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

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]:

$\mathrm{SD}\mathrm{change}=\sqrt{[\left(\mathrm{SD}\mathrm{baseline}\right)\text{^}2\mathit{\hspace{0.17em}}+\mathit{\hspace{0.17em}}\left(\mathrm{SD}\mathrm{final}\right)\text{^}2\mathit{\hspace{0.17em}}-\mathit{\hspace{0.17em}}\left(2\mathrm{R}\times \mathrm{SD}\mathrm{baseline}\times \mathrm{SD}\mathrm{final}\right)}$

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.

Figure 1. 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.

Studies	Country	Study Design	Training background/health status	Sample size		Trial Duration (d)	Mean Age		Mean BMI		Intervention
				IG	CG		IG	CG	IG	CG	Loading	Creatine Type	How to use	Type of exercise	Control group
Balsom et al. 1993	Sweden	parallel, PC, DB	18 trained males/healthy	9	9	6	25.6	27.3	NR	NR	Just loading	CrM	20 g/d for 6 days	AT	Glucose
Mujika et al. 1996	France	parallel, PC, DB	20 trained male and female swimmers/healthy	10	10	5	NR	NR	NR	NR	Just loading	CrM	20 g/d for 5 days	AT	Lactose
Terrillion et al. 1997	USA	crossover, PC, DB	24 trained male runners/healthy	12	12	5	21	21	NR	NR	Just loading	CrM	20 g/d for 5 days	AT	Sucrose
Vanderberghe et al. 1997	Belgium	parallel, PC, DB	19 not trained females/healthy	10	9	74	NR	NR	NR	NR	loading + long maintenance	CrM	20 g/d for 4 days +5 g/d for 70 days	RT	Maltodextrin
Noonan et al. 1998a	USA	parallel, PC, DB	20 trained male college athletes/healthy	13	7	56	19.4	20.4	NR	NR	loading + long maintenance	CrM	20 g/d for 5 days +8.5 g/d for 51 days	CT	Dextrose
Noonan et al. 1998b	USA	parallel, PC, DB	19 trained male college athletes/healthy	13	6	56	19.7	20.4	NR	NR	High dose maintenance	CrM	20 g/d for 5 days +26.1 g/d for 51 days	CT	Dextrose
Kreider et al. 1998	USA	parallel, PC, DB	25 trained male football player/healthy	11	14	28	NR	NR	NR	NR	High dose maintenance	CrM	15.75 g/d for 28 days	RT	Phosphagen HP (glucose, taurine, disodium phosphate, potassium phosphate)
Oopik et al. 1998	Estonia	cross over,PC	6 trained male karate athletes/healthy	6	6	5	22.5	22.5	NR	NR	Just loading	CrM	20 g/d for 5 days	CT	Glucose
Maganaris et al. 1998	UK	crossover, PC, DB	10 active males/healthy	10	10	5	28	28	NR	NR	Just loading	CrM	10 g/d for 5 days	RT	Glucose polymer
Bermon et al. 1998a	France	parallel, PC, DB	16 not trained males and females/healthy	8	8	52	71.8	69.3	25.4	26.4	loading + long maintenance	CrM	20 g/d for 5 days +3 g/d for 47 days	NO	Glucose
Bermon et al. 1998b	France	parallel, PC, DB	16 not trained males and females/healthy	8	8	52	71	69.3	24.7	25	loading + long maintenance	CrM	20 g/d for 5 days +3 g/d for 47 days	RT	Glucose
Vukovich et al. 1998a	USA	parallel,PC,DB	24 active males/healthy	12	12	21	23.3	21.3	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +10 g/d for 16 days	RT	CHP (solid form)
Vukovich et al. 1998b	USA	parallel,PC,DB	24 active males/healthy	12	12	21	21.9	22.3	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +10 g/d for 16 days	RT	CHO (powder form)
Kelly et al. 1998	Australia	parallel, PC	18 trained males/healthy	9	9	26	25.5	28.1	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +5 g/d for 21 days	RT	Glucose
Mckenna et al.1999	Australia	parallel, PC, DB	14 active males and females/healthy	7	7	5	19	21	NR	NR	Just loading	CrM	30 g/d for 5 days	NR	Dextrose
Francaux et al. 1999	Belgium	parallel, PC, DB	18 not trained males/healthy	8	10	63	NR	NR	NR	NR	loading + long maintenance	CrM	21 g/d for 5 days +3 g/d for 58 days	RT	Maltodextrin
Rawson et al. 1999	USA	parallel, PC, DB	20 not trained males/healthy	10	10	30	66.7	66.9	NR	NR	Loading + short maintenance	CrM	20 g/d for 10 days +4 g/d for 20 days	NR	Dextrose
Pearson et al. 1999	USA	parallel, PC, DB	16 trained male football players/healthy	8	8	70	NR	NR	NR	NR	maintenance	CrM	5 g/d for 70 days	RT	Placebo capsules (NR)
Leenders et al. 1999a	USA	parallel, PC,DB	18 trained male swimmers/healthy	9	9	14	19.8	19	NR	NR	Loading + short maintenance	NR	20 g/d for 6 days +10 g/d for 8 days	AT	Maltodextrin solution 6%
Leenders et al. 1999b	USA	parallel,PC,DB	14 trained female swimmers/healthy	7	7	14	19.1	19.4	NR	NR	Loading + short maintenance	NR	20 g/d for 6 days +10 g/d for 8 days	AT	Maltodextrin solution 6%
Peeters et al. 1999a	USA	parallel, PC, DB	18 active males/healthy	11	7	42	NR	NR	NR	NR	loading + long maintenance	CrM	20 g/d for 3 days +10 g/d for 39 days	RT	Maltodextrin powder
Peeters et al. 1999b	USA	parallel, PC, DB	16 active males/healthy	9	7	42	NR	NR	NR	NR	loading + long maintenance	Cr phosphate	20 g/d for 3 days +10 g/d for 39 days	RT	Maltodextrin powder
Haff et al. 2000	USA	parallel, PC, DB	36 trained male and female collegiate track-and-field athletes/healthy	15	21	42	19.9	19.9	NR	NR	High dose maintenance	CrM	22.41 g/d for 42 days	RT	Rice flour and magnesium stearate
Schedel et al. 2000	Japan	parallel, PC, DB	10 trained males by endurance or resistance exercise/healthy	5	5	7	24	23	22.4	22.8	Just loading	CrM	30 g/d for 7 days	CT	Identical beverage without Cr
Deutekom et al. 2000	Netherlands	parallel, PC, DB	23 trained male rowers/healthy	11	12	6	NR	NR	NR	NR	Just loading	CrM	20 g/d for 6 days	CT	Maltodextrin
Mihic et al. 2000	Canada	parallel, PC, DB	30 not trained males and females/healthy	15	15	5	22.4	22.4	NR	NR	Just loading	CrM	20 g/d for 5 days	NR	Glucose polymer
Hamilton et al. 2000	USA	parallel, PC, DB	24 trained females/healthy	11	13	7	22.5	23.9	NR	NR	Just loading	CrM	25 g/d for 7 days	RT	Polycose
Larson-Meyer et al. 2000	USA	parallel, PC, DB	13 trained females/healthy	7	6	91	19.3	19	NR	NR	loading + long maintenance	CrM	15 g/d for 7 days +5 g/d for 84 days	CT	cool water + PowerAde powder
Volek et al. 2000	USA	parallel, PC, DB	19 trained males/healthy	10	9	84	25.6	25.4	NR	NR	loading + long maintenance	CrM	25 g/d for 7 days +5 g/days for 77 days	RT	Cellulose powder
Becque et al. 2000	USA	parallel,PC,DB	23 active males/healthy	10	13	42	NR	NR	NR	NR	loading + long maintenance	CrM	20 g/day for 5 days +2 g/day for 37 days	RT	Flavored, sucrose drink
