Creatine Supplementation for Homocystinuria

Overseen By Kendall Plant, BSc

Age: 18 - 65

Sex: Male

Trial Phase: Academic

Sponsor: University of British Columbia

Disqualifiers: Metabolic, Neurological, Genetic, Immune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 week

6 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must be in good health and free of any concurrent illnesses to participate.

What data supports the effectiveness of the treatment Creatine Monohydrate for Homocystinuria?

Creatine supplementation has been shown to lower homocysteine levels in individuals with a specific genetic variation (MTHFR 677TT), which may suggest potential benefits for managing homocystinuria, a condition characterized by high homocysteine levels. ^{1 2 3 4 5}

Is creatine supplementation safe for humans?

Creatine monohydrate is generally considered safe for healthy adults when taken at a daily dose of 3 grams, although it may cause minor side effects like stomach upset and muscle cramps. Other forms of creatine have less safety data, but creatine nitrate and creatine monohydrate have been shown to be safe in short-term studies. ^{3 6 7 8 9}

How is creatine supplementation different from other treatments for homocystinuria?

Creatine supplementation is unique because it is primarily known for increasing muscle strength and performance, especially in athletes and individuals with neuromuscular diseases, rather than directly treating homocystinuria. Unlike other treatments that might target the specific metabolic pathways involved in homocystinuria, creatine works by enhancing energy production in muscles, which may offer indirect benefits. ^{1 2 3 4 10}

What is the purpose of this trial?

Homocystinuria is a rare and inherited metabolic disorder, people with this condition don't have an enzyme needed to break down an amino acid called homocysteine. When the body can't break down the homocysteine made from another amino acid methionine, it becomes toxic to the heart, brain, and bones. We are constantly eating methionine, a building block of protein, so a common treatment is eating a low-protein diet with medical foods and vitamin pills. This can be hard to follow due to bad tastes and missing out on foods a person enjoys, especially in children. The goal of this study is to provide participants with a supplement containing creatine, another amino acid related to methionine and homocysteine, and learn if it lowers homocysteine production in healthy adult men. We would ultimately like to see if creatine supplements are a potential alternate treatment of Homocystinuria in this proof of concept study, before studying individuals with the condition. Researchers in this study want to know: * How does the bodies digestion of isotope methionine change in breath and urine when creatine is taken in healthy young adult men? * How do levels of homocysteine, methionine and related metabolites change in the blood when creatine is taken by healthy young adult men? Participants will: * Complete two (2), 8-hour study days on-site. * Eat a lower protein diet for one (1) week before the first study day, and eat a lower protein diet with creatine supplements for one (1) week before the second study day. * During both study days eat special hourly meals of controlled amino acids and nutrients, along with a methionine isotope. (An isotope is a stable labelled amino acid that is colourless, odorless, tasteless, and safe for consumption. In the lab we can detect this isotope in breath and urine samples collected during the study day). * Provide samples of breath, urine and blood. (Researchers will also take body measurements (height weight), and use non-invasive tests to measure body composition and energy needs).

Research Team

Rajavel Elango, PhD

Principal Investigator

University of British Columbia

Eligibility Criteria

This trial is for healthy adult men who can follow a low-protein diet and are interested in participating in a study that investigates the effects of creatine supplementation on homocysteine levels. Participants will need to commit to two 8-hour study days, adhere to dietary requirements, and provide various samples.

Inclusion Criteria

Not claustrophobic (a clear hood will be placed over your head for approximately 20 min to measure energy expenditure)

Not enrolled in any other research studies

I am a cisgender male.

Exclusion Criteria

Smokers

I have taken creatine supplements recently or am currently taking them.

Following a non-traditional dietary pattern (e.g. Keto diet, Atkins diet, paleo diet, intermittent fasting, strict vegan, calorie-restricted diet etc.)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Participants follow a controlled diet of 1g protein/kg body weight/day for 7 days before the baseline study day

1 week

1 visit (8-hour study day)

Treatment

Participants follow a controlled diet of 1g protein/kg body weight/day and take 20g creatine supplement for 7 days before the treatment study day

1 week

1 visit (8-hour study day)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Creatine

Trial Overview The study tests if creatine supplements can lower homocysteine production by monitoring changes in digestion of methionine (using an isotope) and measuring blood levels of homocysteine, methionine, and related metabolites after taking creatine.

Participant Groups

Group I: Treatment - Creatine Supplementation 20mg Experimental Treatment 2 Interventions

Each participant will complete a supplemented study day. For 7 days prior to the study day each participant will eat a controlled diet of 1g protein/kg body weight/day, and the provided 20mg creatine supplement.

Group II: Baseline - no creatine supplementation Experimental Treatment 1 Intervention

Each participant will complete a baseline study day. For 7 days prior to the study day each participant will eat a controlled diet of 1g protein/kg body weight/day.

Creatine is already approved in United States, European Union for the following indications:

Approved in United States as Creatine Monohydrate for:

• Dietary supplement for muscle growth and performance
• Potential treatment for post-concussive symptoms

Approved in European Union as Creatine Monohydrate for:

• Dietary supplement for muscle growth and performance
• Potential treatment for post-concussive symptoms

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Findings from Research

There are potential risks associated with uncontrolled supplementation of pure creatine monohydrate (Cr.H2O) in athletes, as the body has a natural feedback mechanism that regulates creatine production.

