Folate vs L-methylfolate: Exploring the Benefit of Vitamin B9 for Mental Health
What is folate?
Folate, less commonly known as vitamin B9, is a water soluble B-vitamin that plays a role in the synthesis of amino acids and the formation of DNA6. You may have heard of it’s synthetic form, folic acid, and the role it plays in pregnancy and fetal health.
Once digested, folate is broken down into 5-methyltetrahydrofolate (also referred to as 5-MTHF or L-methylfolate), the biologically active form of folate (what your body can use). 5-MTHF is used to create methionine, which is further metabolized to S-adenosylmethionine (also known as SAMe). SAMe is a key compound used in critical physiological processes, such as the biosynthesis of neurotransmitters (serotonin, dopamine, and epinephrine) and DNA.
How does it relate to mental health?
Folate, through a series of complex reactions, aids in the biosynthesis of dopamine, serotonin, and epinephrine- a lack of these neurotransmitters would present as depressive symptoms. If folate intake is low (or if your body isn’t adequately converting folate to 5-MTHF, discussed in the next section) SAMe levels will also decline, eventually resulting in low neurotransmitter levels. Additionally, 5-MTHF has been shown to stabilize, enhance, and even act as a substitute for tetrahydrobiopterin (BH4), another key component of neurotransmitter synthesis5. BH4 is highly susceptible to oxidation and a folate-involved enzyme can regenerate BH4 for use in neurotransmitter synthesis.
Homocysteine is a derivative of methionine. If you recall, the active form of folate, 5-MTHF, is used to create methionine and then SAMe. Once SAMe is used in reactions, it becomes homocysteine. At this point, homocysteine is further metabolized (some studies have shown that homocysteine is inflammatory and can cause oxidative stress4). There are a few different routes homocysteine can take and one of those routes involve 5-MTHF. If there is not adequate 5-MTHF, homocysteine build up in the body. More research is needed, but high levels of homocysteine have been linked to dementia, Alzheimer’s, and depression4.
Numerous studies have found that low folate status increases the risk of depression and that people diagnosed with depression had lower folate status than people who have never been diagnosed with depression5. B12 is another water-soluble vitamin that works closely with folate and shares similar biological pathways. Studies have shown that high homocysteine levels, in conjunction with low B12 and low folate status, were all common markers in patients with depression5. Other studies have found that people with high homocysteine levels also have low folate, SAMe, and neurotransmitter levels in the cerebrospinal fluid (the fluid in tissues that surround the brain)5.
MTHFR Polymorphisms
Your MTHFR gene provides the genetic instructions for creation of the MTHFR protein, which processes folate. Everyone has two copies of the gene, one from each parent. Like all genes, variants may be possible. A gene variant is a small change in the DNA sequence that makes up the gene. A genotype is the combination of both copies of the gene. The MTHFR gene has three genotypes- MTHFR 677 CC, MTHFR 677 CT, or MTHFR 677 TT1. Individuals with the MTHFR 677 TT and MTHFR 677 CT genotypes have significantly diminished MTHFR activity, as well as low folate levels and high homocysteine levels in the blood3. 20%-53% of people may have inherited one T copy and 3-32% may have inherited two T copies3. A meta-analysis found that there is a 36% greater chance of depression in someone with the TT genotype compared to someone with the CC genotype 2. Genetic testing ordered by your doctor can help you determine what MTHFR genotype you have, so you can adjust your folate intake and/or supplementation (as recommended by your doctor) accordingly.
Supplementation
5-MTHF supplements are significantly more effective than folic acid supplements in raising plasma 5-MTHF levels (by seven fold), regardless of MTHFR genotype5. A small 6 week trial found that 81% of severely depressed patients saw improvement in depressive symptoms after 6 weeks of high dose 5-MTHF (50mg/day)5. Numerous studies have found that 5-MTHF supplementation (doses ranging from 15-50mg/day) enhanced the efficacy of serotonergic and other psychotropic medications5.
New research has found that there is a correlation between low levels of folate in the blood and worsened responses to SSRIs and tricyclic antidepressants, and vice versa. Further research found that 500mcg per day of folic acid (the synthetic form of folate) in addition to the regularly prescribed SSRI increased the effectiveness of the drug in depressed patients. Another study found that doses ranging from 15-30mg per day of folinic acid (an intermediate metabolite of folic acid) in addition to regularly prescribed SSRI improved symptoms of depression more effectively than the SSRI alone5.
A mental health professional, such as the staff here at Modyfi, can guide you through different supplementation options.
Food Sources
Humans cannot synthesize folate on our own, so it must be obtained through the diet. Green leafy vegetables are one of the richest sources of folate in the diet (the name “folate” is derived from the Italian word for “foliage”). Legumes (such as lentils, garbanzo beans, and lima beans), mushrooms, brussels sprouts, broccoli, strawberries, asparagus, and liver are all good sources of folate. Most grains and cereals are fortified with folic acid6. The bioavailability of folate is about 50%, but is largely dependent on the individual, as well as food preparation, and the food matrix3 (the relationship between different nutrients and non-nutrient components of different foods). The bioavailability of folic acid is much higher than that of folate, ranging from 85-100%3.
Other Nutrient Interactions
Vitamins B6, B12, and folate work together to play a role in the metabolism of homocysteine. Large supplemental doses of B6 may increase the body’s folate requirement and large supplemental doses of folate may increase the body’s requirement for B12. Make your doctor aware of any current supplements you take3.
Vitamin C, a natural antioxidant, may limit the degradation of enzymes that aid in folate absorption. A small-scale study found that vitamin C supplementation enhanced folate levels when taken in conjunction with 5-methyltetrahydrofolic acid compared to 5-methyltetrahydrofolic acid alone7.
The mental health professionals at Modyfi focus on whole-person care, taking special attention to consider mind, body, and fitness when creating treatment plans. When you’re ready we are here. Schedule an appointment today.
Centers for Disease Control and Prevention. (2020). MTHFR gene, folic acid, and preventing neural tube defects. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html.
Gilbody, S., Lewis, S.; Lightfoot, T. (2006). Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and PSYCHIATRIC Disorders: A huge review. American Journal of Epidemiology, 165(1), 1–13. https://doi.org/10.1093/aje/kwj347
Higdon, J. (2014). Folate. Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/folate.
Miller, A. L. (2003). The methionine-homocysteine cycle and its effects on cognitive diseases. Alternative Medicine Review, 8(1), 7–19. https://doi.org/PMID: 12611557
Miller, A. L. (2008). The methylation, neurotransmitter, and antioxidant connections between folate and depression. Alternative Medicine Review , 13(3), 216–226. https://doi.org/PMID: 18950248.
U.S. Department of Health and Human Services. (2021). Folate- Health Professional Fact Sheet. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/.
Verlinde, P. H., Oey, I., Hendrickx, M. E., Van Loey, A. M., & Temme, E. H. (2007). L-ascorbic acid improves the serum folate response to an oral dose of [6s]-5-methyltetrahydrofolic acid in healthy men. European Journal of Clinical Nutrition, 62(10), 1224–1230. https://doi.org/10.1038/sj.ejcn.1602840