Brenner et al. 2000	USA	parallel, PC, DB	16 trained female lacrosse players/healthy	7	9	35	18.1	19.5	NR	NR	Loading + short maintenance	CrM	20 g/d for 7 days +2 g/d for 28 days	CT	Sucrose
Skare et al. 2001	Norway	parallel, PC, SB	18 trained male sprinters/healthy	9	9	5	NR	NR	NR	NR	Just loading	CrM	20 g/d for 5 days	CT	Glucose
Green et al. 2001	USA	parallel, PC, DB	19 trained male recreational athletes/healthy	9	10	6	26.3	24.1	NR	NR	Just loading	CrM	20 gr/d for 6 days	NR	Sucrose and maltodextrin
Rockwell et al. 2001	USA	parallel, PC, DB	16 trained males/healthy	8	8	4	20.5	21.6	NR	NR	Just loading	CrM	20 g/d for 4 days	RT	Sucrose + Hypo energy diet
Op t Eijnde et al. 2001	Belgium	crossover, PC, DB	11 not trained males/healthy	11	11	5	20.7	20.7	NR	NR	Just loading	CrM	20 g/d for 5 days	RT	Maltodextrin plus citrate
Bemben et al. 2001	USA	parallel, PC, DB	17 trained male football players/healthy	9	8	63	19.4	19.3	NR	NR	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 58 days	CT	Glucose solution (containing sodium phosphate, exact protocol as the Cr group)
Chrusch et al. 2001	Canada	parallel, PC, DB	30 not trained males/healthy	16	14	84	70.4	71.1	27.9	25.7	loading + long maintenance	CrM	26.4 g/d for 5 days +6.2 g/d for 79 days	RT	CHO mixture
Kern et al. 2001	USA	parallel, PC, DB	19 active males/healthy	9	10	28	22.4	22.2	NR	NR	Loading + short maintenance	CrM	21 g/d for 5 days +10 g/d for 23 days	CT	Phosphagen HP matrix
Parise et al. 2001a	Canada	parallel, PC, DB	14 active females/healthy	7	7	8	NR	NR	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +5 g/d for 3 days	CT	Glucose polymer
Parise et al. 2001b	Canada	parallel, PC, DB	13 active males/healthy	7	6	8	NR	NR	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +5 g/d for 3 days	CT	Glucose polymer
Wilder et al. 2001a	USA	parallel,PC,DB	13 trained male football players/healthy	8	5	70	NR	NR	NR	NR	maintenance	CrM	3 g/d for 70 days	CT	Dextrose
Wilder et al. 2001b	USA	parallel,PC,DB	12 trained male football players/healthy	8	4	70	NR	NR	NR	NR	loading + long maintenance	CrM	20 g/d for 7 days +5 g/d for 63 days	CT	Dextrose
Willoughby et al. 2001	USA	parallel, PC, DB	16 not trained males/healthy	8	8	84	NR	NR	NR	NR	maintenance	CrM	6 g/d for 84 days	RT	Dextrose
Hespel et al. 2001	Belgium	parallel, PC, DB	22 not trained males and females/healthy	11	11	84	NR	NR	NR	NR	ND	CrM	20 g/d for 14 days +15 g/d for 21 days +5 g/d for 35 days	RT	Maltodextrin
Coxe et al. 2002	Australia	parallel, PC, DB	12 trained female soccer players/healthy	6	6	6	NR	NR	NR	NR	Just loading	CrM	20 g/d for 6 days	AT	glucose polymer
Gotshalk et al. 2002	USA	parallel, PC, DB	18 not trained males/healthy	10	8	7	65.4	65.7	NR	NR	Just loading	CrM	25.32 g/d for 7 days	NR	Cellulose
Kilduff et al. 2002	UK	parallel, PC, DB	32 trained males/healthy	21	11	5	24.5	24.5	NR	NR	Just loading	CrM	20 g/d for 5 days	RT	Glucose polymer
Wilder et al. 2002a	USA	parallel, PC, DB	13 trained males/healthy	8	5	70	18.8	19.2	NR	NR	maintenance	CrM	3 g/d for 70 days	CT	Dextrose
Wilder et al. 2002b	USA	parallel, PC, DB	12 trained males/healthy	8	4	70	18.8	19.2	NR	NR	loading + long maintenance	CrM	20 g/d for 7 days +5 g/d for 63 days	CT	Dextrose
Walter et al. 2002	Germany	crossover, PC, DB	34 not trained males and females/DM1	34	34	56	44.13	44.13	NR	NR	loading + long maintenance	CrM	10.6 g/d for10 days +5.3 g/d for 46 days	NO	Microcrystalline cellulose
Huso et al. 2002	USA	crossover, PC, DB	10 active males/healthy	10	10	21	NR	NR	NR	NR	Loading + short maintenance	CrM	20 g/d for 4 days +2 g/d for 17 days	RT	Maltodextrin
Warber et al. 2002	USA	parallel, PC, DB	26 active males/healthy	13	13	5	30.5	33.4	NR	NR	Just loading	CrM	24 g/d for 5 days	NR	Identical sports bars
Kutz et al. 2003	USA	parallel, PC, DB	17 not trained males/healthy	9	8	28	NR	NR	NR	NR	High dose maintenance	CrM	30 g/d for 14 days +15 g/d for 14 days	RT	Multodextros + rice brane + sucrose
Vukovich et al. 2003	USA	control trail	24 trained males/healthy	12	12	7	NR	NR	NR	NR	Just loading	CrM	21 g/d for 7 days	RT	Regular diet
Lehmkuhl et al. 2003	USA	parallel,PC,DB	19 trained male and female young track and field athletes/healthy	10	9	56	19.4	20.1	NR	NR	loading + long maintenance	CrM	21.2 g/d for 7 days +2.1 g/d for 49 days	CT	Potato starch
Burke et al. 2003a	Canada	parallel, PC, DB	18 active male and female young track and field athletes/healthy	10	8	56	31	34	NR	NR	loading + long maintenance	CrM	16.8 g/d for7 days +4.2 g/d for 49 days	CT	Maltodextrin
Burke et al. 2003b	Canada	parallel, PC, DB	24 active male and female young track and field athletes/healthy	12	12	56	33	32	NR	NR	loading + long maintenance	CrM	16.8 g/d for7 days +4.2 g/d for 49 days	CT	Maltodextrin
Van Loon et al. 2003	Netherlands	parallel, PC, DB	19 not trained males/healthy	9	10	42	20.6	21.3	20.4	21.2	loading + long maintenance	CrM	20 g/d for 5 days +2 g/d for 37 days	NO	Glucose + Maltodextrin
Zajac et al.2003	Poland	parallel, PC, DB	25 trained male basketball players/healthy	12	13	30	NR	NR	NR	NR	maintenance	CrM	ND	CT	CHO
Eijnde et al. 2003a	Denmark	parallel,PC,DB	46 not trained males/healthy	23	23	180	63.9	62.2	NR	NR	maintenance	CrM	5 g/d for 180 days	CT	Placebo capsules (NR)
Eijnde et al. 2003b	Denmark	parallel,PC,DB	20 not trained males/healthy	10	10	360	65.3	61.8	NR	NR	maintenance	CrM	5 g/d for 360 days	CT	Placebo tablets (NR)
Kambis et al. 2003	USA	parallel, PC, DB	22 not trained females/healthy	11	11	5	NR	NR	NR	NR	Just loading	CrM	24.3 g/d for 5 days	NR	Corn starch
Brose et al. 2003a	Canada	parallel, PC, DB	15 not trained males/healthy	8	7	98	68.7	68.3	NR	NR	maintenance	CrM	5 g/d for 98 days	RT	Dextrose
Brose et al. 2003b	Canada	parallel, PC, DB	13 not trained females/healthy	6	7	98	70.8	69.9	NR	NR	maintenance	CrM	5 g/d for 98 days	RT	Dextrose
Watsford et al. 2003	Australia	parallel, PC, DB	20 not trained males/healthy	9	11	28	NR	NR	NR	NR	Loading + short maintenance	NR	20 g/d for 7 days +10 g/d for 21 days	NO	Placebo capsules (NR)
