High Dose Folate vs. Broad-Spectrum Nutrition for Methylation Support

The issue of high-dose folate has come up a lot lately, as a number of supplement companies offer folate in excess of 2,000 mcg and sometimes a lot more in products targeted for methylation and homocysteine metabolism. While some references are made to support this, the truth is that the literature is sparse on support of such high doses of folate for any application. Older data has not been validated at all on high-dose folate in certain women's reproductive health concerns, for example.  And, in fact, there appears to be diminishing returns on high-dose folate, as research published in the American Journal of Clinical Nutrition showed that doses of folate of 800 mcg and 2,000 mcg had precisely the same effect on reductions of homocysteine (see my previous post).  

"There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment." (Altern Med Rev. 2008 Sep;13(3):216-26) And there are no studies at all to my knowledge that show superior results in high dose folate vs. multiple nutrients.  (​If you know of any, please send them my way.)​
   

While the risk of toxicity of high dose folate is low, keep in mind that supplementation with folate can mask a B12 deficiency. 

In the supplement industry, a "more must be better" approach is often promoted among supplement companies and some practitioners, and this, of course, is the mindset of more ​conventional practitioners, as this is more consistent with the traditional medical model.  Providing mega-doses of any one substance is closer to a pharmacological approach rather than a holistic or complementary one.  ​But again, what does the preponderance of literature say?  As far as I can tell, there are no studies showing benefit of high dose folate vs. combining moderate ​folate amounts ​with other supportive nutrients.  

Truly holistic practitioners must resist the temptation to always believe that more is better.  An older study on vitamin E, for example, showed that mega-doses given to smokers actually seemed to increase the risk of lung cancer.  Why?  Because certain compounds given in mega doses in isolation of other supportive nutrients may turn out to be pro-oxidants rather than antioxidants.  

Thus, the most effective approach may be the one that addresses the potential folate deficiency, along with other deficiencies (B12, for example) while offering a comprehensive plan that takes into account a variety of supportive measures.​

Thus, methylation as a whole (and hence effective homocysteine metabolism)​ is less a situation of a singular nutrient and more a breadth of supportive accessory nutrients, such as zinc, B6, B12, betaine, molybdenum, N-acetylcysteine, and others. In other words, the more "natural" and effective approach is likely not high-dose folate but rational folate intake coupled with other methylation support nutrients. 

Folate and Homocysteine: Is There Diminishing Returns?

By now it is common knowledge that B-vitamins, particularly folate, B6, and B12, are extremely important to metabolize the amino acid, homocysteine, which is an intermediate in the metabolism of methionine and cysteine, and has been implicated in vascular disease.

Recently I had the opportunity to review a nutritional product that was touted as a supreme homocysteine support product.  It looked good, actually, but something stood out to me that is apparently not common knowledge among practitioners and supplement manufacturers.

The more-is-better idea is a common mindset among holistic pill poppers and those recommending them.  However, the idea that more is better does not apply to many things, and folate's role in homocysteine metabolism is one of them.

The supplement I reviewed has over 2,000 mcg of folate, which impresses many casual observers.  However, it must be noted that according to a study on homocysteine and folate published in The American Journal of Clinical Nutrition, even very low dose folate supplementation of 200 mcg lowers homocysteine significantly, and most notably, there was no difference in high dose folate supplementation and moderate dose supplementation in lowering homocysteine levels. (See chart below.)  Moderate dosing of 800 mcg lowers homocysteine by 23%, but pushing the dose up to 2,000 mcg did not show any additional benefit.  Even very high dosing at 5,000 mcg showed only minimal additional benefit of a mere two percentage points.  

What might make more sense in achieving the perfect formula for homocysteine metabolism is to keep the folate levels moderate in order to keep the cost down and make room for other important nutrients that aid in the methylation cycle and renal clearance of homocysteine -- nutrients such as molybdenum, N-acetylcysteine (NAC), manganese, betaine, etc.

NAC, in particular, is an important antioxidant that serves many roles in the body.  For example, it is an amazingly powerful antioxidant that supports liver detoxification and glutathione levels in the body, but it is also important for renal clearance of homocysteine.  Therefore, significant amounts of NAC (500 mg or more) should be considered to support those with elevated homocysteine or who have had a history of issues along these lines.

Consider supplementation that supports all four levels of homocysteine clearance (see below).

VITAMIN C: Still a Superstar and Growing in Fame Even More

Since the 1970s, Vitamin C has enjoyed superstar status, partly due to Dr. Linus Pauling's Nobel Prize winning work.  But for the past several years, good ole' ascorbic acid has been making a rebound in the research, as this "old news" vitamin has been showing great promise for a number of health applications other than just immunity.  

For example, research has shown that vitamin C protects against endothelial dysfunction, high blood pressure, and the blood vessel changes that precede heart disease.1-3 Additional research is discovering that vitamin C can be helpful in preventing asthma,4 protecting against cancer,5 and supporting healthy blood sugar levels in diabetics.6

While often taken for granted, vitamin C is a critical supplement in improving cardiac health and avoid degenerative diseases.  

