Due to an increase in the physical demands and pressure of competition, many athletes now explore any potential avenues that may give them a competitive edge. An ever-increasing number of athletes have turned to nutritional supplements and ergogenic aids in an attempt to improve their performance (Maughan et al 2004, Kristiansen et al, 2005). One such ergogenic aid which has risen to prominence in recent years is creatine monohydrate and many high profile athletes have been linked with use of the substance (Dalbo et al, 2008).
After its discovery in the 1830’s by a French scientist called Chevreul (Balsom et al 1994, Bird 2003), early work suggested that ingesting creatine can dramatically boost the creatine content in the muscle (Folin and Dennis, 1912). Since then, studies undertaken in a variety of sports have demonstrated the benefits of creatine supplementation for sporting performance (Balsom 1993, Birch et al 1994, Burke et al, 1996, Meir 1995, Redondo et al 1996). The purpose of this review, is to critically evaluate the use of oral creatine supplementation in improving athletic performance. As well as looking at the evidence regarding sporting performance, this review will also explore the health impacts of creatine supplementation, particularly focusing on the possible effects on the body’s immune system.
Proposed Mechanism of Creatine Action
Muscle contraction occurs through the interaction between actin and myosin filaments. Energy for muscle contraction is provided by the hydrolysis of adenosine triphosphate (ATP)by myosin ATPase in muscle fibres. (Williams 1999) ATP attaches to the myosin head, detaching it from the actin filament, and is then hydrolysed, activating myosin and providing energy for the next cross bridge formation. (Cooke 2004) The ATP in skeletal muscle can only provide energy for a few seconds of high intensity, anaerobic exercise.To prolong activity, ATP must be regenerated rapidly, through the rephosphorylation of adenosine diphsophate (ADP).ATP regeneration isenhanced by the presence of phosphocreatine (PCr) within the muscle fiber. (Bemben 2005; Clark 1997). Through the action of the enzyme creatine kinase (CK), PCr hydrolysis occurs, providing a free phosphate for the regeneration of ATP. This is a reversible reaction, allowing the rephosphorylation of creatine when energy is available through aerobic metabolism: ADP + PCr + H+< ----------------------------- >ATP + Cr The hydrolysis of PCr also acts as a buffering system, reducing the concentraton of hydrogen ions within the muscle cells, and therefore delaying the lactic acidosis which impairs muscular contraction.
Although the hydrolysis of PCr can prolong high intensity activity, there is a limited store of PCr within the muscle and it is depleted quickly, meaning activity is only prolonged through this mechanism for an extra few seconds. (Billaut and Bishop, 2009) Dietary supplementation with creatine, can increase the total creatine content, andimportantly the level of PCr within muscle fibres. (Harris et al 1992) It is proposed that with an increased concentration of PCr within skeletal muscle, performance benefits in repeated bouts of short-duration, high-intensity activity may be seen. (ACSM 2009;; Bemben et al 2001; Hamilton et al 2000; Tarnopolsky and MacLennon 2000; Romer et al 2001; Volek et al 1997)
Muscle Supplementaion and Muscle Creatine Concentration
The oral administration of creatine monohydrate has been shown to increase muscle creatine concentration. (Balsom et al 1993, 1994; Becque et al 2000; Burke et al 1996; Hamilton et al 2000; Romer et al 2001) Published literature has regularly suggested creatine monohydrate to be supplemented through an 100g acute loading regime, through 20-25g/day, 4-5 times a day for 5-7days. (Maughan 1995; Nuttall 1994) Hultman et al's (1996), investigation into the effects of creatine supplementation of 20g/day in 5g doses for 6 days resulted in an increase in total creatine concentration by ~20% supplementation. Similar increases have been shown in studies by Greenhaff (1994), Balsom (1995) and Izquierdo (2002). Balsom (1994) showed plasma creatine levels to increase by between five and ten times approximately one hour after ingesting creatine monohydrate.
