From: sbharris@ix.netcom.com (Steven B. Harris )
Subject: Re: Folic acid
Date: 10 Oct 1995
Newsgroups: misc.health.alternative

In <45e5b1$kcs@newsbf02.news.aol.com> mannro@aol.com (MannRo) writes:

>Is it possible to overdose folic acid (consuming about 1200mg daily in
>supplement form)?  If so, what might the symptoms be?  Thanks.


   Some people have claimed that folate is a seizure potentiator, but
this seems only to be true for people with pre-existing seizure
disorders.  Otherwise, it's about as non-toxic as any substance I know
of.  I fed it to mice at UCLA for their entire lifespans of 3 plus
years, at a concentration of 1 part per thousand (!) in the dry diet
(something like 750 milligrams a day for a person, equivalent, at
least), and saw no effect at all.  In fact, there may have been a
slight anti-cancer effect (I'm still analyzing data).  But it certainly
didn't hurt the mice.   Other, shorter term but higher dose studies in
other labs have also been negative for folate toxicity.  The only
reason the FDA worries about folate is that enough of it prevents the
anemia of B12 deficiency, causing people to get the nerve and brain
damage of low B12 syndrome (which are potentially more permanent)
before anyone makes the diagnosis.


                                       Steve Harris, M.D.

From: sbharris@ix.netcom.com (Steven B. Harris)
Subject: Re: What doctors don't know about nutrition.
Date: 24 May 1996
Newsgroups: misc.health.alternative,sci.med.nutrition

In <31A422A1.2F2A@itsa.ucsf.edu> Nimnodius <nodrog@itsa.ucsf.edu>
writes:

>Dave Blake wrote:
>
>> I was in Hopkin Med Program for a while as a part of my program's
>> training. There, you get a one hour lecture on the water soluble
>> vitamins. To be specific, you learn all the B vitamin pathways and the
>> pathway for Vitamin C.
>>
>> In addition, you receive another course in nutrition that takes about 3
>> hours per week for about 8 weeks.
>>
>> Is 25 hours of coursework enough ? You can judge.
>
>Everyone is so caught up on these number of course hours as if you can
>parcel them out. So, you've got 25 hours called "nutrition". What about
>the hour on nutrition and diabetes given in the endocrine lectures?
>Nutrition and cholesterol in the cardiovascular section? Nutrition in the
>postoperative patient on the surgical rotation.
>
>Anyway, you missed my question. Without going on and on about course
>hours, please tell me SPECIFICALLY what clinical nutrition problems or
>treatments are physicians ignorant of?


   Can I play devil's advocate?  In 1982 when I was in medical school,
nobody knew of the connection between folate and birth defects.  I had
to read about it in prevention magazine, for God's sake.  It took
another decade for it to get into mainstream medical recommendations,
and didn't get FDA endorsement until a few more years beyond that.  But
there were several good intervention studies even in 1982.  It was just
that nobody paid attention to them.  No drug reps for folate.

   We are in the identical position right now with vitamin E.

   There is the little problem of standard of proof.  Have we proved
that cigarettes cause cancer?  That exercise will extend your life?
Where are the placebo controlled double blind studies, please?  Can a
proof be epidemiologic?  At what point does it become a proof, then?
In what year did we prove that cholesterol lowering prevented deaths?
Surely it was before last years' Simvastatin trials....   Er, wasn't
it?

   The real problem here is not that medicine requires good evidence
for treatment protocols.  The real problem is that medicine's standards
for such evidence varies according to taste and prejudice.  Nutrition
has taken the full force of that hypocritical situation for years.
It's in the nature of the unpatentable treatments that nutrition
offers.

                 Steve Harris, M.D.

   Who's seen many a malnourished person who nobody has ever paid
attention to, diet-wise, ever; but who have for years nevertheless
managed to find some doc to take time to manage their pharmaceuticals.
Oddly enough.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: sci.med.nutrition
Subject: Re: folic acid
Date: 27 Apr 1998 15:45:09 GMT

In <893683948.141593@mnementh.southern.co.nz> Brian Sandle
<bsandle@southern.co.nz> writes:

>I remember reading in the `Vitamin Bible' by Earl Mindell, I think,
that people with glandular cancer should avoid folate supplementation,
which is the only other warning besides that it masks vitamain B12
deficiency neurology in some, which I think Steven Harris has recently
written of, though I didn't quite understand him.<

