Creatine can protect the brain, improve mood and memory, scientists have shown

Scientists have discovered that creatine can do more than just build muscle: it boosts brain resilience, improves mood, and supports cognitive function through biochemical pathways activated by exercise.

Creatine supplementation is widely recognized for its ability to increase muscle mass and strength, as well as improve athletic performance. A recent review in the journal Frontiers in Nutrition examined its effects on brain and muscle health via the brain-muscle axis.

Introduction

Both the brain and skeletal muscle consume enormous amounts of energy during activity. Creatine is a key regulatory molecule in both organ systems, preventing damage during periods of intense energy demand. It provides a rapid supply of energy in the form of ATP, reduces oxidative stress, and fights inflammation.

What is creatine?

Creatine, or methylguanidine acetate, is a nitrogen-rich molecule formed from the amino acids arginine, glycine, and methionine. It is synthesized primarily in the liver and brain, but can also be obtained from beef, fish, or pork and consumed as a supplement.

Creatine affects multiple cellular pathways and has a variety of effects. Results include improved energy balance, anti-inflammatory effects, muscle hypertrophy, and improved glucose regulation.

Creatine and the Muscle-Brain Axis

Voluntary muscle cells release myokines, signaling proteins that affect distant organs, including the brain. Myokines may act through the muscle-brain axis to influence brain health and potentially contribute to overall physical performance, not just strength or endurance gains.

By penetrating the blood-brain barrier, myokines stimulate neuronal proliferation, promote the formation of new neural pathways, and improve the efficiency of existing neural circuits. In this way, they enhance cognitive abilities and suppress undesirable behavioral changes. They also protect neurons from inflammation and oxidative stress damage, preserving cognitive function, especially in age-related or pathological stress.

The muscle-brain axis is thought to be a two-way interactive communication system involving myokines, especially brain-derived neurotrophic factor (BDNF), cathepsin B, interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), irisin, and lactate. BDNF is a key neurotrophic protein responsible for neurogenesis and neuroplasticity, and improves memory.

Most of the BDNF in the blood comes from the resting brain or during physical activity. Acute physical exercise causes a short-term increase in BDNF levels. Myokines affect lipid metabolism, stimulating the conversion of inactive white fat to active brown fat. They also promote bone formation and improve endothelial function.

Creatine as a source of energy

Creatine enters cells via a transporter molecule. Although a third remains in free form inside the cell, most is phosphorylated to phosphocreatine (PCr). This is the source of active phosphate for ADP, which converts it to ATP.

This rapid increase in PCr stores in muscle facilitates rapid ATP resynthesis, providing rapid energy during high-intensity activities such as sprinting or strength training. This process is most pronounced in tissues with high energy demand - muscle, brain and heart.

Creatine Supplements

When combined with strength training, creatine supplementation helps increase lean body mass and muscle strength. It improves training adaptation and recovery. These effects may occur by triggering the release of myokines, thereby promoting anabolism in muscle cells.

Creatine regulates the balance between anti-inflammatory and inflammatory responses to intense exercise. It may help prevent injury and maintain stable body temperature during exercise.

In addition to directly stimulating myokine production, creatine influences other signaling pathways associated with myokine regulation, such as the mTOR pathway. For example, creatine supplementation increases levels of IGF-1, a growth factor that improves neuronal proliferation and synaptic plasticity.

Creatine-induced improvements in anaerobic performance during repeated bouts of high-intensity muscular activity may be beneficial in cyclic sports that require rapid acceleration or finishing sprints, such as track cycling.

Notably, lactate is a myokine and a product of anaerobic muscle metabolism. However, blood lactate concentrations were not increased following short-term creatine supplementation. Lactate promotes increases in BDNF levels, possibly due to increased myokine production caused by increased ATP with creatine supplementation.

Creatine supplements may also help with neurodegenerative diseases, including Huntington's and Parkinson's, and may protect the central nervous system from damage associated with concussions. Preliminary research also suggests health benefits for the mother during pregnancy, a reduced risk of depression, and possible use for age-related muscle weakness.

Creatine as a neuroprotector

There is evidence that creatine is a neurotransmitter. It is found in synaptic vesicles, sites of neurotransmission, and appears to influence signaling by cortical neurons. Mitochondrial activity in hippocampal neurons is also enhanced by creatine. This, combined with its antioxidant activity, ability to reduce oxidative stress, and effects on neurodevelopment and electrophysiological changes, suggests that creatine may have a neuroprotective effect.

Creatine supplementation supports more intense workouts by stimulating the release of BDNF and other myokines. Creatine acts indirectly on the brain through myokines, acting as a quick source of energy.

Creatine influences exercise-induced release of neurotransmitters and cytokines such as serotonin and dopamine, which improve neural function and promote neuroplasticity. It is also important for emotion regulation, suggesting that creatine may reduce symptoms of depression.

There is evidence that creatine exerts rapid antidepressant effects via myokine-related pathways, with or without cognitive behavioral therapy. In a recent pilot study, 5 g/day of creatine combined with CBT for 8 weeks produced greater reductions in depression scores than CBT alone, although larger studies are needed.

Creatine as a metabolic regulator

Creatine supplementation improves glucose metabolism by increasing insulin sensitivity. Insulin directly influences levels of key myokines that act through the muscle-brain axis. It promotes glucose uptake into muscle cells via GLUT-4, potentially enhancing myokine release in response to exercise.

Conclusions

Creatine supplementation has been strongly associated with physical performance and increased myokine production. Creatine not only impacts muscle performance, but also brain health and cognitive function. It may help prevent inflammatory muscle damage and promote recovery from exercise and depression. However, due to differences in study design, dosage, and individual responses, these effects should be interpreted with caution. More clinical research is needed to confirm whether creatine directly increases BDNF or other myokine levels.

There are several biologically relevant pathways that explain the association of creatine with BDNF, including increased PCr availability or activation of PGC-1α in skeletal muscle during exercise, leading to increased irisin and then BDNF.

Other factors may include increased creatine-dependent calcium levels and mTOR activation in muscle cells. However, the effects of creatine supplementation on BDNF and other myokine levels remain unknown. Such studies could confirm the benefits of creatine supplementation for physical and mental health via the muscle-brain axis.