Creatine is a molecule produced in the body, where it stores high-energy phosphate groups in the form of phosphocreatine (creatine phosphate).
During periods of stress, phosphocreatine releases energy to aid cellular function. This is what causes strength increases after creatine supplementation, but this action can also aid the brain, bones, muscles, and liver. Most of the benefits of creatine are provided through this mechanism.
Creatine can be found in some foods — mostly meat, eggs, and fish. Creatine supplementation confers a variety of health benefits, notably neuroprotective and cardioprotective. It is often used by athletes to increase both power output and lean mass.
Stomach cramping can occur when creatine is supplemented without sufficient water. Diarrhea and nausea can occur when too much creatine is supplemented at once, in which case doses should be spread out over the day and taken with meals.
Recommended dosage, active amounts, other details
There are many different forms of creatine available on the market, but creatine monohydrate is the cheapest and most effective. Micronized creatine monohydrate dissolves in water more easily, which can be more practical.
Creatine monohydrate can be supplemented through a loading protocol. To start loading, take 0.3 gram per kilogram of bodyweight per day for 5–7 days, then follow with at least 0.03 g/kg/day either for three weeks (if cycling) or indefinitely (without additional loading phases).
Muscle Fiber Composition
When assessing type I muscle (slow twitch) against type II muscles (fast twitch) in response to creatine supplementation, it seems that glycogen accumulation may only occur in the latter as assessed in rats, where the soleus muscle is a model for slow twitch muscle fibers and the gastrocnemius is a model for fast twitch. This is similar to human creatine distribution, which seems to accumulate in type II muscles rather than type I.
Using information from a meta-analyses of 16 studies conducted on creatine and its influence on power and strength, (with or without exercise in all age groups above 16, but placebo controlled and without crossover) studies that tended to have a 5-7 day loading period with continued maintenance thereafter noted that, in regards to studies assessing 1-3 rep bench press strength in trained young men, that 7 studies (four of which are online) totalling 70 people using creatine and 73 persons in placebo resulted in a 6.85kg increase in strength relative to placebo, the benefits of which peaked at 8 weeks. This meta-analysis also quantified a significant increase in squat strength (9.76kg) yet failed to find a significant influence on peak biceps contraction power, which may have been influenced by the two null studies being in elderly persons while the positive study was statistically outweighed, but noted an 1.8-fold increase in power associated with creatine over placebo. The other meta-analysis conducted the following yearcalculated effect sizes for creatine supplementation and noted no significant differences between genders or when comparing trained against untrained individuals. The mean effect size of exercises lasting below 30s (those that use the creatine-phosphate system) was 0.24+/-0.02 and performed significantly better than placebo, where exercise increased performance by 4.2+/-0.6% while the addition of creatine enhanced this to 7.5+/-0.7%.
According to the two meta-analyses on the topic, Creatine significantly increases power when supplemented in both sexes over a period of time up to 8 weeks (where improvement over placebo is maintained, rather than being enhanced further). The rate of which power is derived from a resistance training regimen appears to be up to 78.5% greater with creatine relative to placebo, and in active trained men who are naive to creatine, this can be quantified at about 7kg for bench and 10kg for squat over 8 weeks
Resistance exercise enhances the rate of creatine uptake into muscle cells in the muscles that are actively engaged. Initially thought to be a byproduct of enhanced blood flow, the enhanced creatine uptake is now thought to be due to allosteric modifications of the creatine transporter, which enhances its maximal capacity.
One study reported elevated creatine uptake in response to supplementation (and independent of exercise) in athletes versus non-athletes, suggesting that long-term modifications in muscle tissue is a byproduct of exercise.
Muscle Growth and Hypertrophy
Creatine supplementation can also increase muscle fiber size independent of protein synthesis, as increasing water content in muscle cells increases their diameter. After 20g creatine was ingested (alongside dextrose at a 1:7.5 ratio) type I, IIa and IIx fibers increased in diameter by 9, 5, and 4% respectively.
This cellular influx may also decrease protein oxidation rates, which leads to increases in nitrogen balance and indirectly increases muscle mass. This lowering of protein oxidation is from signalling changes vicariously through cell swelling and appears to upregulate 216 genesin a range of 1.3 to 5-fold increases, with the largest increase seen in the protein involved in satellite cell recruitment, sphingosine kinase-1. Most importantly for muscle hypertrophy, the protein content of PKBa/Akt1, p38 MAPK, and ERK6 increased 2.8+/-1.2 fold. Sixty-nine genes are also downregulated after creatine supplementation, to less notable degrees.