   B12 is needed for making myelin in nerves, and also for regenerating
a form of folate after it as donated a methyl to make thymidine to make
DNA.  With no B12, you can't make myelin, and suffer nerve damage.
Also, you can't regenerate folate, and lose it.  Generally, then, you
don't get enough new folate in the diet to make up for the lost folate,
and not enough to make DNA.  This stops cells from dividing, and that
hits your bone marrow first, which is one of the places cells divide
fastest.  That gives you anemia, and the particular kind from lack of
B12 was called "pernicious anemia," and used to be fatal.  It was like
a diagnosis of leukemia.  If you take enough folate you don't need to
regenerate it, however, and all your DNA synthesis can go on-- the
anemia is fixed!  However, you still can't make myelin, so the nerve
damage (which is permanent if it goes on for long enough) continues.
The fear about folate supplments is that people would not become
anemic, so their doctors would not suspect B12 deficiency if they had
it, until the nerve damage grew so severe as to cause the diagnosis to
be made that way (perhaps too late to save all the nerves).  Doses of 5
mg a day of folate are enough to mask B12 deficiency that way.


>> They no longer make anything larger than 1 mg in the US, even by
>> prescription. It's 1 mg or nothing. Silly, but true. Especially when
>> the prenatals are 0.8 mg.
>
>So how much would 3 months supply cost at 15 mg daily including
>prescription(s)?

    You can probably buy 1000 tabs of the 1 mg generic for $30.

>Is it allowable to bring it in to USA if travelling?

   Sure.  I'm reminded by an earlier discussion, by the way, that there
IS a more potent vitomer of folate available by prescription in the US,
and that's the reduced form called leucovorin.  It's generally used
only as a rescue form of folate for cancer treatment with methotrexate,
but it can also be used for people with severe folate needs, such as (I
suppose) people with bowel absorption problems.  It will serve
perfectly well wherever folate is needed, and perhaps even better.
Cost is considerably higher, but calcium leucovorin tabs at 5 mg can be
had at many pharmacies.  I wonder whether or not it would be more
effective than folate for bringing down homocysteine levels?  That
system is said to be saturated at doses of 0.7 mg or so of folate, but
perhaps this occurs only because of a lack of folate reductase, which
you might be able to get around with leucovorin.  In other words, with
leucovorin you might be able to pump the system a little harder.  I'll
have to do a medline search and see if anyone has tried it.

                                  Steve Harris, M.D.

From: "Steve Harris" <SBHarris123@ix.netcom.com>
Newsgroups: sci.med.nutrition
Subject: Re: Folic Acid Manufacture &c?
Date: Fri, 27 Apr 2001 02:15:04 -0600

"DRCEEPHD" <drceephd@aol.com> wrote in message
news:20010427035009.06365.00000959@ng-cb1.aol.com...
> >Subject: Re: Folic Acid Manufacture &c?
> >From: Brian Sandle bsandle@shell.caverock.net.nz
> >Date: 4/26/01 8:04 PM Central Daylight Time
> >Message-id: <988333574.62051@cobalt.caverock.co.nz>
>
> The structure of folic can be found at:
>
> http://www.pharmcentral.com/
>
> > Folic acid (the synthetic form of folate B vitamins in
> >   foods) is widely used in vitamin supplements.
>
> Is this a suggestion that "natural" folic acid is different from
> "synthetic" folic acid?

Well, it is, you know.  Most of the crap hanging off the folate in foods
isn't necessary for its vitamin function, and isn't included when they make
it synthetically.




..

From: "Steve Harris" <SBHarris123@ix.netcom.com>
Newsgroups: sci.med.nutrition
Subject: Re: folic acid/B12 ratio
Date: Fri, 27 Apr 2001 19:26:09 -0600

"Fred Thomas" <fredt@stellartron.com> wrote in message
news:j7mG6.424$u7.49453@e3500-chi1.usenetserver.com...
> EHa7494854 <eha7494854@aol.com> wrote in message
> news:20010427174854.04830.00001144@ng-fa1.aol.com...
> > Let me put it a different way. The main reason I take more than 800
> > mcg/d of folate is not because I think it's going to lower
> > homocysteine more than 800 mcg/d will. So I might be better off
> > phrasing the question like this: does taking 3 mg/d of B12 pose any
> > problems (aside from the ones the L-carnosine person mentioned)? Is it
> > toxic? Thanks...
> >
> > EAH
>
> Neither folic acid nor B12 are toxic.  If we're nice, maybe Steve Harris
> will tell us about the time he fed folic acid to lab animals like it was
> mashed potatoes.  If I recall correctly, they got the human equivalent of
> grams/day and it didn't affect their lifespans.


