Efficacy of Alternative Forms of Creatine Supplementation on Improving Performance and Body Composition in Healthy Subjects: A Systematic Review : The Journal of Strength & Conditioning Research

Secondary Logo

Journal Logo

Brief Review

Efficacy of Alternative Forms of Creatine Supplementation on Improving Performance and Body Composition in Healthy Subjects: A Systematic Review

Fazio, Carly1; Elder, Craig L.2; Harris, Margaret M.1

Author Information
Journal of Strength and Conditioning Research: September 2022 - Volume 36 - Issue 9 - p 2663-2670
doi: 10.1519/JSC.0000000000003873
  • Free

Abstract

Introduction

Creatine (Cr) is one of the most researched ergogenic aids with consistent evidence supporting its safety and efficacy in improving high-intensity exercise performance and overall body anthropometry (27). Creatine is a nonessential amino acid that is synthesized endogenously in the kidneys and liver from the 3 amino acids glycine, arginine, and methionine (1,18,27,44). In addition, it is estimated that consuming a balanced diet provides roughly 1–2 g of Cr per day, primarily from meat and seafood (4,44). It is located in small quantities in the brain, liver, kidney, and testes but ∼95% of the total body Cr pool is located in skeletal muscle, of which approximately 40% is free Cr and 60% is in the phosphorylated form, phosphocreatine (PCr) (17,22,30).

During short-duration, high-intensity exercise, adenosine triphosphate (ATP) is degraded into adenosine diphosphate and a phosphate group, generating the energy needed by the skeletal muscles (31). The primary role of Cr is to combine with a phosphate group to form PCr through the enzymatic reaction of creatine kinase (27). Phosphocreatine is then used by the muscle cell to rapidly regenerate ATP for further muscle contractions (2,7,19,20). Cr supplementation can increase muscle Cr and PCr concentrations by 20–40%, and this increased availability is vital because the accumulation of phosphate and other metabolites is purported to be responsible for muscular fatigue (17,21,27,38).

The most effective and commonly used way to achieve this increase in muscle Cr content is a loading strategy consisting of 5 g of Cr monohydrate (CrM) 4 times per day for 5–7 days (or approximately 0.3 g·kg−1 body weight [BW]) (17,21). Hultman et al. (21) demonstrated that a similar increase could be achieved by supplementing the diet with 3 g of Cr per day over 1 month. However, due to the more gradual increase in muscle Cr content, this method may have less of an effect on exercise performance until muscle Cr stores are fully saturated (27). Once muscle Cr stores are fully saturated, Cr stores can generally be maintained by ingesting 3–5 g·d−1 (27).

The most extensively studied form of Cr for use in nutritional supplements is Cr monohydrate (CrM) (27). Alternative forms of Cr have recently been introduced to the market, labeled with claims of superior efficacy to CrM despite the apparent lack of evidence supporting these claims (25). Researchers examining the effects of magnesium-creatine chelate and Cr malate have suggested that changes in chemical structure may allow creatine to enter the cell through an additional pathway or avoid degradation to creatinine, respectively (32,36). Other studies examining Cr nitrate supplementation highlight nitrate's ability to improve aerobic exercise performance and suggest a potential synergist effect (13). Similarly, the proposed ergogenic effects of pyruvic acid and citric acid supplementation have been used to support Cr pyruvate and Cr citrate supplementation despite the lack of convincing evidence that either increases exercise capacity (24,42). Multiple alternative forms of creatine claim superior solubility, bioavailability, and digestion compared to CrM, eliminating gastrointestinal side effects and the need for creatine loading (36,42).

The purpose of this review is to provide an update to the current literature regarding the cost and efficacy of alternative forms of Cr supplementation in improving exercise performance and body composition.

Methods

Experimental Approach to the Problem

A systematic literature search of peer-reviewed studies published in English was conducted in April 2019 using electronic databases including Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Medline, and Google Scholar in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (29).

Subjects

Inclusion criteria were determined using the PICO(S) framework (focusing on the population, intervention, comparison, outcomes, and study design). The population comprised of healthy human males or females of any age and fitness level. The intervention involved a chronic (>1 day) Cr supplementation protocol, with all alternative forms of Cr acceptable. The intervention (creatine) was compared to a placebo (e.g., dextrose, fructose, maltodextrin, etc.). Studies that were based on exercise performance, exercise capacity, or body composition measures. The study design included only randomized, double-blind, placebo-controlled (RDBPC) trials.

Procedures

An electronic search of the literature was conducted using the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Medline, and Google Scholar to identify all relevant articles. Two researchers conducted the review separately. The following alternative forms of creatine are available on the market and were used in the search: Creatine a-amino butyrate, a-ketoglutarate, anhydrous, buffered, citrate, creatinate, decanoate, ethyl ester, gluconate, hydrochloride (HCl), ketoisocaproate, malate, magnesium chelate, methyl ester HCl, nitrate, phosphate, pyroglutamate, pyruvate, and taurinate. Each of these alternative forms of Cr was individually searched in combination (i.e., “and”) with the words “supplement” AND “exercise” OR “training,” OR “athlete,” OR “performance,” OR “body composition,” OR “fat-free mass,” OR “lean mass” within the title of the articles. Articles were assessed for eligibility against the inclusion/exclusion criteria. Reference lists of published journal articles and reviews on creatine were also screened to ensure that all relevant studies were included.