British researchers, for example, studied the effects of vitamin C supplementation (250 mg/day) on atherosclerosis in 40 healthy adults.7 Before the study, subjects with low pre-supplementation levels of vitamin C had 30% greater monocyte adhesion than normal, putting them at higher risk for atherosclerosis. Impressively, after six weeks of supplementation, the rate of this dangerous monocyte adhesion actually fell by 37%!  

OTHER HEALTH BENEFITS OF VITAMIN C IN THE RESEARCH

• Ascorbic acid, or vitamin C, is a potent antioxidant with increasingly diverse uses in health promotion and disease prevention. 
• Every step in the progression of atherosclerosis can benefit from the antioxidant power of vitamin C, from preventing endothelial dysfunction and altering lipid profiles and coagulation factors to preventing blood vessel changes that can lead to strokes and other vascular catastrophes. 
• Vitamin C supplements reduce cellular DNA damage that is the vital first step in cancer initiation and also reduce the inflammatory changes that allow a malignant cell to grow into a dangerous tumor.  Additionally, vitamin C has been shown to be chemoprotective, showing protection from both the toxic effects of chemotherapy drugs, but also increasing the anti-tumor activity of chemotherapy, while perhaps reducing the risk of getting cancer in the first place.  8,9,10,11,12,13,14
• Vitamin C supplements enhance the health-promoting effects of exercise and reduce exercise-induced oxidative damage. 15
• Vitamin C supplements also dramatically combat the oxidative damage caused by smoking and exposure to tobacco smoke. 16
• In respiratory conditions, vitamin C supplements help avert or shorten the duration of common colds and may mitigate the risk of serious respiratory conditions like asthma.17, 18,19
• Vitamin C supplements can speed the clearance of the stomach disease-causing bacterium Helicobacter pylori and cut the risk of gastric cancer it causes.  20,21

While all the above benefits can be obtained by taking basic ascorbic acid, the effects may be enhanced by either adding other antioxidants to the mix, or providing a buffered and better absorbed forms.  Vojdani et al at Drew Medical College showed in 1993 that an admixture of vitamin C metabolites, presursors, and asorbates, along with a more bioavailable form of vitamin C, ascorbyl palmitate, was able to not only provide better uptake into the white blood cell, but the effect on leukocyte activity and overall immunity was profoundly better than ascorbic acid alone.22  This exact formula used in the Drew Medical College study is patented and available commercially in only one place.  Ascorbic acid products are typically not patented and are bountiful on the market.  

Still another study showed that a buffered admixture vitamin C supplement increased the natural killer (NK) cell activity 10-FOLD in 78% of patients who had decreased NK, T and B cell function due to chemical exposure!  T and B cells also returned to normal.23  

Yes, while vitamin C is sort of yesterday's news in a market of trendy supplements now too long to list, it remains one of the most powerful and effective vitamins in the world for overall health. 

References

1. Rossig L, Hoffmann J, Hugel B, et al. Vitamin C inhibits endothelial cell apoptosis in congestive heart failure. Circulation. 2001 Oct 30;104(18):2182-7. 2. Fotherby MD, Williams JC, Forster LA, Craner P, Ferns GA. Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons. J Hypertens. 2000 Apr;18(4):411-5. 3. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003 Feb 25;107(7):947-53. 4. Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, et al. Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. Am J Respir Crit Care Med. 2002 Sep 1;166(5):703-9. 5. Guz J, Dziaman T, Szpila A. Do antioxidant vitamins influence carcinogenesis?. Postepy Hig Med Dosw.(Online.). 2007;61:185-98. 6. Afkhami-Ardekani M, Shojaoddiny-Ardekani A. Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian J Med Res. 2007 Nov;126(5):471-4.  7. Woollard KJ, Loryman CJ, Meredith E, et al. Effects of oral vitamin C on monocyte: endothelial cell adhesion in healthy subjects. Biochem Biophys Res Commun. 2002 Jun 28;294(5):1161-8. 8. Bast A, Haenen GR, Bruynzeel AM, Van d, V. Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials. Cardiovasc Toxicol. 2007;7(2):154-9. 9. bdel-Latif MM, Raouf AA, Sabra K, Kelleher D, Reynolds JV. Vitamin C enhances chemosensitization of esophageal cancer cells in vitro. J Chemother. 2005 Oct;17(5):539-49. 10. Chen J, Kang J, Da W, Ou Y. Combination with water-soluble antioxidants increases the anticancer activity of quercetin in human leukemia cells. Pharmazie. 2004 Nov;59(11):859-63. 11. Chen J, Wanming D, Zhang D, Liu Q, Kang J. Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells. Pharmazie. 2005 Jan;60(1):57-61. 12. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst. 2000 Dec 6;92(23):1881-8. 13. Maramag C, Menon M, Balaji KC, Reddy PG, Laxmanan S. Effect of vitamin C on prostate cancer cells in vitro: effect on cell number, viability, and DNA synthesis. Prostate. 1997 Aug 1;32(3):188-95. 14. Wei DZ, Yang JY, Liu JW, Tong WY. Inhibition of liver cancer cell proliferation and migration by a combination of (-)-epigallocatechin-3-gallate and ascorbic acid. J Chemother. 2003 Dec;15(6):591-5. 15. Thompson D, Williams C, McGregor SJ, et al. Prolonged vitamin C supplementation and recovery from demanding exercise. Int J Sport Nutr Exerc Metab. 2001 Dec;11(4):466-81. 16. Block G, Jensen C, Dietrich M, et al. Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation. J Am Coll Nutr. 2004 Apr;23(2):141-7. 17. Romieu I, Trenga C. Diet and obstructive lung diseases. Epidemiol Rev. 2001;23(2):268-87. 18. Trenga CA, Koenig JQ, Williams PV. Dietary antioxidants and ozone-induced bronchial hyperresponsiveness in adults with asthma. Arch Environ Health. 2001 May;56(3):242-9. 19. Tecklenburg SL, Mickleborough TD, Fly AD, Bai Y, Stager JM. Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med. 2007 Aug;101(8):1770-8. 20. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst. 2000 Dec 6;92(23):1881-8. 21. Chuang CH, Sheu BS, Kao AW, et al. Adjuvant effect of vitamin C on omeprazole-amoxicillin-clarithromycin triple therapy for Helicobacter pylori eradication. Hepatogastroenterology. 2007 Jan;54(73):320-4. 22.  Vajdoni, A, et al.  In Vivo Effect of Ascrobic Acid on Enhancement of Human Natural Killer Cell Activity.  Drew University of Medicine and Science, Published in Nutritiona Research, Vol. 13, pp. 753-764, 1993. 23. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312

