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Creatine supplementation protocols with or without training interventions on body composition: a GRADE-assessed systematic review and dose-response meta-analysis.

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Affiliations

  • 1. Ahvaz Jundishapur University of Medical Sciences, Student research committee, Ahvaz, Iran.
      Authors
    • Pashayee-Khamene F 1
    • Heidari Z 1
    (2 authors)
  • 2. Shahid Beheshti University of Medical Sciences, Cancer Research Center, Tehran, Iran.
      Authors
    • Asbaghi O 2
    (1 author)
  • 3. Ahvaz Jundishapur University of Medical Sciences, Nutrition and Metabolic Diseases Research Center, Ahvaz, Iran.
      Authors
    • Ashtary-Larky D 3
    (1 author)
  • 4. Shahid Beheshti University of Medical Sciences, Faculty of Medicine, Tehran, Iran.
      Authors
    • Goudarzi K 4
    (1 author)
  • 5. Brandon University, Department of Physical Education Studies, Brandon, MB, Canada.
      Authors
    • Forbes SC 5
    (1 author)
    • Show all (9)

ORCIDs linked to this article

Journal of the International Society of Sports Nutrition, 23 Jul 2024, 21(1):2380058
https://doi.org/10.1080/15502783.2024.2380058 PMID: 39042054 PMCID: PMC11268231

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Abstract 

Background

Despite the robust evidence demonstrating positive effects from creatine supplementation (primarily when associated with resistance training) on measures of body composition, there is a lack of a comprehensive evaluation regarding the influence of creatine protocol parameters (including dose and form) on body mass and estimates of fat-free and fat mass.

Methods

Randomized controlled trials (RCTs) evaluating the effect of creatine supplementation on body composition were included. Electronic databases, including PubMed, Web of Science, and Scopus were searched up to July 2023. Heterogeneity tests were performed. Random effect models were assessed based on the heterogeneity tests, and pooled data were examined to determine the weighted mean difference (WMD) with a 95% confidence interval (CI).

Results

From 4831 initial records, a total of 143 studies met the inclusion criteria. Creatine supplementation increased body mass (WMD: 0.86 kg; 95% CI: 0.76 to 0.96, I2 = 0%) and fat-free mass (WMD: 0.82 kg; 95% CI: 0.57 to 1.06, I2 = 0%) while reducing body fat percentage (WMD: -0.28 %; 95% CI: -0.47 to -0.09; I2 = 0%). Studies that incorporated a maintenance dose of creatine or performed resistance training in conjunction with supplementation had greater effects on body composition.

Conclusion

Creatine supplementation has a small effect on body mass and estimates of fat-free mass and body fat percentage. These findings were more robust when combined with resistance training.

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J Int Soc Sports Nutr. 2024; 21(1): 2380058.
Published online 2024 Jul 23. https://doi.org/10.1080/15502783.2024.2380058
PMCID: PMC11268231
PMID: 39042054

Creatine supplementation protocols with or without training interventions on body composition: a GRADE-assessed systematic review and dose-response meta-analysis

Fereshteh Pashayee-Khamene, a Zeinab Heidari, a Omid Asbaghi, b Damoon Ashtary-Larky, c Kian Goudarzi, d Scott C Forbes, e Darren G. Candow, f Reza Bagheri, g Matin Ghanavati, h and Fred Dutheil i
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ABSTRACT

Background

Despite the robust evidence demonstrating positive effects from creatine supplementation (primarily when associated with resistance training) on measures of body composition, there is a lack of a comprehensive evaluation regarding the influence of creatine protocol parameters (including dose and form) on body mass and estimates of fat-free and fat mass.

Methods

Randomized controlled trials (RCTs) evaluating the effect of creatine supplementation on body composition were included. Electronic databases, including PubMed, Web of Science, and Scopus were searched up to July 2023. Heterogeneity tests were performed. Random effect models were assessed based on the heterogeneity tests, and pooled data were examined to determine the weighted mean difference (WMD) with a 95% confidence interval (CI).

Results

From 4831 initial records, a total of 143 studies met the inclusion criteria. Creatine supplementation increased body mass (WMD: 0.86 kg; 95% CI: 0.76 to 0.96, I2 = 0%) and fat-free mass (WMD: 0.82 kg; 95% CI: 0.57 to 1.06, I2 = 0%) while reducing body fat percentage (WMD: −0.28 %; 95% CI: −0.47 to −0.09; I2 = 0%). Studies that incorporated a maintenance dose of creatine or performed resistance training in conjunction with supplementation had greater effects on body composition.

Conclusion

Creatine supplementation has a small effect on body mass and estimates of fat-free mass and body fat percentage. These findings were more robust when combined with resistance training.

KEYWORDS: Creatine supplementation, body composition indices, meta-analysis

1. Introduction

Creatine, a non-protein organic amino acid [1], is synthesized from arginine, glycine, and methionine [2]. Within a cell, ~ 66% of creatine is stored as phosphocreatine (PCr) with the remainder stored as free creatine [2]. Creatine is degraded non-enzymatically into creatinine at a rate of 1–2% per day, which needs to be replaced via endogenous production and/or through exogenous sources (i.e. red meat, seafood, creatine supplementation). The combination of endogenous production (primarily in the liver and kidneys) and habitual dietary sources of creatine causes ~ 80% intramuscular creatine saturation levels [3]. The addition of creatine supplementation further augments these levels by ~ 20% [4]. Mechanistically, elevated stores of PCr will enhance the capacity to rapidly re-synthesize adenosine triphosphate (ATP). Furthermore, creatine is pleiotropic and can alter calcium, glycogen, protein kinetics, insulin-like growth factor-1, myogenic regulatory factors, satellite cells, inflammation, and oxidative stress [5].

The most common creatine supplementation protocols use either absolute or relative dosing strategies. From an absolute perspective, one strategy is to ingest 20 g/day for 5–7 (referred to as the creatine loading phase) followed by 2–5 g/day thereafter (creatine maintenance phase) [6]. This strategy is well established to increase intramuscular creatine stores and/or exercise performance [6,7]. Alternatively, 3 g/day (without the creatine loading phase) can be adopted and will saturate intramuscular creatine stores in ~28 days [8]. Relative dosing strategies (0.03 to 0.14 g/kg/day) may account for individual differences in body mass [3] and have been shown to be effective over time [9,10].

To date, only a single systematic review involving older adults has been performed that examined the influence of different creatine dosing strategies and resistance training on measures of fat-free mass [11]. Results showed no significant differences between low (≤5 g/day) vs. high (>5 g/day) doses of creatine, with and without a creatine loading phase, on gains in estimates of fat-free mass. Fat mass was not assessed in this review. The effects of different creatine dosing strategies on measures of body composition in younger adults remains to be elucidated. Beyond dosing strategies, creatine supplementation appears to be more efficacious when combined with resistance training compared to creatine supplementation alone [12]. However, it is worth noting that other types of physical activity, such as high-intensity interval training (i.e. repeated sprints) may also benefit from creatine supplementation [13]. For example, Nemezio et al. found greater gains in fat-free mass following 5 days of creatine supplementation (20 g/day) in 19 male amateur cyclists [14].

Another gap in the literature involves the efficacy of different forms of creatine. Creatine monohydrate is the most studied and predominant form of creatine often included in dietary supplements [6,15–17]. Based on empirical research, creatine monohydrate undergoes little degradation during the digestive processes and is nearly completely absorbed by muscle tissue, with an approximate retention rate of 99% after oral consumption [18]. However, manufacturers of dietary supplements have introduced alternate forms of purported creatine. The physical and chemical properties of these variants are theorized (not proven) to provide greater bioavailability and efficacy compared to creatine monohydrate [16]. Nevertheless, the available evidence is insufficient to establish the superiority or safety of these various alternate forms of creatine, whether used alone or in combination with other nutrients, compared to creatine monohydrate. The impact of different forms of creatine supplementation on body composition remains to be systematically evaluated.

Therefore, the purpose of this systematic review is to provide a comprehensive evaluation of creatine supplementation on body composition including an analysis of potential modifiers, such as dosing protocols, alternative forms of creatine, and mode of exercise. Further, this systematic review evaluated several components of body composition including body mass, body mass index, and estimates of fat mass, body fat percentage, and fat-free mass. There is animal research showing that creatine supplementation plays an important role in fat bioenergetics and influences whole-body energy expenditure [19–21] which may influence body fat percentage over time. To date, two meta-analyses have been performed showing that the combination of creatine supplementation and resistance training results in very small reductions in body fat percentage compared to resistance training alone [21,22]. Lastly, there is evidence that sex [12] and age [23] differences may exist regarding muscle changes over time, however, the effects on other indices of body composition are unknown. Collectively, this study aimed to systematically review randomized controlled trials (RCTs) evaluating the effects of creatine supplementation on body composition and to determine if the dosing protocol, exercise type, or alternative forms of creatine, as well as sex and age, influence the results.

2. Materials and methods

2.1. Search strategy and study selection

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were selected among the various methods for reporting systematic reviews and meta-analyses, to perform this study [24]. This study has been registered in PROSPERO (CRD42023416349). Up to July 2023, an exhaustive search was conducted in PubMed, Scopus, and ISI Web of Science, as well as other online databases, to identify relevant articles, with no date or language limitation. The following search items in titles and abstracts were used; ((Creatine[Title/Abstract]) AND (“Body Weight”[Title/Abstract] OR “Body Mass Index”[Title/Abstract] OR “Weight Loss”[Title/Abstract] OR Obesity[Title/Abstract] OR “Waist Circumference”[Title/Abstract] OR “Quetelet Index”[Title/Abstract] OR BMI[Title/Abstract] OR “Weight Reduction”[Title/Abstract] OR “Abdominal Obesity”[Title/Abstract] OR “Central Obesity”[Title/Abstract] OR “Visceral Obesity”[Title/Abstract] OR obese[Title/Abstract] OR overweight[Title/Abstract] OR “fat mass”[Title/Abstract] OR “Body Fat”[Title/Abstract])) AND (Intervention[Title/Abstract] OR “Intervention Study”[Title/Abstract] OR “Intervention Studies”[Title/Abstract] OR “controlled trial”[Title/Abstract] OR randomized[Title/Abstract] OR random[Title/Abstract] OR randomly[Title/Abstract] OR placebo[Title/Abstract] OR “clinical trial”[Title/Abstract] OR Trial[Title/Abstract] OR “randomized controlled trial”[Title/Abstract] OR “randomized clinical trial”[Title/Abstract] OR RCT[Title/Abstract] OR blinded[Title/Abstract] OR “double blind”[Title/Abstract] OR “double blinded”[Title/Abstract] OR trial[Title/Abstract] OR trials[Title/Abstract] OR “Pragmatic Clinical Trial”[Title/Abstract] OR “Cross-Over Studies”[Title/Abstract] OR “Cross-Over”[Title/Abstract] OR “Cross-Over Study”[Title/Abstract] OR parallel[Title/Abstract] OR “parallel study”[Title/Abstract] OR “parallel trial”[Title/Abstract] OR OR[Title/Abstract]).

2.2. Eligibility criteria

All studies that met the following criteria were included: 1) RCTs evaluating the effects of creatine supplementation on body composition as an outcome (body mass, body mass index, fat mass, body fat percentage, and fat-free mass) with a control group, 2) studies conducted on adults (≥18 years), 3) that received creatine supplementation as an intervention, 4) studies with at least 4 days of the intervention period, 5) parallel or crossover designs, 6) studies with outcome reporting at the beginning and the end of the intervention.

2.3. Exclusion criteria

All studies that followed these features were excluded after the full-text assessment: 1) ecological, review, animal, and observational studies, 2) studies executed on individuals younger than 18 years of age, and 3) studies without randomization or placebo or control groups.

