Iain Campbell, a researcher in Scotland, has lived with Bipolar disorder for much of his life. After trying the ketogenic diet, he discovered life-changing improvements in his symptoms — and now wants to learn if it can do the same for others. He shared his recent findings at the Metabolic Health Summit in Clearwater, Fla., on Jan. 25, 2024.
Tina Russell for NPR
Iain Campbell was gazing out the bus window on his way to work when he first sensed something radical was reshaping how he experienced the world. The inkling emerged from an altogether ordinary observation: He felt peaceful, maybe even happy as he watched the trees along the road pass by. “I hadn’t experienced that in a really long time, probably since I was a kid,” says Campbell, who lives in Edinburgh, Scotland. “I didn’t know what was going on at the time, but I thought this might be what it feels like to be normal.”
Campbell had lived with bipolar disorder for much of his life. Mental illness runs in his family, and he’d lost loved ones to suicide. Over the years, he tried different treatments, but it had become “increasingly difficult to live with.” What had changed? A few weeks earlier, he’d started a new diet. Campbell dealt with unwanted weight gain and metabolic troubles, a common side effect of psychiatric medications. In an effort to lose weight, he drastically cut back on carbs and instead focused on protein and fat. It turns out he’d unknowingly entered ketosis: A metabolic state where the body switches from glucose as its primary energy source to ketones, which come from fat. He started learning about the ketogenic diet, which is high fat and very low carb, on podcasts and YouTube videos. Soon, he was tracking his ketone levels, courtesy of an at-home blood test. “I realized it was actually the ketone level that was making this shift in my symptoms in a way that nothing else ever had,” he says. “It struck me as really significant, like life-changing.”
How exactly was a diet performing this alchemy? Campbell decided to pursue a PhD in mental health at the University of Edinburgh, hoping to do his own research and learn if it could help others.
In online forums, people with bipolar disorder were sharing similar anecdotes — they were finding improvements in their mood, increased clarity and fewer episodes of depression. But as Campbell searched for ways to launch a proper clinical trial to test the diet’s effectiveness, he became discouraged. “It was really like you were considered wacky,” he says, “At one point, I thought nobody’s going to pay for this research.” He put together a 45-minute video summing up the biological rationale for using the ketogenic diet in bipolar disorder and posted it on social media, not expecting much after that.
The ketogenic diet avoids most carbs and instead focuses on high-fat foods, proteins and vegetables. Katie Hayes Luke for NPR
But some doctors had already started researching it after seeing the potential in their practice, among them Chris Palmer, a psychiatrist at Harvard Medical School and McLean Hospital. Palmer had his own revelation about the diet a few years earlier, which he detailed in a 2017 case report. Two patients with schizo-affective disorder had “truly dramatic, life-changing improvement in their psychotic symptoms,” he says. In early 2021, he started working with the eldest son of Jan and David Baszucki, a wealthy tech entrepreneur. Their son Matt had bipolar disorder and had been on many medications in recent years. Jan Baszucki enlisted Palmer’s help as her son gave the ketogenic diet a try. “Within a couple of months, we saw a dramatic change,” she says. Inspired, she started contacting clinicians and researchers, looking to bring more visibility — and funding — to the treatment. Since rigorous data on the diet is still lacking, she wants to see researchers conduct large clinical trials to back up anecdotes like her son’s recovery. Soon a big-time philanthropist was in touch with Campbell, ready to pay for his bipolar study – and others. Now, around a dozen clinical trials are in the works, testing the diet’s effect on mental illness, most notably for bipolar disorder, schizophrenia and depression, but also for conditions like anorexia, alcoholism and PTSD. “The research and the clinical interest is suddenly exploding,” says Dr. Georgia Ede, a psychiatrist in Massachusetts, who began using the ketogenic diet in her own practice about a decade ago.
The classic ketogenic diet contains an eye-popping amount of fat, roughly 90% of calories coming from that alone. Other versions have come along that dial down the fat and allow more room for protein and slightly more carbohydrates.
Dr. Chris Palmer (left) signs a copy of his book, Brain Energy, for Addanilka Ramos during the Metabolic Health Summit in Clearwater Fla. Palmer has been researching the keto diet for years. Tina Russell for NPR
Serious followers may buy a device to measure ketone levels in their blood, to track whether they’ve entered a range that means they’re experiencing what’s called nutritional ketosis. The diet’s entrance into the mainstream has fed plenty of debate about its merits, with some medical groups raising concerns. Yet, there’s also growing attention — and clinical trials underway — on its potential, not only for obesity but a variety of other conditions. “It’s not a fad diet,” says Dr. Shebani Sethi, who’s leading research into the diet’s potential for mental health at Stanford University. “It’s a medical intervention.” The ketogenic diet was developed over a hundred years ago for pediatric epilepsy and has seen a resurgence in that field over the last three decades. “It’s a general standard of care for epilepsy,” says Dr. Eric Kossoff, a pediatric neurologist at Johns Hopkins University. This track record in epilepsy, the thinking goes, paves the way for its adoption in psychiatry. There are links between the conditions. Medications developed for seizures are regularly prescribed for a range of psychiatric conditions such as bipolar disorder. “We use them off label, even when we don’t have studies to suggest or prove that they are helpful for people with mental illness,” says Palmer, “So, in many ways, this is nothing new.”
