GLP-1 Meds & Positive Psychiatry - A Deep Science Dive For Clinicians

GLP-1 medications are everywhere right now, but the most important conversation might be the one we are not having loudly enough: what do GLP-1 receptor agonists do to the brain? I go full geek mode on the neurobiology behind incretin mimetics and why semaglutide and tirzepatide may end up mattering to psychiatry as much as they matter to endocrinology.

We start with anatomy and access. Endogenous GLP-1 is produced in the gut, but it is also produced by neurons in the brainstem and projected into regions that shape mood, anxiety, memory, and reward. From there, we explore how exogenous GLP-1 drugs can influence the central nervous system through selective blood-brain barrier entry points and vagal afferent pathways, and why receptor “real estate” in the hippocampus, amygdala, VTA, and nucleus accumbens changes the clinical story.

Then we dive into mechanisms that matter for positive psychiatry: intracellular signaling (cAMP, kinases, CREB), neurotrophic support through BDNF, and the promise of neuroplasticity as more than a buzzword. We also unpack neuroinflammation and microglia, including how GLP-1 signaling may suppress inflammatory cascades, reduce oxidative stress, and create conditions where cognition and emotional regulation can recover. Finally, we connect GLP-1 to “food noise,” maladaptive salience, and dopamine spiking, highlighting how better top-down executive control could translate into real-world agency without blunting joy in most individuals.

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Transcript

Why GLP-1 Matters In Psychiatry

Rakesh Jain, MD, MPH 0:07

What role do GLP1 medications play in psychiatry? And the question is, what role do they really play in positive psychiatry? Hmm. That is going to be the question we're going to explore today. Hello dear friends, this is Rakesh Jayan and welcome to this podcast on positive psychiatry. And today, let me offer you a caution before we go any further. This is going to be a deeply geeky, highly scientific conversation about the role of GLP1 medications in psychiatry, particularly positive psychiatry. But in some ways, this kind of geekiness, this kind of focus on the scientific principles of GLP1 medications, I think the time is right. These medications potentially are going to revolutionize not just medicine, but really revolutionize psychiatry. So I thought we really should dive into the neurobiology of how these incretin mimetics, that's the technical word for them, incretin mimetics, could potentially change the face of psychiatry. So for the past decade or so, the medical narrative around these incretin mimetics, or we generally call them GLP1 receptor agonists, just remember GLP1 is just one of the many incretins we have. Just one of them. Sure, probably the most important, but just one of them. And we're going to learn how to utilize a number of incretins to help our patients. But the question really is: how can they be of any importance in psychiatry? I thought they were all about diabetes, all about weight loss. We've looked at the pancreas, we've looked at the hemoglobin A1C, we talked about gastrointestinal motility. We've even seen, you know, reversal of weight challenges, of cardiac issues, even the data that cancer risk is reduced when people are on incretins. But for us, the clinicians, the researchers committed to the principles of positive psychiatry, we're going to have to ask a different set of questions because we have to look higher. When I say higher, I'm talking about the central nervous system. We're going to have to talk about how these medications cross the boundaries of mere local metabolism and explore the complex architecture of the central nervous system as it pertains to these incretin mimetics. Will you do me a favor and remember that word, incretin, I-N-C-R-E-T-I-N? Because for the next several decades to come, psychiatry will be using that word a lot. So we're going to shift our motivation. We're going to talk about how depression and anxiety and cognitive clarity, are these just things that are byproducts of the weight loss that patients have? Is that why they improve? Or is this a more direct result, perhaps a molecular dialogue that that takes place in the critical, critical parts of the human brain? So we're going to dive deep into the compelling non-fluff scientific evidence. And I will provide you with evidence that GLP1 receptor agonists are not just metabolic tools. They are in fact potent neurotrophic and neuroprotective molecules. And the exact biological pillars are in fact pretty well articulated, but it'll require us to better understand the neuroscience here. We need to start talking about how does a medication like a GLP1 agonist improve resilience? Because it does. And could it have a role in improving flourishing? And that's of course where positive psychiatry gets very interested. But you know, first things first, right? We have to establish the baseline anatomy. The anatomy, the neuroanatomy, the neurophysiology, and the neurochemistry of these medications. So buckle up, folks. Let's go.

