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“A Randomized Double-Blind Evaluation of the Gastrointestinal, Body Composition, Stress Response and Cognitive Function Impacts of Creatine Supplementation in Healthy Adults”, Kalman et al 2021

2021-kalman.pdf: “A Randomized Double-Blind Evaluation of the Gastrointestinal, Body Composition, Stress Response and Cognitive Function Impacts of Creatine Supplementation in Healthy Adults”⁠, Douglas S. Kalman, Corbin Hohl, Brent Petersen, Sarah Flynn, Cassandra Evans, Jose Antonio, Jaime Tartar et al (2021-10-28; backlinks; similar):

Creatine monohydrate is a popular ergogenic aid used by athletes, adolescents and older individuals. There are various forms of creatine supplements that are on the market, however, creatine monohydrate is the most popular. Creatine itself is considered as less stable in solution when left in solution over time. Advances in product development and science may allow for a more stable aqueous solution of creatine. One major concern of ready-to-drink creatine supplements is the potential adverse gastrointestinal effects.

In this randomized, double-blind, placebo-controlled design, the potential gastrointestinal effects of stabilized creatine (CreaBev®) as compared to standard creatine monohydrate versus control was tested. Subjects were randomly assigned to receive the CreaBev® supplement, creatine monohydrate supplement or no supplement (control). Subjects were instructed to consume one serving of the supplement (delivering 5 gm creatine) on a daily basis for 28 days. Subjects underwent baseline testing and end of study testing. The Severity of Dyspepsia Analysis (SODA) questionnaire and National Institutes of Health (NIH) Cognitive Test Toolbox were used to evaluate GI effects and cognition. Additional testing included body composition analysis (including fluid balance), and exploratory measurement of the stress biomarkers, salivary alpha amylase and cortisol⁠.

Following the consumption of CreaBev, no adverse gastrointestinal side effects were reported. Cognition via the Dimension Change Test statistically-significantly improved (pre: 104 ± 14 to post: 116 ± 14; p = 0.0017) in the CreaBev group. There was no observed differences in total body fluid status over the 28 days between the groups (p > 0.05) No statistically-significant differences in levels of salivary alpha amylase, cortisol and anthropometrics were observed.

The use of CreaBev did not cause any adverse GI effects and improved cognitive performance on the Dimension Change Test.

[Keywords: creatine, gastrointestinal, bloating, cognition, dietary supplement]

“Creatine Supplementation and Brain Health”, Roschel et al 2021

“Creatine Supplementation and Brain Health”⁠, Hamilton Roschel, Bruno Gualano, Sergej M. Ostojic, Eric S. Rawson (2021-01-18; backlinks; similar):

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (eg. cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans.

There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (eg. exercise, sleep deprivation) or chronic, pathologic conditions (eg. creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression).

Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.

[Keywords: phosphorylcreatine, dietary supplement, cognition, brain injury, concussion]

“Does the Combination of Resistance Training and a Nutritional Intervention Have a Synergistic Effect on Muscle Mass, Strength, and Physical Function in Older Adults? A Systematic Review and Meta-analysis”, Choi et al 2021

“Does the combination of resistance training and a nutritional intervention have a synergistic effect on muscle mass, strength, and physical function in older adults? A systematic review and meta-analysis”⁠, MoonKi Choi, Hayeon Kim, Juyeon Bae (2021; ; similar):

Background: Health-promoting interventions are important for preventing frailty and sarcopenia in older adults. However, there is limited evidence that nutritional interventions yield additional effects when combined with resistance training. This systematic review and meta-analysis aimed to compare the effectiveness of nutritional interventions with resistance training and that of resistance training alone.

Methods: Randomized controlled trials published in peer-reviewed journals prior to July 2020 were retrieved from databases and other sources. The articles were screened according to the inclusion and exclusion criteria. The methodological quality of the included studies was assessed using Cochrane’s risk of bias tool 2. A meta-analysis was performed using the RevMan 5.4 program and STATA 16 program.

Results: A total of 22 studies were included in the meta-analysis. The results of the meta-analysis showed no statistically-significant differences between groups in muscle mass, muscle strength, or physical functional performance. In the subgroup analysis regarding the types of nutritional interventions, creatine showed statistically-significant effects on lean body mass (n = 4, MD 2.61, 95% CI 0.51 to 4.72). Regarding the other subgroup analyses, there were no statistically-significant differences in appendicular skeletal muscle mass (p = .43), hand grip strength (p = .73), knee extension strength (p = .09), chair stand test results (p = .31), or timed up-and-go test results (p = .31). In the meta-regression, moderators such as the mean age of subjects and duration of interventions were not associated with outcome variables.

Conclusions: This meta-analysis showed that nutritional interventions with resistance training have no additional effect on body composition, muscle strength, or physical function. Only creatine showed synergistic effects with resistance training on muscle mass.

Trial Registration: CRD42021224843 .

“Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills?”, Cutsem et al 2020

2020-vancutsem.pdf: “Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills?”⁠, Jeroen Van Cutsem, Bart Roelands, Bert Pluym, Bruno Tassignon, Jo Verschueren, Kevin De Pauw, Romain Meeusen et al (2020-01; backlinks; similar):

Purpose: The importance of the brain in sports was recently confirmed by the negative effect of mental fatigue (MF) on sport-specific psychomotor skills. Creatine supplementation improves strength but can also improve cognitive functioning. To explore the role of creatine in combating MF, we evaluated whether creatine supplementation counteracts the MF-associated impairment in sport-specific psychomotor skills.

