Essentials: Understanding & Conquering Depression

Cold Exposure: Dopamine

Whenever I'm asked if I could take just one supplement, what that supplement would be, I always say AG1. If you'd like to try AG1, you can go to drinkag1.com slash Huberman.

"I'd like to take a quick break Thank you. work. They should work because they operate in the very same biochemical pathways that antidepressants that are prescribed to people do. I'd like to take a quick break and acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80% of nonstick pans, as well as utensils, appliances, and countless other kitchen products. As I've discussed before in this podcast, these PFASs or forever chemicals like Teflon have been linked to major health issues, such as hormone disruption, gut microbiome disruption, fertility issues, and many other health problems. So it's really important to try and avoid them. This is why I'm a huge fan of Our Place. Our Place products are made with the highest quality materials and are all completely PFAS and toxin-free. I especially love their titanium always pan pro. It's the first nonstick pan made with zero chemicals and zero coating. Instead, it uses pure titanium. This means it has no harmful forever chemicals and does not degrade or lose its nonstick effect over time. It's also beautiful to look at. I cook eggs in my Titanium Always Pan Pro almost every morning. The design allows for the eggs to cook perfectly without sticking to the pan. I also cook burgers and steaks in it, and it puts a really nice sear on the meat. But again, nothing sticks to it, so it's really easy to clean, and it's even dishwasher safe. I love it, and I basically use it constantly. Our place now has a full line of Titanium Pro cook that uses its first of its kind titanium nonstick technology. So if you're looking for non-toxic long lasting pots and pans, go to fromourplace.com slash Huberman and use the code Huberman at checkout. Right now, our place is having their biggest sale of the season. You can get up to 30% off all products now through May 12th, 2025. With a hundred day risk-free trial, free shipping and free returns, you can try Our Place with zero risk and see why more than 1 million people have made the switch to Our Place Kitchenware. Again, that's from ourplace.com slash Huberman to get up to 30% off. Now I want to talk about something that at least for me was quite surprising when I first learned about it for sake of treatment of mood disorders. And that's creatine. Creatine has a number of very important functions throughout the body. For those of you that are into resistance training and actually for those of you that are into endurance training as well, creatine has achieved a lot of popularity in recent years because supplementation with creatine can draw more water into muscles and can increase power output from muscles. However, there's also a so-called phosphocreatine system in the brain, and that phosphocreatine system has everything to do with the dialogue between neurons and these other cell types called glia. But the phosphocreatine system in the forebrain in particular, in the front of our brain, has been shown to be involved in regulation of mood and some of the reward pathways, as well as in depression. The American Journal of Psychiatry in 2012 published a study which was a randomized double-blind placebo-controlled trial of oral creatine monohydrate. And what it found is that it could augment or enhance the response to a selective serotonin reuptake inhibitor, in particular in women with major depressive disorder. So like EPA, creatine supplementation seems to either lower the required dose of SSRI that's required to treat depression, or can improve the effectiveness of a given dose of SSRI. However, there are other studies that have looked directly at creatine supplementation in the absence of SSRIs, and those are interesting as well. So let's talk a little bit more about novel therapeutic compounds for the treatment of major depression. One is ketamine, which is getting increasing interest in psychiatric clinics in various experimental and clinical studies. They create dissociative anesthetic states. So dissociative states where people don't feel as closely meshed with their emotions and their perceptions. Clinically, what's described in the trials for ketamine and things like it, that people who are depressed will take ketamine, will experience a kind of separateness from their grief and from their emotions, and that possibly there's plasticity. There actually shifts in the neural circuitry such that their emotions don't weigh on them so heavily. It's not always about just getting people peppy and excited and happy. There also seems to be a requirement for getting them distanced from their own grief. And this brings us back to something that we talked about way back at the beginning of this episode, which was this particular feature of the anti-self confabulation, that everything that happens is a reflection that I should say for the depressed person, that everything that happens is a reflection of how life is bad and their experiences just point to the fact that nothing is going to get better. This is the common language of depression. If this is very depressing to hear me talk about, it is heavy. And that's what it's like to hear these things. It's even heavier, of course, for somebody to experience them. And those beliefs, those patterns of guilt and grief and anhedonia and delusional anti-self confabulations, those are the things that eventually, if they get severe enough, start to convert into things like self-harm,ilation and in the most tragic of cases, of course, suicide. And so I think we can look to these treatments such as ketamine and its use in the clinic as ways for people to get distanced from the negative affect that they feel isn't just inside them or overwhelms them, but that for the very severely depressed person, they feel is them. Another category of treatments that's being actively explored now in laboratories and in the psychiatry realm are the psychedelics. And that's a huge category of compounds. However, one in particular, psilocybin is one that's being most intensely and actively pursued for its capacity to treat major depressive disorder. But let's focus on psilocybin for its capacity to rewire neural circuits and alleviate depression. There have been anecdotal data or evidence over the years that psilocybin has this capacity. How does psilocybin work? Well, psilocybin engages or increases serotonin transmission, meaning it increases the amount of serotonin, mainly by acting at these 5H2A receptors. But where in the brain does it happen and what are the major effects? First, let's talk about