Book & Papers


Creatine Supplementation for Health and Clinical Diseases

Creatine supplementation is one of the most studied and effective ergogenic aids for athletes. The multifaceted mechanisms by which creatine exerts its beneficial effect include increasing energy capacity, increasing protein synthesis, and decreasing protein breakdown, leading to increased muscle mass and physical performance. While these well-recognized creatine effects benefit the athlete, creatine may also serve as a potential clinical and therapeutic supplementary treatment to conventional medical interventions. Several studies have examined the effects on conditions such as diabetes, sarcopenia, osteoporosis, cancer, rehabilitation, and pulmonary and cardiovascular health.

This book aims to provide comprehensive reviews of creatine supplementation effects for health and clinical diseases.

Dr. Richard B. Kreider
Dr. Jeffrey R. Stout


Featured papers

Creatine in Health and Disease

Richard B. Kreider and Jeffery R. Stout

Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.

Keywords: ergogenic aids; cellular metabolism; phosphagens; sarcopenia; cognition; diabetes; creatine synthesis deficiencies; concussion; traumatic brain injury; spinal cord injury; muscle atrophy; rehabilitation; pregnancy; immunity; anti-inflammatory; antioxidant; anticancer

Kreider, R.B.; Stout, J.R. Creatine in Health and Disease. Nutrients 202113, 447.


Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

Diego A. Bonilla, Richard B. Kreider, Jeffrey R. Stout, Diego A. Forero, Chad M. Kerksick, Michael D. Roberts and Eric S. Rawson

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl−-dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4−]2− and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3−]−. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states.

Keywords: creatine kinase; energy metabolism; cell survival; bioinformatics; systems biology; cellular allostasis; dynamic biosensor

Bonilla, D.A.; Kreider, R.B.; Stout, J.R.; Forero, D.A.; Kerksick, C.M.; Roberts, M.D.; Rawson, E.S. Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients 202113, 1238.


Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health

Anna Maria Muccini, Nhi T. Tran, Deborah L. de Guingand, Mamatha Philip, Paul A. Della Gatta, Robert Galinsky, Larry S. Sherman, Meredith A. Kelleher, Kirsten R. Palmer, Mary J. Berry, David W. Walker, Rod J. Snow and Stacey J. Ellery

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research “road forward” to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.

Keywords: creatine; nutritional supplements; fertility; pregnancy; newborn; development; brain injury

Muccini, A.M.; Tran, N.T.; de Guingand, D.L.; Philip, M.; Della Gatta, P.A.; Galinsky, R.; Sherman, L.S.; Kelleher, M.A.; Palmer, K.R.; Berry, M.J.; Walker, D.W.; Snow, R.J.; Ellery, S.J. Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health. Nutrients 202113, 490.


Creatine Supplementation in Children and Adolescents

Andrew R. Jagim and Chad M. Kerksick

Creatine is a popular ergogenic aid among athletic populations with consistent evidence indicating that creatine supplementation also continues to be commonly used among adolescent populations. In addition, the evidence base supporting the therapeutic benefits of creatine supplementation for a plethora of clinical applications in both adults and children continues to grow. Among pediatric populations, a strong rationale exists for creatine to afford therapeutic benefits pertaining to multiple neuromuscular and metabolic disorders, with preliminary evidence for other subsets of clinical populations as well. Despite the strong evidence supporting the efficacy and safety of creatine supplementation among adult populations, less is known as to whether similar physiological benefits extend to children and adolescent populations, and in particular those adolescent populations who are regularly participating in high-intensity exercise training. While limited in scope, studies involving creatine supplementation and exercise performance in adolescent athletes generally report improvements in several ergogenic outcomes with limited evidence of ergolytic properties and consistent reports indicating no adverse events associated with supplementation. The purpose of this article is to summarize the rationale, prevalence of use, performance benefits, clinical applications, and safety of creatine use in children and adolescents.

Keywords: ergogenic aid; dietary supplement; youth; athletes

Jagim, A.R.; Kerksick, C.M. Creatine Supplementation in Children and Adolescents. Nutrients 202113, 664.


Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations

Benjamin Wax, Chad M. Kerksick, Andrew R. Jagim, Jerry J. Mayo, Brian C. Lyons and Richard B. Kreider

Creatine is one of the most studied and popular ergogenic aids for athletes and recreational weightlifters seeking to improve sport and exercise performance, augment exercise training adaptations, and mitigate recovery time. Studies consistently reveal that creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations. In this respect, supplementation consistently demonstrates the ability to enlarge the pool of intracellular creatine, leading to an amplification of the cell’s ability to resynthesize adenosine triphosphate. This intracellular expansion is associated with several performance outcomes, including increases in maximal strength (low-speed strength), maximal work output, power production (high-speed strength), sprint performance, and fat-free mass. Additionally, creatine supplementation may speed up recovery time between bouts of intense exercise by mitigating muscle damage and promoting the faster recovery of lost force-production potential. Conversely, contradictory findings exist in the literature regarding the potential ergogenic benefits of creatine during intermittent and continuous endurance-type exercise, as well as in those athletic tasks where an increase in body mass may hinder enhanced performance. The purpose of this review was to summarize the existing literature surrounding the efficacy of creatine supplementation on exercise and sports performance, along with recovery factors in healthy populations.

Keywords: supplementation; ergogenic aid; athletic performance; weightlifting; resistance exercise; training; muscular power; recovery; muscular adaptation; muscle damage

Wax, B.; Kerksick, C.M.; Jagim, A.R.; Mayo, J.J.; Lyons, B.C.; Kreider, R.B. Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations. Nutrients 202113, 1915.


The Application of Creatine Supplementation in Medical Rehabilitation

Kylie K. Harmon, Jeffrey R. Stout, David H. Fukuda, Patrick S. Pabian, Eric S. Rawson and Matt S. Stock

Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine’s potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation.

Keywords: supplements; muscle damage; recovery; immobilization; atrophy; muscular dystrophy; amyotrophic lateral sclerosis; Parkinson’s Disease; cardiopulmonary disease; mitochondrial cytopathy

Harmon, K.K.; Stout, J.R.; Fukuda, D.H.; Pabian, P.S.; Rawson, E.S.; Stock, M.S. The Application of Creatine Supplementation in Medical Rehabilitation. Nutrients 202113, 1825.


Creatine Supplementation in Women’s Health: A Lifespan Perspective

Abbie E Smith-Ryan, Hannah E Cabre, Joan M Eckerson and Darren G Candow

Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70–80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for performance and health among females. Due to the hormone-related changes to creatine kinetics and phosphocreatine resynthesis, supplementation may be particularly important during menses, pregnancy, post-partum, during and post-menopause. Creatine supplementation among pre-menopausal females appears to be effective for improving strength and exercise performance. Post-menopausal females may also experience benefits in skeletal muscle size and function when consuming high doses of creatine (0.3 g·kg−1·d−1); and favorable effects on bone when combined with resistance training. Pre-clinical and clinical evidence indicates positive effects from creatine supplementation on mood and cognition, possibly by restoring brain energy levels and homeostasis. Creatine supplementation may be even more effective for females by supporting a pro-energetic environment in the brain. The purpose of this review was to highlight the use of creatine in females across the lifespan with particular emphasis on performance, body composition, mood, and dosing strategies.

Keywords: female; dietary supplement; menstrual cycle; hormones; exercise performance; menopause; pregnancy; mood; cognition

Smith-Ryan, A.E.; Cabre, H.E.; Eckerson, J.M.; Candow, D.G. Creatine Supplementation in Women’s Health: A Lifespan Perspective. Nutrients 202113, 877.


Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults

Darren G. Candow, Scott C. Forbes, Ben Kirk and Gustavo Duque

Sarcopenia, defined as age-related reduction in muscle mass, strength, and physical performance, is associated with other age-related health conditions such as osteoporosis, osteosarcopenia, sarcopenic obesity, physical frailty, and cachexia. From a healthy aging perspective, lifestyle interventions that may help overcome characteristics and associated comorbidities of sarcopenia are clinically important. One possible intervention is creatine supplementation (CR). Accumulating research over the past few decades shows that CR, primarily when combined with resistance training (RT), has favourable effects on aging muscle, bone and fat mass, muscle and bone strength, and tasks of physical performance in healthy older adults. However, research is very limited regarding the efficacy of CR in older adults with sarcopenia or osteoporosis and no research exists in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia. Therefore, the purpose of this narrative review is (1) to evaluate and summarize current research involving CR, with and without RT, on properties of muscle and bone in older adults and (2) to provide a rationale and justification for future research involving CR in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia.

