What is the connection between metabolic health and mental health? Dr. Dom D’Agostino—a friend, advisor, and mentor to many of us at Levels—recently sat down with Dr. Iain Campbell and Dr. Bret Scher to talk about how metabolic health and mental health are tightly related.
Dr. Iain Campbell was recently awarded the first Metabolic Psychiatry Research Fellowship at Baszucki Group, investigating the science and application of ketogenic metabolic therapy for bipolar disorder. Dr. Campbell is one of the few scientists in the world researching bipolar disorder who also lives with the condition. After personally sending his illness into remission using ketogenic therapies, he dedicated his career to furthering mental health research in the emerging field of metabolic psychiatry.
Dr. Bret Scher is the director of Metabolic Mind and a board-certified cardiologist and lipidologist, as well as a leading expert on the therapeutic uses of metabolic therapies, including the ketogenic diet. He’s practiced for more than 20 years as a preventative cardiologist and was the medical director of dietdoctor.com.
Dr. Dom D’Agostino is an associate professor in the department of Molecular Pharmacology and Physiology at the University of South Florida. Dom’s labs have developed and tested metabolic-based strategies for targeting CNS oxygen toxicity, seizures, epilepsy, and neurodegenerative diseases. The main focus of this lab over the last 12 years has been investigating the neuroprotective mechanism of the ketogenic diet and metabolic health.
Metabolic Psychiatry Enters the Mainstream
Dominic D’Agostino: I am honored to be among Dr. Bret Scher and Dr. Iain Campbell. Maybe both of you guys could briefly discuss your background and what you do and how both of you are spearheading this whole movement, advancing the science-application advocacy of metabolic psychiatry.
Bret Scher: I’ll jump in. I’d love to transition and introduce Iain a little bit, too. I’m a cardiologist by training, but in my cardiology practice I really focused on cardiometabolic health and how metabolic health related to so many other disease issues. I did deep dives on metabolic health, nutritional therapy, and lifestyle interventions to improve metabolic health, with ketogenic therapies being a big part of that.
With my focus on metabolic health, I then started to transition to this connection between metabolic health and mental health. That’s when I met the Baszuckis and was fortunate enough to meet Iain Campbell and hear his story as well. I became enthralled with this opportunity within mental health—within psychiatry—to focus on metabolic health and metabolic therapies as potential treatments for psychiatric illnesses.
I have to give a lot of credit to someone like Iain and Matt Baszucki and others who’ve shared their stories and are, like Iain, helping further the science. That’s what got me connected with Metabolic Mind, where I’m now the director, which focuses on putting forth education about this connection between metabolic and mental health and metabolic therapies as treatment for mental illness.
I’m happy to be here today to share this, and Dr. Iain Campbell has been a shining light for me as an example of someone who’s lived with mental illness, who’s treated it with nutritional therapies, and who’s sharing his story with the world to help educate and inspire others while also doing the research. It’s such a great combination.
Iain Campbell: Thank you. Yes, I’m the Baszucki Brain Research Fellow in Metabolic Psychiatry at Edinburgh University. I have a PhD in global health from the University of Edinburgh. I also am diagnosed with bipolar type II, and I’ve been using ketogenic metabolic therapy for seven years now.
I originally found out about ketogenic metabolic therapies through listening to podcasts like you were doing, Dom, and promoting this as a therapy for cancer and for neurological disorders, like epilepsy and other conditions. I had no idea at the time it would have an effect on my mental health, but it was more effective than any treatment I’d ever tried in my life in ameliorating the symptoms of bipolar. It was such a dramatic turnaround for me after having tried many things that haven’t worked. I felt I needed to spend as much time as I could the rest of my life trying to tell people about this and try to explore and understand how many people this could help.
Dominic D’Agostino: Iain, you’re really like the poster child for this. You live with a disorder, and you’ve more or less managed it, or maybe even put it into remission to some extent, with ketone-metabolic therapies.
We’re really here to discuss the link between metabolic health and mental health. Levels has an immense appreciation for that. They’ve even funded a collaborative study at University of South Florida with Dr. Allison Hall. We’re looking at CGM and low-carb diets in the context of looking at normal healthy people. Even a low-carb diet or ketogenic diet implemented in normal healthy people without bipolar depression improves scores on mental health questionnaires like PHQ-9 and GAD-7 and a variety of others.
My intro into Levels was actually through Jen Baszucki. I think she’s a Levels user. It was Casey or Josh who connected me. Devices and emerging technologies like continuous glucose monitoring are very valuable tools.
Iain, tell us about the research you’re doing through your fellowship and how you’re designing that protocol, specifically ketone-metabolic therapies or dietary therapies and the different things you’re looking at.
Iain Campbell: We just conducted a pilot trial with 27 participants with bipolar disorder going on a ketogenic diet for eight to 10 weeks, with two-week washout periods. We were assessing feasibility and acceptability of the diet for preparation for a future randomized-controlled trial. We were also looking at psychiatric outcome measures and metabolic outcome measures.
