Welcome to the huberman Lab podcast where we discuss science and science based tools for everyday life.
I'm Andrew huberman, and I'm a professor of neurobiology
and Ophthalmology at Stanford school of medicine.
Today we are discussing ketamine. Ketamine is a fascinating compound and it's one that nowadays is being used both clinically for the treatment of depression and suicidality and PTSD. And it is also a drug that is commonly abused. That is ketamine is often used recreationally and it has a high potential for abuse. So today we are going to discuss both
'The the research on the clinical benefits of ketamine as well as the risks of ketamine. We're going to discuss the mechanisms of action by which ketamine produces what are called dissociative States? I will Define for you. What a so-called k-hole is in. Scientific terms, I will talk about dosages of ketamine. I'll talk about delivery routes of ketamine and throughout, I will be emphasizing both the clinical benefits and the risks, that is the potential harms of using ketamine out of the appropriate clinical context. So by the end of today's episode,
You will understand thoroughly what ketamine is how it works in the brain and body to produce dissociative States and to relieve depression and you will understand how it can actually change neural circuitry. This is an important thing to understand about ketamine the acute or immediate effects of ketamine. While one is under the influence of ketamine are, just part of the story of how ketamine, modifies, the brain for the treatment of depression, suicidality, and PTSD. And by extension, when people use ketamine recreationally,
And there are those immediate acute effects of ketamine, 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 you're nervous. Systems ability to change in response to experience, and we will be talking about neuroplasticity, not just in the context of ketamine, but as a general theme, for how your nervous system changes, anytime you learn anything. And in that discussion, you're going to hear a lot about bdnf or brain. Derived neurotrophic
Brain. Derived neurotrophic factor is a critical molecule for all forms of learning and memory and changes to your nervous
system.
So in addition to learning about ketamine and how it works clinically and its relevance to recreational use and abuse. You will also learn a lot about neuroplasticity and bdnf 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 desire and effort to bring zero cost to Consumer information.
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Okay, let's talk about ketamine. I realize that many people have heard of
ketamine,
but most people don't realize that ketamine is very similar to another drug called PCP or phencyclidine which goes by the street names, angel dust or Sherm it has 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 lore was that PCP would eliminate
Nate people's perception of pain and would make them violent. You know,
you'd hear these stories in 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 or 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, methamphetamine, it was lumped into that category nowadays. When we hear about ketamine, rarely do people mention that ketamine and
CP actually have the same mode of
action more or less. Okay. I'm not talking about the specifics. I'm talking broadly. They have the same mode of action in the brain
that both of them are dissociative anesthetics. And nowadays, usually when we hear about ketamine, we are hearing about its benefits. We are hearing that it
can help cure depression. We are hearing that it can help reduce or cure suicidality that it can be used to treat
PTSD. And indeed all of that is true in the appropriate clinical
context at the appropriate dosages and given that the appropriate frequency
ketamine has proven to be
A miraculous drug for
some people, not all people
for the treatment of depression,
suicidality and PTSD.
That said, ketamine also has a very high potential for abuse and so it may come as no surprise, that we often hear about ketamine nowadays. Also, in the context of its use at parties, you hear about
people going into so-called K holes which is a particular State associated with
overdoing, the dosage of ketamine a
little or a lot. We'll get back to that a little bit later.
What it is, how dangerous it is etcetera. In any case, ketamine is an incredible drug very similar to
PCP phencyclidine
and it is a drug that nowadays there is crossover between the clinical uses of ketamine for treatment of depression, Etc. And its recreational use. What do I mean by that? What I'm referring to is people accessing ketamine legally,
for the purpose of treating depression,
but taking that ketamine out of the clinic, out of the doctor's office, which is a very
different set of conditions than most of the studies
that have been done on ketamine and its role in depression
and not surprisingly.
If there is increased access to a drug like ketamine, really any drug
that has a potential for abuse. Then we also see an increase in
the number of people that are using that drug
recreationally and some of them do
indeed get addicted to
ketamine. So I know many of you are probably wondering, can you get addicted to ketamine? Indeed, people can get addicted to ketamine. There are some people who like its effects enough that they find themselves.
Held to use ketamine, even though the use of ketamine is degrading their overall life
performance. So work school, relationships, finances, Etc.
That said
ketamine does have these established clinical uses.
So nowadays the landscape around ketamine
is 0 so different than it was 10 or 20 years ago when it was lumped, very
closely with PCP phencyclidine and really, just looked at as a drug of abuse, there were some early cases in the 1970s of the use of ketamine in
order to treat.
It PTSD. This was mainly in soldiers in Vietnam or people coming back from
Vietnam but really the clinical use of ketamine for the treatment of depression, suicidality.
And
PTSD 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 ketamine
in the clinical and recreational
context. So how is it 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
As 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 explain to you a little bit about the history of depression and its treatment.
What we observe starting about the middle of the last century. So around 1950 but
really taking off in the early 1980s and 90s is the so-called mano, a mean,
hypothesis of depression, monoamines as the name, suggests are synthesized from amino acids. That's a good way to
Remember monoamines
monoamines include things like serotonin, dopamine
and norepinephrine. Although there are other monoamines as well.
Monoamines art neurotransmitters 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 neural circuits in lots of different brain areas, as well as within the body, right? Your gut has sir
Tone in and need serotonin. Dopamine, also plays important roles in the body. Etc, etc. The mono a mean, hypothesis of depression is really centered around.
The idea that it is
deficiencies in these monoamines either serotonin or dopamine or norepinephrine 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
monoamines in any form of depression.
However, it is very clear that drugs
That
increase certain monoamines so drugs like Prozac or Zoloft, the increase serotonin or drugs, like blue, prior on, which is often called Wellbutrin, which is its commercial name, which increases dopamine and
norepinephrine can often provide
relief for certain symptoms of depression in some people.
However, what we've learned over the last 30 or 40 years, is that drugs that are designed to
increase certain monoamines in order to treat depression
only work in about 40 percent
of depressed people that take
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 it 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 Zoloft or Paxil or from prior own find that the side effects which include things like dry.
Mouth, although more commonly reductions or increases in
appetite were vast reductions in libido
or changes in their sleep, patterns, Etc. 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 60% of depressed people who do not respond to those drugs at all. Now, I want to be very clear, things like ssris things, like Wellbutrin, have helped a tremendous. Number of people get relief from depressive symptoms and in many
Cases have warded off suicidality 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 40%, but
for all people suffering from depression.
