65. Dr. Austin Perlmutter: Why You're Addicted to Bad Habits (And How to Reverse It)

What if the reason you can't focus, feel chronically overwhelmed, or keep slipping into the same unhealthy habits… isn't a discipline problem, it's your brain's biology working against you? In this episode of Extend, I'm joined by Dr. Austin Perlmutter, board-certified internal medicine physician and neuroscientist, to explore how inflammation hijacks your brain's decision-making and what you can do to take back control. We dig into why modern life wires your brain for reactivity over intention, the shocking impact of neuroinflammation on mood and behavior, and how daily habits are either fueling the fire or calming the system. You'll learn practical tools to reduce brain-body inflammation, support cognitive clarity, and make better choices even under stress. Dr. Austin Perlmutter, MD is a board-certified internal medicine physician, neuroscientist, and New York Times bestselling author. Let's dive in! We Also Discuss: Why Brain Health Isn't Just in Your Head The Overlooked Link Between Metabolism and Mental Clarity What Chronic Inflammation Is Really Doing to Your Brain How Long-Term Stress Rewires Your Biology Rethinking Depression: It's Not Just in the Mind Can You Rewire Your Brain? The Science of Neuroplasticity Are Psychedelics the Future of Mental Health? The Brain-Sleep Connection You Can't Afford to Ignore Thank You to Our Sponsors: TruNiagen: Whether you are looking to stay sharp, feel more energized or simple age better, go to https://www.truniagen.com/IFit: If you are looking to elevate your home gym fitness experience with the best in fitness tech, choose IFIT. Go to https://www.ifit.com/NextHealth: Your destination for cutting-edge health optimization—from IV therapy to hormone balancing. Explore at https://www.next-health.com/Vitaboom: For supplements you can trust and wellness solutions tailored to your health, visit https://vitaboom.com/ Learn more about Dr. Shah: Website: https://www.drshah.com/ Clinic: https://www.next-health.com/ Instagram: https://www.instagram.com/darshanshahmd/ Learn more about Dr. Austin Perlmutter: Website: https://www.austinperlmutter.com/ Instagram: https://www.instagram.com/draustinperlmutter/ Lichen air: Get 10% off at https://lichen-air.myshopify.com/?rfsn=8715882.7adc91 using code DRSHAH10 Sources: Effects of different physical activities on brain-derived neurotrophic factor https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.981002/full?utm_source=chatgpt.com Dr. Austin's research on Tartary Buckwheat: www.bigboldhealth.com http://www.bigboldhealth.com/

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

• 0:03Dr. Darshan Shah?

  Welcome to Extend with me, Dr. Darshan Shah, a podcast dedicated to cutting-edge science, research, tools, and protocols designed to help you extend your health span. Having become one of the youngest doctors in the country at the age of 21, and trained and board-certified at the Mayo Clinic, I've accumulated three decades of practice as a board-certified surgeon and longevity expert. Over that time, I've discovered that a mere 20% of health knowledge yields 80% of the results when it comes to your health span. We're living in a new era where we are creating a new healthcare system, no longer focused on disease management, but achieving optimal health and vitality. Join me as I interview world-renowned experts, offering you a step-by-step guide to proactively avoid disease, and most importantly, extend your health span.

• 0:50Dr. Darshan Shah?

  What if we already had the science to optimize our brain to such a level that we can unlock the missing link to sustained, optimal brain function, focus, and attention? And even improve our health span and lifespan? In today's episode of Extend, I'm joined by my friend Austin Perlmutter. He's an MD and a brain health expert and bestselling author. He's leading the charge in helping people get unstuck from their mental patterns that sabotage their health and specifically their brain health. We're going to break down what's really going on with things like decision fatigue, chronic stress, inflammation, and brain aging. And now you can regain control of your brain starting with your daily habits. Dr. Austin Perlmutter is a board-certified internal medicine physician.

• 1:34Dr. Darshan Shah?

  He's a New York Times bestselling author and a thought leader at the cutting edge of brain health and conscious decision-making. He has a background in neuroscience and a passion for addressing the root causes of chronic disease. Dr. Perlmutter specializes in the intersection of mental clarity, inflammation, and modern-day living. He co-authored the book Brainwash, which offers us a science-based path to reclaiming our modern minds from the chaos of the modern world. Through his work, Austin empowers individuals to make better decisions for their health by understanding how biology, the environment, and behavior all intersect, you guessed it, in our brain. I'm so excited to dive into this conversation because what he teaches us today could truly change

• 2:18Dr. Darshan Shah?

  the way we think, the way we feel, and the way we live. Let's get started.

• 2:26Dr. Darshan Shah?

  Dr. Austin Promater, thank you so much for joining us here at the Extend Podcast.

• 2:30Speaker 01

  I'm so excited for this conversation.

• 2:31Dr. Darshan Shah?

  Yeah, this is great. You know, I've been peripherally kind of following your rise here over the last few years and it's just so inspiring to see that you've really doubled down on brain health and educating the public in the world on a lot of things that a lot of people don't get to really talk about or hear about a lot because it's kind of taboo, things like depression, anxiety, mood disorders. Like, a lot of times, you don't hear a lot about this because it's one of those topics you don't even admit that you might have an issue with, right? And so...

• 3:02Speaker 01

  That's, it's so true. I mean, the fundamental point, I'll just lead with this, is that brain health is the only thing that matters. And when I realized this, I recognized there was no other path for me. Because if you were to sit and think about the way we generally consider medicine or health outcomes, we think about, well, your blood pressure should come down and it matters because, well, higher blood pressure increases your risk of stroke and heart attack. We think about cholesterol levels for similar reasons. We maybe think about blood sugar levels. These are all surrogates for the only thing that matters, which is, are you enjoying your life? Are you thinking clearly? Are you enjoying your relationships? And then you say, well, what determines whether that is the case? And it is 100% a reflection of what is happening here in your brain. So, again, when I understood

• 3:46Speaker 01

  that, when I was able to apply that in my life and understood how many people were struggling with brain issues, cognitive issues, psychological issues, just trouble getting their brains to be in a place where they could enjoy the day, then I recognized that there was so much work to do. So, it's been incredibly gratifying. There's still so much more work to do.

• 4:04Dr. Darshan Shah?

  You're right. I mean, like, I think about the practice of medicine, right? We check someone's blood pressure, then we treat it with a blood pressure medication. We check someone's blood work, their hemoglobin A1C, then we treat them with metformin. Never are you taught in medical school or in residency or whatever to assess how is someone feeling up here and use that as a biomarker of doing something about it.

• 4:26Speaker 01

  You're so right. I think it's still the case that when we look at brain-related issues, and the interesting thing about that is those are kind of siloed. We have mental health issues, which are issues of the mind.

• 4:37Dr. Darshan Shah?

  Right.

• 4:37Speaker 01

  And then we have cognitive issues like Alzheimer's, diseases of the brain. Somehow they're different, but still we're talking about screening for a person who hits the criteria for a diagnosis. And until you get there, it's really not something where there's much to do or even much to talk about. In terms of prioritization, and I'm sure you've seen these data, looking at rates of depression, looking at rates of suicide in doctors, they're dramatically higher than the general population. So clearly something isn't really falling into place here. It's not necessarily a system that prioritizes these things either honestly for patients, until things get so bad that they can go into a treatment algorithm, or for the people who are learning how to treat patients. So it speaks to the fact that those are just not really the most important variables, even though objectively they are the only variables that matter.

• 5:22Speaker 01

  That is the cornerstone, in my opinion at least, of what true health represents. It's being able to wake up, to enjoy your day, to think clearly, to communicate clearly, to spend time with the people you care about in a meaningful way. All of this requires your brain to be functioning well. And so every variable that we think about in terms of what we should be doing for health has to funnel into that primary outcome. And it is the case, and this is not necessarily just an issue with healthcare, but it's an issue with the modern world, where we have moved to a place of kind of mitigating psychological pain while actually worsening overall brain health. The things that we do to try to feel better actually worsen our overall brain health. And it is such a liability for every person.

• 6:06Dr. Darshan Shah?

  Yeah, I mean, it has so much unpacked there and I can't wait to have this conversation with you because it's something I've been wanting to talk about for a while. Because you know, I dive a lot into biomarkers and cardiovascular health and you know, muscular health. The brain is such a black box and I think people, even the people listening to this and leading their day to day lives, I think we're all kind of conditioned to look at the things that are going on in our brain as something that we should just self-manage somehow, you know? And just we should, we need to get, if we're depressed, we just need to figure out how to get happier. If we are anxious. We just need to figure out it's stress less and we've got to and we almost look at it as something that is

• 6:49Dr. Darshan Shah?

  a negative when we look at ourselves in the mirror to have these these emotions and these feelings. When really they're an indicator of number one, our brain health, but also our overall physiological health, right?

• 7:01Speaker 01

  You're a hundred percent right. There is something really challenging about the fact that our sense of identity comes from the brain. And so to challenge that seems odd, seems off to say, I'm not feeling well today, instead of being curious and saying, well, what's happening within my brain? We say, oh, that's that's something's wrong with me. Or I'm kind of losing my my thinking. I'm not thinking is clearly that's something that's going on with me. It's my fault, right? It's it's an identity issue. And if a person has an issue with their knee, if the knee isn't functioning well, right? They will go in and say, my knee hurts. It's making a creaking noise. Things feel like they're grinding against each other. Let's get an x-ray. I don't feel like it's necessarily me. It's the knee. I mean, it's part of me.

• 7:45Speaker 01

  But I'm not going to be embarrassed about telling friends, hey, I'm having some knee issues. But when it's a brain thing, it's somehow separate from all of that. And I think what's happened is not only does it take us away from understanding the beauty of what's actually in the brain, but it gets us to a place where when we finally get to caring enough to get a diagnosis, we want to find a simple solution to that problem. I mean, the brain is, depending on the study you look at, has something around eighty billion neurons, around eighty billion, what are called glial cells, historically thought of as support cells, but they do a whole lot more. And you have somewhere in the neighborhood of a hundred trillion synapses connections. It is by far the most complex part of the body, right?

• 8:26Speaker 01

  And it's maybe one of the most complex and mysterious things in this planet, on this planet. And still we distill it down to saying, well, your mood is low, therefore what you need is more serotonin. Done, right? So it's very easy to then go to these places of saying, despite the complexity, it's a simple manifestation of, in this case, a neurotransmitter issue. Now, that's interesting because we've seen recently a lot of pushback against the idea that depression is a serotonin deficient. The evidence just isn't there. But it follows with this continuum of saying, I'm not going to do anything about it because I'm embarrassed. Or I don't know what to do. I'll finally see a doctor. I will get a prescription for a medication that should tweak a neurotransmitter and then no depression.

• 9:09Speaker 01

  But depression is one of the manifestations of what happens in us, to our brains in our lives. And I, I keep thinking about a scenario that happened back when I was in the VA hospital. And how I would use the same depression algorithm for the person who had experienced a significant life event of the loss of a spouse.

• 9:27Dr. Darshan Shah?

  Sure.

• 9:27Speaker 01

  For example, versus somebody who had a chronic illness. So let's say they had diabetes and they were chronically inflamed. And they were both experiencing similar symptoms. They felt withdrawn. They felt like life wasn't as meaningful anymore. But the assumption is that in both cases, the issue was a serotonin deficiency. And that using a drug that increased levels of serotonin signaling in the brain would be the fix for both. Rather than saying, you know, there are so many things going on in this person's life and in this person's brain. Maybe serotonin plays a small role in this, but could it be the case that in the person with diabetes? That there is an issue with brain metabolism, there's an issue with brain inflammation. And the person who is undergoing all this stress around the loss of a spouse is having HPA dysfunction.

• 10:11Speaker 01

  Those are different systems. They interact with each other. But still it was a blanket solution in terms of the first line therapy being an SSRIs, NRI. And or psychotherapy as opposed to asking about what in this complex web of what is within our brains. Is actually driving this experience that we might call depression. But is so much more than that because again, we're talking about billions and billions of cells interacting through trillions of connections. You can't just distill it down to a simple algorithm.

• 10:41Dr. Darshan Shah?

  Yeah. And your brain is interacting with the rest of your body and your metabolism constantly as well. So your point is really well taken that with SSRIs. Drugs like Prozac, et cetera, we are really just treating a manifestation of the disease with the, with. A very complicated disease with a pill. And you're really just covering up the underlying cause.

• 11:04Speaker 01

  I think that is true. I mean, I think psychoactive drugs have absolutely a place. Yeah. And when we look at SSRIs, still the most commonly prescribed set of antidepressants, side effect profile is miserable. Withdrawal profile can be up to 50% of people who come off of these medications experiencing significant withdrawal symptoms. And depending on the research that you look at, the efficacy of SSRIs in leading to substantial improvements in depression is hardly better than placebo. Again, not taking away from the idea that these drugs have a place to be used, but if we're asking this question of, hey, a person's experiencing poor mental health in the context of depression, and we're saying the issue is serotonin deficiency, and we're

• 11:46Speaker 01

  prescribing drugs that in theory should augment serotonin transmission, then we would expect that the vast majority of people would see dramatic benefits when they started these medications. Right. And they simply don't. Right. So what it tells us is either the drugs don't work on that system, and there's an argument that that's the case, or it's not serotonin. It is a bigger story. There are more pathways involved. It's not as though it's just a convergent point. And so what the research has made abundantly clear now is that pathways like impaired neuroplasticity and neuroinflammation and neurometabolism, vascular changes in the brain, all of these things combine to shape how we think, how we act, and how we feel. And mood is one

• 12:28Speaker 01

  component of that story. But I want to expand it out here again. We talked about how there are cognitive issues and there are psychiatric conditions. It's not as though these things exist in different places. There is a reason why a person with diabetes is at a significantly higher risk for developing depression and dementia. It's because these pathways are shared. There's a reason why somebody with high levels of peripheral inflammation is at dramatically higher risk for developing depression and Alzheimer's disease. It's because there are shared pathways. Right. And I think when you begin to take a step back, then it gets really exciting. Because what we know is, unlike, you know, this hope that an SSRI is going to fix depression but not work on systemic pathways, we know that we can look at immune function, metabolic function, how to augment neuroplasticity as

• 13:14Speaker 01

  Strategies not only to improve mood, but to protect cognition across the lifespan and to think better right now. So I think that it changes the landscape completely.

