Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review
Abstract
:1. Introduction
2. Methods
3. Bioavailability
3.1. Methods to Assess Bioavailability
3.1.1. Assess Chemical Structure
3.1.2. Assess Changes in Blood Creatine Content
3.1.3. Assess Changes in Tissue Creatine Content
4. Physio-Chemical Properties
5. Stability
6. Solubility
7. Purported Creatine Related Compounds
8. Strong Evidence to Support Bioavailability, Efficacy, and Safety
Creatine Monohydrate
9. Some Evidence to Support Bioavailability, Efficacy, and Safety
9.1. Creatine Salts
9.1.1. Creatine Citrate
9.1.2. Creatine Pyruvate
9.2. Magnesium Creatine Chelate
9.3. Creatine Ethyl Ester
9.4. Creatine HCl
9.5. Creatine Nitrate
9.6. Buffered Creatine Monohydrate
10. No Evidence to Support Bioavailability, Efficacy, and Safety
10.1. Other Creatine Salts
10.2. Creatine Serum
10.3. Creatyl-L-Leucine
10.4. Creatinol-O-Phosphate
11. Regulatory Status
11.1. United States
11.2. International Regulation
11.3. Assessment and Guidance for Industry
- (1)
- Only consider developing creatine supplements that contain a creatine molecule. Alteration of the chemical structure of creatine in any way is assumed to change the chemical activity and biological function and may negate any benefit of creatine supplementation. Additionally, binding creatine to other compounds may prevent creatine from being liberated in vivo, thereby making the form of creatine non-bioavailable or less bioavailable source of creatine.
- (2)
- Companies who develop new forms of creatine should conduct toxicology studies in animals to establish that high dose ingestion is safe and conduct clinical trials in humans to validate safety. We then recommend obtaining FDA GRAS status or Self-Affirming GRAS status.
- (3)
- Pharmacokinetic studies must be performed to show that the novel form of creatine is degraded into creatine and increases blood creatine levels to physiological levels necessary to promote creatine uptake into tissue (e.g., >200–500 µmol/L or 25–65 µg/L).
- (4)
- Bioavailability studies should be conducted to show recommended doses increase muscle and/or brain creatine content.
- (5)
- Placebo, double blind, and randomized clinical trials should be performed to substantiate that the form of creatine provides ergogenic benefit and does not cause any untoward side effects.
- (6)
- Comparative effectiveness trials at recommended and equivalent doses must be performed to show a new form of creatine increases muscle and/or brain creatine content to a greater degree than CrM to substantiate those claims.
- (7)
- Comparative effectiveness trials at recommended and equivalent doses must also be performed to determine if a new form of creatine is more effective and/or a safer alternative to CrM to substantiate those types of claims.
- (8)
- Supplement companies should clearly declare the source and amount of creatine contained in their products so consumers can know if they are taking effective doses.
- (9)
- Claims made about a form of creatine should be based on research conducted on that form of creatine at recommended doses, not untested hypotheses, speculation, assumptions, and/or marketing hyperbole. Such practices only undermine the scientific validity and consumer confidence about creatine supplementation.
- (10)
- Pure CrM is the only source of creatine with strong evidence of bioavailability, efficacy, and safety and considered as GRAS by the FDA, approved for use in the EU and Australia, and evaluated for safety by Health Canada.
- (11)
- Consumers should only consider taking supplements that contain sources of creatine that research has shown is bioavailable, effective, safe, and devoid of impurities.
12. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Molecular Formula | Molecular Weight (g/mol) | Theoretical Percent Creatine by MW † | Difference from CrM (%) |
---|---|---|---|---|
Creatine (Creatine Anhydrous) | C4H9N3O2 | 131.13 | 100.0 | 13.8 |
Creatine Monohydrate | C4H11N3O3 | 149.15 | 87.9 | 0.0 |
Magnesium Creatine | C4H9MgN3O2 | 155.44 | 84.4 | −4.0 |
Creatine Ethyl Ester | C6H13N3O2 | 159.19 | 82.4 | −6.3 |
Methyl-Amino-Creatine | C5H12N4O2 | 160.17 | 81.9 | −6.9 |
Creatine Hydrochloride | C4H10ClN3O | 167.59 | 78.2 | −11.0 |
Creatine Methyl Ester Hydrochloride | C5H12ClN3O2 | 181.62 | 72.2 | −17.9 |
Creatine Nitrate | C4H10N4O5 | 194.15 | 67.5 | −23.2 |
Creatinol-O-Phosphate | C4H12N3O4P | 197.13 | 66.5 | −24.3 |
Tri-Creatine Citrate | C14H26N6O11 | 585.50 | 67.2 | −23.5 |
Phospho-Creatine | C4H10N3O5P | 211.11 | 62.1 | −29.3 |
Creatine Pyruvate | C7H13N3O5 | 219.20 | 59.8 | −31.9 |
Creatine Beta-Alaninate | C7H16N4O4 | 220.23 | 59.5 | −32.3 |
Creatine Lactate | C7H15N3O5 | 221.21 | 59.3 | −32.6 |
Creatine Benzyl Ester | C11H15N3O2 | 221.26 | 59.3 | −32.6 |
Di-Creatine Citrate | C14H26N6O11 | 454.39 | 57.7 | −34.3 |
Creatine Sulfate | C4H11N3O6S | 229.21 | 57.2 | −34.9 |
Creatine Pyruvate Monohydrate | C7H15N3O6 | 237.21 | 55.3 | −37.1 |
Di-Acetyl Creatine Ethyl Ester | C10H17N3O4 | 243.26 | 53.9 | −38.7 |
Creatine Sulfate Monohydrate | C4H13N3O7S | 247.23 | 53.0 | −39.7 |
Creatine Ethyl Ester Pyruvate | C9H17N3O5 | 247.25 | 53.0 | −39.7 |
Sodium Creatine Phosphate | C4H8N3Na2O5P | 255.08 | 51.4 | −41.5 |
Creatine Taurinate | C6H16N4O5S | 256.28 | 51.2 | −41.8 |
Creatine Pyroglutamate | C9H16N4O5 | 260.25 | 50.4 | −42.7 |
Creatine Malate | C8H15N3O7 | 265.22 | 49.4 | −43.8 |
Creatine Glutamate | C9H16N4O6 | 276.25 | 47.5 | −46.0 |
Creatine Orotate | C9H13N5O6 | 287.23 | 45.7 | −48.1 |
Creatine Carnitine | C11H24N4O5 | 292.33 | 44.9 | −49.0 |
Creatine Ethyl Ester Malate | C10H19N3O7 | 293.27 | 44.7 | −49.1 |
5-Hydroxytryptamine Creatine | C14H21N5O3 | 307.35 | 42.7 | −51.5 |
Creatine Trinitrate | C4H12N6O11 | 320.17 | 41.0 | −53.4 |
Creatine α-ketoglutarate | C11H20N4O7 | 320.30 | 40.9 | −53.4 |
Creatine Citrate | C10H17N3O9 | 323.26 | 40.6 | −53.9 |
D-Gluconic Acid Creatine Salt | C10H21N3O9 | 327.29 | 40.1 | −54.4 |
Creatine Monohydrate Dextrose | C10H23N3O9 | 329.30 | 39.8 | −54.7 |
Creatine Hydroxycitrate | C10H17N3O10 | 339.26 | 38.7 | −56.0 |
Disodium Creatine Phosphate Tetrahydrate | C4H18N3Na2O10P | 345.15 | 76.0 | −13.6 |
Creatine Phosphate Lactate | C13H22N3O15P | 491.30 | 26.7 | −69.6 |
Creatine-CoA | C25H43N10O17P3S | 880.70 | 14.9 | −83.1 |
Reference | Participants | Design | Duration | Dosing Protocol | Findings | Side Effects |
---|---|---|---|---|---|---|
Short-term Studies (<14 Days) | ||||||
Greenhaff et al. [71] | 8 healthy males | SB | 5 days | 4 × 5 g CrM | CrM ↑ TCr by 25% and PCr resynthesis following electrically evoked isometric contractions. | None reported |
Balsom et al. [161] | 7 males | SB | 6 days | 4 × 5 g CrM | ↑ in total muscle total creatine (18%), weight (1.1 kg), and 5 × 6 s cycling sprint performance and PCr recovery | None reported |
Green et al. [20] | 24 healthy men | RDBP | 5 days | 4 × 5 g CrM followed by 93 g CHO or CHO | Ingesting CrM with CHO ↑ muscle TCr and glycogen | None reported |
Vandenberghe et al. [162] | 9 healthy non-vegetarian males | RDBPC | 5 days with 5 week washout | 25 g/day CrM or PLA | CrM ↑ muscle PCr by 11% and 16% after 2 and 5 days. PCr resynthesis rate was not affected. | None reported |
Bellinger et al. [163] | 20 endurance cyclists | RDBP | 7 days | 20 g/day CrM or PLA | CrM ↑ muscle creatine content by 30% and decreased TAN contribution to sprint | None reported |
