Jay Feldman  0:05  
We've all been lied to about serotonin, but we'll be digging into the truth about serotonin in today's episode of the energy balance podcast, a Podcast where we explore health and nutrition from the bioenergetic view and teach you how to maximize your cellular energy, to maximize your health. In today's episode, we'll be discussing why serotonin is not the happy hormone. We'll be talking about how serotonin relates to stress and energy balance. We'll also discuss whether SSRIs are effective for depression, and the real drivers of depression and anxiety as always. To check out the show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where I'll link to the studies and articles and anything else that we discussed throughout today's episode. And with that, let's get started.

All right, so for today's episode, we're going to be digging through a paper, and the paper is titled, is serotonin an upper or a downer, the evolution of the serotonergic system and its role in depression and the antidepressant response. Let us know if you guys like this style of episode, if you want us to do more episodes like this, where we break down a study in more detail and kind of expand on it and and share that with you. And, yeah, with that, the last thing I want to mention before we dig in is that there are parts of this paper that, of course, we don't agree with, just like any, you know, any paper or any piece of content, like, there's a lot of really great things in here, and it really flips a lot on its head as far as serotonin goes, and its relationship with things like depression and anxiety, and also energy balance and stress. So it's a really important paper to go through and tease out some of those important pieces. But again, we're going to be highlighting just certain parts that we think are really important to discuss. There are certain parts in here that I mean are worth reading through. So we definitely recommend that you guys redo the paper, which is rather long. But in addition to that, there are going to be some parts that we don't agree with. We aren't going to be focusing on those in today's episode. We're just going to focus on really the shift in perspective of what the role of serotonin is, whether we want to actually be increasing it, which is kind of the general narrative, right? Serotonin is the happy hormone. It increases when you do anything good, whether it's exercise or meditation or, I don't know, when you're happy, just in general, like, you know, anything going on in your environment that makes you happy, it increases serotonin. And this challenges that notion, which, I mean, there's a ton out there challenging that notion that is really, has really pointed to that being a feature of more, more related to marketing for drugs, as opposed to actually anything to do with the reality of what's going on in terms of our neurotransmitters. And we've discussed that a little bit in the past. I've also written an article talking about depression and the kind of how ineffective SSRIs are, and what that what that kind of illustrates in terms of the serotonin hypothesis, this idea that, you know, low serotonin causes depression, and serotonin is, you know, produced when we're when we're happier. So, you know, we've, we've kind of expanded on it in those places. But in this article, we'll really dig into some of those details and also really expand upon the role of serotonin in relationship to energy and energy balance, which, of course, is the central feature underlying our health. So before we dig in, Mike, is there anything you want to mention?

Mike  3:28  
No, let's jump in.

Jay Feldman  3:30  
Cool. Alright, so we'll just start by kind of giving you guys the overview of what they discuss in this paper, very briefly. Basically, they're talking about three different claims. The first is that serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The second claim they talk about they state. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy and then their third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. So basically, three claims here. First is that there's actually an increase in serotonin and serotonin transmission in depressive phenotypes and depression. Second is that kind of talking about the paradox of SSRIs potentially being effective for this, and that's and the role of serotonin in energy, or the relationship between those two, is going to be something that'll that's crucial to resolve that paradox. Then thirdly is that the symptom reduction from those sorts of drugs is not actually due to the direct effects, but actually a compensatory mechanism. So that's kind of the three overall points that they're making this paper. Just so you guys have that as a framework as we dig through the quotes and kind of jump around through it. Is there anything you want to mention there Mike?

Mike  4:53  
Nope. Let's jump in

Jay Feldman  4:55  
Cool. So, Mike, do you want to start us off with this first quote?

Mike  4:59  
Sure. The first quote we're starting off with here they say, melancholia, which is a combination of weight loss, insomnia and agitation, agitation, slash retardation, is considered by many to be the biological core of depression. It is the most common and reliably diagnosed subtype, often accounting for 50% or more of clinical episodes. Melancholia is associated with high end hypothalamic pituitary adrenal activity, which is a physiologic indicator of stress. So the there's two major types of depression. There's sort of subtypes, so depression itself is a diagnosis, but then there's melancholia, and then there's atypical depression. The major form of depression is melancholia, and it's, it's characterized by weight loss, insomnia, agitation and retardation. And when they talk about retardation, they mean to like, perhaps in like, a very clinical sense, maybe not in a politically correct sense, in normal terms like mental retardation. And the reason they describe it this way is because people who have melancholic depression have pretty significant deficits in their cognitive function and so and then they also experience states of agitation with that. And one thing that's in that they're showing here is that melancholia is associated with heightened hypothalamic pituitary adrenal axis activity. So the HPA axis is the major axis associated with stress, or actually not even associated that drives stress, and you're seeing this heightened in depression. And so the other thing that they're going to talk about with this paper, and or that they do talk about in this paper and turn on its head, is the idea that serotonin is the happy hormone. And then instead, what we're seeing here is serotonin is a stress hormone that's involved specifically in the regulation of energy expenditure and is tied directly in with the hypothalamic pituitary adrenal axis, which is something that Dr Peat and the bioenergetic like in his work, he's described at large like extensively, which kind of counters the current narrative, where we see this idea that serotonin is, like, you know, associated with all This stuff we want to boost and we want to want to take 5-HTP and all these different components to try to get certain serotonin levels up. And at first in the research, what we were seeing, and you know, despite Dr Pete, is that peripheral serotonin is actually a negative regulator of metabolism, so it literally is the break on metabolism. But central serotonin is good. And so there's some paradoxes there. But now what this paper is turning on its head is showing and discussing that central serotonin is also directly involved in the depression state with the hypothalamic pituitary adrenal axis, and that the central serotonin is basically involved directly in driving the stress state. It's it, and we'll, we'll get into it a bit more detail here, but it's involved in a shifting energy regulation, which the hypothalamic pituitary adrenal axis is as well,

