Vitamin B12 plays a key role in methylation, energy production, red blood cell formation, and neurological function. Individuals with MTHFR variants may rely more heavily on active B12 forms like methylcobalamin or adenosylcobalamin, depending on methylation response.
Many of us are living with MTHFR mutations and are unaware of our MTHFR status, and a small number of us are taking advantage of knowing the MTHFR genes we have. If you do not know what MTHFR is, or would like to learn more about MTHFR, read our introduction to MTHFR here. Certain MTHFR mutations, such as MTHFR C667T or MTHFR A129C, contribute to many health and fertility problems. This article will discuss how MTHFR mutations negatively impact the methylation pathway and vitamin B12 levels, and also offer advice on what you can do to have better health outcomes living with an MTHFR mutation.
What’s the connection between MTHFR and vitamin B12
Folate and vitamin B12 are the most important cofactors working with enzymes in the methylation cycle. The methylation cycles begins with folate. Folate is converted into its active form (5-methyltetrahydrofolate) through the folate cycle, and MTHFR is directly responsible for the creation of folates active form. MTHFR deficiencies lead to a shortage of the active form of folate within the body and negatively impacts the conversion of homocysteine to methionine. Low active folate levels can lead to a build of of homocysteine and lack of methionine in the body and can lead to several health problems (more on high homocysteine levels can be found here).
High homocysteine levels can also be caused by low vitamin B12 levels because vitamin B12 is the cofactor needed by the enzyme responsible for converting homocysteine to methionine. Without adequate vitamin B12 levels a build of homocysteine begins occuring, and can be made even worse in combination with harmful MTHFR mutations. If you are curious to find out if you have MTHFR, we have different MTHFR testing kits available.
Australia – https://www.mthfrproducts.com.au/collections/mthfr-gene-test-kits
International –
What you need to know about vitamin B12 levels and MTHFR mutations
People living with MTHFR mutations commonly have issues with vitamin B12. They often show the symptoms of vitamin B12 deficiency, but when they get tested their vitamin B12 levels are normal. A healthy vitamin B12 level is between 500-800 µmol. You may be asking, why would a person suffer from the symptoms of vitamin B12 deficiency if they have healthy vitamin B12 levels?
The answer involves MTHFR mutations. MTHFR mutations impact the bodies ability to use vitamin B12. This happens because certain MTHFR mutations (C667T and A129C) lower the amount of active folate being produced in the body, and the use of vitamin B12 requires the active form of folate. Vitamin B12 deficiency can be occurring while vitamin B12 levels are at levels not typically associated with deficiency due to the presence of deleterious MTHFR mutations. If you are one of the unlucky people with symptoms of vitamin B12 deficiency and vitamin B12 levels within the normal range, the best things you can do would be to increase your folate intake through supplementation and eating more folate containing foods.
We sell a variety of supplements for folate and Vitamin B deficiencies that can be found here, a guide to folate supplementation can be found here, and you can learn more about what foods are high in folate here.
Symptoms of vitamin B12 deficiency
MTHFR mutations and vitamin B12 deficiencies commonly work together to produce elevated homocysteine levels which can damage the nervous system, leading to cognitive impairment, and increased risk of Alzheimer’s Disease and dementia. Elevated homocysteine levels are also associated with increased risk for cardiovascular issues such as strokes and heart attacks. Symptoms of vitamin B12 deficiency include: fatigue, irritability, anxiety, low energy, depression, forgetfulness, constipation, new food sensitivities, hot and cold flashes, sore muscles, pale skin, numbness, tingling, and dermatitis.
How to overcome B12 issues
There comes a time when it’s time to take health matters into your own hands. What’s the best way to overcome vitamin B12 deficiency and elevated homocysteine levels? There a a few for of vitamin B12 supplements available on the market. We will go over each form of vitamin B12 and tell you how to determine if it’s the right one for you.
Cyanocobalamin
Cyanocobalamin is a form of vitamin B12 derived from cyanide poison, and for this reason should be avoided. Long term supplementation with cyanocobalamin can have systemic toxic effects on the body amd even lead to kidney failure! Another downside of supplementing with cyanocobalamin is that it’s a form of vitamin B12 that requires an extra chemical reaction to occur within the liver until it becomes something your body can use. Making it more difficult to breakdown for those living with MTHFR mutations.
