Amino Acids (2011) 40:1369–1383
`DOI 10.1007/s00726-011-0874-6
`
`R E V I E W A R T I C L E
`
`Analysis of the efficacy, safety, and regulatory status
`of novel forms of creatine
`
`Ralf Jäger · Martin Purpura · Andrew Shao ·
`Toshitada Inoue · Richard B. Kreider
`
`Received: 10 July 2010 / Accepted: 30 November 2010 / Published online: 22 March 2011
`© The Author(s) 2011. This article is published with open access at Springerlink.com
`
`Abstract Creatine has become one of the most popular
`dietary supplements in the sports nutrition market. The
`form of creatine that has been most extensively studied and
`commonly used in dietary supplements is creatine mono-
`hydrate (CM). Studies have consistently indicated that
`CM supplementation increases muscle creatine and phos-
`phocreatine concentrations by approximately 15–40%,
`enhances anaerobic exercise capacity, and increases train-
`ing volume leading to greater gains in strength, power, and
`muscle mass. A number of potential therapeutic benefits
`have also been suggested in various clinical populations.
`Studies have indicated that CM is not degraded during
`normal digestion and that nearly 99% of orally ingested
`CM is either taken up by muscle or excreted in urine.
`Further, no medically significant side effects have been
`reported in literature. Nevertheless, supplement manufac-
`turers have continually introduced newer forms of creatine
`
`Invited paper presented at the Creatine in Health and Sport 2010
`conference. Submitted to Amino Acids, 15 June 2010.
`
`R. Ja¨ger · M. Purpura
`Increnovo LLC, 2138 E Lafayette Pl, Milwaukee,
`WI 53202, USA
`
`A. Shao
`Council for Responsible Nutrition, 1828 L Street NW,
`Suite 510, Washington, DC 20036, USA
`
`T. Inoue
`Healthy Navi Co., Ltd., 3-18-1-801, Minami-rokugo,
`Ota-ku, Tokyo 144-0045, Japan
`
`R. B. Kreider (&)
`Exercise and Sport Nutrition Lab, Department of Health and
`Kinesiology, Texas A&M University, 158 Read Building,
`TAMU 4243, College Station, TX 77843-4243, USA
`e-mail: rkreider@hlkn.tamu.edu
`
`into the marketplace. These newer forms have been pur-
`ported to have better physical and chemical properties,
`bioavailability, efficacy, and/or safety profiles than CM.
`However, there is little to no evidence that any of the newer
`forms of creatine are more effective and/or safer than CM
`whether ingested alone and/or in combination with other
`nutrients. In addition, whereas the safety, efficacy, and
`regulatory status of CM is clearly defined in almost all
`global markets; the safety, efficacy, and regulatory status of
`other forms of creatine present in today’s marketplace as a
`dietary or food supplement is less clear.
`
`Keywords Creatine · Dietary supplements ·
`Ergogenic aids · Exercise · Performance
`
`Introduction
`
`Creatine (N-(aminoiminomethyl)-N-methyl glycine) is an
`ingredient commonly found in food, mainly in fish and
`meat, and is sold as a dietary supplement in markets around
`the world. Its use as an ergogenic aid and possible treat-
`ment
`for
`certain neuromuscular disorders
`is well
`documented in scientific literature (Buford et al. 2007;
`Kreider et al. 2010). In recent years, the popularity of
`creatine has risen dramatically, especially among athletes.
`In the USA alone, creatine-containing dietary supplements
`make up a large portion of the estimated $2.7 billion in
`annual sales of sports nutrition supplements (NBJ 2009).
`Accompanying this explosive growth in sales has been
`the introduction of different forms of creatine. Creatine
`monohydrate (CM), first marketed in the early 1990s, is the
`form most commonly found in dietary supplement/food
`products and most frequently cited in scientific literature.