Endogenous GLP-1 And Brain Pathways

Rakesh Jain, MD, MPH 5:00

So the endogenous GLP1 peptide, please remember, we have it. All of us have it. So the endogenous GLP1 we have is a product of a particular gene expression in the human DNA. It's actually called the pre-proglucagon gene. And peripherally, out in the body, it is secreted by the intestinal cells in the human small intestine. These cells are called the L cells. And the L cells, when they detect nutrition arriving, guess what? It starts the production of this particular substance that we call GLP1. But I want you to know this that even in the human brain, not just in the human small intestine, but the human brain, we have a discrete number of neurons. I'll tell you what it is in just a second. But those neurons actually also secrete GLP1, peptide. It's not just in the human body, but also in the human brain. Where do these neurons live? Well, they live in a particular part of our lower part of our brain called the medulla oblongata, right? It's just above the spinal column, medulla oblongata. Let's just call it the medella. In the medella, there's a group of neurons that are called the nucleus of the solitary tract. Nucleus of the solitary tract, or let's just call it NST for short. In the technical literature, NST is how it's typically referred to. Well, from these neurons that live in the NST, these GLP1 producing neurons now project widely through the entire brain. Where are they going? Well, they go to the hypothalamus. They go to the amygdala, even the hippocampus. And guess what? They go to the mesolimbic reward circuits. And each of these organs that I just mentioned, if you're in the world of psychiatry, it immediately got your attention, didn't it? Hypothalamus, amygdala, hippocampus, mesolimbic reward circuits. Yes, because this is exactly where mood lives, both normal and abnormal. Anxiety lives. This is also where addictions live. And quite interestingly, these are also central stations for positive psychiatry. But what about outside delivered GLP1 agonists, or let's just call them exogenous long-acting agents like semaglutide or terzepatide?

How GLP-1 Drugs Reach The Brain

Rakesh Jain, MD, MPH 8:00

These are the generic names for medications that are household names now. Ozempeg, GOV, right? These are names we have heard so much about Monjaro, Zebbount. You could literally go to any park in America and say these words, and half the people will know exactly what you mean. So how do these peripherally injected or orally administered medications come into the central nervous system? Because as you know, both of these classes of medications, these semaglutides in particular, we have ways of delivering it orally, just with a daily medication. How does that work now? Well, these exogenous medications, exogenous of course, means you know this well, from the outside, when these come into the body, they are able to somewhat cross the blood-brain barrier, but only at certain critical entry points, not everywhere. So they pass through the brainstem and the what's called the circumventricular organs, where the barrier is leakier and highly vascularized. So the systemic GLP1 receptor agonists engage in a sensory afferent pathway. So these are pathways that go into the brain. They stimulate the vagal afferent fibers that transmit signals directly to the brainstem. Excuse me. So we have not just a peripheral signal, but a peripheral signal that knocks on the door of the brain. And interestingly, the drone act, the brain actually cracks open the door for these medications to come into the brain. Now, this is why we want to map the density of the GLP1 receptors in the human brain. And what we find is there's an extraordinary alignment with the structures that are part of psychiatric pathology. There's an overlap. GLP1 receptors are located in all those regions. Can we dive into it a little bit further? So, folks, when we start looking at the brain to see where exactly these receptors are located, we find them in one of the most extraordinary places of the hippocampus. And that are the pyramidal cells, the pyramidal neurons. And they're called pyramidal because they're actually kind of large. They're triangular in shape. And they are the seedbed of adult neurogenesis and memory formation. You got that, didn't you? So GLP1 receptors are not just important in the hippocampus, but they are literally on probably the most important cell lines in that part of our brain, the hippocampus, where we adults actually form new cells. We form memories. And we also find them in amygdala. And the amygdala, of course, is the apparatus for threat appraisal. We also find them in the ventral tegmental area called the VTA. Why would I give a flip about it? Because that's where dopamine lives. And nucleus succumbents, why do I care about nuclear succumbents? Because nucleus succumbens is not just where dopamine lives, but also serotonin. Also, that's the one part of the human brain that is most aligned with positive emotion. It is aligned with accurate reward salience. So what the last few years have shown us are that GSP1 receptors have chosen evolutionarily from a development perspective to be in all the right places where mood lives, anxiety lives, reward lives, addiction lives. And how could psychiatry, particularly positive psychiatry, not be interested in such a particularly important receptor? So in positive psychiatry, as you know, our aim is never just to reduce symptoms. Our aim is the activation of growth parameters, the restoration of cognitive reserves, and of course the strengthening of psychological fortitude.

