Methylfolate is crucial to DNA synthesis and detoxifying homocysteine. What role does it play in pregnancy, development, and mental health? Find out here.
What is L-Methylfolate?
Folate, otherwise known as vitamin B9, is one of the 13 essential vitamins. Vitamins come in different forms called vitamers that often need to be converted in the body to active forms of the vitamin. The active form of folate in the body is L-methylfolate, also known as levomefolic acid, which can cross both cell membranes and the blood-brain barrier [1].
A critical role of L-methylfolate is to act as a regulator of a class of neurotransmitters called monoamines. The three different neurotransmitters it helps make are [2]:
Folate can’t be synthesized by the body, so it must be ingested either through food or supplements [3].
Folate vs. Folic Acid
The synthetic form of folate is folic acid, which can be found in fortified foods such as bread and cereals, and multivitamins [2, 4].
Dihydrofolate is the dietary form of folate and can be found in green vegetables, egg yolk, legumes, grains, nuts, some fruits, yeast, and organ meats like liver and kidneys [2, 4].
Both folic acid and dihydrofolate are converted into L-methylfolate in the body by a specific enzyme. It is then transported into the brain where it increases the production of the three neurotransmitters mentioned above [2].
Unmetabolized folic acid has been associated with an increased incidence of prostate cancer, lower cognitive test scores, and smaller red blood cells. Some researchers and health professionals have therefore started recommending L-methylfolate supplements rather than folic acid [5, 6].
MTHFR & Folate Conversion
Although many people take L-methylfolate supplements, much of the naturally ingested L-methylfolate actually comes in the form of different folates such as folic acid and dihydrofolate [2, 4].
The conversion of these folates to L-methylfolate is crucial because L-methylfolate can cross the blood-brain barrier, while the other forms of folate can’t [4].
L-methylfolate is typically regulated as a medical food. Some doctors may prescribe it for the purpose of slowing the cognitive decline that is seen in many mental disorders, including Alzheimer’s, mania, and depression.
Many of these disorders are linked to mutations in the gene that produce the enzyme that converts folate into L-methylfolate, 5, 10-methylenetetrahydrofolate (MTHFR) [7, 8, 9, 4].
Mutations in MTHFR can lead to decreased methylfolate production. Mutations in MTHFR are relatively common, and there are up to 30 different kinds of MTHFR mutation variations [4].
What is Methylation?
Methylfolate is responsible for many methylation reactions all throughout the body. Methylation reactions occur when methylfolate donates a methyl group (three hydrogens bonded to one carbon atom) to another molecule [4].
Methylation reactions are crucial for processes such as cell division and DNA and RNA synthesis. Methylation of DNA and RNA plays a crucial role in epigenetics, the mechanism by which gene activity changes without modifying the DNA sequence [10].
Summary of Mechanisms
L-Methylfolate is involved in:
- Methylation [4]
- DNA/RNA synthesis [10]
- Conversion of homocysteine to methionine [4]
Homocysteine is a toxic amino acid that is particularly damaging to blood vessels (endothelial cells). High levels of homocysteine lead to increased inflammation and risk of coronary heart disease [4].
L-methylfolate methylates homocysteine into the less-toxic methionine, an essential amino acid [4].
Health Benefits (Likely Effective)
According to the FDA, L-methylfolate is a naturally occurring folate found in foods and is generally recognized as safe. It has been approved as a food additive, but not as a treatment for any medical purpose or health claim. Talk to your doctor before supplementing.
1) Pregnancy Outcomes
Folate deficiency during pregnancy is dangerous and can lead to disorders in both the fetus and the mother. Because of the importance of supplementation, the U.S. government began mandating the addition of more folic acid into grain products (140µg/100g) in January 1998 [3, 11].
Folic acid is a more common supplement than L-methylfolate. However, new research in women both with and without MTHFR variants suggests that L-methylfolate could be more effective. In a study of 144 women of childbearing age, those who took L-methylfolate experienced a greater increase of folate levels in their red blood cells than those who took folic acid [12].
Neural Tube Defects (NTD)
Supplementation with folic acid or L-methylfolate helps prevent neural tube defects, which are defects of the brain, spine, and spinal cord [12].
Pregnant women with a family history of NTD are recommended to take 5mg of folate (usually as folic acid) daily, while all other pregnant women are typically advised to take 0.4-1mg daily [12].
