An Evidence Based Review of Creatine

Introduction to Creatine

Creatine was first discovered by a French scientist, Chevrewul in 1835, and is derived from the Greek word kreas (flesh).¹ Creatine is a non-essential molecule that is produced endogenously, primarily in the liver, and to a lesser degree the pancreas and kidneys. It is an amine constructed from three amino acids, arginine, glycine, and methionine.^2,3 Of the three amino acids, only methionine is considered indispensable. It can be obtained exogenously from dietary food sources and/or supplementation. Food sources rich in creatine include red meat, rabbit, and fish.^2-4 Most adults who consume meat and fish get approximately 1 to 2 grams per day from diet.^2,3 Whereas vegetarians and vegans consume very small amounts, and therefore rely on endogenous production.³ While this coupled with endogenous production is enough to prevent a creatine deficiency, which is rare, it is not enough to significantly improve performance.^3,5 Although research trials with creatine began in the early 1900’s, supplementation with creatine did not gain popularity until the early 1990’s. At this time it was discovered that supplementation with creatine increased the metabolically-active pool of creatine, namely phosphocreatine (Pcr).⁶

Background and Science Principles: Energy Systems & ATP

Creatine is one of the most popular ergogenic sports supplements available today. The popularity of creatine is matched by it repeatedly being demonstrated as the most effective ergogenic supplement for increasing strength, power, and lean mass when combined with resistance training.^2,5,7,12 Some evidence suggests it may also improve high-intensity sprints and endurance training.^2,5,8-11 Understanding the energy systems of the body is fundamental to understanding the role and potential benefits of creatine supplementation. Adenosine triphosphate (ATP) is a high-energy molecule used by all cells in the body for energy. In terms of exercise and sports performance, the focus is on its role in skeletal muscle. The potential energy in ATP is stored in the phosphate bond. When the bond is broken (hydrolyzed), energy is released for the cell to perform work, such as the force needed for the contraction and consequent relaxation of skeletal muscle. ATP that is stored in skeletal muscle, where exercise, even at the highest intensities will only exhaust 20-30% of stored ATP. This will lead to exhaustion, however it also indicates a large pool of stored ATP is not available to be used in force production.¹³ Therefore, ATP is rapidly replaced to provide energy. When ATP is hydrolyzed, it becomes adenosine diphosphate (ADP), a lower energy molecule that must be rephosphorylated to ATP. The body has three energy systems to replenish ATP, namely creatine phosphate, anaerobic glycolysis, and oxidative phosphorylation.^3,13The table below summarizes the power output, amount of ATP replenished, and example activities for each energy system.

Predominant Energy System	Power output	Amount of ATP replenished	Example Activities
Creatine phosphate	80-100%	Very small	40 yard sprint, vertical jump, bench press (all performed at maximum effort)
Anaerobic glycolysis	60-80%	Small	200 M sprint, 400 M sprint
Oxidative phosphorylation	<60%	Large	5K run, triathlon

It is important to note that each of the three energy systems can be simultaneously active during a given exercise and/or sport. However, one is generally going to be the predominant source of energy.³ Although evidence suggests creatine supplementation can benefit sports and exercise that predominantly exhaust any one of the three energy systems, the creatine phosphate system is most directly affected, followed by anaerobic glycolysis, and then oxidative phosphorlylation.^2,7-12Creatine exerts its benefits within the creatine phosphate energy system by increasing phosphocreatine (PCr) levels. Like ATP, PCr stores its energy within the phosphate bond, and it is stored in skeletal muscle and other tissue.³ However, unlike ATP, the energy in the phosphate bond of PCr is not used directly to provide energy for force contraction. Rather when ATP is hydrolyzed to ADP, the high energy phosphate from PCr is used to rephosphorylate ADP into ATP. Therefore, PCr acts as a high energy reservoir for skeletal muscle. The ability to replenish ATP is one of the limiting factors during high intensity, short-term exercise.^2,5The net effect of creatine supplementation on energy is an accelerated rate of ATP resynthesis.

