Glorious Glutamate - The Spark Behind Mood, Learning, and Positive Psychiatry

Glutamate is everywhere in the brain, but we’ve treated it like an afterthought. Rakesh Jain, MD, MPH joins us with a bold, clinically grounded argument: if we want real progress in depression, PTSD, anxiety, schizophrenia, OCD, addiction, and chronic pain, we have to understand glutamate as the main network driver, not just another neurotransmitter on a list. 

We talk through why glutamate is both essential and dangerous, and why the right model isn’t “raise it” or “lower it,” but regulate it across regions and across time. Rakesh explains the two glutamate patterns that matter for symptoms, the overlooked role of glia and astrocytes, and the dizzying complexity of NMDA and AMPA receptors that makes one-size-fits-all treatment a fantasy. We also connect glutamate to brain circuitry, including default mode network rigidity in depression and the switching role of salience and executive networks. 

Then we get practical and future-facing: what ketamine may be doing (including replicated evidence of opioid involvement), why durability remains a challenge, and why the field is shifting from NMDA to AMPA, mTOR, BDNF, and other neuroplasticity pathways. We explore classic psychedelics as rapid glutamate modulators, the rise of plastogens and biased 5-HT2A agonists, surprising links between GLP-1 agonists and glutamatergic control, and why neuromodulation depends on glutamate signaling. We close with a needed corrective: exercise, mindfulness meditation, sleep, and psychotherapy are not “extras” but powerful glutamate interventions. 

