Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review

In the paper

“Peak concentrations of creatine were significantly higher with CPY (CrM 761.9 ± 107.7, CC 855.3 ± 165.1, CPY 972.2 ± 184.1 µmol/L) while AUC values did not significantly differ among treatments (2384 ± 376.5, 2627 ± 506.8, 2985 ± 540.6 mM/h, respectively).”

What the sources say

• Disputed

  The Results report that peak creatine concentration was significantly higher with creatine pyruvate than with creatine citrate (p = 0.010), but not significantly higher than with creatine monohydrate (p = 0.075). Table 3 reports a significant overall difference in AUC among treatments (ANOVA p = 0.023), contrary to the claim that AUC values did not significantly differ. The quoted concentration values come from the one-hour measurements in Table 2, not the peak-concentration measurements in Table 3. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [63] Harris, 2007, Comparison of new forms of creatine in raising plasma creatine levels, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured

In the paper

“There is also no evidence that supplementation of micronized versions of CrM (i.e., CrM with smaller mesh size particles) are more bioavailable than CrM with normal mesh sized particles [138,139,140] or consuming CrM in effervescent fluid promotes greater creatine retention or performance benefits [22,141].”

What the sources say

• ?Not checked — no full text of the sourcecites [138] Pakulak, A., Candow, D.G., Totosy de Zepetnek, J., Forbes, S.C., and Basta, D. (2021). Effects of Creatine and Caffeine Supplementation During Resistance Training on Body Composition, Strength, Endurance, Rating of Perceived Exertion and Fatigue in Trained Young Adults. J. Diet. Suppl., 1–16. source
• ?Not checked — no full text of the sourcecites [139] Tibirica, 2019, Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets, Fundam. Clin. Pharmacol. source
• ?Could not verify

  The Methods section says the study used micronized creatine monohydrate, but it does not compare its bioavailability with normal-mesh creatine monohydrate. The cited paper therefore does not establish the claim attached to this citation. The separate claim about effervescent fluid is cited to other sources. (LLM, conf=0.76)

  cites [140] Moraes, 2014, Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults, Nutr. J. sourceExperimental — accuracy not yet measured
• Not checked yetcites [22] Greenwood, 2003, Differences in creatine retention among three nutritional formulations of oral creatine supplements, J. Exerc. Physiol. Online
• ?Not checked — no full text of the sourcecites [141] Falk, 2003, Effects of effervescent creatine, ribose, and glutamine supplementation on muscular strength, muscular endurance, and body composition, J. Strength Cond. Res. source

In the paper

“For a dietary source of creatine to be bioavailable, creatine must be: (1) absorbed as creatine into the blood and transported to tissues [2,25]; (2) transported into tissue via tissue-specific creatine transporter genes (e.g., CRT1 or SLC6A8 in muscle) [6,7]; and (3) increase tissue and cellular creatine and PCr content by a physiologically meaningful amount to influence metabolic activity (e.g.,”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Brosnan, 2016, The role of dietary creatine, Amino Acids source
• Supported

  The citation is attached to the first step, absorption into the blood and transport to tissue. The Bioavailability section describes creatine uptake as two steps: uptake into the bloodstream, then uptake into the target tissue. The transporter genes and percentage increases appear in separate clauses and are not attributed to this citation in the supplied sentence. (LLM, conf=0.92)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [6] Wallimann, 2011, The creatine kinase system and pleiotropic effects of creatine, Amino Acids sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [7] Bonilla, D.A., Kreider, R.B., Stout, J.R., Forero, D.A., Kerksick, C.M., Roberts, M.D., and Rawson, E.S. (2021). Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients, 13. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [5] Kreider, R.B., and Stout, J.R. (2021). Creatine in Health and Disease. Nutrients, 13. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [12] Harris, 1992, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation, Clin. Sci. source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [15] Kreider, 2017, International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [20] Green, 1996, Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans, Am. J. Physiol. source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [24] Wax, B., Kerksick, C.M., Jagim, A.R., Mayo, J.J., Lyons, B.C., and Kreider, R.B. (2021). Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations. Nutrients, 13. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [47] Vandenberghe, 1997, Long-term creatine intake is beneficial to muscle performance during resistance training, J. Appl. Physiol. source

In the paper

“The most extensively studied and effective form of creatine found in nutritional supplements that professional organizations recommend for use is creatine monohydrate (CrM) [14,15,17,18].”

What the sources say

• Supported

  The Muscle building supplements section states that creatine monohydrate is the most extensively studied and clinically effective form of creatine for use in nutritional supplements. It also quotes the ISSN position stand endorsing creatine monohydrate as an effective ergogenic supplement and describing conditions for its use by younger athletes. (LLM, conf=0.92)

  cites [14] Kerksick, 2018, ISSN exercise & sports nutrition review update: Research & recommendations, J. Int. Soc. Sports Nutr. source
• Supported

  The ISSN position statement explicitly calls creatine monohydrate the most extensively studied and clinically effective form of creatine for use in nutritional supplements, in terms of muscle uptake and increased high-intensity exercise capacity. Because this is the society’s own position statement, it also supports the claim that a professional organization recommends its use. (LLM, conf=0.94)

  cites [15] Kreider, 2017, International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine, J. Int. Soc. Sports Nutr. source
• ?Not checked — no full text of the sourcecites [17] Thomas, 2016, Position of the Academy of Nutrition and Dietetics, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and Athletic Performance, J. Acad. Nutr. Diet source
• Partly supported

  The 'Supplement Proposed Mechanism of Action Evidence for Efficacy' section identifies creatine monohydrate and gives a recommended dose; the 'Overview' describes performance benefits from creatine loading. Our copy does not establish that monohydrate is the most extensively studied or most effective form relative to other forms, or that multiple professional organizations recommend it. (LLM, conf=0.86)

  cites [18] Maughan, 2018, IOC Consensus Statement: Dietary Supplements and the High-Performance Athlete, Int. J. Sport Nutr. Exerc. Metab. sourceExperimental — accuracy not yet measured

In the paper

“Additionally, while mixing CrM in common juices and beverages with pHs ranging from 2.5–3.5 [61] would enhance solubility, it would also promote the conversion of creatine to creatinine over time [66].”

What the sources say

• Supported

  The citation to this paper is attached to the pH of common juices and beverages, not the claims about creatine solubility or conversion. The Results report mean pH values of 3.48 for juices, 2.99 for fruit drinks, and 3.12 for sodas, supporting the cited approximate pH range; the full measured ranges are wider. (LLM, conf=0.90)

  cites [61] Reddy, 2016, The pH of beverages in the United States, J. Am. Dent. Assoc. source
• Not checked yetcites [66] Howard, A.N., and Harris, R. (1999). Compositions Containing Creatine and Aloe Vera Extract. (No. 6,168,802), U.S. Patent.

