Vitamin B-9 is a water-soluble, essential nutrient which occurs naturally as “folate”, but can be synthesized and is often added to food and nutritional supplements as “folic acid”. Although vitamin B-9 is necessary for a number of crucial actions in the body (i.e. replication of DNA, making healthy red blood cells/protection from some types of anemia, and sufficient neurotransmitter production for mental health), low folate status is one of the most common nutritional deficiencies. Not consuming enough folate-rich foods is the primary reason for this deficiency, but many people have interfering health issues that prevent natural folate absorption, and others still are born without the ability to metabolize this vitamin properly. 

What affects my folate levels?

It has been estimated that more than half of the human population carry an inherited mutation in the MTHFR gene. MTHFR is a gene that provides instructions to make an enzyme called methylenetetrahydrofolate reductase, a key factor in a chemical reaction that breaks down folate (or folic acid) to its active form, L-methylfolate (5-MTHF). This reaction is also required to convert the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins such as the neurotransmitters; dopamine, serotonin, melatonin, and epinephrine. Shortages in these neurotransmitters are often related to major depression and other psychiatric disorders.

While some people with MTHFR mutations live a normal life without experiencing symptoms, others will experience a drop in enzyme efficiency by 30-70%, depending on the type of mutation they’ve inherited. In these cases, folate doesn’t get converted to L-methylfolate, homocysteine is not efficiently broken down into methionine, and the production of our most important brain chemicals slows way down, dramatically affecting mood and energy levels. But a low mood is not the only risk of an L-methylfolate deficiency. Unconverted folate and homocysteine levels build up in the blood without consistent conversion, and elevated homocysteine in the blood is a known, independent risk factor for heart disease, stroke, and other forms of cardiovascular disease. 

Only a genetic test by your doctor can confirm whether or not you have an MTHFR mutation, but if you do, L-methylfolate supplementation could circumvent many of these metabolic complications. 

What does it mean to be “Fortified” in your diet?

Since research has shown that folate deficiency is such a common nutritional problem, and the risks are high, many foods have been “fortified” or have had synthetic folic acid added to their formulas. However, several studies have suggested that too much folic acid may have adverse effects if it builds up, unmetabolized in the bloodstream, especially in the elderly. Folic acid is much slower to break down than natural folate, even in individuals with healthy folate metabolism, and requires the help of the liver and other tissues for activation. This is a slightly different mechanism of action than that of folate, which is mostly biotransformed directly after absorption by the gut. On the other hand, L-methylfolate bypasses the entire folic acid metabolism cycle completely and has been shown to be more effective than folic acid for increasing circulating active folate. L-Methylfolate is also highly effective at reducing homocysteine levels (with or without an MTHFR mutation). It is better absorbed and interacts with fewer medications than folic acid. Several studies have suggested that fortified food would provide greater benefits to a wider range of individuals if folic acid were replaced with L-methylfolate in the future.

What other health conditions?

There are a handful of diseases, unrelated to the MTHFR mutation, that can affect the absorption of folate by the gastrointestinal system. Crohn’s disease, celiac disease, alcoholism, severe kidney diseases, and certain cancers can all interfere with getting enough folate from food or supplements. There are also a whole host of medications that can interfere as well, causing folate deficiency. Some of these medications include phenytoin (Dilantin), trimethoprim-sulfamethoxazole, methotrexate, and sulfasalazine. 

How Can L-Methylfolate Help?

L-methylfolate can be taken as a dietary supplement to bring your circulating levels of active folate up to a level that can help properly clear homocysteine, supply the brain with precursors for neurotransmitters, and allow for healthy red blood cell production. Dietary or nutritional supplements cannot make claims that they can be used to treat conditions or diseases, and so L-methylfolate is not considered to be a treatment. It is, however, the only active ingredient in the medical food, Deplin®, which boasts a nutritional formula directly suited to those suffering from depression. 

Of course, you should always consult your physician before making a change to your health regimen, but your body can skip the folic acid cycle while getting all the benefits of vitamin B-9 with L-methylfolate. If you do have an MTHFR mutation, L-methylfolate may be what your body has literally been missing for a lift in your mood and energy levels. 

References:

DEPLIN Website. Covington, LA: Alfasigma USA, Inc.; 2017. www.deplin.com

Lamers, Yvonne, et al. “Supplementation with [6 S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women.” The American journal of clinical nutrition 79.3 (2004): 473-478.

LeBano, Lauren. “L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?” Psyche Congress Network. May 8, 2013. www.psychcongress.com/article/l-methylfolate-promising-therapy-treatment-resistant-depression

Leech, Joe. “L-Methylfolate (5-MTHF): Your Must-Read Beginner’s Guide.” Diet vs. Disease. May 13, 2018. https://www.dietvsdisease.org/l-methylfolate-5-mthf/

Miraglia, Niccolo, et al. “Enhanced oral bioavailability of a novel folate salt: comparison with folic acid and a calcium folate salt in a pharmacokinetic study in rats.” Minerva ginecologica 68.2 (2016): 99-105.

Papakostas, George I., et al. “L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.” American Journal of Psychiatry 169.12 (2012): 1267-1274.

Patanwala, Imran, et al. “Folic acid handling by the human gut: implications for food fortification and supplementation–.”The American journal of clinical nutrition 100.2 (2014): 593-599.

Scaglione, Francesco, and Giscardo Panzavolta. “Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.” Xenobiotica 44.5 (2014): 480-488.

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Venn, Bernard J., et al. “Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study.” The American journal of clinical nutrition 77.3 (2003): 658-662.