2.4. Data extraction

The records were screened primarily for eligibility based on the title and abstract. Next, the full text of the studies was assessed for the possibility of being included in this meta-analysis. Ultimately, the following data were extracted: the name of the first author, the year of publication, the location of the study, the study design, the sample size in each group, the characteristics of the subjects such as mean age, sex, and body mass index, the doses of creatine administered for the intervention, the duration of the interventions, the mean changes and standard deviation (SD) of the markers during the study for both the intervention and control groups. When a study provided multiple data at different time points, only the most recent was considered. It is important to acknowledge that in the current study, any references to fat mass and fat-free mass are to their estimation values.

2.5. Quality assessment

The quality of the articles that were qualified was assessed by two separate researchers applying the Cochran scoring method [25]. The risk of bias was evaluated based on seven criteria, which are as follows: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Accordingly, terms such as “Low,” “High,” or “Unclear” were used to estimate each field. Moreover, any dissemblance was elucidated by the corresponding authors.

2.6. Data synthesis and statistical analysis

To identify the overall effect sizes, weighted mean differences (WMD) and the SD of measures were extracted from both intervention and control groups applying the random-effects model following the protocol of DerSimonian And Laird [26]. Moreover, without mean changes reporting, it was calculated by using this formula: mean change = final values − baseline values, and SD changes were calculated by the following formula [24]:

SD change=[SD baseline\^2 + SD final\^2 − 2R×SD baseline×SD final

Also, standard errors (SEs), 95% confidence intervals (CIs), and interquartile ranges (IQRs) were converted respectively to SDs using the Hozo et al. protocol [27]. The random-effects model that accounted for between-study variations was applied to detect the overall effect size. Additionally, the Between-studies heterogeneity was checked by Cochran’s Q test and measured by using the I-squared statistic (I2) [28]. I2 >40% or p-values <0.05 were considered significant between-studies heterogeneity. Furthermore, to check potential sources of heterogeneity [29], subgroup analyses were conducted following the preplanned criteria, including study duration (≤30 days vs. >30 days), baselines of body composition indices (body mass index: 18.5–24.9 kg/m2 vs. 25.0–29.9 kg/m2), supplementation protocols (≤5 g/day vs/> 5 g/day, with and without loading and with and without maintenance doses), training status (active vs. trained vs. non-active), exercise (aerobic vs. resistance vs. combined vs. no exercise), age (≤40 vs. >40 years of age), sex (males vs. females), and creatine type (creatine monohydrate vs. alternative forms of creatine). Moreover, a sensitivity analysis was executed to determine the impact of each specific study on the overall estimation [30]. The possibility of publication bias was checked using Egger’s regression test and the visually inspected funnel plot examination [31]. Meta-regression analysis using the random-effects model was undertaken to investigate the potential association between changes in dose and duration with body composition variables. Statistical analysis was carried out applying STATA, version 11.2 (Stata Corp, College Station, TX). The p-values <0.05 were considered statistically significant in all analyses.

3. Results

3.1. Study selection

As mentioned in Figure 1, at first, an exhaustive systematic search was conducted in online datasets and resulted in finding 4831 studies. Then, 1241 studies were identified as duplicates, and 3292 unrelated studies were removed after a comprehensive assessment of the titles and abstracts. Moreover, 157 studies without desired data reporting were excluded following the full-text evaluation of the studies. Finally, according to the inclusion criteria, 143 studies were identified.

Flow chart of study selection for inclusion trials in the systematic review.

3.2. Study characteristic

Ultimately, 143 qualified articles with 172 study arms were included, with 3655 participants (2069 in the intervention group and 1922 in the control group). All included studies had the publication date of between 1993 and 2023. The duration of the intervention in all included trials was from four days [32] to 365 [33] days. The sample size of all studies in this meta-analysis varied from 6 [34] to 109 [33] participants. Moreover, the design of 124 studies was parallel RCT [9,32,33,35–156], and the design of 19 was crossover [34,81,157–173]. The qualified studies were mainly conducted in the USA [9,32,38,39,42,43,45–47,51–53,55–57,60–63,66–69,74,77,78,81,84,86,87,89,91,93,95,97,101,103,105,107–109,111,113,114,116–118,120,124,126,137,138,147,148,152,153,157,160,166,167,169,170,173], the UK [71,85,102,133,142,158,165], Sweden [35], Iran [112,121,143], Australia [41,44,70,76,98,99], France [36,40], Belgium [37,48,65,159,162], Estonia [34,128], Japan [49,82], Netherland [50,139,156], Canada [54,59,64,72,80,90,96,106,130–132,134,145,149,163], Norway [58], Germany [88,92,104,161,168], Poland [75,119], Denmark [73], Thailand [79], Spain [83], Switzerland [164], Portugal [94], Brazil [33,100,115,123,125,127,129,141,144,146,150,155,172], Scotland [174], Italy [110], Mexico [171], Finland [122,136], New Zealand [135], and Turkey [140]. Twenty-one studies were performed on females [33,37,51,52,55,70,77,81,90,94,95,103,115,122,124,125,130,132,138,140,173], 81 studies on males [9,32,34,35,38,39,42,45–50,56–58,60–64,66–69,71,73,75,76,78,79,82–84,88,89,93,96,98–101,104–112,114,118–120,123,126–129,136,137,139,143–145,147,148,150,151,156–158,160,165–167,169,171], and the others were conducted on both [36,40,44,53,54,59,65,72,74,80,85–87,91,92,97,102,116,117,121,131,133–135,141,142,146,149,153–155,161–164,168,170,172]. The characteristics of the included studies are indicated in Table 1.

Table 1.

Characteristic of included studies in meta-analysis.

