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A

Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is doctor Chris Palmer. Doctor Chris Palmer is a medical doctor specializing in psychiatry at Harvard Medical School. He is the world expert in the relationship between metabolic disorders and psychiatric disorders. He treats a variety of different conditions, including psychosis, including schizophrenia, as well as attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety disorders, and depression, among others. He is best known for understanding the relationship between how metabolism and these various disorders of the mind interact. And indeed, today he describes not only his own fascinating journey into the field of psychiatry, but also his clinical and research experience using diet, that is, different forms of nutrition in order to treat various psychiatric disorders. He describes some remarkable case studies of individuals and groups of people who have achieved tremendous relief from the types of psychiatric disorders that I just mentioned a few moments ago, as well as new and emerging themes as to how metabolism and the mind interact to control things like obesity. Indeed, he raises the hypothesis that perhaps obesity in many cases is the consequence of a brain dysfunction, as opposed to the consequence of a metabolic dysfunction that then impacts the brain. During today's episode, he shares with us his overriding hypotheses about the critical roles that mitochondrial function and dysfunction play in mental health and mental illness, and how various particular types of diets, ranging from the ketogenic diet to modified ketogenic diet, and even just slight adjustments in carbohydrate intake, can be used in order to change mitochondrial function and bring relief for various psychiatric illnesses. He also highlights the essential and important theme that various diet interventions, including the ketogenic diet, were not first developed for sake of weight loss, but rather were developed as treatments for neurologic conditions such as epilepsy. Today, he shares with us how the foods that we eat alone end in combination, and how fasting, both intermittent fasting and more lengthy fasts, can interact with the way that our brain functions to strongly control the way that we think, feel, and behave. What's wonderful is that Doctor Palmer not only explains the science and his clinical expertise, but also points to various actionable measures that people can take in order to improve their mental health. I'd like to mention that Doctor Palmer is also the author of a terrific new book. The title is Brain Energy, a revolutionary breakthrough in understanding mental health and improving treatment for anxiety, depression, OCD, PTSD and more. I've read the book and it is a terrific read. I came away from this book with a much evolved understanding of how the various psychiatric disorders that I just described, as well as ADHD, emerge in people, and it has completely revised my understanding about the possible origins of various psychiatric disorders and the best ways to treat them, including both with medications but also with nutritional approaches. If you'd like to learn more about Doctor Palmer's work and the book, please go to chris palmermd.com dot. We also provide links to the book and to his website in our show. Note captions before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools for the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium, and potassium, the so called electrolytes, and no sugar. Now, salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios, and we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science backed electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drinkelement. That's lmnt.com huberman to claim a free element sample pack with your purchase. Again, that's drinklimentlmnt.com hubermandhenne Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga, Nidra sessions, and NSDR non sleep deep rest protocols. I started using the waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations, and that had a lot of different types of meditations to place the brain and body into different states, and that he liked it very much. So I gave the waking up app a try, and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions. For those of you who don't know, yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations. And there's excellent scientific data to show that yoga Nidra and something similar to it called non sleep, deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's wakingup.com huberman to access a free 30 day trial. And now for my discussion with doctor Chris Palmer. Chris, Doctor Palmer, thank you for being here.

B

Thank you Andrew, for having me.

A

I have a lot of questions for you, and I'm really excited about this topic because I think most people know what mental illnesses, or they have some idea what that is. Most people have some idea what nutrition is. Fewer people certainly know how closely those things can interact. And I think everybody is familiar with the feeling of a food, or the ingestion of a food making them feel good. In the short term, we eat a food that tastes delicious to us, or that we associate with something nice and we feel good mentally and physically. Whereas when we eat something that gives us food poisoning or maybe even something that just doesn't taste that great, or that we associate with a bad experience, we feel less good in the short term. But I believe that very few people understand or are familiar with the fact that nutrition and our mental health interact in this very intimate, maybe even causal way. And that is something that occurs over long periods of time. Meaning what I ate yesterday, the day before, maybe even ten years ago, could be impacting the way that my brain and body are making me feel now. So if you would, I'd love for you to just tell us about a little bit of the history, in particular your history with exploring the relationship between nutrition and mental health. And then we can dive into some of the more particulars of ketogenic diets versus other diets and some of the truly miraculous findings that you and others are coming up with based on real patients and real experiences of people who suffer and then find relief by altering their nutrition.

B

Sure. You know, this story really starts with my own personal story, and I don't need to go into great detail, but to set the stage, when I was a kid, I definitely had mental illness. Started with OCD. A series of events happened in my family. My mother had a horrible kind of psychotic break and all sorts of adverse childhood events for me. She and I were actually homeless together for a while. I went on to have subsequent depression, suicidality, all sorts of things. But somehow or another, I pulled myself together and got through medical school. Actually did quite well in medical school. Got an award for being one of the top students, and then was doing my internship in residency at Harvard. And at that point in time, I was diagnosed with metabolic syndrome. So had high blood pressure, horrible lipids, and prediabetes, and I was doing everything right, supposedly. I was on a low fat diet, and I was exercising regularly. And year after year, my doctor kept telling me diet and exercise. I kept asking him, what diet, what exercise? I was doing everything he kept telling me to do. Everything was getting worse. My blood pressure kept going higher. And at some point, he kind of said, you're going to have to go on medication. I need to put you on something for your prediabetes, something for your cholesterol, and something for your blood pressure. So three pills out of the gate, and I'm like, I'm only in my twenties.

A

Were you overweight?

B

No. Technically, no. I had a gut, so that's a sign of insulin resistance. I know now, I didn't know it then, but. And he actually kind of leaned in at one point and said, you know, do your parents have diabetes? Yeah. Do your parents have high blood pressure? Yeah. Are your parents overweight? Yeah. Oh, I'm really sorry. It's genetic. Basically, you're screwed. It's your genes. You're just gonna have to bite the bulletin and take meds. And as a physician, I knew what that meant. I knew that I'm in my twenties. If I'm already on three meds for metabolic syndrome, I'm going to be screwed by the time I'm 40 or 50, and I'm probably going to be having heart attacks. And I'd heard through the rumor mill that the Atkins diet could somehow help people improve their cholesterol and pre diabetes. I actually didn't really believe it. I was highly skeptical, and I believed everything I was taught in medical school. Why would my professors lie to me that they knew what they were talking about? Low fat diet was the thing to do, and the Atkins diet was clearly dangerous and reckless. But I had been trying the medical dogma for years, and it wasn't working for me. And so for whatever reason, I decided, this is going to be my last attempt at something different, and then I'll just bite the bullet and go on meds. So I tried the Atkins diet. I did my own special version of it. I still avoided red meat because I was terrified of red meat. And, you know, I tried to do a healthy version, which is probably more like the South beach diet. You know, this was before the South beach diet was invented. But within three months, my metabolic syndrome was completely gone.

A

So blood pressure normalized, lipids normalized. Did your weight change, or you mentioned that you were of healthy weight, but that you had a bit of abdominal fat.

B

So I lost the abdominal fat. I probably lost about ten pounds through this process, but everything got normal. And when I went back to my doctor, he was shocked. He actually said, what the hell are you doing?

A

During the time before you switched to this new diet, how was your mental health, if you don't mind me asking? Because it sounded like you're very clear that there was metabolic syndrome, or you were headed towards more severe metabolic syndrome. You mentioned OCD. I actually am familiar with this. As a kid, I had a low level Tourette's grunt and probably obsessive still, to some extent, although not full blown, clinically diagnosed OCD. So I can relate somewhat, if you're willing. What was the context of all that before and after this nutritional switch?

