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* There is evidence that CrS increases brain creatine, but this response may be dose and/or duration dependent. CrS provides some benefits during acute periods of metabolic stress such as sleep deprivation, mental fatigue, and hypoxia. Emerging clinical data also suggest potential therapeutic effects from CrS for Alzheimer’s disease, major depressive disorder, and mild traumatic brain injury (mTBI), although findings across conditions remain preliminary and inconsistent. Further, CrS shows some promise for improving aspects of sleep quality.
Creatine Supplementation and the Brain: Have We Put the Cart Before the Horse?
Darren G. Candow, Jedd Pratt, Nicholas Fabiano, Ali Gordji-Nejad, Aaron Smith , Eric S. Rawson, Terence Moriarty, Scott C. Forbes
Abstract
Creatine is an important regulator of brain bioenergetics, yet the efficacy of creatine supplementation (CrS) in the brain remains largely unknown. Measurement of brain creatine using proton (1H) and phosphorus (³1P) magnetic resonance spectroscopy is highly sensitive to voxel placement, signal quality, analysis pipelines, and reporting conventions which can obscure the detection of biological responses to CrS. There is evidence that CrS increases brain creatine, but this response may be dose and/or duration dependent. CrS provides some benefits during acute periods of metabolic stress such as sleep deprivation, mental fatigue, and hypoxia. Emerging clinical data also suggest potential therapeutic effects from CrS for Alzheimer’s disease, major depressive disorder, and mild traumatic brain injury (mTBI), although findings across conditions remain preliminary and inconsistent. Further, CrS shows some promise for improving aspects of sleep quality. The purpose of this narrative review is to: (1) outline methodological considerations in the quantification of brain creatine, (2) discuss the divergent effects of CrS on brain creatine levels and measures of brain function, (3) examine the purported mechanistic actions of CrS for improving brain health and function, (4) highlight critical gaps and limitations which should be considered moving forward, and (5) identify future research directions involving CrS and the brain.
Brain creatine levels: methodological and biological variability
Accurately quantifying and interpreting variability in brain creatine levels is a critical aspect underpinning our understanding of its role in brain health and cognitive function. This section provides an overview of methodological and biological factors that can contribute to variability across reported brain creatine levels.
Creatine supplementation: dose and divergent effects
Alzheimer's disease
CrS supplementation offers several practical advantages as a potential Alzheimer’s disease therapy: it is inexpensive, widely available, has an excellent safety profile, and has demonstrated excellent tolerability in patients with Alzheimer’s disease (Smith, Choi, et al. Citation2025). As a potential adjuvant therapy targeting brain bioenergetics, a pathological feature that precedes symptomatic Alzheimer’s disease, CrS supplementation warrants continued investigation as part of a comprehensive approach to AD prevention and treatment.
Creatine and mood disorders
Overall, the combination of CrS and antidepressant therapies provides some benefits for those with MDD when compared to placebo. However, the effects of CrS alone or in combination with exercise are unknown. Caution is advised when interpreting these results as most of the studies were short in duration and did not allow for the assessment of efficacy and safety for mental disorders which often require life-long treatments. Further, the studies were largely ‘proof-of-concept’ with small sample sizes, leading to underpowered analyses to detect changes in psychiatric symptoms.
Mild traumatic brain injury
Results across studies showing a pre- and post-brain injury treatment effect from CrS are encouraging. However, results of multiple double-blind placebo-controlled randomized controlled trials designed to investigate the potential benefits of CrS (compared to placebo) on recovery from mTBI are unavailable but several are currently being performed (Bødker and Marcussen Citation2023); Clinicaltrials.gov ID NCT06208813, NCT05562232, NCT0558906). The theoretical basis for a beneficial effect of CrS as a neuromodulator matches the neurometabolic cascade/pathology of mTBI. From a practical perspective, CrS is safe, effective, inexpensive, and widely available. Also, new data indicates that dietary creatine is decreasing (Korovljev et al. Citation2021) and daily intake is now significantly lower than accepted estimates (Ostojic Citation2025), which indicates greater need for supplementation. Collectively, the preliminary findings suggest that CrS should be considered for those at risk for mTBI, such as athletes and military personnel.