Jay Feldman  7:49  
Right. Yep, and there. And we haven't actually gone into that relationship yet in this quote, as far as the relationship between serotonin and stress, but what they are talking about here and highlighting is that there's increased activity of the HPA axis, as you said, that's our stress axis. That's where all of our stress hormones are, or what is leading to the production of those that is increased in depression, or at least in the most common form of depression, being melancholia. So that's really that, that central point here. And then, as you were saying, Mike, we'll dig into, later on, the relationship between serotonin and this kind of presentation. So hopping into this next quote, we're talking a bit about anxiety and the relationship between anxiety and serotonin, and then we'll talk about that, of course, with depression as well. But it's important to mention that the there's they kind of talk about there being a large overlap between depression and anxiety and them having similar drivers, and they find that here when they're talking about the relationship with serotonin. So they state they found a fourfold increase in 5-HIAA in patients diagnosed with panic disorder compared to healthy subjects. They also found a strong positive correlation between 5-HIAA and the severity of symptoms, as well as reduced 5-HIAA with chronic SSRI administration, and that is a metabolite. The 5-HIAA is metabolite of serotonin, so they're using it as a marker of serotonin activity, basically. And so they're basically seeing increased serotonergic activity as much as fourfold in patients with panic disorder, and also a strong correlation between this serotonin metabolite and the severity of symptoms, and they also see a reduction in this activity with chronic SSRI administration. We'll get back to SSRIs a bit later, and how short term, they actually can increase serotonin or do increase, but long term, due to compensatory effects, actually decrease it, so they then stay at the state at the end here. Indeed, many researchers consider anxiety to be a state of elevated serotonin transmission. So again, we'll be getting into this with depression itself. And I talk about that throughout the paper. There's this relationship between increased serotonin activity and depression, and you see that same. With anxiety as well. So again, as you're saying, flipping this on its head, this idea that these are states of low serotonin is just totally, I mean, nearly entirely fabricated. And there's some really good papers that I've referenced in the past talking about how this is that whole narrative is really just marketing. It's really just a way to market certain drugs, as opposed to it being anything near the reality of what's seen. And so we're seeing that here with anxiety, just as with depression.

Mike  10:27  
Yeah, I think the original research, where they were looking at trying to understand what was causing depression, like what was the neurotransmitter basis, they were using drugs to determine the effects, and they didn't even fully know some of the mechanisms of these drugs. So they were, they were pulling together the ideas based on indirect mechanisms, right? So like you take a drug, you see what happens, and you get to see this outcome. And so they eventually stumbled upon the the some drugs that blocked serotonin, or seemingly blocked serotonin, and other drugs that actually seemingly increase serotonin or depleted monoamine, monoamine. So that's serotonin, norepinephrine and epinephrine. And what they found with some of these drugs, which later actually has been turned on its head, and they talk about that in this paper, is that these things would the drugs that they thought were blocking serotonin weren't, and then the drugs that they thought were increasing serotonin were increasing it, but like the SSRIs, but they weren't having an effect in the short term, they were having effect in the long term. And so I think this, like using these indirect markers with these different drugs, led to this idea that serotonin was actually the the mediator that we wanted to increase, and part of that was, again, like they weren't directly measuring these things. They were indirectly trying to get a sense of how things were working by playing around with these different pharmaceuticals and seeing what the effects were from there, and then kind of going based on the known mechanisms of action of those drugs at that period of time, and the reason why they had to go in this direct route, or either even the reason why they had to use something like the five hydroxy indo acetic acid, which is a 5-HIAA marker, is because measuring brain serotonin, like turnover in humans is like it's not possible at this point in time, so you needed to have proxy markers. And so for the rest of this paper, we're going to be looking at things like 5h i A and then the 5-HIAA to 5-HT ratio, so the five hydroxy indole acetic acid to five hydroxy tryptophan ratio, which is going to give us an idea of what's going on with serotonin signaling. So we're still relying on indirect markers. And I think the because they used indirect markers, initially in terms of looking at the drugs and some of the different measurements, it led to these weird interpretations that wound up just being spun into marketing about serotonin being the happy hormone. And now, as we get more information, and we that you have researchers here that are parsing things together starting to say, well, actually, this is not increasing serotonin is not beneficial. These states are actually characterized by high serotonin, and especially in multiple different regions of the brain, as we're going to talk about. And so when we're looking at these people with anxiety, the reason they're even mentioning them in this paper is because depression anxiety co occur. So they tend to come together. Usually people are depressed. Either alternate between depression and anxiety or like, have the like the presentation together. And what they're showing here in healthy subjects, you through this marker, 5-HIAA, which is, again, some metabolite of serotonin. They're saying, hey, look, 5-HIAA is actually really high in these people. And that would, that would fly in the face of the idea that serotonergic signaling is actually lower, it's actually higher. And so, so we get to this, like, okay, like, here's multiple pieces of evidence that we're going to go through. This is one in humans, but we'll go through them in animals as well, where we're seeing like, hey, serotonin is actually high in all of these states that are really bad, like that we that we don't, that we don't want to be in. And so it the researchers saying, like, look, this is flipping this on its head, right? This is saying, If serotonin is high in all these states, how could it be the happy hormone? And then the other thing is, you know, it's not basically, what we're seeing is that it's not. So that's where we're going to get through now and then later. What we'll talk about is like, Well, why are these drugs that increase serotonin supposedly effective? And so, like, we'll go through these next pieces here. But I think just to give the like, a frame and an overarching perspective for people understand, like, where these these components are coming from.

Jay Feldman  14:43  
Yeah, yeah, exactly. Those are all important things. And you know, to highlight and what we'll be going through now are a number of quotes that are talking about situations that increase, increase serotonin. And these are, you know, if you're of the belief, if you're coming. From this, you know, the stall process that serotonin is the good, happy hormone. It's produced anytime you're, you know, you're in that kind of situation, like you're satisfied and content and and, you know, maybe you were, like, there was some, like, play or food, or, like, some hedonic activity, or, you know, anything like that. You're expecting those to be ties when you would increase serotonin, if it's the happy hormone. And these are all very clear situations that are the opposite, intensely stressful situations that all increase serotonin. And so we'll just, it's a, you know, it's really important to highlight these, because it just demonstrates how far off this idea is that serotonin is, that is like the, you know, having higher levels and doing things to increase serotonin, like, that's our goal, that is, that is the way to become happier. Do you want to go through with the first one here Mike?