So that's where ketamine enters the picture prior to the 1990s. They were mainly studied in
neuroscience and pharmacology, Laboratories for their abuse.
He's and for their anesthetic properties. So ketamine is a dissociative 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 your anesthesiologist about, you know, what sorts of drugs are you, giving me to go under? What sorts 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 into anesthesia, your anesthesiologist is rarely giving you just one.
One Drug typically, they're giving you one drug to, you know kill off
a little bit of anxiety and
maybe eliminate a little bit of pain sometimes and then they'll give you another drug to drop you into a deeper plane of anesthesia. And then
nowadays there are sophisticated ways
to monitor your plane of anesthesia and their sophisticated ways to if necessary, get you out of a deep plane of anesthesia. If that plane of anesthesia is too
deep. When I talk about a plane of
anesthesia, I'm just talking about going from Full wakefulness to, you know, of reduction in anxiety, to falling asleep to asleep, too.
A point where even if someone were to
pinch your toe or your arm,
like really intense, pinch that you
wouldn't wake up from that,
okay? So ketamine has the property of being an anesthetic, it kills the response to pain and at certain doses, it can bring you into deep
planes of anesthesia at lesser dosages. It can take you into transition points between awake and deeply anesthetized, and it's really that transition point between awake and deeply anesthetize,
which we are going to call the dissociative State. It's kind of this liminal
Ate a little bit like dreaming, it can have some dreamlike qualities to
it. That's the state that has most often been sought after, or employed for the treatment of depression, suicidality, and
PTSD, which brings up a really important point, which is that when people use ketamine recreationally, it's not clear. Exactly what plane of
anesthesia or dissociation. They are actually seeking and this
is why we hear about some of the desired effects of ketamine that are
driving people to use it recreationally. And why we also hear about people having
Some
unpleasant, or even very unpleasant or dangerous
experiences, when using ketamine recreationally, because we're talking about a drug that has a
lot of different effects depending on the dosages. And is, will soon talk about individuals vary tremendously in their response to different
dosages of ketamine and the delivery route for ketamine whether or not it's delivered
orally in the form of a pill or put sublingually and what's called a troche that dissolves under the tongue or it's injected?
And then that's injected into the
vein or intramuscularly Etc.
Each of those can produce very different effects in 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 90s is that laboratory is that we're studying animal models, what we call preclinical models of things like depression and learning, and memory and to some extent ketamine. 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 in Laboratories. That involves taking
Oh, a rat or a mouse and putting it into a small
container. Like it looks like a beaker or a jar. Sometimes it's a tray and it has water in it and you might be surprised to learn perhaps not that if you put a rat or a mouse into
water it will swim, okay? So it's treading water in order to keep its head
above water and not drown. I realize for some of you, this might be a bit of an aversive topic to hear about animal
research, but this is one of the
common preclinical models of depression, which is
put a rat or a mouse into water. Let it swim
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, it will just give up and it will just start syncing. And then of
course, the researcher needs to rescue the rat or Mouse.
Put it back into its home cage. Dry it off, give it some food Etc.
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't
ask mice or rats if they are depressed.
Store happy I suppose. You can ask them but they're not going to answer in any kind of meaningful way.
So we can only look at their behavior in order to understand whether or not they have a
sense of happiness or a sense of depression. And of course that's very hard to gauge in an animal model of any kind, you can make guesses based on other behaviors. Like are they
grooming regularly? Are they eating regularly, you know, things that more or 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
Nickel
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 rat or 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 rats 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.
And sped
up or prolong the duration over which the animal would attempt to save its own 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. One of the most prominent symptoms of depression, for instance, is consistently waking up around 2:30 or 3:30 in the morning and not being able to fall back asleep again. Now, keep in mind, it is not the case that if you're waking
Up at 2:30 or 3:30 in the morning and you can't fall back asleep 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 inability to imagine the future in any kind of meaningful or positive way Etc. 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 ketamine, this dissociative anesthetic, but they were injected with dosages of ketamine. That were below. What would induce full
anesthesia? 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 ketamine is what's called an nmda
receptor
blocker. Now when I say blocker, I'm not getting into the details of what specific form
of blocker it is but I do want to mention
that a blocker
is sometimes referred to as an antagonist.
Whereas something that promotes the activity of a
receptor is called an Agonist. Okay. So if you can just
remember that ketamine is an
nmda receptor antagonist or blocker then you should be fine for the rest of
Today's conversation
now, I haven't told you what nmda is nmda stands for
n-methyl-d-aspartate and you do not need to remember that
but the surprise for researchers was that this drug ketamine is allowing animals to fight for their life for longer. So it
has this sort of property of
overcoming what we call learned helplessness or a sense of helplessness AKA antidepressant effects, and we also know that it's an nmda receptor.
Or blocker and that's perplexing because we
also know that the nmda receptor is critical for changing neural circuitry in the brain. It's critical for neural
plasticity. So put differently here's a drug that
blocks the receptor. That's critical for neural, plasticity for changes in the brain and yet somehow it's allowing these animals to fight for their 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 of the
vessel. Now, in general, there are two kinds of scientists. There are scientists that take a look at a set of findings like that and say, oh, here's a drug, that's supposed to be terrible for us. It's an anesthetic and it blocks nmda receptors. And nmda receptors are good for
neuroplasticity and
somehow it's also allowing these animals to swim longer and I would say, one category of scientists would just look at that and just say, wow, that is a
big.
Ball or tangle of confused facts. Like how does one even reconcile 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 neuroplasticity, but somehow is relieving depression, I'm gonna walk away from that. I'm going to work on something far simpler, and then there's this other category of scientist which thank goodness exists. Who looks at
that apparent contradiction of. Okay, there's a drug which blocks plasticity. Plasticity is
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, hmm. I like a good puzzle,
right? The more complex, the puzzle, the more interesting and they start digging in with preclinical studies and they start talking to clinicians.
Who are treating patients for depression? And like I said, thank goodness these sorts of scientists exist and thank goodness. They did that.
Because it turned out that when clinicians tried ketamine in
depressed patients as a means to relieve depression, it
Had remarkable effects.
