Nutrients Review: Risk of Adverse Outcomes in Females Taking Oral Creatine Monohydrate: A Systematic Review and Meta-Analysis

Authors and Affiliations

• Deborah L. de Guingand, Kirsten R. Palmer, Rodney J. Snow, Miranda L. Davies-Tuck, and Stacey J. Ellery

  • The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia

  • Contact: miranda.tuck@hudson.org.au (M.L.D.-T.), stacey.ellery@hudson.org.au (S.J.E.), deborah.deguingand@hudson.org.au

  • Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia

  • Monash Health, Monash Medical Centre, Melbourne, Australia

  • Institute of Physical Activity and Nutrition, Deakin University, Melbourne, Australia

Abstract

• Creatine Monohydrate (CrM) is commonly used as an ergogenic aid and for potential therapeutic benefits.

• Prior studies on adverse outcomes of CrM mainly included male or mixed-sex populations.

• A systematic search focused on female participants was performed to report adverse outcomes; out of 656 identified studies, only 58 included females.

• 29 studies monitored adverse outcomes, involving 951 participants, with no serious adverse events reported.

• No significant differences in total adverse events across groups.

• Authors recommend future studies on female CrM supplementation should enhance reporting of adverse outcomes.

Keywords

• creatine monohydrate; supplementation; adverse outcomes; safety; human; female

1. Introduction

• Creatine Kinase Circuit: Key for cellular bioenergetics and ATP production, crucial in skeletal muscle.

• Historical Use of CrM: Used to enhance sports performance and may modify neurodegenerative or musculoskeletal disorders.

  • Mixed results reported for effectiveness in conditions like Huntington’s disease, amyotrophic lateral sclerosis, and other muscular dystrophies.

• Publications on Safety: Over 80 reviews on performance benefits; only 34 addressed safety, none sex-specific.

• Lack of Data in Women: Significant athlete demographics, including auto-immune disorders and major depressive disorders.

• Review Objective: Consolidate evidence regarding adverse outcomes in females using CrM.

2. Methods

2.1 Study Selection

• Inclusion Criteria: Trials with female populations, explicit adverse outcome reporting, encompassing various study types (randomized controlled trials, open-label trials, etc.).

  • Excluded: studies with pediatric or known creatine deficiency populations.

• Ethics: All studies had requisite human ethics approval.

2.2 Search Strategy

• Databases: Medline, Embase, Web of Science, Scopus, SPORTDiscus, ScienceDirect, CINAHL, Cochrane.

• Keywords: Included specialized terms for creatine and adverse event reporting.

• Manual Search and Contact: Engaged with trial authors when necessary to clarify data.

2.3 Data Extraction

• The lead author managed data extraction, sorting symptoms by organ systems, and compiling data suitable for analysis.

• Data Types: Serious adverse events, adverse effects, weight gain, etc.

2.4 Data Analysis and Statistical Methods

• Characteristics of studies organized in tables.

• Studies categorized as ergogenic (muscle-related) or therapeutic (cognitive function improvement).

• Pre-menopausal females defined as those aged 13-49 years.

• Outcomes assessed: deaths, serious and minor adverse events.

2.5 Risk of Bias

• Utilized Cochrane Handbook for systematic reviews and GRADE assessment.

3. Results

3.1 Search Characteristics

• 6964 articles retrieved; 29 final studies included after screening.

3.2 Study and Participant Characteristics

• 951 participants across included studies. Mixed methodology for collecting adverse outcomes.

3.3 Risk of Bias

• Low risk observed across most domains with selective reporting being the most reliable category.

3.4 Deaths

• No deaths reported in any included studies.

3.5 Adverse Outcomes

• Majority reported adverse events related to CrM usage, with some studies highlighted adverse events including mild symptoms (e.g., bloating).

  • Risk Ratio (RR) for total adverse events: RR 1.24 (95% CI 0.51, 2.98) indicated no significant differences.

3.6 Gastrointestinal Events

• Most frequent adverse events noted in gastrointestinal system, such as nausea and bloating.

• RR for gastrointestinal events: RR 1.09 (95% CI 0.53, 2.24); no significance found between groups.

3.7 Renal System

• 14 studies verified renal functions, with no significant differences across groups for renal biomarkers like serum creatinine.

3.8 Hepatic System

• Biomarkers of liver function showed no significant differences across groups.

3.9 Body Composition Effects

• 23 studies involved body composition measures, with meta-analysis showing no significant weight gain attributable to CrM.

3.10 Cardiovascular Effects

• Adverse cardiovascular effects minimally assessed; no serious events attributed to CrM.

3.11 Dosing Regimens

• Varied dosing reported: loading doses ranging from 15-30 grams across studies, with medium-term regimens lasting longer.

3.12 Withdrawals and Loss

• Total attrition rate across studies was 14%.

4. Discussion

• First comprehensive review on adverse outcomes in female CrM users.

• Confirmed lack of correlation between CrM use and serious adverse outcomes in females.

• Endorses findings from earlier reviews indicating no significant safety concerns regarding CrM.

5. Strengths and Limitations

• Study design was generally robust; limitations include small sample sizes.

• Reporting biases present; passive event reporting can under- or overestimate actual adverse events.

6. Conclusions

• CrM supplementation in females appears safe across different dosing regimens, with no significant adverse impacts observed.

• Future research recommended for larger homogenous groups focusing on safety reporting in CrM supplementation.

Supplementary Materials

• Files detailing the search strategies, adverse events tally, and withdrawals provided.

Author Contributions

• D.L.d.G. led the research design and analysis. Collaboration on manuscript revisions involved all authors.

Funding and Acknowledgments

• No external funding; acknowledgments noted to Monash University for resource support.

Abbreviations

• ATP: Adenosine triphosphate

• CI: Confidence Interval

• CrM: Creatine Monohydrate

• I2: Heterogeneity statistic

• MD: Mean Difference

• Pl: Placebo

• RR: Risk Ratio

References

• [Selective reference list included in original text]

This systematic review and meta-analysis investigated the risk of adverse outcomes of oral Creatine Monohydrate (CrM) supplementation in females. Despite CrM's common use as an ergogenic aid, prior safety studies predominantly featured male or mixed-sex populations.

Key Findings:

• A systematic search identified 58 studies including females, with 29 (encompassing 951 participants) monitoring adverse outcomes.

• No serious adverse events or deaths were reported across any included studies.

• Risk Ratio (RR) for total adverse events was $1.24$ (95% CI $0.51, 2.98$), indicating no significant differences in total adverse events between CrM and control groups.

• Gastrointestinal events were the most frequent mild symptoms, but their RR was $1.09$ (95% CI $0.53, 2.24$), showing no significant difference.

• Renal and hepatic biomarkers showed no significant differences.

• Meta-analysis revealed no significant weight gain attributable to CrM.

• Varied CrM dosing regimens were reported, with a total attrition rate of 14% across studies.

Conclusion:

CrM supplementation in females appears safe across different dosing regimens, with no significant adverse impacts observed. The review, the first comprehensive analysis for females, confirms existing findings of no significant safety concerns. Authors recommend future research for larger, homogenous groups focusing on enhanced safety reporting.