www.JainUplift.com

Transcript

The Case For Glutamate

Rakesh Jain, MD, MPH 0:00

Look at the title I picked. The spark behind the storm and the stillness. I do think we have made the mistake of thinking of glutamate as only useful when we jack it up. And I want to completely shatter that myth because it's a combination of both. So let's go ahead and get started. I think my mouse is not working. Would you kindly help me? So I'm going to tell you this story in seven chapters. This is the disconnected. Would you kindly help me with that? I'm seeing different things here compared to this screen. Okay. See? Glutamate. Imbalance. We gotta work this out. So there are seven reasons why you and I really need to get to know glutamate even better than we perhaps did. The first reason is it is the single most commonly found neurotransmitter in the human cortex and the human midbrain and the spinal column. It's 40% of the entire neurotransmitters that we own. Serotonin is 1%. Glutamate is half. Norepinephrine is one. If you put them together, we have prayed at the wrong altar for almost 70 some years. Two, it's also the single most potent neurotransmitter ever discovered by scientists. Three, it is also the most important neurotransmitter involved in learning cognition and mood ever discovered. Four, it is also the single greatest source of synaptogenesis and neuronal plasticity ever discovered. Five, it is also, interestingly, the greatest creator of GABA, its greatest nemesis. It practices democracy in a way that I've never seen practiced ever before. Six, it is also the single most toxic neurotransmitter ever discovered. Glutamate has paradoxes up and down the chain. And of course, seven, this is shocking. It's only been about 30 years since we thought of it as a neurotransmitter because there's so much in the human brain. The thought was it was not acting as a neurotransmitter. So we're all in the last 30 years trying to catch up with the glutamate sciences. So really the question in some ways is does glutamate now have our attention? It does. It truly does. What do we know about its discovery? What's the evolutionary perspective here? What is this kombu doing here? This is what we use to make soup, miso. That's one of the major ingredients. And the story of glutamate and kombu is tied. A scientist, a chemist actually from Japan, Mr. Aikida, came home, had miso soup, wasn't tasting very good. Asked Mrs. Aikida, what's wrong? She said you forgot to go to the market. You didn't bring home seaweed. Kombu. And said, Oh, just missing that seaweed. Now this tastes flat. Where's the umami? He took the umami to concept next day, went to the market. This is actually a true story. In 1908, took kombu back to his lab to discover what is that substance that is the umami of taste. Glutamate. That's the discovery of glutamate. But this is far more interesting. Glutamate is so much older than any living species. It is so very ancient. Let me just show you how it came about. Big Bang is actually when glutamate got created. Number two, eukaryocytes as they emerged for the first time absorbed glutamate into signaling. In other words, we didn't make glutamate, glutamate made us. Three, plants. Man, they learned how to use glutamate billions of years before us. What were they doing with it? At that time they were using it, and they still do, as hormone signaling molecules. And it's only now in the animal evolution, which is very late, have we learned to use glutamate as a neurotransmitter. This is the evolution of glutamate. It's the mammalian brain that has learned how to really flourish. If not for glutamate, we would not be who we are. It's not possible. And what we have done with glutamate for the first time, no other species does it. Plants don't have this. Only animals then further modified glutamate to create this whole family of receptors called AMPA, NMDA, and other G protein leg changers. So if you want to look at this from a stylistic perspective, you might want to put your eyes on this. Glutamate was born pretty much when the earth was born. Very long after that, the first early microbes, scrounging around for something to help them, used what was in nature, glutamate. Primitive animals found a way to move them into the nervous system. Humans finally took glutamate and made it their best friend. 40% of your brain, as you sit across from me, is glutamate. 92% of every action potential you ever created since you were about a two-month-old fetus. Oh, it's important. What do we know about its neurobiology? And I hope you noticed I did not put a neuron in the middle. Psychiatry did get it wrong in the sense we thought neurons are more important than glia cells. Not true. Glia, Greek for glue. Incorrect. Incorrect. They're not glued, they outnumber neurons by a factor of 10. They're also incredibly active. Neurons are a lot like college-age kids. They're constantly dependent on their parents for money, and constantly dependent on their parents to take away the dirty laundry. Astroglia and other cells, but primarily astroglia, do that. And astroglia need glutamate for functioning. Pretty much they control the way they control the college-age wayward kid is through not dollars, but something more valuable than dollars, glutamate. It's a complex life. It's a complex life. But in this complexity lives opportunities. Because when things are complex, you have more targets. It's when things are simple, it's when you don't have targets. That's why the serotonin world has been so flat for the last 30, 40 years. Because we hit our glass ceiling, the moment, literally, when we discovered Prozac. Oh, we