Hydroxocobalamin
Hydroxocobalamin is more bioavailable than cyanocobalamin and does not require extra reactions occuring in the liver before the body can use it. For this reason, hydroxocobalamin is recommended for people with MTHFR mutations, known methylation issues, and is the best supplement for anyone living with low blood pressure. Hydroxocobalamin should be taken as a preventative measure against complications that arise from vitamin b12 deficiencies, high homocysteine levels, and methylation issues.
Methylcobalamin
Methylcobalamin is another form of vitamin B12 that does not require extra processing in the liver, making it a great alternative to taking cyanocobalamin. Methylcobalamin is often taken to improve cardiovascular problems, cognitive impairments, behavioral issues associated with autism, and circadian rhythm disturbances.
Adenosylcobalamin
Adenosylcobalamin is great to take alongside methylcobalamin to obtain the full spectrum of benefits that can be derived from vitamin B12 supplementation. Adenosylcobalamin is the form of vitamin B12 associated most closely with improving energy levels in people who are deficient in vitamin B12.
Here are your best options for solving your B12 issues
Vitamin B12 deficiencies are fairly common, and now you have learned more about how to fix vitamin B12 deficiencies. If you are living with an MTHFR mutation, are vegetarian/vegan, or are susceptible to vitamin B12 deficiency for other reasons, you now have more tools in your tool box for understanding and dealing with vitamin B12 deficiencies. If you have troubles solving your vitamin B12 deficiency on your own, the next best step is to take what you have learned/tried to your doctor and work with them to solve your health issues associated with vitamin B12 deficiency.
However , before you go and see your doctor, it’s important to start supplementing with vitamin B12 and other B vitamins right away if you suspect you are deficient.
If you are looking for a more in-depth and personalized approach to MTHFR, vitamin B12 deficiency, or fertility issues than check out our patient resource center.
Best Forms of B12 for MTHFR
Not all B12 supplements are created equal, especially if you have an MTHFR gene mutation. Understanding the different forms helps you choose the most effective option for your genetic profile and symptoms.
The four main forms of B12:
1. Methylcobalamin (Methyl-B12)
What it is: The active, methylated form of B12 that’s ready for immediate use in methylation reactions.
Best for:
- MTHFR mutations (C677T, A1298C)
- Supporting methylation directly
- Neurological symptoms (brain fog, neuropathy)
- Depression and mood disorders
- Elevated homocysteine
Advantages:
- No conversion required — immediately bioavailable
- Directly supports methylation cycle
- Crosses blood-brain barrier easily
- Lowers homocysteine effectively
Potential downsides:
- Can cause “overmethylation “symptoms in sensitive individuals (anxiety, insomnia, irritability)
- May need to start with very low doses
- Not ideal for those with histamine issues or “overmethylators”
Typical dosage: 500-5000mcg daily (start low)
2. Hydroxocobalamin (Hydroxy-B12)
What it is: A precursor form that your body converts into both methylcobalamin and adenosylcobalamin as needed.
Best for:
- People sensitive to methyl-B12
- Those with histamine intolerance or mast cell issues
- “Overmethylators” or those with anxiety from methylated vitamins
- Detoxification support (binds to toxins like cyanide and nitric oxide)
- Balanced, gentle B12 support
Advantages:
- Body controls conversion rate (less likely to cause overmethylation)
- Supports detoxification pathways
- Well-tolerated by most people
- Longer-lasting in the body than methyl-B12
Potential downsides:
- Requires conversion (may be less efficient with severe MTHFR mutations)
- Slightly less direct methylation support than methyl-B12
- Can be harder to find in supplements
Typical dosage: 1000-5000mcg daily
3. Adenosylcobalamin (Adeno-B12)
What it is: The active form of B12 used in mitochondria for energy production.
Best for:
- Chronic fatigue and low energy
- Mitochondrial dysfunction
- Supporting cellular energy (ATP production)
- Combining with methyl-B12 for comprehensive support
Advantages:
- Directly supports energy production
- Doesn’t add methyl groups (won’t cause overmethylation)
- Essential for mitochondrial function
- Complements methylcobalamin well
Potential downsides:
- Doesn’t directly support methylation
- Less commonly available as standalone supplement
- Often needs to be combined with other B12 forms
Typical dosage: 1000-3000mcg daily
4. Cyanocobalamin (Avoid for MTHFR)
What it is: Synthetic form of B12 containing a cyanide molecule.
Why to avoid with MTHFR:
- Requires multiple conversion steps to become active
- MTHFR mutations impair these conversions
- Contains cyanide (though small amount)
- Least bioavailable form
- Found in most cheap multivitamins and fortified foods
Bottom line: Choose methylcobalamin, hydroxocobalamin, or adenosylcobalamin instead.