Mike  15:49  
Sure. So what they say here, and what they're talking about, is starvation. They say starvation triggers depressive symptoms in humans during periods of fasting. Keep that in mind. And starvation, extracellular 5-HIAA and serotonin increase in the hypothalamus. The other thing that I want to mention here, they say a little bit lower down, as they say during, or they say, You're during prolonged starvation, the ability to synthesize serotonin could be reduced by a lack of dietary tryptophan. However, the metabolism of muscle tissue could liberate tryptophan to replace the declining serotonin levels. So basically, what we see here is, when people are starved or they're fasting, it triggers depression. And there's different, there's different, like there's different types of depression, even with this so you have starvation induced depression, sickness induced depression, inescapable stress induced depression. And so starvation is one model in the animals where they actually induce suppression and depression. And what you're seeing is elevated serotonin concentrations, and the substrate to produce that serotonin is actually coming from muscle degradation. So this ties in with multiple pieces that both you and I have discussed before, Jay and that's like big in the bioenergetics fears that fasting and and like fasting and starvation, number one, are stressful. They do lead to catabolism of muscle tissue, what you see here as they discuss in this study. And then two, this is actually induces a serotonergic state and depression together. And there's a reason that they're going together to kind of deal with the starvation state. The serotonin job is to upregulate and adjust metabolic processes to help you deal with the starvation and the fasting. And so when people, someone tells you now, like, Hey, you should be fasting because it raises serotonin. You should be like, Nah. Not a good idea like this. Not ideal to do that, because I'm going to be number one in a catabolic state, which is something that we see people like Dr Peter Tia, like super pontzer fasting, saying at one point, like, Hey, I lost 20 pounds of muscle in three years doing this fasting stuff, and in two it can increase the depressive like state by up regulating serotonergic signaling. Now this is supposed to happen in these states because serotonin is balancing energy homeostasis, but to optimize for this is not good. Like the idea isn't to fast and then block serotonin signaling. The idea is just not too fast. I mean, unless you have, like, a serious gut issue and you're trying to use it to, like, get things under control for a very specific intervention, sure, but in like, normal circumstances, this wouldn't be ideal for multiple levels, and that includes muscle catabolism, which we're seeing here with the release of tryptophan. And this is actually something that Dr Peat had discussed in one of his articles, pretty specifically, where he was saying that when people are fasting or they're they are break, they're under stress, they will release these metabolites from muscle tissue, including tryptophan and these different amino acids that will trigger these inflammatory or these negative responses. And so the release of tryptophan and conversion to serotonin. Tryptophan is converted to serotonin actually creates this depressive like state. So, yeah, overall, like, not really a good state.

Jay Feldman  19:12  
Yeah, definitely. And again, if you're trying to look for other ways to increase serotonin, we'll talk about some like, you know, trying to get an infection, chronic social defeat, inescapable shock. We've got lots of options here as different ways we can increase serotonin. So you can do those instead of your fasting. Obviously, we're, as we're getting out with this paper, doing something to increase serotonin probably is not a good idea. And also, fasting has tons of other negatives that we've talked about quite a few times before, and the serotonergic system is intimately involved with the stress response that occurs in general, as we'll get to but also specifically in fasting. And I'll cite a paper in the notes talking about how during fasting, there's an increase in serotonin produced in the gut as well, and this is integral for the increase in lipolysis and gluconeogenesis. Basically an integral part of the stress response and also in driving insulin resistance. And so when they actually block the serotonin production, it improves insulin sensitivity. So yeah, just again, fits perfectly in with all of these things that that we're going through. And so with that, we'll talk about infection here. And so they state infection also triggers depressive symptoms during immune challenge. The 5h i a slash or the 5h i A to 5h t ratio is elevated in the hypothalamus and remains elevated while the organism is sick. The same ratio is elevated in the hippocampus as well. By themselves, pyrogenic cytokines also increase serotonin, serotonin transmission. And these are, you know, like the interleukins, TNF alpha, basically all of the things that are involved with inflammation. In this case, they're talking about it in response to infection. But basically what they're saying is that this is a, a way to trigger depressive symptoms, and B, a way to increase serotonin. And so again, just another piece of evidence that we're talking about here tying serotonin to stress, damage, irritation, basically not good things, the opposite of happiness. And if you are dealing with depression, anxiety, or any other symptoms related to a high serotonin, high stress state, it's important to make sure that you're adjusting your diet in a way to decrease serotonin, and as we'll continue to discuss throughout this paper, the solution for doing so is to increase your energy production and decrease stress. When it comes to creating a diet to do exactly that, there's a lot of conflicting information out there, and that's why I've created the energy balance food guide to help you determine exactly what to eat to maximize your energy production and reduce stress, which also happens to help with improving your digestion and sleep and energy, as well as weight loss and hormones and so much more. The energy balance Food Guide is a one page infographic that organizes foods on a spectrum based on how effectively they support your metabolism, and it also has a separate spectrum that adjusts the scale for you in the case that you're dealing with various digestive symptoms and accounts for, you know, all of the different factors you want to consider if you are dealing with suboptimal gut health. The Food Guide makes it extremely easy to get started with a bioenergetic approach to optimizing your health. So head over to Jay Feldman wellness.com/guide to download your free energy balance Food Guide,

Mike  22:22  
yeah, yeah. And I think, I think it's important to understand why this is happening, right? So when you're under, when you're sick, or when you're inflamed, when you have these things going on in the body, the body is up regulating serotonergic signaling as a way to partition energy utilization, and they'll talk about this later in the paper. So the idea here is that when you have this sickness, your body's like, okay, we need to, we need to reprioritize our energies towards dealing with the sickness or the infection that we have going on, and shut down other areas. And this is what so like, you start to see decrements and reproductive function, growth and repair and cognition during sickness, because those energetic resources are being shifted and shunted towards dealing with the sickness, directly towards dealing with the infection. And this is also the same idea with the starvation and the fasting or even excessive exercise that we've talked about in the past day, with the constrained energy model, where the body has so much energetic resource that it can use on a regular basis, and so it needs to have a bunch of systems in place to shift around those resources, and things like infection and things like starvation and fasting or excessive exercise, and some of the other components that we'll Talk about below will trigger serotonin, and serotonin is basically controlling it, one of the systems involved and controlling this distribution and utilization of energy. So basically, it's like a whole logistical network that's saying, All right, well, we need to, we have this infections like, we really need to figure that out, so we're going to prioritize resources for this infection. And so in these circumstances, like it's happening for a reason, but it that's coming at the cost, like every single stress system of the function of other tissues, right? If you help regulate the hypothalamic pituitary axis, but you also see in all of these states, and then you subsequently down down regulate the thyroid signaling, which you also see in all these states, what happens is you start to break down muscle tissue, you start to impair immune function. In the long run, you start to increase fatty acid oxidation, and then all of these things are like involved with the stress response. And this is also why it's so important to get any latent infections or differing components under control, because even if your diet is pristine and lifestyle is pristine, but you still have this chronic infection, it could be shifting your resources towards dealing with the infection and not allow you to heal in other areas. And so this is, you know, while we have these systems in place to help manage these things in the long run, they do beat up on the system, and they're not ideal to optimize for overall and this. Know, this paper is basically showing, like, look, this is where serotonin is involved in this so, like, it also in other areas, ideally wouldn't be a good thing to prioritize to,

Jay Feldman  25:12  
yeah, and that'll be a huge focus of the paper later on, talking about the relationship between serotonin, the stress systems and energy and as a way to compensate and respond to a stressor, and kind of reorganize and re recalibrate, repartition and response to what's going on environmentally. Yeah. Do you want to go ahead and and share this quote on inescapable shock? Sure.