Cognition
Overall, there is growing evidence that CrS can enhance certain cognitive domains, particularly aspects of memory and executive functioning, especially under conditions that challenge brain bioenergetics. Emerging research on neuroplasticity, myokine signaling, and neurotransmitter modulation indicates that creatine’s cognitive impact may extend beyond the traditional thought of PCr buffering alone. Future research is warranted to clarify optimal dose-response and CrS duration. Studies combining CrS with neuroimaging (e.g. Functional Near-Infrared Spectroscopy, Functional Magnetic Resonance Imaging, electroencephalogram) may help detail brain region specific effects, especially in the prefrontal cortex and hippocampus. Personalized approaches considering baseline brain creatine content, age, and dietary intake may offer more precise cognition-related CrS recommendations and improved brain benefits. Taken together, CrS represents a promising nutritional strategy to support cognitive functioning, especially in metabolically stressed populations
Sleep
In conclusion, clear evidence exists that poor sleep habits can stress the brain leading to impairments in physical and cognitive performance. Alterations in sleep status can impact the energetic stores found in the brain and a limited number of studies have evaluated the extent to which creatine availability may modulate brain and sleep performance. Early consensus from these studies, which require much more scientific exploration, indicate that increasing creatine availability can reduce sleep need and may help improve task performance when sleep deprived or improve perceived indicators of sleep quality. With widespread indications of inadequate sleep and many populations of people who routinely stress their mental faculties (shift work, firefighters, athletes, trans meridian travel, etc.), future research into the potential for creatine to acutely and chronically improve both sleep quantity and quality will be of significant interest.
Summary
CrS does have the ability to increase brain creatine levels across numerous populations. Increased brain creatine availability is the primary physiological mechanism by which CrS is proposed to confer neurological benefits, however the optimal CrS strategy needed to achieve these benefits remains unknown (Figure 2). There is uncertainty surrounding the reliability and repeatability of brain creatine measurements, largely due to insufficient methodological reporting and studies demonstrating poor reproducibility of brain creatine estimates. Consequently, the interplay between CrS, brain creatine availability, and health and/or performance outcomes remains unclear. A future research priority is the establishment of normative data on biological variability in response to CrS across different brain regions. Further, a better understanding of how periods of metabolic stress (e.g. sleep deprivation, hypoxia, strenuous exercise, mental fatigue) influence the efficacy of CrS across a variety of dosing strategies is needed. Finally, whether CrS alone provides meaningful therapeutic benefits for those with Alzheimer’s disease, clinical depression or brain injury or improves cognition and sleep in healthy and clinical populations remains to be determined.
Creatine Supplementation and the Brain: Have We Put the Cart Before the Horse?
Darren G. Candow, Jedd Pratt, Nicholas Fabiano, Ali Gordji-Nejad, Aaron Smith , Eric S. Rawson, Terence Moriarty, Scott C. Forbes
Abstract
Creatine is an important regulator of brain bioenergetics, yet the efficacy of creatine supplementation (CrS) in the brain remains largely unknown. Measurement of brain creatine using proton (1H) and phosphorus (³1P) magnetic resonance spectroscopy is highly sensitive to voxel placement, signal quality, analysis pipelines, and reporting conventions which can obscure the detection of biological responses to CrS. There is evidence that CrS increases brain creatine, but this response may be dose and/or duration dependent. CrS provides some benefits during acute periods of metabolic stress such as sleep deprivation, mental fatigue, and hypoxia. Emerging clinical data also suggest potential therapeutic effects from CrS for Alzheimer’s disease, major depressive disorder, and mild traumatic brain injury (mTBI), although findings across conditions remain preliminary and inconsistent. Further, CrS shows some promise for improving aspects of sleep quality. The purpose of this narrative review is to: (1) outline methodological considerations in the quantification of brain creatine, (2) discuss the divergent effects of CrS on brain creatine levels and measures of brain function, (3) examine the purported mechanistic actions of CrS for improving brain health and function, (4) highlight critical gaps and limitations which should be considered moving forward, and (5) identify future research directions involving CrS and the brain.
Brain creatine levels: methodological and biological variability
Accurately quantifying and interpreting variability in brain creatine levels is a critical aspect underpinning our understanding of its role in brain health and cognitive function. This section provides an overview of methodological and biological factors that can contribute to variability across reported brain creatine levels.