went up an inch or two when we discovered atypicals. But look where we are. What progress have we made in 30, 35 years? Zero. Because how do you go if there is no complexity? So we'll be walking our way through these complexities in just a minute or two. But please get to know despite what you and I got taught that glutamate is present continuously, it's not. It follows two very different patterns. And in psychiatric illnesses, both are impaired. There's excessive burst activity, which leads to panic, anxiety, rumination, but they also have impaired drip, drip, drip irrigation abnormalities, which leads to underlying fatigue, discognition. So when we offer interventions to our patients, it's flat out illogical to think of only just one or the other. You might want to think about glutamate as the mighty Mississippi. The mighty Mississippi wasn't created at a single fountain head, nor does it end itself in a single source. Glutamate is a lot like that. Glutamate is the royal road to getting to opioid receptors, to getting to norepinephrine, to getting to serotonin, and multitudes of other things. So all of a sudden, even though we keep calling it glutamate, as I will show you in a minute, the story of glutamate is a story of autoreceptors and heteroreceptors. Just hold that thought for a second or two. Oh, magnificent NMDA receptor. The single most complex receptor ever discovered. But here's the problem. We assume there's one NMDA receptor. We completely forgot the NMDA receptor is a quatromere. It's four different units that come together. Each of these units, we have many subtypes. I'll give you an example. NR1, there are nine human isoforms. NR2 has four. If you think of the permutations and combinations, we humans don't have NMDA receptors. We had 80 different NMDA receptors that all have different behaviors. AMPA humans have 50 different kinds of AMPA receptors. And we make the assumption there's only one NMDA. NMDA, depending on wherein the brain is distributed, can act as an inhibitor or an exciter. No, we don't have an NMDA receptor. We have NMDA receptors. And glutamate, by the way, is actually not all that interesting, as you can see from this illustration to the NMDA receptor. It's just one of very many docking stations this receptor has. This receptor deserves the title of magnificence. If you and I spend our entire careers learning how to modulate NMDA, it would be a very good career. There are about 80 of them. So far we've studied three. But the real star is not the NMDA. The real star is the AMPA. I think we may have hit the glass ceiling until we discover more isoforms of NMDA, but AMPA, we're just beginning. We'll see why AMPA is so interesting. But also please remember there are at least 40 to 50 different subtypes of AMPA receptors in the human brain that do not behave similarly. This is perhaps the reason why most of us aren't psychotic continuously or constantly sedated. This may be the reason why ketamine, as an example, simply doesn't behave as a monolith in terms of benefits or harm. It's so pleomorphic. It also explains why so many people have this miraculous response to ketamine. But about a third of patients, nothing. We make the assumption there's one. There isn't one. Even serotonin is simple. Serotonin only has 14 receptors. That's it. That's it. But not this. So if you put the AMPA and the NMDA, and then you start to markinate, then you start talking about the multitudes of metabotrophic receptors this neurotransmitter has. There's about 500 people in this room. There are 500 completely different, unlinked variations in our glutamatergic system. Are we making progress? Big time. I even put a date. I'd almost never do this. I finished the slide deck on December 27th, fairly inabriated. Let me be honest. It was after Christmas. And this paper got published on December 23rd. It is one of the most remarkable papers ever published in all of neuroscience because now this came from the Allen Institute from Seattle. Now we have the ability, now scientists have the ability to look at the behavior of a single vesicle of glutamate. Not a neuron, not a system. I'm talking a single vesicle. As a result, expect our ability to understand medications, to develop medications, to individualize treatments, to expand dramatically. If you're going to be reading four or five papers on glutamate, this may be one of them. And this particular marker is called glue sniffer. Very, very clever. But I just wanted to give you a hint about how active the world of glutamate research is. Sanjay and his colleagues, that was a really very lovely presentation they did just about an hour ago or so. They talked a great deal about brain circuits. They're completely right. Glutamate is the electricity of the brain. So default mode network is what you and I spend about 90% of our living time. If you're not depressed, congratulations. I'm in my own head. That's terrific. That's self-referential autobiographical memory. Depressed people, 95-98%. What differentiates a depressed brain from a non-depressed brain is not default mode network activity. It's the ability to break out of it using your salience network in order to go to your central executive network. That's what differentiates it. But who is going to help me switch out into salience? It's actually glutamate. Look at the evidence on the right. Brain circuitry is the way to start understanding depression. No longer should we think about regionalism. We should think broader. And if we do, the only real neurotransmitter, well, check it out. The only real neurotransmitter that matters is glutamate and glutamate's own daughter, GABA. Between