cAMP CREB And BDNF Neuroplasticity

Rakesh Jain, MD, MPH 12:40

So let's do this. Let's kind of think about not just the periphery, but for a second, let's leave the periphery behind. We will descend beneath the surface of the receptor, the GLP1, to examine the exact molecular workings, the signaling pathways. How do GLP1 receptors actually create the action that allows for mental health to improve? So we're going to now enter, we're going to leave the cell surface, and now we're going to go into the cells. We're going to go into the neurons, into the glia cells. So formally, folks, just visualize this. We're entering the intracellular environment. This is where the promise of neuroplasticity transforms from a clinical idea into a reality. So when an agonist binds to that receptor we just talked about, the central GLP1 receptor, by the way, you now know that even medications given peripherally are able to cross into the brain. When that happens, this interaction with that receptor that we've already had, we've had it from the time we were born, it actually leads to a change in the receptor. This is called an conformational change. This leads to the activation or increase in production of stimulatory G proteins. These proteins, when they go up, they kick off a cascade. And what we have is an increase in cyclic AMP. You should really care about this. We all should care about it because cyclic AMP is the currency of the human brain. When you have that in higher amounts, action happens. It's like dollars in your pocket. Action happens when we have money, right? Cells need money too, metaphorically, that's cyclic AMP. Because cyclic AMP kicks off the great factories of the human cells. Those are called protein kinases. And when these get activated, now we have a cascade. We have a cascade of downstream production of proteins, the proteins that are necessary, not just for the control of psychiatric symptoms, but also for the generation of positive emotions. Woof, that was a lot of academic stuff for you and I to digest. But we need to appreciate, don't we, that these medications, these GLP ones, aren't simple weight loss medications, as if that's not important enough. But they really do have a rather important role to play all the way in the very core of the human brain, and therefore have a very important role in the treatment of mental illness, but quite likely in the improvement of mental wellness. So we could keep going, we could keep going into the neurobiology, but maybe what I'll do is I'll just remind you that the Kreb, C-R-E-B, that's a molecular switchboard for synaptic maintenance. And once it's phosphorylated, which literally means it's turned on, it's like a light switch when it's turned on, that kicks off the production of certain peptides that you know well, such as brain-derived neurotrophic factor. It's also known as BDNF. And BDNF has become pretty world-famous now for its importance. And what we know based on post mortem brain studies, and also because of in vivo neuroimaging, that chronic stress, systemic metabolic dysfunction, so having obesity, having diabetes, having hypertension, and including having depression, these deplete both the hippocampus and the prefrontal cortical BDNF. That's right. Now you see the connection, don't you? And this depletion will trigger the cell not dying, but the cell's dendrites, its connections, its branches withering away. And that's a problem. Because while the cell is not dead, the cell is definitely not functioning well. And GLP1 agonists or incretin mimetics, they actually go around this problem. They, in fact, reverse many of the challenges we talked about. So if you think of the conversation we've had in the last five minutes, a GLP1 agonist arrives to the cell. It attaches itself to the GLP1 receptor, which we've had forever since we were born, really. It creates a conformational change, which creates a G protein link change in the cell. Now remember, we have left the cell wall. We have left the outside of the restaurant. We are in the restaurant. We have placed our order, but the real action is the kitchen. The kitchen is where the proteins are made. Your meat, your fish, all that, that's where that's made. And guess what? The same thing happens in the human cell. The trek B is these are kinases, these are activated, and then they signal, they signal the DNA, they signal the RNA, please produce more proteins that we need in order for human health to happen. So this through the lens of positive psychiatry allows us to appreciate that GLP1s are so much more than weight loss medications. Because when we upregulate the BDNF system through the incretin pathway that we just talked about, we're not simply providing repair. We're in fact improving structural density. And that structural density is directly correlated with the health of not just the neurological system, but the psychological system. All right? So neuroplasticity is the ability of the human brain to change itself appropriately when a stressor arrives, and to change itself back to its normal state when the stressor leaves. That's neuroplasticity. It's crucial. It's a crucial trait of human beings. But neuroplasticity cannot thrive in a toxic environment, psychological or even physical. And yes, obesity is indeed

