46 replies to this topic

[Michael]

All:

No time to properly address the stuff that's come up in teh recent resveratrol thread, except for this one idea: high-dose folic acid (often advocated; in this case, for IGF1 modulation).

I'm gonna greatly increase my (undeserved) reputation as an anti-supplement fanatic by strongly urging people to scale back the folic acid content of all supplements to the RDA (200 mcg) for a full daily dose -- ie, treat the RDA as the UL (Upper Limit).

I'm going to beg folks to actually read and consider the evidence -- none of it absolutely slam-dunk, but all of it worrisome -- before deciding that I'm either just showing the aforementioned bias, or a sleeper agent for Quackwatch/NCAF/Big Pharma.

Starting with colon (and other) cancers; ironically, both the fact, and the mechanism, whereby crystalline folic acid gains higher bioavailability vs food folate, appears to make it riskier, when for years, the supplement industry had always pointed to this higher bioavailability as a reason to FAVOR supplement use (dietary folates being low-bioavailability & thus unreliable).

Folate and cancer prevention: a closer look at a complex picture

Scientists question folic acid fortification

Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK

A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial

Low folate levels may protect against colorectal cancer

Methylation of the ESR1 CpG island in the colorectal mucosa is an 'all or nothing' process in healthy human colon, and is accelerated by dietary folate supplementation in the mouse.

Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon

Then there's the failure of methylating suupplements to protect against heart disease -- and in some cases, the hints of worse outcomes for users -- complete with some plausible mechanisms:

Homocysteine trials -- clear outcomes for complex reasons

(That was up to 2006, and there've been several subsequent null or slightly harmful clinical trial outcomes subsequently, such as "Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial").

Loscalzo J.
Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism?
Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):3-5. No abstract available.
PMID: 12524215 [PubMed - indexed for MEDLINE]

There's never been a good reason for almost anyone to take more than 400 µg of folic acid, at which dose the effect on homocysteine seems maxed out anyway, even in the elderly:

"A dose-response trial with a randomized, double-blind, parallel-group, placebo-controlled design was carried out among 316 Dutch men and women aged 50-75 y. Subjects received daily for 12 wk either a placebo or 1 of the 6 following folic acid doses: 50, 100, 200, 400, 600, or 800 micro g. ... An adequate dose of folic acid was defined as the dose that induced >or= 90% of the maximal reduction in homocysteine concentration. ... From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g".

I'm not saying that any of this is a conclusive conviction of supra-RDA folic acid as a killer; I am saying it's not worth the gamble.

-Michael

[ajnast4r]

isnt the rda for 20+yrs 400mcg

[sUper GeNius]

All:

I'm gonna greatly increase my (undeserved) reputation as an anti-supplement fanatic by strongly urging people to scale back the folic acid content of all supplements to the RDA (200 mcg) for a full daily dose -- ie, treat the RDA as the UL (Upper Limit).

-Michael

Thanks for the info Michael. As far as you being a fanatic, I don't think many here believe that, (other members, feel free to correct me.)

Having devoted your life to CR, however, I do think there is a possibility for bias, one that should be kept in mind when evaluating the information you present.

edit: I would like to see some discussion on the possibility of depression among CR practitioners. It would be a *serious* side effect, and certainly seems at least as likely as your folic acid hypothesis.

Edited by FuLL meMbeR, 09 June 2008 - 11:35 PM.

[zoolander]

I think that the information that you provided may disturb a few people considering that most of the high quality multivitamin/mineral formulas on the market have 800mcg of folic acid in them. For example, both LEF's Life Extension Mix and AOR's Ortho-Core have 800mcg in a day's serve. That's double the adequate daily dose as calculate in the above study and 4 times the RDA or what you are suggesting we should consider the UL. Most, I think, would get most of their supplemental folic acid from their multi.

Anyhow, caution is always a good thing. Thanks for the heads up Micheal. I'll have a read over the studies that you provided

[ajnast4r]

I'll have a read over the studies that you provided

would love to hear your opinion once you finish reading them over zoo

[zoolander]

Cool. Give me about 6-12 months. I've gotta finish my thesis first

[krillin]

My rules are 1) use folinate (I take 800 mcg 4 days/week) to make sure you don't have any unmetabolized folate floating around and 2) start early in life, rather than waiting until you are a breeding ground for polyps. The prospective cohort studies say you need to take it for at least 15 years before you benefit. The study Michael linked to closed up shop after 6-8 years and used people who were already growing polyps, which tells me that the study was cunningly designed to set up folate to fail.