It's true and I wish I'd published it. I still may, since I have all the
data yet on cards.

Yeah, I fed them 1 part PER THOUSAND in the dry diet (actually 1.25 PPT of
the 80% spray-dried Hoffman LaRoche product), from weaning to natural death.
That would be somewhere around a gram of folate a day (yes, 1,000,000 mcg,
hundreds of times the RDI) for a person eating a lb a day of dry
carbohydrate, protein, and fat.   The mice actually ate around 7 grams a day
if you compared them on a wt/wt basis with people, since mice have a faster
metabolism and eat a lot more per body wt. (I personally think that vitamin
intakes should be compared per kcal, however, since rodent and human
nutritional needs scale approximately that way, so % dry diet is probably
the more fair number for nutrients).

In any case, all that folate had absolutely no effect at all on lifespan,
which averaged (for these slightly restricted mice) a bit under 3 years (34
mo as I recall), with max lifespan 3.5 years.  Controls were the same. You
can see that these experiments were done under excellent conditions with a
long lived hybrid strain.

I think the mice were fairly restricted, corresponding about to people on a
careful healthy, low cal diet. My cats have caught a lot of Mus musculus in
my back yard that are a lot fatter, and look a lot more like my 45 g ad lib
mice (a mildy restricted animal might run 10 grams less). So I don't think
that dietary restriction merely reproduces wild ad lib conditions. Probably
it reproduces wild "life is hard" conditions. It certainly is healthier for
the animals' life span, at least if they aren't breeding, and are protected
from infection, predation, and periods of starvation (which may or may not
correspond with what's best for the average wild mouse or the average "wild"
human).

Since running this experiment I've lost all fear of folate. <g>.  Which may
be an overgeneralization, but there you are. It's WAY down on my list of
possibly toxic nutrients. Along with CoQ10 and chromium (III), I might add.


SBH

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology
Subject: Re: high dose folate & breast cancer
Date: Sat, 11 Dec 2004 18:07:30 -0500
Message-ID: <cpfune$d5j$1@reader1.panix.com>

Zee wrote:
> Is folate supplementation, ie) to lower homocysteine levels, dangerous
> for women? And if it is, will it be for men too? Breast cancer is not
> only a disease of women.

Hard to know from this study, but the results are at least mildly
concerning. Others have worried that folate can promote cell turnover
and so could increase the risk of tumors. I would guess we'll see a
series of other articles looking at long term outcomes after trials of
folate to see if there's evidence of increased cancer risk. These
current data are very preliminary.

--
David Rind
drind@caregroup.harvard.edu

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology,sci.med
Subject: Re: high dose folate & breast cancer
Date: Sun, 12 Dec 2004 15:16:05 -0500
Message-ID: <cpi926$3oe$1@reader1.panix.com>

zwalanga wrote:
> Yes. Mildly concerning. But I take 5 mg folate daily, presumably to
> lower homocysteine which may or may not affect my risk for heart
> disease. Previously, I took statins, which may or may not lower my risk
> for heart disease. Both then, for prevention, but not real proof either
> does that. And although I am not 70, I *am* now being evaluated for a
> type of cancer. Statins have shown increase in cancer in at least one
> clincial trial. Folate may increase breast cancer. I am not a scientist
> and I don't read these things the same way you do. But I think I can
> spot a rat when one scurries through my dreams.
>
> http://www.cspinet.org/integrity/press/200409231.html
>
> "The one study that looked at elderly patients over 70 did not show a
> significant reduction in heart disease deaths, but it did show a
> statistically significant increase in cancer deaths. The authors of the
> NCEP report dismissed the finding by combining the cancer data with
> data from other studies that included much younger patients;"

I wouldn't view this as "spotting a rat". The people recommending folate
to lower homocysteine levels believe they are recommending something
good and helpful. That they might turn out to be wrong is just reality.

In the absence of definitive evidence (like a large randomized trial of
folate supplementation for primary prevention of heart disease) we're
all left with making our best guesses about what does or does not make
sense to do. Personally, if my only risk factor for coronary heart
disease were an elevated homocysteine level, I would not take high dose
folate supplementation.

And, in general, if I thought my risk for coronary heart disease were
too high because of some series of risk factors, I would take a statin
whatever those risk factors actually were. That's because my
interpretation of the various evidence is that just about everyone can
expect around a 25 percent reduction in their risk of coronary disease
by taking a statin. This relative reduction translates into a pretty
small absolute decrease in people at low risk and a pretty large
absolute decrease in people at high risk, but it's there for just about
every group of people that has been studied. (People on dialysis are
probably an exception to this.)

