Studies on the safety of creatine supplementation

Doubtful allegations of adverse effects of creatine supplementation have been released through the press media and through scientific publications. In the present review we have tried to separate the wheat from the chaff by looking for the experimental evidence of any such claims. Anecdotal reports from athletes have appeared on muscle cramp and gastrointestinal complaints during creatine supplementation, but the incidence of these is limited and not necessarily linked to creatine itself. Despite several unproved allegations, liver (enzymes, urea) and kidneys (glomerular filtration urea and albumin excretion rates) show no change in functionality in healthy subjects supplemented with creatine, even during several months, in both young and older populations. The potential effects (production of heterocyclic amines) of mutagenicity and carcinogenicity induced by creatine supplementation have been claimed by a French Sanitary Agency (AFSSA), which might put consumers at risk. Even if there is a slight increase (within the normal range) of urinary methylamine and formaldehyde excretion after a heavy load of creatine (20 g/day) this is without effect on kidney function. The search for the excretion of heterocyclic amines remains a future task to definitively exclude the unproved allegation made by some national agencies. We advise that high-dose (>3–5 g/day) creatine supplementation should not be used by individuals with pre-existing renal disease or those with a potential risk for renal dysfunction (diabetes, hypertension, reduced glomerular filtration rate). A pre-supplementation investigation of kidney function might be considered for reasons of safety, but in normal healthy subjects appears unnecessary.     

Effects of repeated creatine supplementation on muscle, plasma, and urine creatine levels

The purpose of this case study was to examine the effects of repeated creatine administration on muscle phosphocreatine, plasma creatine, and urine creatine. One male subject (age, 32 years; body mass, 78.4 kg; height, 160 cm; resistance training experience, 15 years) ingested creatine (20 g.d(-1) for 5 days) during 2 bouts separated by a 30-day washout period. Muscle phosphocreatine was measured before and after supplementation. On day 1 of supplementation, blood samples were taken immediately before and hourly for 5 hours following ingestion of 5 g of creatine, and a pharmacokinetic analysis of plasma creatine was conducted. Twenty-four-hour urine collections were conducted before and for 5 days during supplementation. Muscle phosphocreatine increased 45% following the first supplementation bout, decreased 22% during the 30-day washout period, and increased 25% following the second bout. There were no meaningful differences in plasma creatine pharmacokinetic parameters between bouts 1 and 2. Total urine creatine losses during supplementation were 63.2 and 63.4 g during bouts 1 and 2, respectively. The major findings were that (a) a 30-day washout period is insufficient time for muscle phosphocreatine to return to baseline following creatine supplementation but is sufficient time for plasma and urine creatine levels to return to presupplementation values; (b) postsupplementation muscle phosphocreatine levels were similar following bouts 1 and 2 despite 23% higher presupplementation muscle phosphocreatine before bout 2; and (c) the increased muscle phosphocreatine that persisted throughout the 30-day washout period corresponded with maintenance of increased body mass (+2.0 kg). Athletes should be aware that the washout period for muscle creatine to return to baseline levels may be longer than 30 days in some individuals, and this may be accompanied by a persistent increase in body mass.     

Effects of creatine supplementation on performance and training adaptations

Creatine has become a popular nutritional supplement among athletes. Recent research has also suggested that there may be a number of potential therapeutic uses of creatine. This paper reviews the available research that has examined the potential ergogenic value of creatine supplementation on exercise performance and training adaptations. Review of the literature indicates that over 500 research studies have evaluated the effects of creatine supplementation on muscle physiology and/or exercise capacity in healthy, trained, and various diseased populations. Short-term creatine supplementation (e.g. 20 g/day for 5–7 days) has typically been reported to increase total creatine content by 10–30% and phosphocreatine stores by 10–40%. Of the approximately 300 studies that have evaluated the potential ergogenic value of creatine supplementation, about 70% of these studies report statistically significant results while remaining studies generally report non-significant gains in performance. No study reports a statistically significant ergolytic effect. For example, short-term creatine supplementation has been reported to improve maximal power/strength (5–15%), work performed during sets of maximal effort muscle contractions (5–15%), single-effort sprint performance (1–5%), and work performed during repetitive sprint performance (5–15%). Moreover, creatine supplementation during training has been reported to promote significantly greater gains in strength, fat free mass, and performance primarily of high intensity exercise tasks. Although not all studies report significant results, the preponderance of scientific evidence indicates that creatine supplementation appears to be a generally effective nutritional ergogenic aid for a variety of exercise tasks in a number of athletic and clinical populations.     

Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion.

The total creatine pool size [Cr(total); creatine (Cr) + phosphocreatine (PCr)] is crucial for optimal energy utilization in skeletal muscle, especially at the onset of exercise and during intense contractions. The Cr(total) likely is controlled by long-term modulation of Cr uptake via the sodium-dependent Cr transporter (CrT). To test this hypothesis, adult male Sprague-Dawley rats were fed 1% Cr, their muscle Cr(total) was reduced by approximately 85% [1% beta-guanidinoproprionic acid (beta-GPA)], or their muscle Cr(total) was repleted (1% Cr after beta-GPA depletion). Cr uptake was assessed by skeletal muscle (14)C-Cr accumulation to Cr and PCr by using hindlimb perfusion, and CrT protein content was assessed by Western blot. Cr uptake rate decreased with dietary Cr supplementation in the white gastrocnemius (WG; 45%) only. Depletion of muscle Cr(total) to approximately 15% of normal increased Cr uptake in the soleus (21%) and red gastrocnemius (22%), corresponding to 70-150% increases in muscle CrT content. In contrast, the inherently lower Cr uptake rate in the WG was unchanged with depletion of muscle Cr(total) even though CrT band density was increased by 230%. Thus there was no direct relationship between apparent muscle CrT abundance and Cr uptake rates. However, Cr uptake rates scaled inversely with decreases in muscle Cr(total) in the high-oxidative muscle types but not in the WG. This implies that factors controlling Cr uptake are different among fiber types. These observations may help explain the influence of initial muscle Cr(total), time dependency, and variations in muscle Cr(total) accumulation during Cr supplementation.     

Exploring the therapeutic role of creatine supplementation

Creatine (Cr) plays a central role in energy provision through a reaction catalyzed by phosphorylcreatine kinase. Furthermore, this amine enhances both gene expression and satellite cell activation involved in hypertrophic response. Recent findings have indicated that Cr supplementation has a therapeutic role in several diseases characterized by atrophic conditions, weakness, and metabolic disturbances (i.e., in the muscle, bone, lung, and brain). Accordingly, there has been an evidence indicating that Cr supplementation is capable of attenuating the degenerative state in some muscle disorders (i.e., Duchenne and inflammatory myopathies), central nervous diseases (i.e., Parkinson’s, Huntington’s, and Alzheimer’s), and bone and metabolic disturbances (i.e., osteoporosis and type II diabetes). In light of this, Cr supplementation could be used as a therapeutic tool for the elderly. The aim of this review is to summarize the main studies conducted in this field and to highlight the scientific and clinical perspectives of this promising therapeutic supplement.     

Effect of a defined lacto-ovo-vegetarian diet and oral creatine monohydrate supplementation on plasma creatine concentration

This study examined the effects that preceding creatine supplementation with a lacto-ovo-vegetarian diet would have on plasma creatine concentration. Twenty-six healthy moderately fit omnivorous men were assigned to either a 26-day lacto-ovo-vegetarian (LOV; n = 12) or omnivorous (Omni; n = 14) diet. On day 22, subjects were also assigned in a double-blind manner either creatine monohydrate (CM; 0.3 g.kg(-1).day(-1) + 20 g Polycose) or an equivalent dose of placebo (PL) for 5 days. Blood samples were taken on days 1, 22 and 27. Consuming a LOV diet for 21 days was effective in reducing plasma creatine concentration (p < 0.01) in the LOV group. Regardless of diet, the CM group showed an increase in plasma creatine concentrations from day 22 to 27, whereas the PL group's levels remained the same (p < 0.05). Although the LOV diet caused a deprivation effect in plasma creatine concentration relative to the Omni diet, concurrent supplementation with creatine resulted in no difference in plasma creatine concentrations between the LOV and Omni diet groups. Dietary advice should be provided to LOV athletes that supplementation with creatine may help to increase their muscle stores of creatine, and thus their ATP resynthesis capabilities, to levels similar to those of omnivores.     