the major effects, because I think that's what people are interested in. The study that I'd like to highlight is a fairly recent one. It was published in May of 2021 in Journal, excuse me, of the American Medical Association Psychiatry, so JAMA Psychiatry, and it's entitled Effects of Psilocybin Assisted Therapy on Major Depressive Disorder, a Randomized Clinical Trial. Basically what they did was they screened for patients to come into the clinic. These were people that suffered from major depressive disorder and administered either one or two rounds of psilocybin. Typically it was 20 milligrams per kilogram of body weight. So it depends on body weight. What's really striking about this study is that there was a very significant improvement in mood and affect and relief from depressive symptoms in anywhere from 50 to 70% of the people that were subjects in the study who received the psilocybin treatment. These are really enormous and significant effects. What's really interesting is there are some common themes to psilocybin administration and experience that lead to relief from depressive symptoms, but they are subjectively, excuse me, subjectively very varied, meaning that whether or not people feel they had a good experience or a bad experience, whether or not people thought about their parents or thought about the color of the ceiling doesn't seem to have too much of an impact on whether or not they receive relief during these studies, in these clinical studies. It seems like different people can have lots of different experiences and still receive benefit. It's somehow rewiring associations between events, emotional events, past events, current events, and future events in ways that allow people to get some sort of relief or distance from these narratives, these depressive stories about their past and present, and allow them to see new opportunity and optimism in the future. One of the most common questions I get for this podcast is about different diets, different regimes, different nutritional plans, things like keto, ketogenic diet, or vegan diets, or intermittent fasting, or the all meat diet, the so-called lion diet, et cetera. There are actually really interesting data relating nutrition and diet to major depressive disorder. There have been some explorations of whether or not a vegan diet can improve symptoms of depression. Not a lot of data, not impressive data. There have been very few controlled studies looking at the carnivore all meat diet. However, the ketogenic diet has been explored for its ability to relieve certain symptoms of depression, in particular to what's called maintain euthymia. Euthymia is the kind of state of equilibrium between a manic episode and a depressive episode in a manic bipolar person. Euthymia is that kind of place in the middle where people feel neither too high nor too low. And there are some interesting studies looking at the ketogenic diet for maintaining euthymia in manic depressives, but also in people with major depressive disorder. The ketogenic diet, by way of increasing ketone metabolism or shifting brain's metabolism over to ketones, tends to modulate GABA such that GABA is more active and adjusts the so-called GABA glutamate balance. This is getting technical, but glutamate is an excitatory neurotransmitter. GABA is inhibitory neurotransmitter, and their balance is vital for neuroplasticity, for maintaining healthy levels of activity in the brain, et cetera. And so there is decent evidence that people with major depressive disorders, in particular, the people with major depressive disorders that are refractory, meaning they don't respond to classical antidepressants, can benefit, it seems, from the ketogenic diet. It's really interesting that eating in a particular way, lowering carbohydrates to the point where you rely on ketogenic metabolism in the brain increases GABA and can provide some relief for depressive symptoms. And that in particular, that seems to have positive effects in people that are refractory or don't respond to classic antidepressants. So today, we've covered what at least feels to me like a tremendous amount of material. This topic of depression is indeed an enormous topic to try and get our arms around. We talked about the symptomology, we talked about some of the underlying neurochemistry and biology, and then we talked about approaches to deal with it that are really grounded in the neurochemistry and biology. I just want to recap a few of those tools and what those things are. So number one, don't overwhelm your pleasure centers, either through activities or compounds. It might seem counterintuitive, but you're setting yourself up for anhedonia and depression if you do that. Second of all, talked about the norepinephrine system and how the norepinephrine system is really deficient in many forms of major depression and in depression. There is now more deliberate pursuit of norepinephrine-inducing activities that are healthy, that aren't adrenaline-seeking per se, things like exercise that will increase our levels of noradrenaline. I'd be remiss if I said that these activities could completely eliminate depressive symptoms in people with major depressive disorder. I don't think that's the case. And again, I want to acknowledge that people with major depressive symptoms often don't have the energy, the willingness or the capacity to engage in some of these activities, but things like cold showers, deliberate cold showers, things like regular exercise, they aren't just feel good activities. They actually engage the norepinephrine system and keep that system tuned up and allow us to increase our norepinephrine levels at will on a regular basis. And their mood enhancing effects are real effects that at the level of neurochemistry. Then we talked about EPAs, these essential fatty acids. And it's clear that for most people, getting above a thousand milligrams and probably even closer to 2000 milligrams per day of EPAs can be beneficial for mood, especially in attempts to treat or offset major depressive disorder. We also talked about exercise and how EPA and exercise on a regular basis can offset these inflammatory pathways. And then we talked about the prescription compounds and the compounds that are being used mainly in the course of studies and of psychiatry and depression, things like ketamine, psilocybin and related compounds. And then lastly, we talked about ketosis, which may not be right for everybody, but might be right for certain individuals out there who are grappling with this. I want to thank you for embarking on this journey of trying to understand what is depression, how does it work, and how to treat it. And thank you for your interest in science."