I suppose it could turn out that statins increase the risk of cancer,
but there's certainly no strong evidence in that direction currently. In
fact, there's some weak evidence to suggest that they decrease the risk
of various cancers. In any case, in the large trials of statins overall
mortality has been pretty consistently reduced. So if statins have bad
side effects, they do not seem to be large enough to overwhelm the
favorable effects of statins on mortality, at least in people at
increased risk for coronary heart disease.

--
David Rind
drind@caregroup.harvard.edu

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology,sci.med
Subject: Re: high dose folate & breast cancer
Date: Sun, 12 Dec 2004 18:19:10 -0500
Message-ID: <cpijpe$6tn$1@reader1.panix.com>

Juhana Harju wrote:
> High dose supplementation is probably not wise, but wouldn't 400 µg be a
> sensible dose?
> Below is an article about some positive effects of fortification with
> folic acid (not any dosages mentioned).
>
> http://www.sciencedaily.com/releases/2004/03/040308074315.htm

Maybe. But even if the analysis in the above study is correct, it's
possible that you could be decreasing the risk of strokes but increasing
the risks of cancer. This is not to say that I think a daily supplement
with 400 mcg of folate is a bad idea -- just that we really don't have
strong evidence on the issue the original poster raised as to whether
folate supplementation could have harmful effects.

--
David Rind
drind@caregroup.harvard.edu

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med.cardiology
Subject: Re: Niacin + other B vitamins?
Date: 14 Jun 2005 18:57:26 -0700
Message-ID: <1118800645.983231.267600@g43g2000cwa.googlegroups.com>

>>Thank you for a very informative reply.  With regard to folate -- or
folic acid -- what is the dose for the best effect on homocysteine?  And
why is it limited by law?  Is there an overdose danger? <<

COMMENT:

The studies show a plateau effect around 600 mcg, but I'd double that
to give some looseness at the corners <g>. Especially if you're a big
guy. Folate is dirt cheap, unless you buy from the wrong people. At
Target you can get 250 of the 800 mcg pills for about $4.

The law limits folate due to old fears that it would mask B12 deficient
people, since all B12 deficiency symptoms except the nerve damage, are
due to low folate.  So they were afraid people would get nerve damage
and wouldn't be diagnosed. But the public scandle about babies with
neural defects born to folate deficient mothers has caused the addition
of folate to flour, and the FDA has mostly given up on this question.
But the law on how much folate can be in pills hasn't changed due to
bureaucratic inertia.

Folate is non-toxic. I once did an experiment feeding mice folate at
levels of 1 part per thousand dry diet. That would be several GRAMS a
day for a human.  No effect on life span, either positive or negative.

SBH

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology
Subject: Re: Niacin + other B vitamins?
Date: Tue, 14 Jun 2005 22:08:23 -0400
Message-ID: <d8o2eu$jpk$1@reader1.panix.com>

Steve Harris wrote:
> Folate is non-toxic. I once did an experiment feeding mice folate at
> levels of 1 part per thousand dry diet. That would be several GRAMS a
> day for a human.  No effect on life span, either positive or negative.
>
> SBH

I think that overstates the level of knowledge about the safety of
folate supplementation. There have been at least theoretical concerns
that folate can promote cell replication and thus, potentially, tumor
growth. This is not to suggest that I think folate supplementation is
likely to be dangerous, but I would not be willing to definitively state
that high dose supplementation is non-toxic.

--
David Rind
drind@caregroup.harvard.edu

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med.cardiology
Subject: Re: Niacin + other B vitamins?
Date: 15 Jun 2005 11:13:52 -0700
Message-ID: <1118859232.874569.189490@o13g2000cwo.googlegroups.com>

>>I think that overstates the level of knowledge about the safety of
folate supplementation. There have been at least theoretical concerns
that folate can promote cell replication and thus, potentially, tumor
growth. This is not to suggest that I think folate supplementation is
likely to be dangerous, but I would not be willing to definitively
state that high dose supplementation is non-toxic. <<

COMMENT:

In theory ANY nutrient needed for cells to grow, promotes cell
replication!  You need folate for DNA repair and there's a lot of
theoretical suggestion it might be anticarcinogenic in large amounts.
One of the abstracts below notes that dietary folate suppresses
replication of natural killer cells--- something you DON'T want when it
comes to cancer risk.I'd be more impressed if you know of any studies
showing that folate supplementation in tumor bearing animals makes them
do worse. I can't find any.  All in all, it's hard to tell how all this
comes out, but that's why we do experiments.  That's why I did the one
I did.