Which form should you choose?
Choose methylcobalamin if:
- You have confirmed MTHFR mutations
- Elevated homocysteine levels
- Neurological or mood symptoms
- You tolerate methylated supplements well
Choose hydroxocobalamin if:
- Sensitive to methyl-B12 (anxiety, insomnia)
- Histamine intolerance or MCAS
- Need gentle, balanced B12 support
- Want detoxification benefits
Choose adenosylcobalamin if:
- Chronic fatigue is your primary concern
- Mitochondrial dysfunction
- Want to combine with methyl-B12 for comprehensive support
Consider combination formulas: Many practitioners recommend combining forms:
- Methyl-B12 + Adeno-B12 (methylation + energy)
- Hydroxy-B12 + Adeno-B12 (gentle + energy)
- All three forms for comprehensive support
The bottom line: For MTHFR mutations, methylcobalamin is typically most effective for supporting methylation and lowering homocysteine. However, hydroxocobalamin is better tolerated by sensitive individuals and those with histamine issues. Adenosylcobalamin excels for energy support. Avoid cyanocobalamin entirely with MTHFR mutations.
B12 vs B9 (Folate) for MTHFR — How They Work Together
B12 and folate (B9) are often discussed separately, but they work as an inseparable team in the methylation cycle. Understanding their relationship is crucial for managing MTHFR mutations effectively.
The methylation partnership:
Think of B12 and folate as dance partners — they need each other to perform properly. Here’s how they work together:
Folate’s role:
- Dietary folate converts to 5-MTHF (active folate) via the MTHFR enzyme
- 5-MTHF donates a methyl group to homocysteine
- This requires B12 as a cofactor for the enzyme methionine synthase
- The result: homocysteine converts to methionine
B12’s role:
- B12 (as methylcobalamin) acts as a cofactor for methionine synthase
- It helps transfer the methyl group from 5-MTHF to homocysteine
- Without adequate B12, folate gets “trapped” and can’t donate its methyl group
- This is called the “methyl trap”
What happens when one is deficient:
Low B12 with adequate folate:
- Folate can’t function properly (methyl trap)
- Homocysteine rises despite good folate levels
- Methylation slows down
- Can mask B12 deficiency symptoms initially
Low folate with adequate B12:
- Not enough methyl groups available for donation
- Homocysteine rises
- Methylation impaired
- DNA synthesis affected
Both low:
- Severe methylation impairment
- Very high homocysteine
- Anemia (megaloblastic)
- Neurological damage risk
Why MTHFR mutations affect this partnership:
With MTHFR mutations:
- Your body can’t efficiently convert folate to 5-MTHF
- This creates a bottleneck in the methylation cycle
- Even with adequate B12, you don’t have enough active folate to work with it
- Result: elevated homocysteine, poor methylation
The solution: Bypass the MTHFR bottleneck by taking pre-methylated folate (5-MTHF) that doesn’t require conversion.
Why you need both for MTHFR:
Taking only methylfolate without B12:
- May improve methylation initially
- Can deplete B12 stores over time
- May not fully lower homocysteine
- Neurological symptoms may persist
Taking only B12 without methylfolate:
- Won’t bypass MTHFR enzyme bottleneck
- Methylation remains impaired
- Homocysteine may stay elevated
- Less effective for MTHFR mutations
Taking both together:
- Synergistic effect on methylation
- More effective homocysteine reduction
- Better symptom improvement
- Supports complete methylation cycle
Other B vitamins that support the partnership:
B6 (as P5P):
- Cofactor for homocysteine conversion to cysteine
- Supports transsulfuration pathway
- Helps prevent homocysteine buildup
B2 (riboflavin):
- Required for MTHFR enzyme function
- Particularly important for C677T homozygous mutations
- Can improve MTHFR enzyme efficiency by up to 50%
Choline or TMG (betaine):
- Alternative methylation pathway
- Provides methyl groups independently of folate
- Helpful backup when folate pathway is impaired
Food sources to support both:
B12-rich foods:
- Meat, fish, eggs, dairy
- Shellfish (especially clams, oysters)
- Liver and organ meats
- Fortified plant milks (for vegans)
Folate-rich foods:
- Dark leafy greens (spinach, kale)
- Asparagus, Brussels sprouts, broccoli
- Legumes (lentils, chickpeas, black beans)
- Avocado
- Avoid synthetic folic acid (fortified breads, cereals)
Signs you’re taking the right amounts:
✓ Homocysteine normalizing (below 10 μmol/L, ideally 6-9)
✓ Energy improving
✓ Brain fog clearing
✓ Mood stabilizing
✓ Sleep improving
✓ No adverse reactions
MTHFR B Vitamin Checklist
Use this quick reference guide to ensure you’re supporting your MTHFR mutation with the right B vitamins in the optimal forms and doses.
