Due to the popularity associated with creatine supplementation since the first published reports in the early 1990s, a number of other questions have been evaluated and considered regarding its efficacy. For example, the majority of the published literature on creatine has been completed using male athletes, leading to much less information being available on how creatine supplementation impacts females. Previous work has highlighted gender-specific differences in creatine production and turnover, which lays the foundation for gender considerations for creatine [4]. In regard to research involving exercise performance in females, Vandenberghe et al. [39] reported that creatine supplementation increases intramuscular PCr levels, muscle mass, and strength when compared to those females who took a placebo. Other research by Hamilton [147] showed improvements in upper-body exercise capacity, and Tarnopolsky showed improvements in high-intensity exercise performance [148], whereas Kambis et al. [149] reported improvements in knee extension muscle performance. Similarly, excellent potential exists for creatine to support the health and function of older populations. Although nearly all of the original research on creatine used young, athletic populations, research in the past 10–15 years has highlighted creatine’s ability to increase the ability to perform daily living activities, to delay fatigue, and to improve muscle mass in older populations [150,151,152,153,154,155,156,157,158].

Overwhelmingly, the majority of research that has examined the potential of creatine to impact exercise performance has been conducted using the monohydrate version. Although several other forms of creatine have been proposed and marketed as alternatives, none have been shown to offer benefits above and beyond those seen with monohydrate. In this respect, a number of studies have been completed comparing various alternative forms of creatine, and the interested reader is directed to the following papers: [3,4,5,30,159,160,161,162,163]. In this respect, one must also realize that several studies have sought to examine the impact of combining creatine with other ingredients, such as beta-alanine [164,165], beta-hydroxy-beta-methylbutyrate (HMB) [96,166,167,168,169,170,171], glutamine [72], sodium bicarbonate [47], carbohydrates [22,44,99,172,173], and protein [22,59,99] to examine the potential for any synergistic outcomes. Furthermore, the interested reader is encouraged to read the critical review on this topic by Jäger et al. [159].

The level of creatine uptake is a key consideration, as it relates to the potential for health and performance outcomes. In this respect, one of the key considerations that has been identified in the literature is the presence of ‘responders’ and ‘nonresponders’. This concept was discussed in a 1999 review by Demant and Rhodes, in which they summarized the available literature and highlighted the fact that identical supplementation regimens could lead to increases in intramuscular PCr levels, whereas the same regimen may cause limited to no changes in other people following a similar supplementation regimen [20]. To illustrate this point, Kilduff et al. [174] identified subjects in their study as responders and nonresponders based on the magnitude of change seen in intramuscular PCr. When examined together, peak force was not changed due to supplementation, but when evaluated separately, the responders significantly increased their peak force production after creatine supplementation. Later, Syrotuik et al. [175] completed an analysis aiming to build a physiological profile of responders and nonresponders. In terms of creatine uptake, a commonly discussed factor that may dictate the extent to which intramuscular PCr levels change in response to creatine supplementation is the level of vegetarianism observed by the individual. In this respect, it is well known that meat-containing foods and products contain the highest amounts of creatine, and thus people who refrain from eating meats tend to consume the lowest amounts of creatine in their diet. Several papers are available that have examined the impact of creatine supplementation on people who follow various types of vegetarianism, with initial reports showing that vegetarians do, indeed, have lower levels of intramuscular PCr [176,177]. Shomrat and colleagues [178] were some of the first to examine this question and concluded that creatine supplementation equally impacted the ability of vegetarian and non-vegetarian individuals to generate peak power after an identical regimen of supplementation. Furthermore, additional studies by Watt [179] and Lukaszuk [180] highlighted the fact that creatine supplementation in vegetarian people can impact intramuscular and plasma levels of creatine in a similar fashion. Furthering this aim, reviews by Venderley and Kaviani concluded that creatine supplementation could be an effective strategy for vegetarian individuals to increase their intramuscular levels of PCr, a key factor that may impact an individual’s ability to perform high-intensity exercise [176,177]. Finally, interested readers are encouraged to review the following articles by Antonio [4], as well as the International Society of Sports Nutrition’s position on creatine [3].