In the paper

“The solubility of creatine in water increases linearly with increasing temperature. In this regard, about 6 g of creatine dissolves in one liter of water at 4 °C (39.2 °F) while 14 g/L are dissolved at 20 °C (68 °F), 34 g/L are dissolved at 50 °C (122 °F); and, 45 g/L are dissolved at 60 °C (140 °F) [25].”

What the sources say

• Supported

  The Solubility section states that creatine’s solubility increases with temperature, describes the relationship as almost linear, and gives all four temperatures and amounts exactly as cited. The claim’s ‘linearly’ is a slight simplification of ‘almost linear.’ (LLM, conf=0.94)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids source

In the paper

“Since stomach acid is generally less than 2.5, less than 1% of CrM is degraded to creatinine during digestion and 99% of creatine is taken up by tissue or excreted in urine after ingestion [12,25,58,59].”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Harris, 1992, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation, Clin. Sci. source
• Partly supported

  The Stability section (page unavailable) says pH below 2.5 can prevent creatine degradation and that conversion to creatinine in the gastrointestinal tract is minimal. The Bioavailability section (page unavailable) says intestinal absorption of creatine monohydrate is close to 100% and discusses tissue uptake and urinary excretion. It does not give the claimed thresholds of less than 1% degraded or 99% taken up by tissue or excreted, nor state that stomach acid is generally below pH 2.5. (LLM, conf=0.88)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] Persky, 2003, Pharmacokinetics of the dietary supplement creatine, Clin. Pharmacokinet. source
• Partly supported

  The Discussion estimates that at stomach pH near 2, about 1% of a 2 g dose converts to creatinine within the first hour, and describes gastrointestinal conversion overall as negligible. It also says creatine appearing in blood is taken up by tissues or eliminated in urine. But it does not establish less than 1% conversion throughout digestion: it says a larger proportion may degrade during the longer intestinal transit. Page numbers were not provided in our copy. (LLM, conf=0.88)

  cites [59] Deldicque, 2008, Kinetics of creatine ingested as a food ingredient, Eur. J. Appl. Physiol. sourceExperimental — accuracy not yet measured

In the paper

“creatinine levels were also significantly increased throughout training with MgCr-C (0.83 to 1.87 mmol/L) compared to placebo (0.92 to 0.82 mmol/L), which is higher than reported in other long-term CrM studies during training in hot and humid environments that administered 5–10 g/day of CrM for 21 months in well-trained athletes [144].”

What the sources say

• Partly supported

  The Results report that creatinine rose significantly from 0.83 at baseline to 1.87 after four weeks of MgCr-C, while it did not change significantly in the placebo group. The increase did not continue throughout training: creatinine fell to 1.38 by week 16. The Results give the placebo endpoint as 0.85, not 0.82, and the Discussion gives the creatinine unit as mg/dL, not mmol/L. Our copy does not support the claimed comparison with CrM studies conducted in hot and humid environments. (LLM, conf=0.91)

  cites [191] Zajac, A., Golas, A., Chycki, J., Halz, M., and Michalczyk, M.M. (2020). The Effects of Long-Term Magnesium Creatine Chelate Supplementation on Repeated Sprint Ability (RAST) in Elite Soccer Players. Nutrients, 12. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [144] Greenwood, 2003, Creatine supplementation during college football training does not increase the incidence of cramping or injury, Mol. Cell. Biochem. source

In the paper

“This provides a powder containing 87.9% creatine that readily dissociates into creatine and water upon oral ingestion.”

What the sources say

• Partly supported

  The Physio-chemical properties section (page unavailable) states that creatine monohydrate contains 87.9% creatine and has one molecule of water of crystallization per molecule of creatine. The Solubility section says it dissolves in water, but our copy does not establish that it readily dissociates into creatine and water upon oral ingestion. (LLM, conf=0.84)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids sourceExperimental — accuracy not yet measured

In the paper

“Moreover, that most purported “forms” of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy.”

What the sources say

• Supported

  The Summary (page unavailable) says the efficacy and safety of most newer creatine forms were not well established. The Regulatory status > Analysis section (page unavailable) describes newer forms as typically more expensive and says basic safety data are lacking; the Bioavailability section also identifies one form with less efficient bioavailability than creatine monohydrate. Together these support the claim’s qualified, either/or characterization. (LLM, conf=0.90)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids source

In the paper

“Research has clearly shown that CrM is not degraded into creatinine during normal digestion, it is nearly 100% bioavailable [12,25,58,59], and markedly increases blood and tissue creatine content.”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Harris, 1992, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation, Clin. Sci. source
• Supported

  The Abstract says creatine monohydrate is not degraded during normal digestion, and the Bioavailability section says its intestinal absorption is close to 100%. The Bioavailability section discusses plasma creatine after ingestion, while the Abstract reports increases of approximately 15–40% in muscle creatine and phosphocreatine. Our copy provides no page numbers for these passages. (LLM, conf=0.91)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids source
• ?Not checked — no full text of the sourcecites [58] Persky, 2003, Pharmacokinetics of the dietary supplement creatine, Clin. Pharmacokinet. source
• Supported

  The Protocol identifies the supplement as creatine monohydrate. The Discussion says conversion to creatinine during gastrointestinal transit is negligible and arterial bioavailability likely nearly 100%; the Plasma concentrations and Erythrocyte concentrations sections report substantial increases after supplementation. The paper qualifies bioavailability as arterial, rather than venous. (LLM, conf=0.91)

  cites [59] Deldicque, 2008, Kinetics of creatine ingested as a food ingredient, Eur. J. Appl. Physiol. source

In the paper

“CrM supplementation has been reported to improve acute exercise performance particularly in intermittent high-intensity exercise bouts as well as enhance training adaptations in adolescents [78,79,80,81,82], young adults [29,55,83,84,85,86,87,88,89,90,91,92], and older individuals [8,77,93,94,95,96,97,98,99,100,101].”

What the sources say

• Not checked yetcites [78] Cornish, 2006, The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players, J. Sports Med. Phys. Fit.
• ?Not checked — no full text of the sourcecites [79] Dawson, 2002, Effects of 4 weeks of creatine supplementation in junior swimmers on freestyle sprint and swim bench performance, J. Strength Cond. Res. source
• ?Not checked — no full text of the sourcecites [80] Grindstaff, 1997, Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers, Int. J. Sport Nutr. source
• ?Not checked — no full text of the sourcecites [81] Juhasz, 2009, Creatine supplementation improves the anaerobic performance of elite junior fin swimmers, Acta Physiol. Hung. source
• Not checked yetcites [82] Silva, 2007, Effect of creatine on swimming velocity, body composition and hydrodynamic variables, J. Sports Med. Phys. Fit.
• Partly supported

  The Methods describe young adult men undertaking resistance training, and the Results report increased lean mass in the CrM group. However, the Results (Study 2: chronic supplementation) say only the high-dose creatine nitrate group improved bench-press outcomes relative to placebo, and there were no significant treatment effects in the intermittent sprint test. This paper therefore does not support the claimed CrM performance benefit over placebo, particularly for intermittent high-intensity exercise; it also did not study adolescents or older individuals. (LLM, conf=0.84)

  cites [29] Galvan, 2016, Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [55] Kreider, 1998, Effects of creatine supplementation on body composition, strength, and sprint performance, Med. Sci. Sports Exerc. source
• ?Not checked — no full text of the sourcecites [83] Stone, 1999, Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players, Int. J. Sport Nutr. source
• ?Not checked — no full text of the sourcecites [84] Bemben, 2001, Creatine supplementation during resistance training in college football athletes, Med. Sci. Sports Exerc. source
• ?Not checked — no full text of the sourcecites [85] Hoffman, 2006, Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes, Int. J. Sport Nutr. Exerc. Metab. source

In the paper

“Creatine monohydrate was the first source of creatine marketed as a dietary supplement and remains the most common source of creatine found in dietary supplements [25].”