Ann Intern Med. 1998 Oct 1;129(7):517-24.
Comment in: ACP J Club. 1999 Mar-Apr;130(2):51.
Ann Intern Med. 2003 Mar 4;138(5):430-1.
Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study.
Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC.
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

BACKGROUND: High intake of folate may reduce risk for colon cancer, but the dosage and duration relations and the impact of dietary compared with supplementary sources are not well understood. OBJECTIVE: To evaluate the relation between folate intake and incidence of colon cancer. DESIGN: Prospective cohort study. SETTING: 88,756 women from the Nurses' Health Study who were free of cancer in 1980 and provided updated assessments of diet, including multivitamin supplement use, from 1980 to 1994. PATIENTS: 442 women with new cases of colon cancer. MEASUREMENTS: Multivariate relative risk (RR) and 95% CIs for colon cancer in relation to energy-adjusted folate intake. RESULTS: Higher energy-adjusted folate intake in 1980 was related to a lower risk for colon cancer (RR, 0.69 [95% CI, 0.52 to 0.93] for intake > 400 microg/d compared with intake < or = 200 microg/d) after controlling for age; family history of colorectal cancer; aspirin use; smoking; body mass; physical activity; and intakes of red meat, alcohol, methionine, and fiber. When intake of vitamins A, C, D, and E and intake of calcium were also controlled for, results were similar. Women who used multivitamins containing folic acid had no benefit with respect to colon cancer after 4 years of use (RR, 1.02) and had only nonsignificant risk reductions after 5 to 9 (RR, 0.83) or 10 to 14 years of use (RR, 0.80). After 15 years of use, however, risk was markedly lower (RR, 0.25 [CI, 0.13 to 0.51]), representing 15 instead of 68 new cases of colon cancer per 10,000 women 55 to 69 years of age. Folate from dietary sources alone was related to a modest reduction in risk for colon cancer, and the benefit of long-term multivitamin use was present across all levels of dietary intakes. CONCLUSIONS: Long-term use of multivitamins may substantially reduce risk for colon cancer. This effect may be related to the folic acid contained in multivitamins.

PMID: 9758570

Cancer Epidemiol Biomarkers Prev. 2002 Mar;11(3):227-34.
The influence of folate and multivitamin use on the familial risk of colon cancer in women.
Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE, Giovannucci EL.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Charles_Fuch@dfci.harvard.edu

Low intake of folate and methionine and heavy alcohol consumption have been associated with an increased overall risk of colon cancer, possibly related to their role in methylation pathways. We estimated the relative risk (RR) of colon cancer according to a history of colorectal cancer in a first-degree relative and categories of folate, methionine, and alcohol intake in a prospective cohort study of 88,758 women who completed family history and detailed food frequency questionnaires. During 16 years of follow-up, colon cancer was diagnosed in 535 women. The inverse association of folic acid with colon cancer risk was greater in women with a family history. Compared with women who consumed 200 microg or less of folic acid/day, the age-adjusted RR of colon cancer for those who consumed >400 microg/day was 0.81 (95% confidence interval, 0.62-1.07) in women without a family history of colorectal cancer and 0.48 (95% confidence interval, 0.28-0.83) in women with a family history (P for interaction = 0.02). The influence of family history was markedly diminished by use of multivitamins containing folic acid (P for interaction = 0.04). High levels of dietary methionine also reduced the effect of family history (P for interaction = 0.05), whereas moderate to heavy alcohol consumption increased the risk associated with family history (P for interaction = 0.004). Other risk factors for colorectal cancer did not significantly modify the influence of family history. Our results suggest that higher intake of folate and methionine, regular use of multivitamins containing folate, and avoidance of moderate to heavy alcohol consumption may diminish the excess risk of colon cancer associated with a family history of the disease.

PMID: 11895870

[eldar]

Cancer Epidemiol Biomarkers Prev. 2002 Mar;11(3):227-34.
The influence of folate and multivitamin use on the familial risk of colon cancer in women.
Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE, Giovannucci EL.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Charles_Fuch@dfci.harvard.edu