If you eat a lot of produce, you can easily get as much as 5 mg of
folate in your diet alone. That's the prescription tablet amount, and
is 6 of the 800 mcg OTC pills. It's more than enough to lower your
homocysteine by this mechanism as much as it can be done. Perhaps we
should set that as the provisional max. If this was much was bad for
you, it would have shown up as a big oncogenic effect in vegans and
other salad freaks. But the opposite is the case.


1: Carcinogenesis. 2004 Jan;25(1):69-76. Epub 2003 Sep 11.

Effects of dietary folate and aging on gene expression in the colonic
mucosa of rats: implications for carcinogenesis.

Crott JW, Choi SW, Ordovas JM, Ditelberg JS, Mason JB.

Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition
Research Center on Aging at Tufts University, 711 Washington Street,
Boston, MA 02111, USA. jimmy.crott@tufts.edu

Folate depletion and aging are risk factors for colorectal cancer. We
investigated the effects of folate status and aging on gene expression in
the rat colon. Young (weanling) and older (12 month) rats were fed folic
acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks.
Gene expression was measured in colonic mucosal scrapings (n = 3 per
group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion
induced the up-regulation of immune-related genes, urokinase and
inducible nitric oxide synthase and the down-regulation of adhesion
molecules (protocadherin-4, nidogen and integrin alphaV) and vascular
endothelial growth factor in young rats. The abbreviated response to
depletion in old rats (62 changes versus 136 in the young) included
up-regulation of caspase-2 and deleted in colon cancer.  Gene expression
changes due to aging were more abundant in folate depleted than
supplemented rats (38 versus 119 genes, respectively). In
folate-deficient rats, aging induced the down-regulation of
immune-related genes, urokinase, p53, insulin-like growth factor binding
protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced
the down-regulation of vascular endothelial growth factor and caspase-2.
Lower expression of adhesion molecules and higher expression of urokinase
with folate depletion in young rats may indicate that cell detachment and
migration, cancer-related processes, may be modulated by folate status.
An age-related decline in p53 and IGF-BP3 expression was only observed in
folate depleted animals, indicating that folate supplementation may
reduce the risk for age-associated cancers by suppressing deleterious
changes in the expression of certain genes.

PMID: 12970065 [PubMed - indexed for MEDLINE]



2: Carcinogenesis. 2003 May;24(5):937-44.

Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced
mammary tumorigenesis in rats.

Kotsopoulos J, Sohn KJ, Martin R, Choi M, Renlund R, McKerlie C, Hwang
SW, Medline A, Kim YI.

Department of Nutritional Sciences, University of Toronto, Ontario,
Canada.

Epidemiologic studies have suggested that dietary folate intake is
inversely related to breast cancer risk. However, epidemiologic evidence
has not been consistent nor has it provided unequivocal support for this
purported inverse relationship. This study investigated the effect of
dietary folate on N-methyl-N-nitrosourea (MNU)-induced mammary
tumorigenesis in rats.  Weanling, female Sprague-Dawley rats were fed
diets containing either 0 (deficient; n = 22), 2 (basal dietary
requirement, control; n = 20) or 8 mg (supplemented; n = 20) folate/kg
diet for 30 weeks. At 50 days of age, rats received an i.p.  injection of
MNU (50 mg/kg body wt). At necropsy, all macroscopic mammary tumors were
identified and examined microscopically. The effect of dietary folate on
genomic DNA methylation in mammary tumorigenesis was determined by the in
vitro methyl acceptance assay. The incidence of mammary adenoma and
adenocarcinoma in the folate-deficient group was lower than that of the
control and folate-supplemented groups (55 versus 90 and 75%,
respectively, P = 0.043).  Kaplan-Meier analyses also demonstrated a
similar trend in the rates of appearance of either adenoma or
adenocarcinoma (P = 0.06). In contrast, folate supplementation did not
significantly modulate mammary tumorigenesis compared with the control
group. Although mammary tumors were significantly hypomethylated compared
with non-neoplastic mammary tissues in each dietary group (P < 0.03),
folate status did not significantly affect the extent of DNA methylation.
The data suggest that dietary folate deficiency of a moderate degree
suppresses, whereas folate supplementation at four times the basal
dietary requirement does not significantly modulate, mammary
tumorigenesis in this model. The role of folate in mammary tumorigenesis
needs to be clarified for safe and effective prevention of breast cancer.

