Ketogenic Diet Review and Update with Dr. Matt Bernstein

Explore the transformative potential of the ketogenic diet for mental health with expert Dr. Matt Bernstein, a pioneer in metabolic psychiatry. Learn how targeting metabolic dysfunction can profoundly improve psychiatric outcomes in bipolar disorder, schizophrenia, depression, and epilepsy, with fewer side effects than traditional treatments. Discover actionable insights on diet, metabolism, and brain health backed by the latest scientific research. Tune in to revolutionize your understanding of nutrition's role in mental wellness! By listening to this episode, you can earn 1.75 Psychiatry CME Credits. https://www.psychiatrypodcast.com/cme-program Link to blog. https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-237-ketogenic-diet-review-update-dr-matt-bernstein Link to YouTube video. https://youtu.be/4AtMlzuqiRI

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:13David Puder?

  All right. Welcome back to the podcast. I am joined today with Dr. Matt Bernstein. He is a psychiatrist in, let's see, multiple roles at this point, but you were mostly private practice for most of your career.

• 0:27Speaker 01

  Actually, I started off as an inpatient doctor at McLean Hospital on the schizophrenia and bipolar inpatient unit for about eight years. So, and I've always throughout my career taken care of people with serious illness. It's a real passion of mine.

• 0:40David Puder?

  Okay. So you did inpatient for eight years, then you went outpatient psychiatry.

• 0:46Speaker 01

  I work at this program that is a team-based approach with people with complex illness called Ellenhorn, and I'm the chief medical officer there. And I also have a private practice. And I also now have opened a program called Accord, which is focused on metabolic treatments for mental health.

• 1:02David Puder?

  Okay. And so conflicts of interest, we were talking about this. Is it a conflict of interest that you're part of Metabolic Mind as an advisory board? I think I want to mention that. I think you've been given that position because you are bringing patients into ketosis in your practice and you have some expertise on this. But you're not like, there's no drug companies, there's no supplements that you sell, you don't have any, other than your private practice and your roles there.

• 1:30Speaker 01

  That's right. And Metabolic Mind is a nonprofit focused on education around metabolic and mental health.

• 1:37David Puder?

  Okay. Yeah. And so today, we're going to be talking about the ketogenic diet. It's going to be kind of an update. I had Chris Palmer on here a couple of years ago when his book came out. And there have been quite a bunch of studies since then. And I wanted to go through each one of those with my audience. I also wanted to kind of pull from you just the practical things that you've learned. You've been putting people into ketosis for a little over three years, you said, as kind of part of the practice of what you do with severe mental illness, with bipolar, with schizophrenia, and with other types of mental illness as well.

• 2:15Speaker 01

  Correct. Yeah.

• 2:16David Puder?

  And just to give my audience kind of like an idea. From what I learned from you is when you started three years ago, you were doing this really by yourself. You would put people in intermittent fasting. You would see if they responded positively that and then maybe move them to ketosis later on. And then in the last year, you've started this kind of inpatient setting, not traditionally like what we would consider like a partial program, but people come, they learn how to, they get into ketosis. Is that correct?

• 2:49Speaker 01

  Yes. Well, just to clarify a little bit, when I was doing in private practice, I would often combine intermittent fasting with MCT oil, which is medium chain triglyceride oil. It's a derivative of coconut oil and it's extremely ketogenic as a fat. So people may have heard of this drink called a bulletproof coffee where they put butter and MCT oil in it, or heavy cream and MCT oil actually tastes a little better. So if someone's fasted overnight for 12 hours and they have one of those drinks in the morning with the MCT oil and the fat, but nothing else, and then they can wait another four or five hours before they have their first meal, they often can get some ketones just from doing that one intervention. Not high levels, but a little bit of ketone, a little bit of ketosis,

• 3:33Speaker 01

  maybe a BHB, beta hydroxybutyrate level of, let's say, you know, 0.3 or 0.5. But that's enough for a lot of people to feel a difference. In many ways, they often feel some cognitive clarity, some extra energy. They don't feel hungry. And so that's a little taste of sort of what ketosis might start feeling like for them. And many people try that and love it and feel energized. And they say, well, you know, they come back to me and say, what was that? That was, that was amazing. That wasn't just like coffee. That was super amazing. And then they're really open to learning more about this whole science and potentially going further in their metabolic therapy.

• 4:11David Puder?

  Really cool. Okay. You know, I first got introduced to the ketogenic diet actually through, I was at a conference giving a talk on psychogenic seizures. I was running a program for people with psychosomatic issues. And so I was at this neurology conference and it was put on by some ketogenic foundation. And I was like, what is this? Like, is this really being used for people with seizures? Like, how does that work? And so tell me like, a little bit of that history, just to kind of prime us for this idea.

• 4:46Speaker 01

  Sure. Yeah, I mean, we can go back really far in history to, you know, pre-agriculture times. And we can go back to Hippocrates where they were using fasting to treat seizures in 5th century B.C. But of course fasting is not a very sustainable treatment to maintain ketosis. I mean, eventually you have to eat and you'll break your ketosis unless you're eating ketogenic. So that didn't really get figured out until 1921. A doctor at the Mayo Clinic published a small case series of some kids that he put into a, what he called a starvation mimicking diet or a ketogenic diet. They knew about ketones at that point. And he figured out how to create a diet where the body will make high levels of ketones.

• 5:31Speaker 01

  And he reversed epilepsy in three kids, I think it was. And then, you know, published that and published the theory behind it. And then it really took off. People started publishing rapidly in the 1920s about using ketogenic diets to treat seizures. And that literature just kept growing where eventually there's now 12 randomized controlled trials showing that ketogenic diets work in both kids and adults with epilepsy. And it not only works, it works with people who are drug resistant. So that's really important point because some of these kids and adults are on, you know, three different seizure medications at a time. They've tried, you know, eight or 10 of them. They still can't get control.

• 6:14Speaker 01

  And then the ketogenic diet can still work in those really treatment refractory situations in a good percentage of the time.

• 6:23David Puder?

  Yeah, I'm curious, what level of the beta hydroxy butyrate are they getting to to get into a place where it's actually helpful for their seizures?

• 6:34Speaker 01

  Well, interestingly, you know, the literature is pretty old and people weren't measuring beta hydroxy butyrate levels daily through most of these trials. You know, often they're measuring it, you know, once a week or even less. And so we don't even know in the epilepsy literature that well, how, you know, high of a level of BHB you need to get most of the time. They more measure it based on the ratio of the diets. That was usually the sort of how they measure the intervention. So in a ketogenic diet, we think of a ratio, the classic one, when in 1921 was a four to one ratio of calories from fat compared to calories from protein and carbohydrates combined. And yeah, almost no one does a four

• 7:17Speaker 01

  to one anymore, ever. I mean, that's like a really, really extreme diet. You're getting, you know, almost 90% of your calories from fat. And you think about that, you're going to be protein deficient on that diet, almost certainly. You're even below probably the RDA, US RDA, protein levels, which are too low for most people anyway. And so what they learned also, you know, as they were doing these studies in epilepsy is that you could reduce the ratio and still get the same benefits in almost everyone. And so they ended up with more like two to one ratios, or even 1.5 to one ratios. There was even a study that was really interesting at the Mass General epilepsy clinic, they had people on a waiting

• 8:00Speaker 01

  list to get into the ketogenic diet program. And they put them on, you know, just on their own, the families, they just told them, eat this low glycemic index diet, which is really more liberal, much more liberal than even like a one to one diet, you know, but it's all, all the carbs are from whole foods. And they're still low carbohydrate. You're not, you're not eating anything that's going to raise your blood sugar rapidly. And those kids did almost as well as the kids on ketogenic therapy. They didn't even, they weren't able to correlate it with the beta hydroxybutyrate levels. So, and we'll get to this in one of the studies, you know, we are really still early in trying to figure out the science of, does it, do people really need a BHB

• 8:40Speaker 01

  level in a high range? And when I say a high range, I mean, above two or 2.5, that's, that's really deep ketosis for, for someone. But could there, you know, could people get some of the same benefits, at least a subset of people at a much lower BHB level? We don't really know all the answers to that yet.

• 9:00David Puder?

  Okay. Yeah, that's good. This is good, good practical information because, you know, as we're thinking about our patients with mental health, we want to monitor like compliance. I know compliance is to some degree related to the success of if, if they're, if this is going to be successful.

• 9:17Speaker 01

  And interestingly, it's, it's a treatment where we actually can measure the level of the treatment much better than with most medication therapies. So I can see if someone's, you know, their BHB level, I like to check them daily for people, especially in the first few months. And we really can see, is the, is the treatment causing this biomarker to change that I want to change? As opposed to, you know, if I prescribe any antidepressant and most antipsychotics and mood stabilizers, I can't know even what the level of the treatment is in their blood. Whereas in this, I can, which is cool.

• 9:51David Puder?

  Okay. So let's talk a little bit about the bidirectional relationship between metabolic issues and brain disorders. And I, I almost recognize like, because I'm so much on Twitter and there's so much antipsychiatry there, there's this kind of sense that, you know, schizophrenia isn't even a brain disease, depression isn't even a brain disease. So, so we're going even further than that and saying, actually, no, and metabolic stuff influences this to a high degree. Tell me about the bidirectional relationship here.

• 10:22Speaker 01

  Yeah. Yeah. Well, of course, these are brain diseases. I mean, that, that I think, you know, is without a doubt. We, there's so much data. But, but what we are saying though is that You know, the mind and the body are intricately connected and that the brain is influenced by the metabolism, what's going on all throughout the body and the metabolism in the brain itself. So, so, you know, there's, there's multiple studies. I think the one that I really find interesting is this one, it's Perry from Jammer Psychiatry. I think it's 2021. And they, they measured kids longitudinally. So this not only was showing a bidirectional relationship, but showing a, you know, before and after a little bit. So these kids, they

• 11:05Speaker 01

  were measuring their metabolic health and mental health and they followed them for a lot of years. And the kids with the worst metabolic health in childhood had much higher risk of severe mental illness when they got into their twenties. And so they looked at I think the, the data showed that the highest quartile of insulin levels at age nine compared to the lowest levels of insulin at age nine, there was a threefold increased risk of schizophrenia in their twenties. So I mean, that's a really big change just from insulin levels. And we know from other studies that insulin resistance is involved in all these mental illnesses, including schizophrenia.

• 11:45David Puder?

  Yeah, that, that doesn't surprise me. It kind of makes me think about how there's a lot of data on increased rates of schizophrenia in lower SES groups. And I think about how lower SES groups often, just by the nature of what's available, are kind of consuming more highly processed foods, increasing insulin, increasing metabolic disease. And maybe that's a big part of it. Probably there's also just increased risk of different types of traumas, neglect, that kind of stuff as well. But, okay, so this is, this specific study, it's called Longitudinal Trends in Childhood Insulin Levels and Body Mass Index and Association with Risks of Psychosis and Depression in Young Adults.

• 12:29Speaker 01

  Right. Yeah, the other, the depression part, I think it was at puberty, the, the kids who gained the most weight had a fivefold increase risk of major depression in their twenties.