Zone 2 Cardio Discussion

The pathway involves something called IDO, indolamine, which converts tryptophan into kynurine. Kynurine actually acts as a neurotoxin by way of converting into something called quinolinic acid.

"The pathway involves something called IDO, indolamine, which converts tryptophan into kynurine. Kynurine actually acts as a neurotoxin by way of converting into something called quinolinic acid. And quinolinic acid is pro-depressive."

Resistance Training Discussion

The pathway involves something called IDO, indolamine, which converts tryptophan into kynurine. Kynurine actually acts as a neurotoxin by way of converting into something called quinolinic acid.

"The pathway involves something called IDO, indolamine, which converts tryptophan into kynurine. Kynurine actually acts as a neurotoxin by way of converting into something called quinolinic acid. And quinolinic acid is pro-depressive."

Creatine: Brain

I'd like to take a quick break Thank you. They should work because they operate in the very same biochemical pathways that antidepressants that are prescribed to people do.

"I'd like to take a quick break Thank you. work. They should work because they operate in the very same biochemical pathways that antidepressants that are prescribed to people do. I'd like to take a quick break and acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80% of nonstick pans, as well as utensils, appliances, and countless other kitchen products. As I've discussed before in this podcast, these PFASs or forever chemicals like Teflon have been linked to major health issues, such as hormone disruption, gut microbiome disruption, fertility issues, and many other health problems. So it's really important to try and avoid them. This is why I'm a huge fan of Our Place. Our Place products are made with the highest quality materials and are all completely PFAS and toxin-free. I especially love their titanium always pan pro. It's the first nonstick pan made with zero chemicals and zero coating. Instead, it uses pure titanium. This means it has no harmful forever chemicals and does not degrade or lose its nonstick effect over time. It's also beautiful to look at. I cook eggs in my Titanium Always Pan Pro almost every morning. The design allows for the eggs to cook perfectly without sticking to the pan. I also cook burgers and steaks in it, and it puts a really nice sear on the meat. But again, nothing sticks to it, so it's really easy to clean, and it's even dishwasher safe. I love it, and I basically use it constantly. Our place now has a full line of Titanium Pro cook that uses its first of its kind titanium nonstick technology. So if you're looking for non-toxic long lasting pots and pans, go to fromourplace.com slash Huberman and use the code Huberman at checkout. Right now, our place is having their biggest sale of the season. You can get up to 30% off all products now through May 12th, 2025. With a hundred day risk-free trial, free shipping and free returns, you can try Our Place with zero risk and see why more than 1 million people have made the switch to Our Place Kitchenware. Again, that's from ourplace.com slash Huberman to get up to 30% off. Now I want to talk about something that at least for me was quite surprising when I first learned about it for sake of treatment of mood disorders. And that's creatine. Creatine has a number of very important functions throughout the body. For those of you that are into resistance training and actually for those of you that are into endurance training as well, creatine has achieved a lot of popularity in recent years because supplementation with creatine can draw more water into muscles and can increase power output from muscles. However, there's also a so-called phosphocreatine system in the brain, and that phosphocreatine system has everything to do with the dialogue between neurons and these other cell types called glia. But the phosphocreatine system in the forebrain in particular, in the front of our brain, has been shown to be involved in regulation of mood and some of the reward pathways, as well as in depression. The American Journal of Psychiatry in 2012 published a study which was a randomized double-blind placebo-controlled trial of oral creatine monohydrate. And what it found is that it could augment or enhance the response to a selective serotonin reuptake inhibitor, in particular in women with major depressive disorder. So like EPA, creatine supplementation seems to either lower the required dose of SSRI that's required to treat depression, or can improve the effectiveness of a given dose of SSRI. However, there are other studies that have looked directly at creatine supplementation in the absence of SSRIs, and those are interesting as well. So let's