What is the relationship between Methylenetetrahydrofolate Reductase (MTHFR) variants and neurotransmitter production?

From the Guidelines

MTHFR variants, particularly the 677TT genotype, require oral 5-MTHF treatment to support proper neurotransmitter function and methylation processes. MTHFR gene variants can impact neurotransmitter production and function by affecting methylation processes, which are crucial for synthesizing neurotransmitters like serotonin, dopamine, and norepinephrine 1. These variants reduce the enzyme's ability to convert folate to its active form (methylfolate), which is needed for methylation reactions that produce neurotransmitters and regulate their breakdown.

When considering treatment, it is essential to note that folic acid in doses equal to the RDA (400 mg/day) can lower plasma homocysteine levels by 25-30%, and an additional 7% reduction can be achieved by cobalamin (B12) 0.02-1 mg/day co-administration 1. However, for individuals with MTHFR variants, particularly the 677TT genotype, oral 5-MTHF treatment should be considered to bypass the metabolic block caused by the variant.

Key considerations for treatment include:

• Supplementing with methylfolate (L-methylfolate) at 400-1000 mcg daily to support proper neurotransmitter function
• Vitamin B12 (methylcobalamin form) at 500-1000 mcg daily to work synergistically with methylfolate
• Possibly adding SAMe (S-adenosylmethionine) at 200-400 mg daily to directly support methylation pathways
• Starting with lower doses and gradually increasing as needed, while monitoring for side effects like irritability or headaches
• Maintaining a balanced diet rich in leafy greens, legumes, and quality proteins to support neurotransmitter production.

From the Research

MTHFR Variants and Neurotransmitters

• The MTHFR gene plays a crucial role in the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for the methylation of homocysteine to methionine 2.
• Polymorphisms in the MTHFR gene, such as 667C>T (rs1801133) and 1298A>C (rs1801131), can reduce enzyme activity, leading to hyperhomocysteinemia and potentially affecting neurotransmitter synthesis 2.
• Research suggests that MTHFR polymorphisms may be associated with various neurological and psychiatric disorders, including Autism Spectrum Disorder, Alzheimer's disease, Schizophrenia, and Major Depressive Disorder 2.
• A study found that adjunct therapy with folate (L-Methylfolate or folic acid) improved depression scores, response, and remission rates in patients with major depressive disorder receiving selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI or SNRI) monotherapy 3.
• The interaction between serum folate and vitamin B12 with MTHFR genotypes may also impact the risk of ischemic stroke, with certain genotypes responding better to folic acid treatment 4.

Impact on Neurotransmitter Synthesis

• The one-carbon cycle, which involves the MTHFR enzyme, is essential for methionine and folate metabolism, as well as protein, DNA, and RNA synthesis 5.
• Impaired MTHFR function may lead to elevated homocysteine levels, which can affect neurotransmitter synthesis and potentially contribute to various neurological and psychiatric disorders 5.
• Folate, as a cofactor in the one-carbon cycle, plays a critical role in maintaining methionine and homocysteine balance, and its supplementation may help alleviate symptoms of depression and other neurological disorders 3.