“Folate” is a general term referring to various formations of vitamin B-9. B-9 is a water-soluble, essential nutrient which occurs naturally in some foods, but can also 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. efficient replication of DNA, making healthy red blood cells, and sufficient neurotransmitter production for balanced mood and mental health), low folate status is one of the most common nutritional deficiencies, and that statistic only increases as we age [1]. 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 folic acid properly. 

Many foods are marketed as being “fortified” or have had synthetic folic acid added to their formulas to supply consumers with more B-9. 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 [2]. 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.

What makes L-Methylfolate Different?

L-Methylfolate is the biologically active form of folate. Normally, when your body absorbs folate or synthetic folic acid it must undergo a conversion to L-methylfolate, through a process referred to as the folic acid cycle, before it can be used for its various purposes in the body. L-methylfolate completely bypasses the entire folic acid metabolism cycle and has been shown to be more effective than folic acid for increasing circulating active folate in the body [3].

How does L-methylfolate affect the brain?

In terms of your mental health, L-methylfolate is 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. Although L-methylfolate is a nutrient, not a medicine, it is the only active ingredient in the medical food Deplin, often recommended to those taking antidepressants [4]. While SSRI medicines work by blocking reabsorption of neurotransmitters, L-methylfolate can support your brain in producing sufficient levels of the needed neurotransmitters for balanced mood and energy [5]. Although medical foods, like Deplin, require a prescription, L-methylfolate can be purchased directly by consumers, no prescription necessary.

This same process (conversion of homocysteine to methionine) has been implicated in the development of dementia in the elderly [6]. Raised blood levels of homocysteine have been observed in elderly people with mild cognitive impairment, vascular dementia, and Alzheimer’s Disease, and has since been associated with an increased risk for both cognitive decline and dementia [5]. It is possible then, that supplementing L-methylfolate, to keep homocysteine levels from elevating, may support cognitive longevity and mental clarity in our later years.

Without sufficient L-methylfolate, homocysteine levels can build up, causing a potentially serious condition known as hyperhomocysteimia, a known, independent risk factor for heart disease, stroke, and other forms of cardiovascular disease [7]. 

If your nutritional supplement delivers folate in the form of L-methylfolate, your body can use the nutrient for its various purposes immediately upon absorption, rather than relying on the folic acid cycle and all of the other precursors to activate folic acid. L-Methylfolate is also highly effective at reducing homocysteine levels (with or without an MTHFR mutation) [7]. 

What can cause low folate?

It has been estimated that at least half of the human population carry an inherited mutation in the MTHFR gene [8]. MTHFR is a gene that provides instructions to make an enzyme called methylenetetrahydrofolate reductase, a key factor in the folic acid cycle. 

While some people with MTHFR mutations live a normal life without experiencing symptoms, others will experience a drop in enzyme efficiency by 30-70% [9], depending on the type of mutation they’ve inherited. In these cases, folic acid 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. 

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. 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 [10]. 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 [11].

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. It is safe to take, even if you have normal, functioning copies of the MTHFR gene, and is generally thought to be an all-around more efficient folate supplement than folic acid [6]. If you do have an MTHFR mutation and/or folate deficiency, L-methylfolate may literally be exactly what your brain has been missing for a lift in your mood and energy levels. 

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 an L-methylfolate supplement. L-Methylfolate supplements can be purchased in a range of doses, depending on your diet, current folate status, genetic predisposition, and doctor’s recommendations. Metabolic Maintenance also provides L-methylfolate as the folate source in many of its multivitamin/mineral formulas. The superior quality of L-methylfolate makes it a more expensive ingredient than synthetic folic acid, but the increase in bioavailability for all consumers, regardless of genetics, and the potential impacts on your health make this ingredient worth investing it.


  1. Clarke, Robert, et al. “Vitamin B12 and folate deficiency in later life.” Age and ageing 33.1 (2004): 34-41.
  2. Hauser, W. Allen. “Folic acid supplementation: too much of a good thing?.” Journal of Neurology, Neurosurgery & Psychiatry 80.5 (2009): 468-468.
  3. Greenberg, James A., et al. “Folic acid supplementation and pregnancy: more than just neural tube defect prevention.” Reviews in Obstetrics and Gynecology 4.2 (2011): 52.
  4. DEPLIN Website. Covington, LA: Alfasigma USA, Inc.; 2017. www.deplin.com
  5. 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.
  6. McCaddon, Andrew, and Peter R. Hudson. “L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer’s disease-related cognitive decline.” CNS spectrums 15.S1 (2010): 2-5.
  7. 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.
  8. Kaiser Permanente. “Basic Information About the MTHFR Gene.” The Permanente Medical Group, Inc. Copyright 2015, last reviewed 2018. https://mydoctor.kaiserpermanente.org/ncal/Images/GEN_MTHFR_tcm63-938252.pdf
  9. Rao, Dowlathabad Muralidhara, et al. “Comparative modeling of methylentetrahydrofolate reductase (MTHFR) enzyme and its mutational assessment: in silico approach.” International Journal of Bioinformatics Research 2.1 (2010): 5-9.
  10. Said, Hamid M. “Intestinal absorption of water-soluble vitamins in health and disease.” Biochemical Journal 437.3 (2011): 357-372.
  11. Penn State Hershey. “Possible Interactions with: Vitamin B9 (Folic Acid)” Milton S Hershey Medical Center. Copyright 2011. http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000993