Chris Palmer, MD — Brain Energy for Mental Health, The Potential of Metabolic Psychiatry, and More | Transcription

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Introduction

Start (00:00)

Hello boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode of The Tim Ferriss Show. This is your host Tim Ferriss, obviously. My guest today, I'm very excited to have this guest with us today, Dr. Christopher M. Palmer. Dr. Christopher Palmer is a Harvard psychiatrist and researcher working at the interface of metabolism and mental health. And he probably doesn't know this, but I have wanted to have him on for probably six to 12 months and have been looking for the right window and the right context. We'll come back to that. Dr. Palmer is the director of the Department of Postgraduate and Continuing Education at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School. For over 25 years, he has held administrative educational research and clinical roles in psychiatry at Harvard. He has been pioneering the use of the medical ketogenic diet and the treatment of psychiatric disorders, conducting research in this area, treating patients, writing and speaking around the world on this topic. He has developed the first comprehensive theory of what causes mental illness, integrating existing theories and research into one unifying theory, the brain energy theory of mental illness. You can learn more a lot more and read many fascinating case studies in his new book, Brain Energy, subtitle A Revolutionary Breakthrough in Understanding Mental Health, and Improving Treatment for Anxiety, Depression, OCD, PTSD, and more. You can find them on Twitter and Instagram @chrispaulmermd. And you can find all things Chris Palmer at chrispaulmermd.com. Chris, welcome to the show. It's so nice to see you. >> It's great to be here, Tim. Thanks.

Understanding Metabolic Psychiatry And Its Implications

How a woman overcame her 53-year streak of chronic paranoid schizophrenia. (01:41)

>> I need to give credit where credit is due to Dr. Dominic D'Agostino, who first put your work on my radar and within several minutes of watching a closed session video, within which you spoke on stage with one of your patients. I knew this podcast had to happen. And that's in part because I think we will find a very curious overlap, a Venn diagram of your clinical work and exploration of research and some of my own personal experiences. So in a sense, this is a very selfish endeavor for me because I am so eager to learn more about your work. And why don't we begin right in the action with a case study? Could you please tell the story, and I do not know the full story at all. I really just have a prompt in front of me. And that is the story of a 70 year old woman who had chronic paranoid schizophrenia for 53 years. Why don't we start there, if you wouldn't mind. I'm going to actually use her real name because she gave me permission to use her real name. In the book I call her Mildred, but her real name is Doris. And Doris had a horrible childhood. She had a lot of PTSD, depression, other things. By the time she turned 17, she was diagnosed with schizophrenia. She had daily hallucinations and delusions. Over the ensuing decades, she tried numerous antipsychotics, mood stabilizers, antidepressants and other medicines. None of them worked to stop her symptoms. She slowly but surely gained massive amounts of weight. And by the time she was 68, she was miserable, hated herself, hated her life. From the ages of 60, age 70, she tried to kill herself at least six times and was hospitalized for those suicide attempts. And at the age of 70, she was referred to a weight loss clinic at Duke University, where they were using the ketogenic diet as a weight loss method. And she decided to give it a try for whatever reason. And within two weeks, not only did she begin losing weight, but she spontaneously reported that her long standing auditory hallucinations were going away. Within months, all of her symptoms of schizophrenia were in full and complete remission. Within six months, she was off all psychiatric medications and remained in full and complete remission. Doris went on to live for another 15 years. She lost 150 pounds, so the weight loss thing was secured but much more important. She remained symptom free from symptoms of schizophrenia. She remained off psychiatric medications. She remained out of psychiatric hospitals. She never tried to kill herself again. And when I last spoke with her, she actually said she was happy to be alive. She attributed her recovery primarily to God that she really felt that it was a miracle from God. And she asked me to tell her story far and wide to anyone who would listen. In the hopes that it might help even one other human being spare the suffering she endured for decades. Sadly, Doris passed away this past January of COVID pneumonia.

The backstory of Brain Energy‘s dedication. (05:30)

That's an incredible story. I mean, it's an incredible story on a whole lot of levels. And less people say that's an end of one. I find it fascinating, but the plural of anecdote is not equal data. There are not only many other case studies, and I'm familiar with some of your clinical case studies, but there seems to be an increasingly high volume of literature studies and other evidence to support some of the mechanisms that you're exploring with your patients. And before we get to exploring some of the mechanisms, which I have quite a few questions about because I'm so personally interested. And for those who don't know, I have had lifelong challenges related to hereditary depression and other psychiatric, I hesitate to call them disorders, but that's probably the most awkward but appropriate label at the moment. Let's dive into some of your personal history. And I think perhaps an easy way to do that is to look at the dedication, start with the dedication of your new book, Brain Energy, and the dedication is to your mother. And it reads, "My futile attempts to save you from the ravages of mental illness, lit a fire in me that burns to this day. I'm sorry I didn't figure this out in time to help you. May you rest in peace." If you're open to it, would you mind sharing the backstory on that dedication? I haven't really done this publicly yet, but so my mom actually is a woman who had two lives. And the first part of her life up until about age 42 was that she wanted a simple middle-class family life. She and my father wanted a big family. They were Catholic. They wanted four kids. They ended up with eight kids. And it's a Catholic thing. That's all she wanted. My father was a pharmacist. He started his own pharmacy and he needed help. So she helped him. She and he both worked 12-hour days, six days a week to get that pharmacy started. She would always take the youngest kid with her to work. She was often breastfeeding, one of them. But that was the life she wanted. And she was 42. Some horrible stuff happened in her family of origin with her siblings and everyone. All beyond her control, she had nothing to do with any of it, but it put enormous stress and burden on her. And she had what she called a nervous breakdown. That's how it started. And I think it started with what we would call depression. It quickly led to depression with suicidal ideation. And then shortly thereafter, it led to psychotic symptoms. She began to think that she was Mary Magdalene reincarnated. She thought the world was ending. She thought this priest that she had gone to for counseling was Jesus Christ reincarnated. And it was the second coming of Christ and she was somehow involved. She would get paranoid and she became convinced that my father was actually the actual devil incarnate. And that led to them getting divorced. And the divorce courts were not kind to her at all. She lost everything. She lost all of her savings. She got none of it. She didn't get any partial ownership of the business. She had worked her ass off to help start. And she lost custody of all eight kids. I was, I think about 13 when that happened. And I knew she was going to die. And so I went to live with her. And it was not a good scene. It was not good at all. We were actually homeless for a while. So my first day of high school was from a homeless shelter. And I could go on and on. But the fast forward of her story is that she lived the rest of her life with a psychotic disorder. She never got better. Her life was decimated. She was able to take care of herself, which was great. She worked various part time jobs and bought a small home and paid for it with her own money. And she inherited a chunk of money from my grandfather, like $100,000. That she was extraordinarily frugal, so that was enough for her to live on for pretty much the rest of her life. And she, you know, she had obesity and diabetes and eventually a massive heart attack and died of heart failure. Thank you for being willing to share that. Sure. It's hard to say anything, of course.

Chris’ thoughts on DSM-5 diagnostic categories. (11:13)

