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]

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.
Chwalbinska-Monteta [34] observed a significant decrease in blood lactate accumulation when exercising at lower intensities as well as an increase in lactate threshold in elite male endurance rowers after consuming a short loading (5 days 20 g/d) CM protocol. However, the effects of creatine supplementation on endurance performance have been questioned by some studies. Graef et al [35] examined the effects of four weeks of creatine citrate supplementation and high-intensity interval training on cardio respiratory fitness. A greater increase of the ventilatory threshold was observed in the creatine group respect to placebo; however, oxygen consumption showed no significant differences between the groups. The total work presented no interaction and no main effect for time for any of the groups. Thompson et al [36] reported no effects of a 6 week 2 g CM/d in aerobic and anaerobic endurance performance in female swimmers. In addition, of the concern related to the dosage used in these studies, it could be possible that the potential benefits of creatine supplementation on endurance performance were more related to effects of anaerobic threshold localization.
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Creatine citrate is creatine bound to citric acid, or citrate. Creatine citrate does not differ greatly from monohydrate in regard to absorption or kinetics.[83] Note that creatine citrate is more water-soluble than monohydrate,[84] but creatine absorption is generally not limited by solubility. The increased water solubility may play a factor in palatability.
If you’ve been training longer than 6–12 months, you can split your workouts into upper- and lower-body days. The most common setup is to train upper body one day and lower the next so that each area gets trained twice in one week. If you train four days per week, you can train upper body on Monday, lower Tuesday, rest Wednesday, and then do upper body again on Thursday, lower body on Friday, and then rest on the weekend.
The general strategy adopted by most present-day competitive bodybuilders is to make muscle gains for most of the year (known as the "off-season") and, approximately 12–14 weeks from competition, lose a maximum of body fat (referred to as "cutting") while preserving as much muscular mass as possible. The bulking phase entails remaining in a net positive energy balance (calorie surplus). The amount of a surplus in which a person remains is based on the person's goals, as a bigger surplus and longer bulking phase will create more fat tissue. The surplus of calories relative to one's energy balance will ensure that muscles remain in a state of anabolism.
Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) is a synthetic analogue of creatine in a cyclic form. It serves as a substrate for the creatine kinase enzyme system, acting as a creatine mimetic. Cyclocreatine may compete with creatine in the CK enzyme system to transfer phosphate groups to ADP, as coincubation of both can reduce cyclocreatine’s anti-motility effects on some cancer cells.[96] 

Creatine is a hydrophilic polar molecule that consists of a negatively charged carboxyl group and a positively charged functional group [64]. The hydrophilic nature of creatine limits its bioavailability [65]. In an attempt to increase creatines bioavailability creatine has been esterified to reduce the hydrophilicity; this product is known as creatine ethyl ester. Manufacturers of creatine ethyl ester promote their product as being able to by-pass the creatine transporter due to improved sarcolemmal permeability toward creatine [65]. Spillane et al [65] analyzed the effects of a 5 days loading protocol (0.30 g/kg lean mass) followed by a 42 days maintenance phase (0.075 g/kg lean mass) of CM or ethyl ester both combined with a resistance training program in 30 novice males with no previous resistance training experience. The results of this study [65] showed that ethyl ester was not as effective as CM to enhance serum and muscle creatine stores. Furthermore creatine ethyl ester offered no additional benefit for improving body composition, muscle mass, strength, and power. This research did not support the claims of the creatine ethyl ester manufacturers.
The pancreas is one of the extrahepatic (beyond the liver) organs that can synthesize creatine, alongside the kidneys.[486][487] Freshly prepared pancreatic β-cells will normally secrete insulin in response to glucose stimulation, and it appears that phosphocreatine is required for this effect, since phosphocreatine is increased in response to glucose[488] alongside an increase of the ADP:ATP ratio. They appear to close ATP sensitive potassium channels (KATP channels), causing a release of insulin secondary to calcium release.[488] Both phosphocreatine[488] and ADP[489] are implicated, but it seems that despite the channel being sensitive to ATP,[490] the concentration of ATP in a pancreatic cell (3-5mM[491][492]) is already above the activation threshold (in the micromolar range[493]) and thus a further increase would not have an appreciable effect.

Wilkinson, S. B., Tarnopolsky, M. A., MacDonald, M. J., MacDonald, J. R., Armstrong, D., & Phillips, S. M. (2007). Consumption of fluid skim milk promotes greater muscle protein accretion after resistance exercise than does consumption of an isonitrogenous and isoenergetic soy-protein beverage. The American Journal of Clinical Nutrition, 85(4), 1031-1040.