So it was about the year 2000. When the first sets of papers about the clinical use of ketamine for the treatment of Depression
started to emerge. Now, we have to remember the context in which all of this was happening, you know, in
2000 drugs like Prozac and some of the similar ssris
selective serotonin reuptake Inhibitors things like Wellbutrin
were really hitting the
market in full force. And as
we talked about earlier, some people were getting relief. Some
people were 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 were taking those drugs were not getting relief
so there was a real urgent. Need to find other
drugs for the treatment of depression
and ketamine at least based on its apparent profile of being a dissociative anesthetic would seem like the last drug
that you'd want to use to treat depression, right?
It dissociates people even hear about
dissociation as a symptom of depression.
And yet what happened was a small number of very pioneering clinicians, started to explore the use of
Ketamine 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 and 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 ketamine, for the treatment of depression, is entitled, antidepressant effects of ketamine in depressed patients. This is a paper that I provided a link to, in the show. No captions. It's a small study, okay. So it doesn't involve many
X at all, really? Just has seven
subjects. All of whom had major depression
and they did intravenous injections with half a milligram per kilogram of body weight of ketamine. Now that dosage half a
milligram per kilogram of body weight, 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 ketamine such as oral pill form ketamine, we're sublingual ketamine and as it relates to things like the k-hole or the dissociate,
Eight or the various effects that ketamine can have depending on the dosage and the delivery
route. Meanwhile, going back to this study. What they found is that when they injected patients with
severe depression with ketamine, the
effects of ketamine took place
within minutes within 10 or 15 minutes, and that they
experience a sort of peak euphoric State, okay? So they're not inducing deep
anesthesia, right? At this dosage, they're getting people into a kind of euphoric dreamy
semi dissociative state that
occurred within 15 minutes and really peaked about 45 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 affects makes perfect
sense. If you look at say the half-life of ketamine which is how long it takes for half of the drug to be active in the system, Etc, but what was really interesting about this study and others like it is that the patients experienced
From their depression, almost immediately after taking the
drug. So, within minutes to
hours, and that it persisted for several days after taking the ketamine,
okay? So the dissociative euphoric dreamlike effects of ketamine take place very quickly. They're very, very
Salient, right? The person basically is just lying there. Experiencing this euphoric dreamlike dissociative State and they get some relief from their depression immediately. And yet there's
Instant relief from that depression, which lasted at least three days out from the treatment.
Now, a key theme of today's discussion is going to be that the antidepressant effects of ketamine appear to be fairly short-lived at least when one is
exploring one or two treatments with ketamine. In other words, the
typical Contour is that people will take
ketamine get this euphoric dreamlike dissociative effect. Come out of that,
feeling some immediate relief from their depression. This is one of the things that makes ketamine and Incredibly attractive drug for the treatment of
Russian, 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 mono a mean hypothesis of depression, which drove the discovery and development
of all these drugs. Like, ssris Wellbutrin etcetera.
Those drugs often can
provide support for people with depression again. Only 40% of people get true relief from their depression.
Now 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 treatments for depression, even same day, treatments for depression. And based on this study, it appeared that ketamine was and indeed,
Still Remains that drug now. I
certainly don't want to position
ketamine 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 warrant calling it a miracle drugs.
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 is a topic. We'll
get into a little bit later. When we talk about
anti-depressive behaviors and the role of ketamine and 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 ketamine could provide significant decreases in not just depression and suicidality but also
The feelings of helplessness and
worthlessness that are associated with major depression. And again, it could do that in people. That also were not responding to other forms of depression treatment such as ssris, Etc.
So, while we don't want to call it a miracle, drug ketamine turned out to be and remains an
incredible drug for the treatment of depression in certain cases.
Now, in addition to that ketamine has been shown in clinical studies, to provide relief, not just for treatment-resistant depression.
Action 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 or referring
to when we talk about
depression, but ketamine has also been shown to be effective in treating.
Bipolar depression, sometimes called bipolar disorder OVO, more commonly nowadays called, bipolar depression. I didn't entire episode by the way, on, bipolar depression, if you want to know what it is and what it isn't, how it differs from borderline personality disorder, Etc. You can go to huberman live.com, just put into the search function.
Polar and it will take you to that episode.
Ketamine is also been shown to be useful for the treatment of
PTSD, and for OCD obsessive-compulsive disorder,
and for anxiety, and for various forms of substance addiction. So ketamine is not a miracle drug, but it does seem to have broad
application and to be very successful at the, for
the treatment of a lot
of major psychiatric challenges now, just because ketamine 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 here is. Yes, ketamine 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 antidepressant effects of ketamine often wear off
so that creates a situation where
people perhaps need to take ketamine every week and yet it
creates enough of a dissociative
Meaning it takes people enough out of their normal daily routine that the prospect of people taking ketamine
every week is actually not that feasible. And
also because of some of the
propensity for ketamine 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 ketamine every week to treat the depression that they can become so called hooked on ketamine. Now, fortunately there have been studies of ketamine
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, taking ketamine twice per week for a duration of three weeks total. And what they find is
that yes, after the first time they take it, they get some relief from depression. They take it 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's also some so-called durability to the
effect, such that
If people do this twice a week dosing regimen. So ketamine twice a week for three weeks total,
they find that when they end that three weeks, they get some ongoing relief from their depressive
symptoms, which can extend months or more before they have to repeat the twice a week for three weeks regimen. Now, certainly not all studies of using ketamine for the treatment of depression have used that exact dosage, regiment twice a week for three weeks and take some time off, repeat twice a week. For three weeks to take some time off. Repeat
some have explored given category.
I mean, 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, they're a bunch of different studies out there. But when one looks at all of those studies and mass together, it's very clear that ketamine is providing relief from depressive symptoms immediately and 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're hearing it. It's very
likely that ketamine 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 euphoric dissociative dreamlike state. That one
experiences when they are under the influence of
ketamine, the second mechanism seems to provide relief from depression.
In the days and
weeks that follow the ketamine
treatment. And there also appears to be a third mechanism by which ketamine can induce long
lasting changes in the nervous system
and it is those three mechanism, 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 ketamine to provide this incredible relief from depression. So
next, we're going to turn to what those mechanisms are because in understanding those mechanisms
Seems you will understand how ketamine 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.
