Clinical Diagram · Methylation · Neurotransmitters · DNA Repair
The Methylation Cycle — How Your Body Makes Everything That Matters
Methylation is a biochemical process occurring billions of times per second. It produces neurotransmitters, repairs DNA, controls inflammation, metabolises hormones, and determines how your body responds to stress. Select your MTHFR variant below to see how variants alter the cycle — and what it means clinically.
Select MTHFR Variant — see how efficiency changes
No MTHFR variant detected. The methylation cycle is running at full efficiency. Dietary folate and food sources of methylfolate convert normally, SAMe production is adequate, and neurotransmitter synthesis has full cofactor support. Folic acid from fortified foods and supplements converts normally via MTHFR.
Clinical implications
What happens when the cycle is impaired
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Neurotransmitter depletion
SAMe is required to synthesise serotonin, dopamine, and noradrenaline. When MTHFR variants reduce methylfolate availability, SAMe production falls — and neurotransmitter synthesis falls with it. This is why antidepressants show reduced efficacy in MTHFR variant carriers: the substrate they need is insufficient upstream.
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Elevated homocysteine
When the cycle is blocked, homocysteine accumulates rather than being remethylated back to methionine. Elevated homocysteine damages endothelial cells, promotes atherosclerosis, increases clotting risk, and is independently associated with depression, cognitive decline, and dementia. Measurable from a standard blood draw.
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Depleted glutathione
The trans-sulfuration pathway converts homocysteine to cysteine and then to glutathione — the body's master antioxidant. When the methylation cycle is blocked upstream, glutathione synthesis is impaired. This is why poor methylators often have elevated oxidative stress markers on OAT testing.
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Altered gene expression
DNA methylation — attaching methyl groups to DNA cytosine residues — controls which genes are expressed and which are silenced. SAMe provides the methyl groups. Impaired methylation produces hypomethylation of genes that should be silenced (including inflammatory genes and oncogenes in some contexts), and hypermethylation of genes that should be active.
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Oestrogen imbalance
The COMT enzyme (catechol-O-methyltransferase) methylates oestrogen metabolites, converting potentially genotoxic catechol oestrogens into safe methoxy oestrogens. Impaired methylation allows catechol oestrogen accumulation — associated with oestrogen dominance symptoms, fibrocystic breasts, endometriosis, and increased breast cancer risk.
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The folic acid problem
Folic acid (synthetic) requires MTHFR to convert to active methylfolate. In variant carriers, unmetabolised folic acid (UMFA) accumulates — potentially blocking folate receptors and worsening the methylation deficit it was intended to address. Methylfolate (5-MTHF) bypasses MTHFR entirely. This distinction determines whether supplementation helps or hinders.
How to assess your methylation status
The markers that map this pathway
Methylation status is not directly visible — it requires indirect markers that reflect the function of the cycle at different points. The most clinically useful are:
Homocysteine — the most sensitive functional methylation marker. Elevated homocysteine means the remethylation step is impaired (B12, methylfolate, or both insufficient). Target: below 7 µmol/L functionally; NHS "normal" up to 15 µmol/L is too permissive.
MTHFR genotype — C677T and A1298C variants via genetic testing. Determines whether folic acid or methylfolate is the correct supplement form.
Active B12 (holotranscobalamin) — more sensitive than serum B12 for detecting functional deficiency. Methylmalonic acid (MMA) is the functional deficiency marker.
OAT (Organic Acids Test) — reveals mitochondrial function, oxidative stress (glutathione depletion), and neurotransmitter metabolites that reflect the downstream outputs of the methylation cycle.
DUTCH Plus — maps oestrogen metabolite pathways via COMT, directly reflecting methylation capacity in oestrogen metabolism.