• 12:40David Puder?

  Yeah, these odds ratios are very high.

• 12:42Speaker 01

  Yeah.

• 12:43David Puder?

  So this is an adjusted odds ratio of five with psychosis and psychotic disorder 3.2. So, wow, very high.

• 12:56David Puder?

  Puberty onset major increase in BMI was associated with depression odds ratio 4.46, but not psychosis. So people who had gained weight right around puberty, that was more depression.

• 13:11Speaker 01

  So that's an interesting one because there's some before and after effects. So a suggestion of causality, certainly not proof, but some of these other studies look at rates of obesity leading to higher rates of depression. And if you're depressed, you have a higher risk of becoming obese afterwards as well. So that was a separate study. And similar things with diabetes. And there's some work by Cynthia Calhoun, where talk about one of her other papers, where she looks at much worse course in bipolar disorder if someone has insulin resistance, prediabetes or diabetes, they have a much more chronic and tractable course of their bipolar illness as well. So there's a lot

• 13:56Speaker 01

  of things in the literature about this bidirectional relationship.

• 14:02David Puder?

  Part of me wonders with that, if the medications are part of that difficulty, right? Because let's say someone has more severe mania, they may need higher doses of medication. Those higher doses of medication may naturally come with increased obesity, like if they're on lithium, Zyprexa, and they're still not getting better. And then you increase the Zyprexa, and now they've gained maybe 20 or 30 pounds in the next six months.

• 14:36Speaker 01

  Yeah, you're bringing up a super important point. These medications, I worked on an inpatient unit, I appreciate greatly that these medications are wonderfully important and effective in acute illness. And they save lives. I mean, I've seen medications save lives dozens and dozens of times when people are acutely ill. I've also seen ECT save lives. And I'm a big believer in medical treatment for severe illness. But what I think I'm coming to is that they're really good in the acute phase and they may actually impair recovery. They may impair long-term outcomes if we continue to use them at high doses in maintenance.

• 15:21Speaker 01

  And that that's that's a real concern. And of course, I have many people on maintenance medications and, you know, I'm a practicing, you know, psychopharmacologist. So, but it's really concerning to me that I think the data is now starting to really show us how dangerous they are metabolically and how important metabolism is for long-term outcomes.

• 15:40David Puder?

  Right.

• 15:41Speaker 01

  And so, you know, put this all together and I think as a field, we have a real problem to contend with.

• 15:48David Puder?

  Yeah, you know, I'm an outpatient psychiatrist too, and I treat people long-term. And it's like, it's kind of like you get them stable. They need to be on the antipsychotics. If someone's psychotic and they're stomping the shower because they see spiders and they're screaming. You know, this is a traumatic state to leave them in if we don't treat them. And I think people are antipsychiatry who just think, oh, why don't you just use, you know, natural means? Why don't you just tell them to exercise? It's like, no, you don't understand severe mental illness if you think you can get someone like that to exercise, period, right? You need to get them out of the psychosis. But then, once they're stable, it's like, okay, how do I get them to exercise? How do I change their diet?

• 16:32David Puder?

  And then how do I carefully monitor them? There's a lot of nuance there and like decreasing their meds. Some people are super risk averse and so they never decrease the meds ever. I'm a little bit more willing to decrease the meds and then try to catch early on if they're decompensating. But not everyone's like that.

• 16:55Speaker 01

  Yeah, I mean, I think this is a good opportunity to talk about this paper by Lex Wonderink from 2013. If we can go into that now because it's exactly on this topic. And you know, this is not a new paper. This came out, you know, 2013. It's a group from the Netherlands. But I think it's incredibly important for everyone to know about. This is super influential in my career, treating people with antipsychotics. So they were doing a dose reduction study and people, they took, they took all the people who had first break psychosis in their Cashman area. And they offered to be in this study about dose reduction and discontinuation of antipsychotics.

• 17:37Speaker 01

  So they got them stable, first episode psychosis, six months of stability to enter the study. And then they put them in a randomized into two groups. So one was dose reduction, dose discontinuation in collaboration between the patient and the doctor. So that's really important. It wasn't just a schedule that was preordained. You know, the doctor and the patient both could input into what the right timing was of dose reductions and, and even to stop dose reductions if they wanted to. But their goal was to try to get the dose as low as possible and even towards zero if they could. And the other arm of the study was maintenance treatment, sort of by APA guidelines. You know, a low dose of an antipsychotic, but, but not changing, not trying to reduce the dose towards discontinuation.

• 18:22Speaker 01

  And they kept them in that, you know, randomized setting or, you know, different arms for 18 months, I believe. And in that first 18 months, as we would imagine, there was more relapse in the dose reduction group, actually more than double the relapse rates. So, you know, like 43% relapse in that first 18 months versus, I think, 21% relapse. So, you know, if you stop there, you say, you know, why should anyone be reducing medication? You know, this is a bad idea. But they didn't. They, they did a follow-up five years later. So it was seven years after the first episode, five years after they were first in that, in that randomized treatment groups.

• 19:06Speaker 01

  So essentially after the 18 months, let's say, you know, they They were allowed to do whatever they wanted. You know, so it was just sort of, you know, go and live out in the wild, basically. Not, you're not in a study anymore. But then they contacted them again five years later and they did this very thorough evaluation on, on like 80% of the people that were in the original study. So they ended up studying over 100 people. It was like 103 people at the seven year mark from their first episode of psychosis. And they had tremendously improved outcomes. So they were measuring this very fancy functional recovery scale and they were measuring the PANS. Those are their sort of two things that they were evaluating. And both were much better in the dose reduction group at seven years.

• 19:51Speaker 01

  So that was really fascinating. And in the, in the end, they did a, you know, a Kaplan Meyer plot of relapse rates and the lines ended up crossing. So you had more relapse in the dose reduction group in those first years, but by about year three or four, they were having fewer relapse rates than the people who were in the maintenance treatment group in the first 18 months. So really, really interesting. And just to give you, you know, the listeners a little bit of, of the data, in terms of symptoms on the PAN scale at the seven year mark, they were almost the same in terms of symptomatic recovery. You know, about 69% in the dose reduction group, 67% non-significant change in terms of symptomatic remission.

• 20:35Speaker 01

  But the functional remission was way different. So the dose reduction group at seven years had a 46% functional remission compared to a 19.6% functional remission in the maintenance group. And if you add those two things together, symptomatic and functional remission, they had this term called recovery. You had to have both symptomatic remission and functional remission to meet the criteria for what they called true recovery. And true recovery rates in the dose reduction group were 40.4% versus 17.6%. It's a huge difference. The p-value is, you know, .004. And so, you know, that's, that's an amazing study.

• 21:18Speaker 01

  It shows that, you know, if we try to reduce doses in those first periods of time, maybe not in the first six months, but if you wait for some stability and then, you know, in the next 18 months, you really try to reduce the dose, you're going to get better long-term remission rates.

• 21:35David Puder?

  Yeah, that's really interesting. There's so many questions I have from this. Like, one is, are you reducing people with borderline personality disorder? Because sometimes they can present early on with something that looks like psychosis, suicidality, you know, because we know from other data that those patients don't need to be on antipsychotics, right?

• 21:56Speaker 01

  Yes, although, you know, first episode psychosis, I don't think there's too many borderlines lumped together in a first episode psychosis study. I mean, you know, working on an inpatient unit, someone comes in, if they're really psychotic, I mean, they're hearing voices and they're having these sort of first rank Schneiderian psychotic symptoms, you know, thought broadcasting, thought withdrawal, that's not just borderline personality disorder. And so, you know, I do assume that they did a pretty good evaluation. You know, this is a pretty serious academic group that did this study. So, yeah, maybe a few slip in, but I don't think that's a big, big portion of it.

• 22:34David Puder?

  I think that the key takeaway from here is that we may have good reason to be a little bit willing to try the dose reduction.

• 22:45Speaker 01

  Yeah.

• 22:46David Puder?

  And to monitor and then to also, you know, think about other ways of treating people long term.

• 22:54Speaker 01

  Yeah, I agree. I think it's important that the psychiatrists recognize that the patients are often coming in and saying, you know, can I be on a lower dose of this medication? You know, I don't like the way it makes me feel. I'm gaining all this weight. I'm sluggish. I'm tired. I can't think. And the psychiatrist is thinking to themselves often, well, I'm taking a huge risk to lower this dose. We have a risk of some relapse. And that's seen in the study too, of course, there is that risk, but there's also reward potential in the long term for this person. And that's just, that's an important just other side of the ledger for people to have in their minds that it's not, you're not just doing this because someone might feel better in the short term, have fewer side effects. They really have a much better chance of recovering, you know, five, seven years

• 23:38Speaker 01

  later, if we try to get their dose down. And there's real science there. And there's been some follow-up studies that have looked at the same question and come up with some similar things, but no one has done the full seven-year study, as far as I can tell. It's really the length of time that mattered because, you know, the relapse rates were so much higher in the first few years. If you just stop there, you just think, you know, this is a terrible idea. And so that was the really important part of the study is how long the follow-up was.

• 24:04David Puder?

  This is good. I think there's been a sense in the psychiatry community that if someone has schizophrenia, they probably need to be on meds the rest of their life.

• 24:11Speaker 01

  Right.

• 24:12David Puder?

  This is not the other extreme where it's like, just take them off. This is you have a provider who knows the patient, who's taking educated moments of reduction.

• 24:26Speaker 01

  Right.

• 24:27David Puder?

  And so I think that that is part of the study as well that we need to pay attention to. It's not just you're listening to this, you're a patient and you're like, okay, I'm just going to get off this medication. It's like, well, you're, you're going to find a psychiatrist or a provider who's maybe willing to go down, monitor, go down, monitor, you know, in a very sort of mindful way.

• 24:50Speaker 01

  Yeah. And there's a whole art and science to medication reduction as well, which I don't think we have time to go into all of that right now. But, you know, it's important to look at certain things. A couple of things I would say is, you know, make sure the person's not using substances. If you're thinking about dose reductions, make sure they've been stable for a period of time. Make sure there's some family support and other eyes on someone, not just your own, to catch things early. And it's really important to catch, catch things early and potentially go back up on the dose, especially if it's getting serious. Although we may tolerate a little bit of symptoms. That's part of the art of this is, you know, when we first reduce, we might get a little more symptoms, but is it an amount

• 25:31Speaker 01

  of symptoms that is tolerable and containable without it turning into a full episode? That's, that's sort of the art of it and how well you know your patient and things like that.

• 25:40David Puder?

  Yeah, that's good. Okay. So let's talk about patient selection for metabolic interventions.

• 25:46Speaker 01

  Yeah.

• 25:46David Puder?

  What are some of the things that jump out at you as like, this is the person that you're thinking about using these things?

• 25:52Speaker 01

  I wish I knew a lot of science behind this. It's right now, it's really, we're, we're still in the early stages of figuring out who this is going to be best for. So, I mean, the biggest criteria in my mind as a clinician is, can I get them motivated to do it? Because if they don't want to do it, we're, we're not going to get anywhere. And so if someone's willing to listen to me about some- Some of the data and some of the anecdotes and some of the potentials of benefits for them. If they're willing to understand how to do this, are they organized enough to be able to do this at home? Or do they have enough support around them where family and a team that can help them do this? Those are end up becoming those practical things are probably the most important criteria right now.