• 13:24Dr. Darshan Shah?

  Absolutely.

• 13:25Speaker 01

  Last thing I'll say on this is the typical thinking is you go through life. And at some point, if you reach the criteria for having major depression, then we'll put you on a drug that should decrease your symptoms. But all of those years and all of those moments leading up to that where mood changes, it's not like you wake up one day for most people. And are depressed where yesterday you were doing just fine for the last 30 years. It's a spectrum, it's a continuum. It's just like neurodegenerative diseases, like Alzheimer's disease to think we shouldn't worry about Alzheimer's until. You know, you bring your mom into the clinic and they say, you know, this is a clear scenario where she has Alzheimer's and here are the drugs we can offer. The best time to intervene is much earlier.

• 14:05Speaker 01

  And so one of the main points that I want people to understand is if you're listening to this and you're asking, when should I be working on my mood? When should I be working on my cognition? It's right now. It's not when you have to see your doctor. And the reality is that your best chance of thinking clearly and feeling good for most people is in your hands. It happens outside the doctor's office because these are like anything today, chronic illnesses. The compounding effect of decisions we make over decades, rather than the singular outcome. Of something that happened when you finally got to the doctor's office and got the diagnostic.

• 14:41Dr. Darshan Shah?

  Yeah, that's so profound. And you said so many really important points that I want to highlight. Number one is that mood disturbances, whether it be depression, anxiety, what have you, and cognitive issues, whether it be Alzheimer's, Parkinson's, whatever it might be. These are all really one of the same thing. They're brain disorders that are happening from a few root causes. You mentioned four, neuroplasticity issues, neuroinflammation, or the other two?

• 15:06Speaker 01

  We talked about neurometabolism and vascular issues.

• 15:08Dr. Darshan Shah?

  Neurometabolism, go ahead.

• 15:10Speaker 01

  There are more, so neurotransmitters absolutely play a role. There are a number of other systems within the brain. But I think that for the focus of this conversation, I really think that neuroimmune, neurometabolic and neuroplastic are some of the most directly accessible. In terms of lifestyle intervention and that's what makes them so interesting.

• 15:28Dr. Darshan Shah?

  Exactly.

• 15:29Speaker 01

  And so, go ahead.

• 15:30Dr. Darshan Shah?

  No, I was just gonna say, I mean, I do agree, those are the three most important ones that we have the most control over. And I think that's what we should focus on because like you said, you know, I had this conversation with Dr. David Perlmutter, your dad, about righting the ship early. And if you focus on these, these root causes earlier and even make a one degree change or a two degree change over years, you could have a massive change in your health outcomes, right?

• 15:55Speaker 01

  That's it. It's compounding interest, right? That's exactly what we're talking about. The first place I think people need to start with this, though, is just understanding that your brain doesn't exist separate from the rest of your body. And I think that's still a prevailing mentality, which is you do things for your body, interesting, but for your brain, the only things that you can really do are either get a prescription or maybe do some meditation. Right? And the point being here that the brain is absolutely linked to what happens throughout the body. And so I think these three systems that we just described are excellent examples of this. So maybe let's start with metabolism.

• 16:27Dr. Darshan Shah?

  Yeah, that's a great one to start on because that is, I would say, very deep interconnections with the rest of your body and your habits, right? So let's talk about neurometabolism. Would you mind defining that a little bit first?

• 16:38Speaker 01

  So metabolism more generally is just how your body takes basically building blocks, energy from outside the body, converts it into building blocks, energy inside your cells, and then gets rid of the waste. It can be more complicated than that, but it's basically just the movement of energy through the system, the movement of building blocks through the system. And as it relates to the brain, what we're talking about is how your brain does those same things. Now, the brain, for anyone out there listening, is using up a ton of your energy right now. In order to function, I mean, one of the advantages we have as humans, we have these incredible brains, but they require a lot of energy. And so-

• 17:12Dr. Darshan Shah?

  What percent of your-

• 17:13Speaker 01

  Right. So the statistics are something around our brain is two to 3% of our body weight, but uses up around 20% of our energy. Now, the energy is primarily in the form of glucose. And why that's important is why there's this kind of bias against saying sugar is bad. The reality is that for most people and most of the time, your brain is running on sugar. It doesn't mean that added sugar in your diet, or even sugar in your diet in general, is necessary or helpful. Full to your health. But when we're talking about blood sugar, specifically circulating glucose, that is the primary fuel source for your brain cells. Importantly, the real estate in your brain, similar to Beverly Hills, where we're having this conversation, is very expensive. There's not room for a bunch of extra storage, which means that unlike the rest of your body where you have adipocytes, where you have glycogen stores, you don't really have access to that fuel.

• 17:58Speaker 01

  So you have to import it all. It's kind of its own little island. Where do you import it from? Well, it comes from the bloodstream. You have to take the glucose from the bloodstream through these glucose transporters through the blood brain barrier. And that's where it gets access to your neurons. Now, your neurons, roughly 50% of your brain cells are using up roughly 70% of the fuel. So they're definitely the most energy intensive parts of your brain. And really, really interesting here, the neuronal fuel use corresponds to the parts of your brain that are being used. So when you're thinking about one thing and using certain parts of your brain, uh, that's actually the areas of your brain that get increased blood flow and use up increased glucose.

• 18:37Dr. Darshan Shah?

  Thus the scans that you can do.

• 18:39Speaker 01

  Thus the scans, right? So that's the whole idea behind it. So again, your neurons are using up the majority of your glucose. They use it up primarily to repolarize because when a neuron transmits data from one neuron to another, it has to shoot data across the synapse and it has to use, uh, basically polarization or depolarization, chemical and charge base gradients to move that data. So it uses up the majority of that glucose to recharge after it sends data. What's really, really interesting, though, and what we're now learning is that as it relates to brain metabolism, other cells are also involved. And so without getting super technical here, you have a host of other glial cells. These are these generally thought of as accessory cells, but they actually do a whole lot.

• 19:21Speaker 01

  Astrocytes are the most important glial cell for metabolism. And what's now been shown is that astrocytes not only form a part of the blood brain barrier, but they form this kind of three-way synapse with neurons where they facilitate the metabolism and kind of the collection of metabolic signaling between these neurons. And in particular, what they can do is they can take glucose, convert it into lactate. And use that as an alternative fuel source for neurons that are firing pretty quickly. So you basically have this reserve of fuel. And what that means is astrocyte health is incredibly important to neuronal health.

• 19:56Dr. Darshan Shah?

  Sure.

• 19:57Speaker 01

  So this integrated metabolism. Last thing I'll just say here, ketones always very important. So the brain can and does enjoy running on ketones. But unless you're doing a very long fast, for the most part, you're still using glucose as your primary fuel source.

• 20:11Dr. Darshan Shah?

  Right.

• 20:12Speaker 01

  So that's the context in which it's important to understand that brain metabolism is occurring. Brain metabolism is obviously essential then for how we think, how we act and how we feel. Because in order for data to move from one neuron to another neuron, you need a ton of energy. It's why the majority of mitochondria in your neurons are located near the synapse. It's why neurons can have up to one to two million mitochondria per neuron. So I'm not doing the calculations, but somewhere around 80 billion neurons times 2 million per. Okay, so it's a big number. It's a big number.

• 20:43Dr. Darshan Shah?

  Lots of zeros.

• 20:44Speaker 01

  But if we think about what this relates to around diseases around cognition, I think the most interesting thing is that as we look at age-related cognitive decline, as we look at Alzheimer's disease, what you see is a decrease in the brain's utilization of glucose. And so the the assumption here and the the terminology around Alzheimer's being type 3 diabetes is that if we could get more access to brain fuel, then it might mitigate some of the issues associated with the fall off of brain metabolism as we age. And there are researchers now who are looking at how this might relate to mental health conditions. Chris Palmer being a good example. But the point here being that in order to think, act or feel in any way, your brain needs perpetual access to fuel.

• 21:29Dr. Darshan Shah?

  Right.

• 21:29Speaker 01

  One last thing I'll say on this.

• 21:30Dr. Darshan Shah?

  Yes.

• 21:31Speaker 01

  Because, you know, it's interesting, we could say, okay, I want my brain to get enough fuel. Then we ask this question of how does brain metabolism link to systemic metabolism?

• 21:40Dr. Darshan Shah?

  Right.

• 21:40Speaker 01

  And, you know, we have a lot of friends who are expert on this subject about how our metabolic health is being compromised. The latest data I've seen is the UNC study saying that around 88% of Americans have at least one aspect of metabolic dysfunction. And that's looking at kind of just. A couple of core metrics, it likely expands when you add in additional metabolic markers like uric acid. But when we look at correlations, as I already said, between conditions like type 2 diabetes and brain health outcomes, as a metabolic disease correlating with a worse brain health outcome, it absolutely is going to speak to this dynamic interplay between systemic metabolism and brain metabolism. And for anyone who's out there questioning whether this stuff is real, the data I would bring in is, ask what happens when somebody goes incredibly hypoglycemic.

• 22:25Speaker 01

  Ask what happens when somebody is in the hospital with DKA, diabetic ketoacidosis. How is their cognition? And the answer is very bad, right? If you lose your blood sugar levels and go very hypoglycemic, you can enter a coma-like state. And that can happen very acutely with DKA, with diabetic ketoacidosis. Altered mental state is a very common symptom. And the reason is because your brain depends on systemic metabolic state in order to function clearly. So I think it has a lot of implications for what we do each day as it relates to protecting our brain health long-term, and some really interesting implications as it relates to what's happening each day, to just think clearly, to show up at your office and think clearly, to be in relationship with other people, and be able to hold the balance.

• 23:07Speaker 01

  And so, not to go too far on this tangent, but even looking at healthy people who have fluctuations in blood sugar levels, very high, very low, there's now some correlation with issues with brain metabolism. And I think that's super interesting, because we're starting to get to the root of, what does it look like at the early stages in terms of things that we can either measure or get some surrogate markers of that may correlate with long-term brain metabolic dysfunction?

• 23:33Dr. Darshan Shah?

  Right. It's such a great point, because one of the things that I talk to my patients about, we use continuous glucose monitors a lot. And it's so interesting to know that you and Casey Means went to medical school together.

• 23:43Speaker 01

  Residency.

• 23:44Dr. Darshan Shah?

  Residency together.

• 23:45Speaker 01

  We're both at OHSU.

• 23:46Dr. Darshan Shah?

  That's amazing. So, a lot of metabolic talk in that residency program probably between the two of you guys.

• 23:53Speaker 01

  Not I so so that's an interesting point. When I was thinking about specifically brain metabolism, I thought to myself, what did I learn about this in training? And again, we learned about this in the context of diabetes, certainly the most common metabolic disease. There are there are a number of brain metabolic diseases, but diabetes is certainly the most common because people will come in hypo or hyperglycemic, either because they had a primary diabetic complication or because they had a different issue, they had a disease. So maybe they had some sort of cardiovascular event, or maybe they had sepsis or some other infectious disease and their blood sugars will go wonky. What we learned is we need to keep people's blood sugar level, right? Using insulin, using snacks, using glucose in the bloodstream. The goal was to keep it level.

• 24:38Speaker 01

  The question really didn't come up, though, which is what is the most optimal routine for protecting brain health from diabetes outside? Certainly, we knew about stroke. Certainly, we knew that having poorly regulated blood sugar was a predisposing factor to, again, cardiovascular disease, but also dementia. But we never really brought up this question as to how do things like insulin resistance affect brain function? And from a dietary perspective, is there a difference between trying to manage diabetes towards diet lower in carbohydrates that can actually restore some of our endogenous insulin sensitivity? So we don't require as much insulin versus just managing it with medication? And the best example of this was just the goal was always to get people to eat the same

• 25:21Speaker 01

  meals each day, didn't matter how much carbohydrate was in it, as long as it was consistent. So we could kind of manage the blood sugar.

• 25:28Dr. Darshan Shah?

  Yeah.

• 25:28Speaker 01

  And I think it's just things have changed so much now, in part because of the data we're starting to get through CGM and understanding that every person is different and not just diabetics, which is it's such a game changer. I personally use a CGM, I'm sure you have many times as well. I think getting the insights in real time, not only in terms of what the blood sugar is doing, but how it makes you feel.

• 25:48Dr. Darshan Shah?

  Right.

• 25:48Speaker 01

  It's just a completely new game in terms of how we look at this.

• 25:51Dr. Darshan Shah?

  Absolutely. And so my point on that was that wearing a CGM has been a game changer, not just for the people that have some level of metabolic dysfunction.

• 26:00Speaker 01

  Which is most people.

• 26:01Dr. Darshan Shah?

  Which is most people anyway, but also. So even if you don't, because what you'll find is when you're having constant spikes and and crashes, that you are not thinking clearly, your energy levels are off, you need to maybe take more naps in the evening versus or in the afternoon versus not take a nap that day. There's a lot of things that having those spikes can affect on your day to day life. And those spikes is actually what adds up to long term metabolic dysfunction in the future as well. So my point of that is even if you don't have a problem with metabolic dysfunction, it's still useful to see this data and to understand how it's affecting your day to day envi- your day to day mood, your day to day energy levels, all of that.

• 26:45Speaker 01

  I think I think you're absolutely right. And it goes back to what we're saying before, which is I think typical that people, even if they're not consciously aware that something's happening in their brain, they're obviously aware that something is going wrong. I'm experiencing stress. Where does that occur? I don't know. I just feel stressed. Or I'm feeling sleepy. Where does that occur? Oh, I don't know. I just feel sleepy. Or my mood feels, I'm getting angry. I just feel enraged. But it's never really the question of, well, what does that represent?