Low intake of folate and methionine and heavy alcohol consumption have been associated with an increased overall risk of colon cancer, possibly related to their role in methylation pathways. We estimated the relative risk (RR) of colon cancer according to a history of colorectal cancer in a first-degree relative and categories of folate, methionine, and alcohol intake in a prospective cohort study of 88,758 women who completed family history and detailed food frequency questionnaires. During 16 years of follow-up, colon cancer was diagnosed in 535 women. The inverse association of folic acid with colon cancer risk was greater in women with a family history. Compared with women who consumed 200 microg or less of folic acid/day, the age-adjusted RR of colon cancer for those who consumed >400 microg/day was 0.81 (95% confidence interval, 0.62-1.07) in women without a family history of colorectal cancer and 0.48 (95% confidence interval, 0.28-0.83) in women with a family history (P for interaction = 0.02). The influence of family history was markedly diminished by use of multivitamins containing folic acid (P for interaction = 0.04). High levels of dietary methionine also reduced the effect of family history (P for interaction = 0.05), whereas moderate to heavy alcohol consumption increased the risk associated with family history (P for interaction = 0.004). Other risk factors for colorectal cancer did not significantly modify the influence of family history. Our results suggest that higher intake of folate and methionine, regular use of multivitamins containing folate, and avoidance of moderate to heavy alcohol consumption may diminish the excess risk of colon cancer associated with a family history of the disease.

PMID: 11895870

This is a bit off topic, but the methionine part really puzzled me. Wasn't methionine restriction supposed to be beneficial and perhaps mimic CR? Now this study is saying that low levels of methionine may increase cancer risk...I'm confused.

[krillin]

This is a bit off topic, but the methionine part really puzzled me. Wasn't methionine restriction supposed to be beneficial and perhaps mimic CR? Now this study is saying that low levels of methionine may increase cancer risk...I'm confused.

The paper says

The mechanisms by which folate may modify the effect of family history are unclear. Folate and methionine are important factors in DNA methylation, whereas alcohol antagonizes methylation pathways (45) . Genomic and proto-oncogene- specific DNA hypomethylation seems to be an early and consistent event in colon carcinogenesis (46, 47, 48, 49, 50) . In addition, folate is required to convert deoxyuridylate into thymidylate. Blount et al. (51) demonstrated that folate deficiency was related to massive misincorporation of uracil into human DNA and increased chromosomal breaks, and these changes were reversible with folate supplementation.

[Michael]

All:

isnt the rda for 20+yrs 400mcg

For food folate, yes. Precisely because of the bioavailability difference, the RDA for supplemental folic acid is only half of that for food. See this chart of the Dietary Reference intakes from teh Institute of Medicine:

Note: Given as dietary folate equivalents (DFE). 1 DFE = 1 µg food folate = 0.6 µg of folate from fortified food or as a supplement consumed with food = 0.5 µg of a supplement taken on an empty stomach.

I think that the information that you provided may disturb a few people considering that most of the high quality multivitamin/mineral formulas on the market have 800mcg of folic acid in them. For example, both LEF's Life Extension Mix and AOR's Ortho-Core have 800mcg in a day's serve. That's double the adequate daily dose as calculate in the above study and 4 times the RDA or what you are suggesting we should consider the UL. Most, I think, would get most of their supplemental folic acid from their multi.

Well, yes -- or if they're taking a "standard" B50 pill, or any number of things. However, as I've always said, unless your diet is composed entirely of fries, Coke, and fast-food burgers with the lettuce, ketchup, and tomato thrown out, absolutely no one should be taking a full daily dose of any commercial multivitamin. You are absolutely guaranteed to get too much of many nutrients, and to create or exacerbate imbalances in others. I can only offer a sincere mea culpa, combined with some pleading reference to Luke 23:34, on OrthoCore, and refer you to this post for all of the many reasons not to take LEF Mix.

My rules are 1) use folinate (I take 800 mcg 4 days/week) to make sure you don't have any unmetabolized folate floating around and 2) start early in life, rather than waiting until you are a breeding ground for polyps.

That doesn't fully address the notion of (reinforcement of) de novo epimutational methylation.

The prospective cohort studies say you need to take it for at least 15 years before you benefit.

Careful. The two reports you cite (1,2) are actually from the same cohort (the Nurses' Health Study ), and while the first (1) seemed to find a general protective effect, the second (2) only found a significant effect in people with a family history of colon cancer, in whom such advice (long-term, low-dose, preventive supplementation) might still be reasonable:

Compared with women who consumed 200 microg or less of folic acid/day, the age-adjusted RR of colon cancer for those who consumed >400 microg/day was 0.81 (95% confidence interval, 0.62-1.07 [ie, not distinguishable from null hypothesis -MR]) in women without a family history of colorectal cancer and 0.48 (95% confidence interval, 0.28-0.83) in women with a family history (P for interaction = 0.02). The influence of family history was markedly diminished by use of multivitamins containing folic acid (P for interaction = 0.04).

I would like to see some discussion on the possibility of depression among CR practitioners. It would be a *serious* side effect, and certainly seems at least as likely as your folic acid hypothesis.