What the sources say

• Supported

  The Introduction says creatine monohydrate was first marketed in the early 1990s, that alternate forms entered the marketplace later, and that it is the form most commonly found in dietary supplement products. The Regulatory status > USA section likewise dates its US market appearance to 1993 and describes alternate forms entering afterward. (LLM, conf=0.92)

  cites [25] Jager, 2011, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine, Amino Acids source

In the paper

“Zajac et al. [191] reported that 5.5 g/day of MgCr-C supplementation during 16 weeks of soccer training improved repeated sprint ability performance compared to placebo.”

• Also stated in: § 9.2. Magnesium Creatine Chelate · plain

  “this study did not compare the effects of consuming MgCr-C to CrM, and performance changes were consistent with other studies conducted on CrM supplementation.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [191] Zajac, A., Golas, A., Chycki, J., Halz, M., and Michalczyk, M.M. (2020). The Effects of Long-Term Magnesium Creatine Chelate Supplementation on Repeated Sprint Ability (RAST) in Elite Soccer Players. Nutrients, 12. source

In the paper

“Some creatine salts are less stable when compared to CrM. For example, storage of tri-creatine citrate at 40 °C (104 °F) for 28 days results in formation of 770 ppm of creatinine compared to no measurable amount with CrM powder [63].”

What the sources say

• ?Could not verify

  The Methods (Supplementation Protocol; page not provided) say that all three creatine products contained less than 100 ppm creatinine, but give no storage conditions or stability comparison. Searches for 770 ppm, 40 °C, 28 days, and storage stability found no passage supporting the claimed result. (LLM, conf=0.76)

  cites [63] Harris, 2007, Comparison of new forms of creatine in raising plasma creatine levels, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured

In the paper

“The researchers found that peak serum creatine increased to a greater degree with CrN + CrM supplementation (CrM 118.6 ± 12.9, CrN 163.8 ± 12.9; CrN + CrM 183.7 ± 15.5 µmol/L) while muscle creatine increased to a greater degree with CrN ingestion (CrM 2.1%, CrN 8.0%, CrN + CrM 9.6%).”

What the sources say

• Partly supported

  The Results (Single-dose experiment) report the quoted peak serum creatine values, and the Results (5-day intervention) report the quoted muscle-creatine increases. But the combination tested was creatine nitrate plus creatinine (CN-CRN), not creatine nitrate plus creatine monohydrate (CrN + CrM). The greatest muscle-creatine increase was also with CN-CRN (9.6%), rather than creatine nitrate alone (8.0%). (LLM, conf=0.90)

  cites [209] Ostojic, 2019, Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men, Food Sci. Nutr. sourceExperimental — accuracy not yet measured

In the paper

“First, this is only a theoretical modeling study. The researchers did not directly compare Cr-HCl to CrM intake on plasma or tissue creatine content.”

What the sources say

• Partly supported

  The Methods (§2.2) describe an experimental rat study that administered creatine monohydrate and measured plasma and tissue samples, so the paper was not only a theoretical modeling study. The Results (§3.4) show that the creatine hydrochloride versus monohydrate comparison was simulated rather than directly tested, supporting the second sentence. (LLM, conf=0.90)

  cites [199] Alraddadi, E.A., Lillico, R., Vennerstrom, J.L., Lakowski, T.M., and Miller, D.W. (2018). Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth. Pharmaceutics, 10. sourceExperimental — accuracy not yet measured

In the paper

“In a double-blind manner, 36 resistance-trained participants were randomly assigned to ingest 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).”

What the sources say

• Supported

  The Abstract Methods states that 36 resistance-trained participants were randomly assigned in a double-blind study to CrM, recommended-dose KA (the buffered creatine), or KA at CrM-equivalent doses. The Experimental design section confirms the three groups and their dosing schedules. The Results clarify that 36 participants completed the study after 41 were initially recruited. (LLM, conf=0.94)

  cites [28] Jagim, 2012, 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. source

In the paper

“Recommended dosages generally range between 300–600 mg ingested 1–2 h prior to exercise [204,205,206].”

What the sources say

• Partly supported

  The Introduction (page unavailable) recommends at least ~6 mmol of nitrate, a dose within the claimed 300–600 mg range. But it specifies ingestion 2–3 hours before exercise, not 1–2 hours, and does not recommend 300–600 mg as a general dosage range. (LLM, conf=0.88)

  cites [204] Tan, R., Cano, L., Lago-Rodríguez, Á., and Domínguez, R. (2022). The Effects of Dietary Nitrate Supplementation on Explosive Exercise Performance: A Systematic Review. Int. J. Environ. Res. Public Health, 19. sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results (Subgroup analyses; page unavailable) say there were insufficient data to analyze effects by daily nitrate dose. The Discussion’s athlete perspective describes a personal protocol of 500 ml of beetroot juice 2–3 hours before exercise, not a recommendation of 300–600 mg 1–2 hours beforehand. Searches for those dose and timing ranges found no supporting passage in our copy. (LLM, conf=0.76)

  cites [205] Gao, 2021, The effects of dietary nitrate supplementation on endurance exercise performance and cardiorespiratory measures in healthy adults: A systematic review and meta-analysis, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured
• Partly supported

  Section 2.1 gives a likely effective dose of 5–9 mmol (310–560 mg), broadly consistent with the claimed 300–600 mg range. It recommends taking an acute dose 2–3 hours before exercise, not 1–2 hours, and says effects are not statistically significant when nitrate is taken less than 2 hours beforehand. No page number is provided in our copy. (LLM, conf=0.89)

  cites [206] Macuh, M., and Knap, B. (2021). Effects of Nitrate Supplementation on Exercise Performance in Humans: A Narrative Review. Nutrients, 13. sourceExperimental — accuracy not yet measured

In the paper

“These findings suggest that CrN can be a bioavailable source of creatine proportional to the amount of creatine delivered during the loading phase (i.e., 54.6 g for CrN-High versus 73.8 g for CrM), but not more bioavailable than CrM when equivalent doses are ingested.”