• 27:10Dr. Darshan Shah?

  Right.

• 27:11Speaker 01

  What what systems are leading to it? And I think some people would look at this as detracting from the magic of what makes humans, humans. It's like you don't want to peel back the curtain too much because you might see the little actors inside and it'll ruin the illusion that you are the driver of this whole experience, you know? And so I actually go the completely opposite way. I become fascinated with some of these newer hypotheses that are asking what is actually driving our actions. So some of that data talks about how the state of the gut, specifically the microbiome, may be driving how we think, how we act, how we feel. And so is it possible that our bacteria and the other microbes have a bigger say in who we are, that we're just a vessel to carry them through?

• 27:55Speaker 01

  There's some similar kind of theories around psychedelics. The point here being if you open it up a little bit and just get curious and say, you know, this me, this identity, this this sense of permanence, that it's the same person going in day to day is so untrue. And that if you think Think about what's happening in your brain. The reason you know things today that you didn't know yesterday is because something is different. You don't have the same brain today that you had yesterday and you'll have a new brain tomorrow. Similar to the cells in your body that are being replaced, there's no permanent me, right? So that means what an opportunity, but it can be a little bit scary. So CGMs open that up a little bit where we start to say, oh, this blood sugar level that I'm measuring here,

• 28:39Speaker 01

  specifically, I guess, interstitial blood, but when we look at what's happening in our blood, that it has an effect on all these other variables, you start to say, look, not that I am a machine, but I am a sum total of a number of biological processes occurring in real time. And I can intervene on that, right? I can start directing that and not just being the responder to what's going wrong in my body. So I think it it changes the game. It can lead to a little bit of a mind warpy place when you start to appreciate that the you is not the same you as yesterday, the same you as tomorrow. But what an opportunity to change yourself for the better.

• 29:14Dr. Darshan Shah?

  Oh, absolutely. You know, it's so funny because it brings up a patient of mine that I'm seeing. He brings his wife to every appointment because his wife is the one that kind of monitors his overall state of health. And one of the things that we always talk about is his mood in the in the marriage and the relationship. And a few weeks ago, she told me, she said, you know what? Ever since he's been wearing the continuous glucose monitor and keeping his blood sugar stable, he's been a lot less moody, he's been a lot less irritable. And he was sitting there right then and there, he said the same thing. And he's like, it's so weird for me to think that my mood was really not under my control as much as I thought it was. It was really my blood glucose controlling my mood.

• 29:56Dr. Darshan Shah?

  And you know, this whole conversation around what controls what is kind of like, well, you were saying, it's one of these things where you're opening up the door to seeing what's really controlling a lot of your behaviors and your mood, et cetera. And one of them being blood glucose is actually a revelation to people. But on the other end of that, what I will say is that they are so much happier.

• 30:17Speaker 01

  Right.

• 30:17Dr. Darshan Shah?

  Right?

• 30:18Speaker 01

  Agency is an incredibly important variable. And we still exist in this world where we're kind of being told, having something going wrong with your brain, the solution is the quick fix. This this transcends just the medical establishment and it gets us to the way that people interact. The primary driver of human behavior is escaping psychological pain. Why people do the things that they do. And so if that's the case, and we were to ask, well, psychological pain originates in the brain, certainly with other inputs, systemic metabolism, the gut. But psychological pain is a reflection of what's happening in our brain. What are the solutions that we're turning to to get rid of that? Is it blindly scrolling on social media for a few hours that's going to, for an instant,

• 31:02Speaker 01

  distract us so that we're not feeling the psychological pain, but afterwards? Increased stress because of social comparison? Is it going to be food, unhealthy food, that we preferentially turn to when we experience psychological pain, that for a moment gets rid of the pain and in the long run increases our risk for mental health disorders?

• 31:21Dr. Darshan Shah?

  Right.

• 31:21Speaker 01

  I think that's kind of the setup we find ourselves in, which is everyone's acting to try to optimize their brain health in a way, meaning to get rid of the short-term problems. But in the long run, they're actually having the exact opposite effect on the brains that they are creating. And it works really well if you are a company that sells solutions that never actually fix the underlying problem.

• 31:44Dr. Darshan Shah?

  Yeah. Which are most companies that are selling pharmaceuticals and some of these other solutions.

• 31:50Speaker 01

  Monthly recurring revenue.

• 31:51Dr. Darshan Shah?

  Exactly.

• 31:52Speaker 01

  So it's not going to fix it.

• 31:53Dr. Darshan Shah?

  Right, exactly. You know, conspiracy theories aside, though, our brain was developed through evolution to minimize short-term pain, right? And so with no concern for long-term protection, right?

• 32:06Speaker 01

  It's a really good point. Your brain, my brain, they're not there to get us to be happy.

• 32:11Dr. Darshan Shah?

  Right.

• 32:12Speaker 01

  That's a fringe effect.

• 32:13Dr. Darshan Shah?

  Right.

• 32:13Speaker 01

  Our brains want us to survive and they want us not to be in pain. And when you take that programming and put it into the world we exist in today, I don't think this is conspiracy theory at all. I think it's just our brains are optimizing towards the wrong variables.

• 32:27Dr. Darshan Shah?

  Absolutely.

• 32:27Speaker 01

  And so the health outcomes that we experience, whether it's mental health or physical health, being poor is the expected result of this hardware existing in this world.

• 32:38Dr. Darshan Shah?

  Exactly.

• 32:38Speaker 01

  So it's just, it's, there's no surprises here.

• 32:41Dr. Darshan Shah?

  Right.

• 32:41Speaker 01

  I mean, I think sometimes people say, oh, well, you know, look, people, if they just exercise more. Eat healthier food, weren't on social media all the time. There's a reason people don't eat healthy food. There's a reason people don't exercise more. And there's a reason people are on social media all the time. The brain says, this is great. You know, this is the easiest outcome for me to feel better and not die. And so this is the outcome that we should expect to see. People becoming less and less happy and more and more unhealthy.

• 33:06Dr. Darshan Shah?

  Yeah, absolutely.

• 33:11Dr. Darshan Shah?

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• 33:49Dr. Darshan Shah?

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• 34:28Dr. Darshan Shah?

  You know, I wanted to just double click on one thing you said a little bit earlier because I get asked this question all the time about the use of ketones as a fuel for the brain. I think there's been a few studies showing that it could be potentially beneficial in people that are experiencing mood disorders and even cognitive disorders. But what is your feeling about this? And how does this fit into the big picture?

• 34:48Speaker 01

  Right, so thinking about this in the context of simplifying things, I am generally not a proponent of people going dramatically on to some sort of a ketogenic diet or even taking exogenous ketones. And the reason being, anything that I recommend in broad brushstrokes is going to be based on principle, you know, the Pareto principle, whether it's 80% or 90% benefit from the least amount of work possible. There you go. And the point here being that for most people and most of the time, the goal is to find a sustainable path forward. I am interested in area under the curve. I'm not interested in the spikes and I'm not interested in the troughs. So the goal is to maximize the quality of your life experience over decades, not over the next few weeks, not to get you into the swimsuit for the summer season. And so if we look at that, then the question

• 35:32Speaker 01

  is what do people stick to long term, decreased risk for nutrient deficiencies? And that's why I generally recommend something more akin to a Mediterranean pattern diet, which is not a ketogenic diet. Right. Now, what I do think is the ketogenic diet can be a powerful tool for people with specific conditions. And the research, I was just discussing this with a gentleman yesterday who had, he was on a bunch of kind of new diabetes meds and he had seen some amazing improvements. But I told him about the work, looking at a ketogenic diet on basically reversing diabetes and decreasing and completely reversing, in some people's cases, reliance on medications. So in instances in which people have issues with carbohydrate metabolism, with metabolic function in general, I think the ketogenic diet is very interesting. There's

• 36:14Speaker 01

  some preliminary data in Alzheimer's disease, not necessarily looking at cognition, but on improved other metrics, so functional status. And so those are the scenarios where I think it's most relevant, is looking at people with pre-existing metabolic dysfunction, whether that's brain-related or systemic-related. I think that can be really interesting. But last thing I'll say on that front is, I think that the concept of moving towards a diet that is lower in refined carbohydrates is wonderful. The liability is that as people adopt any sort of extreme diet, of which the ketogenic diet can be one, is that you're removing nutrients that have been consistently studied to be associated with better health. And I think the biggest liability there is fiber. So most people don't get enough fiber to start with. You should get around 30 grams or more a day. And the ketogenic diet tends

• 36:56Speaker 01

  to just take people off of carbohydrates. Higher fiber consumption is associated with higher quality of life and longer life and better cognition. So I would say that's kind of the concern with it. In a perfect world, you're working with a health practitioner that can tailor something like that to your goals. So I'm interested. You know, I think that the cell science is certainly there. It is incredibly interesting that the brain is able to use ketones across the lifespan, even as glucose metabolism drops off. And I think there's a ton of promise. But do I generally recommend it to the average person? I don't.

• 37:29Dr. Darshan Shah?

  I'm exactly on the same page as you. I think it could be a potential intervention, but for a specific time period, long term, definitely, it is actually more damaging in some ways as well as what I've seen in most of my patients. Now, I have some people that have been on the keto diet for 10, 15 years and, you know, there's always the bell shaped curve of people, right? Like, that's probably an outlier, where someone can be on the diet for a long time and have just nothing but benefits. I think most people fall somewhere in the middle where it's a good intervention.

• 38:00Speaker 01

  And I think what you just brought up is such an important point. So you're working with patients, one on one, where you can see, this is what works for you, and it's not what's going to work for somebody else. The issue we have right now is that these N of one cases, while they matter so much to the individual, are basically broadcast as the universal solution.

• 38:16Dr. Darshan Shah?

  Exactly.

• 38:17Speaker 01

  And so the ketogenic diet is a good example. Any restrictive diet is a good example. Somebody tries, you know, the orange juice diet and says that I reversed my diabetes, that's not going to happen properly, but let's say they did. It doesn't mean that's a good recommendation for the general public. So I love the idea of the N of one stories, but I think it works really well in the context of actual medical care and not in the context of, I have very unique biology, and also I'm not giving you all the facts, and also I have a new product line based on this being the solution. So there's a lot of intrinsic bias and some, I think, dilution of value.

• 38:48Dr. Darshan Shah?

  Right, exactly. I mean, you know, just because something works so well for one, what you're saying is just because something works so well for one person, and they go out there and market the heck out of it and sell you products for it, they have a different motivation for themselves personally.

• 39:02Speaker 01

  Right.

• 39:02Dr. Darshan Shah?

  You have to look at yourself as an N of one, and the only way you're going to know if that's going to work for you or not is to give it a try and monitor yourself as well. And no one's going to do that for you, except for you. So, you know, even if you go to a doctor and you say, I want to go try the ketogenic diet, if you're not self-monitoring,

• 39:21Speaker 01

  Right.

• 39:21Dr. Darshan Shah?

  you're, the way you feel, the way you're sleeping, the way your biomarkers are changing, your wearable devices, you're not going to get good data, and you might be on a path towards actually a detrimental result in your biology. So it's so important to be participatory in your healthcare and monitor yourself.

• 39:38Speaker 01

  It's essential. I think. A person's best chance at being healthy is not their doctor, it's themselves.

• 39:44Dr. Darshan Shah?

  Exactly.

• 39:44Speaker 01

  Right? In, in general, now there are certain cases for which that's not the case, but for most people and for most chronic diseases, the best chance you have at avoiding disease and improving health is for you to be the main agent of your health change. If you wait for your doctor, you're not doing it right. Now, I think a doctor is an essential or a medical practitioner is an essential part of that. It can be a health coach, it can be going to see your, your typical doctor, it can go, going to see an interventional doctor, it can be going to see an integrative doctor. But, most health happens outside the clinic. So, I think that's just a really empowering message too, that you are the most important person in determining health or disease for most conditions.

• 40:25Dr. Darshan Shah?

  Absolutely. You have to become the CEO of your own health or the boss of your own biology. No one's gonna care as much as you do, and we have to stop outsourcing our health to a doctor or to somebody else. Like, it's our personal responsibility.

• 40:36Speaker 01

  We say as doctors, right?

• 40:37Dr. Darshan Shah?

  Exactly. As doctors, we say that. Let's talk about neuroinflammation and your, and the immune system of your brain.

• 40:44Speaker 01

  Right.

• 40:44Dr. Darshan Shah?

  Listen, can you kind of define that a little bit for us? Because I feel like this is such an important part of our brain that we are just now finally focusing in on an understanding of its importance around the glial cells, etc. So I'd love to hear your big picture explanation, why it's important and how we can affect it.

• 41:00Speaker 01

  Sure. Most people are familiar with inflammation in their bodies. They've probably heard the term before. And inflammation can look like a, a raised welt that's red, it's swollen. It may look like pain in the knee, it may look like an allergic reaction. We maybe have some familiarity with the term in the body. But, similar to what we were talking about earlier with the, the knee issues, you know, if your knee is creaky, if your knee is painful, you say, there is a problem here.

• 41:24Dr. Darshan Shah?

  Right.

• 41:24Speaker 01

  But your brain, the inside of your brain does not have pain receptors. So what does it look like if inflammation is in the brain? Well, what it looks like is altered mental status. What it looks like is altered cognition. And these are things that are historically attributed to other causes.

• 41:40Dr. Darshan Shah?

  So can we double down on that real quick? Cause I want, I want people to know what it looks like.

• 41:44Speaker 01

  Sure.

• 41:44Dr. Darshan Shah?

  So when you say altered mental status, altered cognition, brain fog is one way to. Describe it in people's everyday terminology.

• 41:52Speaker 01

  Right, so let's look at the extremes. So the person with the highest levels of inflammation in general is going to be the person in the ICU having sepsis, basically an overwhelming response to usually a bacterial pathogen.

• 42:06Dr. Darshan Shah?

  They're like comatose.

