Effects of guanidinoacetic acid and creatine monohydrate supplementation on markers of health and cognitive function

Plain English summary of protocol

Background and study aims
Creatine monohydrate (CrM) supplementation (e.g., 4 x 5 g or 20 g/d for 5-7 days and 3 – 6 g/d for 4-12 weeks) increases muscle creatine and phosphocreatine (Cr) content by 20% - 40%, and brain creatine and phosphocreatine content by 5% - 15%, thereby improving the ability to produce energy during high-demand states. While most studies have evaluated the effects of CrM supplementation on physical exercise performance several studies have reported that high-dose creatine supplementation can increase brain phosphocreatine content leading to improved cognitive function. Creatine is obtained in gram quantities from meat and fish and is synthesized in the body when dietary availability is low (2 – 4 grams/kg). In over 30 years of research, clinical trials involving creatine monohydrate supplementation have reported no adverse health risks other than a small amount of weight and muscle mass gain (a desired effect). Conversely, several health benefits have been reported throughout the lifespan.

Guanidinoacetic Acid (GAA) is a precursor in the natural synthesis of creatine in muscle, the heart, and particularly in the brain. Since some animals more effectively convert GAA to creatine, GAA has been added to the feed of animals consumed by humans (e.g., chickens, pigs, etc.) as a means of increasing muscle mass at EFSA-approved dosages of 1,200 mg/kg/d. GAA has also been used as a nutrient in human nutrition since the 1950s and is sold as an ingredient for dietary supplements. No adverse effects have been reported from GAA supplementation (1.2 – 4.8 grams/day for 4 – 12 weeks), although a non-clinically significant increase (≈ 3.5 μmol/L) in homocysteine levels was reported when supplementing the diet with 4.8 g/d for 4 weeks and although values remained within normal ranges (5 – 20 μmol/L) and were well below values considered to be high risk (> 50 μmol/L). Since GAA supplementation has been reported to increase energy levels in the brain more effectively than CrM, dietary supplementation with GAA (with and without CrM) may be an effective way to improve cognitive function. For this reason, GAA supplementation has been suggested to be a novel nootropic to improve cognitive function and brain health. However, while there is strong theoretical rationale, the effects of GAA supplementation (with or without CrM supplementation) on cognitive function have not been studied, particularly in active aging populations who may benefit.

The purpose of this study is to evaluate the effects of GAA supplementation with and without CrM on markers of cognitive function and health markers in older adults.

Who can participate?
Healthy adult volunteers aged between the ages of 45 and 75 years.

What does the study involve?
Participants will be randomly assigned to one of three groups. All groups will follow the same exercise and diet program, but the supplements will differ:

Group 1: Placebo for both GAA and CrM.
Group 2: GAA supplement plus a placebo for CrM.
Group 3: GAA supplement plus CrM supplement.

The supplements (or placebos) will be provided in stick packs for double-blind administration. Participants will take two doses per day, one with breakfast and one with dinner, for 12 weeks.

What are the possible benefits and risks of participating?
Possible benefits of participating include increased insight into one's health and fitness status (i.e., anthropometric measurements, vital sign measurements, lab values, DXA body composition and bone density values, etc.). Possible risks of participation include complications from the blood draws (i.e., pain, dizziness, nausea, etc.), radiation exposure from the DXA scan (< 1 mRem per scan), side effects of the supplements (i.e., bloating, cramping, diarrhea, etc.), and possible
allergic reactions to the supplements.

Where is the study run from?
WoodNext Foundation, USA.

When is the study starting and how long is it expected to run for?
September 2025 to June 2026.

Who is funding the study?
WoodNext Foundation, USA.

Who is the main contact?
Dr Richard Kreider, rbkreider@tamu.edu

Contact information

Dr Richard Kreider
Principal investigator, Scientific

675 John Kimbrough Blvd.
#118
College Station
77843-4253
United States of America

ORCID ID	0000-0002-3906-1658
Phone	+1 9794581498
Email	rbkreider@tamu.edu

Mr Christopher Rasmussen
Public

675 John Kimbrough Blvd.
Suite #206
College Station
77843-4253
United States of America

ORCID ID	0009-0005-8941-3067
Phone	9794581741
Email	crasmussen@tamu.edu

Study information

Eligibility

Locations

Countries of recruitment

• United States of America

Study participating centres

Results and Publications

Editorial Notes

20/11/2025: Internal review.
18/11/2025: Possible benefits and risks were added to the plain English summary of protocol.
14/11/2025: Study’s existence confirmed by the Texas A&M University Institutional Review Board (IRB), USA.