22 replies to this topic

[Michael]

All:

I was just asked by PM about the latest, rather strong confirmation of an elevated risk of cancer in users of folic acid supplements. The person noted that the mechanism is probably because of increased folic acid availability for nucleotide synthesis, for which many cancers have an unusually-high demand, so that the risk would be to people who already have a cancer in their body, whereas "the rest of us" wouldn't be providing 'permission' for growth to nonexistant cancers.

The same basic issue has been raised in other instances, as with benfotiamine and putative telomerase activators. I keep meaning to do a big post on this subject, and keep being put off by the detailed argumentation and documentation that would be required to lay out the case in detail (see eg. Niner's intelligent (but flawed ) analysis of the telomerase case). I'm going to just accept for the moment that I'm not going to get around to such a post for the foreseeable future, and make the broad point:

The thing is, everyone has a (pre)cancerous cell or 12 in hir body at any given time, and the great majority of men over 70 have actual, albeit generally slow-growing, prostate cancer tumors:

Several autopsy studies published in the 1940s and 1950s confirmed high rates of tumour foci in the prostate gland, including the study by Franks, which estimated that 31% of men aged >50 years who died of other causes had some evidence of prostate cancer. A recent autopsy study on 314 African American and 211 Caucasian (sic) men aged 20–80 years who died of trauma in Detroit ... demonstrated a high prevalence of prostate cancer that increased progressively with advancing age and was similar at all ages in African American compared with Caucasian men (around 10%, 30%, 40%, 45%, 70% and 80% in the 3rd, 4th, 5th, 6th, 7th and 8th decades, respectively). When this ubiquity of microscopic prostate cancer is placed in the context of lifetime risks of clinical or fatal prostate cancer (about 10% and 3%, respectively for a man aged 50 years in the USA), these data indicate that local or distal progression of early cancer is far from inevitable within a man's lifetime. Put another way, only a minority of prostate tumours are highly aggressive and life-threatening, while the majority are slow-growing and indolent.

The autopsy studies, started by Rich, offer insights into prostate cancer aetiology. For example, the similarity in prevalence of autopsy prostate cancer in African American and US white men is mirrored by findings of little variation in autopsy prostate cancer between countries. Yet, paradoxically, compared with US white men, African American men have higher prostate cancer incidence (137 per 105 vs 100 per 105) and mortality rates (34 per 105 vs 16 per 105) and there are 60-fold and 12-fold higher rates of prostate cancer incidence and mortality, respectively, amongst African American vs Chinese men. The explanation for the inconsistencies in patterns of disease between autopsy compared with incidence and mortality data remain unclear, but could reflect a role for environmental or genetic factors in prostate cancer progression, and/or indicate differences in the availability and use of healthcare.

(1)

The question is whether the cell has the time to acquire the additional mutations, or blood supply, or whatever, before the senescence and apoptosis machinery or the immune system takes care of it. Giving it any extra growth stimulus or removing any barrier opens up its chances of escaping controls. And of course, an extra round of replication is not just extra time, but extra risk, since

Replication errors are the main source of mutations. It has been estimated that uncorrected replication errors occur with a frequency of 10-9 - 10-11 for each nucleotide added by DNA polymerases. Since a cell division requires synthesis of 6 X 109 nucleotides, the mutation rate is about one per cell division.

Similarly, in principle high IGF1 "ought" to be safe unless you have a pre-existing cancer -- but in the population, naturally high IGF1 is linked to increased risk of colon, ovarian, and other cancers.

The creation of any kind of permissive environment for an unregulated round of cell division is a bad situation, and doing so voluntarily with a convenient capsule for a few hours every day for decades is an exceptionally poor one.
-Michael

1: Martin RM. Commentary: prostate cancer is omnipresent, but should we screen for it? Int J Epidemiol. 2007 Apr;36(2):278-81. PubMed PMID: 17567642; PubMed Central PMCID: PMC2764984.

