Folate, folic acid, methylfolate

Balancing cellular growth and health with avoiding cancer

I recently listened to a podcast  - an old one from 2020 - about methylation. It was a high-quality podcast with a well-spoken doctor who sells supplements and genetic reports to functional medicine doctors. He stated that it's ridiculous to think that high-dose folic acid causes cancer, but that on the other hand, almost everyone has methylation cycle problems and should instead take high-dose methylfolate supplements (which he sells).

He was an excellent speaker, an MD, and an "expert in the field". But I just didn't think that what he was saying matched the research on the topic...  And no, I'm not talking about the folic acid vs. methylfolate debate here. Instead, I'm questioning whether higher amounts of folate, whether folic acid, methylfolate, or even folate from food are beneficial.

In writing about MTHFR and DHFR genetic variants, I had come across studies that made me cautious about whether higher doses of folate were right for everyone. There are pros and cons to folate, and I see the positive benefits being touted without the trade-offs being discussed. While I understand that there may be a role for high doses of folate in certain situations, including under supervision for psychiatric illness or for megaloblastic anemia, my concern is that there is a balance between promoting cellular health and not fueling cancer growth that is not being explained by people who promote supplement sales.

For example, the MTHFR C677T variant, which reduces the formation of the active form of folate, methylfolate, is associated with a number of negative health outcomes, and many clinicians immediately recommend higher doses of methylfolate.

But... carrying two "bad" copies of the MTHFR C677T variant also significantly reduced the risk of colon cancer and a number of other types of cancer.[ref][ref][ref][ref]

Folate is needed for cells to replicate, which is one reason it is essential during pregnancy. However, cancerous tumors, which grow and divide rapidly, also thrive when folate is abundant. One of the first successful anti-cancer drugs was an anti-folate, which blocks cancer cell growth by reducing folate.[ref]

The delicate balance between promoting healthy cells and not fueling cancer growth is key to longevity and healthspan. 

With this background in mind, I did a bit of digging in the research to see what studies show about high doses of methylfolate or high doses of folic acid.

Background context: 
The US RDA for folate is 400 mcg/day of dietary folate equivalents (DFE), and the tolerable upper limit is 1,000 mcg/day from supplements or fortification (for adults, lower for teens and children).[ref] Most of the 'high dose' studies used 1000 mcg (1 mg) per day of folic acid or methylfolate, but a few used 4 mg (4,000 mcg) per day. For reference, a 1 c. serving of Cheerios has about 200 mcg of added folic acid,  a serving of bread has ~150 mcg of added folic acid, and a cup of white rice has ~200 mcg of added folic acid.[ref]

Someone who eats a lot of cereal, enriched flour, or enriched rice may end up getting quite a bit of folic acid even without taking supplements. 

1 DFE = 1mcg of folate from food = 0.6 mcg folic acid or 0.5 methylfolate

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Why could folate be a problem?

In short, one theory among researchers is that folic acid and folate help prevent the DNA damage that can lead to cancerous mutations. Folate plays many roles in cellular health. But the flip side is that once a cancer mutation has taken hold, folate helps the cancer grow. Folate is essential for cell growth, and cancer cells use a lot of folate.[ref]

Let's take a look at some of the studies that raise questions about folate increasing cancer risk or growth: 

A randomized, placebo-controlled trial evaluated the effect of 1 mg/day of folic acid in preventing colorectal cancer in a group of 987 adults. Participants were followed for 6 to 8 years, with colonoscopies performed to determine the prevalence of colorectal adenomas. While there was no increase in the risk of colorectal adenomas after the first three years, follow-up 3-5 years later showed that the folic acid group had an increased risk of recurrence of advanced adenomas with high malignant potential (67% increased relative risk).[ref]

In bladder cancer patients, a 5-year prospective study showed that both moderate and high folic acid intake significantly increased the risk of recurrence by 65-80%.[ref]

Of note here, both the bladder and colorectal cancer trials were in adults who were likely at a higher cancer risk. 