What the sources say

• Partly supported

  The Results (Study 2: chronic supplementation) show that CrN-High increased muscle creatine after seven days, supporting CrN as a source of creatine; the increase was smaller than with CrM. However, the Methods (Testing methodology) describe equal masses of the two supplements, not equivalent amounts of creatine, so the study does not directly establish their relative bioavailability at equivalent creatine doses. The cited 54.6 g and 73.8 g figures are not stated in the passages of our copy found for this claim. (LLM, conf=0.83)

  cites [29] Galvan, 2016, Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance, J. Int. Soc. Sports Nutr. sourceExperimental — accuracy not yet measured

In the paper

“Results revealed that 7 days of creatine loading (12 g/day of CrM and CrN) significantly increased muscle creatine content in the CrM (7.1 mmol/kg DW) and CrN-High (4.6 mmol/kg DW). However, no difference was seen compared to placebo was observed when ingesting 4 × 1.5 g/day of CrN for 7 days or after 28 days of taking 1.5 or 3 g/day of CrN.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [29] Galvan, 2016, Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance, J. Int. Soc. Sports Nutr. source

In the paper

“Dalton et al. [36] reported that ingestion of 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.”

What the sources say

• Supported

  The Conclusion (section 5.4) reports that 3 g and 6 g doses did not alter hemodynamic responses to a postural challenge or significantly alter fasting clinical blood profiles in the healthy men and women studied. The Performance discussion (section 5.2) reports improvements in some high-intensity exercise measures after short-term supplementation, rather than an impairment. (LLM, conf=0.92)

  cites [36] Dalton, R.L., Sowinski, R.J., Grubic, T.J., Collins, P.B., Coletta, A.M., Reyes, A.G., Sanchez, B., Koozehchian, M., Jung, Y.P., and Rasmussen, C. (2017). Hematological and Hemodynamic Responses to Acute and Short-Term Creatine Nitrate Supplementation. Nutrients, 9. source

In the paper

“Gufford et al. [194] reported that CEE converted to creatinine in a linear manner as pH levels dropped below 8.0 and that CEE was mostly stable at a pH of 1.0.”

What the sources say

• Partly supported

  The Results (pH-Dependent CEE Stability) report a linear relationship between pH and the logarithm of the conversion rate constant only from pH 2.5 to 8.0, not at all pH levels below 8.0. The same section says CEE was most stable at pH 1.0, where it primarily hydrolyzed to creatine rather than cyclizing to creatinine. (LLM, conf=0.88)

  cites [194] Gufford, 2013, pH-dependent stability of creatine ethyl ester: Relevance to oral absorption, J. Diet. Suppl. sourceExperimental — accuracy not yet measured

In the paper

“As shown in Figure 16, rats fed CrM experienced significant increases in creatine concentrations in arterial plasma (+7-fold), portal vein plasma (+10-fold), muscle creatine content (+1.63-fold from control, and +1.53-fold from CLL) while tending to increase brain creatine content (p = 0.052) compared to controls.”

What the sources say

• Supported

  The Results report approximately 7-fold higher creatine in abdominal-aorta plasma and 10-fold higher creatine in portal-vein plasma in CrM-fed rats (Figure 4), plus 1.63-fold higher quadriceps creatine than controls and 1.53-fold higher than CLL-fed rats (Figure 5). They describe the brain difference as a trend, not a significant increase (adjusted P = 0.052); the Discussion explicitly calls the plasma and muscle increases significant. (LLM, conf=0.94)

  cites [221] da Silva, R.P. (2022). The Dietary Supplement Creatyl-l-Leucine Does Not Bioaccumulate in Muscle, Brain or Plasma and Is Not a Significant Bioavailable Source of Creatine. Nutrients, 14. source

In the paper

“The researcher concluded that provision of large doses of CLL to rats did not increase creatine bioaccumulation indicating that CLL is poorly absorbed by the intestine and is not a bioavailable source of creatine.”

What the sources say

• Supported

  The Discussion explicitly concludes that rats given large dietary doses of CLL did not show increased creatine concentrations in plasma, muscle, or brain, and that CLL was poorly absorbed by the intestine and was not a bioavailable source of creatine. It also notes that the assay cannot establish that no CLL was absorbed, a distinction the citing sentence preserves by saying “poorly absorbed.” (LLM, conf=0.95)

  cites [221] da Silva, R.P. (2022). The Dietary Supplement Creatyl-l-Leucine Does Not Bioaccumulate in Muscle, Brain or Plasma and Is Not a Significant Bioavailable Source of Creatine. Nutrients, 14. source

In the paper

“While this study indicates that higher than recommended doses of CEE can positively affect training adaptations, this study did not assess the effects of CEE supplementation on blood or muscle creatine content or compare the efficacy of CEE supplementation to CrM.”

What the sources say

• Supported

  The Introduction recommends 0.5–5 g of CEE daily; the Supplementation protocol used 20 g daily for five loading days, and the Conclusions report positive effects on body weight and leg strength in underweight non-athlete men. The Blood sampling section lists hormone assays but no creatine assay, and the protocol compares CEE with placebo, not creatine monohydrate. The higher-than-recommended dose applies to the loading phase, not the 5 g maintenance phase. (LLM, conf=0.91)

  cites [197] Arazi, 2019, Effect of creatine ethyl ester supplementation and resistance training on hormonal changes, body composition and muscle strength in underweight non-athlete men, Biomed. Hum. Kinet. source

In the paper

“while CEE supplementation promoted a significant increase in muscle total creatine content after 27 days of supplementation compared to those ingesting a placebo, those taking CrM observed significantly greater increases compared to the placebo and CEE groups (Figure 10C).”

What the sources say

• Partly supported

  The Results (Muscle creatine, Figure 2; page not provided) report higher total muscle creatine in both CEE and CRT than in placebo, and an increase in CEE at day 27. The Discussion (Serum and Muscle Creatine; page not provided) explicitly says CRT was not significantly greater than CEE in total muscle creatine, contrary to the claim's final comparison. (LLM, conf=0.90)

  cites [27] Spillane, 2009, 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. sourceExperimental — accuracy not yet measured

In the paper

“In the United States (US), congress enacted the Dietary Supplement Health and Education Act (DSHEA) of 1994 that placed dietary supplements in a special category of foods under the jurisdiction of the FDA.”

What the sources say

• Supported

  The Background section, under “Definition and regulation of dietary supplements,” says Congress passed DSHEA in 1994, placing supplements in a special category of foods. The same section states that the FDA regulates the dietary supplement industry as a result of DSHEA. (LLM, conf=0.95)

  cites [14] Kerksick, 2018, ISSN exercise & sports nutrition review update: Research & recommendations, J. Int. Soc. Sports Nutr. source
• Not checked yetcites [234] (2020, October 26). New Dietary Ingredients in Dietary Supplements-Background for Industry, Available online: https://www.fda.gov/food/new-dietary-ingredients-ndi-notification-process/new-dietary-ingredients-dietary-supplements-background-industry.

In the paper

“Phosphate loading has been found to increase myocardial ejection fraction during exercise and maximal aerobic capacity [231,232] and is considered an ergogenic aid for endurance athletes [14].”

