Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review

[Technoid]

Recently published narrative review on the possible dangers of excess folate.

mdpi.com/2072-6643/15/21/4699

[wedgewood]

A quite disturbing ( and very long ) read . I’m now inclined to make sure that I get my B9 ( folate in food , folic acid in tablet form) from natural sources .

I have read somewhere that it’s more or less impossible to overdose on folate in food I suppose it’s always better to obtain vitamins from natural sources . But P.A. patients have no choice when it comes to B12. Thank goodness that we can’t overdose on it .

Thanks Technoid .

[JGBH in reply to wedgewood]

It is quite concerning. I, like many people who have hypothyroidism and RA plus B12 deficiency (absorption problems) take a daily B complex (of good quality) … as the name indicates it contains folate (B 9) and I eat plenty of varied green vegetables too. So not sure what to do now.

This reply is also addressed to Technoid… and thank you for the link Technoid.

[wedgewood in reply to JGBH]

I’m sure that the amount in a B complex tablet is modest . Some people take a 5mg tablet which I’m sure will cause problems for some , if taken over an extended period .

it’s good to be aware .

[JGBH in reply to wedgewood]

That’s reassuring… thank you.

[Technoid in reply to JGBH]

Although the paper does contain some alarming data, particularly when its synthesized in a long paper like this, there are a number of caveats.

When there is a definitive takeaway from a paper this is very often summarized in the Conclusions section. But the authors are careful not to provide any such definite takeaways, despite the title of the paper.

Instead they call for more research to elucidate the possible mechanisms behind observed correlations of high folate status and disease. They mention the limitation that many of the studies are in mice and may not translate to humans. But for sure there seems to be some concerning signals, although the signals are not yet strong enough to make definitive conclusions yet.

I am not medically trained but my approach to folate supplementation would be:

(1) investigate what the dietary folate intake is with a tool such as Cronometer

(2) investigate if, given that the intake is adequate, is serum folate adequate?

- In B12 deficiency (pre-treatment), folate trap can exist which traps folates in a particular form, this can mean (FlipperTD can correct me), that serum folate is high but that is because most of the folate is sitting unused, in methyl trap. As B12 becomes available, folate is processed normally and total folate normalizes, while the proportion of folate that was trapped in one particular form comes down.

(3) If serum folate is low despite good dietary intake and adequate B12, is it because there is an absorption or other physiological problem?

(4) If the answer to 3 is yes, then its wise to supplement as needed to boost folate to adequate levels, ideally not going over 400mcg folate but if a severe deficiency is present, then short-term higher doses may be needed or prescribed even up to 5mg for severe deficiency.

Proviso: Some people feel that they do better on high doses of folate (>400mcg) despite adequate serum folate. I don't have a good explanation for that but I still feel that there is some "smoke" around high folate intakes, and even if there is no "fire", there seems to be enough reason to be cautious at present not to exceed the tolerable upper limit of 1mg unless correcting a deficiency.

I do not supplement folate in any form (except nutritional yeast!) but I get 1mg from a whole foods diet and have no absorption issues so my experience is certainly not universally applicable.

[JGBH in reply to Technoid]

Thank you for your comments.

[MrsTuft]

Very interesting. My own experiments have found that I’m best with 400mcg Folinic acid per day. No supplementation, or higher than 400mcg Folinic, or any folic acid, all make me feel unwell. It was a bone of contention with another B12 group who state 5mg folic acid a day. I simply couldn’t do it. They made me scared I won’t get well with my daily injections without it. 2 years in and I’m significantly improved but not better and it worries me.

[Technoid in reply to MrsTuft]

Did they provide any reasoning/evidence for this alleged 5mg of folic acid a day dosage?

[MrsTuft in reply to Technoid]

No but there are hundreds of people who’ve fully recovered doing it.

[Technoid in reply to MrsTuft]

Right. But would they have fully recovered had they not taken that dose of folate but a more moderate dose? That can't be answered from their experience which is always the problem with anecdotal reports - no control group to contrast with.

[WIZARD6787 in reply to Technoid]

Hey Technoid,

And the problem with testing done with a control group are they are given the label of the gold standard and it is often a golden standard. That and the ethical limits and bias on the part of the person people performing the test.

I have seen statistical analysis that concluded 47 % of medicial studies are later refuted.

There are no studies that support 1 mg EOD as opposed to less or more. It is all anecdotal.

I do not know the effects of what ever amount of folic acid I administer are, long term or short term. I understand and live that no one else does either. I do that with most things.