And I hesitate to even follow that with anything, but number one, I'm grateful that you shared it because I think it informs who you are and informs the work that you do in the world and has helped to forge this drive and passion and dedication that you have with your clients. And I have to imagine with the many case studies and the many more certainly that have not been discussed publicly for a million different reasons, that you have helped save a lot of people from life sentences to psychotic disorders. And my hope with this conversation, it's not even really a hope. It is a hope, but it's almost a certainty that people will be listening who are either directly affected personally or directly affected with family members or somehow indirectly affected by what we would consider psychiatric disorders or psychotic disorders. It is incredibly, incredibly prevalent. And this might be a clumsy segue, but I do think it could be a helpful one, especially for those who feel lost in a world of infinite information and conflicting advice. Let's begin with definitions. So could you explain your position on, well, first defining what the DSM-5 diagnostic categories are, what this is, is a tool, and then your current evaluation or perspective on DSM-5 diagnostic categories? DSM-5 is kind of the Bible of psychiatry. And it's what all mental health professionals have to use to make a diagnosis. If you want to treat patients and get reimbursed by insurance, you have to assign a diagnostic label if no label is assigned, you don't get paid. If pharmaceutical companies want to develop pills for psychiatric disorders, they have to abide by these labels and study pills for specific labels. And the assumption is that these labels are all discrete, separate illnesses, and they define a set of symptoms, but more importantly, they define a prognosis and a life trajectory sometimes. They also define treatments that can work and treatment approaches and how long people might need treatment. And in many of those ways, the diagnostic labels are actually useful, and I'm not here to challenge any of that. I think understanding what symptoms people are having and understanding what treatments might be helpful to reduce those symptoms is actually really invaluable, and that's great. But the reality is that every diagnostic label in DSM is a syndrome. And what that means is that it's just a constellation of signs and symptoms that we put together, and no one knows what causes any of them. And the real answer is that when researchers have looked at all of the diagnostic categories, it turns out that there are two major problems with DSM. And the two major problems with DSM are heterogeneity and comorbidity. And what that means is so heterogeneity means that if you see two people with OCD or with autism spectrum disorder, they can have extraordinarily different symptoms. They can look and function very differently from each other, and it can seem like there's no way they have the same brain disorder or brain illness or whatever we want to call it. So that's heterogeneity. The comorbidity part is even more confusing because it turns out if you have one psychiatric disorder and you're getting mental health treatment, there is an overwhelming probability that you have more than one. And you can mix and match them however you'd like. And this is really important because it implies that maybe our diagnostic labels, number one, are not valid constructs. And number two, maybe our diagnostic labels are not as distinct as we think they are. Because when, you know, if I look at people with eating disorders and they're all more likely to have depression and OCD, but I look at people with schizophrenia and they're all more likely to have depression and OCD. And I look at people with personality disorders and they're more likely to have depression and OCD. The boundaries between these diagnostic labels really start to fall apart and you kind of start to wonder what's going on. Much more importantly, when we look at the root causes, the root causes that we do know about for mental disorders. It turns out there is no single root cause for any singular psychiatric diagnosis. And this goes all the way down to the level of genetics. Specific genes even do not confer risk. There is no one gene that confers risk for only one disorder like schizophrenia or bipolar or autism. One gene confers risk for numerous different disorders. So there might be one gene that confers risk for schizophrenia and bipolar and autism and epilepsy and other diagnoses. And so even if you look at a single root cause like something so concrete as a gene, they're not distinct entities. And the reality is that the National Institute of Health abandoned the DSM-5 diagnoses about a decade ago, recognizing these aren't valid constructs and we're not really getting anywhere assuming they are. Man, but it's a bitch to get insurance reimbursement if you don't have the right codes to work with, I guess. Absolutely. Absolutely. Got to play the game, I suppose. You know, when you're talking about the no one gene conferring singularly increased risk for one isolated psychiatric disorder, I was thinking, "Wow. I got to buy one, get one free with my card that I pulled from the deck. Buy one, get four free." Oh, what luck. Absolutely.

Chris’ first exposure to the ketogenic diet. (18:00)

So this begs all sorts of questions, including what are, if any, the plausible underlying mechanisms that could explain these constellations of comorbidities. And perhaps we could start with the ketogenic diet and just how it landed on your radar. And I understand the scope of your research and work is far beyond the ketogenic diet, but I think it may be a useful wedge for working into some valuable terrain. How did that first end up on your radar? Was it because of patients like Doris from a ringing her name correctly who were by, not necessarily happenstance, but outside of your care were sent to weight loss clinics using the ketogenic diet and you observed these ancillary but very powerful benefits? And how did your familiarity develop from there? So my familiarity actually began with my own story. So I told you a little bit about my mom and, you know, when I went to live with her, even before that happened, I had my own challenges with mental illness. And after I went through that hell with her and homelessness and everything else, it only spiraled down. And by the time that I was in my twenties, I actually had gotten to a good place. I was not clinically depressed anymore. I wasn't impaired. I was actually getting through medical school. I had finished medical school, actually won an award for being one of the top students. And I was doing my psychiatry residency at Harvard. And so, you know, anybody looking from the outside would say this guy is doing well enough. He's clearly is not impaired by a mental disorder. But I had metabolic syndrome. So blood pressure was up. Cholesterol and lipid levels were awful. I had prediabetes and year after year, my doctor kept telling me diet and exercise. I was doing a super low fat diet. I was exercising regularly. It was not doing anything. It was all the numbers were just getting worse. And he finally kept pushing meds and was like, you're going to have to go on meds. And I'm like, damn, dude, I'm like in my twenties and you're putting me on meds already. And that means I'm going to have a heart attack by the time I turn 45. Like that is not okay. And I am not going to accept this as my final answer. And so I'd heard through the grapevine about low carb diets. At that point, it was the Atkins diet. And I had heard that it was helping some people reverse their diabetes or improve their cholesterol levels and other things. It went against everything I'd been taught. But I decided to give it a shot. Really just kind of as my Hail Mary pass. And within three months, my metabolic syndrome was completely gone. Everything was better. But the thing that I noticed was I had dramatic improvement in mood, energy, sleep, confidence. I became a different person, a person I had never been in my entire life, even during good times. I had never felt that good. So I, of course, am recommending this to friends and family who want to lose weight or shed a few pounds. And some of them are reporting equal results. So within a couple of years, I start using it in patients with treatment, resistant depression. And lo and behold, they worked for at least some of them. Didn't work for everyone, but it worked for some of them. I think the pivotal moment that really changed everything for me was actually in 2016 when I had a long, standing patient, schizoaffective disorder, which is crossed between schizophrenia and bipolar. And he asked for my help to lose weight. He had tried 17 different medications. None of them worked. He was tormented by his illness in similar ways to Doris. I start this diet within two weeks. He's losing weight. And I start to notice this antidepressant effect in him. I'm like, well, that's interesting. Within six to eight weeks, he too spontaneously started. It didn't happen right away for him. Took six to eight weeks, but he spontaneously reports hallucinations. Delusions are going away. You know, that man went on to lose 160 pounds. He kept it off to this day and has had a new life, has had the ability to do things he had not been able to do. So to kind of get back to your question, those were the serendipitous things that just happened in my life that I didn't set out on a path, like prove the ketogenic diet as a thoughtful intervention. It's snuck in the side door. Totally. It actually snuck in the side door and smacked me in the face. I was like, what the hell is going on here? Like this is impossible. And you know, for people who know the keto diet is like a fat weight loss diet or whatever, it is a 100 year old evidence based treatment for epilepsy. And that was a really important clue to me because we use epilepsy treatments in psychiatry all the time. You know, medications like Depacote, Tegretol, Lemicbil, Topomax, Valium, Klonopan, Xanax, all of those are anti-seizure treatments. And we use them in tens, if not hundreds of millions of people worldwide all the time. And so I quickly recognize, well, wait, if this diet actually stops seizures and we use anti-seizure treatments all the time, maybe that's the reason it's working. And wow, this is shocking because it's like really working. And then I learned about the decades of neuroscience research that we have, documenting what exactly the ketogenic diet is doing to the brain, changes neurotransmitters, changes calcium channel regulation, changes gene expression actually. The gut microbiome is involved, inflammation, it's doing all sorts of things. And armed with all of that information, my career took off. Like I started doing, you know, more research, collaborating with researchers around the world and everything else. Is it fair, this term came up in the video that I watched.

Metabolic psychiatry. (24:57)

And in fact, the conference name, I think had at least some descriptor of this. Metabolic psychiatry, is that a fair description of at least a component of what you do? Or would you use a different label? I think metabolic psychiatry is definitely an emerging field. There are lots of researchers, neuroscientists, clinicians, philanthropists backing this right now. The bazooki brain research fund, funded by David and Jan Bazooki, founder of Roblox. They are really backing this with passion. I think at the end of the day, the brain energy theory is bigger than just psychiatry. The brain energy theory is about metabolism, ultimately mitochondria, and how it affects human health and how that can have an impact on the brain. But it's more than the brain. I mean, you know, the brain is part of the human body and the human body impacts the brain. And so I'm actually more interested in like the big picture. Like if you climb the mountain and look down or if you see the entire forest from the trees, you see the big picture. We're really talking about a new way to understand human health. And that includes mental health, but it also easily segues into physical health. So my only qualm with metabolic psychiatry is that it's focused on psychiatry. And I am a psychiatrist. I'm passionate about helping people with mental disorders make no mistake. I'm not looking to start a weight loss clinic for just any Joe or Jane who want to lose weight. That's not really my passion. But yeah, I am going to be helping people lose weight and improve their physical abilities and prevent cancer and prevent diabetes or reverse diabetes. So it's more than psychiatry.