• 42:07Speaker 01

  Correct, they're out of it. I mean, we can look at data showing that around sixty to seventy percent of ICU patients experience delirium. And one of the main variables, metabolic is part of this, but one of the main variables that conventional medical research describes as driving this is elevated levels of inflammation in the brain. We also saw this in the context of COVID. It was a wonderful case study in terms of understanding what inflammation does to the brain. The outcomes have been really horrifying as we look at what happened with people in the hospital. So there was, in essence, something called a cytokine storm that we saw in certain patients where the immune system revved up, produced a ton of inflammatory markers, and this correlated with alterations in mental status. What we've seen now, long term, in the context of long COVID, is a number of people with

• 42:51Speaker 01

  enduring psychological and cognitive issues. What are the drivers of this? It's thought to be neuroinflammation as a cornerstone of it. So how does neuroinflammation exist within the brain? As I've said, there are two major cell types within the brain. There are neurons, and then there are glial cells. And of the glial cells, there are a couple to be aware of. You have oligodendrocytes, they're responsible for creating myelin sheets around our neurons. We have astrocytes, that I've already mentioned in the context of metabolic integration, blood-brain barrier. And then you have microglial cells, something around fifteen or so percent of total brain cells, which accounts for around twenty billion or so cells. Now, what makes them so interesting is that your microglial cells are, in essence, sentinels.

• 43:31Speaker 01

  Their role is to pay attention to what is happening in the local environment and transmit that data into signals which are called cytokines. These are immune signals. And so they form a 3D web that basically is able to sample from the entire brain to figure out what is the danger level? What's the threat level? And based on the intel they receive, they physically and functionally change the way that they work. So they will kind of morph into a Different shape and you can think of this as almost going into a Hulk like shape or more of a kind of pacifist type shape. They have terms like M1 and M2 microglial cells. Because really what they are is a type of immune cell called a macrophage. Which people may know a white blood cell that floats around in the bloodstream, but in the brain,

• 44:17Speaker 01

  they have, as in the body, they have a number of different tasks beyond just microbe defense. So again, this web of these microglial cells and they're listening for danger.

• 44:26Dr. Darshan Shah?

  Yeah.

• 44:27Speaker 01

  So what does that danger look like? Well, it can be an immune threat that we would typically think about like bacterial infection. So if you have bacterium that gets in the brain, which hopefully you don't, microglial cells are your first responders. If you have chronic viral infections, so herpes and other viruses that can have a brain effect, microglial cells can be involved. But what's really, really important is that these immune cells also react to other forms of stress. And so here we're talking about damage, we're talking about psychological stress, we're talking about they are listening to damage to your neurons or higher levels of psychological stress. And then they are responding by augmenting, increasing inflammatory signaling.

• 45:09Dr. Darshan Shah?

  So psychological stress can also cause inflammation.

• 45:13Speaker 01

  It can, and the pathways are kind of unique and perhaps a little bit debated. But the way that I would structure this for listeners is if your immune system is listening for danger, things that it thinks will damage your cells, things that it thinks may kill you. Psychological stress is one of those things. So whether you take in a dangerous input because you have microbes in your gut that are getting into the bloodstream and producing a molecule called LPS, or whether you're seeing and hearing stressful stuff on the news, your brain still intuit, interprets that data as being the outside world is dangerous and I need to rev up my defenses. What does that look like? It's increasing inflammation.

• 45:55Speaker 01

  It's really important to understand, though, that inflammation is not a binary good-bad thing. So the same molecules that are produced by microglial cells that at large levels have been associated with a higher risk for developing Alzheimer's, PTSD, schizophrenia, different anxiety disorders and depression are also positive in the sense of regulating neuroplasticity at lower levels. So all of these things are to say, it's a balancing act, right? I think of this from the perspective of kind of eustress-distress. If the body is never stressed, that is not optimized living and function. Right. That's the person spending their day on the couch, right? That is the person perpetually kind of eating junk food, not stretching their brains. We need a little bit of stress to build resilience in our bodies and in our brains,

• 46:40Speaker 01

  and a key integrator of that is these microglial cells. But what I would say for people who are saying, "Well, are they good, bad, or otherwise?" is that a enhanced inflammatory activation of microglial cells may be one of the most important pathways for mental health and cognitive disorders. So how they are activated, whether it's good or bad or otherwise, is really, really important. One last thing I'll say on this. So a lot of my research has been focused specifically on depression. There are a number of reasons for this. One is I've suffered from depressive symptoms in the past, and I've just got super interested in knowing what was going wrong. That was outside of a treatment algorithm. But when we think about what is driving depression, as we talked about at the start, you know, we've historically believed there's a serotonin issue. Yeah. And if we can just increase serotonin, it goes away.

• 47:25Speaker 01

  And it just never materialized. Now, it worked well because these drugs that were blockbuster drugs were supposedly targeting serotonin pathways. But if you take a healthy person with no mental health issues and you inject them with a molecule called LPS, lipopolysaccharide, people may have heard of this in the context of leaky gut, it's also sometimes called endotoxin. People will experience depressive symptoms. Almost immediately. And why is that so important? Because what we're saying here is depression isn't just some sort of a manifestation of a weak brain. What we're saying is that depression is a manifestation of alterations in biological pathways, of which inflammation may be one of, if not the most important. So then we start to say, okay, what do you do about it? And that's where I've definitely spent a lot of my time.

• 48:10Dr. Darshan Shah?

  Yeah. So I want to double click on a couple of things because like you said, LPS, which is produced basically by bacterial infection, can lead to inflammation, which then leads to these mood disorders, depression being one of them. So I think a lot of people look at depression as like, this is something primarily going on my brain. It's really a symptom of something else going on, causing inflammation, right? And so can I ask you a question about being on your device for scrolling social media, let's say for hours and hours a day, or listening to bad news all the time, which is 90% of our news? Can that also lead to inflammation in the brain?

• 48:45Speaker 01

  It can. A number of different pathways. So one is we know that alterations to the HPA axis, elevation of cortisol can increase gut permeability. You have a bunch of LPS in your gut right now, and that's okay, because it's not coming into your body. So increased permeability can lead to increased systemic inflammation, which can then promote neurological inflammation or neuroinflammation. But when we think about what's happening in the brain as it relates to what we're consuming, now when we experience psychological stress, that leads to activation of basically two pathways, right? One being activation of the HPA axis, when we think about cortisol, and the other one being sympathetic overdrive. So molecules like norepinephrine and epinephrine. And these have kind of differing effects on the immune system, both within the brain and the body.

• 49:28Speaker 01

  So sympathetic stimulation can actually raise inflammation, whereas in the initial phases, the activation of the HPA axis suppresses inflammation. Long term, what seems to happen here is in the context of chronic stress, what it actually does is raises chronic but low levels of inflammation. And that's important because there's a huge difference between the inflammation a person experiences when they're sick. So that person was sepsis in the hospital, which certainly is a risk factor for all sorts of cognitive issues, but the major form of inflammation that we want to work About in the body as well as in the brain is chronic low level inflammation. So we're not talking about crazy high levels. What we're talking about is kind of the thorn in the foot. That's perpetually creating pain.

• 50:09Speaker 01

  It's basically slowly biasing your brain towards a less healthy state.

• 50:14Dr. Darshan Shah?

  Yeah.

• 50:14Speaker 01

  And that's why it's so problematic because a person doesn't come in and say, oh, my God, my brain is 100% altered since yesterday. I can't think straight. My mood is absolutely destroyed. It's this smoldering thing which over time predisposes to these mood disorders and cognitive disorders. So a person with higher levels of systemic inflammation is at a higher risk for developing depression. But it's not going to happen overnight.

• 50:36Dr. Darshan Shah?

  Yeah.

• 50:37Speaker 01

  Similarly, if a person has higher levels of systemic inflammation predisposes them to Alzheimer's, but it's not going to happen overnight. So the subtleties that are really important, and that's why the chronic stress is such an issue.

• 50:48Dr. Darshan Shah?

  Yeah.

• 50:48Speaker 01

  Because it's so easy. I mean, the latest stats are 11 hours a day for Americans engaging in media, which four hours are watching TV, a little over two hours are on social media. Consider what is the content that we are consuming.

• 51:00Dr. Darshan Shah?

  Yeah.

• 51:01Speaker 01

  News in particular. I mean, I love the idea of being informed. For most people, per the APA, the American Psychological Association, the news is a top source of stress.

• 51:10Dr. Darshan Shah?

  Wow.

• 51:10Speaker 01

  So we have to be thinking about that in context. One last thing I'll say on that. Even if you're not on board with the idea that social media and watching the news perpetually is a great source of stress, the opportunity cost is humongous. You are spending 11 hours of your day consuming media. You're probably not going to be getting out for a walk in nature, which is an anti-stress intervention. You're probably not going to be making a delicious meal, which is an anti-stress intervention and provides you with the nutrients you need to support good brain health.

• 51:37Dr. Darshan Shah?

  Right.

• 51:37Speaker 01

  So not to say you shouldn't be on social media, but to say, I was asked this on a podcast the other day. What's my take? And I said, if I had a lever that I could pull that would just remove social media from the face of the earth, would I pull it? And the answer is I would. I would do that. But I think it's it's here to stay, and so we have to find ways to navigate it.

• 51:54Dr. Darshan Shah?

  Yeah, absolutely. I mean, I think what you said about, you know, 11 hours a day on some sort of device. It's absolutely true in what I see in the general population. However, I think once I had that realization myself that it was. Becoming more and more a part of my life.

• 52:10Speaker 01

  Right.

• 52:10Dr. Darshan Shah?

  And understanding how to relate it to my day to day stress. Cutting it out led to me having the time to do these other things like going for a walk, going to the gym, et cetera. So it's like a double advantage. It's almost like a synergistic effect of cutting some of it out too.

• 52:25Speaker 01

  Hundred percent the case.

• 52:26Dr. Darshan Shah?

  Yeah, yeah. You know, on the cortisol pathway, one of the things I think about is, you know, we're all living in a stressful life. It's just, life is just stressful. How can we mitigate some of that stress on a day to day basis?

• 52:39Speaker 01

  I always start with saying you don't want to get rid of stress. Mitigate is a good word because the goal is to still experience some eustress and have less distress. We want good stress in our life. I think Jeff Krasnow is about to be putting a book out on this exact topic. But the point being, we want to integrate the right types of stress. So these are, these are things that we can actually address. For example, public speaking, when I started, I was stressed and I did it. And then my brain said, you can do this. So that is a good stress. Learning a new language. I was in Mexico yesterday practicing my Spanish. It's a little stressful because almost invariably I'm going to, you know, make some mistakes. But it's a good stress because it's forcing your brain to try to make new connections and to grow you as a person.

• 53:22Speaker 01

  The distress that we really want to focus on are the things that are kind of psychologically running in the background that we don't solve, that are there perpetually. And so there are a number of different ways to target this. I'd say very practically speaking, if you are a person who is experiencing high levels of distress, you know, it's nice to talk about meditation. It's nice to talk about the walk in nature exercise, but seeking professional care can be an absolute game changer. And just having a person to talk to, to work through some of these things. I was listening to a lecture yesterday and they were talking about how we've kind of had the drop off in community as a cornerstone of how we function. It was actually by James Mascol. And how we've outsourced all these things and that historically we could talk to people, friends, family about these things.

• 54:06Speaker 01

  And now it's gotten weird for a lot of people. So the therapist can step in, but I don't think it has to be a therapist. I think finding community is huge.

• 54:13Dr. Darshan Shah?

  Right.

• 54:14Speaker 01

  As far as ways to mitigate it in a typical day, I think meditation or mindfulness is really important. Not only do those things decrease stress, they're also associated with lower levels of inflammatory markers. And interestingly enough, can increase a level of something called brain derived neurotrophic factor, which boosts brain connectivity at a very basic level, I guess is one way to say it. I love nature exposure. There's a study that came out of Ann Arbor, Michigan. They looked at 20 minutes of urban nature exposure and it decreased salivary cortisol. And what's amazing about nature is it's largely free, it's largely accessible. You don't have to do it perfectly.

• 54:49Dr. Darshan Shah?

  No.

• 54:50Speaker 01

  You know, you don't have to do a two week extravaganza. If you want to, great. But just simply being outside, being in nature, and if you can't be outside, get some plants for your home, ideally ones that don't require too much work, if you're like me. But finding ways to bring that into your life, because all these things have been shown to improve stress levels.

• 55:07Dr. Darshan Shah?

  Yeah.

• 55:08Speaker 01

  You know, exercise, I know I brought that up, but exercise can help to reduce excess cortisol. And I really do think about stress as just the body's reaction to an unmet need. So finding ways to kind of shift that anxiety about needing to do something into something that you could see as accomplishing a task,

• 55:25Dr. Darshan Shah?

  Sure.

• 55:25Speaker 01

  of which exercise is a great example can be really helpful.

• 55:28Dr. Darshan Shah?

  So one of the other things I like to always recommend to people is the definition of chronic stress is stress that has prolonged and uninterrupted over time. So interrupting that stress in, I like that you put a timer on my desk that every 45 minutes I stop whatever I'm doing and I get up and I walk around or I go outside or I go have a cup of coffee or go talk to a friend or something. And I think what that does is it gets your cortisol level, which is slowly increasing to then dip again.

• 55:56Speaker 01

  Yeah.

• 55:56Dr. Darshan Shah?

  And it gives it a chance to recover. Whereas if your cortisol is this on constant secretion mode all the time, it just resets to that new level of being normal, to your point. And then you just keep building on top of that over time. So interrupting stress, even taking a day to have self-care on the weekends or taking vacations, I think is super important.