B

So before the nutritional switch, I was still struggling with low grade depression and OCD. Again, it wasn't necessarily interfering with my ability to function, because I was functioning at a high level. I mean, anybody looking from the outside, you're a top student. You just got into one of the most competitive. Actually, at that point, it was the most competitive residency program in the country for psychiatry. So they would have looked at me and said, you're fine. I wasn't. I was actually on medications. I was trying different medications, trying to figure out how to feel better, how to stop obsessing so much, how to not be so depressed. And I found that those medications, they actually came with more side effects for me than benefits. I was on Prozac for a long time. It totally messed up my sleep. And then the psychiatrist was like, you need pills to help you sleep now. And I'm like, that's not really resonating very well with me. And I'm now a psychiatrist. I'm in my psychiatry residency. And I'm thinking, you know what? That's just not sitting well with me. That you're going to prescribe more and more meds for all the side effects that you're causing. And yet, at the same time, I wanted to feel better, and I was learning chemical imbalances. This is what we do to get rid of depression and OCD. You're supposed to take your pills. So I was taking my pills. I was in psychotherapy. I had been in psychotherapy on and off for years. I had received much more intensive treatment when I was younger, and that was essentially worthless for me. It actually probably just caused harm at the end of the day.

A

Psychoanalysis.

B

Various psychotherapies, not psychoanalysis per se, but some of them were psychoanalytically oriented psychotherapies. I was actually hospitalized at one point, had been put on lithium and imipramine, which is a tricyclic antidepressant, and other things. And they were actually horrible. They were horrible. They did nothing beneficial for me. I gave them a decent amount of time to work. I really wanted to feel better. So at the time that I tried this diet, I certainly wasn't impaired in the same way. I wasn't struggling that much, but I still had these low grade symptoms, was trying to feel better. And the thing that was the most striking to me after doing the diet for three months was not the fact that my metabolic syndrome was gone. That was my goal. And it was a seemingly miraculous achievement because I got rid of everything with one dietary change. But the thing that I noticed was dramatic improvement in my mood, energy, concentration, and sleep. For the first time in my life, I started waking up before my alarm went off and feeling rested. That never happened to me before. I was meticulous about planning when my alarm went off and how many times I could push the snooze button in order to be on time for wherever I needed to be, whether it was school or the hospital or whatever. I had this good system. I was never late for anything. But that was shocking to me, that I felt so good. And, you know, one of the things that I've often said to people, prior to the diet, I always felt like there are two types of people in the world. There are haves and have nots. There are these happy, peppy people who just are so positive, and they've got energy, and they have this saying they like to work hard and play hard. And I always understood working hard. I totally got that because I was a hard worker and I understood the value of hard work, and you got to do something useful with yourself. But I never understood who the hell wants to play hard? Who's got energy for that? Aren't you tired from working so hard? How on earth do these people have energy to go and play hard? And I assumed that they were just part of the haves in the world, and they were just lucky and privileged. They either had good genetics or maybe they had good childhoods or good parents or something. Something that I didn't have.

A

The kids with genuine smiles in the yearbooks.

B

Yes, exactly.

A

Whereas the rest. And by the way, I really appreciate you sharing some of your personal story, because I think it is very important for people to hear and understand that people like yourself, who are extremely high functioning and accomplished, that the road was, from everything I'm hearing and understanding, very choppy internally at times, and that you've overcome a lot in order to get there and also have been going through what sounds like a very long, iterative process of trying to figure out what works and what doesn't work, to finally arrive at a solution and then make that the basis of much of the work that you're doing today for other people. I think it's very important, because I think many people share with you this notion that there are indeed two groups, a happy group and a fated to be unhappy group. And it speaks to the fact that your story rather speaks to the fact that what we see is not always what's going on internally with people. And that this notion of there just being two groups, that the happy or the haves and the have nots, can't be the way that it works. And there are probably many more people suffering than we realize, and that there is an important need for tools to overcome that suffering. So I really just here, even early in our discussion, I just want to extend a genuine thanks, because so much of what I hear from people is, you know, questions about health and mental health and physical health. But that clearly point to the fact that many people are struggling to varying degrees, and even the people who are in this category of great childhood and happiness could do far better for themselves, and then also for other people so thank you for that. I want to know, at the point where you realized that nutrition can play a profound role in how you feel and operate in a large number of domains, you were still a student or a resident at that point?

B

I was a resident at that point.

A

Did you decide that you were going to explore this in a professional context?

B

Not yet.

A

Okay, so what was the journey forward into the work that you're doing now?

B

So the next step was that I just had friends and family who saw me, saw that I had improved my health, saw that I lost some weight pretty easily. In particular, I remember, like, my sister and sister in law, they got really pissed at me one thanksgiving because I could resist all the pumpkin pie and apple pie and everything else. They were like, how the hell are you doing that? How are you resisting all of this food? I said, I don't crave it anymore. I don't want it. I'm fine. I'm just. I'm having turkey and green beans, and that's good enough for me. So I got them to do the diet, and they, too, noticed dramatic improvement in their moods and energy and sleep and everything else. So within a few years, the primary thing I noticed is this powerful antidepressant effect. And now I'm an attending physician. I've got all these patients in my clinical practice with treatment resistant mental illness. I'm in a tertiary care hospital, so I almost never get somebody off the street with their first episode of depression out of the gate. As part of my career, I get treatment resistant mental disorders. So I get people who've already been to six plus psychiatrists, therapists. They've usually tried dozens of different medications. They've been in decades of psychotherapy. They've often had ECT and other things, and nothing's working. And I'm thinking, you know, well, we're kind of out of options for these other people, and this diet is having this really powerful antidepressant effect. I think I'm going to try it and just see if any of my patients are game to try it to see if it might help them. Sure enough, it did. Didn't help everyone, and not everybody was interested and or able to do it, but some of the ones who were able to do it ended up having a remarkable and powerful antidepressant effect. One woman actually became hypomanic within a month, and she had been depressed pretty much nonstop for over five years. Chronically depressed, suicidal, in and out of hospitals. And I saw her become hypomanic. And I'm thinking, wow, this really is a powerful antidepressant effect. Like, this is amazing. This is like a medication, but better, because it actually is working for her. But I laid low at that point because at that point, we didn't have many clinical trials of the safety or efficacy of the Atkins diet for even weight loss or diabetes, let alone any mental disorders. I really actually felt like I'm on the fringe here, and this is not going to be met with praise by anyone. So I'm just going to lay low, I'm going to offer it to patients. And I went along that way up until 2016.

A

And may I just ask about the diet? When you say Atkins diet, so this is low to zero starch, so low carbohydrate diet, certainly low sugar. And was it traditional Atkins? Were you tailoring it to the individual patient, depending on their psychiatric symptoms, whether or not they were overweight or not overweight? I'm assuming you're not a nutritionist, so how did you prescribe a nutrition plan for your patients? And what was involved in making sure that they adhered to that? Maybe even some of the things you observed in terms of who was more willing to try this or not try this, any observations or maybe even data?

B

So early on, I was winging it and I was, you know, the first few patients, it was, try this AtkinS diet, I want to see ketosis. So I was going for ketones.

A

So they were pricking their finger and they were doing a blood ketone test.

B

I didn't know about blood ketone monitors, if they existed back then. So we were using urine strips, which.

A

Are not quite as accurate, but still useful as a general guide, from what I understand. Is that right?

B

Absolutely. And so I was strongly recommending that patients achieve urinary ketosis. And the interesting thing is, I noticed a pattern that when they were trying the diet and not getting ketones, they often did not get a clinical benefit. It was once they got into ketosis that I began to notice the clinical benefit and the powerful antidepressant effect.

A

So probably any nutrition plan, aka diet, that elevated ketones in the urine to the point where you would say, this person is in ketosis, or they would say, I'm in ketosis. That was a step in the right direction, independent of exactly what they were eating or not eating to get there, including fasting. At that time, probably fasting wasn't as popular now, thanks to the incredible work. I think it's incredible. And he is a former colleague, and I know there's a lot of controversy about fasting, but I think for many people, fasting is a powerful tool. For others, it's a less useful tool, but of Sachin, panda and others. But fasting certainly will limit your carbohydrate intake and get you into ketosis. Correct?

B

It will.

A

Did you have any patients fast or do intermittent fasting?