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E forms. Not all but many forms of neuroplasticity. Now I realize some of you might be familiar with so-called ligands and receptors but most of you probably are not a ligand. Is a chemical that binds to a receptor 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 receptors you're hearing about receptors
on the outside of the cell,
so the nmda receptor does not exist in our
Ron's in order to bind ketamine, it's, they're actually to bind all sorts of other things that are endogenous that are naturally made by us, but ketamine has a very high. What's called Affinity has a very high probability of binding to the nmda receptor, if it's introduced to our bloodstream. So when ketamine is taken in pill form, sublingual form, meaning under the tongue when it's injected into the muscle or the vein, it gets into the bloodstream and then it's able to cross easily across the blood-brain barrier.
Our so-called BBB blood-brain barrier, the blood-brain barrier keeps a lot of things out of the brain, but ketamine can very readily pass across the
blood-brain barrier.
Once, it's in the brain, it has a very high affinity for meaning in knows how to seek out and bind to those nmda receptors. Now the simplest way to explain how nmda receptors ordinarily contribute to neuroplasticity is that they represent what's called an and gate and a nand gate. As the name, suggests is a function in a cell or a
System where two things have to be present. In fact, for those of you that have a bit of an engineering or computer programming background, you'll be familiar with an gates. For those of you that don't, don't worry about it, I'm going to explain what an and gate is right now. An and 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 say neuroplasticity to occur.
The nmda receptor. As I mentioned earlier, as a receptor on the surface of neurons and it binds glutamate, which is a molecule that
We all make in our brain and it activates other
neurons. It's what's called an excitatory neurotransmitter.
Now, there are lots of different receptors for glutamate and those receptors are binding glutamate all the time. However, in order to activate the nmda receptor, there has to be a lot of glutamate present. And it has to happen
over a very brief period of time.
So, the nmda receptor is an and gate in the sense that glutamate 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 happen. So it's a
receptor that responds primarily to unusually high or frequent levels of electrical activity. Let's place this in real world context, so it makes a bit more sense. I like most all of you and moving my arms around a lot throughout the day. Now, as an adult, my motor cortex, the area of my brain that controls motor. Coordination of my limbs has connections from my brain, to my spinal cord, for my spinal cord, my muscles, and that's what 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 yerba mate. 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 a receptors. For those of 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 motor. Limb 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 are 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
32, 1.2 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 is the neurons that are involved in generating,
That motor sequence of 1, 2 3, 3 2 1, 1 2 3, 3 2, 1 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 responsible for generating, that motor Behavior would be able to detect it as unusually frequent unusually, high levels of activity in the circuits that generate that behavior and the increase in glutamate. That's impinging on the neurons in that circuit. Would bind the nmda receptor making it change several important.
Certain things, the first of, which is that your nervous 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 atypical for them and they are firing a lot more and so the neurons are going to bind glutamate. The nmda receptor is going to be activated. And then
Downstream of nmda receptor. Activation are a bunch of what we call intra cellular processes. A bunch of things that happen in the cells to try and make that behavior occur again, and again, if needed. But without the huge energetic, demand, you've experienced this. Before, when you're trying to learn something and it feels sluggish, it feels hard, it's frustrating. And then eventually you learn it and
it's very facile, it's very easy.
One of the reasons for that is that when the nmda receptor is activated by these infrequent, or unusual patterns of activity,
It can then recruit other glutamate receptors that the more typical kind the ampa type receptors to the cell surface. And then those receptors can simply bind the glutamate 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, Etc. So, to just step back from this, the way to think about the nmda receptor is that activation of the nmda receptor only occurs under conditions of unusually high, or
Simply unusual patterns of activity.
That the nmda receptor. Yes. Controls neural activity. In the immediate sense. Like when it's activated,
it's changing the patterns of activity in the neuron sure.
But it also can engage gene expression and introduce 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 hypertrophy, right?
If you overload muscles properly through resistance training of any kind, and then give them a period of rest. There's recruitment of specific things to the muscle fibers, as well as recruitment of changes. In the nerves that innervate that control the contraction of those muscles. And then those muscles grow, they get stronger etcetera and they are 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
Now, I realize that's a lot of details about nmda receptors and
neuroplasticity, but really, if we needed to pick one biological mechanism that resides at the center of many, many important forms of neuroplasticity, it would be the nmda receptor
and it's functions that I just told you
about. So now that you have that in mind that these nmda receptors are critical at detecting unusual activity, making changes to cells. So the cells
can then respond to that activity. In the future. You
have in mind the conceptual basis for understanding how ketamine works, because as
As I've mentioned several times, already ketamine is an nmda
receptor blocker antagonist. 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? 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 brain, you have those excitatory neurons.
Neurons that when they are activated, electrically, they activate or excite other neurons. At least they try to, they release neurotransmitter into the synapse, which is the little gap between neurons. The neurons on the other side have receptors, they bind those neurotransmitters in this case glutamate which is the
major excitatory neurotransmitter in the
brain and then there's a high probability that those other
neurons will be excited that they will be electrically active. That's one major type of so-called neurotransmission in the brain, the other major type of neurotransmitter
his mission in the brain is called inhibitory neurotransmitter, and
inhibitory neurotransmitter ssion, involves neurons that release the neurotransmitter Gaba or sometimes also
another molecule called glycine but mostly Gaba. When
Gaba is released, it has the property of
reducing the probability that the next neuron will be electrically active. In fact, Galvez
job is to bind to receptors on the next cell and to make it less electrically active. So we've got excitatory neurotransmission
and we have inhibitory.
Neurotransmission and just to
place inhibitory, and excitatory, neurotransmission
into
context. If you think about a condition like epilepsy, which involves seizures of either, the smaller type called petit
mal seizures, or grand mal seizures, which are the type in which people have
body-wide convulsions,
they are often disengaged from whatever is going on around
them in those moments there, shaking quite a lot at cetera. There are many causes of seizures, but to get to the heart of what a seizure is it is essentially run.
Away excitation in the brain, a small region of the brain becomes, especially
electrically active, and then it spreads out from that Foci that focus of the excitation and that recruits a lot of neurons in a fairly nonspecific way. Creating these seizure-like motor patterns in the body and patterns of activity in the brain that can involve disengagement from immediate experience and lack of perception sometimes there's or there's a whole discussion to be had about seizure. And by the way, seizure can occur in a lot of different.