[scottl]

Hi Michael,

I'm not really into a long discussion either but since I started this I would just like to state:

1. It has always been clear to me that the optimum supplementation regimen for someone without cancer e.g. statistically almost everyone under 40 on the board, is not necessarily the same as that of someone with an established cancer. One can think of this as certain nutrients can be thought to "feed" tumors. Everything is risk/benefit. Is it a good idea to have extra folic acid if you already have a tumor probably not.

2. You are lumping people with a precancerous cell or several and people with a full blown tumor. I have questions as to the validity of this assumption. For example (perhaps I used this in my PM) I would not give someone with an established melanoma supplemental tyrosine, but I doubt tyrosine would do much in a person with one genetically damaged melanocyte which is "trying" to become a cancer.

3. "albeit generally slow-growing, prostate cancer tumors"

Most prostate cancers are very slow growing, and a small percentage are very agressive. Can one really upregulate the slow growing kind into a more agressive kind with supplementation? I'm skeptical, but don't know all the recent studies.
---------------------------------------------------------------------------------------------------

This doesn't belong here, but rather then put this in another PM, I'll just post this here. In your PM you wrote:

"There certainly is an optimum: what a normal, healthy body needs, and no more"

The normal healthy body of a sedentary 20 year old? A 45 year old marathoner or weight lifter?
You know better than I the genetic variations possible from one human to another. None of those mandate higher levels of some nutrients?
ANd what of people who aren't healthy, with various illnesses.

My 3c.

Oh and I won't be posting here regularly, just agreed to help with the supplement design, well and PM you.

I hope all is well.

Edited by scottl, 23 November 2009 - 07:02 PM.

[kismet]

What MR said (especially ad. scottl's 2.) logically follows from our knowledge of cancer biology (and what I've seen represented in textbooks), but I am wondering if there is experimental confirmation of it? More importantly the problem with folic acid is that there are hardly any known benefits; obviously none demonstrated in the healthy, where they're less probable anyway (better baseline Hcy levels, higher dietary folate intakes, lower absolute CVD risk, etc)
Who wants to exchange a very probable cancer risk for very putative CVD benefits?

Edited by kismet, 23 November 2009 - 08:16 PM.

[Michael]

What MR said (especially ad. scottl's 2.) logically follows from our knowledge of cancer biology (and what I've seen represented in textbooks), but I am wondering if there is experimental confirmation of it?

ISTM that the findings with megadose thiamin in experimental animals, the similar (biphasic, time-course-dependent) findings with folate in preclinical cancer models along with these recent clinical trial results, and (for telomerase) the finding that at least constitutive TERT upregulation increases cancer risk in 2 different mouse lines (1,2) constitute just such evidence. Alternatively, what kind of evidence would you want to see?

Who wants to exchange a very probable cancer risk for very putative CVD benefits?

And of course, the case for those benefits (and thus these and other trials) were made based on extensive epidemiological evidence; there is no such evidence for the bennies of benfotiamine or telomerasse activation in normal, healthy humans, and only the above rather nasty mixed benefits for telomerase activation.

-Michael

1: Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, Castrillon
DH, Horner JW, Weiler SR, Carrasco RD, DePinho RA. Constitutive telomerase
expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci U S A.
2002 Jun 11;99(12):8191-6. Epub 2002 May 28. PubMed PMID: 12034875; PubMed
Central PMCID: PMC123043.

2: González-Suárez E, Samper E, Ramírez A, Flores JM, Martín-Caballero J, Jorcano
JL, Blasco MA. Increased epidermal tumors and increased skin wound healing in
transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in
basal keratinocytes. EMBO J. 2001 Jun 1;20(11):2619-30. PubMed PMID: 11387197;
PubMed Central PMCID: PMC125492.

[Blue]

It should be noted that not all placebo controlled studies have found an increase in cancer from folate. This study used both higher dose and longer duration than the other studies and found if anything a decrease in cancer:

"Context Folate, vitamin B₆, and vitamin B₁₂ are thought to play an important role in cancer prevention. Objective To evaluate the effect of combined folic acid, vitamin B₆, and vitamin B₁₂ treatment on cancer risk in women at high risk for cardiovascular disease.