• 26:37Speaker 01

  You know, do they still have symptoms that are bothering them? Do they have a they have a reason? Do they want to be on a lower dose of their medication? Are they having symptoms that are still getting in the way? Are they having side effects that are getting in the way of their full recovery? You know, what's motivating them to do this, to do something different?

• 26:56David Puder?

  Yeah, I think since, uh, you know, I've been talking about exercise diet for a decade with my clients. Not everyone's ready for it, right? But I slowly talk about it when they have pain points when they come in. You know, like, hey, can we try instead of changing your med? Can we try to address the pain point with exercise or with diet? It's like, right? They're not always amendable to it. Absolutely. Sometimes they are.

• 27:26Speaker 01

  Sometimes they are. And I think, you know, it's really another thing that I look at and try to use as a motivational point is, you know, do they have another metabolic condition going on that we can also treat with this intervention? And that may be the thing that motivates them the most, actually. And it's okay if my patient's main motivation is to lose the 40 or 50 pounds that they gained on their medications. Even if my main motivation is to improve their symptoms and reduce their side effects and improve their brain health. You know, we can sort of meet in the middle and, you know, come up with this and agree on the same plan, even though our motivations might be, you know, somewhat different. Sometimes they they just say, oh, if it's going to help me lose weight, great, I'll do it. And they don't really believe me about the mental health benefits. But then a couple of months later, then they believe me.

• 28:12David Puder?

  Yeah.

• 28:13Speaker 01

  Yeah.

• 28:13David Puder?

  Yeah, I find myself pulling up some of the studies and just showing them the data, you know, or I'll I'll send them the studies or send them little summaries of the studies. Like I had an OCD patient the other day and I was like, look, in this one case study, that there's this person that had a benefit. We could try this and see, you know, if it has a benefit. I also agree, side effects, you know, one of the things that people have a lot when they get into outpatient psychiatry is they have side effects, sexual side effects, you know, reduced libido on SSRIs on different medications. And so like, they may want, they may not care about that when they're in the midst of a suicidal,

• 28:54David Puder?

  you know, place. But when they get more stable, they start caring about these kind of things. They start caring about their weight again.

• 29:02Speaker 01

  Absolutely. Yeah. Yeah. They start, you know, people, and they realize that their quality of life is not as good as they want it to be, even if their symptoms are better. You know, they don't have the functional recovery that they're hoping for. And that's always what I have my eye on. It's not just reduction of symptoms. I mean, all, so many studies are all just about looking at, you know, these scores on these scales, which have to do with symptoms, and that's important. But, you know, it's really what matters is can people live their life in the way that they want to? And often, the side effects are really getting in the way of that.

• 29:34David Puder?

  The other thing, I don't know if you felt this, but with patients who are prediabetic, they have metabolic disease, these patients sometimes can be a little bit more motivated. And I tell them, like, look, if, if you get to a point where you need to be on insulin, you will gain 15 pounds in the first couple of months. I remember reading those studies where, you know, they started people on insulin and they gained weight. And I was like, wait, why are they gaining weight right away? And it's because the insulin is shoving the extra glucose into fat.

• 30:02Speaker 01

  That's right.

• 30:03David Puder?

  That's what the, that's what happens when you inject insulin.

• 30:06Speaker 01

  Well, and not just insulin. Most diabetes treatments are actually making the disease worse over time. You know, they're, they're reducing glucose, which is great, and, you know, reducing some of the secondary effects. But they're ultimately causing more insulin and Gaining weight and more insulin resistance, which is essentially furthering the fundamental process of diabetes, which is insulin resistance. And I can't not mention the fact that ketogenic diets reverse type 2 diabetes as well. And that's been shown in multiple long-term studies now. And that's a whole separate topic of how effective ketogenic diets are in these really severe conditions like type 2 diabetes and epilepsy.

• 30:49Speaker 01

  And yet, they are not considered first-line treatments at all in the medical community. I don't want to get on too much of a soapbox, but that's something to really ponder, I think, for people. We have these treatments, dietary treatments, that reverse these really significant diseases. And yet, we don't offer them even to people. Most of the public doesn't even know the fact that ketogenic diets reverse type 2 diabetes. Most doctors don't even know that.

• 31:17David Puder?

  Yeah. Yeah. Yeah, I was looking into this before it became a thing for psychiatry. I have a couple of textbooks that I got on ketogenic diet when I was looking at it. It's like, really interesting that it... I think it's hard to get people on it. And so, I think we'll eventually get to a part of this talk where it's like, let's talk about the practical side.

• 31:39Speaker 01

  It's really going against the grain of, not to use a pun, but against the grain of how we eat and how we've been taught to eat by our government and how the medical community teaches people how to eat. This is really going against the grain. So, yeah, it is... It does feel like a radical thing to do, to go on a diet like this.

• 32:01David Puder?

  Let's take some time going through some of the key studies that have come out in the past couple of years.

• 32:07Speaker 01

  Sure.

• 32:08David Puder?

  On ketogenic diet and mental health. And by the way, if you're listening to this and you're getting lost in the studies and you want to look at it deeper, we are going to have a good handout. We're 24 pages in right now. So, we'll have that on the website, psychiatrypodcast.com. Let's start with Culkin et al., 2022.

• 32:27Speaker 01

  Yeah.

• 32:29Speaker 01

  Yeah, so really interesting study. They call this the Trio BD Study, treating insulin resistance with metformin as a strategy for treatment-resistant bipolar depression. So they took a group of people with treatment resistance, you know, very well-defined treatment resistance. They had to be failed at least two standard treatments for bipolar depression at the right doses for the right amount of time. Most of them had been on at least eight treatments lifetime for their bipolar and still were stuck in depression pretty chronically. So these are pretty ill people. There were 45 of them, both bipolar one and bipolar two, and all of them also had insulin resistance, measured by this score called the HOMO IR,

• 33:11Speaker 01

  which is kind of complicated, but it's an easy blood test to order, and I order it on everyone now. You know, and I think that's a good clinical pearl we can get into later. What is the HOMO IR? So it's a fasting insulin and a fasting glucose, and they do a calculation based on a formula, and that tells you essentially how insulin resistant someone is. It's not the best measure of insulin resistance, it's just the easiest one to get. The real best measure of insulin resistance is a glucose tolerance test, which is a real bear of a test to order and for anyone to do. So we generally don't do that, and we do this shortcut test called the HOMO IR. So it's just a single blood draw, doesn't cost that much. You can

• 33:53Speaker 01

  even just get a fasting insulin without the fasting glucose, or you can do the calculation yourself and save a little money. So it's a really important test, I think, because it's essentially, that's the root cause of prediabetes. That's the step before prediabetes, even if someone's hemoglobin A1C is nice and, you know, nice and low, 5.1 or 5.2, and you say, great, this person looks metabolically healthy, they still might already be insulin resistant. Because that's insulin resistance starts, you know, sometimes 10, 15 years before the diabetes process. And insulin resistance is highly correlated with brain illness and mental illness. And in this study, we'll see how important it is for bipolar depression. That's the important point about this study.

• 34:37Speaker 01

  So they randomized these 45 people, 25 on placebo, 20 on metformin, high dose metformin, which people are probably familiar with as a diabetes medication that does have some effect on insulin resistance. And so of those 20 who were on metformin, 10 of them converted to being insulin sensitive on the HOMA IR. And then one of the people in the placebo group actually converted to being insulin sensitive. And then they followed these people using the Madris and other scales as well. The Madris was the primary outcome at week 14. And they had a really significant difference in the people who converted to being insulin

• 35:19Speaker 01

  sensitive versus the people who remained insulin resistant in terms of their response on the Madris and on these other scales like Hamilton Anxiety Scale, the CGI Clinical Global Impression for Bipolar, and the GAF Scale. All were significantly better in the people who were converted to being insulin sensitive compared to the people who remained insulin resistant.

• 35:43David Puder?

  Wow, yeah, this is really interesting stuff. And this is just metformin?

• 35:47Speaker 01

  Just metformin.

• 35:48David Puder?

  We're not talking about diet. We're not talking about exercise. We're just talking about metformin.

• 35:53Speaker 01

  Yeah, just metformin. Now, metformin is, even in the study, you see is not that powerful at reversing insulin resistance. It only was able to do it in 50% of the people, and they were using high dose metformin, which, as some users probably know, does have some side effects. There's a lot of GI side effects when you get the dose of metformin up to 2,000 a day, which is generally what they were trying to do in the study. Some people stayed on 1,500 a day. And even at that high dose of metformin, only half of them could convert to being insulin sensitive. But it is something to know for someone who isn't willing to do big dietary changes, but they're willing to take metformin. You know, this is something to consider. Measure their insulin resistance. See if they're insulin resistant.

• 36:36Speaker 01

  If they are, you know, put them on a high dose of metformin and see if they can convert to being insulin sensitive and see if that improves their bipolar depression. You know, I think this is a, this is a really well done study, you know, quadruple blind, placebo controlled, you know, this is, this is a rigorous scientific study. So, you know, this is the kind of thing, it's small, of course, you know, only 45 patients, but, but I think there's enough there to say, given how safe metformin is, that it's a reasonable, a reasonable thing to try for people who aren't willing to do diet.

• 37:06David Puder?

  Yeah. So, okay, just a couple of things to reiterate here. Homo IR is how they define insulin resistance and we can order this fasting insulin, fasting glucose, and we can, we can put this in calculators online. It's like you multiply them times each other and you divide it by 405.

• 37:28Speaker 01

  Right. Well, it depends on what units. You have to pay attention to the units that you're giving it. Yeah. These, these are using the, not the units from the US, they're the Canadian units, which are different. And, or, you know, at Quest Diagnostics and probably the other big labs around, you can just order the home IR and, and they'll do it for you. And there's actually a little bit of a fancier one that Quest Diagnostics does, they send it to a specialty lab and they use the C protein that's part of insulin as well and it makes it a little more accurate.

• 37:58David Puder?

  Oh, that's cool.

• 38:00Speaker 01

  Yeah.

• 38:01David Puder?

  I also think that sometimes ordering a lab like this and showing a patient like, hey, you are insulin resistant.

• 38:08Speaker 01

  Right.

• 38:09David Puder?

  Hey, we need to start treating this. We have a target, we have a number. There's something about that that can increase. It's, it's not like we're just talking about diet and exercise and, you know, we're, we have a, we're talking about something physiologically going on that we can intervene, especially early, before it becomes a bigger issue.

• 38:31Speaker 01

  It's an incredibly important point. Yeah, people really believe lab work. Like, something about that feels so real to my body here, I need to fix it. And, you know, no matter what we say about diet, because it'll help your, your mental health, they may not believe it, but when you start seeing the lab work, that really gets people's attention. I've found that to be true almost universally.

• 38:56David Puder?