What we saw was very interesting because there’s a significantly increased cardiovascular risk with bipolar disorder. In fact, in the UK, over 70% of people with serious mental illness die of physical, preventable diseases. There’s two to three times the risk of Type 2 diabetes in people with bipolar disorder and there’s a very strong energy component the disorder that’s under-recognized in the research.
Ketosis speaks to all of these mechanisms, but it’s also a therapy used for epilepsy, and anticonvulsants are used to treat bipolar disorders. We share medications with epilepsy. This other effective therapy for epilepsy is coming into focus for bipolar. There’s a lot of scientific background to why we want to conduct this study.
Also, many patients—like myself, like Matt Baszucki—are coming forward, with the help of Bret sharing this in Metabolic Mind and these other channels. It’s a real patient movement to raise awareness about this because the people are reporting remission of symptoms— substantial benefits. We want to try and understand what’s really happening, and we’ll be publishing a paper in the next couple of months.
In the trial, we found substantial changes in participants’ metabolic profile alongside their psychiatric symptoms, their brain imaging, and other parameters we looked at that would be considered very beneficial for bipolar disorder. It speaks to many of the aspects of bipolar pathophysiology that are important, like glutamate in the brain, serum lactate levels, and the psychiatric symptoms associated with bipolar.
We’re very excited to share these results. We presented this at the ISBD (International Society for Bipolar Disorders) conference, in Chicago. I was there with Bret. We presented alongside Shebani Sethi’s work at Stanford and Georgia Ede’s study with Dr. Albert Danan. It was the first time people really saw this as a serious scientific area for bipolar disorder, and that we would want to study this and then look at the mechanism shared with anticonvulsants.
Bret Scher: I was in the crowd for that presentation at this international bipolar meeting and saw people’s attention and heard them talking after the fact. For a lot of people, it was an introduction to ketogenic therapies. It was pretty remarkable, because the data presented were impressive and really got people’s attention. It’s such an important step, because we can talk about it all we want. We can share stories all we want, but for the treating physician who’s maybe a little skeptical, they need data, they need studies—and that’s what they now have.
The reaction in the room was really dramatic. We’re going to see this take off in large part because of what Iain and Dr. Shebani Sethi and Albert Danan and Georgia Ede are doing—not just clinically, not just from an education standpoint, but from a research standpoint. It’s impressive to see.
Dominic D’Agostino: Iain, it wasn’t at ISBD, but I saw probably a similar presentation at Keto Live in Switzerland. Have there ever been any kind of dietary therapy clinical trials presented at ISBD? That’s a massive step in the direction of hitting the mainstream for this disorder. Was everybody in shock that something like nutritional intervention can have an effect?
Iain Campbell: Keep in mind we were a small sample size. We were trying to present this as a feasibility and acceptability study, but we were also sharing the outcomes they were measuring in psychiatric symptoms and metabolic symptoms. Alongside Shebani and Georgia’s data, we were showing substantial changes in psychiatric symptoms—beneficial changes in brain imaging and metabolomics. The profile of benefits speaks to the whole gamut of what goes wrong in bipolar disorder. A lot of people were surprised and excited, and lots of psychiatrists who I know were previously skeptical, came up afterwards and said, “We want to launch research in this area.”
This makes complete scientific sense: We’re using these anticonvulsants to treat bipolar, and here’s another anticonvulsant therapy that’s showing effectiveness. Let’s try to explore the mechanisms of this and understand more about it. We received a very warm response and a very open response, and people were wanting to jump in and get involved in this, which is all you can ask for at these conferences. It’s fantastic.
Bret Scher: There was a big focus on this increased cardiometabolic risk for patients with bipolar disorder. Whether it’s from the underlying cause itself or from the medications or a combination of both, it’s clear patients with the disorder are at higher risk. There was some discussion about nutrition in general and lifestyle in general to counteract or to address that increased cardiometabolic risk.
We can share stories all we want, but for the treating physician who’s maybe a little skeptical, they need data, they need studies—and that’s what they now have.
But here’s an intervention—nutritional ketosis, ketogenic therapy—that not only addresses that increased cardiometabolic risk, but looks like it also addresses the psychiatric symptomatology. You get a dual effect rather than just saying, “We use drugs for the bipolar disorder and then try to counteract the increased cardiometabolic risk with lifestyle.” Here’s a lifestyle and that can do both. That’s something that really gets a lot of people’s attention, and rightly so.
Dominic D’Agostino: There is an appreciation of and discussion about things like insulin resistance and the development of metabolic health problems. We are privy to that in our little niche of a community of metabolic psychiatry.
But within the breadth of the individuals at this conference, was this completely new to them? Was there a little bit of pushback? I’m wondering if there was a question-answer session after the presentation of the data, when people might look up what a ketogenic diet is and see the macronutrient ratios. Bret, as a cardiologist and lipidologist, you have been a voice of reason when it comes to discussing the cardiometabolic implications of these dietary therapies.
Bret Scher: You’re spot on. There definitely was some concern. People expressed how they believed that low-carb diets increase your risk of death and high-fat diets increase your risk of heart disease and LDL is going to go through the roof. There definitely were those concerns. There was probably the most discussion ever of LDL at a psychiatry conference.