Francaux et al. [164] | 14 physically active males | RDBP | 14 days | 3 × 7 g of CrM or PLA | CrM ↑ MRS PCr by ~20% and PCr repletion by 15% and 10% during 40% and 70% MVCs. | None reported |
Preen et al. [116] | 14 physically active men | RDBP | 5 days | 20 g/day CrM or PLA | CrM increase TCr stores and work during 80-min of repeated cycling sprint exercise. | None reported |
Burke et al. [165] | 20 male resistance-trained athletes (18–32 years) | RDBP | 5 days | 4 × 5 g CrM, 4 × 5 g CrM + 25 g Sucrose, or 4 × 5 g CrM + 25 g Sucrose + 250 mg α-LA or PLA | CrM ↑ body weight (2.1 kg) with no differences among groups, TCr was ↑ more in the CrM + sucrose + α-LA group. | None reported |
Longer-Term Studies (>14 days) | ||||||
Vandenberghe et al. [47] | 19 young female volunteers | RDBP | 10 weeks phase I (n = 19); 10 weeks phase II (n = 13) | 4 × 5 g CrM for 4 days, 5 g/day thereafter or PLA | CrM ↑ muscle PCr, strength, and exercise capacity | None reported |
Kreider et al. [55] | 25 American college football players during offseason resistance and agility training | RDBP | 28 days | CrM 15.75 g/day with glucose or glucose PLA | ↑ FFM, ↑ strength, ↑ muscular endurance, ↑ 6 × 6-s cycling sprint performance with 30-s rest | None reported |
Volek et al. [113] | 19 healthy resistance-trained males | RDBP | 12 weeks | CrM 5 × 5 g for 7 days, 5 g/day for 11 weeks or PLA | ↑ FFM, strength, and muscle morphology | No differences |
Kreider et al. [166] | 51 American college football players during offseason resistance and agility training and spring football | RDBP | 12 weeks | 20 g/day and 25 g/day of CrM with CHO and PRO; CHO only; or CHO + PRO only | CrM groups ↑ FFM, ↑ strength, ↑ muscular endurance. No changes in blood chemistry panels. | CrM groups had less GI complaints than those ingesting CHO and CHO + PRO. |
Tarnopolsky et al. [167] | 23 young healthy but untrained males | RDBP | 8 weeks | 10 g/day CrM with 75 g CHO or PLA | CrM with CHO promoted greater ↑ in body mass and FFM during training. | None reported |
Willoughby et al. [168] | 22 untrained males during resistance-training | RDBP | 12 weeks | CrM 6 g/day or PLA | CrM promoted > increases in body mass, FFM, thigh volume, muscle strength, myofibrillar protein content, and myosin heavy chain mRNA expression for Type I, IIa, and IIx fibers | None reported |
Burke et al. [108] | 18 vegan and 24 non-vegan (20 men, 22 female) | RDBP | 56 days | 0.25 g/kg FFM/d of CrM for 7 days, 0.0625 g/kg FFM/d for 49 days or PLA | TCr content was lower in vegans. CrM ↑ PCr, TCr, and gains in bench press strength, isotonic work, Type II fiber area, and FFM during resistance training. | None reported |
Lyoo et al. [73] | 15 males (23–35 years) | RDBP | 56 days | 2 × 0.15 g/kg CrM for 7 days, 2 × 0.015 g/kg CrM for 49 days or PLA | CrM ↑ brain PCr (3.4%), Pi (9.8%), and Cr (8.1%) while decreasing β-nucleoside triphosphate (NTP) by 7.8%. | None reported |
Newman et al. [169] | 17 healthy active but untrained men | RDBP | 33 days | 4 × 5 g CrM + 3.75 glucose for 5-days, 3 g CrM + 3 g glucose thereafter or PLA | CrM ↑ muscle TCr after loading and maintenance doses. CrM had no effects on muscle glycogen, glucose tolerance or insulin sensitivity. | None reported |
Tarnopolsky et al. [170] | Moderately active younger (13 men, 14 women; 19 resistance-trained men; Older resistance-trained men (15) and women (15) | RDBP | 5 days; 8 weeks; 14 weeks | 4 × 5 g CrM for 5 days; 10 g/day CrM with 75 g dextrose for 8 weeks during training; 5 g/day CrM + 2 g/day dextrose for 14 weeks during training or PLA | CrM ↑ muscle TCr in each study compared to placebo. CrM nor training influenced creatine transporter protein content. Citrate synthase was increased in older participants. | None reported |