I can't imagine why you'd think so: I know of no evidence at all supporting such a notion, and plenty to directly refute it, as I hope to post shortly in the Calorie restriction forum.

-Michael
References

1. Ann Intern Med. 1998 Oct 1;129(7):517-24.
Comment in: ACP J Club. 1999 Mar-Apr;130(2):51.
Ann Intern Med. 2003 Mar 4;138(5):430-1.
Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study.
Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC.
PMID: 9758570

2. Cancer Epidemiol Biomarkers Prev. 2002 Mar;11(3):227-34.
The influence of folate and multivitamin use on the familial risk of colon cancer in women.
Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE, Giovannucci EL.
PMID: 11895870

Edited by Michael, 21 July 2008 - 01:02 AM.

[krillin]

According to a new analysis, it may be a good idea to keep taking folic acid even if you develop cancer.

I also found something that may possibly further damn synthetic folic acid. Although the study found that folic acid supplement users were protected, dihydrofolate reductase inhibitors increased the cancer risk more than other kinds of folate antagonists. That could be due to harm from unreduced folic acid.

Unrelated to cancer, my third reference found that 722–1150 mcg folate was best for sperm quality.

J Clin Oncol. 2008 Jul 1;26(19):3222-8.
Prediagnostic plasma folate and the risk of death in patients with colorectal cancer.
Wolpin BM, Wei EK, Ng K, Meyerhardt JA, Chan JA, Selhub J, Giovannucci EL, Fuchs CS.
Department of MedicalOncology, Dana-Farber Cancer Institute, Boston, MA, USA. bwolpin@partners.org

PURPOSE: Although previous studies have demonstrated an inverse relationship between folate intake and colorectal cancer risk, a recent trial suggests that supplemental folic acid may accelerate tumorigenesis among patients with a history of colorectal adenoma. Therefore, high priority has been given to research investigating the influence of folate on cancer progression in patients with colorectal cancer. PATIENTS AND METHODS: To investigate whether prediagnostic levels of plasma folate are associated with colorectal cancer-specific and overall mortality, we performed a prospective, nested observational study within two large US cohorts: the Nurses' Health Study and Health Professionals Follow-Up Study. We measured folate levels among 301 participants who developed colorectal cancer 2 or more years after their plasma was collected and compared participants using Cox proportional hazards models by quintile of plasma folate. RESULTS: Higher levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality. Compared with participants in the lowest quintile of plasma folate, those in the highest quintile experienced a multivariable-adjusted hazard ratio for colorectal cancer-specific mortality of 0.42 (95% CI, 0.20 0.88) and overall mortality of 0.46 (95% CI, 0.24 0.88). When the analysis was limited to participants whose plasma was collected within 5 years of cancer diagnosis, no detrimental effect of high plasma folate was noted. In subgroup analyses, no subgroup demonstrated worse survival among participants with higher plasma folate levels. CONCLUSION: In two large prospective cohorts, higher prediagnostic levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality.

PMID: 18591557

Pharmacoepidemiol Drug Saf. 2007 Oct;16(10):1111-9.
The use of folic acid antagonists and the risk of colorectal cancer.
Coogan PF, Rosenberg L.
Slone Epidemiology Center, Boston University, MA 02215, USA. pcoogan@bu.edu

PURPOSE: Since folate is associated with a reduced risk of colorectal cancer, we hypothesized that folic acid antagonists might increase the risk. We used data from a population-based case control study of medication use and colorectal cancer to evaluate the hypothesis. METHODS: Case patients with adenocarcinoma of the colon or rectum were ascertained from participating hospitals in Massachusetts and the Massachusetts cancer registry (MCR) from January 1, 2001, through November 30, 2004. Age-, sex-, and precinct-matched control subjects were chosen from Massachusetts town lists. Information on folic acid antagonist use and other relevant data were obtained from 1809 cases and 1809 matched controls by telephone interview and by a self-administered dietary questionnaire. We used logistic regression models to estimate odds ratios among 1229 case patients and 1165 control subjects who provided satisfactory dietary information and did not have Crohn's disease or ulcerative colitis. RESULTS: The odds ratio for colorectal cancer among regular users of folate-containing supplements was 0.7 (95%CI 0.6-0.9). The odds ratio for regular use of folic acid antagonists was 1.3 (95%CI 0.9-1.9). Contrary to expectation, the odds ratio was reduced in the highest category of alcohol consumption (OR = 0.5, 95%CI 0.2-1.2). The odds ratio was higher among users of drugs that inhibit dihydrofolate reductase (OR = 1.6, 95%CI 0.9-2.8) than drugs that work through other mechanisms (OR = 1.2, 95%CI 0.7-1.9). CONCLUSIONS: Our data provide little support for the hypothesis that regular folic acid antagonist use increases the risk of colorectal cancer. However, there is a suggestion that dihydrofolate reductase inhibitors specifically may increase the risk.