I’m glad I was there and able to speak up and point out that in the “studies” that show low-carb is harmful or increases risk of heart disease, participants have 40% of their calories from carbs. That’s their definition of low-carb, which is completely different from a ketogenic intervention. We really are talking about two separate things. The physiologic changes that occur with a ketogenic intervention are dramatically different from just the 40% carbs. One study had 20% carbs—still not ketogenic. People need to realize we’re talking about ketogenic therapies, and we can’t extrapolate generic, so-called low-carb data to that.
For the majority of the people, LDL doesn’t go up. Iain, Shebani, and Georgia, all presented data about LDL and cardiac risk. In general, LDL doesn’t go up, and Shebani even presented her evidence that cardiac risk was the same or went down. We have to get over the preconceived notions that this is by definition a harmful diet for your heart, where LDL is going to go up. That’s not the case for the vast majority of the people. Even if LDL goes up a little bit, the overall calculated cardiac risk goes down because of all the metabolic improvement. There’s definitely a lot of education that needs to go on, especially in groups that maybe aren’t as familiar with ketogenic therapies.
Dominic D’Agostino: It’s an aggregate of cardiometabolic biomarkers, like blood pressure medication. Hemoglobin A1C and other things like continuous glucose monitoring are looking at things like glycemic variability and then, of course, ketone levels, if you’re using a ketogenic intervention.
Iain Campbell: If there was anyone people could have speed dialed at that moment when they asked about cardiometabolic risk, it would be Bret. The fact we are able to give quite robust feedback on that was fantastic. The physical and cardiometabolic aspects of bipolar are major topics of any bipolar conference.
Using Biomarkers to Better Understand Our Mental State in Real Time
Dominic D’Agostino: Was there any discussion or general consensus among everyone presenting on the biomarkers we should be paying attention to in regards to mental health and bipolar, specifically?
Iain Campbell: It’s very difficult to isolate biomarkers in bipolar disorder. You’re trying to measure the activity in the brain, and you’re of course getting a signal from the serum, but we’re never sure how reliable it is.
The systematic reviews have consistently, for around 70 years now, highlighted elevated lactate as being the most significantly altered biomarker in the serum of people with bipolar disorder. This is also reflected in brain magnetic resonance spectroscopy. Lactate is considered a biomarker in bipolar disorder. You can’t use it to diagnose anything, but there’s definitely elevated lactate.
This has been related to the literature on mitochondrial dysfunction, the hypothesis being that this is glycolysis running on overdrive. It fits with metabolic dysfunction in general—there’s mitochondrial dysfunction and increased glycolysis. It also ties in with what you’re saying about insulin resistance in the brain, and we’ve always known that insulin resistance causes havoc with the rest of the body.
For some reason, we’ve assumed that the brain wasn’t affected in some way. The scientific understanding has evolved to the point where we now understand that insulin is extremely important in the brain. If you look at some of the bipolar medications, they act on insulin-signaling mechanisms. The primary target of lithium is the phosphatidyl and acetol cycle, and there’s been an untold amount spent on studying this mechanism for pharmaceutical intervention. It’s actually a key component of insulin signaling, as are many of the other drug targets, like GSK-3, studied in bipolar disorder. The actual way we treat this at the moment speaks to these metabolic aspects.
Dominic D’Agostino: Bret, can you follow up on lactate as a mitochondrial metabolic biomarker that could be implicated here?
Bret Scher: I want to answer the question by focusing on the question you posed about whether or not there was a consensus. Definitely, no: there was not a consensus. We’re still using fasting glucose as the measurement, which we know is a misleading metric. Things like CGM—looking at your average daily glucose, your glycemic variability—is much more informative than just fasting glucose. There’s definitely some education that needs to go on.
There was one talk about insulin and HOMA-IR that mentioned CGMs, which is certainly a step in the right direction, but that was one out of many. There definitely needs to be some education from that standpoint. Lactate is a fascinating marker that we should be following. That’s going to take some time to adopt as well, as people get familiar with it and learn how to use it.
It’s clear we’re on the cutting edge of learning more about how to monitor metabolic health, and that what we have been doing with fasting glucose is woefully inadequate. We’re going to keep learning more and getting more comfortable with things like lactate and CGMs and blood pressure and A1C and fasting insulin and HOMA-IRs. And we’ll get more comfortable analyzing all of those together to assess metabolic health, and then using that as the broader picture of cardiometabolic health.
There also was a lot of discussion about LDL. As we know, we have to go way past LDL to assess cardiovascular risk, and look at the whole picture. It’s clearly emerging, and groups like Levels are certainly leading the way when it comes to getting beyond just fasting glucose and getting more intensive measurements of glycemic control.
Dominic D’Agostino: Do you think there’s an opportunity to look at stress hormones, for example, and maybe catecholamines or maybe more importantly, cortisol? We’re looking at a big data set now for Dexcom. That dawn response is ubiquitous among healthy individuals and across the board, and people who have dysregulated cortisol or hypercortisolemia are maybe at higher risk. Is that something we should be looking at in this population?
