Creatine: the small molecule quietly rewriting the story of brain energy

Richard Moore
Dec 9, 2025
11 min read

Most people first encounter creatine as a “gym supplement” - something you mix into a shaker before lifting weights. But if you follow the research trail rather than the marketing, creatine keeps appearing in a very different setting: clinical trials in amyotrophic lateral sclerosis (ALS), Parkinson’s disease and cognitive ageing. It is not a cure for neurodegenerative disease and should never be presented as one. Yet as the evidence base has grown, so has the sense that creatine tells us something important about how the brain’s energy system unravels in these conditions.

This is not a miracle story. It is a story about what happens when the brain’s power supply starts to fail, and why a small molecule that buffers energy in muscle has become part of a much bigger conversation about neurodegeneration.

When the brain’s power grid starts running on backup

The human brain is an energy-hungry organ. It accounts for roughly 20% of the body’s resting energy use, yet it can store very little fuel. Every thought, movement and memory depends on a constant supply of adenosine triphosphate (ATP) generated in mitochondria, the tiny power stations inside our cells. In many neurodegenerative diseases, this system starts to falter early: mitochondrial function declines, oxidative stress rises and ATP production becomes less reliable (Johri & Beal, 2012; Wu et al., 2019).

At that point, neurones are less like relaxed conductors of an orchestra and more like air-traffic controllers trying to coordinate flights during a rolling blackout. Signals can still get through, but the margin for error shrinks dramatically.

Creatine sits just downstream of these failing power stations. Through the phosphocreatine system, it acts a little like a buffer tank in a city’s water network: when demand suddenly surges, the tank releases stored pressure to prevent taps running dry. In cells, phosphocreatine donates phosphate groups to rebuild ATP quickly, smoothing out the peaks and troughs in energy use (Xu et al., 2024; Marshall et al., 2025). Creatine cannot fix the underlying mitochondrial defects, but it can help an unstable system ride out pressure spikes with fewer failures. That deceptively simple role is what first drew researchers to test creatine in ALS.

ALS/MND: strong theory, sobering trials

Amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), involves progressive loss of motor neurones and intense metabolic strain on both nerve and muscle. Early on, results from animal models suggested that creatine might extend survival, and this led to clinical trials in humans. A large double-blind, placebo-controlled trial randomised 175 people with ALS to creatine monohydrate 10 g per day or placebo and followed them for survival and function (Groeneveld et al., 2003). The trial was stopped when the interim analysis showed no meaningful difference in survival or rate of functional decline between groups. In other words, creatine did not change the overall trajectory of the disease.

A later Cochrane review pooled available randomised trials and reached the same conclusion: creatine supplementation did not significantly improve survival or global functional outcomes in ALS, despite being well tolerated (Pastula et al., 2012).

However, the story does not end there. The same research group that ran the ALS trial also used the cohort to examine safety. In a long-term, placebo-controlled study of 10 g creatine per day for around 10 months, they found no significant difference in markers of kidney function or serious adverse events between the creatine and placebo groups (Groeneveld et al., 2005). Creatine caused more water retention and some gastrointestinal symptoms, but no signal of renal damage.

A useful analogy here is a delivery company whose main depot is slowly shutting down. Giving drivers more fuel and better tyres helps them complete individual journeys more smoothly – and creatine appears to support muscle energetics in this way – but it does not stop the depot itself from closing. ALS is driven by upstream processes in motor neurones that creatine simply cannot reach.

Parkinson’s disease: the mega-trial that reset expectations

Parkinson’s disease is often described in terms of dopamine loss, but mitochondrial dysfunction and impaired cellular energy metabolism are also central features (Johri & Beal, 2012). Early pilot work suggested creatine might help support brain energy and slow progression, and this idea was considered strong enough to justify a very large trial.

The National Institute of Neurological Disorders and Stroke (NINDS) funded the Long-Term Study 1 of the Exploratory Trials in Parkinson’s Disease (NET-PD LS-1). In this phase 3 randomised clinical trial, more than 1,600 people with early Parkinson’s disease were assigned to creatine monohydrate 10 g per day or placebo, on top of standard dopaminergic therapy, and followed for at least five years (Kieburtz et al., 2015).

The results were sobering. A planned interim analysis showed that creatine was unlikely to provide a meaningful benefit on a combined measure of clinical progression, and the trial was stopped early for futility. The final analysis confirmed that long-term creatine did not improve global clinical outcomes compared with placebo (Kieburtz et al., 2015).