The increase in plasma creatine also increases the blood/muscle concentration gradient, thus leading to a rise in the amount of blood borne creatine being transported and trapped in the muscle cell. Havenetidis (2003) has shown blood creatine levels to remain elevated for only a short period of time, with a half-life of 60-90 minutes. Thus, repeating this dose around 4-5 times per day at regular intervals aids the movement of creatine from the blood into the muscle cell at a constant rate, through the constantly elevated plasma creatine levels. Although studies have shown creatine uptake during an acute loading protocol to be at its highest within the first two to three days of supplementation (Hultman 1996; Rossiter 1996), acute loading periods of less than five days have not been shown to increase the muscle creatine pool effectively. Odland’s (1996) investigation involved subjects ingesting 5g doses 4 times/day for just 3 days resulting in no significant elevation of muscle plasma creatine. An alternative method of low-dose maintenance loading has also been shown to increase muscle creatine concentration as effectively as the more traditional acute loading method. (Hultman, 1996) Burke’s (2000) double-blind study followed a protocol of 7.7g creatine supplementation per day for 21 days.
Creatine benefits in participants’ peak force, total work until fatigue as well as elevated mean peak power for a longer period were all observed. However, as Hultman (1996) rightly states, an acute loading regime should be favoured as although the low dose method will elevate muscle creatine concentration to a comparable level, it will do so less rapidly. Interestingly, creatine supplementation protocols relating to subject’s body mass have also been shown to increase total muscle creatine levels (Rossiter 1996; Flanagan 2004). However, more research is needed in this area, before conclusive recommendations can be made. It has become increasingly common to orally supplement creatine by using an initial acute loading phase, followed my a maintenance phase. (Bemben and Lamont 2005; Brenner et al 2000; Maughan 2009) Havenetidis (2003) studied the effects of three varying acute creatine loading protocols (10 grams per day, 25 grams per day and 35 grams per day all in 5 gram doses for 4 days). Both the 25g and 35g doses elicited around an 11% increase in repeated sprint performances compared with baseline measure. These results go some way to validating the use of 25g/day doses, in line with other research regarding an upper limit of creatine use. If this limit is exceeded, the remaining creatine is unlikely to benefit physical performance and will be excreted. (Brosnan and Brosnan 2007)
Responders and Non-responders
Whilst creatine supplementation has been shown to increase total muscle creatine levels, the extent of this increase varies between individuals. Some individuals referred to as “non-responders” show little or no increase in total muscle concentration where others have shown significant increases. (Greenhaff 1994; Hespel 2001; Syrotuik and Bell 2004) There have been several suggested reasons for non-response to creatine supplementation, however these remain unclarified. (Maughan 2009) Greenhaff’s (1994) study involved eight participants undergoing biopsy samples from the vastus lateralis muscle after various recovery times (0, 20, 60 and 120 seconds) from receiving an intense electricallyevoked isometric contraction. The same protocol was repeated in the other leg after supplementing 20g of creatine for the preceeding five days. Although five subjects showed increased total muscle creatine levelsand phoshocreatine resynthesis during recovery, there were little effectsfrom ingesting creatine (5-7% in total muscle creatine and no increase in phosphocreatine resynthesis) seen in the remaining three participants.
The data suggests the remaining three subjects were non-responders to creatine. Conversely, responders to creatine have shown muscle creatine increases of >30%following oral ingestion creatine. (Rawson 2003) Whilst the reasons for such variability in the levels of increase in muscle creatine concentrations following oral ingestion of creatine are often debated, the strongest determinant of muscle creatine uptake appears to be the initial level of creatine in that particular muscle. (Greenhaff 1994, Rawson 2003) Evidence suggests that individuals with larger initial muscle creatine contents will show little to no increase in creatine content post-supplementaion whereas those with lower initial creatine levels will exhibit an increased response. (Casey and Greenhaff 2000; Greenhaff 1994, Rawson 2003) Syrotuik and Bell (2004) studied the physiological difference in attributes between responders and non-responders showing responders to displaying lower initial creatine concentrations. Responders also displayed a larger percentage of type II muscle fibres and exhibited greater fat free mass.
However, due to the small sample size, a generalised conclusion cannot be drawn and further research into the area is required. Studies have shown vegetarian subjects to exhibit a greater increase in total muscle creatine than meat eating individuals when using creatine supplementation (Greenhaff et al1994; Harris et al 1992) with Bulford et al (2007) suggesting that vegans might experience an increase in muscle creatine levels of 20-40% when taking oral creatine supplementation, compared with only up to a 20% increase for those with high initial muscle creatine content. Shomrat et al’s (2000) study showed greater improvements in anaerobic performance in vegetarians compared to non-vegetarians as a result of creatine supplementaion.When omnivorous subjects in Lukaszuk et al’s (2002) study followed a three week lacto-ovo-vegetarian diet, their muscle creatine content was reduced, and they experienced insignificant rises following creatine supplementation when compared with a placebo.