What the sources say

• ?Not checked — no full text of the sourcecites [231] Kreider, 1990, Effects of phosphate loading on oxygen uptake, ventilatory anaerobic threshold, and run performance, Med. Sci. Sports Exerc.
• ?Not checked — no full text of the sourcecites [232] Kreider, 1992, Effects of phosphate loading on metabolic and myocardial responses to maximal and endurance exercise, Int. J. Sport Nutr. source
• Supported

  The citation to this source is attached to the characterization of phosphate loading as an ergogenic aid for endurance athletes, not to the preceding ejection-fraction finding. The Performance enhancement supplements section describes phosphate’s proposed ergogenic action and reports improvements in aerobic capacity and other performance measures, while noting mixed results across studies. (LLM, conf=0.88)

  cites [14] Kerksick, 2018, ISSN exercise & sports nutrition review update: Research & recommendations, J. Int. Soc. Sports Nutr. source

In the paper

“As seen in Figure 10A, fasting serum creatine levels significantly increased only in the CrM group.”

• Also stated in: § 9.3. Creatine Ethyl Ester · plain

  “CEE supplementation had no effect on fasting serum creatine levels compared to a placebo.”

What the sources say

• Supported

  The Results (Serum creatine; no page given) report significant serum creatine increases at days 6, 27, and 48 only for the creatine monohydrate (CRT) group. The Methods (Muscle biopsies and venous blood sampling; no page given) state that participants fasted for eight hours before each blood draw. (LLM, conf=0.91)

  cites [27] Spillane, 2009, 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. source

In the paper

“There was some evidence that ingesting higher doses of CrM-Alk increased muscle creatine content after 28 days (6.2 ± 29.2; 27.3 ± 49.1%, respectively), but these values were less than observed with CrM (23.5 ± 49.0; 50.4 ± 44.8%, respectively).”

What the sources say

• Supported

  Table 6 (Results, Muscle creatine analysis) reports the quoted percentage changes for the higher-dose buffered creatine group (KA-H) and CrM: KA-H's mean changes were smaller at both day 7 and day 28. The first value in each pair is from day 7, not day 28. The Results also report no significant group-by-time interaction, so the comparison describes the observed means rather than a statistically established difference between groups. (LLM, conf=0.92)

  cites [28] Jagim, 2012, 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. source

In the paper

“A number of studies have indicated that dietary nitrates, typically ingested in the form of beet root juice or nitrate powder, can improve endurance [203] and explosive exercise capacity [204].”

What the sources say

• Supported

  The Results and Conclusions report that dietary nitrate supplementation can improve time-trial performance, particularly in less-trained athletes. The Discussion (§4.3) identifies beetroot juice and encapsulated potassium nitrate among the forms studied. This source is attached to the endurance claim [203]; the separate explosive-exercise claim is cited to [204]. (LLM, conf=0.90)

  cites [203] Hlinský, T., Kumstát, M., and Vajda, P. (2020). Effects of Dietary Nitrates on Time Trial Performance in Athletes with Different Training Status: Systematic Review. Nutrients, 12. source
• Supported

  Citation [204] is attached to the explosive-exercise claim, not the endurance claim cited to [203]. The Discussion reports that dietary nitrate has the potential to improve sprint-type and resistance-type explosive performance; the Study Characteristics section identifies beetroot juice as the nitrate source in all but one reviewed study, which used potassium nitrate salts. (LLM, conf=0.91)

  cites [204] Tan, R., Cano, L., Lago-Rodríguez, Á., and Domínguez, R. (2022). The Effects of Dietary Nitrate Supplementation on Explosive Exercise Performance: A Systematic Review. Int. J. Environ. Res. Public Health, 19. source

In the paper

“Results revealed that the plasma creatine AUC over a 5 h period for CrM (5634.4 ± 1949.8 μmol/L) was significantly greater than the placebo (1012.4 ± 1882.2 μmol/L), CrN-Low (2342.0 ± 3133.3 μmol/L, p = 0.004), and CrN-High (1761.7 ± 3408.8 μmol/L, p = 0.007) treatments with no differences seen between the CrN dosages.”

What the sources say

• Supported

  The Results for Study 1 (Plasma creatine and nitrate) give the quoted AUC values and report that CrM was significantly greater than placebo, CrN-Low, and CrN-High. The same passage reports no significant difference between the CrN dosages, and the Fig. 2 caption specifies that AUC was measured over 5 hours post-ingestion. (LLM, conf=0.95)

  cites [29] Galvan, 2016, Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance, J. Int. Soc. Sports Nutr. source

In the paper

“Given the health benefits of creatine, availability of ineffective sources of creatine or recommendations to take less creatine than needed to increase creatine stores in the muscle and/or brain can limit the benefits theses populations may derive from creatine supplementation [5].”

What the sources say

• Partly supported

  Section 3 (Metabolic Role; page unavailable) gives doses used to increase muscle creatine and notes that some clinical populations need higher doses to increase brain creatine. Sections 4 and 6.1 describe potential health benefits, but the copy does not establish that ineffective creatine sources are available or directly assess whether such sources limit those benefits. (LLM, conf=0.84)

  cites [5] Kreider, R.B., and Stout, J.R. (2021). Creatine in Health and Disease. Nutrients, 13. sourceExperimental — accuracy not yet measured

In the paper

“To date, we are unaware of any study that has evaluated the effects of CC or CPY on muscle or brain creatine content.”

In the paper

“Thus, there is substantial evidence to support the safety and efficacy of CrM supplementation (see Table 2).”

• Also stated in: § Creatine Monohydrate · boosted

  “CrM is classified as having strong evidence from pharmacokinetic and tissue bioavailability studies, numerous randomized and controlled clinical trials, and a long-history of safety assessed in clinical trials and historical widespread use supporting bioavailability, efficacy, and safety.”

In the paper

“Since MgCr-C contains about 84.4% of creatine by molecular weight (see Table 1), it could theoretically serve as a good source of creatine if creatine easily dissociates from MgCr-C and equimolar amounts of creatine were consumed compared to CrM.”

In the paper

“Results revealed that CrM and MgCr-C were both effective in increasing performance with no differences observed between types of creatine ingested.”

What the sources say

• ?Not checked — no full text of the sourcecites [190] Selsby, 2004, Mg2+-creatine chelate and a low-dose creatine supplementation regimen improve exercise performance, J. Strength Cond. Res. source

In the paper

“Therefore, there are no studies indicating that CC is more bioavailable, more effective, or a safer source of creatine than CrM. Given this, CC is categorized as having limited evidence to support bioavailability, efficacy, and safety.”

In the paper

“Results revealed that body water increased with MgCr-C, but not CrM while torque and power increased similarly with CrM and MgCr-C.”

What the sources say

• ?Not checked — no full text of the sourcecites [189] Brilla, 2003, Magnesium-creatine supplementation effects on body water, Metabolism source

In the paper

“We are aware of no data showing that MgCr-C increases blood creatine levels or promotes greater creatine retention in skeletal muscle. Thus, there are no data supporting that MgCr-C is more bioavailable to tissue than CrM.”

