Creatine supplementation may be able to enhance lifespan, secondary to increasing intracellular carnosine stores. Carnosine is the metabolic compound formed from beta-alanine supplementation, and in a mouse-model for premature aging (senescence-accelerated premature aging, SAMP8) creatine supplementation without any beta-alanine has been shown to increase cellular carnosine stores.[126] That being said, the aforemented SAMP8 study noted an increase in carnosine levels at middle age, but not old age in the mice.[126] A human study using 20g of creatine for one week in otherwise healthy people failed to find an increase in intracellular carnosine stores.[126]
Prohormones are precursors to hormones and are most typically sold to bodybuilders as a precursor to the natural hormone testosterone. This conversion requires naturally occurring enzymes in the body. Side effects are not uncommon, as prohormones can also convert further into DHT and estrogen. To deal with this, many supplements also have aromatase inhibitors and DHT blockers such as chrysin and 4-androstene-3,6,17-trione. To date most prohormone products have not been thoroughly studied, and the health effects of prolonged use are unknown. Although initially available over the counter, their purchase was made illegal without a prescription in the US in 2004, and they hold similar status in many other countries. They remain legal, however, in the United Kingdom and the wider European Union. Their use is prohibited by most sporting bodies.
It is suggested [16,37] that another mechanism for the effect of creatine could be enhanced muscle glycogen accumulation and GLUT4 expression, when creatine supplementation is combined with a glycogen depleting exercise. Whereas it has been observed [38] that creatine supplementation alone does not enhance muscle glycogen storage. Hickner et al [15] observed positive effects of creatine supplementation for enhancing initial and maintaining a higher level of muscle glycogen during 2 hours of cycling. In general, it is accepted that glycogen depleting exercises, such as high intensity or long duration exercise should combine high carbohydrate diets with creatine supplementation to achieve heightened muscle glycogen stores [39].
In patients with DM1 given a short loading phase (10.6g for ten days) followed by a 5.3g maintenance for the remainder of an 8-week trial noted that supplementation resulted in a minor improvement in strength (statistical significance only occurred since placebo deteriorated) and no significant difference was noted in self-reported perceived benefits.[565] Maintaining a 5g dosage for four months also failed to significantly improve physical performance (handgrip strength and functional tests) in people with DM1, possible related to a failure to increase muscular phosphocreatine concentrations.[566]
One study on 27 otherwise healthy men supplementing creatine (0.3g/kg loading for a week, 0.05g/kg thereafter for 8 weeks) with a thrice weekly exercise regiment noted that alongside greater increase in lean mass and power relative to placebo at 4 and 8 weeks, myostatin in serum decreased to a greater extent with creatine (around 17% at 8 weeks, derived from graph) than it did with placebo (approximately 7%).[356] Increases in GASP-1, a serum protein that inhibits the actions of myostatin by directly binding to it,[357] were not different between groups.[356]
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Creatine supplementation appears to be somewhat similar to TMG supplementation in the sense that they both promote localized synthesis of phosphatidylcholine, effluxing triglycerides from the liver into serum and thus potently protecting from diet-induced fatty liver. The concentration at which this occurs is within the range supplemented by humans.
Creatine may preserve dopamine synthesis in the striatum of mice (while protecting against dopaminergic depletion) when fed to mice at 2% of the diet for one week prior to MPTP toxicity[230]. This is possibly secondary to increasing tyrosine hydroxylase activity, the rate-limiting step of dopamine biosynthesis.[210][235] Two percent creatine was as protective as 0.005% rofecoxib (a COX2 inhibitor), but the two were additive in their protective effects (highly synergistic in regard to DOPAC by normalizing it, but not synergistic in preserving HVA).[230]

A 2011 survey of 33 supplements commercially available in Italy found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body.[47] Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro-1,3,5-triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable. Two studies reviewed in 2007 found no impurities.[41]
It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio.[334] It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.[334][336][337]
Creatine is marketed as "nature's muscle builder" and "the most legitimate sports supplement around." Professional and amateur athletes alike are gobbling up this alleged ergogenic aid, hoping to increase their strength and performance. Creatine supplementation is claimed to increase muscle power by playing a role in the transfer of energy to help the muscle contract. Supplement labels state that "creatine is converted to phosphocreatine, which is important for short energy bursts such as sprinting and weight lifting" and that "depletion of phosphocreatine can result in muscle fatigue and fading muscle power." Claims are also made that supplementation increases muscle body mass.