Mike  25:36  
So just to preface this quote briefly, what they're going to talk about here is inescapable shock, which is a model of inescapable stress, where they basically just keep electrically shocking the rats, and there's nothing they can do about it. So what they say is inescapable shock is a common rodent model of depression, and it increases extracellular serotonin in the medial prefrontal cortex, ventral hippocampus and dorsal periaqueductal Gray, basal, letter basal, lateral amygdala and nucleus accumben accumbens. So I know these are big words. These are all portions of the brain, and they say inescapable shock also increases the activity of serotonergic neurons as indexed by C-FOS expression, suggesting that the increase in extracellular serotonin is caused by an increase in serotonergic transmission. Since the five hydroxy indolecetic acid to five hydroxytryptin ratio is our main index of serotonin transmission, it is perhaps more telling that inescapable shock increases this ratio across many regions, including the locus coeruleus, brain stem, Thalamus, hypothalamus, striatum, frontal cortex and hippocampus. So basically, all they're showing here is that in states of inescapable shock, which, which would be comparable, or that's this is kind of how they would induce a learned helplessness state is characterized by this elevated serotonin level. And the way they're measuring that is through that 5-HIAA to 5-HT ratio. And so again, another circumstance where we're seeing like, pretty negative events, pretty negative environmental factors are strongly triggering increases in brain serotonin levels, which I don't know, I don't know if, like, if I want to really go about increasing my serotonin, if it involves being continuously shocked and developing learned helplessness and things like this. So again, I say that, like it with a with a bit of sarcasm. The general idea here is that pretty significant circumstance, pretty significant negative circumstances, are driving increased serotonin in the brain, and this is not ideal to optimize for. And so, like, just another piece of evidence, another feather in the cap here to say that, you know, we shouldn't be optimizing for centrally increased serotonin levels. And serotonin may not actually be the happiness hormone,

Jay Feldman  27:55  
right? Yep, it's the shock hormone,

Mike  27:58  
the the inescapable shock hormone.

Jay Feldman  28:02  
Yeah. So I'll mention these next two. I'll just kind of fly through the next two because they're they're very similar, yep. So the first one we talk about chronic social defeat states in rats. Chronic social defeat has been found to increase extracellular serotonin in the DRN, as well as 5-HIAA levels in the amygdala and hippocampus and the 5-HIAA to 5-HT ratio in the midbrain and hypothalamus in mice, chronic social defeat has been found to increase the 5-HIAA to 5-HT ratio in the hypothalamus and hippocampus, and then going on to chronic mild stress. They state that in chronic mild stress, serotonin transmission as indexed by 5-HIAA, or the ratio with 5-HT, is elevated in many regions, including the PFC, hypothalamus, hippocampus and amygdala. So again, two other scenarios, and I don't know exactly how they're creating the chronic social defeat, but in any case, situations that that would produce the opposite of happiness, increased serotonin. We're seeing that pretty clearly here. And there's one other that's that's worth mentioning that I'll let you share real quick, which is looking at using SSRIs in neonates.

Mike  29:14  
Yep. So what they say here is adult rats exposed to SSRIs as neonates show increased serotonin transmission, indexed by the five hydroxyl in the indole acetic acid to five hydroxychlofen ratio in the hypothalamus, and exhibit a depressed behavioral profile. So essentially, if you have rats when they're when they're neonates, when they're young, and you give them SSRIs when they're adults, they actually develop a depressed behavioral profile, so you literally just develop depressed brats. And the reason that this is significant is because SSRIs job is to increase the amount of serotonin inside the synapse. Right It blocks the reuptake of the serotonin by the neuron, so you just get higher serotonergic signaling and. And so the idea here would be that when you have higher acerog signaling as a child or as a neonate, it actually changes the brain chemistry going forward to predispose the individual towards actually an increased depressed profile, at least in what we're seeing in the rats, which again, would be counter to what you would think? You would think that if these rats had higher serotonin when they're younger, then they would be happier rats, and possibly happier across their lifespan, because the general models that higher amounts of serotonin actually increase the happiness or is the happiness hormone. So this flies directly in the face of that pretty significantly, especially in conjunction with the other pieces of evidence that

Jay Feldman  30:43  
we mentioned, right? And this is not inducing any form of stress. It's just manipulating the amount of the extracellular serotonin with the drug. So you can't blame it on, you know, some other aspect of the intervention here. I mean, you could say it's some other effect of the SSRIs, but it's supposed to be the opposite effect anyway. So, you know, they're showing and they see also, they see the increased serotonin transmission alongside the depressive behavioral profile, those two things going hand in hand. And again, we didn't highlight as many the points here talking about the relationship between increased serotonin activity and transmission with depression in animals and humans. We were kind of showing situations where stress increases serotonin production. But throughout this paper, they cite quite a few different examples and lines of evidence, suggesting that we mentioned with with anxiety, but also depression, are states of higher serotonin and higher serotonergic activity. So the next section we'll kind of dig into here is talking about the relationship between serotonin and the serotonergic system and energy balance. And along with that stress, and this is something that, of course, goes far beyond serotonin itself, we talk about the relationship between energy and health. We also talk about how when there is a lack of energy, that is the central thing that triggers stress, which is then a way to deal with the stress at hand, like to deal with the stressor, to deal with whatever we're needing to handle by up regulating our emergency or backup energy production, but at a cost, right? So we're re redistributing our fuel and our energy to handle what is most important in the moment at the cost of long term health. We've talked about this in a number of different scenarios, including the constrained model of energy expenditure from Herman pontzer. And then they talk about a very similar idea here, and they state multicellular organisms are composed of specialized cells with different functions that respond to environmental contingencies, and these responses depend on ATP produced by mitochondria or Glycolysis in the cytosol. Multicellular organisms must therefore coordinate the distribution of important energetic resources, including glucose, fatty acids and amino acids, throughout the organism with regional mitochondrial activity patterns. We propose that the serotonergic system evolved to promote energy regulation, which we define as the coordination of metabolic processes with the distribution and utilization of limited energetic resources to meet adaptive demands. So very similar to what we were just describing is basically that serotonin is involved in this reprioritization, and the main things that tend to be involved on the stress end are things like cortisol, adrenaline and glucagon, and we see their impact on the opposite end, the kind of high metabolism, low stress end, which would be the thyroid hormones and reproductive hormones, and these, both of these systems kind of work in opposition. And what we're seeing, and we'll dig into it further, but we've already kind of seen it clearly, is that serotonin tends to be on that stress side. It's a central part of the redistribution from that side of of saying we're not in an optimal environment, we're actually in a pretty stressful, rough environment, a low energy environment, and how do we properly respond to that? And that's where serotonin comes in.