What this tells us is not that creatine “does nothing”, but that it does not override the complex set of processes driving Parkinson’s disease. Alpha-synuclein aggregation, neuroinflammation, synaptic loss and network-level changes all sit upstream of the ATP buffering step that creatine influences. You can think of creatine here as adding stabilisers to the bike’s wheels: it may help with balance and confidence, but it cannot repair a bent frame.

At the same time, the NET-PD LS-1 trial provided an important safety signal: long-term, high-dose creatine was generally well tolerated in a large Parkinson’s disease population, something that supports its use as an adjunct, rather than a disease-modifying therapy.

Cognitive ageing and brain stress: where creatine looks most interesting

The most rapidly evolving part of the creatine literature is not in advanced dementia or late-stage disease, but in cognitive ageing and brain stress. Instead of asking “Can creatine reverse established pathology?”, these studies pose a slightly different question: “Can creatine help brains cope better when they are pushed hard?”

A 2018 systematic review of randomised trials found that oral creatine supplementation can improve short-term memory and intelligence/reasoning in healthy adults, especially under conditions of high cognitive demand, although effects on other domains were less consistent (Avgerinos et al., 2018). Building on this, a 2024 systematic review and meta-analysis pooled data from 13 trials and reported that creatine monohydrate significantly improved memory, attention time and processing speed in adults, while having less clear impact on global cognition or executive function (Xu et al., 2024). The certainty of evidence was rated moderate for memory and low for other domains, highlighting that more work is needed.

Specific stress models give us a closer look at mechanisms. In one trial, participants were kept awake for 24 hours, then tested on demanding cognitive tasks. Compared with placebo, creatine supplementation improved mood and performance on tasks that heavily stress the prefrontal cortex, the brain region involved in planning and complex decision-making (McMorris et al., 2006). A 2024 study went further, combining sleep deprivation with sophisticated brain imaging and found that a single dose of creatine improved cognitive performance and altered cerebral high-energy phosphate levels during sleep loss (Gordji-Nejad et al., 2024).

Here, creatine acts like a temporary external battery pack for a laptop with a worn-out internal battery: it does not upgrade the processor, but it stops the system from crashing quite so quickly under load.

In older adults, the picture is cautiously encouraging but still incomplete. A 2025 systematic review of creatine and cognition in people aged 55 and over identified six studies and concluded that most reported a positive association between creatine (either supplemental or dietary) and cognitive outcomes, particularly in memory and attention, but emphasised the small number and variable quality of trials (Marshall et al., 2025). Cross-sectional data from the US National Health and Nutrition Examination Survey (NHANES) similarly found that older adults with higher dietary creatine intake tended to perform better on cognitive tests, even after adjusting for confounders, though this cannot prove causality (Ostojic, 2021).

At the same time, a recent narrative review has pointed out that creatine’s effects on cognition are not universally positive and that research designs, dosing strategies and baseline brain creatine levels may all help explain mixed results (McMorris, 2024). That reminder to stay critical is important: the signal is promising, but far from definitive.

Muscles, mobility and frailty: creatine’s other axis of support

While the brain evidence is still emerging, the story in muscle and physical function is much more robust, and this has direct relevance for neurodegenerative conditions characterised by weakness and frailty.

Randomised trials in older adults show that creatine supplementation – particularly when combined with resistance training – can increase muscle mass and strength, improve functional measures such as chair-stand performance and may help reduce fall risk (Gualano et al., 2014; Candow et al., 2019; Forbes et al., 2021). A 2019 review on ageing muscle and bone highlighted creatine’s potential to support muscle quality and anti-inflammatory effects in older populations, though again calling for more large trials (Candow et al., 2019).

A 2025 narrative review focusing on older adults concluded that creatine monohydrate has multiple benefits in this group and may have applications in age-related sarcopenia, frailty and metabolic diseases (Candow et al., 2025).

For someone living with ALS, Parkinson’s disease or early cognitive decline, muscle strength, walking speed and balance are not cosmetic concerns; they are central to independence. In this context, creatine’s ability to support the “hardware” of movement may be just as important as its softer, emerging effects on the “software” of cognition.

Safety in 2025: one of the most scrutinised supplements we have

One reason creatine keeps coming back into serious medical discussion is its safety record. In a large ALS cohort, long-term supplementation at 10 g per day did not worsen kidney markers or increase serious adverse events compared with placebo (Groeneveld et al., 2005).