Cerebral energetic effects of creatine supplementation in humans

There has been considerable interest in the use of creatine (Cr) supplementation to treat neurological disorders. However, in contrast to muscle physiology, there are relatively few studies of creatine supplementation in the brain. In this report, we use high-field MR (31)P and (1)H spectroscopic imaging of human brain with a 7-day protocol of oral Cr supplementation to examine its effects on cerebral energetics (phosphocreatine, PCr; ATP) and mitochondrial metabolism (N-acetyl aspartate, NAA; and Cr). We find an increased ratio of PCr/ATP (day 0, 0.80 +/- 0.10; day 7, 0.85 +/- 09), with this change largely due to decreased ATP, from 2.7 +/- 0.3 mM to 2.5 +/- 0.3 mM. The ratio of NAA/Cr also decreased (day 0, 1.32 +/- 0.17; day 7 1.18 +/- 0.13), primarily from increased Cr (9.6 +/- 1.9 to 10.1 +/- 2.0 mM). The Cr-induced changes significantly correlated with the basal state, with the fractional increase in PCr/ATP negatively correlating with the basal PCr/ATP value (R = -0.74, P < 0.001). As NAA is a measure of mitochondrial function, there was also a significant negative correlation between basal NAA concentrations with the fractional change in PCr and ATP. Thus healthy human brain energetics is malleable and shifts with 7 days of Cr supplementation, with the regions of initially low PCr showing the largest increments in PCr. Overall, Cr supplementation appears to improve high-energy phosphate turnover in healthy brain and can result in either a decrease or an increase in high-energy phosphate concentrations.     

Effect of low-dose, short-duration creatine supplementation on anaerobic exercise performance

To examine the efficacy of a low-dose, short-duration creatine monohydrate supplement, 40 physically active men were randomly assigned to either a placebo or creatine supplementation group (6 g of creatine monohydrate per day). Testing occurred before and at the end of 6 days of supplementation. During each testing session, subjects performed three 15-second Wingate anaerobic power tests. No significant (p > 0.05) group or time differences were observed in body mass, peak power, mean power, or total work. In addition, no significant (p > 0.05) differences were observed in peak power, mean power, or total work. However, the change in the rate of fatigue of total work was significantly (p < 0.05) lower in the creatine supplementation group than in the placebo group, indicating a reduced fatigue rate in subjects supplementing with creatine compared with the placebo. Although the results of this study demonstrated reduced fatigue rates in patients during high-intensity sprint intervals, further research is necessary in examining the efficacy of low-dose, short-term creatine supplementation.     

Effect of creatine supplementation on sprint exercise performance and muscle metabolism

The aim of thepresent study was to examine the effect of creatine supplementation(CrS) on sprint exercise performance and skeletal muscle anaerobicmetabolism during and after sprint exercise. Eight active, untrainedmen performed a 20-s maximal sprint on an air-braked cycle ergometerafter 5 days of CrS [30 g creatine (Cr) + 30 g dextrose perday] or placebo (30 g dextrose per day). The trials wereseparated by 4 wk, and a double-blind crossover design was used. Muscleand blood samples were obtained at rest, immediately after exercise,and after 2 min of passive recovery. CrS increased the muscle total Crcontent (9.5 ± 2.0%, P < 0.05, mean ± SE); however, 20-s sprint performance was not improved byCrS. Similarly, the magnitude of the degradation or accumulation ofmuscle (e.g., adenine nucleotides, phosphocreatine, inosine 5'-monophosphate, lactate, and glycogen) and plasma metabolites (e.g., lactate, hypoxanthine, and ammonia/ammonium) were also unaffected by CrS during exercise or recovery. These data demonstrated that CrS increased muscle total Cr content, but the increase did notinduce an improved sprint exercise performance or alterations inanaerobic muscle metabolism.

     

Combined creatine and sodium bicarbonate supplementation enhances interval swimming

This study examined the effect of simultaneous supplementation of creatine and sodium bicarbonate on consecutive maximal swims. Sixteen competitive male and female swimmers completed, in a randomized order, 2 different treatments (placebo and a combination of creatine and sodium bicarbonate) with 30 days of washout period between treatments in a double-blind crossover procedure. Both treatments consisted of placebo or creatine supplementation (20 g per day) in 6 days. In the morning of the seventh day, there was placebo or sodium bicarbonate supplementation (0.3 g per kg body weight) during 2 hours before a warm-up for 2 maximal 100-m freestyle swims that were performed with a passive recovery of 10 minutes in between. The first swims were similar, but the increase in time of the second versus the first 100-m swimming time was 0.9 seconds less (p < 0.05) in the combination group than in placebo. Mean blood pH was higher (p < 0.01-0.001) in the combination group than in placebo after supplementation on the test day. Mean blood pH decreased (p < 0.05) similarly during the swims in both groups. Mean blood lactate increased (p < 0.001) during the swims, but there were no differences in peak blood lactate between the combination group (14.9 +/- 0.9 mmol.L(-1)) and placebo (13.4 +/- 1.0 mmol.L(-1)). The data indicate that simultaneous supplementation of creatine and sodium bicarbonate enhances performance in consecutive maximal swims.     