talk a little bit more about novel therapeutic compounds for the treatment of major depression. One is ketamine, which is getting increasing interest in psychiatric clinics in various experimental and clinical studies. They create dissociative anesthetic states. So dissociative states where people don't feel as closely meshed with their emotions and their perceptions. Clinically, what's described in the trials for ketamine and things like it, that people who are depressed will take ketamine, will experience a kind of separateness from their grief and from their emotions, and that possibly there's plasticity. There actually shifts in the neural circuitry such that their emotions don't weigh on them so heavily. It's not always about just getting people peppy and excited and happy. There also seems to be a requirement for getting them distanced from their own grief. And this brings us back to something that we talked about way back at the beginning of this episode, which was this particular feature of the anti-self confabulation, that everything that happens is a reflection that I should say for the depressed person, that everything that happens is a reflection of how life is bad and their experiences just point to the fact that nothing is going to get better. This is the common language of depression. If this is very depressing to hear me talk about, it is heavy. And that's what it's like to hear these things. It's even heavier, of course, for somebody to experience them. And those beliefs, those patterns of guilt and grief and anhedonia and delusional anti-self confabulations, those are the things that eventually, if they get severe enough, start to convert into things like self-harm,ilation and in the most tragic of cases, of course, suicide. And so I think we can look to these treatments such as ketamine and its use in the clinic as ways for people to get distanced from the negative affect that they feel isn't just inside them or overwhelms them, but that for the very severely depressed person, they feel is them. Another category of treatments that's being actively explored now in laboratories and in the psychiatry realm are the psychedelics. And that's a huge category of compounds. However, one in particular, psilocybin is one that's being most intensely and actively pursued for its capacity to treat major depressive disorder. But let's focus on psilocybin for its capacity to rewire neural circuits and alleviate depression. There have been anecdotal data or evidence over the years that psilocybin has this capacity. How does psilocybin work? Well, psilocybin engages or increases serotonin transmission, meaning it increases the amount of serotonin, mainly by acting at these 5H2A receptors. But where in the brain does it happen and what are the major effects? First, let's talk about the major effects, because I think that's what people are interested in. The study that I'd like to highlight is a fairly recent one. It was published in May of 2021 in Journal, excuse me, of the American Medical Association Psychiatry, so JAMA Psychiatry, and it's entitled Effects of Psilocybin Assisted Therapy on Major Depressive Disorder, a Randomized Clinical Trial. Basically what they did was they screened for patients to come into the clinic. These were people that suffered from major depressive disorder and administered either one or two rounds of psilocybin. Typically it was 20 milligrams per kilogram of body weight. So it depends on body weight. What's really striking about this study is that there was a very significant improvement in mood and affect and relief from depressive symptoms in anywhere from 50 to 70% of the people that were subjects in the study who received the psilocybin treatment. These are really enormous and significant effects. What's really interesting is there are some common themes to psilocybin administration and experience that lead to relief from depressive symptoms, but they are subjectively, excuse me, subjectively very varied, meaning that whether or not people feel they had a good experience or a bad experience, whether or not people thought about their parents or thought about the color of the ceiling doesn't seem to have too much of an impact on whether or not they receive relief during these studies, in these clinical studies. It seems like different people can have lots of different experiences and still receive benefit. It's somehow rewiring associations between events, emotional events, past events, current events, and future events in ways that allow people to get some sort of relief or distance from these narratives, these depressive stories about their past and present, and allow them to see new opportunity and optimism in the future. One of the most common questions I get for this podcast