✓ Essential B Vitamins for MTHFR
B9 (Folate)
- Form: 5-MTHF (methylfolate), NOT folic acid
- Dose: 400-800mcg daily minimum (up to 5mg for some conditions)
- Why: Bypasses MTHFR enzyme bottleneck
- Look for: Quatrefolic®, Metafolin®, or L-5-MTHF on labels
B12 (Cobalamin)
- Form: Methylcobalamin OR hydroxocobalamin (avoid cyanocobalamin)
- Dose: 500-1000mcg daily minimum (up to 5000mcg for deficiency)
- Why: Essential cofactor for methylation, lowers homocysteine
- Choose methylcobalamin for: Direct methylation support
- Choose hydroxocobalamin for: Sensitive individuals, histamine issues
B6 (Pyridoxine)
- Form: P5P (pyridoxal-5-phosphate), the active form
- Dose: 5-50mg daily, but will be highly individualised
- Why: Supports transsulfuration pathway, prevents homocysteine buildup
- Avoid: Regular pyridoxine HCl (requires conversion)
B2 (Riboflavin)
- Form: Riboflavin or riboflavin-5-phosphate
- Dose: 10-100mg daily (higher doses for C677T homozygous)
- Why: Required cofactor for MTHFR enzyme function
- Benefit: Can improve MTHFR enzyme efficiency up to 50%
✓ Supporting Nutrients
- Magnesium
- Zinc
- Choline or TMG (Betaine)
How to Choose a B12 Supplement for MTHFR
- Look for methylcobalamin or hydroxocobalamin
- Avoid cyanocobalamin
- Check for fillers or artificial folic acid
- Sublingual/ spray forms often absorb better
Frequently Asked Questions About B12 and MTHFR
Which form of B12 is best for MTHFR?
For most people with an MTHFR gene mutation,methylcobalamin (methyl-B12) is the preferred form because it is already active and directly supports methylation. It does not require conversion by the body, making it easier to utilise—especially for those with impaired methylation pathways.
However, some individuals are sensitive to methyl donors. In these cases,hydroxocobalamin oradenosylcobalamin may be better tolerated, as they provide B12 support without strongly stimulating methylation.
Read more about Importance of vitamin B12 and MTHFR
Can you take methyl-B12 and methylfolate together?
Yes.Methyl-B12 and methylfolate are often taken together because they work synergistically in the methylation cycle. Taking one without the other can sometimes create imbalance or worsen symptoms.
For best results:
- Start withlow doses
- Increase slowly
- Monitor symptoms such as anxiety, irritability, or insomnia
Working with a practitioner experienced in MTHFR is recommended.
Should you take a B-complex instead of single B12?
It depends on your individual needs. Ahigh-quality activated B-complex can be beneficial because methylation relies on multiple B vitamins, including B2, B6, folate, and B12.
However, if you are sensitive to methylated nutrients or already reacting to supplements, starting withsingle-ingredient B12 may be safer before introducing a full B-complex.
How do you know if you’re deficient in B12?
Common signs of B12 deficiency include:
- Fatigue or low energy
- Brain fog or memory issues
- Numbness or tingling in hands and feet
- Mood changes, anxiety, or depression
- Poor concentration
Blood tests can help assess deficiency. In addition to serum B12, more accurate markers include methylmalonic acid (MMA) and homocysteine levels, especially for people with MTHFR mutations.
Is hydroxocobalamin better for overmethylators?
Yes,hydroxocobalamin is often better tolerated by overmethylators. Unlike methyl-B12, it does not directly donate methyl groups and can actually help buffer excess methylation.
People who experience anxiety, agitation, headaches, or insomnia from methyl-B12 may benefit from switching to hydroxocobalamin under practitioner guidance.
What is “overmethylation”?
The term “overmethylation” is somewhat misleading. What’s usually happening is:
- Methyl under-utilization — your body produces methyl groups but can’t use them efficiently due to blockages. We call it a methylblock.
- Excessive methyl supplementation — taking too much methylfolate or methyl-B12 for your needs
- COMT mutations — slow breakdown of neurotransmitters, causing buildup when you add more methyls
Histamine issues — methylation can increase histamine in some people