Creatine supplementation: dose and divergent effects
Alzheimer's disease
CrS supplementation offers several practical advantages as a potential Alzheimer’s disease therapy: it is inexpensive, widely available, has an excellent safety profile, and has demonstrated excellent tolerability in patients with Alzheimer’s disease (Smith, Choi, et al. Citation2025). As a potential adjuvant therapy targeting brain bioenergetics, a pathological feature that precedes symptomatic Alzheimer’s disease, CrS supplementation warrants continued investigation as part of a comprehensive approach to AD prevention and treatment.
Creatine and mood disorders
Overall, the combination of CrS and antidepressant therapies provides some benefits for those with MDD when compared to placebo. However, the effects of CrS alone or in combination with exercise are unknown. Caution is advised when interpreting these results as most of the studies were short in duration and did not allow for the assessment of efficacy and safety for mental disorders which often require life-long treatments. Further, the studies were largely ‘proof-of-concept’ with small sample sizes, leading to underpowered analyses to detect changes in psychiatric symptoms.
Mild traumatic brain injury
Results across studies showing a pre- and post-brain injury treatment effect from CrS are encouraging. However, results of multiple double-blind placebo-controlled randomized controlled trials designed to investigate the potential benefits of CrS (compared to placebo) on recovery from mTBI are unavailable but several are currently being performed (Bødker and Marcussen Citation2023); Clinicaltrials.gov ID NCT06208813, NCT05562232, NCT0558906). The theoretical basis for a beneficial effect of CrS as a neuromodulator matches the neurometabolic cascade/pathology of mTBI. From a practical perspective, CrS is safe, effective, inexpensive, and widely available. Also, new data indicates that dietary creatine is decreasing (Korovljev et al. Citation2021) and daily intake is now significantly lower than accepted estimates (Ostojic Citation2025), which indicates greater need for supplementation. Collectively, the preliminary findings suggest that CrS should be considered for those at risk for mTBI, such as athletes and military personnel.
Cognition
Overall, there is growing evidence that CrS can enhance certain cognitive domains, particularly aspects of memory and executive functioning, especially under conditions that challenge brain bioenergetics. Emerging research on neuroplasticity, myokine signaling, and neurotransmitter modulation indicates that creatine’s cognitive impact may extend beyond the traditional thought of PCr buffering alone. Future research is warranted to clarify optimal dose-response and CrS duration. Studies combining CrS with neuroimaging (e.g. Functional Near-Infrared Spectroscopy, Functional Magnetic Resonance Imaging, electroencephalogram) may help detail brain region specific effects, especially in the prefrontal cortex and hippocampus. Personalized approaches considering baseline brain creatine content, age, and dietary intake may offer more precise cognition-related CrS recommendations and improved brain benefits. Taken together, CrS represents a promising nutritional strategy to support cognitive functioning, especially in metabolically stressed populations
Sleep
In conclusion, clear evidence exists that poor sleep habits can stress the brain leading to impairments in physical and cognitive performance. Alterations in sleep status can impact the energetic stores found in the brain and a limited number of studies have evaluated the extent to which creatine availability may modulate brain and sleep performance. Early consensus from these studies, which require much more scientific exploration, indicate that increasing creatine availability can reduce sleep need and may help improve task performance when sleep deprived or improve perceived indicators of sleep quality. With widespread indications of inadequate sleep and many populations of people who routinely stress their mental faculties (shift work, firefighters, athletes, trans meridian travel, etc.), future research into the potential for creatine to acutely and chronically improve both sleep quantity and quality will be of significant interest.
Summary
CrS does have the ability to increase brain creatine levels across numerous populations. Increased brain creatine availability is the primary physiological mechanism by which CrS is proposed to confer neurological benefits, however the optimal CrS strategy needed to achieve these benefits remains unknown (Figure 2). There is uncertainty surrounding the reliability and repeatability of brain creatine measurements, largely due to insufficient methodological reporting and studies demonstrating poor reproducibility of brain creatine estimates. Consequently, the interplay between CrS, brain creatine availability, and health and/or performance outcomes remains unclear. A future research priority is the establishment of normative data on biological variability in response to CrS across different brain regions. Further, a better understanding of how periods of metabolic stress (e.g. sleep deprivation, hypoxia, strenuous exercise, mental fatigue) influence the efficacy of CrS across a variety of dosing strategies is needed. Finally, whether CrS alone provides meaningful therapeutic benefits for those with Alzheimer’s disease, clinical depression or brain injury or improves cognition and sleep in healthy and clinical populations remains to be determined.
