The findings offer cautious optimism, but they also highlight how much remains unknown. While some clinical trials reported meaningful improvements in depression symptoms, others found no benefit at all, leaving scientists with an intriguing question rather than a clear answer.

Reviewing the Clinical Evidence

Instead of conducting a new experiment, researchers led by Bassam Jeryous Fares of the University of Ottawa analyzed existing research. After reviewing the available literature, they identified six published reports covering five randomized controlled trials, in which participants received either creatine or a placebo without knowing which treatment they were taking.

The studies were carried out in South Korea, the United States, Brazil, Israel, and India. Together, they included 238 participants at the start of the trials, with 126 receiving creatine and 112 receiving placebo. Participants averaged 36 years of age, and most were women. Two of the studies enrolled only women.

Four trials focused on people with major depressive disorder, while one involved participants with bipolar disorder who were experiencing a depressive episode. Because the studies differed substantially in their design and methods, the researchers did not combine the data into a single statistical analysis. Instead, they evaluated each study individually.

Mixed Results Across Depression Studies

The review revealed a divided picture.

Two of the five trials, both involving women with major depressive disorder, found that creatine provided additional benefits. In one study, participants who took five grams of creatine each day alongside the antidepressant escitalopram experienced greater reductions in depressive symptoms after eight weeks than those receiving escitalopram with a placebo. The improvement was considered large by conventional statistical standards, with a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale, and more participants achieved remission.

Another study paired creatine with cognitive behavioral therapy. Participants receiving creatine showed a greater reduction in depression symptoms on a standard assessment than those receiving therapy with a placebo.

The remaining three trials, however, found no meaningful benefit.

One study reported that neither five nor ten grams of creatine per day improved symptoms in people whose depression had not responded to medication. Another found no advantage over placebo among adolescent girls, even when different doses were tested. A third trial involving people with bipolar disorder also showed no improvement.

Researchers also noted an important safety concern. Two participants with bipolar disorder who received creatine developed hypomania or mania, suggesting that creatine may affect people differently depending on their underlying condition.

Why Scientists Think Creatine Could Affect the Brain

The idea that creatine could influence depression is grounded in the brain’s enormous energy demands.

Although creatine is best known for helping muscles rapidly regenerate adenosine triphosphate, the molecule that powers cells, the brain also depends heavily on this energy system. Previous research has found changes in brain creatine metabolism among people with mood disorders, leading scientists to investigate whether disruptions in cellular energy production could contribute to depression.

Creatine may also influence dopamine and serotonin, two neurotransmitters that play important roles in mood regulation and are targeted by many antidepressant medications.

Still, the review’s authors emphasize that these connections remain theoretical. Existing studies show correlations rather than proof that altered creatine metabolism directly causes depression, and the disorder itself involves many biological pathways.

“The signal is interesting, but it is not a verdict,” said Bassam Jeryous Fares, first author of the review and a student in the Faculty of Medicine at the University of Ottawa. “Two trials pointed one way and three pointed another. That is not the kind of evidence on which you change clinical practice. It is the kind that tells you the question is worth further exploration.”

Nicholas Fabiano, corresponding author and a psychiatry resident at the University of Ottawa, also urged caution.

“Creatine appears to be a safe intervention. The adverse events we found were limited to mild gastrointestinal discomfort. We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone.”

Larger Studies Are Still Needed

The researchers stress that the current evidence is too limited to support routine use of creatine for depression.

The clinical trials were relatively small, included disproportionately more women than men, and varied in quality. Two studies were judged to have a low risk of bias, while the remaining three raised some concerns, primarily related to participant assignment and missing data. As a result, the findings cannot yet be applied broadly.

The review calls for larger and longer clinical trials that extend beyond eight weeks. Researchers also recommend studying creatine alongside exercise and investigating whether different doses produce better outcomes, while recognizing that higher doses may not necessarily lead to greater benefits.

