First used in the 1920s as a treatment for drug-resistant epilepsy (DRE), the ketogenic diet is now drawing renewed attention from an unlikely group of researchers — psychiatrists.
Spurred by growing evidence linking metabolic dysfunction to serious mental illness, scientists are investigating whether the high-fat, low-carbohydrate diet could serve as an adjunctive treatment for treatment-resistant depression (TRD), schizophrenia, and bipolar disorder.
Up to 40% of patients with serious mental illness experience metabolic syndrome, and researchers are zeroing in on this link in the hopes of uncovering a new therapeutic frontier.
“Metabolic dysfunction is not peripheral to psychiatry, it is central to understanding both disease burden and treatment response,” Shebani Sethi, MD, founding director of the Metabolic Psychiatry Clinical program at Stanford University in Stanford, California, told Medscape Medical News.
“Despite early observations of metabolic abnormalities in conditions like schizophrenia nearly a century ago, this line of research was overlooked and is now being rediscovered,” said Sethi, who is also a clinical associate professor of psychiatry and behavioral sciences.
With more than a dozen clinical trials currently underway and a sharp uptick in research published on the diet over the past few years, understanding how nutrition influences mental illness may still be in its infancy. But how strong is the current evidence and what do existing studies suggest about its use in different psychiatric disorders?
Among people with psychiatric illness, metabolism is often impaired, which can drive mitochondrial dysfunction and oxidative stress in the brain, worsening psychiatric symptoms.
“The connection between metabolic and mental health is real and runs deep. Metabolic dysfunction doesn’t just happen alongside mental illness — it can actually contribute to causing it through multiple biological pathways,” Uma Naidoo, MD, nutritional psychiatrist, and director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, told Medscape Medical News.
The ketogenic diet shifts the body’s metabolism from burning glucose to burning fat which research suggests can regulate impaired brain function and reduce inflammation.
While the exact mechanism is unclear, it’s thought that the diet changes neurotransmitter signaling, increasing production of the neurotransmitter gamma-aminobutyric acid and reducing neural hyperactivity.
In addition, when ketosis is achieved, antioxidant pathways are activated, leading to reduced oxidative stress and a reduction of inflammatory cytokines associated with mental illness. Interrelated mechanisms such as changes to the gut microbiome and improved insulin resistance may also be involved.
Given the ketogenic diet’s longstanding success in treating DRE, researchers began investigating whether it might also benefit patients with resistant psychiatric disorders.
The ketogenic diet’s recent popularity stems largely from its use as a weight-loss diet, fueled in part by celebrities and online influencers. But experts say there are key differences between using the diet to lose weight and using it to treat psychiatric illness.
In addition, weight loss itself may not be behind the diet’s potential mental health benefits. In a recent randomized trial, patients with TRD experienced antidepressant effects despite no weight change.
Evidence for Depression?
Researchers suspect that the ketogenic diet alters the brain’s metabolism, reducing neuroinflammation and depressive symptoms.
A 2025 meta-analysis of 50 studies showed that ketogenic diets were associated with small-to-moderate reductions in depressive symptoms. Those who followed very low-carbohydrate diets and who achieved a confirmed state of ketosis (measured by ketone levels in the blood) seemed to experience stronger antidepressant effects.
“It’s important to note that this level of improvement is comparable to that seen in meta-analyses of antidepressant trials,” Christopher Palmer, MD, founder and director of the Metabolic and Mental Health Program at McLean Hospital in Boston, told Medscape Medical News.
Additional small pilot trials have also shown encouraging results using the ketogenic diet as an adjunctive therapy for depression, with findings from a recent trial suggesting potential utility for TRD.
In what is the first randomized clinical trial among patients with TRD, the ketogenic diet was associated with modest improvements in depression after 6 weeks compared to a plant-forward control diet. However, after the trial’s support ended, patients found it difficult to follow the diet and had no subsequent improvement, said study investigator Min Gao, PhD, senior researcher at Nuffield Department of Primary Care Health Sciences, University of Oxford in Oxford, England.
The overall benefit was small, and mechanistic studies are needed to understand exactly how antidepressant effects are conferred before introducing the diet into clinical practice, Gao told Medscape Medical News.
Palmer, who also is an assistant professor of psychiatry at Harvard Medical School, struck a more optimistic note.
“Treatment-resistant depression is a challenging condition to treat, affecting millions of people, so any signal above an active control is important,” he said. “We desperately need new treatment strategies.”
For Schizophrenia and Bipolar?
The first evidence of the ketogenic diet’s potential benefit for schizophrenia dates back to the 1960s when 10 women with treatment-resistant schizophrenia reported improved symptoms while following the diet, in addition to standard treatment.