In medicine inductive reasoning is often the best that can be done. It is often seen as following the scientific method of repeatable testing which is rare. Often the testing is 'scientific' as the results are repeatable within certain parameters. The deduction based on the testing are inductive and not proved repeatable.

One also has to include the unchecked fraud in scientific studies as a factor.

The gold standard technology is if you do this this will happen in this amount of time. Every time.

The standard in medicine is consensus. With each applied scientist/physician choosing who they agree with.

If you have an infection the dose, frequency, length of time and form of penicillin you are prescribed is not consistent from physician to physician. The confidence is the only constant.

[Technoid in reply to WIZARD6787]

Agreed that the double-blind randomized controlled trial is often referred to as the gold standard. But I think this an unjustified oversimplification - for example in nutrition science, certain questions will never be answered by a randomized controlled trial because of the prohibitive cost and length of such a trial since many of the health issues from diet takes decades to develop, in addition to the unlikelihood that it pass an ethical review board.

And as you alluded to, obviously the quality of the science is only as good (or as honest) as the scientists performing the study. This is why peer review is helpful. But is not perfect and yes I know fraud does happen (I posted some videos covering that in my "Doing Your Own Research" post).

But just because there are caveats with the intepretation of science does not mean that its useless and we should just forget about trying to learn anything that way and instead rely on accumulated anecdotes.

Personal experience is important but I think it's only one way we can gain knowledge and it has significant limitations, many of which the scientific methods is well positioned to address, but for various reasons, it might not be addressing a particular question as well as we wish that it would - like why PA patients seems to need more B12 than makes any physiological sense from our current (obviously flawed) understanding of the condition.

I agree that there is no studies on the effect of 1mg EOD injection and obviously in a sense the forum members are performing an experiment with very frequent B12 injections whose long term outcomes are unknown. All we have is the lack of any good evidence that B12 can be overdosed or cause negative health effects at very high doses.

But I think the Folic Acid case is a bit different as we do have some plausible mechanistic reasoning for why folic acid could be an issue at high doses, some suggestive evidence from animal studies and correlations. I definetely agree its not conclusive but it's not at all clear to me that there are "NO" concerns with ultra-high folic acid supplementation.

In my opinion, the evidence suggests that those taking ultra-high folic acid doses (1mg+) without having a deficiency, may be taking some risks by doing so, as we do not seem to have strong evidence of safety, and some possible indications of harm, which is not the case for high dose B12.

I know that some people are absolutely convinced they need to take 5mg folic acid every day and nothing will change their mind on it. But I think that doing so based on purely anecdotal evidence and where there is no mechanistic logic or reasoning behind it, along with a lack of safety data and suggestive evidence of possible harm, is, in my opinion, unwise.

[WIZARD6787 in reply to Technoid]

Hey Technoid,

I use due caution with every supplement.

I a couple of years ago did some work on the testing for folic acid and at the time was not able to evaluate the reliability of testing with regards to the amount to administer. Maybe I should revisit that.

Peer review sounds so wonderful. It is not. There is the peer review in scientific journals which is advertising driven. One cannot expect cases of fraud to be retracted as history has shown. It does happen, fraud is more likely ignored.

Most often peer review is political in nature as a entity in charge of creating guidelines has a period of open comment. Thing is any comment that goes against the consensus is most often ignored. Not always.

Science is grant driven and has been since the church was the government entity in charge of funding science.

I was in York England and speaking to a scientist and asked him why is the science in Europe so much different that the USA. He replied "The government here decides what science to fund but do not decide our findings. In the USA the government decides what results they want proven.

I love science and am a scientist. Where the breakdown comes for me is when scientists do not accept they are just people and start to pretend they are more than that which they are not.

True scientists face the best that can be done is as far as we know so far. Does not mean science does not have value it is not as wonderful as some try and portend.

I call the period after the world wars to present as the gray ages. After the world wars it was expected that science would have all answers and this led to unrealistic expectations and conclusions.

You know how to spot a false prophet? They predict the future.

It is worthy of note to me that physicians do not have a longer life expectancy.

Good fun for me to discuss. Beats making the hard decisions of what to do! 🙂

[Technoid in reply to WIZARD6787]

Nothing that I disagree with you on there Wizard. My "Doing Your Own Research" post (linked in my profile) has a video and article with some interesting ideas on how to improve the quality and reliability of the scientific process and outputs.

[Sunnysidoop]

I have high folate without supplementation, which I find somewhat perplexing

[meme in reply to Sunnysidoop]

So do I !

