Are Antioxidants (Gasp!) Dangerous?

Although it could make me roughly as popular as boiled-over microwave oatmeal, I think it's time I bring some emerging research to light. Yes, perhaps it's time we take a more cautious look at antioxidant supplements and decide whether they're really all they're cracked up to be.

A growing number of new studies are slowly getting many professionals to revise their opinions on the stuff. Do you take vitamin E, C or an antioxidant blend? Do you have strong opinions regarding your current dose? If so, read on.

Mounting Questions

First, and perhaps the straw that broke squatter's back, is the large American Heart Association analysis (2) of several studies. This was more than just a single research study with a small number of subjects. Whether you consider it overblown by the media or not (actually, I do), seeing an overall increase in death in those subjects taking 400 IU or more of vitamin E daily should nonetheless be enough to get your attention. Do we need this much when the RDA is just 30IU (15mg) for adult men?

And what about co-ingestion with other anti-thrombotic (clot-reducing) supplements like ginkgo, fish oils and NSAIDS such as aspirin or ibuprofen? And let's not even get into the addition of hypertensive agents like ephedra. Would these combinations increase the risk of a cerebrovascular accident ("blown hose") under a 400-pound squat attempt? Is a 400 or 800 IU daily capsule (181-354mg synthetic vitamin E) now considered harmful despite the "official" upper limit of 1000 mg per day? What are the alternatives?

Enter the other antioxidant big boy, vitamin C. As another vitamin with a history of low-toxicity and a correspondingly high "tolerable upper limit" of 2000mg per day, there's nothing wrong with supplementing a gram or two every day, right? Heck, it's even water-soluble and therefore more easily excreted.

Unfortunately, there's more to it. Vitamin C supplementation (500mg for six weeks) has been shown to actually induce pro-oxidant effects in healthy humans, as measured by DNA damage. (31) Very high doses (500mg/kg) in rats cause superoxide radical generation, induce P450 liver enzymes (particularly risky to even moderate drinkers) and, again, DNA damage. (29, 31)

In fact, this DNA fragmentation thing is mentioned quite a bit in academic publications. (29, 31, 26, 32, 33) A dose of 12.5mg per kilogram of body weight, when given with NAC, has even been shown to worsen eccentric muscle damage. (11) Then there's that new study showing a dose-dependent worsening of osteoarthritis in animals – as can also occur in veteran weight lifters – complete with a recommendation not to exceed the current 90mg RDA. (24)

Vitamin C may also be involved in creating and preserving (not protecting against) cancerous cells, (10, 25) thickening arteries at 500mg, (25) and worsening iron overload, particularly in persons with this common genetic disorder – not good for oxidative stress. (11, 13, 14, 15, 18)

We also need to consider, however controversial, rebound scurvy symptoms like bloody gums that occur when tablets aren't at arm's length, and at least some conclusions that the common cold argument has been "overstated." (20)

This isn't looking like a one-sided positive consensus in the scientific literature anymore, is it? Hey, don't shoot the messenger. Recent findings are important, yes, but let's also remember that they don't yet constitute unanimous condemnation among all healthcare authorities. We can't be content with selective citations, either pro or con. There's just too much out there on both sides to ignore. At the very least, we should stay abreast of new research, both positive and negative. (Yes, there's a ton of positive research out there too, even in this article's references, but we already know a lot about that.)

So, based on what's now available, should we instead be turning to "newer" antioxidants like pine bark, carnosine, green tea and grape seed extracts? (Check out some interesting references below!) If our old standbys, E and C, are "bad," what now?

Because of the above findings and still others, the American Heart Association, the same group who actually broke the mold surrounding dietary supplements and started suggesting fish oil capsules for certain individuals (1), came forward this past August with an advisory not to take antioxidant supplements. (3) Ugh! But what about the decades of earlier data? Are all those studies that showed benefits and low toxicity now wrong?

Good point. But like it or not, it appears that the AHA isn't satisfied with the existing positive evidence. The new recommendation is plain: avoid antioxidant supplements. If you're getting hot under your defensive collar by now, have no fear. I don't disagree with you.

Does It Apply to Us?

First, heart patients, like those who populated November's rather scary vitamin E review, are not bodybuilders. Hence, the research may not be especially applicable. Not only are most of us free of their multitude of cardiovascular medications, we also have our training stress and recovery to consider!