After completion of the searches, articles were reviewed. The 2 researchers compared their findings, discussing any discrepancies. The final selection of articles was analyzed and interpreted with the results of the relevant studies presented below. The search strategy is summarized in Figure 1.

F1
Figure 1.:
Flowchart of article selection.

To compare average costs of the alternative forms of Cr to CrM, each form of Cr was individually searched in combination with “supplement” and “buy” OR “purchase” on Google. The “certified product search” on NSFsport.com, Informed-sport.com, and Informed-choice.org was used to identify all relevant third-party certified Cr supplements.

Results

Characteristics of Randomized Controlled Trials

Details of the studies' characteristics, interventions, and outcomes are provided in Table 1. Results from a total of 548 subjects are represented across the 17 reviewed studies. The sample sizes ranged from 10 to 61, and reported mean ages ranged from 20 to 75 years based on available studies. Two studies provided limited or no age data (40,42). Eleven articles were related to recreationally active subjects, one to weight-trained subjects, 4 to athletes, and one to untrained elderly subjects. There were 2 studies that included only female subjects, 5 studies with male and female subjects, and 9 studies that included only male subjects. One study (3) did not specify the sex of subjects.

Table 1 - Effects of alternative forms of creatine supplementation on exercise performance and body composition.*
Ref Gender Size (n) Age (y) Experimental conditions Protocol Duration Variables Results
(9) M
F
Recreationally active
31
30
21 ± 2
21 ± 3
I: Cr citrate
P: Placebo
See footnote 1
I: 5g Cr citrate 4×/day
P: dextrose
2 and 6 d AWC; BW Significant increase in BW in men
(10) F
Physically
active
10 22 ± 5 I: Cr citrate
P: Placebo
I: 5g Cr citrate
4×/day
P: dextrose
2 and 5 d AWC; BW Significant increase in AWC
(12) M
F
Recreationally active
24
26
22 ± 3
21 ± 1
I: Cr citrate
P: Placebo
I: 5g Cr citrate 4×/day
P: dextrose
5 d ARC; BW Male I group exhibited higher ARC compared to male P group
(14) M Recreationally active 43 23 ± 5 I: Cr citrate
P: Placebo
C: Control
I: 5g Cr citrate
2×/day
P: dextrose
C: none
30 d o 2peak; TTE; VT; Wtotal; BW Significant improvements in V̇o 2peak and TTE occurred in I and P groups. Only I group significantly improved VT
(24) M
Athletes
49 27 ± 4 I1: Cr citrate
I2: Cr pyruvate
P: Placebo
I1: 5g Cr citrate
I2: 5g Cr pyruvate
P: not spec.
28 d BW
Body fat %; forearm circumference; Pmean; oxygen uptake to mean power ratio; contraction velocity; N; relaxation velocity; oxygen consumption during rest
I1 and I2 significantly increased BW, forearm circumference, Pmean and contraction velocity.
I2 significantly increased N, relaxation velocity, and oxygen consumption during rest
(33) M
F
Recreationally active
27
28
22 ± 3
21 ± 2
I: Cr citrate
P: Placebo
I: 5g Cr citrate 4×/day
P: fructose
5 d Vo 2max; CV; TTE; VT; BW No significant differences were observed between groups
(34) F
Recreationally trained
15 22 ± 2 I: Cr citrate
P: Placebo
I: 5g Cr citrate 4×/day
P: dextrose
5 d EMGFT; BW Increase in EMGFT and BW
(37) M
F
Untrained elderly
7
8
75 ± 6 I: Cr citrate
P: Placebo
I: 5g Cr citrate
4×/day for 7 d
2×/day for 7 d
P: not spec.
14 d; 4–6 wk washout period PWCFT; GRIP; STS; BW Significant increases in GRIP and PWCFT
(45) M
Recreationally trained
16 22 ± 3 I: Cr citrate
P: Placebo
I: 5g Cr citrate 4×/day
P: fructose
5 d EMGFt; BW Significant increase in BW
(35) M
Recreationally active
30 20 ± 2 I1: CEE
I2: CrM
P: Placebo
I1: CEE 0.30 g·kg−1 FFM (loading) and 0.075 g·kg−1 FFM (maintenance)
I2: CrM 0.30 g·kg−1 FFM (loading) and 0.075 g·kg−1 FFM (maintenance)
P: dextrose
7 wk 1RMBP; 1RMLP; Pmean; PP; BW; body fat %; FM; FFM No significant differences were observed between groups
(3) Not spec.
Recreationally active
35 22 ± 3 I1: MgO-CrM
I2: MgC-cre
P: Placebo
I1: 800 mg MgO + 5g CrM
I2: 5g MgC-cre
P: maltodextrin
2 wk TKE; Wtotal; Pmean; BW Significant increase in BW with I1; I2 had significant TKE increase; I1 and I2 increased Pmean
(32) M
