Why B Vitamins Make Some People Feel Worse (The MTHFR Gene Explained)

If you've ever taken a B vitamin supplement and felt more tired instead of energized, you're not imagining things. There's a genetic reason some people don't respond well to standard B vitamins.

At Naturopathic Physicians Group in Scottsdale, Dr. Steven Katz and Dr. Loreena Ryder regularly work with patients who've struggled with unexplained fatigue, brain fog, or mood issues despite taking what should be helpful supplements. One common factor? The MTHFR gene mutation.

MTHFR affects how your body processes certain B vitamins, particularly folate. Understanding whether you have this genetic variation can help explain puzzling health patterns and guide you toward supplements and foods that actually support your body instead of working against it.

What Is MTHFR?

MTHFR stands for Methylenetetrahydrofolate Reductase. It's an enzyme that helps your body break down and use folate, also known as vitamin B9.

The MTHFR gene contains the instructions for making this enzyme. When you have a variation in this gene, the enzyme doesn't work as efficiently. This means your body may have a harder time processing folate and using it in important chemical reactions.

There are two common naturally occurring variants: C677T and A1298C. You can inherit one variant (heterozygous) or both (homozygous) from your parents. The more variants you have, the less active the enzyme tends to be.

About 60% of the population has at least one MTHFR variant. This doesn't mean everyone with the variant will have symptoms. Genetics create tendencies, not certainties. But for some people, especially those with other health challenges, MTHFR can be a significant piece of the puzzle.

Why Methylation Matters

The MTHFR enzyme is part of a process called methylation. This is a chemical reaction that happens billions of times per second in your body, affecting numerous functions:

Neurotransmitter production. Your brain needs methylation to create serotonin (for mood regulation), dopamine (for focus and motivation), norepinephrine (for alertness), and melatonin (for sleep).

Energy production. Your cells use B vitamins in the process of converting food into usable energy.

Detoxification. Methylation helps your liver process and eliminate toxins, excess hormones, and waste products.

Homocysteine recycling. MTHFR helps convert homocysteine (a potentially inflammatory amino acid) into methionine, a beneficial building block for proteins.

DNA maintenance. Methylation plays a role in turning genes on and off and supporting DNA repair.

When methylation doesn't work efficiently, these processes can be affected. This doesn't happen overnight, and it doesn't affect everyone the same way. But over time, some people notice patterns.

Common Health Patterns Associated with MTHFR

Research has found associations between MTHFR variants and various health conditions. It's important to note that "associated with" doesn't mean "causes." MTHFR is one factor among many that might contribute to health challenges.

Energy and fatigue. Without adequate B vitamin processing, cellular energy production can be affected. Some people with MTHFR variants report persistent fatigue that doesn't improve with rest or standard vitamin supplements.

Mood and mental health. Since methylation is needed for neurotransmitter production, MTHFR variants have been studied in relation to depression, anxiety, and mood regulation challenges.

Focus and cognitive function. Brain fog, difficulty concentrating, and memory issues may relate to inadequate neurotransmitter production. MTHFR has been studied in relation to ADHD and autism spectrum conditions, though the relationship is complex.

Cardiovascular health. When MTHFR function is reduced, homocysteine levels can rise. Elevated homocysteine is associated with inflammation in blood vessels and increased cardiovascular risk.

Pregnancy considerations. Folate is critical for fetal neural tube development. Women with MTHFR variants may need higher levels of the methylated form of folate during pregnancy to support healthy development.

Dr. Ryder emphasizes that MTHFR isn't a diagnosis in itself. It's genetic information that helps explain why some interventions work better than others for certain people.

The Fortified Foods Problem

Here's where things get interesting. If you have an MTHFR variant, the very foods marketed as "vitamin-enriched" might not be helping you the way you'd expect.

By law, many processed foods must be fortified with nutrients that were lost during manufacturing. Bread, pasta, cereals, and many dairy products are fortified with synthetic folic acid.