In the paper

“Consequently, there is no data showing that MgCr-C increases blood or muscle creatine and there is only limited data showing potential ergogenic effect. There is also no evidence that MgCr-C is more bioavailable, efficacious, and/or a safer source of creatine than CrM.”

In the paper

“As of this writing, no PubMed indexed articles have been published on Cr-HCl and muscle creatine retention or performance. However, several articles have been published in non-indexed journals from Brazil that have been cited in marketing materials.”

In the paper

“gains in fat-free mass were greatest in the CrM group (+1.7 kg), but supposedly not significantly different than observed with 5 g/day of Cr-HCL (+1.6 kg) that were reported to be significantly different than controls (+1.1 kg) and those ingesting 1.5 g/day of Cr-HCl (+1.1 kg).”

What the sources say

• Not checked yetcites [65] Avelar, 2015, Creatine HCl and Creatine Monohydrate Improve Strength but Only Creatine HCl Induced Changes on Body Composition in Recreational Weightlifters, Food Nutr. Sci.

In the paper

“CrM was assessed at a saturation pH of 8.6 while Cr-HCL was measured at a saturation pH of 0.3.”

What the sources say

• ?Not checked — no full text of the sourcecites [179] Gufford, 2010, Physicochemical characterization of creatine N-methylguanidinium salts, J. Diet. Suppl. source

In the paper

“there is no evidence that ingesting recommended doses of CEE is effective or that ingesting typical CrM loading, and maintenance doses of CEE is more effective than CrM.”

In the paper

“there is no evidence that Cr-HCl is absorbed more effectively than CrM in humans; Cr-HCl promotes greater muscle creatine retention than CrM at equivalent doses; or, that lower doses of Cr-HCl are as effective as standard supplementation protocols with CrM.”

In the paper

“No alternative form of creatine has shown superior bioavailability, efficacy or safety compared to CrM.”

• Also stated in: § 12. Summary · plain

  “However, there is no evidence that other “forms” of creatine are more bioavailable, effective, or safer forms of creatine compared to CrM.”

In the paper

“Creatine monohydrate can be legally sold throughout the world although some countries limit the amount to of CrM that can be included per dose (e.g., no more than 3–5 g/serving).”

In the paper

“For example, studies published in 2003 clearly showed that creatine serum was not a bioavailable source of creatine, yet it continues to be sold as a creatine-containing product.”

In the paper

“The bioavailability, efficacy, safety, and regulatory status of other purported sources of creatine are less clear, with only a few having some data supporting efficacy compared to placebo (see Table 7).”

In the paper

“While alternative forms of creatine are unlikely to pose a health risk, they are typically more expensive than CrM.”

In the paper

“Since our last review in 2011, more data is available about several forms of creatine and several now have data providing some support as to efficacy and safety while others do not.”

In the paper

“Alternatives to CrM continue to be prevalent in the marketplace, including several that do not appear to meet regulatory requirements in several countries.”

In the paper

“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.”

In the paper

“CrM remains the only source of creatine that has substantial evidence of bioavailability, efficacy and safety and is considered GRAS by the U.S. FDA, is approved for use with accompanying health claims in the EU, has been extensively reviewed and approved by Health Canada, and is approved to be sold in major global markets.”

In the paper

“Of these, the FDA initially rejected some of the IND notification applications, yet the forms were sold for years before finally submitting an acceptable IND notification application or Self-Affirming GRAS.”

In the paper

“To do so, the creatine salt must deliver physiologically effective doses of creatine (i.e., 3–5 g per serving) to the blood and tissue in an equivalent manner as CrM to be comparatively effective.”

In the paper

“Thus, there is consensus among professional organizations that CrM is an effective nutritional ergogenic aid that may benefit athletes involved in numerous sports and individuals initiating exercise training to promote health and fitness.”

In the paper

“One of the limitations in terms of developing consumer products containing CrM is that CrM powder is not highly soluble. For example, when mixing CrM in solution, some CrM residue remains at the bottom of the glass requiring consumers to add more fluid, swirl, and quickly ingest to ensure they consumed all the creatine.”

In the paper

“These studies indicate that CPY can serve as effective source of creatine to increase blood creatine content and a few short-term studies suggest there may be some ergogenic values.”

In the paper

“This paper was conducted as a systematic review of the literature related to sources of creatine marketed as ingredients for dietary supplements or found in dietary supplements, food products, and/or beverages marketed as containing creatine.”

In the paper

“In support of this contention, classic experiments by Harris et al. [12] indicated that a dose of orally ingested creatine should ideally increase plasma creatine levels to greater than 500 µmol/L (75 µg/mL) to optimize tissue uptake.”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Harris, 1992, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation, Clin. Sci. source

In the paper

“However, ingestion of one oral dose of 5 g of CrM (equivalent to about 1.1 kg of uncooked beef) resulted in plasma creatine levels of about 800 µmol/L (120 µg/mL) after 1 h of ingestion. It sustained plasma creatine above 200 µmol/L (30 µg/mL) for over 4–5 h (see Figure 2A).”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Harris, 1992, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation, Clin. Sci. source

In the paper

“While these studies provide evidence that CC can serve as a viable source of creatine by increasing blood creatine level in a similar manner as CrM and there is some data supporting the ergogenic benefit compared to placebo”

In the paper

“In this regard, CrM contains 87.9% creatine whereas creatine citrate (40.6%), di-creatine citrate (57.7%), creatine pyruvate (59.8%), and creatine HCl (78.2%) contain less creatine by weight compared to CrM.”

In the paper

“Co-ingesting CrM with carbohydrates [20,21,22] and carbohydrate and protein [23] promotes more consistent and greater creatine retention.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Green, 1996, Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans, Am. J. Physiol. source
• ?Not checked — no full text of the sourcecites [21] Green, 1996, Carbohydrate ingestion augments creatine retention during creatine feeding in humans, Acta Physiol. Scand. source
• Not checked yetcites [22] Greenwood, 2003, Differences in creatine retention among three nutritional formulations of oral creatine supplements, J. Exerc. Physiol. Online
• ?Not checked — no full text of the sourcecites [23] Steenge, 2000, Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans, J. Appl. Physiol. source

In the paper

“Purported sources of creatine that increase blood levels of creatine but do not increase tissue levels of creatine in physiologically effective amounts (i.e., 20–40% in muscle and 10–20% in brain) are not bioavailable sources of creatine.”

In the paper

“Despite this clear scientific evidence, guidance from professional organizations, and regulatory challenges of selling other forms of creatine in the global marketplace, companies continue to market “new forms” of creatine that are purportedly more stable, bioavailable, and/or effective than CrM.”

In the paper

“some of the creatine in CEE converts to creatinine during digestion and therefore it is less bioavailable than CrM.”