12 g of creatine for two weeks prior to an endurance running test (65-70% VO2max for an hour) is able to attenuate the increase in lactate and the tryptophan/Branched Chain Amino Acids ratio, and also attenuated the increase in serum protein catabolites, suggesting an anti-catabolic effect.
Nutrient Timing and Dosing
One study in swimmers using 2g of creatine daily failed to find an increase in skeletal muscle creatine content and did not find any alterations in skeletal muscle metabolism during exercise relative to placebo.
The lowest dose of creatine sufficient to increase muscular creatine stores in otherwise healthy but sedentary persons (2 grams) appears to be insufficient for athletes
In otherwise healthy bodybuilders, supplementation of creatine at 5g either immediately before or after a weight training session (with no directive on days without training) over the course of four weeks noted that while both groups improved, there was no significant difference between groups overall and this null result has been found in another study with 0.1g/kg creatine thrice weekly over 12 weeks in otherwise healthy adults. It has been suggested that post-workout may be favorable (based on magnitude-based inference) since more individuals experience benefits with post-workout when compared to pre-workout despite no whole-group differences.
In contrast to the above null effects, ingestion of creatine both before and after a workout (alongside protein and carbohydrate) over 10 weeks seems to promote muscle growth more than the same supplement taken in the morning away from the time of workout. Benefits of creatine around the workout, relative to other times, has been hypothesized to be related to an upregulation of creatine transport secondary to muscle contraction (a known phenomena).
The benefits of creatine supplementation appear to be more prominent when taken closer to the resistance training workout than when compared to supplementation at other times of the day, and at this moment in time it seems this benefit applies equally to taking creatine before the workout and/or after the workout
Creatine supplementation appears to be effective at increasing power output in anaerobic cardiovascular exercise, and has been implicated in increasing the lactate threshold as well as time to volitional fatigue within 6 days after starting supplementation (20g daily, divided into 4 doses with 15g glucose).
Interactions with Hormones
Creatine has been shown to influence androgen levels. Three weeks of creatine supplementation has been shown to increase dihydrotestosterone (DHT) levels, as well as the DHT:testosterone ratio with no effects on testosterone levels. In contrast, creatine supplementation has been shown to increase testosterone levels when taken concurrent with a 10-week resistance training program.A study in male amateur swimmers also noted that a creatine loading phase (20g daily for six days) was able to increase testosterone levels by around 15% relative to baseline.
The reasons for differences in the effect of creatine on testosterone vs. DHT across studies are not clear, but also not mutually exclusive. A measured increase in DHT could indicate that testosterone levels were increased by creatine, but rapidly converted to DHT through a homeostatic mechanism. Differences in study subject populations, methodology, or the presence and type of concurrent exercise could also be contributing factors. At any rate, the literature collectively suggests that creatine has the general ability to cause a modest increase in androgen levels in men.
The effects with low doses of creatine seem to be more chronic in nature, as low dose creatine supplementation has not been shown to acutely increase androgen levels. However, acute dosing of creatine at higher levels (100 mg/kg) has been shown to elicit a moderate increase in testosterone levels.
Creatine has been shown to have a subtle but positive effect on androgen levels in men. The particular androgen, (testosterone vs. DHT) and the extent to which it is affected tends to vary by study. The effects of creatine on androgen levels in women are unknown, as no studies on women currently exist.
A pilot study in otherwise healthy men at rest, given a single bolus of 20 g creatine noted a spike in growth hormone secretion over the next six hours with a high variability of 83+/-45%.
In elite swimmers, the growth hormone response to sprints appears to be attenuated (39%) following creatine loading, although after a 3g maintenance phase (22-27 weeks), this attenuation was reduced to less than 5%. Elsewhere in swimmers, resting growth hormone is unaffected by the loading phase, suggesting that this is an exercise exclusive effect.
Creatine may increase growth hormone secretion at rest while being able to blunt exercise-induced growth hormone secretion somewhat. The blunting effect is small in magnitude in maintenance and larger during loading. This is similar to the interactions with Arginine and growth hormone
Insulin secretion seems to have interplay with creatine supplementation, however this is only clinically significant during the first few days of loading when myocyte stores of creatine are depleted. The effect is mediated through high level of insulin release and it appears to be independent of the creatine transporter.
