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. The receptor follows Michaelis-Menten kinetics with a Vmax obtained at concentrations higher than 0.3-0.4mmol/L, with prolonged serum concentrations above this amount exerting most of its saturation within two days.
When creatine supplementation is combined with heavy resistance training, muscle insulin like growth factor (IGF-1) concentration has been shown to increase. Burke et al  examined the effects of an 8 week heavy resistance training protocol combined with a 7 day creatine loading protocol (0.25 g/d/kg lean body mass) followed by a 49 day maintenance phase (0.06 g/kg lean mass) in a group of vegetarian and non-vegetarian, novice, resistance trained men and women. Compared to placebo, creatine groups produced greater increments in IGF-1 (78% Vs 55%) and body mass (2.2 Vs 0.6 kg). Additionally, vegetarians within the supplemented group had the largest increase of lean mass compared to non vegetarian (2.4 and 1.9 kg respectively). Changes in lean mass were positively correlated to the modifications in intramuscular total creatine stores which were also correlated with the modified levels of intramuscular IGF-1. The authors suggested that the rise in muscle IGF-1 content in the creatine group could be due to the higher metabolic demand created by a more intensely performed training session. These amplifying effects could be caused by the increased total creatine store in working muscles. Even though vegetarians had a greater increase in high energy phosphate content, the IGF-1 levels were similar to the amount observed in the non vegetarian groups. These findings do not support the observed correlation pattern by which a low essential amino acid content of a typical vegetarian diet should reduce IGF-1 production . According to authors opinions it is possible that the addition of creatine and subsequent increase in total creatine and phosphocreatine storage might have directly or indirectly stimulated production of muscle IGF-I and muscle protein synthesis, leading to an increased muscle hypertrophy .
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.
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 has been investigated for its effects on depression, due to the significant changes occurring in brain morphology and neuronal structure associated with depression and low brain bioenergetic turnover in depression, perhaps related to abnormal mitochondrial functioning, which reduces available energy for the brain. The general association of low or otherwise impaired phosphate energy systems (of which creatine forms the energetic basis of) with depression, has been noted previously. Due to associations with cellular death and impaired bioenergetics with depression, creatine was subsequently investigated.
In humans, studies that investigate links between serotonin and creatine supplementation find that 21 trained males, given creatine via 22.8g creatine monohydrate (20g creatine equivalent) with 35g glucose, relative to a placebo of 160g glucose, was found to reduce the perception of fatigue in hot endurance training, possibly secondary to serotonergic modulation, specifically attentuating the increase of serotonin seen with exercise (normally seen to hinder exercise capacity in the heat) while possibly increasing dopaminergic activity (conversely seen to benefit activity in the heat).
This suppression of creatine synthesis is thought to actually be beneficial, since creatine synthesis requires s-adenosyl methionine as a cofactor and may use up to 40-50% of SAMe for methylation (initially thought to be above 70%, but this has since been re-evaluated) though the expected preservation of SAMe may not occur with supplementation. Reduced creatine synthesis, via preserving methyl groups and trimethylglycine (which would normally be used up to synthesize SAMe), is also thought to suppress homocysteine levels in serum, but this may also not occur to a practical level following supplementation.
A: Depending upon your experience level, preference, recovery capacity, and time available, you’ll likely find that 3-5 strength training sessions per week is the sweet spot. If you’re just getting started with weight training, then you should stick with 3 days per week and work your way up. Novices and early intermediates can handle 4 days per week with a split such as an upper lower and seasoned intermediate lifters may be able to handle 5 sessions per week depending upon the programming, recovery, and nutrition strategies that are in place.
A loading phase of 10g creatine monohydrate for two weeks and 4g for the final week in subjects with MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes) has been noted to increase physical strength relative to baseline, although the poor VO2 max seen in these subjects was not affected. A case study exists in which a patient with a relatively novel mutation in their mitochondrial function (affecting cytochrome B) experienced benefits from creatine at 10g daily. Researchers examining another case of MELAS found both cognitive and physical benefits with 5g creatine supplementation, while four controlled case studies of 100-200mg/kg daily in children with myopathies found improved muscular endurance (30-57%) and muscular power (8-17%) after 100-200mg/kg daily for at least three months.
“Compared to training for strength, intensity is going to drop during the hypertrophy phase of a program, with intensity sitting between 50 and 75 percent of the person’s 1RM, the maximum weight he or she can lift for one rep,” says Ava Fitzgerald, C.S.C.S., C.P.T., a sports performance coach with the Professional Athletic Performance Center in New York.
Syndromes caused by problems metabolizing creatine. Some people have a disorder that prevents their body from making creatine. This can lead to low levels of creatine in the brain. Low levels of creatine in the brain can lead to decreased mental function, seizures, autism, and movement problems. Taking creating by mouth daily for up to 3 years can increase creatine levels in the brain in children and young adults with a disorder of creatine production called guanidinoacetate methyltransferase (GAMT) deficiency. This can help improve movement and reduce seizures. But it doesn't improve mental ability. Arginine-glycine amidinotransferase (AGAT) deficiency is another disorder that prevents the body from making creatine. In children with this condition, taking creatine for up to 8 years seems to improve attention, language, and mental performance. But taking creatine does not seem to improve brain creatine levels, movement, or mental function in children who have a disorder in which creatine isn't transported properly.
Anti-depressive effects have been noted in woman with major depressive disorder when 5g of creatine monohydrate was supplemented daily for 8 weeks in combination with an SSRI. Benefits were seen at week two and were maintained until the end of the 8-week trial. The improvement in depressive symptoms was associated with significantly increased prefrontal cortex levels of N-acetylaspartate, a marker of neuronal integrity, and rich club connections, which refers to the ability of nerons to make connections to one another.