Eckerson et al. 2004	USA	crossover, PC, DB	10 active females/healthy	10	10	5	NR	NR	NR	NR	Just loading	Cr citrate	20 gr/d for 5 days	CT	Dextrose powder
Kinugasa et al. 2004	Japan	parallel,PC,DB	12 not trained males/healthy	6	6	5	22.5	22.2	NR	NR	Just loading	CrM	20 g/d for 5 days	NO	Maltodextrin
Javierre et al. 2004	Spain	parallel, PC	19 active males/healthy	10	9	5	NR	NR	NR	NR	Just loading	CrM	20 g/d for 5 days	NR	Placebo capsules (NR)
Volek et al. 2004	USA	parallel, PC, DB	17 trained males/healthy	9	8	28	20.7	21.3	NR	NR	Loading + short maintenance	CrM	26 g/d for 7 days +4.33 g/d for 21 days	RT	Cellulose powder
Ball SD et al. 2004	USA	crossover, PC, DB	10 active males/healthy	10	10	21	NR	NR	NR	NR	Loading + short maintenance	CrM	20 g/d for 4 days +2 g/d for 17 days	RT	Maltodextrin
Tarnopolosky et al. 2004	Canada	crossover, PC, DB	34 not trained males and females/DM1 patients	34	34	120	41	41	NR	NR	maintenance	CrM	5 g/d for 120 days	NO	Dextrose and cellulose fiber
Taes et al. 2004	Belgium	crossover, PC, DB	45 not trained males and females/Hemodialysis patients	45	45	28	71	69	NR	NR	maintenance	CrM	2 g/d for 28 days	NO	Lactose
Anomasiri et al. 2004	Thailand	parallel, PC, DB	38 active males/healthy	19	19	7	NR	NR	NR	NR	ND	CrM	10 g/d for 7 days	AT	Orange juice powder
Eckerson et al. 2005a	USA	parallel, PC, DB	15 active males/healthy	10	5	6	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 6 days	CT	Dextrose
Eckerson et al. 2005b	USA	parallel, PC, DB	15 active females/healthy	10	5	6	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 6 days	CT	Dextrose
Eckerson et al. 2005c	USA	parallel, PC, DB	15 active males/healthy	10	5	6	NR	NR	NR	NR	Just loading	Cr phosphate	20 g/d for 6 days	CT	Dextrose
Eckerson et al. 2005d	USA	parallel, PC, DB	15 active females/healthy	10	5	6	NR	NR	NR	NR	Just loading	Cr phosphate	20 g/d for 6 days	CT	Dextrose
Perret et al. 2005	Switzerland	crossover, PC, DB	6 trained male and female competitive wheelchair athletes/healthy	6	6	6	33	33	NR	NR	Just loading	CrM	20 g/d for 6 days	AT	Maltodextrin
Ahmun et al. 2005	UK	crossover,PC,DB	14 trained male rugby players/healthy	14	14	5	20.6	20.6	NR	NR	Just loading	CrM	20 g/d for 5 days	CT	Dextrose powder
Mendell et al. 2005	USA	parallel, PC, DB	16 active males and females/healthy	8	8	5	26	26	NR	NR	Just loading	CrM	20 g/d for 5 days	NO	Solka-Floc (cellulose) plus Gatorade
Fuld et al. 2005	UK	parallel, PC, DB	25 not trained males and females/patients with COPD	14	11	84	61.7	63.7	23.2	24.3	loading + long maintenance	CrM	17.1 g/d for 14 days + 5.7 gr/d for 70 days	CT	Glucose polymer
Hoffman et al. 2005	USA	parallel, PC, DB	40 not trained males/healthy	20	20	6	21.7	21.1	NR	NR	ND	CrM	6 gr/d for 6 days	NR	Cellulose powder and methylcellulose
Kuethe et al. 2006	Germany	crossover, PC, DB	13 not trained males and females/congestive heart failure patients	13	13	42	58.2	58.2	NR	NR	High dose maintenance	CrM	20 g/day for 42 days	NO	Placebo capsules (NR)
Hille et al. 2006	USA	crossover, PC, DB	11 trained males/healthy	11	11	7	NR	NR	NR	NR	Just loading	CrM	21.6 g/day for 7 days	NR	Placebo capsules (NR)
Norman et al. 2006	Germany	parallel, PC, DB	31 not trained males and females/Patients with colorectal cancer	16	15	56	65.1	61.61	25.13	24.62	loading + long maintenance	CrM	20 g/day for 7 days +5 g/d for 49 days	NR	Cellulose
Ferguson et al. 2006	Canada	parallel, PC, DB	26 trained females/healthy	13	13	70	NR	NR	NR	NR	loading + long maintenance	CrM	19.71 g/d for 7 days + 1.97 gr/d for 63 days	RT	Placebo capsules (NR)
Pluim et al. 2006	Germany	parallel,PC,DB	24 trained male tennis players/healthy	14	10	34	22.5	22.8	NR	NR	Loading + short maintenance	CrM	22.1 g/d for 6 days +2.2 g/d for 28 days	AT	Maltodextrin and dextrose
Rogers et al. 2006	USA	parallel, PC, DB	30 not trained males and females/healthy	15	15	84	NR	NR	NR	NR	maintenance	CrM	3 g/d for 84 days	RT	Maltodextrin
Hoffman et al. 2006	USA	parallel, PC, DB	33 trained male football players/healthy	17	16	70	NR	NR	NR	NR	maintenance	CrM	10.5 g/d for 70 days	RT	Dextrose
Smith et al. 2007	USA	parallel, PC, DB	15 trained females/healthy	7	8	5	22.4	22.3	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	NR	Dextrose
Stout et al. 2007	USA	crossover, PC, DB	15 not trained males and females/healthy	15	15	14	74.5	74.5	NR	NR	Loading + short maintenance	Cr citrate	20 g/d for 7 days +10 g/d for 7 days	NO	Flavored powder blend
Silva et al. 2007	Portugal	parallel, PC, DB	16 trained female competitive swimmers/healthy	8	8	21	16.3	15.7	NR	NR	High dose maintenance	CrM	20 g/d for 21 days	AT	Maltodextrin solution 6%
Wright et al. 2007	USA	crossover, PC, DB	10 active male s/healthy	10	10	7	25.7	25.7	NR	NR	Just loading	CrM	20 g/d for 7 days	AT	Sucrose and maltodextrin drink
De Souza junior et al. 2007	Brazil	parallel, PC, DB	18 active male s/healthy	9	9	42	25	23	NR	NR	loading + long maintenance	CrM	30 g/d for 7 days +5 g/d for 35 days	RT	Maltodextrin
Cribb et al. 2007a	Australia	parallel, PC, DB	15 active male s/healthy	8	7	77	25	24	NR	NR	loading + long maintenance	CrM	25 g/d for 7 days +8.4 g/d for 70 days	RT	CHO
Cribb et al. 2007b	Australia	parallel, PC, DB	11 active male s/healthy	6	5	77	25	24	NR	NR	loading + long maintenance	CrM	25 g/d for 7 days +8.4 g/d for 70 days	RT	Whey protein
Hass et al. 2007	USA	parallel, PC, DB	20 not trained males and females/healthy	10	10	84	62.8	62.2	NR	NR	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 79 days	RT	Lactose monohydrate
Chilibeck et al. 2007	Canada	parallel, PC, DB	18 trained male rugby union football players/healthy	9	9	56	27	26	NR	NR	maintenance	CrM	9.5 d/d for 56 days	CT	Glucose
Cribb et al. 2007	Australia	parallel, PC, DB	21 active males/healthy	10	11	70	26	26	NR	NR	maintenance	CrM	8.9 g/d for 70 days	RT	PRO-CHO supplement
Walter et al. 2008	USA	parallel, PC, DB	16 trained males/healthy	8	8	5	26.1	23.1	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	NR	Fructose powder
Eckerson et al. 2008	USA	parallel, PC, DB	32 active males/healthy	17	15	30	22	20	NR	NR	maintenance	Cr citrate	5 g/day for 30 days	CT	Dextrose