How ketosis affects the human body (e.g., sleep, mood, weight). (27:01)

Yeah, the Cartesian mind body duality doesn't actually pan out very well when everything is connected with blood vessel scent, so on and so forth. So let's take a closer look at some of the outcomes and I'll share some of my personal history as a way of making that segue. So I have experimented with the ketogenic diet since '96 or '97, I would say, and initially experimented with the ketogenic diet, a cyclical ketogenic diet with one day of carbohydrate loading, following a glycogen depletion workout. It's a bit of a long story for athletic purposes. So I was using it to lose body fat and improve my body composition while maintaining some degree of muscular growth and anabolism by spiking insulin once a week with this carbohydrate loading. And it worked spectacularly well. I was using it for athletic performance, but much later now I've done a fair amount of fasting, quite a bit of ketogenic dieting. And when people ask me for fat loss, there are many options. There are actually quite a few really good options. But the point I make is if you suffer from depression or anxiety, personally I have found nothing close to as dramatic as the ketogenic diet for eliciting a significant change. And it's so noticeable for me that if I'm using, say, an Abbott Labs precision extra device to measure ketone concentrations and millimolars, predictably based on how I feel in terms of not just mood, but mental acuity. It's a speed of cognitive turnover. I know it's not a technical term, it's a speed of computation, short-term memory. I can tell when my body clicks over past, say, 0.7 millimolars, predictably. I can guess where I am between 0.7 and say 1.0 millimolars based on mood and cognition. And furthermore, over the span of several days, and typically I kickstart ketosis with a period of fasting. I just find that the easiest for me personally. But I recognize the adherence challenges that I can pose for a lot of folks. I also seem to, and this is leading to a question to worry, I also notice that when I am in reasonably established ketosis, because I think a lot of people think they're in ketosis when they're eating a ketogenic meal once a day and that we can get to. But when I am measurably in ketosis, my need for sleep also goes down dramatically. And I would say I wake up whether I want to or not after six hours of sleep and I feel fully refreshed. I don't experience the morning grogginess that I typically do. The question is, what the hell is going on? So biochemically from a genetic on off switch perspective, what is happening in the body that contributes to some of these experiences and effects? A brilliant question. And I don't think we have all the answers because this is a relatively new field in terms of looking at the effects of the ketogenic diet on mental states. And certainly in terms of looking at it, in terms of people with exclusive or primary mental disorders, researchers have looked at it for other things. So the first thing I'll say is you're actually, everything you described is spot on with what I see clinically in dozens of patients and what I hear from patients around the world. And it's one of the challenges. I want to point this out, you're highlighting the decreased need for sleep is one of the biggest risks of using this intervention in people who have had a history of psychosis. And the reason is because for you, it sounds like it has not been a major problem. I've definitely seen people who have gotten hypomanic while they especially while they're keto adapting to the point that they're actually only getting two hours of sleep a night. And they can't sleep more than that. And sometimes they recognize this may not be optimal for me. And other times they just think, well, you know, I've got a lot of time now to be productive and get all sorts of shit done. So, I mean, one guy actually was going for 20 mile runs starting at like 3 a.m. in the morning. And he complained that he couldn't maintain a normal weight. And he wondered why. And I'm like, dude, you're like sleeping two hours a night and you're running 20 miles every day. What did you expect? Some basic math can explain this. Yeah. Yes. Absolutely. You know, the effects on sleep are complicated because some studies like in epilepsy patients, for instance, have found that the ketogenic diet actually dramatically improves sleep overall. But a lot of those patients are sleeping too much and often because they're on medications that are extraordinarily sedating. And so those studies come to the conclusion, ketogenic diet improves sleep. It normalizes it. People wake up feeling more refreshed. It's a great thing. This issue of hypomania and mania is very poorly understood. I'm one of the only people in the planet who seems to recognize it as hypomania and mania. So we've got a lot of work to do in terms of understanding it. I'll give you an evolutionary speculation about what I think is happening. Widely speculative. We don't have the research for this. But I've seen this a lot, not just with ketogenic diet, but with anything that induces a kind of ketosis and a fasting state or a fasting mimicking state. So I've seen this in patients who fast for five, seven days or whatever. And there are actually some studies in Muslim patients during Ramadan, especially patients who have bipolar disorder during Ramadan. They start fasting. They are much, much more likely to have sleep problems and they are much, much more likely to have subsequent mood episodes. But primarily hypomanic and manic, but also depressive for some people. So I think that we've got enough evidence, and I certainly have enough anecdotal evidence to say decreased sleep is a thing. It's a real thing. It's observed. We've got some studies to document it. Why would the body need less sleep? Or why would the body get less sleep while in a ketogenic state? My assumption is just going with a common sense evolutionary perspective, which is the body thinks it's actually starving. It's drought. There's a drought or famine or something. Something is going on. Food supply is scarce. That's why you have high ketones. And so the high ketones are actually activating brain regions to get you, number one, more energy, more confidence. And more time, you don't need to be sleeping right now. You've got to find food and find it fast. And so it gives people more energy to actually go out, seek, explore, hunt, whatever, looking for food sources. Again, wild speculation, at least in my mind, it kind of makes sense.

Examining the mood elevation of ketosis on a bio-cellular level. (35:12)

From an evolutionary perspective, it definitely makes sense. And does the mood improvement reflect, in your opinion, increased release of norepinephrine or something along those lines? Or is it remedying via ketones, this alternate fuel source, which the brain and the heart and some other tissues really love, is the presence of ketones remedying and underlying glucose metabolism disorder that is in part causal. With the conditions that end up getting pulled from the DSM-5, how would you explain, even if it's just a tentative hypothesis, the mood elevation that people experience? Because it is so noticeable. It is not subtle for me in the least. No. I will share my personal story too, because I've been in and out of ketosis for many years, and I find the exact same thing. And quite honestly, sometimes the inability to sleep or sleep an adequate amount of time is the rate limiting factor for me. And I'm like, I can't go with this little sleep or this long. This is not going to turn out well for me if I stay on this trajectory. I know enough. You know, there are lots of people with lots of different opinions, and we know at least like 40 different mechanisms of action of the ketogenic diet. Like I said, neurotransmitters, all sorts of things. So how exactly is it resulting in this improved mood? There's going to be debate. I actually firmly believe, based on this larger theory and kind of connecting all of the dots, I actually firmly believe that it really does come down to mitochondria. And some people call it mitochondrial dysfunction. There's another group of researchers that like to call it sub-optimal mitochondrial function. I wouldn't want to upset this mitochondria. Because that's different than dysfunction, whatever. What it means at the end of the day, and we may get to this, mitochondria are actually much, much more than just powerhouses. But powerhouse function is a critically important function. And we have evidence from numerous data sources, from blood work, from lumbar punctures, from autopsy studies, to all of the neuroimaging studies that we're doing, functional MRI, PET scans, spec scans, all of these studies, all of them converge on mitochondria and functions of mitochondria. And what all of these studies suggest is that people with mental disorders across the board tend to have regions of the brain. So it's not the entire body. Like metabolism is cell-specific and tissue-specific. So you can have one cell that's actually ready to die because it's metabolically failing. You can have another brand new healthy cell that's actually thriving in the same human body. So it's important to keep that in mind. But what all of this research says is that some brain regions and some people are metabolically compromised. Their brain tissue is not getting enough energy, and it also has higher levels of reactive oxygen species, which can produce inflammation and all sorts of problems. But we know this, and again, tons of evidence and different lines of evidence all pointing in the same direction, even genetic studies. Like when you look at, well, what is this gene doing and what's happening in the brains of people with these genetic defects, you time it again, see mitochondrial or metabolic impairment or dysfunction. And what I think the ketogenic diet is doing is it is, I imagine a cell that's only running on, it's a six-cylinder engine and it's only running on three cylinders. And you give it ketones and ketones are like rocket fuel for this engine and all of a sudden all six cylinders come online and that cell is firing. And for most people, that's a good thing. And it gives people energy and everything else. If that metabolically compromised cell actually is in great disrepair, if it is like really miserably maintained and in great disrepair, giving it all this rocket fuel all at once can actually be really dangerous and can result in a whole host of other symptoms. Did you elaborate on what a dangerous case would look like?

When ketosis can be dangerous. (40:13)

Because presumably we're not talking about, and please correct me if we're on ketoacidosis, right? In the case of, say, a type 1 diabetic who has comorbidities and they have high ketones and high glucose dangerous situation, in what way or in what fashion would this manifest as dangerous? So one of the consequences of metabolic dysfunction of a cell, one of the big themes, there are several consequences. I kind of break them into five buckets depending on where and when. There are two primary ones for an adult, say, who is just going, you know, who's developing new onset symptoms. And the shocking thing is that they're polar opposites. So the cell can either become underactive, which means it's failing to work because it doesn't have enough energy and that makes sense, common sense, really easy to understand. But the other consequence of metabolic dysfunction is actually that cell can become what's called hyperexcitable. It can actually become overactive. And you know, some easy examples of overactive or hyperexcitable cells are a muscle spasm or a heart arrhythmia or somebody with chronic pain who's experiencing pain because their pain nerve is hyperexcitable. It's firing when it really shouldn't be firing or it's not stopping when it should stop. And so metabolically compromised cells are prone to this hyperexcitability. And the challenge with ketones for some people is that you rush in this ultra clean kind of high octane fuel and the cell becomes hyperexcitable. And the way that translates in terms of brain function is it for somebody who's got a hyperexcitable or a metabolically compromised anxiety pathway or anxiety system, they could have a panic attack or feel more anxious early on. But for other people, it can result in psychosis. It can result in OCD symptoms. It can result in all sorts of things. Agitation, the extreme case of hyperexcitability in the brain is actually a seizure.

