From the Guidelines
For individuals with MTHFR and slow COMT mutations, I strongly recommend a targeted supplement approach including methylfolate (400-1000 mcg daily), methylcobalamin (B12, 500-1000 mcg daily), magnesium glycinate (200-400 mg daily), and vitamin B6 as P5P (25-50 mg daily) to support proper methylation pathways and manage stress responses. This recommendation is based on the most recent and highest quality study available, which suggests that using methylcobalamin and 5-methyltetrahydrofolate instead of cyanocobalamin and folic acid may be more efficacious in preventing stroke and other conditions related to homocysteine metabolism 1.
Key Considerations
- Start with lower doses and gradually increase to avoid overmethylation symptoms like anxiety or insomnia.
- Monitor your response to these supplements and adjust dosages accordingly, as individual needs vary based on specific genetic variants and overall health status.
- For slow COMT, which can lead to higher catecholamine levels, adding NAC (600 mg daily) and limiting stimulants like caffeine can help manage stress responses.
- Vitamin D3 (2000-5000 IU daily) and omega-3 fatty acids (1-2 g daily) provide additional methylation support.
Supporting Evidence
- A study published in Stroke in 2022 found that reduced risk of first ischemic stroke in participants with both folate and B12 below the median, particularly in methylene tetrahydrofolate reductase 677 CC carriers 1.
- The study also suggested that future studies of stroke prevention with B vitamins should use methylcobalamin and 5-methyltetrahydrofolate, instead of cyanocobalamin and folic acid, and possibly vitamin B6 and riboflavin should also be added.
- Another study published in The Lancet Healthy Longevity in 2025 recommended a personalized assessment to identify vitamin and nutrient deficiencies, and considered supplements such as vitamin D, B12, and folate for individuals with deficiencies 1. However, the most recent and highest quality study 1 takes precedence in guiding the recommendation for individuals with MTHFR and slow COMT mutations.
From the FDA Drug Label
Betaine Anhydrous for Oral Solution acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Betaine Anhydrous for Oral Solution was observed to lower plasma homocysteine concentrations in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect.
The recommended supplement for individuals with Methylenetetrahydrofolate Reductase (MTHFR) mutations is Betaine Anhydrous for Oral Solution, as it has been shown to lower plasma homocysteine concentrations in patients with MTHFR deficiency. However, there is no information in the provided drug labels about Catechol-O-Methyltransferase (COMT) activity or supplements recommended for individuals with slow COMT activity. Therefore, no conclusion can be drawn about supplements for individuals with both MTHFR mutations and slow COMT activity 2, 2, 2.
From the Research
Supplements for MTHFR Mutations and Slow COMT Activity
- Individuals with MTHFR mutations may benefit from supplementation with B vitamins, particularly folate and vitamin B12, to lower plasma total homocysteine levels 3, 4, 5, 6
- Folinic acid and l-methylfolate supplementation have been shown to be effective in reducing serum total homocysteine levels in healthy adults, with individuals with the MTHFR 677TT genotype experiencing a significantly higher reduction in serum tHcy levels 4
- The MTHFR 677C→T genotype has been found to modulate the effect of B-vitamin supplementation on homocysteine concentration, with TT homozygous subjects exhibiting a lower 5-year decrease in tHcy concentrations compared to CC or CT subjects 5
- Supplementation with methylfolate, vitamin B6, and vitamin B12 has been shown to be beneficial in lowering homocysteine concentrations and improving pregnancy outcomes in patients with recurrent pregnancy loss and MTHFR mutations 6
- Folate supplementation, particularly with L-methylfolate, may be a useful adjunctive treatment for depression, especially in individuals with MTHFR polymorphisms that affect folate metabolism 7