them, they got the market entirely cornered. It's almost 99% of the activity is determined by these two. So these pathological conditions of OCD, addictions, depression, the brain actually sees depression as a state of over-rigid default mode network existence. Yes, sadly, these hyperconnected states are in fact caused by glutamate. So be careful. Don't start saying I want to improve your glutamate and therefore you'll get better. About half of pathologies in psychiatry are because of that. Simplistic thinking belongs nowhere in this conversation on glutamate. I know this is going to be further adding salt to the wound. And about two or three years ago, a lot of people who I know here, we became very riled up when Stanford and Schatzburg published that paper about opioids and ketamine works partly through the opioid system, and we're up in arms. Remember that? Somebody say yes? Okay, fine. Good. Well, I'm sad to tell you that has now been replicated by a completely different group of researchers. And this is coming from King's College. Very good people. I know these people personally, they have demonstrated one more time, and this time using MRS signaling. So now the believability of this data has gone up. Part of the way ketamine works, what percentage? I'm not sure, but at least 25%, maybe perhaps more percent, is through the opioid system. That is both an opportunity and a risk. You heard David's conversation right before me, where he alerted you, cautioned you, watch out. This is one of the reasons he's asking you to watch out. This may also be the reason why ketamine occasionally suffers from a problem of tachyphylaxis. Poop out. So I'm not here to paint ketamine in a good light or a bad light. It is what it is. But the evidence now is quite convincing that the opioid system is involved. But by the same token. By the same token. Eva, yesterday you had a great talk on liminal approaches to ketamine. And I think you were right. Love is at the center of it. But is it oxytocin? That's what we got told. Not so much. Oxytocin is entirely subservient to glutamate. Entirely. Oxytocin doesn't know how to be released unless glutamate says, it's okay, you can come on out and play. So the elicidity of love, convincingly, is actually glutamate. You guys ever been in love? Ever felt lust? Yes and yes. Ever felt the loss of someone leaving you when you don't want to be left? Well, you should thank glutamate for all three of the above. It is. It's quite convincing. And we even know which brain region lights up when you feel love, lust, or loss. Glutamate. It is the glutate. You guys doing okay? Okay, we're 20 minutes into it. The torture is just beginning. So let's go. Let's ramp it up. So far we've had some fun, but it's time to get to work. Glutamate and psychiatric disorders. Oh, this is the curve. This is the curve that we get lost on. What are we aiming for, guys? What are we aiming for? Do we want to increase glutamate? Do we want to decrease glutamate? Which one do we want to do? And perhaps we can take the question even one further level up. Are we wanting to do both in the same human brain at the same time, but in different regions? Are we ready to think about glutamate as if it's 2026? So I will let you answer that in a few minutes. But at the moment, please realize way before a psychiatric illness arrives, stress diathesis arrives. We tend to think about disorders as you didn't have it and you had it. It's like a myocardial infarcture. I don't think there is such a prodrome to myocardial infarction. You have it, you don't have it. Stroke. You didn't have it at 12.03, at 12.04, you have a stroke. But that's not true for psychiatric illnesses. And this is where the opportunity with glutamate is. I'm going to do a lot of conversation about non-pharmacological treatments because I think, hate to tell you this, as I'm looking at you and I look at the man in the mirror every single day, I think I'm very biased towards medications. It's not right. The role of stress in glutamate pathology is profound and it actually increases glutamate. Stress typically increases glutamate. And that itself is a cascade. You don't believe me? I can convincingly show it to you. Look at this data. It's very new. Just came out last year. Almost all the references I'm sharing with you are from last year because so much happens in the world of glutamate. We're looking at schizophrenia. But schizophrenia has acute psychosis or first episode psychosis, or you have someone who's had it for 40 years. They both have glutamate pathology, but in completely different directions. So if you're suffering from psychosis and you're relatively early in your psychotic life, you're in the red zone. You actually have way too much glutamate. But by the time you burned into chronic disorder, that very same fire has now left nothing but smoldering embers. So it's not a disorder of too much or too little. It's a disorder of both at different phases of your disorder. That's schizophrenia. Is that true with PTSD? One more time, the answer is yes. Glutamate has its grubby paws all over that disorder, too. In fact, so much so, this may explain why SSRIs, SNRIs have not been very effective. They just haven't been. As we look at the MRS magnetic resonance spectroscopy signature in the human brain, which is a very accurate signature, by the way, what we find is trauma isn't the provocator of glutamate. It's trauma that's converted into PTSD. So the rise in glutamate is not the problem. It's actually adaptive. Look, let me rephrase that question. What do you want your heart rate to be, high or low? What would you prefer?