StudiesCountryStudy DesignTraining background/health statusSample size
Trial Duration (d)Mean Age
Mean BMI
Intervention
IGCGIGCGIGCGLoadingCreatine TypeHow to useType of exerciseControl group
Balsom et al. 1993Swedenparallel, PC, DB18 trained males/healthy99625.627.3NRNRJust loadingCrM20 g/d for 6 daysATGlucose
Mujika et al. 1996Franceparallel, PC, DB20 trained male and female swimmers/healthy10105NRNRNRNRJust loadingCrM20 g/d for 5 daysATLactose
Terrillion et al. 1997USAcrossover, PC, DB24 trained male runners/healthy121252121NRNRJust loadingCrM20 g/d for 5 daysATSucrose
Vanderberghe et al. 1997Belgiumparallel, PC, DB19 not trained females/healthy10974NRNRNRNRloading + long maintenanceCrM20 g/d for 4 days +5 g/d for 70 daysRTMaltodextrin
Noonan et al. 1998aUSAparallel, PC, DB20 trained male college athletes/healthy1375619.420.4NRNRloading + long maintenanceCrM20 g/d for 5 days +8.5 g/d for 51 daysCTDextrose
Noonan et al. 1998bUSAparallel, PC, DB19 trained male college athletes/healthy1365619.720.4NRNRHigh dose maintenanceCrM20 g/d for 5 days +26.1 g/d for 51 daysCTDextrose
Kreider et al. 1998USAparallel, PC, DB25 trained male football player/healthy111428NRNRNRNRHigh dose maintenanceCrM15.75 g/d for 28 daysRTPhosphagen HP (glucose, taurine, disodium phosphate, potassium phosphate)
Oopik et al. 1998Estoniacross over,PC6 trained male karate athletes/healthy66522.522.5NRNRJust loadingCrM20 g/d for 5 daysCTGlucose
Maganaris et al. 1998UKcrossover, PC, DB10 active males/healthy101052828NRNRJust loadingCrM10 g/d for 5 daysRTGlucose polymer
Bermon et al. 1998aFranceparallel, PC, DB16 not trained males and females/healthy885271.869.325.426.4loading + long maintenanceCrM20 g/d for 5 days +3 g/d for 47 daysNOGlucose
Bermon et al. 1998bFranceparallel, PC, DB16 not trained males and females/healthy88527169.324.725loading + long maintenanceCrM20 g/d for 5 days +3 g/d for 47 daysRTGlucose
Vukovich et al. 1998aUSAparallel,PC,DB24 active males/healthy12122123.321.3NRNRLoading + short maintenanceCrM20 g/d for 5 days +10 g/d for 16 daysRTCHP (solid form)
Vukovich et al. 1998bUSAparallel,PC,DB24 active males/healthy12122121.922.3NRNRLoading + short maintenanceCrM20 g/d for 5 days +10 g/d for 16 daysRTCHO (powder form)
Kelly et al. 1998Australiaparallel, PC18 trained males/healthy992625.528.1NRNRLoading + short maintenanceCrM20 g/d for 5 days +5 g/d for 21 daysRTGlucose
Mckenna et al.1999Australiaparallel, PC, DB14 active males and females/healthy7751921NRNRJust loadingCrM30 g/d for 5 daysNRDextrose
Francaux et al. 1999Belgiumparallel, PC, DB18 not trained males/healthy81063NRNRNRNRloading + long maintenanceCrM21 g/d for 5 days +3 g/d for 58 daysRTMaltodextrin
Rawson et al. 1999USAparallel, PC, DB20 not trained males/healthy10103066.766.9NRNRLoading + short maintenanceCrM20 g/d for 10 days +4 g/d for 20 daysNRDextrose
Pearson et al. 1999USAparallel, PC, DB16 trained male football players/healthy8870NRNRNRNRmaintenanceCrM5 g/d for 70 daysRTPlacebo capsules (NR)
Leenders et al. 1999aUSAparallel,
PC,DB		18 trained male swimmers/healthy991419.819NRNRLoading + short maintenanceNR20 g/d for 6 days +10 g/d for 8 daysATMaltodextrin solution 6%
Leenders et al. 1999bUSAparallel,PC,DB14 trained female swimmers/healthy771419.119.4NRNRLoading + short maintenanceNR20 g/d for 6 days +10 g/d for 8 daysATMaltodextrin solution 6%
Peeters et al. 1999aUSAparallel, PC, DB18 active males/healthy11742NRNRNRNRloading + long maintenanceCrM20 g/d for 3 days +10 g/d for 39 daysRTMaltodextrin powder
Peeters et al. 1999bUSAparallel, PC, DB16 active males/healthy9742NRNRNRNRloading + long maintenanceCr phosphate20 g/d for 3 days +10 g/d for 39 daysRTMaltodextrin powder
Haff et al. 2000USAparallel, PC, DB36 trained male and female collegiate track-and-field athletes/healthy15214219.919.9NRNRHigh dose maintenanceCrM22.41 g/d for 42 daysRTRice flour and magnesium stearate
Schedel et al. 2000Japanparallel, PC, DB10 trained males by endurance or resistance exercise/healthy557242322.422.8Just loadingCrM30 g/d for 7 daysCTIdentical beverage without Cr
Deutekom et al. 2000Netherlandsparallel, PC, DB23 trained male rowers/healthy11126NRNRNRNRJust loadingCrM20 g/d for 6 daysCTMaltodextrin
Mihic et al. 2000Canadaparallel, PC, DB30 not trained males and females/healthy1515522.422.4NRNRJust loadingCrM20 g/d for 5 daysNRGlucose polymer
Hamilton et al. 2000USAparallel, PC, DB24 trained females/healthy1113722.523.9NRNRJust loadingCrM25 g/d for 7 daysRTPolycose
Larson-Meyer et al. 2000USAparallel, PC, DB13 trained females/healthy769119.319NRNRloading + long maintenanceCrM15 g/d for 7 days +5 g/d for 84 daysCTcool water + PowerAde powder
Volek et al. 2000USAparallel, PC, DB19 trained males/healthy1098425.625.4NRNRloading + long maintenanceCrM25 g/d for 7 days +5 g/days for 77 daysRTCellulose powder
Becque et al. 2000USAparallel,PC,DB23 active males/healthy101342NRNRNRNRloading + long maintenanceCrM20 g/day for 5 days +2 g/day for 37 daysRTFlavored, sucrose drink
Brenner et al. 2000USAparallel, PC, DB16 trained female lacrosse players/healthy793518.119.5NRNRLoading + short maintenanceCrM20 g/d for 7 days +2 g/d for 28 daysCTSucrose
Skare et al. 2001Norwayparallel, PC, SB18 trained male sprinters/healthy995NRNRNRNRJust loadingCrM20 g/d for 5 daysCTGlucose
Green et al. 2001USAparallel, PC, DB19 trained male recreational athletes/healthy910626.324.1NRNRJust loadingCrM20 gr/d for 6 daysNRSucrose and maltodextrin
Rockwell et al. 2001USAparallel, PC, DB16 trained males/healthy88420.521.6NRNRJust loadingCrM20 g/d for 4 daysRTSucrose + Hypo energy diet
Op t Eijnde et al. 2001Belgiumcrossover, PC, DB11 not trained males/healthy1111520.720.7NRNRJust loadingCrM20 g/d for 5 daysRTMaltodextrin plus citrate
Bemben et al. 2001USAparallel, PC, DB17 trained male football players/healthy986319.419.3NRNRloading + long maintenanceCrM20 g/d for 5 days +5 g/d for 58 daysCTGlucose solution (containing sodium phosphate, exact protocol as the Cr group)
Chrusch et al. 2001Canadaparallel, PC, DB30 not trained males/healthy16148470.471.127.925.7loading + long maintenanceCrM26.4 g/d for 5 days +6.2 g/d for 79 daysRTCHO mixture
Kern et al. 2001USAparallel, PC, DB19 active males/healthy9102822.422.2NRNRLoading + short maintenanceCrM21 g/d for 5 days +10 g/d for 23 daysCTPhosphagen HP matrix
Parise et al. 2001aCanadaparallel, PC, DB14 active females/healthy778NRNRNRNRLoading + short maintenanceCrM20 g/d for 5 days +5 g/d for 3 daysCTGlucose polymer
Parise et al. 2001bCanadaparallel, PC, DB13 active males/healthy768NRNRNRNRLoading + short maintenanceCrM20 g/d for 5 days +5 g/d for 3 daysCTGlucose polymer
Wilder et al. 2001aUSAparallel,PC,DB13 trained male football players/healthy8570NRNRNRNRmaintenanceCrM3 g/d for 70 daysCTDextrose
Wilder et al. 2001bUSAparallel,PC,DB12 trained male football players/healthy8470NRNRNRNRloading + long maintenanceCrM20 g/d for 7 days +5 g/d for 63 daysCTDextrose
Willoughby et al. 2001USAparallel, PC, DB16 not trained males/healthy8884NRNRNRNRmaintenanceCrM6 g/d for 84 daysRTDextrose
Hespel et al. 2001Belgiumparallel, PC, DB22 not trained males and females/healthy111184NRNRNRNRNDCrM20 g/d for 14 days +15 g/d for 21 days +5 g/d for 35 daysRTMaltodextrin
Coxe et al. 2002Australiaparallel, PC, DB12 trained female soccer players/healthy666NRNRNRNRJust loadingCrM20 g/d for 6 daysATglucose polymer
Gotshalk et al. 2002USAparallel, PC, DB18 not trained males/healthy108765.465.7NRNRJust loadingCrM25.32 g/d for 7 daysNRCellulose
Kilduff et al. 2002UKparallel, PC, DB32 trained males/healthy2111524.524.5NRNRJust loadingCrM20 g/d for 5 daysRTGlucose polymer
Wilder et al. 2002aUSAparallel, PC, DB13 trained males/healthy857018.819.2NRNRmaintenanceCrM3 g/d for 70 daysCTDextrose
Wilder et al. 2002bUSAparallel, PC, DB12 trained males/healthy847018.819.2NRNRloading + long maintenanceCrM20 g/d for 7 days +5 g/d for 63 daysCTDextrose
Walter et al. 2002Germanycrossover, PC, DB34 not trained males and females/DM134345644.1344.13NRNRloading + long maintenanceCrM10.6 g/d for10 days +5.3 g/d for 46 daysNOMicrocrystalline cellulose
Huso et al. 2002USAcrossover, PC, DB10 active males/healthy101021NRNRNRNRLoading + short maintenanceCrM20 g/d for 4 days +2 g/d for 17 daysRTMaltodextrin
Warber et al. 2002USAparallel, PC, DB26 active males/healthy1313530.533.4NRNRJust loadingCrM24 g/d for 5 daysNRIdentical sports bars
Kutz et al. 2003USAparallel, PC, DB17 not trained males/healthy9828NRNRNRNRHigh dose maintenanceCrM30 g/d for 14 days +15 g/d for 14 daysRTMultodextros + rice brane + sucrose
Vukovich et al. 2003USAcontrol trail24 trained males/healthy12127NRNRNRNRJust loadingCrM21 g/d for 7 daysRTRegular diet
Lehmkuhl et al. 2003USAparallel,PC,DB19 trained male and female young track and field athletes/healthy1095619.420.1NRNRloading + long maintenanceCrM21.2 g/d for 7 days +2.1 g/d for 49 daysCTPotato starch
Burke et al. 2003aCanadaparallel, PC, DB18 active male and female young track and field athletes/healthy108563134NRNRloading + long maintenanceCrM16.8 g/d for7 days +4.2 g/d for 49 daysCTMaltodextrin
Burke et al. 2003bCanadaparallel, PC, DB24 active male and female young track and field athletes/healthy1212563332NRNRloading + long maintenanceCrM16.8 g/d for7 days +4.2 g/d for 49 daysCTMaltodextrin
Van Loon et al. 2003Netherlandsparallel, PC, DB19 not trained males/healthy9104220.621.320.421.2loading + long maintenanceCrM20 g/d for 5 days +2 g/d for 37 daysNOGlucose + Maltodextrin
Zajac et al.2003Polandparallel, PC, DB25 trained male basketball players/healthy121330NRNRNRNRmaintenanceCrMNDCTCHO
Eijnde et al. 2003aDenmarkparallel,PC,DB46 not trained males/healthy232318063.962.2NRNRmaintenanceCrM5 g/d for 180 daysCTPlacebo capsules (NR)
Eijnde et al. 2003bDenmarkparallel,PC,DB20 not trained males/healthy101036065.361.8NRNRmaintenanceCrM5 g/d for 360 daysCTPlacebo tablets
(NR)
Kambis et al. 2003USAparallel, PC, DB22 not trained females/healthy11115NRNRNRNRJust loadingCrM24.3 g/d for 5 daysNRCorn starch
Brose et al. 2003aCanadaparallel, PC, DB15 not trained males/healthy879868.768.3NRNRmaintenanceCrM5 g/d for 98 daysRTDextrose
Brose et al. 2003bCanadaparallel, PC, DB13 not trained females/healthy679870.869.9NRNRmaintenanceCrM5 g/d for 98 daysRTDextrose
Watsford et al. 2003Australiaparallel, PC, DB20 not trained males/healthy91128NRNRNRNRLoading + short maintenanceNR20 g/d for 7 days +10 g/d for 21 daysNOPlacebo capsules (NR)
Eckerson et al. 2004USAcrossover, PC, DB10 active females/healthy10105NRNRNRNRJust loadingCr citrate20 gr/d for 5 daysCTDextrose powder
Kinugasa et al. 2004Japanparallel,PC,DB12 not trained males/healthy66522.522.2NRNRJust loadingCrM20 g/d for 5 daysNOMaltodextrin
Javierre et al. 2004Spainparallel, PC19 active males/healthy1095NRNRNRNRJust loadingCrM20 g/d for 5 daysNRPlacebo capsules (NR)
Volek et al. 2004USAparallel, PC, DB17 trained males/healthy982820.721.3NRNRLoading + short maintenanceCrM26 g/d for 7 days +4.33 g/d for 21 daysRTCellulose powder
Ball SD et al. 2004USAcrossover, PC, DB10 active males/healthy101021NRNRNRNRLoading + short maintenanceCrM20 g/d for 4 days +2 g/d for 17 daysRTMaltodextrin
Tarnopolosky et al. 2004Canadacrossover, PC, DB34 not trained males and females/DM1 patients34341204141NRNRmaintenanceCrM5 g/d for 120 daysNODextrose and cellulose fiber
Taes et al. 2004Belgiumcrossover, PC, DB45 not trained males and females/Hemodialysis patients4545287169NRNRmaintenanceCrM2 g/d for 28 daysNOLactose
Anomasiri et al. 2004Thailandparallel, PC, DB38 active males/healthy19197NRNRNRNRNDCrM10 g/d for 7 daysATOrange juice powder
Eckerson et al. 2005aUSAparallel, PC, DB15 active males/healthy1056NRNRNRNRJust loadingCr citrate20 g/d for 6 daysCTDextrose
Eckerson et al. 2005bUSAparallel, PC, DB15 active females/healthy1056NRNRNRNRJust loadingCr citrate20 g/d for 6 daysCTDextrose
Eckerson et al. 2005cUSAparallel, PC, DB15 active males/healthy1056NRNRNRNRJust loadingCr phosphate20 g/d for 6 daysCTDextrose
Eckerson et al. 2005dUSAparallel, PC, DB15 active females/healthy1056NRNRNRNRJust loadingCr phosphate20 g/d for 6 daysCTDextrose
Perret et al. 2005Switzerlandcrossover, PC, DB6 trained male and female competitive wheelchair athletes/healthy6663333NRNRJust loadingCrM20 g/d for 6 daysATMaltodextrin
Ahmun et al. 2005UKcrossover,PC,DB14 trained male rugby players/healthy1414520.620.6NRNRJust loadingCrM20 g/d for 5 daysCTDextrose powder
Mendell et al. 2005USAparallel, PC, DB16 active males and females/healthy8852626NRNRJust loadingCrM20 g/d for 5 daysNOSolka-Floc (cellulose) plus Gatorade
Fuld et al. 2005UKparallel, PC, DB25 not trained males and females/patients with COPD14118461.763.723.224.3loading + long maintenanceCrM17.1 g/d for 14 days + 5.7 gr/d for 70 daysCTGlucose polymer
Hoffman et al. 2005USAparallel, PC, DB40 not trained males/healthy2020621.721.1NRNRNDCrM6 gr/d for 6 daysNRCellulose powder and methylcellulose
Kuethe et al. 2006Germanycrossover, PC, DB13 not trained males and females/congestive heart failure patients13134258.258.2NRNRHigh dose maintenanceCrM20 g/day for 42 daysNOPlacebo capsules (NR)
Hille et al. 2006USAcrossover, PC, DB11 trained males/healthy11117NRNRNRNRJust loadingCrM21.6 g/day for 7 daysNRPlacebo capsules (NR)
Norman et al. 2006Germanyparallel, PC, DB31 not trained males and females/Patients with colorectal cancer16155665.161.6125.1324.62loading + long maintenanceCrM20 g/day for 7 days +5 g/d for 49 daysNRCellulose
