It is time to rethink how we’re using folate, and its derivatives, methylfolate and folinic acid.

Recent research suggests that people who routinely take more than 1000 μg of folic acid per day may be at increased risk of cognitive decline, asthma, impaired immune function, and certain types of cancer (Fardous AM, et al. Nutrients. 2023; Pfeiffer CM, et al. J Nutr. 2015).

Excessive, unmetabolized folate might actually increase rather than decrease the risk of certain birth complications (Silva C, et al. Porto Biomed J. 2017). That’s ironic, given that prevention of neural tube defects (NTDs) is the main objective of the federal government’s 1998 mandate for enrichment of cereals and wheat products, and a prime reason why clinicians recommend folate supplements.

In light of the emerging research over the last decade, we have to ask ourselves: In our zealous efforts to prevent NTDs and help people who are “under-methylators,” are we in fact creating other health problems?

Excessive folate supplementation can lead to an accumulation of unmetabolized folate acid, which can stop the methylation cycle. This is the exact opposite of what we want to see.

My goal here is to explore the potential health impacts of excessive folate intake, which can sometimes be as problematic as folate deficiency. I also want to consider possible alternatives to mandatory fortification that could help reduce NTDs without the potentially negative health consequences of excess folate.

Folate’s Multiple Functions

In order to make more intelligent recommendations, and to sort through the muddle of folate research, it’s important to go back to the basics: What is folate? How is it metabolized? What does it do for us?

Folate, aka Vitamin B9, is essential to cellular function. It is necessary for synthesis of DNA and RNA, for metabolism of amino acids, for cell division, and for maturation of red blood cells. Eukaryotic cells cannot synthesize folate de novo, meaning that it must be obtained from food sources, typically plants. It’s interesting to reflect on the fact that the word “folate” derives from the Latin “folium,” meaning leaf.

Folate deficiency is common, and associated with multiple metabolic problems and congenital anomalies, most notably NTDs. So, there is good reason behind the impulse for supplementation. But like everything, too much a good thing can make it a bad thing.

It’s important to keep in mind that synthetic forms of folate (folic acid), which are very common in dietary supplements, are different from natural plant-derived folate. They only contain one glutamyl group, whereas natural folates are polyglutamyl. Once the glutamyl groups are removed by pancreatic enzymes the folate molecule is sent to the liver to be converted to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR).

Note that this is a rate-limiting step. If a patient reacts poorly to folate supplementation, it might not be an MTHFR issue, as most practitioners would assume. Rather, it could be a liver or pancreatic problem that needs to be explored.

THF undergoes further transformation to 5-10-Methylene THF (folinic acid), and to 5-Methyl tetrahydrofolate (5-MTHF). Folinic acid is used for nucleotide synthesis, whereas 5-MTHF recycles homocysteine into methionine. Methionine becomes S-adenyl methionine (SAMe), which is a methyl donor and is involved in many physiological functions  

Methylenetetrahydrofolate reductase (MTHFR) converts 5-10-methylene THF into 5-MTHF. This reaction is controlled by the level of SAMe, not by the level of homocysteine. It also requires zinc, B12, and, indirectly, riboflavin.

Folate deficiency is definitely problematic and supplementation does make sense. But at the same time, we need to keep in mind that overdoing it can sometimes be equally problematic.

Ironically, if homocysteine or S-adenoylhomocysteine are high, then SAM-e stops reacting and giving its methyl group. The SAMe level rises, which ends up shutting down methylfolate production. This may be why some people improve following methylfolate supplementation, which quickly unblocks the methylation cycle. However, this effect is temporary. I find that many of my patients feel better for a short time while taking methylfolate, but then they get worse.

Dangers of Unmetabolized Folate.

Excessive folate supplementation can lead to an accumulation of unmetabolized folate acid (UMFA), which can stop the methylation cycle. This is the exact opposite of what we want to see when we recommend folate supplementation. Several studies have reported detrimental changes in methylation because of too much UMFA (Alnabbat KI, et al. Nutrients. 2022). UMFA may also bind to folate receptors, thus blocking the normal transport of folate to places where it is needed.

While folate is generally considered safe and beneficial when taken in recommended amounts—the current RDA for adults is 400 μg–excessive intake beyond 1000 μg per day raises several concerns:

• Masking Vitamin B12 Deficiency: One of the most significant risks of excessive folate intake is its potential to mask vitamin B12 deficiency. Folate and Vitamin B12 work together for many functions including the production of red blood cells. B12 is also required for optimal cognitive function. B12 deficiency can cause macrocytic anemia and neurological damage. High levels of folate can correct the hematological effects of B12 deficiency, but it does so without correcting the neurological damage. Thus elevated folate levels can mask lab results that might otherwise be seen in regular bloodwork (Bonetti F, et al. J Am Geriatr Soc. 2015. An Y, et al. Clin Epigenetics. 2019).

• Masking Anemia of Other Causes: Similar to masking of vitamin B12 deficiency, excessive folate intake can also mask anemia caused by other factors, such as iron deficiency. Iron-deficiency anemia is prevalent worldwide and requires specific treatment, which might be delayed if folate levels are artificially elevated.