• 56:15Speaker 01

  Yeah, I totally agree with you. I mean, I don't know how you experience stress, but I've had different versions of the same kind of thing. One of them is you'll be going along, things are going great, and then you just have this pang of you forgot or need to or haven't done something. And then, you know, it's almost like I can feel the secretion of the cortisol in my body. And so I've tried to just be a little bit more reflective of why that's happening. A lot for me is kind of around this hyper productivity mentality that I've had for a long time. I think, you know, going to med school and stuff certainly doesn't help. You're perpetually validated for staying up all night and, you know, perpetually trying to outdo other people and trying to just come to terms with this, this person

• 56:57Speaker 01

  within me that is never going to be content with anything that's happening.

• 57:01Dr. Darshan Shah?

  Right.

• 57:01Speaker 01

  As opposed to saying, oh, no, I have this stress and I need to deal with it right now. But I think, again, these are scenarios where actually talking to somebody, a trained professional can be super helpful so that you can create a little bit more objective space around that experience as opposed to immediately identifying with the part of you that's saying, yes, I am a stressed person and this is definitely the top priority, even though it's 10:30 at night and I'm trying to go to sleep.

• 57:23Dr. Darshan Shah?

  Yeah, that is so true. I want to circle back around to depression because I know you've done a lot of work in depression. I'd love to hear kind of your, you know, your take on depression is different. And I talked to Christopher Palmer about this and a lot of brain researchers. And I feel there is kind of a movement now going to, rather than treating the, you know, neurochemical problems with depression, actually looking at the root causes. And I'd love to hear your take on depression and specifically for, you know, I'm sure 50% of the people out there, what is the number have some level of depression?

• 57:56Speaker 01

  The latest numbers I've heard, it's something like 300 million people around the world.

• 57:59Dr. Darshan Shah?

  Wow.

• 58:00Speaker 01

  So it's, it's substantial. But I think the, the really important point here is that's talking about major depression, right? Algorithm kind of diagnosed condition, a disease state, DSM, as opposed to the understanding that depression maybe is the eventual outcome of things that are happening in a continuum.

• 58:17Dr. Darshan Shah?

  Right.

• 58:18Speaker 01

  So some people feel really crappy but don't have depression, but they have a lot of those symptoms. And I think this gets us to The core of saying, well, what is driving that?

• 58:27Dr. Darshan Shah?

  And to your point, just real quick to emphasize on that, there's times where I feel depressed. And I'll go online, I'll take a depression questionnaire and I'll say, nope, you're not depressed.

• 58:36Speaker 01

  Right.

• 58:37Dr. Darshan Shah?

  And that's absolutely not true. Just because I don't get diagnosed with the DSMR criteria for depression, doesn't mean I'm not somewhere along the criteria on the spectrum, right?

• 58:46Speaker 01

  I think like most things in medicine, you know, there are, there are people and there are states in which a person is, is experiencing a very extreme variant for a number of different reasons, either because of a genetic predisposition or other reasons why they're having such a severe case of depression, that the right next step is immediately to go to a doctor, start medications, potentially even hospitalization. What I do think though, is we have vastly under emphasized everything getting up to that point. And the question of, you know, you're not going to be a candidate for medication right now, but you are a candidate for lifestyle change. So in terms of the pathways that I focused on the most, I think, again, neuroplasticity or the neurotrophic hypothesis

• 59:29Speaker 01

  is the one we haven't discussed so far. Neuroinflammation is certainly coming to the forefront. It says a lot about why so many people with long COVID and who have viral infections have a high risk of getting depression. And also coming back to the LPS study, it was initially found that when people were being treated with immunomodulating therapies for hepatitis, that they had much higher rates of developing depression. And we actually see that in certain cases, certain anti-inflammatory drugs are not only being used for certain cases of depression, but people who happen to be taking them for other reasons with conditions that are more pro-inflammatory have lower rates of developing depression. It's really interesting and it also gets us to another topic we might touch on, which is how psychedelics might factor into that. But let's talk about real quick, kind of the neurotrophins

• 1:00:13Speaker 01

  and how the neuroplastic kind of theory of depression factors in, because we've talked about neurometabolism and neuroimmunity and neuroinflammation.

• 1:00:20Dr. Darshan Shah?

  Yeah, let's go there now. And that'll lead into the conversation about psychedelics, right?

• 1:00:24Speaker 01

  Great. And I think just in general, molecules that we can consume.

• 1:00:27Dr. Darshan Shah?

  Yes.

• 1:00:27Speaker 01

  That have positive impact on our brains using these pathways. So the kind of neurotrophin idea is that we have. Have these factors that are secreted in our blood. They're also secreted in our brains that have positive effects on how our brains are wired. And neuroplasticity at a basic level is the physical and functional changes in our brain structure and function that are a reflection of environmental inputs. So the idea here being your brain's chronically being rewired for the better or for the worse. Not necessarily a good thing. I think that's an important point to make. It's not more neuroplasticity, better. It's wiring it the right way.

• 1:01:05Dr. Darshan Shah?

  Exactly.

• 1:01:06Speaker 01

  As it relates to depression, I'll just kind of nail this point home. The serotonin hypothesis is kind of, it's been debunked. It no longer makes sense as the dominant reason to understand why people get depressed. Because the drugs that are used to target depression, serum levels of things that relate to serotonin, brain studies do not basically provide enough data that serotonin is the driver of depression.

• 1:01:29Dr. Darshan Shah?

  Wow.

• 1:01:29Speaker 01

  So then we look at these other things. And as it relates to these neurotrophins, so let's talk about this neurotrophin, neurotrophic theory of what's driving depression. What we know is that our brains are constantly being rewired by our experiences in the world and that one set of molecules that seem to have an outsized impact, positive impact, on how they are rewired are these neurotrophins, of which the first one was nerve growth factor and the most common one in terms of what's happening in our brain and for the literature is brain-derived neurotrophic factor. This is B D N F. Research would indicate that lower levels of B D N F correlate with higher levels of developing depression and that people who respond to traditional antidepressants are also the people whose levels kind of come up in response to therapy.

• 1:02:13Speaker 01

  So that's really interesting. I would note also that serum levels of B D N F do correlate with levels of B D N F within the brain, but they're not necessarily the same thing. So the B D N F that seems most important in terms of what is directly influencing our risk for developing depression and potentially treatment response is primarily produced by neurons. Interestingly, microglial cells, astrocytes also can produce B D N F. So we want them to be healthy. We want them to participate in this. So then the question is, if we increase B D N F levels, can we start to treat depression? Is that a modality that we can use? Or if we understand the things that lower B D N F levels, inflammation, chronic stress, is that a way to understand what is driving depression?

• 1:02:57Speaker 01

  What I love is it gets us right to lifestyle intervention.

• 1:02:59Dr. Darshan Shah?

  Yeah.

• 1:03:00Speaker 01

  The best way to increase BDNF levels in humans is exercise. And so, just to kind of provide a tangible thing here, 2022 systemic review looked at 39 trials, 2,000 plus people, and they compared levels of BDNF using five different types of exercise. So there was aerobic exercise, aerobic plus resistance, just resistance. There was combined, which was kind of like stretching and balance. And then there was high intensity interval training. And the age range was amazing. It was 15 year olds up to 92 year olds. So, you know, you can't really complain that they didn't capture the right audience. Three weeks to six months, exercising two days to seven days a week, usually between 30 and 60 minutes a day.

• 1:03:42Speaker 01

  And what they found is that the best intervention for increasing BDNF levels in this entire age range was resistance training, which I thought was super, super interesting.

• 1:03:52Dr. Darshan Shah?

  What an incredible study, by the way.

• 1:03:53Speaker 01

  Yeah. Really cool study.

• 1:03:55Dr. Darshan Shah?

  We'll reference this in the show notes, but this is a really cool study because, you know, I always try, whenever I have a patient that asks me like, you know, I only have time 30 minutes, three times a week, what do you want me to do? I'm like, resistance training, just go straight to resistance because that's what's going to give you the most physiological benefit for maintaining muscle mass. And then that leads to your metabolism, leaves your muscle better metabolic health, but also most powerful in increasing BDNF, you're telling me.

• 1:04:21Speaker 01

  Yeah. Yeah, it's really interesting. And again, the connections here are super compelling because, you know, if we want to just go right to it, we're asking about levels of what is basically a myokine, a muscle derived modulator of the system, specifically something like a cytokine, an immune cytokine. Where are the biggest muscles, the skeletal muscles that have the highest chance of doing all this stuff? So not just producing the myokines, but sucking the glucose out of the bloodstream, providing these immune benefiting effects. The answer is lower extremity muscles, right? Your glutes, your lower extremity muscles. And the funny thing is, so in college, it was all about, you know, you don't want to skip leg day because you just don't want to be a wimp, right? You have to get in there and do squats, but it was most.

• 1:05:06Speaker 01

  Because you didn't want to be a wimp. And now I'm telling people, don't skip leg day because your skeletal muscles are actually the best glucose sinks. They're actually the top producers of myokines like Iresin that are going to have benefits to your brain, reducing neuroinflammation, augmenting BDNF. So the point here being exactly as you've already alluded to, resistance training going in for 30 minutes is an amazing intervention and it helps to understand why research like the Hunt study demonstrates that people who exercise are at a lower risk, dramatically lower risk of developing depression. And it may actually be a treatment for depression. So all of the things kind of come together. The pathways are the way they do.

• 1:05:42Dr. Darshan Shah?

  Right. Along other molecules for depression, can you talk a little bit about nutritional molecules? And just dietary pattern in general, what are your thoughts there? Are there specific supplements that can help as well?

• 1:05:54Speaker 01

  I'm definitely a believer in the idea that food is something that can heal us. I think it's important to draw the line between the difference between something like a pharmaceutical and food. Kind of by definition, a pharmaceutical needs to have an observable effect on physiology. Right? So a beta blocker is not the same thing as a carrot. And you know, diltiazem is not the same thing as a sweet potato. With that said, food is packed with molecules that have a significant impact on our health. It's just more of a longitudinal effect, right? A compounding effect. There are certain molecules in our food like caffeine, for example, that have a direct and observable effect on brain function. I am one of the people who really enjoys and feels good after a cup of coffee.

• 1:06:38Speaker 01

  It is a significant mood booster for me and the second cup of coffee. Third cup of coffee is where I try to draw the line because then it's a more significant crash. But it's clear that something in this food has a direct and impactful effect on our brain function. As we look at mental health disorders, the groups of molecules within the food that I'm interested in, beyond the vitamins, I'm sure you've had many people talk about the impact of, you know, vitamin B on depression. Maybe omega threes on depression, which is another interesting one, is going to be looking at groups of molecules found in food, specifically tryptamines and polyphenols. Kind of different ends of the spectrum in terms of what they do. So let's start with the. Polyphenols. Polyphenols are a type of phytochemical. They are nutrients. Technically,

• 1:07:22Speaker 01

  they're not nutrients, but they're molecules found in plants, of which there are 8,000 plus. Polyphenols give plants their colors. They help defend plants against bugs and UV radiation. Polyphenols are also signaling molecules that plants use to create their own microbiome. This network they have was called the rhizosphere, where they speak to microbes in the soil and create this symbiotic relationship.

• 1:07:46Dr. Darshan Shah?

  Wow.

• 1:07:47Speaker 01

  So really interesting stuff. Polyphenols in our diet, though, have been studied to be one of the kind of core constituents of some of the benefits gained from something like the Mediterranean diet. And historically, they were seen as throwaway molecules. They're not vitamins, they're not minerals, they're not fat, carbs, and proteins. They can't do anything. Now, we know that polyphenols can act in a number of different ways in the body. And, you know, still, I think it's a little bit less nuanced than it needs to be because we think about polyphenols as antioxidants. And people have heard of these molecules, quercetin, risperatrol, EGCG, which is found in green tea. In terms of what it does, though, for our brains, what we're now understanding is people with higher consumption of polyphenols in general tend to have better brain health. One study looked specifically at quercetin intake, and it found that it was correlated with better

• 1:08:32Speaker 01

  brain health outcomes. But then there's this question of, okay, so, polyphenols, these nutrients in food, seem to influence biological pathways, decrease risk for metabolic issues, immune issues. Is it just antioxidants? And the answer is no. We are just publishing research with my team at Big Bold Health, looking at how polyphenols, specifically from tartary buckwheat, Himalayan tartary buckwheat, impact epigenetic signaling. And one of the signals that we found using some complex science, but basically looking at pathway-specific effects, is that they had a significant impact on glial cell pathways, meaning that consumption of dietary polyphenols influences glial cells in this analysis. What this actually means is that we can start to go from a scenario where we say, just,

• 1:09:16Speaker 01

  you know, eat colorful foods, also spices, by the way, top source of polyphenols in the diet. Sorry, most concentrated source. Coffee is the most common source.

• 1:09:24Dr. Darshan Shah?

  Coffee's the most common.

• 1:09:25Speaker 01

  For our Americans. Yeah, I mean, if you're eating a bunch of turmeric and stuff, maybe it's a different scenario. But for most people, it's coffee.

• 1:09:32Dr. Darshan Shah?

  Yeah, so India is the opposite because they have a lot of spices, not too much coffee.

• 1:09:36Speaker 01

  Right.

• 1:09:37Dr. Darshan Shah?

  So they get most of their polyphenols from spices.

• 1:09:39Speaker 01

  That makes total sense. That makes total sense.

• 1:09:41Dr. Darshan Shah?

  Yeah.

• 1:09:41Speaker 01

  So the point here being, though, that we're going to get to the place pretty soon that understanding the polyphenolic makeup of a plant will become important, just like understanding that this food is a good source of zinc, or this food is a good source of vitamin B1. And so those are important things, and also the polyphenols are important. So as it relates to brain function, polyphenols may act on immune, on metabolic pathways. There are a couple of studies, and I'd say that not the majority of studies, but a couple of studies showing that polyphenolic composition, when consumed, influences BDNF levels in humans. So we're starting to see exactly what they do, but the point being, there is data in food, in the colors of the vegetables that you eat, in the flavor of the spices that you consume, that is influencing these pathways.

• 1:10:25Dr. Darshan Shah?

  Right, right.

• 1:10:26Speaker 01

  So that's polyphenols. The other slightly more controversial pathway relates to tryptamines.