X. Of course, it can occur in epilepsy that can occur after a head injury Etc, will 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 neurons and excitatory neurons are in this kind of push, pull that for somebody that doesn't
experience. Seizures puts
the brain in Balance so they don't have seizures, right? The inhibitory neurons are suppressing the activity of many neurons, so that those many neurons. Don't get run away,
excitation.
And you don't get seizures. The
excitatory neurons are feeding back onto the inhibitory neurons. So everything is kept in Balance. There isn't too much inhibition there isn't too much excitation
everything's in Balance. Okay, so now you understand
that there are nmda receptors
and these are critical for many forms of neuroplasticity. You also understand that there are
excitatory neurons, which
stimulate the electrical activity of other neurons
and that there are inhibitory neurons in your
brain that inhibit or suppress the activity of other.
Neurons and that you need excitatory and inhibitory communication between
neurons at all times and that it 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 into today's discussion which is about ketamine.
Which is that ketamine
blocks that nmda receptor and there's the conundrum I keep coming back to which
is you need neural plasticity in order
to get relief from depression.
So what researchers have discovered is that yes ketamine blocks the nmda receptor it actually quiets down neurons it prevents neurons from being as active as they normally would be. And yet, somehow, almost paradoxically it increases neuroplasticity in brain circuits that are involved.
In mood and
reward in self-reflection, we'll get into what those brain circuits are in a little bit.
The way it works. Is that ketamine binds to the nmda receptor present on inhibitory neurons and in doing so dramatically reduces the amount of inhibition coming from those inhibitory neurons on to excitatory neurons when that happens. The excitatory neurons in specific circuits of the brain are allowed to increase their activity. They do.
Ooh, what's called bursting? Bursting is a pattern of electrical
activity. Whereby,
normally one of these excitatory neurons is releasing glutamate in a pattern that
might look or sound like this 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'd hear the firing the
action, potential of those neurons as a current. That's what it actually sounds like on the Audio Monitor 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 ketamine has been brought into the system. Binds that nmda
receptor blocks, the output of those inhibitory neurons onto the excitatory neuron. Now the excitatory neuron is firing in bursts.
And those bursting patterns of electrical activity are the absolute perfect patterns of activity that induce not just 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 realize what I just told you is a lot of information. In fact, what I just described represents essentially what I
I would teach to an advanced undergraduate /, graduate course, Medical School course on neuroplasticity and how ketamine works. So, keep in mind that we're having a discussion here, that is at a fairly high level. And if you could understand even a tiny fraction, even just one bit, what I just described you're doing great. If 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 ketamine and how it works because it does have these sort of cryptic.
Oceans of engaging neuroplasticity in ways that aren't obvious. If you just asked, you know,
what is ketamine do when you inject
it? What is ketamine
produce in 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. So I'm going to tell it to you again in just very top Contour terms, somebody takes a pill or an injection or sublingual ketamine. It makes its way into the blood stream and then it makes its way into the brain. Once it's in the brain, it binds to
To a particular category of receptors called the nmda receptor. The nmda receptor is a receptor that normally is quiet sent. It's just kind of sitting there. It doesn't tend to do a lot under normal conditions of everyday life. However, the nmda receptors typical function, okay, so when there's no ketamine in the body or brain
is to detect abnormal levels of neural activity and in doing so, recruit changes to cells receptors Etc.
Change the neurons in ways that allow them to
respond to that activity in the future without having to be under such big metabolic demand and they do that by recruiting more receptors Etc. Much in the same way as when you overload a muscle in the gym, it will eventually recover if you allow it to recover
and it will get stronger through the addition of a bunch of
new proteins that nerve
communication of. That muscle will change the muscle and the nerve to
muscle connection change, it gets stronger and sometimes it gets bigger and
And
stronger in the same way in, Iran can change the way it functions in response
to experience and neurons, don't know
experience of life in any other way, except the
patterns of electrical activity and chemical activity that impinges on them, okay? Now, ketamine the drug binds to and blocks that nmda receptor. So the obvious conclusion would be that ketamine prevents neuroplasticity and that's not what happens. We know that ketamine 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 ketamine binds to and blocks those nmda receptors on inhibitory neurons. The inhibitory neurons are the neurons that normally suppress the activity of other neurons.
So when ketamine binds to the nmda receptor, the
activity of those inhibitory neurons is reduced and as a consequence excitatory communication between neurons in those mood related circuits increases and
Increases in a way that recruits
neuroplasticity that strengthens those connections and makes them more likely to be active in the future. Now, it is not the case. At least at clinical doses. That ketamine induces seizures. It certainly can at higher doses, but at clinical doses when
ketamine, suppresses the
activity of those inhibitory neurons and the
excitatory neurons ramped up their activity, the ramping up their activity, a lot and enough to create changes.
In those neural circuits associated 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 will get into the specifics of those circuits in a little bit.
But ketamine is not creating the kind of enormous increases in
excitatory communication between neurons. That leads to that runaway excitation. Now the point of the discussion we just had over the last 10 minutes or so with 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 and nervous system that
We all have this ability to change
our own brain circuits. No other organ in the body
as far as we know and 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 it's important to understand the difference between inhibitory and excitatory 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. It's also about neurons preventing the activation of other neurons that's just Central.
Everything not just preventing seizures but it's Central to learning it. Central to vision is Central to hearing, is Central to creativity. It is at the core of brain function. And the other reason to have the discussion, we just did, is that ketamine has this
incredible property, it can literally change the neural
circuits that generate mood. That generate your feelings of
well-being, but it does so through a somewhat convoluted
pathway, right? It blocks, the receptor that everyone thinks is involved in neuroplasticity and in doing so.
So it actually creates
neuroplasticity. Now even though I just
described all of that to you over the last 10 minutes or so,
keep in mind that what I just described to you as a
process that actually occurs in the brain takes many, many days, it involves cells changing gene expression, making new proteins new receptors,
anytime we say neuroplasticity, even 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.
Even weeks. So the process I just described of how ketamine creates neuroplasticity through blockade of nmda receptors,
is very likely to be the process. That
explains the longer term changes in mood and affect that are associated with ketamine therapy for the treatment of depression.
Now, it is possible that ketamine
blocking the nmda receptor is also responsible for some of the immediate effects of ketamine that people experience when they take the drug, the dissociation
In the, in some cases, Euphoria and that sort of dreamlike state that it can put people into.