Effects of Creatine Supplementation on Recover

Bassit et al¹⁴ demonstrated a protective effect from creatine supplementation. Specifically, they took blood samples from Ironman triathletes 36 hours before and 60 hours after the race. They measured several markers of muscle damage (creatine kinase, lactate dehydrogenase, aldolase, glutamic oxaloacetic acid transaminase, and glutamic pyruvic acid transaminase), and found that while all five markers increased in the participants receiving a placebo following the race, creatine supplementation decreased three of the five markers and prevented a rise in the other two.¹⁴

Creatine supplementation can also decrease oxidative stress via antioxidant activity. The proposed mechanism is via scavenging free radical oxidation that results from nitric oxide production (needed for vasodilation).² Cooke et al¹⁵ found that in addition to antioxidant activity, that it may also enhance the buffering capacity of muscle. Specifically, they speculate that it may reduce calcium-activated proteases. This in turn minimizemyolemma and further influxes calcium into the muscle.¹⁵

Study Showing Just 7 Days on Creatine Improved Performance

In a 2011 study with recreational, resistance trained males, Rahimi¹⁶ found that 7-days of supplementation with creatine at a loading dose (4 x 5 g/d) not only significantly improved performance, but also reduced DNA damage and lipid peroxidation induced by resistance training.¹⁶The measurable ergogenic benefit of the antioxidant effect and enhanced recovery from creatine supplementation, is the ability for resistance trained athletes to perform better during subsequent training sessions. Recreational athletes and especially elite athletes in various sports, undertake training sessions on a given muscle group two to three days following a previous training session. Improvement in strength recovery allows athletes to train with a higher load than they otherwise would be able to. The net effect of this likely explains the greater mass and strength gains observed in resistance training athletes supplementing with creatine.^2,7-8,11-12

Effect of Creatine Supplementation on Aerobic Performance

While an abundance of research has demonstrated creatine supplementation benefits for strength, hypertrophy, and anaerobic endurance, there is also evidence demonstrating positive effects on aerobic endurance. In a randomized, double blind, placebo controlled trial, Chilibeck et al⁸ sought to determine if increased body mass from creatine supplementation would adversely affect aerobic endurance in rugby union players. The researchers stressed that these were rugby union players, as opposed rugby league players, which have been used in past studies involving creatine and rugby. Rugby union requires more aerobic endurance, muscular strength, and muscular endurance. This is due to more continuous play, scrums, unlimited tackles, and heavier weight forwards. While players supplementing with creatine increased lean body mass and improved anaerobic endurance over the placebo group, there was no adverse effect on aerobic endurance.⁸

Hadjicharalambous et al⁹sought to examine if supplementation with creatine could influence perception of effort during prolonged exercise in the heat, and consequently improve endurance performance. Specifically, the researchers took endurance-trained males and had them exercise on a stationary bike in a climactic chamber. The intensity was based on pre-testing, so a rate could be established where fatigue would set in at 40-60 minutes for each subject. Only the creatine responders (based on estimated Cr uptake) improved endurance performance, which was measured by time improvements to exhaustion. The creatine responders time to exhaustion was 51.7 ± 7.4 min vs. 47.3 ± 4.9 min for non-responders.The enhanced thermal tolerance is speculated to be a result of increased total body water in creatine responders.⁹

In another randomized, double blind, placebo controlled trial Graef et al¹⁰ investigated the effects of creatine citrate supplementation and high intensity interval training (HIIT) on cardiorespiratory fitness. HIIT is a form of exercise that can induce similar adaptations as aerobic training in a time efficient manner. No differences between the creatine and placebo group were observed in terms of total work done or VO_2PEAK.However, ventilatory threshold increased in the creatine group.¹⁰

Generally endurance activities lasting more than 150 seconds, predominantly rely on oxidative phosphorylation as the main energy system. Most research suggests that continuous activity lasting longer than 150 seconds mitigates the benefits from creatine supplementation. However, as demonstrated above there are benefits creatine supplementation can yield for endurance activities. Also some evidence suggests that creatine supplementation may cause a change in the predominant energy system utilized during aerobic activity, which in turn may improve endurance performance.²

Effect of creatine supplementation on anaerobic exercise, hypertrophy, and body composition

Chillibeck et al⁸ observed that creatine increased lean body mass and improved anaerobic endurance in rugby union players.⁸Spillane et al¹⁷ examined the effects of how seven weeks of supplementation with creatine monohydrate, creatine ethyl ester, or placebo combined with resistance training affected body composition, muscle mass, and muscle strength and power. All three groups improved in terms of muscle strength and power (1-RM bench press and leg press). The placebo group and creatine monohydrate group decreased fat mass, however dietary recall was used to determine energy intake. Finally subjects receiving creatine monohydrate had the greatest increase in thigh muscle mass based on DEXA scans.¹⁷