B

I did. I had some patients who did what Atkins had called a fat fast, where they eat primarily fat. So they either fast and or they eat primarily fats to try to get into a state of ketosis. So for some patients, it was actually quite easy to get into ketosis, especially overweight and obese patients. They have a lot of fat stores on their body, and actually limiting carbohydrates usually results in high levels of ketosis for them.

A

And they probably feel better too, I imagine, because when we limit our starch intake, we start to excrete a lot of water. People can get some pretty quick weight loss. That, even though it may not be fat loss, makes them feel literally a little lighter and maybe a little more energetic. Is that right?

B

Absolutely. And as the years went on, the field was advancing. More research was coming out. People were getting a little more sophisticated with blood ketone monitoring, with different versions of ketogenic diets. And I was evolving my practice. The thing that completely upended everything that I knew as a psychiatrist, though, was when I helped the patient in 2016 lose weight. So this was a patient, 33 year old man with schizoaffective disorder. He had been my patient for eight years. Now.

A

Could you clarify for people what schizoaffective disorder is? I'm not a clinician, but as I recall, it's like a low level of schizophrenia. So there might be some auditory hallucinations. If I met this person, I might think they're kind of different, quote unquote weird. But they would not seem necessarily scary to me and typically to other people. And I mean that with respect, of course, but oftentimes people with schizophrenia can seem just like you don't even know how to interact with them because their world seems so altered, because they have all these so called positive symptoms, hallucinations, and they're talking to people that no one else can see, et cetera. Is that schizoaffective?

B

So. No, actually. So schizoaffective is the same as schizophrenia. Essentially. The only difference is it's schizophrenia with superimposed mood episodes.

A

Oh, so it's actually more severe than it can be. Okay, so I have it backwards.

B

So schizoaffective disorder is essentially schizophrenia, and plus some mood episodes, maybe.

A

I'm thinking of schizotypal.

B

Schizotypal is the low grade kind of mild paranoia or kind of eccentric beliefs and other things.

A

Okay, so folks out there, I have my nomenclature backwards. Schizotypal is the quote unquote low level schizophrenia or schizoid like schizoaffective is as.

B

Or full blown schizophrenia plus full blown, usually bipolar symptoms.

A

And now it's absolutely clear who the clinician in the room is. Thank you for that reminder.

B

No worries. So this man had schizoaffective disorder. He had daily auditory hallucinations. He had paranoid delusions. He could not go out in public without being terrified. He was convinced that there were these powerful families, that they had technologies that could control his thoughts. They could broadcast his thoughts to other people. They were trying to hurt him. They had targeted him for some reason. He wasn't quite sure why. He had some suspicions and beliefs about maybe when he did this bad thing when he was eleven years old, that's why they decided to target him. This man was tormented by his illness. Tormented. It ruined his life. He had already tried 17 different medications and none of them stopped his symptoms. But they did cause him to gain a lot of weight.

A

These are the medications, as I recall, for schizophrenia. The classical ones are dopamine receptor blockers. Cause people to huge increases in prolactin. That's why sometimes men will get breast development and they'll put on a lot of weight and they'll be catatonic or movement disorders. They make you feel like, I have to imagine, given how good most things that release dopamine make us feel, that blocking dopamine receptors with antipsychotics makes people feel lousy, horrible.

B

And it's a huge challenge in our field because a lot of patients don't want to take them. And then you get these rebound effects. If patients are on them for several months and then they stop them cold turkey, they can get wildly psychotic and ill end up aggressive or hospitalized or sometimes dead. So that's him. He weighs 340 pounds. And for whatever reason, he gets it in his head, I'm never going to get a girlfriend if I don't lose some weight. He also recognizes I'm never going to get a girlfriend because I'm a loser. I'm schizophrenic, I live with my father, I have nothing going for me. But I could at least try to address one of these awful, horrible things about myself and maybe I could lose some weight. So he asked for my help, for a variety of reasons, we ended up deciding to try the ketogenic diet. Now, at this point, I have no anticipation that the ketogenic diet is going to do anything for his psychiatric symptoms, because this man has schizoaffective disorder. That's not depression. Depression is very different. They're totally different disorders. So he decides to give it a try. Within two weeks, not only does he start losing weight, but I begin to notice this dramatic antidepressant effect. He's making better eye contact, he's smiling more, he's talking a lot more. I'm thinking, like, what's gotten into you? Like, you're coming to life. Like, I've never heard you talk this much. I've never seen you so excited or present or alive. I haven't changed his meds at all. The thing that upended everything that I knew as a psychiatrist was six to eight weeks in. He spontaneously starts reporting, you know those voices that I hear all the time, they're going away. And he says, you know how I always thought that there were all these families who were controlling my thoughts and out to get me and they had targeted me? And I'm thinking, oh, yeah, I. We've been talking about that for eight years. We could talk about that again. He says, you know what? Now that I think about it, I don't think that's true. And now that I say it, it sounds kind of crazy. It probably never was. I've probably had schizophrenia all along, like everybody's been trying to tell me, and I think it's going away. That man went on, he's now lost 160 pounds and kept it off to this day.

A

Wow.

B

He was able to do things he had not been able to do since the time of his diagnosis. He was able to complete a certificate program. He was able to go out in public and not be paranoid. He performed improv in front of a live audience. At one point, he was able to move out of his father's home and live independently. That completely blew my mind as a psychiatrist, and I went on a scientific journey to understand what in the hell just happened.

A

That is indeed mind blowing. I'd like to take a quick break and acknowledge one of our sponsors, athletic greens. Athletic greens, now called ag one, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics in athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, etcetera. And they'll give you a year's supply of vitamin D, three k, two. Again, that's athleticgreens.com huberman to get the five free travel packs and the year's supply of vitamin D, three k, two I have a couple of questions. First of all, did he stay on any kind of antipsychotic or other medication? If so, were the dosages adjusted? Excuse me, while undergoing this remarkable transition, because as we know, it's not an either or medication or nutrition changes. It can be both. And then the other question is one of adherence. I think about someone with schizoaffective disorder who's suffering from all the sorts of things that you described. How does somebody like that organize themselves in order to stay on a ketogenic diet? And I say this with all the seriousness in the world. I think there are a lot of people who do not have schizotypal or schizoaffective disorder who have trouble, they claim, adhering to a ketogenic diet. It's not the easiest diet. Certainly in its extreme form, at first, it's not the easiest diet to stick to. So how did he do it? This sounds like a remarkable individual, and I'd also like to just know your general thoughts about adherence to things. When people are back on their heels mentally, how do they get motivated and stick to something? So the questions were medication, yes or no? If yes, dosage adjusted, yes or no? And if people are suffering from depression or full blown psychotic episodes, how does one ensure that they continue to adhere to a diethouse?

B

So in terms of medications, he has remained on medication. So early on, I wasn't adjusting anything. I was just in disbelief and shocked that this was happening. I didn't know what was going on. Over the years, we have slowly but surely tried to taper him off his meds. He has been on meds for decades. He started medications when he was a young child. His brain has developed in response to all sorts of psychiatric medications, and it has not been easy to try to get him off. So we are. We continue to try to get him off medication, and it's challenging and difficult. And I just want to say for any listeners, it is. Getting off your meds is very difficult and dangerous, and you need to do it with supervision, with a mental health professional or a prescriber, because it is dangerous. When people reduce their meds too much, they can get wildly symptomatic.

A

Is that true for depression as well?

B

It's true for any psychiatric medication. The brain makes adaptations in response to psychiatric medications. And when you stop them cold turkey, some people are fine, but I wouldn't recommend finding out because I've seen patients when they stop antidepressants, I've seen patients get floridly depressed and suicidal within three months. I had one patient almost quit her job because she became convinced that, well, my life sucks and it's all because of my boss. And I know that she's just a horrible human being and she's abusing me. And I was like, whoa, whoa, whoa. I think this is related to your medication change. We got her back on her meds within three days. She said, oh, my God, I can't believe that happened. Like, I almost quit my job. And that would have been the most illogical and irrational decision I've ever made in my entire life. But somehow it seemed so real just several days ago and now that I'm back on this medication, and it doesn't mean that she needs the meds, but it doesn't mean that he needs the meds. It means that meds need to be adjusted very safely and cautiously and gradually. So that's the medication piece. The adherence piece was not easy for him and for other patients. It is very rare that I have a patient who I can say, do the ketogenic diet, come see me in three months and let me know how it's going. That almost never happens. It has happened, I think, on two.