unknown 22:01

Low.

Treatments Beyond Ketamine And NMDA

Psychedelics Reset The Default Mode

Plastogens GLP-1 And AMPAkine Pipeline

Exercise Meditation Sleep Psychotherapy

Rakesh Jain, MD, MPH 22:02

Low? Well, if you're exercising, you'll have a vasovagal episode. You'll pass out. So what's the opposite of low? High, okay. If you have high, then all you're going to have is panic attacks at night. So which one do you want to have? It's neither. I want to have high when I need high, and I need low when I need low. And have you not noticed people who exercise chronically and vigorously really can increase their heart rates to very high levels when they're exercising, but they're able to drop it to unusually low rates when they're not. See, that's adaptive. The ability to do up and down at very high levels appropriately is adaptive. That is lost in our patients with psychiatric illnesses. So we must drop this simplistic conversation of glutamate, I want to increase it. Glutamate, I want to decrease it. That's too simple. And it's also grossly incorrect. It damages people. And many, many of you do chronic pain management. Good for you. It's hard work. And in chronic pain management, the evidence of glutamate's involvement is up and down the entire chain. And that chain starts all the way from our second messenger, our second neuron, the second order in my spinal column, which is highly glutamaturgically controlled, which is the reason why people who have psychiatric illnesses have such a dramatically increased pain magnification, even with exactly the same stimuli. These people aren't complainers, they just feel pain more intensely. Inflammation, particularly chronic inflammation, particularly American style of chronic inflammation, which is a combination of stress, insomnia, and diet. Glutamate is deeply involved with it. Some other time we should have a bigger conversation about glutamate and its role in inflammatory conditions. Ah, let me, with some great joy, show you the next section. Glutamate-centric therapies, what's established, what's emerging. It is, Sanjay you are right. It's almost dizzying as to how many changes are about to appear. So ask yourself this question. The glutamate spark, which was the title of my presentation. Do you want to light it or do you want to put it out? Do you want this rakesh or do you want this rakesh? The right answer is you want both. And he needs to do the right thing at the right time. Because if the house is a fire already, please don't light another candle. Which is what you heard from our colleague who said, do not give people exposure therapy while they are on ketamine. Is that not what you said? What she said is don't light a candle when the house is on fire. But by the same token, don't blow it out when the house is cold. So this is our call to duty. Look, so far we've had a tremendous opportunity to just play around. We only had one real, maybe two real glutamaturgic drugs. It didn't matter that much whether we made mistakes in thinking or not. But as we get into this era, rapidly evolving era of new discoveries, it won't work. We'll have to think about do I need to increase, do I need to decrease, do I need to increase, decrease at the same time in different parts of the human brain? There are many, many roads to Rome, folks, many, many roads. And each one of them is valid. Let me show you some of the major highways that'll take us to Rome. Oh my. See, this is why I am so infatuated with glutamate. I, as you heard Sandhya, say I did a research fellowship almost, golly, it's almost approaching 40 years now. And I was told not to focus on glutamate because it was a wasteland. I was told to focus on cooler stuff like acetylcholine and stuff like that. I'm glad I was stubborn. I'm still stubborn, by the way, so that hasn't changed. But the neuroplasticity hypothesis of depression, which you've heard a lot about, is genuinely correct. I started out kind of worried that it was just a fad, but the data is replicating itself. And if you could squint, look at how many targets we have to improve neuroplasticity. Ketamine, I know this conference is called ASKP. I am aware of that. But ketamine is a relatively poor second cousin. And ketamine's days are numbered. I do believe in the next 10 years this meeting will not be called ASKP. Because it won't fit. We don't have a meeting called methotrexate centric interventions. Even though we love methotrexate for its importance. There's no annual meeting focused on aspirin anymore. There will be no meetings focused on ketamine in 10 years, which is not to put down ketamine. It's just to kind of talk about the progress we're about to make, I believe. But let's see, let's see. So let's do this. Let's do a deeper dive into this, but this time look at it from a phenomenological perspective. Glutamate is not an antidepressant. It is so much bigger than that. Just looking at the data, it's quite clear that, okay, let's think about an elevator. An elevator moves from the ground floor to the 30th floor. But here's the question: how? Did something push it up or did something pull it up? SSRIs, using that as an example, seem to be push-up drugs. They seem to work much more on the limbic system, and therefore the perception of depression is reduced. Glutamatic drugs appear to be pull-up drugs. That's why when you look at things like, oh, let's see, completely different symptoms such as energy, happiness, enthusiasm, resilience, glutamatic interventions improve it in a way that we simply don't see with other interventions. In other words, the approach to treating psychiatric disorders with this class of medications appears to be very, very different. I actually don't even think they're antidepressants. That's a side benefit of them, but I think they are much broader than that. I think they're resilience enhancers. And when resilience is enhanced, of course, the symptoms of depression and suicidality diminish. They are very fast, as you can see in this data, but please be aware, a large number of patients, a large, up to 50% of patients, do not see the improvement. We must be careful not to let a strikingly impressive p-value or an effect size. We should not let that fool us into believing this is what most patients get. They don't. In other words, if you keep focusing on NMDA receptors, you being you the specialty, we will not be treating a lot of patients adequately. NMDA receptor is the least interesting of all glutamate receptors. It is also true that's the one today we know how to intervene with, but that shouldn't change the fact it's actually not all that interesting. Boy, you guys aren't kicking me off the stage. That's very kind of you. Because I'm being pretty rough on both, not rough, I think I'm being pretty honest on both ketamine and on NMDA. There are many approaches to it. Nitrous oxide is certainly one of them. The reason why I'm drawing your attention to this is because this is under very active investigation in phase two and phase three studies. And it's being supported by a very unusual player. The American Foundation for Suicide Prevention, which is typically not an organization that funds research, is actually funding research at Washu at Washington University, looking at this as a suicide intervention that can be used in emergency room