PMID: 17600846

Hum Reprod. 2008 May;23(5):1014-22.
The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men.
Young SS, Eskenazi B, Marchetti FM, Block G, Wyrobek AJ.
School of Public Health, University of California, 2150 Shattuck Avenue, Suite 600, Berkeley, CA 94704-7380, USA.

BACKGROUND: Little is known about the effect of paternal nutrition on aneuploidy in sperm. We investigated the association of normal dietary and supplement intake of folate, zinc and antioxidants (vitamin C, vitamin E and beta-carotene) with the frequency of aneuploidy in human sperm. METHODS: Sperm samples from 89 healthy, non-smoking men from a non-clinical setting were analysed for aneuploidy using fluorescent in situ hybridization with probes for chromosomes X, Y and 21. Daily total intake (diet and supplements) for zinc, folate, vitamin C, vitamin E and beta-carotene was derived from a food frequency questionnaire. Potential confounders were obtained from a self-administered questionnaire. RESULTS: After adjusting for covariates, men with high folate intake (>75th percentile) had lower frequencies of sperm with disomies X, 21, sex nullisomy, and a lower aggregate measure of sperm aneuploidy (P <or= 0.04) compared with men with lower intake. In adjusted continuous analyses, total folate intake was inversely associated with aggregate sperm aneuploidy (-3.6% change/100 microg folate; 95% CI: -6.3, -0. 8) and results were similar for disomies X, 21 and sex nullisomy. No consistent associations were found between antioxidant or zinc intakes and sperm aneuploidy. CONCLUSIONS: Men with high folate intake had lower overall frequencies of several types of aneuploid sperm.

PMID: 18353905

[Mind]

The main point I take away from this discussion - the point that comes out of many supp discussions - is that if you have a good diet, you need very little or no supplementation to remain in an optimal state of health.

[Dmitri]

All:

No time to properly address the stuff that's come up in teh recent resveratrol thread, except for this one idea: high-dose folic acid (often advocated; in this case, for IGF1 modulation).

I'm gonna greatly increase my (undeserved) reputation as an anti-supplement fanatic by strongly urging people to scale back the folic acid content of all supplements to the RDA (200 mcg) for a full daily dose -- ie, treat the RDA as the UL (Upper Limit).

I'm going to beg folks to actually read and consider the evidence -- none of it absolutely slam-dunk, but all of it worrisome -- before deciding that I'm either just showing the aforementioned bias, or a sleeper agent for Quackwatch/NCAF/Big Pharma.

Starting with colon (and other) cancers; ironically, both the fact, and the mechanism, whereby crystalline folic acid gains higher bioavailability vs food folate, appears to make it riskier, when for years, the supplement industry had always pointed to this higher bioavailability as a reason to FAVOR supplement use (dietary folates being low-bioavailability & thus unreliable).

Folate and cancer prevention: a closer look at a complex picture

Scientists question folic acid fortification

Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK

A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial

Low folate levels may protect against colorectal cancer

Methylation of the ESR1 CpG island in the colorectal mucosa is an 'all or nothing' process in healthy human colon, and is accelerated by dietary folate supplementation in the mouse.

Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon

Then there's the failure of methylating suupplements to protect against heart disease -- and in some cases, the hints of worse outcomes for users -- complete with some plausible mechanisms:

Homocysteine trials -- clear outcomes for complex reasons

(That was up to 2006, and there've been several subsequent null or slightly harmful clinical trial outcomes subsequently, such as "Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial").

Loscalzo J.
Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism?
Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):3-5. No abstract available.
PMID: 12524215 [PubMed - indexed for MEDLINE]

There's never been a good reason for almost anyone to take more than 400 µg of folic acid, at which dose the effect on homocysteine seems maxed out anyway, even in the elderly:

"A dose-response trial with a randomized, double-blind, parallel-group, placebo-controlled design was carried out among 316 Dutch men and women aged 50-75 y. Subjects received daily for 12 wk either a placebo or 1 of the 6 following folic acid doses: 50, 100, 200, 400, 600, or 800 micro g. ... An adequate dose of folic acid was defined as the dose that induced >or= 90% of the maximal reduction in homocysteine concentration. ... From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g".