Mike  33:57  
Yeah. I think the value of this, this model that they're discussing here is the centrality of energy metabolism in understanding serotonin. And I think the problem with some of the serotonin research, like even as I've tried to go through it in the past, is that there's not really a unifying understanding of serotonin that allows you to start to parse it across different contexts, because you're always looking at serotonin. And the general theme of the research is serotonin good, which is extremely simplistic, like extremely simplistic, and not helpful to understand things in any way. Whereas this model starts to put serotonin as a central regulator in energy metabolism and and the redistribution and utilization of resources, and then it allows you to understand that in different contexts. So are you extremely stressed? Are you sick? Are you you know? Are you dealing with starvation and the. And basically in these different circumstances, you could say, oh, these under these circumstances, and serotonin is jaw. Its job is to redistribute resources in this type of way, which the researchers talk about a little bit early on in the paper. They kind of give a table where you see the different different effects, the different symptoms in the different models, and that can kind of be explained by the serotonergic signaling. So this, it's this model ties in also really well with the bioenergetic perspective, where we look at the stress systems and we look at the energy systems and the sex steroid systems and all of these different components. Through this lens of energy metabolism and redistribution of resources, you get this nice, unifying lens and comprehensive perspective that allows you to actually understand these things in context, whereas the traditional research and models for serotonin don't actually provide any useful lens to understand things. It's just these reductionistic pathways relying on indirect markers and indirect metabolites with drugs, and so that's like you get like this really like, like piecemeal, uh, perspective, whereas this is starting to unify everything together and making it central around the idea that in these different states, serotonin is shifting metabolism to help you manage or cope with these external circumstances. And I think it also is helpful, because it like, say, for example, I have clients, many clients, who are dealing with depressive symptoms or extreme anxiety, and it's coming out of either life events or doing the low carb or the fasting and the chronic exercise stuff, or having, like, chronic infections and metabolic dysregulation. And it's like, the symptoms that they're experiencing isn't just all in their head. It is a function of serotonin. It's a function of what serotonin does in the brain and across the whole body. And it's like, so if you are ruminating, if you are if you are feeling like you have no energy to do anything. It's like, yeah, that is, that is serotonin. You are shifting your resources towards thinking through things and ruminating on them and focusing on them. And you're that's not You're not having the resources for your reproductive hormone. Testosterone could be low. Estradiol and progesterone in the cycle can be off, and you're just stuck in like you're tired, you don't have energy to go do these components. Like, yes, your body is under this stress state and redistributing through the serotonergic signaling. It's creating these depressive, ruminating, anxiety type symptoms. And this also gives you pathways to be like, Okay, if I can, I can help kick somebody out of the hole, because I can start to say, Okay, we need to get the stress systems down, so the hypothalamic pituitary axis down. We need to get the serotonergic signaling down. And so like, what are all the ways that I can actually do this, through diet, through supplements, through if you're using hormones or medications, through lifestyle interventions, you can start to kick this person out of the hole. And because now you actually have a tangible mechanism to say, like, Oh, this is why this is happening instead of it. Oh, it's just all in your head, or where you go to the doctor and you have all these problems. Oh, you're just stressed. And then there's like, there's okay, I'm stressed, but like, what do I do about that? And it's like, well, I don't know. You just like, you know, go get a massage and do some yoga. It's like, that doesn't solve these specific problems. If you once you specifically identify the issue and understand it, then you have options, or you can start to figure out options to treat it. But if you don't have it because your models are not good, then you're you kind of get left in this place. Was like, Oh, I don't really know how to solve this. And that's why understanding this perspective and having this lens is so helpful to start solving these problems,

Jay Feldman  38:42  
right? Definitely, and, and as we'll kind of get to, when they talk about some of these things, and kind of go through the solutions, they kind of have it backward. And we'll talk about how, in terms of the relationship between energy and serotonin, how we can kind of manipulate that, so to speak, or just improve our our metabolic health, in order to head in the direction of reversing this sort of state. So to kind of move on here and talk about that, and we'll kind of get into this relationship with energy. Do you want to share this next quote? Sure,

Mike  39:16  
so they say here, based on the on the foregoings based on everything before we propose that the homeostatic equilibrium level serotonin transmission increases in situations that require shift in the balance of metabolically expensive processes to adaptively respond to environmental contingencies. So basically, all they're saying is that when you have circumstances where you have to shift metabolic sub resources around, right? So I guess a good analogy for this is if you have a country, so say, like the United States, and you have a big hurricane, like Hurricane Katrina, and it wipes out a whole portion of the south and New Orleans. And everything going on, then you need serotonin is kind of like this emergency system that kicks in and says, Hey, we need to redistribute and divert a lot of resources to these specific areas at the expense of these other areas to help solve this problem. So serotonin isn't is like, kind of like, that command molecule that's involved in shifting all these things around, and so it's released is saying, like, hey, we have a problem. Let's lower reproduction, let's lower cognition, let's lower energy activity levels, and let's improve, like, increase immune signaling, and let's increase rumination and analytical thought processes so that you can kind of gear things depending on the circumstance, whether it's sickness, whether it's social defeat, whether it's what's it called a chronic like learned helplessness type stress, you can kind of deal with these circumstances. So that's all this quote is saying here,

Jay Feldman  40:58  
right? And that and connecting now with what's going on earlier is that is a piece of the kind of depression experience, right? Is it is that is a also a part of this redistrict, redistribution of of resources. So, yeah, I'll kind of go through some of these next quotes, expanding on this a little further. So they state, indeed, elevated serotonin levels during exercise are associated with fatigue, an indicator of energetic stress. We suggest that serotonin is elevated during exercise because the fall in glycogen forces a reprioritization in energy allocation during recovery, serotonin levels fall as glycogen is replenished and allocation pattern patterns normalize. So one of the main things, whether we're talking low carb fasting, or, you know, caloric restriction, or, in this case, exercise, one of the main things that mediates the stress is a lack of fuel, right? That fuel is being used or there's not enough coming in. And as that happens, we see an increase in the stress systems to help, basically, as they say, with reprioritization in terms of energy allocation, where we need to make sure that we are producing and releasing enough energy or enough fuel, and in the right places in order to deal with whatever's, whatever we're being faced with. In this case, it's it's exercise, driving that, that stress. And then we see the exact opposite relationship, where as you recover, as glycogen levels increase, basically as you are no longer in this stress state, this low energy state, the serotonin starts to go down. And we see that very clearly here when with exercise and, you know, as we're talking about in a number of other situations, Yep,

Mike  42:35  
yeah. I mean, that was, we've talked about this before, the central fatigue hypothesis. And that was, that was the central fatigue hypothesis. Like the mechanistic component, was the idea that you would just get more tryptophan in the brain as you kind of depleted some of the larger amino acids that would normally compete. But this is actually changing it a little bit, because it's saying, no, it's actually related to, like, an energetic shift from exercise, right from the depleting energetic resources. So that's an interesting shift. And again, trying to put things through this energy lens,