The creatine transporter (CrT) is positively regulated by proteins known to be involved in sensing and responding to the cellular energy state, including the mammalian target of rapamycin (mTOR[158]). Upon activation, mTOR stimulates SGK1 and SGK3[159][160] to act upon PIKfyve[161] and subsequently PI(3,5)P2[162] to increase CrT activity.[161] Beyond mTOR, SGK1 also is stimulated by intracellular calcium[163] and a lack of oxygen (ischemia).[164] Because transient ischemia is associated with increased reactive oxygen species (ROS) production after blood flow is restored (reperfusion) it has been hypothesized that muscle contraction may increase creatine uptake through a similar ROS-mediated mechanism.[165]
Jager et al [60] observed 1.17 and 1.29 greater peak plasma creatine concentration 1 hour after ingesting creatine pyruvate compared to isomolar amount of CM and creatine citrate respectively. However time to peak concentration, and velocity constants of absorption and elimination, was the same for all three forms of creatine. Although not measured in this study it is questionable that these small differences in plasma creatine concentrations would have any effect on the increase of muscle creatine uptake. Jäger et al [61] investigated the effects of 28-days of creatine pyruvate and citrate supplementation on endurance capacity and power measured during an intermittent handgrip (15 s effort per 45s rest) exercise in healthy young athletes. The authors used a daily dose protocol with the intention to slowly saturate muscle creatine stores. Both forms of creatine showed slightly different effects on plasma creatine absorption and kinetics. The two creatine salts significantly increased mean power but only pyruvate forms showed significant effects for increasing force and attenuating fatigability during all intervals. These effects can be attributed to an enhanced contraction and relaxation velocity as well as a higher blood flow and muscle oxygen uptake. On the other hand, the power performance measured with the citrate forms decreases with time and improvements were not significant during the later intervals. In spite of these positive trends further research is required about the effects of these forms of creatine as there is little or no evidence for their safety and efficacy. Furthermore the regularity status of the novel forms of creatine vary from country to country and are often found to be unclear when compared to that of CM [62].
A study using creatine at 0.02% of a face cream (confounded with 8% glycerol and 0.4% Guarana) was able to exert a skin-tightening effect over 6 weeks, reducing wrinkles and jowl volume.[541] Combination therapy has also been used with creatine and folic acid (both in vitro[543] and in vivo), resulting in increased skin firmness and reduced coarse and fine wrinkles.[544]
Studies conducted in vegetarians tend to show cognitive enhancement in youth, possibly due to a creatine deficiency, as compared to omnivores.[272][60][61] Vegetarian diets have lower levels of circulating creatine prior to supplementation, but attain similar circulating levels as omnivores when both groups supplement.[272][273] Building on the latter, supplementation of creatine monohydrate in a loading protocol (20g daily in orange juice) in omnivores does not alter levels of creatine in white matter tissue in the brain (test subjects: competitive athletes).[274] In most of the parameters that vegetarians experience benefits, omnivores fail to experience statistically significant benefits[275], except possibly when sleep deprived, where the cognitive improvements rival that seen in vegetarians.[276] Elderly people who are omnivorous may also experience increases in cognition to a similar level, in regard to long-term memory as well as forward number and spatial recall, although the study in question failed to find any significant benefit on backward recall or random number generation,[38] the latter of which is a test for executive working memory.[277]
^ "Popular sports supplements contain meth-like compound". USA Today. October 25, 2013. Cohen said researchers informed the FDA in May about finding the new chemical compound in Craze. The team found the compound — N,alpha-diethylphenylethylamine — has a structure similar to methamphetamine, a powerful, highly addictive, illegal stimulant drug. They believe the new compound is likely less potent than methamphetamine but greater than ephedrine.