  Yeah. Okay, let's talk about Sethi et al. 2024. This was a four-month pilot trial involving patients with bipolar disorder and schizophrenia. Let's go through this one.

• 39:09Speaker 01

  So yeah, so Shabani Sethi has a metabolic psychiatry clinic at Stanford, and this is her pilot trial. It's important to say right off the bat, the rest of the trials we're talking about do not have control groups. So these are, these are uncontrolled trials. And so, you know, that's just a caveat we have to put out there.

• 39:28David Puder?

  And I think that's, that's the state of where we're at today, which is important that this is, this is just the beginning of the field. But I think it's important to educate my audience on this, despite there not being randomized trials, you know, that we're maybe a couple of years away from randomized trials. I'm guessing if we were to do an update in two years, we'll have two or three of them. How many do you think we'll have in two or three years?

• 39:55Speaker 01

  I agree with you. Yeah, a few. But there's probably about five or six randomized controlled, big randomized controlled trials going on right now. Some of them will probably take a little longer than two years to come out. But they're, they're bigger trials, they're randomized controlled trials, and almost all of them have a really cool basic science component. And we're going to get to one of the, one of the pilot trials has an MRS component. But all of these ones that are going on now have metabolomics and genomics and MRS or functional MRI. So we're going to see a lot more science coming out in the next couple of years, which I'm incredibly excited about. But yeah, the state of the field, we're very early in terms of the clinical data. I mean, we're really telling a whole story here, you know, about not just, you know,

• 40:40Speaker 01

  the power of these diets, but how important it is to think about reducing medications. How can you reduce medications with something else to take its place? A whole story about having biological markers to look at as psychiatrists when we're doing interventions. But yes, the clinical trial data is in its infancy and, you know, most of it is non, non-controlled, as we said.

• 41:05David Puder?

  Okay, so in these participants, a large proportion, 76% were bipolar, 24% some form of schizophrenia. They had a high adherence to ketosis, eighty to a hundred percent, which is really good.

• 41:19Speaker 01

  Yep. And, and just this was a one point five to one diet as well, without patients. So not a heated ratio, you know? And, you know, they weren't measuring ketones daily, they were measuring them weekly. And they only said adherent was greater than a point five BHB, which is not very high from a clinical perspective. So we're not even talking about getting people into deep ketosis here. We're just talking about kind of a, a mild ketogenic diet that people could follow.

• 41:48David Puder?

  Good point, good point. It's really helpful. And I think that's, that's helpful because, you know, when I, when I put patients on this type of diet, what I do nowadays is I have like the keto mojo.

• 42:00Speaker 01

  Yeah.

• 42:01David Puder?

  And for a hundred bucks, they can get a bunch of test strips, they can get a little device, they prick their finger, they don't have to do it every day, but I want to see, you know, are they getting into ketosis? And so this, according to this study, point five would be getting into far enough to get the benefit, which is interesting.

• 42:19Speaker 01

  Yeah. Yeah. But, you know, people may get more benefit if they get, and I see this clinically, they may get more benefit, they get their levels above one or, you know, with, with more severe illness like schizophrenia, bipolar, schizoaffective, or severe major depression, I, I actually try to shoot for above two a lot of the time, especially in the beginning, to try to really see a true, a robust response, really robust response.

• 42:42David Puder?

  Okay. And neither of us have any ties to these, these companies that are selling these devices. Just, we're not promoting what we financially are benefiting from here.

• 42:53Speaker 01

  Right.

• 42:54David Puder?

  You know, it's, it's so interesting because like, there's no, there's no drug reps for the ketogenic diet, right? Like when I started talking about exercise a decade ago, you know, doing podcast episodes on it six years ago, articles before that is like, there's no person coming to a psychiatrist's office talking about exercise. But at the biggest psychopharm conference, it's out of Nevada, it's one of the big ones, they spent the whole time talking about lifestyle stuff.

• 43:26Speaker 01

  Amazing.

• 43:27David Puder?

  This last year, and I was like, oh my gosh, like the field is changing. You know, and that's really exciting to me because it's like six years ago, people thought I was crazy for talking about strength training and, you know, mental health. So we've come a long ways. And, um, okay, but let's get into like what this study actually found.

• 43:47Speaker 01

  Yeah, yeah. So they looked at some different outcomes. Um, the one that I thought was interesting was the CGI, the clinical global impression. The average improvement was 31% on the CGI, which is significant. And, you know, there were 33% of people were considered recovered at baseline, up to 75% of people recovered based on the CGI at the end. And then really cool thing too, was that there was a difference between the adherent group and the semi adherent group. So the people who followed the diet better and had higher beta hydroxybutyrate levels had a 92% recovery by the end versus only a 50% recovery at the end for the semi adherent group. So there's this, you know, sort of suggestion of a dose response that

• 44:30Speaker 01

  we're seeing in that. There's also a significant improvement in life satisfaction, 17% improvement, another 17% improvement in the global assessment of functioning, the GAF. These are all highly significant. 19% improvement in sleep, 32% reduction in the BPRS for the people with psychotic disorders. And the metabolic outcomes were, were really good, too. All the people who had metabolic syndrome when they started were taken out of metabolic syndrome. So, I mean, in every one of these studies that we're going to go through, you know, we can talk about mental health outcomes and metabolic outcomes. The metabolic outcomes are really nice in all of these studies, like really strong metabolic improvements.

• 45:12David Puder?

  36% reduction in visceral adiposity, which I think is very interesting because that there's a lot of links to visceral adiposity and future issues.

• 45:25Speaker 01

  Absolutely. I mean, that's the, that's the dangerous kind of fat. That's the fat that's hanging around your organs, not, you know, subcutaneous fat. There are a lot of people who are metabolically healthy who have a lot of subcutaneous fat. But if you have visceral fat, by definition, even if you're not overweight at all, you can be have a normal BMI, have visceral adiposity, and you are metabolically very unhealthy. We have 30% of people in America have fatty liver disease right now, almost exclusively from metabolic causes. It used to be all from alcohol, you know, 50 years ago. Now it's all from metabolic issues from food, and that's very dangerous. This is a sign that, you know, you're going to have multiple problems going forward.

• 46:05Speaker 01

  You know, diabetes and everything that comes from that, heart disease, cerebrovascular disease, all that's going to happen if you have got a lot of visceral adipose tissue.

• 46:15David Puder?

  Yep. Other things, I did a big dive on this the other day, that, you know, can decrease that is vigorous exercise.

• 46:22Speaker 01

  Yeah.

• 46:23David Puder?

  But 36% is a lot. It's a lot of reduction. So.

• 46:28Speaker 01

  Yeah. And I see this all the time because I measure visceral adipose tissue at our clinic. We have a machine that measures that. It's one of the things that we always see benefits. As well as in the home IR, we always see benefits when people are doing ketogenic diet.

• 46:43David Puder?

  So just to go back over the number, 32% reduction in psychotic symptoms in the brief psychiatric rating scale. That's, that's cool.

• 46:53Speaker 01

  Yeah.

• 46:54David Puder?

  That's cool. This is impressive. And this is only a four-month pilot trial. You know, this is only four months.

• 47:03Speaker 01

  That's right.

• 47:04David Puder?

  Those huge reductions.

• 47:05Speaker 01

  That's right. And yeah, these interventions are meant to be long-term. And what I say to people is, you know, with most medications, you're getting most of the benefits in the first couple of months. But that's not true with this. This is, you get benefits accruing month after month after month. The longer someone is doing these changes like ketogenic diets and exercise, the benefits just keep accruing over time.

• 47:30David Puder?

  Yeah.

• 47:30Speaker 01

  Year later, two years later, I mean, you know this, you see people keep exercising, they keep getting more and more benefits as they keep doing it.

• 47:38David Puder?

  Metabolic health is physical health, you know, like how, how well your mitochondria are functioning.

• 47:45Speaker 01

  Absolutely.

• 47:46David Puder?

  It relates to how your brain is going to function. I've been looking at studies on creatine recently in mental health, and it seems, there seems to be a really nice link there as well. It's helping the mitochondria function better.

• 48:00Speaker 01

  Yes.

• 48:00David Puder?

  So, okay, let's go to Danin et al. 2022.

• 48:04Speaker 01

  Yeah, so this was, uh, this one I think is really fascinating. So this is a doctor in Toulouse, France, who, who, towards the end of his career, learned about ketogenic diets. And then he, he actually convinced his sister's family, I believe, to put his nephew on a ketogenic diet, who had both seizures and autism. And this boy had an incredible response to the ketogenic diet for both seizures and autism, is my understanding. And he was just blown away. And he said, all right, I, I want to try this in my, in my inpatient unit. And so he was an inpatient doctor his whole career. He had all these patients who were coming in and out of the hospital. And he offered this intervention to 31 inpatients. Some of them were admitted

• 48:47Speaker 01

  just to do this intervention. Some were just getting admitted for other reasons. But these are people with chronic, severe, you know, sort of intractable illness, schizoaffective disorder, severe major depression, and bipolar disorder. And he put them on a whole foods ketogenic diet. He added some vitamins, not high doses. I don't think the vitamins were all that significant in this, but he did, it's important to add. This is also a non-controlled trial, but they mentioned in the paper that, you know, that these individuals could all serve as their own controls to some extent, because they'd all been admitted to these hospital units before and never had these kinds of outcomes before. But they didn't have measurements of those previous studies. So they just sort of mentioned that as a

• 49:28Speaker 01

  throwaway. But I think it's interesting. So they measured adherence just by doing urinary ketones, which is not the best way to measure ketones, but you can see them in the urine. They only measured it once during the study. So really, we don't have a good sense of, you know, whether people were truly in ketosis or not. But they just measured it based on compliance with the diet, which was done by a dietitian. And, you know, they, it came in like meal boxes that they were just given essentially on the unit. And interestingly enough, they were only on the unit six days a week. And in France, they get to go home on Sunday, even if you're an inpatient, and you just go back to the unit on Monday. So they weren't, you know, they weren't having the diet, actually, even seven days a week.

• 50:08Speaker 01

  And so they said excellent compliance in 39%, good compliance in 43%, fair compliance in 43%. Eighteen percent. And then they measured rating scales. So the Ham D, twenty-three people got that. The Madras, twenty-one people got that. The people who had depressive symptoms and the people with psychotic symptoms, there were ten of those, had the PANS done as well. And then they did the CGI on twenty-seven out of twenty-eight. Only twenty-eight people completed the study out of the thirty-one. Three people just, you know, couldn't do the diet. And you had to do the diet for fourteen, only fourteen days. Some of them did it for much longer, but fourteen days minimum was considered someone who did the diet and had their outcomes measured at the end. And the reductions in these rating scales are like mind-blowing.

• 50:53Speaker 01

  It's almost, you almost can't believe how, how well these people did. So the Ham D went from twenty-five point four average to seven point seven average.

• 51:04David Puder?

  Which is, which is basically remission. I mean, that's like huge, that's a huge reduction. That's going from depressed to not depressed.

• 51:12Speaker 01

  Right. The effect size, they, they give a Cohen's D for effect size, three point one on the Ham D. I mean, it's just like mind-blowing.