In 2003, Burke et al did further study comparing the effects of creatine on weight training between vegetarians and non-vegetarians. 24 non-vegetarian and 18 vegetarian subjects were split into four groups (vegetarians with creatine, vegetarians with placebo, non-vegetarians with creatine, non-vegetarians with placebo) undertook the same eight week resistance training programme with their 1 rep max leg press and bench press measured. Not only did the subjects supplementing with creatine exhibit a larger increase in bench press, isokinetic work, type II fibre, whole body lean tissue, plasma creatine and total creatine levels when compared with placebo (P < 0.05), results also showed vegetarians to have a larger increase in total creatine, plasma creatine, lean tissue and total work performance than non-vegetarians (P <0.05). It was interesting to note a significant correlation between change in muscle creatine levels and initial muscle creatine levels. Whilst providing evidence suggesting an ergogenic effect of creatine supplementation on resistance training, the study also suggested that individuals with lower levels of initial creatine content, such as vegetarians, are likely to be more responsive to creatine supplementation.(Hespel 2001) Â
Ergogenic Effects of Creatine Supplementation
Oral creatine supplementation has regularly been demonstrated to improve performance in repeated short bursts of high intensity activity for sports that primarily rely on energy provided from the ATP-PC energy system eg. weight-lifting and sprinting. (ACSM; 2009; Becque et al 2000; Hamilton et al 2000; Kurosawa et al 2003; Lehmkuhl et al 2003; Prevost et al 1997; Tarnopolsky and MacLennon 2000; Romer et al 2001; Warber et al 2002; Yquel 2002) Though some studies have shown negative or no effect of creatine supplementation (Hamilton-Ward et al 1997; Kurosawa et al 1997; Ruden et al 1996, Thompson et al 1996)
In these studies, low doses have often to be used, as well as crossover study methods with insufficient time to washout the creatine. Another feature of these studies are the small sample sizes used. It might also be the case that the variability in response to creatine in participants could be attributed to the lack of positive effects found in these studies. As a result, although the majority of studies indicate that creatine supplementation may help with short-duration, high-intensity exercise, this might not be the case with every individual. Conversely, though some data has suggested that aerobic activity in endurance sports such as long distance running can be enhanced through creatine supplementation (Nelson et al 2000; Prevost et al 1997; Rossiter et al 1996), the majority of evidence so far suggests that there is no benefit of creatine to be gained as these events do not primarily use energy derived from the ATP-PC system. (Biwer et al 2003; Branch 2003; Branch and Williams 2002; Terjung et al 2000)
In 2000, Rossouw et al studied the effects of creatine loading on weight lifting performance. Using a creatine and a placebo group, the thirteen participants performed 1 rep max deadlift, with the results showing a significant improvement in performance after five days creatine supplementation. This evidence suggests that acute creatine supplementation may be an effective pre-competition strategy for improving lifting performance and might also be relevant to other athletes performing high intensity, short duration activity. However, as this study used paired t tests to explore just within group change, the scientific advantage of using a placebo group was nullified.
When measuring the effects of creatine supplementation on strength gains in a group of college american footballers, Wilder et al’s (2001) was one of the rare studies to show no increase in gains when either a low dose (3 grams per day) or a high dose (20 grams per day for 5 days followed by a 5 grams per day maintenance dose) of creatine was supplemented. However when Bemben et al (2001) used a similar participant group, the athletes showed a greater improvement in strength, anaerobic power and peak torque when using creatine compared with placebo. This difference in results might be due to a higher maintenance dose used in Bemben et al’s study. However, another possible reason might be that the guidelines in Wilder et al’s study for participants to have only not been ingesting creatine for four weeks prior to research whereas participants in Bemben et al’s study indicated no previous creatine supplementation. Skare et al (2001) studied the effects of creatine performance on sprint performance as 18 male sprinters were split into either a creatine group or placebo group.