Ferguson et al. 2006Canadaparallel, PC, DB26 trained females/healthy131370NRNRNRNRloading + long maintenanceCrM19.71 g/d for 7 days + 1.97 gr/d for 63 daysRTPlacebo capsules (NR)
Pluim et al. 2006Germanyparallel,PC,DB24 trained male tennis players/healthy14103422.522.8NRNRLoading + short maintenanceCrM22.1 g/d for 6 days +2.2 g/d for 28 daysATMaltodextrin and dextrose
Rogers et al. 2006USAparallel, PC, DB30 not trained males and females/healthy151584NRNRNRNRmaintenanceCrM3 g/d for 84 daysRTMaltodextrin
Hoffman et al. 2006USAparallel, PC, DB33 trained male football players/healthy171670NRNRNRNRmaintenanceCrM10.5 g/d for 70 daysRTDextrose
Smith et al. 2007USAparallel, PC, DB15 trained females/healthy78522.422.3NRNRJust loadingCr citrate20 g/d for 5 daysNRDextrose
Stout et al. 2007USAcrossover, PC, DB15 not trained males and females/healthy15151474.574.5NRNRLoading + short maintenanceCr citrate20 g/d for 7 days +10 g/d for 7 daysNOFlavored powder blend
Silva et al. 2007Portugalparallel, PC, DB16 trained female competitive swimmers/healthy882116.315.7NRNRHigh dose maintenanceCrM20 g/d for 21 daysATMaltodextrin solution 6%
Wright et al. 2007USAcrossover, PC, DB10 active male s/healthy1010725.725.7NRNRJust loadingCrM20 g/d for 7 daysATSucrose and maltodextrin drink
De Souza junior et al. 2007Brazilparallel, PC, DB18 active male s/healthy99422523NRNRloading + long maintenanceCrM30 g/d for 7 days +5 g/d for 35 daysRTMaltodextrin
Cribb et al. 2007aAustraliaparallel, PC, DB15 active male s/healthy87772524NRNRloading + long maintenanceCrM25 g/d for 7 days +8.4 g/d for 70 daysRTCHO
Cribb et al. 2007bAustraliaparallel, PC, DB11 active male s/healthy65772524NRNRloading + long maintenanceCrM25 g/d for 7 days +8.4 g/d for 70 daysRTWhey protein
Hass et al. 2007USAparallel, PC, DB20 not trained males and females/healthy10108462.862.2NRNRloading + long maintenanceCrM20 g/d for 5 days +5 g/d for 79 daysRTLactose monohydrate
Chilibeck et al. 2007Canadaparallel, PC, DB18 trained male rugby union football players/healthy99562726NRNRmaintenanceCrM9.5 d/d for 56 daysCTGlucose
Cribb et al. 2007Australiaparallel, PC, DB21 active males/healthy1011702626NRNRmaintenanceCrM8.9 g/d for 70 daysRTPRO-CHO supplement
Walter et al. 2008USAparallel, PC, DB16 trained males/healthy88526.123.1NRNRJust loadingCr citrate20 g/d for 5 daysNRFructose powder
Eckerson et al. 2008USAparallel, PC, DB32 active males/healthy1715302220NRNRmaintenanceCr citrate5 g/day for 30 daysCTDextrose
Gotshalk et al. 2008USAparallel, PC, DB27 not trained females/healthy1512763.3162.98NRNRJust loadingCrM20.13 g/d for 7 daysNRCellulose
Deacon et al. 2008UKparallel, PC, DB80 not trained males and females/Participants with COPD38425467.668.328.125.7loading + long maintenanceCrM20 g/d for 5 days + 3.76 gr/d for 49 daysCTLactose
Eliot et al. 2008 aUSAparallel, PC, DB20 not trained males/healthy101098NRNRNRNRmaintenanceCrM2.14 g/d for 98 daysRTSport drink
Eliot et al. 2008 bUSAparallel, PC, DB22 not trained males/healthy111198NRNRNRNRmaintenanceCrM2.14 g/d for 98 daysRTwhey protein +Sport drink
Little et al. 2008Canadaparallel, PC, DB23 active males/healthy11121022.822.8NRNRmaintenanceNR8 g/d for 10 daysNRSucrose-based fruit punch
Jager et al. 2008 aGermanyparallel, PC, DB25 trained male athletes/healthy1692826.826.3NRNRmaintenanceother5 g/d for 28 daysNRPlacebo tablets
Jager et al. 2008 bGermanyparallel, PC, DB24 trained male athletes/healthy1682826.726.3NRNRmaintenanceCr citrate5 gr/d for 28 daysNRPlacebo tablets
Sakkas et al. 2009USAparallel, PC, DB38 not trained males/HIV positive participants191998444423.723.7loading + long maintenanceCrM20 g/d for 5 days +4.8 g/d for 93 daysRTPlacebo capsules (NR)
Bazzucchi et al. 2009Italyparallel,PC,DB16 trained males/healthy88526.723.323.324.2Just loadingNR20 g/d for 5 daysNRMaltodextrin
Spillane et al. 2009aUSAparallel, PC, DB15 active males/healthy1054820.3620.16NRNRloading + long maintenanceCrM20 g/d for 5 days +5 g/d for 42 daysRTMaltodextrin
Spillane et al. 2009bUSAparallel, PC, DB15 active males/healthy1054820.8320.16NRNRloading + long maintenanceother20 g/d for 5 days +5 g/d for 42 daysRTMaltodextrin
Herda et al. 2009aUSAparallel, PC, DB18 trained males/healthy13530NRNRNRNRmaintenanceCrM5 g/d for 30 daysCTCellulose
Herda et al. 2009bUSAparallel, PC, DB19 trained males/healthy14530NRNRNRNRmaintenanceother1.25 g/d for 30 daysCTCellulose
Herda et al. 2009cUSAparallel, PC, DB21 trained males/healthy16530NRNRNRNRmaintenanceother2.50 g/d for 30 daysCTCellulose
Fukuda et al. 2010aUSAparallel, PC, DB24 active males/healthy12125NRNRNRNRJust loadingCr citrate20 g/d for 5 daysCTDextrose
Fukuda et al. 2010bUSAparallel, PC, DB26 active females/healthy12145NRNRNRNRJust loadingCr citrate20 g/d for 5 daysCTDextrose
Hickner et al. 2010USAparallel, PC, DB12 trained males/healthy662825.529NRNRmaintenanceCrM3 gr/d for 28 daysATdry milk and orange-flavored carbohydrate
Saremi et al. 2010Iranparallel, PC, DB16 not trained males/healthy885623.8522.28NRNRloading + long maintenanceCrM23.3 g/d for 7 days +3.88 g/d for 49 daysRTCellulose
Camic et al. 2010USAparallel, PC, DB22 active males/healthy101228NRNRNRNRmaintenanceother5 g/d for 28 daysNOMaltodextrin
Smith et al. 2011aUSAparallel, PC, DB27 active males/healthy13145NRNRNRNRJust loadingCr citrate20 g/d for 5 daysNRFructose powder
Smith et al. 2011bUSAparallel, PC, DB28 active females/healthy14145NRNRNRNRJust loadingCr citrate20 g/d for 5 daysNRFructose powder
Neves JR et al. 2011Brazilparallel, PC, DB24 not trained females/Postmenopausal women with knee osteoarthritis131184585628.529.7loading + long maintenanceCrM20 g/d for 5 days +5 g/d for 79 daysRTDextrose
Rawson et al. 2011USAparallel, PC, DB20 not trained males and females/healthy1010422120.525.125.9maintenanceCrM2.2 g/d for 42 daysNRPlacebo capsules (NR)
Taylor et al. 2011USAparallel, PC, DB29 trained males/healthy1415562119.8NRNRmaintenanceCrM5 g/d for 56 daysRTDextrose
Mohebbi et al. 2012Iranparallel, PC, DB17 trained male and female young soccer players/healthy89717.3817NRNRJust loadingCrM20 g/d for 7 daysATGlucose polymer
Zuniga et al. 2012USAparallel, PC, DB22 not trained males/healthy10127NRNRNRNRJust loadingCrM20 g/d for 7 daysNOMaltodextrin powder
Pericario et al. 2012Brazilparallel, PC, DB18 trained male handball athletes/healthy993217.117.1NRNRLoading + short maintenanceCrM20 g/d for 5 days +5 g/d for 27 daysRTMaltodextrin
Sterkowicz et al. 2012Polandparallel, PC, DB10 trained males Judaists/healthy55422220.422.2726.92maintenanceother4.8 g/d for 42 daysCTPlacebo capsules (NR)
Montes De Oca et al. 2013Mexicocrossover, PC, DB10 trained male TKD practitioners/healthy101042NRNRNRNRmaintenanceCrM3.4 g/d for 42 daysCTMaltodextrin
Aguiar et al. 2013Finlandparallel, PC, DB18 not trained females/healthy99846465NRNRmaintenanceCrM5.0 g/d for 84 daysRTMaltodextrin
Cooke et al. 2014USAparallel, PC, DB20 not trained males/healthy10108461.460.7NRNRloading + long maintenanceCrM20 g/d for 7 days +8.8 g/d for 77 daysRTCHO
Gualano et al. 2014aBrazilparallel, PC, DB30 not trained females/postmenopausal with osteopenia or osteoporosis151516666.166.327.126.8loading + long maintenanceCrM20 g/d for 5 days +5 g/d for 161 daysNODextrose
Gualano et al. 2014bBrazilparallel,PC,DB30 not trained females/postmenopausal with osteopenia or osteoporosis151516667.163.62828.2loading + long maintenanceCrM20 g/d for 5 days +5 g/d for 161 daysRTDextrose
Kresta et al. 2014(a)USAparallel, PC, DB15 active females/healthy872821.521.5NRNRLoading + short maintenanceCrM18.3 g/d for 7 days +6.1 g/d for 21 daysCTMaltodextrin and dextrose
kresta et al. 2014(b)USAparallel, PC, DB17 active females/healthy982821.521.5NRNRLoading + short maintenanceCrM17.7 g/d for 7 days +5.9 g/d for 21 daysCTMaltodextrin and dextrose
Hayashi et al. 2014Brazilcrossover, PC, DB15 not trained males and females/Systemic lupus erythematosus (C-SLE) patients151584NRNRNRNRmaintenanceCrM5.34 g/d for 84 daysNODextrose
Nemezio. et al. 2015Brazilparallel, PC, DB19 active males/healthy10953633NRNRJust loadingCrM20 g/d for 5 daysATDextrose
Aedma et al. 2015Estoniaparallel, PC, DB20 trained male wrestlers/healthy10105NRNRNRNRJust loadingCrM24.8 g/d for 5 daysCTGlucose gelatin capsules
Lobo et al. 2015Brazilparallel, PC, DB109 not trained females/postmenopausal osteogenic women5653365585827.627.5maintenanceCrM1 g/d for 365 daysNODextrose
Candow et al. 2015aCanadaparallel, PC, DB21 not trained males and females/healthy156224535726.526.8maintenanceCrM7.7 g/d for 224 daysRTMaltodextrin (Corn-starch)
Candow et al. 2015bCanadaparallel, PC, DB18 not trained males and females/healthy12622455572926.8maintenanceCrM8.7 g/d for 224 daysRTMaltodextrin (Corn-starch)
Chilibeck et al. 2015Canadaparallel, PC, DB33 not trained females/healthy15183645757NRNRmaintenanceCrM6.9 g/d for 364 daysRTMaltodextrin
Deminice et al. 2015Brazilparallel, PC, DB13 trained males/healthy76718.518.322.123.2Just loadingCrM22 g/d for 7 daysATMaltodextrin
Wilkinson et al. 2016UKparallel, PC, DB35 not trained males and females/patients with stable RA1520846357.224.727.8loading + long maintenanceCrM20 g/d for 5 days +3 g/d for 77 daysNOFlavored drink powder
Forbes et al. 2016Canadaparallel, PC, DB17 active females/healthy982823.822.4NRNRLoading + short maintenanceCrM19.32 g/d for 5 days +6.44 g/days for 23 daysATMaltodextrin
Pinto et al. 2016BrazilParallel, PC, DB27 not trained males and females/healthy13148467.467.1NRNRmaintenanceCrM5 g/d for 84 dayRTMaltodextrin powder
Collins et al. 2016New Zealandparallel, PC, DB16 not trained males and females/healthy9798706930.930.1maintenanceCrM5 g/d for 98 daysRTMaltodextrin + whey
Johannsmeyer et al.2016Canadaparallel, PC, DB31 not trained males and females/healthy1417845857.6NRNRmaintenanceCrM7.83 g/d for 84 daysRTMaltodextrin
Backx et al. 2017Finlandparallel, PC, DB30 not trained males/healthy15152123232323.5Loading + short maintenanceCrM20 g/d for 5 days + 5 gr/day for 16 daysNOMaltodextrin and dextrose monohydrate
Wilborn et al. 2017USAparallel, PC, DB17 trained females/healthy8956222023.223.8maintenanceCrM5 g/d for 56 daysRTWhey protein
Karamat et al. 2017Netherlandsparallel, PC, TB16 not trained males/healthy887NRNR22.124.2NDNR5 g/d for 7 daysNRPlacebo capsules (NR)
Atakan et al. 2018Turkeyparallel, PC, DB30 trained female futsal players/healthy1515719.620.722.1719.83Just loadingCrM14.5 g/d for 7 daysATMaltodextrin
Wang et al. 2018USAparallel, PC, DB30 trained male athletes/healthy1515282020NRNRLoading + short maintenanceCrM20 g/d for 6 days +2 g/d for 22 daysCTCarboxymethyl cellulose powder plus dextrose
Vanbavel et al. 2019Brazilparallel, PC, DB49 active males and females/healthy311821333223.322.9maintenanceCrM5 g/d for 21 daysNRMaltodextrin
Arazi et al. 2019Iranparallel, PC, DB16 not trained males/healthy884220.8720.37NRNRloading + long maintenanceother20 g/d for 5 days +5 g/d for 37 daysRTRice flour
Almeida et al. 2020Brazilparallel, PC, DB18 active males/healthy99722.724.2NRNRJust loadingCrM24.2 g/d for 7 daysRTDextrose
Marini et al. 2020Brazilparallel, PC, DB28 not trained males and females/hemodialysis patients14142841.8641.7922.7621.93Loading + short maintenanceCrM20 g/d for 7 days +5 g/d for 21 daysNOMaltodextrin
Candow et al. 2020Canadaparallel, PC, DB38 not trained males/healthy18203645856NRNRmaintenanceCrM9.3 g/d for 364 daysRTMaltodextrin (Corn-starch)
Delextrat et al. 2020aUKparallel, PC, DB22 trained male and female team- and racket sport players/healthy11112825.625.2NRNRmaintenanceCrM5 g/d for 28 daysCTRice flour
Delextrat et al. 2020bUKparallel, PC, DB22 trained male and female team and racket sport players/healthy1210282624.2NRNRmaintenanceCrM5 g/d for 28 daysCTRice flour + beta-alanine
Anders et al. 2021USAparallel, PC, DB22 trained males/healthy12102819.820.6NRNRmaintenanceCrM2.4 g/d for 28 daysCTCellulose
Pakulak et al. 2021aCanadaparallel, PC, DB10 active males and females/healthy55422223NRNRmaintenanceCrM7.6 g/d for 42 daysRTCellulose powder
pakulak et al. 2021bCanadaparallel, PC, DB10 active males and females/healthy55422219NRNRmaintenanceCrM7.4 g/d for 42 daysRTCellulose powder
Bonilla et al. 2021USAparallel, SB16 active males/healthy8856NRNR23.8925.02maintenanceCrM7.6 g/d for 56 daysRTCluster-set resistance training (CS-RT)
Butchart et al. 2022Canadaparallel, PC, DB8 not trained participants/stroke survivors5370517329.227.4loading + long maintenanceCrM25.4 g/d for 7 days +8.4 g/d for 63 daysRTcorn-starch maltodextrin
Almeida et al. 2022Brazilparallel, PC, DB34 active males/healthy17172823.123.8NRNRLoading + short maintenanceCrM21.9 g/d for 7 days +2.1 g/d for 21 daysRTDextrose
Dinan et al. 2022aUSAparallel, PC, DB18 trained male and female athletes/healthy12656NRNRNRNRmaintenanceCrM5 g/d for 56 daysRTmaltodextrin
Dinan et al. 2022bUSAparallel, PC, DB16 trained male and female athletes/healthy11556NRNRNRNRmaintenanceCrM5 g/d for 56 daysRTmaltodextrin
Askow et al. 2022USAparallel, PC, DB18 not trained male and female athletes/healthy8101428.530.325.824.7maintenanceCrM5 g/d for 14 daysRTmaltodextrin
Moore et al. 2023aUSAcrossover, PC, DB30 active females/healthy3030525.424.523.623.1Just loadingCrM20 g/d for 5 daysNRcrystal light
Moore et al. 2023bUSAcrossover, PC, DB30 active females/healthy3030525.424.523.623.1Just loadingCrM20 g/d for 5 daysNRcrystal light

