Creatine synthesis primarily occurs in the liver and kidneys.[2][16] On average, it is produced endogenously at an estimated rate of about 8.3 mmol or 1 gram per day in young adults.[16][17] Creatine is also obtained through the diet at a rate of about 1 gram per day from an omnivorous diet.[16][18] Most of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, and other tissues.[17][18]

There have been a few reported renal health disorders associated with creatine supplementation [73,74]. These are isolated reports in which recommended dosages are not followed or there is a history of previous health complaints, such as renal disease or those taking nephrotoxic medication aggravated by creatine supplementation [73]. Specific studies into creatine supplementation, renal function and/or safety conclude that although creatine does slightly raise creatinine levels there is no progressive effect to cause negative consequences to renal function and health in already healthy individuals when proper dosage recommendations are followed [73-77]. Urinary methylamine and formaldehyde have been shown to increase due to creatine supplementation of 20 g/d; this however did not bring the production outside of normal healthy range and did not impact on kidney function [56,78]. It has been advised that further research be carried out into the effects of creatine supplementation and health in the elderly and adolescent [73,75]. More recently, a randomized, double blind, 6 month resistance exercise and supplementation intervention [79] was performed on elderly men and women (age >65 years) in which subjects were assigned to either a supplement or placebo group. The supplement group was given 5 g CM, 2 g dextrose and 6 g conjugated linoleic acid/d, whilst the placebo group consumed 7 g dextrose and 6 g safflower oil/d. CM administration showed significantly greater effects to improve muscular endurance, isokinetic knee extension strength, fat free mass and to reduce fat mass compared to placebo. Furthermore the supplement group had an increase in serum creatinine but not creatinine clearance suggesting no negative effect on renal function.

In a study on Alpha-Lipoic Acid, 1,000mg of ALA paired with 100g sucrose and 20g creatine monohydrate was more effective in increasing muscular creatine levels relative to creatine alone and creatine combined with sucrose.[600] This apparent augmentation of creatine uptake into muscle cells was used alongside a loading period. Another study investigating a nutrient mixture (150g glucose, 20g creatine, 2g/kg bodyweight glycerol) on heat tolerance in trained athletes found that replacing one third (50g) of the glucose with 1g ALA resulted in no significant differences between groups (in regard to heat tolerance and cardiovascular performance) despite the reduction of 50g carbohydrate.[601]
One study demonstrated that daily supplementation with 5 g of creatine monohydrate increased the intracellular creatine and PCr content of quadriceps muscle in 17 human subjects. Those with the lowest initial total creatine content had the greatest increase. In addition, exercise enhanced creatine uptake in muscle. No adverse effects were reported [5].
Studies that use a dosage range typical of creatine supplementation (in the range of 5g a day following an acute loading period) note increases to total body water of 6.2% (3.74lbs) over 9 weeks and[608] 1.1kg over 42 days.[609] Interestingly, some studies comparing creatine paired with training against training itself fail to find a significant difference in percentage of water gained (which is inherently to activity) with standard oral doses of creatine[609][607][610] (although low dose creatine supplementation of 0.03g/kg or 2.3g daily doesn’t appear to increase water retention[611]) despite more overall water weight being gained, due to an equal gain of dry mass in muscles. One study has quantified the percentage increase in mass of muscle cells to be 55% water, suggesting the two groups are fairly equal.[609]
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