Creatine is endogenously formed from the amino acids arginine, glycine, and methionine, and is involved in muscular contraction; approximately 95% is stored in skeletal muscle, particularly type 2 fibers. Two-thirds of intramuscular creatine is phosphocreatine (PCr) and the remaining one-third is free creatine.

In most individuals, the upper storage levels of creatine are approximately 160 mmol/kg of dry muscle mass. Small amounts are also found in other tissues, including the brain and testes.

Dietary creatine is found primarily in red meat and seafood. Individuals who consume creatine-rich foods may have higher tissue creatine levels than those who do not, such as vegans and vegetarians.

The body has a limited capacity for creatine synthesis. Between 1% and 2% of intramuscular creatine is metabolized into creatinine and excreted in the urine. Therefore, the body requires 1 to 3 g per day to maintain normal creatine stores, depending on an individual’s muscle mass. PCr is used to generate adenosine triphosphate (ATP) in muscles. Low PCr levels result in lower levels of ATP, and ATP is the currency for the body’s energy. Creatine supplementation can increase the capacity of ATP production.

Endogenous creatine synthesis occurs in the brain and nervous system. Creatine transporters are found in the blood-brain barrier, neurons, and oligodendrocytes, which indicates that brain PCr is not solely influenced by dietary intake from food. Previous reviews demonstrate a great potential for creatine supplementation to support brain health and cognitive processing (by way of increasing brain ATP). In particular, deficits in brain PCr that may be caused by aging and acute stressors (such as sleep deprivation or chronic conditions), or by creatine synthesis enzyme deficiencies, may offer a potential field for creatine support.

It is widely recognized that the ATP/creatine kinase/PCr system plays a role in maintaining central nervous system homeostasis. In a review published in Nutrients, Forbes and colleagues explored the impact that creatine monohydrate supplementation has on a variety of neurological and mental health conditions. 

Robust evidence supports the importance of creatine monohydrate supplementation for individuals with creatine deficiency syndromes that are known to deplete creatine brain stores. However, there are mixed results for cognitive function and memory benefits. Large doses (20 g per day for 7 days) of creatine were shown to improve measures of memory in aging adults 68 to 85 years old, including forward number recall, backward and forward spatial recall, and long-term memory. Additionally, vegetarians who supplemented with creatine (5 g per day) had improvements in working memory. 

Mitochondrial damage, oxidative stress, and energy depletion are prevalent factors across neurodegenerative diseases. Forbes and colleagues demonstrate that creatine may have a potential neuroprotective role by increasing brain energy, reducing oxidative stress, and mitigating mitochondrial damage, but more empirical evidence is needed. 

Several mental health disorders have been characterized as having brain bioenergetic abnormalities and lower creatine levels in certain brain regions. Interventional studies using ¹H-magnetic resonance spectroscopy have shown that lower prefrontal cortex creatine levels are associated with increased incidence of depression and lower mood. In a mouse model of Alzheimer’s disease-related depression, creatine supplementation was shown to support mood in amyloid β_1-40treated mice. Other pre-clinical animal models demonstrated there is clear support for the potential use of creatine for depression. This improvement in animal models was shown to be correlated with the ability of creatine to activate the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. Small-scale human clinical trials have also observed clinically relevant improvements in depression symptoms with creatine monohydrate supplementation; however, more large-scale clinical trials are needed. 

The researchers also found that creatine supplementation may have neuroprotective effects following traumatic brain injury (TBI) or concussion. These injurious conditions correlate with the overactivation of the N-methyl-D-aspartate (NMDA) receptor caused by an indiscriminate release of glutamate. This leads to increased cellular calcium ions (Ca²⁺) that can cause nerve damage, neuronal death, and dysfunction. Animal models show that creatine supplementation can mitigate glutamate excitotoxicity, reduce oxidative stress and Ca²⁺ response to NMDA receptor stimulation, and increase cellular ATP/PCr concentrations. 

Research is inconsistent or lacking to support the benefits of creatine supplementation for individuals with mental health concerns or neurodegenerative diseases. However, the science shows preliminary benefits of creatine to support cognitive function, healthy moods, and brain function for TBI or concussion. 

By Caitlin Higgins, MS, CNS