Design, Setting, and Participants In the Women's Antioxidant and Folic Acid Cardiovascular Study, 5442 US female health professionals aged 42 years or older, with preexisting cardiovascular disease or 3 or more coronary risk factors, were randomly assigned to receive either a daily combination of folic acid, vitamin B₆, and vitamin B₁₂ or a matching placebo. They were treated for 7.3 years from April 1998 through July 31, 2005.

Intervention Daily supplementation of a combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, and 1 mg of vitamin B₁₂ (n = 2721) or placebo (n = 2721).

Main Outcome Measures Confirmed newly diagnosed total invasive cancer or breast cancer.

Results A total of 379 women developed invasive cancer (187 in the active treatment group and 192 in the placebo group). Compared with placebo, women receiving the active treatment had similar risk of developing total invasive cancer (101.1/10 000 person-years for the active treatment group vs 104.3/10 000 person-years for placebo group; hazard ratio  , 0.97; 95% confidence interval [CI], 0.79-1.18; P = .75), breast cancer (37.8/10 000 person-years vs 45.6/10 000 person-years, respectively; HR, 0.83; 95% CI, 0.60-1.14; P = .24), or any cancer death (24.6/10 000 person-years vs 30.1/10 000 person-years, respectively; HR, 0.82; 95% CI, 0.56-1.21; P = .32).

Conclusion Combined folic acid, vitamin B₆, and vitamin B₁₂ treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during the folic acid fortification era."

http://jama.ama-assn.org/cgi/content/abstract/300/17/2012

Edited by Blue, 23 November 2009 - 08:54 PM.

[kismet]

I was wondering (which I failed to spell out) if there was some elegant experimental design that can (and did) differentiate between accelerating actual, manifest cancer (which would go on to become cancer anyway just more slowly and which rodents generally suffer from) and actually enabling precancerous cells which would never become cancer to escape & make it. That's a purely academic thought.

From a practical POV the preclinical and the evidence from actual RCTs is worrying enough. Although, the null result from the large study blue mentioned is somewhat surprising.

As always the totality of evidence is more important. Interestingly (& apparently) more recent studies generally confirm the risk of folic acid (the new report(s) + the study earlier this year on prostate cancer). I've only seen a meta-analysis for colorectal cancer (and I don't know how many studies they looked at) but it also suggests increased cancer incidence (PMID: 19863600) There's certainly more to it, but why take such an unnecessary risk.

Edited by kismet, 23 November 2009 - 10:38 PM.

[NDM]

Do you concede that at least for those who drink moderate/large amounts of alcohol some folate supplementation is still desirable?

[bobman]

Do you concede that at least for those who drink moderate/large amounts of alcohol some folate supplementation is still desirable?

If you drink enough alcohol to need need 800mcg of folate just to strike a balance I'd suggest that 1)you may want to reduce your drinking and 2) you should have regular blood work to determine your folate levels. It is impossible to gauge whether or not you're talking too much of a substance without empirical data. If you're simply eating eggs to get your folic acid, fine. But if you are supplementing with synthetic vitamins, and choosing to take large doses of them without monitoring, I'd suggest you're being reckless.

Edited by AlexK, 24 November 2009 - 06:51 AM.

[NDM]

Do you concede that at least for those who drink moderate/large amounts of alcohol some folate supplementation is still desirable?

If you drink enough alcohol to need need 800mcg of folate just to strike a balance I'd suggest that 1)you may want to reduce your drinking and 2) you should have regular blood work to determine your folate levels. It is impossible to gauge whether or not you're talking too much of a substance without empirical data. If you're simply eating eggs to get your folic acid, fine. But if you are supplementing with synthetic vitamins, and choosing to take large doses of them without monitoring, I'd suggest you're being reckless.

Oh mine, what a harsh and disciplinarian tone... I had in mind something like a rule "For every night when you have more than 3 drinks take 400 mcg of folate" - currently this would mean for me 2-3 days/week.