I'm not saying that any of this is a conclusive conviction of supra-RDA folic acid as a killer; I am saying it's not worth the gamble.

-Michael

200 mcg? I thought it was 400 mcg; all the supplements I have used lists 400 mcg as being the 100% daily value.

[waldemar]

I am still worried about the results of the studies of the original post. As far as I see the other posts have neither really refuted nor confirmed the original studies.

My fruit juice is fortified with folic acid. I eat fruits and vegetables and also take Ortho Core with 800 mcg. Is that really a problem?

[stephen_b]

From wiki,

Unmetabolized folic acid is associated with a reduction in natural killer cell cytotoxicity which reduces the immune system's ability to defend against malignant cells.[77] However, the study also showed that dietary baseline intake of folate may have inverse effects of prostate cancer.

In Folate intake and bowel cancer risk (PMID: 19499262):

Indeed, there is some evidence of potential harm in increased risk of prostate cancer. Possible reasons for the apparent divergence in findings from the observational and intervention studies include the use of (unphysiologically) large doses of folic acid in the intervention studies whereas smaller intakes of food folates appeared to offer "protection" against CRC in case-control and prospective cohort studies. With intakes of folic acid greater than 400 mug/day, unmetabolised folic acid appears in peripheral blood and there are suggestions that this folic acid may have adverse effects e.g. reduced cytotoxicity of Natural Killer cells. Until the benefit-risk relationship associated with mandatory fortification with folic acid has been clarified (and, in particular, the possible risk of inducing extra cases of bowel or other cancer), it would seem wise to delay further mandatory folic acid fortification.

To me this is good evidence for avoiding folic acid. It is also suggestive that l-methylfolate supplementation, which is more like the folate in food, may help prevent prostate cancer.

[eason]

I am still worried about the results of the studies of the original post. As far as I see the other posts have neither really refuted nor confirmed the original studies.

My fruit juice is fortified with folic acid. I eat fruits and vegetables and also take Ortho Core with 800 mcg. Is that really a problem?

I think it is a concern. (Sorry AOR) I would ditch the multivitamin, do a chron-o-meter on nutrient intake, and supplement nutrients when needed individually. Edit: I wouldn't drink fruit juice either.

Edited by eason, 12 January 2010 - 07:55 PM.

[ScrapBrain]

Any updates?

[kismet]

Yes, seems there is neither much of a risk nor benefit to folic acid supplementation. (resulting in a terrible risk/benefit ratio)

I haven't read the paper, but:
“Individual participant data were obtained for a meta-analysis of 8 large, randomized, placebo-controlled trials of folic acid supplementation involving 37 485 individuals at increased risk of cardiovascular disease. The analyses involved intention-to-treat comparisons of first events during the scheduled treatment period. There were 9326 major vascular events (3990 major coronary events, 1528 strokes, and 5068 revascularizations), 3010 cancers, and 5125 deaths. Folic acid allocation yielded an average 25% reduction in homocysteine levels. During a median follow-up of 5 years, folic acid allocation had no significant effects on vascular outcomes, with rate ratios (95% confidence intervals) of 1.01 (0.97-1.05) for major vascular events, 1.03 (0.97-1.10) for major coronary events, and 0.96 (0.87-1.06) for stroke. Likewise, there were no significant effects on vascular outcomes in any of the subgroups studied or on overall vascular mortality. There was no significant effect on the rate ratios (95% confidence intervals) for overall cancer incidence (1.05 [0.98-1.13]), cancer mortality (1.00 [0.85-1.18]) or all-cause mortality (1.02 [0.97-1.08]) during the whole scheduled treatment period or during the later years of it.”

Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals.
Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists' Collaboration.
Arch Intern Med. 2010 Oct 11;170(18):1622-31. Review.
http://archinte.ama-...act/170/18/1622

[maxwatt]

0/0 = ?

A complication with folic acid supplementation is the existence of the MTHFR genetic polymorphism in the population. According to SNPedia, approximately 11% of the population is homozygous for this SMP, whilst another 38% is heterozygous. This results in a reduced ability to metabolize folic acid to its biologically functional form. Homozygotes have about 30% efficiency of conversion, heterozygotes 60%. I suspect that failure to control for the existence of this polymorphism confounds the results of these studies. If roughly half the subjects are helped while the half who do not efficiently process folic acid are harmed, what is the result?