Weight-trained
31 20 ± 3 I1: MgC-cre
I2: CrM
P: Placebo
I1: 2.5g MgC-cre
I2: 2.5g CrM
P: maltodextrin
10 d 1RMBP; WBP; body mass I1 and I2 significantly increased WBP
(36) M
Judoists
10 21 ± 3 I: Cr malate
P: Placebo
I: 0.07 g·kg−1 LBM Cr malate
P: not spec.
6 wk BW; BMI; FFM; FFMI; FM; FMI; body fat %; WR PPR; FI; toPP; tuPP; V̇o 2max; %V̇o 2max; SJFT I Group had significantly higher values of FI and %V̇o 2max.
(40) M
Sprinters and long-distance runners
38 19–30 I: Cr malate
P: Placebo
I: 0.07 g·kg−1 LBM Cr malate
P: potato starch
6 wk BW; body fat %; LBM; BMI; PPR; PPa; Wtotal; V̇o 2max; D Significant increases in PPR, PP, TW, BW, and LBM in I sprinters as well as a significant reduction in relative V significant increase in D observed in I long-distance runners
(8) M
F
Recreationally active
18
10
22 ± 4 I1: Cr nitrate
I2: Cr nitrate
P: Placebo
I1: 3g Cr nitrate
I2: 6g Cr nitrate
P: dextrose
6 d with 7-d washouts 1RMBP; bench press repetitions; 1RMLP leg press repetitions; leg press recovery; time trial performance; Pmean 1RMBP and 1RMLP significantly increased above baseline for I2; significant improvement in leg press recovery with I2
(13) M
Recreationally active
48 21 ± 3 I1: Cr nitrate
I2: Cr nitrate
I3: CrM
P: Placebo
I1: 1.5g Cr-nitrate
I2: 3g Cr-nitrate
I3: 3g CrM
P: dextrose
28 d BW; FM; FFM; body fat %; bench press performance [bench press repetitions; WBP; PPBP; PBP; average velocity]; sprint performance [Pmean; PPS; WS] I2 and I3 significantly increased FFM; I2 significantly increased WBP, PPBP, and PBP
(42) M
Well-trained endurance athletes
14 Not spec. I: Cr pyruvate
P: Placebo
I: 3.5 g Cr-pyruvate (2×/day)
P: maltodextrin
1 wk Time trial [PT; Wtotal]; sprint test [PPS; Pmean; FI] No significant differences were observed between groups
*M = male; F = female; I = intervention; Cr = creatine; P = placebo; AWC = anaerobic working capacity; BW = body weight; ARC = anaerobic running capacity; C = control; V̇o2peak = peak oxygen consumption; TTE = time to exhaustion; VT = ventilatory threshold; WTOTAL = total work done; Not spec. = not specified; Pmean = mean power; N = force; V̇o2max = maximal oxygen consumption; CV = critical velocity; EMGFT = electromyographic fatigue threshold; PWCFT = physical working capacity at fatigue threshold; GRIP = maximal isometric grip strength; STS = sit to stand; CEE = creatine ethyl ester; CrM = creatine monohydrate; FFM = fat-free mass; 1RMBP = 1 repetition maximum bench press; 1RMLP = 1 repetition maximum leg press; PP = peak power; FM = fat mass; MgO-CrM = magnesium oxide + CrM; MgC-Cre = magnesium-creatine chelate; TKE = knee extension peak torque; WBP = bench press total work; LBM = lean body mass; BMI = body mass index; FFMI = fat-free mass index; FMI = fat mass index; WR = relative total work; PPR = relative peak power; FI = fatigue index; toPP = time to obtain peak power; tuPP = time to maintain peak power; %V̇o2max = anaerobic threshold; SJFT = special judo fitness test; PPA = absolute peak power; D = total distance; PPBP = peak power bench press; PBP = average power bench press; PPS = peak power sprint; WS = sprint total work; PT = power output.
A third treatment group was omitted for use of phosphate salts.

Of the various forms of Cr, there were few that were studied: Cr citrate (n = 9 studies), Cr ethyl ester (CEE) (n = 1), magnesium-creatine chelate (n = 2), Cr malate (n = 2), Cr nitrate (n = 2), and Cr pyruvate (n = 2). Human studies examining the effects of other forms of Cr could not be identified. Only 3 studies compared an alternative form of creatine to CrM.

Dosages ranged from 1.5 g·d−1 to 20 g·d−1. Some protocols dosed out equal amounts among all subjects, whereas others dosed based on kilograms (kg) of BW. There were numerous dependent variables used to assess exercise performance and body composition. For the purpose of this review, the variables are grouped into the categories aerobic and anaerobic performance measures, body composition, or other variables and discussed accordingly within each form of Cr for which studies were found (Cr citrate, CEE, magnesium-creatine chelate, Cr malate, Cr nitrate, and Cr pyruvate).

