Folate Part III: Fortification and antifolate medications.

Too much of a good thing?

Hello and welcome back to the folate series! So far, we have talked about:

Part I: the importance of folate for healthy circadian biology (and vice versa)

Part II: the REAL dietary choices we need to make to optimize folate (hint: it's not spinach)

Today, we're going to talk about synthetic B-vitamins.

What’s in your multivitamin?

This wraps around to where this whole inquiry started for me:

Should all pregnant women REALLY be supplementing with Folic Acid?

Care providers recommend folic acid to all women who want to conceive. At the same time, unmetabolized synthetic folic acid is associated with cancer, depression and cognitive impairment.

Quoted from: Folate Part I: Folate and Methylation

I have since learned folic acid also plays into newborn jaundice

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. Jaundice rates are up to 50-60%, making it now the number one reason babies have extended hospital stays.

If the new theory correlating newborn jaundice with folic acid is true, in most cases, it may be preventable by getting folic acid out of pregnant women’s supplements and food supply...

and by educating mothers about their circadian health choices.

But what would that mean for preventing neural tube defects, the whole reason we started supplementing with folic acid in the first place?

As you remember from Part I, folate is the main methyl donor that powers the circadian rhythm. Folate levels fluctuate throughout the day based on:

• solar exposure

• dietary consumption

• production of folates by the gut flora

• time spent in darkness

As well as other factors related to folate transport in and out of cells and tissues. These processes, we are coming to find out, vary greatly based on a woman’s genetic heritage. This means folate status is not easy to test, as it requires repeated testing over time and doesn’t give any picture about the many processes involves besides the blood level of folate.

Here's the scoop on folic acid:

Natural folates degrade under rough treatment (temperature, pH, and even by time itself). Back in the 1940's, people discovered synthetic folic acid. Folic acid remains stable under storage, and the body can (kind-of) convert it to folate. This seemed like a solution for the problem of neural tube defects. It did help. But, supplementation for pregnant women turned into fortification for the general population.

Guess what!? The general population does not need so much folic acid.

Especially when the enzyme to convert folic acid to folate is scarce in the body. When a person eats more folic acid than they can convert via enzyme, they end up with a build-up of folic acid over time. So now, there is too much unmetabolized folic acid in the general AND pregnant population. This overabundance has led to cancer, depression, cognitive impairment and newborn jaundice.

Industry pundits then have the gall to blame people for "overconsuming" enriched products.

But what is the mechanism by which folic acid can have such consequences? And what can we do?

The problems with folic acid

1. Placental transport is facilitated by Reduced folate carrier (RFC). RFC has low affinity for folic acid compared with natural folates

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. That means the placenta is even less efficient than the rest of the body in using folic acid. This really calls into question the whole reason we started messing around with folic acid in the first place.

2. Folic acid causes a masked B12 deficiency. (Is it a coincidence that jaundice rates correlate with B12 deficiency rates? These researchers say no.)

From all aspects of this perspective research, folic acid supplementation during pregnancy not only leads to folate deficiency due to malabsorption of synthetic folic acid, but also causes high levels of un-metabolized pteroylmonoglutamic acid which is one of the main cause and masking of cobalamin deficiency in pregnant women. Vitamin B12 deficiency is a great concern since it leads to the increasing of bilirubin in neonates which cause neonatal jaundice after delivery. Many factors in prenatal nutrition can chelate folate like sulfur deficiency and high levels of glyphosate in the diet, therefore, the replacement of synthetic folic acid with natural folate may help absorption and reducing the amount of un-metabolized folic acid serum in the blood of pregnant women.

Source: Synthetic Folic Acid Supplementation during Pregnancy Increases the Risk of Neonatal Jaundice in Newborns by Soroush Niknamian B.Sc and Somayeh Zaminpira (2016)

Too much of a good thing?

Folate deficiency is one of the most common nutritional deficiencies in the world. Folates are a vital part of our biology. Some believe folates—and not skin cancer—are the reason for greater skin pigmentation near the equators

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. The processes that regulate folate in the body are still mysterious to scientists.