A

Occasions, but that is, if I understand correctly, what perhaps not you, but many psychiatrists do with medication. It's. Here's your prescription. Let's talk in a month or three months.

B

Yes.

A

So that's a variable that it's probably worth us exploring a little bit here as the conversation continues.

B

Absolutely.

A

You know that frequent contact and making micro adjustments or macro adjustments to medication or nutrition could be meaningful.

B

Absolutely. So with this particular patient early on, he was actually pretty adherent. I was seeing him once a week, and so I could do a lot of education. I was weighing him, I was checking his ketones, I was checking his glucose levels. At that point, I had a blood ketone monitor in my office, so I knew whether he was compliant or not, which is so beneficial in doing clinical work and research on this diet. It's the only diet where within seconds I can have an objective biomarker of compliance or noncompliance.

A

Such a key point, and again, brings to mind for me the parallel with medication. I mean, a patient can say they're taking their medication, and unless they're in a hospital setting where somebody's checking under their tongue and all of this, they very well could not be taking it or taking more. And you and I both know that blood draws for neurotransmitter levels are complicated because you want to know what's in the brain and what's functional in the brain. And I have to imagine that most people there prescribed drugs for any number of different psychiatric conditions, are not giving blood every time they talk to their psychiatrist or psychologist.

B

No, no. And when we looked at, on that front, when we've looked at studies of compliance, the majority of patients are at least somewhat non compliant with prescription medications. It's not on purpose. They forgot. They take it at night. They were out late, they were off their routine. They forgot to brush their teeth because that's when they take their meds. And so because they, you know, it was so late, they just crashed when they got home, they forgot to take their meds. Happens all the time. If it's a medication that people take more than once a day, the noncompliance rates are much higher because it's just easy to forget. So it's not that people are willfully, you know, disobeying their doctors or anything else. It's just hard to remember to take meds consistently every day.

A

When you say measuring ketones, I want to drill into this a little bit because it does seem that the presence of ketones and somebody being, quote unquote in ketosis turns out to be the key variable. Certainly in your book, that's one of the major takeaways, although there were many important takeaways that people get into ketosis, do they have to stay in ketosis? So, for instance, I've followed the, I don't any longer, but I've tried in the past the so called cyclic ketogenic diet, where every third or fourth day, get some pasta or rice, et cetera. And that was interesting as an experiment. But to stay in ketosis, what sort of blood levels of ketones do you like to see in your patients? What is the range that you think most people could aspire to?

B

So, it really depends on the patient and what I'm treating, quite honestly, and I don't think every patient needs the ketogenic diet. For some patients, simply getting rid of junk food can make a huge difference in a mood disorder, for instance.

A

So a junk food, meaning highly processed food, food that could last on the shelf a very long time, highly processed.

B

Foods that are usually high in both sugar, carbohydrate, and carbs and fats, those seem to be the worst foods. That combination, high sugar, high fat, seems to be the worst combination for metabolic health. And lo and behold, we've got emerging data that suggests that strongly suggests it's also bad for mental health. Depression and anxiety are the most common mental disorders, and so we have the best data for those disorders. But we actually have a lot of data with even bipolar disorder and schizophrenia, that insulin resistance in particular, and insulin signaling in the brain, is impaired in people with chronic mental disorders, kind of across the board, all the way from chronic anxiety, depression, to bipolar, to schizophrenia and even Alzheimer's disease. We know that patients with all of those disorders have impaired glucose metabolism and that the insulin signaling system in the brain, which is different than insulin signaling in the periphery, seems to somehow, possibly be playing a role. So to step back from that. So for some patients, I might just want to decrease glucose and insulin levels, and I can do that by getting rid of sweets for other patients, like patients with schizoaffective disorder, or schizophrenia or bipolar disorder, especially if it's chronic. If I'm using it as a brain treatment, then I do want a ketogenic diet. And I usually want reasonably high levels of blood ketones. Usually for depression, I want to see at least greater than probably 0.8 millimole. For psychotic disorders and bipolar disorder, I usually want to see levels greater than 1.5. That's what I'm shooting for, if at all possible. And so, yeah, I think that's what I'd go for.

A

Yeah. And sorry, I didn't mean to imply that people need to be in ketosis in order to see some mental health benefits from changing their diet. You make very clear in your book, and we'll go into this in more detail, that avoiding insulin resistance reversing insulin resistance and essentially trying to reverse what earlier you described as this metabolic syndrome, which is a bunch of different things, is the target. And for some people, getting rid of highly processed foods and focusing mainly on non processed or minimally processed foods will really help. For others, going straight to the full blown ketogenic diet will be of most benefit. I'd like to back up a little bit in history and get to something which I find incredibly interesting, which is epilepsy and the longstanding use of ketogenic diet and fasting to treat epilepsy. And the reason I want to rewind to that point in history is that I think that for a lot of listeners and people out there who are familiar with how changing your diet or changing your exercise can positively impact sleep and weight and all these things, and it cascades into feeling better, that makes perfect sense. But for a lot of the world, still, the idea that changing or using nutrition as a dissection tool or as a treatment tool to understand and treat mental illness is still a kind of heretical idea that to them, it kind of falls in the, okay, well, that's like a woo science or something like that. Now, obviously, you're board certified physician and psychiatrist at arguably one of the finest medical schools in the world, Harvard medical School. Even though I'm in the Stanford side, we acknowledge our east coast.

B

You're the Harvard of the west.

A

We're not going to talk.

B

We're the Stanford of the east coast.

A

That argument could go back and forth a number of times, but, you know, this is, you're a serious clinician and a serious scientist, and you're a serious thinker. But for a lot of people out there, the notion of using diet, they immediately think, ah, well, that makes perfect sense. Or I think there's a category of people who think, well, yeah, didn't atkins die of a heart attack? You know, I hear that a lot. You know, so, like, that was crazy. You know, like, people immediately discard the Atkins diet for that reason, which I do think is throwing the baby out with the bathwater. But it's an interesting thing nonetheless. And then I think that the majority of people sit in the middle and just want to see science and medicine come up with treatments that work. And I have to say, I'm very relieved to hear what you said earlier, which was, you never said that people should come off their medication and just become, go on a ketogenic diet and everything will be cured. You're certainly not saying that.

B

No.

A

And rather, you're saying, if I understand correctly that nutrition needs to be considered one of the major tools in the landscape of effective tools, and that it can be very effective, evidenced by the story that you shared, and there are many other stories in there as well, of truly miraculous transformations. So let's talk about epilepsy and how the ketogenic diet is not just used for epilepsy, epilepsy, but is one of the oldest, if not the oldest, examples of the use of nutrition to treat a condition of the nervous system that can be incredibly debilitating, even deadly.

B

Yeah. And the reality is that this literature and this clinical history and all of the research we have was the godsend that I needed to do the work that I'm doing. Otherwise, I would have been discredited on day one. Chris Palmer's claiming that a dietary change can influence schizophrenia or schizoaffective disorder. That's impossible, and he's a quack. But the thing that immediately got me credibility was I didn't focus on it as a diet. I did a deep dive into the epilepsy literature. So the ketogenic diet, unbeknownst to most people, was actually developed 100 years ago, 1921, by a physician for one and only one purpose, to treat epilepsy. It wasn't developed as a weight loss diet. It wasn't developed as the diet that all human beings should follow. And the reason it was developed is because of this long standing observation, since the time of hippocrates, that fasting can stop seizures. Now, fasting is not a healthy diet. Fasting is the process of no diet. So we now understand a tremendous amount of science. Most people think going without food is bad, and they equate it with starvation. But, in fact, when we go without food, it causes tremendous shifts in metabolism, both brain and body metabolism. And it puts the body into a mode of autophagy and conservation of resources and all sorts of things that are beneficial to human health. And this is why fasting has been used as a therapeutic intervention in almost every culture and almost every religion for millennia. But for the most part, that was all thought to be religious folklore. That was just crazy talk. And those stupid people way back then thought God cured everything, and so they fasted, and they just assumed that they were getting better. Well, in 1921, one physician used intermittent fasting on a child with seizures and found that, oh, lo and behold, this religious folklore stuff has something to it. It actually worked. The problem with fasting is that you can only fast for so long before you starve to death. And that's not a very effective treatment.