How mitochondrial dysfunction can trigger a host of ailments. (42:37)

Well, the more you know, folks, be careful out there. So mitochondria, just to underscore mitochondria for a moment. So the powerhouses of the cell, I mean, the origin story of mitochondria, we can leave aside. I mean, it's fascinating just to look into how we ended up with mitochondria in our bodies. But for the purposes of this conversation, the powerhouses of the cell, I think it's, I want oxidative phosphorylation, they generate the vast majority are all of ATP, adenosine triphosphates. Let's just consider that for our purposes and feel free to pick this apart. But the basic energy of the body for most people, most of the time, there are a bunch of exceptions. The reason mitochondrial function and dysfunction is of great interest to me personally is not just because of the depression, but a pet theory slash hypothesis that I developed after a severe case of Lyme disease about eight to 10 years ago. I don't remember the exact timing. I grew up on Eastern Long Island. Everybody gets Lyme disease, almost everybody. My mom also has the alpha-galactose allergy inflicted by an infection from the lone star tick, so she can have anaphylactic shock if she consumes any mammalian protein, including gelatin, which isn't everything. So I grew up surrounded by ticks and tick-borne disease. And I developed very severe Lyme symptoms. It was confirmed through a number of different tests as a Lyme infection. There are other co-infections, but let's focus on Lyme for the minute. And the first thing that this lab told me was, number one, you're aware you've already had Lyme. Are you not? And they highlighted the fact that I had long-term antibodies, which raised questions for me about whether my depressive episodes, which started around adolescence, were in fact as simple, I mean, that's probably not the right word, as a hereditary genetic predisposition, which there appears to be a component of that, at least based on my genome sequencing. Or if in addition to that, maybe a catalyst or accelerant was this first infection with Lyme disease. And the reason I mentioned that is the second time I had Lyme disease and the symptoms, I made a very significant mistake. And that was I looked for the bull's eye rash. The bull's eye rash didn't appear. And therefore, I didn't start any type of antibiotic treatment. And it turned out this is going somewhere. Don't worry. It's a little long-winded, but it'll go somewhere that even without the dermatological symptoms, many people can be dermatologically asymptomatic and still develop Lyme disease, which is exactly what happened to me. And the only reason I wanted to get tested is my speech started to slur. I was forgetting close friends' names, common words. It was taking me five to ten minutes to get out of bed in the morning because my joints were so in so much pain from inflammation. And I went through all of the standards of care. I did the antibiotics, which had some effect, but I was in this energetic, no man's land. I was incredibly fatigued all the time. I felt as a result, these two things are often correlated for me, depressed. What I would describe is depressed. And I continued to have what felt like dementia on some level for probably six to nine months until I decided, and I can't remember what catalyzed this. I don't think it was the Lyme, but I did a week-long extended fast. And by two and a half days in, and I was measuring my ketone levels, which I think is actually really helpful if people are trying to get a grasp on these things, all of those symptoms literally vanished by the time I got to 1.2, 1.3 millimolars. And not only did the symptoms evaporate, but I continued to fast, and then I continued on a sub-caloric ketogenic diet for a period of time afterwards. And that was an effect. And again, I'm not a doctor. I don't play one on the internet, so I'm not giving medical advice. But this approach with Lyme and ketogenic diet has now been replicated across probably half a dozen of my friends. I should say this is true Lyme disease and not someone who is dissatisfied with life and depressed and diagnosis shopping for Lyme disease, looking for an external cause, which is a different story. But in this case, once I saw the remission of symptoms and then I got off of the ketogenic diet with the well-founded fear that I would revert back to my previous state, I did not revert to my previous state. So that's probably explaining that maybe beyond the grasp or beyond the scope of this conversation. But what that raised for me as a question was, are the symptoms of Lyme disease caused by some type of impairment of mitochondrial function or glucose metabolism? It just seemed like a very fair question to ask. And I know this is an interview about Lyme disease. But what should we know about mitochondria? If someone is not familiar with mitochondria or maybe they just have the basics like I lay it out, what do you find interesting about mitochondria or perhaps aspects of mitochondria that would be helpful for this conversation? So sorry for the TED Talk. Thanks for listening. No worries. It's a perfect segue into this. So the real answer is that mitochondria connect all of the dots of every factor known to play a role in mental illness, whether it's neurotransmitters, stress, trauma, hormones, all of them. And I can come back to them if you want, but let me follow up on your story. So you had an infection, high levels of inflammation. Those high levels of inflammation are good. They're good for your body because your body is being assaulted by this bacterium, the bacteria. And it's going to kill you if your body doesn't mount a defense. So the inflammation that you were experiencing was good and healthy, but yes, it made you feel like shit. And it impaired your brain function. We have direct evidence that inflammation and inflammatory cytokines and specific ones actually impair mitochondrial function and/or change mitochondrial gene expression. So we know that that's happening. For the most part, that might be a normal adaptive response because again, your body's mounting a defense for its survival. And so it's allocating resources to fighting off this bacteria. And that means resources need to come away from somewhere else. Some cells are going to suffer as a result of the need to fight off this life-threatening thing. And we have direct evidence that some brain cells have a reduction in mitochondrial function. I think for people who are already on the edge, people who've had depression in the past, maybe people who have a genetic vulnerability or other type of vulnerability, that reduction can be too much for them because those brain cells are already maybe operating at slightly reduced capacity or even maybe moderately reduced capacity. And then when you throw an infection on top of it, it just pushes those cells over the edge and then they begin to malfunction. And that results in what we call symptoms of mental illness. It's not just Lyme disease though. So we've got lots of research, decades of research, showing that inflammation, especially from infections, can result in brain disorders, mental disorders, neurological disorders. We know this with certainty. So one study looked at kids who developed an infection that was serious enough to be hospitalized and they had, again, 80 something percent increased risk of developing a mental disorder, most of them within the three months following a hospitalization. And the mental disorders were across the board. These kids in the next three months developed autism, schizophrenia, OCD, learning disabilities, seizures, all sorts of problems, which again is consistent with this more unifying model of how to think about mental illness. These aren't discrete entities, but they're obviously discrete symptoms and symptoms matter. Well I can stop there or I can share two. No, no, keep going. I'll share one or two tidbits to highlight why mitochondria are so important to this theory. Yeah, please. So one, neurotransmitters. Everybody knows neurotransmitters play a role in mental illness. Turns out mitochondria play a critical role in the production, the direct production, but also the release and the regulation of major neurotransmitters, including dopamine, serotonin, GABA, glutamate, and others. So mitochondria actually are taking food, you know, broken down food, whether that's carbohydrates, fats, proteins, and they're converting it into two different things primarily. They're converting it into a fuel source, they're burning it all the way down, and then that fuel gets used to create either ATP or heat. So it's fuel or it's building blocks for other things. It's building blocks to make new proteins or make membranes or other things. And the mitochondria are actually producing some of the primary building blocks for those neurotransmitters. But in fact, researchers have looked at cells and if they take the mitochondria out of the synapse, for instance, but flood the synapse with ATP, so it's still got lots of energy. It's got energy available. The neurotransmitters actually don't get released. The mitochondria are playing a direct role in actually releasing the neurotransmitters. And then I'll just share hormones too. So, you know, everybody has heard about, you know, steroid hormones, cortisol, estrogen, testosterone, progesterone. Producers actually control the first step in the synthesis of all of those hormones. And so if they are dysfunctional, if there is a problem with mitochondria, you may have a problem with producing those hormones. Wow.

Dietary methods for sustaining ketosis over the long term. (54:27)