Willoughby et al. [171] | 22 untrained males during resistance-training | RDBP | 12 weeks | 6 g/day CrM or PLA | CrM promoted > ↑ in muscle CK, myogenin, and MRF-4. | None reported |
Reference | Participants | Design | Duration | Dosing Protocol | Findings | Side Effects |
---|---|---|---|---|---|---|
Creatine Salts | ||||||
Jäger et al. [63] | 3 females and 3 males | RDBPC | 1 oral dose with 7 day washout | 5 g CrM 6.7 g CC 7.3 g CPY | Creatine peak AUC was higher with CPY with no differences in absorption kinetics | None reported |
Smith et al. [180] | 15 recreationally active women (22.3 ± 0.6 yrs) | RDBP | 5 days | 20 g/day of CC | CC loading delayed the onset of neuromuscular fatigue during cycle ergometry. | None reported |
Jäger et al. [174] | 49 healthy males (26.5 ± 4 yrs) | RDBP | 28 days | 5 g/day of CC, CPY, or PLA | CPY and CC ↑ intermittent handgrip exercise of maximal intensity. Some evidence CPY might benefit endurance exercise. | None reported |
Graef and coworkers [181] | 43 recreationally active men (22.6 ± 5 yrs) | RDBP | 5 days/week for 6-weeks | 2 × 5 g/day of PLA or CC on training days | CC increases ventilatory anaerobic threshold (PLA 10%, CC 16%). No differences in time to exhaustion or total work. | None reported |
Smith et al. [172] | 55 active men (27) and women (28) | RDBP | 5 days | 4 × 5 g/day of CC or PLA | CC did not positively or negatively affect maximal aerobic capacity, critical velocity, time to exhaustion, or body mass. | None reported |
Fukuda et al. [182] | 50 recreationally active men (24) and women (26) 22 ± 3 yrs | RDBP | 5 days | 4 × 5 g/day of CC or PLA | CC loading ↑ anaerobic running capacity (+23%) with no effect in PLA group in men but not women. | None reported |
Stone et al. [83] | 42 American football players | RDBP | 5 weeks | 0.22 g/kg/day of PLA, CrM, caPYR, or CrM + caPYR | CrM and CrM + caPYR ↑ strength, FFM, and power output. No difference from PLA or caPYR alone. | GI issues with caPYR. None reported with CrM |
Van Schuylenbergh et al. [175] | 14 well-trained male endurance athletes (4 cyclists, 10 triathletes) | RDBP | 7 days | 2 × 3.5 g of CPY with 8 g CHO or PLA | CYP had no effects on 1-h time trial steady-state power output, interval sprints, total work lactate, or heart rate. | None reported |
Nuuttilla et al. [187] | Olympic canoeists | RDBP | 7 days | 7.5 g/day of CPY or PLA | CPY improved paddle rate and lowered blood lactate suggesting an improvement in aerobic exercise efficiency. | None reported |
Magnesium Creatine Chelate | ||||||
Brilla et al. [189] | 35 recreationally active men | RDBP | 14 days | 800 mg/day magnesium (Mg) and 5 g/day Cr as Mg oxide plus Cr or MgCr-C | Body mass and power ↑ in both Cr groups while intracellular and extracellular water and peak torque only increased in the MgCr-C group | None reported |
Selsby et al. [190] | 31 resistance-trained men | RDBP | 10 days | 2.5 g/day of PLA, Cr or Mg-Cr | Both Cr groups improved bench press total work compared to PLA. No differences between groups. | None reported |
Zajac et al. [191] | 20 elite soccer players | RDBP | 16 weeks | 5.5 g/day of r MgCr-C or PLA | MgCr-C ↑ 35 m repeated sprint performance, total time, average power, and peak power with no changes in PLA group. | MgCr-C ↑ serum creatinine compared to PLA |
Creatine Ethyl Ester | ||||||
Spillane et al. [27] | 30 healthy males (20.4 ± 1.7 yrs) | RDBP | 47 days | 0.30 g/kg FFM for 5-days, 0.075 g/kg FFM for 42 days of PLA, CrM, or CEE | CEE ↑ in muscle TCr after 27-days compared to PLA. However, CrM observed significantly greater ↑ in TCr compared to PLA and CEE. CEE did not promote > training adaptations. | CEE ↑ serum creatinine twofold > than PLA and CrM. None reported with CrM. |