A

And this child was ingesting water? Correct. It was just food elimination.

B

Fast food elimination. So no special diet. But the problem with fasting for epilepsy is that as soon as people start eating a normal diet again, their seizures usually come right back, oftentimes with a vengeance. And so it can be a good short term intervention. The fasting can take a few days, because it can take a few days to get ketosis, and then you can get some relief from chronic seizures. But it's not a good long term treatment, because, again, people will starve to death as soon as they start eating, seizures come back. So it was actually Doctor Russell Wilder at the Mayo Clinic who developed the ketogenic diet with one and only one purpose. He wanted to see, can we mimic the fasting state using this special diet to see if it might stop seizures long term? And lo and behold, it worked. Early results were extraordinarily positive. 50% of patients who used the ketogenic diet became seizure free, and another 35% had a 50% or greater reduction in their seizure frequency. So about 85% efficacy rate.

A

Sorry to interrupt. I didn't mean to do that there. Was it just for pediatric epilepsy or for adult epilepsy as well?

B

So, back in the 1920s, we didn't have many anti epilepsy treatments, and a lot of adults were struggling as well, so they were using it on anybody who would do the diet. By the 1950s, pharmaceuticals were coming out, and we had many more anticonvulsant treatments. And there's no question they work for a lot of people. That's great. And taking a pill is so much easier than doing this diet. So the diet pretty much fell out of favor, and nobody was using it from the 1950s to about the seventies. But lo and behold, even to this day, people with epilepsy, about 30%, don't respond to the current treatments that we have available. 30% will have treatment resistant epilepsy, which means they continue to have seizures no matter how many anticonvulsants they're taking, even if they've had brain surgery. It just doesn't stop their seizures. And so, in the 1970s, the ketogenic diet was resurrected at Johns Hopkins for these treatment resistant cases. And lo and behold, it works. Not for all of them, but it works. And about one third become seizure free. And these are people who've tried everything, and nothing's working. So one third becomes seizure free, another third get a clinical benefit, meaning a 50% or greater reduction in their seizure frequency. And the other third, it doesn't seem to work. It's not always clear if that's because of non compliance or if that's because the diet's just not working. But about a third, a third, a third seizure freedom, reduction in seizures, or it just doesn't work. And so the reality, the godsend for me is that we have decades of neuroscience research, the ketogenic diet and what it is doing to the brain. We know that the ketogenic diet is influencing neurotransmitter levels, in particular, glutamate, gaba, adenosine. It changes calcium channel regulation and calcium levels, which is really important in the function of cells. It changes gene expression. It reduces brain inflammation. It changes the gut microbiome, and there are. Gut microbiome is a huge topic right now, and there are some researchers who argue that is the primary benefit of the ketogenic diet. It's changing the gut microbiome in beneficial ways. So it's doing a lot of things. It obviously improves insulin resistance, lowers glucose levels, lowers insulin levels, which improves insulin signaling. The key for my research that I've outlined, the real magic is that this diet stimulates two processes that relate to mitochondria. It stimulates a process called mitophagy, which is getting rid of old and defective mitochondria and replacing them with new ones. And it also stimulates a process called mitochondrial biogenesis, which means that after people have done the ketogenic diethyde for a while, months or years, many of their cells in their bodies and brains will have more mitochondria. And those mitochondria will be healthier. And I believe that is the reason the ketogenic diet is such a powerful treatment, not only for epilepsy, but also for people with chronic mental disorders.

A

Would you mind listing off a few of the mental disorders? And I know this is not meant to be inside ball, but we should distinguish between psychiatric disorders and neurological symptoms and diseases. The fields of psychiatry and neurology hopefully someday will just emerge. But, for instance, typically, if somebody is presenting with something that looks like Alzheimer's dementia, they'll talk to a neurologist, whereas if somebody is presenting with symptoms like schizophrenia, bipolar, they'll talk to a psychiatrist. But if you wouldn't mind wearing a dual hat, could you just quickly list off some of the neurologic and psychiatric disorders for which ketogenic, or let's just say nutrition changes, have been shown to improve symptoms significantly? And then maybe we can dive into a couple of these, as well as get more deeply into these two very interesting aspects of mitochondrial function and repair and turnover.

B

Yeah. So the field, in terms of nutritional psychiatry, it's a broad field, and it's in its infancy, is the real answer. If you're looking for randomized controlled trials documenting efficacy in large numbers of patients with these disorders. We don't have them. They're underway now, but we don't have them yet. What we do have are case studies. We have a lot of mechanistic science papers by some of the leading neuroscientists and psychiatrists in the world, and neurologists in the world, kind of outlining. This is everything we know that the ketogenic diet is doing. These are the problems in the brains of people with these chronic mental or neurological disorders. So we know that they should work. But the disorders range from chronic depression to. We've got a trial underway for PTSD. We've got one actually decent pilot trial from the National Institutes of Health for the ketogenic diet for alcohol use disorder, of all things. And we can go into that a little more. We've got a couple of pilot trials of the ketogenic diet for Alzheimer's disease disease. We've got. And those are randomized controlled trials. We've got case studies of the ketogenic diet for chronic depression, bipolar disorder, and schizophrenia. The largest study that we've got in that mental health sphere is a pilot study of 31 patients admitted to a french hospital. 28 of those patients were able to do the diet and stay on the diet. So 10%, off the bat, non compliant, couldn't do the diet. So we need to include that. But of the 28 patients who were able to do, and these were 28 patients with treatment resistant mental disorders, chronic depression, bipolar, and schizophrenia. Of the patients who were able to do the ketogenic diet, 100% had at least some improvement in symptoms. 46% had remission of illness. Remission of illness that does not happen with current treatments, and 64%, I think, were discharged on less medicine than they went into the hospital on. So it wasn't that the people were prescribing more medicine, and that's why they were being discharged on less medication. We've got, at least, again, the hardcore scientists are gonna say, show us the randomized controlled trials with hundreds of patients, and we've got five randomized controlled trials underway, now funded primarily through philanthropy. I can tell you that we've talked about that one index patient, but at this point, I have now treated dozens of patients, and I've heard from hundreds of patients who've been treated by other clinicians, researchers, or I've just heard from patients from around the world who have shared stories of complete remission of long, chronic mental disorders like bipolar disorder and schizophrenia off of psychiatric meds. Some of them, not all of them, but some of them are able to get off all psychiatric meds and remain in remission again, I think I didn't say this before, but it's really important to mention for people who might be unfamiliar with the mental health field and its connection with epilepsy, the reason that it's such an important connection is that we use epilepsy treatments in psychiatric patients every day in tens of millions of people. So a lot of people don't know this, but I'll list off some names that a lot of your listeners may have heard of, and they probably know them as psychiatric drugs, but in fact, these are epilepsy drugs. Depakote, Tegretol, Lamictal, Topamax, neurontin, or gabapentin, Valium, Klonopin, Xanax. Those are all medications that stop seizures. And many of them were developed initially for seizures, but we in the mental health field quickly steal them and start using them in tens of millions of people, even if they're off label. So that means we don't have research studies documenting that they're effective, but we go ahead and use them anyway, because the reality is far too many patients aren't getting better with the FDA approved treatments that we do have to offer. So psychiatrists are just winging it in some cases, and we're just throwing whatever we can at them. And we absolutely include epilepsy treatments. So, in many ways, using the ketogenic diet as a treatment for serious mental disorders is nothing new at all. It's an established, evidence based treatment for epilepsy. We use evidence based treatments for epilepsy across the board for a wide range of mental disorders. And so, in many ways, that's all I'm doing with a ketogenic diet. It just happens to be a diethouse.