Keywords: sarcopenia; osteoporosis; osteosarcopenia; frailty; cachexia

Candow, D.G.; Forbes, S.C.; Kirk, B.; Duque, G. Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults. Nutrients 202113, 745.


Creatine Supplementation and Brain Health

Hamilton Roschel, Bruno Gualano, Sergej M. Ostojic and Eric S. Rawson

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 (e.g., 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 (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., 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

Roschel, H.; Gualano, B.; Ostojic, S.M.; Rawson, E.S. Creatine Supplementation and Brain Health. Nutrients 202113, 586.


Potential of Creatine in Glucose Management and Diabetes

Marina Yazigi Solis, Guilherme Giannini Artioli and Bruno Gualano

Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a wide variety of clinical conditions, such as cancer, muscle dystrophy and neurodegenerative disorders. Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise training, may improve glucose metabolism in health individuals and insulin-resistant individuals, such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro, improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise induces numerous metabolic benefits, including increases in insulin-independent muscle glucose uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with exercise training could result in additional improvements in glucose metabolism when compared with each intervention separately. The possible mechanism underlying the effects of combined exercise and creatine supplementation is an enhanced glucose transport into muscle cell by type 4 glucose transporter (GLUT-4) translocation to sarcolemma. Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the possible therapeutic role of creatine supplementation on glucose management and as a potential anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps.

Keywords: dietary supplements; exercise; skeletal muscle; glycemic control; type 2 diabetes mellitus

Solis, M.Y.; Artioli, G.G.; Gualano, B. Potential of Creatine in Glucose Management and Diabetes. Nutrients 202113, 570.


The Role of Creatine in the Development and Activation of Immune Responses

Eric C. Bredahl, Joan M. Eckerson, Steven M. Tracy, Thomas L. McDonald and Kristen M. Drescher

The use of dietary supplements has become increasingly common over the past 20 years. Whereas supplements were formerly used mainly by elite athletes, age and fitness status no longer dictates who uses these substances. Indeed, many nutritional supplements are recommended by health care professionals to their patients. Creatine (CR) is a widely used dietary supplement that has been well-studied for its effects on performance and health. CR also aids in recovery from strenuous bouts of exercise by reducing inflammation. Although CR is considered to be very safe in recommended doses, a caveat is that a preponderance of the studies have focused upon young athletic individuals; thus there is limited knowledge regarding the effects of CR on children or the elderly. In this review, we examine the potential of CR to impact the host outside of the musculoskeletal system, specifically, the immune system, and discuss the available data demonstrating that CR can impact both innate and adaptive immune responses, together with how the effects on the immune system might be exploited to enhance human health.

Keywords: innate immunity; adaptive immunity; nutritional supplements; inflammation; macrophage polarization; cytotoxic T cells; toll-like receptors

Bredahl, E.C.; Eckerson, J.M.; Tracy, S.M.; McDonald, T.L.; Drescher, K.M. The Role of Creatine in the Development and Activation of Immune Responses. Nutrients 202113, 751.


Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy

Bo Li and Lili Yang

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.

Keywords: creatine; T cell antitumor immunity; metabolic regulator; cancer immunotherapy

Li, B.; Yang, L. Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy. Nutrients 202113, 1633.