Folic acid is not the same as natural folate. It's a synthetic form that requires multiple conversion steps before your body can use it. If you have reduced MTHFR enzyme activity, you may not convert folic acid efficiently.

What happens to unconverted folic acid? It can build up in your system and potentially block receptors that natural folate would use. Some people report feeling worse when they consume large amounts of fortified foods.

This explains why someone might eat "healthy" fortified cereals, take a standard multivitamin with folic acid, and still feel tired and foggy. They're getting plenty of folic acid, but their body can't convert it into the form it actually needs.

The solution isn't to avoid all folate. It's to focus on natural folate from whole foods and, when supplementing, use the methylated form that your body can use directly.

Natural Sources of Folate

These whole foods contain natural folate that doesn't require the same conversion process as synthetic folic acid:

Leafy greens (spinach, kale, collard greens, Swiss chard)

Broccoli and Brussels sprouts

Asparagus

Beets

Citrus fruits

Beans and lentils

Nuts and seeds

Organic eggs

Avocado

Notice these are all whole, unprocessed foods. You won't find "fortified" on the label because nature already put the nutrients there in usable forms.

Testing for MTHFR

At Naturopathic Physicians Group, we use several tests to understand whether MTHFR is relevant to your health picture:

MTHFR Genetic Test

This is a one-time blood or saliva test that identifies whether you have the C677T or A1298C variants, and whether you have one copy (heterozygous) or two copies (homozygous).

Knowing your MTHFR status doesn't change your treatment dramatically, but it helps explain patterns and guides supplement selection.

Homocysteine

This blood test measures current homocysteine levels. The standard reference range considers levels under 15 μmol/L normal, but functional medicine practitioners prefer to see levels under 10 μmol/L for optimal cardiovascular health.

Elevated homocysteine suggests that methylation may not be working efficiently, whether due to MTHFR variants or other factors like B vitamin deficiencies.

Folate and B12

Serum levels of these vitamins help identify deficiencies that might be contributing to symptoms.

Methylmalonic Acid (MMA)

This is a more sensitive marker for B12 status than serum B12 alone. When B12 is low, MMA rises. This helps catch deficiencies early.

Dr. Katz notes that conventional annual labs rarely include homocysteine or MMA testing unless there's a specific indication. But these markers can provide valuable information about how well your methylation pathways are functioning.

The discussion of these tests is for educational purposes only. Please consult a medical professional who knows your personal history before pursuing testing.

Natural Support for MTHFR

If you have an MTHFR variant or suspect your methylation isn't working optimally, here are evidence-based strategies:

Use Methylated B Vitamins

Instead of folic acid and standard B12, look for:

• Methylfolate (also called 5-MTHF or L-methylfolate): This is the active form of folate that doesn't require MTHFR enzyme conversion

• Methylcobalamin: The methylated form of B12 that supports both methylation and nerve health

• P5P (Pyridoxal-5-Phosphate): The active form of B6, since MTHFR can also affect B6 conversion

These forms bypass the conversion steps that might be impaired and provide your body with nutrients in forms it can use immediately.

Focus on Whole Foods

Emphasize naturally folate-rich foods listed above. Reduce consumption of heavily fortified processed foods, especially if you notice they don't make you feel good.

Support Digestive Health

You can take the best supplements in the world, but if your gut isn't absorbing nutrients properly, they won't help. Address any digestive issues including food sensitivities, inflammation, or imbalanced gut bacteria.

Manage Stress

Chronic stress depletes B vitamins faster and can impair methylation. Support your stress response with adequate sleep, stress management techniques, and adaptogenic herbs when appropriate.

Stay Hydrated

Methylation produces waste products that need to be eliminated. Drinking adequate water supports detoxification pathways. A general guideline is half your body weight in ounces daily.

Support Regular Detoxification

This doesn't mean extreme cleanses. It means supporting your body's natural detox processes through:

• Daily bowel movements

• Adequate fiber intake

• Reduced exposure to environmental toxins where practical

• Supporting liver function with whole foods nutrition

Consider SAMe

S-Adenosylmethionine (SAMe) is a supplement that provides methyl groups for various reactions throughout your body. Some people find it helpful for supporting methylation, mood, and joint health.