`The introduction into the marketplace of alternate forms of
`
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`creatine, beginning in the late 1990s, was presumably an
`attempt to differentiate the multitude of creatine-containing
`products available to consumers and improve certain
`attributes such as solubility and efficacy. However, the
`legal and regulatory status of these various forms of crea-
`tine in the USA and other markets around the world is at
`best uncertain. To date, with the exception of Japan, CM is
`the only form of creatine to be officially approved or
`accepted in key markets such as the USA, European Union
`(EU), Canada and South Korea. The continued presence of
`other forms of creatine in the marketplace, especially in the
`US, may be due to a multitude of factors. These include,
`but may not be limited to, a lack of awareness or under-
`standing on the part of marketers of applicable laws and
`regulations, intentional noncompliance with the law, and/or
`inadequate enforcement of the law. The public health
`implications of widespread distribution and use of these
`unauthorized forms of creatine is unknown and warrants
`careful monitoring.
`New forms of creatine are marketed with claims of
`improved physical, chemical, and physiological properties
`in comparison to CM. Claims include improved stability
`when combined with other
`ingredients or
`in liquids,
`improved solubility in water, improved bioavailability, and
`even an increase in performance. This review will evaluate
`the available literature on new forms of creatine and
`compare them to available data on CM in terms of efficacy
`and safety. In addition, the current international regulatory
`status of the various forms of creatine that are commer-
`cially available will be examined.
`
`Methods
`
`This analysis represents a systematic review of the litera-
`ture on the various forms of creatine available in the global
`marketplace as dietary supplements, food supplements, or
`natural health products. For technical and performance
`comparisons,
`literature searches were performed by
`searching the Medline database of the US National Library
`of Medicine of the National Institutes of Health. The search
`strategy involved entering the various creatine search terms
`(Table 1), along with the technical or performance aspect
`of interest (e.g., solubility, stability, bioavailability, per-
`formance). In addition, a patent research was performed by
`searching the database of the World Intellectual Property
`Organization (WIPO),
`the European Patent Office,
`the
`Japan Patent Office, and the United States Patent and
`Trademark Office. Articles were reviewed, analyzed, and
`interpreted, with results of the relevant studies presented
`below.
`For the assessment of the current regulatory status of the
`various forms of creatine, the Web sites of regulatory
`
`123
`
`Table 1 Creatine content of different forms of creatine
`
`Form of creatine
`
`Creatine
`content (%)
`
`Difference
`in CM (%)
`
`Creatine anhydrous
`
`100.0
`
`CM
`
`Creatine ethyl ester
`
`Creatine malate (3:1)
`
`Creatine methyl ester HCl
`
`Creatine citrate (3:1)
`
`Creatine malate (2:1)
`
`Creatine pyruvate
`Creatine α-amino butyrate
`Creatine α-ketoglutarate
`Sodium creatine phosphate
`
`Creatine taurinate
`
`Creatine pyroglutamate
`
`Creatine ketoisocaproate
`
`Creatine orotate (3:1)
`
`Carnitine creatinate
`
`Creatine decanoate
`
`Creatine gluconate
`
`87.9
`
`82.4
`
`74.7
`
`72.2
`
`66
`
`66
`
`60
`
`56.2
`
`53.8
`
`51.4
`
`51.4
`
`50.6
`
`50.4
`
`45.8
`
`44.9
`
`43.4
`
`40.2
`
`+13.8
`0
`−6.3
`−15.0
`−17.9
`−24.9
`−24.9
`−31.7
`−36.0
`−38.8
`−41.5
`−41.6
`−42.4
`−42.7
`−47.9
`−49.0
`−50.7
`−54.3
`
`bodies for key markets around the world were accessed
`(USA: US Food and Drug Administration; Canada: Health
`Canada; EU: European Commission; Japan: Ministry of
`Health, Labor and Welfare; Korea: Korea Food and Drug
`Administration). Information derived from these sites was
`used to determine the legal and regulatory framework
`governing creatine products in these markets and the cur-
`rent regulatory status of the various forms of creatine as
`dietary supplements, food supplements, and natural health
`products.
`
`Physio-chemical properties
`
`Creatine crystallizes from water as monoclinic prisms
`holding one molecule of water of crystallization per mol-
`ecule of creatine. Continued drying of CM results in a loss
`of the water of crystallization at around 100°C, yielding
`anhydrous creatine. Creatine is a weak base with a pkb
`value of 11.02 at 25°C. As a result, creatine can only form
`salts with strong acids, having a pka value of less than 3.98.