• Increased Cancer Risk: There is some evidence suggesting that very high intake of folate, particularly from supplements, may increase the risk of certain cancers. Two studies have pointed to a potential link between excessive folate intake and increased risk of colorectal cancer. Although the mechanisms are not fully understood, the association is noteworthy (Kim YI. Gut. 2006. Kherbek H, et al. Ann Med Surg (Lond). 2022). Excess folate has been linked with increased risk of several other types of cancer including breast cancer, prostate cancer, and hepatocarcinoma (Fardous AM, et al. Nutrients. 2023). Folate itself is probably not directly carcinogenic, and it is clear from the research that some folate is protective against some types of cancer. But some researchers are concerned that excess folate can interact with other nutrients and genetic factors in ways that raise risk.

• Potential for Cognitive Impairment: Some studies have raised concerns that excessive folate can lead to cognitive impairment and decline, particularly in older adults and in those with low B12 but high folate levels (Molloy AM. Am J Clin Nutr. 2020). High levels of folate have been associated with cognitive decline and may exacerbate existing neurological conditions, although more research is needed to establish a definitive link (Fardous AM, et al. Nutrients. 2023).

• Interaction with Pharmaceuticals: Folate supplements can interact with certain drugs, including anti-epileptic drugs and methotrexate. These interactions can reduce the efficacy of the drugs, and may trigger adverse effects. This underscores the importance of medical supervision when taking supplements

• Gestational Problems: While folate supplementation prevents NTDs, it may lead to other problems if continued at high doses past the first trimester. Some researchers have suggested that excess unmetabolized synthetic folic acid can raise the risk of autism spectrum disorders (ASD) and other neurocognitive problems in exposed children (Wiens D, DeSoto CM. Brain Sciences. 2017). But the jury’s still out on that, and according to the Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) trial, which involved 119 mother-child pairs, continued supplementation of 400 μg/d folic acid through to the end of pregnancy led to improved cognitive function in exposed children (Caffrey A, et al. BMC Medicine. 2021).

• Other Potential Problems: There are published studies linking excessive folic acid exposure to a host of different clinical conditions including dysregulation of the immune system in post-menopausal women (Troen AM, J Nutr. 2006), airway inflammation and atopic dermatitis in neonates (Kiefte-deJong JC, et al. J Nutr. 2012) and colitis (Kominsky DJ, et al. J Immunol. 2011).

Balancing Folate Intake

The point here is not to vilify folic acid supplementation. Folate deficiency is definitely problematic and supplementation does make sense. But at the same time, we need to keep in mind that overdoing it can sometimes be equally problematic. To mitigate the potential risks associated with excessive folate intake, we need to take a balanced and moderate approach. I suggest the following:

• Meet But Don’t Exceed RDA: The current RDA for folate is 400 μg per day. That’s a good target level, and in most cases it is best not to go above it. Aim to meet your patients’ folate needs through a varied diet that includes folate-rich foods such as leafy greens, beans, and if needed supplementation. Avoid synthetic folates, if possible, to prevent the buildup of UMFA.
• Consider Individual Needs: Certain populations, such as pregnant women and those with specific medical conditions, may require higher folate intake. But not beyond the first trimester. If a patient knows she is trying to get pregnant you could supplement with folate until conception. Testing for the C677T variant of the MTHFR gene could be helpful, since it is associated NTDs and other negative outcomes.
• Monitor Vitamin Levels: Regular health check-ups that include monitoring of vitamin levels, especially vitamin B12, are crucial for identifying any deficiencies or imbalances early on. But be clear about the proper tests to run with each patient and make sure you’re measuring fasting levels. A big meal containing a lot of folate or B12 prior to a test will give misleading results. For some patients, it makes sense to consider RBC folate testing.
• Avoid Excessive Supplementation: I have worked with many patients who were previously advised to take as much as 5 mg of methylfolate (without any B12, I might add). This is generally not safe for most people. Most studies show that NTDs can be prevented with dosages much lower than that.

Folate remains a vital nutrient with significant health benefits at appropriate physiological levels. Excessive folate intake can lead to unintended consequences, from masking underlying health problems to potentially increasing risks for serious disorders.

By understanding the risks associated with excessive folate intake and adopting a balanced approach to nutrition, we can help our patients optimize health while minimizing potential harm. While working with patients to improve their folate status, it’s vital that we also check other factors like B12, zinc, and riboflavin.

Keep in mind that the “more is better” mindset is widely prevalent in our culture. Patients may think they’re doing themselves a favor by taking high levels of folic acid. It is important that we educate them about potential problems associated with over-fortification and supplementation. As with many nutrients, moderation is key.

END

Gil Winkelman, ND, MA is a Naturopathic Physician with over 25 years of experience treating mental health and neurological issues. He is the creator of an online course Why Folates Make Anxiety Worse and the AskDrGil Podcast, where he speaks about various topics related to holistic health. He lives in Honolulu, Hawaii.