[Michael]

Do you concede that at least for those who drink moderate/large amounts of alcohol some folate supplementation is still desirable?

What AlexK said -- and even then, the benefit appears mostly in people who also have a pre-existing family history of colon cancer,(1) and is for 400 vs <200 mcg folate/d, which one can readily get from a well-designed, vegetable-rich diet. Also, I wouldn't rely on blood folic acid levels, or at least not blood levels alone: blood levels of most vitamins and minerals are completely uninformative about biological status; a panel of Hcy and B12 bioactivity assays would be more informative. And, if you're going to supplement, I would use a relatively small dose, and use methyltetrahydrofolate rather than folic acid.

-Michael

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

[Blue]

Another study:

"Background: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. Objective: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conducted a cost-efficient, double-blind, randomized trial among participants of 2 large prospective cohorts, the Health Professionals Follow-Up Study and the Nurses' Health Study.

Design: Participants were randomly assigned to receive folic acid (1 mg/d) (n = 338) or placebo (n = 334) for 3–6.5 y. The primary endpoint was any new diagnosis of adenoma during the study period (May 1996–March 2004). Secondary outcomes were adenoma by site, stage, and number of recurrent adenomas. Associations were also examined by plasma folate concentrations at baseline.

Results: Incidence of at least one recurrent adenoma was not significantly associated with folic acid supplementation [relative risk (RR): 0.82; 95% CI: 0.59,1.13; P = 0.22]. Among participants with low plasma folate concentrations at baseline (7.5 ng/mL), those randomly assigned to receive folic acid experienced a significant decrease in adenoma recurrence (RR: 0.61; 95% CI: 0.42, 0.90; P = 0.01), whereas for subjects with high folate concentrations at baseline (>7.5 ng/mL), supplemental folic acid had no significant effect (RR: 1.28; 95% CI: 0.82, 1.99; P = 0.27, P_interaction = 0.01). Contrary to findings from another clinical trial, there was no evidence for an increased risk of advanced or multiple adenomas.

Conclusions: Our results do not support an overall protective effect of folic acid supplementation on adenoma recurrence. Folic acid supplementation may be beneficial among those with lower folate concentrations at baseline."
http://www.ajcn.org/...cn.2009.28319v1

So very mixed results among studies with was seems similar groups of patients. The human placebo studies we have have looked at either patients with cvd disease/increased risk (primarily intended to study folate's influence on homocysteine) or patients with an earlier precancerous growths in the colon. In both cases some studies find a protective effect, while some studies find a promoting effect on cancer! There may be some factor that influence the effect of folate on cancer that differs between groups. High dietary folate would seem a possible answer which when added to supplementation cause to high a level. But if so, why then did the Women's Antioxidant and Folic Acid Cardiovascular Study, which I cited above, which used the largest dose of folate to a group likely to have a high dietary folate and living in the US with its food folate supplementation, not have an increase in cancer?

Edited by Blue, 24 November 2009 - 09:28 PM.

[kismet]

Science is not black and white. As you state risk may (and most probably does) differ among groups depending on (unkown) variable(s). This is the very definition of a dangerous gamble, though.  We're not in the business of playing russian roulette so any discussion should be purely academic. (oh, and keep in mind we're not deficient either)
All studies presented so far show null or negative results. That's not a pattern we'd expect by chance and much less if folic acid was beneficial to healthy, young, folate-replete individuals.

Not even the models look pretty, but they emphasise just how much people may be playing with fire:
Even when folate supplementation is started in young adulthood (around age 20 years), our model calculations suggest that a 10% to 15% promotional effect of folate is sufficient to eliminate any protective effect associated with a 40% reduction of all 3 critical mutation rates in the model (i.e., the rates of both APC mutations and the rate-limiting event defining the adenoma-carcinoma transition)...Our model suggests that, in individuals who are older when supplementation is initiated, an increase in colorectal cancer rates is expected to be seen after a period of ∼10 years
http://cebp.aacrjournals.org/content/17/6/1360.full

Edited by kismet, 24 November 2009 - 10:31 PM.