Lipid Management with Niacin: nicotinic acid vs. IHN

The question has come up a few times lately about straight niacin (nicotinic acid) vs. slow release niacin, or inositol hexanicotinate (IHN).  Some claim that there is conclusive evidence that IHN does not work at all for managing lipids.  Well, that's not really the case.

Straight niacin is less expensive than IHN and has been the subject of a lot of very impressive research on lipid management.  In some circles it is considered the gold standard, in fact, for cholesterol management, and is declared the treatment of choice for reducing blood lipids by the Expert Panel of the National Cholesterol Education Program (NCEP).

However, the beef against niacin is that some people flush with it.  I am one of those people, and let me tell you, a strong niacin flush is NO FUN!  The "flush" is a burning, tingling sensation on the skin that is due to a temporary increase in prostaglandins leading to cutaneous vasodilation when too much is taken too soon.  The flush is very temporary, but WOW!  It can be very uncomfortable for some people who are sensitive to it.  And some people like myself can't seem to get to the point where they eventually don't flush when using nicotinic acid.  

Enter, then IHN, which does not reach maximum serum levels for 10 hours after ingestion and has practically zero flushing potential.  

There is indeed some evidence that IHN has very little impact on overall cholesterol or LDL/HDL ratios.  That evidence is by no means conclusive, however, especially when you compare it to the evidence showing that it does have benefit.  (There is also "evidence" that fish oil and herbs have no benefit, after all, so...)  

IHN consists of six molecules of niacin and one molecule of inositol.  It is metabolized in the body into its component parts, allowing for the positive benefits associated with high doses of niacin without the many side effects.  When administered orally, IHN results in a sustained increase in serum levels of free niacin and, in human studies, is better tolerated than regular niacin.

Studies showing that IHN improves lipid profiles date as far back as the early 1960s.1,2,3  An in vitro study showed that IHN was more effective than niacin in reducing hypercholesterolemia.4  When given to rabbits on a fatty diet, IHN resulted in normalization of all lipid fractions, including cholesterol.5  In humans, IHN has been shown by two research groups to produce a reduction in cholesterol that was even more profound than that produced by niacin.1

I have worked with practitioners for over two decades now who have used IHN extensively in their practices and have the lab results to prove that it does indeed work for many people.  It might not be a 100% effective, but neither is straight niacin, and neither are statins.  

Niacin supports healthy blood lipid levels via its inhibition of catecholamine stimulated lipolysis in adipose tissue, its affect on hepatic lipoprotein synthesis, and its support of healthy high-density lipoprotein levels.  So whether by nicotinic acid or by IHN, niacin appears to be a great option in the battle against cardiovascular disease.  

References:

1. Welsh AL, Ede M. Inositol hexanicotinate for improve nicotinic acid therapy. Int Record Med. 1961;174:9-15. 2. Sommer H. Nicotinic acid levels in the blood and fibrinolysis under the influence of the hexanicotinic ester of m-inositol. Arzneim Forsch. 1975;15:1337. 3. Dorner VG, Fischer FW. The influence of m-inositol hexanicotinate ester on the serum lipids and lipoproteins. Arzneim Forsch. 1961;11:110-113. 4. El-Eneim AMA, Hafez YS, Salem H, Abdel M. The role of nicotinic acid and inositol hexanicotinate as anticholesterolemic and antilipemic agents. Nutr Reports Int. 1983;28:899-911.