Stars of the show, top of the marquee, mitochondria. All right, I'm definitely going to be doing more reading on mitochondria. Now, let me ask a question or present a situation and a question that I imagine is coming on to the minds of many people listening. That is Tim Ferriss. If ketogenic diets are so amazing and you feel so much better, why aren't you always in ketosis? And so I want to answer that in the desk for your input. First, I will just lay out that for the sleep piece, what I've noticed to myself, this is especially true with extended fasting, is that whether the sleep, let's just say six hours long, feels restful or not, often depends on my electrolyte consumption. So if I am not consuming carbohydrates and I'm just splitting off tons of water because I don't have the retention capabilities, sometimes I can, at least personally, I can develop lower back pain, might be kidney related and I think it's probably, it might be a colon or a jic response. I'm getting a little outside of my depth here, but in terms of rapid heart rate, trying to go to sleep that seems to be largely remedied by additional supplemental electrolyte intake. However, the challenge for me is often one of not dietary compliance. I happen to be a cholesterol hyper absorber. So sometimes on the ketogenic diet, I do see my lipid profiles go completely cuckoo bananas. And for many people, that's not the case. But for me, I have witnessed that. So I have some long term considerations. I'm already taking things like a zetamab to control for some of the risk factors. Personally, I'm not recommending that for anybody. Talk to your doctor. But for people who have no familiarity with the ketogenic diet and you're trying to help someone sustain ketosis for a period of time, what approach do you take? Do you use cream like they did with children for a long time in the studies looking at epilepsy? What is the approach that you take to make it as easy as possible for people to stick with it? Well, and I think you raise a really good point that not everybody should be or needs to be on a ketogenic diet or in ketosis long term. So for the patients that I'm working with, they usually have serious brain disorders that almost all of them are disabled by their symptoms. And so like epilepsy, where somebody's having multiple seizures every single day, they have a very serious brain disorder that needs immediate and consistent medical intervention. And so if you're using a ketogenic diet in those situations, most of those patients do need it consistently. And in a way, I know people want a one size fits all answer and I have to tell you, I have to just have to level with you, there isn't one. So for an obese patient, so if I'm working with somebody who weighs 340 pounds, I can get high levels of ketones in that person by just carb restriction alone. So tell them to just eat less than 20 grams of carbs a day. I don't really even have to get into any limits on protein and I usually don't have to recommend that they eat more fat or fat sources because they have so much body fat to tap into. And usually in those cases, we want to tap into that body fat because they're usually interested in losing some of it. And so in those people, I'm going to recommend carb restriction and that's about it. And usually it's pretty easy for them to maintain very high levels of ketones and get the therapeutic brain effects as a result. Once that same person loses enough of that body fat or if I have a different patient coming to me who's already thin or athletic, that person is going to need to probably moderate the amount of protein they're eating and consume more fat than they really think they should be eating. I mean, we're both laughing because I know what that means. Yeah. No, when I introduce people to a ketogenic diet and I tell them how much fat I want them eating, they're just like, you've got to be joking. There's no way that's healthy. There's no way I can do that. But yeah, so lots of ways to do it. I mean, you can create like fat bombs. Heavy whipping cream is really a great tool. Some people drink it straight and just, you know, they drink it like milk. You can actually put a little bit of water in it to water it down if you want it to be a little more like milk. It's also really good in coffee. Really good in coffee. Great in coffee. It's great if you whip it and then it's whipped cream. It's delicious. Yeah. You can use artificial sweeteners. If you want, I usually recommend something like Stevia or monk fruit. You can put vanilla in it. You can put cocoa powder in it and then it's chocolate or vanilla and you can freeze it and it becomes ice cream. I mean, you can do a lot of things with it to make it palatable and sustainable. But yeah. So do you start people off with directions? Let's just say they have lower percent body fat. So they're not necessarily bodybuilders. Let's just say they're somewhere between a 20 percent body fat or less. And assuming that means they're going to need to modify their intake to increase the percentage of their dietary calories from fat, would you rather than say change each meal to have X, Y and Z composition, say have supplemental fat bombs, have some supplemental heavy cream. And that's how you'll basically move the slider such that you're getting something like 70 percent of your calories from, from fat. I'm not sure if that's the target range, but you would add the fat as opposed to change all the meals. Yeah. So you're adding the fat. So low carb is the baseline. And then, you know, the protein may need to vary. I want to make sure they're getting adequate protein. But it's not an all you can eat meat fest necessarily. For most people, quite honestly, it's usually a work in progress because everybody has different dietary preferences. Some people like salads and if they like salads, I'm going to say, okay, have lots of salads. Put some crumbled blue cheese on it. Maybe some almonds in there and avocado in there and douse it with as much olive oil as you can tolerate. And you know, whatever that is, vinegar and oil, a lot of oil, that could become a very high fat thing. And some people may love that. Other people hate it. And so other people are going to lean more toward really fatty steaks or they want sweets, in which case, yeah, we're going to be doing fat bombs and whipped cream and ice cream and other things. So it is there are lots of strategies, which is good because that way we can like figure out what does this person like and let's make it sustainable. I have one friend.

Common ketosis mistakes. (01:01:52)

I was an MD, very, very competent MD who was in ketosis for two years, two to three years straight. And his general approach was skip breakfast. So intermittent fast, maybe some coffee with heavy cream and then have a large salad, lots of greens. But in terms of actual net carbohydrates, pretty low with steak, cheese, tons of oil, and then having sort of a moderate protein dinner that would be on the smaller side. And just so people know, and please correct me if I'm getting this wrong, but the reason a lot of folks have an aversion, I think a lot of it is cultural conditioning to attempt to do ketosis by simply going low carb. And they end up going very, very high protein. So they think that they can do a green salad with like a mountain of lean chicken breast and make it work. But the body is really crafty. It happens to like ATP. So the body will take the excess protein or a portion of it and convert it in the liver, I think, through a process called gluconeogenesis to glucose. So then oops, you end up not being able to sustain the higher levels of ketones because your body just does not need them. If you have high glucose levels, your body is getting what it needs and your body is pretty smart about resource allocation. Definitely feel free. And you'd like to add to that. Any other common mistakes that you observe or things that people don't think will affect ketosis that tends to affect ketosis in unexpected ways? Any common pitfalls you'd like to highlight? You know, honestly, there are so many. It's hard to put them into one category. The nice thing about the ketogenic diet is that there is an objective measure of whether you're doing it right or not and it's measure your ketones. Yeah. If you're able to measure your blood ketones, measure your blood ketones, and then do the detective work to figure out why you're not achieving the results you want. And you know, with a variety of patients, so the detective work, which gets to your exact question, like, what are the pitfalls? I've seen people eating a lot of keto labeled junk food from the grocery store Costco. Keto brownies all day long. It's got keto on the label, so it must be okay. And it's filled with soluble corn fiber and, you know, sugar alcohols and other stuff that clearly is not necessarily natural and low and behold, takes a lot of people out of ketosis and prevents weight loss and prevents the brain benefits and lots of other things that you want to be achieving. So that's probably the single biggest pitfall is all the keto labeled junk food.

Psychiatric medications, metabolism, and controversy. (01:04:56)

Yeah. If it seems too good to be true, folks, probably is. I remember doing keto way back in, you know, '97, '98, '99 and man, the landscape was barren. I mean, it was pork rinds and heavy cream. And not meat and eggs and water and unsweetened iced tea. That was basically it. But you can make it work. Let me ask you about a note I have in front of me, which I would love to hear you elaborate on. And that is some psychiatric medications, imperme-tabolism, even though they can reduce some of the symptoms of presumably associated disorders in the short run. Could you speak to that maybe give examples because this is certainly deeply interesting to me? So let me at least preface this discussion with kind of a caution up front. So I'm going to say some things that may get people really upset and especially if you're on these psychiatric medications. And I want to just say for the record, it is really difficult and dangerous to get off psychiatric medications, especially if you've been on them for years or decades. So please do not stop your medication on your own. Please don't taper it on your own. Work with your health care professional and do it in a safe way. You're going to hear that I am an advocate of sometimes trying to help people get off medication. So I'm not trying to say you must take your meds for the rest of your life. But I'm just saying, please don't do it in a dangerous way because lots of people end up in the hospital or suicidal or dead. Yeah, no DIY folks, please. I know people who have committed suicide after stopping things called turkey or attempting to taper but not informing their doctors. So please be very careful and only do any type of removal of meds with professional supervision. Thank you. So with that said, this is probably going to be the single most controversial part of the theory because what I'm ultimately what I'm saying is that mental disorders are metabolic disorders of the brain and so that means metabolic impairment in the body and or brain can result in mental symptoms. And yet we know many of our treatments directly in paramatabolism. So we know a lot of antipsychotics, mood stabilizers, even some antidepressants and others cause people to gain weight, sometimes massive amounts of weight, they can cause type 2 diabetes, they can cause cardiovascular disease and all of the risk factors for cardiovascular disease. So they can cause hypertension, they can cause abnormal lipids, which we think contribute to cardiovascular disease. And those are all metabolic problems. That's not controversial at all. They're metabolic problems. These pills are causing these metabolic problems. They are right on the FDA package inserts of these meds. So everything I just said is fact non-controversial. So the logical question from many people is, well, then Chris, your theory must be wrong because these pills work. And if they're impairing metabolism, then that pretty much disproves your theory. How would this make sense otherwise? And quite honestly, this was actually one of the biggest things I struggled with in developing this theory. I kind of was on this path, metabolism, mitochondria, wow, that seems to be the connecting, it's connecting a lot of dots. And that was actually one of the obstacles for me. Was that exact question? Like, how can I understand that? And it's not that I want to deny that the medications do reduce symptoms because they do reduce symptoms. I've seen it work firsthand as a psychiatrist. I've seen these medications reduce symptoms. And I'm not here to say all of the clinical trials are a big lie and scam from pharmaceutical companies. I don't think they are. So I had to try to understand like, well, then what's going on? It kind of does disprove my theory. So I've got to come up with an explanation. At the end of the day, the explanation is this dichotomous reaction of a cell to metabolic impairment. So when a cell is metabolically compromised, there are some other things that it can do, but the two for our purposes right now are underactive or overactive or hyperexcitable. And what we're really focused on are hyperexcitable cells. So hyperexcitable cells are producing experiences from your brain networks, but they're producing these experiences at the wrong time or the wrong intensity or they're not stopping when they should. That's what hyperexcitability does. So a hyperexcitable pain cell causes pain when you shouldn't have pain. A hyperexcitable brain cell is producing an experience and sensation cognition something that should not be happening when it happens. And that could be anxiety, depression, hallucinations, whatever. In order to stop a hyperexcitable cell, there are kind of two strategies you can use. So one would be to slowly but surely restore the metabolic health of that cell through strategies that Tim, you've used yourself, exercise, ketones, fasting, meditation, other things. Those are going to restore metabolic health to those cells and allow those cells to function normally again. But the other way to stop a hyperexcitable cell is to basically put a straight jacket on it. And to stop it from functioning almost altogether. And that's what a lot of the pills that we prescribe are doing. They are impairing mitochondrial function so that that cell has trouble firing at all. And that means that symptoms of hyperexcitability can stop. And so for some people, if you're having a panic attack and somebody gives you a pill and it makes that stop, that can feel really good. If you're having a seizure, it can be life-saving. If you're psychotic and violent, that can be life-saving. So I'm not trying to say these pills should never be used or they don't have a time in a place because they think they do. But if you take that pill long term, that pill is like putting a straight jacket on that cell. It's suppressing the function of that cell over the long run. And what that means is that that cell becomes weaker over the long run. And that may very well end up making the illness even worse in the long run. That is the theory, there are lots of people who have been preaching that message for decades who are going to say, "Dah, Chris Palmer, where the hell have you been?" And then there are other people who are going to say, "Chris Palmer, how dare you say that? That is blasphemy and you are now a dangerous quack." So I know I'm going to get responses from all over the place. But if you understand the science, if you understand the basic science and all of the evidence, that is a real possibility. Are there any worse defenders because it has too much of a negative connotation?