Note: Abbreviations: IG, intervention group; CG, control group; DB, double-blinded; SB, single-blinded; PC, placebo-controlled; CO, controlled; RA, randomized; NR, not reported; F, Female; M, Male; NR, not reported; DM1, Myotonic muscular dystrophy type 1; RA, Rheumatoid Arthritis.

3.3. Quality assessment

Evaluating the general risk of bias mentioned 111 studies with a low risk of bias [32,33,36,38–40,42–46,48,49,51–57,60–62,64–66,68,69,72–74,76,77,79–81,84–86,90–94,96–109,111–120,122–129,131,132,134–140,142–145,147–150,152–155,158–163,165–168,170–173], 17 studies with a high risk of bias [34,37,41,47,58,70,71,78,82,87,88,121,141,151,156,157,169], and the others indicated an unclear risk of bias [9,35,50,59,63,67,75,83,89,95,110,130,133,146,164] (Table 2).

Table 2.

Risk of bias assessment.

StudyRandom sequence generationAllocation concealmentSelective reportingOther sources of biasBlinding (participants and personnel)Blinding (outcome assessment)Incomplete outcome dataGeneral risk of bias
Balsom et al. 1993HHLHLULFair
Mujika et al. 1996UULLLHLGood
Terrillion et al. 1997HHLLHHLWeak
Vanderberghe et al. 1997HHLLLHLWeak
Noonan et al. 1998aUULLLHLGood
Noonan et al. 1998bUULLLHLGood
Kreider et al. 1998UULLLHUGood
Oopik et al. 1998HHLLHHLWeak
Maganaris et al. 1998UULLLHLGood
Bermon et al. 1998aUULLLULGood
Bermon et al. 1998bUULLLULGood
Vukovich et al. 1998aUULLLHLGood
Vukovich et al. 1998bUULLLHLGood
Kelly et al. 1998UULLHHHWeak
Mckenna et al. 1999UULLLHLGood
Francaux et al. 1999UULULULGood
Rawson et al. 1999UULLLHLGood
Pearson et al. 1999UUULLHLGood
Leenders et al. 1999aUULLLHLGood
Leenders et al. 1999bUULLLHLGood
Peeters et al. 1999aHHLLLHLWeak
Peeters et al. 1999bHHLLLHLWeak
Haff et al. 2000UULLLULGood
Schedel et al. 2000UULLLHLGood
Deutekom et al. 2000UUHLLHLFair
Mihic et al. 2000UULLLHLGood
Hamilton et al. 2000UULLLULGood
Larson-Meyer et al. 2000UULLLHLGood
Volek et al. 2000UULLLHLGood
Becque et al. 2000HLLULULGood
Brenner et al. 2000UULLLULGood
Skare et al. 2001HHLHHHLWeak
Green et al. 2001UULULUHGood
Rockwell et al. 2001UULLLHUGood
Op t Eijnde et al. 2001UULLLHLGood
Bemben et al. 2001UULLLULGood
Chrusch et al. 2001UULLLULGood
Kern et al. 2001UULLLHLGood
Parise et al. 2001aUUHLLHLFair
Parise et al. 2001bUUHLLHLFair
Wilder et al. 2001aUULLHHLFair
Wilder et al. 2001bUULLHHLFair
Willoughby et al. 2001UULLLHLGood
Hespel et al. 2001UULULULGood
Coxe et al. 2002HUHLLHLWeak
Gotshalk et al. 2002UULULULGood
Kilduff et al. 2002HHLLLHLWeak
Wilder et al. 2002aUULLHHUFair
Wilder et al. 2002bUULLHHUFair
Walter et al. 2002UULLLHLGood
Huso et al. 2002UULLLULGood
Warber et al. 2002UULLLHLGood
Kutz et al. 2003HHLLLHLWeak
Vukovich et al. 2003HHLHHHHWeak
Lehmkuhl et al. 2003UULLLHLGood
Burke et al. 2003aLLLLLULGood
Burke et al. 2003bLLLLLULGood
Van Loon et al. 2003HHLLLHLWeak
Zajac et al. 2003UULHLHLFair
Eijnde et al. 2003aUULULULGood
Eijnde et al. 2003bUULULULGood
Kambis et al. 2003UULLLULGood
Brose et al. 2003 aUULLLULGood
Brose et al. 2003 bUULLLULGood
Watsford et al. 2003UULLLHUGood
Eckerson et al. 2004UULULLLGood
Kinugasa et al. 2004HHLLLHLWeak
Javierre et al. 2004UULUHHLFair
Volek et al. 2004UULLLHLGood
Ball SD et al. 2004UULLLULGood
Tarnopolosky et al. 2004LLLLLHLGood
Taes et al. 2004UULLLHLGood
Anomasiri et al. 2004UULULULGood
Eckerson et al. 2005aUULULULGood
Eckerson et al. 2005bUULULULGood
Eckerson et al. 2005cUULULULGood
Eckerson et al. 2005dUULULULGood
Perret et al. 2005UHLLLHLFair
Ahmun et al. 2005UULLLULGood
Mendell et al. 2005HHLHLHLWeak
Fuld et al. 2005UULULULGood
Hoffman et al. 2005UUHLLHLFair
Kuethe et al. 2006HULULULGood
Hille et al. 2006UULULULGood
Norman et al. 2006LLLLLHLGood
Ferguson et al. 2006UULLLULGood
Pluim et al. 2006UUHLLHHWeak
Rogers et al. 2006UULLLHLGood
Hoffman et al. 2006UULLLULGood
Smith et al. 2007UUHLLHLFair
Stout et al. 2007UULLLHLGood
Silva et al. 2007UULLLHLGood
Wright et al. 2007HHLHHHLWeak
De Souza junior et al. 2007UULULULGood
Cribb et al. 2007 aUULLLULGood
Cribb et al. 2007 bUULLLULGood
Hass et al. 2007UULLLHLGood
Chilibeck et al. 2007UULLLULGood
Cribb et al. 2007UULLLULGood
Walter et al. 2008UULLLHLGood
Eckerson et al. 2008UULULULGood
Gotshalk et al. 2008UULLLHLGood
Deacon et al. 2008LLLLLLHGood
Eliot et al. 2008 aUULLLULGood
Eliot et al. 2008 bUULLLULGood
Little et al. 2008UULLLHLGood
Jager et al. 2008 aUULLLHLGood
Jager et al. 2008 bUULLLHLGood
Sakkas et al. 2009LLLLLHUGood
Bazzucchi et al. 2009UHLULUHFair
Spillane et al.2009aUULLLHLGood
Spillane et al. 200 bUULLLHLGood
Herda et al. 2009aUULULULGood
Herda et al. 2009bUULULULGood
Herda et al. 2009cUULULULGood
Fukuda et al. 2010aUULULULGood
Fukuda et al. 2010bUULULULGood
Hickner et al. 2010HULLLHLFair
Saremi et al. 2010LLLLLHUGood
Camic et al. 2010UULLLULGood
Smith et al. 2011aUULLLHLGood
Smith et al. 2011bUULLLHLGood
Neves JR et al. 2011LLLLLHLGood
Rawson et al. 2011LULLLHLGood
Taylor et al. 2011UULLLHLGood
Mohebbi et al. 2012HHLLLHLWeak
Zuniga et al. 2012UULLLHLGood
Pericario et al. 2012UULLLHUGood
Sterkowicz et al. 2012UULLLHLGood
Montes De Oca et al. 2013UULLLULGood
Aguiar et al. 2013ULLLLULGood
Cooke et al. 2014UULLLHLGood
Gualano et al. 2014aLLLLLULGood
Gualano et al. 2014bLLLLLULGood
Kresta et al. 2014(a)UULLLHUGood
kresta et al. 2014(b)UULLLHUGood
Hayashi et al. 2014ULLLLULGood
Nemezio et al. 2015ULLLLULGood
Aedma et al. 2015HULLLULGood
Lobo et al. 2015LULLLHLGood
Candow et al. 2015aULLLLULGood
Candow et al. 2015bULLLLULGood
Chilibeck et al. 2015LLHLLLHFair
Deminice et al. 2015UULLLULGood
Wilkinson et al. 2016LLLLLHHFair
Forbes et al. 2016LLLLLULGood
Pinto et al. 2016LULLLHLGood
Collins et al. 2016ULLLLHLGood
Johannsmeyer et al. 2016LLLLLHLGood
Backx et al. 2017UULLLULGood
Wilborn et al. 2017UULLLHLGood
Karamat et al. 2017LLLHLLLGood
Atakan et al. 2018LULULULGood
Wang et al. 2018UULLLHLGood
Vanbavel et al. 2019UULLHHHWeak
Arazi et al. 2019UUHULULGood
Almeida et al. 2020UULULULGood
Marini et al. 2020UHLLLHLFair
Candow et al. 2020LLLLLLLGood
Delextrat et al. 2020aUULLLULGood
Delextrat et al. 2021bUULLLULGood
Anders et al. 2021UULLLULGood
Pakulak et al. 2021aUULLLHUGood
pakulak et al. 2021bUULLLHUGood
Bonilla et al. 2021LULLHULGood
Butchart et al. 2022UULLLULGood
Almeida et al. 2022UULULULGood
Dinan et al. 2022aLLLLLULGood
Dinan et al. 2022bLLLLLULGood
Askow et al. 2022ULLLLULGood
Moore et al. 2023aLLLLLULGood
Moore et al. 2023bLLLLLULGood

Note: L; low risk of bias; H, high risk of bias; U, unclear risk of bias.

