Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity
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Welcome to the huber man lab podcast, where we discuss science and science space tools for everyday life. I ander huberman and i'm a professor of neurobiology and optimize gy at stanford school of medicine. Today we are discussing kadee.

Kadee is a fascinating compound and it's one that nowadays being used both clinically for the treatment of depression and suicide, duality and ptsd. And IT is also a drug that is commonly abused, that is, kedem an is often used recreationally, and IT has a high potential for abuse. So today, we are going to discuss both the research on the clinical benefits of cademy as well as the risks of cademy.

We are going to discuss the mechanisms of action by which academie produces what are called the social states. I will define for you what I so called k hall is in scientific terms. I will talk about dosages academy.

I will talk about delivery routes academy. And throughout, I will be emphasizing both the clinical benefits and the risks, that is, the potential harms of using academy out of the appropriate clinical context. So by the end of today's episode, you will understand thorough what kem man is, how IT works in the brain and body to produce associated states and to relieve depression.

And you will understand how you can actually change neural circuitry. This is an important thing. Understand about chemin, the acute or immediate effects of cademy, while one is under the influence academy, are just part of the story of how academy modifies the brain for the treatment of depression, suicide, P T S D.

And by extension, when people use kadee ine recreationally, there are those immediate acute effects of kadee. But there are also long term changes in the brain that are important to understand. During today's discussion, we will also be talking a lot about neuroplasticity or your neural systems ability to change in response to experience.

And we will talk about neuroplasticity not just in the context academy, but as a general theme for how your nervous system changes any time you learn anything. And in that discussion, you're going to hear a lot about bdnf or bring arrive neutrophil factor brain to new trophic factor is a critical molecule for all forms of learning and memory and changes to your nervous system. So in addition to learning about cademy and how IT works clinically and its relevance to recreational use and abuse, you will also learn a lot about neuroplasticity and B D N F and what it's doing in your brain right now as you learn.

Before we begin, i'd like to emphasize that this podcast is separate from my teaching and research roles at stanford. IT is, however, part of my desired effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, i'd like to thank sponsors of today's podcast.

Our first sponsor is element. Element is an electoral light drink with everything you need and nothing you don't. That means plenty of salt magnesium in patache, this so called electronic and no sugar.

Now, salt, magnesium and potash are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electroliers ts need to be present in the proper ratio. And we now know that even slight reductions, intellectual al, light concentrations or dehydration of the body can lead to deficits.

And cognitive and physical performance element contains a science back electronic ratio of one thousand milligrams, that one gram of sodium, two hundred milligrams of potassium and sixty milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I and of electric lights. And while I do any kind of musical training and after physical training as well, especially if i've been sweating a lot, if you'd like to try element, you can go to drink element that's element t dot com slash huberman to claim a free element sample pack with your purchase.

Again, that drink element element dot com slash huberman. Today's episode is also brought to us by waking up, waking up as a meditation APP that includes hundreds of meditation programs, mindfulness trainings, yoga eja sessions and n sdr non sleep depressed protocols. I started using the waking up up a few years ago because even though i've been doing regular meditation since my teens, and I started doing yoga edra about a decade ago, my dad mentioned to me that he had found an APP turned out to be the waking up APP, which could teach you meditations of different durations, and that had a lot of different types of meditations to place the bringing the body into different states, and that he liked IT very much.

So I gave the waking up up a try, and I too found IT to be extremely useful, because sometimes I only have a few minutes to meditate, other times have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up up has lots of different types of yoga ea sessions.

Those you don't know yogananda a is a line very still, but keeping an active mind is very different than most meditations. And there is excEllent scientific data to show that yoga eza and something similar to IT called non sleeve deep breath or nsd r, can greatly restore levels of cognitive and physical energy even, which is to a short ten minute session. If you'd like to try the waking up, you can go to waking up dot com slash huberman and access a free thirty day trial.

Again, that's waking up dot com slash huberman in to access a free thirty day trial. Okay, let's talk about kadee. I realized that many people have heard of kadee, but most people don't realize that Katherine is very similar to another drug called pcp, or fend cycling, which goes by the street names, Angel dust or shame, that as some other street names as well.

When I was growing up, I heard a lot about pcp. They taught us about IT in school. You'd hear about IT on cop shows on television.

And the law was that pcp would eliminate people's perception of pain and would make them violent. You'd hear these stories, drug education classes, that when people are on pcp, they're punching light poles and breaking their hands. You know, they can fight off eight or ten police officers who are trying to handcuff them.

I don't know whether not any of that is true or not, but we heard a lot about pcp. And IT was associated with drugs of abuse, things like cocaine, meth, m fedex. IT was lumped into that category nowadays, when we hear about kadee, rarely do people mention that kadeem and pcp actually have the same mode of of action more or less.

Okay, i'm not talking about the specifics. I'm talking broadly. They have the same motive action in the brain that both of them are social anesthetics and nowaday.

Usually when we hear about academy, we are hearing about its benefits. We are hearing that I can help cure depression. We are hearing that I can help reduce or cure suicide duality.

That IT can be used to treat P, T, S, D. And indeed, all of that is true in the appropriate clinical context, at the appropriate dosages. And given that the appropriate frequency domine has proven to be a maculate drug for some people, not all people, for the treatment of depression to a ideality and P, T, S D.

That said, kadee also has a very high potential for abuse. And so IT may come as no surprise that we often hear about kadee nowadays, also, in the context of its use at parties, you hear about people going into so calk holes, which is a particular state associated with overdoing the dosage of academy a little or a lot. We'll get back to that a little bit later.

What IT is, how dangerous is, is at sara. In any case, at amy is an incredible drug, very similar to pcp, fence cycling and IT is a drug that nowadays there is crossed between the clinical uses of cademy ine for treatment of depression, IT set up and it's recreational use. What do I mean by that? What i'm referring to is people accessing academy legally for the purpose of treating depression, but taking that kadee out of the clinic, out of the dockery office, which is a very different set of conditions.

Most of the studies that have been done on kadee en in its rolling depression. And not surprisingly, if there is increased access to a drug like kadee, really any drug that has a potential for abuse, then we also see an increase in the number of people that they are using that drug recreationally. And some of them do indeed get addicted. academy.

So I know many of you are probably wondering, can you get addicted? academy? Indeed, people can get addicted. academy.

There are some people who like its effects enough that they find themselves compelled to use academy, even though the use academy is degrading their overall life performance. So work, school relationships, finances at sea. That said, kadee does have these establish clinical uses.

So nowaday, the landscape around kadee is also so different then IT was ten or twenty years ago when I was lumped ed very closely with pcp for cycling and really just looked at as a drug of abuse. There were some early cases in the thousand and seventy of the use of academy in order to treat ptsd. This was mainly in soldiers in vietnam or people coming back from.

But really the clinical use of academies for the treatment of depression, suicide, delity and P T, S. D. Has really just taken off in the last five to ten years. And that's what's brought us to this new landscape of interest and understanding and use of cademy in the clinical and recreational context.

So how is that? That a drug that at one time was really just viewed as a street drug that was bad, bad, bad is now being prescribed widely and has all this interest surrounding IT. And really, this has to do with our understanding of what depression is and what depression isn't.

So i'd like to just take one or two minutes and explained you a little bit about the history of depression and its treatment, what we preserve, starting about the middle of the last centuries, around twenty and fifty. But really taking off in the early one, nine hundred and eighties and nineties, is the so called mono ami hypothesis of depression. Mono amens, as the name suggests, are synthesized from amino acid, is a good way to remember mono amens.

Mono amans include things like serotonin doping and north and afan, although the other mono amines as well, mono amines are neurotransmitters ors, or more specifically, they are neuromodulators, meaning they change the activity of neural circuits in the brain and body. They can ramp up levels of activity in lots of different brain areas, where they can reduce the activity of neurosis, cuts in lots of different brain areas, as well as within the body, right? Your god has serotonin and need serotonin, the, and also plays important roles in the body.

At at sea, the mono a hypothesis of depression is really centered around the idea that IT is deficiencies in these monopoles, either set, tony or doping or nor up or some combination of those that gives rise to depression. Now in reality, there is very little, if any, evidence that there is a deficiency of mono amans in any form of depression. However, IT is very clear that drugs that increase certain mono amans, so drugs like prozac s all off the increase, tony, or drugs like repairing, which is often called well button, which is its commercial name, which increases dopamine and or and can often provide relief for certain symptoms of depression in some people.

However, what we've learned over the last thirty or forty years is that drugs that are designed to increase certain mono amans in order to treat depression, only working about forty percent of depressed people that take them, and they have a lot of side effects. Now some people are lucky enough that they can use a low enough dose, or perhaps even a high enough dose, that gives them relief from their depressive symptoms but does not give them side effects that make IT so uncomfortable for them to use that drug that they would choose rather to not take that drug. However, a lot of people that do get depression relief from things like so off, or axel, or from repair ron, find that the side effects, which include things like dry mouths of little more commonly, reductions or increases in appetite, or vast reductions in label, or changes in their sleep patterns at set a, that those side effects really make IT impossible, or at least very uncomfortable, for them to take those drugs.

And of course, there are the sixty percent of depressed people who do not respond to those drugs at all. Now I want to be very clear. Things like sss, things like well button, have helped a tremendous number of people get relief from depressive symptoms, and in many cases, have warded off suicide late as well.

However, there are also a great number of people who have experienced a lot of side effects and problems from these drugs, hence the desire to find other compounds that can treat depression without creating similar side effect profiles. And that ideally can provide relief, not just for forty percent, but for all people suffer from depression. So that's where kedem en enters the picture.

Prior to the one thousand nine hundred nineties, they were mainly studied in neuroscience and pharmacology laboratories for their abuse properties and for their anaesthetic properties. So kadee is a socia tive anesthetic. It's actually used to induce certain forms of anesthesia for surgery. It's not always used, but it's often used.