Nor are we guinea pigs (at least not in a literal sense) or a group of cells floating in a dish. We're mostly healthy adult males. Is there anything out there directly pertinent to us? As one positive example, a new study focusing on "our" population did recently find lower systolic blood pressure after 12 weeks on large daily amounts of antioxidants (1000mg vitamin C, 800mg vitamin E, 10mg folate). (36) That's cool. But we're even more than just "healthy adult males." We are highly active athletes.

You're right in thinking that even a brief bout of exercise can significantly kick-up oxidative stress. And this is to say nothing of eccentric muscle damage and reperfusion injury (obstructed and re-opened blood flow) that's possible during weight training. (26) As a positive example here, 400mg vitamin C supplemented for three weeks prior and one week post-exercise was indeed shown to reduce eccentric force losses. (22) Hence, we definitely shouldn't write-off all doses of antioxidants just yet.

So What Can We Do?

As mentioned, we athletes aren't generally heart patients and aren't even "normal" by sedentary standards. We have an increased need to protect against oxidation (elevated metabolic rate during and post-exercise), tissue damage (eccentric contractions or "negatives") and arguably even fish oil intake (possible pro-oxidative effects despite many benefits).

So what can we do if not take ongoing large doses of antioxidant supplements? Well, for one, those who are concerned can tone down their supplement doses and even use them cyclically. Dose and duration of intake are huge factors in determining whether these compounds are anti- or paradoxically pro-oxidant in nature!

We can also increasingly go to the natural source, whole foods. Obviously many foods contain antioxidant vitamins, minerals and phytochemicals (often in inimitable combinations). Imagine then, how quickly the vitamin C (not E, so much) would mount-up considering a mere 250mg tablet and a diet rich in fruits and vegetables!

So, let's look at a few foods that are extremely fast to prep and eat, and are convenient and portable:

  • Green tea, black tea, even a little medium roast coffee!
  • Plums! (A bag of dried plums [i.e. prunes] is handy as a car snack.)
  • Citrus! Oranges (even "Mandarin" style in their own juice), lemons and limes.*
  • Grapes (anthocyanins, reveratrol, etc.)
  • Berries! (more anthocyanins/ polyphenols)
  • Red bell pepper (a big time vitamin C source!)
  • Tomatoes, carrots, pumpkin (carotenoids can decline in the body under stress)
  • Olive oil! (phenolics)
  • Even functional foods like orange juice with added E and C

Here's an irresistible whole food quote from Sánchez-Moreno and colleagues:

"In fact, in the present study, consumption of 250 mg vitamin C, contained in two glasses of orange juice (500 mL), significantly increased plasma vitamin C from a range of 30–50 to a range of 60–90 µmol/L in just three hours. The increased concentration was maintained as long as the subjects were drinking the orange juice, which suggests that this is an efficient means of increasing vitamin C concentrations in the body.

"In other studies, blood concentrations of vitamin C were manipulated through the use of high vitamin C intake in the form of tablets (2000 mg), and vitamin C concentrations reached 116 µmol/L two hours after ingestion and 95 µmol/L after taking 500 mg, which suggests that high-dose supplements might not be the most efficient way of increasing the body's pool of vitamin C."

This is by no means a complete listing. If you're into scanning large amounts of new scientific material and can interpret inferential statistics, I'd love to hear your suggestions and conclusions on the antioxidant supplement vs. food topic!

When digging through hardcore literature on Medline or other databases, however, we need to be careful regarding the methodology of whole food studies. Since the assays used to assess total antioxidant capacity of common fruits and veggies differ, you'll find different conclusions among studies as to which are "best." The obvious recommendation is to eat as large a variety as possible.

The Cyclical Use Theory

Regarding supplements, let's examine the cyclical use theory. Just like the natural cycles surrounding seasonal foods, we might consider supplemental antioxidant support only during periods of accelerated training stress. I'm not referring to periodizing low-rep negative training with higher-rep functional training, but rather I'm considering those times of the year that you're specifically gearing up for an event.

Even non-competitors often gear up for early summer with added cardio and even stimulants (fat burners.) A boosted metabolic rate, however attractive for fat loss, does jack-up oxidative stress. Hard training can outstrip the body's endogenous (internal) up-regulation of antioxidant enzymes, too. (26) And I'd be remiss not to at least mention that 1,500mg of vitamin C could potentially reduce overtraining effects. You see, this dose can even lower cortisol levels. (30) But considering this fairly whopping amount, there are probably better ways to do it, like meditation (38) and coffee reduction, if excessive.

