The Depression and Anxiety Experts

Methylfolate: The Vitamin That Helps Depression

The COVID-19 era is extremely stressful – as many as 30-50% of people who survive the infection experience depression and anxiety. One vitamin that might help is the folic acid metabolite, methylfolate.

You may be familiar with folic acid (folate, vitamin B9) as a prenatal vitamin. It’s used to prevent neural tube defects such as spina bifida in babies due to its essential role in development of the nervous system.

You may not be aware of folic acid’s role in treating depression.

Folic acid is an important building-block for the essential neurotransmitters serotonin, norepinephrine and dopamine that are thought to be low in depression. Folic acid is actually not the active ingredient. It is metabolized by an enzyme called MTHFR into methylfolate, the only form of folic acid that crosses the blood brain barrier.

“The kicker is that all people can actually take methylfolate
because it’s the active molecule that works in the the brain.” 

One potential problem with folic acid is that not everyone converts it into methylfolate efficiently due to genetic variants of the MTHFR enzyme.  About 46% of patients have normal MTHFR enzyme activity. Approximately 43% have moderately reduced MTHFR activity and about 1 in 10 have 70% reduced MTHFR enzyme activity, which is considered severe. In practice, this means that about half of patients can take regular folic acid but the other half are better off taking methylfolate. The kicker is that all people can actually take methylfolate because it’s the active molecule that works in the the brain.

Why is this important? Because methylfolate has been shown to be helpful for depression that does not respond to regular medications, i.e. it is added to regular antidepressant treatment. Research shows that you need to treat six people to get one positive response, which is actually pretty good for a nutritional supplement in a person with severe depression. Here is a review article if you want to read more about the data.

It can also be used as a stand-alone medication for depressive symptoms but who responds is more controversial. The people most likely to benefit are those who don’t metabolize folic acid efficiently because of the previously mentioned variants in the MTHFR gene.

Of course, people with low folic acid levels (folate deficiency) are likely to especially benefit from treatment. Folate deficiency can lead to depression, apathy and a picture of dementia. I don’t see too many cases of folate (or B12 deficiency) in my clinical practice because they are picked up by primary care doctors who often test for it when they diagnose anemia.

In my professional practice, I use methylfolate in addition to prescribed antidepressants. I find that some patients feel a dramatic benefit within days of starting methylfolate. Others don’t feel much but I see a reduction in their depression and anxiety scores in my monthly measurements. Some people don’t find any benefit at all.

Most readers who are not in psychiatric care will be interested in trying methylfolate as a mono-therapy.

My advice would be to try taking 15mg for 1-4 weeks on a trial basis to see if you feel any different. If it does not help, you can stop taking it. If it helps, continue taking it for 6-12 months.

There are side-effects from methylfolate, but they are mild and infrequent. These include a sense of discomfort, nausea, rash and allergy. Reducing the dose might lessen side-effects. There are also concerns that long-term use might increase certain cancers and cardiovascular disease, but the data are not robust. Nevertheless, as a prudent measure, I recommend that you consider stopping methylfolate after about one year.

In my recent newsletter, Should Psychiatrists Do Genetic Testing Before Prescribing? I discussed the MTHFR gene variants that determine how people metabolize folic acid. I find it helpful to know if a person has one of the genetic variants where folic acid is processed slowly – it makes a stronger case for methylfolate supplementation.

Given the high rates of anxiety, depression and stress associated with the COVID-19 pandemic (and the associated isolation, political and economic upheaval), many people ask what supplement might help? Methylfolate is a vitamin that you could consider trying.

However, it’s also important to remember that methylfolate is not a miracle cure. If you have severe symptoms or thoughts that life is not worth living, or are using drugs and alcohol excessively, consult a health care provider immediately. We have many effective medications and psychotherapies for depression and anxiety. If you think that I might help with depression or anxiety, or if you have questions about the use of methylfolate, please call me to set up a virtual appointment. I am happy to assist.

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