This is something that if you've ever had a surgery, you might want to ask you in a theologist about, you know, what sorts of drugs are are you giving me to go under? What sort of drugs are you keeping me to stay under? And maybe even what sorts of drugs are you giving me to bring me out of anesthesia? Because IT turns out that when you go in to anesthesia, you're an easy logic, is rarely giving you just one drug.

Typically, they are giving you one drug to kill off a little bit anxiety and maybe eliminate a little bit of pain sometimes, and then they will give you another drug to drop you into a deeper plane of anaa. And the nowadays are sophisticated ways to monitor your plane of anesthesia. And there are sophisticated ways to, if necessary, get you out of a deep plan of anesthesia if that plane of Vanessa a is too deep.

When I talk about a plane of annexation, i'm just talking about going from full wakefulness to, you know, a reduction in anxiety to falling asleep to a sleep to the point where even if someone were to pinch your toy, your ARM like really intense pinch, that you wouldn't wake up from that. okay. So kat mean, has the property of being an anesthetic.

IT kills the response to pain. And at certain doses, IT can bring you into deep plains of anesthesia. At lesser dosages, IT can take you into to transition points between awake and deeply and excited. And it's really that transition point between awake and deeply and exercise, which we are going to call the associative state, is kind of this liminal state a little bit like dreaming and can have some dreams like qualities to IT.

That's the state that has most often been sought after, are employed for the treatment of depression, suicidality and ptsd, which brings up a really important point, which is that when people use kadeem recreationally, it's not clear exactly what plain of anesthesia or association they are actually seeking. And this is why we hear about some of the desired effects academy that are driving people to use IT record, why we also hear about people having some unpleasant, even very unpleasant or dangerous experiences when using kadee recreationally. Because we're talking about a drug that has a lot of different effects depending on the dosages.

And as well soon talk about individuals vary tremendously in their response to different dosages of academy and the delivery route for academy, whether not it's delivered early in the form of appeal or puts subsequent ally in what's called a troll that dissolves under the tongue or it's injected, and then that injected into the vain or inter muscular y eta. Each of those can produce very different effects, terms of the speed of onset of the drug and the type of effects that IT produces in the brain and body. So what happened in the early nineties is that laboratories that we're studying, animal models, what we call preclinical models of things like depression and learning and memory, and to some extent, academy, but mainly focusing on learning and memory and depression, made an interesting discovery.

There's a certain preclinical model of depression that's pretty common. And laboratories that involves taking a rat or a mouse and putting IT into a small container, like looks like a beaker or a jar. Sometimes it's a tray, and I has water in IT.

And you might be surprised to learn, perhaps not, that if you put a rater mouse into water, IT will swim OK. So it's trading water in order to keep its head above water and not drown. I realized for some of you, this might be a bit of universities topic to hear about animal research, but this is one of the common preclinical models of depression, which is put a ratter, a mouse into water.

Let IT swim and see at what point IT gives up, because what happens is if you put a rat or mouse into water, IT will attempt to save its own life by swimming. But at some point I will just give up and you will just start thinking. And then of course, the researcher needs to rescue the radama, put IT back into its home cage, dry IT off, give IT some food IT.

This preclinical model is called the model of learned helplessness, and it's become a prominent preclinical model of depression. Because, of course, we can ask mice or rats if they are depressed or happy. I suppose you can ask them, but they are not going to answer in any kind of meaningful way. So we can only look at their behavior in order to understand whether not they have a sense of happiness or a sense of depression.

And of course, that's very hard to gage in an animal model of any kind, you could make guesses based on other behaviors, like are they grooming regularly? Are they eating regularly? You know, things that more less parallel what we think of as health or lack of health in a human who's happy or depressed. But in the context of trying to understand depression in these preclinical animal models, having a behavior that you can really quantify carefully across a lot of different animals and conditions is really beneficial. So this thing of putting a radar mouse into water and seeing how long IT takes before they give up to save their own life is called the model of learned helplessness.

And what IT allowed researchers to do was to take graves and mice, put them into water, see how long IT took before they gave up, and then to give them different drugs to see whether or not any of those drugs either hastened, sped up or prolong ged, the duration over which the animal would attempt to save on life. This actually has a meaningful parallels to human depression. You know, one of the hallMarks of depression is that people stop thinking positively about their future.

Depression, of course, can include a lot of other symptoms. You know, one of the most prominent symptoms of depression, for instance, is consistently waking up around two thirty or three thirty in the morning and not being able to fall back and sleep again. Keep in mind, that is not the case that if you're waking up at two thirty or three thirty in the morning and you can't fall back to sleep, that you are absolutely depressed.

That's simply not the case. But that pattern of lack of sleep plus some other things like lack of anticipation of a positive future and ability to imagine the future in any kind of meaningful or positive way at set up, are part of the key features of what we call a major depressive episode. So this preclinical model of learned helplessness allowed researchers to test a lot of different drugs and establish which drugs at which dosages allowed animals to fight for their life longer when placed into water.

It's really that simple as a model, but IT revealed some very interesting things, at least one of which is that when animals were injected with academy, the associate anesthetic, but they were injected with dosages of kedem that were below what would induce full and sesia, these animals would swim for their life for a lot longer. Now, to some extent, that ought to be surprising, and in fact, was surprising to researchers, because academy is what's called an N M D A receptor blocker. Now, when I say blocker, i'm not getting into the details of what specific form blocker IT is, but I do want to mention that a blocker is sometimes referred to as antagonist, where something that promotes the activity of a reception is called an agonist.

Okay, so if you can just remember the academy is an nmda recept antagonist or blocker, then you should be fine for the rest of today's conversation. Now, I haven't told you what N M D A is. N M D A S N method, D, S sparta.

And you do not need to remember that, but the surprise for researchers was that this drug academy is allowing animals to fight further life for longer. So IT has the sort of property of overcoming what we call learn helplessness, or a sense of helplessness. A, K, A and I depression effects.

And we also know that it's an M B A receptor antagonist or blocker. And that's perplexing because we also know that the N M D, A recept is critical for changing neural circuitry in the brain, is critical for neural plastique. So put differently, here's a drug that blocks the receptor that's critical for neural plastics, for changes in the brain.

And yet somehow it's allowing these animals to fight further life longer. It's somehow giving them more of a sense of hope, at least that's the subjective interpretation of what one observes when a mouse or rat is swimming for much longer, when IT would otherwise just give up and sink to the bottom, the vessel. Now, in general, there are two kinds of scientists.

There are scientists that take a look at a set of finding like that and say, oh, here's a drug. That's what to be terrible for us. It's an anesthetic. And IT blocks, mda receptors and nmda receptors are good for neuroplasticity. And somehow it's also allowing these animals to swim longer.

And what's, say, one category of scientists, which just look at that and just say, wow, that is a big baller tangle of confused facts like, how does one even recognize of that right? Brain change ought to be good and perhaps even lie at the heart of our ability to recover from depression. This is drug that blocks in a place to see, but somehow is relieving depression. I'm going to walk away from that. I'm going to work on something far simpler.

Er and then there's this other category of scientists which think goodness exists who looks at that apparent contradiction of, okay, there's a drug which blocks plasticity, plasticity thought to be important for getting over depression and yet the drug can provide some relief from depression, at least in these preclinical animal models and they say, hm, I like a good puzzle, right? The more complex to puzo, the more interesting. And they start digging in with three clinical studies, and they start talking declinations who are treating patients for depression.

And like I said, thank goodness these sorts of scientists exist. And thank goodness st. They did that because IT turned out that when clinicians tried kadee in depressed patients as a means to relieve depression, IT had remarkable effects. So IT was about the year two thousand when the first sets of papers about the clinical use of team me for the treatment of depression started to emerge.

Now we have to remember the context in which all of this was happening, knowing two thousand drugs like prosaic and some of similar assess ze selective serotonin reuptake, ken, hibs, things like, well butrint were really hitting the market in full force. And as we talked about earlier, some people were getting relief. Some people getting relief with a lot of side effects and therefore deciding not to take those drugs.

And a lot of people, the majority of people that we're taking those drugs, we're not getting relief. So there was a real urgent need to find other drugs for the treatment of depression. And kadee, at least based on it's apparent profile of being a deal anesthetic would seem like the last drug that you'd want to use to treat depression.

Hided associates, people even hear about association as a symptom of depression. And yet what happened was a small number of very pioneering clinton started to explore the use of adee in the clinic for the treatment of depression, and in particular, for depression that did not respond to any other treatment. So there was a real critical need to find other compounds in a bit more motivation to test some of these, let's call them a typical compounds for the treatment of depression.

So one of the first landmark papers in the use of aiming for the treatment of depression is entitled inside depression effects of cademy depressed patients. This is a paper that I provided a link to in the showed captions. It's a small study. okay? So IT doesn't involve many subjects at all, really just has seven subjects, all of whom had major depression, and they did intros ious injections with half a milligram per kilogram of body weight academy.

Now that dosage, half a milligram per kilogram M, A body wait turns out to be very important for today's discussion because it's going to serve as a reference point for later discussions when we get into other modes of delivery of cademy, such as oral pill, form academy or substance ual cademy, and as IT released to things like the cahall or the deserted state or the various effects that adem can have, depending on the dosage and the delivery right. Meanwhile, going back to the study, what they found is that when they injected patients with severe depression with cademy, the effects of academy took place within minutes, within ten or fifteen minutes, and that they experiences a sort of p fox state OK. So they're not inducing deep.