• 1:10:31Dr. Darshan Shah?

  Yes.

• 1:10:31Speaker 01

  And so this is starting to talk about psychedelics. And I think that, you know, we've moved a little bit more towards a pharmaceutical model of psychedelics.

• 1:10:39Dr. Darshan Shah?

  I just saw that there's a nasal spray for ketamine.

• 1:10:42Speaker 01

  Yeah.

• 1:10:42Dr. Darshan Shah?

  That's been approved, that's doing incredibly well now.

• 1:10:45Speaker 01

  Yeah.

• 1:10:45Dr. Darshan Shah?

  Yeah, I could talk a little bit about that one, too.

• 1:10:47Speaker 01

  For sure.

• 1:10:48Dr. Darshan Shah?

  Yeah.

• 1:10:48Speaker 01

  So let's just do kind of some groundwork here.

• 1:10:51Dr. Darshan Shah?

  Yeah.

• 1:10:51Speaker 01

  Psychedelics are variably defined, depending on who you talk to. They're classic psychedelics. And so these are molecules that resemble serotonin, LSD, DMT, psilocybin, that's really what you want to think about there. Then you have dissociatives, like ketamine. Slightly different pathway, actually, probably more neuroplasticity than anything else. It acts on NDMA receptors, and it changes glutamate signaling in the brain.

• 1:11:12Dr. Darshan Shah?

  Okay.

• 1:11:13Speaker 01

  And then you have molecules like MDMA, which are kind of a composite of multiple pathways, the pathogens, the things that change the way you feel about the world and other people. As we look at psychedelics for mood disorders, there are lots of studies, and probably other guests that are far better at talking about this than I am, I think what the data would suggest is, compared to conventional mental health treatments, in a much smaller sample set. Psychedelics appear to be, in certain cases, much more impactful. And so I've had the pleasure of speaking to many of the kind of top people in the space. But I had one conversation with a gentleman named Anthony Bosses, and he was one of the researchers who did the initial study looking at psilocybin for end-of-life depression, finding that a single dose of psilocybin

• 1:11:56Speaker 01

  led to enduring remission of depression that lasted for years. You just don't see that for conventional antidepressants. We've seen a lot more being done around conditions like PTSD, anxiety, also addiction, but really depression being kind of one of the fundamental mental health conditions where we've seen psychedelics having play. So psychedelics, coming back to the original point, are found in foods. So they're found in fungi, they are found in certain plants, they're found in certain toad, which you're probably not going to eat, but the point being, they naturally occur in our environment. And as we look at the effect of these things that naturally occur in certain food sources on our bodies and specifically on our brains, what gets me super excited

• 1:12:38Speaker 01

  is that when we look at the pathways that are involved, it's the exact pathways we've been talking about. So it is a sigma receptor, it is a serotonin 2A receptor. And the fascinating thing about this is, you know, we've thought about the serotonin receptor as being relevant because it's expressed in the cortex areas of the brain involved with thinking and emotion, but it's also present on immune cells. Yeah. And so now they've started to look at studies asking what happens to neuroplasticity and immunity when people take psychedelics. A subset of studies show that, I think it was ayahuasca and LSD, that both correlated with increases in BDNF levels. There's a little bit for ketamine, again, kind of a different mechanism. There's also a host of studies showing that immune markers change in people who use psychedelics.

• 1:13:23Speaker 01

  And there is a signal that psychedelics are a stressful experience, right? So measures of HPA axis function actually go up, along with increases in inflammation in certain cases. But what seems to happen may be actually similar to what we see with exercise. Exercise is a pro-inflammatory action. Right. You measure people's levels of the cytokine interleukin-6. After the exercise, it spikes, but then it drops because then you have an increase in other cytokines like interleukin-10 that suppresses inflammation. So I think psychedelics are, could be this hormetic, if you will, stressor. And over time improves the overall state of brain function through some of these pathways.

• 1:14:04Dr. Darshan Shah?

  That's so interesting.

• 1:14:05Speaker 01

  Last thing I'll just say on this, so I'm working with a small group of people and we're researching how psychedelics can act on the immune system by way of epigenetics. And just to kind of tease this because I think it is fascinating, there's been a little bit of work already done on MDMA, but we don't know as much as far as why classic psychedelics, like psilocybin, for example, can have such an enduring effect on mental health. What other thing in life can you do one time and it leads to enduring improvement in mental health for years? It can't just be a little change in serotonin. That's not how it works. Something happens at a deeper level and epigenetics, meaning the regulation of how our DNA is used, is one potential explanation for this. So there's already some initial data coming out that's super interesting, looking at

• 1:14:49Speaker 01

  age clocks and what psychedelics, specifically ayahuasca, do to age clocks, meaning your biological age, but also to immune cells and subsets. So this is, this is really interesting stuff. I think it's going to change the entire way we look at mental health.

• 1:15:07Dr. Darshan Shah?

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• 1:15:51Dr. Darshan Shah?

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• 1:16:06Dr. Darshan Shah?

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• 1:16:47Dr. Darshan Shah?

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• 1:16:58Dr. Darshan Shah?

  Is there a role of psychedelics in neurometabolism as well?

• 1:17:02Speaker 01

  Yeah, I think that's a little bit more complicated. Again, there is this sigma receptor that certain psychedelics, specifically classic psychedelics, seem to activate. And it is a kind of integrative receptor in that it has effects on both metabolic and immune-related pathways. Key to this too is this BDNF pathway. And so, BDNF is really a downstream effect of metabolic pathways being activated, which is interesting, right? So it's related to mTOR signaling and neuroplasticity. And not to go down the whole AMP kinase and mTOR pathway. But the understanding here is that the receptors that are activated at the cell membranes and within the cells, which psychedelics can act on, do have downstream metabolic consequences. I think it's a little bit less clear what happens.

• 1:17:45Speaker 01

  I haven't seen the data yet as it relates to whether changes in typical metabolic parameters change when people take psychedelics. But one thing we are looking at here is what happens with the microbiome when people take certain psychedelics, which we know has a direct impact on how our body processes energy, food. So there could be a pathway there that's also relevant.

• 1:18:06Dr. Darshan Shah?

  The psychedelics affecting your microbiome?

• 1:18:08Speaker 01

  Psychedelics affecting the microbiome.

• 1:18:10Dr. Darshan Shah?

  So interesting.

• 1:18:11Speaker 01

  Yeah.

• 1:18:11Dr. Darshan Shah?

  And is that through a nutritional effect or is that through something else?

• 1:18:15Speaker 01

  Well, it's an interesting question. We're specifically looking at ayahuasca. And so with ayahuasca, there are some pretty significant GI symptoms.

• 1:18:23Dr. Darshan Shah?

  Yes.

• 1:18:23Speaker 01

  That occur in the context of the use.

• 1:18:25Dr. Darshan Shah?

  I've heard, I've never done it before, but I've heard of some of those.

• 1:18:27Speaker 01

  So it's, it could be a number of different things, right? It could be the actual psychedelics interacting with the microbes in the gut. It could be the effects of the psychedelics on the immune system, which then interact with the microbes in the gut. But bottom line is epigenetics, the microbiome, the immune system. These are systems where creating small ripple effects that can get marched out can have long-term implications in terms of health. And so psychedelics are maybe one of the ways that we can get into some of those pathways in a really powerful way and a really targeted way, hopefully in the future.

• 1:19:02Dr. Darshan Shah?

  It just kind of reminds me of the analogy, you know, when you're, when you're talking about all these various effects of psychedelics is nature produces, if you want to call them drugs, they're not really drugs. When nature produces such complicated drugs that do so many different things and so many different pathways.

• 1:19:18Speaker 01

  Yeah.

• 1:19:19Dr. Darshan Shah?

  And here we are, you know, trusting our pharmaceutical industry to make these little molecules like SSRIs that do one thing and just test that one thing.

• 1:19:28Speaker 01

  Which they don't, right? Which is why there's such high levels of side effects.

• 1:19:31Dr. Darshan Shah?

  Right, exactly. And so it's like, you know, we, we've created this massive pharmaceutical industry, which look, I'm not knocking them. They've done some incredible work in cancer therapies, et cetera. But it's so far behind what's happened in evolution and in nature that is just mind blowing to me that we haven't studied psychedelics more in, since the beginning of medicine, actually, right?

• 1:19:53Speaker 01

  I mean, people, I mean, I guess people are using probably a foxglove as the joxin, maybe, maybe many millennia ago. But people have been using psychedelics in rituals and for, you know, better brain health for thousands of years. I, I've kind of had, I don't want to say shifting positions, but I've had shifts in how I talk about this in terms of how I approach psychedelics. As a doctor, I think the, the default is to say, well, we haven't fully studied these things. And until that randomized controlled trial with eight million people comes out, we're not quite sure whether this is reasonable. What I would say is, look at base rates of mental health in the United States and around the world right now. Despite all of the amazing new drugs that have come out in the last decades, are rates of depression and anxiety significantly better than they were a few years ago? And the answer is no.

• 1:20:39Speaker 01

  And the reason for that is because these are not things that are necessarily getting to the root causes of why people are depressed. Because depression isn't a serotonin deficiency. So fluoxetine is not going to necessarily solve this problem for people. But what psychedelics do is they change the way you see the world and yourself. And they do that in real time. There are very few things that exist on the planet that can provide a portal to the understanding that the real world that you thought was so substantial is actually a facade. And that what is true is love and connection and finding meaning in things that are not what we are perpetually told matter. So my bias would be that I think it's awful that psychedelics have been kind of seen as

• 1:21:24Speaker 01

  so dangerous that we have to approach them with such caution. Given that, for example, how many people, hundreds of thousands, really millions of people each year, dying of alcohol and related complications? That is a psychoactive drug that has enduring and directly observable effects. Not just on, you know, people dying of alcohol-related stuff, but on metabolic health, on immune health. For example, here's a little tip. Hangover severity correlates with levels of systemic immune markers like interleukin-6 and CRP. You want to know what you're doing that is bad for your brain? It's drinking enough to be hungover. Exactly. It's a direct correlate, right? So psychedelics, on the other hand, yes, there is some liability associated with changing the way that you see the world.

• 1:22:06Speaker 01

  Yes, there are case studies of people who have died using psychedelics almost exclusively when they're using them either in a mixture with unregulated substances or where they're using them outside of kind of clinical oversight. But the idea that we are doing well enough without investing in some of these things and making them a little bit more available to people is Just insane. And I will just say this explicitly, as a person who has used psychedelics, there is nothing else in my life that has provided the level of insight that that did. And I'm not trying to say that I'm recommending that for people, but I do think it is important for people to hear the stories from doctors where it's saying, I have done conventional medical training, I have seen what modern medicine can do,

• 1:22:49Speaker 01

  and there is absolutely a need for something that connects people and doesn't just target biology as the only outcome that matters.

• 1:22:56Dr. Darshan Shah?

  Right. No, I fully agree with you. And I think, you know, I think for people that are looking into psychedelics, it's important to go to someone that's a trained practitioner, that's helping you kind of sort through this and have a good experience, because I've seen the opposite also happen, where people have bad experiences because they're using it recreationally, they use it at the right time, at the wrong time, in the wrong circumstances, and it causes a negative appearance.

• 1:23:17Speaker 01

  So that's what I would say is it's set in setting, and you need to be working in the context where you're creating the right opportunity for healing. Actually, one of the liabilities, I think, around ketamine therapy, which again, some people would say is a psychedelic, some people would just say is a dissociative, is that you go in, you get your ketamine, and then you go back to your life. And you don't really create the opportunity to wire your brain towards benefit. And so, one of the things seems to be that psychedelics are potent neuroplasticogens, meaning that they open up the opportunity to wire your brain in a different way. And so if that's the case, then there's this question of, are you doing it in the right direction? So the recreational use of a couple of grams of psilocybin, then expecting it's going to fix your life, doesn't really make that much sense to me.

• 1:24:00Speaker 01

  But in the scenarios where we've seen from these clinical trials from Hopkins and other institutions, being able to make that more available to more people feels like a really important movement in medicine, based on the data we have so far. So this isn't saying we just legalize recreational use and just assume that people will do well. There's some interesting correlations with marijuana right now, but it is saying that I think we're way too closed off in terms of looking at things that are mind altering as positives, given how open we are to the fact that so many people are using alcohol and the outcomes that that's provided.

• 1:24:33Dr. Darshan Shah?

  Absolutely. What is your advice as someone that's looking, they say they're suffering from? Some degree of depression, anxiety, a trauma in the past, in fact. What is your recommendation to them now on how to do, involve psychedelics in a productive fashion? How should they go about it? Are there websites? Are there places they can go?

• 1:24:52Speaker 01

  So the goal is, and I think MAPS does a good job of this. Yeah, so there's a, the goal is to find, in the States at least, a clinical study. That's still the main way you can get it. In addition, ketamine, there are certain centers, there are certain providers. So Dr. Drew Ramsey and others that I know of that are doing this in a really intentional way. But I think that there is a huge variability in the way that ketamine is administered today and the way that those treatment facilities have set up follow-up for people. There are many places and many organizations that will do international psychedelics. And I think here the key is to understand that there is an incredible heterogeneity. There's kind of a profit grab right now where it's saying, we're gonna do the ceremony and you're gonna be better, and they're really not creating that experience.

• 1:25:33Speaker 01

  So I think MAPS, Multidisciplinary Association for Psychedelic Study, is a really great starting point to start to understand this a little bit more and to connect into potential pathways to apply it.

• 1:25:44Dr. Darshan Shah?

  And do they have a listing of centers that you can go to, state by state?

• 1:25:48Speaker 01

  I think what they have is a listing of where they are doing the studies right now. That was based on my last take, but we can check and I can give you the update for the show notes.

• 1:25:56Dr. Darshan Shah?

  Yeah, that'd be fantastic. I think also when people go internationally, like you said, it's a money grab right now and people are purporting themselves to be high-end psychedelic retreat centers. And in reality, they're just overcharging people and don't have licensed practitioners. And so, do you have any words of warning or some advice on choosing the right places to go internationally?