[Blue]

Science is not black and white. As you state risk may (and most probably does) differ among groups depending on (unkown) variable(s). This is the very definition of a dangerous gamble, though. We're not in the business of playing russian roulette so any discussion should be purely academic. (oh, and keep in mind we're not deficient either)
All studies presented so far show null or negative results. That's not a pattern we'd expect by chance and much less if folic acid was beneficial to healthy, young, folate-replete individuals.

Not even the models look pretty, but they emphasise just how much people may be playing with fire:
Even when folate supplementation is started in young adulthood (around age 20 years), our model calculations suggest that a 10% to 15% promotional effect of folate is sufficient to eliminate any protective effect associated with a 40% reduction of all 3 critical mutation rates in the model (i.e., the rates of both APC mutations and the rate-limiting event defining the adenoma-carcinoma transition)...Our model suggests that, in individuals who are older when supplementation is initiated, an increase in colorectal cancer rates is expected to be seen after a period of ∼10 years
http://cebp.aacrjournals.org/content/17/6/1360.full

At least the last study I cited found folate beneficial (for those with low folate concentrations).

The simulation may not be that good since none of the negative studies were that long.

Here is the possible missing factor. Selenium.
"Selenium is an essential trace element that has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer, 2) evaluate possible effect measure modifiers, and 3) evaluate potential biases associated with the use of postdiagnostic serum selenium measures. The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n = 1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens, which were used to measure serum selenium. Individuals who had both high serum selenium (> 140 mcg/l) and high reported folate (> 354 mcg/day) had a reduced relative risk of colon cancer [odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.4-0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR = 1.1, 95% CI = 0.7-1.5) as was the risk for those with low selenium and high folate (OR = 0.9, 95% CI = 0.7-1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study."
http://www.ingentaco...000002/art00002

That would explain why the European CVD folate study found a negative effect while the US CVD one did not since selenium levels are much lower in Europe. On the other hand it is not obvious that the Aspirin/Folate Polyp Prevention Study, which found the negative effect on colon and prostate cancer, should differ regarding selenium from the folate supplement and adenomas study I cited above, which found a positive/neutral effect, and used data from the Health Professionals Follow-Up Study and the Nurses' Health Study. From what I can see all of these studies on patients with colon adenomas where in the US. But maybe health professionals consume more selenium due to the presumed benefits from selenium.

Edited by Blue, 24 November 2009 - 11:19 PM.

[kismet]

At least the last study I cited found folate beneficial (for those with low folate concentrations).

Why, yes, in a subset analysis that is completely irrelevant to healthy (i.e. folate-replete) individuals and if we want to mess with weak P-values, the cited study showed a trend for increased cancer incidence in the other subset (higher baseline folate), consistent with the meta-analysis & also consistent with the pattern of null and negative findings in the populations that matter.

Edited by kismet, 25 November 2009 - 11:14 AM.

[Blue]

At least the last study I cited found folate beneficial (for those with low folate concentrations).

Why, yes, in a subset analysis that is completely irrelevant to healthy (i.e. folate-replete) individuals and if we want to mess with weak P-values, the cited study showed a trend for increased cancer incidence in the other subset (higher baseline folate), consistent with the meta-analysis & also consistent with the pattern of null and negative findings in the populations that matter.

Nothing in the study said that those with low folate concentrations were not "healthy". Also, since this was a US study with its food folate supplementation, one would expect those with low folate concentrations to be higher in other nations. If we want to mess with weak P-values, then the study with highest dose and longest duration, the Women's Antioxidant and Folic Acid Cardiovascular Study, showed benefits from very high folate supplementation.

Edited by Blue, 25 November 2009 - 11:35 AM.

[Michael]

At least the last study I cited [(2) below] found folate beneficial (for those with low folate concentrations).