Microglia Neuroinflammation And Oxidative Stress

Rakesh Jain, MD, MPH 19:45

an environment of toxicity. So now we're going to shift our attention from the neuron to the immune system of the brain and explore how GLP1 receptors modulate our other brain cells, which are not neurons, they're glia cells. And particularly we're going to focus on microglia. No, today we won't be focusing that much on astrocytes, which are really important, but on microglia, which are fewer in number, but man, they punch way above the weight class. That's microglia. So let's do this. Let's keep diving into this conversation on GLP1 receptors and positive psychiatry. Neuroinflammation finally has caught the interest and attention of not just the researchers in psychiatry, but also clinicians. And what we unpacked previously was the intracellular signaling of, say, particular neurotransmitters, say, for example, neurotrophins. But what about inflammation? What about, in particular, neuroinflammation? Well, why should we care about neuroinflammation? Well, think about this. While psychiatry has made great strides in helping patients with mood difficulties, we really haven't done very much with, say, for example, cognitive difficulties. We haven't done very much with the structural stagnation that happens in many patients with depression. And it does appear that challenges low-grade neuroinflammation if it's not appropriately treated, particularly when a person faces repeat psychological insults, that leads to these non-neuronal immune cells in the human brain to be overactivated. Now, which are these which are these cells in the human brain that produce inflammation? We thought inflammation was only from the periphery. Those lymphocytes are supposed to do that, those neutrophils are supposed to do that. Well guess what? Microglia in particular, and to some degree astrocytes as a supporting cast in the human central nervous system do the very same thing. They produce inflammation to protect us. But having said that, that inflammation, if it becomes chronic, particularly low-grade chronic, has real problems. So let's talk about microglia, shall we? So microglia, they live right in the human brain. They are close to astrocytes, they're close to neurons, they're often touching them. And did you know that they even can move? They're the only cells in the human central nervous system that actually have mobility. So when microglia transition from their surveying the normal resting state, they become these amoeboid. Let me say that again. Amoeboid. They look actually like amoeba. That's called the pro-inflammatory M1 phenotype. They then reprogram themselves and they become engines of cellular degradation. They intensely secrete pro-inflammatory cytokines. Some of them are actually almost household words in psychiatry, interleukin 1 beta, interleukin 6, tumor necrosis factor alpha or TNF alpha. Now these cytokines, they crosslink to these neurons that we're interested in. The neurons involved with serotonin, norepinephrine, dopamine, acetylcholine, heck, even glutamate, even GABA. So when they are overactivated, the microglia, they can drive cellular aptosis. Another fancy word for saying poor health of our cells. And they can actually cause degradation of glucose transport systems. So what do we do about this? What do we do about it? Well, we should also appreciate that these GLP1 receptors are not just on the human neurons, which we talked about about 10 minutes ago. They're also highly expressed, meaning they're found on both astrocytes and yes, even on microglia throughout the prefrontal cortex. They are there. So when a systemic agonist, that could be my own body producing normal amounts of GLP1, or I take GLP1 medications from the outside, be it a tablet or a weekly injection or whatever that might be, it actually profoundly interrupts the inflammatory cascade. It can directly suppress the activation of the NLRP3 inflamosome. That is a system, it's a multiprotein complex that acts as the master gateway for the processing and release of this interleukin-1 beta. That is a useful substance, but too much is quite honestly too much. It's quite toxic to neuronal health. So what we're seeing, the downstream clinical implications are in fact quite remarkable. When we have inflammation and we have normal amounts of GLP1, either from the human body or delivered from the outside, there is a profound reduction in the microglia M1 specialization. It comes back. It comes back, returns to its more adaptive, repair-oriented nature, which is the M2 phenotype. So we have the M1 phenotype that's an angry, hostile. Appropriately so. Look at microglia, change of the microglia into the M1 subtype. But it is now evident when GLP1 is present, these microglia can change themselves more readily into the M2 phenotype. And the M2 phenotype is anti-inflammatory, a really important thing to remember. Something else that's really interesting with GLP1 medications is that they help seal the barrier and cool the immune tinder box of the human brain, of the cortex in particular. And these agents can, in fact, reduce brain-derived oxidative stress. Because yeah, there's a lot of oxidative stress in individuals who are going through emotional dysregulation. And by doing so, psychological flourishing becomes a real possibility. So, in the lens of positive psychiatry, we're not just reducing inflammation as in number. No, that's not our interest. What we're in fact doing is we're taking off these chemical shackles that neuroinflammation produces and effects on the human brain. And if you take off these chemical shackles of neuroinflammation, more neuroplasticity is allowed in to help the individual and the brain thrive unhindered. So let's now fully engage