And a this dosage are getting people into a kind of view, four dreamy, semi desert tive state that occurred within fifteen minutes, and really peaks about forty five minutes to an hour after they were injected with the drug, and that the total effects of the drug, in terms of euphoria, were effectively over by about two hours or so. And that time course of effects makes perfect sense if you look at, say, the half life of teamin, which is how long IT takes for half of the drug to be active in the system at, said a. But what was really interesting about this study, and others like IT, is that the patients experience released from their depression almost immediately after taking the drug, so within minutes to hours, and that IT persisted for several days after taking academy.

okay. So the associate of you for a dream like effects academy take place very quickly. They're very, very sAiling, right? The person basically is just lying there experiencing the euphoric, dreamlike associated state, and they get some relief from their depression immediately.

And yet there's persistent released from that depression, which asked at least three days out from the treatment. Now a key theme of today's discussion is going to be that the anti depression effects of cademy appeared to be fairly short lived, at least when one is expLoring one or two treatments with cademy. In other words, the typical countour is that people will take kadee, get this, you, for a dream like associate of effect, come out of that feeling some immediate relief from their depression.

This is one of the things that makes cademy an incredibly attractive drug for the treatment of depression, especially depression that hasn't responded to other forms of treatment, which is that people get relief very, very quickly indeed, the same day that they initiate the treatment. Now this is especially important when you think about the fact that the monovalent hypothesis of depression, which drove the discovery and development of all these drugs, like access, arise while putin IT set those drugs, often can provide support for people with depression. Again, only forty percent of people get true relief from their depression.

And again, there are some side effect issues or major side effect issues in some cases, that have to be dealt with. But even the positive effects, even under the best conditions, often times those effects don't kick in for weeks or months after somebody initiates taking the drug. Now that might not seem like a long time to wait for some of you, but if you are somebody suffering from depression, even another day, even another hour with depression seems almost unmanageable.

And sadly, many people who have these forms of depression will go on to commit suicide. So IT is ever so important that there be rapid treatment for depression, even the same day treatment for depression. And based on this study that appeared red, that kadee was, and indeed still remains, that drug.

Now I certainly don't want to position kadee in your mind as a miracle drug for depression. In fact, I don't actually believe in miracle drugs. I don't think that there is any compound that alone can produce all the desired effects that one wants without any negative effects in a way that could warned calling IT a miracle drug.

That's just not how biology works. There's always an interplay between pharmacology, between our behaviors and what we choose to do or not do this. The topic will get into a little bit later when we talk about anti depressive behaviors and the role of academy in bringing about anti depressive behaviors for the relief of depression.

Now with that said, the study that I just mentioned, as well as many, many other studies that followed, emphasize that academic could provide significant decreases in not just depression and suicidal ty, but also the feelings of helplessness and worthlessness that are associated with major depression. And again, I could do that in people that also were not responding to other forms of depression. Treatment such as access arise at sara.

So well, we don't want to call IT a miracle drug. Kadeem turned out to be and remains an incredible drug for the treatment of depression in certain cases. Now in addition to that, cademy has been shown in clinical studies to provide relief, not just for treatment resistance depression of the major depression type, right? There's many different forms of depression, but major depression is the one that we're Normally thinking about.

We're referring to when we talk about depression. But kadee has also been shown to be effective in treating bipolar depression, sometimes called bipolar disorder, although more commonly nowadays called bipolar depression. I didn't entire episode, by the way, on bipolar depression.

If you want to know what IT isn't, what IT isn't, how IT defers from borderline personality disorder at seta, you can go to huberman lab dot com, just put into the search function by polar, and IT will take you to that episode. Kadee has also been shown to be useful for the treatment of P T S D and for O C D obsessive compulsive disorder, infor anxiety and for various forms of substance addiction. So kadee is not a miracle drug, but IT does seem to have broad application and to be very successful for the treatment of a lot of major psychiatric chAllenges.

Now just because kadima has shown these incredible applications, IT also has some serious problems that are directly related to how IT works in the brain, or at least from what we understand of how IT works in the brain. And what i'm referring to hear is, yes, kadee is very rapid acting. IT can often provide relief from depression almost immediately, meaning same day.

However, IT is very short lived. After about three days or a week or so, the anti depression effects of academy often wear off. So that creates a situation where people perhaps you need to take kadee every week, and yet IT creates enough of a dissociated state, meaning IT takes people enough out of their Normal daily routine that the prospect of people taking academy every week is actually not that feasible.

And also because of some of the propensity for cademy to become a drug of abuse, that is, for IT to be habit forming and or addicting. One also worries that if people are doing academy in every week to treat the depression, that they can become so called hooked on academy. Now fortunately, there have been studies of teaming and how IT works, not just in the short term, but in the longer term, that have LED to some very important clinical studies that have explored.

For instance, people take academy twice per week for a duration of three week's total. And what they find is that, yes, after the first time they take IT, they get some relief from depression. They take a second time that week, they get some relief from depression, and they do the same thing the next week and the next week. And when they do that, they get relief from depression the whole way through that entire three weeks.

But IT turns out that there is also some so called durability to the effect, such that if people do this twice a week, dosing region, so can have been twice a week for three weeks total, they find that when they in that three weeks, they get some ongoing relief from their depressive symptoms, which can extend months or more before they have to repeat that twice a week for three weeks. Regiment, now certainly not all studies of using kadee for the treatment of depression have used that exact doses. Regiment, twice a week for three weeks, and take some time off.

repeat. Twice a week for three weeks. Take some time off. repeat. Some have explorer giving academy once per week, or even three times per week, or doing IT once a week for five weeks and then taking an extended period of time off before repeating the treatment schedule.

There are a bunch of different studies out there, but when one looks at all of those studies and mass together, it's very clear that academy is providing released from depressive symptoms immediately end in the days after the treatment, but that when those treatments are stacked fairly closely together, that there is some durability, some ongoing relief from depression. And what this tells us is very important. In fact, I hope everybody really highlight this in their minds as they are hearing IT.

It's very likely that kadee is acting by at least two and probably three different mechanisms in order to provide relief from depression. One of those mechanisms induces relief from depression very quickly and seems to be associated with that you four associated dream like state that one experiences when they are under the influence academy. The second mechanism seems to provide relief from depression in the days and weeks that follow academie treatment, and there also appears to be a third mechanism by which kadeem can induce long lasting changes in the nervous system.

And this is those three mechanisms, short, medium and long term mechanisms, that produce the kinds of changes in neurochemistry, and more importantly, changes in actual neural circuit wiring, that allows academy to provide this incredible relief from depression. So next we're gonna turn what those mechanisms are, because in understanding those mechanisms, you will understand how kadee provides this relief from depression. But you'll also come to understand the more important, broader theme of what depression is really all about at a neural circuit level, and how relief from depression is all about neuroplasticity.

I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens. Athletic Greens, now called ag one, is a vitamin, mineral, probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic Greens since two thousand and twelve, so i'm delighted that they're sponsoring the podcast.

The reason I started taking athletic Greens and the reason I still take athletic Greens once are usually twice a day, is that IT gets to be the probiotics that I need for god. Health, our god is very important, is populated by got microbiome that communicate with the brain, the immune system and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic Greens are optimal and vital for microbiology, alth.

In addition, athletic Greens contains a number of adaptations, vitamin minerals, that make sure that all of my foundational nutritional needs are met and IT tastes great. If you'd like to try athletic Greens, you can go to athletic Greens dot com slash huberman and theyll give you five free travel packs that make IT really easy to mix up athletic Greens while you're on the road, in the car, on the plane, at sea, and they'll give you a year supply of vitamin d three k two. Again, that's athletic Green dot comm slash huberman en to get the five travel packs in the year supply of vitamin three k two.

So how is kadee really working? We already established that kadee blocks the M D A receptor, and that the M D A receptor is critical for many forms, not all, but many forms of neuroplasticity. Now I realized some of you might be familiar with so called legins and receptors, but most of you probably are not.

A legend is a chemical that binds to a recept. And a receptor is like a little parking spot on the outside of a cell. There can also be receptors inside of cells.

But most of the time when we're talking about nerve cells, neurons, and you hear the word receptions, you're hearing about receptors on the outside of the cell. So the N M D A recept does not exist in our neurons in order to bind kadee. It's they are actually to bind all sorts of other things that are india genes that are naturally made by us.

Academy has a very high what's called affinity, has a very high probability of binding to the nmda receptor if IT introduced to our bloodstream. So when kedem is taken in pilot subsequent al form, meaning under the tongue, when it's injected into the muscle of the vain, IT gets into the bloodstream and then it's able to cross easily across the blood brain barrier, so called bbb blood brain barrier. The blood brain barrier keeps a lot of things out of the brain, but academic can very readily pass across the blood brain barrier once it's in the brain.

IT has a very high affinity for meaning. IT knows how to seek out and bind to those nmda receptors. Now, the simplest way to explain how nmda resettling ordinary contribute to neuroplasticity is that they represent what's called an end gate and an engage, as the name suggests, is a function in a cell or in a system where two things have to be present.

In fact, for those of you that have a bit of an engineering or computer programing background you'll be familiar with, and gates, for those of you that don't don't worry about IT, i'm going to explain what an end gate is right now. An end gate in the context of nervous system function is when two things are present, like chemical a and chemical b, both have to be present in order for some process saying neuroplasticity to occur. The nmda recept, as I mentioned earlier, as a recept on the surface of neurons and IT bind glue to mate, which is a molecule that we all make in our brain.

And IT activates other neons. It's what's called an exciting dator neurotransmitter. Now there are lots of different receptors for glue mate, and those recept tors are binding good to make all the time.

However, in order to activate the nmda receptor, there has to be a lot of gloomy present, and IT has to happen over a very brief period of time. So the N, M, D, A receptor is an end gate in the sense that glue to mate has to be present and to bind IT. And IT has to get a lot of electrical activity, a lot of input in order for that to happens.