A

I love it. I love it. And I should say I love it, because we had a guest on here early days of the podcast. He's a colleague of mine at Stanford. He's a bioengineer and a psychiatrist, phenomenal scientist and psychiatrist Carl Diceroth, who won the Lasker prize and so on and so forth. And he made a really important point, which should have been obvious to me, but wasn't until he said it, which was the psychiatrist has tools, just like the surgeon has tools, but the tools are language and observing behavior. Those are the dissection tools for what's going on in someone's brain. And then, as a neuroscientist, I'm familiar with the neurotransmitters and neuromodulators. And you mentioned that there are these tools of altering brain chemistry, which are of the sorts of drugs you just listed off, or antidepressants or antipsychotics that fall into these major bins of adjusting dopamine or adjusting serotonin or some combination of dopamine, serotonin, epinephrine, adenosine, and on and on and on. And it seems to me it's an incredible field, but that the field is still very much in its infancy, that it wasn't but 100 years ago that people were measuring bumps on the head as a way to diagnose phrenology, that there's still so much to learn. And so when I hear you say adjusting nutrition or putting people into a ketogenic state, or even just eliminating highly processed foods, sugars, et cetera, taking care of metabolic syndrome, and then observing tremendous relief in clinical syndromes or symptoms, rather, of psychiatric disorders, it makes perfect sense to me. It's yet another dissection tool and a tool for altering brain chemistry. I think that if I think about the landscape, the sort of sociology out there of, again, there seem to be these bins, like a third of people saying, of course, diet and exercise and social connection and limiting stress, that's the good stuff. That's the stuff that we know really works. And then about a third of people are sort of unclear, and then a third of people think, well, if it's not a prescription drug, then it just has no place in medicine. And hopefully that's changing. And certainly the work that you're doing is going to be important in that transition that I think we will see. I'd like to talk about mitophagy and mitochondrial biogenesis. I think most people learn that the mitochondria are the energy factories of cells, and that indeed they are. As a neuroscientist, what I know about them is that they are present everywhere in neurons, not just in the so called cell body, but you can find mitochondria in the furthest little bits of neurons. And neurons can be quite big, very large, in fact, meters long or more in some cases, in some species, including us, depending on how tall somebody is, it could be many meters, or several meters, rather. And that mitochondria do a lot of stuff besides just produce energy, because I think people hear mitochondria energy, and they think, oh, so these patients felt better, they lost weight, they have more energy, and then they're doing better. Here we're talking about remission of auditory hallucinations, people feeling suicidal, and then changing their diet and feeling like life is something they can deal with and maybe even function extremely well, and et cetera. So maybe we could just talk about mitochondria for a moment and then talk about these two major effects. What are some of the other things that mitochondria are important for in neurons and maybe other cells of the brain? Because as an access point for all this, I think it would be great if people could learn a little mitochondrial biology.

B

Yeah, no. So I guess the first thing that I'll say is that this field is one of the most cutting edge fields in medicine right now. 20 years ago or so, I think the majority of research scientists thought of mitochondria as nothing more than little batteries. They take food and oxygen and turn it into ATP. And that's really important. Yeah, we get that. But they're just little batteries. That's all they are. And so one of the reasons that this work is so important is because it combines cutting edge research in the metabolic field and the aging field, and we can start to pair it with the mental health and neurological health field. So mitochondria, you know, one scientist gave me this analogy. He said, if you think of the cell as a computer, a lot of people think of mitochondria as the power cord to that computer, because they're providing the power, and they are, in fact, the power cord to that computer. But actually, their real function is the motherboard of that computer. So mitochondria are directing and allocating resources throughout a cell. That is their primary function. And then they happen to be powerhouses as well. And so to give some clear examples, mitochondria play a direct role in the production and release and regulation of some really key neurotransmitters, including serotonin, dopamine, glutamate, acetylcholine. Those are pretty powerful neurotransmitters.

A

Yeah, I would call those. I would consider those. I know you listed more than three, but the primary colors of neurotransmission, any one of those in excess or deficiency is going to have profound negative effects on a nervous system, or it's going to alter the way that people and animals feel, think, move, remember, et cetera.

B

And so, as part. So mitochondria are providing both some of the building blocks, if you will, for some of those molecules, they're part of the Krebs citric acid cycle. Some of the intermediate products actually go into making those neurotransmitters. Much more importantly, mitochondria provide the energy for the production of those neurotransmitters. And fascinatingly, mitochondria are directly related to the release of neurotransmitters. ATP alone is not enough. There have been some research studies that have actually found that mitochondria move along the membrane of the synapse to release batches of vesicles of neurotransmitters. And that if the mitochondria are removed from the synapse and researchers flood that cell with ATP, neurotransmitters usually are not getting released. Mitochondria are doing other things. We don't entirely even understand what all they're doing or how they're doing it, but they're doing other things than just providing the power. Another really important example is that mitochondria are actually the primary regulators of epigenetics, if you look at any one factor. So one study actually found that they're responsible for the expression of about 60% of the genes in a cell. And so, and mitochondria do this through a lot of ways that have been known for years and sometimes decades. So, mitochondria are directly related to the levels of reactive of oxygen species in a cell. They are managing calcium regulation in cells. And we know that those things play a role in epigenetic expression. We know the levels of ATP to ADP or AMP also play a role and mitochondria are doing those things. But it turns out mitochondria are actually doing much more sophisticated things than even those in terms of gene expression. Mitochondria at least play a role in all of the aspects of the human stress response. So when humans are stressed, either physically or psychologically, there are several things that happen. Increased cortisol, increased adrenaline, noradrenaline, inflammation and gene expression in particular in the hippocampus, occur with the stress response. And one group of researchers actually genetically modified mitochondria in four different ways and found that all of the stress response, all those four buckets of stress response were impacted in one way or another, implying that mitochondria are somehow playing a role in those, in terms of their role in cortisol. We know that mitochondria actually have the enzyme required for the synthesis of steroid hormones that includes cortisol, estrogen, testosterone and progesterone. Some names that maybe everybody's heard of. That means that if mitochondria are in short supply or dysfunctional, the production of those hormones may become dysregulated. Mitochondria play a direct role in inflammation, and they turn the inflammatory system both on, or they at least play a role in turning the inflammatory system both on and off. I think I'm not gonna be able to quote the exact study and author, but one paper in cell actually identified mitochondria as the key regulator in turning certain inflammatory cells off, and that when you inhibit mitochondrial function, those cells don't turn off that mitochondrial levels of reactive oxygen species are a key signaling process to turn the inflammatory process off. Another study found that macrophages. So macrophages are an important immune cell that play a role in healing. So if you cut yourself, your body will get send inflammation that way and send immune cells that way to try to heal your skin. And macrophages play an important role in that healing. One group of researchers tried to figure out, how do macrophages know to switch between the different phases of wound healing? Because the macrophages do different things in the different phases of wound healing. And the conclusion of all of their research was that it's mitochondria. Mitochondria are sending the essential signals that change the state of the macrophages to induce these different phases of wound healing. So I've just talked about neurotransmitters, hormones, epigenetic expression, inflammation. For anybody familiar with the mental health field, they know these are like some of the key variables that researchers have been struggling with for decades, trying to figure out how do these fit together? We know that all of those buckets can be disrupted in people with mental disorders. And our field has struggled to understand, but how do they fit together? How can we make sense of this disruption? And I believe once you understand the science of mitochondria, you can actually connect all of the dots of the mental illness puzzle.