• 1:26:16Speaker 01

  Here's one thing I would just say, and this is a more general word of wisdom, which is, don't go with the people who say they have all the answers. And I think that that's, that's become a far more significant liability in the psychedelic space, which is, everyone becomes a guru and everyone says that this thing, whatever it is, is going to solve for all your problems. There is nothing out there that I'm aware of that is capable of doing that. And the reason is, because if you want to participate in the real world, you are perpetually in a cycle of doing a little better and doing a little worse. And the people who are out there saying they've achieved enlightenment. But who are also selling you their programs and their products. Those things kind of don't go hand in hand for me.

• 1:26:54Dr. Darshan Shah?

  Yeah.

• 1:26:55Speaker 01

  So I would say, you know, there are a number of different ways to kind of validate these things. One is to talk to people who have been through these programs. One is to look at kind of the people who are running it. But I think, again, I haven't seen a great way to standardize without just throwing out some names of some groups that I like. That I would tell people, this is a surefire way to know. So I think the cleanest way is to go through a clinical study still at this point. Otherwise, you're still in this place of trying to determine the quality of some of these centers that are happening internationally through various channels.

• 1:27:25Dr. Darshan Shah?

  Yeah, I think it's really difficult and unless you know someone like yourself that's done a little bit more of a deep dive. Maybe one day you'll publish a registry or a list that you feel that you feel good about. But it's definitely the Wild West a little bit still with psychedelics. And I think, but I am very encouraged and very happy to see that we've gotten back to the point where it's being researched again. It's not being completely discredited by the medical establishment as it's being a drug, you know.

• 1:27:52Speaker 01

  Yeah, no. That's where I was even a few years ago when I was in training. We were talking about psychedelics in the same, you know, breath as heroin and cocaine. There's these recreational drugs that'll rot your brain. I remember we had, we were presented this kind of case series of people who had used MDMA and had seen some really significant brain damage. As though it was a reflection of the pure MDMA, which since then we've seen very clearly is not the case. It's usually the contaminants. It gets to much larger conversations about, you know, what is the role of the government? What should be regulated? What are the liabilities associated with giving people access to mind altering chemicals?

• 1:28:28Dr. Darshan Shah?

  Right.

• 1:28:28Speaker 01

  And what are the outcomes associated with that? What I will say is if you look at kind of data, survey based data, people who have used psychedelics in the United States. You see the outcomes tend to actually be pretty good in terms of people don't feel, I mean, that they're getting addicted to them. That's not really the mechanism of these molecules. And actually they have potency in some cases in mitigating other addictions. But that it improves quality of life, you know, that people who have had psychedelic experiences say it's one of the top most spiritual connected experiences of their life. People who use psilocybin feel Feel more connected to nature, people who use MDMA feel more connected to other people. And these are not the only ways to get there, which I think is really important to understand. But if you were to look at, independent of psychedelics as an agent of change.

• 1:29:10Speaker 01

  If you were to look at the, the real issue with how we are kind of living today. Again, coming back to brain state, the whole premise of Brainwash, the book I wrote with my dad, is that we are disconnected. And that disconnection from other people, from nature, from health, translates into a self-perpetuating brain state where we continue to make decisions that create more disconnection. And psychedelics in many ways are a connector, but so is calling up a friend. So is having coffee with somebody that you haven't seen in a while, engaging in community. And it kind of feels like, what I don't like is certain people saying, I'm going to continue to have an unhealthy life, burn the candle at both ends, do a little recreational psychedelics, and then claim that I've found the balance.

• 1:29:55Speaker 01

  And it's just like anything, it's like any supplement, any drug. My belief is that it's all about sustainability. And so there is a big risk with psychedelics or conversations like that. Or whether it's an ice bath or whatever, it's not to say it doesn't work. It's to say that you shouldn't look at one of these things as the fix.

• 1:30:13Dr. Darshan Shah?

  Yes.

• 1:30:14Speaker 01

  The fix is to find balance and do the basics well.

• 1:30:16Dr. Darshan Shah?

  Right, absolutely. I mean, the way I look at a lot of this is, sometimes you need these things to get you over the hump, right? But then it should always be in combination with changes you're making in your lifestyle on a day-to-day basis, year-to-year basis, month-to-month basis. And if you need something to get you over the hump, or maybe a little bit sustained to, while you're making changes, it's a positive thing. However, if you're looking at it as replacement to making those changes, it's never going to add up to what you're thinking it's going to be.

• 1:30:46Speaker 01

  Absolutely. I mean, it's, it's the same mentality of I'm just going to do this next social post and then I'm going to be famous. Like, that's not actually how it works, right? You have to think about not over-indexing towards the cases of people who are telling you a fake story because they're trying to sell you a product.

• 1:31:00Dr. Darshan Shah?

  Right.

• 1:31:00Speaker 01

  And you have to start thinking about, are the people who are really successful, or what are they doing? And what they're doing is they're making healthy choices, most of the time, most of the Days. And so I definitely think there's a role for things like supplementation. But as an adjunct, right? If you're not paying attention to your sleep, if you're not getting regular exercise, if you're not eating real food, don't expect that you're going to take a couple of grams of anything. Creatine monohydrate, which I actually do take. I think creatine is wonderful, but that's not going to necessarily fix the fact that you're not feeling connected to your community. So it's all of these things in this larger context of trying to index towards connection and away from what the modern world increasingly seems to want us to do, which is

• 1:31:40Speaker 01

  to disconnect and pursue the short term fix at the expense of long term wellness.

• 1:31:46Dr. Darshan Shah?

  Absolutely. So I always like to kind of wrap up these conversations because we talked about a lot of things. Neuroinflammation, neuroplasticity, psychedelics. And I think for the average person out there, there's so much information and what, you know, we talked about the Pareto principle, the 20% of the information that's going to give you the 80% of the, the, the change. So for someone that's experiencing mood disturbances or disorders, or just a change in their mood towards depression, anxiety, what have you, where would you tell someone to start? What's the first thing they should do? What's the second and the third thing?

• 1:32:17Speaker 01

  I mean, the first thing I would do is say, if it's significant, if it's severely impacting your quality of life, is to seek professional help. I think getting integrated into a care system is so important, not necessarily because of the pharmaceutical management, but because for many people these days, that's the main person that's on your team. We have trouble connecting with friends, family and getting that type of access. And so a psychotherapist, a medical practitioner can really be an amazing advocate for you and just keep tabs.

• 1:32:45Dr. Darshan Shah?

  Can I say one thing on that too, which I think a lot of people don't understand or they don't think about, is that this is a very complicated topic as we've heard on this entire podcast. We talked about a lot of complex science, in-depth treatment modalities. There's a lot here. And when you're seeking professional help, you're not just finding someone to talk to. What you're seeking is someone that understands a lot of this science and understands the training in how to help someone through these things. And that's who you're looking for, right? And so you're looking for someone with expertise.

• 1:33:14Speaker 01

  Instagram expert.

• 1:33:15Dr. Darshan Shah?

  Exactly.

• 1:33:16Speaker 01

  That's a really, really important point. I just want to highlight. So these are real and significant topics.

• 1:33:21Dr. Darshan Shah?

  Exactly.

• 1:33:22Speaker 01

  If people have, I think there's a huge liability in conflating these two things. One is the person who requires intensive management of treatment resistant or refractory depression, like in an inpatient setting, and the person who's saying, I'm feeling a little bit down and I want to do something to improve my mood today. The split point is very different as far as management. And so that's why I'm always going to say with anything related to mental health, because of that continuum, and because of how significant the kind of end of that continuum is, if it's a real big deal, skip ahead. You don't need to be saying, oh, well, if I just take a couple of omegas a day, then maybe this will go away when I'm really feeling down on my luck. I'm not getting out of bed, I'm not going to work, I can't think straight.

• 1:34:06Speaker 01

  That's where getting somebody on your team who knows the science as far as, here's what you can do to help people with depression at the severe cases is really important. So I just want to echo what you're saying.

• 1:34:16Dr. Darshan Shah?

  Yeah.

• 1:34:16Speaker 01

  What I would say, though, is for everyone who's out there saying, what can I do to improve my mental state? As far as a day to day thing, understanding it's not an overnight success. You don't wake up tomorrow and you're happy for the rest of your life. I don't think happiness is even a helpful word. What does that mean? The goal is to enhance contentment, to enhance balance, to enhance well being over the lifespan. So what are the best studied things to do? I always start when it comes to the brain with one thing, which is to optimize sleep. And the reason for that is, I can't tell you how many times I have sat across from a patient or a person, and they have all the things, right? They're saying, I'm not thinking clearly, my blood pressure is off the wall, I have bad cholesterol numbers, there's this pain in my foot. And there's all these different things that you can work on.

• 1:35:00Speaker 01

  But as it relates to, you know, coming back to the core idea, how do you optimize brain function so that you can be a little bit more enjoying of life? If I tell somebody to exercise, or I tell somebody to eat a healthier meal, or I tell somebody to meditate, all these things to help bring their brain function back to normal, or to a better state, I should say, most of those things are not fun. They're not pleasant. The person who is struggling with metabolic health and I tell them, you really start to, you need to start exercising. It's like, oh, I never thought of that. Right? Or, hey, you probably shouldn't go to the drive-through junk food restaurant three times a day. Oh, no, I really thought that was good. I never saw the correlation between the french fries and the excess body fat. But sleep is enjoyable.

• 1:35:44Speaker 01

  It is intrinsically pleasurable and it demonstrably improves cognitive outcomes. People who skip out on a night of sleep, the next day will eat somewhere in the neighborhood of 300 extra calories, primarily from unhealthy food sources. People who skip out on a night of sleep will feel worse regarding their mood. They will have worse focus, worse attention, and their cognition and memory will be impaired. On the other side of this, getting a good night of sleep, and what we're talking about here is trying to optimize towards seven to nine hours. For most people, some people say, oh, well, I'll need four hours. There's this very small subset of people who can get by. And chances are, if you're listening, you're not one of them. Seven to nine hours of quality sleep each night is going to set your brain up for a state of better enjoyment of life

• 1:36:28Speaker 01

  and increase the odds of your being able to make other healthy decisions. And so we could go through all the different research in terms of what sleep deprivation does to metabolic parameters, to immune parameters, to BDNF and neuroplastic parameters. But the bottom line is if you're going to start somewhere, it's improving your sleep tonight. My quick tips on this would be, one, you want your room to be dark. You want your room to be quiet. And you want your room to be at a lower temperature than you think. Somewhere around 65 degrees Fahrenheit is what's been studied. So that's a good thing. The next thing, as far as taking stuff away, is going to be caffeine, specifically in the afternoon. Caffeine has a half-life of six hours. If you have a cup of coffee at 6:00 PM, half of that caffeine is still in your system at midnight. So for me, it's 2:00 PM. For some people, it might be noon.

• 1:37:11Speaker 01

  Some people might be a little later, but I'd say most people, if they're struggling with sleep, you really want to restrict your caffeine intake. Alcohol is another one. Alcohol sedates people and detracts from quality of sleep. It disrupts normal sleep architecture. So any alcohol you're drinking before bed, really in the hours before bed, is a major liability in terms of getting quality. Sleep. Other things here would be getting evaluated for OSA restless leg syndrome, all the other stuff.

• 1:37:35Dr. Darshan Shah?

  Right.

• 1:37:35Speaker 01

  Optimizing sleep, I think, is the first and most powerful way to improve your brain health in the shortest amount of time. I think you recently had Luisa Nicole on too to talk. She's another wonderful person on this topic, but we've jammed out on this in many different stages. And the the really powerful thing that she and I talk about is just how how valuable this is in terms of transforming a person's relationship with their brain. So seven to nine hours of sleep, I'd say, is of any of the nonnegotiables, really the one that tends to be most challenging for people because they always replace it with other things. Some of them are reasonable, kids. Some of them are maybe things we can work on, like work.

• 1:38:14Speaker 01

  And some of them, for most people, is the next or two hours on TikTok while they're laying in bed, which nobody needs.

• 1:38:21Dr. Darshan Shah?

  No, no, exactly. And the tip that I give to my patients is there's one thing you start doing to improve your sleep is get to bed at the same time every single day, no matter what. And then, once you start doing that, it just sets the ball in motion to to and maybe make it a little bit earlier than you thought you needed it to be.

• 1:38:39Speaker 01

  What I like to say is set an alarm clock for sleep. You're gonna do one for when you wake up, and it's equally important. Because there's this funny thing where there's there's the the night you and the morning you.

• 1:38:49Dr. Darshan Shah?

  Yes.

• 1:38:49Speaker 01

  And like, they don't actually get along. They have very different goals in life. The night you wants to watch another episode of Love is Blind. The morning you says, why would I possibly stay up for that when I'm tired today? I can't think straight. I need to drink all this coffee. And the goal is to integrate these two people. This is a bigger topic, I'll just brush on. But the the delta, the distance between the person you are now and your future self is an incredibly important predictor of health outcomes. And so there's a rate at which we kind of discount our future self. Meaning a rate at which we prioritize me now versus me in a week or me in a year.

• 1:39:31Speaker 01

  And that rate predicts getting all of these different metabolic and immune and chronic disease conditions. Because the more we make decisions optimized towards. Towards our future selves, the better our chances are that we're healthy across the lifespan. And one psychological framework that I love is something called episodic future thinking. And the idea is you imagine your future self and you develop empathy and compassion for your future self. And so to bring this back to the topic, as you're there thinking about, am I going to scroll some more? Am I going to eat something? Am I going to turn on the lights and just mess around for another hour before bed?

• 1:40:11Speaker 01

  Think about tomorrow. Think about how you're going to feel when you wake up in your bed tomorrow morning, either super tired or feeling well rested and excited for the day. And so bridging that gap allows you to actually create habits towards a better tomorrow and in doing so for the rest of your life.