settings. Okay, some updates. Let me offer that to you. Does one plus one equal what? Well, how do we do one plus one with NMDA receptor antagonism? But today we only have two tools. This is the only paper I found. It actually came out this year. And this is the only one at the moment. It's only got three patients in it. But we got to start somewhere. These are patients who were not doing great on eschetamine. They were then augmented with dextromethorphan buproprion combination. It's by a group of researchers I really trust, John Zajeka and colleagues have been for 30 plus plus years doing great work at Rush in Chicago. And this is what they found. This is an opening shot across the bow, but it does tell us even the NMDA receptor, if it is approached from different angles, please remember the way ketamine approaches NMDA receptor and the way dextromethorphan approaches NMDA receptor are actually different. One is non-competitive, another one is uncompetitive, which mechanistically matters to the receptor. Two out of three of these patients converted into responders. One actually had a terrific response, one had a decent response, but the third patient had no benefit. It's the rule of thirds here again. But the very fact you can augment an NMDA with an NMDA shows you we gotta know our pharmacology inside out. This is not time for tough war. This is time for bigger thinking. Mementine, which is another pretty weak, but it's an NMDA receptor antagonist. I'm happy to show you using a biological marker, not just are you better, are you not better, but actually using proton magnetic resonance spectroscopy, which is a very cool technology, they showed that mementine only works in those individuals who have autism where there is an abnormality of glutamate found. In other words, it's not broad spectrum. It's only if it's got something to work on that it works. Well, and also it works in the region we know that's involved with socialization, the pregenual anterior cingulate cortex, the number one region in the human brain involved in mood dysregulation. You don't believe me? Check this out. It's the same study. Individuals who did not have a signature of significant glutamatagic abnormality, mammantine did not work. So now we have, I got the smoking gun and also have a video of you shooting the victim. No, I got I got the evidence. We have the evidence that if I intervene at glutamate, but it'll only work in those where there is something for it to work on. It's like trying to drive on ice. If you don't have traction, your car doesn't go anywhere. Neuromodulation. A number of you are experts at neuromodulation. Please continue doing so. Neuromodulatory science is making rapid progress, and neuromodulatory science is also deeply dependent on glutamate. If you experimentally block glutamate, almost nothing works, including neuromodulation. So glutamate is not just the Vishnu, the god of origin of mood and of the neurotransmitters, it's also the final common pathway. So neuromodulation is very involved. But what's the most powerful glutamatergic intervention available to humanity? What do you think it might be? Wanna see it? Okay, check it out. You see what's written on the biceps? It's actually this serotonin receptor called 5HD2A. Serotonin, I thought we just kind of put down serotonin, but I'm talking about 5-HT2A, and here's why. Glutamate neurons have on them, studded, heavily studded on them, is the 5HD2A receptor that's pretty much acting as the adult in the room. Hey, chill. Shh. Behave. Sit down. Sit down. Sit down. So the world's most powerful 5HD2A agonists are psychedelics. A particular kind of psychedelic. Classic psychedelics. So what's a classic psychedelic? It would be a medication, would be a substance or medication that goes to the 5HD2A receptor and tells us, you better wake up and you better wake up now. Let me show you the evidence in a second, but it's quite possible that classic psychedelics are the single most potent rapid glutamate modulators on the planet. And what do they do? That's the more important question. So if your goal is to go after the default mode network, we don't have a faster technology than a 5C2A classic. We just don't. Not even ketamine can come close to it. So what's the evidence? It's actually very striking. What happens when you give someone a psychedelic, whether they have depression or anxiety, is complete dramatic asynchronicity. The default mode network looks like it's not convulsing. Let me back up a little bit. Have you guys ever watched in the sky starlings create a group and they dance? And you can, you know what I'm talking about? The starlings look like. Who's leading it? When they make a lift, who was the leader? When they turn right, who was the leader? I don't know. That's the default mode network. There is no leader. It's leaderless, yet it knows how to dance together. What these medications do is take out the leader. There's profound asynchronicity, but only lasts for a certain length of time. And when that's gone, all of a sudden a leader is established. Who's that leader? She showed us the leader. The ventromedial prefrontal cortex comes back and exerts its right. I will think before I feel, rather than I'll feel, and then I am left to my own devices. This is two months after a single dose of ayahuasca. Two months, 60 days later, we were talking earlier about ketamine has a problem. It does have a problem in the sense of durability, right? Ketamine sometimes reminds me of a Kardashian marriage. Like really fun. But by the time the weekend's over, the Kardashians have being silly here, but am I not right in some ways? We talked about the durability problem. We're talking a matter of days, two days, three days, a week from the experts on stage. That's a problem. But it's not ketamine's fault. It's the target that we chose. Or the target we had available. All we had was NMDA. But when I give you a psychedelic, NMD is actually on the sidelines. I don't even not that interested in NMDA anymore. I'm going straight to AMPA. I'm just going straight to MTOR. By doing that, I can have with one dose, this is actual measurement of ketamine metabolism. Two months later, two months later, 60 days later, this clear signature that my glutamine has actually gone down. And it's highly correlated to improvements. So that massive increase, like that exercise that I did, so to speak, leads to very strong, massive, persistent changes down the road. I think I will end up being right on it, but I think I maybe end up being more right than even I want to be, because even glutamate may be not that necessary. So this is a brand new class of drugs that I think you're very familiar with. They're called plastogens. It's a fancy word, it doesn't fit it, but we'll call it whatever it is. There's a company, there's multiple companies, but there's one in particular called Delexis that has developed this drug called Tabernanthalog. It's a 5HD2A agonist, but it's what we now call biased agonism, meaning when you stimulate 5HD2A, just hang with me for a second. Two different pathways get activated. One of them leads to this profound psychedelic effect. Another pathway leads, it's called the beta-restin pathway. It leads to all the improvements we are looking for, such as track B activation, mTOR activation, antidepressive