So, in addition to a daily multi-vitamin/multi-mineral (many now have 150-200% vitamins E and C anyway), here are some err-on-the-side-of-caution supplemental suggestions during ramped-up training times:

  1. Low dose E (200 IU daily) or the lowest dose of tocotrienols you can find. If necessary, take a half-tablet.
  2. Vitamin C (250mg once or maximally twice daily, AM and PM). Beware vitamin C's ability to increase iron absorption, contradictorily increasing oxidative tissue damage! (See my eep the Iron on the Bar article for more info.)
  3. A simple one-shot approach would be Protegra or related off-brands (a moderate-dose mix of antioxidant vitamins and minerals) on alternating training weeks. Now here's a practical quote: "...the well-known reversibility of the inductive phenomenon responsible for O2.- over-generation, suggests that human risk following typical vitamin C supplementation may be easily controlled by providing a discontinuous supply (e.g. alternate weeks)." (29)
  4. Pine bark (pycnogenol), grape seed extract (proanthocyanidin) and miscellaneous antioxidant-related compounds like MSM and SAMe: limit intake to a half-dose or weekends-only intake until more research arrives.

Cutting Edge vs. Recklessly Overdone

Does all the seemingly conflicting research presented in this article frustrate you? Welcome to nutrition. It's a world where consensus forms slowly and we have to think for ourselves based on as much scientific evidence (not emotional conviction) as we can scrounge.

Thank God for the Think Tank! Without a constant flow of new data and discussion, we might get excited enough to sailor's dive into things, head-first and prematurely, only to ruefully come around to more moderate decisions later. Our purpose here was just to reveal that there's indeed a darker side to all the cool antioxidant research we usually hear. Maybe it'll even help you make decisions a little more slowly in the future.

We can walk a balance between cutting edge and recklessly overdone. The concept is as old school as one can imagine. Aristotle's 2300 year-old "moderation in all things" is as true of supplements as it is of whole foods. Mild recovery enhancement isn't worth blowing a hose under the squat bar or needlessly damaging your DNA or ending up with early arthritis. I sincerely doubt these things will actually happen to you, but any sane person at least performs a risk-to-benefit analysis.

They say the passions of youth become the regrets of maturity, so just decide how close you're willing to cut it. With a balanced research perspective (pro and con), it's time to determine how you will gain some benefits without the repercussions of overdoing it.