Bret Scher: It certainly makes sense. As I’m sure you know with cortisol, the timing of measurement makes a difference, and how you measure it makes a difference. A lot of those things need to be worked out and be consistent. As a society, we can say we’re not very good at managing our stress. It’s clear that stress impacts our health, our metabolic health, and our mental health.
Dominic D’Agostino: Especially in the context of this population. Maybe anxiety disorders are on the rise and maybe that’s a contributing factor for triggering an event. Bipolar disorder is very cyclic, and maybe it’s seasonal.
There are different things that can trigger the disorder, including anxiety, and maybe it could follow some kind of stress biomarker. That’s a fruitful area for research that remains untapped, and one I’ve personally been interested in.
We’ve done some research in the military and with NASA looking at, operationally, how these stress biomarkers can be elevated. When we go back and look at the cardiometabolic biomarkers, we see that they’re dysregulated, too. Is the cortisol impacting that, or are there other factors? Is the nature of the operational activity impacting cardiometabolic biomarkers, or is it being driven by the stress hormones? It’s something to look at.
Iain Campbell: Absolutely. One of the most well-known features of bipolar disorder, going back to the 60s when Jean-Pierre Falret was talking about fully circular madness, was this circadian aspect. When you disrupt someone’s circadian rhythm, they’ll have episodes, and if you improve someone’s circadian rhythm, they’ll have less. It’s almost like the body’s energy regulation is being dysregulated by bipolar.
Falret was sitting with patients in the hospital, observing them. He was saying that depression was especially conspicuous, and during mania, patients have unlimited energy and work all day and night. You can actually take someone who’s depressed and keep them up until 2:00 or 3:00 in the morning, and this will help them to feel better.
If you have someone who’s manic and disrupt their sleep, they can become worse. There’s a really strong circadian aspect. When you wear a CGM, this becomes apparent with the dawn effect. I did this myself: I wore a CGM for a year, and seeing this morning cortisol rise you described is significant.
In our study, we saw that glucose and ketones correlate to participants’ psychiatric symptoms. It’s something happening in real time. It’s not just the extended effects of cortisol over time—the daily effects of cortisol and glucose surges could be really interesting to study.
The Power of Exercise in Metabolic and Mental Health
Dominic D’Agostino: We know stress plays a huge role in mental health and its management, and perhaps bipolar. It leads to the question of stress biomarkers we can measure—cortisol in particular, which we’ve done some research on. This is influenced profoundly by the situation, but also by circadian variability and sleep. Do we know if metabolic therapies can impact stress in that way?
Iain Campbell: The circadian aspect of bipolar has been recognized right from the start, since the earliest clinical observations by Emil Kraepelin, who was seeing patients be very active at nighttime and sleep during the day. This was reflected in even the earliest papers on bipolar by Jean Falret, where he was calling it “circular insanity,” where it follows this pattern of circadian dysregulation.
You can help people with bipolar through light therapies that realign their circadian rhythm. People can also have episodes brought on by circadian rhythm disruption. The main thing I noticed in the morning while using CGM was the dawn effect, the cortisol surge in the morning.
We also measured daily ketone and glucose levels in our patients, and we were looking at the correlation with their psychiatric symptoms, which were also measured daily. We found these positive correlations with the things you’d want to improve—like better mood and better energy—and negative correlations with things like anxiety and impulsivity.
This speaks to a really important point about bipolar: in the euthymic state, there’s actually a huge degree of variation on a daily basis in someone’s symptoms. Even in people who are euthymic, the attempted suicide rates for bipolar are between 25 and 60%. Even though we’re saying in studies that a lot of people are achieving clinical euthymia, they still don’t want to live. That’s not an outcome any of us feel good about, as patients or clinicians.
We want to understand what this variation and the so-called euthymic state are? CGM could give us a great deal of potential information about that, through cortisol and metabolic parameters. It’d be really interesting for future research.
Bret Scher: The question of stress is really fascinating. One of the amazing parts of Iain’s data that he presented was this correlation between ketone levels and psychiatric symptoms. As we know, ketone levels can change throughout the day, and there are a number of different things that could impact that. Stress hormones certainly could be one of them.
I’d be fascinated to learn more about the role of changing stress hormones and altering ketone levels, and then how that impacts symptoms of mental illness or even mental clarity, executive function, thought processes, and energy levels—and how all that is intertwined.
You can think of different interventions. If you know your ketones drop at a certain point, you do certain interventions to try and raise them—whether that’s managing stress hormones or taking an exogenous ketone or taking MCT oil or doing some other type of intervention to raise those ketones back up in a circular pattern. How does that impact your cognitive function, your mental health? That’s a fascinating area of discovery. Iain was one of, if not the first to really show this data that there is a direct correlation between ketone levels and symptoms of mental health.
Dominic D’Agostino: We want an elevation of cortisol in the morning, but not so much in the evening. Maybe that could be indicative. Another thing you brought up, Bret, is other things that could be used to modulate or augment metabolic physiology to improve these things, including an elevation of ketones. Exercise is a big lever we can pull. Not everybody’s going to do it, but I know Iain is a huge advocate of exercise—strength training and exercise in general.