Animal studies may offer another clue. Experiments have shown that creatine can affect depression like behavior differently in male and female rodents, a finding that could help explain why the human studies involving mostly women produced the strongest positive results.

For now, creatine remains an intriguing possibility rather than a proven treatment. A supplement long associated with building muscle is now attracting growing interest from scientists searching for new ways to treat depression.

The peer-reviewed research article, “Creatine as a treatment for depression,” was published in Brain Medicine and is available through Open Access beginning June 30, 2026.

The research, published in The Lancet Digital Health, found that more than 98% of people identified by their general practitioners as eligible for statin therapy were at low predicted risk of developing a serious muscle disorder over the following 10 years. The findings suggest that fears about severe muscle related side effects may be overstated for most people who could benefit from treatment.

New Tool Aims To Personalize Statin Decisions

The researchers also uncovered a significant treatment gap. More than 60% of people who were eligible to take statins were not using them, even though some faced a high risk of heart attack or stroke. The team believes the new calculator could improve conversations between patients and clinicians by providing personalized estimates of risk instead of relying on general statistics or broad concerns about side effects.

The calculator, available through the Oxford University Innovation software store, is based on a clinical prediction model developed and tested using anonymized health records from more than 5.6 million people registered with GP practices across England. Researchers built the model using data from more than 1.7 million people and then validated its accuracy with records from another 3.9 million.

How the Statin Risk Calculator Works

The model analyzes 22 routinely collected health factors to estimate the likelihood of developing a serious muscle disorder over one, five, and 10 years. These factors include age, sex, ethnicity, body mass index, smoking status, existing medical conditions, previous muscle problems, vitamin D deficiency, medication use, and whether a person has been prescribed statins.

Researchers expect the calculator to be used alongside cardiovascular risk assessment tools such as QRISK. Together, these tools could help doctors and patients weigh both the benefits of lowering the risk of heart attacks and strokes and the potential risk of serious muscle complications when deciding whether statin treatment is appropriate.

Putting Statin Side Effects Into Perspective

Statins are among the most commonly prescribed medications for preventing cardiovascular disease. However, worries about muscle related side effects often discourage people from starting treatment or lead them to stop taking the medication, even when the potential benefits are substantial.

The researchers emphasized that their work focuses only on serious muscle disorders that result in hospital admission or death, not the milder muscle aches and pains that some people experience. Previous research has shown that many mild muscle symptoms reported during statin treatment are not actually caused by statins and should not prevent patients from beginning therapy. Although serious muscle disorders are much less common, understanding the possibility of these rare events remains important when balancing the risks and benefits of treatment.

Dr. Ting Cai, Research Fellow in the Nuffield Department of Primary Care Health Sciences, University of Oxford, and lead author of the study, said:

“Serious muscle disorders are one of the most widely discussed concerns about statins, but our findings suggest that the risk is very low for the vast majority of people who may benefit from treatment. Understanding a person’s risk can help put those concerns into perspective, support more informed treatment decisions and provide reassurance. For the small number of people at higher risk, it gives clinicians a clearer basis for discussing monitoring, checks or alternative treatment options.”

Personalized Risk Could Improve Treatment Decisions

Professor James Sheppard, Professor of Primary Care Research at the University of Oxford and a senior author of the study, said:

“Treatment decisions are often based on estimates of a person’s future cardiovascular risk, but much less information is available about their individual risk of adverse outcomes. This research helps address that gap by providing a way to estimate a person’s risk of serious muscle disorders alongside their cardiovascular risk. Bringing those two pieces of information together could support more personalized and better-informed decisions about statin treatment.”

Professor Constantinos Koshiaris, Assistant Professor of Medical Statistics at the University of Nicosia Medical School and a senior author of the study, said:

“Clinical decisions are often based on estimates of potential benefit, but understanding potential harms is equally important. This model provides a way to quantify that risk at an individual level, helping support more balanced discussion about treatment options.”