• 1:40:31Dr. Darshan Shah?

  I love that. I love that. So we said, uh, sleep was the second thing. Uh, third?

• 1:40:36Speaker 01

  So in terms of optimizing brain function in general, I'd say actually I'd start with sleep. The other things that I think are, are really essential are the exercise. And we talked about this already. So in terms of exercise, I think it's a mix of aerobic and resistance. There are kind of slightly differing benefits. It's not just about B D N F. It's about immune regulation and metabolic benefit. I think that that can look differently for different people. I think you've spoken about zone two aerobic conditioning. I think it doesn't have to be going all out and doing these incredible bursts. So it can be an incline on the treadmill. It's a little bit boring. I've found that certain treadmills have solitaire, which makes me very happy. But finding a way to just do some aerobic conditioning and then mixing that in with the resistance.

• 1:41:18Speaker 01

  And so to that end, I would say with resistance training and basically just lifting weights or putting stress on muscles, which can be body weight as well. I think if you haven't done it before, be careful because as we've already described, it's the area under the curve. It's the long term. So if you go to the gym and you say, I'm going to do this crazy deadlift because I heard this guy talk about it on a podcast and you pull a back muscle on the first day and then you're out for two months, that's very

• 1:41:44Dr. Darshan Shah?

  That's worse than

• 1:41:44Speaker 01

  Right. That's much worse than not doing it all.

• 1:41:46Dr. Darshan Shah?

  Right.

• 1:41:47Speaker 01

  So I actually think working with a trainer at least initially is helpful if you're Into resistance training, especially if you're older and you don't have necessarily the stability or necessarily the support from other muscles that you might have before. Right. But here again, prioritizing large muscle groups, compound exercises. So doing biceps curls is not as good as doing pull ups. Right. Similarly, even doing leg extensions, not as good as doing squats, but the goal here is just to load your muscles. And that will enhance all aspects of your health, including your brain health. As it relates to diet, obviously, it's a complex subject. The Mediterranean diet is at this time, the best studied diet for overall cognition and for mental health. There's a variant called the MIND diet. It's very similar. It kind of incorporates attributes of the DASH diet,

• 1:42:31Speaker 01

  which was designed for hypertension. Sure. But the Mediterranean diet in general is the best studied diet for brain health. And people will say, oh, well, what does it mean? And that's complicated because the Mediterranean is a large region. Yeah. What it means is in essence, prioritizing a diet that is rich in minimally processed foods. So if people have messed with your food a lot, that is a good indication that you should not eat that food. What it means is more fish and poultry as opposed to red meat. What it means is eating a diversity of different plant foods. So a lot of the things we talked about before are being rich in polyphenols. So that means nuts and seeds and it means green, uh, leafy greens. Whole grains are part of it. I know there's some kind of discussion as to what that means. I think there's a spectrum in terms of what you're eating in carbohydrate sources.

• 1:43:16Speaker 01

  So eating, uh, you know, even something like brown rice is going to have a far lower polyphenol content than something like this. Uh, Himalayan tartary buckwheat, which is actually, if it's sprouted, can be up to several thousand times higher than many conventional grains. And then it's olive oil. So olive oil as a standalone food has been studied and has been linked to decreased risk of dementia. And that's even controlling for other dietary variables. So I think consuming a bit of olive oil each day is a good decision. There's some consideration around wine and alcohol. We can get into that. I lean towards alcohol is a neurotoxin at a cell level. Systemically, people who drink a little bit of alcohol are not at a lower, or sorry, are not at a higher risk of developing Alzheimer's and mood disorders from what I can tell.

• 1:44:03Speaker 01

  Doesn't mean you should start drinking. It means if you are going to consume alcohol optimized towards one to two at the most drinks in one sitting. And I think there's a huge difference here between a mixed sugary drink and a glass of red wine. So those are kind of the core precepts, I'd say, of diet. As it relates to supplementation, I think the best literature to date is around creatine monohydrate at five grams a day. There are other forms of creatine, they don't have as much data behind them, but creatine seems to actually have an effect on brain energetics, which is super cool because it can help to regenerate ATP, especially in people who are stressed or otherwise using up a lot of brain power. Omegas, I think, are super important. Omega three, specifically EPA and DHA, somewhere between 500 milligrams and one gram a day seems to be the sweet spot. You can get it from diet. Most people don't.

• 1:44:47Speaker 01

  I think if you are going to get it from supplementation, be very careful as to where your fish oils are coming from. A lot of them are, not only are they coming from unsustainable sources, but the fish oils aren't really quality regulated. So you can be consuming oxidized fats. I think a multivitamin, if a person is not eating a balanced diet, is probably a good idea, but specifically towards kind of core brain health nutrients, B vitamins, magnesium, zinc. And then beyond that, I think it's really helpful to work with somebody who knows what they're doing. So they can look at your levels of things like vitamin D and other molecules that sometimes can be dysregulated, but aren't universal.

• 1:45:20Dr. Darshan Shah?

  Exactly.

• 1:45:20Speaker 01

  So that's the food piece. I guess that would be our step three, sleep, exercise, and food.

• 1:45:25Dr. Darshan Shah?

  Exactly. Beautiful. That was such a great summary of brain health in general. I mean, we've talked about so many things. I'm just really excited for what you're doing in your work. What's coming next for you?

• 1:45:39Speaker 01

  We, yeah, many things coming next. One of the areas that I'm really focusing on a lot now is probably the single most underrepresented variable for brain health. And it's the air quality that we breathe. So one of the tips that I haven't necessarily gotten into in this episode, but I certainly will in future conversations, is that if you consider the things that are variables that are impacting the quality of your brain health right now, you're not eating that many times a day. You know, you do sleep for several hours a day. You might exercise for 30 minutes to an hour, but you're breathing 20,000 times a day. And research has shown increasingly that the quality of what you breathe, specifically the PM 2.5, so the particulate matter,

• 1:46:22Speaker 01

  has a direct and observable impact on brain inflammation. And so, research shows that higher exposure to PM 2.5 elevates activation of microglial cells, correlates with higher rates of depression and dementia and anxiety. And that's just published in GEMA in the last couple of years.

• 1:46:37Dr. Darshan Shah?

  When you say PM 2.5, you mean the particle size, right? Less than 2.5 microns.

• 1:46:42Speaker 01

  That's correct. So 2.5 and below. There's a spectrum of different sizes. What makes the 2.5 so dangerous is that they can penetrate into the bloodstream, whereas the larger molecules like the PM10s tend to get stuck in the respiratory tree, so they can be cleared. There's also ultrafine, which is even smaller. The 2.5s have been the most studied. And so, quick tips on this one, just for those who are saying, "Oh, I haven't heard of that." Number one is that the majority of your time is spent indoors. 90% of a person's time is indoors. The majority of your air pollution exposure is occurring indoors. The majority of your air pollution comes from the activities that you choose in your home, which means cooking. You need to vent when you're cooking. It also means paying attention to the stuff that you're introducing unnecessarily.

• 1:47:27Speaker 01

  Incense is a top contributor to indoor air pollution if you use it. Incense increases levels of PMs by up to five times more than a similar amount of smoking a cigarette. Scented candles are, can be, very potent sources of indoor air pollution. The little air fresheners that people put in their cars are potent sources of volatile organic compounds. So, we can get into this more later, but the point here being, don't introduce unnecessary air pollutants in your home and use a filtration system of some sort if you live in a place where there are high levels of air pollutants. For those who are wondering, 99% of people live in a place where there are higher than healthy levels of air pollutants.

• 1:48:06Dr. Darshan Shah?

  99% of people?

• 1:48:07Speaker 01

  This is from the World Health Organization. So, it's pretty substantial. It doesn't mean every day. It just means that almost everyone is being exposed to high levels of air pollutants that directly relate to cardiovascular diseases, neurologic conditions, respiratory dysfunctions, birth problems, as well as Infertility, higher rates of obesity. So you'll be hearing more about this, I'm sure.

• 1:48:29Dr. Darshan Shah?

  Yeah, it sounds like you're doing a lot of work in this. I'd love to have you back on and talk more about this. Yeah, I think one thing that I found to be a game changer was actually buying an air quality meter that actually measures the particles in the in the air. And they can buy them pretty cheaply now. I think they're less than 50 bucks and they connect to an app on your phone. They tell you and you know, you'd be surprised at when and where you are exposed to high levels of air pollutants.

• 1:48:52Speaker 01

  It is, I think it is the hidden threat.

• 1:48:55Dr. Darshan Shah?

  Yeah.

• 1:48:55Speaker 01

  So as I was just in Mexico City, you know, they've made some big strides, but it's still a very polluted city and we're sitting in LA, also a place that has made some major strides, but still a lot of air pollution. So it remains a challenge. What I would say, just as kind of a teaser to why this conversation is so relevant, it's not just about the smoke and the haze that you see. So many people, up to around a third to half of people, experience a sensitivity to chemicals in their environment. And historically, doctors like me have said, well, you are just a sensitive person. There's no biological reason why you should feel off if you're in an unventilated building, or why when there's a perfume in the air, or whatever chemicals they spray when you walk into the the store in the mall, that you should be experiencing these symptoms.

• 1:49:40Speaker 01

  And the reality is that these are people who are hypersensitive, yes, but they're actually picking up a danger signal because these are chemicals that have a significant impact on not just our bodies, but how our brains function.

• 1:49:52Dr. Darshan Shah?

  Yeah, so that's and your body's actually telling you it's getting overwhelmed by the amount of chemicals if you're feeling allergic or whatever.

• 1:49:58Speaker 01

  Well, it's saying this is not a safe place.

• 1:50:00Dr. Darshan Shah?

  Right.

• 1:50:01Speaker 01

  Right, so it is a danger signal because it is not a safe place because those chemicals can wreak havoc in your body.

• 1:50:06Dr. Darshan Shah?

  Right, amazing. Well, I'm so excited to have you back on in the future to talk more in depth about that topic and many others and just really appreciate having you on. Thank you so much for joining us.

• 1:50:15Speaker 01

  Yeah, thanks so much for the conversation.

• 1:50:21Dr. Darshan Shah?

  That was such a great conversation with Dr. Austin Perlmutter that I'm going to go and do something different today. This time I took so many notes that I just want to get out there again about my top 10 from this episode. So we're going to go through my top 10 takeaways from this episode with Dr. Austin Perlmutter, beginning with number one, your brain is biologically wired to make unhealthy decisions. Modern life has overwhelmed our prefrontal cortex. So that's the part of the brain responsible for conscious decision making. And it's handing over the reins of our decisions to our emotional brain, making it harder to resist temptation and easier to fall into patterns of burnout. Number two, burnout isn't just an emotional condition. It's actually a biological state. So chronic

• 1:51:06Dr. Darshan Shah?

  stress actually physically alters our brain and it weakens our capacity for focus, motivation, and willpower. So when you're burned out, it's not just you being lazy or undisciplined. It's actually your brain is depleted and those connections have separated. Number three, it's been shown over and over again, and Dr. Perlmutter confirmed it, that the food we eat shapes our decision. Ultra-processed food diets increase inflammation in the brain, they reduce neuroplasticity, and they make it harder to think clearly or make intentional choices. What you eat literally can rewire how you behave. Number four, brain fog is a warning sign. It's not just a nuisance or a symptom. So if you're feeling sluggish

• 1:51:47Dr. Darshan Shah?

  or scattered, or just can't really think straight, those are not normal feelings. These are tied to metabolic dysfunction, inflammation, and disconnection in key neural pathways responsible for clarity and memory. So if you're feeling brain fog, go get checked out with some blood work and let's see what's causing it. Number five, social media is hijacking our brain's reward system. Every time you scroll your social media, you are injecting your brain with more dopamine. And this is training it to crave that instant gratification and is shortening your attention span over time. That's going to make it harder for you to stay present, calm, or focused. So if you're doom scrolling for more than five or 10

• 1:52:29Dr. Darshan Shah?

  It's a day you really want to set that timer on your apps to cut that off. Number six, disconnection from other people is actually a root cause of chronic disease. We now have a lot of big studies that show that the more disconnected you are and the more socially isolated you are, you become more metabolically imbalanced, you become mentally disengaged. And this is actually going to drive inflammation and poor health outcomes. Number seven, mindfulness isn't just a buzzword that we're hearing. It's actually a biological intervention. So even a few minutes a day of present moment awareness has been shown to reduce stress hormones, increase your prefrontal activity and improve your long-term decision-making. This is a really powerful technique.

• 1:53:13Dr. Darshan Shah?

  So try to disconnect whether you're meditating or doing some breath work. This is really helpful and actually biologically changes your brain. Number eight, fixing your brain actually can start with fixing what's going on in your body. So things like sleep, movement, light exposure, nutrition directly impact our brain's ability to regulate emotions, make decisions and recover from stress. Really important to take care of yourself. Number nine, you can train your brain to make better choices. So small, consistent routines like morning sunlight, even walking after meals and breath work literally can strengthen the circuits responsible for conscious control and delayed gratification. And finally, number 10, better health starts in your brain with better thinking.

• 1:53:58Dr. Darshan Shah?

  If you want to change your habits, you have to change your brain. And that begins by understanding how the modern world is shaping your mind without your permission. Thank you so much for listening to this episode. I think it's a great one to forward on to your friends and family. Please let us know how you felt about this episode by sending us an email or a comment on my website. And always, please give us a rating and have your friends follow this podcast too. Thank you for listening.

• 1:54:26Dr. Darshan Shah?

  Thank you so much for listening to the podcast today. Please remember to subscribe if you liked this episode and give us a good review and share a link with your friends. It really helps to support all of our efforts. I also want to remind you that the information shared on this podcast is for educational purposes only and is not intended to replace professional medical advice, diagnosis, or treatment. Please consult with your healthcare provider or physician before making any decisions or taking any action based on what you hear today, especially if you have any underlying health conditions or on any medications. Your doctor knows your personal health situation the best, and it's always important to seek their guidance.