Arazi et al. [197] | 16 resistance trained males | RDBP | 42 days | 4 × 5 g/day of PLA or CEE for 5 days, 5 g/day for 37 days | CEE during resistance-training ↑ body weight and leg press strength while percent body fat ↓ with some evidence of an ↑ in testosterone and growth hormone. | None reported. |
Creatine HCl | ||||||
de França et al. [65] | 40 healthy males and females | RDBP | 28 days | 5 g/day PLA, 1.5 g/day of Cr-HCl, 5 g/day of Cr-HCl, or 5 g/day CrM | Reported some effects on skinfold determined fat mass and FFM and leg press strength but gains in CrM were greater than Cr-HCl | None reported. |
Yoshioka et al. [201] | 11 healthy elite Brazilian gymnasts | RDBP | 30 days | 5 g/dayay of CrM or 1.5 g/dayay of Cr-HCL with 3.5 g/dayay of resistant starch | Skinfold caliper determined FFM, strength, and BIA determined total body water was increased to a greater degree in the CrM group (CrM + 1.81 L vs. Cr-HCL +0.24 L). | None reported. |
Tayebi et al. [202] | 36 resistance trained men | RDBP | 7 days | 20 g/day CrM, 3 g/day CrM, 3 g/day Cr-HCL, or PLA | 3 g/day of Cr-HCl did not promote greater gains in performance or hormonal responses than 3 or 20 g/day of CrM. | None reported. |
Creatine Nitrate | ||||||
Ostojic et al. [209] | 10 healthy men | RDBPC | 1 oral dose | 3 g CrN + 3 g CNN, 3 g CrN, 3 g CrM | CrN + CNN ingestion promoted a greater increase in serum creatine AUC levels (183.7 ± 15.5, 163.8 ± 12.9, and 118.6 ± 12.9 µmol/L, respectively). | None reported. |
Ostojic et al. [209] | 10 healthy men | RDBPC | 5 days | 3 g/day CrN + 3 g/day CNN, 3 g/day CrN, 3 g/day CrM | MRS determined muscle creatine content increased to a greater degree with CrN + CNN (9.6%, 8.0%, 2.1%, respectively) | Irregular bowel movement (1 CrN and CrN + CNN), Excessive sleepiness (1 CrN), Seldom stomach bloating (1 CrM). CrN + CNN decrease eGFR determined kidney function. |
Galvan et al. [29] | 13 males | RDBPC | 1 oral dose with 7 day washout | 1.5 g CrN (CrN-Low), 3 g CrN (CrN-High), 5 g CrM or a placebo | CrM ↑ plasma Cr AUC to a greater degree than PLA, CrN-Low, and CrN-High while plasma nitrate ↑ in CrN treatments. | None reported. |
Galvan et al. [29] | 48 active males | RDBP | 28 days | 4 × 5 g PLA, 4 × 1.5 g/day of CrN (CrN-Low), 4 × 3 g/day CrN (CrN-High), 4 × 3 g/day CrM for 7 days and 1 dose/d for 21 days | Creatine loading (12 g/day of CrM and CrN) ↑ muscle TCr in the CrM (7.1 mmol/kg DW) and CrN-High (4.6 mmol/kg DW) groups. CrM maintained ↑ muscle TCr. CrN-Low had no effects on TCr compared to PLA after 7 and 28 days. 3 g/day of CrN was not sufficient to maintain elevated muscle TCr after 28 days. | None reported. |
Dalton et al. [36] | 28 participants (18 men, 10 women) | RDBPC | 6 days | 3 g/day of PLA. 3 g/day CrN, 6 g/day CrN. | Up to 6 g of CrN for 6-days does not negatively affect resting hemodynamics, response to a postural challenge, the ability to perform high-intensity exercise, or clinical chemistry profiles. | None reported. |
Joy et al. [212] | 58 young males and females (24.3 ± 4 yrs) | R | 28 days | Control group, 1 g/day CrN, 2 g/day CrN with other nutrients | 1–2 g/day of CrN supplementation during training had no adverse effects on clinical blood chemistries compared to a non-supplemented group. | None reported. |
Buffered Creatine | ||||||
Jagim et al. [28] | 36 resistance trained males | RDBP | 28 days | CrM (4 × 5 g/day for 7 days, 5 g/day for 21 days); CrM-Alk at recommended doses (1.5 g/day for 28 days); or CrM-Alk with equivalent doses to CrM (4 × 5 g/day for 7 days, 5 g/day for 21 days). | Neither recommended doses nor loading and maintenance equivalent doses of CrM-Alk promoted greater changes in muscle TCr, body composition, strength, or anaerobic capacity compared to CrM. Recommended doses did not ↑ TCr. | None reported. |
Reference | Participants | Design | Duration | Dosing Protocol | Findings | Side Effects |