Gotshalk et al. 2008	USA	parallel, PC, DB	27 not trained females/healthy	15	12	7	63.31	62.98	NR	NR	Just loading	CrM	20.13 g/d for 7 days	NR	Cellulose
Deacon et al. 2008	UK	parallel, PC, DB	80 not trained males and females/Participants with COPD	38	42	54	67.6	68.3	28.1	25.7	loading + long maintenance	CrM	20 g/d for 5 days + 3.76 gr/d for 49 days	CT	Lactose
Eliot et al. 2008 a	USA	parallel, PC, DB	20 not trained males/healthy	10	10	98	NR	NR	NR	NR	maintenance	CrM	2.14 g/d for 98 days	RT	Sport drink
Eliot et al. 2008 b	USA	parallel, PC, DB	22 not trained males/healthy	11	11	98	NR	NR	NR	NR	maintenance	CrM	2.14 g/d for 98 days	RT	whey protein +Sport drink
Little et al. 2008	Canada	parallel, PC, DB	23 active males/healthy	11	12	10	22.8	22.8	NR	NR	maintenance	NR	8 g/d for 10 days	NR	Sucrose-based fruit punch
Jager et al. 2008 a	Germany	parallel, PC, DB	25 trained male athletes/healthy	16	9	28	26.8	26.3	NR	NR	maintenance	other	5 g/d for 28 days	NR	Placebo tablets
Jager et al. 2008 b	Germany	parallel, PC, DB	24 trained male athletes/healthy	16	8	28	26.7	26.3	NR	NR	maintenance	Cr citrate	5 gr/d for 28 days	NR	Placebo tablets
Sakkas et al. 2009	USA	parallel, PC, DB	38 not trained males/HIV positive participants	19	19	98	44	44	23.7	23.7	loading + long maintenance	CrM	20 g/d for 5 days +4.8 g/d for 93 days	RT	Placebo capsules (NR)
Bazzucchi et al. 2009	Italy	parallel,PC,DB	16 trained males/healthy	8	8	5	26.7	23.3	23.3	24.2	Just loading	NR	20 g/d for 5 days	NR	Maltodextrin
Spillane et al. 2009a	USA	parallel, PC, DB	15 active males/healthy	10	5	48	20.36	20.16	NR	NR	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 42 days	RT	Maltodextrin
Spillane et al. 2009b	USA	parallel, PC, DB	15 active males/healthy	10	5	48	20.83	20.16	NR	NR	loading + long maintenance	other	20 g/d for 5 days +5 g/d for 42 days	RT	Maltodextrin
Herda et al. 2009a	USA	parallel, PC, DB	18 trained males/healthy	13	5	30	NR	NR	NR	NR	maintenance	CrM	5 g/d for 30 days	CT	Cellulose
Herda et al. 2009b	USA	parallel, PC, DB	19 trained males/healthy	14	5	30	NR	NR	NR	NR	maintenance	other	1.25 g/d for 30 days	CT	Cellulose
Herda et al. 2009c	USA	parallel, PC, DB	21 trained males/healthy	16	5	30	NR	NR	NR	NR	maintenance	other	2.50 g/d for 30 days	CT	Cellulose
Fukuda et al. 2010a	USA	parallel, PC, DB	24 active males/healthy	12	12	5	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	CT	Dextrose
Fukuda et al. 2010b	USA	parallel, PC, DB	26 active females/healthy	12	14	5	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	CT	Dextrose
Hickner et al. 2010	USA	parallel, PC, DB	12 trained males/healthy	6	6	28	25.5	29	NR	NR	maintenance	CrM	3 gr/d for 28 days	AT	dry milk and orange-flavored carbohydrate
Saremi et al. 2010	Iran	parallel, PC, DB	16 not trained males/healthy	8	8	56	23.85	22.28	NR	NR	loading + long maintenance	CrM	23.3 g/d for 7 days +3.88 g/d for 49 days	RT	Cellulose
Camic et al. 2010	USA	parallel, PC, DB	22 active males/healthy	10	12	28	NR	NR	NR	NR	maintenance	other	5 g/d for 28 days	NO	Maltodextrin
Smith et al. 2011a	USA	parallel, PC, DB	27 active males/healthy	13	14	5	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	NR	Fructose powder
Smith et al. 2011b	USA	parallel, PC, DB	28 active females/healthy	14	14	5	NR	NR	NR	NR	Just loading	Cr citrate	20 g/d for 5 days	NR	Fructose powder
Neves JR et al. 2011	Brazil	parallel, PC, DB	24 not trained females/Postmenopausal women with knee osteoarthritis	13	11	84	58	56	28.5	29.7	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 79 days	RT	Dextrose
Rawson et al. 2011	USA	parallel, PC, DB	20 not trained males and females/healthy	10	10	42	21	20.5	25.1	25.9	maintenance	CrM	2.2 g/d for 42 days	NR	Placebo capsules (NR)
Taylor et al. 2011	USA	parallel, PC, DB	29 trained males/healthy	14	15	56	21	19.8	NR	NR	maintenance	CrM	5 g/d for 56 days	RT	Dextrose
Mohebbi et al. 2012	Iran	parallel, PC, DB	17 trained male and female young soccer players/healthy	8	9	7	17.38	17	NR	NR	Just loading	CrM	20 g/d for 7 days	AT	Glucose polymer
Zuniga et al. 2012	USA	parallel, PC, DB	22 not trained males/healthy	10	12	7	NR	NR	NR	NR	Just loading	CrM	20 g/d for 7 days	NO	Maltodextrin powder
Pericario et al. 2012	Brazil	parallel, PC, DB	18 trained male handball athletes/healthy	9	9	32	17.1	17.1	NR	NR	Loading + short maintenance	CrM	20 g/d for 5 days +5 g/d for 27 days	RT	Maltodextrin
Sterkowicz et al. 2012	Poland	parallel, PC, DB	10 trained males Judaists/healthy	5	5	42	22	20.4	22.27	26.92	maintenance	other	4.8 g/d for 42 days	CT	Placebo capsules (NR)
Montes De Oca et al. 2013	Mexico	crossover, PC, DB	10 trained male TKD practitioners/healthy	10	10	42	NR	NR	NR	NR	maintenance	CrM	3.4 g/d for 42 days	CT	Maltodextrin
Aguiar et al. 2013	Finland	parallel, PC, DB	18 not trained females/healthy	9	9	84	64	65	NR	NR	maintenance	CrM	5.0 g/d for 84 days	RT	Maltodextrin
Cooke et al. 2014	USA	parallel, PC, DB	20 not trained males/healthy	10	10	84	61.4	60.7	NR	NR	loading + long maintenance	CrM	20 g/d for 7 days +8.8 g/d for 77 days	RT	CHO
Gualano et al. 2014a	Brazil	parallel, PC, DB	30 not trained females/postmenopausal with osteopenia or osteoporosis	15	15	166	66.1	66.3	27.1	26.8	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 161 days	NO	Dextrose
Gualano et al. 2014b	Brazil	parallel,PC,DB	30 not trained females/postmenopausal with osteopenia or osteoporosis	15	15	166	67.1	63.6	28	28.2	loading + long maintenance	CrM	20 g/d for 5 days +5 g/d for 161 days	RT	Dextrose
Kresta et al. 2014(a)	USA	parallel, PC, DB	15 active females/healthy	8	7	28	21.5	21.5	NR	NR	Loading + short maintenance	CrM	18.3 g/d for 7 days +6.1 g/d for 21 days	CT	Maltodextrin and dextrose
kresta et al. 2014(b)	USA	parallel, PC, DB	17 active females/healthy	9	8	28	21.5	21.5	NR	NR	Loading + short maintenance	CrM	17.7 g/d for 7 days +5.9 g/d for 21 days	CT	Maltodextrin and dextrose
Hayashi et al. 2014	Brazil	crossover, PC, DB	15 not trained males and females/Systemic lupus erythematosus (C-SLE) patients	15	15	84	NR	NR	NR	NR	maintenance	CrM	5.34 g/d for 84 days	NO	Dextrose