Creatine Citrate

The effect of Cr citrate supplementation on exercise performance and body composition was assessed in 9 studies (9,10,12,14,24,33,34,37,45). Results were inconsistent. Three of these studies examined the effect of Cr citrate on aerobic performance measures and reported no significant effect between treatment and placebo groups on peak oxygen consumption, maximal oxygen consumption (V̇o2max), time to exhaustion, critical velocity, or oxygen consumption to mean power ratio (14,24,33). A study on recreationally active men reported that Cr citrate supplementation at 5 g per day for 30 days significantly improved ventilatory threshold (16 vs. 10% improvement in placebo) during a graded exercise test (GXT) on a cycle ergometer (14). However, another study evaluating the effects of 5 g of Cr citrate supplementation for 10 days on recreationally active men and women found no significant differences between groups for the post-test values after a GXT on a treadmill (33). Six studies examined the effect of Cr citrate on anaerobic capacity, and significant effects were reported in 3 of these studies on anaerobic running capacity (ARC), mean power (Pmean), and maximal isometric grip strength (12,24,37). Eckerson et al. (10) conducted an RDBPC trial examining the effects of 2 and 5 days of Cr citrate loading (20 g·d−1 ) on anaerobic working capacity (AWC) in physically active women. After 5 days of loading, AWC was significantly greater (22.5%) when compared to placebo. In a similar study, Eckerson et al. (9) assessed the effects of 2 and 6 days of Cr citrate loading in physically active men and women using the same critical power test. The results showed a 13–15% increase in AWC in both sexes, although this result was not statistically significant from placebo (1–3% decline). No significant effects were reported in other studies for total work done (Wtotal) and force (N) (14,24). All 9 studies examined the effect of Cr citrate on body composition. Four studies reported a significant increase in BW (0.8–1.4 kg vs. 0.1–0.3 kg in placebo) (9,24,34,45), whereas 5 reported no differences between groups (10,12,14,33,37). Jager et al. (24) also found a significant increase in forearm circumference, but no change in overall body fat percentage. For other variables, significant improvements were found in contraction velocity by 20% (24) and physical working capacity at fatigue threshold (37). Two studies examined the effect of supplementation on electromyographic fatigue threshold, and although one reported a significant 17% improvement (34), the other showed a nonsignificant 13.7% increase (45). Jager et al. (24) reported no change in relaxation velocity with supplementation, and Stout et al. (37) also reported no change in sit-to-stand.

Creatine Ethyl Ester

The effect of CEE supplementation on anaerobic capacity and body composition was assessed in one study (35). No significant differences between CEE and placebo were observed for any performance or body composition measures.

Magnesium-Creatine Chelate

The effect of magnesium-creatine chelate (MgC-Cre) supplementation on anaerobic capacity and body composition was assessed in 2 studies (3,32). For anaerobic variables, Brilla et al. (3) conducted a study assessing both MgC-Cre and magnesium oxide plus CrM (MgO-CrM) and reported significant increases in power (P) with both supplements (14.4 and 10.3%, respectively, vs. 5.2% in placebo). However, only MgC-Cre significantly increased knee extension peak torque (MgC-Cre, 9.2%; MgO-CrM, 7.3%; placebo, 3.2%). Selsby et al. (32) compared 2.5 g daily of CrM and MgC-Cre with placebo. They reported a significantly higher amount of bench press total work performed by MgC-Cre and CrM groups versus placebo (19.8%, 18.6%, and −0.7%, respectively). By contrast, no difference was reported for Wtotal in Brilla et al. (3). Selsby et al. (32) also reported no change between groups for 1 repetition maximum bench press (1RMBP). Regarding body composition, Brilla et al. (3) reported significant increases in BW with MgO-CrM but not MgC-Cre (0.8 vs. 0.4 kg), and Selsby et al. (32) reported no change in body mass during the supplementation period. Neither study reported the effects of supplementation on aerobic performance measures or other variables.

Creatine Malate

The effect of Cr malate supplementation on exercise performance and body composition was assessed in 2 studies (36,40). Both studies examined aerobic performance measures. In sprinters and long-distance runners, the effect of 6 weeks of supplementation with Cr malate was assessed using anaerobic and GXTs (40). Tyka et al. (40) reported a significant increase in total distance (+645 m vs. +45 m, creatine malate vs placebo, respectively) in supplemented long-distance runners but also noted no improvement in V̇o2max with long-distance runners and a significant reduction in relative V̇o2max in supplemented sprinters (−2.52 vs. −0.61 ml·kg−1·min−1) (40). In a study on judoists, Sterkowicz et al. reported a significant improvement in anaerobic threshold (80.8 vs. 76.1 %V̇o2max) (36) but also found no significant improvement in V̇o2max. The effect of Cr malate on anaerobic capacity was also examined, and Tyka et al. reported significant change increases of 1.05 vs. 0.05 W·kg−1 in relative peak power (PPR), absolute peak power change of 101 vs. 10 W, and Wtotal for supplemented sprinters (change of 1.91 vs. 0.68 kJ). Sterkowicz et al. reported no change in PPR, relative total work, time to obtain peak power, or time to maintain peak power. Regarding body composition, Tyka et al. reported significant increases in BW (2.15 vs. 0.75 kg) and lean body mass (1.29 vs. 0.09 kg) in supplemented sprinters compared to the placebo group, but no changes in body composition of long-distance runners. Sterkowicz et al. also reported no differences between groups for any body composition measure. For other variables, Sterkowicz et al. reported a significant improvement in fatigue index (FI), but no change was observed after supplementation in the sport-specific measure special judo fitness test.