It was recently thought all pregnant women were at risk for neural tube defects from lack of folates. Now we are finding out different genotypes have different methods of handling folates. Two women with the same lifestyle could have different outcomes in their pregnancies based on their unique heritage. This points to a need to get away from the one-size-fits-all supplementation schemes. What works for some, will not woork for others.

When there is too much folate, or folic acid, adverse outcomes occur. This can happen several ways:

1. Too much in the food supply (due to fortification, because remember: natural folates tend to be scarce)

2. Too much supplementation of folic acid

3. Indoor lifestyle lacking sunshine (sunlight, particularly UV, regulates folate by breaking it down)

Smokers who have high folic acid intakes have higher rates of cancer. In fact, doctors use antifolate medications in chemotherapy! It makes sense when you think about how folate and the circadian rhythm control making new cells. Break the body's ability to make new cells by blocking folate, and the cancer cells will also be stopped. This seems like it would have to be a short-term solution. And yet, arthritis, psoriasis, infections, and malaria are also sometimes treated with anti-folates.

A gentle approach to balancing folates

Folates are also known as B9, one of the B vitamins. The B Vitamins are not grouped for their physical similarity; they don't look alike at all. Instead, they are a group for their functional similarities. We have tried to isolate supplementation and the effects they have. The results have been disappointing, as I've been sharing about folic acid. Folate, B12, and B6 have each had their day in the limelight, but the data have never lived up to the initial optimism. The latest line of thinking is actually to go back to the beginning.

Historical sources of B vitamins

Most of the B vitamins come from plant sources. This was a big deal for the plant-based movement. When scientists figured out how to make B12 in a lab, it seemed like a new vegetarian, or even vegan, future was possible. Again, the data has not been able to back this optimism.

Leafy greens are the most well-known source of folates.

Looking back into history, we see that plants have not been a reliable food source for humans. Instead, plants made up a greater or lesser part of the diet based on seasonal availability. This means more plant-foods towards the equator, and fewer toward the poles. And yet, all peoples in all locations have had eras of robust health while eating locally with varying ratios of plant and animal based foods as the seasons allow.

Sometimes, nature provides few greens.

What does this mean for B vitamins? In the past, many humans relied on B vitamins sequestered by animals. These animal-derived B vitamins also tend to be chemically changed to be more bioavailable to humans.

Most importantly, B vitamins were never consumed in isolation. It turns out, our bodies don't use B vitamins in isolation, either. We have been so focused on folate... and B12... and B6... we haven't been watching how a lack of any one of the other B vitamins also breaks the very cycles we want to improve by adding one or the other of them. Functionally, the B vitamins are a group.

To get back to our human roots would be to get back to a local, seasonal diet rich in the foods most abundant to our locale and season. It would also include strict adherence to the local day/night cycle, with plenty of daytime sunshine and dark, quiet nights. Remember, these cellular cycles are under circadian control. A perfect diet in a disrupted environment still will not work. Conversely, a less than ideal diet within a perfectly circadian environment may still work (remember how intestinal flora may be more important than diet for folate production?). This is part of why two people eating the same diet can have such different health outcomes.

So, this local, seasonal diet and lifestyle sounds idyllic, but is this possible? Yes! Only, we have to give up:

1. Foods fortified with synthetic B vitamins, to restore the natural balance

2. Isolated B vitamin supplements, to resore the natural balance

3. Imported foods, to increase appetite for local foods

4. Spending all our time indoors and using lots of artificial light after sunset, to restore circadian rhythmicity

At that point, the world of local foods, whether plant- or animal-based, offers a diet rich in B vitamins that also supports the daily circadian rhythms by which we best function.

How does local eating fit into your lifestyle? Do you have any tips for making this work in today’s world? Please share below!

1. Niknamian, S., and Zaminpira, S. (2016). Synthetic Folic Acid Supplementation during Pregnancy Increases the Risk of Neonatal Jaundice in Newborns. Journal of Multidisciplinary Engineering Science and Technology, 3:12.

2. Shulpekova, Y., Nechaev, V., Kardasheva, S., et al. (2021). The Concept of Folic Acid in Health and Disease. Molecules, 26, 3731.

3. Williams, J.D., Jacobson, E., Kim, H., Kim, M., and Jacobson, M.K. (2012). Folate in Skin Cancer Prevention. Subcellular Biochemistry, 56: 181–197.