The creatine group showed significant improvements in both 100m and repeated sprint performance, while the placebo group showed no improvement in times. However, this study is unclear as to whether simply a paired t-test was usedor a group by time evaluation was used. The positive benefits on sprint performance have also been shown in numerous other studies (Izquierdo et al 2001; Cox et al 2002; Romer et al 2001) and research so far generally suggests that creatine supplementation is useful in improving sprint performance. It has been suggested that uptake of muscle creatine when ingested with carbohydrate can increase due to stimulatory effect of insulin on muscle creatine transport. (Green et al 1996; Steenge 1998)
Though, whilst this might be true, the performance effect caused by the extra carbohydrate does not appear to be significantly larger than when creatine supplementation is used alone. Theodorou (2005) examined the effects of creatine supplementation alone and with carbohydrate on repeated bouts of maximal swimming. Whilst all participants increased their swimming performance when compared to no creatine supplementation at all, there was no significant difference in the extent of these improvements between either group. The results suggest that although carbohydrate supplementation might increase the uptake of muscle creatine, it doesn’t appear to improve performance in repeated bouts of maximal swmming when compared with creatine supplementation alone.
It has also been suggested that when exercise training is combined with supplementation, there is a synergistic effect, leading to enhanced athletic performance to a greater extent than training or creatine supplementation alone (Harris et al 1992; Brannon et al 1997), however further research is needed in this area. It is also important to note that whlst caffeine can be regarded as an ergogenic aid in its own right, it has been shown to negate the positive ergogenic effects of creatine supplementation and whilst further research is required to validate these claims, athletes should take caution when considering using both substances together. (Vandenberghe 1996; Hespel et al 2002)
Creatine and The Immune System
The immune system serves to identify and protect the body from pathogens and mount appropriate inflammatory responses to infection and trauma. There is some evidence to suggest that intensive exercise can adversely affect the immune system by impairing the function of neutrophils (Nieman et al 1995; Hack et al 1995; Pyne et al 1995) and causing a reduction in the number of white blood cells in the bloodstream (Hoffman-Goetz and Pederson, 1994). It has been proposed that athletes may be predisposed to upper respiratory tract infections due to altered immune responses. (Peters-Futre 1997; Nieman 1994; Pederson and Bruunsgaard 1995)
In Shephard et al’s (1995) study, however, it was found that many athletes reported fewer infections when training intensively. To date, there is no evidence to suggest that creatine supplementation has an affect on exercise-induced immunosuppression. However, other ergogenic aids such as glutamine have been linked with a reduction in exercise induced immunosuppression. Importantly, it has been shown that glutamine plasma concentrations decline after exericse, and that this can impair the function of the lymphocytes. (Newsholme and Parry-Billings 1990; Keast et al 1995) This is important because it may infer that glutamine dietary supplementation could optimise glutamine levels, and therefore lymphocyte function after exercise. This idea was demonstrated in a study of marathon runners, which suggested glutamine supplementation reduced the incidence of upper respiratory tract infections. (Castell et al 1996)
However, other studies have demonstrated that although glutamine supplementation achieved higher glutamine plasma concentrations, this did not alter the exercise induced lymphocyte dysfunction. (Rohde et al 1998; Krzywkowski et al 2001) Rohde et al’s (1998) study used eight healthy male participants undertaking three separate cycle ergometer tests with two hours gap in between tests. Participants worked at 75% vo2 max for 60, 45 and 30 minute bouts respectively. In a randomised cross-over study, participants received either nine equal doses of glutamine (100mg glutamine/kg of body weight) or placebo thirty minutes before the end of each exercise, at the end of each exercise, as well as thirty minutes after the end. Arterial blood samples were used to determine levels of glucose concentration. Arterial plasma glutamine concentration levels decreased from baseline when measured two hours after completing the last exercise in the placebo group. Conversely, when athletes supplemented with glutamine, plasma glutamine concentrations were maintained above original levels.
However, the numbers of circulating lymphocytes and the phytohemagglutinin-stimulated lymphocyte proliferative response in both glutmaine and placebo groups declined two hours after each exercise. The primary finding of the paper showed that glutamine supplementation failed to influence the exercise-induced decline in LAK cell activity, nor influence differences in any of the leukocyte subpopulations examined. Whilst Castell et al’s (1996) findings suggested glutamine had positive effects on the number of respiratory tract infections suffered, Rohde et al’s (1998) study showed glutamine not to be of use in the cycling loads used in this study. However, further studies might be necessary to investigate timing and size of doses, as well as the the effects of glutamine on other areas of immune function.