`Creatine forms salts by the protonation of its guanidine
`moiety (see Fig. 1). In addition to salt formation, creatine is
`able to act as a complexing agent.
`Creatine salts such as citrate, maleate, fumarate, tartrate
`(Negrisoli and Del Corona 1997), pyruvate (Pischel and
`Weiss 1996), ascorbate (Pischel et al. 1999), and orotate
`(Abraham and Jiang 2005) were first introduced to the
`marketplace as early as the late 1990s. Creatine and acids
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`
`NH2
`
`H2N
`
`N
`CH3
`
`O
`
`O
`
`+
`
`HA
`
`H2O
`
`A
`
`H2N
`
`NH2
`
`N
`CH3
`
`O
`
`OH
`
`Creatine
`
`Strong Acid
`
`Creatine-Salt
`
`Fig. 1 Creatine salts
`
`with multiple acid moieties such as citric acid can form
`salts as well as complexation products. The first acid
`moiety of citric acid is strong enough (pka = 3.09) to form
`a salt with creatine; however,
`the other two moieties
`(pka2 = 4.75, pka3 = 5.41) should only be able to form
`complexes with creatine. A salt, a salt-complex combina-
`tion, or a simple physical mixture can be differentiated by
`measurement of the enthalpy changes of neutralization,
`which ranges usually in the area of −55 to −66 kJ/mole for
`the salt formation to less than −5 kJ/mole for the change in
`complexation enthalpy to no changes in enthalpy for a
`physical mixture (1995). A “tricreatine citrate” is actually a
`complex of creatine citrate with two additional creatine
`moieties, resulting in a molecule with a ratio of creatine to
`citrate of 3:1.
`In addition to creatine and its salts, derivatives of cre-
`atine such as creatine ester or even creatine alcohols are
`currently marketed as dietary supplements in the USA (see
`Fig. 2). Both ingredients do not contain creatine as such,
`since they have been chemically altered. While it
`is
`assumed that the human body will transfer those molecules
`into creatine upon intake,
`there are no published data
`available to base firm conclusions.
`The amount of creatine in different forms of creatine
`varies. Creatine monohydrate contains 87.9% of creatine,
`whereas the creatine content in other forms of creatine is
`lower with the exception of creatine anhydrous (see
`Table 1). Commercial creatine salts are formed in solution
`or by mechanical processes such as milling or grinding
`under the presence of residual water. Complexes are
`formed by the subsequent replacement of the solvating
`molecules by the new ligands.
`
`Solubility
`
`correlation between solubility and temperature is almost
`linear. One liter of water dissolves 6 g of creatine at 4°C,
`14 g at 20°C, 34 g at 50°C, and 45 g at 60°C. The solubility
`of creatine can also be increased by lowering the pH of the
`solution. This principle is the basis for the improved sol-
`ubility of creatine salts, since creatine salts lower the pH of
`water due to the nature of acid moiety. Creatine monohy-
`drate dissolves at 14 g/L at 20°C resulting in a neutral pH
`of 7. A saturated solution of tricreatine citrate in water has
`a pH of 3.2; whereas a saturated solution of creatine
`pyruvate even has a pH of 2.6 (pyruvic acid is a stronger
`acid than citric acid). The decrease in pH results in an
`increase in solubility: 29 g/L creatine citrate at 20°C, and
`54 g/L creatine pyruvate at 20°C. Normalized by the rel-
`ative amount of creatine per molecule (monohydrate
`87.9%, citrate 66%, pyruvate 60%), creatine citrate
`(19.14 g/L) shows a 1.55-fold and creatine pyruvate
`(32.4 g/L) a 2.63-fold better solubility when compared with
`the monohydrate (12.3 g/L). Whereas the creatine deriva-
`tive creatinol-O-phosphate (5 g/L at 20°C) has inferior
`solubility, dicreatinol sulfate (1,370 g/L at 20°C) shows
`superior solubility when compared with CM, creatine salts,
`or creatine esters (Godfraind et al. 1983; Gastner et al.
`2005).
