Folate Deficiency and Mental Health: A Brief Overview

Folate Deficiency and Mental Health: A Brief Overview 

With more people facing mental health challenges these days, folate is finally getting the attention it deserves. 

Folate plays a crucial role in mental wellness. Folate deficiency is now known to be a key factor in developing a mental disorder. Research has suggested that low folate or low folic acid levels may be linked to major depressive disorder [1] and bipolar affective disorder [2]. Low folate is less likely to be a major risk factor for postpartum depression, but may increase the risk for depression outside of pregnancy in women who have a MTHFR genotype. [3]

These findings have led to increasing interest in the potential benefits of L-Methylfolate, the active form of folate. Evidence suggests that methylfolate may aid in supporting not only mental health but behavioral disorders such as autism. [4]

This article will cover the relationship between folate, its active form methylfolate, and current insights into how methylfolate benefits mental well-being.

What is folate?

Folate (vitamin B9) is a nutrient essential for optimal human health and development. Folate is involved in numerous reactions within the body that are crucial to normal function, including the processing and synthesis of important lipids, amino acids, and DNA. Deficiency in folate can lead to serious health outcomes including anemia and impairments in reproductive health and fetal development.

Sources of folate

Folate is found naturally in a wide variety of foods. Some good sources include:

• Leafy green vegetables: Spinach, kale, turnip greens.

• Liver and organ meats.

• Legumes: Lentils, beans (pinto, garbanzo, black beans), peas.

• Fruits: Citrus fruits (oranges and grapefruit), bananas, papayas, avocados.

• Whole grains: Quinoa, whole wheat, barley, oats, brown rice, buckwheat, millet

• Fortified foods: Many countries add folic acid (the synthetic form of folate) to foods such as cereals, bread, pasta, and rice.

• Eggs

• Seafood: Crab, salmon

• Nuts and seeds: Sunflower seeds, pumpkin seeds

• Dairy products: Milk, yogurt, cheese

Other vegetables: Beets, Brussels sprouts, broccoli

It's important to note that folate is water-soluble and can be lost during cooking. Steaming is the best way to preserve the folate content of vegetables.

Folate's role in the brain

Folate has been linked to brain function and mood in several ways. 

To begin with, folate is involved in regulating a chemical called tetrahydrobiopterin (BH4). BH4 is an enzymatic cofactor required for the synthesis of serotonin and dopamine, two chemicals in our brain that play an important role in mood. [5] Dopamine provides a sense of temporary pleasure, while serotonin contributes to long-lasting feelings of happiness or well-being.

Less folate typically means less dopamine and serotonin, which can lead to depression.

Folate works alongside vitamins B12 and B6 in converting the amino acid homocysteine to methionine, another amino acid. Methionine is a precursor for S-adenosylmethionine (SAMe), a compound also involved in producing and regulating chemicals in the brain that affect our mood. Research has shown that low levels of methionine are prevalent in depression, likely due to low neurotransmitter production. [6] This has been noted as one of the symptoms of low folic acid (or low folate).  

In addition, elevated levels of homocysteine have been linked to both depression and cardiovascular disease. [7] Depression and anxiety are also associated with higher homocysteine levels. [8] Other folic acid deficiency symptoms in adults include sleeplessness, irritability, poor cognitive function, and fatigue. [9]

Studies have also shown that people with lower levels of folate are less likely to respond to antidepressants. However, those with higher levels tend to have better response rates. [10] Folate is therefore often prescribed for those with treatment-resistant depression. 

Links to specific mental health conditions

Much research has been dedicated to learning about folate’s role in mental health conditions bipolar affective disorder, and schizophrenia.

Folate is found to be abnormally synthesized in people with various psychiatric conditions. Patients with bipolar disorder are shown to have significantly lower serum folate levels than the controls. This is believed to be due to the role of the active form of folate (L-methylfolate) in creating dopamine, norepinephrine, and serotonin. This is also involved in the efficacy of antidepressants. [11]

Folate deficiency has been noted as a risk factor for schizophrenia in various studies. Rates of schizophrenia were shown to double in the Netherlands and China following famines, suggesting that reduced folate intake during early neurodevelopment can increase the risk of developing schizophrenia. [12] Elevated homocysteine in women during the third trimester of pregnancy is also associated with a two-fold increased risk of their children developing schizophrenia later in life. [13]

Those with autism are often found to have difficulties with folate or methionine metabolism, which has led researchers to suggest that folate–methionine cycle may play a key role in autism. Studies in autistic children have shown that levels of cysteine, folate, and vitamin B12 are significantly lower than in control groups. Autistic children are also found to have higher levels of homocysteine than non-autistic children. [14]

Genetics and folate

Before folate can participate in all these processes and produce the necessary neurotransmitters, it must first be activated. The enzyme required for activating folate is called methylenetetrahydrofolate reductase (MTHFR), which is produced by the MTHFR gene. 