signal. Well, our psychedelics, classic psychedelics, only know how to stimulate both. These new drugs actually know how to stimulate one preferentially. This class of drugs preferentially goes after the beta restin pathway. As a result, there is no psychedelic effect. In fact, you don't even need glutamate anymore. Even glutamate, it's possible in 15, 20 years, may not be necessary. Check this green box out. It's really important you do that. Because many of you are much younger than me and you will be in practice 20, 30 years from now. It's quite possible that even these classic psychedelics will get replaced by these classes of drugs because they can directly activate both the TREC B system and the MTOR system. Now, have we proven this beyond a shadow of a doubt? Not yet, not in human models, but those phase three studies have started. So by the time ASKP rolls around next year, I suspect you're going to have an entire forum on these medications. There's an entirely unexpected glutamate modulator available now. Entirely unexpected, and that is yep, GLP1s. This is very unexpected. In fact, check this out. The way GLP1 agonists work, we thought were so simple, so straightforward, a creditance, you know, simple, simple stuff. I like simple. But apparently the brain is not that interested in simple. GLP1 receptors are very involved in GABA inhibition, which is really important for glutamate. It completely bypasses the NMDA receptor. See, NMDA receptor, its prominence is dropping with the newer drugs, goes straight for AMPA, and AMPA stimulated, of course, the evidence is quite impressive that BDNF goes up, which of course is through the TRECP system. So when a lot of our patients who are going to get, for a variety of indications, GLP once, it's quite likely we're also offering them a glutamatergic intervention. More on this to come, obviously, in the next few years from Manish and from other colleagues, including us. Okay. Are they bitter rivals, NMDA and AMPA? Is this what they are? Jealous? Or is this what they are? At the moment, look, no matter what we talk about today, we still have to practice in 26 and 27, 28. I think NMDA receptors and AMPA receptors are our best friends, and we should not be fighting them. I'm looking at my time. I'm going a little bit too long. I still have seven minutes. Am I okay? Okay, okay, okay. I may go five minutes over. Is that sort of okay? All right. You guys will be okay with that? Okay, okay. So this is a class that you want to get to know. NMDA receptor positive alloceric modulators. We have struggled hard to come up with good compounds, but I will tell you, every failure has led to improvement. Every failure, and we've had failures, 20 failures, 30 failures. But because of every failure, we're coming up with drugs like, for example, the last one, the Zell quinstinol, which is based on repastinol, which did fail badly. But because that failed, we have better compounds in either phase two or phase three studies. What would be the advantage of that? Huge. Because now, if you got an NMDA receptor positive allostatic modulator, it'll only work when you need it. See, positive allostatic modulator. So the chances are the side effect burden of these drugs would be very different. In fact, NMDA targeting antidepressants are being developed, but the goal is to go after the AMPA receptor. There seems to be almost 100% convergence in the field that we may have hit the glass ceiling with NMDA. But the AMPA, we're just starting. We're just starting out. In fact, this is where the next two slides are where I think psychiatry is going to be thrilled that now that we have direct ampokines that have failed, and as a result of the failure, we have better ampokines. We can now go after mTOR, and there's one particular in compound. I have underlined. There's several. There's several. There's so many that I think we might have as many ampekines in the next five to ten years as we have SSRIs. We have six SSRIs in America. There's no reason we can't have six ampekines in the next 10 years. The leader is Osa Vampator. It just published, when I said just, in the middle of 25, its first phase two. Impressive. Like, shouldn't have been that impressive, impressive. And as you can see at the very bottom, the current status is there are two large multi-center randomized phase three FDA quality studies progressing. If this hits, in the next 24 to 36 months, we will have our first ampokine available. And it's an oral drug. There are also intravenous short-acting 5H2A classic psychedelics in development, bertisolocin. Coming from Big Pharma, this is Big Pharma's first true psychedelic for intravenous use. It will not touch NMDA. It'll only be a 5H2A agonist of profound ability. It makes psilocybin look like a well-behaved pussy cat, comes roaring in like a tiger, but also leaves clean, rapid, patient dischargeable in three hours. A very different world is about to come at us. But look at the right, very old drug, scopolamine. Scopolamine is an AMPA receptor glutamate surge compound. Has very good data. It's now being studied in late phase 2B studies for major depression. See, those of us who call ourselves interventionalists, I genuinely think in 10 years it'll be a very large cupboard. Right now, our cupboard is well relatively bare. But look at the mechanism it's going after. Muscarinic acetylcholine antagonists. So this is a very small list, a very short list. And I did that only because I don't have much more space on it. But there are, I would say, between 40 to 50 different drugs in development that are all glutamaturgic. I published a paper in 2024. It's the only paper I've ever written where there were 600 references. But needed it. We're talking about glutamate. It's a 24 paper. It's already horribly out of date. That's how rapidly progress is happening. Okay. This is a section I've been dying to present to you. So far, what we've done is, I think, interesting, but this is what I'm wanting to talk about. And this is an admission on my part that just because I have an MD degree behind my name, I've actually made the mistake of not appreciating how important non-pharmacological allies are. In those of us who want to help our patients with glutamate, I really want you to, on this section, think with me. The only intervention we've ever found, ever found, that does both at the same time, increase glutamate and increase GABA is physical exercise. Just do this. Think about after a good workout, how do you feel? It's a very interesting combination of two opposites. You feel energetic and calm. You feel excited yet focused. These should be complete opposites. This leave on the opposite sides of a spectrum. But this is acute exercise. So do you look what with acute exercise what happens? Glutamate and GABA go up, but look what happens with in those of us who exercise on a chronic basis, who are regular exercisers. Actually, glutamate goes way down. That's a very good signal. The fact that you're not carrying that much glutamate around is actually very good. So let's go back. What is your goal? Do you want to increase glutamate or do you want to decrease glutamate? And of course the answer is physical exercise is perhaps the most, it's the closest to the perfect glutamate modulator I've yet found. Did you guys exercise today?