General Low risk < 2 high risk.

General moderate risk = 2 high risk.

General high risk > 2 high risk.

4. Meta-analysis

4.1. Effect of creatine supplementation on body composition in adults

4.1.1. Effect of creatine supplementation on body mass and body mass index

Analyzing 154 overall effect sizes demonstrated a significant increase in body mass following creatine supplementation (WMD: 0.86 kg; 95% CI: 0.76 to 0.96; p < 0.001) (Figure 2A). However, no degree of heterogeneity was found (I2 = 0.0%). Evaluating the results of subgroup analysis showed that the effect of creatine supplementation on body mass was independent of age, sex, activity status of participants, trial duration, intervention dose, loading protocol, type of creatine, and type of training program during the intervention (Table 3). Overall, results from the random effects model indicated that creatine supplementation failed to change body mass index (WMD: 0.20 kg/m2; 95% CI: −0.17 to 0.58; p = 0.299) (Figure 2B). Moreover, no degree of between-studies heterogeneity was observed (I2 = 0.0%) (Table 3).

Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of creatine supplementation on A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); E) and FFM (kg).

Continued

Table 3.

Subgroup analyses of creatine supplementation on body composition in adults.

 Number of effect sizesWMD (95%CI)P-valueheterogeneity
P heterogeneityI2P between sub-groups
Subgroup analyses of creatine on body mass (kg)
Overall effect1540.86 (0.76, 0.96)<0.0011.0000.0% 
Trial duration (d)      
≤30890.87 (0.77, 0.98)<0.0011.0000.0%0.490
>30650.76 (0.47, 1.06)<0.0011.0000.0%
Intervention dose (g/d)      
≤5680.91 (0.78, 1.04)<0.0011.0000.0%0.256
>5860.80 (0.65, 0.94)<0.0011.0000.0%
Baseline BMI (kg/m2)      
Normal (18.5–24.9)150.81 (0.11, 1.51)0.0221.0000.0%0.523
Overweight (25–29.9)90.48 (−0.24, 1.22)0.1950.9980.0%
Sex      
Male930.89 (0.78, 1.01)<0.0011.0000.0% 
Both330.57 (0.24, 0.91)0.0011.0000.0% 
Female270.86 (0.62, 1.09)<0.0010.8240.0%
Participant’s age      
<40750.93 (0.82, 1.04)<0.0011.0000.0%0.077
>40290.60 (0.7825 0.95)0.0011.0000.0%
Activity status      
Trained580.94 (0.76, 1.12)<0.001<0.0010.0%0.179
Active450.86 (0.74, 0.99)<0.0010.9940.0%
Non-active510.60 (0.28, 0.91)<0.001<0.0010.0%
Along with exercise      
AT170.95 (0.58, 1.32)<0.0010.9930.0%0.068
CT400.59 (0.31, 0.88)<0.0010.9970.0%
No exercise170.50 (0.08, 0.92)0.0180.9920.0%
RT570.89 (0.76, 1.01)<0.0011.0000.0%
Loading      
Just loading480.54 (−0.14, 1.23)<0.0010.9980.0%0.685
Loading + short maintenance220.91 (0.78, 1.05)<0.0011.0000.0%
Maintenance430.98 (0.60, 1.36)<0.0011.0000.0%
High dose maintenance61.26 (0.03, 2.48)0.0360.9970.0%
loading + long maintenance320.66 (0.26, 1.07)0.0020.9750.0%
Type of creatine      
CrC120.89 (0.65, 1.13)<0.0010.4232.2%0.971
CM1280.85 (0.74, 0.96)<0.0011.0000.0%
Other50.98 (−0.00, 1.98)0.0520.26120.4%
Subgroup analyses of creatine on BMI (kg/m2)
Overall effect130.20 (−0.17, 0.58)0.2991.0000.0% 
Trial duration (d)      
≤3050.31 (−0.22, 0.84)0.2540.9960.0%0.568
>3080.08 (−0.45, 0.63)0.7490.9990.0%
Intervention dose (g/d)      
≤5120.18 (−0.21, 0.59)0.3641.0000.0%0.850
>510.30 (−0.78, 1.38)0.589--
Baseline BMI (kg/m2)      
Normal (18.5–24.9)60.25 (−0.27, 0.79)0.3440.9770.0%0.779
Overweight (25–29.9)50.14 (−0.41, 0.71)0.6100.9920.0%
Sex      
Male30.41 (−0.31, 1.14)0.2670.9620.0%0.769
Both80.08 (−0.45, 0.61)0.7680.9990.0%
Female20.22 (−0.58, 1.02)0.5930.9230.0%
Participant’s age      
<4040.28 (−0.31, 0.88)0.3520.9950.0%0.585
>4060.05 (−0.51, 0.62)0.8490.9930.0%
Activity status      
Active10.30 (−0.81, 1.41)0.597--0.945
Trained40.29 (−0.56, 1.16)0.4990.9930.0%
Non-active80.15 (−0.29, 0.61)0.4990.9950.0%
Along with exercise      
CT10.53 (−1.61, 2.67)0.628--0.990
No exercise30.16 (−0.58, 0.91)0.6630.9920.0%
AT10.30 (−0.78, 1.38)0.589--
RT50.08 (−0.60, 0.76)0.8190.9890.0%
Loading      
Just loading10.30 (−0.78, 1.38)0.589--0.932
Loading + short maintenance10.08 (−2.27, 2.43)0.947--
Maintenance60.23 (−0.30, 0.77)0.3901.0000.0%
loading + long maintenance4−0.05 (−0.82, 0.71)0.8930.9620.0%
Type of creatine      
CM110.14 (−0.26, 0.56)0.4811.0000.0%0.805
Other10.53 (−1.61, 2.67)0.376--
Subgroup analyses of creatine on FM (kg)
Overall effect620.05 (−0.24, 0.35)0.7031.0000.0% 
Trial duration (d)      
≤30150.34 (−0.21, 0.89)0.2270.9210.0%0.233
>3047−0.06 (−0.41, 0.29)0.7421.0000.0%
Intervention dose (g/d)      
≤5350.25 (−0.16, 0.67)0.2310.9990.0%0.183
>527−0.15 (−0.58, 0.27)0.4870.9920.0%
Baseline BMI (kg/m2)      
Normal (18.5–24.9)8−0.25 (−0.78, 0.27)0.3490.9170.0%0.287
Overweight (25–29.9)100.29 (−0.47, 1.05)0.4570.9750.0%
Obese (≥30)1−3.60 (−9.91, 2.71)0.264--
Sex      
Male300.28 (−0.13, 0.69)0.1850.9910.0%0.494
Both21−0.14 (−0.64, 0.34)0.5560.9880.0%
Female10−0.29 (−1.16, 0.58)0.5150.9770.0%
Participant’s age      
<4030−0.12 (−0.63, 0.38)0.6191.0000.0%0.775
>4021−0.02 (−0.51, 0.46)0.9170.9200.0%
Activity status      
Active150.01 (−0.59, 0.62)0.9660.7460.0%0.891
Trained180.17 (−0.38, 0.73)0.5421.0000.0%
Non-active290.01 (−0.42, 0.44)0.9590.9920.0%
Along with exercise      
CT11−0.14 (−0.81, 0.52)0.6670.7650.0%0.927
No exercise50.26 (−0.58 1.10)0.5460.9910.0%
AT2−0.09 (−1.14, 0.95)0.8640.5900.0%
RT400.09 (−0.30, 0.48)0.6580.9980.0%
Loading      
Just loading50.15 (−0.77, 1.08)0.7460.9920.0%0.859
Loading + short maintenance70.51 (−0.55, 1.58)0.3450.3569.6%
Maintenance28−0.08 (−0.60, 0.44)0.7640.9980.0%
High dose maintenance20.28 (−0.70, 1.28)0.5730.6980.0%
loading + long maintenance20−0.02 (−0.50, 0.46)0.9270.9830.0%
Type of creatine      
CM590.05 (−0.24, 0.35)0.7231.0000.0%0.934
Other20.01 (−2.01, 2.04)0.693--
Subgroup analyses of creatine on BFP (%)
Overall effect89−0.28 (−0.47, −0.09)0.0040.9680.0% 
Trial duration (d)      
≤3036−0.30 (−0.65, 0.04)0.0840.3417.5%0.512
>3053−0.16 (−0.41, 0.08)0.2000.9990.0%
Intervention dose (g/d)      
≤551−0.04 (−0.29, 0.20)0.7340.9860.0%0.005
>538−0.60 (−0.89, −0.30)<0.0010.9030.0%
Baseline BMI (kg/m2)      
Normal (18.5–24.9)7−0.26 (−0.74, 0.21)0.2790.9950.0%0.549
Overweight (25–29.9)8−0.08 (−0.44, 0.28)0.6680.7120.0%
Sex      
Male55−0.36 (−0.61, −0.11)0.0050.5930.0%0.622
Both18−0.15 (−0.68, 0.37)0.5580.9960.0%
Female16−0.18 (−0.52, 0.16)0.2990.9340.0%
Participant’s age      
<4045−0.19 (−0.52, 0.13)0.2440.9980.0%0.779
>4020−0.13 (−0.44, 0.17)0.4010.9980.0%
Activity status      
Active18−0.04 (−0.80, 0.73)0.9200.06735.7%0.063
Trained37−0.56 (−0.86, −0.26)<0.0010.9680.0%
Non-active34−0.10 (−0.37, 0.17)0.4741.0000.0%
Along with exercise      
CT22−0.83 (−1.22, −0.44)<0.0010.7410.0%0.022
No exercise7−0.32 (−0.82, 0.17)0.2020.7240.0%
AT6−0.37 (−1.14, 0.39)0.3410.9030.0%
RT43−0.02 (−0.30, 0.25)0.8640.9110.0%
Loading      
Just loading12−0.10 (−0.61, 0.41)0.6991.0000.0%0.177
Loading + short maintenance150.14 (−0.63, 0.93)0.7110.28814.8%
Maintenance32−0.59 (−0.91, −0.28)<0.0010.5270.0%
High dose maintenance5−0.17 (−1.03, 0.69)0.6980.7630.0%
loading + long maintenance25−0.14 (−0.45, 0.16)0.3630.9960.0%
Type of creatine      
CrC1−0.10 (−3.42, 3.22)0.953--0.720
CM80−0.31 (−0.51, −0.11)0.0020.9210.0%
Other40.21 (−0.85, 1.28)0.6930.7810.0%
Subgroup analyses of creatine on FFM (kg)
Overall effect950.82 (0.57, 1.06)<0.0011.0000.0% 
Trial duration (d)      
≤30311.07 (0.48, 1.66)<0.0010.9960.0%0.357
>30640.76 (0.49, 1.03)<0.0011.0000.0%
Intervention dose (g/d)      
≤5520.77 (0.46, 1.08)<0.0011.0000.0%0.663
>5430.89 (0.49, 1.29)<0.0010.9810.0%
Baseline BMI (kg/m2)      
Normal (18.5–24.9)71.12 (0.59, 1.65)<0.0010.8290.0%0.270
Overweight (25–29.9)80.39 (−0.34, 1.13)0.2930.9050.0%
Obese (≥30)1−0.40 (−6.69, 5.89)0.901--
Sex      
Male511.20 (0.80, 1.60)<0.0011.0000.0%0.120
Both250.60 (0.21, 0.99)0.0020.9700.0%
Female180.54 (0.03, 1.06)0.0361.0000.0%
Participant’s age      
<40480.89 (0.45, 1.33)<0.0011.0000.0%0.955
>40270.87 (0.53, 1.22)<0.0010.9960.0%
Activity status      
Active260.71 (0.01, 1.41)0.0451.0000.0%0.194
Trained321.31 (0.72, 1.90)<0.0010.9990.0%
Non-active370.71 (0.42, 1.01)<0.0010.9940.0%
Along with exercise      
CT261.00 (0.48, 1.52)<0.0010.9340.0%0.143
No exercise70.24 (−0.26, 0.75)0.3470.8540.0%
AT61.19 (−0.09, 2.48)0.0680.9890.0%
RT480.99 (0.64, 1.35)<0.0011.0000.0%
Loading      
Just loading100.88 (−0.36, 2.13)0.1651.0000.0%0.828
Loading + short maintenance190.52 (−0.24, 1.29)0.1790.9990.0%
Maintenance320.72 (0.32, 1.12)<0.0010.9120.0%
High dose maintenance31.34 (−0.40, 3.09)0.1310.9760.0%
loading + long maintenance310.93 (0.57, 1.29)<0.0010.9960.0%
Type of creatine      
CM890.82 (0.57, 1.06)<0.0011.0000.0%0.997
Other30.91 (−3.06, 4.88)0.6530.8340.0%