Creatine Nitrate

The effect of Cr nitrate (CrN) supplementation on anaerobic capacity and body composition was assessed in 2 studies (8,13). In a study evaluating the effects of 3 g per day (CrN-Low) or 6 g per day (CrN-High) of Cr nitrate supplementation for 6 days, Dalton et al. (8) reported significant increases in press (1RMBP) of +6.1 vs 0.7 kg, 1 repetition maximum leg press of +24.7 vs. 13.9 kg, and leg press recovery in the CrN-High group. No significant changes in bench press repetitions, leg press repetitions, Pmean, or time trial performance were reported in either supplemental group. In another study, supplementation with placebo, 1.5 g CrN, 3 g CrN, 5 g CrM (monohydrate), or 3 g of Cr nitrate for 28 days resulted in significant increases compared to placebo in average bench press power (PBP) (382 + 93 placebo vs. 456 + 105 CrM vs. 396 + 93 low CrN vs. 489 + 90 high CrN) and Pmean for anaerobic sprint performance (682 ± 142 placebo vs. 720 ± 141 CrM vs. 709 ± 107 low CrN vs. 798 ± 61 high CrN) but no significant changes in other parameters (13). However, these values did show higher CrM and high CrN values compared to placebo and low CrN (13). For example, although statistical significance was not reached, anaerobic sprint peak power was 1,487 for placebo, 1,622 for CrM, 1,656 for low CrN, and 1784 high CrN groups. Galvan et al. also reported significant increases in fat-free mass (using DXA) after 28 days of Cr nitrate and CrM supplementation but no change in BW, body fat percentage, or fat mass (13). Although CrM and high CrN were not deemed to be different from each other, values did show consistently that high CrN dosing had slightly higher values in power bench press and sprint performance than CrM.

Creatine Pyruvate

The effect of Cr pyruvate supplementation on exercise performance and body composition was assessed in 2 studies (24,42). Jager et al. (24) examined the effects of 5 g of Cr pyruvate daily for 28 days on aerobic performance measures. They noted a significant increase in oxygen consumption during rest periods, but no significant effect on oxygen uptake to mean power ratio. Both studies examined the effects of Cr pyruvate on anaerobic capacity. Jager et al. (24) reported significant improvement in Pmean after supplementation during 9 intervals, but Van Schuylenbergh et al. found 7 g per day for 7 days resulted in no significant effect (42). Jager et al. also reported significant improvements in N ∼4%, whereas Van Schuylenbergh et al. found no differences in Wtotal, peak power sprint, or power output over time (42). Jager et al. also noted significant changes in BW (1.8% increase) and forearm circumference (29 pre vs. 29.7 cm post) with Cr pyruvate, but no effect on body fat percentage (24). Finally, Jager et al. reported significant effects of supplementation on contraction velocity and relaxation velocity (10–14% across the intervals tested) (24), whereas Van Schuylenbergh et al. (42) found no significant effect of Cr pyruvate on FI.

Adverse Events

All Cr supplements were well tolerated, and no adverse events were reported. No significant differences in side effects between groups were found in any study. In addition, no subjects dropped out of any study due to side effects related to supplement protocol.

Discussion

Results from this review are inconclusive as to the impact of alternative forms of Cr supplementation. This is due to many factors, including a paucity of RDBPC studies in existence, inconsistent dosing, inconsistent outcome measures, and lack of assessment of baseline Cr levels before supplementation. Of the studies found, Cr citrate has been studied more than other alternative forms of Cr and has produced inconsistent results. In light of these results, existing evidence suggests best practice of supplementation to be only in the form of CrM. Creatine anhydrous, Cr decanoate, Cr gluconate, and Cr HCl are presently found on the market, but no clinical research has been conducted on these forms. Three additional studies were identified evaluating alternative forms of Cr; however, they were not included due to an absence of all relevant inclusion criteria. These studies examined Cr phosphate, Kre-alkalyn (buffered creatine), and Cr malate, and found similar inconsistent results (26,31,41). In the likelihood that future forms of creatine will continue to be developed and marketed, the following discussion includes several considerations consumers and researchers should be aware of when evaluating future products or forms of creatine. These issues include the gold standard (or ideal type of study design) against how future forms of creatine should be measured to provide an adequate comparison against the well-studied CrM, ways that creatine levels can be measured within studies, the ability for someone to be a creatine “responder,” and safety issues of alternative forms of creatine. Finally, the cost-efficacy of products compared to CrM will also be discussed because it relates to the results of our search efforts.