Swim performance following creatine supplementation in Division III athletes

Creatine (Cr) supplementation has yielded inconsistent results when applied to competitive swimming. To further define the role of Cr, we tested the hypothesis that a Cr supplementation group of Division III swimmers would demonstrate enhanced performance when compared with placebo. In order to test this hypothesis, 8 male and 7 female collegiate Division III swimmers were assigned in a random, double-blind manner into either a Cr supplementation group (0.3 g Cr.kg(-1) body mass) or a placebo group. Loading was maintained for 5 days followed by a 9-day period where Cr-supplemented subjects consumed 2.25 g Cr regardless of body weight. A 50- and 100-yd sprint was performed prior to and following the supplementation regimens. The Cr supplementation group decreased their finish times in both the 50- and 100-yd sprints. Support of the hypothesis suggests that Cr supplementation for swimming events is effective for singular effort sprints of 50 and 100 yd in Division III athletes.     

The effects of creatine supplementation on high-intensity exercise performance in elite performers

The aim of this research was to determine whether creatine supplementation at a dose of 20 g · day⁻¹, given in 4 × 6-g doses (5 g creatine monohydrate and 1 g glucose) for 5 days, was effective in improving kayak ergometer performances of different durations. Sixteen male subjects with the following characteristics [mean (SEM)]: age 21 (1.2) years, height 170.2 (1.7) cm, weight 75.3 (2.3) kg, Σ8 skinfolds 59.3 (2.6) mm, and maximal oxygen consumption 67.1 ± (4.3) ml · kg · min⁻¹, undertook three maximal kayak ergometer tests of 90, 150 and 300 s duration on a wind-braked kayak ergometer (CON). Two groups were then randomly formed, with one group taking the supplement (SUP) while the other took a placebo (PLAC). No pre-test differences existed between the SUP and the PLAC groups in any of the variables measured. After supplementation each group then repeated the same kayak ergometer tests as performed previously and after a 4-week “washout period” the groups took either the PLAC or SUP for another 5 days and then completed the final tests. The SUP group completed significantly more work than either the CON or PLAC groups in all of the tests (90 s, P < 0.01; 150 s, P < 0.001; 300 s, P < 0.05). Body mass remained stable throughout the test period in both the CON and PLAC groups, but both were significantly less than the SUP body mass of 77.3 (1.0) kg (P < 0.01). The results of this work indicate that creatine supplementation can significantly increase the amount of work accomplished during kayak ergometer performance at durations ranging from 90 to 300 s. Accepted: 8 January 1998     

Comparison of creatine monohydrate and carbohydrate supplementation on repeated jump height performance

Creatine monohydrate (CrMH) supplementation aids the ability to maintain performance during repeated bouts of high-intensity exercise, including jump performance. However, carbohydrate supplementation may also provide similar benefits and is less expensive. This study compared the effects of an energy-free placebo, 2 different caloric concentrations of carbohydrate drinks, and a CrMH supplement on repeated jump heights. Sixty active males (mean age, 22 +/- 3.2 years) performed 2 sets of countermovement static jump height tests (10 jumps over 60 seconds) separated by 5 days to determine the differential effects of the placebo, carbohydrate, and CrMH on jump height sustainability over 10 jumps. Subjects were randomly assigned to groups (15 subjects per group) to receive daily doses (x5 days) of carbohydrate drinks containing 100 or 250 kilocalories (kcal), a 25-g CrMH supplement, or an energy-free placebo. After 5 days, the CrMH group experienced a significant weight gain (+1.52; +/-0.89 kg, p < 0.01), while the other groups did not. The 2 levels of carbohydrate and CrMH supplements were all significantly better at sustaining jump height than the energy-free placebo over the final 3-4 jumps. The 250-kcal carbohydrate-supplemented group experienced a level of benefit (p < 0.01) that was at least equal to that of the CrMH group (p < 0.05), suggesting that the higher dose of carbohydrate was as effective as CrMH in maintaining repeated bouts of high-intensity activity as measured by repeated static jumps. Given the equivalent performance improvement and the absence of weight gain, the carbohydrate supplementation could be considered the preferred option for weight-conscious power athletes involved in activities that require repeated- motion high-intensity activities.     