Jay Feldman  43:09  
yeah, yeah, exactly. And kind of continuing on the energy lens, they start to dig into SSRIs and the relationship with energy production and show some pretty remarkable effects of SSRIs in terms of our metabolism. Do you want to start with sharing that one? Mike, sure

Mike  43:27  
they say the increase in extracellular cellular serotonin causes corresponding disruption to energy homeostasis, and rodents, acute SSRI treatment has been shown to increase glutaminergic activity in the rodent prefrontal cortex, promote glycolytic activity in the hippocampus, inhibit oxidative phosphorylation in liver and brain mitochondria, and inhibit the consumption of blood borne glucose throughout the brain. So this is actually really whoops

Jay Feldman  43:56  
what I was just saying, like the usage of the effects of serotonin, like, you know, sorry, we're just blocking your, your mitochondrial respiration,

Mike  44:06  
yeah. And I think the the thing that's nice about this, this paper, is that, again, there's been this discrepancy in some of the research, where what they talk about and say is that peripheral serotonin is like the the the hibernation hormone, right? The torpor hormone, and it's the break on metabolism. In some of the papers, that's how they describe it, well, but Central is like, really, the happiness hormone? And what this paper is pulling together is showing is like, no, it's still not the happiness hormone, like, it's still directly impairing energy metabolism. And what you're seeing here is serotonergic signaling across the Brainer from from the SSRIs is actually lowering the the the energy production in the liver and brain mitochondria, and actually impairing the utilization of glucose throughout the brain, which is not ideal. That's highly problematic considering glucose in most circumstances is the ideal and primary substrate that the brain is using on a regular basis. And I say in most because in others, like in other circumstances, you can have ketogenesis or ketones, but they still wouldn't make up the majority of or they still wouldn't make up the entirety of glucose utilization. You would, you would still have glucose utilization in those states. So blocking that in general is problematic. And something to consider here is that in states of dementia and Alzheimer's, what you may see is a lowering of glucose utilization across the brain and a lowering of metabolic function. So I'd be curious if serotonin and elevated serotonergic signaling was directly involved in some of these neurodegenerative states through inhibiting the utilization of substrate through the brain. I'll just put that in there as kind of like a little tangential sidebar,

Jay Feldman  45:52  
sure, sure. And it's worth mentioning that even if you had ketones, it wouldn't circumvent this, because they talk about it not only inhibiting glucose utilization, but also just general oxidative phosphorylation in the mitochondria, in the in the brain. So you'd still have issues utilizing ketones in any case. And it's also, they also mention it in the liver. So it's not just something that's that's affecting the nervous system here, when you're using the SSRIs and seeing the increase in serotonergic activity, and we talk all the time about things that impair glucose utilization, things that impair mitochondrial respiration, how this is the central issue when it comes to our health. And we talk about how that is what causes insulin resistance. Like that basically, is insulin resistance? Well, here we see serotonin as one of the primary things implicated in that, one of the many things that can inhibit energy production, which pretty much anything in the stress pathways does, right when we're talking adrenaline, cortisol, you know, we've and glucagon. We've referred to some studies in the past, or gone through some studies where, you know, short term, you'll increase, you'll increase energy production in response to the stress, but long term, it'll be directly or pretty substantially impaired. And basically we're seeing that here, where you're seeing a dramatic impairment in efficient mitochondrial respiration as a result of the the stress hormone serotonin. Basically, yep. So in this next quote, they talk a little bit about how SSRIs can lead to symptom reduction. They aren't particularly effective in general. So the amount of symptom reduction obviously isn't that that dramatic, but they can reduce symptoms, of course, in some cases, and they talk about why that is. And as we just, as they just pointed out, initially, serotonin dramatically impairs respiration, but then there's a compensatory effect, which is what they're saying is basically responsible for the any positive effects from the SSRIs. So they state, we hypothesized that it's the brain's compensatory responses to SSRI treatment, rather than the direct pharmacological properties of SSRIs, that are responsible for reducing depressive symptoms. And I'll go on and state the next quote, where they state, we propose that the brain is attempting to restore energy homeostasis, rather than serotonin homeostasis, the return of extracellular serotonin to equilibrium conditions is only one component of the homeostatic response to the energy dysregulation caused by SSRI treatment. So we just talked a bit about the energy dysregulation, the impairment in oxidative phosphorylation and energy production, and that causes a compensatory response that is then going to be responsible for reducing the depressive symptoms, which they talk about in the in the next quote here, if you want to jump to that, to that one, Mike, sure,

Mike  48:32  
they say the acute effects of SSRI treatment disrupt energy homeostasis by exacerbating glutaminergic activity in the frontal brain regions which, according to the glutamate the glutamate hypothesis, should worsen symptoms. The brain develops compensatory responses over chronic treatment that reverse the energy disruptions and reduce symptoms. Specifically, both the reduction in the synthesis of serotonin and the tonic activation of the 5-HT1A recept hetero receptor act to reverse the elevated glutaminergic activity induced by the direct effects of Sri treatment. If the 5-HT1A hetero receptor is still activated as extracellular serotonin returns the baseline over chronic treatment, glutam, glutaminergic activity would fall below equilibrium conditions producing the actual antidepressant effect. We therefore explain the symptoms, reducing the symptom, reducing effects of antidepressant medications, as do the brain's attempt to restore energy homeostasis. Homeostasis alterations to the serotonergic system are needed to accomplish this. But these alterations cannot all all be explained in terms of restoring serotonin homeostasis. So basically, what they're saying is chronic treatment of with SSRIs actually increases serotonergic signaling, and through this serotonin receptor, the 5-HT1A receptor, actually worsens the amount of glutamate that's produced in the in the frontal brain regions. And glutamate is an excitatory neurotransmitter with high amounts being. Actually destructive and damaging to the brain and creating oxidative stress in the brain tissue. And so what's happening over time is, when you chronically hit this pathway, you pushing out all the serotonin because the synapse can't take it back. It alters this balance in the gluminergic system through that 5-HT1A receptor, at least, is what they're hypothesizing. And then what winds up happening is, after a period of time, and this is what we see with SSRIs, is after a number of weeks, maybe a month, you start to see that glutaminergic signaling should actually start to decrease, and symptoms should improve through the brain trying to manage this effect, right? So it's like this overload effect of serotonin and glutaminergic signaling, and the brain compensatory, lowers the serotonergic and glutaminergic signaling over a month period of time as it adjusts to the simulation. And this is what they're saying. Why there's this initial response, it actually worsens people's symptoms, at least anecdotally, was with the serotonergic drugs, the SSRIs, and over the long term, it actually improves symptoms, and this is mainly due through the brain trying to deal with this increased stress response. And to be fair, I don't think this is actually the best way to go about solving this problem, right? It's you're creating a problem for a short period of time to basically, like, dysregulate to a large extent, this system and to lower the glutamineergic signaling. I feel like there's definitely a better way where you just directly start to either affect the external factors that are driving this and treat it from its core, right? So if you have an infection, like, treat the infection, treat the sickness, or treat the external event, or shift what's going on with energy metabolism and and then see the the serotonerging gloom. Energy Systems regulate from there, rather than try to like, like stronghold strong arm them down through overloading the brain's serotonergic signaling, which obviously is not ideal, considering what we've been talking about with the serotonergic signaling effect on on energy metabolism the brain, and not to mention that the SSRIs also increased peripheral serotonergic signaling, which at this point we know is problematic, like it's not a good thing, and that's why I think we see a variety of really crappy side effects with these drugs, including weight gain, insomnia, anxiety in some people, etc, and long term negative effects of these drugs as well, right? There's a on the rape forum, Georgie at one point, like, went through, like, tons and tons of studies showing all the negative effects of serotonergic drugs over the long term, outside of just what it does on the on the brain?