To compare efficacy of alternative forms of creatine to CrM, the ideal study would be a three-armed RDBPC study examining the 3 groups: CrM, a Cr alternative, and placebo. Only 3 studies are currently available comparing an alternative form of Cr to CrM in this fashion (13,32,35). A simplified version of Table 1 is presented in Table 2, which includes these 3 studies. Each study tested a different form of Cr: CEE, MgC-Cre, and Cr nitrate. Of these 3 studies, Galvan et al. was the only intervention that found significant results in the alternative Cr group (Cr nitrate) relative to CrM. However, the author notes, “…it is important to understand that [this study] was not a CrM efficacy study, but rather an assessment of Cr nitrate” (13). Furthermore, he concluded that, “…there was no evidence that Cr nitrate at recommended or twice recommended doses is more efficacious than CrM at the doses studied” (13). Consumers should consider multiple features when choosing a Cr supplement and dosing parameters including changes in intramuscular creatine content, evidence of responders vs. nonresponders, safety, and cost-effectiveness.

Table 2 - Studies that compared alternative forms of Cr to CrM and placebo.*
Ref Population Supplement protocol Duration Results
(35) M (n: 30)
Recreationally active (age: 20 ± 2 y)
I1: CEE 0.30 g/kg FFM (loading) and 0.075 g/kg FFM (maintenance)
I2: CrM 0.30 g/kg FFM (loading) and 0.075 g/kg FFM (maintenance)
P: dextrose
7 wk No significant differences were observed between groups (repeated-measures ANOVA)
(32) M (n: 31)
Weight-trained (age: 20 ± 3 y)
I1: 2.5g MgC-cre
I2: 2.5g CrM
P: maltodextrin
10 d I1and I2 significantly increased WBP (ANOVA using % change difference)
(13) M (n: 48)
Recreationally active (age: 21 ± 3 y)
I1: 1.5g Cr nitrate
I2: 3g Cr nitrate
I3: 3g CrM
P: dextrose
28 d I2 and I3 significantly increased FFM; I2 significantly increased WBP, PPBP, and PBP (repeated-measures MANOVA)
*M = male; I = intervention; CEE = creatine ethyl ester; FFM = fat-free mass; CrM = creatine monohydrate; P = placebo; MgC-Cre = magnesium-creatine chelate; WBP = bench press total work; Cr-creatine; PPBP = peak power bench press; PBP = average power bench press; ANOVA = analysis of variance.

Some researchers have tested the kinetics of plasma Cr absorption after the ingestion of various forms of Cr compared to CrM, and one study found that Cr pyruvate supplementation may produce slightly higher peak plasma concentrations compared to CrM and tricreatine citrate (TCC) (23). However, the absorption and elimination were not different between groups, and these small differences in kinetics are unlikely to have an effect on resulting muscle Cr concentration (23). By contrast, other studies comparing serum Cr levels after ingestion of CrM and Cr nitrate or CEE have reported significantly higher serum Cr concentrations after CrM ingestion (13,35). In a study by Greenwood et al. investigating whole-body Cr retention, TCC in an effervescent form did not enhance whole-body Cr retention more than CrM (16). In this review, the above results were not determined to be substantial on exercise outcomes because it is ultimately the total change in intramuscular Cr stores, not plasma Cr levels, that provides ergogenic benefit (6,15,17,32). More studies comparing CrM to other forms of Cr are still needed.

There is evidence of responders and nonresponders to Cr supplementation. Subjects with low initial levels of intramuscular Cr exhibit a more significant response to Cr supplementation, which may account for varying degrees of performance and body composition changes seen in the above studies (5,39). Because vegetarians have lower total Cr levels compared to nonvegetarians, the overall increase in muscle Cr content is likely to be greater and therefore elicit a more ergogenic response (5). Despite evidence of dietary creatine affecting intramuscular creatine levels, none of the articles included in this review used dietary restricted subjects, nor did they separate vegetarians from nonvegetarians for independent analysis. Similarly, females have been reported to have ∼10% higher baseline intramuscular Cr levels and may therefore exhibit characteristics similar to Cr nonresponders (11,12). Four articles included in this review analyzed females and males separately. Dalton et al., Eckerson et al., and Smith et al. found no significant differences after Cr nitrate or Cr citrate supplementation for performance outcomes between sexes, whereas Fukuda et al. reported a significant increase (23%) in ARC for men, but not in women (12%) after Cr citrate supplementation (8,9,12,33). Despite similar changes in performance outcomes, Smith et al. did report a significant increase in BW values for males after Cr citrate supplementation (0.8 kg) but a nonsignificant increase for females (0.25 kg) (33).

The current literature does not support anecdotal claims of CrM supplementation increasing the risk for injury, dehydration, muscle cramping, or gastrointestinal distress (27). The International Society of Sports Nutrition position stand on the safety of Cr supplementation by Kreider et al. provides conclusive evidence that CrM is safe to consume and well tolerated in healthy individuals regardless of age or training status (27). Safety of alternative forms of Cr, however, has not been substantiated due to limited scientific data. Although not a part of the systematic review, there have been 2 case studies reported in the literature of elevated creatinine levels after consuming creatine ethyl ester (28,43). This can be explained by the fact that creatine ethyl ester (but not CrM) is degraded by stomach acid to creatinine. In addition, although some exercisers anecdotally claim that other alternative forms are easier on the gastrointestinal tract and/or cause less total body bloating, these claims also have not been substantiated.