Side Effects and Health Issues
A commonly reported adverse effect of creatine supplementation is the increase in body mass caused due to the osmotic load associated with increased creatine levels resulting in increased water retention. (Mesa 2002; Robinson et al 1999; Wilder 2001; Wyss 2000) As a result of an 100g acute creatine loading, body mass increases can range from 1-3kg. (Greenhaff 1994; Balsom 1995; Rossiter 1996; Yquel 2002) This increase in body mass might either be beneficial, or detrimental to athletic performance, dependent on the sport or activity untaken.
There have also been anecdotal reports suggesting creatine supplementation can increase the incidence of muscle cramping, however, there is no evidence to support this. If muscle cramps are experienced, they are mostly likely a result of the high intensity of the exercise (Terjung et al 2000; Poortmans and Francaux 2000) or lack of adequate hydration. (Bemben et al 2005) Links have also been made between the use of oral creatine supplementation with negative renal effects, with Poortmans and Francaux (2000) claiming these to originate in 1998. These claims related to a decreased glomerular filtration rate (GFR) in a male who had previously been diagnosed with kidney disease. (Pritchard and Kalra, 1998)
Since then, further individual case studies have been published, citing the negative effects on kidney function caused by creatine supplementation. (Koshy et al 1999, Thorsteinsdottir et al, 2006) Whilst creatine is a constituent of glomerular filtration rate and necessitates renal excretion, there is no substantial evidence to suggest renal dysfunction can be caused by healthy adult supplementing creatine in normal doses (less than 25 grams per day). Furthermore, studies by Poortmans and colleagues have repeatedly suggestedcreatine supplementation to cause no detrimental effects to renal function in short, medium and long-term studies. (Poortmans and Francaux 1999, Poortmans et al 1997, Poortmans et al, 2005) In 2003, Kreider et al compared athletes using creatine supplementation with a control group. Whilst there were so significant differences in the creatinine levels of creatine users and the control group, it was noted that during intense training sessions, most of the athletes showed elevated creatinine levels.
This would suggest that most of the athletes would be suffering from kidney problems if elevated serum creatine levels were the sole determinant of renal dysfunction, which is clearly not the case. Whilst the kidney problems have been reported in case studies, no link between ingestion of oral creatine and renal dysfunction in healthy adults has been seen in controlled, large scale studies. Results of long-term safety trials suggest no long-term side effects for athletes, clinical patients or children with creatine synthesis deficiency. (Kreider et al 2003; Poortmans and Francaux 1999; Robinson et al, 2000; Schilling et al, 2001 Williams et al, 1999) It has also been suggested that the use of creatine also has some positive health effects including decreased recovery time from injury (Hespel et al 2001; Jacobs et al 2002; Tarnopolsky 2000), positive neuroprotective effects (Ferrante et al 2000; Hausmann et al 2002; Sullivan et al 2000; Wyss et al 2002; Zhu al 2004) and decreased incidence of heat stress (Greenwood et al 2003; Kilduff et al 2004; Volek et al 2001) and musculoskeletal injuries (Greenwood et al 2003; Schilling et al 2001; Tyler et al 2004), although further reseach is needed in this area.
Evidence from short and long-term studies suggests that creatine supplementation in healthy adults appear to be safe, providing users don’t exceed the recommended dose (less than 25 grams per day). It is, however, recommended that individuals with pre-existing renal dysfunction avoid creatine supplementation. (ACSM 2009)
Conclusion The majority of evidence suggests that creatine supplementation is useful in improving performance in repeated bouts of high-intensity, short-duration exercise e.g. sprinting and weightlifting. ACSM; 2009; Bemben et al 2001; Hamilton et al 2000; Kurosawa et al 2003; Lehmkuhl et al 2003; Volek et al 1997; Warber et al 2002; Yquel 2002) However, regular positive effects as a result of creatine supplementation on aerobic activty appear unlikely. (Biwer et al 2003; Branch and Williams 2002; Terjung et al 2000) Although there may be substantial benefits to be gained from oral supplementation of creatine, individuals with high initial muscle creatine levels may not respond tosuppplementation as well as those with lower initial muscle creatine levels. (Hespel 2001; Rawson 2003; Syrotuik and Bell 2004) Whilst claims have been made concerning the negative effects of creatine supplementation, such as the risks of renal dysfunction and muscle cramping, controlled long-term studies suggest that there are no associated risks in healthy adults. Individuals with pre-existing renal dysfunction however, should avoid creatine supplementation. (ACSM 2009)
Whilst creatine monohydrate is still the most popular creatine form on the market, it wouldn’t be fair to overlook some of the newer forms of creatine that are currently available and their individual merits. As creatine monohydrate may cause bloating in some users, many report improved results and less bloating from alternative types of creatine.