By offering personalized estimates of both potential benefits and risks, the researchers hope the calculator will help patients and healthcare providers make more confident, evidence based decisions about statin treatment and long term cardiovascular disease prevention.

The online calculator based on the model will be available through the Oxford University Innovation software store as the STRATIFY-StatinMD Risk Calculator — Academic use.

The study was funded by a British Heart Foundation PhD Scholarship (ref: FS/19/13/34235). James Sheppard and Constantinos Koshiaris were supported by the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship, ref: 211182/Z/18/Z) and the National Institute for Health and Care Research (NIHR) School for Primary Care Research. Richard McManus was supported by an NIHR Senior Investigator award. Richard Hobbs was partially supported by the NIHR Applied Research Collaboration Oxford and Thames Valley.

“Our findings show that the brain is far more active and capable during unconsciousness than previously thought,” said Dr. Sameer Sheth, professor and Cullen Foundation Endowed chair of neurosurgery and a McNair Scholar at Baylor. “Even when patients are fully anesthetized, their brains continue to analyze the world around them.”

Recording Brain Activity During Anesthesia

To investigate what the unconscious brain is capable of, Sheth and his colleagues recorded the activity of hundreds of individual neurons in the hippocampus, a brain region involved in memory. The recordings were made while patients undergoing epilepsy surgery were under general anesthesia. These procedures gave researchers a rare opportunity to study this part of the brain directly.

The team used Neuropixels probes, an advanced technology that had never before been used in the hippocampus for this type of research. This allowed them to observe how the brain responded to sounds and language even when patients had no conscious awareness.

The Brain Continued Processing Language

The first experiment exposed patients to a series of repeating tones with occasional unexpected sounds mixed in. The researchers found that neurons in the hippocampus consistently detected these unusual tones. Even more interesting, the brain became better at recognizing them over time, suggesting that learning or neural plasticity was still taking place during anesthesia.

The researchers then increased the complexity of the experiment by playing short stories while continuing to record brain activity. The hippocampus showed clear evidence of processing language in real time. Patterns of neural activity revealed that the brain could distinguish different parts of speech, including nouns, verbs, and adjectives.

The team also made another surprising discovery. Neural signals could be used to predict upcoming words before they were spoken.

“The brain appears to anticipate what comes next in a story, even without conscious awareness,” said Sheth, who is also Director of The Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories within the Duncan Neurological Research Institute at Texas Children’s Hospital.

“This kind of predictive coding is something we associate with being awake and attentive, yet it’s happening here in an unconscious state,” said Dr. Benjamin Hayden, professor of neurosurgery at Baylor.

Rethinking Consciousness

The findings suggest that important cognitive abilities, including language comprehension and prediction, may not depend on conscious awareness. Instead, consciousness itself may arise from communication across multiple brain regions rather than from activity within a single area such as the hippocampus.

The researchers also noted similarities between the brain’s predictive behavior and artificial intelligence (AI). Just as large language models generate text by anticipating the next word, the hippocampus appeared to make similar predictions during language processing. Understanding these shared principles could help scientists better understand both biological and artificial intelligence.

The work may also contribute to future communication technologies, including speech prosthetics designed for people who have lost the ability to speak.

“Can we use these signals to deploy and run a speech prosthetic for some of the parts of the brain that are damaged by stroke or injury? These are questions that we can now consider in relation to this part of the brain,” said Dr. Vigi Katlowitz, first author and a neurosurgery resident with Baylor.

More Research Is Needed

The researchers caution that the findings should be interpreted carefully. The study examined only one type of general anesthesia, so the results may not apply to other unconscious states such as sleep or coma. In addition, the research focused on a single brain region, and it remains unclear how broadly these processes occur throughout the brain.

“This work pushes us to rethink what it means to be conscious,” said Sheth. “The brain is doing much more behind the scenes than we fully understand.”

