In a recent video analysis, Dr. Lily Johnston, a board-certified vascular surgeon specializing in cardiometabolic prevention, explored an overlooked aspect of creatine supplementation alongside fitness coach Tom DeLauer.
What she discovered challenges conventional thinking about this popular supplement.
While most athletes focus on creatine’s muscle-building benefits, the real story involves methylation pathways, homocysteine levels, and amino acid conservation.
The implications could reshape how clinicians approach patients with methylation defects.
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The Hidden Metabolic Cost of Making Creatine
DeLauer emphasized a startling fact: creatine synthesis consumes approximately 40% of the body’s methyl groups—more than any other single biochemical reaction.
These methyl groups, donated by S-adenosylmethionine (SAM), are essential for DNA repair, neurotransmitter production, and liver detoxification.
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Making creatine inside your body burns through almost half of your body’s methyl groups. The same methyl groups that you need for DNA repair and for neurotransmitter production, so things like dopamine and serotonin.
According to research published in the American Journal of Physiology, the methylation of guanidinoacetate (GAA) to form creatine uses more SAM than all other methyltransferase reactions combined.
This massive demand means mood regulation, detoxification capacity, and gene expression must compete for remaining methyl groups.
Natural Creatine Production: The Numbers
DeLauer revealed that the body manufactures approximately 1 gram of creatine daily through a two-step process.
First, arginine and glycine combine in kidneys to form GAA. Then GAA travels to the liver for methylation by SAM, creating creatine.
Diet provides roughly another gram from meat and fish, potentially reaching 3 grams with conscientious animal protein intake.
Most supplement protocols recommend 5-10 grams daily—far exceeding natural production and dietary intake combined.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
The Glycine Connection
Beyond methyl groups, creatine synthesis depletes glycine reserves. Dr. Brad Stanfield’s research indicates the body needs approximately 10 grams of glycine daily just for collagen turnover.
Endogenous synthesis produces only 3 grams, while typical diets provide 2-5 grams.
This creates a 5-gram daily shortfall before accounting for glycine’s other critical roles:
- Glutathione synthesis: Master antioxidant production
- Collagen formation: Joint, skin, hair, and connective tissue health
- Detoxification: Bile acid conjugation
- Sleep support: 5 grams before bed may improve sleep quality
Every molecule of glycine that your body burns through to make creatine is a molecule that is not going towards your glutathione. It’s not going towards your collagen, and it’s not going towards your detox pathways.
When creatine synthesis consumes available glycine, collagen supplements become less effective since glycine gets diverted to creatine production instead of reaching intended targets.
Does Supplementation Shut Down Natural Production?
Dr. Johnston addressed concerns about dependency. Research in the Virtual Nutrition Show confirmed that creatine supplementation down-regulates enzymes initiating endogenous synthesis.
However, unlike testosterone replacement, this shutdown reverses immediately upon discontinuation.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
The body responds to demand. When supplemental creatine stops, natural production resumes without creating lasting deficits.
Unlike hormone pathways subject to receptor down-regulation, creatine supplementation doesn’t impair long-term production capacity.
The Homocysteine Question
DeLauer suggested creatine supplementation could lower homocysteine, a cardiovascular risk marker. Dr. Johnston found this claim particularly intriguing for patients with methylation pathway problems.
This has huge implications for patients who have methylation pathway problems. So, that is anybody who has elevated homocysteine or an MTHFR mutation.
She consulted Open Evidence, which returned a B- grade—moderate evidence with mixed results. Animal studies showed robust effects, with creatine reducing plasma homocysteine by 25% in rats.
Human trials painted a different picture.
The Bangladesh Trial: Gold Standard Evidence
The largest rigorous study involved 458 Bangladeshi adults in a double-blind, randomized, placebo-controlled trial. Participants received 3 grams of creatine daily for 12 weeks.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
Results showed creatine significantly lowered plasma GAA by 10%, confirming down-regulation of endogenous synthesis. However, it did not lower plasma homocysteine on average.
Among participants receiving both creatine and folic acid, those experiencing GAA decline also showed correlated homocysteine reduction—suggesting the methyl-sparing mechanism operates but proves insufficient alone.
Folic acid alone reduced homocysteine by 23%. Combined creatine plus folic acid reduced it by 21%—essentially no additional benefit from creatine.
Special Populations May Benefit More
Two smaller studies suggested specific groups might respond better:
- Vegan subjects with hyperhomocysteinemia: 5 grams daily for 3 weeks normalized homocysteine in the elevated subgroup
- MTHFR 677TT homozygote case report: Dramatic drop from 33 to 17 micromoles per liter after 1 month on 5 grams daily
Individuals with wild type or heterozygous MTHFR showed no benefit.
This suggests creatine may help when folate-dependent remethylation is impaired, baseline homocysteine is elevated, or dietary creatine intake is low.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
Practical Recommendations
Both DeLauer and Dr. Johnston emphasized quality and dosing strategy.
Choosing Quality Creatine
Dr. Johnston strongly recommended NSF Sport Certified creatine monohydrate. Third-party testing reveals many products don’t contain advertised creatine levels.
Creapure, a German-manufactured creatine, represents another quality option.
Avoid gummy formulations unless intentionally using glucose for absorption enhancement. Otherwise, unnecessary carbohydrates and calories provide no additional benefit.
Optimal Dosing Strategy
DeLauer recommended age-based dosing:
- Under 30: 5 grams daily minimum
- Over 30: 10 grams daily, especially with connective tissue concerns
- Timing: Split doses throughout the day or sip in water for steady methylation support
Loading phases are unnecessary. Consistent daily intake provides sufficient down-regulation of endogenous synthesis.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
Complementary Supplementation
To maximize freed glycine and methyl groups:
- Collagen or bone broth: Additional glycine sources
- N-acetylcysteine (NAC): Works synergistically with freed glycine for glutathione production
- Ground beef with connective tissue: Natural collagen and glycine
Dr. Johnston’s Clinical Takeaway
After reviewing evidence, Dr. Johnston concluded creatine supplementation alone won’t reliably lower homocysteine in most patients.
I was prepared to say that this might be practice changing for me. I don’t think it’s a bad idea. I think creatine is a really interesting supplement, but right now I still believe based on at least this trial that methylated B supplementation is probably still the mainstay foundational therapy.
Methylated B vitamins remain the foundation for patients with elevated homocysteine or MTHFR mutations.
Creatine offers substantial benefits—muscle preservation, cognitive support, and potentially reduced metabolic burden—but shouldn’t replace established methylation support protocols.
Special populations may experience greater homocysteine reduction: vegans, those with severely impaired methylation, or individuals with baseline hyperhomocysteinemia. For these groups, creatine supplementation alongside methylated B vitamins warrants consideration.
The theoretical rationale remains compelling. Sparing 40% of methyl groups theoretically supports better neurotransmitter synthesis, DNA repair, and detoxification. Conserving glycine should enhance collagen production, glutathione synthesis, and possibly sleep quality.
If you want something simple that actually works, this is one of the most effective tools I’ve used to build strength, conditioning, and endurance without needing a full gym setup.
- Full-body training with one weight using swings, squats, and presses
- Solid cast iron build that feels stable and lasts for years
- Comfortable grip that makes high-rep workouts easier to handle
However, translating biochemical mechanisms into measurable clinical outcomes requires robust evidence—which currently shows creatine works best as part of comprehensive methylation support rather than standalone therapy.