`
`Stability
`
`Stability in solid form
`
`Creatine monohydrate powder is very stable showing no
`signs of degradation over years, even at elevated temper-
`atures. To detect a potential degradation of creatine, one
`must measure the content of its degradation product, cre-
`atinine (see Fig. 3), which can be quantified by HPLC at
`levels as low as 67 parts per million (ppm). At room
`temperature and even at an increased temperature of 40°C
`(104°F), CM shows no signs of degradation (i.e., creatinine
`levels stay under the quantification limit of 67 ppm) after
`more than 3 years. As Fig. 3 shows, even when stored at
`60°C (140°F), creatinine (106 ppm) was only detected after
`a period of 44 months (Ja¨ger 2003).
`
`Stability in solutions
`
`One major limitation of creatine as an ampholytic amino
`acid is its rather low solubility in water. The solubility of
`creatine in water
`increases with temperature and the
`
`As shown in Fig. 4, in contrast to its stability in a solid
`state, creatine is not stable in aqueous solution due to an
`
`Fig. 2 Chemical structure of
`creatine and creatine derivatives
`
`NH2
`
`H2N
`
`O
`
`N
`CH3
`
`O
`
`NH
`
`H2N
`
`O
`
`N
`CH3
`
`O
`
`CH3
`
`H2N
`
`NH
`
`N
`CH3
`
`O
`O P
`OH
`
`OH
`
`Creatine
`
`Creatine Ethylester
`
`Creatinol-O-Phosphate
`
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`Fig. 5 Effect of pH on creatine stability in solution. Adapted from
`Howard and Harris (1999)
`
`ingredient. If creatine is not consumed immediately after it
`has been dissolved in water, it should be stored at a low
`temperature to retard the degradation.
`The degradation of creatine can be reduced or even
`halted by either lowering the pH under 2.5 or increasing the
`pH. A very high pH results in the deprotonation of the acid
`group, thereby slowing down the degradation process by
`making it more difficult for the intramolecular cyclization.
`A very low pH results in the protonation of the amide
`function of the creatine molecule, thereby preventing the
`intramolecular cyclization (see Fig. 6). This effect also
`occurs under the acidic conditions in the stomach, hence
`preventing the breakdown of creatine. The conversion of
`creatine to creatinine in the gastrointestinal tract is minimal
`regardless of transit time (Persky et al. 2003; Harris et al.
`1992b; Deldicque et al. 2008).
`
`Stability of other forms of creatine
`
`Some creatine salts appear to be less stable when compared
`with CM. Tricreatine citrate results in creatinine levels of
`770 ppm at 40°C (104°F) after 28 days of storage. How-
`ever, the addition of carbohydrates has been shown to
`increase stability of some creatine salts (Purpura et al.
`2005). Creatine salts are not expected to have a greater
`stability in solution; however, the pH lowering effect of the
`salt might reduce stability compared to CM in the same
`environment.
`Tallon et al. (Child and Tallon 2007) compared the
`stability of creatine ethyl ester (CEE) head to head with
`CM and found that CEE was actually less stable than CM.
`It was concluded that the addition of the ethyl group to
`creatine actually reduced acid stability and accelerated its
`breakdown to creatinine. The degradation of creatine and
`
`Fig. 3 Stability of creatine monohydrate powder. Adapted from Ja¨ger
`(2003)
`
`intramolecular cyclization (Howard and Harris 1999). The
`rate of creatine degradation in solution is not dependent on
`its concentration, but on pH. Generally, the lower the pH
`and higher the temperature, the faster is the degradation.
`This solid-state and degradation properties have been
`thoroughly investigated as early as the 1920s (Edgar and
`Shiver 1925; Cannon et al. 1990) and more recently by
`Dash et al. (2002), as well as Harris et al. (Howard and
`Harris 1999). These researchers found that whereas crea-
`tine was relatively stable in solution at neutral pH (7.5 or
`6.5), a lowering of pH resulted in an increased rate of
`degradation and after only 3 days of storage at 25°C cre-
`atine degraded significantly: 4% at pH 5.5; 12% at pH 4.5;
`and 21% at pH 3.5 (see Fig. 5). Similarly, Ganguly et al.