Controversial Aspects Of Psychiatric Medication And Advantages Of Ketogenic Diet

Indications that a medication impairs more than improves a patient’s condition. (01:12:54)

But are there any particular drugs that stand out to you as having a time and a place to be used but that are particularly powerful at disrupting metabolic integrity if they're used chronically without any type of cycling off? The easy answer is, and I could get into all of the science documenting at the cellular level how and why this has been supported. But we really don't need that. The easy answer is just look at the human being in front of you. If they are gaining massive amounts of weight, if they feel extraordinarily slowed down and now they're sleeping 14 hours a day, 16 hours a day, and they can barely function and their cognition is trashed. They can't think anymore. They can't read a book anymore. They can't hold the job. They can't do school. Those are all signs of metabolic impairment of brain cells. So those are the medications that I would be most worried about. And it can differ among people. If one person is taking a medication and having all of those side effects that I just listed and yet another person is taking maybe a lower dose of that same medication and is finding it beneficial and still able to function in life and still able to do everything they want to do and not gaining lots of weight and not becoming too diabetic, then all the power to that person and all the power to that treatment, and I would be in full support of that treatment. And I'm not at all here to deny that treatments can work for some people, but I didn't really say this, but I just want to say this in case people think Chris Palmer is way too pessimistic. Who the hell is this guy? The real answer is that mental disorders are now the leading cause of disability on our planet. And it's not because people aren't getting treatment. A lot of those people are getting treatment and it's because our current treatments fail to work for them. That is a fact and that is why I am so passionate about this work because I want to help those people who are being told there's nothing more we have to offer you. There's nothing more we can do. Just take your pills and stop complaining. I want to help them.

Resources to share with doctors open to conversation about these issues. (01:15:40)

If we wanted to take a moment to act as patient advocates, so many patients, many people who are taking psychiatric medications or medications for psychiatric conditions will not have doctors who are familiar with the many functions and purposes of mitochondria, how the ketogenic diet and ketones interplay with energetic production and can alleviate, say, inflammation. For those people who don't know, you can find lots of literature to support this. Many types of ketones, including I think beta hydroxybutyrates, probably one of the most obvious to search for, are highly anti-inflammatory. Another observation I had when deep into ketosis is that many of my chronic pains decreased significantly, including tendinosis and other issues. For people who don't have a doctor who is well-versed in these things, but let's assume for the moment that their doctor is open-minded to continued education, are there any resources that you would suggest? I would imagine that your book is certainly one of them, the book being Brain Energy. Are there other resources you might suggest that a patient asks their doctor if they're willing to read up on so that they can have these conversations? Absolutely. You can go to my website, chrispalmermd.com, or you can go to a website that is about to launch brainenergy.com. I will be posting free resources, studies, lay articles. Already on my website, I've got lay press articles if you just want to better understand these treatments and the science behind them, but I've also got links to the medical peer review literature. That's important if you're trying to get your healthcare practitioner to take this seriously and at least have a discussion with you about using this as a treatment option. Even if you can't understand what that article is saying because it's written in medical language, you can print it out and give it to your healthcare provider. That will build some credibility. Don't go and just say, "Oh, I saw this YouTube video on the internet." It was great and I think you should do this. If you arm yourself with some of this scientific literature, you're more likely to get a good response from your healthcare practitioner to at least work with you or consider it with you. I mentioned Harvard when you mentioned Dr. Christopher Palmer and not YouTube.

Why quitting psychiatric medication cold turkey is a bad idea. (01:18:24)

I mentioned Harvard before you mentioned YouTube. Pro tip. The next question I'd love to ask, "Well, actually, I'll make an observation which is not necessarily an accurate observation, but as I'm thinking about your description of some of these common medications that can disrupt metabolic function, sometimes to good short-term clinical effect, as you mentioned, if somebody is psychotic and at risk of injuring or killing themselves, these medications have a role. If someone is currently on these medications, let's say they recognize some of the symptoms, weight gain, lethargy, sacrificed cognition. They don't necessarily, and this is not medical advice, but just an hypothesis, need to rush to get off of these medications. It seems to me that they could also potentially consider adding dietary interventions, exercise, etc., that could act as a counterbalance so that they are facilitating some cellular rejuvenation or metabolic efficiency while they are continuing to use these medications. It's not all or nothing. It's not remove all of these components and then add all of these components. It can be parallel tracks. Is that fair to say? It is essential to say. When I have patients come to me who say, "I want to try this ketogenic diet thing," they stay on all of their current meds. Taking people off their meds is dangerous. Please hear that. The way that I think about it is it means that those cells are now almost shriveled up. Those cells are struggling because they have been suppressed for so long. When you take those meds away, they're going to become hyper-excitable immediately. As energy rushes into those cells, they're going to become hyper-excitable. It's like taking a cast off of a broken leg and then saying, "Go run. It's not a good idea." The first step is exactly what you said. Maybe implement some other strategies, dietary change, ketogenic diet, or otherwise. Let's remove all the junk food and the sugar and some other stuff that's inflammatory. That might be enough of a first step for some people. Add some exercise. Try to get your sleep under control. Then, if that is working, and especially if it's working in a profound way, then maybe slowly but surely over time. See if you can slowly but surely taper your meds.

Thoughts on the efficacy of exogenous ketones. (01:21:10)