The effect of creatine supplementation on glucose uptake in rat skeletal muscle

Glucose transport in muscle is a function of the muscle metabolic state, as evidenced by the increase in glucose transport which occurs with conditions of altered aerobic metabolism such as hypoxia or contractile activity. The energy state of the muscle can be determined by the muscle phosphocreatine concentration. Dietary supplementation of creatine has been shown to increase both phosphocreatine (PCr) and creatine (TCr) levels in muscle, although not in the same proportion, so that the PCr/TCr ratio falls suggesting an altered energy state in the cell. The purpose of this study was to determine the effect of increased creatine content on glucose uptake in muscle. PCr and TCr were determined in plantaris muscles from rats following five weeks of dietary supplementation of creatine monohydrate (300 mg/kg/day). (3)H-2-deoxyglucose uptake was measured in epitrochlearis muscles incubated in the presence or absence of a maximally stimulating dose of insulin. Despite a significant increase in creatine content in muscle, neither basal nor insulin-stimulated glucose uptake was altered in creatine supplemented rats. Since PCr levels were not increased with creatine supplementation, these results suggest that the actual concentration of PCr is a more important determinant of glucose uptake than the PCr/TCr ratio.     

The effects of polyethylene glycosylated creatine supplementation on muscular strength and power

The purpose of the present investigation was to examine the effects of 28 days of polyethylene glycosylated creatine (PEG-creatine) supplementation on 1-repetition maximum bench press (1RMBP) and leg extension (1RMLE), mean power (MP), and peak power (PP) from the Wingate Anaerobic test and body weight (BW). This study used a randomized, double-blind, placebo-controlled, parallel design. Twenty-two untrained men (mean age ± SD = 22.1 ± 2.1 years) were randomly assigned to either a Creatine (n = 10) or Placebo (n = 12) group. The Creatine group ingested PEG-creatine (5 g·d), whereas the Placebo group ingested maltodextrin powder (5 g·d). All subjects performed bench press and bilateral leg extension exercises to determine their 1RM values, and 2 consecutive Wingate Anaerobic Tests (separated by 7 minutes) on a cycle ergometer to determine MP and PP before supplementation (day 0) and after 7 (day 7) and 28 (day 28) days of supplementation. The results indicated that there was a significant (p < 0.05) increase in 1RMBP between days 0 and 28 for the Creatine group but not for the Placebo group. There were no significant changes, however, in 1RMLE, MP, PP, or BW for the Creatine or Placebo group. These findings indicated that 28 days of PEG-creatine supplementation without resistance training increased upper body strength but not lower body strength or muscular power. These findings supported the use of the PEG-creatine supplement for increasing 1RMBP strength in untrained individuals.     

Effect of creatine supplementation on cycle ergometer exercise in a hyperthermic environment

In order to examine thermoregulatory response to creatine (CR) supplementation, competitive male cyclists and triathletes (n = 7, VO2max = 50.6 +/- 0.8 ml x kg(-1) x min(-1)) completed three 1-hour hyperthermic (ambient temperature = 38.7 +/- 1.0 degrees C, relative humidity = 33 +/- 4%) exercise sessions at 181 +/- 12 W (50% of Wmax, approximately 66% of VO2max). Subjects completed a baseline (BL) session, then 2 sessions following 5 days of CR (20 g x d(-1)) and placebo (PL, 20 g x d(-1)) administered in a double-blind counterbalanced crossover manner with > or = 28-day washout. Pre-exercise BL, CR, and PL body mass were unchanged, with similar decreases in postexercise mass among the three conditions. Tympanic temperature, heart rate, systolic blood pressure, perceived exertion, and lactate, cortisol, and aldosterone concentrations increased similarly during BL, CR, and PL exercise. A greater (p = 0.013) estimated decrease in plasma volume occurred following BL (-16.5 +/- 2.0%) and PL (-17.6 +/- 1.7%) exercise compared to CR (-13.5 +/- 2.1%). Creatine supplementation reduces plasma volume loss during 1 hour of hyperthermic exercise but does not appear to otherwise change thermoregulatory response to hyperthermic exercise.