Why, yes, in a subset analysis that is completely irrelevant to healthy (i.e. folate-replete) individuals

Nothing in the study said that those with low folate concentrations were not "healthy". Also, since this was a US study with its food folate supplementation, one would expect those with low folate concentrations to be higher in other nations.

The cutoff used here as 'low' was 7.5 ng/mL, which is 17.5 nmol/L. While serum folate, like most nutrients, is not a reliable indicator of functional status, "If serum folate is < 3 μg/L or ng/mL (< 7 nmol/L), deficiency is likely" according to the Merck Manual. Per NHANES, however,(1) serum folate <17.5 nmol/L puts you in teh bottom 25th percentile for adult American men, and in either the bottom 25th or even 10th percentile (depending on age group) for women (see the Supplemental Table 1), but this is with mandatory fortification; prior to fortification in NHANES III, mean serum folate was 12 nmol/L (Table 2), so <17.5 would not have been unusual prior to then. Yes, the Standard American Diet really does suck . I'd be very surprised if a diet of no (or no fortified) grain, but rich in vegetables, wouldn't cover all needed ground -- but I don't have data to hand to demonstrate that, tho' my own diet provides several multiples of the DRI RDA.

OTOH, NB that (2) was for "recurrent colorectal adenoma": these are high-risk people who have already had a cancer, and not likely directly extrapolable to the population at large. It's odd, because one might expect such folks to be more vulnerable to folate-fueled growth permissiveness, with occult cancer cells still lurking about, rather than benefitting from maintenance of appropriate methylation as a preventive mechanism.

IAC, as has already been noted, the balance of evidence based on meta-analysis seems to suggest a poor risk-benefit analysis even in the general population, let alone in (hopefully) healthfully-eating, exercising life-extensionists not abusing alcohol and (mostly) with no specific family history.

-Michael

1: Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey .
1999-2000. Am J Clin Nutr. 2005 Aug;82(2):442-50. PubMed PMID: 16087991.

2. Wu K, Platz EA, Willett WC, Fuchs CS, Selhub J, Rosner BA, Hunter DJ,
Giovannucci E. A randomized trial on folic acid supplementation and risk of
recurrent colorectal adenoma. Am J Clin Nutr. 2009 Oct 28. [Epub ahead of print]
PubMed PMID: 19864409; PubMed Central PMCID: PMC2777472.

[stephen_b]

Michael, I posted this in another thread:

In Folic acid fortification: the good, the bad, and the puzzle of vitamin B-12, an editorial appearing in the American Journal of Clinical Nutrition:

• Is the balance between folate and vitamin B-12 status equally as important as the absolute concentrations of these vitamins? The application of mathematical modeling may help to answer this question (18).
• By what mechanisms does a high folate status in persons with a low vitamin B-12 status cause anemia and cognitive impairment?
• Is unmetabolized folic acid the culprit? Data from a small number of subjects in the United States indicate that folic acid accounts for 16% of the plasma folate in persons whose total plasma folate concentration is >50 nmol/L (19). More data on the prevalence and concentrations of folic acid in the blood are needed, the factors that influence it, and the effects it has on folate one-carbon metabolism.
• Given the recent findings, would it be safer to use methylfolate instead of folic acid as a supplement?
• Is the imbalance between folate and vitamin B-12 associated with any other adverse effects, particularly in vulnerable sectors of the population (eg, pregnant and lactating women and infants)? A preliminary report from India suggests that such an imbalance (low vitamin B-12 and high folate status) in pregnant mothers may have adverse effects on the health of their children (20).
• Is the complex relation between folate and cancer (8, 17) possibly a reflection in part of folate's interaction with vitamin B-12?

(emphasis mine). It looks like the facts are not all in, but that it is evidence in support of methylfolate being safer than folic acid.

Unmetabolized folic acid gets lumped in with plasma folate, and it might be what's causing the harm.

[Blue]

List of folate placebo studies and cancer. Have I missed any?

