Can creatine boost human memory?

Memory is defined as the ability to process and retain information. Memory can be categorised into short-term memory (STM) and long-term memory (LTM), which are associated with several neural systems and mechanisms. STM relies on existing networks and post-translational modifications, while LTM involves structural and functional changes in neural networks, requiring de novo gene expression. The consolidation of memory is a multi-step process that stabilizes fragile memory traces after encoding. It involves cellular or molecular consolidation as well as systems consolidation. Various molecular pathways are crucial for LTM formation including CREB (cAMP response element-binding protein) and C/EBP (CCAAT/enhancer-binding protein) cascades, which are activated following memory encoding. 

As an inbuild human nature, we generally remember incidents that are more emotionally charged than emotionally neutral experiences. Stress and associated glucocorticoid release can modulate memory consolidation through glucocorticoid receptors (GRs) that activate several intracellular signalling pathways, including CREB, MAPK (mitogen-activated protein kinase), CaMKII (calcium/calmodulin-dependent protein kinase II), and BDNF (brain-derived neurotrophic factor). These pathways contribute to both the strengthening of beneficial memories and the potential formation of maladaptive memories linked to stress-related psychopathologies. While the activation of the GR/BDNF pathway is essential for effective memory consolidation under normal stress conditions (where stress is beneficial), prolonged or excessive stress and abnormal levels of glucocorticoids can suppress the BDNF response and impair memory processes.

Activated glucocorticoid receptors (GRs) quickly boost the translation of Arc protein and may play a role in moving the TrkB receptor to the cell membrane and/or promoting the release of BDNF. When BDNF binds to TrkB, it triggers the receptor’s phosphorylation, activating pathways like ERK1/2, Akt, and PLCγ. At the same time, activated GRs also lead to the rapid phosphorylation of CaMKIIα through transcription-dependent mechanisms. These pathways, whether working independently or together, converge on the phosphorylation of CREB, which in turn stimulates the production of more BDNF. This newly created BDNF keeps these pathways active, resulting in ongoing phosphorylation of CREB, CaMKIIα, and phosopho-synapsin-1, a downstream target of CaMKIIα. In this way, GR activation engages both pre-synaptic and post-synaptic processes to enhance memory consolidation.

Prokopidis, K., Giannos, P., Triantafyllidis, K. K., Kechagias, K. S., Forbes, S. C., & Candow, D. G. (2023). Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. Nutrition Reviews, 81(4), 416-427.

Effects of Creatine

Creatine is a naturally occurring nitrogenous organic acid that plays a crucial role in cellular energy metabolism. While it is widely recognized for its benefits in muscle performance and strength, creatine also has significant effects on brain function, particularly in retaining memory. Creatine is synthesized endogenously from the amino acids glycine, arginine, and methionine, primarily in the liver, kidneys, and pancreas. Once synthesized, creatine is transported through the bloodstream to various tissues, including the brain, where it is phosphorylated to form phosphocreatine (PCr). This phosphorylated form serves as a rapid reserve of high-energy phosphate groups that can be readily used to regenerate adenosine triphosphate (ATP), the primary energy currency of cells. The brain, being the most metabolically active organ, consumes approximately 20-25% of the body's total glucose-derived energy at rest. Because neurons require a continuous supply of ATP for numerous functions, including synaptic transmission and maintenance of membrane potentials, creatine’s role in energy buffering becomes vital.

Research has shown that creatine supplementation increases total creatine content in the brain, which in turn helps maintain cellular ATP levels during cognitive tasks. For example, studies using magnetic resonance spectroscopy (MRS) have demonstrated that oral creatine supplementation increases brain creatine levels, particularly in regions involved in high-order cognitive functions, such as the prefrontal cortex and hippocampus. Creatine’s neuroprotective effects are primarily attributed to its ability to maintain ATP levels and prevent energy failure during metabolic stress. Neuronal cells are particularly vulnerable to energy deficits, which can lead to cell death via apoptosis or necrosis. By buffering ATP levels, creatine prevents the activation of energy-dependent apoptotic pathways and maintains ionic gradients, reducing excitotoxicity caused by excessive glutamate release.

In various models of neurodegenerative diseases, creatine has been shown to reduce neuronal damage and improve outcomes. For example, in animal models of Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), creatine supplementation has been associated with delayed disease progression and reduced neuronal cell loss. The ability of creatine to stabilize mitochondrial function and reduce oxidative stress further contributes to its protective effects.

Cognitive tasks, especially those requiring working memory and complex problem-solving, significantly increase the demand for ATP. By enhancing the phosphocreatine energy shuttle, creatine supplementation can improve cognitive performance under conditions of high mental workload or metabolic stress. In older adults, creatine supplementation has been associated with improvements in cognitive tasks that require memory and executive function. This population often experiences declines in cognitive performance due to reductions in brain energy metabolism and mitochondrial dysfunction. Creatine supplementation has been shown to enhance mitochondrial function by stabilizing the mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS). This stabilization helps prevent mitochondrial dysfunction, which is implicated in the pathophysiology of neurodegenerative diseases and age-related cognitive decline.

Moreover, several scientific studies found that creatine administration boosted the levels of both ubiquitous creatine kinase (uCK) and its brain-specific form (CK-B) in the hippocampus of mice. Since PGC-1α is known to trigger FNDC5/irisin expression, which is crucial for BDNF-dependent brain plasticity, researchers looked into how creatine affects the expression of PGC-1α, FNDC5, and BDNF genes in the hippocampus. The results were exciting: creatine treatment increased the levels of PGC-1α, FNDC5, and BDNF mRNA, along with the amount of BDNF protein. Additionally, it enhanced the phosphorylation of Akt, boosted the levels of the protective proteins Bcl2 and Bcl-xL, and lowered the levels of the pro-apoptotic protein BAD in the hippocampus. These findings suggest that creatine's antidepressant-like effects may be linked to its ability to activate Akt and increase neuroprotective proteins in the brain.

Is creatine supplementation beneficial?

Creatine supplementation has shown benefits in specific populations and under certain conditions. In people with creatine-deficient syndromes, where brain creatine stores are depleted, supplementation can partially reverse symptoms like learning delays and seizures, indicating its crucial role in brain function. 

In healthy humans, the effects of creatine on cognitive functioning and memory are mixed. Some studies have found that creatine supplementation improves memory, particularly in the elderly and vegetarians. For example, elderly participants aged 68-85 who took 20 grams of creatine per day for 7 days showed significant improvements in memory tasks, including number recall and spatial recall, compared to those who received a placebo. Similarly, vegetarians who took 5 grams of creatine daily for 6 weeks demonstrated improvements in working memory. Furthermore, creatine supplementation led to better memory performance in vegetarians compared to meat eaters, likely because of the lower baseline creatine levels in vegetarian diets.

However, the benefits of creatine supplementation are not universal. Some studies have reported no significant effects on memory in children, adults, and older adults, highlighting the variability in response. These inconsistent findings may be due to differences in study methodologies, such as dosage and duration of creatine supplementation, as well as variations in participant characteristics like age, sex, and dietary habits. While creatine supplementation is widely recognized for its benefits in enhancing muscle performance and supporting cognitive function, there are potential negative effects associated with its use, particularly when taken in excessive amounts or over prolonged periods. One of the most common concerns is the impact of creatine on kidney function. Although research has not conclusively shown that creatine damages the kidneys in healthy individuals, there is concern that long-term use or high doses could exacerbate existing kidney conditions. Dehydration is another potential risk, as creatine draws water into muscle cells, which may lead to an increased risk of dehydration and electrolyte imbalances, particularly during intense exercise or in hot climates.