Anemia
Pregnant women usually have reduced hemoglobin (protein that carries oxygen in the blood) levels, which leads to anemia in 5% of pregnancies [3].
In one retrospective study, 58 pregnant women taking prenatal supplements along with L-methylfolate had significantly higher hemoglobin levels at the time of delivery than 54 women taking prenatal supplements with folic acid [13].
Preterm Birth
Low blood folate levels have been linked to shorter pregnancy times [3].
A study of 34,480 women found that supplementing with folate for longer than one year significantly decreased the chances of preterm birth. The length of folate supplementation (> 1 year) was equally as important as supplementing itself [3].
Other
Supplementing with folate has also been shown to reduce risks of other pregnancy problems such as heart defects and orofacial clefts, which are openings that may form in the mouth and lip [14, 15].
2) Depression
One study of 123 patients with either depression or schizophrenia found that a third of them had folate deficiencies. Patients with folate deficiencies were given either methylfolate or placebo. The patients given methylfolate improved significantly compared to placebo both clinically and socially, especially in mood, and the difference in improvements increased with time [9].
In another study of 68 depression patients who did not respond to conventional antidepressants (selective serotonin reuptake inhibitors, or SSRIs), 15 mg/day of L-methylfolate was given for 12 months. Of the 68 patients, 26 recovered completely from their depression and 35 experienced a reduction in the severity of their depression (remission), leaving only 7 who did not improve [16].
None of the patients who had a full recovery experienced a relapse or recurrence of their symptoms during the trial [16].
In another study, 147 patients given only SSRIs were three times more likely to become hospitalized than patients given SSRIs plus L-methylfolate supplements [17].
Depression is a complex condition, and many drugs and supplements might work for some people but not others. Some researchers believe that L-methylfolate supplementation could be more effective in depression patients with these traits [2]:
- Decreased levels of folate or any other folate by-products in the blood
- Unresponsive to common antidepressants
- Low folate levels as a result of:
- Alcohol addiction
- Eating disorders
- Pregnancy
- Gut disorders
- High homocysteine levels
- Drugs that interfere with folate metabolism
When homocysteine is converted to methionine by L-methylfolate, S-adenosylmethionine (SAM-e) concentrations rise. SAM-e is responsible for donating methyl groups to fat molecules that line our cell membranes and in the formation of the neurotransmitter serotonin [4].
Potential Benefits (Possibly Effective)
These potential benefits have been studied in humans and produced promising results. However, some of these studies used folic acid supplements rather than L-methylfolate, leading to a lack of specificity and a source of doubt. Further trials of L-methylfolate, specifically, will be required to confirm any benefit.
As always, talk to your doctor before supplementing, and never use L-methylfolate in place of something your doctor prescribes.
3) Schizophrenia
In a study of 91 schizophrenic patients, low blood folate was associated with the severity of negative symptoms of schizophrenia. The authors suggested that poor diet and cigarette smoking could be responsible for the low folate [18].
In a study (DB-RCT) of 140 schizophrenic patients, only those given folic acid with vitamin B12 supplementation improved negative symptoms considerably. Treatment response was further associated with a mutation in the FOLH1 gene, which is one of the genes responsible for metabolizing methylfolate [19].
All the patients in the previously mentioned study had been on antischizophrenic drugs for six months prior or longer, but had shown no improvements in symptoms [19].
In another study of 35 schizophrenic patients, L-methylfolate not only improved symptoms but also produced beneficial physiological changes in the brain [20].
The patients given L-methylfolate supplements showed increased cortical thickness in the medial prefrontal cortex (mPFC), which was correlated to a partial restoration of structure and function of the mPFC [20].
The medial orbitofrontal cortex (mOFC), which normally deactivates during tasks requiring working memory, is dysfunctional in schizophrenic patients. The patients receiving L-methylfolate supplementation showed increased deactivation [20].
Schizophrenia is a highly complex and poorly understood disorder. Further studies will be required to determine the role of folate supplementation and FOLH1 gene mutations in people with schizophrenia [19].
4) Alzheimer’s Disease
People with Alzheimer’s disease are more likely to have reduced folate levels compared to healthy people. Researchers are therefore investigating whether L-methylfolate supplements can improve symptoms in those patients [21].
Alzheimer’s disease is an inflammatory condition which is linked to higher levels of tumor necrosis factor (TNF)-α, an inflammatory molecule, and amyloid beta plaques in the brain. In one study of 121 patients newly diagnosed with Alzheimer’s, folic acid significantly reduced levels of TNF-α and amyloid beta [21].