In addition to sleep and diet, I think of exercise as a metabolic therapy. In regards to your participants in the study, and the feasibility of looking at exercise, perhaps there’s a diet-exercise synergy going on, where one and one equals three when you combine the two together. What are your thoughts on how we could research that or get some insights into that?
Iain Campbell: The ketogenic diet is one metabolic therapy, and there are so many things that affect metabolism—circadian rhythm, exercise, sleep. They’re all interrelated. They’re all acting on similar underlying pathways, which are also some of the pathways we manage through medication in bipolar disorder. Combining exercise and diet is an absolute no-brainer for mental health.
Just anecdotally, I am a different person if I exercise—if I do a run in the morning and bring down my glucose levels. One of the most important things that helped me realize that was looking at a CGM and seeing this surge in the morning. I was able to see something happening with my metabolism in the morning, which made the symptoms much worse if I didn’t manage it. When I go for a run, I can flatten a lot of that glucose curve and feel much, much better throughout the rest of the day. This is something that could be revealed by more people wearing CGMs and examining this.
Dominic D’Agostino: Years ago, UCB pharmaceuticals, makers of the anticonvulsant drug Keppra, held a meeting in Belgium. They were very interested in the ketogenic diet and its potential synergy with this anti-epileptic drug.
We’re discussing a metabolic therapy which would at least be in the context of an adjuvant, but which also may be a replacement for drug therapy along the line. For people who are already on pharmacotherapy, there could be some synergy with these metabolic interventions, and also diet. Exercise is a huge lever that is altering our metabolism.
I’m not suffering, at least that I know of, of any mental disorder. Exercise always kept me sane, so to speak, in grad school. I self-medicate with exercise and just default to that. I established those early patterns early in life. Without that, I don’t know where I would be. I see that in other graduate students and people in academia, too. It’s such a powerful therapy in and of itself.
Bret Scher: Exercise has a dual therapy effect. One is the endorphins that come from exercise. I don’t know studies on this, but it’s clear that some people get them and some people don’t. Some people just feel great with exercise and some people maybe don’t, from the endorphin side.
The other part is metabolic health. Like you said, exercise is a metabolic therapy, and practically everybody’s going to get that benefit by maintaining or building lean muscle mass, by doing cardio and improving your blood sugar and your insulin and your glucose sensitivity. Those things are going to improve your metabolic health, which then will translate, to some degree, to mental health as well. There’s that dual-pronged approach to exercise improving people’s overall mental wellbeing.
Dominic D’Agostino: I’ve seen a few papers on how exercise elevates circulating levels of lactate in the millimolar concentration. Lactate freely crosses the blood-brain barrier via the monocarboxylic acid transporter to restore brain energy. Our brain would have free access to this alternative fuel.
Lactate is underrated. Before I even started in ketones, I was interested in alpha L-Polylactate, which is a source of alternative fuel. I’m still very interested in that. Exercise does so many different things. Muscle is an endocrine organ. It’s releasing myokines and other factors that are altering brain health and maybe stabilizing our mood. The lactate question is something that’s interesting, too. At rest, if lactate is elevated, that’s a telltale sign of metabolic mitochondrial dysfunction. It feeds into that mitochondrial etiology of mental health.
Iain Campbell: The lactate question is also interesting because exercise is also a trigger. It generally improves people in depression states. I’ve definitely experienced this. Intense exercise can be a trigger for mania in people with bipolar disorder.
If you do the moderate-intensity, below-lactate-threshold exercise, it appears to be beneficial. With the higher intensity exercise, people can get manic. I find that really fascinating in the context of what you’re saying about lactate because you’re importing this additional fuel source into the brain and you’re having heightened power and activity of the brain in some of the studies I’ve seen.
Combining exercise and diet is an absolute no-brainer for mental health.
It’s also importing glutamate alongside the lactate. Is glutamate and lactate flooding the brain after exercise a risk factor for manic episodes? What does that say about what a manic episode is?
I have a paper about this I just published called “The Metabolic Overdrive Hypothesis. Hyperglycolysis and Glutaminolysis in Bipolar Mania.” This post-exercise state is a significant risk for mania, but it also reveals an interesting aspect of mania that we were showing a ketogenic diet improved, which is increased glutamate metabolism in the brain.
We’re showing between an 11 and 13% reduction in glutamate in the brains of people in our pilot study. This was a marker of a response to anticonvulsants as well. These unique metabolic states could reveal aspects of the condition we could use to optimize ketogenic diet intervention.
Dominic D’Agostino: With the glutamate in, did you also look at GABA? Work in our animal model shows that glutamate can stay the same or go down, but we have correspondingly higher levels of GABA. We do immunocytochemistry for glutamic acid decarboxylase 65 and 67, and these are always elevated with diet therapy, but also with a ketone-ester therapy, which makes me think that the ketones are altering the enzymatic production of the enzyme, and maybe the activity of that enzyme, to make more glutamate and GABA. This is one of the underlying theories we’re working on.
