The MTHFR–B12 Connection: A Clear Scientific Breakdown

A lot of people hear about MTHFR and B12 but don’t realise how tightly linked they are in basic human biochemistry.
Here’s a straightforward, science-based explanation that may help anyone trying to understand their symptoms or lab results.

🔬 What MTHFR Actually Does

The MTHFR gene produces an enzyme called methylenetetrahydrofolate reductase.
Its primary role is to convert 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF) — the active, methylated form of folate.

5-MTHF is essential because it donates a methyl group to homocysteine in a reaction that cannot happen without both:

✔️ Active Folate (5-MTHF)

and

✔️ Vitamin B12 (Methylcobalamin)

This reaction is known as methionine synthase activity, and it sits at the core of the methylation cycle.

🧠 Why B12 Is Required for MTHFR to Work Properly

Even if your body produces plenty of 5-MTHF, it cannot be used without B12.

Here’s the biochemical pathway:

1️⃣ MTHFR enzyme produces 5-MTHF

This is the only form of folate that can donate a methyl group to homocysteine.

2️⃣ B12 acts as a cofactor in the methionine synthase reaction

It accepts the methyl group from 5-MTHF and transfers it to homocysteine.

3️⃣ Homocysteine is converted into methionine

Methionine is used to create SAMe (S-adenosylmethionine) — the “universal methyl donor” for over 200 enzymatic reactions, including:

• neurotransmitter production (dopamine, serotonin, norepinephrine)
• DNA methylation
• hormone regulation
• myelin formation (nerve insulation)
• detoxification pathways

❗️❗️❗️ If B12 is low, this entire cycle slows down

This causes 5-MTHF to become “trapped” and homocysteine begins to rise.

📈 What Happens When the MTHFR–B12 Pathway Fails

When folate and B12 cannot complete the methionine synthase reaction, it can lead to:

• Elevated homocysteine

A known risk factor for cardiovascular, neurological, and cognitive issues.

• Impaired neurotransmitter synthesis

Can contribute to anxiety, depression, irritability, and attention issues.

• Reduced myelin integrity

Which may cause tingling, numbness, neuropathy or balance issues.

• Slower methylation

Affects detoxification, inflammation control, hormone regulation and energy.

• “Functional” B12 deficiency

Blood levels can appear normal, but the pathway is still blocked.

🧪 The Form of B12 Matters

Many people with MTHFR variants struggle with certain forms of B12.

Most common but least effective:

❌ Cyanocobalamin

Requires multiple conversion steps. MTHFR variants often struggle here.

More bioactive and supportive:

✔️ Methylcobalamin (directly usable, supports methylation)
✔️ Hydroxocobalamin (long-acting, good for neurological support)

These forms bypass bottlenecks and supply methylation directly.

🧬 Why This Information Matters

The folate cycle and B12 cycle are not separate, they are two halves of the same engine.

If one side fails, both fail.

This is why someone can have:

• Normal Folate Levels
• Normal B12 Levels

…yet still experience symptoms or high homocysteine.

Because the issue is not the vitamin level, it’s the conversion pathway.