During a creatine loading phase, it is possible for insulin secretion to enhance the rate of uptake into myocytes. When the myocytes are saturated with creatine (seen after 3 days of loading), then this insulin effect seems to disappear.
In vitro studies on endothelial cells have noted that the benefits of creatine against atherosclerosis (via immune cell adhesion to the endothelial cell) are blocked with the pharmaceutical ZM241385, a high affinity adenosine A2A receptor antagonist; this particular receptor subset (A2A rather than other adenosine receptors) and its inhibition are similar to Caffeine, suggesting that caffeine may have an inhibitory effect on this mechanism of creatine.
Although the anti-atherosclerotic properties of creatine are not well studied at this point in time, they appear to be dependent on the A2A receptor (caffeine’s target) not being inhibited
Co-ingesting creatine with Caffeine partially negated the benefits of creatine supplementation (at 5mg/kg bodyweight) during the loading phase in one study. The exact mechanism is not known, but might be related to opposing actions on muscle contraction time. However, another study in trained men found that co-ingestion of 300 mg Caffeine per day during creatine loading at 20 g per day (split into 4 doses) had no effect on bench press 1RM, time to fatigue, or sprinting ability.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 see any possible effects.
However, caffeine does not negate the benefits of creatine loading when not coingested, but just taken before exercise in the same dosage. This result indicates that loading creatine without caffeine on a daily basis, but saving caffeine for select workouts, may be an effective strategy as creatine does not adversely affect Caffeine’s ergogenic effects and may enhance creatine’s effectiveness in anaerobic exertion if the two compounds are alternated.
The effects of creatine and caffeine coingestion when it comes to human interventions on physical performance are not yet clear
The combination of creatine and β-alanine appears to augment prolonged (4 week) beneficial changes in body composition (more muscle, less fat) relative to creatine alone.
Trimethylglycine (TMG; betaine) is a dietary supplement and component of Beetroot which is known as a methyl donor, contributing to metabolic processes in the body which require a methyl group either directly (the methylation of homocysteine) or indirectly via replenishing the active form of folate or via replenishing S-Adenosyl Methionine (SAMe). As the synthesis of creatine (via GAMT) requires a donation from SAMe, it is thought that TMG can aid in creatine synthesis (which has been noted in the rat liver in the absence of creatine supplementation).
The one study to investigate this claim noted that the addition of 2g of supplemental TMG to 20g supplemental creatine failed to outperform creatine by itself in increasing muscular creatine stores or power output.
Although TMG is indirectly involved in the synthesis of creatine, the evidence at this point in time does not support an additive nor synergistic role of TMG supplementation alongside creatine
Alpha-Lipoic Acid (ALA)
In a study with Alpha-Lipoic Acid, 1,000mg of ALA paired with 100g sucrose and 20 g creatine monohydrate was more effective in increasing muscular creatine levels relative to creatine alone and creatine combined with sucrose. 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 body weight 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 regards to heat tolerance and cardiovascular performance) despite the reduction of 50g carbohydrate.
A study in swine noted increased water retention (via a PY value) in the group fed both creatine and alpha-lipoic acid at a dose of 24g and 600 mg daily; respectively.
COX-2, a pro-inflammatory enzyme, is sometimes a therapeutic target for both muscle soreness and some degenerative diseases that are exacerbated by inflammation. COX-2 inhibitors (in this study, rofecoxib) and creatine monohydrate both appear to protect dopaminergic neurons from being destroyed by toxins, and can protect in an additive manner; suggesting possible usage of both to reduce the risk of Parkinson’s Disease.
There are no clinically significant side-effects of creatine supplementation acutely. Numerous trials have been conducted in humans with varying dosages, and the side-effects have been limited to gastrointestinal distress (from too much creatine consumption at once) and cramping (from insufficient hydration).
A dose of 5g daily has strong evidence for not causing any adverse side effects and 10g has been used daily for 310 days in older adults (aged 57+/-11.1) with no significant differences from placebo. Such a dose has also been demonstrated for long-term safety in Parkinson’s Disease, and at least one small retrospective study in athletes (surveying persons taking creatine for up to or over a year) failed to find any significant differences in a battery of serum health parameters. Other studies measuring serum parameters also fail to find abnormalities outside the normal range.