Iain Campbell: Absolutely. There’s a glutamate-GABA balance in the brain, and it appears that glutamate is reduced and that GABA’s increased in people on a ketogenic diet. One of the proposals I made in this paper I just published was that glutamate is also a metabolic substrate in the brain. This was Hans Krebs’ original focus on glutamate in his early papers. If glutamate is used as a metabolic substrate in the brain, this is fulfilling a similar role to ketones. If you provide ketones, it reduces the need for glutamate to be metabolized in this way.
If you have glutamate being used as a metabolic substrate in the brain, you get several of the markers of bipolar disorders, such as decreased N-acetyl aspartate using up the aspartate pool. You get an increased level of glutamate. Bringing those down with a ketogenic diet in that context would make a lot of sense. In the same way we’re looking at the role of metabolism in psychiatric disorders, we could also look at some of these neurotransmitters that have been prominent in bipolar through a metabolic lens to understand some of these states of mania and depression.
Dominic D’Agostino: I think of glutamine with glutamine synthesis. The astrocytes take up the glutamate from the exercise and then convert the glutamate back into glutamine. Then it gets transported back to the neurons and glutamate is synthesized. That’s a whole other area that’s not really discussed much in neuroscience. But that idea of glutamate being a carbon source for fuel and for ATP is very interesting.
Bret Scher: You guys are getting deep into the science here. I wanted to take a step back to look at the broader perspective. We’re talking about a nutritional intervention that changes the neurotransmitters of the brain. That in itself is pretty remarkable.
People talk about improving their metabolic health by going on a low-calorie Mediterranean diet or by just reducing calories by 500. Those aren’t going to change the physiology of your brain, nor the neurotransmitters of your brain. That’s why it’s so important, as we talk about a ketogenic diet in this setting, to emphasize that it’s actually a ketogenic medical intervention that changes the neurotransmitters in the brain.
Dominic D’Agostino: That’s a super important point. That overarching change in our metabolic physiology impacts brain energy metabolism and brain neuropharmacology. I just interviewed someone yesterday about how intermittent fasting changes the whole microbiome. Low-carb intermittent fasting could be equally as powerful.
The Ketogenic Diet as a Prescription-Strength Intervention
Dominic D’Agostino: What’s the potential of a low-carb diet—defined as under 100 grams of carbs, and sticking to fibrous carbs instead of sugars and starches—or intermittent fasting having an equal benefit? Are the benefits linked to a loss of body weight or changes in body composition, and could you achieve that through other dietary means? Is that one of the things changing our mental health? I’m trying to discern whether it’s the ketogenic therapy and the elevation of ketones versus just body composition or metabolic markers.
Bret Scher: It’s a fascinating question. A lot of this is taking what we have and making best guesses from it. We need dedicated studies looking specifically at this question, which haven’t been done, but I’m sure will be done.
We have to look at it from two different aspects: one is improving metabolic health, and the other is changing the fuel source for the brain. When it comes to improving metabolic health, then yes, a low-carb, 75-gram, fibrous-carbohydrate diet combined with exercise and sleep is going to improve metabolic health for just about everybody. It may not be the most powerful intervention, but it’s going to be a powerful intervention that’s going to help people improve their metabolic health. By improving metabolic health, you will see benefits from mental health. The next question is, Is there more?
The more is changing the fuel source for the brain from using glucose to using ketones, bypassing absolutely any potential insulin resistance that exists in the brain. Then you see decreased neuro-inflammation, you see a balancing of the neurotransmitters with increased GABA, and decreased glutamate.
You’re not going to see those things by simply improving your metabolic health. That requires this metabolic shift and fuel shift from glucose to ketones. That’s not to say you’re not going to get any benefit by just focusing on metabolic health with a low-carb diet. You will, but if you want to optimize or intensify the treatment as the medical treatment, that’s where a ketogenic therapy comes in, and changing the fuel source with ketones.
Dominic D’Agostino: Great points and very well stated. A ketogenic diet is more or less a prescriptive diet therapy, or a prescription strength-metabolic therapy, as opposed to a low-carb diet. A ketogenic diet truly is, in action, a prescription-strength diet therapy, and it’s prescribed in epilepsy. It has a wide track record.
As I got more and more into this research, I realized people didn’t know about the epilepsy research, which was my wheelhouse, and the overlap between the anti-epileptic drugs and bipolar, too. That may be some common mechanism there. It makes sense that you may need to achieve and sustain that therapeutic ketosis to get that continuing benefit on the brain in this context.
Bret Scher: That’s well said. With that, I’ll put in a selfless plug that we have a number of videos on this topic, and especially that connection between epilepsy and mental health and ketogenic therapies, at our Metabolic Mind YouTube channel.
The Future of Therapeutic Ketogenic Diets, Metabolic Psychiatry, and Educational Outreach
Dominic D’Agostino: What are some practical steps individuals can take to improve their metabolic health and in turn, positively impact their mental health? We’ve been talking largely about psychiatric disorders and bipolar, but by being a researcher as well as a patient, you have a unique knowledge and a broader context. What are some actionable things one can do in regards to dietary approaches or metabolic-based approaches?