---|---|---|---|---|---|---|
Creatine Serum | ||||||
Harris et al. [38] | 6 males | R | 1 oral dose with 7 day washout | Water Control, 5 mL CS (purportedly delivering 2.5 g CrM), 2.5 g CrM | CrM ↑ plasma Cr while CS had no effects and was similar to water. Analytic chemistry analysis showed < 10 mg of creatine and 90 mg creatinine in CS sample. | None reported. |
Kreider et al. [27] | 40 males (18–30 years) | RDBP | 5 days | 5 mL PLA, 5 mL of CS (recommended dose purportedly providing 2.5 g of CrM); 8 × 5 mL/day CS (purportedly providing 20 g/day of CrM); and 4 × 5 g doses of CrM (20 g/day) | CrM increased muscle creatine stores. Consumption of CS at recommended and 8× recommended levels had no effect. | None reported. |
Creatyl-L-Leucine | ||||||
Reddeman et al. [189] | Rats | Open Label | 90 days | Repeated-dose oral gavage toxicity study at doses of 1250, 2500, and 5000 mg/kg body weight per day. | There was no genotoxic activity observed in an in vivo mammalian micronucleus test at concentrations up to the limit dose of 2000 mg/kg body weight per day. The no observed adverse effect level from the 90-day study was determined to be 5000 mg/kg body weight per day, which was the highest dose tested for male and female rats. | None reported. |
da Silva [221] | 24 rats | R | 7 days | Control diet, a diet containing 4.0 g/kg/day CrM, or a diet containing 6.56 g/kg/day CLL | CrM ↑ [creatine] in arterial plasma (+7-fold), portal vein plasma (+10-fold), muscle TCr (+1.63-fold from control, and +1.53-fold from CLL) while tending to increase brain creatine content compared to controls. CLL did not increase blood, muscle, and brain creatine content above rats fed a control diet with values lower than CrM. | None reported. |
Creatinol-O-Phosphate | ||||||
Nicaise et al. [233] | - | - | - | Intramuscular and intravenous injection | COP↑ handgrip performance. | None reported. |
FDA Generally Recognized As Safe (GRAS) | ||||
---|---|---|---|---|
Purported Creatine Source Submitted | FDA Report Number | Submission Year | Intended Dosage | FDA Response |
Creatine Monohydrate (Creapure®) | GRN 931 | 2020 | 1 g creatine (1.12 g creatine monohydrate) as an ingredient in “energy” drinks, protein bars and powders, milk shakes, meal replacement powders and bars, meat analogs, and powdered drink mixes (excluding infant formula. | FDA has no questions at this time. |
Self-Affirmed Generally Recognized As Safe (GRAS) | ||||
Purported Creatine Source Submitted | FDA Report Number | Submission Year | Intended Dosage | FDA Response |
Creatine chelated with Mg (Creatine MagnaPower®) | 2013 | |||
New Dietary Ingredient Notifications (NDIN) * | ||||
Purported Creatine Source Submitted | FDA Report Number | Submission Year | Intended Dosage | FDA Response |
Creatine Pyruvate | RPT28 | 1998 | 5–10 g/day in 2 equal doses | Filed by FDA without substantive comments. |
Creatine Ethylesters [Brand: Cre-Ester™] | RPT154 | 2002 | Maximum daily dose of 30 g | Objected by the FDA. |
Creatine Ethylesters [Brand: Cre-Ester™] | RPT190 | 2002 | 0.5–5.0 g/day | Objected by the FDA. |
Tricreatine Orotate | RTP201 | 2003 | 1–2 g 3 ×/day (3–6 g/day) | Objected by the FDA. |
Creatine ethyl ester HCL [Brand: CE2™] | RTP249 | 2004 | 500 mg–5 g/day | Objected by the FDA. |
Creatine from creatine ethyl ester HCL [Brand: CE2™] | RTP264 | 2004 | 500 mg–3 g/day | Objected by the FDA. |
Beta Creatine | RPT660 | 2010 | 4.5–7.5 g/day creatine 3–6 g/day beta-alanine | Objected by the FDA. |
Creatine Nitrate | RTP696 | 2011 | 1.5 g serving, maximum dose 3 g/day | Objected by the FDA. |
Creatine Nitrate | RPT993 | 2017 | 750 mg per day | Acknowledged with no objections by FDA. |
Creatine acesulfame | RPT1064 | 2018 | 10 g per day | Objected by the FDA. |