Placebo folate studies
Patients with precancerous colon growths

Aspirin/Folate Polyp Prevention Study
http://jama.ama-assn...act/297/21/2351
http://www.ncbi.nlm....pubmed/19276452

The United Kingdom Colorectal Adenoma Prevention Trial
http://www.emekmed.c..... Adenomas.pdf

Health Professionals Follow-Up Study and the Nurses' Health Study
http://www.ajcn.org/...cn.2009.28319v1

No name
http://www.ncbi.nlm....les/PMC2731275/

Patients with CV disease/risk

Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial
http://jama.ama-assn...ourcetype=HWCIT

Women's Antioxidant and Folic Acid Cardiovascular Study
http://jama.ama-assn...act/300/17/2012

Edited by Blue, 25 November 2009 - 11:11 PM.

[Blue]

"Conflicting data have emerged from preclinical and clinical studies that examined the relationship between folic acid and the risk of recurrence of colorectal adenomas. To determine precisely that relation, we planned this metaanalysis. We searched literature to identify interventional randomized, placebo-controlled studies where folic acid in specific dose and for specific duration was administered to evaluate its effect on the recurrence of adenomatous colorectal polyps. Five eligible trials were identified. The total number of patients with history of colorectal adenomas in the folate and the placebo groups was 805 and 775 patients, respectively. Our analysis showed that folate supplementation had no protective effects on the recurrence of colorectal adenomas [odds ratio = 1.08 (95% CI; 0.87, 1.33; P = 0.49)], nor has a positive outcome on the number of recurrent polyps per patient (P = 0.41). Examination of folic acid dose effect showed that the two studies that have used folic acid as 1 mg/day favored folic acid over placebo with an odds ratio of 0.62 (95% CI; 0.48, 0.80). However, the overall effect for all included studies was not significant [odds ratio = 0.78 (95% CI; 0.49, 1.24; P = 0.30)]. We found significant heterogeneity between trials, moreover, included trials exhibit inconsistency in methodological quality. The present metaanalysis has failed to show potential benefit for folate supplementation. Future trials should examine the effect of different dosage and duration. Moreover, the confounding effect of dietary and life style habits should be carefully controlled."
http://www.ncbi.nlm....pubmed/19757214

Looking through the literature there seems to be a striking anti-supplement or anti-folate bias. The folate-cause-cancer Aspirin/Folate Polyp Prevention Study is cited by hundreds of other paper while the other placebo controlled trials finding no or positive effects of folate supplementation are not mentioned.

Edited by Blue, 26 November 2009 - 09:50 PM.

[meat250]

double flawed study

heres what they have to say:

NPA Responds to Controversial JAMA Study



On November 18, The Journal of the American Medical Association (JAMA) released research indicating an associated increased risk of cancer and death from any cause if the study subjects had received treatment with folic acid and vitamin B12, said the Natural Products Association (NPA). NPA has since released a statement to help clear up some of the issues presented in this study.

“This is an analysis of two studies—the NORVIT [the Norwegian vitamin trial, a 2005 randomized trial of homocysteine-lowering with B-vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction] and WENBIT [Western Norway B-vitamin intervention trial presented at the European Society of Cardiology Congress 2007],” explained Daniel Fabricant, PhD, vice president of scientific and regulatory affairs.

“Despite the authors’ justification for the analysis, previous review has indicated the NORVIT might not have been adequately powered and the factorial design might have been too complex, thus rendering the trial incapable of isolating the effect of folate per se,” he added. “Being combined with the WENBIT, which was terminated early, and which wasn’t without its design flaws either, creates a scenario in which two flawed studies are combined to yield one larger flawed study. This does not seem to be in the best interest of medical science or public health.”

Fabricant also stated that most of the subjects in both trials were also being treated with beta-blockers and statins, and some were also being treated with ACE inhibitors and diuretics, “yet there are no numbers, no analysis on the effects these interventions may have on the incidence of cancer. There is no adjustment of the baseline effect for these interventions, yet the authors adjusted the baseline for smoking, age and sex, which are all factors in the development of cancer. We have no way of determining these factors’ impact on this study as they just decided to leave that out, like ordering off of an a la carte menu,“ said Fabricant.