Burke et al⁷ observed that creatine supplementation, combined with a high-volume, heavy load (>70% 1-RM) resistance training program increased type II muscle fiber area of the vastus lateralis by 28% for the creatine users vs. 5% for the placebo group.⁷

In a recent study of elite Brazilian soccer players, Claudino et al¹¹sought to determine if creatine monohydrate could improve their performance. To test the effects of creatine supplementation, the researchers measured lower limb muscle power. They had the subjects perform a countermovement jump (CMJ); performance was assessed by using a strain-gauge force plate. CMJ performance consisted of 8 jumps with 1 minute of rest between each jump. Subjects had to keep to their hands on their chest to keep the jumps similar in terms of technique. In other words, athletes could not use a technique that may involve using the upper body, such as swinging their arms to increase the jump, taking the better technique variable out of the assessment. At baseline both groups had comparable jumping performance. After intervention the placebo group jumping performance was 0.7% lower than baseline scores and the creatine groups jumping performance was 2.4% greater than baseline. The decrease and relatively low improvement in the creatine group (not statistically significant) is attributed to progressive training-induced lower limb decline due to the rigors of the pre-season games and training. The main effect demonstrated in this study is the ability of creatine supplementation to offset these effects, leading to the jumping performance improvement. The effect in the macro (from baseline to the end of the study) is likely due to the elevated levels of creatine phosphate, leading to a lesser decrease in force production throughout training sessions in the creatine group. However, this could not be verified as taking a muscle biopsy from elite athletes in the pre-season was not feasible.¹¹

Ziegenfuss et al¹² recently examined the effects of a dietary supplement containing creatine monohydrate on power and golf swing performance. The golf swing is an anaerobic movement that can benefit from improved club head speed. Improving club head speed can be accomplished by improved power output. Researchers assessed power by bench press throws, and upper body strength by 1-RM bench press as it is closely correlates with the strength and power needed in a golf swing. Golf swing performance was measured by a 3-D swing analysis system. Power, best drive, and average distance significantly improved in the supplemented group. At baseline the supplemented group had significantly greater maximal strength and peak power production than the placebo group, this may have affected the results of the study.

Creatine Responders vs. Non-responders

A possible confounding variable in much of the research is individual difference in terms of response to creatine supplementation. It is a common limitation in many of the studies I reviewed, and can be viewed in table 2 below. Not everyone responds to creatine supplementation. Hadjicharalambous et al⁹ initially determined that creatine supplementation had no effect on endurance performance. However, upon dividing participants into responders and non-responders based on their intramuscular creatine uptake, they determined that the responders had a significant performance increase over non-responders (51.7 ± 7.4 min vs. 47.3 ± 4.9 min).⁹

Burke et al⁷ studied 42 recreationally active individuals (male and female) to compare changes in insulin-growth factor (IGF-I) content from resistance training and creatine supplementation. The individuals were randomized in blocks and classified as vegetarian (lacto-ovo or vegan) or non-vegetarian. Within the creatine group vegetarians, in spite of lower caloric and protein intake gained an average of 2.4 vs. 1.9 kg/lbm for non-vegetarians.Also Pcr levels in the creatine group had an increase of 37% for vegetarians vs. 11% for nonvegetarians.⁷Vegetarians rely on endogenous production of creatine due to a lack of exogenous sources in their diets.³Therefore, they tend to have a lower initial level of total muscle creatine content.^3,7This leads to them having a greater potential to improve performance from creatine supplementation.

Response to creatine supplementation amongst individuals can be divided into three classes, responders, quasi responders, and non-responders.² Creatine responders tend to have the characteristics listed below:

Lower initial level of total muscle creatine content.²
Greater population of type II muscle fibers.²
Larger cross sectional area for type I and type II muscle fibers.²
Possess higher potential to improve performance in response to creatine supplementation.²

Ideally, when feasible (requires a muscle biopsy) researchers should assess intramuscular creatine uptake to determine if non-response played a role in the results of a given study.