Nemezio. et al. 2015	Brazil	parallel, PC, DB	19 active males/healthy	10	9	5	36	33	NR	NR	Just loading	CrM	20 g/d for 5 days	AT	Dextrose
Aedma et al. 2015	Estonia	parallel, PC, DB	20 trained male wrestlers/healthy	10	10	5	NR	NR	NR	NR	Just loading	CrM	24.8 g/d for 5 days	CT	Glucose gelatin capsules
Lobo et al. 2015	Brazil	parallel, PC, DB	109 not trained females/postmenopausal osteogenic women	56	53	365	58	58	27.6	27.5	maintenance	CrM	1 g/d for 365 days	NO	Dextrose
Candow et al. 2015a	Canada	parallel, PC, DB	21 not trained males and females/healthy	15	6	224	53	57	26.5	26.8	maintenance	CrM	7.7 g/d for 224 days	RT	Maltodextrin (Corn-starch)
Candow et al. 2015b	Canada	parallel, PC, DB	18 not trained males and females/healthy	12	6	224	55	57	29	26.8	maintenance	CrM	8.7 g/d for 224 days	RT	Maltodextrin (Corn-starch)
Chilibeck et al. 2015	Canada	parallel, PC, DB	33 not trained females/healthy	15	18	364	57	57	NR	NR	maintenance	CrM	6.9 g/d for 364 days	RT	Maltodextrin
Deminice et al. 2015	Brazil	parallel, PC, DB	13 trained males/healthy	7	6	7	18.5	18.3	22.1	23.2	Just loading	CrM	22 g/d for 7 days	AT	Maltodextrin
Wilkinson et al. 2016	UK	parallel, PC, DB	35 not trained males and females/patients with stable RA	15	20	84	63	57.2	24.7	27.8	loading + long maintenance	CrM	20 g/d for 5 days +3 g/d for 77 days	NO	Flavored drink powder
Forbes et al. 2016	Canada	parallel, PC, DB	17 active females/healthy	9	8	28	23.8	22.4	NR	NR	Loading + short maintenance	CrM	19.32 g/d for 5 days +6.44 g/days for 23 days	AT	Maltodextrin
Pinto et al. 2016	Brazil	Parallel, PC, DB	27 not trained males and females/healthy	13	14	84	67.4	67.1	NR	NR	maintenance	CrM	5 g/d for 84 day	RT	Maltodextrin powder
Collins et al. 2016	New Zealand	parallel, PC, DB	16 not trained males and females/healthy	9	7	98	70	69	30.9	30.1	maintenance	CrM	5 g/d for 98 days	RT	Maltodextrin + whey
Johannsmeyer et al.2016	Canada	parallel, PC, DB	31 not trained males and females/healthy	14	17	84	58	57.6	NR	NR	maintenance	CrM	7.83 g/d for 84 days	RT	Maltodextrin
Backx et al. 2017	Finland	parallel, PC, DB	30 not trained males/healthy	15	15	21	23	23	23	23.5	Loading + short maintenance	CrM	20 g/d for 5 days + 5 gr/day for 16 days	NO	Maltodextrin and dextrose monohydrate
Wilborn et al. 2017	USA	parallel, PC, DB	17 trained females/healthy	8	9	56	22	20	23.2	23.8	maintenance	CrM	5 g/d for 56 days	RT	Whey protein
Karamat et al. 2017	Netherlands	parallel, PC, TB	16 not trained males/healthy	8	8	7	NR	NR	22.1	24.2	ND	NR	5 g/d for 7 days	NR	Placebo capsules (NR)
Atakan et al. 2018	Turkey	parallel, PC, DB	30 trained female futsal players/healthy	15	15	7	19.6	20.7	22.17	19.83	Just loading	CrM	14.5 g/d for 7 days	AT	Maltodextrin
Wang et al. 2018	USA	parallel, PC, DB	30 trained male athletes/healthy	15	15	28	20	20	NR	NR	Loading + short maintenance	CrM	20 g/d for 6 days +2 g/d for 22 days	CT	Carboxymethyl cellulose powder plus dextrose
Vanbavel et al. 2019	Brazil	parallel, PC, DB	49 active males and females/healthy	31	18	21	33	32	23.3	22.9	maintenance	CrM	5 g/d for 21 days	NR	Maltodextrin
Arazi et al. 2019	Iran	parallel, PC, DB	16 not trained males/healthy	8	8	42	20.87	20.37	NR	NR	loading + long maintenance	other	20 g/d for 5 days +5 g/d for 37 days	RT	Rice flour
Almeida et al. 2020	Brazil	parallel, PC, DB	18 active males/healthy	9	9	7	22.7	24.2	NR	NR	Just loading	CrM	24.2 g/d for 7 days	RT	Dextrose
Marini et al. 2020	Brazil	parallel, PC, DB	28 not trained males and females/hemodialysis patients	14	14	28	41.86	41.79	22.76	21.93	Loading + short maintenance	CrM	20 g/d for 7 days +5 g/d for 21 days	NO	Maltodextrin
Candow et al. 2020	Canada	parallel, PC, DB	38 not trained males/healthy	18	20	364	58	56	NR	NR	maintenance	CrM	9.3 g/d for 364 days	RT	Maltodextrin (Corn-starch)
Delextrat et al. 2020a	UK	parallel, PC, DB	22 trained male and female team- and racket sport players/healthy	11	11	28	25.6	25.2	NR	NR	maintenance	CrM	5 g/d for 28 days	CT	Rice flour
Delextrat et al. 2020b	UK	parallel, PC, DB	22 trained male and female team and racket sport players/healthy	12	10	28	26	24.2	NR	NR	maintenance	CrM	5 g/d for 28 days	CT	Rice flour + beta-alanine
Anders et al. 2021	USA	parallel, PC, DB	22 trained males/healthy	12	10	28	19.8	20.6	NR	NR	maintenance	CrM	2.4 g/d for 28 days	CT	Cellulose
Pakulak et al. 2021a	Canada	parallel, PC, DB	10 active males and females/healthy	5	5	42	22	23	NR	NR	maintenance	CrM	7.6 g/d for 42 days	RT	Cellulose powder
pakulak et al. 2021b	Canada	parallel, PC, DB	10 active males and females/healthy	5	5	42	22	19	NR	NR	maintenance	CrM	7.4 g/d for 42 days	RT	Cellulose powder
Bonilla et al. 2021	USA	parallel, SB	16 active males/healthy	8	8	56	NR	NR	23.89	25.02	maintenance	CrM	7.6 g/d for 56 days	RT	Cluster-set resistance training (CS-RT)
Butchart et al. 2022	Canada	parallel, PC, DB	8 not trained participants/stroke survivors	5	3	70	51	73	29.2	27.4	loading + long maintenance	CrM	25.4 g/d for 7 days +8.4 g/d for 63 days	RT	corn-starch maltodextrin
Almeida et al. 2022	Brazil	parallel, PC, DB	34 active males/healthy	17	17	28	23.1	23.8	NR	NR	Loading + short maintenance	CrM	21.9 g/d for 7 days +2.1 g/d for 21 days	RT	Dextrose
Dinan et al. 2022a	USA	parallel, PC, DB	18 trained male and female athletes/healthy	12	6	56	NR	NR	NR	NR	maintenance	CrM	5 g/d for 56 days	RT	maltodextrin
Dinan et al. 2022b	USA	parallel, PC, DB	16 trained male and female athletes/healthy	11	5	56	NR	NR	NR	NR	maintenance	CrM	5 g/d for 56 days	RT	maltodextrin
Askow et al. 2022	USA	parallel, PC, DB	18 not trained male and female athletes/healthy	8	10	14	28.5	30.3	25.8	24.7	maintenance	CrM	5 g/d for 14 days	RT	maltodextrin
Moore et al. 2023a	USA	crossover, PC, DB	30 active females/healthy	30	30	5	25.4	24.5	23.6	23.1	Just loading	CrM	20 g/d for 5 days	NR	crystal light
Moore et al. 2023b	USA	crossover, PC, DB	30 active females/healthy	30	30	5	25.4	24.5	23.6	23.1	Just loading	CrM	20 g/d for 5 days	NR	crystal 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.