FWIW, some sources recommend supplementation with the tetrhydromethyl folate, which is the biologically form of folate. Since I learned via 23andme.com and Promethease that I am homozygous for the MTHFR SNP, I began supplementing tetramethyl folate. Whether this is wise I cannot tell, nor is a blood panel likely to be definitive. It does seem to function as an antidepressant.

Edited by maxwatt, 03 May 2011 - 02:57 PM.

[niner]

There is a MAJOR difference between food-derived "folate" and synthetic "folic acid". I'm using "quotation marks" around both of those terms because they are grossly incorrect as chemical nomenclature. Chemists make a stink over names because chemical names (at least the long IUPAC names) precisely specify the chemical structure, down to the individual atoms and stereochemistry. There are computer programs that can translate a name to a structure and vice versa, using a rule-based method, not a simple look-up of stored data. A good human chemist can do the same thing. The mistake that is being made in folate nomenclature is that the difference between the "ate" and "ic acid" ending is supposed to mean that the "ate" version is the anion of an oxy-acid, while the "ic acid" version is the protonated form of the same acid. If this were the case, a simple pH change would be all that was needed to switch between the two forms. Synthetic folate is the monoglutamate form, while food folate from vegetable sources is mainly a polyglutamate. The polyglutamate form has to be cleaved to the monoglutamate by an enzyme in the gut before it can be used. Interestingly, meat and bread contain more monoglutamate, though both are seen in various proportion in all food sources.

In J. Nutr. 132: 1307–1312, 2002., they examined the relationship between dietary folate forms (mono/poly ratio) to plasma folate concentration. This is only a rough estimate of bioavailability due to known problems with FFQs and the fact that plasma folate is not as good a measure as RBC folate, for which data was not available. Nevertheless, they report a significant effect in men, but not women.

From the multivariate model, we calculated that in men, a
50 mcg/d higher intake of monoglutamate folate was associated
with 27% higher plasma folate levels, whereas a 50 mcg/d
higher intake of polyglutamate folate intake was associated
with a higher plasma folate level of only 8%. This suggests
that, in men, monoglutamate folate was a three times stronger
determinant of plasma folate levels than polyglutamate folate.
For women, a 50 mcg higher intake of monoglutamate folate
was associated with 11% higher levels of plasma folate,
whereas this was 16% for a 50 mcg higher polyglutamate folate
intake.

This suggests that synthetic monoglutamates might be less dangerous for women. They bring up the food matrix effect in their discussion:

Little is known about the role of food matrix and its
interaction with different chemical folate forms in folate bioavailability.
Van het Hof et al. (36) and Castenmiller et al.
(37) compared the effects of consumption of whole-leaf spinach
with that of chopped spinach on plasma folate levels. Both
authors concluded that disruption of the vegetable matrix
resulted in higher folate bioavailability.

Grandma always said "chew your food"...

In the decade since this paper was written, someone may have looked further into the mono/poly differences.

[kismet]

I suspect that failure to control for the existence of this polymorphism confounds the results of these studies. If roughly half the subjects are helped while the half who do not efficiently process folic acid are harmed, what is the result?

I am pretty sure this must have been tested in an RCT at some time in the past. They did subgroup analysis in the above analysis, if anyone could send me the JAMA paper we can see if any included studies tested this hypothesis.

But your concern is unlikely to be of any practical relevance: they tested in the general population with probably already sub-RDA intakes (at least in countries w/ no fortification?) and still failed to find an effect, in spite of decreased Hcy (!), while any decent life-extensionist will be getting >>400mcg from diet. Supplementation would be very unlikely to yield further improvements with any genotype.

Edited by kismet, 03 May 2011 - 06:04 PM.

[Logan]

What is the general opinion of the supplemental l methylfolate(metafolin)? I take 800 mcg a day as I am on 500 mg of extended release Depakote.

[maxwatt]

What is the general opinion of the supplemental l methylfolate(metafolin)? I take 800 mcg a day as I am on 500 mg of extended release Depakote.

It is my understanding that metafolin does not bypass the enzyme that is deficient in those with the MTHFR polymorphism. It is not the same substance as methyl tetra hydro folate. Thorne and LEF carry the right form of the vitamin.

Perhaps I am not correct about this, but the ad literature for metafolin (Solgar;s supplement) is sufficiently impenetrable I cannot tell what it is chemically.

[rwac]

What is the general opinion of the supplemental l methylfolate(metafolin)? I take 800 mcg a day as I am on 500 mg of extended release Depakote.

It is my understanding that metafolin does not bypass the enzyme that is deficient in those with the MTHFR polymorphism. It is not the same substance as methyl tetra hydro folate. Thorne and LEF carry the right form of the vitamin.