PMID: 12771039 [PubMed - indexed for MEDLINE]



3: J Nutr. 2002 Jun;132(6):1361-7.

Severe folate deficiency impairs natural killer cell-mediated
cytotoxicity in rats.

Kim YI, Hayek M, Mason JB, Meydani SN.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
youngin.kim@utoronto.ca

Dietary folate deficiency enhances, whereas folate supplementation
suppresses, the development of several cancers. This study investigated
the effect of folate deficiency on natural killer cell (NK)-mediated
cytotoxicity, which is important in immune surveillance against tumor
cells. In Experiment 1, severe folate deficiency was induced in rats by
feeding an amino acid-defined diet containing 0 mg folate and 10 g
succinylsulfathiazole/kg diet. Control and folate-supplemented rats were
fed the same diet containing 2 (basal requirement) and 8 mg folate/kg
diet, respectively. Severe folate deficiency at the end of wk 5 was
associated with 20% growth retardation, a 60% reduction in lymphocyte
counts and significantly impaired NK-mediated cytotoxicity compared with
the control and folate-supplemented groups (P < 0.02). The lesser degree
of severe folate deficiency achieved by wk 4 was not associated with
impaired NK-mediated cytotoxicity. Folate supplementation at 4x the basal
requirement did not significantly enhance NK-mediated cytotoxicity at
either time point. In Experiment 2, moderate folate deficiency was
induced in rats by feeding the same diet without succinylsulfathiazole.
NK-mediated cytotoxicity in the moderately folate-deficient rats (without
growth retardation or lymphopenia) was not significantly different from
that in controls. Although severe folate deficiency may have adverse
effects on NK-mediated cytotoxicity, moderate folate deficiency, a degree
of depletion associated with an increased risk of several cancers,
appears not to affect NK-mediated cytotoxicity in rats.  Furthermore, a
modest level of folate supplementation above the basal requirement does
not enhance NK-mediated cytotoxicity. These data collectively suggest
that NK-mediated cytotoxicity is not a likely mechanism by which folate
status modulates carcinogenesis.

PMID: 12042459 [PubMed - indexed for MEDLINE]



4: Cancer Res. 2000 Oct 1;60(19):5434-40.

Effects of dietary folate on intestinal tumorigenesis in the apcMin
mouse.

Song J, Medline A, Mason JB, Gallinger S, Kim YI.

Department of Medicine, University of Toronto, Ontario, Canada.

Dietary folate appears to be inversely related to colorectal cancer risk.
This study investigated the effects of dietary intervention with folate
or the development of intestinal polyps in Min (Apc +/-) mice. Weanling
Mil mice were fed diets containing 0, 2 (basal requirement), 8, or 20 mg
folate/kg diet. At 3 and 6 months of dietary intervention, 50% of the
mice from each group were sacrificed, and the small intestine and colon
were analyzed for polyps and aberrant crypt foci (ACF). Serum folate
concentrations accurately reflected dietary folate levels (P < 0.001). At
3 months no significant difference in the average number of total small
intestinal polyps was observed among the four groups. However, increasing
dietary folate levels significantly reduced the number of ileal, but not
duodenal or jejunal, polyps in a dose-dependent manner (P-trend = 0.001);
folate supplementation at 20 mg/kg diet was associated with a 68-78%
reduction in the number of ileal polyps compared with the other three
diets (P < 0.007). The number of ileal polyps was inversely correlated
with serum folate concentrations (P = 0.03). At 3 months, increasing
dietary folate levels significantly decreased the number of colonic ACF
in a dose-dependent manner (P = 0.05); the control and two folate
supplemented diets significantly reduced the number of colonic ACF by 75
100% compared with the folate-deficient diet (P < 0.04). The number of
colonic ACF was inversely correlated with serum folate concentration (P =
0.05). No significant difference in the number of colonic adenoma was
observed among the four groups at 3 months. At 6 months, no significant
differences in the average number of total small intestinal, duodenal,
and jejunal polyps, colonic adenomas, and colonic ACF wer observed among
the four groups. However, the folate-deficient diet had 62-76% lower
number of ileal polyps compared with the control and two
folate-supplemented diets (P < 0.003). Serum folate concentrations, but
not dietary folate levels, were directly correlated with the number of
ilea polyps (P = 0.006).  These data suggest that dietary folate
supplementation suppresses the development of ileal polyps and colonic
ACF in this model However, at later time points, folate supplementation
appears to have an opposite effect on ileal polyps.  These data generally
support the role of folate in intestinal tumorigenesis suggested in
epidemiological studies and chemical carcinogen animal models.
Notwithstanding the limitations associated with this model, these data
suggest that the optimal timing and dose of folate intervention need to
be determined for safe and effective folate chemoprevention.