There’s also a well-documented association between a variety of psychiatric conditions and metabolic problems like high blood sugar and insulin resistance, Type 2 diabetes, obesity and hypertension.
Some people use at-home devices to measure ketone levels in the blood to track whether they’ve entered nutritional ketosis. Will Stone/NPR
People with psychiatric disorders are at an increased risk. And it’s not just that psychiatric meds can cause weight gain and other issuses. Research shows these problems can arise even before someone with serious mental illness takes medication or is diagnosed. “We’ve known for a long time that there’s something going on in the metabolism of the brain that’s not quite right in people with severe mental illness,” says Dr. Dost Öngür, chief of the division of Psychotic Disorders at McLean Hospital and a professor at Harvard Medical School. This evidence of energy problems in the brain and elsewhere in the body has accumulated over the decades in psychiatry — unrelated to the ketogenic diet. “We can’t say that there’s a causal relationship, but there are a lot of connections that should be explored further,” says Öngür whose work has focused on this theme in bipolar and schizophrenia. All of this data is strong enough to suspect that “metabolic problems may be more than just innocent bystanders,” that they may, in fact, play a direct role in the development, severity or course of psychiatric conditions,” says Ede.
The theory behind keto’s power So, how exactly could a diet that stops seizures also exert powerful effects on tough-to-treat psychiatric illness? Even after decades, scientists who study epilepsy aren’t exactly sure why it works for that illness. “It’s impacting so many different mechanisms,” says Dominic D’Agostino, a professor of molecular pharmacology and physiology at South Florida University who studies the ketogenic diet. That’s why he likes to characterize the diet as being more like a “shotgun” than a “bullet.” During ketosis, the body essentially changes metabolic gears. It increasingly draws on ketones — made from the breakdown of fat in the liver – instead of glucose. “We know this happens on a ketogenic diet,” says Kossoff, “Ketones can be used for energy, but how that helps seizures is the next tricky question.” Because the diet eliminates carbohydrates, blood sugar comes down and insulin sensitivity improves. “You take pressure off of your really delicate insulin signaling system,” says Ede, while offering cells another fuel that could bring parts of the “brain back online that may have been stuttering.” Palmer and other scientists believe problems with mitochondria — the powerhouses of the cells that produce energy — are central to mental illness. “This is likely due to mitochondria’s essential role in maintaining key brain function,” says Ana Andreazza, a professor of pharmacology and psychiatry at the University of Toronto. In her lab, Andreazza studies what biological pathways make people with psychiatric illness more vulnerable to mitochondrial dysfunction. Cumulative damage to these vital power houses ultimately leads to a “metabolic shift” that wreaks havoc in myriad ways — what’s apparent in their increased production of lactate. “The findings are compelling for many psychiatric disorders,” she says. It’s possible the ketones help the mitochondria by relieving oxidative stress — a harmful build up of free radicals, she says, and by providing an energy source that circumvents the dysfunctional machinery in the mitochondria. “Once you trend towards more normal mitochondrial function and metabolic health, that’s restoring neurotransmitter systems, it’s even restoring blood flow to the brain,” says D’Agostino.
Keto diet followers have to get used embracing larger amounts of fat in their diet. The classic form calls for 90% of calories from fat. Katie Hayes Luke for NPR
The effect of ketosis on the mitochondria is one hypothesis for why keto diets could work, but it may not be the whole story. Much of the data on how the diet affects the brain come from research into epilepsy and other neurological diseases like Alzheimer’s and Parkinson’s. Scientists find serious mental illnesses like schizophrenia, major depression and bipolar disorder share notable similarities with these conditions: Inflammation in the brain, oxidative stress, mitochondrial dysfunction, and issues with glucose and insulin. Research suggests ketosis can be beneficial on these fronts, although human studies are limited. Some of the larger clinical trials now underway for keto diets will seek to pin down what’s going on. For example, Dr. Deanna Kelly is trying to determine if the diet’s potential benefits emerge from the microbiome in the gut. “You’re potentially changing the way bacteria are functioning and that could affect your behavior and your brain,” says Kelly, a professor of psychiatry at the University of Maryland, who’s leading an inpatient trial on the ketogenic diet for schizophrenia. Other scientists are studying the diet’s effect on neurotransmitters like GABA — which acts as a kind of brake in the brain. Dr. Mary Phillips, who has studied how dopamine affects the reward circuit in bipolar disorder, thinks that may help explain its therapeutic effects. She hopes her clinical trial of bipolar and the keto diet, which launched recently, also gets at a very practical question: “How do you know which people the ketogenic diet is going to work for?” says Phillips, a professor of psychiatry at the University of Pittsburgh, “It’s not the easiest diet in the world to get started on.” Much of the current evidence on its potential for mental health comes from case reports, observational data and open trials that have laid the groundwork for more rigorous studies. The research that exists shows improvements in both mental and metabolic health. Iain Campbell’s small pilot study, designed to test the feasibility of a randomized controlled trial, found patients lost an average of about 10 pounds and had “significant reductions” in blood pressure. “As the ketone level went up, we saw their mood improved, their energy improved, their anxiety decreased and their impulsivity decreased,” says Campbell who’s now a Baszucki research fellow in metabolic psychiatry at the University of Edinburgh. Their blood lactate levels, a sign of mitochondrial dysfunction, dropped as did glutamate in the brain, an effect also seen with anti-seizure medications. A recent study from Toulouse, France, is the largest to look at hospitalized patients with severe mental illness.