I’m going to cover this in detail in a bit, but for right now, just know this: it’s VERY possible (and common) to gain weight fast in the hopes of gaining muscle fast. The problem, however, is that the majority of the “weight” a person in this scenario will end up gaining will be body fat rather than muscle mass. This is something that needs to be avoided at all costs, and I’ll show you how a little later.
Co-ingesting creatine with caffeine partially negated the benefits of creatine supplementation (at 5mg/kg bodyweight) during the loading phase in one study.[590] The exact mechanism responsible for this effect is not known, but might be related to opposing actions on muscle contraction time.[591] However, another study in trained men found that co-ingestion of 300mg caffeine per day during creatine loading at 20g per day (split into 4 doses) had no effect on bench press 1RM, time to fatigue, or sprinting ability.[592] However, this study also found that creatine alone or when combined with caffeine had no effect on any of these parameters over placebo, either. Thus, the study may have been underpowered or done in too short a time frame (the test was done after only 5 days of loading) to observe any possible effects.[592]
In people with COPD given either glucose placebo (40.7g) or creatine supplementation (5.7g creatine with 35g glucose) thrice daily for two weeks followed by a single dose for ten weeks, supplementation was associated with improvements in muscular strength and endurance, but not cardiovascular exercise potential.[579] A later trial of larger power using a loading phase of 22g creatine with a maintenance phase of 3.76g during rehabilitative exercise failed to replicate the improvements in skeletal muscle performance despite increased body weight seen with creatine,[580] and the failure to improve cardiovascular performance during aerobic exercise seen in both aforementioned studies has been replicated elsewhere after eight weeks supplementation, during which muscular performance was, again, unaffected.[581]
The last survivors of the pro-hormone supplements, which were removed from sale last January, estrogen-blocking supplements aren't pro-hormones but do inhibit the enzyme aromatase, which converts androgens into estrogens. In normal men that enzyme is ubiquitous, being present in such tissues as muscle, brain and skin. About 20 percent of the free testosterone circulating in the blood is converted into estrogen by way of aromatase.
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]
Creatine ethyl ester is more a pronutrient for creatinine rather than creatine,[74] and was originally created in an attempt to bypass the creatine transporter. It is currently being studied for its potential as a treatment for situations in which there is a lack of creatine transporters (alongside cyclocreatine as another possible example).[77] Its efficacy may rely on intravenous administration, however.

Creatine supplementation has been noted to improve general wellbeing and health status (assessed by St George’s Respiratory questionnaire[582]) of people with COPD over two weeks loading (17.1g daily with carbohydrates) and ten weeks of 5.7g maintenance.[579] The studies that failed to find improvements with creatine supplementation on muscular performance also failed to find improvements in this rating scale, relative to placebo.[580][581]
Although creatine supplementation has been shown to be more effective on predominantly anaerobic intermittent exercise, there is some evidence of its positive effects on endurance activities. Branch [28] highlights that endurance activities lasting more than 150s rely on oxidative phosphorylation as primary energy system supplier. From this meta analysis [28], it would appear that the ergogenic potential for creatine supplementation on predominantly aerobic endurance exercise diminishes as the duration of the activity increases over 150s. However it is suggested that creatine supplementation may cause a change in substrate utilization during aerobic activity possibly leading to an increase in steady state endurance performance.
Heath bent his legs — each thigh about 32 inches around, bigger than his waist — and lifted the black case. Inside was his latest Mr. Olympia trophy. In bodybuilding, it is called the Sandow, and Heath has won the last six, most recently in Las Vegas in September. Arnold Schwarzenegger, still the world’s most famous bodybuilder, won six in a row, too, and then a seventh a few years later. Two men, Lee Haney and Ronnie Coleman, have won eight.
The incidence of liver damage from herbal and dietary supplements is about 16–20% of all supplement products causing injury, with the occurrence growing globally over the early 21st century.[2] The most common liver injuries from weight loss and bodybuilding supplements involve hepatocellular damage with resulting jaundice, and the most common supplement ingredients attributed to these injuries are catechins from green tea, anabolic steroids, and the herbal extract, aegeline.[2]
Another study demonstrated that females receiving 4 days of high-dose creatine intake (20 g/day) followed by low-dose creatine intake (5 g/day) during 10 weeks of resistance training (3hours/week) increased muscle PCr concentrations by 6%. Also, maximal strength of the muscle groups trained increased by 20-25%, maximal intermittent exercise capacity of the arm flexors increased by 10-25% and fat-free mass increased by 60% [11].
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