Creatine Supplementation Myths

Largely due to the popularity of creatine supplementation, many myths have been attributed to creatine. The sources are generally from anecdotes and media reports linking creatine supplementation to anabolic steroid use. Buford et al⁵ in the position stand of the International Society of Sports Nutrition on creatine supplementation have identified purported myths:

All weight gained from creatine supplementation is due to water retention.⁵
Creatine supplementation causes renal distress.⁵
Long term effects of creatine supplementation are a mystery.⁵
Creatine supplementation is banned as a PED and it is unethical to use.⁵
Creatine supplementation causes cramping, dehydration, and/or altered electrolyte status.⁵

Creatine Supplementation Facts

In direct contrast to the myths surrounding creatine supplementation, evidence accumulated from numerous studies on creatine supplementation has demonstrated the following facts:

There is no scientific evidence that short- or long term creatine use has any detrimental effects in otherwise healthy individuals.⁵
In addition to being safe, creatine is possibly beneficial for preventing injury and cramping.^2,5
Creatine monohydrate is the most effective form of supplemental creatine.^2,5
Creatine is the most effective ergogenic nutritional supplement available today for increasing both lean mass and high-intensity exercise capacity.^2,5

Creatine and Sports

In addition to the above, many sports governing bodies approve creatine supplementation for athletes competing under their jurisdiction. Specifically, creatine is not on the banned lists of the National Collegiate Athletic Association (NCAA) or the World Anti-Doping Agency (WADA).^18-19

Creatine supplementation is banned as a PED and it is unethical to use.⁵
Creatine supplementation causes cramping, dehydration, and/or altered electrolyte status.⁵

Creatine Dosage

There are two evidence based dosing protocols for creatine monohydrate supplementation:

With a loading phase: 20 g/d or 0.3 g/kg/d taken in 4 divided doses of ~5 g for 3-5 days. This is followed by a maintenance dose of 3-5 g/d or 0.03 g/kg/d for the duration.^2,5
No loading phase: 3-5 g/d or 0.03 g/kg/d for the duration.^2,5

Creatine is often taken with a carbohydrate and/or protein containing beverage. Some evidence suggests insulin plays a role in increasing skeletal muscle uptake of creatine.^2,5 However, based on field observation, anecdotal evidence, and a review of the published evidence it is unclear if the performance benefits by addition of protein and/or carbohydrates are due to greater uptake of creatine or from the carbohydrates/protein itself. In light of this and based on research demonstrating benefits, water alone can also be effective.^2,5

Conclusion on Creatine

Creatine supplementation has been repeatedly demonstrated to be safe, effective, and ethical.² Numerous studies have demonstrated that creatine supplementation can improve anaerobic endurance, strength, and lean body mass when combined with exercise.^2,7-8,11-12It may also improve aerobic endurance.^2,9,10 In addition to performance, creatine can improve recovery and possibly prevent injury.^2,5

Table 1. Comparison of Supplementation Protocols and Effectiveness of Peer-Reviewed Studies on Creatine

Reference	Trial Design	Trial Length	Sport/Level	Participants (Total (n), gender, age).	Form of Supplement	Dosage &Timing of Supplementation	Effective
Manjarrex-Montes de Coa, et al.²⁰	Randomized, double blind, placebo controlled, crossover design	18 weeks (includes 6 week washout period)	Taekwondo Practitioners / Recreational	n = 12 M 18-22 y	Creatine monohydrate powder	0.05 g/kg. (~4 g/d for 80 kg) Single dose, daily, exact timing not given.	No
Chilibeck PD, et al.⁸	Randomized, double blind, placebo controlled	8 weeks	Rugby union players / Recreational	n = 19 M 24-30 y	Creatine monohydrate capsules*	0.1g/kg. (~8 g/d for 80 kg) Single dose daily, exact timing not given	Yes
Hadjicharalambous M, et al.⁹	Randomized, double blind, placebo controlled	7 Days	n/a / Endurance trained	n = 21 M 22-32 y	Creatine monohydrate powder	20g/d. 5 g – 4x/day	Yes
Spillane M, et al.¹⁷	Randomized, double blind, placebo controlled	48 Days	Resistance training / Recreational	n = 42 (30 completed) M 18 – 23 y	Creatine monohydrate / Creatine ethyl ester powder	Days 1 – 5: 10 g/d/am 10 g/d/pm Days 6 – 48: 5 g/d/AM	Yes
Graef JL, et al.¹⁰	Randomized, double blind, placebo controlled	30 Days	HIIT / Recreational	n = 43 M 18 – 27 y	Creatine citrate powder	10g/d 5 g – 2 x/day/5 days/week; one taken 30 min prior and one dose immediately following training	Yes
Burke DG, et al.⁷	Randomized, double blind, placebo controlled	56 Days	Resistance training / Recreational	n = 42 M – 24 F – 18 28 – 44 y	Creatine monohydrate powder	7 d at 16.8 g/d (4.2 g – 4x/day) 49 days at 4.2 g/d (after training or in the am)	Yes
Claudino JG, et al.¹¹	Randomized, double blind, placebo controlled	49 Days	Elite soccer players	n = 14 M 17 - 19 y	Creatine monohydrate powder	7 days at 20 g/d (5 g – 4x/day) 42 days at 5 g/d	Yes
Ziegenfuss TN, et al.¹²	Randomized, double blind, placebo controlled	30 Days	Average – Above average golfers	n = 27 M 23 – 37 y	Creatine monohydrate powder (supplement had caffeine, vitamin D, & boron)	14 days at 10 g/d (5 g - 2x/day) 14 days at 5 g/d	Yes