So it's a receptor that responds primarily to unusually high or frequent levels of electrical activity. Let's places in real world context so that IT makes a bit more sense. I like most all of you in moving my arms around a lot throughout the day. Now, as an adult, my motor cortex, the area of my brain that controls motor ordination of my limbs, has connections from my brain to my spinal cord, from my final cord to my.

And that sweat allows me to move my limbs under conditions of just moving my limbs and doing things throughout the day, drinking a cup of coffee or your burmah, you know, walking outside to view some sunlight in the morning, doing the things that I do every single day and that I already know how to do. Glutamate is definitely involved in that process. Glutamate binding to its other receptor types, which are called amp receptors.

For those you that want to know that's involved in that process, it's typical levels of activity. If, however, I were to sit down at this desk and be commanded to or decide to do some specific motorway movement, let's say, move my hand in a three dot sequence for those of you watching, you can see this. For those of you that they're listening, don't worry about.

It's not very interesting to watch. The point is just that i'm going to put my finger down in one, two, three points on the desk in front of me and then three, two, one point coming back to me. Now that's obviously a motor sequence that I can perform.

I just did IT so clearly I can perform IT. But if I were to do that for, let's say, an hour, what would happen? And is the neurons that are involved in generating that motor sequence of one, two, three, three, two, one, one, two, three, three, two, one would be active over and over and over again.

And what would likely happen because of that unusual, Frankly, motor behavior is that the neurons are responsible for generating that motor behavior would be able to detect IT as unusually frequent, unusually high level of activity in the circuits that generate that behavior. And the increase in the glutamate that's in pinching on the neurons in that circuit would bind the N M D. A receptor, making IT change several important things, the first of which is that your nerve system is capable of changing, but that's an energetically demanding process.

So the incredible thing about neuroplasticity is that when you generate an unusually high or just an unusual pattern of activity, motor activity, or you're hearing a new language, you're trying to learn that, or you're navigating a new city, the neurons are firing in ways that are a typical for them, and they are firing a lot more. And so the neurons are going to bind glue to mate. The M, D, intercept going to be activated.

And then downstream of M D, A recept activation are a bunch of what we call inter cellar processes, a bunch of things that happened in the cells to try make that behavior occur again and again, if needed. But without the huge energetic demand you've experiences before when you're trying to learn something and IT feels sluggish, feels hard, it's frustrating. And then eventually you learn IT and it's very fast. Ile, it's very easy.

One of the reasons for that is that when the N M D A receptor is activated by these infrequent or unusual patterns of activity, IT can then recruit other glutamate receptors that the more typical kind, the Amber type receptors to the cell surface, and then those receptors can simply bind the glue to mate and allow that behavior to occur without this whole process that's involved in neuroplasticity having to engage and do things like build new proteins in the cell, build new machinery at SATA. So they just step back from this. The way to think about the N M D.

A receptor is that activation of the nmda receptor only occurs under conditions of unusually high or simply unusual patterns of activity that the N M D A recept, yes, controls neural activity in the immediate sense, like when it's activated, it's changing the pattern of activity in the neuron, sure. But IT also can engage gene expression and introduced new receptors to the cell. Basically giving the cell the ability to then recreate the same patterns of activity without having to do IT in such a metabolically demanding way.

In fact, a good analogy for all of this is the way that muscles can hyperdrive phy, right, if you overload muscles properly through resistance training of any kind, and then give them a period of rest, there is recruitment of specific things to the muscle fibers, as well as recruitment of changes in the nerves that innovate, that control the contraction of those muscles. And then those muscles grow, they get stronger at sea, and they're able to function and use that new strength and new growth. And you don't have to damage those muscle fibers or trigger those adaptations over and over again to maintain them because you have this new capability.

And I realized that a lot of details about mda receptors in neuroplasticity, but really, if we needed to pick one biological mechanism that resides at the center of many, many important forms of neuroplasticity, that would be the mda recept and its functions that I just told you about. So now that you have that in mind that these NBA recept tors are critical at detecting unusual activity, making changes to cells so those cells can then respond that activity in the future, you have in mind the conception basis for understanding how kadee works. Because, as i've mentioned several times already, kadee is an N M D, A recept blocker tagged ist.

And yet we know that a lot of the changes in the brain that underlie the transition from a depressed state to a non depressed state involve neuroplasticity. So what's going on there? Well, what's going on there? IT turns out to be extremely interesting, and you can understand IT very easily if you understand that there are essentially two major types of neurons in the, you have those excited tory neurons, meaning neurons, that when they are activated electrically, they activate or excite other neurons.

At least they try to. They released neurotransmitter or into the synapse, which is the little gap between neurons. The neurons on the other side have receptors.

They bind those newer transmittals, in this case, lutin ate, which is the major excited tory or transmitter in the brain. And then there is a high probably that those other neurons will be excited that they will be electrically active. That's one major type of so called neuro transmission in the brain.

The other major type of neuro transmission in the brain is called inhibitory. Neuro transmission inhibitory ory neurotransmitters involves neurons that release the neurotransmitter gaba, or sometimes also another molecule called glen, but mostly gab. When gaba is released, IT has the property of reducing the probability that the next neuron will be electronically active.

In fact, gab s job is to bind the receptors on the next cell and to make IT less electronically active. So we've got excited tory neuro transmission, and we have inhibitory ory neurotransmitter, just a place in hibbard, ory and excitation neurotransmitters. Into context, you think about a condition like epilepsy, which involves seizure of either the smaller type type petite malle seizures, or grand malls, seaside, which are the type in which people have boyfriend convultions.

They are often disengage from whatever is going on around them. In those moments, they're shaking quite a lot at sea. There many causes of seizure, but to get to the heart of what a seizures is, IT is essentially runaway excitation in the brain, a small region of the brain becomes especially electronically active.

And then IT spreads out from that foci, that focus of the exit. And that recruits a lot of neurons in a fairly nonspecific way, creating the seizure like motor patterns in the body and patterns of activity in the brain that can involve this engagement from immediate experience and lack of perception sometimes. So ora, there is a whole discuss to be had about season. And by the way, seizures can occur in a lot of different context, of course, that can occur an epilepsy that can curr after head injury at settle. We'll cover seizure in a future episode of this podcast, of course.

But one of the major causes of seizure, and by extension, lack of seizure, is that ordinarily inhibitory, neons and excited tory neurons in this kind of push pool that for somebody that doesn't experience seizures, puts the brain in balLance so they don't have seizure, right? The inhibitory neurons are suppressing the activity of many neurons so that those many neurons don't get run away excess. You don't get seizure.

The excitable neurons are feeding back onto the inhibitory irons. So everything is kept in baLance. There is in too much information, there is in too much excitation.

Everything's in baLance. okay. So now you understand that there are mda receptors, and these are critical for many forms of neuroplasticity. You also understand that there are exciting itri neurons, which stimulate the electrical activity of other neurons, and that there are inhibitory ory neurons in your brain that inhibit or suppressed the activity of other neurons, and that you need exhibitors and inhibitory ory communication between neurons at all times, and that he has to remain in baLance, and that the nmda receptor is Normally just sort of sitting there, not doing a whole lot unless levels of neural activity are elevated above their Normal baseline. And then you can get changes in the neural circuits, and those changes can be very long lasting.

And let's not forget the piece of information most pertinent to today's discussion, which is about cademy, which is that kadee blocks, that nmda recept. And there's a kunder I keep coming back to, which is you need neural plastics ity in order to get relief from depression. So what researchers have discovered is that, yes, kadee blocks the N M D.

A receptor. IT actually quiet down neurons. IT prevents neurons from being as active as they Normally would be.

And yet somehow almost paradise IT increases neuroplasticity in brain circuits that are involved in mood, in reward, in self reflection, will get into what those brain circuits are in a little bit. The way IT works is that academy binds to the M. D.

A receptor present on inhibitory neurons, and in doing so, dramatically reduces the amount of inhibition coming from those inhibitory irons onto excitant ory neurons. When that happens, the excited storing neurons in specific circuits of the brain are allowed to increase their activity. They do.

It's called bursting. Bursting is a pattern of electrical activity whereby Normally one of these excited torn neurons is releasing glutamate in a pattern that might look or sound like this. IT actually doesn't make a sound in the brain. But if you were to record from one of these neurons, which people have done many times over, and then you were to convert the electrical signal in those neurons to an audio monitor, you would hear the firing, the action potential of those neurons as a, that's what that actually sounds like on the audio on sounds like a little bit of static. But if the Normal firing of the neuron is, which is the pretty typical baseline firing of the neurons in the relevant circuits to mood that i'm going to be discussing under conditions where a kadee has been brought into the system bines that nmda recept blocks the output of those inhibitory ory neurons onto the excitement ory neuron. Now the excited tory neuron is firing in birth.

And those bursting patterns of electrical activity are the absolute perfect patterns of activity that induce, not a short term, but long term changes in the neural circuits associated with reward, with dopamine release, with disappointment and with mood in ways that are directly relevant to suppressing or providing relief from the symptoms of major depression. Now, I realized what I just told you as a lot of information.

In fact, what I just described represents essentially what I would teach to an advanced under graduate slash graduate course, medical school course on neuroplasticity and how kadeem works. So keep in mind that we're having a discussion here that is, is a fairly high level. And if you could understand even a tiny fraction, even just one bit at what I just described, you're doing great.

You could understand more outstanding just to make sure that everyone's on the same page as we move forward because I do want to make sure that everyone understands kadee and how IT works because he does have these sort of cypher functions of engaging neuropathy in ways that aren't to obvious. If you just ask, you know, what does kedem an do when you inject IT? What does kate demean producing terms of a feeling state? And then, you know, how does somebody get relief from depression that can all start to get a little bit muddled unless you understand the following? I'm going to tell IT to you again and just very top count our terms.