Country | Responsible Agency | Primary Regulations/Statutes | Regulatory Status of Creatine |
---|---|---|---|
Australia | Department of Health, Therapeutic Goods Administration (TGA). | Dietary supplements are considered complimentary medicines and regulated under the Therapeutic Goods Act (TGA) of 1989 [241] and 1990 TGA regulations [198]. Medicinal products are categorized as lower risk medicines that can be listed on the Australian Register of Therapeutic Goods (ARTG) [198] while higher risks medicines must be registered with the ARTG [241]. | As of this writing, of the 90,988 products listed in the ARTG database, only 25 products contain creatine. Of these, CrM is the only source of creatine listed as an ingredient. |
Canada | Health Canada [242] | Natural and Non-prescription Health Products Directorate (NNHPD) of Health Canada [242]. The NNHPD maintains a compendium of articles that reviews the safety and efficacy of licensed NHP’s [243]. CrM was assigned a monograph by the NNHPD that overviews research on CrM to substantiate safety and efficacy. Only products containing CrM can benefit from an abbreviated licensing process by referencing the monograph. Applicants using all other creatine forms are required to submit their own evidence of safety and efficacy for review as part of the pre-market licensing process. | As of this writing, 20 compounds purported to contain creatine are included in the NHP Ingredient Database [244] including creatine, creatine-alpha-ketoglutarate, creatine ethyl ester, creatine ethyl ester HCl, creatine gluconate, creatine HCl, creatine hydroxycitrate, creatine monohydrate, creatine nitrate, creatine orotate, creatine phosphate, creatine pyroglutamate, creatine pyruvate, creatine taurinate, dicreatine malate, disodium creatine phosphate, magnesium creatine chelate, polyethylene glycosylated creatine, polyethylene glycosylated creatine HCl, and tricreatine citrate. Creatinol-O-phosphate is listed as a medicinal product in the NHP database [244]. |
China | New Food Safety Law of the People’s Republic of China and the Administrative Permission Law of the People’s Republic of China, CFDA [198]. | Nutritional supplements in China must be orally ingested, have at least one of 22 preventive functions as recognized by the Ministry of Health, and cannot be a curative drug [198]. Imported supplements must be approved by the National Medical Product Administration while foods are supervised by the State Administration for Market Regulation) [198]. | Importers of dietary supplements and foods containing creatine must submit notification materials for review and approval before being allowed to be sold in China. Since CrM and other forms of creatine are produced in China, they would seemingly be legal to consume. However, it is unclear which forms of creatine are allowed to be imported into China. |
European Union (EU) | European Commission Directive on Food Supplements [245,246,247] | The European Food Safety Authority (EFSA) evaluates scientific health claims. Creatine is considered a substance that may be added for specific nutritional purposes in foods for particular nutritional uses (FPNU) [246]. | In 2004, EFSA indicated that the use of creatine in foods for nutritional use was not a matter of concern provided that the source had high purity (99.95%), did not contain impurities, and that dose of up to 3 g/day of supplemental creatine which is similar to the normal daily turnover rate of creatine was unlikely to pose any risk [248]. EFSA substantiated scientific health claims of CrM include: (1) CrM increases physical performance during short-term, high intensity, repeated exercise bouts, endurance capacity, and endurance performance [249], (2) CrM increases attention and improves memory [250], and, (3) CrM (at least 3 g/day) in combination with resistance training and improved muscle strength. All studies cited were performance on pure CrM so the regulatory status of other “forms” of creatine in the EU are less clear. |