Methods: In 23°C, 14 healthy participants (4 females, 10 males; mean ± SD, age = 24 ± 3 yr, mass = 74 ± 13 kg, height = 179 ± 9 cm) performed a 90-min mentally fatiguing task (counterbalanced, crossover, and double-blinded; ie. Stroop task) in two different conditions: after a 7-d creatine supplementation (CR; 20 g·d−1) and after a 7-d calcium lactate supplementation (placebo [PLAC]), separated by a 5-wk washout. In both conditions, a 7-min sport-specific visuomotor task, a dynamic handgrip strength endurance task, and a 3-min Flanker task was performed before and after the mentally fatiguing task. Physiological and perceptual responses were measured throughout the protocol.

Results: Handgrip strength endurance was higher in CR compared with PLAC (p = 0.022). MF impaired visuomotor response time (+4.4%; p = 0.022) and Flanker accuracy (−5.0%; p = 0.009) in both conditions. Accuracy on the Stroop task was higher in CR compared with PLAC (+4.9%; p = 0.026). Within the perceptual and physiological parameters, only motivation and vigor (p ≤ 0.027) were lower in CR compared with PLAC.

Conclusion: Creatine supplementation improved physical (strength endurance) and prolonged cognitive (Stroop accuracy) performance, yet it did not combat MF-induced impairments in short sport-specific psychomotor or cognitive (Flanker) performance. These results warrant further investigation in the potential role of creatine in combating the MF-associated decrements in prolonged (eg. 90-min soccer game) sport performance and suggest a role of brain phosphocreatine in MF.

[Keywords: creatine supplementation, phosphocreatine, mental exertion, cognitive fatigue, visuomotor response time, cognitive performance]

“Effects of Creatine Supplementation on Cognitive Function of Healthy Individuals: A Systematic Review of Randomized Controlled Trials”, Avgerinos et al 2018

2018-avgerinos.pdf: “Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials”⁠, Konstantinos I. Avgerinos, Nikolaos Spyrou, Konstantinos I. Bougioukas, Dimitrios Kapogiannis (2018-01-01; backlinks)

“Does Brain Creatine Content Rely on Exogenous Creatine in Healthy Youth? A Proof-of-principle Study”, Merege-Filho et al 2016

2016-meregefilho.pdf: “Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study”⁠, Mr. Carlos Alberto Abujabra Merege-Filho, Dr. Maria Concepción Garcia Otaduy, Dr. Ana Lúcia Sá-Pinto et al (2016-01-01; backlinks)

“Dual N-Back Meta-Analysis”, Branwen 2012

DNB-meta-analysis: “Dual n-Back Meta-Analysis”⁠, Gwern Branwen (2012-05-20; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

Does DNB increase IQ? What factors affect the studies? Probably not: gains are driven by studies with weakest methodology like apathetic control groups.

I meta-analyze the >19 studies up to 2016 which measure IQ after an n-back intervention, finding (over all studies) a net gain (medium-sized) on the post-training IQ tests.

The size of this increase on IQ test score correlates highly with the methodological concern of whether a study used active or passive control groups⁠. This indicates that the medium effect size is due to methodological problems and that n-back training does not increase subjects’ underlying fluid intelligence but the gains are due to the motivational effect of passive control groups (who did not train on anything) not trying as hard as the n-back-trained experimental groups on the post-tests. The remaining studies using active control groups find a small positive effect (but this may be due to matrix-test-specific training, undetected publication bias, smaller motivational effects, etc.)

I also investigate several other n-back claims, criticisms, and indicators of bias, finding:

“Nootropics”, Branwen 2010

Nootropics: “Nootropics”⁠, Gwern Branwen (2010-01-02; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar)

“Cognitive Effects of Creatine Ethyl Ester Supplementation”, Ling et al 2009

“Cognitive effects of creatine ethyl ester supplementation”⁠, Jonathan Ling, Minos Kritikos, Brian Tiplady (2009-12; backlinks; similar):

Supplementation with creatine-based substances as a means of enhancing athletic performance has become widespread. Until recently, however, the effects of creatine supplementation on cognitive performance has been given little attention. This study used a new form of creatine—creatine ethyl ester—to investigate whether supplementation would improve performance in 5 cognitive tasks, using a double-blind, placebo-controlled study.

Creatine dosing led to an improvement over the placebo condition on several measures. Although creatine seems to facilitate cognition on some tasks, these results require replication using objective measures of compliance. The improvement is discussed in the context of research examining the influence of brain energy capacity on cognitive performance.

“Non-enzymatic Hydrolysis of Creatine Ethyl Ester”, Katseres et al 2009

2009-katseres.pdf: “Non-enzymatic hydrolysis of creatine ethyl ester”⁠, Nicholas S. Katseres, David W. Reading, Luay Shayya, John C. DiCesare, Gordon H. Purser (2009-01-01; backlinks)

“Oral Creatine Monohydrate Supplementation Improves Brain Performance: a Double-blind, Placebo-controlled, Cross-over Trial”, Rae et al 2003

“Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial”⁠, Caroline Rae, Alison L. Digney, Sally R. McEwan, Timothy C. Bates (2003; ; backlinks; similar):

Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialed successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency, adenosine triphosphate and its regulator, adenosine diphosphate. In this work, we tested the hypothesis that oral creatine supplementation (5 g d(-1) for six weeks) would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and intelligence (Raven’s Advanced Progressive Matrices), both tasks that require speed of processing. These findings underline a dynamic and significant role of brain energy capacity in influencing brain performance.

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