The discussion of these supplements is for educational purposes only. Please consult a medical professional who knows your personal history before starting any new therapies.

Special Considerations for Pregnancy

If you're planning to become pregnant or are currently pregnant, the MTHFR conversation becomes especially important.

Folate is critical for preventing neural tube defects in developing babies. Most prenatal vitamins contain folic acid, but women with MTHFR variants may benefit more from methylfolate.

Dr. Ryder recommends that women with known MTHFR variants or a history of pregnancy complications discuss methylated prenatal vitamins with their healthcare provider. The goal is ensuring adequate folate in the form your body can actually use.

This doesn't mean folic acid is dangerous. For women without MTHFR variants, standard prenatal vitamins work fine. But for those with variants, methylfolate may offer better support.

When MTHFR Might Not Be the Answer

MTHFR has become somewhat trendy in wellness circles. It's important to keep perspective.

Not everyone with fatigue, mood issues, or brain fog has an MTHFR variant. And not everyone with an MTHFR variant has symptoms. Genetics create tendencies, but they interact with diet, lifestyle, stress, sleep, gut health, and many other factors.

If you test positive for MTHFR but feel great and have no health concerns, you don't need to do anything different. The variant is just information.

If you have symptoms but test negative for MTHFR, that doesn't mean your symptoms aren't real. It means the answer lies somewhere else—perhaps nutrient deficiencies from other causes, digestive issues, hormonal imbalances, chronic infections, or other root causes.

MTHFR is one piece of a complex puzzle. It's worth investigating if it fits your pattern, but it's not the only explanation for health challenges.

What Life Can Look Like with Proper Support

When people with MTHFR variants switch to methylated B vitamins and support their methylation pathways, some notice significant changes:

Energy improves. The persistent fatigue that didn't respond to standard supplements starts lifting. Daily tasks feel more manageable.

Mental clarity returns. Brain fog decreases. Focus and concentration improve. Memory works better.

Mood stabilizes. For some people, supporting methylation helps with mood regulation in ways that surprised them.

Sleep normalizes. When your body can produce adequate melatonin, falling asleep and staying asleep becomes easier.

Cardiovascular markers improve. Homocysteine levels come down into optimal range, reducing long-term cardiovascular risk.

Not everyone experiences dramatic changes. For some, the benefits are subtle. For others, it's life-changing. The only way to know is to test, try the appropriate interventions, and observe how your body responds.

Questions to Ask Your Healthcare Provider

If you're curious about MTHFR, here are questions that can guide productive conversations:

• Would MTHFR testing be appropriate for my health situation?

• Can we check my homocysteine levels on my next blood panel?

• Are my folate and B12 levels optimal, not just "normal"?

• Should I be taking methylated forms of B vitamins instead of standard forms?

• Could any of my current medications be affecting my B vitamin levels?

If your current provider isn't familiar with MTHFR or dismisses your questions, you might benefit from working with someone who takes a more comprehensive approach to health.

Moving Forward with Clarity

MTHFR isn't a disease. It's genetic information that can help explain patterns and guide more effective interventions.

If you've struggled with unexplained fatigue, mood issues, or health challenges that haven't responded to standard approaches, understanding your MTHFR status might provide valuable insight.

The good news is that supporting methylation is straightforward: eat whole foods rich in natural folate, reduce fortified processed foods if they don't serve you, use methylated B vitamins when supplementing, support your gut health, manage stress, and stay hydrated.

These strategies support everyone's health, whether or not MTHFR is part of your picture.

At Naturopathic Physicians Group, Dr. Katz and Dr. Ryder help patients understand their unique biochemistry and design personalized approaches that actually work for their bodies.

Schedule your consultation at https://naturopathicgroup.com/contact

Understanding your body's needs isn't complicated. It just requires the right testing, the right information, and practitioners who take the time to connect the dots.