Creatine is classified as a "dietary supplement" under the 1994 Dietary Supplement Health and Education Act and is available without a prescription. Creatine is not subjected to FDA testing, and the purity and hygienic condition of commercial creatine products may be questionable [21]. A 1998 FDA report lists 32 adverse creatine-associated events that had been reported to FDA. These include seizure, vomiting, diarrhea, anxiety, myopathy, cardiac arrhythmia, deep vein thromboses and death. However, there is no certainty that a reported adverse event can be attributed to a particular product [22]. A recent survey of 28 male baseball players and 24 male football players, ages 18 to 23, found that 16 (31%) experienced diarrhea, 13 (25%) experienced muscle cramps, 7 (13%) reported unwanted weight gain, 7 (13%) reported dehydration, and 12 reported various other adverse effects [23].
Zinc is important to produce the male hormone testosterone and in building the immune system. Magnesium is an essential component of the nervous system and for maintaining heart health. Both have a range of important biochemical function. Zinc and magnesium are often marketed to bodybuilders in combination in a supplement called ZMA. Zinc is in whole grains, seeds, nuts and particularly meat and oysters. After years of research, no evidence exists to show that either mineral offers bodybuilding or athletic performance enhancement in excess of the recommended dietary requirements.

Weight training is primarily an isotonic form of exercise, as the force produced by the muscle to push or pull weighted objects should not change (though in practice the force produced does decrease as muscles fatigue). Any object can be used for weight training, but dumbbells, barbells, and other specialised equipment are normally used because they can be adjusted to specific weights and are easily gripped. Many exercises are not strictly isotonic because the force on the muscle varies as the joint moves through its range of motion. Movements can become easier or harder depending on the angle of muscular force relative to gravity; for example, a standard biceps curl becomes easier as the hand approaches the shoulder as more of the load is taken by the structure of the elbow. Originating from Nautilus, Inc., some machines use a logarithmic-spiral cam to keep resistance constant irrespective of the joint angle.
Natalie Digate Muth, MD, MPH, RD, is the ACE senior consultant for healthcare solutions, a practicing pediatrician and registered dietitian. Recognized as a Certified Obesity Specialist, Natalie has written for more than 50 publications and, in 2012, published her first book, 'Eat Your Vegetables' and Other Mistakes Parents Make: Redefining How to Raise Healthy Eaters.
Yang, L., Calingasan, N. Y., Wille, E. J., Cormier, K., Smith, K., Ferrante, R. J., & Beal, M. F. (2009, June). Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases [Abstract]. Journal of Neurochemistry. 109(5):1427-39. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19476553
Weight training has also been shown to benefit dieters as it inhibits lean body mass loss (as opposed to fat loss) when under a caloric deficit. Weight training also strengthens bones, helping to prevent bone loss and osteoporosis. By increasing muscular strength and improving balance, weight training can also reduce falls by elderly persons. Weight training is also attracting attention for the benefits it can have on the brain, and in older adults, a 2017 meta analysis found that it was effective in improving cognitive performance.[38]
After supplementation of creatine monohydrate (loading phase, followed by 19 weeks maintenance), creatine precursors are decreased by up to 50% (loading) or 30% (maintenance), which suggests a decrease in endogenous creatine synthesis during supplementation.[38] This appears to occur through creatine’s own positive feedback and suppression of the l-arginine:glycine amidinotransferase enzyme, the rate-limiting step in creatine synthesis, as levels of intermediates before this stage are typically elevated by up to 75%.[38]
The first open label trial on ALS failed to significantly alter lung function as assessed by FEV (when comparing the rate of decline pretreatment relative to treatment).[545] Creatine has elsewhere failed to benefit lung function at 5g daily for months relative to control[546] and failed to significantly attenuate the rate of lung function deterioration over 16 months at 10g daily[505] and 5g daily over nine months.[507]

Homocysteine is an endogenous metabolite involved in methylation processes in the body. Mildly elevated homocysteine appears to be an independent risk factor for both cardiovascular[302] and atherosclerotic disease,[303] where if the 8-10μM normal range is elevated by around 5μM, it is thought to confer 60-80% greater risk of atherosclerotic disease[303]. Although it may not independently cause problems,[304] it may play a causative role in the context of the whole body system, since it is atherogenic by augmenting LDL oxidation[305] and promoting conversion of macrophages into foam cells.[306]
Despite a possible decreasing creatine content in the muscles when maintenance is deemed suboptimal, the overall retention of weight and lean mass is merely additive over time. This is thought to be due to increases in skeletal muscle production (increase in body weight) compensating for the progressive declines in water and glycogen content (decreases in body weight).