Food Noise Dopamine And Executive Control

Rakesh Jain, MD, MPH 27:45

the clinical flourishing. We have to address motivation. We have to examine how the brain has its own appraisal system, reward mechanism. And so we need to now shift our attention with this conversation from neuromodulation to desire. And we're going to come into the mesolimbic circuit and we're going to examine how GLP1 can shift dopamine tone, which can reduce brain noise and restore command and control back to the prefrontal cortex. So now we're going to transition to talk about the mesolimbic cascade. And to do that, we're going to first look at the concept of maladaptive salience. Isn't it true in daily clinical practice, our patients often come to us inundated by a phenomena that we call food noise? Right? Food noise is not just an isolated metabolic trick of the human brain. It's a manifestation of the hyper-responsive nature of the brain's salience pathway. Salience is what one puts importance upon. It can be in many people a constant, aggressive demand by the brain eat, eat, eat. This is plugging of the amygdala stripped reward system. It steals human attention. It takes over our cognitive effort and truly undermines self-directed willpower. This is not just about food, though. In some ways, depressive thoughts, also anxiety. These are loops of thinking. So the neurobiological loop of impulsiveness and compulsive wanting, that's mediated by the ventral tegmental area. We already met that before, right? VTA. And this ventral tegmental area is very heavily dopaminergic. Not only is it dopaminergic, it sends a lot of its signals to nucleus succumbents, which, if you recall from our conversation a few minutes ago, is really the seat of pleasure and joy. So when a patient cognitively is appraising a highly salient, rewarding cue, maybe they are at a bar. Maybe they are at a pizza restaurant. It can trigger an acute spike in dopamine in the nucleosuccumbents even before they have touched the alcohol, even before they have touched the pizza. It is so wild. So what this does, it creates an exaggerated motivational salience to something that hasn't even happened. That's how the brain can react and sometimes abnormally. So this is the mechanistic engine room of anxiety-driven consumption, this compulsive reward seeking and the fragmentation of the person's cognition. So where does GLP1 come into this? Well, this is how the modulatory impact of GLP1 receptor agonism comes right in, because GLP1 receptors are densely found on the dopamine neurons of the VTA. Right? Remember the VTA is where the dopamine is produced and then it's shot out to the rest of the human brain. But then on the gabbergic medium spiny neurons, also in the nucleus succumbens, we also have, we also have GLP1s there. So GLP1s are really interesting receptors. They live not just on the greatest excitatory neuron of the human brain, excitatory neurotransmitter of the human brain, glutamate, and its buddy, dopamine, but they're also found on the greatest inhibitory system in the human brain, which is GABA. Oh my gosh. So when GLP1s come in from the outside, they dampen the amplitude. They tap down that dopamine spike that happens. And as a result of that, the person has more agency to make a decision. Now the decision could still be the wrong decision, but at least they had the chance to think it out and not automatically respond to the nuclear succumbers. This is a really important point for positive psychiatry because we're not trying to completely eliminate all spiking from the dopamine system. That would be terrible. That would induce amotivation, it'll induce apathy. That's not what we want to do. But by regulating this phasic dopamine spiking, what we preserve is the tonic level, the underlying level, which allows someone to have equanimity, joy, happiness, satisfaction. All of those are important things. So we are not trying to help someone lose their capacity for joy. All we want to do with GLP1 is to take away those excess spikes, the spikes that lead to both behavioral and cognitive excesses that lead to challenges. So do we have data to support all these big words that I've been throwing out at you? And the truth is we do. We do. Functional MRI studies reveal a profound functional coupling that occurs when receptor, GLP1 receptor agonists are found at appropriate levels in the human person. The central salience network, that's the, if you the boss brain, the one that guides us and tells us what's right, what's not right, where we should, you know, go do our efforts, where we should avoid doing things. All of that with the presence of a GLP1 receptor agonist comes back online. That is a very positive thing. So what we see is an enhancement of top-down executive command from, as I said, the boss brain. The boss brain, if you want to think about it from an anatomic perspective, is the dorsolateral prefrontal cortex. And this part, when it comes down, allows us to make decisions with our wise mind, with not just gratification in mind, but delayed gratification in mind with executive foresight. And that is brought back online thanks to improvement in the GLP1 tone. So, colleagues, this is the biological embodiment of positive psychiatry in action because we're not just managing behavior, we're optimizing the brain's intrinsic network infrastructure that allows the human mind to move from the constant reactivation management of cravings to the proactive creation of a healthy, self-directed existence. Can we measure this clinically? Sure we can. Sure we can. We can actually map this in Kretin biology directly to objective measures of flourishing and resilience. And maybe we can have a conversation about that right now.