Iain Campbell: When you speak to people with bipolar, you hear again and again that the early morning is the worst time. It’s when you wake up and you’re faced with this state of depression. And the state of depression is not so much feeling sad—it’s like a state of physiological crisis that the body plunges into, where people go into catatonic states of depression where they can’t move and there’s increased lactate in their blood. They feel like they’ve run a marathon even though they’ve not even moved an inch. It really is that state of complete physical exhaustion that happens for no apparent reason. It just comes over people during these episodes. This makes people very hopeless.
Even if they have a family they care about more than anything in the world, or friends or a job, they can’t physically summon the energy to interact with it. It’s very discouraging for people. I’ve been there for many, many years, and it took me a very, very long time to realize that metabolism had anything to do with that state. Now, if I maintain ketosis, I don’t have to experience that state of physical exhaustion. We’re still trying to understand why that happens and what this benefit provides. For me, maintaining ketosis is the only thing that’s ever turned the dial on these severe depressive episodes. I come out of them when I go into ketosis.
I’m also someone who, like with epilepsy, has to stay on the diet. If I come off of it, I experience those depressive episodes, so I need to maintain the diet over a long time. Ketosis and exercise are the one-two punch that can make me functional, and enable me to do things I want to do and look after my family and do my job. If you can find that combination, it could be really helpful for people.
I don’t recommend it until we have RCTs, and I would prefer people speak to their psychiatrist and a dietician and do this very carefully. We need to understand a lot more about this. For me, that has been what’s really helped, the ketosis, plus exercise, for the depression, especially.
Dominic D’Agostino: Iain, you stumbled upon this dietary therapy, and then without the use of, from my understanding, a registered dietician or clinician, you started doing this yourself. I get so many emails and many reach out to me just looking for resources. You’re working on the Metabolic Mind front through education, advocacy, and research. In addition to being a patient yourself, you’re at the forefront of this.
Did you have an open communication with your doctor? How can healthcare professionals collaborate and ensure this is where people can get help? What do we tell people who may be dealing with this? Where should they go?
Iain Campbell: When I first learned about this, I did it to lose weight. I was experiencing suicidal depressions. I really was aware, at a certain point, that I wasn’t going to survive this condition much longer. I had a wife and a family and I wanted to do lots of things, and I realized this just wasn’t going to happen. I told myself, “I’m at least going to try and be as physically healthy as possible. This is my last go at this.”
I did an Atkins diet. I got the Atkins diet book, and I did a very strict version of it. I realized I needed to be in ketosis. When I saw the weight loss—I lost about 50, 60 pounds—I saw that, at the same time, my psychiatric symptoms were going away, which to me was completely remarkable after trying this.
For me, maintaining ketosis is the only thing that’s ever turned the dial on these severe depressive episodes. I come out of them when I go into ketosis.
The only available resources I had were your podcast appearances and your shows on Bulletproof Radio and all the people telling me about this for physical health. It was really affecting my brain as well. When I was reading your research, I thought, This has to do with epilepsy and neurons and membrane potentials. It really spoke to me as someone who researched bipolar disorder scientifically. I wish I could have done it with support from a psychiatrist who understood metabolic psychiatry and these aspects of it.
I was very much doing it just for my physical health, but was also experiencing these mental health benefits. What I’d love in the future is for people to get this feedback and start this as early as possible and potentially avoid the whole course of the illness. That’s my hope, especially as someone who has kids who are susceptible to bipolar. That would be the best possible outcome. I’m not sure how frequent that is in epilepsy, but I know it does happen.
Dominic D’Agostino: It’s often overwhelming for people and families when parents reach out to me to prepare a ketogenic diet and put their child on it, and in some conditions, they’re averse to the high fat intake.
We universally agree that we need a standardized ketogenic therapy. When you give a person a drug, you want to make sure that drug is standardized. If there’s a clinical response and outcomes are measured, you could say that this particular therapy did this particular outcome. If you have a wide range of studies using a modified Atkins diet, or a clinical diet, or a low-glycemic index diet, it’s important to start with a universal ketogenic diet from there.
There are certain services coming online like Cook Keto, for example. I’m an advisor for them, but they haven’t kicked off yet. They’re looking for funding. That will actually make therapeutic clinical ketogenic diets that just go to your doorstep. It’s like having a drug delivery to your doorstep.
Do you think that’s going to be important, or do you think it’s just education, from the nutritional front along with monitoring, like continuous glucose monitoring, so you can course correct and adjust your diet as you go? Can people do this themselves?
Iain Campbell: I totally agree. We need to have some standardization of the diet with epilepsy, like the Charlie Foundation-type recommendations. Bret’s work at Metabolic Mind is working toward having outreach to patients like the Charlie Foundation has with epilepsy patients. It’s making a huge impact already, and we’re seeing people experience the benefits.
Having meal deliveries would be fantastic. One of the things about going into ketosis is that, like we were saying about exercise, the brain is flooded with metabolites. When you add ketones into the brain, people can become mildly hypomanic during the transition. Chris Palmer talked about this for a long time, as did Georgia Ede.
In our pilot study, we found we could completely manage and avoid this by having a two-week or extended adaptation period where we gradually introduce the diet. It’d be interesting to look at delivery and, like you said, standardization, to see what’s best for people with these mental health conditions and how we can do it the safest way possible, with the expertise of dieticians like Beth Zupec and Helen Grossi. People like this are completely invaluable for the therapeutic use of the diet in epilepsy.