Study	Random sequence generation	Allocation concealment	Selective reporting	Other sources of bias	Blinding (participants and personnel)	Blinding (outcome assessment)	Incomplete outcome data	General risk of bias
Balsom et al. 1993	H	H	L	H	L	U	L	Fair
Mujika et al. 1996	U	U	L	L	L	H	L	Good
Terrillion et al. 1997	H	H	L	L	H	H	L	Weak
Vanderberghe et al. 1997	H	H	L	L	L	H	L	Weak
Noonan et al. 1998a	U	U	L	L	L	H	L	Good
Noonan et al. 1998b	U	U	L	L	L	H	L	Good
Kreider et al. 1998	U	U	L	L	L	H	U	Good
Oopik et al. 1998	H	H	L	L	H	H	L	Weak
Maganaris et al. 1998	U	U	L	L	L	H	L	Good
Bermon et al. 1998a	U	U	L	L	L	U	L	Good
Bermon et al. 1998b	U	U	L	L	L	U	L	Good
Vukovich et al. 1998a	U	U	L	L	L	H	L	Good
Vukovich et al. 1998b	U	U	L	L	L	H	L	Good
Kelly et al. 1998	U	U	L	L	H	H	H	Weak
Mckenna et al. 1999	U	U	L	L	L	H	L	Good
Francaux et al. 1999	U	U	L	U	L	U	L	Good
Rawson et al. 1999	U	U	L	L	L	H	L	Good
Pearson et al. 1999	U	U	U	L	L	H	L	Good
Leenders et al. 1999a	U	U	L	L	L	H	L	Good
Leenders et al. 1999b	U	U	L	L	L	H	L	Good
Peeters et al. 1999a	H	H	L	L	L	H	L	Weak
Peeters et al. 1999b	H	H	L	L	L	H	L	Weak
Haff et al. 2000	U	U	L	L	L	U	L	Good
Schedel et al. 2000	U	U	L	L	L	H	L	Good
Deutekom et al. 2000	U	U	H	L	L	H	L	Fair
Mihic et al. 2000	U	U	L	L	L	H	L	Good
Hamilton et al. 2000	U	U	L	L	L	U	L	Good
Larson-Meyer et al. 2000	U	U	L	L	L	H	L	Good
Volek et al. 2000	U	U	L	L	L	H	L	Good
Becque et al. 2000	H	L	L	U	L	U	L	Good
Brenner et al. 2000	U	U	L	L	L	U	L	Good
Skare et al. 2001	H	H	L	H	H	H	L	Weak
Green et al. 2001	U	U	L	U	L	U	H	Good
Rockwell et al. 2001	U	U	L	L	L	H	U	Good
Op t Eijnde et al. 2001	U	U	L	L	L	H	L	Good
Bemben et al. 2001	U	U	L	L	L	U	L	Good
Chrusch et al. 2001	U	U	L	L	L	U	L	Good
Kern et al. 2001	U	U	L	L	L	H	L	Good
Parise et al. 2001a	U	U	H	L	L	H	L	Fair
Parise et al. 2001b	U	U	H	L	L	H	L	Fair
Wilder et al. 2001a	U	U	L	L	H	H	L	Fair
Wilder et al. 2001b	U	U	L	L	H	H	L	Fair
Willoughby et al. 2001	U	U	L	L	L	H	L	Good
Hespel et al. 2001	U	U	L	U	L	U	L	Good
Coxe et al. 2002	H	U	H	L	L	H	L	Weak
Gotshalk et al. 2002	U	U	L	U	L	U	L	Good
Kilduff et al. 2002	H	H	L	L	L	H	L	Weak
Wilder et al. 2002a	U	U	L	L	H	H	U	Fair
Wilder et al. 2002b	U	U	L	L	H	H	U	Fair
Walter et al. 2002	U	U	L	L	L	H	L	Good
Huso et al. 2002	U	U	L	L	L	U	L	Good
Warber et al. 2002	U	U	L	L	L	H	L	Good
Kutz et al. 2003	H	H	L	L	L	H	L	Weak
Vukovich et al. 2003	H	H	L	H	H	H	H	Weak
Lehmkuhl et al. 2003	U	U	L	L	L	H	L	Good
Burke et al. 2003a	L	L	L	L	L	U	L	Good
Burke et al. 2003b	L	L	L	L	L	U	L	Good
Van Loon et al. 2003	H	H	L	L	L	H	L	Weak
Zajac et al. 2003	U	U	L	H	L	H	L	Fair
Eijnde et al. 2003a	U	U	L	U	L	U	L	Good
Eijnde et al. 2003b	U	U	L	U	L	U	L	Good
Kambis et al. 2003	U	U	L	L	L	U	L	Good
Brose et al. 2003 a	U	U	L	L	L	U	L	Good
Brose et al. 2003 b	U	U	L	L	L	U	L	Good
Watsford et al. 2003	U	U	L	L	L	H	U	Good
Eckerson et al. 2004	U	U	L	U	L	L	L	Good
Kinugasa et al. 2004	H	H	L	L	L	H	L	Weak
Javierre et al. 2004	U	U	L	U	H	H	L	Fair
Volek et al. 2004	U	U	L	L	L	H	L	Good
Ball SD et al. 2004	U	U	L	L	L	U	L	Good
Tarnopolosky et al. 2004	L	L	L	L	L	H	L	Good
Taes et al. 2004	U	U	L	L	L	H	L	Good
Anomasiri et al. 2004	U	U	L	U	L	U	L	Good
Eckerson et al. 2005a	U	U	L	U	L	U	L	Good
Eckerson et al. 2005b	U	U	L	U	L	U	L	Good
Eckerson et al. 2005c	U	U	L	U	L	U	L	Good
Eckerson et al. 2005d	U	U	L	U	L	U	L	Good
Perret et al. 2005	U	H	L	L	L	H	L	Fair
Ahmun et al. 2005	U	U	L	L	L	U	L	Good
Mendell et al. 2005	H	H	L	H	L	H	L	Weak
Fuld et al. 2005	U	U	L	U	L	U	L	Good
Hoffman et al. 2005	U	U	H	L	L	H	L	Fair
Kuethe et al. 2006	H	U	L	U	L	U	L	Good
Hille et al. 2006	U	U	L	U	L	U	L	Good
Norman et al. 2006	L	L	L	L	L	H	L	Good
Ferguson et al. 2006	U	U	L	L	L	U	L	Good
Pluim et al. 2006	U	U	H	L	L	H	H	Weak
Rogers et al. 2006	U	U	L	L	L	H	L	Good
Hoffman et al. 2006	U	U	L	L	L	U	L	Good
Smith et al. 2007	U	U	H	L	L	H	L	Fair
Stout et al. 2007	U	U	L	L	L	H	L	Good
Silva et al. 2007	U	U	L	L	L	H	L	Good
Wright et al. 2007	H	H	L	H	H	H	L	Weak
De Souza junior et al. 2007	U	U	L	U	L	U	L	Good
Cribb et al. 2007 a	U	U	L	L	L	U	L	Good
Cribb et al. 2007 b	U	U	L	L	L	U	L	Good
Hass et al. 2007	U	U	L	L	L	H	L	Good
Chilibeck et al. 2007	U	U	L	L	L	U	L	Good
Cribb et al. 2007	U	U	L	L	L	U	L	Good
Walter et al. 2008	U	U	L	L	L	H	L	Good
Eckerson et al. 2008	U	U	L	U	L	U	L	Good
Gotshalk et al. 2008	U	U	L	L	L	H	L	Good
Deacon et al. 2008	L	L	L	L	L	L	H	Good
Eliot et al. 2008 a	U	U	L	L	L	U	L	Good
Eliot et al. 2008 b	U	U	L	L	L	U	L	Good
Little et al. 2008	U	U	L	L	L	H	L	Good
Jager et al. 2008 a	U	U	L	L	L	H	L	Good
Jager et al. 2008 b	U	U	L	L	L	H	L	Good
Sakkas et al. 2009	L	L	L	L	L	H	U	Good
Bazzucchi et al. 2009	U	H	L	U	L	U	H	Fair
Spillane et al.2009a	U	U	L	L	L	H	L	Good
Spillane et al. 200 b	U	U	L	L	L	H	L	Good
Herda et al. 2009a	U	U	L	U	L	U	L	Good
Herda et al. 2009b	U	U	L	U	L	U	L	Good
Herda et al. 2009c	U	U	L	U	L	U	L	Good
Fukuda et al. 2010a	U	U	L	U	L	U	L	Good
Fukuda et al. 2010b	U	U	L	U	L	U	L	Good
Hickner et al. 2010	H	U	L	L	L	H	L	Fair
Saremi et al. 2010	L	L	L	L	L	H	U	Good
Camic et al. 2010	U	U	L	L	L	U	L	Good
Smith et al. 2011a	U	U	L	L	L	H	L	Good
Smith et al. 2011b	U	U	L	L	L	H	L	Good
Neves JR et al. 2011	L	L	L	L	L	H	L	Good
Rawson et al. 2011	L	U	L	L	L	H	L	Good
Taylor et al. 2011	U	U	L	L	L	H	L	Good
Mohebbi et al. 2012	H	H	L	L	L	H	L	Weak
Zuniga et al. 2012	U	U	L	L	L	H	L	Good
Pericario et al. 2012	U	U	L	L	L	H	U	Good
Sterkowicz et al. 2012	U	U	L	L	L	H	L	Good
Montes De Oca et al. 2013	U	U	L	L	L	U	L	Good
Aguiar et al. 2013	U	L	L	L	L	U	L	Good
Cooke et al. 2014	U	U	L	L	L	H	L	Good
Gualano et al. 2014a	L	L	L	L	L	U	L	Good
Gualano et al. 2014b	L	L	L	L	L	U	L	Good
Kresta et al. 2014(a)	U	U	L	L	L	H	U	Good
kresta et al. 2014(b)	U	U	L	L	L	H	U	Good
Hayashi et al. 2014	U	L	L	L	L	U	L	Good
Nemezio et al. 2015	U	L	L	L	L	U	L	Good
Aedma et al. 2015	H	U	L	L	L	U	L	Good
Lobo et al. 2015	L	U	L	L	L	H	L	Good
Candow et al. 2015a	U	L	L	L	L	U	L	Good
Candow et al. 2015b	U	L	L	L	L	U	L	Good
Chilibeck et al. 2015	L	L	H	L	L	L	H	Fair
Deminice et al. 2015	U	U	L	L	L	U	L	Good
Wilkinson et al. 2016	L	L	L	L	L	H	H	Fair
Forbes et al. 2016	L	L	L	L	L	U	L	Good
Pinto et al. 2016	L	U	L	L	L	H	L	Good
Collins et al. 2016	U	L	L	L	L	H	L	Good
Johannsmeyer et al. 2016	L	L	L	L	L	H	L	Good
Backx et al. 2017	U	U	L	L	L	U	L	Good
Wilborn et al. 2017	U	U	L	L	L	H	L	Good
Karamat et al. 2017	L	L	L	H	L	L	L	Good
Atakan et al. 2018	L	U	L	U	L	U	L	Good
Wang et al. 2018	U	U	L	L	L	H	L	Good
Vanbavel et al. 2019	U	U	L	L	H	H	H	Weak
Arazi et al. 2019	U	U	H	U	L	U	L	Good
Almeida et al. 2020	U	U	L	U	L	U	L	Good
Marini et al. 2020	U	H	L	L	L	H	L	Fair
Candow et al. 2020	L	L	L	L	L	L	L	Good
Delextrat et al. 2020a	U	U	L	L	L	U	L	Good
Delextrat et al. 2021b	U	U	L	L	L	U	L	Good
Anders et al. 2021	U	U	L	L	L	U	L	Good
Pakulak et al. 2021a	U	U	L	L	L	H	U	Good
pakulak et al. 2021b	U	U	L	L	L	H	U	Good
Bonilla et al. 2021	L	U	L	L	H	U	L	Good
Butchart et al. 2022	U	U	L	L	L	U	L	Good
Almeida et al. 2022	U	U	L	U	L	U	L	Good
Dinan et al. 2022a	L	L	L	L	L	U	L	Good
Dinan et al. 2022b	L	L	L	L	L	U	L	Good
Askow et al. 2022	U	L	L	L	L	U	L	Good
Moore et al. 2023a	L	L	L	L	L	U	L	Good
Moore et al. 2023b	L	L	L	L	L	U	L	Good