In a recent clinical trial of 30 Alzheimer’s and dementia patients with high homocysteine, a supplement including L-methylfolate (alongside methylcobalamin and NAC) reduced brain deterioration in the hippocampus and cortex of the brain [7].
The authors suggested that the conversion of homocysteine may have slowed brain deterioration and improved cognitive function [7].
Additional trials are required to determine whether L-methylfolate (or other forms of folate) might be helpful to Alzheimer’s patients with or without high homocysteine.
Other Potential Benefits with Insufficient Evidence
These potential benefits have been studied in humans, but either the evidence comes from extremely small studies, or available results are contradictory. Talk to your doctor before using L-methylfolate in these conditions.
5) Bipolar Disorder
Bipolar disorder is characterized by periods of depression and mania.
The Montgomery Asberg Depression Rating Scale (MADRS) is used to measure the degree of depression in patients with a higher score number being worse [8].
Mania is a state of heightened arousal, elevated mood, and increased energy. The Young Mania Rating Scale (YMRS) is used to score mania with higher numbers signifying worse mania [8].
In a study of 10 patients with bipolar depression, L-methylfolate in combination with conventional treatment reduced the average MADRS score from 23.4 to 13.9 and the average YMRS from 3.2 to 2.7 [8].
Six out of the 10 patients showed at least a 50% improvement in MADRS score and the other four experienced a reduction in the severity of their depression (remission) [8].
Larger and more robust human trials will be required to determine whether L-methylfolate is helpful to people with bipolar disorder.
6) Autism
In a study of 29 autistic children, folic acid supplementation improved sociability and cognitive and verbal symptoms. However, excess folic acid supplementation during pregnancy has been associated with increased rates of autism in offspring, leading some researchers to suggest that unmetabolized folic acid could be a risk factor for autism [22, 23].
Mutations in the gene encoding the enzyme 5,10-methylenetetrahydrofolate (MTHFR) disrupt the enzyme’s ability to convert folic acid into L-methylfolate. L-methylfolate decreased symptoms of aggressive and disruptive behavior in an autistic child with an MTHFR C667T mutation [24].
Further studies are required to determine whether any form of folate is helpful or harmful in people (especially children) with autism.
Areas for Future Research
Researchers are currently investigating L-methylfolate in other contexts, but no clinical evidence supports the use of L-methylfolate for any of the conditions listed in this section. Below is a summary of the existing cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
7) Immune System
T cells are the part of the immune system that provides short-term defense against pathogens. A cell study showed that folate deficiency led to decreased production of T-cells [25].
Increasing folate levels increased the T-cell levels to normal levels [25].
Other studies have shown that deficiencies in folate also lead to decreased responses of T-cells and antibodies to certain pathogens. This ultimately leads to decreased resistance to infections [26].
Requirements & Dietary Sources
Folate, or vitamin B9, is considered an essential nutrient. As with most nutrients, the best and most available sources of folate is from food. The NIH recommends that adults get 400 mcg of folate per day, increasing to 600 mcg for pregnant and lactating mothers [27].
Liver is by far the best dietary source of folate. Other good sources include green vegetables like spinach, asparagus, and brussels sprouts [27].
Safety & Side Effects
Folate is a required nutrient, and L-methylfolate is generally recognized as safe. Some reported side effects of L-methylfolate supplementation include [8]:
- dry mouth
- fatigue
- headaches
Overconsumption of L-methylfolate may also mask vitamin B12 deficiencies. It’s important to talk to your doctor about supplementation to make sure your lab markers are normal [3].
Dosage
Many of the commercial L-methylfolate supplements contain between 5,000 mcg (5 mg) and 1,000 mcg (1 mg). However, many studies have used doses of up to 15 mg to see intended effects [9].
Consult your physician to determine the appropriate supplement dose for you.
Drug Interactions
1) Drugs that May Reduce Folate Absorption
Certain drugs can decrease folate levels leading to decreased L-methylfolate concentrations in the brain due to interfering with absorption. Some examples are listed below [4]:
- Antacids
- Alcohol
- Oral contraceptives
- Metformin
- Some statin drugs
- Anticonvulsants
- Valproate
- Carbamazepine
- Phenytoin
- Lamotrigine
A study done on 36 children taking Carbamazepine and 30 children taking Valproate showed that these medications reduced folic acid levels in the blood significantly [28].