However, it’s estimated that around 50% of the global population has some form of genetic mutation that prevents the MTHFR from functioning properly. [15]

The MTHFR C677T mutation is the most common mutation, and is among the genes associated with the increased risk for autism in individuals and in mothers of children with autism. [16]

Different forms of folate in treatment

Folate deficiency medications typically include folic acid supplements. However, the only form of folate that can bypass the MTHFR mutation is the biologically activated form, L-methylfolate. [17] L-methylfolate is also the only form that can cross the blood-brain barrier and regulate the formation of tetrahydrobiopterin cofactor (BH4). 

For these reasons, those with the MTHFR mutations (both C677T and A1298C) may benefit from L-methylfolate over folic acid. 

L-methylfolate increases central neurotransmitter levels and thereby improves the effectiveness of antidepressants, particularly in people with treatment-resistant depression. [18]  In a 60-day randomized trial, patients prescribed an SSRI (Selective serotonin reuptake inhibitors) with L-methylfolate had a greater response rate than patients taking the placebo. [19]

A real-world study involving patients who took L-methylfolate either together with antidepressants or alone reported significant improvements in depressive symptoms and functioning, with 67.9% of patients responding and 45.7% achieving remission over 12 weeks.

Patient medication satisfaction and compliance were very high, with over 90% of patients taking every dose or nearly every dose of l-methylfolate. [20]

As methylfolate works alongside vitamin B12, a combined supplement such as Methyl-Life’s® L-Methylfolate 7.5mg of B12 may be even more effective for those with depression. This highly rated product contains methylfolate as the internationally-patented Magnafolate® PRO together with hydroxocobalamin and adenosylcobalamin, the active forms of B12 shown to naturally support healthy mood.

Life stages and folate

Women have higher requirements for folate during pregnancy, and low maternal folate levels are linked to neural tube defects (NTDs). Taking an L-methylfolate supplement is shown to prevent NTDs. [21]

While there is little research into L methylfolate benefits for postpartum depression, some research shows that pregnant women who took folic acid supplements for more than six months had a lower prevalence of postnatal depression compared to those who took folic acid for fewer than six months. This suggests that higher folate levels during pregnancy may decrease the risk of postnatal depression. [22]

As L-methylfolate is the natural and biologically active form of folate, it is safe to take during pregnancy. As explained above, methylfolate is also more beneficial to women who have the MTHFR mutation and cannot metabolize folic acid. A suitable option would be Methyl-Life’s® Methylfolate 2.5mg, which is a lower dose but highly absorbable version of the purest methylfolate currently available. 

The takeaway

The role of folate in supporting healthy mood has powerful implications for mental health. Numerous studies have confirmed that folate is a vital component of neurotransmitter synthesis, and also that folate deficiency increases the risk of depression and other mental illnesses. 

Those who cannot metabolize the synthetic form of folate - folic acid - due to the MTHFR genetic mutation are advised to take the active form - L-methylfolate - instead. L-methylfolate supplementation is shown as significantly effective in improving symptoms of depression due to its ability to bypass the MTHFR mutation. 

 Always seek advice from your healthcare professional before starting a new supplement regime. 

References

1. https://pubmed.ncbi.nlm.nih.gov/28759846/

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805488/

3. https://pubmed.ncbi.nlm.nih.gov/21772318

4. https://www.sciencedirect.com/science/article/pii/S0753332221013287

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573752/

6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315550/

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372975/

8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566365/

9. https://www.ncbi.nlm.nih.gov/books/NBK535377

10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616

11. https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2269-2

12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394629

13. https://pubmed.ncbi.nlm.nih.gov/17199052/

14. https://jjbs.hu.edu.jo/files/vol13/n2/Paper%20Number%2018.pdf

15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630484/

16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10106103

17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968318

19. https://pubmed.ncbi.nlm.nih.gov/23212058/

20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

21. https://pubmed.ncbi.nlm.nih.gov/23482308/

22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707678/