That is possible. But it's very clear that the nmda receptor blockade is critical for the neuroplastic changes, that are going to occur over
the days and weeks following ketamine treatment. And if you think back to our earlier discussion, when we were talking about the to
time a week over three week type regimen of taking ketamine or some variant on that now, it's might start to make sense as to
why yes.
There is immediate and short-term benefit of taking ketamine for depression in the clinically appropriate setting. Of course I'm not talking about recreational use right now
but that also there's some durability of those
effects that even after the three weeks of taking ketamine twice per
week, people often will experience weeks or months of
relief from depression when they're not doing the weekly ketamine therapy sessions. So that longer term relief that I'm referring to as durability of the treatment is very likely to be the
whence of actual neural. Circuitry wiring
now, there's an additional and very
important facet to this whole discussion about neuroplasticity in response to ketamine treatment for depression. If you recall that the burst firing that induces, that plasticity, I told you, it
induces plasticity by didn't tell you
how now you already could imagine some of the mechanisms, it could be insertion of those
new glutamate receptors. Those a 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 to understand is the thing I mentioned at the beginning of today's
episode, bdnf, which stands for brain-derived neurotrophic,
factor brain-derived neurotrophic,
factor is an incredible molecule. I should mention that, it's one of many growth factors in the brain
and it has
its own set of receptors. It binds to something called the track of be receptor. Trk be Trek, be receptor.
When bdnf binds to track be receptors on neurons. It does
a lot of things, it sets off a whole
Cascade of things including
Adding the insertion of new glutamate receptors so that those neurons become extra sensitive to any input. They get. So that's one form of change that bdnf can create bdnf, can
also alter the overall shape of neurons. It can
cause neurons to grow new branches, so that it can receive new inputs. From other
neurons anytime bdnf is discussed in popular books or the popular press people will talk about it as quote, unquote,
fertilizer for
neurons. I don't really like that term because
It really undervalues the total number of things that bdnf can do bdnf, actually can act as its own, kind of neurotransmitter, it can actually stimulate other neurons and it does a bunch of other things. But
for sake of this discussion about ketamine understand that that burst firing of neurons
that very high frequency firing of neurons, can invoke the release of bdnf in ways that make those circuits very plastic very
quickly. And in addition to that, there's some evidence
Is that ketamine itself may be able to cause release
of bdnf, directly without having to go through all of the mechanisms that I overwhelmed you with a few minutes ago or hopefully didn't overwhelm you with but that I talked to you, a few minutes ago. Now, what's especially exciting about bdnf in the context of ketamine therapy for depression, is that it appears
based on both preclinical and clinical studies, that bdnf, isn't just one of the
ways in which ketamine can invoke neuroplasticity.
And these improvements in
mood, it may actually be required. It may be the
central process to all of that. Now it can
still be Downstream of all that nmda
receptor stuff that we talked about before.
But there are several lines of evidence that suggests that ketamine, induced release of bdnf is one of the core mechanisms by which ketamine
can relieve depression.
Now there are several lines of
evidence to support what I just said about bdnf in the context of ketamine. First of all,
in mice, that lack
bdnf, they have no bdnf, they can't
make bdnf because they don't have the gene for bdnf. We call those bdnf. Knockout mice in those mice. If you
give them ketamine and you
put them into that learned helplessness tasks that we talked about a bit earlier where you put them into water and see how long they swim. Normally
ketamine would allow a mouse to swim longer to
fight for its life longer. Will it no longer does that in a bdnf knockout Mouse. And the only thing that's different about that Mouse as far as we know, is the lack of bdnf.
And there are ways to make sure that its lack of bdnf in the specific neurons that are relevant to everything. We're talking about not just that their limbs don't work as well at cetera. In other words, all the appropriate control experiments have been done. That's preclinical data because it comes from animal
models. In addition to that, depressed, people who have a mutant form of bdnf. So these humans are not Knockouts for bdnf, they can make bdnf, but the bdnf doesn't function. Normally in those people,
they have a very reduced
Just response to ketamine treatment for depression.
Suggesting that bdnf action is at least one of the critical functions that
allows ketamine to relieve
depression. And as I mentioned earlier, ketamine can actually invoke the release of bdnf and get this. There's some evidence that ketamine itself can bind to the track be receptor. That is it can bind to the bdnf receptor. It
can mimic bdnf. So this is an entirely different way of thinking about ketamine.
We normally hear about nowadays, we hear a lot about ketamine and ketamine therapy. We also here, fortunately, about some of the problems of ketamine abuse and we will talk about some of those concerns a little bit later. And we hear about
bdnf, this so-called brain fertilizer, but rarely, if ever do, we hear that ketamine
itself can mimic the effects of bdnf in the brain
but researchers and clinicians are definitely paying attention to this,
and it's starting to raise what I consider a very exciting model of how ketamine could provide relief for
Session, which is that? It's acting as a growth factor in the brain. Or at least it's mimicking, the action of growth factors,
allowing the specific, neural circuits that
control things like mood outlook on the future, self reflection, Etc, allowing those 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 that ketamine is relieving depression in ways that are entirely different from any other kind of treatment. Now, in an earlier episode about psilocybin and its potential role.
The treatment of depression.
I went into a lot of depth about how
psilocybin can induce neural plasticity to provide 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, don't worry, I'll tell you right now. It was a pretty straightforward model psilocybin, looks a lot like serotonin chemically except that
psilocybin. Binds a particular receptor when that receptor is bound, it allows these brain wide changes, those brain White
Changes seem to change one's reflection on oneself so called ego dissolution changes in mood that are stable over time, etc. Etc. It was
all pretty straightforward with
ketamine, it's clear. There are multiple mechanisms involved. And perhaps most importantly with ketamine it's that immediate relief that occurs at day of or close to day of treatment and in the days afterwards and it's that
long term relief that very likely is the consequence of nmda receptor suppression burst activity in neurons Within These mood related.
Gets bdnf, being released and changing neural circuit. Strengthening them in order to give elevated mood as a consequence of that bursting activity and ketamine mimicking bdnf. In other words, ketamine 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. And last over time, I'd like to just take a brief break and thank one of our sponsors which is element.