Role of Creatine in the Heart: Health and Disease

Maurizio Balestrino

Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation (throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine) increases creatine content even in the normal heart, and it is generally safe. In heart failure, creatine and phosphocreatine decrease because of decreased expression of the creatine transporter, and because phosphocreatine degrades to prevent adenosine triphosphate (ATP) exhaustion. This causes decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction, and it is a predictor of mortality. Thus, there is a strong rationale to supplement with creatine the failing heart. Pending additional trials, creatine supplementation in heart failure may be useful given data showing its effectiveness (1) against specific parameters of heart failure, and (2) against the decrease in muscle strength and endurance of heart failure patients. In heart ischemia, the majority of trials used phosphocreatine, whose mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system. Nevertheless, preliminary data with creatine supplementation are encouraging, and warrant additional studies. Prevention of cardiac toxicity of the chemotherapy compounds anthracyclines is a novel field where creatine supplementation may also be useful. Creatine effectiveness in this case may be because anthracyclines reduce expression of the creatine transporter, and because of the pleiotropic antioxidant properties of creatine. Moreover, creatine may also reduce concomitant muscle damage by anthracyclines.

Keywords: phosphocreatine; creatine transporter; supplementation; treatment; heart; heart failure; ischemia; myocardial infarction; anthracycline; cardiac toxicity

Balestrino, M. Role of Creatine in the Heart: Health and Disease. Nutrients 202113, 1215.


The Potential Role of Creatine in Vascular Health

Holly Clarke, Robert C. Hickner and Michael J. Ormsbee

Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to the abundance of evidence supporting the ergogenic benefits of creatine supplementation, recent evidence suggests a far broader application for creatine within various myopathies, neurodegenerative diseases, and other pathologies. Furthermore, creatine has been found to exhibit non-energy related properties, contributing as a possible direct and in-direct antioxidant and eliciting anti-inflammatory effects. In spite of the new clinical success of supplemental creatine, there is little scientific insight into the potential effects of creatine on cardiovascular disease (CVD), the leading cause of mortality. Taking into consideration the non-energy related actions of creatine, highlighted in this review, it can be speculated that creatine supplementation may serve as an adjuvant therapy for the management of vascular health in at-risk populations. This review, therefore, not only aims to summarize the current literature surrounding creatine and vascular health, but to also shed light onto the potential mechanisms in which creatine may be able to serve as a beneficial supplement capable of imparting vascular-protective properties and promoting vascular health.

Keywords: creatine; vascular pathology; cardiovascular disease; oxidative stress; vascular health

Clarke, H.; Hickner, R.C.; Ormsbee, M.J. The Potential Role of Creatine in Vascular Health. Nutrients 202113, 857.


Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial

Theo Wallimann, Caroline H. T. Hall, Sean P. Colgan and Louise E. Glover

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that “oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn’s disease”. A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3–5 g of Cr per day for a time of 3–6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn’s disease.

Keywords: pleiotropic effects of creatine (Cr) supplementation; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn’s disease; creatine kinase (CK); phosphocreatine (PCr); creatine transporter (CrT); intestinal epithelial cell protection; intestinal tissue protection; creatine perfusion; organ transplantation; Adenosine mono-phosphate (AMP); activated protein kinase (AMPK); liver kinase B1 (LKB1); mitochondrial permeability transition pore (mPTP); reactive oxygen species (ROS); glucose transporter (GLUT)

Wallimann, T.; Hall, C.H.T.; Colgan, S.P.; Glover, L.E. Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial. Nutrients 202113, 1429.


Chronic Dialysis Patients Are Depleted of Creatine: Review and Rationale for Intradialytic Creatine Supplementation

Yvonne van der Veen, Adrian Post, Daan Kremer, Christa A. Koops, Erik Marsman, Theo Y. Jerôme Appeldoorn, Daan J. Touw, Ralf Westerhuis, Margaretha Rebecca Heiner-Fokkema, Casper F. M. Franssen, Theo Wallimann and Stephan J. L. Bakker

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis, yet, on a daily basis, 1.6–1.7% of the total creatine pool is non-enzymatically degraded to creatinine and subsequently lost via urinary excretion, thereby necessitating a continuous supply of new creatine in order to remain in steady-state. Because of an insufficient ability to synthesize creatine, unopposed losses to the dialysis fluid, and insufficient intake due to dietary recommendations that are increasingly steered towards more plant-based diets, hemodialysis patients are prone to creatine deficiency, and may benefit from creatine supplementation. To avoid problems with compliance and fluid balance, and, furthermore, to prevent intradialytic losses of creatine to the dialysate, we aim to investigate the potential of intradialytic creatine supplementation in improving outcomes. Given the known physiological effects of creatine, intradialytic creatine supplementation may help to maintain creatine homeostasis among dialysis-dependent chronic kidney disease patients, and consequently improve muscle status, nutritional status, neurocognitive status, HRQoL. Additionally, we describe the rationale and design for a block-randomized, double-blind, placebo-controlled pilot study. The aim of the pilot study is to explore the creatine uptake in the circulation and tissues following different creatine supplementation dosages.

