Creatine is normally metabolized into creatinine (note the difference in spelling), which is eliminated by the kidneys under normal conditions. When the kidneys fail and cannot clear the blood as effectively, many metabolites get “backlogged” in the blood. Creatinine is easy to measure and as such it is a biomarker of kidney damage.[623][624] If serum creatinine levels are elevated, the doctor may suspect some kidney damage. Low-dose creatine (≤5 g/day) may not cause alterations in this biomarker in otherwise normal adults[524][625][525] but high doses of supplemental creatine may cause a false positive (an increase in creatinine, due to creatine turning into creatinine, which does not signify kidney damage) and is a diagnostic error.[520][518][626][523][517] Most studies, however, have noted only a small increase in creatinine levels even with doses ≈20 g/day.[524][626][627]
Nitrate-rich foods like beets, radishes, and pomegranates are a great way to boost the production of nitric oxide (NO). Although there's very limited research examining the effects of beet root juice and pomegranate extract on resistance training, these ingredients have previously been shown to increase skeletal muscle blood flow and lead to reduced soreness, which may ultimately lead to improvements in strength and performance.[9,10]
The major controversies regarding creatine are its side effects and the best form to use. Nearly all side effects attributed to creatine, such as muscle cramps, kidney disease and gastrointestinal disturbances, haven't proved significant under controlled scientific scrutiny. Although various claims are made for a variety of creatine supplements, creatine monohydrate, which is 99 percent absorbed, is the best form to use.
Creatine is involved indirectly in whole body methylation processes. This is due to creatine synthesis having a relatively large methyl cost, as the creatine precursor known as guanidinoacetate (GAA) requires a methyl donation from S-adenosyl methionine (SAMe) in order to produce creatine. This may require up to half of the methyl groups available in the human body.[35][122]

One pilot study using 150mg/kg creatine monohydrate for a five day loading phase followed by maintenance (60mg/kg) for the remainder of the five weeks noted that supplementation was associated with fewer muscle symptoms and complaints alongside improved muscular function,[572] yet a later trial trying to replicate the obsevations using 150mg/kg daily for five weeks noted the opposite, that creatine supplementation exacerbated symptoms.[573] 
In fact, in one new study comparing the effects of aerobic exercise versus resistance training on the psychological health of obese adolescents, researchers found that people in the resistance group experienced significantly greater self-esteem and perceived strength over four weeks. But what’s most interesting is that the feeling of getting stronger — rather than any measurable gains — was all it took to give them a boost.
Brain injury. Early research shows that taking creatine by mouth daily for 7 days increases the ability to exercise by increasing lung function in people with a spinal cord injury. However, other research shows that creatine does not improve wrist muscle or hand function. Early research also shows that taking creatine by mouth daily for 6 months reduces amnesia following a traumatic brain injury in children.
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A retrospective study [81], that examined the effects of long lasting (0.8 to 4 years) CM supplementation on health markers and prescribed training benefits, suggested that there is no negative health effects (including muscle cramp or injuries) caused by long term CM consumption. In addition, despite many anecdotal claims, it appears that creatine supplementation would have positive influences on muscle cramps and dehydration [82]. Creatine was found to increase total body water possibly by decreasing the risk of dehydration, reducing sweat rate, lowering core body temperature and exercising heart rate. Furthermore, creatine supplementation does not increase symptoms nor negatively affect hydration or thermoregulation status of athletes exercising in the heat [83,84]. Additionally, CM ingestion has been shown to reduce the rate of perceived exertion when training in the heat [85].
The creatine kinase (CK) enzyme in rat heart tissue appears to have a KM around 6mM of creatine as substrate.[280] and is known to positively influence mitochondrial function as higher cytoplasmic phosphocreatine concentrations (not so much creatine per se) increase the oxidative efficiency of mitochondria[280] This is thought to be due to the transfer of high energy phosphate groups.[280]
Activation of NMDA receptors is known to stimulate Na+,K+-ATPase activity[218] secondary to calcineurin,[219] which which has been confirmed with creatine in hippocampal cells (0.1-1mM trended, but 10mM was significant). This is blocked by NMDA antagonists.[220] This increase in Na+,K+-ATPase activity is also attenauted with activation of either PKC or PKA,[220] which are antagonistic with calcineurin.[219][221]

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[26] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies in the two synthesis enzymes can cause L-arginine:glycine amidinotransferase deficiency caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect, is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[27]
One case study exists of a man with focal segmental glomerulosclerosis who experienced an accelerated rate of GFR decline during supplementation (5g thrice daily for loading, then a 2g maintenance for seven weeks) which was partially reversed upon supplement cessation. This was deemed strong circumstantial evidence, and the brand of supplement was not named.[616] Elsewhere, interstitial nephritis associated with creatine supplementation has been reported in a man, although symptoms arose four weeks after supplementation started with no evidence to support correlation.[617] Some studies involving athletes and various dietary supplements have attempted to draw a correlation with creatine and cases of rhabdomyolysis.[618][619][620][621] Finally, one study in a diabetic person ingesting both metformin and creatine resulting in metabolic acidosis has attempted to place causation on creatine, but it did not establish causation or circumstantial evidence.[622]
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