For people who may be in my position, which is huge fan, convert, true believer in the certainly the psycho-emotional, and I suppose we're looking a little under the hood, energetic benefits of the ketogenic diet, but concerned about some of the long-term cardiac effects due to my cholesterol hyperabsorption, or I should say sterile, really, because there's mosterol and all these other plant sterols are also hyperabsorbed, which can cause issues. What is your current position on use of exogenous ketones or ketones supplements as a way to perhaps partially achieve some of what you have seen with dietary interventions? Is it possible? Is it contraindicated? I always have a divided position on this because I look at, and this may be an unfair comparison, but I look at say ketoacidosis, and I think to myself, it really doesn't make sense to me from an evolutionary perspective that it would be good for you to have normal or elevated glucose levels while simultaneously pushing ketones to two or three millimolars with exogenous ketone consumption that doesn't at least at face value seem like that would be without risk. How would you suggest I think about this? The real answer is I don't think anybody knows for sure. A lot of people are really interested in exogenous ketones, and obviously it's so much easier to drink ketones than do a ketogenic diet. So no question about that. The first fact I want to just share, the first observation I want to share is that there are tens of thousands of children with treatment resistant epilepsy who are using ketogenic diets to control their epilepsy. Exogenous ketones have been around for years. We do not yet have even one case report of one child being able to transition off a ketogenic diet to exogenous ketones and maintain the benefits of seizure improvement or seizure freedom. Trust me, thousands of parents and neurologists and others have almost certainly tried it. Do I have documentation of that? No, because they're not reporting it because it didn't work out. So there's no way to really... But it would be a hell of a lot easier for everybody involved, so you have to assume they would have tried it. I have to assume... I have to assume... I have to assume that some of these patients with epilepsy gave it a shot. I know with certainty I've talked with patients with bipolar disorder and other disorders, for instance, who were using a ketogenic diet to control their symptoms. They did try exogenous ketones, went off the diet, and symptoms came back sometimes with a vengeance. I've used it in clinical practice as well with patients, and I've not seen a significant benefit of exogenous ketones. So those observations make me think a couple of things. One is that the ketogenic diet is doing a lot. It's improving insulin, signaling, it's changing the gut microbiome, improving hormones, all sorts of things. But when you force your liver to make ketones, because that's where most of the ketones in the human body are made, and interestingly, they're made by mitochondria. So it is actually the mitochondria in the liver that are making the ketones. And help me help you, mitochondria. Well, so one of the things that's happening when somebody's on a ketogenic diet is actually you're getting this thing called mitochondrial biogenesis in the liver, which means that your liver cells are actually making more mitochondria to meet this demand. That's a big deal. That in and of itself might be improving the health of your liver and the ability of your liver to send kind of healthier metabolic signals to your brain and throughout your body, the liver plays a profound role in terms of metabolic health. We know that. And there are lots of signals that gets really complicated really quickly. But the bottom line is increasing mitochondria in cells, confers health benefits pretty much across the board. Because they're healthy mitochondria, if you increase defective ones, that's not going to do very much. But I actually sadly think exogenous ketones are not going to be the magic answer. Could they play a role for some people? Probably. They might be good, like on an as needed basis, or they might be a good rescue for somebody who's using a ketogenic diet, balls off the wagon, gets really sick, needs a quick rescue. Maybe exogenous ketones would help that person in that situation. I don't know. Yeah. From a first person subjective experience, I can say, having consumed a lot of exogenous ketones of many, many different types, that for certain types of physical performance, or physical performance at altitude, in any hypoxic state, the supplemental ketones can be very helpful. That applies in my case to intermittent fasting also. So if I'm intermittent fasting, and let's say I have podcasts recorded in the morning, but I haven't eaten in 12 hours, whatever it might be, supplemental ketones plus some caffeine does a lot of heavy lifting for a short period of time. But I have not experienced the extended durable mood elevating effects or cognitive benefits from exogenous ketones that I have from the ketogenic diet. There's no comparison in my experience. I do find, and also, I'll tell it's not like a broken record, not medical advice, fasting. It's a shame that you just can't get extended fasting studies and humans through IRB these days. I wish that were different, but don't just DIY long-term fast folks. But for me personally, when I am segwaying into, say, a three-day fast, which would be my most typical duration of fast, I have done up to 10 days, but more typically I'll do three days, I will use exogenous ketones on my first day of full fasting, which is typically 12 to 18 hours after beginning a fast, after an early dinner, to allow me to eke out one more productive day of work on a Friday. The use of exogenous ketones as a booster shot or an accelerant that assists with the segway into ketosis, I do find quite helpful, but I do not find it in any way to replicate the psychological or energetic benefits of the ketogenic diet. Sadly, it would be a lot easier. It would. I think that's so helpful, but it certainly lines up with what I've seen in other people too. Now, if you had to specifically, and I know we've been going for a while, so we're going to probably maybe we'll do around two some time, but a quick note, because I thought from a historical perspective, this was fun to see at least.

Ketogenic diet as treatment for schizophrenia. (01:28:33)

So we were talking about ketogenic diet and epilepsy. Now not using the term ketogenic diet, no doubt, but this knowledge, this observation goes all the way back to Hippocrates that fasting can stop seizures. I always get a dumb smile plaster to my face when I see that, which is all just once new again, in a sense. And look, I mean, people had humors and spirits and all sorts of things that at least as it stands right now, we believe to be false, but doesn't mean they got everything wrong. So I do find the fasting maybe in the same bucket, cold baths for depression, which were prescribed for a long time. I think there may be something to that as well. Like you can do that and get some norepinephrine in the system, or you could use a selective norepinephrine reuptake inhibitor, but really is it that different? I'm not sure. So that is a digression. I just had to mention that because I love the historical note. In the case of schizophrenia specifically, because this can be such a challenging diagnosis slash condition with the recognition that one person next to the other, both with the same diagnosis could present very differently. Do you have any additional color to add theories for why this type of metabolic intervention in the ketogenic diet seems to help specifically with schizophrenia? Yeah. Yeah. So this goes back again to in many ways, this is nothing new. Oh, although this may sound new and groundbreaking. So in the 1940s, some of the first biological studies of people with mental illness included actually drawing blood from the veins of people with bipolar disorder and schizophrenia. At that time, they were usually labeled the same thing. They were usually just called schizophrenic. Oh, man, I would have been schizophrenic also. Man, another two for one, probably sadly, be careful when you're born, folks. Be careful when you're born. Exactly. They would draw blood from their veins and they noticed that people with these diagnosis had higher levels of lactate in their blood than people who did not have a psychiatric diagnosis. And that if they exercised them, the spike in lactate was even more pronounced. So this difference in lactate production has been observed for 80 years now. And that is a, for those of you who don't know, this is a metabolic marker of stress, either hypoxia, which directly stresses mitochondria because mitochondria are the only thing in the cell that's using oxygen or it's a direct kind of indication of mitochondrial impairment. The mitochondria can't keep up with the energy demands. And so the cell starts using glycolysis as kind of a backup fuel source and spills out lactate into the bloodstream as consequence. Now that's actually probably a really good thing because the lactate actually can be used as a fuel source from other cells. And so this lactate is a signal of metabolic stress, but it's an adaptive response. So the increased lactate, we don't want to just get rid of it and not address the metabolic problem. But then all of the neuroimaging studies beginning in the 1990s in particular when we had functional neuroimaging studies, the PET scans, all of the lines of evidence were converging on mitochondria and oxidative stress or glucose, hypometabolism or other things. In 2000, that was the year that the first group of researchers proposed the mitochondrial theory of bipolar disorder. By 2004, numerous other researchers were jumping on the bandwagon of the mitochondrial theory of bipolar disorder. Within a couple of years that quickly segued also to include schizophrenia and within a few more years that quickly also included major depressive disorder. So depression by polar and schizophrenia have all had enormous support from numerous lines of evidence. This goes to genetic, you know, what do these genetic things do? Like people who have these genetic predispositions to bipolar disorder, what are those genes actually causing? They're causing metabolic impairment in the cells. That's what they're causing. They're causing dysfunction at the synapse, which almost always includes mitochondria because mitochondria are hyperpopulated at synapses. And so in many ways, the mitochondrial theory of schizophrenia, bipolar disorder, depression, is actually nothing new. And I know those researchers, if this theory takes off, those researchers are going to be pissed because they're going to say like, "F, Chris Palmer, like a week we came up with this theory. This is our theory. This is not his theory." And in many ways, I fully respect and acknowledge and am filled with gratitude to all those people. I just climbed up on their shoulders and just added to what they've been doing. It's not like I'm creating this new, fanatical theory of what causes mental illness. I'm simply putting all of the foundation together and climbing up on other people's shoulders. I'm so glad to be having this conversation. And I suppose not to be too tend-centric, but in part because the descriptions, the theories, the underlying physiology, and how all these things tie together with respect to the presentation of, in quotation marks, psychiatric disorders map perfectly to my personal experience. And just because Tim considers himself an end of one doesn't prove scientific truth, however, it makes a lot of sense. There's no aspect of this that to me seems out of left field and a non-sequitur from the understanding of basic cellular metabolism. Right? It just makes sense to me that sure, if you have 20 children in a preschool class and you don't feed any of them lunch, that three hours later, you're going to have 30 grumpy kids and each grumpy kid is going to have a different behavior. Maybe once throwing blocks, maybe once crying in the corner. But the underlying cause is actually fairly straightforward and it is a fundamental underlying cause that can explain all of these different emergent behaviors rather than trying to treat the block throwing and the crying all separately with the different combination of drugs. That is a perfect analogy because right now the mental health field says this child has block throwing disorder, this child has grumpy disorder, this child has handwriting disorder and this child has defiant disorder, he spoke back to me in a really poor manner and we label those different things and then we assume they are different disorders and they certainly different behaviors and they might require different interventions. Like one child might need discipline and another maybe not but you can solve the whole all of it by feeding them. Yeah, exactly.

Why you need to take radical ownership of your own health advocacy. (01:36:49)

I'm very excited by not just the presentation of these ideas but hopefully the conversation and the debate that this will produce and I'm always so happy to have conversations like this on the podcast because I hate to say it folks but you need to be your own advocate. You have to be your own health advocate and you cannot expect other people to do it for you. Even the best intention and most competent of doctors, the way things are currently structured in our healthcare system, they may simply not have the available bandwidth and time depending on where and how they operate to do the requisite research or quarterback some of the exploration of these metabolic interventions and see you really need to take ownership, radical ownership of your own advocacy and this podcast, your book, the resources that you'll have on your website are some simple ways to do that. Unfortunately also the mechanisms, if you take an afternoon to try to educate yourself, they are reasonably easily understood. This is not quantum physics we're talking about which is not to minimize it in any sense but you can gain a basic understanding as a lay person of the building blocks that you are dealing with and I should say also because this is important that brain energy is not solely focused. I know we've dedicated a lot of time to the ketogenic diet but it explores many other levers and factors so not just diet and not just the ketogenic diet with in diet but exercise, relationships, removing metabolic toxins, there are other levers that you can pull with the objective of this type of metabolic reboot or metabolic rejuvenation and I suppose I would ask just a few questions in closing and one is knowing what you do of exercise, having looked at that as a variable. Are there any particular forms of exercise that seem to demonstrate effectiveness for mitochondrial health or addressing some of the conditions that you're used to seeing as a clinician?