Keywords: creatine; intradialytic creatine supplementation; hemodialysis; muscle; protein energy wasting; clinical trial; muscle weakness; chronic fatigue; cognitive impairment; depression; anemia

van der Veen, Y.; Post, A.; Kremer, D.; Koops, C.A.; Marsman, E.; Appeldoorn, T.Y.J.; Touw, D.J.; Westerhuis, R.; Heiner-Fokkema, M.R.; Franssen, C.F.M.; Wallimann, T.; Bakker, S.J.L. Chronic Dialysis Patients Are Depleted of Creatine: Review and Rationale for Intradialytic Creatine Supplementation. Nutrients 202113, 2709.


Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.

Keywords: post-viral fatigue syndrome; chronic fatigue syndrome; creatine; GAA; creatine kinase

Ostojic, S.M. Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome. Nutrients 202113, 503.


Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults

Scott C. Forbes, Darren G. Candow, Sergej M. Ostojic, Michael D. Roberts and Philip D. Chilibeck

Creatine supplementation in conjunction with resistance training (RT) augments gains in lean tissue mass and strength in aging adults; however, there is a large amount of heterogeneity between individual studies that may be related to creatine ingestion strategies. Therefore, the purpose of this review was to (1) perform updated meta-analyses comparing creatine vs. placebo (independent of dosage and frequency of ingestion) during a resistance training program on measures of lean tissue mass and strength, (2) perform meta-analyses examining the effects of different creatine dosing strategies (lower: ≤5 g/day and higher: >5 g/day), with and without a creatine-loading phase (≥20 g/day for 5–7 days), and (3) perform meta-analyses determining whether creatine supplementation only on resistance training days influences measures of lean tissue mass and strength. Overall, creatine (independent of dosing strategy) augments lean tissue mass and strength increase from RT vs. placebo. Subanalyses showed that creatine-loading followed by lower-dose creatine (≤5 g/day) increased chest press strength vs. placebo. Higher-dose creatine (>5 g/day), with and without a creatine-loading phase, produced significant gains in leg press strength vs. placebo. However, when studies involving a creatine-loading phase were excluded from the analyses, creatine had no greater effect on chest press or leg press strength vs. placebo. Finally, creatine supplementation only on resistance training days significantly increased measures of lean tissue mass and strength vs. placebo.

Keywords: supplements; hypertrophy; sarcopenia

Forbes, S.C.; Candow, D.G.; Ostojic, S.M.; Roberts, M.D.; Chilibeck, P.D. Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults. Nutrients 202113, 1912.


Timing of Creatine Supplementation around Exercise: A Real Concern?

Felipe Ribeiro, Igor Longobardi, Pedro Perim, Breno Duarte, Pedro Ferreira, Bruno Gualano, Hamilton Roschel and Bryan Saunders

Creatine has been considered an effective ergogenic aid for several decades; it can help athletes engaged in a variety of sports and obtain performance gains. Creatine supplementation increases muscle creatine stores; several factors have been identified that may modify the intramuscular increase and subsequent performance benefits, including baseline muscle Cr content, type II muscle fibre content and size, habitual dietary intake of Cr, aging, and exercise. Timing of creatine supplementation in relation to exercise has recently been proposed as an important consideration to optimise muscle loading and performance gains, although current consensus is lacking regarding the ideal ingestion time. Research has shifted towards comparing creatine supplementation strategies pre-, during-, or post-exercise. Emerging evidence suggests greater benefits when creatine is consumed after exercise compared to pre-exercise, although methodological limitations currently preclude solid conclusions. Furthermore, physiological and mechanistic data are lacking, in regard to claims that the timing of creatine supplementation around exercise moderates gains in muscle creatine and exercise performance. This review discusses novel scientific evidence on the timing of creatine intake, the possible mechanisms that may be involved, and whether the timing of creatine supplementation around exercise is truly a real concern.