A

Super interesting little sub cellular goodies these mitochondria are. I come from a field where people are often divided into lumpers and splitters, and I'm somewhere in between. For those of you who don't know, lumpers are people that like to make things really simple. Lists of no more than three functions, or dividing brain areas into no more than three splitters of people that like to subdivide into a ton of detail. There's a history of scientists being splitters in order to be able to name things after themselves, because there's more territory to go around. If you're splitting than if you're lumping. But we are doing neither here. What I'm hearing is that mitochondria, in addition to being important sources of energy production and output in cells, which of course they are, probably have other roles, and that maybe someday what we call mitochondria, will actually be two or three different little sub cellular organelles. There may be little bits in there that are controlling gene expression and little bits in there that are controlling neurotransmitter production, at least for now. The name is mitochondria. And thank you, by the way, for illustrating some of the other things that they do. Because in the landscape of science education, oftentimes people think, okay, energy production, there'll be a picture or a cartoon of mitochondria, like flexing its muscles. People go, okay, energy mitochondria, mighty mitochondria. And then they'll think, oh, you know, they're just sort of like a dumb jock portion of the cell, right? They're not doing anything sophisticated. And everything you listed off is that they are doing many sophisticated, intricate things within cells. So I think how things are cartooned and discussed actually has an impact, and not just on the general public, but on the medical field and on the science fields. Anyway, that's more science sociology. But now that everyone is well aware that mitochondria are doing a large number of very important things in a very regulated way, let's talk about mitophagy a few years ago, because a Nobel prize was given for autophagy, sometimes called autophagy. Look, people, you can say it either way. People know, hopefully what it means is more important, which is the gobbling up of one's own cells that are dead or injured. This idea of autophagy, of cells being eaten up or within a system, nervous system or other system, has come up again and again. I actually wasn't aware that mitophagy could be such an important lever. So tell us about mitophagy, which I have to presume is the intentional or not gobbling up of mitochondria, presumably to replace them with newer, healthier mitochondria. Is that right?

B

It is. So, in many ways, mitophagy is a subset of autophagy, but it's got its own name because it is specific to mitochondria. There do appear to be some unique regulators of mitophagy compared to autophagy. More broadly, mitochondria actually are playing a role in autophagy itself. And this makes sense because the global picture of autophagy is stimulated by fasting states, or fasting mimicking states. So when your body senses that you don't have enough food, it actually hunkers down and starts to recycle dead old parts in this kind of carefully orchestrated way. And it takes them to lysosomes, they get degraded, and then those degradation products get used for either energy or to build new things. Autophagy is always occurring at a low level, but you can really hyper stimulate the process through fasting, calorie restriction, fasting mimicking diets, other things. And this is why fasting and fast, you know, calorie restriction is so kind of such hot topics in the medical field now is because we, they've been shown to induce longevity. And we think it's probably through that process that you're stimulating the body to kind of become lean and conservative in terms of its allocation of resources. And the body doesn't just destroy the healthiest tissue along with the old dead stuff. It has these processes that identify the old and defective parts first and they go first. And that's what's to beautiful about the whole thing. And that's why fasting is so important. So, mitophagy, we know, plays a really important role because. So there's this term called mitochondrial dysfunction, which some researchers are actually wanting to get rid of and move away from, because, as you just said, mitochondria do so many different things. And different mitochondria, even within the same cell, may very well be specializing in different tasks. And mitochondria, from one cell to another, are sometimes doing very different things. Like, not all mitochondria can produce cortisol. That's specific to specific cells where those genes are getting turned on. So it's not like all mitochondria are producing cortisol, just the ones in your adrenal gland, for instance, are producing cortisol. But there is this term, mitochondrial dysfunction. And it has long been known for decades that mitochondrial dysfunction is associated with everything that ails us, essentially. So in the 1950s, we had a theory of aging that was based on reactive oxygen species, and that essentially, and that's where all the inflammation is bad.

A

For you, comes from all the noise about antioxidants. Like in the nineties, I was like, it contains antioxidants. Not to say antioxidants are bad, but they are certainly not the be all, end all of health.

B

They are not. But that's exactly where that research came from, is that researchers were narrowing in on these reactive oxygen species are highly, highly correlated with all of the diseases of aging and poor health outcomes. Turns out they're also highly, highly correlated with all chronic mental disorders. Interestingly, and so researchers used antioxidants to see if, well, maybe if we can stop, somehow tame these reactive oxygen species, we'll improve health outcomes. Doesn't seem to work. By the 1970s, our understanding of mitochondria and their role in the production of reactive oxygen species expanded, and that led to the mitochondrial theory of aging. So, in the 1970s, we had this mitochondrial theory of aging based primarily and exclusively on reactive oxygen species. Fast forward a couple of decades, that was disproven because we now know reactive oxygen species aren't all bad. They actually serve a signaling process. They're a normal part of human functioning and cellular function. So they're not all bad, but we still know high levels of reactive oxygen species are bad for you. Fast forward to just, I think maybe last year, with this expanded role of all of the different things mitochondria are doing. So David Sinclair published a paper in one of the cell journals, I think, saying that, oh, mitochondria are actually the unifying link of everything that we know about aging. Mitochondria are the cause or defective mitochondria, or defective mitochondrial function. Mitochondrial dysfunction is possibly the unifying cause of aging and all of the aging related disorders. So mitophagy is trying to address all that is trying to say, okay, this is bad, we don't want defective mitochondria, and how can we get rid of old ones or defective ones and replace them with new ones? And I think the most powerful signal and tool that we have right now is, in fact, related to diet. It's calorie restriction that is the oldest, truest, kind of best proven way to prevent aging in a wide variety of animal species, fasting and intermittent fasting. And again, you can only do those things for so long, and then fasting. Mimicking diets can also stimulate this process of mitophagy.

A

Before we talk about mitochondrial biogenesis, and I certainly accept the idea that mitochondria are extremely important in physical health and mental health. That's, for me, is a straightforward conclusion at this point, based on what you've said, what I've read elsewhere, et cetera. And if various diets, including ketogenic diet, including fasting, reducing sugar intake, etcetera, can assist in mitochondrial function and mitophagy, and that's at least one of the levers by which diet can positively impact mental health and physical health, can we conclude that there's something special about low blood glucose in the brain, right? I mean, the sort of common pathway of all of those things, fasting ketogenesis for some people, maybe they. Maybe some people manage, have great insulin management. So just removing sweets, refined sugars, brings down their blood glucose level substantially. They don't need to go on a ketogenic diet in order to relieve a low level depression or something like that. Seems like the common theme here is that glucose levels in the brain need to be reduced, which for me is surprising because neurons love glucose. I mean, there are some really nice studies, one that I can think of recently that was published in neuron. If you just look at the tuning of a neuron, how well a neuron in the brain represents some visual image in the environment. In terms of here, we can just generalize in saying more action potentials, more electrical signals from the neuron, generally correlates with better high fidelity representation. It's like sort of, you know, if everyone's time, someone says, shout, and then someone shouts, the neuron is like the one responding to the order. And these neurons, just when there's high glucose, they are faithful representatives of what's out there in the world. But then when you fast an animal, they become less faithful representatives of what's out there. And yet, when I've done intermittent fasting and I do a kind of modified version of it, my mental clarity is far better than when I've had a big bowl of pasta, probably for other reasons related to serotonin and tryptophan. And so I think for the typical listener out there, I have to imagine it's got to be a little confusing, right? We hear neurons love glucose, they live on glucose. And here we're saying, let's deprive them of some glucose, or let's just bring glucose levels down, or let's switch the fuel source of the brain from glucose to ketones. And now the brain really works the way it's supposed to. So this raises a little bit of a just so story question. Like, why would it be the case that neurons love glucose, and yet if there's too much glucose around, they become sick? And of course, with any. Why would it be story? As I always say, I wasn't consulted at the design phase, and I'm going to presume that you weren't consulted the design phase either. And that if any of us say that we are, then we are probably the patients that need evaluation. So, um, I think there's a name for that, right? There's delusion. Right? Okay. Got my first correct clinical assessment of myself. So, um, how do I get my head around this? Right, you've got me sold on mitochondria. Not that I needed to be sold, but that's an easy, like, yes, yes, absolutely. Yes. The idea that diet can impact mental health and physical health. Yes, absolutely. By way of mitochondria, at least in part. Great. But then, neurons love glucose. So what's going on? Or what do you think is going on?