PMID: 11034085 [PubMed - indexed for MEDLINE]

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.cardiology
Subject: Re: Niacin + other B vitamins?
Date: Wed, 15 Jun 2005 22:38:47 -0400
Message-ID: <d8qok4$3vd$1@reader1.panix.com>

Steve Harris wrote:
> COMMENT:
>
> In theory ANY nutrient needed for cells to grow, promotes cell
> replication!  You need folate for DNA repair and there's a lot of
> theoretical suggestion it might be anticarcinogenic in large amounts.
> One of the abstracts below notes that dietary folate suppresses
> replication of natural killer cells--- something you DON'T want when it
> comes to cancer risk.I'd be more impressed if you know of any studies
> showing that folate supplementation in tumor bearing animals makes them
> do worse. I can't find any.  All in all, it's hard to tell how all this
> comes out, but that's why we do experiments.  That's why I did the one
> I did.
>
> If you eat a lot of produce, you can easily get as much as 5 mg of
> folate in your diet alone. That's the prescription tablet amount, and
> is 6 of the 800 mcg OTC pills. It's more than enough to lower your
> homocysteine by this mechanism as much as it can be done. Perhaps we
> should set that as the provisional max. If this was much was bad for
> you, it would have shown up as a big oncogenic effect in vegans and
> other salad freaks. But the opposite is the case.

There was an editorial I read a year or so ago that expressed concern
about whether folate fortification had been adequately proven safe for
the population, but I can't find it at the moment. I believe it pointed
to some animal or cell data, but since I can't pull it up....

In any case, my concerns are mainly caused by the following study:

TI - Taking folate in pregnancy and risk of maternal breast cancer.
AU - Charles D; Ness AR; Campbell D; Davey Smith G; Hall MH
SO - BMJ 2004 Dec 11;329(7479):1375-6.

The study suggested a possible doubling of breast cancer mortality 35
years after supplementation during pregnancy. There are lots of reasons
to suspect this result was just due to random chance, but it's enough to
make me hesitant to declare folate supplementation to have been proven safe.

--
David Rind
drind@caregroup.harvard.edu

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med.nutrition,sci.med.cardiology,misc.health.alternative
Subject: Re: Folic acid supplementation for 3 weeks decreases heart disease 
	risk
Date: 28 Sep 2005 14:17:13 -0700
Message-ID: <1127942233.282423.8730@g44g2000cwa.googlegroups.com>

Kamalakar Pasupuleti wrote:
>  Most of the one a day vitamin suppliments have 400 mcg of Folic Acid ,
> which is 100 % of daily value . Is that not enough ?
> If an additional quantity need to be taken for hypertension
> what is the safe limit .
>
> Kam


I believe I read somewhere that a dose of 600 mcg or so is the place
where folate's effects on homocysteine levels tops out.

5 mg = 5000 mcg is used in studies because this is a the presciption
dose. If you don't use it, you're stuck with the little OTC pills,
which are either 400 or 800 mcg, never more than that.

OTC folate doses are strictly regulated because the FDA once had horrid
fears that people would mask their B12 deficiency until their nerves
were all demyelinated and their brains fell apart--- without ever
getting anemic or having other other blood problems or symptoms. Which
in theory could actually happen. BUT, the neural tube defect problem in
the country from folate-deficient women was so bad that finally the
USDA prevailed, that it it finally came down to real cases of birth
defects vs. theoretical cases of B12 problems in the elderly. The kids
won, and we're all starting be immersed in folate (now added to flour
and other such products). Which in my mind is a good thing. They did it
right, for once.

Toxicity: there are a few suggestings from the old literature that
gigantic doses of folate given IV might be seizure-ogenic. But attempts
to find toxicity in animal studies have generally failed at all doses.
I regard it as being as free from toxicicy worries as vitamin B1 or B2.
(And I myself pop several of the 800 mcg tabs, which you buy incredibly
cheaply at Target for something like 1 cent each, ever day). But I take
B12, too, in ammounts to make sure that if I ever develop B12
absorption problems, it won't matter and folate won't mask them. I
recommend anybody else going on 800 mcg or more of folate a day, add
1000 mcg of B12 to it, orally (also cheap). That will pretty much safe
you from the B12 absorption worries.