`(2003) reported that creatine monohydrate stored at room
`temperature degraded into creatinine within several days
`but
`that refrigerating creatine monohydrate in solution
`slowed degradation. The rapid degradation of creatine in
`solution precludes the manufacture of shelf-stable standard
`acidic beverages containing efficacious amounts of the
`
`O
`
`HN
`
`N
`
`H3C
`Creatinine
`
`- H2O
`
`HN
`
`OH
`
`+ H2O
`
`NH2
`
`HN
`
`N
`
`H3C
`
`O
`
`Creatine
`
`Fig. 4 Degradation of creatine to creatinine
`
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`NH2
`
`O
`
`+ H2O
`
`- H2O
`
`HN
`
`N
`
`H3C
`
`O
`
`O
`
`HN
`
`HN
`
`N
`
`H3C
`
`NH3
`
`HN
`
`N
`
`H3C
`
`- H2O
`
`+ H2O
`
`OH
`
`O
`
`Creatine at very low pH
`
`Creatinine
`
`Creatine at very high pH
`
`Fig. 6 Very low pH prevents
`creatine degradation
`
`O
`
`HN
`
`HN
`
`N
`
`H3C
`
`eninitaerC
`
`Fig. 7 Degradation of creatine
`and creatine ester
`
`NH2
`
`- ROH
`
`+ ROH
`
`R
`
`O O
`
`H2
`N
`
`HN
`
`N
`
`H3C
`
`pH < 7
`
`pH > 7
`
`HN
`
`N
`
`H3C
`
`OR
`
`O
`
`evitavireD-enitaerC
`
`R = OH (Creatine)
`R = OC2H5 (Creatine Ethyl Ester)
`R = OCH3 (Creatine Methyl Ester)
`
`creatine ester involves intramolecular hydrolysis of a car-
`boxyl acid (in case of creatine) or carboxylic ester (in case
`of creatine methyl- or ethyl ester) under acidic conditions
`and the rate of degradation depends on the leaving group
`(see Fig. 7). It is speculated that the methyl ester or ethyl
`ester groups are better leaving groups than hydroxyl or
`water and, therefore, suggesting that the degradation into
`creatinine should be rather accelerated.
`These findings are also in accordance with the recent
`investigations on the stability of CEE at 37ºC in both water
`and phosphate-buffered saline and the in vitro response of
`CEE to incubation in human plasma by H-NMR analysis
`(Giese and Lecher 2009b). The conversion of CEE to
`creatine by the esterases in human plasma was not detec-
`ted, and the only species detected after the incubation
`period was creatinine. It is concluded that CEE is mostly
`converted into creatinine under physiological conditions
`encountered during transit
`through the various tissues,
`suggesting no ergogenic effect is to be expected from
`supplementation of CEE. The high stability of CM is well
`documented, whereas the stability of newer forms of cre-
`atine (salts, ester, etc.) either has not been investigated or
`appears to be inferior. New forms of creatine contain less
`of the active principal creatine in comparison to CM;
`however, creatine salts can offer an advantage over CM
`with regard to solubility.
`
`Bioavailability
`
`The uptake of creatine is simplified in a two-step approach:
`first, uptake into the blood stream; second, uptake into the
`
`target tissue. The term ‘bioavailability’ refers to both the
`intestinal absorption and the use of a substance by the
`body’s cells and tissues. First indications of a potential
`change of creatine bioavailability can be gathered from the
`amount of creatine taken up into the blood plasma after
`oral administration. However, a change in the total amount
`of creatine in the blood plasma cannot be directly extrap-
`olated to a potential increase in desired performance. An
`increased amount of creatine in the plasma could be the
`result of decreased uptake into the target tissue resulting in
`an actual decrease in overall bioavailability. On the other
`hand, an initial rise in plasma creatine levels, followed by a
`reduction in plasma levels, is an indication of increased
`uptake into the target tissue. This has been demonstrated in
`vivo by combining creatine with insulin-stimulating
`ingredients such as high amounts of glucose or protein
`(Bessman and Mohan 1992; Haughland and Chang 1975;
`Rooney et al. 2002). Conclusive proof of an increase in
`relevant bioavailability can only be gained by assessing the
`amount of creatine reaching the target tissue, the muscle,
`measured by muscle biopsy and/or whole body creatine
`retention assessed by measuring the difference between
`creatine intake and urinary excretion.