is about different diets, different regimes, different nutritional plans, things like keto, ketogenic diet, or vegan diets, or intermittent fasting, or the all meat diet, the so-called lion diet, et cetera. There are actually really interesting data relating nutrition and diet to major depressive disorder. There have been some explorations of whether or not a vegan diet can improve symptoms of depression. Not a lot of data, not impressive data. There have been very few controlled studies looking at the carnivore all meat diet. However, the ketogenic diet has been explored for its ability to relieve certain symptoms of depression, in particular to what's called maintain euthymia. Euthymia is the kind of state of equilibrium between a manic episode and a depressive episode in a manic bipolar person. Euthymia is that kind of place in the middle where people feel neither too high nor too low. And there are some interesting studies looking at the ketogenic diet for maintaining euthymia in manic depressives, but also in people with major depressive disorder. The ketogenic diet, by way of increasing ketone metabolism or shifting brain's metabolism over to ketones, tends to modulate GABA such that GABA is more active and adjusts the so-called GABA glutamate balance. This is getting technical, but glutamate is an excitatory neurotransmitter. GABA is inhibitory neurotransmitter, and their balance is vital for neuroplasticity, for maintaining healthy levels of activity in the brain, et cetera. And so there is decent evidence that people with major depressive disorders, in particular, the people with major depressive disorders that are refractory, meaning they don't respond to classical antidepressants, can benefit, it seems, from the ketogenic diet. It's really interesting that eating in a particular way, lowering carbohydrates to the point where you rely on ketogenic metabolism in the brain increases GABA and can provide some relief for depressive symptoms. And that in particular, that seems to have positive effects in people that are refractory or don't respond to classic antidepressants. So today, we've covered what at least feels to me like a tremendous amount of material. This topic of depression is indeed an enormous topic to try and get our arms around. We talked about the symptomology, we talked about some of the underlying neurochemistry and biology, and then we talked about approaches to deal with it that are really grounded in the neurochemistry and biology. I just want to recap a few of those tools and what those things are. So number one, don't overwhelm your pleasure centers, either through activities or compounds. It might seem counterintuitive, but you're setting yourself up for anhedonia and depression if you do that. Second of all, talked about the norepinephrine system and how the norepinephrine system is really deficient in many forms of major depression and in depression. There is now more deliberate pursuit of norepinephrine-inducing activities that are healthy, that aren't adrenaline-seeking per se, things like exercise that will increase our levels of noradrenaline. I'd be remiss if I said that these activities could completely eliminate depressive symptoms in people with major depressive disorder. I don't think that's the case. And again, I want to acknowledge that people with major depressive symptoms often don't have the energy, the willingness or the capacity to engage in some of these activities, but things like cold showers, deliberate cold showers, things like regular exercise, they aren't just feel good activities. They actually engage the norepinephrine system and keep that system tuned up and allow us to increase our norepinephrine levels at will on a regular basis. And their mood enhancing effects are real effects that at the level of neurochemistry. Then we talked about EPAs, these essential fatty acids. And it's clear that for most people, getting above a thousand milligrams and probably even closer to 2000 milligrams per day of EPAs can be beneficial for mood, especially in attempts to treat or offset major depressive disorder. We also talked about exercise and how EPA and exercise on a regular basis can offset these inflammatory pathways. And then we talked about the prescription compounds and the compounds that are being used mainly in the course of studies and of psychiatry and depression, things like ketamine, psilocybin and related compounds. And then lastly, we talked about ketosis, which may not be right for everybody, but might be right for certain individuals out there who are grappling with this. I want to thank you for embarking on this journey of trying to understand what is depression, how does it work, and how to treat it. And thank you for your interest in science."