Resilience Flourishing And What Comes Next

Rakesh Jain, MD, MPH 35:40

So how do we connect all that we have learned from a deep neurobiological level to human resilience? How do we do that? Well, the way to do that is to appreciate that in pulsive psychiatry, our targets are no longer depression or anxiety. Those are secondary targets. Primary targets are things like executive agility. Targets are emotional flexibility. Those are different targets, but those targets often lead to improvement in things like major depression or anxiety or addictions. And when you reduce those, obviously what you would see is improvement in mental well-being. But what if GLP ones are direct agents at improving mental wellness? What if they improve cognitive flexibility, not just by reducing depression and anxiety and cravings, but by directly making the brain networks work better? Now that's a pretty general statement, work better. What does that mean? But primarily what I'm referring to is cognitive flexibility, to have the ability, the brain's ability to encounter a stressor and take its time using top-down regulation to make a decision that is most likely in the person's best interests. So resilience is not some kind of mystical event. It is in fact a synaptic imperative. It's a synaptic action and re-regulation of the salience network that we talked about before, the stabilization of that phasic dopamine spiking, that living moment to moment, literally praying at the altar of dopamine, which is a really difficult life to live, really does lead to a deterioration of cognitive tolerance. And by bringing that into control, by harnessing that, which GLP1 medications have now been shown to do so repetitively, and every clinician in the world has seen it, when their patients come back and say, hey, that enslavement I had to my food noise no longer exists, is in fact indirect proof. In fact, it's more than indirect proof, that all of a sudden the person's own cognitive strength, flexibility has returned, thankfully, in a manner that serves the patient better. This is literally watching the biological scaffolding for post-traumatic growth in real time, isn't it? It's witnessing not just emotional re-regulation, not just feeding re-regulation, but also cognitive regulation. That's improved too. But you know what? That's not the limit of a horizon. As these GLP1 receptor agonists are making progress, what we're finding is dual action medications, GLP1 and GIP combination medications, maybe GLP, GIP, and amylase. There's a whole bunch of incretins that appear to have different roles in positive psychiatry that in time, in time, we're going to learn to harness for not just the control of various psychiatric disorders, but in the cause of improving positive psychiatry. All of those are going to be really important to us. And that's why, colleagues, it was so important that we engage in this complex task of better understanding these incretin agonists and how, for psychiatry, they are important. They are as important as they might be to a diabetologist or a cardiologist. So, as we start winding down this conversation, perhaps we should summarize what we have learned together because we talk about a lot of things, pretty heavy stuff actually. Several things come to mind immediately. First is we have to stop believing, stop believing that GLP1 receptors live just in the human body. They definitely do. But the human brain at every single level, anatomic level, but also neuronal level, does have the presence of GLP1 receptors. Number two, this matters to neuronal health. Number three, and really importantly, it matters to glia cell health, such as microglia as well as astrocytes. Number four, neuroinflammation has a deeply important relationship with GLP1 receptors. Number five, I might say, well, oxidative stress in the human brain is something that cannot be taken too lightly, and GLP1s are connected to it. And of course, the last point that is of, I think, extraordinary importance is these are not just solitary actions of GLP1 medications. The very networks of the human brain, the default mode network, the reward salience network, the executive function network, all of them, all of them are better and more effective when a GLP1 medication is found, particularly in an individual who is struggling with challenges directly as a result of the dysfunction of any of these networks. So, yeah, this was a pretty heavy conversation, I think. But I thought it was necessary for those of us who are interested in lifestyle psychiatry and positive psychiatry to appreciate these are not simply weight loss and blood sugar-reducing medications. They literally rework the networks of regulation in the human brain. And of course, once we work those networks out appropriately, it's not just psychiatric disorders that clearly see improvement in their pathology, but we also see the reemergence of flourishing at levels that are much higher than we would have anticipated otherwise. Okay, as we end this conversation, I want to thank you for being part of this podcast, Positive Psychiatry with Rakesh Jan. Please be aware that this is just the opening solvo. We are over the upcoming months and years, perhaps even decades, going to appreciate how these really wildly important medications are essential to how those of us interested in psychiatry and positive psychiatry will be utilizing them to help our patients. Until then, I wish you and your patients the very best and goodbye for now.