Micronised Creatine: Micronised creatine differs from monohydrate as it has a larger surface area and smaller molecules, helping to reduce bloat and discomfort. If you are a non-responder to creatine monohydrate then this might be a good bet.
Creatine Ethyl Ester (CEE): The additional ester attached to the creatine molecule in CEE allows for greater absorption, with many users reporting decreased bloat and improved results when compared to monohydrate. CEE is generally more expensive than monohydrate and it is therefore best to try monohydrate first to see how you respond.
Tri and Di Creatine Malate: Again, these are generally regarded as more water soluble and absorbant but are more expensive than the standard creatine monohydrate.
Kre-Alkalyn: Kre-Alkalyn does not convert to waste product creatinine before absorption into muscle tissue. Although there have been no scientific studies on the effectiveness of kre-alkalyn, there is no loading phase required and anecdotal feedback is generally very positive.
Creatine Orotate: Creatine orotate is infamous for its inclusion in the popular Clout by MAN Sports. Creatine is bonded to orotic acid, which aids with optimal cell function and increased ATP levels.
- ATP regeneration is enhanced by the presence of phosphocreatine (PCr) within the muscle fiber. As a result of this, creatine has been shown to improve exercise performance in sports involving repeated bursts of short duration, high-intensity activity, which primarily rely on energy provided from the ATP-PC system.
- There are generally thought to be no known benefits of creatine supplementation on anaerobic activity, although there is some evidence to suggest otherwise.
- It has been suggested that ingesting carbohydrate alongside creatine supplementation can enhance performance beyond creatine supplementation alone due to the stimulatory effect of insulin on muscle creatine transport.
- Claims have also been made regarding the possible synergistic effect when creatine supplementation is combined with exercise training, resulting in a greater increase in performance than when creatine is used alone.
- Athletes should take caution when considering using caffeine and creatine together, as studies suggest that caffeine might negate the ergogenic effects caused by creatine supplementation.
- Creatine supplementation has been shown to increase the osmotic drive within muscle tissue, therefore leading to an increase in body mass due to water retention. Body mass gains from 1-3kg have been seen as a result of an 100g acute creatine loading regime.
- There is some evidence to suggest that creatine may have some positive health benefits, including a reduction in the recovery time from injury and positive neuroprotective effects.
- Acute creatine loading regimes (~25g/day for 5days) have been effective in increasing total muscle creatine content. Low-dose maintenance regimens (~5g/day) have also been shown to increase total muscle creatine, achievingsimilar levels to acute loading regimes, although importantly, the low-dose method will do so less quickly. Over time it has become increasingly popular to supplement creatine using an initial acute loading method followed by a low-dose maintenance phase.
- Most research suggest supplementing creatine in amounts of 20g – 25g per day as there are no ergogenic benefits from supplementing in any amount larger than 25g/day.
- Individuals with low intial levels of muscle creatine (“responders”) e.g. vegetarians are likely to exhibit a greater response to creatine supplementation than those with initially higher creatine levels (non-responders).
- There is no evidence to suggest creatine has an effect on the immune system or levels of exercise-induced immunosupresssion.
- Although claims have been made concerning the adverse effects of creatine supplementationsuch as the risks of renal dysfunction and muscle cramping, controlled long-term studies suggest that there are no associated risks in healthy adults. However, it is important that users do not exceed the recommended dosages (25g/day). Creatine supplementation in individuals with pre-existing renal difficulties is not recommended.
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ACSM Position Stand: Nutrition and Athletic Performance (2009)
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