`Dietary creatine is presumed to have high bioavailability
`since intestinal absorption of CM is already close to 100%
`(Deldicque et al. 2008). However, the response to creatine
`supplementation is heterogeneous, due in part to some non-
`responders, which might be overcome by alternative forms
`of creatine (Greenhaff 1997b; Greenhaff et al. 1993).
`Several studies have examined whether different forms of
`creatine are more effective in terms of promoting muscle
`uptake of creatine than CM. For example, a recent study
`
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`examined the effect of the administration of three different
`forms of creatine on plasma creatine concentrations and
`pharmacokinetics. In a balanced cross-over designed study,
`six healthy subjects were assigned to ingest a single dose of
`isomolar amounts of creatine (4.4 g) in the form of CM,
`tricreatine citrate (TCC), or creatine pyruvate (CPY), fol-
`lowed by measurement of the plasma creatine levels (Ja¨ger
`et al. 2007). Mean peak concentrations and area under the
`curve (AUC) were significantly higher with CPY (17 and
`14%, respectively) in comparison to CM. The findings
`suggest
`that different forms of creatine may result
`in
`slightly different kinetics of plasma creatine absorption,
`although differences in velocity constants of absorption
`could not be detected due to the small number of blood
`samples taken during the absorption phase. The small
`differences in kinetics are unlikely to have any clinically
`relevant effects on muscle creatine elevation during periods
`of creatine loading. A follow-up study including muscle
`biopsies would be required to conclude if the bioavail-
`ability of this specific creatine salt was indeed higher
`(Fig. 8).
`Greenwood et al. (2003) investigated how different
`forms of creatine affect whole body creatine retention.
`Sixteen males were assigned to ingest in a single blind
`manner either 5 g of dextrose, 5 g of CM, 5 g of CM plus
`18 g dextrose, or an effervescent creatine supplement
`consisting of 5 g of TCC (66% creatine) plus 18 g dextrose
`four times/day for 3 days. Creatine retention was estimated
`by subtracting total urinary creatine excretion from total
`supplemental creatine intake over the 3-day period. Results
`revealed that average daily creatine retention over the
`
`Plasma creatine
`µmol/l
`
`5g CM
`
`6.7g CC
`
`7.3g CYP
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`0
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`Fig. 8 Comparison of blood plasma levels of different forms of
`creatine. Adapted from Ja¨ger et al. (2007)
`
`123
`
`Fig. 9 Percentage of creatine retained during a 3-day loading period
`(20 g/day). Adapted from Greenwood et al. (2003)
`
`3-day period was 12.2 ± 1.3, 16.1 ± 2.2, and 12.6 ± 2.5 g/
`day for the CM, CM with dextrose, and effervescent TCC
`groups, respectively. This amounted to whole body crea-
`tine retention of 61 ± 15% for the CM group, 80 ± 11%
`for the CM plus dextrose group, and 63 ± 13% for the
`effervescent TCC group. While creatine retention was
`significantly greater in the CM and dextrose group, no
`significant differences were seen between the CM and
`effervescent TCC groups. These findings suggest that while
`consuming a relatively small amount of dextrose with CM
`can increase whole body creatine retention, supplementa-
`tion of TCC in an effervescent form does not augment
`whole body creatine retention more than CM alone (Fig. 9).
`Over the years, there has been significant commercial
`interest in determining whether creatine could be delivered
`in a liquid form. The thought has been since CM is rela-
`tively insoluble that development of a liquid or suspended
`form of creatine may be more convenient to consume, be
`more readily absorbed into the blood stream, and promote a
`greater efficiency in transport of creatine to the muscle.
`Some companies have even claimed that minimal amounts
`of liquid creatine would need to be ingested because of
`enhanced efficiency in transport through the blood and into
`the muscle. A limitation with these theories is that CM is
`not stable for any substantial length of time in liquid.
`Consequently, while researchers have been working on
`ways to suspend creatine within gels and fluids, it has been
`generally considered to be impractical to develop into a
`product due to limitations in shelf-life. In addition, while
`people may prefer the taste of liquid or gel versions of
`creatine, there is no evidence that these delivery forms
`provide a superior performance benefit.