It is prudent to note that creatine supplementation has been shown to reduce the body’s endogenous production of creatine, however levels return to normal after a brief period of time when supplementation ceases [1,6]. Despite this creatine supplementation has not been studied/supplemented with for a relatively long period. Due to this, long term effects are unknown, therefore safety cannot be guaranteed. Whilst the long term effects of creatine supplementation remain unclear, no definitive certainty of either a negative or a positive effect upon the body has been determined for many health professionals and national agencies [19,78]. For example the French Sanitary Agency has banned the buying of creatine due to the unproven allegation that a potential effect of creatine supplementation could be that of mutagenicity and carcinogenicity from the production of heterocyclic amines [78]. Long term and epidemiological data should continue to be produced and collected to determine the safety of creatine in all healthy individuals under all conditions [78].
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A typical creatine supplementation protocol consists of a loading phase of 20 g CM/d or 0.3 g CM/kg/d split into 4 daily intakes of 5 g each, followed by a maintenance phase of 3-5 g CM/d or 0.03 g CM/kg/d for the duration of the supplementation period [5]. Other supplementation protocols are also used such as a daily single dose of around 3 – 6 g or between 0.03 to 0.1 g/kg/d [15,55] however this method takes longer (between 21 to 28 days) to produce ergogenic effects [5]. Sale et al [56] found that a moderate protocol consisting of 20 g CM taken in 1g doses (evenly ingested at 30-min intervals) for 5 days resulted in reduced urinary creatine and methylamine excretion, leading to an estimated increase in whole body retention of creatine (+13%) when compared with a typical loading supplementation protocol of 4 x 5 g/d during 5 days (evenly ingested at 3 hour intervals). This enhancement in creatine retention would lead to a significantly higher weight gain when people follow a moderate protocol ingestion of several doses of small amounts of CM evenly spread along the day.
Every 4-8 weeks, vary your routine. As your body adapts to stress, you'll hit a plateau where the benefits of weight training will begin to diminish. The only way to prevent this from happening is to change things up, such as by increasing weight and changing exercises. Try a week of really piling the weights on, and do six to eight reps per set at the maximum weight you can manage with proper form. The more lifting experience you have, the more often you should vary your routine.

Creatine may preserve dopamine synthesis in the striatum of mice (while protecting against dopaminergic depletion) when fed to mice at 2% of the diet for one week prior to MPTP toxicity[230]. This is possibly secondary to increasing tyrosine hydroxylase activity, the rate-limiting step of dopamine biosynthesis.[210][235] Two percent creatine was as protective as 0.005% rofecoxib (a COX2 inhibitor), but the two were additive in their protective effects (highly synergistic in regard to DOPAC by normalizing it, but not synergistic in preserving HVA).[230]
In otherwise healthy adults subject to leg immobilization for two weeks while taking 20g creatine daily during immobilization and then 5g daily during eight weeks of rehabilitation, it was noted that the creatine group failed to reduce atrophy during the immobilization (10% reduction in cross sectional area and 22-25% reduction in force output) despite preventing a decrease in phosphocreatine, yet experienced a significantly enhanced rate of regrowth and power recovery.[358] A similarly structured and dosed study has also noted greater expression of skeletal muscle, GLUT4 expression, and a 12% increase in muscle phosphocreatine content.[330]

Arginine mainly benefits the body in two ways. The first of these is by producing nitric oxide. When arginine enters the body, some of it gets converted into nitric oxide. Nitric oxide is important for regulating blood pressure, as it can enlarge the blood vessels. Larger blood vessels allow the body to increase blood flow throughout the body, bringing extra nutrients and oxygen to the muscles during exercise.