[kismet]

Looking through the literature there seems to be a striking anti-supplement or anti-folate bias. The folate-cause-cancer Aspirin/Folate Polyp Prevention Study is cited by hundreds of other paper while the other placebo controlled trials finding no or positive effects of folate supplementation are not mentioned.

I don't get why you waste your time on folate. Did you really not read the literature? You not only must disprove the cancer risk (which is impossible, at best you can call it inconclusive, but it's still a risk and the negative and null results prevail), no, additionally you'd have to somehow disprove the consensus that vitamin B supplementation (incl. folate) is almost worthless for CVD health. Not only is folic acid risky, there are also next to no benefits to outweight the risks. The default position is "do not supplement random substances". There's no meaningful evidence to the contrary for folic acid. This is not bias, it's good science. Please, blue, spend your time on more constructive discussion e.g. debunking paleo myths or discussing promising supplements or SENS or whantnot. 

I'll address some other things later (i.e. Fabricant & misinformation).

Edited by kismet, 27 November 2009 - 12:09 PM.

[Blue]

Looking through the literature there seems to be a striking anti-supplement or anti-folate bias. The folate-cause-cancer Aspirin/Folate Polyp Prevention Study is cited by hundreds of other paper while the other placebo controlled trials finding no or positive effects of folate supplementation are not mentioned.

I don't get why you waste your time on folate. Did you really not read the literature? You not only must disprove the cancer risk (which is impossible, at best you can call it inconclusive, but it's still a risk and the negative and null results prevail), no, additionally you'd have to somehow disprove the consensus that vitamin B supplementation (incl. folate) is almost worthless for CVD health. Not only is folic acid risky, there are also next to no benefits to outweight the risks. The default position is "do not supplement random substances". There's no meaningful evidence to the contrary for folic acid. This is not bias, it's good science. Please, blue, spend your time on more constructive discussion e.g. debunking paleo myths or discussing promising supplements or SENS or whantnot.

I'll address some other things later (i.e. Fabricant & misinformation).

No, the positive results seem to prevail, although non-significantly in the meta-analysis of placebo studies I cited. I know, you cited another meta-analysis of "randomised or pseudo-randomised" studies, but whatever that includes (epidemiological studies? cross-country food fortification studies?) it is less valuable than placebo-controlled studies.

The bias can be seen in another full-text study you mentioned which does not mention any of the null or positive effect studies:
http://cebp.aacrjour.../17/6/1360.full

Folate has positive benefits for several other conditions so it is important to clarify whether it is safe:
http://healthlibrary...;chunkiid=21717

[bobman]

Looking through the literature there seems to be a striking anti-supplement or anti-folate bias. The folate-cause-cancer Aspirin/Folate Polyp Prevention Study is cited by hundreds of other paper while the other placebo controlled trials finding no or positive effects of folate supplementation are not mentioned.

I don't get why you waste your time on folate. Did you really not read the literature? You not only must disprove the cancer risk (which is impossible, at best you can call it inconclusive, but it's still a risk and the negative and null results prevail), no, additionally you'd have to somehow disprove the consensus that vitamin B supplementation (incl. folate) is almost worthless for CVD health. Not only is folic acid risky, there are also next to no benefits to outweight the risks. The default position is "do not supplement random substances". There's no meaningful evidence to the contrary for folic acid. This is not bias, it's good science. Please, blue, spend your time on more constructive discussion e.g. debunking paleo myths or discussing promising supplements or SENS or whantnot. 

I'll address some other things later (i.e. Fabricant & misinformation).

You should probably address B12 and folate deficiency, as well as MTHFR before you make sweeping assertions like this. It is quite clear that taking 10-100x the folate and b12 you need could pose a long term safety risk. As always, more is not better. This is why testing to determine MTHFR, is a good idea, and why blood testing for b12 and folate levels is also a good idea. Indiscriminate consumption? Bad idea.

Edited by bobmann, 28 November 2009 - 12:03 AM.