Perhaps I am not correct about this, but the ad literature for metafolin (Solgar;s supplement) is sufficiently impenetrable I cannot tell what it is chemically.

On the flip side, metafolin is reputed to be L-5-MTHF. And Thorne and LEF may be racemic forms, they don't indicate the isomer ...

[stephen_b]

Spinach is looking better and better.

[maxwatt]

Metafolin.com states Metafolin is (6S)-5-methyltetrahydrofolic acid, calcium salt or L-methylfolate), so it would be a decent supplement. Thanks, rwac. Pure Encapsulations and others state they are the L isomer. Given that supplement manufacturers tend to buy from the same sources, I would be surprised if Thorne is not also using this source.

And Popeye (Stephen_b) thanks for the info on spinach; it contains so much more folate than kale or chard. I am guessing that the vegetable source is 5-MTHF, but again I don't know from convenient sources. Does anybody know?

[Logan]

Metafolin.com states Metafolin is (6S)-5-methyltetrahydrofolic acid, calcium salt or L-methylfolate), so it would be a decent supplement. Thanks, rwac. Pure Encapsulations and others state they are the L isomer. Given that supplement manufacturers tend to buy from the same sources, I would be surprised if Thorne is not also using this source.

And Popeye (Stephen_b) thanks for the info on spinach; it contains so much more folate than kale or chard. I am guessing that the vegetable source is 5-MTHF, but again I don't know from convenient sources. Does anybody know?

I believe someone in this thread mentioned that 5-MTHF is the form in spinach, but I haven't verified this.

[OneScrewLoose]

Yes, seems there is neither much of a risk nor benefit to folic acid supplementation. (resulting in a terrible risk/benefit ratio)

I haven't read the paper, but:
"Individual participant data were obtained for a meta-analysis of 8 large, randomized, placebo-controlled trials of folic acid supplementation involving 37 485 individuals at increased risk of cardiovascular disease. The analyses involved intention-to-treat comparisons of first events during the scheduled treatment period. There were 9326 major vascular events (3990 major coronary events, 1528 strokes, and 5068 revascularizations), 3010 cancers, and 5125 deaths. Folic acid allocation yielded an average 25% reduction in homocysteine levels. During a median follow-up of 5 years, folic acid allocation had no significant effects on vascular outcomes, with rate ratios (95% confidence intervals) of 1.01 (0.97-1.05) for major vascular events, 1.03 (0.97-1.10) for major coronary events, and 0.96 (0.87-1.06) for stroke. Likewise, there were no significant effects on vascular outcomes in any of the subgroups studied or on overall vascular mortality. There was no significant effect on the rate ratios (95% confidence intervals) for overall cancer incidence (1.05 [0.98-1.13]), cancer mortality (1.00 [0.85-1.18]) or all-cause mortality (1.02 [0.97-1.08]) during the whole scheduled treatment period or during the later years of it."

Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals.
Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists' Collaboration.
Arch Intern Med. 2010 Oct 11;170(18):1622-31. Review.
http://archinte.ama-...act/170/18/1622

Homocysteine has been well linked to heart disease, yet lowering it by 25% in this study had no effect on lowering all-cause mortality. I wonder if this was offset by increased cancer incidence of folic acid administration.

[albedo]

Just bumping this up to check if there is any new thinking re folic acid supplementation to lower homocysteine.

I experimented few years ago with the typical supplementation (was 1450 mcg B12 (o/w 1000 mcg metylcobalamin), 85 mg B6, 1600 mcg of folic acid, 2000 mg of TMG) and succeeded to lower homocysteine of about 23% (13-->10 mcmol/l with ref range <16). Since I stopped (for the very reasons given in this thread) I have been ranging 13.0-13.5 (ref. range <16 or <15)

Btw, is there an optimum value for homocysteine you should strive for? I recollect some, I guess quite arbitrarily, set it to 7.5 or 8 (when range is 0-15).

[Sillewater]

Am J Clin Nutr. 2012 Dec 19. [Epub ahead of print]
B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort.

Zschäbitz S, Cheng TY, Neuhouser ML, Zheng Y, Ray RM, Miller JW, Song X, Maneval DR, Beresford SA, Lane D, Shikany JM, Ulrich CM.

Source

Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA and the WHI Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA.

Abstract

BACKGROUND:

The role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake.
OBJECTIVE:

We investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Women's Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake.
DESIGN:

A total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models.
RESULTS:

Dietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01).
CONCLUSIONS:

Vitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk. PMID: 23255571 [PubMed - as supplied by publisher]