Beyond neurological populations, the International Society of Sports Nutrition’s position stand - based on decades of work - concluded that short- and long-term creatine supplementation, in doses up to 30 g per day for five years, is safe and well-tolerated in healthy individuals and various patient groups (Kreider et al., 2017). A 2025 narrative review in Frontiers in Nutrition updated this view, stating that creatine has a well-supported safety profile across the lifespan and that concerns about kidney damage or serious side effects are not supported by the bulk of available data when appropriate doses are used (Kreider, 2025).

Typical brain and ageing studies use 3–5 g per day of creatine monohydrate. Higher intakes, such as 10 g per day in the ALS and Parkinson’s disease trials, have also been used safely under medical supervision (Groeneveld et al., 2003; Kieburtz et al., 2015). Common side effects include mild water retention and occasional gastrointestinal discomfort, which are usually manageable.

There are still important caveats. People with established chronic kidney disease, significant liver disease, complex medication regimens, or who are pregnant or breastfeeding should not start creatine without discussing it with their medical team, because data in those specific groups remain limited.

So what does all of this mean If you’re living with or at risk of neurodegenerative disease?

If you or someone you care about is living with ALS, Parkinson’s disease, mild cognitive impairment or is worried about age-related cognitive decline, it can be emotionally exhausting to hear about “promising” molecules that ultimately do not change the core diagnosis.

The most up-to-date evidence supports a grounded, two-part message:

Creatine does not slow clinical progression or extend survival in ALS or Parkinson’s disease when used as a stand-alone therapy on top of standard care (Groeneveld et al., 2003; Pastula et al., 2012; Kieburtz et al., 2015). There are, so far, no large, long-term randomised trials showing disease-modifying effects in diagnosed dementia.

Creatine does appear to support domains that matter deeply to quality of life: muscle strength, functional mobility, resistance to fatigue and, in some contexts, aspects of cognitive performance under stress or in ageing (Gualano et al., 2014; Candow et al., 2019; Forbes et al., 2021; Avgerinos et al., 2018; Xu et al., 2024; Marshall et al., 2025).

A helpful way to picture this is a train climbing a long hill. Neurodegeneration makes the hill steeper. Creatine does not change the hill, and it does not repair damaged engines, but it can add a little extra fuel and traction. The climb is still hard, and the destination does not change, but the journey may be a bit more stable and less exhausting.

For many people, that kind of support - together with exercise, nutrition, sleep and medical care - can still be meaningful.

A quiet, evidence-based kind of hope

In the age of bold headlines and miracle claims, creatine’s real story is quieter, but also more trustworthy. Recent work in 2024 and 2025 strengthens the idea that creatine can improve memory and processing speed in some adults, protect performance during sleep loss, and support cognition in older people – all while retaining one of the best safety profiles of any supplement in sport or medicine (Avgerinos et al., 2018; Xu et al., 2024; Gordji-Nejad et al., 2024; Marshall et al., 2025; Kreider, 2017, 2025).

It does not promise to halt or reverse neurodegeneration. But it offers a realistic way to support the energy systems that brain and muscle cells depend on, at a time when those systems are under pressure. In a landscape where people living with neurodegenerative diseases are too often promised too much and delivered too little, that kind of grounded, evidence-based help is worth paying attention to.

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References

Avgerinos, K. I., Spyrou, N., Bougioukas, K. I., & Kapogiannis, D. (2018). Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Psychopharmacology, 235(9), 2493–2504.

Candow, D. G., Forbes, S. C., Chilibeck, P. D., Cornish, S. M., Antonio, J., & Kreider, R. B. (2019). Effectiveness of creatine supplementation on aging muscle and bone: Focus on falls prevention and inflammation. Journal of Clinical Medicine, 8(4), 488.

Candow, D. G., & colleagues. (2025). Creatine monohydrate supplementation for older adults: A narrative review. Journal of Dietary Supplements. (Online ahead of print).

Forbes, S. C., Candow, D. G., Ferreira, L. H. B., & Souza-Junior, T. P. (2021). Meta-analysis examining the importance of creatine supplementation for older adults with resistance training. Nutrients, 13(6), 1912.

Gordji-Nejad, A., Matusch, A., Kleedörfer, S., Patel, H. J., Drzezga, A., Elmenhorst, D., Binkofski, F., & Bauer, A. (2024). Single dose creatine improves cognitive performance and induces changes in cerebral high-energy phosphates during sleep deprivation. Scientific Reports, 14, 4937.

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