Keywords: dietary supplements; ergogenic aid; hypertrophy; resistance training; sports nutrition; strength; supplementation

Ribeiro, F.; Longobardi, I.; Perim, P.; Duarte, B.; Ferreira, P.; Gualano, B.; Roschel, H.; Saunders, B. Timing of Creatine Supplementation around Exercise: A Real Concern? Nutrients 202113, 2844.


Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Sergej M. Ostojic

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.

Keywords: toxicity; methylation; hyperhomocysteinemia; creatine; neuromodulation; MCDA

Ostojic, S.M. Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy? Nutrients 202214, 75.


Creatine for the Treatment of Depression

by Brent M. Kious, Douglas G. Kondo and Perry F. Renshaw

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent. 

Kious, B.M.; Kondo, D.G.; Renshaw, P.F. Creatine for the Treatment of Depression. Biomolecules 20199, 406.


Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?

Jose Antonio, Darren G. Candow, Scott C. Forbes, Bruno Gualano, Andrew R. Jagim, Richard B. Kreider, Eric S. Rawson, Abbie E. Smith-Ryan, Trisha A. VanDusseldorp, Darryn S. Willoughby & Tim N. Ziegenfuss

Supplementing with creatine is very popular amongst athletes and exercising individuals for improving muscle mass, performance and recovery. Accumulating evidence also suggests that creatine supplementation produces a variety of beneficial effects in older and patient populations. Furthermore, evidence-based research shows that creatine supplementation is relatively well tolerated, especially at recommended dosages (i.e. 3-5 g/day or 0.1 g/kg of body mass/day). Although there are over 500 peer-refereed publications involving creatine supplementation, it is somewhat surprising that questions regarding the efficacy and safety of creatine still remain. These include, but are not limited to: 1. Does creatine lead to water retention? 2. Is creatine an anabolic steroid? 3. Does creatine cause kidney damage/renal dysfunction? 4. Does creatine cause hair loss / baldness? 5. Does creatine lead to dehydration and muscle cramping? 6. Is creatine harmful for children and adolescents? 7. Does creatine increase fat mass? 8. Is a creatine ‘loading-phase’ required? 9. Is creatine beneficial for older adults? 10. Is creatine only useful for resistance / power type activities? 11. Is creatine only effective for males? 12. Are other forms of creatine similar or superior to monohydrate and is creatine stable in solutions/beverages? To answer these questions, an internationally renowned team of research experts was formed to perform an evidence-based scientific evaluation of the literature regarding creatine supplementation.

Antonio, J., Candow, D.G., Forbes, S.C. et al. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?. J Int Soc Sports Nutr 18, 13 (2021).


Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review

Richard B. Kreider, Ralf Jäger and Martin Purpura

In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other “novel forms” of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported “forms” of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several “forms” of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported “form” of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various “forms” of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a “novel form” of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported “new form” of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.

Keywords: dietary ingredients; ergogenic aids; exercise; performance

Kreider, R.B.; Jäger, R.; Purpura, M. Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. Nutrients 202214, 1035.


Evidence suggesting Creatine as a New Central Neurotransmitter

Xiling Bian, Jiemin Zhu, Xiaobo Jia, Wenjun Liang, Sihan Yu and Yi Rao

It has never been easy to discover a new neurotransmitter, especially one in the central nervous system (CNS). We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Thus, our biochemical, chemical, genetic and electrophysiological results suggest Cr as a neurotransmitter, illustrate a novel approach to discover neurotransmitters and provide a new basis for ID pathogenesis.

Bian Xiling, Zhu Jiemin, Jia Xiaobo, Liang Wenjun, Yu Sihan, Rao Yi (2023) Evidence suggesting creatine as a new central neurotransmitter: presence in synaptic vesicles, release upon stimulation, effects on cortical neurons and uptake into synaptosomes and synaptic vesicles eLife 12:RP89317


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