B

I am not convinced that glucose is the real story. Glucose may, in fact, be a symptom. So we know that. We know that parts of the brain. There have been a couple of studies that just came out in the last couple of weeks, I think, documenting that, actually, astrocytes in the hypothalamus play a key role in glucose regulation throughout the body, and it appears to be a metabolic role, which, in my mind, implies that the mitochondria in those astrocytes are probably playing a key role, because we know mitochondria play a key role in sensing glucose levels. They play a key role in the release of insulin from the pancreas. But mitochondria in the brain is also playing a role in kind of balancing how much glucose is around. And so it's a difficult question, because I think, in some cases, high glucose levels are actually a symptom of metabolic dysfunction somewhere in the body or brain. And when I think about, well, what does that mean? In my mind? Most of the evidence currently is pointing to mitochondrial dysfunction somewhere in the body or brain that is the most likely cause of that dysregulation of glucose levels. But we know that if you consume massive amounts of junk food, sugar, and other things, that you can get dysregulation of glucose levels. The conundrum, though, is that that's not a universal response.

A

And what about the typical person? Like, I've never really liked junk food that much. Maybe as a kid, I can recall liking candy, but I was a sandwich for lunch person for a long time. And as I've changed that out for salad and, uh, maybe a small piece of meat with my salad or something like that, I feel far better during the day, far more alert. But I do eat carbohydrates. I eat starches, typically at night, but I tend to do some very hard training at some point during the day. So I imagine I have some glycogen to repack. Okay, that's me. I only mention that because I'm not in ketosis. As far as I know, I haven't. Unless you brought the strips. I haven't uh, done the blood glucose test today. So what about the typical person who's an omnivore, eating some rice, some pasta, pasta salads, people that are eating, not junk food, massive amounts of sugar, but have blood glucose that's in kind of moderate range, do you think. And here, feel free to speculate. Do you think that those people might feel far better or even a little bit better if they were in a lower glucose state? And I asked this because I think there are a lot of people out there who suffer from full blown depression, but there are also a lot of people who suffer from moodiness and feeling not so great.

B

Subclinical depression burnout is what I would call it.

A

Yeah. And just feeling like some days are great, and then other days they feel lousy for reasons they don't understand, and those make for less dramatic case studies. And yet I have to assume that that description will net a large fraction of the general public.

B

So the way that I kind of break this field, and I'm probably getting too nerdy right now, but I kind of break this field into cause. What's the actual root cause? What are effective treatments? And I really see them as two separate things. Just because the ketogenic diet is an effective treatment does not imply that the cause of the problem was eating carbohydrates. And I think that's a really important distinction. There are many people who disagree with me on that. There's no doubt about it. And everybody's heard people say, sugar is the cause of everything that ails you, or carbs are the cause of everything that ails you. If everybody does a low carb diet or a ketogenic diet, and then they go to. So it must be sugar that was the cause. I don't see it as clearly black and white as that. The calorie restriction, ketogenic diet, carbohydrate restriction, are inducing metabolic changes in the brain and body. And regardless of what the person was eating, they are inducing metabolic changes that can be really beneficial to brain health. So let me just give a clear, black and white example of this, and then I can speak to the broader topic that you brought up about just the general population. The easy example of the ketogenic diet being an I effective intervention for somebody who was not following a bad diet is an infant with epilepsy. There are lots of infants who have uncontrollable seizures. They are drinking breast milk. To the best of our knowledge, that is the primary, most beneficial food source an infant could be consuming. Now, some might say, well, maybe the mother is, you know, whatever. I don't buy that. The mother's breastmilk is, in fact, the optimal food source for that infant, and yet that infant is still seizing. If we put that infant on a ketogenic diet, a lot of those infants seizures will stop. It doesn't mean that the cause of the infant seizures was a bad diet, but it means a dietary intervention can change brain metabolism and improve symptoms in that person. So, going to your broader question about adults, modern day, the real answer. There was just this conference in London, the Royal College of Obesity Medicine, or something like that. That's not the name, but something along those lines. The conclusion of that conference that invited the greatest minds in obesity medicine, the overarching conclusion of that conference was, we don't know what causes obesity. It's really important that we sit with that. We don't know what causes obesity.

A

They don't think excess caloric intake, beyond one's daily metabolic needs, is causing obesity.

B

Some will argue that. And so some will say, yes, it's all energy balance, but why do we have an epidemic of obesity?

A

Well, that's the gazillion dollar question.

B

And some will say it's all the junk food. But we had junk food in the 1970s when I was growing up. I grew up on Kool Aid and Twinkies and King Dongs and ho Hoshe.

A

I'm rewatching. I'm rewatching the Mad Men series now. I love that series, and I'm rewatching it, and I happen to know someone who worked on that series. They research everything for the props and the costumes, everything but right down to diet. And if you look at the diet, it was terrible. It was mostly, yes, there was a lot of excessive amounts of drinking and cigarette smoking, but the diets were terrible. It was pre packaged foods. It was frozen dinners. I mean, that really came to prominence in the seventies and eighties. But even in the fifties, and from what I've been reading, even in the thirties and forties, people were not eating grass fed meat and Brazil nuts with a little bit of broccoli rabe on the side. That is not the typical intake. So something out there, or maybe multiple things, are at play to increase obesity.

B

And at the end of the day, I believe some will call this speculative, but I actually think we've got a tremendous amount of evidence that continues to point in this direction. I believe that mitochondria are the key to the obesity epidemic, that there is something in our environment. So that is either our food environmental toxins, stress levels, poor sleep, not getting adequate sunlight, whatever you want to speculate on, all of the above. All of those things are known to impair mitochondrial function. And if parts of your brain that regulate metabolism and that regulate eating behaviors are not metabolically healthy, it means that they will not stop you from eating. Or it means that your metabolism will not rise to the challenge of ten donuts. Because some people can eat ten donuts and go on staying thin and healthy.

A

Although I totally agree, although I would just like to say that it seems to me that compared to when I was growing up, and again, I haven't run the statistics, there are fewer and fewer of those individuals around now. Just as when I was growing up, it was one or two kids in class that were quite overweight. And then there were some that were mildly overweight, but most were of healthy weight. Nowadays, that's dramatically altered. The landscape is dramatically altered in the other direction. It is rare when I encounter one of those can eat anything type people. I know one, he's actually an employee at Stanford. He's in our media team at Stanford. And this guy, when I take him to lunch, it's like he's in his early seventies and he can eat and he's incredibly lean. He exercises a little bit, but he's one of these mutants that just can eat and eat and eat. And he's lean and he's vital and it's wild and he's an expensive lunch. But those people seem rare. And even those kids are now seem rare.

B

They're getting increasingly rare. And that leads me to think it may be epigenetic factors in the womb environment, so that kids are actually coming out predisposed to obesity.

A

Well, let me ask you about that because I had a note here to ask this later, but I'm going to interrupt you now in order to capture this moment. My understanding is that, well, as everyone knows, we inherit DNA. We get genes from both of our parents and they mix. Although there are incredible data from Katherine Dulock's lab at Harvard and others showing that we actually have entire regions of our brain that carry neurons that are purely of mom's or of dad's DNA, depending on the brain region. This is a wild finding, but it's accurate. And this has actually been known about in terms of heritability of disease, et cetera. Maternal DNA. DNA from mom, genes from our mother. Not to place blame on mothers at all. My understanding is that the mitochondrial DNA come exclusively through the maternal. Is that true?

B

So it's a great question and I've been asked this before, and yeah, psychiatrists are known for blaming mothers. And some might say that I'm, like, trying to redo that whole thing and.