References and Related Reading

  1. AHA Scientific Statement: Fish Consumption, Fish Oil, Omega-3 Fatty Acids and Cardiovascular Disease, #71-0241 Circulation. 2002;106: 2747-2757.
  2. Meeting Report: High doses of vitamin E supplements do more harm than good. Nov 10, 2004; accessed Dec. 12, 2004.
  3. Scientific Advisory: Get antioxidants from food, not supplements, says American Heart Association. Aug3, 2004; accessed Dec. 12, 2004.
  4. Ambrogini P, et al. Effects of proanthocyanidin on normal and reinnervated rat muscle. Boll Soc Ital Biol Sper. 1995 Jul-Aug;71(7-8):227-34.
  5. Arcangeli, P. Pycnogenol in chronic venous insufficiency. Fitoterapia. 2000 Jun;71(3):236-44.
  6. Bagchi, D., et al. Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat Res. 2003 Feb-Mar;523-524:87-97.
  7. Boldyrev, A., et al. Protection of neuronal cells against reactive oxygen species by carnosine and related compounds. Comp Biochem Physiol B Biochem Mol Biol. 2004 Jan;137(1):81-8.
  8. Bolyrev, A., et al. Carnosine, the protective, anti-aging peptide. Biosci Rep. 1999 Dec;19(6):581-7.
  9. Buetler, T., et al. Green tea extract decreases muscle necrosis in mdx mice and protects against reactive oxygen species. Am J Clin Nutr. 2002 Apr;75(4):749-53.
  10. Cerutti, P. Science. 1985 227:375-381.
  11. Childs, A., et al. Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Free Radic Biol Med. 2001 Sep 15;31(6):745-53.
  12. Cho, K., et al. Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokines. Ann N Y Acad Sci. 2001 Apr;928:141-56.
  13. Custer, E., et al. Population norms for serum ferritin. J Lab Clin Med 1995, 126(1): 88-94.
  14. Dantas, W. Hereditary hemochromatosis. Rev Gastroenterol Peru 2001, 21(1): 42-55.
  15. Deugnier, Y., et al. Gender-specific phenotypic Expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. Br J Haematol 2002, 118(4): 1170-1178.
  16. Dupin AM, Stvolinskii SL. Changes in carnosine levels in muscles working in different regimens of stimulation. Biokhimiia. 1986 Jan;51(1):160-4.
  17. Dutka TL, Lamb GD. Effect of carnosine on excitation-contraction coupling in mechanically-skinned rat skeletal muscle. J Muscle Res Cell Motil. 2004;25(3):203-13.
  18. Fleming, D., et al. dietary factors associated with the risk of high iron stores in the elderly Framingham heart study cohort. Am J Clin Nutr 2002, 76(6): 1375-1384.
  19. Hasegawa, J. Inhibition of lipogenesis by pycnogenol. Phytother Res. 2000 Sep;14(6):472-3.
  20. Hemilia, H. Vitamin C supplementation and the common cold–was Linus Pauling right or wrong? Int J Vitam Nutr Res. 1997;67(5):329-35.
  21. Imai, K. and Nakachi, K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ 1995, 310(6981): 693-696.
  22. Jakeman P, Maxwell S. Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise. Eur J Appl Physiol Occup Physiol. 1993;67(5):426-30.
  23. Johnston, C., et al. Orange juice ingestion and supplemental vitamin C are equally effective at reducing plasma lipid peroxidation in healthy adult women. J Am Coll Nutr. 2003 Dec;22(6):519-23.
  24. Kraus, V., et al. Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model. Arthritis Rheum. 2004 Jun;50(6):1822-31.
  25. Leslie, M. Vitamin C: How much do you really need? . Jun 19, 2000; accessed Dec. 10, 2004.
  26. Lowery, L., et al. Antioxidants Supplements and Exercise. In: Sports Supplements (Antonio and Stout, Eds.). 2001; Lippincott, Williams and Wilkins: Philadelphia, PA: 260-278.
  27. Nagai, K. [The inhibition of inflammation by the promotion of spontaneous healing with L-carnosine (author's transl)]. Langenbecks Arch Chir. 1980;351(1):39-49.
  28. Natella, F., et al. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem. 2002 Dec 18;50(26):7720-5.
  29. Paolini, M., et al. The nature of pro-oxidant activity of vitamin C. Life Sci, 1999 64(23): PL273-278.
  30. Peters, E., et al. Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running. Int J Sports Med. 2001 Oct;22(7):537-43.
  31. Podmore, D., et al. Nature. 1998 392: 559.
  32. Puntarulo, S. and Cederbaum, A. Free Rad Biol Med. 1998 24: 1324-1330.
  33. Sakagami, H. and Satoh, K. Anticancer Res. 1997 17:3513-3520.
  34. Sánchez-Moreno, C., et al. Effect of orange juice intake on vitamin C concentrations and biomarkers of antioxidant status in humans. Am J Clin Nutr. 2003 Sep;78(3):454-60.
  35. Sano, A., et al. Procyanidin B1 is detected in human serum after intake of proanthocyanidin-rich grape seed extract. Biosci Biotechnol Biochem. 2003 May;67(5):1140-3.
  36. Schutte, A., et al. Cardiovascular effects of oral Supplementation of vitamin C, E and folic acid in young healthy males. Int J Vitam Nutr Res. 2004 Jul;74(4):285-93.
  37. Stuerenburg HJ, Kunze K. Concentrations of free carnosine (a putative membrane-protective antioxidant) in human muscle biopsies and rat muscles. Arch Gerontol Geriatr. 1999 Sep;29(2):107-13.
  38. Sudsuang, R., et al. Effect of Buddhist meditation on serum cortisol and total protein levels, blood pressure, pulse rate, lung volume and reaction time. Physiol Behav. 1991 Sep;50(3):543-8.
  39. Virgili, F. Ferulic acid excretion as a marker of consumption of a French maritime pine (Pinus maritima) bark extract. Free Radic Biol Med. 2000 Apr 15;28(8):1249-56.
  40. Wander RC, Du SH. Oxidation of plasma proteins is not increased after supplementation with eicosapentaenoic and docosahexaenoic acids. Am J Clin Nutr. 2000 Sep;72(3):731-7.