• 51:18David Puder?

  Yeah, it's ridiculous.

• 51:20Speaker 01

  Right. The, the Madras, similar, even better, twenty-nine point seven to ten point one. The, the, the Cohen's D was three point six. And then in the PANS, ninety-one point four to forty-nine point three. Huge reduction in psychosis. The Cohen's D was three point five. And then in the CGI, Clinical Global Impression, four point nine to two point zero. Now, that's also enormous, you know, three point eight. Now, of course, that's a, that's a raider scale. That's not a self-report scale. So, you know, there's all kinds of ways this study can be criticized from a scientific point of view. You know, there could be bias in many different directions. However.

• 51:58David Puder?

  Sure. Patient selection.

• 52:01Speaker 01

  Yeah.

• 52:01David Puder?

  These, these are the patients who are willing to do it, you know, so they're like healthy, healthy enough to choose to do it, right?

• 52:08Speaker 01

  Trusting of their doctor to, to go through this.

• 52:11David Puder?

  Right. The belief of the doctor could, could have a huge impact, but he's been treating them, it sounded like, for, for years.

• 52:18Speaker 01

  Yeah, most of them are on your care for more than ten, ten years.

• 52:21David Puder?

  Right.

• 52:22Speaker 01

  Some of them longer than that, yeah.

• 52:24David Puder?

  So I, you know, it's like, yeah, this isn't a randomized trial. I'm, I'm not buying the self-randomization type, type thing. But at the same time, for me, it's like, I look at this and I'm like, hey. Okay, this is a big, this is a big impact. We should pay attention to this. This is really interesting.

• 52:44Speaker 01

  Yeah, and some of the other things about the study were interesting. So 64% were discharged on less medication than they came in. Only one person out of all of this was on more medication than they came in. The rest were either had their meds changed and it was somewhat equivalent. So, you know, most people were on less medication despite these incredible improvements. So that's really incredible and great metabolic health improvements as well. All super significant improvements in weight, fasting blood glucose, hemoglobin A1C, blood pressure, liver function tests, total cholesterol, even the LDL went down, which we don't, we don't always see with ketogenic diets. That's a whole separate topic we could get into, but triglycerides went down very significantly, which we always see in ketogenic diets. And most people said

• 53:29Speaker 01

  it was well tolerated. They did a little follow-up and, you know, 46% were still having good adherence in the follow-up. 18% were having partial adherence and 21% had totally stopped doing the diet when they followed them up later. Because it's hard, much harder to do it at home, especially if you didn't get a bunch of education on how to do it at home and you just were, you know, given this, you know, it's not, you did, people need education to learn how to do this. So yeah, huge improvements in metabolic health and generally, you know, people were interested in keeping doing it when they left. And I agree with you that even though it's not controlled, even though there's all kinds of scientific criticisms of this study, which are valid, it's still really impressive to see those kinds of numbers.

• 54:13Speaker 01

  I worked on an inpatient unit. I almost never, ever, ever saw those kinds of improvements in an inpatient stay, you know, unless it was, you know, some kind of, you know, acute manic episode that's, that resolved with the meds or, you know, major depressive episode that someone got ECT and they had that kind of improvement. But otherwise, you just, you don't see those kinds of improvements. And these are not the kind of illnesses that are super, you know, placebo responsive, I would say. Like, we don't even do placebo trials in schizophrenia, you know, so, you know, these are not, these are not, you know, mild to, mild to moderate depression where placebo makes a big difference. These are different kinds of illnesses than that.

• 54:54David Puder?

  Yeah, the other interesting things to me in this study was the systolic blood pressure decreased from 134 to 123. So that's like 10 points, 11 points.

• 55:05Speaker 01

  Yeah.

• 55:05David Puder?

  Triglycerides dropped from 204 to 137. I tend to, you know, triglycerides tend to increase with more carbohydrates. So that makes sense to me.

• 55:16Speaker 01

  Yeah.

• 55:16David Puder?

  Weight dropped about 10 pounds. You know, so the, there's multiple ways to think about, like, as you talk to patients about this, to get them to think about trying this, right?

• 55:31Speaker 01

  Yeah.

• 55:31David Puder?

  We, you know, I've heard from some people, this fear of LDL is increasing. So it's interesting that LDL has dropped 10 points in this study. And we also know that there's difference in types of LDL.

• 55:43Speaker 01

  Right.

• 55:43David Puder?

  Which we, you could probably speak to.

• 55:45Speaker 01

  Yes. Yeah. Yeah. LDL topic is very complex and it's very controversial. I mean, we could, you could do, you know, a whole episode on low carbohydrate diets and LDL. But just the summary points that I think about is, you know, overall cardiac risk goes down on ketogenic diets. That's been seen in big trials. If someone's LDL is high to start, it often stays the same or goes down. Especially if it's someone's overweight and they're losing weight on the ketogenic diet, LDL tends to go down. Where you see the LDLs going up are usually in leaner, fitter people whose LDL is starting at a low point. And then you put them on a ketogenic diet, the LDL sometimes do go up. But they

• 56:28Speaker 01

  still, the overall cardiac risk, even when the LDL goes up, the overall cardiac risk goes down because there's so many other factors that go into cardiac risk, calculators, blood pressure, triglycerides, HDL, total cholesterol, you know, all these, insulin resistance, all those are very important factors. So even when LDL isolated goes up, overall cardiac risk goes down. There are this subgroup of people called lean mass hyper responders, where the LDL goes really, really high.

• 56:56Speaker 01

  And the triglycerides go really low and the HDL goes really high. That's this triad called lean, which constitutes a lean mass hyperresponder. But they've even done studies on that. These people on ketogenic diets whose LDL are on average like astronomically high, like 300, 350, some of them are even 500 in the study that they did. And they had absolutely clean cardiac angiograms compared to a control group that had the same profile, except their LDL was lower and they weren't on a ketogenic diet. The people who had these super high LDL said, a suggestion of actually less cardiovascular disease on the gold standard test, the cardiac angiogram. So that's a study of about 100 people. That literature is still coming out and really interesting.

• 57:40Speaker 01

  But it's really changing this whole story about LDL being so important to cardiac risk. You know, LDL, different subtypes, they're really delivery molecules for energy in many ways, too. They're not just atherogenic molecules and some of them are atherogenic and some of them are not. And so we just measure LDL and that's all we care about. We're missing like, you know, a huge part of the story.

• 58:03David Puder?

  Right. And things like visceral adiposity.

• 58:06Speaker 01

  Right.

• 58:06David Puder?

  Things like triglycerides, things like inflammation, right? That have other impacts. Plus, I mean, if you're in a, you know, for people with mental health issues, you know, there's, there's an inflammatory state often associated with acute illness. So if you're able to get someone out of psychosis, that's going to decrease cortisol, that's going to decrease stress hormones, you know, all sorts of stuff. Like imagine being paranoid and psychotic, getting you out of that state is very good for the brain long term.

• 58:42Speaker 01

  Absolutely. Oh yeah, for the brain and the body. I mean, you know, inflammation, we know is correlated with cardiovascular.

• 58:49David Puder?

  Okay. So this is a really good study. Anything else you want to talk about on this one before we move on?

• 58:54Speaker 01

  No, I think we can move on.

• 58:56David Puder?

  Okay. Let's go to Calabrese et al., 2024.

• 59:01Speaker 01

  Oh, you know, I actually, I didn't.

• 59:03David Puder?

  Do you want to skip this one?

• 59:04Speaker 01

  Yeah, I didn't take notes on that one. And that's a small sort of case series, but I think the the main point on that one is that, you know, people getting into into remission, you know, a few people, you know, just, you know, complete remission. And that's the kind of, there's, there's lots of case reports coming out now, Calabrese. There's another couple of ones by Nicole Laurent, who's a psychologist in in Washington State with both depression, and she had two people with schizoaffective disorder put in complete remission. I mean, literally, CGI is down to zero and off of medications. And so, you know, there's those types of case reports and anecdotes and stories that are now getting published and many of them online. I mean, there's just, there's, there's a lot, there's dozens and

• 59:45Speaker 01

  dozens of people who are being put into remission, coming off of all their medications, just by being on ketogenic diet, exercise, and, you know, maintaining a metabolic regimen. So just fascinating. Yeah.

• 59:57David Puder?

  The, the thing I found interesting about this one was the, it's only three adults, right?

• 1:00:03Speaker 01

  Right.

• 1:00:03David Puder?

  But OCD symptoms improved and binge eating disorder symptoms improved as well.

• 1:00:09Speaker 01

  Oh, yeah.

• 1:00:10David Puder?

  Okay, let's go to Campbell et al. 2025. This is probably one of the most interesting to me.

• 1:00:15Speaker 01

  Yeah, this one's really cool. So Ian Campbell is a researcher at University of Edinburgh. He's very public about the fact that he got into this because he has bipolar disorder and went on a ketogenic diet himself to lose weight and realized totally by happenstance that it completely stabilized his bipolar disorder. And then he got super fascinated in it. And, you know, he's a, he's a PhD researcher, really, really wonderful guy. And so he has a whole group now at University of Edinburgh. There is this whole group that they're doing lots of studies. This is, they came out initially with a clinical study in 2023. This is the same clinical study, but now they're reporting in 2025 on some more outcome measures that are really interesting. And this is all people with bipolar disorder. So.

• 1:00:59David Puder?

  And once again, this is a, this is a pilot study. This is not a randomized trial.

• 1:01:03Speaker 01

  Correct.

• 1:01:04David Puder?

  Six to eight weeks. Interestingly, he describes them as euthymic bipolar patients.

• 1:01:08Speaker 01

  Right.

• 1:01:09David Puder?

  So it's not like they're acutely ill, acutely manic. But the, the thing that I like about this one is how he looks at the brain, what's going on in the brain and.

• 1:01:20Speaker 01

  Yeah, I mean, he's a real scientist. So yeah, he's got this MRS component to this study and also some other really cool aspects. So let's get into it. Yeah. So 27 were recruited, 26 began the study, 20 of them completed the study. They had to be euthymic for three months. They excluded people with severe hyperlipidemia. They were all assigned a dietitian. They were put on also not an extreme form of the diet, but you know, it was a real ketogenic diet, 60 to 75% of calories from fat, 5 to 7% from carbohydrates and the remainder from protein. They did measure ketones daily on this one and blood glucose daily, which is really important for this. They ended up doing these ecological momentary assessments. So essentially, they were texting people

• 1:02:04Speaker 01

  and asking them some questions every day, and they made correlations between their ketone numbers and their responses to these questions that ended up becoming super interesting. They had a dietitian that met with them weekly and was able to adjust the diet to achieve ketosis and weight loss if desired. So this is also really important. Instead of just being given this, you know, program and just let go, they had some really nice dietitian support for these people and they were able to adjust to make sure that they were getting into ketosis and measuring it daily. So the moods remained euthymic throughout the study, except for one person who had a little bit of hypomania that resolved quickly. And we do see that sometimes with bipolar people who go into ketosis. There is sometimes

• 1:02:47Speaker 01

  a little bit of hypomania and a little bit of insomnia that you have to pay attention to as a clinician. If someone's thinking about using these things clinically, that's a really important clinical point. And they did see it in this study. So on these ecological momentary assessments or EMAs, these daily reports, they only had that on a subset of 14 people because I think their technology wasn't working in the first part of the study and they finally got it working. So it was sort of the last 14 people that they were able to do it for. So they had really nice positive correlations between mood and ketones. Positive mood, the P value was less than .001. And there's nice little plots on the study. If you want to look at these, they're nice to look at. Positive correlation.