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).

Figure 2. 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).

Figure 2. Continued

Table 3. Subgroup analyses of creatine supplementation on body composition in adults.

	Number of effect sizes	WMD (95%CI)	P-value	heterogeneity
				P heterogeneity	I^2	P between sub-groups
Subgroup analyses of creatine on body mass (kg)
Overall effect	154	0.86 (0.76, 0.96)	<0.001	1.000	0.0%
Trial duration (d)
≤30	89	0.87 (0.77, 0.98)	<0.001	1.000	0.0%	0.490
>30	65	0.76 (0.47, 1.06)	<0.001	1.000	0.0%
Intervention dose (g/d)
≤5	68	0.91 (0.78, 1.04)	<0.001	1.000	0.0%	0.256
>5	86	0.80 (0.65, 0.94)	<0.001	1.000	0.0%
Baseline BMI (kg/m^2)
Normal (18.5–24.9)	15	0.81 (0.11, 1.51)	0.022	1.000	0.0%	0.523
Overweight (25–29.9)	9	0.48 (−0.24, 1.22)	0.195	0.998	0.0%
Sex
Male	93	0.89 (0.78, 1.01)	<0.001	1.000	0.0%
Both	33	0.57 (0.24, 0.91)	0.001	1.000	0.0%
Female	27	0.86 (0.62, 1.09)	<0.001	0.824	0.0%
Participant’s age
<40	75	0.93 (0.82, 1.04)	<0.001	1.000	0.0%	0.077
>40	29	0.60 (0.7825 0.95)	0.001	1.000	0.0%
Activity status
Trained	58	0.94 (0.76, 1.12)	<0.001	<0.001	0.0%	0.179
Active	45	0.86 (0.74, 0.99)	<0.001	0.994	0.0%
Non-active	51	0.60 (0.28, 0.91)	<0.001	<0.001	0.0%
Along with exercise
AT	17	0.95 (0.58, 1.32)	<0.001	0.993	0.0%	0.068
CT	40	0.59 (0.31, 0.88)	<0.001	0.997	0.0%
No exercise	17	0.50 (0.08, 0.92)	0.018	0.992	0.0%
RT	57	0.89 (0.76, 1.01)	<0.001	1.000	0.0%
Loading
Just loading	48	0.54 (−0.14, 1.23)	<0.001	0.998	0.0%	0.685
Loading + short maintenance	22	0.91 (0.78, 1.05)	<0.001	1.000	0.0%
Maintenance	43	0.98 (0.60, 1.36)	<0.001	1.000	0.0%
High dose maintenance	6	1.26 (0.03, 2.48)	0.036	0.997	0.0%
loading + long maintenance	32	0.66 (0.26, 1.07)	0.002	0.975	0.0%
Type of creatine
CrC	12	0.89 (0.65, 1.13)	<0.001	0.423	2.2%	0.971
CM	128	0.85 (0.74, 0.96)	<0.001	1.000	0.0%
Other	5	0.98 (−0.00, 1.98)	0.052	0.261	20.4%
Subgroup analyses of creatine on BMI (kg/m^2)
Overall effect	13	0.20 (−0.17, 0.58)	0.299	1.000	0.0%
Trial duration (d)
≤30	5	0.31 (−0.22, 0.84)	0.254	0.996	0.0%	0.568
>30	8	0.08 (−0.45, 0.63)	0.749	0.999	0.0%
Intervention dose (g/d)
≤5	12	0.18 (−0.21, 0.59)	0.364	1.000	0.0%	0.850
>5	1	0.30 (−0.78, 1.38)	0.589	-	-
Baseline BMI (kg/m^2)
Normal (18.5–24.9)	6	0.25 (−0.27, 0.79)	0.344	0.977	0.0%	0.779
Overweight (25–29.9)	5	0.14 (−0.41, 0.71)	0.610	0.992	0.0%
Sex
Male	3	0.41 (−0.31, 1.14)	0.267	0.962	0.0%	0.769
Both	8	0.08 (−0.45, 0.61)	0.768	0.999	0.0%
Female	2	0.22 (−0.58, 1.02)	0.593	0.923	0.0%
Participant’s age
<40	4	0.28 (−0.31, 0.88)	0.352	0.995	0.0%	0.585
>40	6	0.05 (−0.51, 0.62)	0.849	0.993	0.0%
Activity status
Active	1	0.30 (−0.81, 1.41)	0.597	-	-	0.945
Trained	4	0.29 (−0.56, 1.16)	0.499	0.993	0.0%
Non-active	8	0.15 (−0.29, 0.61)	0.499	0.995	0.0%
Along with exercise
CT	1	0.53 (−1.61, 2.67)	0.628	-	-	0.990
No exercise	3	0.16 (−0.58, 0.91)	0.663	0.992	0.0%
AT	1	0.30 (−0.78, 1.38)	0.589	-	-
RT	5	0.08 (−0.60, 0.76)	0.819	0.989	0.0%
Loading
Just loading	1	0.30 (−0.78, 1.38)	0.589	-	-	0.932
Loading + short maintenance	1	0.08 (−2.27, 2.43)	0.947	-	-
Maintenance	6	0.23 (−0.30, 0.77)	0.390	1.000	0.0%
loading + long maintenance	4	−0.05 (−0.82, 0.71)	0.893	0.962	0.0%
Type of creatine
CM	11	0.14 (−0.26, 0.56)	0.481	1.000	0.0%	0.805
Other	1	0.53 (−1.61, 2.67)	0.376	-	-
Subgroup analyses of creatine on FM (kg)
Overall effect	62	0.05 (−0.24, 0.35)	0.703	1.000	0.0%
Trial duration (d)
≤30	15	0.34 (−0.21, 0.89)	0.227	0.921	0.0%	0.233
>30	47	−0.06 (−0.41, 0.29)	0.742	1.000	0.0%
Intervention dose (g/d)
≤5	35	0.25 (−0.16, 0.67)	0.231	0.999	0.0%	0.183
>5	27	−0.15 (−0.58, 0.27)	0.487	0.992	0.0%
Baseline BMI (kg/m^2)
Normal (18.5–24.9)	8	−0.25 (−0.78, 0.27)	0.349	0.917	0.0%	0.287
Overweight (25–29.9)	10	0.29 (−0.47, 1.05)	0.457	0.975	0.0%
Obese (≥30)	1	−3.60 (−9.91, 2.71)	0.264	-	-
Sex
Male	30	0.28 (−0.13, 0.69)	0.185	0.991	0.0%	0.494
Both	21	−0.14 (−0.64, 0.34)	0.556	0.988	0.0%
Female	10	−0.29 (−1.16, 0.58)	0.515	0.977	0.0%
Participant’s age
<40	30	−0.12 (−0.63, 0.38)	0.619	1.000	0.0%	0.775
>40	21	−0.02 (−0.51, 0.46)	0.917	0.920	0.0%
Activity status
Active	15	0.01 (−0.59, 0.62)	0.966	0.746	0.0%	0.891
Trained	18	0.17 (−0.38, 0.73)	0.542	1.000	0.0%
Non-active	29	0.01 (−0.42, 0.44)	0.959	0.992	0.0%
Along with exercise
CT	11	−0.14 (−0.81, 0.52)	0.667	0.765	0.0%	0.927
No exercise	5	0.26 (−0.58 1.10)	0.546	0.991	0.0%
AT	2	−0.09 (−1.14, 0.95)	0.864	0.590	0.0%
RT	40	0.09 (−0.30, 0.48)	0.658	0.998	0.0%
Loading
Just loading	5	0.15 (−0.77, 1.08)	0.746	0.992	0.0%	0.859
Loading + short maintenance	7	0.51 (−0.55, 1.58)	0.345	0.356	9.6%
Maintenance	28	−0.08 (−0.60, 0.44)	0.764	0.998	0.0%
High dose maintenance	2	0.28 (−0.70, 1.28)	0.573	0.698	0.0%
loading + long maintenance	20	−0.02 (−0.50, 0.46)	0.927	0.983	0.0%
Type of creatine
CM	59	0.05 (−0.24, 0.35)	0.723	1.000	0.0%	0.934
Other	2	0.01 (−2.01, 2.04)	0.693	-	-
Subgroup analyses of creatine on BFP (%)
Overall effect	89	−0.28 (−0.47, −0.09)	0.004	0.968	0.0%
Trial duration (d)
≤30	36	−0.30 (−0.65, 0.04)	0.084	0.341	7.5%	0.512
>30	53	−0.16 (−0.41, 0.08)	0.200	0.999	0.0%
Intervention dose (g/d)
≤5	51	−0.04 (−0.29, 0.20)	0.734	0.986	0.0%	0.005
>5	38	−0.60 (−0.89, −0.30)	<0.001	0.903	0.0%
Baseline BMI (kg/m^2)
Normal (18.5–24.9)	7	−0.26 (−0.74, 0.21)	0.279	0.995	0.0%	0.549
Overweight (25–29.9)	8	−0.08 (−0.44, 0.28)	0.668	0.712	0.0%
Sex
Male	55	−0.36 (−0.61, −0.11)	0.005	0.593	0.0%	0.622
Both	18	−0.15 (−0.68, 0.37)	0.558	0.996	0.0%
Female	16	−0.18 (−0.52, 0.16)	0.299	0.934	0.0%
Participant’s age
<40	45	−0.19 (−0.52, 0.13)	0.244	0.998	0.0%	0.779
>40	20	−0.13 (−0.44, 0.17)	0.401	0.998	0.0%
Activity status
Active	18	−0.04 (−0.80, 0.73)	0.920	0.067	35.7%	0.063
Trained	37	−0.56 (−0.86, −0.26)	<0.001	0.968	0.0%
Non-active	34	−0.10 (−0.37, 0.17)	0.474	1.000	0.0%
Along with exercise
CT	22	−0.83 (−1.22, −0.44)	<0.001	0.741	0.0%	0.022
No exercise	7	−0.32 (−0.82, 0.17)	0.202	0.724	0.0%
AT	6	−0.37 (−1.14, 0.39)	0.341	0.903	0.0%
RT	43	−0.02 (−0.30, 0.25)	0.864	0.911	0.0%
Loading
Just loading	12	−0.10 (−0.61, 0.41)	0.699	1.000	0.0%	0.177
Loading + short maintenance	15	0.14 (−0.63, 0.93)	0.711	0.288	14.8%
Maintenance	32	−0.59 (−0.91, −0.28)	<0.001	0.527	0.0%
High dose maintenance	5	−0.17 (−1.03, 0.69)	0.698	0.763	0.0%
loading + long maintenance	25	−0.14 (−0.45, 0.16)	0.363	0.996	0.0%
Type of creatine
CrC	1	−0.10 (−3.42, 3.22)	0.953	-	-	0.720
CM	80	−0.31 (−0.51, −0.11)	0.002	0.921	0.0%
Other	4	0.21 (−0.85, 1.28)	0.693	0.781	0.0%
Subgroup analyses of creatine on FFM (kg)
Overall effect	95	0.82 (0.57, 1.06)	<0.001	1.000	0.0%
Trial duration (d)
≤30	31	1.07 (0.48, 1.66)	<0.001	0.996	0.0%	0.357
>30	64	0.76 (0.49, 1.03)	<0.001	1.000	0.0%
Intervention dose (g/d)
≤5	52	0.77 (0.46, 1.08)	<0.001	1.000	0.0%	0.663
>5	43	0.89 (0.49, 1.29)	<0.001	0.981	0.0%
Baseline BMI (kg/m^2)
Normal (18.5–24.9)	7	1.12 (0.59, 1.65)	<0.001	0.829	0.0%	0.270
Overweight (25–29.9)	8	0.39 (−0.34, 1.13)	0.293	0.905	0.0%
Obese (≥30)	1	−0.40 (−6.69, 5.89)	0.901	-	-
Sex
Male	51	1.20 (0.80, 1.60)	<0.001	1.000	0.0%	0.120
Both	25	0.60 (0.21, 0.99)	0.002	0.970	0.0%
Female	18	0.54 (0.03, 1.06)	0.036	1.000	0.0%
Participant’s age
<40	48	0.89 (0.45, 1.33)	<0.001	1.000	0.0%	0.955
>40	27	0.87 (0.53, 1.22)	<0.001	0.996	0.0%
Activity status
Active	26	0.71 (0.01, 1.41)	0.045	1.000	0.0%	0.194
Trained	32	1.31 (0.72, 1.90)	<0.001	0.999	0.0%
Non-active	37	0.71 (0.42, 1.01)	<0.001	0.994	0.0%
Along with exercise
CT	26	1.00 (0.48, 1.52)	<0.001	0.934	0.0%	0.143
No exercise	7	0.24 (−0.26, 0.75)	0.347	0.854	0.0%
AT	6	1.19 (−0.09, 2.48)	0.068	0.989	0.0%
RT	48	0.99 (0.64, 1.35)	<0.001	1.000	0.0%
Loading
Just loading	10	0.88 (−0.36, 2.13)	0.165	1.000	0.0%	0.828
Loading + short maintenance	19	0.52 (−0.24, 1.29)	0.179	0.999	0.0%
Maintenance	32	0.72 (0.32, 1.12)	<0.001	0.912	0.0%
High dose maintenance	3	1.34 (−0.40, 3.09)	0.131	0.976	0.0%
loading + long maintenance	31	0.93 (0.57, 1.29)	<0.001	0.996	0.0%
Type of creatine
CM	89	0.82 (0.57, 1.06)	<0.001	1.000	0.0%	0.997
Other	3	0.91 (−3.06, 4.88)	0.653	0.834	0.0%

