The MTHFR Gene Everyone’s Talking About… But What Does Actual Research Say?

Hey friend — your favorite nerd here.
Strap in, because we’re about to dismantle one of the most overhyped pieces of gene bro-science ever to slither out of TikTok and into your DMs.

I got this question again today - so I wanted to address it here

The $599 Gene Test That Promises “Optimization”

You’ve probably seen a certain Human Biologist that rhymes with “Shrecka” — peddling “the test that unlocks your methylation.”
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This super genetic kit will happily vacuum $599 USD out of your wallet and hand you a report telling you your genes are sub-optimal.

That’s six hundred bucks to learn you might not handle folate like a Marvel mutant.

What the Science Actually Says

Now let’s slam the hype into a metabolic wall.

Every major medical body that’s weighed in agrees:
​Routine MTHFR testing in healthy people is clinically useless.

The famous C677T and A1298C variants? They’re common. Like “one-in-three-people” common.
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Having one doesn’t mean you need IV methylfolate and a shamanic rebirth ceremony in Costa Rica involving Kambo, Aya, and Iboga eye drops (not that there is anything wrong with any of those and I may have test them just to make sure, haha).

Long & Goldblatt (2016) bluntly stated,"...very limited clinical indications for testing" and testing is "not indicated as a non-specific screening test."
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Hickey et al. (2013), Parkhurst et al. (2020), and Deloughery et al. (2022) echoed the same: strong consensus, weak utility, unnecessary cost.

When It Actually Matters

Genetic testing can be life-saving for rare, severe MTHFR deficiency, usually flagged in newborn screening when methylation crashes hard and fast (Barretta et al., 2023; Huemer et al., 2015).
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That’s a metabolic ICU situation — not a justification for a $599 “wellness” report.

The Real-World Cost

Singh et al. (2024) called it straight: “The financial burden of unnecessary MTHFR testing” is massive.
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Translation: people are burning cash on PDFs that do nothing.
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Meanwhile, the same money could buy you a lifetime supply of creatine and a squat rack — both of which actually alter biochemistry and performance. Check out my friends at Driven Nutrition and Rogue if you want to get on that gainZ train.

The Methylation Twist Nobody Tells You About

Here’s where it gets juicy.
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Your body makes about 1–2 g of creatine per day, and that process hijacks up to half your total methylation capacity.​
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Each molecule of creatine costs your liver a methyl group from SAMe — the same methyl donor your MTHFR enzyme helps recycle.

So if you supplement with creatine, you free up SAMe for other jobs and lower homocysteine.
In other words: the same lifter supplement everyone takes for PRs… also supports methylation.

The Data Bomb

• Brosnan & Brosnan (2007): Creatine synthesis is the single largest consumer of methyl groups in the body.
• Da Silva et al. (2009): Creatine (3–5 g/day) lowered homocysteine, especially in MTHFR C677T carriers.
• Deminice et al. (2016): In rodents, creatine normalized methylation under low-folate conditions.
• Wyss & Kaddurah-Daouk (2000): Dietary creatine down-regulates the GAMT enzyme, slashing methyl demand.

That’s not biohacker folklore — that’s biochemistry.

So instead of dropping half a grand on a gene test that tells you about methylation, take a supplement that fixes the bottleneck directly.

My Meathead Prescription

• Skip the overpriced test.
• Consider taking 3–5 g/day creatine monohydrate.
• Train, sleep, repeat.
• Add some B vitamins if you want
• Re-check your homocysteine in 8 weeks — odds are it’ll drop.

You’ll improve methylation and strength for less than the price of one of Shrecka’s influencer T-shirts.

The Takeaway

You can’t “out-test” a trash lifestyle.
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But you can alter your physiology the old-fashioned way: by training hard, sleeping long, doing some cardio son, and taking supplements with actual metabolic leverage.

Much love,

Dr Mike
PS -Don’t let shiny gene reports distract you while your ATP tanks are empty.
Go read yesterday’s creatine newsletter if you missed it, grab a tub, and save yourself $569 of methylated regret.
​→ Yesterday’s Creatine Deep Dive​

References

Barretta, F., Uomo, F., Fecarotta, S., Albano, L., Crisci, D., Verde, A., Fisco, M., Gallo, G., Stagna, D., Pricolo, M., Alagia, M., Terrone, G., Rossi, A., Parenti, G., Ruoppolo, M., Mazzaccara, C., & Frisso, G. (2023). Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency. Genes, 14(5), 980.

Brosnan, J. T., & Brosnan, M. E. (2007). Creatine: Endogenous metabolite, dietary, and therapeutic supplement.Physiological Reviews, 87(4), 1107–1131.

Da Silva, R. P., et al. (2009). Creatine supplementation lowers plasma homocysteine in humans. Clinical Nutrition, 28(1), 25–30.

Deloughery, T., et al. (2022). A call to action: MTHFR polymorphisms should not be part of inherited thrombophilia testing. Research and Practice in Thrombosis and Haemostasis, 6(2).

Deminice, R., et al. (2016). Creatine supplementation prevents homocysteine increase induced by folate deficiency in rats. Nutrients, 8(8), 443. https://doi.org/10.3390/nu8080443

Hickey, S., Curry, C., & Toriello, H. (2013). ACMG Practice Guideline: Lack of evidence for MTHFR polymorphism testing. Genetics in Medicine, 15(2), 153–156.

Huemer, M., Kožich, V., Rinaldo, P., Baumgartner, M., Merinero, B., Pasquini, E., Ribes, A., & Blom, H. (2015). Newborn screening for homocystinurias and methylation disorders: Systematic review and proposed guidelines.Journal of Inherited Metabolic Disease, 38(6), 1007–1019.

Long, S., & Goldblatt, J. (2016). MTHFR genetic testing: Controversy and clinical implications. Australian Family Physician, 45(4), 237–240.

Parkhurst, E., Calonico, E., & Noh, G. (2020). Medical decision support to reduce unwarranted MTHFR genetic testing. Journal of Medical Systems, 44(5).

Singh, A., Ghaffar, Y., Goyal, S., Gaddam, S., & Ramadas, P. (2024). The financial burden of unnecessary MTHFR gene testing. Blood.

Wyss, M., & Kaddurah-Daouk, R. (2000). Creatine and creatinine metabolism. Physiological Reviews, 80(3), 1107–1213.

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Use code DRMIKE to save a few bucks on all Driven products​
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____________________

Mike T Nelson CISSN, CSCS, MSME, PhD
Associate Professor, Carrick Institute
Owner, Extreme Human Performance, LLC
Editorial Board Member, STRONG Fitness Mag

Mike T Nelson is a PhD and not a physician or registered dietitian. The contents of this email should not be taken as medical advice. It is not intended to diagnose, treat, cure, or prevent any health problem - nor is it intended to replace the advice of a physician. Always consult your physician or qualified health professional on any matters regarding your health.

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