`Kreider et al. (2003b) carefully compared the effects
`of ingesting 20 g/day of CM to recommended doses
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`(2.5 g/day of CM), as well as doses that would purportedly
`provide an equivalent amount of CM per day in liquid form
`(20 g/day) on muscle creatine, phosphocreatine, and total
`creatine levels. Subjects donated muscle biopsies prior to
`and following 5 days of supplementing their diet in a
`randomized and double-blind manner with either 5 mL of
`creatine liquid (purportedly providing 2.5 g of CM), 5 mL
`of a flavored placebo, 8 9 5 mL doses of creatine liquid
`(purportedly providing 20 g/day of CM), or 8 9 5 mL
`doses of a flavored placebo. Another group ingested
`4 9 5 g of CM for 5 days as a non-blinded benchmark
`control. This analysis allowed for a comparison of ingest-
`ing recommended doses of liquid creatine to a placebo, as
`well as seven times the amount recommended by the
`manufacturer that would purportedly provide an equal
`amount of CM. The researchers found that CM supple-
`mentation significantly increased muscle free creatine
`content by 31 ± 28%. However, none of the other groups
`experienced any effect on muscle free creatine, phospho-
`creatine, or total creatine content. Moreover, changes in
`muscle creatine and phosphocreatine levels in response to
`CM supplementation were significantly greater than the
`liquid creatine and placebo groups. These findings indicate
`that
`liquid creatine supplementation has no effect on
`muscle phosphagen levels and therefore may have no
`ergogenic value. While other groups have been attempting
`to develop stable forms of liquid and/or gel forms of cre-
`atine with some success, there are no data available to date
`demonstrating that these types of creatine are absorbed
`more efficiently and/or have greater benefit compared to
`CM (Fig. 10).
`An alternative dissolved form of creatine is colloidal
`CM. CM is dissolved in its own crystal water and dispersed
`into a stable protective matrix containing carbohydrates
`(Kessel et al. 2004). The product is claimed to be the only
`solubilized form of powdered creatine in the market,
`
`making it more bioavailable and stable. However, no evi-
`dence has been published to date to substantiate any
`performance or ergogenic benefit
`from this form of
`creatine.
`Creatine ethyl ester has been purported to be a superior
`form of creatine in comparison to CM. However, prior
`studies have shown that it degrades rather quickly to cre-
`atinine when exposed to low pH levels as would be found
`in the stomach (Giese and Lecher 2009a; Katseres et al.
`2009). Theoretically, this would reduce the bioavailability
`of creatine. To test this hypothesis, Spillane et al. (2009)
`compared the effects of supplementing the diet with a
`placebo, CM, or CEE during 42 days of training. Serum
`creatinine and muscle total creatine content was assessed
`prior to and following 6, 27, and 48 days of supplemen-
`tation and training. The researchers found that serum
`creatinine levels were significantly increased in the CEE
`group after 6, 27, and 48 days of supplementation indi-
`cating less efficient bioavailability. In addition, while CEE
`supplementation promoted a modest increase in muscle
`total creatine content, it was increased to a greater extent in
`the CM group. These findings directly contradict claims
`that CEE is more effective in increasing muscle creatine
`stores. Further, the significantly higher creatinine levels
`observed should raise some potential safety concerns about
`potential safety (Fig. 11).
`Several studies have also evaluated whether co-inges-
`tion of creatine with other nutrients may influence creatine
`retention. Initial work by Green and colleagues (Green
`et al. 1996a, b) demonstrated that co-ingesting creatine
`(5 g) with large amounts of glucose (e.g., 95 g) enhanced
`creatine and carbohydrate storage in muscle. Subsequent
`studies by Steenge et al. (2000) found ingesting creatine
`(5 g) with 47–97 g of carbohydrate and 50 g of protein also
`enhanced creatine retention. The researchers suggested that
`
`Fig. 10 Change in muscle-free creatine content in response to 5 days
`of low or high-dose creatine serum and placebo ingestion compared to
`CM. Adapted from Kreider et al. (2003b)
`
`Fig. 11 Changes in total muscle creatine content in response to
`placebo (PLA), creatine monohydrate (CRT), and creatine ethyl ester
`(CEE) supplementation (Spillane et al. 2009). †Significantly different
`from PLA group. *Significant difference from baseline. Reprinted
`with permission
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`creatine transport was mediated in part by glucose and
`insulin. As a result, additional research has been under-
`taken to assess the effect of co-ingesting creatine with
`nutrients that may enhance insulin sensitivity on creatine
`retention.