SBH

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med.nutrition,sci.med.cardiology,misc.health.alternative,
	sci.life-extension
Subject: Re: Folic acid supplementation for 3 weeks decreases heart disease 
	risk
Date: 28 Sep 2005 17:18:30 -0700
Message-ID: <1127953110.016470.186330@z14g2000cwz.googlegroups.com>

David Rind wrote:
> Before pointing to the effects of three weeks of folate on peripheral
> arterial measurments as evidence of saftey and efficacy, I'd suggest
> that people might want to review the results of the NORVIT trial
> presented at the European Society of Cardiology earlier this month:
> www.eurekalert.org/pub_releases/2005-09/esoc-n090505.php
>
> --
> David Rind
> drind@caregroup.harvard.edu


COMMENT:

Wow!  That's a shock. And very unexpected. It's very easy to get
several mg of folate from a normal diet, and in fact if 800 mcg folate
is harmful or a cardiovascular risk, you can't have your 5 servings of
fruits and vegetables. But it's practically impossible to get 40 mg of
B6. So I would be easier to let that go.

Synergism between them, doing something bad??  Total weird.  But looks
like a big, well-constructed study. I'm going to forward it on to
sci.life-extension. Where I predict they'll all pounce on it as being
due to not giving megadoses of ALL the B-vitamins. Sigh.

Quote:

NORVIT, the Norwegian Vitamin Trial, is the first trial to examine
whether high doses of B vitamins prevent recurrent heart disease in
patients who have had a myocardial infarction. A total of 3749 patients
were recruited from 35 Norwegian hospitals. The patients were assigned
to take B vitamins or placebo for more than three years in addition to
standard treatments after a heart attack.

Professor Kaare Harald Bønaa MD, University of Tromsø, Norway,
principal investigator of the NORVIT trial, comments, "The results of
the NORVIT trial are important because they tell doctors that
prescribing high doses of B vitamins will not prevent heart disease or
stroke. B vitamins should be prescribed only to patients who have B
vitamin deficiency diseases."

The participants in the NORVIT trial were divided at random into four
groups that received either 0.8 mg folic acid (a B vitamin) per day, 40
mg vitamin B-6 per day, both 0.8 mg folic acid and 40 mg vitamin B-6
per day, or a placebo capsule per day. Those who took folic acid or
vitamin B-6 alone had a small increase in the risk of cardiovascular
disease. However, among those who took both vitamins the risk increased
by 20 percent. 

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med.nutrition,sci.med.cardiology,misc.health.alternative,
	sci.life-extension
Subject: Re: Folic acid supplementation for 3 weeks decreases heart disease
Date: Wed, 28 Sep 2005 21:12:08 -0400
Message-ID: <dhff1o$irh$1@reader1.panix.com>

Steve Harris wrote:
> David Rind wrote:
>
>>Before pointing to the effects of three weeks of folate on peripheral
>>arterial measurments as evidence of saftey and efficacy, I'd suggest
>>that people might want to review the results of the NORVIT trial
>>presented at the European Society of Cardiology earlier this month:
>>www.eurekalert.org/pub_releases/2005-09/esoc-n090505.php
>>
>>--
>>David Rind
>>drind@caregroup.harvard.edu
>
>
>
> COMMENT:
>
> Wow!  That's a shock. And very unexpected. It's very easy to get
> several mg of folate from a normal diet, and in fact if 800 mcg folate
> is harmful or a cardiovascular risk, you can't have your 5 servings of
> fruits and vegetables. But it's practically impossible to get 40 mg of
> B6. So I would be easier to let that go.
>
> Synergism between them, doing something bad??  Total weird.  But looks
> like a big, well-constructed study. I'm going to forward it on to
> sci.life-extension. Where I predict they'll all pounce on it as being
> due to not giving megadoses of ALL the B-vitamins. Sigh.

Although it certainly raises the specter of real harm, looking at the
totality of secondary prevention studies I think it's more likely that
B-vitamins have no effect and this was just a statistical blip. The
description on the website overstates the results in the arms with
either B6 or folate alone -- there really was no evidence of any effect.
The 20% increase in events in the combined arm was statistically
significant, though.

There are now a bunch of secondary prevention studies looking at various
doses and combinations of B vitamins and most showed neither harm nor
benefit. For studies that did show an effect, other than NORVIT there is
one trial showing harm after percutaneous coronary intervention and one
showing benefit. While it's possible to try to explain these results by
difference in the populations and doses used, I think that we're
probably just seeing some statistical bounce around a null effect.

--
David Rind
drind@caregroup.harvard.edu