Jay Feldman  52:42  
Yeah, definitely. And, and just to clarify also, we're not saying that you're not depressed. You just have an infection, like it's it's there. There's a constellation of factors that will go into affecting our capacity for energy production and will be related to increased stress activity. And what we're basically getting at is that this is a state of low energy, low energy in the brain, low energy systemically, brought on by an elevated stress system, brought on by elevated serotonin. Like those things all go hand in hand, and that's really at the crux, or the core, of what's driving things like depression and anxiety. And there can be a ton of factors. There can be environmental ones. There can be psychological disturbances. There can be like, you know, stressful events, like all sorts of things that can go into that and just and lead to the stress or contribute to the stress. There can also be poor nutrition and a lack of sunlight and movement and things like that, which also contribute to increased stress and a reduced energy production. So there's a lot of factors that can go into that. Of course, here they're citing some of the examples of what they do and are not here, but prior, they're talking about in rats how they'll create a depressive state by things like inescapable shock. Of course, for the for the average person, that's not what's driving their depression, at least I hope not. But you know, just again, to kind of cap off this, this quote in this section here, they're basically saying that initially, yes, there's this increase in serotonin. It causes stress in the nervous system. It disrupts energy production, and then the brain compensates and actually lowers serotonin synthesis. So there's actually a reduction in serotonin in the chronic use of SSRIs, and they talk about that throughout this section. And then there's also some regulation that goes on in terms of the glutamatergic activity to reduce the effects there, and both of those being things that are important, because those are both glutamate and serotonin, are both part of the stress system, as we were saying. And so the brain reducing those is what's actually responsible for the benefits, as you were saying. This is generally not the best way to do that, right? The best way to lower serotonin and lower glutamatergic activity is not by taking something that will increase them and then causing a compensatory response that's basically asking for something that will work for a while, along with side effects that. You were alluding to with the peripheral serotonin and everything. But then, long term, will typically lead to other issues, right? We're not actually getting at what led to the problem in the first place and what led to in this, you know, in most cases, like an increase in something like serotonin in the first place. So, and they, they get into that in these next quotes, and they talk about kind of, what I would say is, like a reverse causality, like they're what they're blaming on as the cause here, I think is, is the opposite of what's of what the actual problem is. So what they state is that in melancholia, and remember, this is the kind of most common presentation of depression, the symptoms reflect a trade off in which energy is reallocated toward cognition at the expense of growth and reproduction. We suggest that the elevation in serotonin transmission coordinates this trade off and helps explain many of the symptoms of melancholia. I'm going to share these next two quotes as well, because I think they're going into the same idea. So this next one, they state the fact that melancholia is highly associated with sustained activation of the HPA axis indicates that melancholia is energetically expensive. One may wonder what this energy is used for, since growth and sexual activity are general, generally inhibited. And then they go on to say another clue that melancholia is energetically expensive is the fact that it is supported by glycolysis. Rodent models of depression show increased expression of glycolytic genes and an increase in glycolytic metabolism. And so what they're kind of saying is that there is depression or melancholia first, and that is energetically expensive, and that is why you see something like increased serotonin and all these other effects, and you see something like the HPA Axis dysfunction or overactivity. And what we're saying is basically, it's the opposite, that the lack of energy and stress is what is driving melancholia. And when you see something like increased glycolytic activity, that is not like, just something that is increased, you know, that requires a high amount of energy, that is stress metabolism right there, that is glucose to lactate, like, that's the most inefficient way we can produce produce energy. And so what we're basically seeing here is that, at least in this presentation of depression that they're discussing, that there is increased HPA Axis activity and reduced efficient energy production and a reliance on glycolysis. And I would say that's actually what is driving the state, that is also driving the increased serotonin activity, and it is also driving the kind of reallocation, reallocation that they describe in terms of the stress effects here the role of serotonin, but that is the central piece, is that there's a lack of energy, or impaired energy production underlying that state that's driving that State, and that's where we want to put our focus. Our focus when it comes to solutions,

Mike  57:44  
yep. And I think it's important to to highlight here specifically what stress actually is. Because I think a lot of people think, Oh, it's just, you know, I, you know, I have to work a lot, or, or I'm, you know, I didn't sleep well, or whatever the different component is but I think if we boil down stress to the idea that it's a mismatch between energy supply and energy demand, where you either have an excessive energy demand, that could be that you didn't sleep well, it could be that you are excessively exercising. It could be that you're fat, that you are dealing with some external event, loss of a loved one, a divorce that's taking a lot of psychological energy or emotional energy. It could be that you are, you know, you're in a work situation where you have to put in tons and tons of hours, and you don't get breaks or time to relax, or things like this. So those are all increased demand states, but you also have a decreased supply state, where you have fasting, where you have starvation, and these different components that will all drive the stress state. And when, if you understand stress through that lens, and you graph this, this hypothesis around serotonin on top, where you understand that serotonin is responding to the energetic state of the individual, and then is dry is being upregulated in states where there's a pretty large energetic mismatch, in conjunction with the hypothalamic pituitary axis, which Its job is to regulate energetic supply and energetic demand. To a large extent, what you're basically seeing is that you know, when you understand that they're there, you can say, Oh, this makes sense. Why all these different states will increase serotonin and create these depressive symptoms, because it's all around the energy supply. It's the central piece here is what's the supply? What's the demand? And also, when you see people who are dealing with something like obesity and like the weight, they're like, Oh, well, why is there? Why are they depressed? Why are they having some of these symptoms? It's like because even though they have a we have to delineate here, they have a great fuel supply. They have a poor energy supply. And this also could explain partly why people gain a ton of weight when they use some of these SSRI drugs, or why serotonin is involved in Tor. Hibernation pretty directly, is that it's controlling the conversion and utilization of fuel into energy. And so it's this. This piece is central. And so I think understanding stress through that lens and in a grafting this, this serotonin definition on here is like helps to put a lot of pieces together, and then you can start to integrate the hypothalamic pituitary adrenal axis, the hypothalamic pituitary thyroid axis, the hypothalamic pituitary gonadal axis for the testicles and the ovaries. And you start to see how all of these hormonal systems actually overlap and interact with each other. Instead of seeing them in these separate reductionistic senses, you start to see, oh, they're actually all integrated. And the central piece that they're all revolving around is energy metabolism and energy supply, not fuel, per se, but energy.