[Technoid in reply to meme]

Meme, previously you mentioned you eat a lot of beans and veg, along with marmite and nutritional yeast. Beans and veg are good folate sources and marmite and nutritional yeast are typically fortified with folic acid so that could explain it.

[wedgewood in reply to Sunnysidoop]

Perhaps you have a very good diet ?

[bookish in reply to Sunnysidoop]

I had nearly top of range folate while on oral B12 and a cheap multi containing a small amount of folic. When I dropped the multi and changed to methyltetrahydrofolate (small dose, building to moderate but never high, so never more than 1000mcg) my serum folate dropped to mid range and has stayed there, as well as symptoms improving (they had already improved a bit changing from cyano to methyl, then to a cleaner brand of methyl, and improved some more with methyl/adenosyl and hydroxo, but the jump with the folate vitamer was significant). I have genetic SNPs in folate cycle, which may explain why, or some of the why, and a long family history of dodgy B12/folate/PA.

[Sunnysidoop in reply to bookish]

Interesting that a multi vit can do that. I'll check what form is in mine (biocare)

[JHEW0836 in reply to Sunnysidoop]

I also have high folate without supplementation. I have had 15 or so B12 injections since January and my folate is still high and my red blood cell count is low.

[Sunnysidoop in reply to JHEW0836]

Thanks for sharing. I was injecting eod for 6 mon at my last test and no change to folate levels. That was 6 months ago and I'm now injecting daily. I'm wondering if its changed

[JHEW0836 in reply to Sunnysidoop]

Are you still symptomatic? I would really like to try the methyl form of folate that bookish speaks of to see if there is any improvement in my symptoms. I learn so much from this group and am thankful to have stumbled across it.

[Sunnysidoop in reply to JHEW0836]

I am, nothing much has changed unfortunately. I've started to get some tingling throughout my LHS after I switched from methyl b12 to hydroxy b12, so hopefully that's some healing happening. I don't know why it's only on the LHS!

[WIZARD6787]

Good discussion! Thank you all!

[helvella]

To throw in my penn'orth...

Until relatively recently, we would see many folate blood test results returned with a single number and a greater than sign like this:

> 4.5

The inference many took was there is no upper level that is, or would ever be, a cause for concern.

More recently, I've noticed quite a number do actually have a distinct reference interval.

Does this reflect a greater understanding and concern about excessive folate levels?

[Regenallotment]

Thanks for sharing,

I read the highlights and conclusions as I’m at work, but have a question, were they looking at all forms of folate supplementation or just Folic Acid?

Are the conclusions the same for say Methylfolate supplementation?

For anyone testing both Monitor my Health and Medichecks will give you a folate test. Medichecks like a venous draw but Monitor my health doesn’t mind a finger prick. I have found these used when checking my levels.

🌱

[Bellabab]

This is a typical nonsense paper from people who hate anything being added to food. This is from the paper itself.

"Abstract

This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk."

In other words there are no know problems at all. Much more dangerous is not having enough folate when supplementing B12 - the more B12 we inject the more folate we need. Its quite difficult to get enough folate from our diet if we are injecting B12. The consultant who treated me after I was rushed into hospital by a paramedic having collapsed made a point of telling me to take 5 mg of folic acid a day.

[bookish]

Thanks for this. Only part way through but the points made re.

Understanding the link between folate status in the parents, offspring, and epigenetic modifications can further our understanding of the origins of adult diseases

and

Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming

ring so true, but in my case not excess folate but functionally inadequate folate, in both myself and my mother. And I suspect that it plays/played a part in the B12D/PA on the other side of the family too.

We need the right amount of the right sort of folate for us individually to process, not just higher doses of the wrong kind which we cannot metabolise easily. Then we might all hit that sweet spot - folate not too low and not too high, homocysteine and MMA at good levels etc etc

Thanks again, shall keep reading when more awake.

[Sunnysidoop]

Interesting for me to read, as both me and my daughter age 6 has high folate too. She takes a low dose multi vitamin

[WIZARD6787]

"... the Institute of Medicine specified a dose of 5,000 mcg/day of folic acid as the Lowest Observed Adverse Effect Level (LOAEL). The tolerable upper intake level (UL) for folic acid was established at 1,000 mcg/day (one-fifth of the LOAEL) to prevent individuals from taking so much folic acid that they reach the LOAEL risk level of 5,000 mcg/day.

cdc.gov/ncbddd/folicacid/fa...

To evaluate one really needs to read the whole web page to understand how this applies to them as a person supplementing with B12.