Due to the claims of improved efficacy of alternative forms of Cr, these supplements are often sold at much higher cost. Table 3 summarizes a cost comparison of all currently available alternative forms of Cr that have been third-party tested and approved (either NSF or Informed Choice/Informed Sport) versus CrM. There were 6 products included for comparison that are sold within the United States and that have no additional supplements added. This table highlights the affordability of CrM at an average of $0.29 per 5-g serving and the exaggerated higher cost of other forms of Cr without substantiation to support these prices.

Table 3 - Cost comparison of third-party certified products.
Form Average price per 5 g serving
Magnesium-creatine chelate $1.50
Creatine hydrochloride $1.10
Buffered creatine $1.00
Creatine monohydrate $0.29

Table 4 summarizes a cost comparison for products that have not been third-party certified. Althougha wide variety of Cr supplements are available, CrM remains the most cost-effective even when accounting for uncertified products. Furthermore, the safety of these products has not been established, and it is strongly recommended that athletes choose third-party certified products to minimize the risk of inadvertent doping and unintended health consequences.

Practical Applications

Despite claims of increased solubility, bioavailability, and superior uptake mechanisms, there is currently no evidence supporting the use of any alternative form of Cr over CrM. Although all forms of Cr (except CEE) were shown to be safe in existing studies, further research is necessary to determine whether alternative forms of Cr are potentially more effective or worth the higher cost. Creatine monohydrate remains as the most studied and cost-effective form of creatine.

Table 4 - Cost comparison of noncertified products.
Form Average price per 5 g serving
Magnesium-creatine chelate $0.45
Creatine hydrochloride $0.42
Buffered creatine $1.51
Creatine anhydrous $0.72
Creatine decanate $0.30
Creatine gluconate $0.65
Creatine ethyl ester $0.53
Creatine monohydrate $0.19

Acknowledgments

The authors report no conflict of interest. No professional relationships or manufacturers will benefit from the results of this study. This report was conducted as a Master′s Research Capstone project, so no funding was given. The results of this study do not constitute endorsement of the product by the authors or the NSCA.