Dominic D’Agostino: Can you talk about the potential for pre-delivered, pre-made, whole-food ketogenic meals and the need for that, particularly in this community or the general population? Is a lack of convenience a barrier to entry for people to implement this? What is the importance of having a standardized ketogenic therapy so we can make sense of the outcome measures?
Iain Campbell: A lot of the barrier to ketogenic diets is people feeling like it might cost more than their normal diet. In our study we saw very high levels of adherence—over 91%, as measured by daily ketone levels. People are willing to do this. When people with bipolar experience the benefits, they are willing to stick with this. Just like in epilepsy, if you prefer the diet over seizures, it’s a very powerful motivator.
There are still times when people fall off or go to a family event and so forth. Having the ability to have pre-prepared meals and pre-delivered meals and snacks and things they could take with them would be really powerful.
It could also be really impactful in low- and middle-income countries where people can’t access psychiatric care. My friend Nomeli lives in Nigeria. She doesn’t have any mental healthcare access of any significant kind. It’s associated with cost and corruption in their government. If you could employ ketogenic diets in low- and middle-income countries, where the vast majority of people with bipolar live and are suffering much more than people in Western countries, this could be a really impactful intervention.
Dominic D’Agostino: People in these countries have no idea about metabolic psychiatry and the potential for dietary therapies to even impact this disorder or other psychiatric disorders, which leads to a lot of the education outreach and advocacy you’re doing.
Tell us about your efforts on the podcast front, creating an educational platform so people have access to this. Much like you finding a podcast on the ketogenic diet, or me talking on The Tim Ferriss Show—that’s maybe the way we need to reach people. Podcasts have been instrumental for Levels to get the message out about metabolic control and CGMs.
Iain Campbell: Absolutely. None of this, and certainly none of my research, would’ve happened without your outreach and letting people know about ketosis. It wasn’t even something on my radar until you started doing the Tim Ferris interviews and the Bulletproof Radio and so forth. I didn’t know it could help me, and I found out about it through physical health. I thought it could help me improve my weight. Then all this came secondary to that.
I want to do that, in my small way, with my own podcast. I do a podcast called Bipolarcast with Matt Baszucki. We bring patients on who want to share their experience. We’ve both shared our own diagnoses and our experiences with keto, and we’ve got about 22 interviews now, with patients and clinicians. We’re trying to make people aware that this is a possibility, because it’s not on the radar for many people at all.
This is made possible by the fellowship the Baszucki Foundation has given me. Their own son had the same experience with bipolar and the ketogenic diet, and they wanted to start outreach. It’s been a wonderful experience, and we’ve started to do fundraisers for people on the podcast. We just got fundraising to do Georgia Ede’s ketogenic training course.
We’re seeing that a lot of the people having this result also want to do their own bit to spread the word—training as dieticians, going back to university to get involved in research, trying to do anything they can. We think, Something is really working for us. That’s not, unfortunately, the normal experience with bipolar disorder. It’s often a long journey of things not working well. People are excited and want to talk about it.
Dominic D’Agostino: In addition to what you’re doing with Bipolarcast, you’re creating an education platform where clinicians could get educational credits to further their education on this front. That’s going to be instrumental. I look forward to talking to Georgia Ede soon about her program and how she’s working to advance it. We’re not going to make inroads until patients can know about it, but they need a network of people who are knowledgeable on implementing these things to have that support.
Iain Campbell: Bret is directing Metabolic Mind to raise awareness about this. He’s one of the first people to really put his name behind this, with all his expertise in ketogenic diet metabolism, and to say, “This is something that could be really helpful.”
You, Dom, are raising awareness about the ketogenic diet, and I just can’t say enough how much it is appreciated by people with mental health conditions. We haven’t had new treatments in over 50 years, really. We’ve had very few new treatments, and those that are given to us have substantial metabolic side effects, where you can put on 20 or 30 pounds, for example. We need adjunct treatments and therapies we can use to manage this and prevent this cardiometabolic risk. Metabolic Mind is reaching out to people through Bret’s work and through Bipolarcast. We’re interviewing patients to talk about what we’re seeing here.
Dominic D’Agostino: The track record for drug treatment is abysmal. From what I’ve seen so far from your data and other emerging data, it’s super encouraging to see this will be ultimately available as a therapy, as a choice, and for people to have those choices.
Big props to Bret for putting his name behind this movement, too, and being at the level that he was. We need more advocates like him, like you, in addition to published research scientists and the rare person who has that interplay between academia and influence with the media. We need that dual ability to really move this, to advance the science application.
Thank you for everything you’re doing, Iain, on the research front, and on the advocacy front. Where can people find you? How can they contribute and how can they learn more about this?
Iain Campbell: I have a Twitter account, @IainCampbellPhD. You can find Bipolarcast on YouTube if you search Bipolarcast or keto bipolar. Metabolicmind.org has lots of information, along with videos by Bret about ketogenic diets for mental health. They’re fantastic and a great resource if you’re looking into this for the first time.
