
9. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008 Mar;87(3):517-33.
10. Kim YI. Folic acid fortification and supplementation–good for some but not so good for others. Nutr Rev. 2007 Nov;65(11):504-11.
11. Ulrich CM. Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr. 2007 Aug;86(2):271-3.
12. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.
13. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330(15):1029-1035
14. Nutr Cancer. 2011 Nov;63(8):1196-207. Epub 2011 Oct 7. Effects of Beta-carotene supplements on cancer prevention: meta-analysis of randomized controlled trials
15. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334(18):1145-1149.
16. Greenberg ER, Baron JA, Karagas MR, et al. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA. 1996;275(9):699-703.
17. Long-term Use of b-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study Am J Epidemiol 2009;169:815–828
18. Tomeo, A.C.; Geller, M.; Watkins, T.R.; Gapor, A. and Bierenbaum, M.L. (1995) Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 30(12):1179-1183.
19. Kooyenga, D.K.; Geller,M.; Watkins, T.R. and Bierenbaum, M.L. (July 29, 1997) Antioxidant-induced regression of carotid stenosis over three-years. Proceedings of the 16th International Congress of Nutrition, Montreal.

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