Does adding other B vitamins change things?
The overall increased risk of cancer was assessed in a long-term follow-up study of an osteoporosis prevention trial involving 2,524 adults who took folic acid (400 µg) and vitamin B12 (500 µg) compared with a placebo. The followup showed that those who were randomized to the folic acid/B12 group had a 13% increased relative risk of overall cancer and a 77% increased relative risk of colorectal cancer.[ref]

Is unmetabolized folic acid the problem, or is it the increase in active folate (methylfolate)? 
A study that looked at folic acid, unmetabolized folic acid, and methylfolate levels found that higher levels of methylfolate (5-methyltetrahydrofolate) were statistically associated with a 58% increased relative risk of advanced or multiple adenomas (benign tumors). The results showed that unmetabolized folic acid was not statistically associated with adenomas.[ref]

What about prenatal exposure?
A large study of children born between 1997 and 2017 looked at the effects on children whose mothers had taken of high doses of folic acid while pregnant. The researchers defined high doses of folic acid as 1,000 mcg  (most prenatal vitamins contain 800 mcg). The results showed an almost threefold increased risk of childhood cancer in children whose mothers had epilepsy and took 1 mg of folic acid. However, there was no increased risk of cancer in children whose mothers had epilepsy but didn't take folic acid. In the group of mothers without epilepsy who took 1 mg of folic acid, there was a smaller (~10%) increased risk of childhood cancer.[ref]

What about dietary folate?
This study surprised me, and I'm still not sure what to make of it. A prospective study looked at dietary folate and skin cancer in middle-aged adults. The median follow-up time for the study was 12 years. The results showed that higher dietary folate intake and higher erythrocyte folate concentration were associated with an increased risk of skin cancer. The increase in relative risk was 79% for people in the top third of dietary folate intake compared to the bottom third. The study was conducted in France from 1994-2002, and there was no fortification of foods with folic acid there.[ref]

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Should everyone avoid folic acid or methylfolate?

I don't want to give anyone the impression that folic acid and/or methylfolate are all bad. Many studies show the benefits of dietary folate and supplemental folic acid. (There aren't very many placebo-controlled clinical trials using methylfolate.) Also, many studies show that eating folate-rich foods is generally good for you. My point here is not to avoid folate, but to put in context the amount alongside your need for folate.

Reducing homocysteine levels with folate has benefits for both heart health and cognitive function. In people with both high homocysteine levels and high blood pressure, one study found that 800 mcg of folic acid helped lower blood pressure and homocysteine levels[ref] Another study of adults aged 50-70 years with high homocysteine levels (≥13 µmol/L) showed that 800 mcg of folic acid for three years had a beneficial effect on cognitive test scores, but only for the participants who had low omega-3 levels.[ref] 

There are studies using methylfolate for psychiatric symptoms that show positive results that are statistically significant at high doses.[ref][ref]

The key to evaluating trials is to look at what outcomes are being tracked (e.g. cancer vs. heart health), the length of time of the intervention (short term vs. long term), and the age of the participants (young vs. old).

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Possibility of impurities in supplements:

To add another twist to this question, a recent study and subsequent recall (in Canada) of some brands of folic acid supplements showed that some 1 mg common folic acid supplements contain low levels of N-nitroso-folic acid, which is carcinogenic. N-Nitroso folic acid can be produced when folic acid reacts with sodium nitrate in a solution.[ref]

When would you have folic acid reacting with nitrates or nitrites in solution (other than in manufacturing)? Well, when nitrites are in the drinking water.

A study published in 2013 looked at the combination of folate intake, nitrate intake from public water sources, and breast cancer risk. The study included more than 20,000 women in Iowa with survey information on dietary folate intake from 1986. The study then followed the women (ages  55-69)  for cancer incidence for a number of years.

Dietary nitrates, nitrites, and nitrites from drinking water were not associated with increased breast cancer in women with a normal or low folate intake. However, there was a 40%  increased relative risk of breast cancer in women with higher nitrate levels in their water who also consumed more than 400 mcg/day of folate.[ref]  Another study on Korean women found a similar result.[ref]

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Conclusion:

I don't have all the answers here, but my take-away from the research is that more is not always better when it comes to folate, folic acid, and methylfolate. To optimize folate, I think individuals need to take into account their age, homocysteine levels, cancer risk factors, family history of cancer, genetic variants in the folate pathway, and how much nitrite is in their water and diet. Plus, there are probably other environmental factors that I don't know about along with interactions with the gut microbiome.[ref]