• 1:03:29Speaker 01

  Between energy and ketones, also P less than point 001. Negative correlations for impulsivity and ketones. And that actually had the biggest effect size of them all. They had the best reduction in impulsivity with, you know, correlation with ketones of all these measures that they did. And also a reduction in anxiety and ketones. All these less than point 001. They did not have a correlation between racing thoughts and ketones that that ended up becoming that was not significant.

• 1:03:58David Puder?

  Now, the the R values for these, you know. Point 2, point 3 for impulsivity, negative point 3 for impulsivity, negative point 2 for anxiety. These aren't huge. These are not huge. This is not like groundbreaking. Is it groundbreaking for you? I mean, I like.

• 1:04:17Speaker 01

  I I just like to see these correlations, like anything with dose response, you know, it's it's exciting. Yeah, I mean, it's not groundbreaking. But of course, these are also people who are starting off and remaining euthymic. These are not symptomatic individuals.

• 1:04:31David Puder?

  But but I think what you're emphasizing here is that they're they're looking at like, like a a spot of like, this is one day. And this is their ketone level.

• 1:04:42Speaker 01

  Right.

• 1:04:42David Puder?

  And as their ketones are higher, their symptoms are all what we would want them to be.

• 1:04:49Speaker 01

  Exactly, right.

• 1:04:50David Puder?

  That's and so that's probably the most interesting thing from those numbers.

• 1:04:54Speaker 01

  Exactly. That's what's interesting about it. Exactly. That there's this, yeah, correlation between the levels of the treatment and the nice things we want to see. And so if someone's not feeling as well, we can say, all right, let's try to get those keto numbers a little higher. I think that's what this says to me. And you'll probably feel a little better. So it's so that's nice. And it's just so so nice to have a a relevant biomarker in psychiatry. I mean, we do psychiatric treatments all the time. And unlike the rest of medicine, we don't have biomarkers to follow that are really relevant and really cool to have one that that seems to have some relevance.

• 1:05:32David Puder?

  Here here's the other thing, and I'm going to just pull up actually the study here for those of you who are watching this on YouTube. So you can see this actual thing and you can pull this pull this study up at home. But when I look at data. I look at, does the data represent a linear line or not?

• 1:05:49Speaker 01

  Yeah.

• 1:05:49David Puder?

  Okay. Because often there's a step, like, once we get to a certain point, we see a huge reduction. And so I actually think if I were this researcher, or if I, what I would say is like, it seems like there's a step in some of these things. And what I mean by that is when you get past, for example, three or 2.5 for the ketones.

• 1:06:13Speaker 01

  Yeah.

• 1:06:13David Puder?

  All of a sudden, there's a drop in impulsivity. And there's like, a huge drop. Okay, do you see that?

• 1:06:20Speaker 01

  Yeah, exactly.

• 1:06:20David Puder?

  Or, or for thoughts and for anxiety, when you get past the two and a half mark, it seems like there's a drop in anxiety, a drop. Yeah, specifically anxiety, there's a drop. Do you see what I'm talking about here? Where it's like, all of a sudden, boom, it's like every number is low.

• 1:06:38Speaker 01

  Yes.

• 1:06:39David Puder?

  And so I think as well, when we think about a small correlation of like a point three or a point two, we miss the overall picture unless we look at one of these nice plots where we see like, no, there's maybe, maybe the data is not best modeled in a linear line. Maybe it's best modeled in like a stepwise approach. And so that was one of my takeaways.

• 1:07:03Speaker 01

  Yeah, I really appreciate you doing that. And it's, it's also, you know, to think about that in the context of this being such a short study too. And I was making that point earlier that, you know, getting the higher levels of ketones in the earlier stages is probably really important. And we see these really nice improvements when you get above like two and a half or three. And I see that clinically all the time. If someone really gets into deep ketosis, they're like, wow, this really feels amazing. That doesn't mean they have to stay in deep ketosis, you know, at month eight or month 24. It may be that they don't have to. We, we see this in the epilepsy literature in the kids that most of them who respond early, they're, they're able to stop the diet after a few years and their illness not only doesn't come back,

• 1:07:48Speaker 01

  it keeps getting better later on, even when they stop diet.

• 1:07:52David Puder?

  Stabilize the brain. So yeah, I had, I had a close friend whose kid was in, had, had sort of like intractable seizures. And I convinced him to get their kid on a ketogenic diet and.

• 1:08:07David Puder?

  They did it for a couple of years and they've kind of moved away more into like, I think more, a lot of Whole Foods, but not as ketogenic and the kid's doing a lot better.

• 1:08:18Speaker 01

  Yeah, amazing.

• 1:08:20David Puder?

  Yeah, so it makes sense to me that if you can stabilize the brain from having seizures for a period of time and you have a kid that's growing up now, every year, it's like their brain is growing up, their brain is developing, their brain is changing.

• 1:08:35Speaker 01

  Right.

• 1:08:35David Puder?

  And so all these epigenetic things, all these new pathways, that makes sense to me. Okay, but the thing that I love about-

• 1:08:44Speaker 01

  If we reverse that cerebral insulin resistance as well, then, you know, we don't have to do that heavy lifting. In the beginning, we're doing this heavy lifting of reversing insulin resistance, you know, getting the mitochondria to be healthy again. And at a certain point, you have enough healthy mitochondria, you may be able to add to that, but the biggest changes may happen in the first, you know, six months, year, but you still continue to get benefits as you keep going with a healthy, healthy lifestyle. And, you know, some amount of ketones are providing that signaling to the mitochondria on an ongoing basis.

• 1:09:21David Puder?

  That's great. So there's this, this one study that I really like, I'll share with you. I don't think you've probably seen this one, but they looked at three groups of people. They looked at people who are more elite level athletes. They looked at people who are average people and they looked at people who are, have some sort of metabolic dysfunction. And they looked at the amount of watts that they could produce on a bike for a given level of lactic acid. And then they looked at the mitochondrial health in the, in these three different groups. And what they found was that, yeah, there's a, there's a big difference in the mitochondrial health. Let me see if I can pull this study up. I want to show you. It's really cool.

• 1:10:05David Puder?

  I think this is, I think this was the most interesting one right here. The relationship between blood lactic acid and exercise output. And the three different groups, the people with metabolic issues, the normal people and the athletic people. And so it's another picture of this like you, you know, mitochondrial health, you know, the ability to produce watts at different, more watts at lower lactic acid threshold, right? Is mitochondrial health. And I think it's kind of feeding into this whole holistic picture that we're giving of how that then can make an impact on our mental health in multiple domains.

• 1:10:44Speaker 01

  Yeah, absolutely. Yeah. And if for those of your listeners who heard Chris Palmer before or read his book, you know, all about mitochondria having all these other important functions besides making energy as well in the brain. And so mitochondrial health is so important for mental health, you know, because of energy, but because of all these other reasons as well. And, and lactic acid is super interesting, too, that, you know, there's now, I think, a lot of data showing that lactic acid improves brain health. And so of course, when we're exercising, we see, we use it as a measure of how healthy our mitochondria are. But if we exceed our lactic acid, acid threshold and make lactic acid frequently, that's going to improve brain health. That's directly correlated to increasing BDNF.

• 1:11:29Speaker 01

  And, you know, that, that's one of the mechanisms. And so we want, we want to exercise and make some lactic acid some of the time. And, and some of the time, right, go exercise right at the threshold as well.

• 1:11:41David Puder?

  Right. Vigorous, vigorous exercise, good for BDNF. Okay. The thing that I love about this study is the, is the MRS data. Cause I think this really shows, you know, what types of the brain are actually impacted. Like the anterior cingulate cortex had an 11.6 decrease with the, you know, there's a decrease in glutamate and glutamine, right?

• 1:12:08Speaker 01

  Yeah, I think it was 13% in the combination of glutamine and glutamate, I believe. And that's really significant. That's big. Cause you know, first of all, we know that glutamine and glutamate get lowered in. Anti-convulsant treatment of bipolar disorder. So that this is a known mechanism by which things like, you know, valproic acid and lamotrigine help in bipolar disorder. This is the one of the mechanisms by which those anti-convulsant medications work. They they lower brain glutamine and glutamate.

• 1:12:40David Puder?

  These are excitatory neurotransmitters, neuromodulators.

• 1:12:43Speaker 01

  Yeah.

• 1:12:44David Puder?

  Actually, interestingly, clozapine, clozapine increases glutamate neurotransmission, which, you know, I'm not quite sure how it relates to this area specifically having decreased because I think you have, you know, sometimes different things going on. But clozapine indirectly improves NMDA glutamate receptors. It blocks 5-HT2A receptors, which inhibits glutamate release. So indirectly boosting glutamate release in the prefrontal cortex. Okay, so maybe that's where it is.

• 1:13:25Speaker 01

  For an area.

• 1:13:26David Puder?

  So if we're boosting in the prefrontal cortex, that maybe has a different impact than in this study when we're seeing it in the anterior cingulate cortex decrease. Okay, so that that makes sense to me is because because in the anterior cingulate cortex, you have emotional regulation, you know, you have cognitive control. So having maybe a blunted there, we have some increased emotional regulation, right? Maybe less rumination, less self like heightened emotional processing.

• 1:13:59Speaker 01

  Yeah, it sort of makes me think about this question that is still puzzling me. And and so, you know, we we know that antipsychotic medications are, you know, obviously really helpful for psychosis, that they're doing something very different to metabolism than what ketogenic diets are, which are also we're now seeing are helpful for psychosis. So how do we explain that? You know, how do we explain why antipsychotics, even though they're harming metabolism, why are they helping with positive symptoms of psychosis, especially in these acute settings, which we know that they do? I mean, clearly they do. And and we just don't know the answer to that question. I've asked it to Chris Palmer and his his answer was interesting.

• 1:14:41Speaker 01

  He says that, you know, when the when the neuron is running out of energy. It can either get hyperexcitable or hypoexcitable. You know, it can either like, you know, start doing too much or get, you know, hypoactive. And that when we replace the energy or fix the energy in the neuron, it's now going to do its job the way it's supposed to. You know, it's not going to become hyperexcitable or hypoactive. And so, you know, it has the ability to sort of get the neurons to do what they're supposed to be doing in different regions. And so it's not like, you know, we're just, just, you know, turning something on or turning something off. You know, medications are kind of blunt in that way. They're just doing one thing.

• 1:15:24Speaker 01

  Whereas this, this has many mechanisms of action that have been shown in the epilepsy literature. And, you know, we just don't know yet in mental health, all these mechanisms. But we're seeing, seeing a nice suggestion here about lowering glutamine and glutamate in the anterior cingulate cortex in bipolar.