The article suggests that instead of pure Cr.H2O, a complex nutritional supplement using natural alpha-ketoglutarate could be a safer and more effective alternative for delivering creatine and other beneficial compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scientific facts behind creatine monohydrate as sport nutrition supplement. Silber, ML.[2017]

In a study involving 36 resistance-trained individuals, traditional creatine monohydrate (CrM) supplementation was found to be more effective than buffered creatine (KA) in increasing muscle creatine content and improving strength, with no significant differences in side effects reported between the two forms.

The results showed that neither the recommended lower dose of KA nor the higher equivalent loading dose provided any additional benefits over CrM, challenging claims that buffered creatine is superior in efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. Jagim, AR., Oliver, JM., Sanchez, A., et al.[2021]

Creatine nitrate (CrN) supplementation at 3 g was well-tolerated and showed no safety concerns, with minimal side effects reported across all treatment groups in a study involving 48 participants over 28 days.

In terms of exercise performance, the CrN-High group significantly increased bench press lifting volume compared to the placebo group, demonstrating that CrN can provide similar performance benefits to traditional creatine monohydrate (CrM).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. Galvan, E., Walker, DK., Simbo, SY., et al.[2018]

In a pilot study with 81 patients and a follow-up study with 21 patients, creatine monohydrate supplementation significantly increased strength measures, including handgrip and knee extensor strength.

The treatment involved administering 10 g daily for 5 days, followed by 5 g daily for another 5 days, demonstrating that short-term creatine use can effectively enhance high-intensity strength in individuals with neuromuscular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Creatine monohydrate increases strength in patients with neuromuscular disease. Tarnopolsky, M., Martin, J.[2019]

A one-month creatine supplementation (5 g/day) significantly reduced plasma homocysteine levels in a subject with the MTHFR 677TT genotype, suggesting a potential therapeutic effect of creatine on methylation processes.

Creatine supplementation may enhance the body's ability to produce sarcosine, which could improve the activity of the MTHFR enzyme, potentially benefiting individuals with reduced enzyme activity due to genetic polymorphisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. Petr, M., Steffl, M., Kohlíková, E.[2020]

Creatine nitrate (CN) supplementation at doses of 1 g and 2 g daily for 28 days was found to be safe for young adults, with no significant adverse effects on most blood safety markers.

While some participants experienced slight increases in blood urea nitrogen (BUN) levels, these changes were minor and not clinically concerning, suggesting that CN could be a viable alternative to traditional creatine monohydrate supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

28 days of creatine nitrate supplementation is apparently safe in healthy individuals. Joy, JM., Lowery, RP., Falcone, PH., et al.[2018]

Creatine monohydrate is generally considered safe for healthy adults at a daily intake of 3 grams, with some minor side effects like gastrointestinal issues and muscle cramps reported.

While most creatine forms are unlikely to pose safety concerns, there are specific safety concerns associated with creatine orotate, creatine phosphate, and magnesium creatine chelate, indicating that not all creatine supplements are equally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Creatine and creatine forms intended for sports nutrition. Andres, S., Ziegenhagen, R., Trefflich, I., et al.[2018]

Creatine monohydrate (CrM) remains the only form of creatine with substantial evidence supporting its bioavailability, efficacy, and safety, as confirmed by a review of various marketed creatine forms.

Despite ongoing claims about other 'novel forms' of creatine, many lack sufficient evidence for effectiveness and safety, and CrM is still the recommended source by professional organizations and regulatory authorities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. Kreider, RB., Jäger, R., Purpura, M.[2022]

The novel creatine blend CN-CRN significantly increased serum creatine levels more than both pure creatine nitrate and regular creatine monohydrate in a study of 10 healthy young men, indicating superior bioavailability.

After 5 days of supplementation, CN-CRN also led to a greater increase in muscle creatine levels compared to the other formulations, while showing no clinically relevant side effects, suggesting it is a safe and effective alternative to traditional creatine supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men. Ostojic, SM., Stajer, V., Vranes, M., et al.[2023]

Creatine supplementation significantly increases creatine levels in vegetarians, often surpassing those found in omnivores, and enhances muscle mass, strength, and endurance, making it beneficial for vegetarian athletes.

While creatine improved various physical and cognitive performance metrics in vegetarians, the evidence on whether it enhances exercise performance more than in omnivores remains mixed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of Creatine Supplementation for Vegetarians Compared to Omnivorous Athletes: A Systematic Review. Kaviani, M., Shaw, K., Chilibeck, PD.[2020]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Scientific facts behind creatine monohydrate as sport nutrition supplement. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Creatine monohydrate increases strength in patients with neuromuscular disease. [2019]

5. Czech Republic pubmed.ncbi.nlm.nih.gov

Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

28 days of creatine nitrate supplementation is apparently safe in healthy individuals. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Creatine and creatine forms intended for sports nutrition. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Benefits of Creatine Supplementation for Vegetarians Compared to Omnivorous Athletes: A Systematic Review. [2020]