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discussed two major mechanisms for how
ketamine can induce neural plasticity leading to improvements in mood and
affect that gives relief 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
I mean works and when I say how can I mean works? I'm
not just talking about how ketamine provides relief for depression. I'm also
talking about why people use ketamine for recreational
purposes and it is the following
yes, ketamine has all these
impacts on excitatory neurons. Inhibitory neurons, bdnf etc. Etc
but ketamine can also bind receptors in the
opioid pathway. Now what is the opioid 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, or at least most of you have
the opioid crisis, refer
specifically to people, taking exogenous opioids, taking opioids, right? So
taking pills that activate particular receptors in the
brain that lead to
analgesia and some cases. So, pain relief that lead to changes in mood.
There's a lot to be
said about the opioid crisis. It's called a crisis, for a reason. Many, many people are
addicted to those compounds. That's a discussion for another time. Keep in mind that The receptors those
Bind to our opioid receptors and those receptors that you and I all have by the
way do not exist
in order to bind drugs that are made by pharmaceutical companies. They exist in our brain and body to bind to the so called endogenous naturally made opioids that we all make. And those receptors have different names of the Mew, opioid receptor, the Kappa opioid receptor etcetera. They tend to have the names of Greek letters to differentiate them
now. Ketamine can bind to various opioid.
Receptors and when opioid receptors are bound, we know that
creates certain affects things like pain relief, things like changes in
psychic States
dissociation. For example,
if enough of them are bound, you can get euphoric States under certain conditions of high dose, binding of ketamine 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 ketamine 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
dissociative mild Euphoria.
Those sorts of states of mind, but where people are still conscious.
When you start getting to dosages of ketamine that are in the range of 1 to 2 milligrams per kilogram of body weight. Now, you're talking about anaesthetic
Doses and when that happens, you're going to
get
full parking full saturation
of all the potential receptors that ketamine combined to those nmda receptors. It's going to block those. It's also going to bind to the so-called Mew opioid receptors and maybe this other type as well. For those of you that want to know you afficionados, also the Kappa type opioid receptors
and so what we've got here is a drug ketamine that is hitting two
different systems, the glutamate related system and the endogenous opioid system and researchers and clinicians.
Have logically started to ask whether or not some are all
of the effects of ketamine are due
to the opioid 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 ketamine
again, it enters the bloodstream and it goes into the brain, but it is metabolized to something called hnk, which has hydroxy nor ketamine. Now, I don't expect
Do you know what hydroxy nor
ketamine is? And I don't expect you to care
about it until I tell you what I'm about to tell you, which is that hydroxy nor ketamine
has an incredible specificity for the Mew, opioid
receptor and maybe that Kappa, opioid receptor as well. In other words,
when we talk about ketamine, that's the drug people take, but when it goes into the body, it's converted into yet.
Another drug and that other drug hydroxy nor ketamine is selectively activating the opioid system.
So this led researchers to
Ask a very important question, which is when a human being takes ketamine, in order to treat their depression and they get some relief from depression. Is that the consequence of neuroplastic changes in all those nmda glutamate, bdnf, related circuits, that we talked about before, where is it? The consequence of something happening in the opioid system. You can't ignore the fact that ketamine has this property of binding to these opioid 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 opioid system could be a major player. If not the major player in this whole depression relief thing and maybe even in the creation of dissociative symptomatology when people take ketamine recreationally. So what researchers / clinicians did is they undertook a series of experiments
where they gave people ketamine for the
relief of depression,
but they also
blocked the opioid receptor system and they did that using a drug called
Naltrexone. So, what I'm about to describe to you as a study done by
my
my colleagues at Stanford School of Medicine. Namely dr. Nolan Williams and Alan schatzberg and colleagues
entitled attenuation of antidepressant and anti suicidal effects of ketamine by opioid receptor
antagonism. And as a
consequence of me, reading you that title a moment ago, you now already
have the conclusion of the study,
what they observed is that when people were giving ketamine, they got relief from depression,
that wasn't surprising again, many studies had shown that before since the early 2000s
If however, individuals were given Naltrexone to
block the opioid receptor pathway
and they were given ketamine, well then, the antidepressant
effects of ketamine were no longer observed. Now that suggests that it is the opioid receptor system that's
responsible
for the antidepressant effects of ketamine. And perhaps this hnk, this hydroxy nor ketamine which is the metabolites of ketamine is the way in which ketamine normally relieves depression.
Now,
a lot of people took note of these studies
because after all, there are probably dozens, if not hundreds of studies looking at the effects of ketamine on all that nmda receptor stuff.
And indeed, neuroplasticity and mood related circuits can't be discounted as one way in which ketamine
provides relief from depression.
But what was very interesting is that in people given ketamine and Naltrexone those people still
experienced the immediate effects of ketamine the
Mild Euphoria, the dissociation. The
feelings that one would normally
expect when people were under the effects of ketamine, but what they didn't
get, were the longer term
changes in mood that we would call relief from depression. Now, of course, the goal of modern Psychiatry is to treat depression. Not to block the effects of these drugs that are capable of treating depression. Now, what this study does, and by the way, there are several studies like it that support these General set of findings that part of the critical role of ketamine in providing relief.
Depression is to activate the opioid system, but what this
study does, is it really points to the fact that when we say ketamine treatment, or we
talked about somebody taking ketamine 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 their, under the influence of the drug. And perhaps most importantly, this calls
to mind, a really important idea, which is that whether or not you're talking about ketamine induced relief from
depression or psilocybin induced relief for depression.
Or MDMA induced relief for PTSD, 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 depend on what particular drug. They took 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
It's
going to be an either/or situation. However, because drugs, like ketamine psilocybin and MDMA, 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 correlate, those two things, they couple those two
things. In fact, they collapse those two things and presume that they're
Variants 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 ketamine and
Naltrexone to block them, you opioid 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 ketamine that one experiences. While interesting, perhaps even profound perhaps great Insight comes to
And when they do that therapy 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's actually what's causing the relief from depression. Now again, I don't think it's an either/or. I like to view the whole situation more or less as a sort of wavefront that the
experience that one
has subjectively. While they are under the influence of a drug like ketamine or psilocybin or MDMA
sets off a series.
Ruiz and in
fact, multiple series, these is that a
word multiple types of processes in the brain? Some of which rely on things. Like nmda receptor bdnf, Etc, type
neuroplasticity others, which rely on the opioid 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 months.
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 relief from depression, but what we're really talking about here are
people who get relief from depression and almost with certainty. When they get relief from depression, they are also starting to do other
things, they're 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.