Dr. Shebani Sethi, a psychiatrist at Stanford is pioneering research in the field of metabolic psychiatry, including the ketogenic diet’s potential for treating serious mental illness. William Stone/NPR
Though three patients couldn’t stick with it, the 28 who did had substantial improvements in their symptoms of depression and psychosis by the third week, says Ede, a co-author of the study. Ultimately, 43% achieved clinical remission. There was no control group, but she points out these patients had been hospitalized before under the care of the same psychiatrist — with the only clear difference in treatment this time being the ketogenic diet. “So we believe the diet probably had something to do with the outcome,” says Ede. At Stanford, Sethi’s pilot study found the majority of patients with schizophrenia or bipolar disorder had “clinically meaningful improvement” on the diet and close to half “achieved recovery.” A quarter of those who entered the study had metabolic syndrome — a cluster of risk factors like insulin resistance and high blood pressure — and by the end, had reversed the condition Dr. Anissa Abi-Dargham, who isn’t involved in the research, calls the initial data “intriguing,” when considered alongside the existing evidence on epilepsy, and metabolic dysfunction in psychiatric illness. “All this together convinces me there is a signal that is worth pursuing in a rigorous way,” says Abi-Dargham, chair of the department of psychiatry and behavioral health at Stony Brook University. But the rush of attention ahead of solid clinical data has raised eyebrows among some psychiatrists. Dr. Drew Ramsey worries the hype has created an unrealistic perception about the ketogenic diet in mental health. For now, he remains skeptical. “Does it work? It works for some people, which is awesome, but most things work for some people in mental health,” says Ramsey, a nutritional psychiatrist. Proponents readily acknowledge the field is still in the early stages. “You have to be modest about this,” says Öngür, “The ketogenic diet is really a test case, but it’s not the silver bullet.” Palmer says the diet is a powerful intervention, but “it’s not going to cure everybody with mental illness, or even necessarily help everybody.”
The groundswell of excitement around a high-fat, minimal carb diet reflects a broader movement to better recognize the link between metabolic health and mental illness. Ketogenic diet research is just one branch of a growing area of research now being called metabolic psychiatry.
Lori Katz, pictured here with her support dog, started the ketogenic diet under Dr. Sethi’s supervision. She quickly started to notice a difference. “It wasn’t just the depressive symptoms, but it was the feeling of lack of control,” she says. The diet “was like a tailwind — just blowing me into a better future. Lori Katz
Shebani Sethi, who coined the term when she launched Stanford’s program in 2015, says the idea is to study how treating metabolic health – tackling conditions like high blood sugar, insulin resistance and obesity – may also improve psychiatric problems. While keto is the most prominent example she says medications are also under study, including drugs that make the body more sensitive to insulin — the hormone that helps usher glucose into cells. This approach is intuitive for Sethi, who trained in obesity medicine and psychiatry. It was in medical school when she first witnessed keto’s potential for her psychiatric patients. A woman with treatment-resistant schizophrenia had tried the diet to lose weight and manage her diabetes. To her surprise at the time, Sethi recalls it also helped the patient with hallucinations. A recent clinical trial underscores the promise of targeting metabolic problems, beyond just the ketogenic diet. Patients with treatment resistant bipolar depression and insulin resistance, but not Type 2 diabetes, were prescribed the diabetes drug metformin. By the end of the study, half of those who took the medication had reversed their insulin resistance — and also found dramatic improvements in their psychiatric symptoms, even though most had been ill for 25 years without any remission. “I was kind of blown away,” says Dr. Cynthia Calkin, a psychiatrist at Dalhousie University in Canada who led the study. “It’s not that metformin is an antidepressant, it’s that it can reverse insulin resistance and that improves outcomes.”
Neither patients nor clinicians are waiting for the results of larger trials to try keto. Online, patients share their experiences with – and challenges – trying the diet. And doctors like Sethi and Ede, who trains other clinicians, regularly treat patients with it.