`Several studies have examined whether co-ingesting
`creatine with D-pinitol
`influences whole body creatine
`retention. In the first study (Greenwood et al. 2001), 12
`male subjects with no history of creatine supplementation
`donated 24-h urine samples for 4 days. After an initial
`control day designed to determine normal daily creatine
`excretion rates, subjects were then matched according to
`body mass and randomly assigned to ingest in a single-
`blind manner either a placebo (4 9 5 g doses of dextrose),
`CM (4 9 5 g), CM with low-dose D-pinitol (4 9 5 g CM
`with 2 9 0.5 g of D-pinitol), or CM with high-dose D-pinitol
`(4 9 5 g CM with 4 9 0.5 g D-pinitol) for 3 days. Whole
`body creatine retention was estimated by subtracting total
`urinary creatine excretion from total supplemental creatine
`intake over the 3-day period. Results revealed that whole
`body creatine retention over the 3-day loading period was
`significantly greater in the low-dose D-Pinitol group in
`comparison to the group ingesting CM alone. However, no
`differences were seen between CM alone and CM with the
`higher dose of D-Pinitol (Fig. 12).
`In a follow-up study, Kerksick et al. (2009) examined
`whether co-ingestion of D-pinitol with CM would affect
`training adaptations, body composition, and/or whole-body
`creatine retention in resistance-trained males. In the study,
`24 resistance trained males were randomly assigned in a
`double-blind manner to CM + D-pinitol or CM alone prior
`to beginning a supervised 4-week resistance training pro-
`gram. Subjects ingested a typical loading phase (i.e., 20 g/
`day for 5 days) before ingesting 5 g/day for the remaining
`
`23 days. Results revealed that creatine retention increased
`in both groups as a result of supplementation. However, no
`significant differences were observed between groups in
`training adaptations. Consequently, additional research is
`needed to determine whether D-pinitol supplementation
`enhances creatine uptake and/or affects the ergogenicity of
`creatine supplementation before firm conclusions can be
`drawn.
`Russian tarragon (Artemisia dracunculus) is an etha-
`nolic extract that is often used as a cooking herb. Studies
`have shown that Russian tarragon (RT) appears to have
`antihyperglycemic activity when combined with CM
`ingestion (Ja¨ger et al. 2008a; Wang et al. 2008). Theoret-
`ically, ingesting RT extract prior to creatine loading may
`enhance insulin sensitivity and thereby promote greater
`creatine absorption/retention. To support this hypothesis,
`Ja¨ger et al. (2008a) reported that RT influences plasma
`creatine levels during the ingestion of CM in a similar
`manner to glucose and protein. However, further research
`is needed to evaluate the effects of RT on creatine uptake
`and retention in muscle before conclusions can be drawn
`(Fig. 13).
`In analysis of this literature, it is clear that CM sup-
`plementation promotes significant
`increases in muscle
`creatine levels in most individuals. There is some evidence
`that co-ingestion of CM with various nutrients (e.g., car-
`bohydrate, protein, D-pinitol) may enhance creatine uptake
`to a greater degree. However, there is no evidence that
`effervescent creatine, liquid creatine, and/or CEE promotes
`greater uptake of creatine to the muscle. Rather, there is
`some evidence that some of these forms of creatine may be
`less effective and/or be of greater clinical concern in terms
`of safety.
`
`Creatine µmol/l
`1000
`
`CM plus RT
`
`CM
`
`750
`
`500
`
`250
`
`
`
`00
`
`200
`
`0
`
`-200
`
`-400
`
`
`
`* ** *
`
`
`
`**
`
`A – B @ 30, 60, 90 & 120 min
`
`0
`
`20
`
`40
`
`80
`60
`Time (min)
`
`100
`
`120
`
`Fig. 13 Influence of Russian tarragon on creatine absorption.
`Adapted from Ja¨ger et al. (2008a)
`
`Fig. 12 Change in whole body creatine r