Japan | Ministry of Health, Labor and Welfare (MHLW) | Dietary substances in Japan are legally classified as food, food additives or “non-drug” (food). The Consumer Affairs Agency started “Foods with Function Claims” which reviews and approves health claims related to dietary supplements. | CrM is considered a “non-drug” [251] that is allowed to be sold as a food ingredient and additive under the Food Sanitation Law [252]. Health claims of CrM for muscle maintenance with exercise was accepted in 2019. Thus, CrM can be imported, distributed, and produced in Japan. CEE has been included on the “non-drug” list. In order for other forms to be imported, distributed, and/or produced in Japan, safety data and similarity of the proposed form to CrM must be submitted and approved by the MHLW [253]. In addition to CrM, creatine citrate and creatine pyruvate have been approved to be imported into Japan. It is unclear whether other forms of creatine can be imported into Japan and sold as dietary supplements. |
South Korea | Ministry of Food and Drug Safety (MFDS) [254]. | Similar to the U.S., new dietary ingredients must have sufficient safety data including toxicology studies in animals and supporting safety and efficacy data from human clinical trials to support efficacy at the recommended daily doses marketed. | An application to register CrM as a dietary supplement was filed in 2005 and approved by the MFDA for use as a dietary supplement 2008 with an accompanying health claim [255]. Given these requirements, forms of creatine reviewed above that have bioavailability data at recommended doses substantiating efficacy and safety seemingly be eligible for approval while those that do not have that data would likely experience more difficulty obtaining approval to sell their form of creatine in South Korea. |
Strong Evidence | Some Evidence | No Evidence |
---|---|---|
Creatine Monohydrate | Creatine Citrate | 5-Hydroxytryptamine Creatine |
Creatine Pyruvate | Creatine Benzyl Ester | |
Magnesium Creatine Chelate | Creatine Beta-Alaninate | |
Creatine Ethyl Ester | Creatine Carnitine | |
Creatine HCl | Creatine Ethyl Ester Malate | |
Creatine Nitrate | Creatine Ethyl Ester Pyruvate | |
Buffered Creatine Monohydrate | Creatine Fumarate | |
Creatine Gluconate | ||
Creatine Glutamate | ||
Creatine Hydroxycitrate | ||
Creatine Lactate | ||
Creatine Malate | ||
Creatine Maleate | ||
Creatine Methyl Ester HCL | ||
Creatine Monohydrate Dextrose | ||
Creatine Orotate | ||
Creatine Phosphate Lactate | ||
Creatine Pyroglutamate | ||
Creatine Pyruvate Monohydrate | ||
Creatine Serum | ||
Creatine Sulfate Monohydrate | ||
Creatine Taurinate | ||
Creatine Trinitrate | ||
Creatine α-ketoglutarate | ||
Creatine-CoA | ||
Creatinol-0-Phosphate | ||
Creatyl-L-Leucine | ||
Di-Acetyl Creatine Ethyl Ester | ||
Disodium Creatine Phosphate | ||
Methyl-Amino-Creatine | ||
Phospho-Creatine | ||
Polyethylene Glycosylated Creatine |
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Kreider, R.B.; Jäger, R.; Purpura, M. Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. Nutrients 2022, 14, 1035. https://doi.org/10.3390/nu14051035
Kreider RB, Jäger R, Purpura M. Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. Nutrients. 2022; 14(5):1035. https://doi.org/10.3390/nu14051035
Chicago/Turabian StyleKreider, Richard B., Ralf Jäger, and Martin Purpura. 2022. "Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review" Nutrients 14, no. 5: 1035. https://doi.org/10.3390/nu14051035