Jay Feldman  1:00:53  
And the part that you're highlighting there is that, that in order to create energy from the fuel that's coming in, there are a lot of things that have to happen. There are a lot of steps from the absorption of that fuel to then the conversion of that fuel to actual usable ATP, and everything from nutrient deficiencies to stress and serotonin to endotoxin to heavy metals, you know, all sorts of different things will impair that process. So we can't just assume that the fuel coming in equals energy, and that's a something that we talk a lot when it comes to calories in, calories out, you know, and issues with that, with that perspective, yep. So do you want to go ahead and share this, this quote, as far as some of their conclusions to round this out so

Mike  1:01:37  
they conclude. Here they start their opening conclusions with the reigning paradigm conceptualizes depression as a state of reduced serotonin transmission, right? So that's the generally accepted perspective. In this paper, we have reviewed a large body of evidence indicating that the opposite appears to be true, where the depressive phenotypes we have considered sickness behavior, starvation, depression and melancholia, serotonin transmission to multiple brain regions appears to be elevated. So basically, first things first, these stress states, these depressed states, are actually a function of elevated serotonin.

Jay Feldman  1:02:13  
Yeah, yep, exactly. And again, flipping the that narrative on its head, that, uh, that these are states of a lack of serotonin, and then tying it back with energy and also cortisol, which I which I like that they mentioned specifically here, where they state. In addition to serotonin, melancholia involves the heightened sustained secretion of cortisol. Serotonin and cortisol both affect aerobic glycolysis and oxidative phosphorylation, and as we've seen throughout this paper, very similar to our previous paper that we went through, talking about mitochondria as key components of the stress response, talking about, or that's the title of it, talking about the impact of stress and the stress hormones on mitochondrial respiration. We talked about how these hormones and serotonin fits right in here, are produced when there's an energy deficit, and basically activate all the emergency pathways to produce energy, which we need to do in that moment, but it comes at a long term cost. You know, in this case, we're talking about serotonin is basically a hibernation hormone taking resources away from elsewhere for those immediate energy demands. Cortisol is also an integral part of that same process. And again, short term stimulation and kind of forced energy production that is stress induced, and normally long term, we would see a severe reduction in in our metabolic rate, a severe reduction in the efficiency with which we produce energy with chronic cortisol secretion, or chronic cortisol exposure, as well as chronic serotonin exposure,

Mike  1:03:41  
Yep, yeah, I think the again, the the energy metabolism piece being central is key with this paper, and helping to integrate serotonin in with the other hormonal systems. So bringing the HP axis is also important, but in a broader sense, we can bring in all of the other accesses and hormonal components as well, even things like leptin and ghrelin and adiponectin and GLP, the GLP and the gut based hormones. You're basically seeing it's all around fuel and energy metabolism, and so I mean, in my mind, as I go through this stuff, I'm starting to paint the picture with all of these pieces integrated, instead of the current medical model. Just like we have this singular pathway that exists in space, not attached to anything else, like, here's just one node that's not attached to anything, and then here's his other node. So it's like a bunch of it's like Jeopardy, right? It's like trivia, disjointed facts where that nothing is integrated. Yeah, it's like, when you you want to have some type of integrating piece, and this is this paper brings in the energy metabolism piece, and then you can start to really understand these other components and actually have a lens with which you, like, are able to work through paradoxes and, like, eliminate them, right? Because there really is no paradox. There's just, like, a lack of integration and understanding at that point. One in time. And so, like, having a unifying piece that's, you know, also correct is extremely important.

Jay Feldman  1:05:06  
Yeah, yeah, no, you're right. And, and I think that's, I mean, that's why we wanted to highlight this paper, right? Is to fit serotonin into that picture. And as you said, that's, you know, whether we're looking at a disease process. You mentioned neurodegenerative diseases. Of course, we've talked about mental health disorders like depression and anxiety, but we've also gone through all sorts of different chronic health issues, from autoimmune diseases to fatty liver disease to hormonal issues on the female side, on the male side, gut issues, all of these things are working through these same pathways, right? It's all under this larger umbrella of our body, sensing how favorable or disfavorable their environments are, and then responding accordingly and compensating for suboptimal environments by producing more body fat, or by turning down reproduction, or by turning down gut function or thyroid activity or detoxification pathways, or cognitive, you know, capacities, that's that's what it all boils down to. And so, as you're saying, this is a perfect example of that, a perfect example of taking this individual neurotransmitter, hormone of serotonin, and fitting it in to this larger picture of metabolism and energy balance. Yep, yep, awesome. Mike. Can you share with the listeners where they can find more of your work?

Mike  1:06:35  
Yeah? So they can find me at my YouTube channel, Mike fave, and they can also find me on my website. Mikefave.com

Jay Feldman  1:06:44  
Perfect. All right, if you did enjoy today's episode, please leave a like or comment. If you're watching on YouTube and if you're listening elsewhere, please leave a review or five star rating. All of those things really do a lot to help support the podcast, and are very much appreciated as always. To check out the show notes for today's episode, where you can take a look at the studies and articles and anything else that we referenced. You can head over to Jay Feldman wellness.com/podcast, and if you are dealing with depression, anxiety or any other high serotonin state, as we discussed, it's basically anything that involves stress. There are a lot of factors to consider that could be contributing everything from our gut health, which is a major driver of serotonin production, to sleep, to hormones, all of those things can lead to a low energy, high stress, high serotonin state. And I go over how to optimize all of these things in the energy balance solution program so that you can maximize your energy, improve your mood, lose weight, improve digestion, get amazing sleep, rebalance your hormones and so much more. The program includes career action steps and strategies, along with personalized guidance from me. And you can check out all the details at Jay Feldman wellness.com/solution, the program includes customized health coaching, a video library on all those you know, including videos on all those topics that I mentioned, as well as resources like the sample meal plan and supplement guide and also a private community so again, you can head over to Jay Feldman wellness.com/solution, to check out all the details with that I'll see on the next episode. You.