Note: Abbreviations: WMD, weighted mean differences; CI, confidence interval; BMI, body mass index.

4.1.2. Effect of creatine supplementation on fat-free mass

Combined results from 95 effect sizes indicated a small, yet significant increase in fat-free mass following creatine supplementation (WMD: 0.82 kg; 95% CI: 0.57 to 1.06; p < 0.001) (Figure 2E). Additionally, we observed no degree of between-studies heterogeneity (I2 = 0.0%). Subgroup analysis revealed that creatine supplementation increased fat-free mass in studies that used combined or resistance training interventions or creatine monohydrate as a supplement. Moreover, using a maintenance dose, or creatine loading with a long maintenance dose had significant effects on fat-free mass. Descriptively, the results appeared to be greater among males (Table 3).

Continued

4.1.3. Effect of creatine supplementation on fat mass and body fat percentage

Pooled data from 62 effect sizes demonstrated no significant effect of creatine supplementation on fat mass (WMD: 0.05 kg; 95% CI: −0.24 to 0.35; p = 0.703) (Figure 2C), with no observed heterogeneity among the studies (I2 = 0.0%) (Table 3). Subgroup analysis failed to show any significant change in the results. According to the results from 89 effect sizes, creatine supplementation resulted in a very small reduction in body fat percentage (WMD: −0.28 %; 95% CI: −0.47 to − 0.09; p = 0.004) (Figure 2D). There was no heterogeneity among studies (I2 = 0.0%). Subgroup analysis revealed a significant reduction in body fat percentage in studies with supplementation dosages of more than 5 g/day, trained participants, and studies that used a combination of creatine supplementation with combined training. Also, studies that used creatine supplementation protocol with a maintenance dose or creatine monohydrate showed a significant reduction in body fat percentage (Table 3).

4.2. Sensitivity analysis

To ascertain the impact of each study on the overall effect size, each trial was excluded from the analysis step by step. Assessing the results of the sensitivity analysis indicated no significant alteration in the total effect of creatine supplementation on body mass, body mass index, fat-free mass, fat mass, and body fat percentage (Table 4).

Table 4.

Publication bias and sensitivity analysis.

Publication bias
 
OutcomesEgger’s testSensitivity
Body weight0.440None
BMI0.533None
FM0.350None
BFP0.212None
FFM0.169None

4.3. Publication bias

The overall results of Egger’s regression test and inspecting the funnel plots provided no evidence of publication bias (Table 4) (Figure 3).

Funnel plots for the effect of creatine supplementation on A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); and E) FFM (kg).

4.4. Non-linear dose-response analysis

The results of the dose-response analysis indicated a significant association between creatine doses with changes in fat mass (p = 0.039; Table 5 and Figure 4C) and fat-free mass (p = 0.008; Table 5 and Figure 4E). Also, a significant association between the duration of creatine supplementation and changes in body mass (p = 0.030; Table 5 and Figure 5A) was observed.

Non-linear dose-response relations between creatine supplementation and absolute mean differences. Dose-response relations between dose (g/day) and absolute mean differences in on A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); and E) FFM (kg).

Non-linear dose-response relations between creatine supplementation and absolute mean differences. Dose-response relations between duration of intervention (week) and absolute mean differences in A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); and E) FFM (kg).

Table 5.

Meta-regression and dose-response.

 Regression
Dose-response
 Dose (mg/d)
Duration (week)
Dose (mg/d)
Duration (week)
VariablesCoefficientp-valueCoefficientp-valueCoefficientp-valueCoefficientp-value
Body Mass−0.460.505−1.380.770−0.060.392−0.560.030
BMI4.480.507−25.700.835−0.070.194−0.270.128
FM−0.330.578−10.240.177−2.020.039−0.650.074
BFP−0.710.3531.590.806−3.450.063−0.560.210
FFM0.910.144−1.740.8101.750.0080.130.454

4.5. Meta-regression analysis

The results of the meta-regression test showed that there was no significant association between the dosage and duration of creatine supplementation and alterations in body composition variables (Table 5, Figures 6,7).

linear dose-response relations between creatine supplementation and absolute mean differences. Dose-response relations between dose (g/day) and absolute mean differences in A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); and E) FFM (kg).

linear dose-response relations between creatine supplementation and absolute mean differences. Dose-response relations between duration of intervention (week) and absolute mean differences in A) body weight (kg); B) BMI (kg/m2); C) FM (kg); D) BFP (%); and E) FFM (kg).

4.6. GRADE analysis

The quality of evidence was assessed using the GRADE protocol in this meta-analysis. The quality of evidence in studies evaluating the creatine supplementation impact on body mass index and fat mass is regarded as moderate. Moreover, the evidence quality in studies aimed to estimate the influence of creatine supplementation on body mass, fat-free mass, and body fat percentage was upgraded to high (Table 6).

Table 6.

GRADE profile of creatine supplementation on body composition in adults.

OutcomesRisk of biasInconsistencyIndirectnessImprecisionPublication BiasQuality
of evidence
Body weightNo serious limitationNo serious limitationNo serious limitationNo serious limitationNo serious limitation[plus sign in circle][plus sign in circle][plus sign in circle][plus sign in circle]
High
BMINo serious limitationNo serious limitationNo serious limitationSerious limitation2No serious limitation[plus sign in circle][plus sign in circle][plus sign in circle][large circle]
Moderate
FMNo serious limitationNo serious limitationNo serious limitationSerious limitation2No serious limitation[plus sign in circle][plus sign in circle][plus sign in circle][large circle]
Moderate
BFPNo serious limitationNo serious limitationNo serious limitationNo serious limitationNo serious limitation[plus sign in circle][plus sign in circle][plus sign in circle][plus sign in circle]
High
FFMNo serious limitationNo serious limitationNo serious limitationNo serious limitationNo serious limitation[plus sign in circle][plus sign in circle][plus sign in circle][plus sign in circle]
High

1- There is no evidence of significant effects of creatine supplementation on BMI and FM..

4.7. Discussion

Overall, the most important outcomes from this comprehensive systematic review and meta-analysis were that creatine supplementation results in a small favorable effect on measures of fat-free mass and body fat percentage over time. Sub-analyses revealed that fat-free mass was significantly increased when (1) creatine was ingested in conjunction with either combined concurrent (aerobic + resistance training) training or resistance training alone, (2) creatine monohydrate was used, and (3) a maintenance dose (with or without a loading phase) was implemented. Moreover, it was shown that research including a daily creatine intake of more than 5 g or studies combining aerobic and resistance training in their experimental design exhibited a significant reduction in body fat percentage. No significant differences were found in any of the variables when subgrouping was done based on sex. However, it was observed that men exhibited a 1.20 kg increase in fat-free mass, while females had a smaller rise of 0.54 kg. Age, training status, and study duration did not appear to influence any of the outcome variables.

5. Loading protocol of creatine supplementation and training intervention

5.1. Creatine and fat-free Mass

In support of several previous systematic reviews and meta-analyses [5,11,12,175–177], creatine supplementation significantly increased estimates of fat-free mass (overall) by 0.82 kg (95% CI: 0.57, 1.06). This was only evident when creatine monohydrate was combined with resistance training or combination of resistance and aerobic training. Alternative forms of creatine (creatine malate, creatine ethyl ester and creatine phosphate) did appear to have a similar mean change in fat-free mass (Monohydrate: 0.82 kg [95% CI: 0.57, 1.06]; Alternative forms: 0.91 kg [−3.06, 4.88]). Few studies have examined the ergogenic effects of creatine-based compounds such as creatine malate, creatine ethyl ester and creatine phosphate, which limits the ability to draw strong conclusions. Sterkowicz et al. conducted a trial to determine the effects of 6-weeks of training with creatine malate supplementation on anaerobic capacity and aerobic power and in judo specific fitness performance. Results showed no effects of supplementation with creatine malate on body composition indices and physical performance compared to control [119]. In this study creatine malate was chosen due to its efficacy during absorption and digestion in the gastrointestinal tract. Another study examined the combined effects of creatine in the form of creatine ethyl ester and resistance training on body composition and muscle strength and power, when compared to creatine monohydrate, creatine ethyl ester failed to show significant improvements in body composition, muscle mass, and strength and power [111]. However, due to the limited number of studies, lack of statistical power, and large variability the alternative forms of creatine did not statistically increase fat-free mass compared to the placebo. Therefore, based on the current meta-analysis, creatine monohydrate is well-studied (n = 89 RCTs), effective (p < 0.001), has a well-developed safety profile [6], and is economical [15]. Additionally, confirmed by a previous review [178], creatine monohydrate is the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety recommended by professional societies and organizations. Future research may be warranted to explore alternative forms of creatine, however, presently it is clear that other forms of creatine are not superior to creatine monohydrate [15].