Somebody takes a pill or an injection or subbing academy. IT makes its way into the bloodstream, and then IT makes its way into the brain once it's in the brain, IT bands to a particular category of recept tors called the N M D A receptor. The N M D A recept is a receptor that Normally quiet ent.

It's just kind of sitting there. IT doesn't tend to do a lot under Normal conditions of everyday life. However, the nmda receptions typical function. okay. So when there's no cademy in the body, your brain is to detect abNormal levels of neural activity and in doing so, recruit changes to sell receptors that that literally changed the neurons in ways that allow them to respond to that activity in the future without having to be under such big meta lic demand.

And they do that by recruiting more receptors that that are much in the same way as when you overload a muscle in the gym, IT will eventually recover if you love to recover. And IT will get stronger through the addition of a bunch new proteins, that nerve communication, that muscle will change the muscle and the nerve to muscle connection change. IT gets stronger, and sometimes they get bigger and stronger in the same way a neuron can change the way IT functions in response to experience.

And neurons don't know experience of life in any other way, expect the patterns of electrical activity and chemical activity that in pines on them. Okay, now keep in the drug buying to end blocks that nda recept. So the obvious conclusion would be that kedem ine prevents neuroplasticity, and that's not what happens.

We know that kadee actually induces neuroplasticity, and IT does so specifically in the brain circuits that control mood, the net consequence being improvements in mood. How does that happen? IT happens because kadee an bines two in blocks, those N M D A receptors on inhibitory neurons.

The inhibitory neurons are the neurons that Normally suppress the activity of other neurons. So when kato mine bines to the N M D A receptor, the activity of those inhibitory irons is reduced. And as a consequence, excited italy.

Communication between neurons in those mood related circuits increases. And the increases is in a way that recruits neural plastic that strengthened those connections and makes them more likely to be active in the future. Now IT is not the case, at least that clinical doses academie induce the seizures.

IT certainly can at higher doses, but at clinical doses when kadee suppresses the activity of those inhibitory urs and the excitation ory neurons ramp up their activity, they're ramming up their activity a lot and enough to create changes in those neural circuits associate with mood. And the changes are in the direction of making those neural circuits more likely to generate positive mood and less likely to generate negative mood. We're get into the specifics of those circuits in a little bit, but kadee is not creating the kind of enormous increases in exciting tory communication between neons that leads to that runaway.

Now the point of the discussion we just had over the last ten minutes or so was several fold. First of all, I do believe it's important to understand the key components of neuroplasticity, which is this remarkable feature of our brain in our system that we all have, right, this ability to change our own brain circuits, no other organ in the body, as far as we know, can direct its own changes, but we can direct our own brain changes. And the nmda receptor is absolutely critical for that.

I also think its important understand the difference between inhibitory ory and excitement ory communication between neurons, because that's just central to understanding brain function. Brain function is a series of accelerators and breaks. It's not all about neurons stimulating other neurons, is also about neurons preventing the activation of other neurons.

That's just central to everything, not just preventing seizures, but is central to learning, is central to vision, is central to hearing, is central to creative IT. IT is at the core of brain function. And the other reason to have the discussion we just did is that cademy has this incredible property.

IT can literally changed the neural circuits that generate mood, that generate your feelings of well being. But he does so throw a somewhat convoluted pathway, right? IT blocks the receptor that everyone thinks is involved in neoplastic. And in doing so, IT actually creates neuroplasticity.

Now, even though I just described all of that you over the last ten minutes or so, keep in mind that what I just described you as a process that actually occurs in the brain takes many, many days. IT involved sells changing gene expression, making new proteins, new receptors. Any time we say neuroplasticity, even when when you read about so called short term neuroplasticity, IT is happening over the course of at least many, many hours and more likely many days or even weeks.

So the process I just described of how kadee creates neuroplasticity through blocking e of mda receptors is very likely to be the process that explains the longer term changes in mood and affect that are associated with academic therapy for the treatment of depression. Now IT is possible that kadee blocking the N M D A receptor is also responsible for some of the immediate effects academy that people experience when they take the drug. The association, in some cases, euphoria and that sort of dream like state that I can put people into that is possible.

But it's very clear that the N M D, A receptor blocker is critical for the neuro plastic changes that are going to occur over the days and weeks following cademy treatment. And if you think back to our earlier discussion, when we were talking about the two time a week over three week type regime of taking cademy or some variant on that now IT might start to make sense as to why, yes, there is immediate and short term benefit of taking kadee for depression in the clinically appropriate setting. Of course, i'm not talking about recreational right now, but that also there are some durability of those effects that even after the three weeks of taking a demy twice per week, people often will experience weeks or months of relief from depression when they're not doing the weekly academic therapy sessions.

So that longer term relief that i'm referred to as durability of the treatment is very likely to be the consequence of actual neural circuit requiring. Now there's an additional and very important facet to this whole discussion about neuroplasticity in response to headey treatment for depression. If you recall that the first firing that induces that plasticity, I told you IT induces plus, see, I didn't tell you how.

Now you already could imagine some of the mechanisms that could be insertion of those new good to make receptors as those ammo receptors that we talked about. However, even for that to happen, a bunch of other things have to happen first. But one of the key ones understand is the thing I mentioned at the beginning of today's episode, B, D, N, F, which stands for brain derived neutrophil tor.

Brain derived new tropic factor is an incredible molecule I should mention that is one of many growth factors in the brain. And IT has its own set of receptors, IT bands to something called the track b receptor, T R K B, track b recept, when B, D, N, F binds to track b recept tres on neurons, IT does a lot of things. IT sets off a whole cade of things, including the insertion of new glutamate receptors, so that those neurons become extra sensitive, any input they get.

So that's one form of change that B, D N F can create. B D N F can also alter the overall shape of neons. IT can cause neurons to grow new branches so that I can receive new inputs from other neurons any time being.

An f is discussing popular books of the popular press. People will talk about IT as quoting fertilizer for neurons. I don't really like that term, because IT really under values, the total number of things that B D N F can do, B D N F actually can act as its own kind of europe transmitter, or you can actually stimulate other neurons.

And IT does a bunch of other things. But for sake of this discussion about cademy, I understand that that burst firing of neurons, that very high frequency firing of neurons, can invoke the release of B, D, N, F in ways that make those circuit s very plastic very quickly. And in addition to that, there is some evidence that kadee an itself may be able to cause release of b DNF directly without having to go through all of the mechanisms that I overwhelming you with a few minutes ago, or hopefully didn't overwhelm you, but that I taught to you a few minutes ago.

Now what's especially exciting about B D N F in the context of kedem in therapy for depression is that IT appears based on both preclinical and clinical studies. That be the enough isn't just one of the ways in which kedem in can invoke inal plasticity. And these improvements in mood IT may actually be required.

IT may be the central process to all of that. Now I can still be downstream of all that nmda recept of stuff that we talked about before. But there are several lines of evidence that suggests that academy induced release of B D N F is one of the core mechanisms by which kadee can relieve depression.

Now there are several lines of evidence to support what I just said about B D N F in the context of cademy. First of all, in mice that lack B D N F, they have no B D N F. They can't make B D N F because they don't have the gene for B D N F. We call those B D N F knockout mice.

In those mice, if you give them academy and you put them into that learned helpless sons task that we talked about a bit earlier, where you put them in the water and see how long they swim Normally, kadee would allow a mouse to swim longer, to fight for its life longer. Well, no longer does that in A B D N F knockout mouse. And the only thing that's different about that mouse, as far as we know, is the lack of B D N F.

And there ways to make sure that it's black A B DNF in the specific neons that are relevant. Everything we're talking about, not just that their limbs don't work as well, it's at in other words, all the appropriate control experiments have been done. That's preclinical data because IT comes from animal models addition to that depressed people who have a mute form of B D N F.

So these humans are not knock out for B D N. They can make B D N F. But the B D N F doesn't function Normally in those people.

They have a very reduced response to keep mean treatment for depression, suggesting that B D N F action is at least one of the critical functions that allows kadeem to relieve depression. And as I mentioned earlier, kadee can actually invoke the release of a bd enough and get this. There's some evidence that kedem in itself combine to the track b recept, that is, IT combine to the B D N F recept.

IT can mimic b DNF. So this is an entirely different way of thinking about kadeem. Then we Normally hear about nowaday. We here a lot about kadee and cademy and therapy.

We also hear, fortunately, about some of the problems of kadee abuse, and we will talk about some of those concerns a little bit later. And we hear about b DNF, this so called brain fertilizer. But rarely, if ever, do we hear that academic itself can mimic the effects of b DNF in the brain. But researchers and clinic are definitely paying attention to this.

And it's starting to raise what I consider a very exciting model of how kadee could provide relief for a depression, which is that is acting as a growth factor in the brain, or at least it's mimicking the action of growth factors, allowing the specific nerval circuits that control things like mood, outlook on the future, self reflection is set, allowing the circuits to change in ways that provide significant relief for major depression. And in doing so, and this is a very important point, IT appears academy is relieving depression in ways that are entirely different from any other kind of treatment. Now, in an earlier episode about slyvia and its potential role for the treat of depression, I went to to a lot of depth about how soliciting ban can induce neural plasticity to provide a relief for major depression in certain individuals under certain conditions.

I do want to highlight that because indeed, it's another case where neuroplasticity is involved. But in that situation, as some of you may remember, or if you don't worry or tell you right now, IT was a pretty straight forward model. Cl sivan looks a lot like serotonin chemically, except that silvan vines a particular reception when that recept is bound.

IT allows these brain wide changes. Those brain wide changes seem to change one's s reflection on oneself, so called the go to solution, changes in move that are stable over time and set at set up. IT was all pretty straightforward with academy.