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).

Figure 2. 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
Outcomes	Egger’s test	Sensitivity
Body weight	0.440	None
BMI	0.533	None
FM	0.350	None
BFP	0.212	None
FFM	0.169	None

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).

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.

Figure 4. 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).

Figure 5. 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)
Variables	Coefficient	p-value	Coefficient	p-value	Coefficient	p-value	Coefficient	p-value
Body Mass	−0.46	0.505	−1.38	0.770	−0.06	0.392	−0.56	0.030
BMI	4.48	0.507	−25.70	0.835	−0.07	0.194	−0.27	0.128
FM	−0.33	0.578	−10.24	0.177	−2.02	0.039	−0.65	0.074
BFP	−0.71	0.353	1.59	0.806	−3.45	0.063	−0.56	0.210
FFM	0.91	0.144	−1.74	0.810	1.75	0.008	0.13	0.454

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).

Figure 6. 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).

Figure 7. 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.

Outcomes	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication Bias	Quality of evidence
Body weight	No serious limitation	No serious limitation	No serious limitation	No serious limitation	No serious limitation	⊕⊕⊕⊕ High
BMI	No serious limitation	No serious limitation	No serious limitation	Serious limitation^2	No serious limitation	⊕⊕⊕◯ Moderate
FM	No serious limitation	No serious limitation	No serious limitation	Serious limitation^2	No serious limitation	⊕⊕⊕◯ Moderate
BFP	No serious limitation	No serious limitation	No serious limitation	No serious limitation	No serious limitation	⊕⊕⊕⊕ High
FFM	No serious limitation	No serious limitation	No serious limitation	No serious limitation	No serious limitation	⊕⊕⊕⊕ 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.

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.

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.

Additional information

Funding

This work was supported by a grant from National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (Project No.43006289)