unknown 48:34

Yes.

Five Predictions And A Wake Up Call

Rakesh Jain, MD, MPH 48:35

Good? The fact I'm only hearing one, I guess what I'm asking you to do is it's you really will have to rethink the importance of physical exercise if you're a believer in glutamate modulation for yourself and for your patients. Exercise is such a good glutamate modulator. Those of us who don't prescribe exercise, and I'm directly quoting presentation from APA in 25. The presentation was, is not prescribing physical exercise in mental health malpractice. Damn. Got my attention. So I went to the presentation and he was right. Do not recommend monitor exercise, encourage, use coaching model, whatever with physical exercise. It's actually malpractice. What's the other intervention we should be talking about? It's actually meditation. Every study I've ever encountered that's high quality with meditation or mindfulness shows something very interesting. Glutamate is invariably reduced immediately after 10 minutes, it's also dramatically decreased on a chronic basis. The correlationships are very strong, 0.45. If you have, if you're interested in the world of glutamate, to ignore exercise and meditation is a mistake not worth making. The third is sleep, but today I don't have the time, so I won't cover that. This is a study that came from Sri Lanka. The reason why I'm showing it to you is because they modulated all three. GABA actually goes up. So if your met if your friends who meditate are sickeningly well balanced, there's a reason for it. The dopamine level is actually higher. It's very possible to be calm and ability to enjoy life goes up. But look at glutamate levels. They're actually quite low in people who meditate on a chronic basis. Insomnia, you know what happens in insomnia, the excitatory inhibitory balance is quite imbalanced. This may be the reason why insomnia is the number one greatest risk factor to developing depression. You may want to stop thinking about insomnia as a symptom, but think of it as a glutamate storm to calm. Because if you calm this glutamate storm right now, there's great rewards for the patient tomorrow. It's probably the only intervention that if you do today, the benefit is like that. And of course, please, oh, let's go back. See, I'm from Texas, I have a trigger finger. Psychotherapy cannot, will not ever be diminished in its importance when it comes to glutamate. The signature of even psychodynamic psychotherapy, any psychotherapy, any psychotherapy, it could be wet, it could be this, it could be anything, the signature, even six months out in the pregenual anterior cingulate cortex, as I said to you, the number one center of the brain that's under challenge, it's persistent and it can last a lifetime. 20 years, 30 years later, you can still see a signature that the person had psychotherapy. So finally, where are we going with glutamate? Look, glutamate is what I do when I do schizophrenia work, glutamate is what I do when I do insomnia, glutamate is what I do when I do bipolar, glutamate is what I do when I do major depression, glutamate is what I do when I do PTSD. I can go on. There are 271 diagnoses in DSM. 271 are deeply engaged with glutamate. Network hypothesis is emerging as the leader, and glutamate is the major network driver. But it's the fourth that wanting you to, in some ways, get excited. The fact that I am worried that NMDA has reached its peak. It's reached its glass ceiling. Only hopefully it does this to you. Appreciate what NMDA has done for us, but but I don't think we're gonna get any more out of this. There's not that much more blood to extract from this turnip. It's okay to look for love in other places. It's okay. It's okay. So I'm going to make some predictions here. And Sandia, will you invite me back in 10 years? Okay, okay. So it's on my calendar. I won't bother you for the next 10 years, but I would love to come back January 30th of 2036, and I've got five predictions. Prediction one is we will use ketamine infrequently. Because we'll have not because ketamine isn't useful. It's because we'll have far more targeted, far more powerful, far more residual effect. Far I think it'll be three-dimensional. We'll have so many options. We'll have so many pathways to get there. But I don't think NMDA receptors going to be it. Prediction number two. Ah, yes. This one I'm actually very confident. We'll be using downstream interventions. We'll be using ampokines, mTOR modulators. We may have NMDA modulators, but they'll be incredibly selective, and we'll be using coagonists. I didn't touch on coagonists just because of time today, but we'll be using that. Prediction number three, we will be using rapid acting, but also please note, rapidly dissipating psychedelics. No longer will we be okay with a psychedelic lasting six hours and that you don't have a control over its tail. My Rocky, when you give me a ketamine infusion, you know 15 minutes later I'll be here 40 minutes later. 90% prediction, psychedelics are going to have exactly that. We're going to have inhalable psychedelics, we will have sublingual psychedelics, we'll have intravenous psychedelics, we'll have intramuscular psychedelics, we're going to have subcutaneous psychedelics. All of these are not my thoughts. These are all phase three development programs. Even if 50% of them hit, we're going to be A-OK. Prediction number four, we're going to use plastogens. Oh gosh, we're going to use plastogens. That'll be for some other time to talk about, but plastogens are probably the single greatest disruptor to psychiatry that I'm foreseeing in the next 10 years. And then my final prediction is we're going to learn the art of never relying just on medications. We are too medication reliant. ASKP, dear friends and colleagues, you are too medication reliant. I am too medication reliant. That's not appropriate. Connections matter, relationships matter, physical exercise matters, sleep matters, mindfulness matters, and they matter a lot. And finally, I thank you for your very kind attention.