Exercise And Health Considerations In Providing Off-Label Medical Advices

Physical exercise for optimizing mitochondrial health. (01:38:50)

At this point we don't have great evidence across the board for exactly which one. So there's one large study over a million Americans that looked at exercise as a prevention tool for mental illness or mental health and what they found was that group sports, cycling, gym activities were best. And I think the theme is cardio and pairing exercise with relationships, pairing exercise with social contact and so you're getting a twofer with that one. You're getting some bonding and friendships and other things. So I would say those are great. The research on exercise as a treatment for mental illness is actually very, it's a mixed bag and some meta-analyses have actually found that exercise does not appear to be an effective treatment for mental illness. And I talk about some of the confounding variables in that and one of the biggest ones is that a lot of medications that impair mitochondrial function which include a lot of psychiatric medications but also include like diabetes medications and some others. If you're taking medications that impair mitochondrial function, those people do not get the same benefits from exercise as people not taking those medications. And we have decent studies, randomized controlled trials of like older adults, exercising, half of them get metformin, half of them don't. The ones who did not get metformin had more mitochondrial benefits and adaptations than the ones who got metformin. Yeah, that's interesting. And we know that metformin appears to impair mitochondrial function at least in some people in many ways. But again, when it comes to psychiatric patients, antipsychotics and others are even more powerful. So with that said, I think the one thing I would say is zone two training. So let me just go to zone two training. And we know that if you improve mitochondria, you know, quantity, quality, that even if you're just doing it in the muscle cells, that translates to brain benefits. And you actually get more mitochondria and you actually get more neuroplasticity in the brain as a consequence of improving your muscle size. And probably zone two training is the be all end all. If you have enough time to do a lot of different types of exercise, I would absolutely say mix it up. Do some cardio, zone two training, maybe include some high intensity, but also, you know, do some isometrics, try to grow your muscles as large as you can or as large as you want. And sure, do some stretching and stress reduction, yoga, other things. Those can be helpful too. All the things. Yeah. All right. Zone two training folks get after it. And I will say also there is there is a book. It is somewhat outdated, but for people who are interested in the sum of the growth factor adaptations related to exercise like release of brain drive neurotrophic factor and things like that. There is a book. It is older. So I don't, I don't recommend it unreservedly because I think that there have been recent discoveries that would probably modify it, but called spark the revolutionary new science exercise in the brain. This is from 2013. So I think that it's worth reading at least a Wikipedia entry on. But zone two training and I will also just add to that that for people who may or may not recognize the word metformin.

A cautionary note for people using medication for off-label results. (01:43:24)

I just want to underscore something and again, feel free to interject. There's no biological free lunch guys. Like if you take a drug that has a high amplitude of effect in X, chances are that's not completely isolated within this complex closed system known as the human body. So there are people who have used metformin for life extension purposes. And I have long been, this is based on conversations with scientists to focus on metformin skeptical of the upside benefit of using metformin if you are in reasonably good metabolic shape. And this example you gave just goes to show it is not just naive, but it is sometimes dangerous, certainly not without risk to take drugs like this. And for people who have no context, I believe metformin is predominantly used as a medication in type two diabetes is that absolutely yes type two diabetes. Yeah, and it's probably off patent now and generics everywhere. I don't know. But I think it was a glucophage or glucophage. I never know how to say that on top of the macrophage, I guess. So glucophage, is that right? Am I getting up for the situation right now? I was screwed up. One of the two. Anyway, you guys get the idea. But if you're repurposing drugs, which many people are, and you got to be careful and some of them are very interesting like rapamycin, which is an immunosuppressant that is not a joke does exhibit some life extension in various species and animal models. But you got to be careful before you introduce sort of a red hot variable like that. You got to do lots and lots of homework. So anyway, that's a good cautionary note as well. So is there anything you'd like to add to that before we begin to wind? I think the only thing I'd like to add to the last thing you said is that if you've got type two diabetes and you're on metformin, there's almost no doubt. Metformin is the best drug for you to probably be taking. Agreed. I need a drug. However, I would also encourage you if you've got type two diabetes, type two diabetes can be reversed. You can use dietary strategies, especially low carb or ketogenic dietary strategies to reverse your diabetes, get off medication and dramatically improve your health. I have seen it time and again, and actually I did it with my father and it was nothing shorter miraculous for him. So yeah. I'll just add another side note, which is probably going to get me in trouble. So I'm going to say it again, folks. I'm not a doctor. I don't play one on the internet. However, one of the reasons I wish it were easier to study extended fasting in humans, which way back in the day you could, I mean, there were some astonishing studies with extended fasting and then that changed. But I have multiple anecdotes. I recognize a plural of anecdote does not equal randomized control. You know, controlled trial. However, I have numerous anecdotes of people I have direct contact with, probably five or six now, who have seemingly regenerated their pancreas' ability, through, I guess, what the beta isid cells to produce insulin as long term type one diabetics using one month of fasting per month. So for five to six months, they do the first, first week of the month, fasting for five to six months. And in multiple cases, it appears to be the case that some people regain the ability to produce at least small quantities of insulin. And that I think is thought to be probably entirely implausible by most folks out there.

Conclusion

Parting thoughts. (01:47:24)

But this is why I'm so excited to be engaged with the science. My foundation supports so much science because we just don't know. There are so many open questions. And in the meantime, that gives me all the more excitement about books like yours, brain energy, subtitle, a revolutionary breakthrough at understanding mental health and improving treatment for anxiety, depression, OCD, PTSD and more, because you are discussing interventions that have in the vast majority of people, very limited downside risk and that are compatible with many other therapies. They don't need to be a monotherapy. It's not either or. Is that fair to say? I mean, it seems fair to say and that's part of why I'm so enthusiastic about this. Absolutely. I think that we definitely have a mental health crisis in the world today. I mean, sky high record numbers of people suffering from depression, anxiety, burnout, etc. And there's no question that a lot of the strategies that I've discussed in the book will address those easy cases. I think the much more shocking and revolutionary thing that I'm also talking about, things like bipolar disorder, which you are, again, you are a perfect testament to so many people that if you have bipolar disorder, you do not have to be disabled for life from it. You do not have to take pills that are going to make you overweight or obese, type two diabetic, impaired cognitively. You can find other strategies to address bipolar disorder. You are simply a model person who figured it out on your own or talked to great smart people who gave you hints along the way or whatever. I don't know how the hell you figured it all out, but you are a shiny example for lots of people. And what I want to say is for all of you who know somebody with schizophrenia or bipolar disorder who are not like Tim Ferriss, there is a better way. So, I really appreciate you saying that I have had a lot of help along the way. And as I've had help, I have tried to showcase the people who have helped me on this podcast. And I think your work is going to help so many people. And it took me a long fucking time to grow through the darkness to find certain tools and what made me so resolute in my desire to have you on the podcast is I listened to you and I looked at the case studies and I listened to the case studies and I looked at the interventions and I said for fuck's sake, pardon my French, but you have assembled many of the tools that took me decades to stumble into eventually and then assemble into some type of portfolio for myself. And for God's sake, if I can save people a whole bunch of time and angst and maybe help them reduce the frequency or intensity or duration of their episodic experiences of these conditions, then I'm all for it. And the easiest way I can do that is to have somebody like you on the podcast. So Chris, I really appreciate you taking the time and people can find you on Twitter and Instagram at Chris Palmer MD, all things Chris Palmer at Chris Palmer. That's my phrase and not yours. Chris Palmer MD dot com. The book again is brain energy subtitle, a revolutionary breakthrough in understanding mental health and improving treatment for anxiety, depression, OCD, PTSD and more. I would emphasize the end more because as we've mentioned multiple times, really using the using, I'm going to really make the most of this preschool example. Just because the kids are all behaving differently, if they didn't eat in three hours, it is entirely possible that there is a shared underlying cause. So why not attempt to address that, especially when the downside risk is minimal and the approach is the implementation is known. There are many ways to approach these things. So Chris, thank you again. I really appreciate you taking the time and I am very optimistic that your work in this book will help many, many people. Thank you, Tim. Thanks for everything you've been doing and you continue to do. Thank you and for everybody listening. We'll link to everything in the show notes, all the names, various studies, etc. The book, of course, and everything else will link to you as usual in the show notes at Tim.blog/podcast. And until next time, be just a little kinder than necessary and that includes being kinder to yourself. If your compassion does not include yourself, it is incomplete. Thank you for tuning in. Thank you. in the show. for all the names, all the names, all the names, all the names, all the names and all the names. We'll see you in the next one. Bye. for all the names. in the show. for all the names, all the names, all the names, all the names, all the names, all the names.