*The researchers stated the dose was 0.1g/kg/day and that the tablets were 2.5g each. They stated on average 9 tablets were taken per day, if the tablets did in fact contain 2.5g of creatine then the dose was far higher. Therefore there must have been filler in the tabs that was not disclosed.

Table 2 Comparison of Effectiveness of Creatine

Reference	Training protocol	Limitations (if any)	Effectiveness of creatine
Manjarrex-Montes de Coa, et al.²⁰	Taekwondo (TKD) training 3 days/week for roughly 2 hours/day.	- Small sample size - Duration - No loading phase. - Possible non-responders - Lack of dietary control	Anaerobic power (30 s Wingate test): No improvement. Body Composition (DEXA scan): No improvement; increased body fat mass over placebo.
Chilibeck PD, et al.⁸	Rugby union players practiced twice/week for ~2 h/session and played one 80 min game/week. Aerobic, anaerobic sprint, and muscular endurance training.	- Dietary recall - No loading phase	Aerobic Endurance (Shuttle run test 20 min repeated bouts every 2 min): No difference. Body composition (BOD POD): Decreased bodyfat, increased lean mass. Muscular endurance (Leg press and bench press): No difference. When combined Cr was effective.
Hadjicharalambous M, et al.⁹	Subjects were endurance trained coming into the study	- Possible non-responders - Duration (7 days)	Aerobic Endurance (time improvement to exhaustion): Increased Body Mass (TBW): Increased Effort perception: Reduced during exercise in the heat.* Thermal Stress: Reduced* *Effect only observed in creatine responders.
Spillane M, et al.¹⁷	Resistance training protocol; 4-day/week, upper and lower body split, each performed 2x/week.	- Untrained subjects, may have benefited from resistance training alone, confounding the results. - Dietary recall	Anaerobic power (30 s Wingate test): All 3 groups improved no difference. Body composition (DEXA scan): All 3 groups gained lean mass. Only the CM and PLA decreased fat mass, CM group had the greatest increase in thigh muscle mass. Muscle strength and power (Leg press and bench press 1RM): All 3 groups improved, no difference
Graef JL, et al.¹⁰	High-intensity interval training (HIIT) performed 5 days/week for 6 weeks	- Low dose (no loading) - Study duration - Possible non-responders - The 110% workload (TWD) measured on the first ride to exhaustion of 3 rides	Body weight: No change Total work done (TWD): No improvement Ventilatory threshold (VT): Increased VO_2PEAK:All groups improved, no difference
Burke DG, et al.⁷	High-volume, heavy load (>70% 1 RM) resistance training program, 4 days/wk. body part split, 8 weeks.	- Dietary recall	Training volume (kg x reps):Increased. IGF-1 levels: Increased Phosphocreatine levels: Increased 37% for vegetarians and 11% for non-vegetarians Muscle Biopsy (in type II fiber area of the vastus lateralis): 28% (Cr) vs. 5% (Pl) increase
Claudino JG, et al.¹¹	Resistance and soccer specific training. (3 x 8-10 reps, 1-3 min recovery) 2x/wk. 50-60 min/session. Sport specific plyometric and training 5x/wk.	- Muscle creatine content not measured - Sample size, n = 14 - Dietary recall - Only anthropometric measures, BW & HT	Countermovement jump (CMJ)Baseline change: Cr group +2.4%; Pl group -0.7%
Ziegenfuss TN, et al.¹²	None indicated, study was “free living” to mirror the lifestyle of average to above average golfers.	- Cr group was significantly stronger at baseline 1-RM bench press & peak power production (bench throws - Dietary recall	1-RM bench press – Both groups improved Bench press throws (peak power production) – Statistically significant improvement in supplemented group Best drive distance – increased 13.6 yards in Cr group, -1.2 y in Pl group

References

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Creatine Guide