Ketogenic Diet: How To

Another category of treatments that's being actively explored now in laboratories and in the psychiatry realm are the psychedelics.

"I'd like to take a quick break Thank you. work. They should work because they operate in the very same biochemical pathways that antidepressants that are prescribed to people do. I'd like to take a quick break and acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80% of nonstick pans, as well as utensils, appliances, and countless other kitchen products. As I've discussed before in this podcast, these PFASs or forever chemicals like Teflon have been linked to major health issues, such as hormone disruption, gut microbiome disruption, fertility issues, and many other health problems. So it's really important to try and avoid them. This is why I'm a huge fan of Our Place. Our Place products are made with the highest quality materials and are all completely PFAS and toxin-free. I especially love their titanium always pan pro. It's the first nonstick pan made with zero chemicals and zero coating. Instead, it uses pure titanium. This means it has no harmful forever chemicals and does not degrade or lose its nonstick effect over time. It's also beautiful to look at. I cook eggs in my Titanium Always Pan Pro almost every morning. The design allows for the eggs to cook perfectly without sticking to the pan. I also cook burgers and steaks in it, and it puts a really nice sear on the meat. But again, nothing sticks to it, so it's really easy to clean, and it's even dishwasher safe. I love it, and I basically use it constantly. Our place now has a full line of Titanium Pro cook that uses its first of its kind titanium nonstick technology. So if you're looking for non-toxic long lasting pots and pans, go to fromourplace.com slash Huberman and use the code Huberman at checkout. Right now, our place is having their biggest sale of the season. You can get up to 30% off all products now through May 12th, 2025. With a hundred day risk-free trial, free shipping and free returns, you can try Our Place with zero risk and see why more than 1 million people have made the switch to Our Place Kitchenware. Again, that's from ourplace.com slash Huberman to get up to 30% off. Now I want to talk about something that at least for me was quite surprising when I first learned about it for sake of treatment of mood disorders. And that's creatine. Creatine has a number of very important functions throughout the body. For those of you that are into resistance training and actually for those of you that are into endurance training as well, creatine has achieved a lot of popularity in recent years because supplementation with creatine can draw more water into muscles and can increase power output from muscles. However, there's also a so-called phosphocreatine system in the brain, and that phosphocreatine system has everything to do with the dialogue between neurons and these other cell types called glia. But the phosphocreatine system in the forebrain in particular, in the front of our brain, has been shown to be involved in regulation of mood and some of the reward pathways, as well as in depression. The American Journal of Psychiatry in 2012 published a study which was a randomized double-blind placebo-controlled trial of oral creatine monohydrate. And what it found is that it could augment or enhance the response to a selective serotonin reuptake inhibitor, in particular in women with major depressive disorder. So like EPA, creatine supplementation seems to either lower the required dose of SSRI that's required to treat depression, or can improve the effectiveness of a given dose of SSRI. However, there are other studies that have looked directly at creatine supplementation in the absence of SSRIs, and those are interesting as well. So let's talk a little bit more about novel therapeutic compounds for the treatment of major depression. One is ketamine, which is getting increasing interest in psychiatric clinics in various experimental and clinical studies. They create dissociative anesthetic states. So dissociative states where people don't feel as closely meshed with their emotions and their perceptions. Clinically, what's described in the trials for ketamine and things like it, that people who are depressed will take ketamine, will experience a kind of separateness from their grief and from their emotions, and that possibly there's plasticity. There actually shifts in the neural circuitry such that their emotions don't weigh on them so heavily. It's not always about just getting people