It's clear their multiple mechanisms involved. And perhaps most importantly, with kadee, is that immediate relief that occurs IT day off or close the day of treatment and in the days afterwards. And it's that long term relief that very likely is the consequences.

N, M, D, A receptor suppression burst activity in neurons within these mood related circuits. B DNF, being released and changing neural circuit, strengthening them in order to give elevated mood as a consequence of that bursting activity. And kadeem mimicking B D N F.

In other words, keates mean acting more or less like a growth factor in the brain in order to make sure that whatever changes occur in those neural circuits to elevate mood are durable, that they really are reinforced in last over time. So basically, i've discuss two major mechanisms for how kadee can induce your plasticity, leading to movements in mood and affect that gives really for depression. Those two mechanisms are linked, or at the very least, are happening in parallel.

They're happening at the same time in the brain. Now just to make matters more interesting, there's an incredible twist into this whole thing of how kadee ine works. And when I say how kadee works, and not just talking about how kadee provides relief for depression, i'm also talking about why people use kadee for recreational purposes.

And this is the following. Yes, kadee has all these impacts on excited turn irons and hibachi irons. B, D, N, F.

At a. But academy can also buying receptors in the opioid pathway. Now what is the opposite pathway? Don't worry here. I'm not going to hit you with a lot of details, but we've all heard of the opioid crisis by now, at least most of you have.

The opioid crisis refers specifically to people taking exogenous oppos taking opiate, right? It's taking pills that activate particular receptors in the brain that lead to analgesia in some cases. So pain relief that lead to changes in mood, there is a lot to be said about the O, P, O, I crisis.

It's called the crisis for reason. Many, many people are addicted to those compounds. That's a discussion for another time. Keep in mind that the receptors those drugs bind to are oped receptions, and those receptors ors that you and I all have, by the way, do not exist in order to buying drugs that are made by five macular al companies.

They exist in our brain and body to buying to these so called endogenous naturally made oids that we all make. And those receptors have different names of the new O P O ID recept. The capa O P O ID receptor is set.

They tend up the names of greek letters to differentiate them. Now, Kevin combined to various oppoi receptors. And when opioid receptors are bound, we know that creates certain effects, things like pain relief, things like changes in psychic states association, for example.

If enough of them are bound, you can get you four states under certain conditions of high dose binding academy to those opioid receptors. You can start getting into planes of anesthesia where people lose consciousness and actually have no response to pain whatsoever. If you recall the clinical studies we talked about earlier where kadee was used to relieve depression.

Well, the dosage used in that study, as you recall, was half a milligram per kilogram of body weight, that is the dosage that will induce these associated mild euphoria, those sorts of states of mine, but where people are still conscious when you start getting to dosages of academies that are in the range of one, two milligrams per kilogram of body weight. Now you're talking about anesthetic doses, and when that happens, you're going to get full parking, full saturation of all the potential receptors academic combine to those nm D A receptor ors. It's going to block those.

It's also going to bed to the social new oppoa reception and maybe the other type as well. For those of you that want to know you if ice anos, also the capa type oppoa receptors. And so what we've got here is a drug, kadee, that is hitting two different systems, the glutamate related system and the inaugural opioid system.

And researchers and clinicians have logically started to ask whether or not summer, all of the effects academy are due to the opposite system, and they want to know which affects those are. Now this is where things start to get really interesting, both in the context of clinical treatment of depression and recreational use. First of all, when people take kadee again, IT enters the bloodstream and IT goes into the brain.

But IT is metabolite ed to something called H N K, which is high draxy nor cademy. Now I don't expect, you know what hydrox y nor kadee is, and I don't expect you to care about IT until I tell you what am about to tell you, which is that hydrox y nor cademy has an incredible specificity for the new opioid receptor and maybe that cap of opioid reception as well. In other words, when we talk about chemmy, that's the drug people take when IT goes into the body, is converted into yet another drug, and that other drug, hydrox y nora's my, is selectively activating the opposite system.

So this LED researchers to ask a very important question, which is when a human being takes kk adee in order to treat their depression and they get some relief from depression, is that the consequence of neuroplasticity ges in all those nmda glutamate b DNF related circuits that we talked about before? Or is IT the consequences, something happening in the opposite system? You can ignore the fact that cademy has this property of binding to these O P O receptors because they have such a powerful effect on our thinking, on our mood, on our state of consciousness.

It's entirely reasonable that the opposite system could be a major player, if not the major player, in this whole depression relief thing, and maybe even in the creation of associated symptomatic gy when people take kadee recreationally. So what researchers slash clinicians did is they undertook a series of experiments where they gave people cheat, mean for the relief of depression, but they also blocked the opioid recept system, and they did that using a drug called now track zone. So what i'm about to describe, he was a study done by my colleagues at stanford school of medicine, namely doctor or newlin Williams and Allen shatner g and colleagues entitled a tannian of anti depression and anti suicidal effects of kedem ine by oppoi receptor antagonism.

And as a consequence of me reading you that title a moment to go, you now already have the conclusion of the study. What they observed is that when people we're giving academy, they got relief from depression. That wasn't surprising.

Again, many studies have shown that before, since the early two thousands, if, however, individuals were given now trick zone to block the opp o recept pathway and they were given academy, then the entire depression effects of kadee were no longer observed. Now that suggests that IT is the opioid receptor, and that's responsible for the entire depression effects of cademy. And perhaps this H N K, this hydroxide, or cademy, which is the metabolic cademy, is the way in which academy Normally relieves depression.

Now, a lot of people took note these studies because, after all, there are probably dozens, if not hundreds, of studies looking at the effects of aiming on all that nmda receptor stuff. And indeed, neuroplasticity and mood related circuits can be discounted as one way in which cademy provides relief from depression. But what was very interesting is that in people given cademy and now track zone, those people still experienced the immediate effects of academy, the mild euphoria, the association, the feelings that one would Normally expect when people were under the effects of cademy but what they didn't get, or the longer term changes in mood that we would call relief from depression.

Now, of course, the goal of modern psychiatric is to treat depression, not to block the effects of these drugs that are capable treating depression. Now what the study does, and by the way, there are several studies like IT that support these general set of finding that part of the critical role of cademy in providing relief depression is to activate the opposite system. But what this study does is that really points to the fact that when we say kadee e and treatment, or we talk about somebody taking kedem recreationally, for that matter, we have to pay attention to what's happening while they are under the influence of the drug.

We also have to pay attention to what's happening in the days and weeks after they are under the influence of the drug. And perhaps most importantly, this calls to mind a really important idea, which is that whether not you're talking about kadee induce reality from depression, or solicit an induced relief for depression, or md ma induce relief for ptst, a topic that I covered on a previous episode of this podcast, we have to step back and look at the idea that the effects of the drug that people experience, whatever those may be, because obviously it's going to spend on what particularly drug they those immediate effects may not actually be related to the long term clinical benefit of those particular drugs. Now I realize that many people might not like that idea, and Frankly, I don't actually think that's the way that IT works.

I don't think it's going to be an either or a situation, however, because drugs like academy suicide de and md ma have such profound effects on people's psychic states when they are under the influence of them, and because, at least in the proper clinical setting and use, they do seem to provide impressive relief from a lot of these psychiatric chAllenges like depression and ptsd. People naturally corporate those two things. They couple those two things.

In fact, they collapse those two things and presume that they're experience of what they saw, what they heard, how they felt while they were under the influence of the drug was actually the stimulus that created the relief from their clinical condition, like depression. But what these data on combined treatment with kedem and nell track zone to block the europium receptor really show us is that that may not actually be the way that IT works. IT may be that the effects of a drug like kedem in that one experiences, while interesting, perhaps even profound, perhaps great insight, comes to one.

When they do that, there be in the proper context, IT is not clear at all that IT is that experience in the effects of those drugs in those immediate minutes and hours that actually what's causing the relief from depression. Now again, I don't think it's an either or. I'd like to view the whole situation more or less as a sort of wave front that the experience that one has subjectively, while they are under the influence of a drug like kedem or silver band or md ma, sets off a series.

And in fact, multiple series. Is that a word? Multiple types of processes in the brain, some of which rely on things like nmda recept, B D N F etta type neuroplasticity, others which rely on the opp o to receptor pathway, and that each of these have different time courses, such that some provide immediate relief in the days and hours after treatment, some in the weeks after treatment, and some more durable, long lasting changes that can occur over month or maybe even years.

And a really important thing to underscore in the context of all this is that throughout today's discussion, we've been talking about drugs and receptors and really from depression. But what we're really talking about here are people who get really from depression, and almost with certainty when they get released from depression, they are also starting to do other things. They are going back to work.

They are engaging in relationships again. They are viewing themselves differently again. Hopefully they're getting morning sunlight and exercising and eating well in doing all the sorts of things that we would call anti depressive behaviors.

And IT is impossible to separate the positive behavioral consequences of a drug treatment for depression from the drug itself in a way that lets us say, okay, kadee relieve depression. And then as a consequence, people went in, did a bunch of behaviors that we're healthy for them, were stopped engaging in behaviors that we're unhealthy for them. So we can think of behaviors as pro depressive, orientally depressive.

In fact, we know that one particular behavior that is viewing blue light in middle of the night between hours of a eleven pm and four am is known to invoke a proud depressive circuit. IT involves a structure called the haben la. Talk about this on previous podcast.

IT tends to lower doped and increase court is all in the day, is following that exposure to light at at sada. So there are pro depressive behaviors. And there are anti depressive behaviors. We know that viewing morning sunlight, getting regular and sufficient amounts of quality sleep, proper nutrition, proper social engagement, there is now a pleath, a of quality research pointing to the fact those are true anti depressive behaviors.

So we can never separate out the effects of a drug from the effects of a drug that feedback on, and combine with the effects of the drug that one is hoping for, in this case, depression relief. okay. So i've been book ending this conversation about cademy at two very divergent levels, meaning we've been talking about high level stuff relief from depressive symptoms.

