Stress, thyroid function, and the brain’s GABA system form a tightly connected feedback loop. Because each system affects the others, disruptions can create a cycle of stress sensitivity, cognitive fog, and emotional imbalance. Understanding this interconnected network allows clinicians and patients to approach symptoms more holistically—focusing on stress regulation, thyroid support, and nervous system balance to restore harmony across the entire neuroendocrine system.
Laura Lewis, MS
Are you debating which supplement to purchase? L-Methylfolate vs folic acid? Or wondering why supplements containing l-methylfolate (vs folic acid) carry a much higher price tag? We’ve got the answers you’re looking for.
First, what is folate?
Vitamin B9 is a water-soluble, essential nutrient which occurs naturally as “folate”. However, folate can be synthesized and is often added to food and nutritional supplements as “folic acid.” Folic acid, while highly-absorbable, is not active in the body. It must be converted to L-methylfolate in the body before it can be used.
Although vitamin B9 is necessary for multiple actions in the body (i.e. replication of DNA, making healthy red blood cells/protection from some types of anemia, and sufficient neurotransmitter production for mental health), low folate status is a common nutritional insufficiency. Insufficiency can be a result of not consuming enough folate-rich foods. It can also be caused by interfering health issues that prevent natural folate absorption, or a genetic inability to metabolize this vitamin properly.
What affects my folate levels?
Approximately half of the human population carry an inherited mutation in the MTHFR gene. [1] MTHFR is a gene that provides instructions to make an enzyme called methylenetetrahydrofolate reductase. This enzyme is a key factor in the breakdown of folate (or folic acid) to its active form, L-methylfolate (5-MTHF).
This reaction also converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins such as the neurotransmitters; dopamine, serotonin, melatonin, and epinephrine. The neurotransmitters are required for healthy sleep and a general sense of well-being.
Some people are not aware of their MTHFR mutation status. Others will experience a drop in enzyme efficiency by 30-70%, depending on the type of mutation they’ve inherited. [2] In these cases, folate doesn’t get efficiently converted to L-methylfolate and homocysteine is not efficiently broken down into methionine.* This may be expressed in one’s mood.
But mood is not the only aspect affected by folate. Unconverted folate and homocysteine must be effectively metabolized. Normal homocysteine levels are associated with a healthy cardiovascular system.* [3]
Only a genetic test can confirm whether or not you have an MTHFR mutation. But, if you do, L-methylfolate supplementation may be an appropriate consideration.*
What does “Fortified” mean?
Many foods have been “fortified” or have had synthetic folic acid added. However, it has been suggested that too much folic acid may accumulate unmetabolized in the bloodstream, especially in the elderly.* [4]
Folic acid is much slower to break down than natural folate, even in individuals with healthy folate metabolism, and requires the help of the liver and other tissues for activation. [5] This is a slightly different mechanism of action than that of food folate, which typically biotransforms directly after absorption by the gut.
On the other hand, L-methylfolate bypasses the entire folic acid metabolism cycle completely and is more effective than folic acid for increasing circulating active folate.* [5] L-Methylfolate is also highly effective at supporting healthy homocysteine levels (with or without an MTHFR mutation).* It is more bioavailable and interacts with fewer medications than folic acid.* [5] Some have suggested that fortified food would provide greater benefits to a wider range of individuals if it contained L-methylfolate (vs folic acid) in the future.* [5]
How Can L-Methylfolate Help?
L-methylfolate can be taken as a dietary supplement to bring your circulating levels of active folate up to a level that can help properly clear homocysteine, supply the brain with precursors for neurotransmitters, and allow for healthy red blood cell production.*
You should always consult your healthcare practitioner before making a change to your health regimen.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Laura Lewis is a clinical researcher and science communicator with a Master of Science degree and a background in nutrition science and integrative health. She brings a decade of experience translating complex clinical data into accessible insights for healthcare practitioners and patients alike.
Laura has contributed to educational programming and strategic content development across the integrative and functional medicine space. Her strengths lie in evidence synthesis, practitioner engagement, and crafting communications that bridge the gap between scientific rigor and real-world application. At ARG, Laura supports clinical content development and educational initiatives that elevate practitioner confidence and product credibility.