• 1:15:42David Puder?

  Yeah, and I think that's a good point. It's like, what is the mechanism? We're not sure.

• 1:15:47David Puder?

  You know, also in the study, they showed there was a decrease in total choline in the anterior cingulate cortex and the posterior cingulate cortex.

• 1:15:57Speaker 01

  Yep. And it's the one myoinositol as well, which is a secondary signaling molecule. I don't know if you know, some people take myoinositol as a supplement for various things. It seems to help with severe OCD and anxiety. There's some, some very small studies looking at that. But I do know a lot of people who take that supplement, actually.

• 1:16:17David Puder?

  There was no significant metabolic change in the right dorsal lateral prefrontal cortex. Which is interesting.

• 1:16:24Speaker 01

  Yeah.

• 1:16:25David Puder?

  But, you know, we're looking at, we're just scratching the surface here. I think was what you're saying as well. It's like, and when we look at diet studies and you look at big changes like this, it's not just one. Upregulation of one protein.

• 1:16:40Speaker 01

  Right.

• 1:16:41David Puder?

  There's probably 10,000 things going on.

• 1:16:44Speaker 01

  Exactly.

• 1:16:44David Puder?

  Which one of those is the thing that's going to make the biggest impact for the patient? We're not sure. Just like in exercise, there's, there's tons of things going on.

• 1:16:53Speaker 01

  Exactly. Exactly right. Yeah, we're doing something that has such a profound effect on physiology that, you know, we, it's very, it's going to be hard to find exactly what the, the one thing is. And that's what they found doing all this research on ketogenic diets in epilepsy, that they've come up with about, you know, seven or eight different mechanisms that various researchers think are really important and the most important one. No one can figure out what the one mechanism is by what, for which it works so well in epilepsy. And I think it's going to end up being the same. And then, and therefore you can't, you know, you can't create a pill that's going to do what exercise does or what a ketogenic diet does for the brain. We'll, we'll never have a pill. Yeah.

• 1:17:38David Puder?

  And, and you, you can't just probably take, um, like the bulletproof coffee type of thing, you know, like that's probably not going to be enough because you're, and just, okay, I'm going to take this supplement and then go on eating a lot of highly processed foods and.

• 1:17:57Speaker 01

  That's right.

• 1:17:58David Puder?

  Foods that are inflammatory.

• 1:17:59Speaker 01

  Good of an effect. Although interestingly, they've done these studies on MCT oil that are fascinating. People with mild cognitive impairment, they do a, a minimail status exam on them and then they give them MCT oil in a fasted state. And then they do a minimail status exam on them an hour later and they get significant improvement. That's from one dose of MCT oil. Just because they made some ketones. And for, for those folks, you know, this mechanism of, you know, brain insulin resistance is probably a really important one. And that immediately gets bypassed by making some ketones because ketones don't need insulin to get into neurons, whereas glucose does need an insulin signal to get into neurons. And so you bypass that blockade right away and you get an immediate boost and an immediate

• 1:18:44Speaker 01

  benefit. But I totally agree with you that that's not enough for most people to have a profound, you know, lasting mental health change, you know, just doing some MCT oil is not going to, not going to do it.

• 1:18:57David Puder?

  Yeah, and I think the other thing that I've been thinking about with this is like, I'm not just, I'm not going to only do this with patients, right? This isn't the only treatment I'm thinking of. Exercise as well.

• 1:19:07Speaker 01

  Oh, yeah. Some of the other things. Yeah, I love to combine all these various important lifestyle things. So ketogenic diet, or even a low-level ketogenic diet, or even just this low glycemic index diet, if that's all someone will do. Just a clean, healthy diet that doesn't have sugar and processed flour and, you know, will make a little bit of ketones. Exercise, especially if we can get them to do some resistance training and some high-intensity work as well. Mindfulness training. And then, you know, some circadian rhythm work as well is super powerful for a lot of our folks. And I talk about that, you know, kind of all day long. Sometimes I feel like the importance of getting out and seeing morning sunlight and blocking

• 1:19:50Speaker 01

  blue light at night and getting outdoors during the day, eating meals at regular times, waking up at regular times, that is incredibly powerful for mental health and physical health. And it's so against the grain of what most people are doing that you can get huge benefits just from making these small interventions.

• 1:20:09David Puder?

  Yep. Yeah, I, um, I think we should kind of get into the practical stuff as much as possible at this point.

• 1:20:21Speaker 01

  Sure.

• 1:20:22David Puder?

  So when someone is getting into ketosis, what are some things that you think they should know? Like, let's say someone's listening to this and they're like, okay, I'm going to try this. Or I'm going to get my son on the ketogenic diet. Like, what are the things that they should consider in that process?

• 1:20:40Speaker 01

  Yeah. Well, first of all, a couple of, you know, absolute contraindications. You can't do a ketogenic diet if you're taking an SGLT2 inhibitor, these drugs that are used for diabetes. So, you know, most people are not on those medications, but that happens to be an absolute contraindication. You can get ketoacidosis from that. Otherwise, you know, there's very few absolute contraindications. If someone's really severely underweight, I wouldn't do it. It is done quite often clinically with people with restrictive eating disorders. We could go into that a little bit, but that might shock people. Sort of shocked me when I first heard about trying this and someone with a restrictive eating disorder. So the things to know are start gradually.

• 1:21:23Speaker 01

  It's not a great idea unless you're really under a team of professional care to do this all at once. So I generally like people to start with, start with cleaning up your diet, get rid of sugar. Try to get rid of some processed flour, do that for a couple of weeks. Keep eating veggies. I like people eating animal protein, but make sure you're getting adequate protein all the time. Those are really important factors. And then just start gradually reducing carbohydrates. So maybe start with one ketogenic meal that has very low carbohydrate for a week. And then the second, you know, then the second week, maybe add in a second meal of the day with very low carbohydrates. And then, you know, by the third or fourth week, you can do all three meals.

• 1:22:06Speaker 01

  And when you're getting rid of all these carbohydrates, so when I'm, you know, just practically speaking, you know, bread, rice, potatoes, you know, we just aren't sugar. We're not eating any of that. Unless you're, unless you're getting a really, you know, well-made ketogenic version of bread, which can, can be done, but it's not easy. We have to replace those calories with healthy fat calories. So what do we mean by healthy fat calories? So there is some controversy in this world. I won't get too much into the weeds, but everyone agrees that monounsaturated fats are healthy. There's, there's really no controversy about monounsaturated fats. So, you know, high in things like olive oil, extra virgin olive oil, avocados, avocado oil, nuts and seeds.

• 1:22:51Speaker 01

  And in their whole form, not, not seed oils, but, but whole seeds and, you know, maybe minimally processed seeds like tahini. It's like ground sesame seeds, for example.

• 1:23:02Speaker 01

  So generally higher in mono- and saturated fats in those foods, all very safe to eat. And then, you know, animal fats, you know, some amount of animal fats are probably healthy and important. They have more saturated fat, they still have the other fats in them as well. But, you know, if they're well cared for animals, there may be some benefits to that. Higher omega threes and grass-fed beef versus not, and grass-fed dairy also has higher in omega threes. Dairy is one of the ways that sometimes people get more of their fats in a ketogenic diet. It tends to be easier and more satisfying if someone tolerates dairy and is willing to eat cheese and cream and things like that. And it's, you know, it often makes things taste delicious.

• 1:23:44Speaker 01

  So, you know, for people who do well with dairy, that's a, that's a good trick. And then, you know, I do generally advise people to avoid a lot of seed oils because they're highly processed and they oxidize very easily. So saturated fats are more stable than these polyunsaturated fats. So, so replacing with healthy fats and because you're going to be eating more fats, you've got to pay attention to

• 1:24:06David Puder?

  The quality.

• 1:24:07Speaker 01

  Your fat content.

• 1:24:09David Puder?

  Olive oil, love it. Okay, so here's my thought. Dark chocolate, okay?

• 1:24:14Speaker 01

  Yeah.

• 1:24:15David Puder?

  So 80%. How much of that can I eat?

• 1:24:20Speaker 01

  Well, okay, so I like chocolate too, by the way. And, and I've found that you can get chocolate that's made with a sweetener called allulose.

• 1:24:31David Puder?

  Allulose, okay.

• 1:24:33Speaker 01

  New sweetener that most people are, you know, heavy-duty scientists are now agreeing is probably the best of the artificial sweeteners of them all. Allulose is a naturally occurring sugar, similar to fructose, that exists in foods like tapioca and corn at very low quantities. So they just purify it out of these other, you know, vegetables. And then you can get it in powdered form. It tastes almost exactly like sugar, but our body doesn't metabolize it. So it ends up being no calories and it tastes sweet and it doesn't seem to raise insulin or blood glucose at all. Some of the other artificial sweeteners actually raise insulin levels and that's problematic because the only way we make ketones is to lower insulin levels.

• 1:25:17Speaker 01

  So allulose doesn't seem to do that and it actually seems to have some GLP-1 activity, which is also fascinating. So some people take high doses of allulose instead of a GLP-1 inhibitor if they can't afford it.

• 1:25:30David Puder?

  Wow, interesting. Okay.

• 1:25:33Speaker 01

  Yeah, interesting.

• 1:25:33David Puder?

  Um, okay, so.

• 1:25:34Speaker 01

  Anyway, so you can get chocolate made from out with allulose or stevia, or just the highest percentage cacao that you can. So there's very little sugar in it. So I mean, there's one company that makes like 95%.

• 1:25:48David Puder?

  Yeah, there's, there's like, there's 100%.

• 1:25:51Speaker 01

  100%. Yeah, 100% maybe, but 95% from a good company that really knows what they're doing can be delicious, I think.

• 1:26:00David Puder?

  Okay, okay. Nice. Okay. Um, what, what's, what's the hardest, uh, what's the hardest thing that you find most patients? Uh, like the hardest step?

• 1:26:11Speaker 01

  Yeah, yeah, yeah. Before I get to that, the, the one of the, the caveat to say to people is if they are going fast into ketosis, they have to really pay attention to drinking tons of fluids and taking electrolytes. Uh, because you, you have this diuresis when you first transition into ketosis that can be, you know, really uncomfortable. There's this idea of keto flu. Some people try this on their own and they say, oh, I hate the way I felt because they went really fast. They didn't replace their electrolytes. They got headaches and low energy and low blood sugar and they felt terrible. So that's why I advocate a slower approach. It's much more likely to feel good. Some amount of measuring ketones is a really good idea. We mentioned blood measurements with a device.

• 1:26:54Speaker 01

  There's also breath devices that are pretty accurate now. And so if someone really doesn't want to poke their finger, they can get a breath meter. Uh, and I found that, you know, if someone's not shooting for, you know, a real, you know, without trying to be super accurate about their ketone levels, they're just more casual about it. That's another approach that we can take. Let's use the breath meter.

• 1:27:15David Puder?

  Okay. Okay. So with the electrolyte supplementation, common question like how much, what, what do they do? Like? What's your, what's your, what's your take on that? Like three to five grams of?

