L-methylfolate is a form of folate, or vitamin B9, that can help regulate serotonin and dopamine levels. Because these chemicals affect mood, some people believe taking l-methylfolate may help with depression.

However, research on this so far has found mixed results. Low folate levels may contribute to depression and a poor response to antidepressant medication. However, not all studies on the subject have found that taking l-methylfolate causes a significant reduction in symptoms.

In some people, l-methylfolate can cause side effects, such as anxiety or digestive symptoms. It is also unsuitable for those who take certain medications or have some health conditions.

This article looks at the role of l-methylfolate in depression and how it may help.

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L-methylfolate is a form of folate, or vitamin B9. Unlike other forms of this vitamin, l-methylfolate is methylated. This means it has undergone a chemical reaction that makes it bioavailable. Bioavailability refers to how easy it is for the body to absorb and use a nutrient.

When a person gets folate from food, the body has to convert it into l-methylfolate to use it inside cells. However, when individuals take l-methylfolate in a supplement, this process is unnecessary. This makes l-methylfolate more bioavailable than other types of vitamin B9, such as folate or folic acid.

L-methylfolate is essential for:

  • cellular function
  • DNA synthesis
  • methylation, a process where a methyl group adds to DNA, proteins, or other molecules
  • producing neurotransmitters such as serotonin, dopamine, and norepinephrine

However, it is worth noting that most people can get enough of this nutrient from their diet. It occurs naturally in foods such as leafy greens and legumes. Folic acid also appears in some fortified foods, such as bread and cereals.

L-methylfolate may improve depression symptoms in some people, but the research on this is inconsistent.

Some evidence links low folate levels to depression and a poor response to antidepressant medication. This might suggest that addressing low folate levels could improve both.

However, an older study from 2012 of 148 adults with major depressive disorder looked at the effects of l-methylfolate alongside selective serotonin reuptake inhibitor (SSRI) treatment.

During the first trial, some participants took 7,500 micrograms (mcg) of l-methylfolate daily for 30 days, followed by 15,000 mcg daily for 30 days, alongside SSRI medication. Another group took SSRIs alone with a placebo.

The researchers found that the group taking l-methylfolate did not improve in comparison with SSRI treatment alone. But when they increased the dose to 15,000 mcg across the whole 60 days during a second trial, the results were different.

In the second trial, the researchers used the same study design with 75 adults who received 15,000 mcg of l-methylfolate daily plus SSRI medications for 60 days. This time, l-methylfolate significantly improved depressive measures compared with the SSRI plus placebo treatment.

More research is necessary to determine if l-methylfolate reliably helps with depression and, if so, what the most effective dose is.

It is unclear if taking l-methylfolate can benefit everyone with depression. As the research has had inconsistent results, it appears that some people benefit while others do not.

The effectiveness of l-methylfolate may depend on various factors, including whether or not someone has a folate deficiency. People with a deficiency may feel the biggest benefit.

Another factor is variations in the MTHFR gene. This gene influences how the body methylates nutrients, including folate. Some people have variants of the gene that make it more difficult for the body to convert folic acid into l-methylfolate, so if they have a deficiency, they may also feel a benefit in taking l-methylfolate supplements.

A 2019 study found that taking l-methylfolate resulted in a 25% reduction in self-reported depression symptoms among 182 people with certain MTHFR gene variants.

L-methylfolate is more bioavailable than folic acid. Folic acid is the synthetic form of folate that manufacturers add to fortified foods and supplements.

However, this does not necessarily make l-methylfolate better. Most people can convert folic acid into l-methylfolate without any problems.

People with variants in the MTHFR gene may not process folic acid as efficiently as others. However, they can still take folic acid. Even if an individual has the MTHFR variants, they can safely and effectively process all forms of vitamin B9.

Whether l-methylfolate supplements are more effective than folic acid for depression specifically is less clear. No studies have compared the two to see how they affect depression symptoms in people with or without MTHFR gene variants.

The recommended daily intake of folate for most adults is 400 mcg. During pregnancy, it is 600 mcg, and while lactating, it is 500 mcg.

However, in depression studies, researchers have used much higher dosages. These dosages vary widely, ranging from 5,000 mcg to 15,000 mcg.

In the 2012 trial, researchers noted that 15,000 mcg was more effective than 7,500 mcg. On the approval of a doctor, a person may wish to start at a low dose and work upward slowly, increasing the dose once per week until they notice a difference.

It may take several weeks for someone to notice any beneficial effects from l-methylfolate, if it works.

Some of the side effects people have reported when taking l-methylfolate include:

  • anxiety
  • agitation
  • digestive symptoms

This supplement may also interact with preexisting medical conditions. For example, if someone takes large amounts of folate, it can mask a vitamin B12 deficiency.

Folate does this by correcting anemia, relieving a person’s symptoms, but without addressing the underlying problem. This can be harmful, as vitamin B12 deficiency can lead to nerve damage over time.

Folate supplements also can interact with some medications, including:

Anyone taking these or other medications can speak with a doctor before taking l-methylfolate.

Anyone with depression or other mental health symptoms can consult a doctor for support. They may recommend safe, effective treatments that are proven to help.

If a person would like to try l-methylfolate alongside depression treatment, they should first discuss this with a doctor. It may help to get blood tests to determine if they have any nutritional deficiencies, such as folate or B12 deficiency.

A doctor can also confirm if it is safe for someone to take l-methylfolate and supervise them in case of any side effects or drug interactions.

Suicide prevention

If you know someone at immediate risk of self-harm, suicide, or hurting another person:

  • Ask the tough question: “Are you considering suicide?”
  • Listen to the person without judgment.
  • Call 911 or the local emergency number, or text TALK to 741741 to communicate with a trained crisis counselor.
  • Stay with the person until professional help arrives.
  • Try to remove any weapons, medications, or other potentially harmful objects if it’s safe to do so.

If you or someone you know is having thoughts of suicide, a prevention hotline can help. The 988 Suicide and Crisis Lifeline is available 24 hours a day at 988. During a crisis, people who are hard of hearing can use their preferred relay service or dial 711 then 988.

Find more links and local resources.

Was this helpful?

L-methylfolate is a bioavailable form of folate, or vitamin B9. It may help improve depression symptoms in some people. However, more research is necessary to confirm its effectiveness.

People taking l-methylfolate may experience side effects, such as digestive symptoms and anxiety. Therefore, anyone considering it needs to consult a doctor to discuss the potential risks and benefits.