In the paper

“(2) the optimal single dose of CrM to increase plasma creatine levels is 5 g, but that ingesting 2–3 g will increase plasma creatine to sufficient levels to promote creatine uptake to tissue;”

In the paper

“(1) consuming 4 × 5 g of CrM per day for 6-days (i.e., creatine loading strategy) significantly increased muscle free creatine content by 33% and returned to baseline within 4-weeks after supplementation;”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Hultman, 1996, Muscle creatine loading in men, J. Appl. Physiol. source

In the paper

“Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.”

In the paper

“Ultimately, the source of creatine must be transported into tissues by creatine-specific transporters and increase tissue levels of creatine in physiologically significant amounts to affect creatine-related metabolism (i.e., 20–40%).”

In the paper

“Therefore, it is classified in the no evidence to support category, and there is no evidence that CS outperforms CrM.”

In the paper

“These reports provide additional data showing CLL is not degraded into creatine upon oral ingestion [222,223,226], CLL does not increase blood creatine content [222,223,226], and CLL does not increase muscle [224,225] or brain creatine content [224] even when administered at doses much higher than found in marketed products containing CLL in humans [222,223,224,225,226].”

What the sources say

• Not checked yetcites [222] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-46. C.D. Cal. Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [223] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-53. C.D. Cal. Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [226] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-133 (C.D. Cal.). Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [224] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-50 (C.D. Cal.). Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [225] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-51. (C.D. Cal.). Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.

In the paper

“Thus, available evidence indicates that CLL is not creatine, CLL is not a bioavailable source of creatine, and CLL is not “super creatine” compared to CrM.”

In the paper

“Consequently, this study shows that CS does not contain creatine and has no bioavailability in the blood [38].”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Harris, 2004, The creatine content of Creatine Serum and the change in the plasma concentration with ingestion of a single dose, J. Sports Sci. source

In the paper

“As can be seen, there are limited published data on these purported sources of creatine, and the available evidence indicates that they are not bioavailable sources of creatine.”

In the paper

“These findings directly refute claims that CEE is more bioavailable source of creatine than CrM and that CEE promotes greater training adaptations than CrM.”

In the paper

“Since salts are relatively weak bonds, it is likely that these creatine salts would increase creatine in the blood at equimolar doses that are generally about 1.3–1.6 times greater than CrM.”

In the paper

“However, we are not aware of any pharmacokinetic or exercise related studies to test this hypothesis and benefits would seemingly be similar and more effectively dosed by co-ingestion of CrM and vitamin C.”

In the paper

“Creatinol in the form of COP is not creatine, nor was it intended to increase muscle creatine content.”

In the paper

“The researchers found that COP administration increased blood phosphate levels as well as urinary excretion of phosphate and creatinine.”

What the sources say

• Not checked yetcites [228] Melloni, 1979, Acute clinical tolerance of creatinol-O-phosphate, Arzneimittelforschung

In the paper

“Thus, CEE is a chemical alteration of creatine and is not actually creatine.”

In the paper

“Childs and Tallon reported that CEE rapidly degrades to creatinine when exposed to stomach acid [34].”

• Also stated in: § 9.3. Creatine Ethyl Ester · plain

  “Giese et al. [35,192] reported that under physiological conditions, CEE non-enzymatically converted to creatinine with no measurable conversion to creatine (see Figure 9).”

• Also stated in: § 9.3. Creatine Ethyl Ester · hedged

  “Katseres and colleagues [193] reported that the half-life of CEE was in the order of one minute suggesting CEE may hydrolyze too quickly to reach muscle cells in its ester form.”

What the sources say

• Not checked yetcites [34] Child, R., and Tallon, M.J. (2007, January 12). Creatine ethyl ester rapidly degrades to creatinine in stomach acid. Proceedings of the International Society of Sports Nutrition 4th Annual Meeting, Las Vegas, NV, USA.
• ?Not checked — no full text of the sourcecites [35] Giese, 2009, Non-enzymatic cyclization of creatine ethyl ester to creatinine, Biochem. Biophys. Res. Commun. source
• ?Not checked — no full text of the sourcecites [192] Giese, 2009, Qualitative in vitro NMR analysis of creatine ethyl ester pronutrient in human plasma, Int. J. Sports Med. source
• ?Not checked — no full text of the sourcecites [193] Katseres, 2009, Non-enzymatic hydrolysis of creatine ethyl ester, Biochem. Biophys. Res. Commun. source

In the paper

“Given this analysis, Cr-HCl is classified in some evidence category to support efficacy compared to placebo. However, claims that Cr-HCl is more bioavailable, effective, and/or a safer source of creatine than CrM are not supported.”

In the paper

“However, pharmacokinetic studies indicated that absorption of COP was complete when administered intramuscularly and distributed primarily to the kidney, liver, and heart and that COP could cross myocardial cell membranes [230].”

What the sources say

• ?Not checked — no full text of the sourcecites [230] Marzo, 1979, Pharmacological and toxicological properties of creatinol O-phosphate. A review, Arzneimittelforschung

In the paper

“However, we are not aware of any pharmacokinetic or exercise related studies to test this hypothesis and benefits would seemingly be similar and more effectively dosed by co-ingestion of CrM and vitamin C.”

In the paper

“Like other creatine salts, adding hydrochloric acid to creatine would be expected to decrease pH and improve solubility.”

In the paper

“The researchers reported some benefits of Cr-HCl and CrM supplementation on leg press and skinfold determine body composition. However, the use of skinfold calipers to estimate body composition and statistical analysis methods employed make it difficult to draw any conclusions.”

What the sources say

• Not checked yetcites [65] Avelar, 2015, Creatine HCl and Creatine Monohydrate Improve Strength but Only Creatine HCl Induced Changes on Body Composition in Recreational Weightlifters, Food Nutr. Sci.

In the paper

“However, since the supplement contained caffeine and other ergogenic nutrients, the benefits cannot be attributed to CrN.”

In the paper

“Results revealed that CrM loading significantly increased total muscle creatine (+31%) and phosphocreatine (+16%) (see Figure 13).”

What the sources say

• Not checked yetcites [26] Kreider, 2003, Effects of serum creatine supplementation on muscle creatine content, J. Exerc. Physiol. Online

In the paper

“However, most studies have used higher than recommended doses, and those studies show that CrN is not more effective than CrM supplementation.”

In the paper

“Claims that oral COP is a source of creatine and/or is more bioavailable than CrM are not supported.”

In the paper

“While mixing creatine in acidic solutions may improve solubility when mixed in water, as noted above, it would have no effect on bioavailability.”

In the paper

“since there is some evidence that ingesting high doses of CEE can increase muscle creatine content and performance compared to placebo, we have categorized CEE in some evidence category.”

In the paper

“Additionally, amide bonds are generally very strong, so pharmacokinetic data would need to show that CLL breaks down into creatine, increases creatine in the blood, and increases tissue creatine content to establish that CLL is a bioavailable source of creatine.”

In the paper

“They reported that Cr-HCl contains about 78% creatine by molecular weight and that Cr-HCl was 37.9 times more soluble in water than CrM at 25 °C.”