Heath says to consume 1.25-2 grams of protein per pound of body weight for growth and he never exceeds a 1:1 meals to protein shake ratio, meaning if he has 3 shakes, he’ll have 3 meals. He suggests if you’re going to drink protein shakes, drink two and have four meals. Also, increase your protein consumption and decrease carbs to look lean. “Once I got to a certain size, I wanted to get leaner so I got to 50% protein, 30% carbs and 20% protein.”
Creatine non-response is when muscular loading of creatine is under a certain threshold (10mmol/L), while “response” to creatine means having more muscular creatine loading (20mol/L or more). There also exists a “grey area” inbetween, where some benefits are achieved but not as many as pure responders will experience. Response appears to be positively correlated with muscle mass and type II muscle fibers.
Lie on your back on the floor and bend one knee so that your foot is flat on the floor. Keeping your opposite leg straight, push your foot into the floor, raising your hips until both thighs are in line with each other. Reverse the motion to return to the starting position. That’s one rep. Complete all your reps on one leg, and then switch legs and repeat.
In regard to liver fat buildup (steatosis), which is normally associated with reduced availability of S-adenosyl methionine[495][496] and a suppression in expression of genes involved in fatty acid oxidation (PPARα and CPT1), creatine supplementation at 1% of the rat diet alongside a diet that induces fatty liver is able to fully prevent (and nonsignificantly reduce relative to the control given standard diets) the aforementioned changes and the state of steatosis, as well as changes in serum biomarkers (glucose and insulin) that accompany steatosis.[125] 
In regard to carbohydrate oxidation during exercise, it appears that rats subject to intermittent physical exercise (which utilizes glycogen) have decreased lactate production during said exercise, suggesting a preservation of glycogen usage. This occurred alongside an increase in glycogen stores.[359] This is thought to be due to phosphocreatine donating phosphate to replenish ATP. Without any changes in whole body metabolic rate, it indirectly causes less glucose to be required to replenish ATP, due to a quota needing to be met during exercise and creatine phosphate taking up a relatively larger percentage of said quota.
After the ingestion of 5g creatine in otherwise healthy humans, serum levels of creatine were elevated from fasting levels (50-100µM) to 600-800µM within one hour after consumption.[135] The receptor follows Michaelis-Menten kinetics with a Vmax obtained at concentrations higher than 0.3-0.4mmol/L,[136] with prolonged serum concentrations above this amount exerting most of its saturation within two days.[137]
Negative regulators of the creatine transporter (CrT) are those that, when activated, reduce the activity of the CrT and overall creatine uptake into cells. As noted above, CrT activity is positively regulated by mTOR.[158] Consistent with the well-known role of AMPK as a suppressor mTOR signaling,[177] CrT activity has also been shown to be inhibited in response to AMPK activation in kidney epithelial cells.[178] Since AMPK suppresses mTOR via upstream TSC2 activation,[179] the negative regulation of AMPK on CrT activity in these cells appears to occur through an indirect mechanism. Although indirect, activation of AMPK has been noted to reduce the Vmax of the CrT without altering creatine binding, and is involved in internalizing the receptors.[178] This pathway seems to max out at around 30% suppression, with no combination of mTOR antagonists and AMPK inducers further suppressing creatine uptake.[178]
If you're a serious strength or physique athlete, you've surely heard that supplements can help you get the most from your intense training sessions and on-point diet. But which supplements? The market is overstuffed like a bodybuilder in a child's blazer! You might be tempted to wander through a digital forest of get-big blogs and personal guru websites, but unfortunately those places can often be rife with misinformation.
Prohormones are precursors to hormones and are most typically sold to bodybuilders as a precursor to the natural hormone testosterone. This conversion requires naturally occurring enzymes in the body. Side effects are not uncommon, as prohormones can also convert further into DHT and estrogen. To deal with this, many supplements also have aromatase inhibitors and DHT blockers such as chrysin and 4-androstene-3,6,17-trione. To date most prohormone products have not been thoroughly studied, and the health effects of prolonged use are unknown. Although initially available over the counter, their purchase was made illegal without a prescription in the US in 2004, and they hold similar status in many other countries. They remain legal, however, in the United Kingdom and the wider European Union. Their use is prohibited by most sporting bodies.
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