peppy and excited and happy. There also seems to be a requirement for getting them distanced from their own grief. And this brings us back to something that we talked about way back at the beginning of this episode, which was this particular feature of the anti-self confabulation, that everything that happens is a reflection that I should say for the depressed person, that everything that happens is a reflection of how life is bad and their experiences just point to the fact that nothing is going to get better. This is the common language of depression. If this is very depressing to hear me talk about, it is heavy. And that's what it's like to hear these things. It's even heavier, of course, for somebody to experience them. And those beliefs, those patterns of guilt and grief and anhedonia and delusional anti-self confabulations, those are the things that eventually, if they get severe enough, start to convert into things like self-harm,ilation and in the most tragic of cases, of course, suicide. And so I think we can look to these treatments such as ketamine and its use in the clinic as ways for people to get distanced from the negative affect that they feel isn't just inside them or overwhelms them, but that for the very severely depressed person, they feel is them. Another category of treatments that's being actively explored now in laboratories and in the psychiatry realm are the psychedelics. And that's a huge category of compounds. However, one in particular, psilocybin is one that's being most intensely and actively pursued for its capacity to treat major depressive disorder. But let's focus on psilocybin for its capacity to rewire neural circuits and alleviate depression. There have been anecdotal data or evidence over the years that psilocybin has this capacity. How does psilocybin work? Well, psilocybin engages or increases serotonin transmission, meaning it increases the amount of serotonin, mainly by acting at these 5H2A receptors. But where in the brain does it happen and what are the major effects? First, let's talk about the major effects, because I think that's what people are interested in. The study that I'd like to highlight is a fairly recent one. It was published in May of 2021 in Journal, excuse me, of the American Medical Association Psychiatry, so JAMA Psychiatry, and it's entitled Effects of Psilocybin Assisted Therapy on Major Depressive Disorder, a Randomized Clinical Trial. Basically what they did was they screened for patients to come into the clinic. These were people that suffered from major depressive disorder and administered either one or two rounds of psilocybin. Typically it was 20 milligrams per kilogram of body weight. So it depends on body weight. What's really striking about this study is that there was a very significant improvement in mood and affect and relief from depressive symptoms in anywhere from 50 to 70% of the people that were subjects in the study who received the psilocybin treatment. These are really enormous and significant effects. What's really interesting is there are some common themes to psilocybin administration and experience that lead to relief from depressive symptoms, but they are subjectively, excuse me, subjectively very varied, meaning that whether or not people feel they had a good experience or a bad experience, whether or not people thought about their parents or thought about the color of the ceiling doesn't seem to have too much of an impact on whether or not they receive relief during these studies, in these clinical studies. It seems like different people can have lots of different experiences and still receive benefit. It's somehow rewiring associations between events, emotional events, past events, current events, and future events in ways that allow people to get some sort of relief or distance from these narratives, these depressive stories about their past and present, and allow them to see new opportunity and optimism in the future. One of the most common questions I get for this podcast is about different diets, different regimes, different nutritional plans, things like keto, ketogenic diet, or vegan diets, or intermittent fasting, or the all meat diet, the so-called lion diet, et cetera. There are actually really interesting data relating nutrition and diet to major depressive disorder. There have been some explorations of whether or not a vegan diet can improve symptoms of depression. Not a lot of data, not impressive data. There have been very few controlled studies looking at the carnivore all meat diet. However, the ketogenic diet