The loss of folic acid led to significantly higher levels of homocysteine in the children taking Valproate and Carbamazepine [28].
2) Methotrexate
Methotrexate has been used to treat psoriasis, which is a disease that causes the formation of red patches on the skin with silver plaques and scales, for over 40 years [29].
However, methotrexate works by inhibiting dihydrofolate reductase (DHFR), an enzyme that metabolizes folic acid. Therefore, L-methylfolate supplementation can work to counteract the mechanisms by which methotrexate heals [29].
A case study on one patient taking both methotrexate for his psoriasis and L-methylfolate for his depression showed the patient developed psoriatic lesions after taking L-methylfolate. Only when the patient stopped taking methotrexate did the lesions disappear [29].
L-Methylfolate in Combination With Other Drugs and Supplements
1) Antidepressants
A study comparing L-methylfolate plus selective serotonin reuptake inhibitors (SSRI, a common antidepressant) therapy (95 patients) with just SSRI therapy (147 patients) showed that adding L-methylfolate greatly enhanced results [17].
For instance, discontinuation rates for L-methylfolate plus SSRI were 17.9% compared to 34% for only SSRI therapy [17].
By 60 days, a major improvement was seen in up to 18.5% of patients on L-methylfolate plus SSRI patients while only 7% of patients on just SSRI showed improvements [17].
The time it took until major improvements showed was 177 days for the patients on L-methylfolate plus SSRI compared to 231 days for patients solely on SSRI [17].
The combined therapy also showed that patients were more likely to adhere to the therapy, and fewer people refused treatment due to lower rates of adverse events [17].
2) Vitamin B12 and N-acetylcysteine
In a study of 67 patients with Alzheimer’s disease, L-methylfolate supplementation with vitamin B12 and N-acetylcysteine significantly slowed deterioration in the brain. The degree to which these compounds interact (and potentially synergize) with each other is not yet clear [7].
3) Cholinesterase Inhibitors (ChI)
Cholinesterase inhibitors prevent the enzyme cholinesterase from breaking down the neurotransmitter acetylcholine.
In a study (DB-RCT) of 57 Alzheimer’s patients, folic acid supplementation appeared to improve the effects of ChI therapy. The patients given both folic acid and ChI therapy significantly improved in performing daily living activities and in social behavior compared to patients only given ChI therapy [30].
This effect has not been investigated with L-methylfolate specifically.
4) Donepezil
Folic acid supplementation along with Donepezil (used to treat Alzheimer’s disease) and natrium diethyldithiocarbamate trihydrate (NDDCT) greatly improved symptoms in those with vascular dementia [31].
The increased effects were seen in the areas of learning, memory, and endothelial dysfunction [31].
L-Methylfolate Genetics (MTHFR)
The enzyme 5,10-methylenetetrahydrofolate (MTHFR) is responsible for the conversion of folate or folic acid into L-methylfolate. Mutations in the gene responsible for MTHFR creation lead to decreased L-methylfolate production from its precursors [4].
Humans have two copies of each gene and different forms of the same gene are called alleles.
There are up to 30 different kinds of mutations in the MTHFR gene. Up to 60% of Americans carry at least one allele with a mutation in the MTHFR gene (heterozygous).
One common mutation is called C677T and it is prevalent in up to 10% of the white people and up to 22% of the Hispanics and Mediterranean populations. Having one allele with this mutation decreases MTHFR activity by up to 35%, while having two alleles with this mutation (homozygous) decreases activity by 70% [32, 19].
One male patient suffering from depression, mania, and obsessive-compulsive disorder (OCD) was screened and found with an MTHFR C677T mutation. Common medications were tried and failed to produce results. Only after L-methylfolate supplementation did the male patient showcase improvements [33].
Another common mutation called A1298C also reduces MTHFR activity [34]. Individuals with two alleles with this mutation show a 68% reduced activity in the MTHFR enzyme [12].
Patients suffering from schizophrenia and bipolar disorder are even more likely than depressed patients to have MTHFR mutations [35].
Researchers are studying L-methylfolate as an alternative to folic acid because it has the potential to bypass these relatively common MTHFR mutations and increase methylation reactions throughout the body [4].
Mutations in the FOLH1 gene can also result in reduced folate levels due to impaired absorption of folate in the gut [36].