Around the same time, antipsychotics were coming onto the market, so these findings got little attention, said Deanna Kelly, PharmD, director of the Maryland Psychiatric Research Center and professor of psychiatry for mental illness research at the University of Maryland, in Baltimore.
Strong recent evidence of the keto diet’s efficacy for schizophrenia or bipolar disorder came from a pilot trial led by Sethi.
After 4 months of consuming a ketogenic diet alongside antipsychotic treatment, all of the patients no longer met criteria for metabolic syndrome. Most achieved ketosis and had clinically significant improvements in both psychiatric symptoms and improved quality of life.
A 2025 pilot study in patients with bipolar disorder showed an association between ketone levels and improvements in mood, anxiety, energy, and impulsivity.
However, most schizophrenia studies published to date are among small and heterogeneous populations, so trials focused solely on schizophrenia are urgently needed, experts said.
Earlier this year, Human and Health Services secretary Robert F. Kennedy Jr. made headlines when he claimed that the ketogenic diet can “cure” schizophrenia.
While there is growing evidence that it can result in improvements in metabolic health and mental health symptoms among people with schizophrenia, experts say the available evidence does not support claims that it can cure the disorder.
“That struck some people in the scientific community the wrong way because there’s nothing that we claim cures the illness yet,” Kelly said.
What Are the Risks?
Clinicians should approach metabolic therapy with the same level of oversight as pharmacologic treatment because the diet is associated with potential risks, researchers said.
Palmer’s recently published case series details nine patients who developed hypomania or mania shortly after initiating the ketogenic diet.
“I strongly, strongly encourage people to work with a healthcare professional who knows what they’re doing,” Palmer said. “It’s not because I think the ketogenic diet is dangerous. It’s because severe mental illness is dangerous and people should not be treating severe mental illness on their own.”
A more common side effect of the diet is “keto flu,” marked by temporary fatigue, dizziness, or nausea as the body undergoes a metabolic switch from burning glucose to fat.
Some patients may not be good candidates for a ketogenic diet, including those who have underweight; have electrolyte imbalances, gallstones, cardiac arrhythmia, type 1 or type 2 diabetes; or are pregnant.
Lab values should be assessed before and during the treatment to assess nutrient deficiencies that could increase the risk for adverse events, Palmer said. For example, patients with selenium deficiency who undergo ketogenic therapy have an increased risk for heart failure.
Carnitine deficiency may also be a contraindicator because patients lacking this naturally occurring compound — which plays a role in fat metabolism — are unable to achieve adequate ketosis.
The ketogenic diet’s high fat content can also affect the efficacy of some psychiatric medications, including antipsychotics and antimanic drugs. As a result, clinicians need to closely monitor patients and adjust medication dose accordingly, Palmer said.
What’s Next?
Although the current evidence is encouraging, it’s still not strong enough to warrant clinical guidelines recommending its use in psychiatric disorders, Kelly said.
“We’re not quite at the place where we could say guidelines recommend that a keto diet is an effective treatment,” she noted. “Right now, it’s thought to be investigational in some regards.”
More well-powered randomized clinical trials of longer duration and follow-up are needed, researchers said. One such study is already underway.
Sethi is leading a randomized controlled trial of 120 adults with schizophrenia, bipolar disorder, and major depressive disorder to evaluate the ketogenic diet’s efficacy on psychiatric symptoms, cognition, metabolic health, and quality of life. She hopes the findings will also shed light on the diet’s underlying mechanisms and help inform future clinical practice.
Other conditions currently under investigation include alcohol use disorder, anorexia nervosa, and narcolepsy. In addition to more research, insurance coverage and clinician training are key next steps for the ketogenic diet to be more broadly integrated into psychiatric practice, Palmer said.
The diet can be demanding and requires significant meal planning and lifestyle changes, which Naidoo said could make social situations and eating out challenging for some patients.
To ensure adherence and efficacy, regular follow-up and individualized dietary adjustments are key, Sethi added. And counseling patients about ketogenic therapy may also require interdisciplinary collaboration, so they need access not only to a mental health professional but also to a dietitian and/or health coaches, Palmer said.
Although he acknowledged that ketogenic therapy can be labor intensive, Palmer said that in his experience, the effort has been worthwhile for patients with treatment-resistant mental illness.
“I can tell you when you’ve treated patients for over a decade and they’ve tried over 30 different medications and they’ve also tried ECT three times and nothing has worked, and then the ketogenic diet allows them to achieve remission and recover, I can very soundly say it is worth it,” he said.
Gao reported having no relevant disclosures. Sethi disclosed founding her company Metabolic Psychiatry Labs. Palmer disclosed having royalties for his book Brain Energy, which outlines the metabolic basis of mental illness, and a psychiatric practice, MH². Kelly reported that her LiveItLaunchIt study was funded by the Baszucki Foundation, which is a private foundation that funds metabolic treatments.
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