• 1:27:29Speaker 01

  Yeah.

• 1:27:30David Puder?

  Salt?

• 1:27:31Speaker 01

  So you could just use sodium if, if you, and, and that generally can work. We're also losing potassium and magnesium as well. So ideally we'd replete those two. There is a salt that's made that's half sodium, half potassium. That's an interesting product that you could use in the beginning and just really, cause now you're making your own food. You're not eating these processed foods, right? Um, you have to really salt your food. And then additionally, you might put some, you know, some of these electrolytes in your water bottle, you know, once or twice a day in the first couple of weeks. Um, and make sure, and like I said, just drink lots and lots of water, you know? You know, six, eight liters of water for sure. Um, and maybe one, yeah.

• 1:28:10David Puder?

  Wow, okay.

• 1:28:11Speaker 01

  Yeah. If you're going fast, especially because there's this big diuresis that happens when you go into ketosis and it takes away a lot of your electrolytes and water. And you can get, you know, really dehydrated otherwise.

• 1:28:23David Puder?

  Okay, I'm gonna have to, I'm gonna have to watch that because I do sauna as well. I'll lose like, I'll lose four, five pounds in the sauna.

• 1:28:32Speaker 01

  Me too. Yeah, yeah, I do that as well. You, you, you should definitely be taking in lots of electrolytes and really pound the water. Yeah. If, if you're gonna, if you're gonna do ketosis and sauna at the same time, especially, yeah, you really gotta be careful.

• 1:28:44David Puder?

  Yeah.

• 1:28:45Speaker 01

  And make sure to get some magnesium because you're losing all these electrolytes.

• 1:28:48David Puder?

  Magnesium, potassium. Do you do, do you do pat potassium pills ever? Or do you tend to do the salt?

• 1:28:54Speaker 01

  I, I generally get these like little electrolyte packets.

• 1:28:57David Puder?

  Okay.

• 1:28:57Speaker 01

  A couple of companies that make them without any sugar at all. Um, and those are, they, they taste good. Um, and they're just really easy and you get a nice blend of those three electrolytes. I also, for some people, it's not a bad idea to take some trace minerals in the early stage as well. You can get a trace mineral supplement because you're losing all these electrolytes too. Especially if you sauna a lot, I would recommend a trace mineral supplement. Because you, you lose, you know, all these important things, you know, zinc and selenium and iodine, all, it's all coming out in your sweat. As well as toxins, but you know, it, you, you, sweat brings out everything. I sweat a lot, so I think about this.

• 1:29:36David Puder?

  I, um, I think I need a sweat mentor here. I need you to send me your, uh. Your mineral recommendations.

• 1:29:45Speaker 01

  Yeah, they can just get a little pill that has all these trace minerals in it. And then you just get the the bigger quantity minerals in an electrolyte packets. It's pretty simple.

• 1:29:54David Puder?

  Yeah.

• 1:29:54Speaker 01

  Yeah.

• 1:29:56David Puder?

  Yeah, that's good. Okay. Any other practical recommendations that you normally tell people?

• 1:30:02Speaker 01

  Let's see. I mean, I probably not the best time to like if you're really, especially if you're going fast and you're, you know, it's not the best time to try to get your personal bests in your exercise routine.

• 1:30:16Speaker 01

  If you're really into exercise, you're not going to want to push yourself to the max in the first couple of weeks. Your body is adapting to a whole new way of producing energy and it's working hard to do that. You're turning on genes that have basically been turned off. We all have the genes to do this, but you know, you know, these genes are our survival genes that that exist because we needed to survive in food scares and food scarce environments our entire evolutionary history. All those genes have been essentially, you know, quieted down through epigenetics through our diet and lifestyle. So we have to turn all these genes back on and it takes some weeks to adapt to that. So I wouldn't, you know, go for personal bests in your, you know, in your training in the first

• 1:31:01Speaker 01

  few weeks. And then even after that, you know, it may take some time to get back to, especially in endurance, you know, if you're trying to train in ketosis, it's really great in the end for endurance. A lot of endurance athletes are ketogenic. It's, you know, because you're essentially teaching your mitochondria to burn fat better. And so, you know, beta oxidation has improved over time in ketosis, but definitely not. In the beginning, there's some adaptation that happens.

• 1:31:30David Puder?

  Yeah, I've heard about people training in ketosis and then competing with some sugar.

• 1:31:34Speaker 01

  Yeah.

• 1:31:35David Puder?

  So it's like they've, they've taught their body to mostly do, do ketosis.

• 1:31:40Speaker 01

  But you don't need that much sugar. Actually, the recent study came out that, you know, people who are these ketogenic athletes, they only needed to add back, I think it was like seven grams of sugar per hour in these long distance endurance things to get, to get all the benefits of, of having some, you know, glucose around. So we don't need to add that much. And our body's making glucose all the time. That's another really important point for people to know. Our brain is. You know, additionally using ketones as fuel, but we never stop using glucose as fuel in our brains and everywhere throughout our body, even if we're in the deepest ketosis and we eat zero carbohydrates.

• 1:32:21Speaker 01

  Our body's making glucose through gluconeogenesis all the time and using it all the time. But we're just making the amount that we need instead of this excess that we need to store as fat.

• 1:32:32David Puder?

  Really good. Okay, we're kind of coming to a, coming to a close here. Any final things you wanted to kind of bring out before we wrap things up?

• 1:32:42Speaker 01

  Yeah, I mean, just trying to put it all together a little bit. You know, we looked at the Wondery study about dose reductions of antipsychotics having better rates of full recovery than people who didn't do a dose reduction. We know about all the metabolic problems with a lot of these antipsychotics and mood stabilizing medications. And just thinking about the long-term health of people with severe mental illness is just, you know, we know that people with severe mental illness die younger, you know, on average, you know, about 15 to 20 years younger than people without it. There's many causes of that, but metabolism is a big cause of it. And I think unfortunately, the medications are a big cause of that. So, you know, thinking about people's long-term future, you know,

• 1:33:26Speaker 01

  we want to think about this as, you know, how do we heal and get to people to recovery long-term? I think this really could have a role for a lot of people out there. And, and I don't want to happen what's happened in epilepsy and in diabetes, where there's been great randomized controlled long-term trials showing that ketogenic diets work, but doctors don't even mention them to people until maybe never, or maybe like five or 10 years into their illness, when people should be given an option. I mean, I just really believe that we, you know, even if you don't, you know, want everyone to do this, or you don't want to do it yourself with your, with your patients, I think, I think people deserve to know about this treatment.

• 1:34:11David Puder?

  Yeah, I think through this process of, of looking at this paper with, looking at these papers with you and kind of rethinking through this.

• 1:34:21David Puder?

  It's like, what I think I would like to do is, I'd like to find a nutritionist in the different states that I'm licensed in, Florida, Texas, California, and someone I can trust, you know, that I can kind of have like a partner with some of these patients. Because it's almost like, you know, I need someone that can kind of hold someone's hand, or the family's hand. I need to find that person.

• 1:34:47Speaker 01

  Yeah, I have a suggestion for you. There's a practice that's nationwide of ketogenic dieticians, registered dieticians, all have experience with ketogenic diets. Now, half their practice is mental health, actually.

• 1:35:01David Puder?

  Great. What's the name of it?

• 1:35:03Speaker 01

  It's Advanced Ketogenic Therapies, run by Denise Potter.

• 1:35:07David Puder?

  Oh, okay.

• 1:35:08Speaker 01

  Yeah, who's been doing these diets for, you know, 20 years with people with epilepsy. But in recent years is really heading into the mental health space. And she has wonderful programs online for people.

• 1:35:20David Puder?

  And then, I also think your program is a great option. I'll just plug that at the end there. You know, just a place to send people. I think there are people that are a good fit for that, who are willing to go and travel and learn the ketogenic diet. And so, I think that that is a really cool resource. It's called Accord?

• 1:35:40Speaker 01

  Yeah, Accord. Yeah. And it's really helpful because there are some people and some families that even with dietitian support, can't seem to get into ketosis at home.

• 1:35:50David Puder?

  Right.

• 1:35:51Speaker 01

  It's hard, you know, and I think they're doing everything right. But, you know, they come to us and we just immerse them in it. We've got a chef and a dietitian, delicious food, exercise, mindfulness, circadian rhythms. People get, you know, this huge benefit in a month or two, and then they're really excited to keep doing this when they get home. So it's sort of like an immersive jumpstart for people.

• 1:36:13David Puder?

  Cool. And then, yeah, I think the final thing is I'm going to be following these randomized trials and maybe, maybe we'll have you, maybe we'll have Chris Palmer come back on. Maybe, maybe we could, you know, when one of these studies comes out, we could, you and me could interview the person that did the study. We could, we could have them on together and talk about their specific study and kind of just continue to educate ourselves. But thank you so much, Matt Bernstein, for coming on. It's been a pleasure. I think you have a lot of practical knowledge. You're obviously, you know, someone who's balanced, a psychiatrist, who's been practicing for a long time. And that's the kind of person I like to have come on to kind of just give your wisdom and your experience. And this

• 1:36:56David Puder?

  is just an added sort of thing that we could think about with each of our patients, like, is this right for them? Give them, you know, mention it, look at the studies ourself, educate ourselves, try, try the diet ourself, so we can learn about it. And don't make the same mistake I made the first time I did it. I, I did not take enough electrolytes in, you know, you lose like six, 10 pounds the first couple of weeks.

• 1:37:25Speaker 01

  Yeah, that's

• 1:37:25David Puder?

  I continued lifting.

• 1:37:27Speaker 01

  Right.

• 1:37:27David Puder?

  I do powerlifting and I would have these horrible spasms after. And my friend, Darcy Tranquil, shout out to her, she was into the ketogenic diet for mental health issues a decade ago.

• 1:37:38Speaker 01

  Oh, wow.

• 1:37:39David Puder?

  She, she was all about it. And called her up and she said, yeah, you need to drink a good liter of bone broth a couple of times a day and you'll be fine. And so, you know, a lot of electrolytes in bone broth, right?

• 1:37:54Speaker 01

  Yes. Yeah. Well, yeah, I really appreciate, appreciate you having me and being able to talk about this topic I'm so passionate about. And it was great to go through it all with you. Yeah, thanks.

• 1:38:06David Puder?

  Cool. So we'll have, on our website, psychiatrypodcast.com.

• 1:38:11David Puder?

  Tied to this episode, we'll have all of your contact information. We'll have all of the articles that we talked about today. You know, this is free. It's not behind a paywall. So please, you can download the PDF. You can share it with people. You can share it with your patients. We're just trying to give information out for free across the world. I know people access these kinds of things and they find it very helpful. And so if this is something you want to dive into deeper, please go there. There's more actually there than we had time to discuss. We've probably discussed about 30 to 40% of what we have on that document. So there's a lot more to dig into.

• 1:38:52David Puder?

  And I'm going to be editing in the next couple of weeks, looking at each thing. And we talk about different groups of people that in particular may be of advantageous benefit to this, from this diet. So yeah, we'll leave it there for today.