We haven't been going into a lot of detail about that, but that's pretty high level. We're talking about thought changes, behavioral changes. They we're calling anti depressive right? Changes in mood and effect that are positive, positive anticipation of the future at seat ta. And then we've also been talking a lot at the other end, which is very reductionist down at the seller molecular level, dug by receptions and binding of receptors in neuroplasticity and track b and all that stuff we completely neglected, meaning I have completely neglected until now.

What bridges those two levels of understanding? And what bridges those two levels of understanding are the neural circuits that actually change when one takes academy, whether not those changes occur quickly, whether not they take a longer period of time, whether not they involve and M D A receptor or or the obo recept systems or both. We know that certain neural circuits change when people take kadee in these patterns of dosage and frequency of about half a milgram per kilogram.

And again, that's the injected form twice per week, over three weeks, and then they get some durable resistance to depression. Fortunately, we can talk about those neural circuits without having to bring about a lot more nomenclature, a lot of new language. And I say, fortunately, because I realized today you've been hit with a lot of new terms.

Now i've already mentioned one of the key brain structures, and that's the haenel la. A few moments ago, I talked about the haben ella and the context of people who get too much bright to light exposure in the ddd of the night that activate the hubble. Ella, it's a sort of a disappointment circuit.

We can call IT that because we know that, that leads to prodest sive symptoms in the animal models and very likely in humans as well. And IT does. So we know by reducing dopamine and increasing cortile, there is evidence that when people undergo kato mine therapy, connections between the haenel la, what we can broadly just talk about is the structure involved in generating a feeling of disappointment.

The connections be the haenel la and the reward circuitry of the brain, which you've talked about several times before on this podcast. But for those of you that are familiar with IT, this is the so called olympic reward pathway as areas like the venture al tegmental area, the nuclear circuits, don't worry all about those names. Just know that this is a brain area that is chock a block full of neurons that release dopamine in which is a molecule that tends to increase mood, increase motivation.

In many ways, we can think about IT, at least for sake of this discussion, as anti depressive. So what we've got is a structure, the haenel la, that Normally provides inhibitory. And now you know what that means in habitats, input to this reward pathway that releases dopamine.

And when people take kadee, that inhibition is lessen, such as the reward pathway is more available for engagement through daily life activities. Now I say available for engagement through daily life activities for a very specific purpose, which is that all of the changes in neural circuits that we're talking about that can come about from taking a drug. Well, those changes don't actually do a whole lot unless those circuits are reinforced by particular behaviors.

So this relates back to what I said just a few minutes ago about pro depressive and anti depressive behaviors. Somebody can take kadee and potentially get relief from depression, but if they continue to engage in pro depressive behaviors, they are not going to get much of any relief from depression. Conversely, if somebody takes academi and they are reducing the amount of output from this disappointment irk this habu la to the reward circuitry of the brain.

And they do engage in behaviors such as seeking out work that stimulates them, seeking out social engagement, taking good care of their body, their mental health, their physical health eeta. Well, those circuits are not designed to respond to, to me, they are designed to respond to particularly patterns of thinking and behavior. So again, we can't forget that when we hear that a drug causes plasticity and the given neurosis irk IT, what is doing is it's biking the baLance or the probability that those neural circuits will be engaged by certain activities, but one still has to engage in those activities.

Now unfortunately, when people tend to have elevations in mood, they tend to move around more. When they tend to move around more, they tend to engaging in more things. When they tend to engage in more things if they have a positive outlook on life, presuming they are engaging in adaptive things, things like social relationships, job related, school related, go related behavior, so it's important to understand that discussion of neural circuit changes in response academy is really discussion of neural circuit changes in response academy that shift one's overall system toward having yet further neural circuit changes in response to daily activities and thereby bolstering health, where in this case, mental health.

Now it's also important understand that rarely, if ever, does a drug provide relief for some sort of clinical chAllenge in just a one trap. Kind of the way to think about this is that most mental processes, and certainly things like depression, are a two way road. You have pro depressive behaviors and circuits, and you have anti depressive behaviors and circuits.

And so perhaps they won. Be surprising to you that there's evidence that kadee treatment can reduce the output from the humana to the reward pathway, this disappointment to reward pathway weakening that making the reward pathway more available for engagement through thoughts and behaviors that are anti depressive. And in addition to that, I can further bolster. The neuroplasticity within the reward pathway itself, in particular, with connections with the frontal cortex. And for those of you that aren't familiar with the frontal cortex, your frontal cortex does a lot of things.

But one of the things that your frontal cortex is absolutely critical for is for establishing context dependent strategy, meaning for allowing you to say, okay, and a given circumstance, what should I do to get the results I want? In another circumstance, what should I do to get the results I want? It's not strategizing of the manipulative type, although I suppose you could be strategizing of how do I get what I need from this social connection, how do I get what I need from my goals and exercise, how do I get what I need from my goals in terms of work or school at set up your frontal cortex is that party or cortex is always turning ideas, is always wondering, am I doing well and are not doing well, and is adJusting your behavior accordingly.

So it's now established that kedem ine can improve connectivity, that is, that can strength in the connections between areas of the brain that are associated with context dependent strategy building and these reward pathways. In other words, IT makes people more sensitive to whether not they are getting the results they want from their efforts and to how to adjust their efforts so that they do get the results they want from those efforts. And there's other evidence that N M D A receptor blockade is not the way the kadeem provides relief from depression.

Namely, there's a drug called memento. Ine is used to actually to treat alzheimer, and IT too is an nda receptor blocker, and IT has no entire depression effects. Now, as you recall, academy is a dissociative anesthetic, and one of its primary effects is to create this feeling of association. For those who that aren't familiar with what association is, association is where people feel separate from their body. They can still think, but it's as if they are observing themselves.

In fact, in anticipation for this episode, I consulted with several different colleges in the department of psychiatry at ten for the school of medicine, and one of them describe the effects of adem as described by a patient of theirs who we are taking cademy for the treatment of depression. And that patient described IT as observing themselves, thinking, observing themselves, doing things, even though they were lying completely still, and perhaps most importantly, describing themselves as being above their body and actually looking down on themselves. From the third person perspective, now that I realized as a foreign experiences to most people, but of course, there are people who experienced association, even while not on academy.

And as many of you know, association is actually one of the primary symptoms of P, T, S, D. And trauma. So this raises that sort of can understand, why is IT that a particular state of mind that associate with P, T, S, D.

And trauma. And in some cases, depression itself, which is induced by a drug like kadee, can provide relief from depression. And that all goes back to the neural plastic changes that we talked about earlier, and more likely, that changes in the new opp o receptor system that we talk about earlier.

But nonetheless, the associative effects academy are so profound for people that take them that I thought i'd spend a minor to explaining what likely causes that associative third personal of self effect. And in so far as we know, IT has to do with an uncoupling of certain brain circuits, in particular neocortical brain circuits. The neocortex is the part of the brain, the lumpy outside part of the brain, that's associated with action planning.

IT does a lot of things really is involved in sensory perception, involved in speech generation, many, many things. But the neocortex has connections to other regions, which are called subcritical regions. And IT seems that when people take kadee or fancy cling in pcp, there's an uncoupling of those networks and quieting of those networks that starts to create a different dominant rythm in the brain.

Some of you may be familiar with rythm in the brain, so called alpha rythm, or alpha patterns of activity that just dominant patterns of activity associated with particular brain states. So for instance, alpha brain ways are associated with alert but calm, relaxed state of mind, where thoughts are sort of free flowing. It's a little bit dream like, but IT isn't really like a dream where anything can happen.

IT has a structure to IT. When people take kadee, the alpha pattern of activity is completely abolished, at least for the duration of time that they're under the influence of the drug, which typically is about an hour to two hours or so. And the different pattern of brain activity, which is called the theatre pattern of brain activity, starts to really emerge as as if IT gets unveiled.

And that data pattern of activity is the one that's associated with a dream like state, is the one that resides more, less at that liminal border between wakefulness and sleep. If you've ever been falling a sleep and you are thinking something like you are running and you kicked your leg is very likely that you are in a data pattern of activity in your brain at that moment, just prior to when you woke up. Well, as when you you're more alert, you see patterns of activity that are higher frequency, things like alpha, beta, idms and so forth.

So academy produces particular patterns of brain activity and the sense of association when it's taken at sub anaesthetic doses. If you were called the clinical study we talked about earlier, they injected half a milligram per kilogram of body weight in order to provide depression relief for those patients. When people take academy, they will take IT by different routes of delivery. And now here we have to expand our conversation to include both the clinical context, research studies and recreational use. Now I do that because typically when people take kadee in a study, in a clinical study, they will get an introvert us into the vein, or an introvert scutter into the muscle injection of half a milligram per ki og m body academy.

However, when people are taking academy recreationally, or when they are accessing academy legally by prescription and taking IT at home, which is becoming a more common practice, they will often take IT orally in pill form, or they will take IT subsequently by putting IT under the tongue in their cheek and the net so called tros dissolves and academy goes into their system. Now, important thing to understand is that when people take adem orally, only twenty five percent of the active form academy mixit into the bloodstream. And when they take IT subsequently, typically only about thirty five percent of the total amount of academy they take is converted into meta icc active kedem that acts on the neurons in their brain.

So when you hear about the dosage is used in studies, they are going to generally involve injections of cademy and far lower doses of adem. Then when you hear about people taking academy early or subsequent ally and so on, for instance, I wait two hundred and twenty pounds. That's one hundred kilograms.

So if I were to be in one of these studies, which I have not been, but if I were, I would be given fifty milligrams academic by way of injection. However, if I were going to try to achieve the same amount of active academy in my bloodstream and brain as I would through injection, I would need to adjust three times as much ackee demand by way of pill, and perhaps a little bit more by way of substance. Ual academy, if I wanted to get the same effects.