A team including scientists from the University of East Anglia (UEA), led by Chinese researcher Dr. Yanfen Zheng, found that naturally occurring soil bacteria can significantly improve plants’ ability to survive in saline conditions.

The study also uncovered a previously unknown way these microbes protect crops such as maize, tomato, and rapeseed from salt stress. The discovery could eventually help farmers grow food on land that has become too salty for conventional agriculture.

Soil salinity threatens global agriculture

Salt buildup in farmland is becoming an increasingly serious problem because of climate change, irrigation practices, and rising sea levels. As salt accumulates in soil, it stunts plant growth, damages roots, and can sharply reduce crop yields.

Prof Jonathan Todd, from UEA’s School of Biological Sciences and the Quadram Institute on the Norwich Research Park, said: “The build-up of salt in farmland is a major and worsening problem — driven by climate change, irrigation and rising sea levels.

“Salt chokes plant growth, damages roots and severely impact entire harvests — putting global food supplies at risk.

“We know that plants rely on communities of microbes around their roots, called the root microbiome, to help them cope with environmental stress. But exactly how these relationships work, and whether they are consistent across crops and soils, has remained largely unclear.

“We found that plants appear to recruit beneficial bacteria in salty soil conditions, which in turn trigger internal changes that strengthen their physical structure and resilience.

“If scientists can harness this natural process, it could mark the beginning of a new era in climate-resilient agriculture.”

Root microbes drawn to salt stressed plants

To better understand these plant and microbe partnerships, the researchers examined root microbiomes from multiple crop species grown in different soil types.

They discovered that a group of naturally occurring bacteria known as pseudomonads consistently gathered around plant roots exposed to salt stress. The same pattern appeared across several crops, including maize, tomato, and rapeseed, suggesting this is a widespread biological response rather than something unique to a single plant.

Genetic analyses also explained why these bacteria perform so well in salty environments.

Prof Todd said: “Compared to other microbes, pseudomonads carry specialized genes that help them tolerate high salt levels, including sodium transport systems and other stress-resistance mechanisms.”

Stronger roots and higher yields

The team then introduced selected pseudomonad strains to soybean plants. In both greenhouse studies and field trials, the bacteria successfully colonized the roots and substantially improved plant growth under salty conditions.

“We found that plants treated with the microbes showed stronger root systems, better development and higher yields compared to untreated plants grown in salty soils,” said Prof Todd.

An unexpected plant defense

The researchers were surprised to discover that the bacteria were not helping plants by reducing salt levels inside their tissues.

“The most surprising thing was finding out how the bacteria helped plants cope.

“For decades, it was thought that plants survive salinity by controlling sodium levels -essentially keeping harmful salt out. But we found no evidence that bacteria influenced sodium transport or ion balance.

“Instead of helping plants manage salt directly, the bacteria stimulated the plant to produce more of a substance called lignin.

“Roots of bacteria-treated plants showed a significant increase in lignin content, with some measurements rising by over 30 percent under salt stress.”

Lignin strengthens plants naturally

Lignin is a strong, woody material that forms part of plant cell walls. It acts like a built in support system, reinforcing plant tissues and helping them withstand environmental stress.

The researchers identified the key genes responsible for increasing lignin production. When those genes were artificially overexpressed, plants performed much better in salty soil.

By contrast, plants that were unable to produce lignin did not benefit from the bacteria, showing that lignin production is essential to the newly discovered protective effect.

Prof Todd said: “We hope this discovery opens up new possibilities for agriculture.

“By harnessing naturally occurring microbes like pseudomonads, bio-based treatments could be developed that help crops grow in saline soils without heavy chemical inputs.

“With vast areas of farmland already affected by salinity and more under threat, microbial solutions could become an essential tool for maintaining crop yields and ensuring food security.”

The findings were published in the journal Science Advances in the paper, “Pseudomonads associated to salt-stressed plants facilitate stress adaption of soybean through enhanced lignin biosynthesis.”