References

1. Balsom PD, Soderlund K, Ekblom B. Creatine in humans with special reference to creatine supplementation. Sports Med 18: 268–280, 1994.
2. Bogdanis GC, Nevill ME, HKA L, Boobis LH. Human muscle metabolism during repeated maximal sprint cycling. J Physiol 467: 1993.
3. Brilla LR, Giroux MS, Taylor A, Knutzen KM. Magnesium-creatine supplementation effects on body water. Metabolism 52: 1136–1140, 2003.
4. Brosnan ME, Brosnan JT. The role of dietary creatine. Amino Acids 48: 1785–1791, 2016.
5. Burke DG, Chilibeck PD, Parise G, et al. Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc 35: 1946–1955, 2003.
6. Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff PL. Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol 271: E31–E37, 1996.
7. Cheetham ME, Boobis LH, Brooks S, Williams C. Human muscle metabolism during sprint running. J Appl Physiol 61: 54–60, 1986.
8. Dalton RL, Sowinski RJ, Grubic TJ, et al. Hematological and hemodynamic responses to acute and short-term creatine nitrate supplementation. Nutrients 9: 1359, 2017.
9. Eckerson JM, Stout JR, Moore GA, et al. Effect of creatine phosphate supplementation on anaerobic working capacity and body weight after two and six days of loading in men and women. J Strength Cond Res 19: 756–763, 2005
10. Eckerson JM, Stout JR, Moore GA, et al. Effect of two and five days of creatine loading on anaerobic working capacity in women. J Strength Cond Res 18: 168–173, 2004.
11. Forsberg AM, Nilsson E, Werneman J, Bergström J, Hultman E. Muscle composition in relation to age and sex. Clin Sci 81: 249–256, 1991.
12. Fukuda DH, Smith AE, Kendall KL, et al. The effects of creatine loading and gender on anaerobic running capacity. J Strength Cond Res 24: 1826–1833, 2010.
13. Galvan E, Walker DK, Simbo SY, et al. Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. J Int Soc Sports Nutr 13: 12, 2016.
14. Graef JL, Smith AE, Kendall KL, et al. The effects of four weeks of creatine supplementation and high-intensity interval training on cardiorespiratory fitness: A randomized controlled trial. J Int Soc Sports Nutr 6: 18, 2009.
15. Greenhaff PL, Bodin K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol 266: E725–E730, 1994.
16. Greenwood M, Kreider R, Earnest C, Rasmussen C, Almada A. Differenecs in creatine retention among three nutritional formulations of oral creatine supplements. J Exerc Physiol Online 6: 37–43, 2003.
17. Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 83: 367–374, 1992.
18. Heymsfield SB, Arteaga C, McManus C, Smith J, Moffitt S. Measurement of muscle mass in humans: Validity of the 24-hour urinary creatinine method. Am J Clin Nutr 37: 478–494, 1983.
19. Hirvonen J, Nummela A, Rusko H, Rehunen S, Harkonen M. Fatigue and changes of ATP, creatine phosphate, and lactate during the 400-m sprint. Can J Sport Sci 17: 141–144, 1992.
20. Hirvonen J, Rehunen S, Rusko H, Harkonen M. Breakdown of high-energy phosphate compounds and lactate accumulation during short supramaximal exercise. Eur J Appl Physiol Occup Physiol 56: 253–259, 1987.
21. Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol 81: 232–237, 1996.
22. Hunter A. The physiology of creatine and creatinine. Physiol Rev 2: 586–626, 1922.
23. Jäger R, Harris RC, Purpura M, Francaux M. Comparison of new forms of creatine in raising plasma creatine levels. J Int Soc Sports Nutr 4: 17, 2007.
24. Jäger R, Metzger J, Lautmann K, et al. The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise. J Int Soc Sports Nutr 5: 4, 2008.
25. Jager R, Purpura M, Shao A, Inoue T, Kreider RB. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids 40: 1369–1383, 2011.
26. Jagim AR, Oliver JM, Sanchez A, et al. A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. J Int Soc Sports Nutr 9: 43, 2012.
27. Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr 14: 18, 2017.
28. Law JP, Di Gerlando S, Pankhurst T, Kamesh L. Elevation of serum creatinine in a renal transplant patient following oral creatine supplementation. Clin Kidney J 12: 600–601, 2019.
29. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting Items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 6: 1–6, 2009.
30. Myers VC, Fine MS. The metabolism of creatine and creatinine: Seventh paper. The fate of creatine when administered to man. J Biol Chem 21: 377–381, 1915.
31. Peeters BM, Lantz CD, Mayhew JL. Effect of oral creatine monohydrate and creatine phosphate supplementation on maximal strength indices, body composition, and blood pressure. J Strength Cond Res 13: 3–9, 1999.
32. Selsby JT, DiSilvestro RA, Devor ST. Mg2+-creatine chelate and a low-dose creatine supplementation regimen improve exercise performance. J Strength Cond Res 18: 311–315, 2004.
33. Smith AE, Fukuda DH, Ryan ED, Kendall KL, Cramer JT, Stout J. Ergolytic/ergogenic effects of creatine on aerobic power. Int J Sports Med 32: 975–981, 2011.
34. Smith AE, Walter AA, Herda TJ, et al. Effects of creatine loading on electromyographic fatigue threshold during cycle ergometry in college-aged women. J Int Soc Sports Nutr 4: 20, 2007.
35. Spillane M, Schoch R, Cooke M, et al. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. J Int Soc Sports Nutr 6: 6, 2009.
36. Sterkowicz S, Tyka AK, Chwastowski M, et al. The effects of training and creatine malate supplementation during preparation period on physical capacity and special fitness in judo contestants. J Int Soc Sport Nutr 9: 41, 2012.
37. Stout JR, Sue Graves B, Cramer JT, et al. Effects of creatine supplementation on the onset of neuromuscular fatigue threshold and muscle strength in elderly men and women (64—86 years). J Nutr Health Aging 11: 459–464, 2007.
38. Sundberg CW, Prost RW, Fitts RH, Hunter SK. Bioenergetic basis for the increased fatigability with ageing. J Physiol 597: 4943–4957, 2019.
39. Syrotuik DG, Bell GJ. Acute creatine monohydrate supplementation: A descriptive physiological profile of responders vs. nonresponders. J Strength Cond Res 18: 610–617, 2004.
40. Tyka AK, Chwastowski M, Cison T, et al. Effect of creatine malate supplementation on physical performance, body composition and selected hormone levels in spinters and long-distance runners. Acta Physiol Hung 102: 114–122, 2015.
41. Tyka AP T, Pilch W, Cebula A, et al. Effects of exercise training and creatine malate supplementation on ventilatory threshold and anaerobic working capacity in long-distance runners. J Kines Exerc Sci 71: 23–30, 2015.
42. Van Schuylenbergh R, Van Leemputte M, Hespel P. Effects of oral creatine-pyruvate supplementation in cycling performance. Int J Sports Med 24: 144–150, 2003.
43. Velema MS, de Ronde W. Elevated plasma creatinine due to creatine ethyl ester use. Neth J Med 69: 79–81, 2011.
44. Walker JB. Creatine: Biosynthesis, regulation, and function. Adv Enzymol Relat Areas Mol Biol 50: 177–242, 1979.
45. Walter AA, Smith AE, Herda TJ, et al. Effects of creatine loading on electromyographic fatigue threshold in cycle ergometry in college-age men. Int J Sport Nutr Exerc Metab 18: 142–151, 2008.
Keywords:

performance; cost; exercise; supplement

© 2021 National Strength and Conditioning Association