So if I were to take fifty milligrams by way of injection in a study, and I went to a different study and they said, okay, we want to recreate that effect. We're going to give you a pill. Typically, they're going to give me one hundred and fifty milligrams of academies in the pill form or two hundred milligrams academy in the tros subsequent al form.

Now it's really important understand this dose dependence according delivery business because I realized that nowadays, especially a lot of people are taking kadee through legal sources, so they're accessing IT legally, but they're taking IT outside the clinic. And more typically, they're taking IT not by way of injection, meaning they are taking higher dose kedem and they're taking IT subsequent ally or orally. So it's very important understand this dose dependence according to motive delivery business.

Now in anticipation of this episode, I put out a request for questions about kadee on twitter, and I got many, many questions, some excEllent ones they're in. But one of the more common questions was what is a key hole in scientific terms? A K hole is what used to describe the subjective experience of when somebody takes kadeem, typically recreationally, and they end up in basically a pu da, an estimated state.

What that means is that they took a dosage that, for them, put them beyond the boundary of the sub anesthetic dose and has them transitioning into the anesthesia level dose academy. Now, I mentioned everything I did about dosages before, because it's very important to know that different people, even if they are of equivalent body weight, are going to respond to a demy differently, depending on how quickly and how thread they metabolize adem. So in the clinical context, injections of kadee into the vain or into the muscle are done at as half a milligram per kilogram.

Those and they have clinicians there, they have researchers there who are paying attention to whether not the person is in a associated state, if they're still conscious, and to see whether or not the person is going into full blown anesthesia. Now that's one of the values of doing kadee en in the context of a legal clinical setting. However, i'd be reused if I didn't acknowledge that a lot of people are getting academy legally but then taking IT at home hopefull, not alone.

Hopefully, they're someone there to monitor them where they're in session with their physician over zoom. That's actually happening more and more these days through tell health. But that itself also has certain risks, right? Because if the purchase need something and they don't have someone there immediately in the room to take care of IT, that could be a very problematic situation.

And of course, there are situations where people are taking kadeem recreationally regardless of how they are requiring IT. They're taking IT and they're guessing how they are going to respond to IT based on some crude understanding of dosages. But when people talk about A K hole, what they're talking about is taking kadee at a dose that for them takes them beyond the mild or perhaps even an extreme association and starts placing them into full blown ana cea.

And that itself actually can be dangerous going into ana sesia like planes of consciousness, while not always deadly, can be deadly. And IT certainly can be, and has been deadly when people start to combine IT with other drugs, in particular drugs like barbiturates or alcohol. So I want to be very clear that the dosage ranges that you hear about when hearing about kadee are extremely broad, and so is the variability to anyone given those.

And so too is. The response to a given dose in a given person, depending on the route of delivery, you need to be very careful about the ability of academy to take you into deep, deep planes of unconsciousness and in some cases, death. And of course, as with any sensitive, one needs to be extremely cautious about doing anything like driving or even walking in traffic or walking anywhere.

In some cases, if one is under the influence academy. Additionally, for those of you that are secure, prone, either due to epilepsy or prior head injure or maybe a seizure prony, you don't know that can mean can to do seizure and IT should be completely obviously, you know why that's the case. Kadee blocks N M D A receptors on inhibitory neurons and quiet their activity, which of course can lead to run away excitation in the brain if you are seizure prone.

When I put out the request for questions about academy on social media, I also got a lot of questions about the different forms of cademy. When I say different forms, that included questions about whether not intro was Better than oral, was Better than substance ual at tara, to be fair, with one exception, the different modes of delivery probably relate more to dosage that actually get some metabolize into anything else. What I mean by that is most people don't know how to equate the clinical dose of half a milligram per kilogram of body weight into a dosage to take earlier, subsequent ally, or in some cases, by the way, people will take erectly.

And the reason people take academy actually, is that rectal administration bypasses the liver, and indeed, kadee can be hard on the liver to metabolite. IT can dramatically increase liver and signs. So often times, people that are taking academy frequently and don't want to create damage to the liver, they will opt for a record administration.

Now I realized that unless it's somehow related your profession, anytime somebody says interacting IT raises a few eyebrows ers and people lean back a little bit, and I get IT. In a future episode of the podcast, I promise to distinguish between the different modes of drugging tabligh m, depending on whether not people take something only subsequently by injection correctly. Another common question I got when I solicited for questions about kadee on social media was about the r versus s versus R S.

Forms academy. And I must tell you, that sent me down a deep, deep, rabid hole of research in which I discovered very contradictory evidence. For instance, I could find papers.

I did find papers that said that the r form of kadeem had a much greater affinity for the mda receptor, then did the s form of kadee. I also found reviews that said the exact opposite. okay.

And there I was sitting with the two reviews in front of one another, wondering if there was something wrong with my visual system, until I called a colleague, dr. r. Nolan William, who's a triple board certified in neurologist, psychiatrist at stanford school of medicine, whose laboratory specializes in the use of kadee for studies of treating depression and for treating depression in the clinical population.

So I asked him, what's the deal here and getting very contradictory evidence, and he spelled IT all out for me. IT appears based on the clinical data in humans and on binding studies that the s form academy is more potent, that is, IT can more robustly buying to the M D A receptor. And in addition to that, the s form of cademy tends to produce less association at a given dosage.

Then does the combined S R form of academic or pure r cademy. He also added and sent me a study that all link in the shown out captions that there was recently clinical trial of our ademi. So pure academy alone and IT failed to relieve depressive symptoms.

So I said, great. Thank you so much. This is now all made very clear to me that academy is the preferred form.

IT produces less association and IT provides Better depression relief. And then he said, no, actually, it's a little more complicated than that. IT appears the situation is the following. The combined S, R form of Katherine seems to be the most potent for relieving depressive symptoms. The s form of cademy is second best in terms of providing relief from depressive symptoms and is the one that's most commonly prescribed nowadays by nasal spray, by oral dosing, by subway ual dosing. And it's what is typically given by way of injection in clinical studies where they do injections and IT appears that the r form academy is the least potent and effective in treating depression.

Now I realized that by putting this out into the larger world and assuming that there are experts academy out there, either by way of user, by clinical study of their own, that I will get a lot of comments back saying, no, actually the r form was more effective for me than the s form versus the S R form set a. Just to reiterate, from the clinical trials that have been done, we know that the combination S R form is more potent and effective than the pure s form, which is still more effective than the pure r form. So that's what we know now based on the clinical studies.

But of course, I acknowledge that any time a drug is out there as a clinical tool and it's being used recreationally, that people are going to explore and they are going to experiment and they are going to find what works best for them. So I certainly invite feedback about what has worked best for you, hopefully, in the clinical context. So whether not people have used kato mine prescription from their doctor, or whether not they participated in a clinical study, or where doing IT recreational, I imagine that I will hear about those experiences, and I will take note of them.

Another commonly asked question I received was, what about microdot of academy? There's a lot of interest in microdot nowaday. People are microdot in suicide de, and people are micro docs, all sorts of things, hoping to get some of the same effects as the micro doses.

But by using dosages of compounds that are below what wouldn't do say in the case for suivant hu cino or in the case academy, below what would induce the kind of association and you four effects that one would have to lie down for a few hours and disengage for the rest of the day. I consulted with my clinical colleagues about this, and they told me that at present, meaning as of yesterday, there is zero publish clinical evidence that they are aware of, and by way of extension, that I am aware of, in which micro do sen. Kadee has been affected for the treatment of depression.

All of the positive effects on depression that i've talked about during this episode are glean from studies where people use this half milligram per kilogram dosage academy, or its equivalent, by way of some other route of administration, not injected, but oil or bilingual. So are there any benefits to micro dos academy as far as the scientific and clinical literature that's published as of today is concerned? The answer is no.

okay. So today we covered a lot of information. We talk about what kedem in is.

Remember, kedem and pcp, Angel dust, very similar compound, both blocked the N M D. A receptor. We also talked about what sort of objective affects that produces association and mild euphoria.

And third person on himself, that's the association. When taken at low dosages and when taking a higher dosages, IT can induce full blown anesthesia and put people into subconscious states. And there's actually a potential, even for seasons and debt, if the dosage just high enough for that person. Again, I want to emphasize that people's dosage sensitivity varies tremendously. Round of delivery will impact that.

And on and on, we also talked about how the nmda recept itself and the activation of this incredible molecule, B D N F brain arrived in a trophic factor seem to be important for at least some of the entire depressive effects of cademy, both in the days and weeks following academy administration. And in addition to that, I described how academic impacts the opioid recept tor system and how we simply cannot overlook the involvement of the opposite receptor system in producing the anti depression effects academy. And we also talk about the brain circuits and the brain waves associated with associated states, and the depression relief that seems to arrive for many people who take cademy.

And I tried to highlight some the unique features of cademy. First of all, that IT does seem to provide depression relief where other approaches have not, but that the depression relief tends to be pretty short lived unless it's applied in this multiple per week over multiple weeks kind of fashion to produce what I call durable changes, which almost certainly involve changes in neuroplasticity, that is, rewiring of brain circuits. And another key point that I highlighted is that we always have to remember that when thinking about how chemicals like kedem, or any other substance for that matter, can modify brain circuits in order to change them and provide relief from depression or some other psychiatric chAllenge, that always, always, always, there is a requirement for engaging in entire depressive behaviors as a way to further reinforce whatever positive changes have come about through the drug treatment.

As a friend and colleague of mine, whose expert in this area once so apply, said, Better living through chemistry still requires Better living. Thank you for joining me for today's discussion about kadee. If you're learning from and or enjoying this podcast, please subscribed our youtube channel.

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