A prior meta-analysis included 22 RCTs with 721 older adults (age: 57–70 years of age, both males and females) who demonstrated an increase in fat-free mass (~1.37 kg, 95% CI: 0.97–1.76 kg) when creatine was ingested during a resistance training program (training 2–3 times/week for 7 to 52 weeks) compared to resistance training and placebo [5]. More recently, Delpino et al. (2022) included 35 studies with 1192 participants that revealed that creatine (with and without exercise) increased fat-free mass by 0.68 kg (95% CI: 0.26–1.11), however, sub-analyses demonstrated that gains in fat-free mass only occurred when creatine was ingested with resistance training (1.10 kg, 95% CI: 0.56–1.65) [12]. In contrast to the present investigation, the findings of Delpino et al. (2022) did not provide a statistically significant disparity in fat-free mass when creatine supplementation was administered in conjunction with a mixed regimen of aerobic and resistance training. In support of our findings, there was no significant effect on fat-free mass when creatine was ingested alone (without exercise). However, it is important to note that some of the observed increases in fat-free mass may be due to increases in body water retention (both extra- and intracellular). It is worth mentioning that several tools were used to measure body composition, such as bioelectric impedance analysis (BIA), BOD POD, hydrostatic weighting, hydro densitometry, skinfold equations, and dual-energy X-Ray absorptiometry. Among them, BIA is an electrical method which has the potential of quantifying total body water, extracellular water, intracellular water in addition to FM, FFM. However, due to the limited number of included studies that used BIA as body composition measurement tools (8 of 143 studies) or provided body water data, more studies are needed to confirm body water retention changes following creatine supplementation. A recent systematic review and meta-analysis involving 10 studies showed that the combination of creatine supplementation and resistance training increased regional measures of muscle accretion (0.10 to 0.16 cm; as measured using ultrasound and peripheral quantitative computed tomography) compared to placebo [23]. Mechanistically, greater fat-free mass from creatine is likely related to its ability to increase high-energy phosphate, glycogen, calcium, and protein kinetics, stimulation of satellite cells and growth factors, or by decreasing inflammation and oxidative stress over time [2,179]. In theory, creatine will allow you to train at a higher training volume, which may enhance training adaptations over time (for a comprehensive review on mechanisms of creatine to enhance muscle see [5]).

5.2. Creatine and Body Fat

The overall pooled analysis in the current review revealed a very small, yet statistically significant decrease in body fat percentage following creatine supplementation (−0.28% [−0.47, −0.09]) compared to placebo. However, there were no significant changes in fat mass or body mass index. In theory, an increase in fat-free mass may increase energy expenditure and influence energy balance resulting in fat loss over time. In addition, in animal models there is evidence that a reduction in the availability of creatine in adipose tissue slows whole-body energy expenditure and increases fat accumulation [19,20]. Despite these potential mechanisms, based on the current review they do not appear to be sufficient to alter absolute fat mass in humans over time and support the notion that the change in body fat percentage is likely due to an increase in fat-free mass. Bonilla et al. provided 7.6 g/day of creatine for 56 days in young resistance-trained males. They found that creatine combined with resistance training increased fat-free mass and decreased body fat percentage over time [148]. Sub-analyses revealed that high-dose creatine (>5 g/day), training status (i.e. being trained), exercise intervention, and the incorporation of a creatine maintenance dose following a creatine loading phase may influenced body fat percentage. In support of our findings, Forbes et al. (2019) observed a statistically significant decrease in body fat percentage when creatine was combined with resistance training [21] without a significant change in absolute fat mass. Nevertheless, there is ongoing debate over the potential efficacy of creatine supplementation in relation to decreasing body fat. Several research investigations have shown that there is no statistically significant difference in FM, BFP, or BMI after the administration of creatine supplements, regardless of whether exercise training is included or not [104,106,180–182]. The period of creatine supplementation in these studies was shorter than 30 days, which may be considered inadequate for achieving changes in body composition. Additionally, workout program was not created with the intention of establishing a well-rounded routine to effectively observe the intended effects on FM.

5.3. Creatine and body Mass

The observed rise in body mass following creatine supplements may be associated with intramuscular fluid retention that occurs due to the osmotic characteristics of creatine [183]. Further, creatine supplementation combined with carbohydrates increases muscle glycogen storage, thereby further increasing water retention [184]. These small alterations in water-induced cell swelling increase myogenic regulatory factors and activate satellite cells involved in muscle hypertrophy [185]. Over time, the increase in body mass is likely due to a combination of water retention and an increase in lean tissue mass. In resistance-trained males (n = 27) receiving either creatine or placebo over 8 weeks had no changes in the ratio of skeletal muscle mass to intracellular water and only the creatine group had a decrease in the skeletal muscle mass to extracellular water ratio [186]. In females, there may be variations in water retention based on the phase of the menstrual cycle [173]. Thirty moderately active females were randomized to either creatine (20 g/day for 5 days) or placebo, with a menstrual phase crossover design. There were significant increases in total body water, extracellular fluid, and intracellular fluid in the creatine condition only during the luteal phase, while no condition differences were noted in the follicular phase. Despite these alterations in fluid retention, body mass was not different between conditions or across the menstrual cycle [173]. These findings appear to support our current meta-analysis which found no sex-related differences. Collectively, creatine supplementation appears to increase body mass compared to placebo by ~0.86 kg.

In relation to the concept of loading protocol, it is worth noting that out of the total 154 research examined, a significant proportion of 48 studies did not include a maintenance phase subsequent to the loading phase. Interestingly, when comparing the collective impact of these studies that only focused on loading, it was shown that the effect on body mass was comparatively lower (0.54 kg) than the studies that used maintenance doses of creatine as part of their supplementation protocol. In accordance with the findings of Rogers et al. a research study used a creatine supplementation regimen of 3 g/d in conjunction with a strength training program spanning a duration of 12 weeks. The findings indicated a significant increase of 2 kg in body mass, which exhibited a notably greater magnitude in comparison to the control group receiving the placebo [187]. Similarly, Herda et al. conducted a study in which they administered a maintenance dosage of creatine supplementation (5 g/d) without implementing any exercise program. The findings of this study demonstrated a notable augmentation in body mass after a 30-day period of creatine supplementation among the participants in the creatine group [188].

A further study conducted by Delextrat et al. yielded findings indicating that a 28-day period of creatine supplementation, without the first loading phase, among athletes involved in rocket sports resulted in a significant rise in body mass within the creatine group. Conversely, no such gain was seen within the placebo or beta-alanine groups [189]. Nevertheless, findings from a prior scoping study revealed that irrespective of varying doses of methods and exercises, favorable outcomes of creatine supplementation on muscular strength, muscle mass, and athletic performance were seen among young, healthy individuals [190]. In terms of training modality, 40 studies included a mix of AT and RT in their training regimen. Additionally, 17 studies exclusively utilized AT, while 57 research employed RT as their primary training protocol. The subgroup analysis revealed that there was a positive effect on body mass across all subgroups when considering different types of exercise, means that despite of exercise types or even no exercise, creatine can increase body mass.

5.4. Dosage of creatine supplementation

Our results shows that studies using doses up to 5 grams of creatine daily (38 studies), demonstrated a statistically significant decrease in BFP. In this regard, after subgrouping based on dosage, the between subgroups heterogeneity was significant (p = 0.005) demonstrating dosage of creatine supplementation is the source of heterogeneity among included studies. however, different dosages did not change the effectiveness of creatine supplementation on FFM and body mass. Future studies should focus on finding the optimum dosage of creatine for attenuating body fat percentages.

5.5. Characteristics of participants that affect body composition indices due to creatine supplementation

Fat-Free Mass

The positive impacts of creatine on FFM were statistically significant irrespective of the age, sex, or whether the individuals were trained or untrained. In addition, participants with a normal body mass index (BMI:18.5 to 24.9) also showed a significant increase in FFM. Also, greater gains in FFM were shown in men. Accordingly, Delpino et al., 2022 did not find any influence from the dosage or type of creatine used or duration of supplementation on fat-free mass. However, they did report greater gains in fat-free mass in males compared to females (males: 1.46 kg [95% CI: 0.47, 2.46], females: 0.29 kg [95% CI: −0.43, 1.01]) [12]. We also found much larger increases in fat-free mass in males (1.20 kg) compared to females (0.54 kg). While no sex mechanisms were determined across these reviews, differing results may be associated with differences in pre-supplementation intramuscular creatine levels [191]. There is some evidence that females may have higher intramuscular creatine stores which may blunt their responsiveness to creatine supplementation [192]. Coincidentally, the findings from the subgroup analysis in this research demonstrated a significant augmentation in the impact of creatine supplementation on FFM in studies with a baseline BMI within the normal range. Given that the BMI data was only available for a limited number of individuals in 16 out of the 95 studies that examined the impact of creatine supplementation on FFM, it is important to use care when interpreting this finding.

5.6. Body fat percentage

Our results showed a significant reduction in BFP in trained individuals, while other characteristics of participants did not affect BFP due to Creatine Supplementation. 37 out of 89 studies conducted on trained individuals indicating training background may be a potential factor affecting BFP after creatine supplementation. Although it is not clear to us why trained individuals may benefit more from creatine supplementation, but more FFM gains (1.31 kg) in these subjects following creatine supplementation may partially explain the reduction of fat percentage.

5.7. Body Mass

Our analysis examined creatine on body mass and included 154 effect sizes. Overall, participants gained 0.86 kg (95% CI: 0.76, 0.96) following creatine supplementation compared to placebo. Trial duration, creatine dose, sex, age, loading protocol, exercise type, type of creatine, and training status did not alter these findings, nor was there any observed heterogeneity between studies. Our findings are partially supported by other systematic reviews and meta-analyses [21,176,193]. For example, Devries and Phillips (2014) conducted a systematic review and meta-analysis in older adults (N = 357, across 12 studies) ingesting creatine supplementation combined with resistance training and noted a significant increase in body mass compared to placebo (1.00 kg: 95% CI: 0.32–1.67 kg; p = 0.004) [194]. In contrast, Forbes et al.. (2019) conducted a systematic review and meta-analysis in older adults (N = 609, across 19 studies) and found a non-significant increase in body mass (0.86 kg: 95% CI, −0.32–2.05 kg; p = 0.15) [21].

5.8. Strengths and limitations

To our knowledge, this is the first meta-analysis that has evaluated the influence of various supplementation protocols, exercise types, training status, supplementation duration and dose, creatine type, sex, and age on body composition (body mass, fat-free mass, fat mass, body fat percentage and body mass index). Our systematic review included a comprehensive analysis of over 160 effect sizes, which increases the statistical power and certainty of our findings. Nevertheless, it is important to acknowledge limitations. Specifically, we found that a significant number of the RCTs included did not examine baseline intramuscular creatine concentrations or changes in creatine levels throughout the duration of the study, nor did they determine the dietary intake of creatine or total protein. One notable constraint of this meta-analysis was that the majority of studies used body composition measures as a secondary outcome. A further limitation is the absence of adequately structured RCTs that have assessed water retention, hence impeding our ability to elucidate the specific processes behind the increase in body mass and lean mass following to creatine supplementation. In future RCTs, it is warranted to assess both intra and extra-cellular hydration, as well as quantifying the intake of creatine from dietary sources. Additionally, it is crucial to use suitable dosages, exercise modalities, and loading protocols in the design of this research.

6. Conclusion

In summary, creatine supplementation has a very small effect on body mass, fat-free mass, and body fat percentage over time. These changes were apparent when creatine was combined with resistance training. Creatine appears to increase fat-free mass more in males compared to females. Collectively, variations in dosing protocols, training status, and age do not appear to influence the effectiveness of creatine supplementation. Based on previous research findings, which did not report any adverse effects related to the use of creatine supplements on the overall well-being of participants, it seems that people who are apparently healthy may experience benefits from the performance-enhancing properties of creatine supplementation.

Disclosure statement

D.G.C. has conducted industry-sponsored research involving creatine supplementation and received creatine donations for scientific studies and travel support for presentations involving creatine supplementation at scientific conferences. In addition, D.G.C. serves on the Scientific Advisory Board for Alzchem (a company that manufactures creatine) and as an expert witness/consultant in legal cases involving creatine supplementation.

Author contributions

MG, DAL, FD, and RB conceptualized and designed the study, interpreted the data, and prepared the manuscript. OA and MG analyzed the data and drafted the initial manuscript. FP, ZH and KG extracted data and drafted the initial manuscript. SF, FD, RB, and DC supervised the project and edited the initial manuscript. All authors contributed to the article and approved the submitted version.

Availability of supporting data

Data sharing is applicable.

Ethical approval and consent to participate

This is a review study, and there was no consent to participate.

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National Nutrition and Food Technology Research Institute

    Shahid Beheshti University of Medical Sciences