What the sources say

• ?Not checked — no full text of the sourcecites [179] Gufford, 2010, Physicochemical characterization of creatine N-methylguanidinium salts, J. Diet. Suppl. source

In the paper

“Thus, while high doses of CrM-Alk may increase muscle creatine content to some degree over time, there is no evidence that CrM-Alk is up to 10 times more bioavailable than CrM and/or recommended doses are efficacious.”

In the paper

“Based on this analysis, these creatine salts are classified in the no evidence to support bioavailability, efficacy, and safety category. Therefore, they cannot be considered more effective than CrM.”

In the paper

“Since acidity in the stomach generally ranges from 1.5 to 3.5, it is likely that some CEE is degraded into creatinine during normal digestion while delivering some level of creatine to blood.”

In the paper

“it is well-known that there are species specific differences in creatine metabolism and storage [200]. Therefore, you cannot directly extrapolate results from mice or rat data to human creatine oral dosing studies.”

What the sources say

• ?Not checked — no full text of the sourcecites [200] Kreider, 2003, Species-specific responses to creatine supplementation, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

In the paper

“Additionally, several of these studies reported that ingesting equivalent doses of CrM promoted significantly greater increases in blood [222,223,226] and tissue creatine content [225] than those ingesting CLL and CLL ingestion was no different than placebo controls [225,226].”

What the sources say

• Not checked yetcites [222] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-46. C.D. Cal. Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [223] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-53. C.D. Cal. Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [226] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-133 (C.D. Cal.). Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.
• Not checked yetcites [225] Monster Energy Co., v. Vital Pharmaceuticals, Inc. et al. (2022, January 15). Case No. 5:18-cv-1882-JGB-SHK, Dkt. 434-51. (C.D. Cal.). Available online: https://www.law360.com/cases/5b8f06c4a5fd16342f7dd1b6.

In the paper

“Additionally, they found that one 5 mL oral dose of CS purportedly providing 2.5 g of creatine had no effect on plasma creatine levels (same as water) whereas ingestion of 2.5 g of CrM increased plasma creatine levels to about 300 µmol/L after one hour of ingestion and declining in a classical manner throughout the next 8 h (see Figure 14A) [38].”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Harris, 2004, The creatine content of Creatine Serum and the change in the plasma concentration with ingestion of a single dose, J. Sports Sci. source

In the paper

“Therefore, CO does not seem to be a good alternative for CrM in dietary supplements particularly when co-ingestion of effective doses of CrM and beta alanine would seeming be more effective.”

In the paper

“These findings suggest a large amount of CEE is converted to creatinine and CEE is less effective in increasing muscle creatine content than CrM.”

In the paper

“In terms of performance, Gavan and colleagues found some ergogenic benefit of CrN supplementation on muscular endurance, but they were unrelated to changes in muscle creatine content, suggesting the ergogenic benefit was primarily due to providing ergogenic levels of nitrate and not creatine at the dosages studied.”

In the paper

“Therefore, buffered creatine monohydrate is classified in some evidence to the support bioavailability, efficacy, and safety categories, but there is no evidence that buffered creatine is better.”

In the paper

“Collectively, these studies show that CS is not a bioavailable source of creatine, and therefore can have no creatine-related efficacy.”

In the paper

“However, there are no data indicating that these creatine salts increase blood creatine content, increase tissue creatine content, have any ergogenic value, are safe for long-term supplementation, or are more effective sources of creatine than CrM.”

In the paper

“Dietary ingredients that were sold in the U.S. prior to October 15, 1994, were considered “grandfathered,” and therefore not NDIs subject to these requirements. This included CrM since it was introduced into the U.S. market in 1993 [236].”

What the sources say

• Not checked yetcites [236] (2020). U.S. Food and Drug Administation (Standard No. GRN, No. 931 Creatine Monohydrate).

In the paper

“However, a limitation to this study is that only a 7-day washout period was observed between treatments. It is well known that it takes about 4 weeks for muscle creatine to return to normal after creatine supplementation [47]. Thus, it is possible that the testing order may have confounded results.”

What the sources say

• ?Not checked — no full text of the sourcecites [47] Vandenberghe, 1997, Long-term creatine intake is beneficial to muscle performance during resistance training, J. Appl. Physiol. source

In the paper

“Additionally, was no evidence that CrM-Alk promoted greater training adaptations than those taking CrM or that participants taking CrM-Alk experienced fewer side effects than those taking CrM.”

In the paper

“Research on CrM has served as the basis to establish professional guidelines, recommendations, and establish regulation.”

In the paper

“Since then, AlzChem Trostberg GmbH (the Germany manufacturer of CrM) voluntary submitted a GRAS application to the FDA that was not acted upon, meaning it could claim that CrM has FDA approved GRAS status [237,238].”

What the sources say

• Not checked yetcites [237] Carlson, S.J. (2021). GRAS Notice No. GRN 000931, Center for Food Safety and Applied Nutrition.
• Not checked yetcites [238] U.S. Food & Drug Administration (2022, January 05). GRAS Notices, Available online: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&sort=GRN_No&order=DESC&startrow=1&type=basic&search=CLL.

In the paper

“While FDA GRAS notifications are published and are accessible to the public, self-affirmed GRAS files are not published, which makes them difficult to search and to validate its content.”

In the paper

“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.”

In the paper

“Once an ingredient is self-affirmed as GRAS, it can be introduced into the food supply, and is then not required to submit an NDI Notification to FDA to be included in dietary supplement under the “present in the food supply” exemption noted above.”

In the paper

“However, it is important to understand that an NDI Notification only indicates that the FDA considers the NDI to be reasonably be considered as safe for human consumption. It does not affirm efficacy and/or validate any claims made about the NDI.”

In the paper

“The legal and regulatory status of CrM in dietary supplements is indisputable because it appeared on the US market in 1993 [236], and there was a large body of evidence showing it was reasonably expected to be safe.”

What the sources say

• Not checked yetcites [236] (2020). U.S. Food and Drug Administation (Standard No. GRN, No. 931 Creatine Monohydrate).

In the paper

“The reason why alternate marketed forms of creatine are in the marketplace without pre-market IND notification is likely due to confusion over legal definitions of dietary supplements, natural health products, and/or food additives in different countries as well as what is meant by chemical alteration in a nutrient.”

In the paper

“However, creatine pyruvate at doses of 5–10 g/day and creatine nitrate at 750 mg per day have not been objected to by the FDA and can be sold as dietary ingredients.”

In the paper

“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.”

In the paper

“After a dietary supplement is entered into the U.S. market, the FDA can restrict or ban its sale if it is deemed adulterated (e.g., unsafe). The FDA works with the Federal Trade Commission (FTC), who has jurisdiction over marketing claims that companies make about dietary supplements in advertising to regulate the dietary supplement industry.”

In the paper

“While alternative forms of creatine are unlikely to pose a health risk, they are typically more expensive than CrM.”

In the paper

“Regardless, confusion of over laws regulating dietary supplements combined with inadequate enforcement by regulators has created an environment where there are often little consequences of non-compliance.”