has been explored for its ability to relieve certain symptoms of depression, in particular to what's called maintain euthymia. Euthymia is the kind of state of equilibrium between a manic episode and a depressive episode in a manic bipolar person. Euthymia is that kind of place in the middle where people feel neither too high nor too low. And there are some interesting studies looking at the ketogenic diet for maintaining euthymia in manic depressives, but also in people with major depressive disorder. The ketogenic diet, by way of increasing ketone metabolism or shifting brain's metabolism over to ketones, tends to modulate GABA such that GABA is more active and adjusts the so-called GABA glutamate balance. This is getting technical, but glutamate is an excitatory neurotransmitter. GABA is inhibitory neurotransmitter, and their balance is vital for neuroplasticity, for maintaining healthy levels of activity in the brain, et cetera. And so there is decent evidence that people with major depressive disorders, in particular, the people with major depressive disorders that are refractory, meaning they don't respond to classical antidepressants, can benefit, it seems, from the ketogenic diet. It's really interesting that eating in a particular way, lowering carbohydrates to the point where you rely on ketogenic metabolism in the brain increases GABA and can provide some relief for depressive symptoms. And that in particular, that seems to have positive effects in people that are refractory or don't respond to classic antidepressants. So today, we've covered what at least feels to me like a tremendous amount of material. This topic of depression is indeed an enormous topic to try and get our arms around. We talked about the symptomology, we talked about some of the underlying neurochemistry and biology, and then we talked about approaches to deal with it that are really grounded in the neurochemistry and biology. I just want to recap a few of those tools and what those things are. So number one, don't overwhelm your pleasure centers, either through activities or compounds. It might seem counterintuitive, but you're setting yourself up for anhedonia and depression if you do that. Second of all, talked about the norepinephrine system and how the norepinephrine system is really deficient in many forms of major depression and in depression. There is now more deliberate pursuit of norepinephrine-inducing activities that are healthy, that aren't adrenaline-seeking per se, things like exercise that will increase our levels of noradrenaline. I'd be remiss if I said that these activities could completely eliminate depressive symptoms in people with major depressive disorder. I don't think that's the case. And again, I want to acknowledge that people with major depressive symptoms often don't have the energy, the willingness or the capacity to engage in some of these activities, but things like cold showers, deliberate cold showers, things like regular exercise, they aren't just feel good activities. They actually engage the norepinephrine system and keep that system tuned up and allow us to increase our norepinephrine levels at will on a regular basis. And their mood enhancing effects are real effects that at the level of neurochemistry. Then we talked about EPAs, these essential fatty acids. And it's clear that for most people, getting above a thousand milligrams and probably even closer to 2000 milligrams per day of EPAs can be beneficial for mood, especially in attempts to treat or offset major depressive disorder. We also talked about exercise and how EPA and exercise on a regular basis can offset these inflammatory pathways. And then we talked about the prescription compounds and the compounds that are being used mainly in the course of studies and of psychiatry and depression, things like ketamine, psilocybin and related compounds. And then lastly, we talked about ketosis, which may not be right for everybody, but might be right for certain individuals out there who are grappling with this. I want to thank you for embarking on this journey of trying to understand what is depression, how does it work, and how to treat it. And thank you for your interest in science."

Cold Exposure: Norepinephrine

I'd be remiss if I said that these activities could completely eliminate depressive symptoms in people with major depressive disorder. I don't think that's the case.

"I'd be remiss if I said that these activities could completely eliminate depressive symptoms in people with major depressive disorder. I don't think that's the case."