NG well and 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, ketamine, relieve depression. And then as a
consequence people went and did a bunch of behaviors that were healthy for them or stopped engaging in behaviors that were unhealthy for
them. So we can think of behaviors as Pro depressive or anti-depressive. In fact, we know that one particular behavior
that is
Ewing blue light in the middle of the night between the hours of say, 11:00 p.m. and 4 a.m. is known to invoke a pro depressive circuit, it involves a structure called the habenula. I've talked about this on previous podcasts, it tends to
lower dopamine and increased cortisol in the days, following that exposure to light
etc. Etc. 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 plethora of
research pointing to the fact that 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 combined, 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 ketamine 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 were calling anti-depressive right? Changes in mood and affect that are positive. Positive anticipation of the future etc. Etc.
And then we've also been talking a lot at this other end, which is very
reductionist down at the cellular and molecular level, talking about receptors and finding a receptors and neuroplasticity and track be and all that stuff. We completely neglected, meaning. I've completely neglected until now what Bridges? Those two levels of understanding
and what Bridges, those two levels of understanding.
Standing are the neural circuits that
actually change when one takes ketamine whether or not those changes occur quickly, whether or not they take a longer period of time whether or not they involved. And I'm DEA receptors, are the opioid receptor systems or both?
We know that certain neural circuits
change when people take ketamine in these patterns of dosage and frequency of about half a milligram 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
habenula a few moments ago, I talked about
the habenula in the context of people who get too much bright light exposure, in the middle of the night that activates the habenula, it's a sort of a disappointment circuit. We can call it that because we know that it leads to Pro depressive symptoms in animal models and very likely in humans as well.
Well, and it does. So we know, by reducing dopamine and increase in
cortisol, there is evidence that when people undergo ketamine therapy connections between the habenula,
what we can broadly just talked about as a structure involved in generating. A feeling of disappointment, the connections between the been Yola and the reward circuitry of the brain, which I've talked about several times before on this podcast. But for those of you that aren't familiar with it, this is the so-called knees Olympic reward pathway as areas like the ventral tegmental area, the nucleus accumbens.
Don't worry at all about those names just know that this is a brain area that is chock-a-block full of neurons that release dopamine 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 habenula
that normally provides inhibitory. And now, you know what? That means, inhibitory input to
this reward pathway that releases dopamine. And when people
Take ketamine that inhibition is
lessened. Such that 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 were 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.
How about Pro depressive and anti-depressive
behaviors? Somebody can take ketamine 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 ketamine and they are reducing the amount of output from this disappointment, circuit this have been Ela to the reward circuitry of the brain and they do engage in behaviors, such as seeking out
work that stimulates them seeking out. So
Social
engagement, taking good care of their body, their mental health, or physical health
Etc. Well, those circuits are not designed to respond to ketamine. They are designed
to respond to particular patterns of thinking and behavior.
So again, we can't forget that when we hear that, a
drug causes plasticity in a given neural circuit. What
it's doing is its biasing, 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. Fortunately
People tend to have elevations in mood, they tend to move around more. When they tend to move around more,
they tend to engage in more things when they tend to engage in more things if they
have a positive outlook on life, presumably they are engaging in adaptive things, things like social relationships, job-related school-related goal related Behavior.
So it's important to understand that a discussion of neural circuit
changes in response to ketamine is really discussion
of neural circuit changes in response to ketamine that shift one's overall system toward having yet,
Further neural
circuit changes in response to daily activities and thereby bolstering health. Or in this case mental health.
Now it's also important to understand
that rarely if ever does a drug provide relief for some sort of clinical challenge in just a one-track, kind of way. 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 it won't be surprising to you that there's evidence.
That ketamine treatment can reduce the output from the habenula 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, it can further, bolster the neural plasticity 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 in 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 it could be, it's 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 etcetera, your frontal cortex.
Texas, that part of your cortex. That's always churning ideas. It's always wondering, am I doing well in my not doing well and is adjusting your behavior accordingly.
So it's now established that ketamine can improve
connectivity. That is it can strengthen 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 or 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 nmda receptor
blockade is not the way that ketamine provides relief from depression,
namely, there's a drug called memantine. It's
used actually to treat Alzheimer's and it too is an nmda receptor blocker and it has no antidepressant effects. Now, as you recall, ketamine is a dissociative anesthetic and one of its primary effects is to create this feeling of dissociation. For those of you that aren't familiar with what dissociation is dissociation 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 colleagues, in the department of Psychiatry at Stanford school of medicine.
And one of them describe the effects of ketamine as described by a
patient of theirs who had taken ketamine 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
And actually looking down on themselves from the third person perspective.
Now, that I realize is a foreign experience to most people, but of course, there are people who experienced Association
even while not on
ketamine. And as many of, you know, dissociation is actually one of the primary symptoms of PTSD and Trauma. So this raises a sort of conundrum. You know, why is it that a particular state of mind that's associated with PTSD and
Trauma. And, in some cases depression itself, which is induced by a drug like
ketamine can provide relief from depression and that all goes
Back to the neuroplastic changes that we talked about earlier and more likely that
changes in the Mew, opioid receptor system that we talked about
earlier. But nonetheless, the dissociative effects of ketamine are so profound for people that take them that I thought I'd spend a minute or two explaining. What likely
causes that dissociative third-person thing of self effect and in
so far as we know it has to do with an uncoupling of certain brain circuits, and particular neocortical brain
circuits. The neocortex is the part of the brain, the lungs
P outside part of the brain
that's associated with action planning. It does a lot of things, really.
It's involved in sensory perception. It's involved in
speech, generation many, many things, but the neocortex has connections to other regions which are called subcortical regions. And it seems that when people take ketamine or phencyclidine PCP, there's a nun, coupling of those networks, a quieting of those networks that starts to create a different dominant rhythm in the brain. Some of you may be familiar with rhythms in the brain
so called
Rhythms or Alpha patterns of
activity. That's just dominant patterns of activity associated with particular brain state. So for
instance Alpha brain waves are associated with an
alert but calm relaxed State of Mind where thoughts are sort of
free-flowing. It's a little bit dreamlike but it isn't really like a dream where anything can
happen. It has a structure to
it when people take ketamine 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 a different pattern of brain activity which is called the Theta pattern of brain activity starts to really emerge. It's as if it gets unveiled
and that Theta pattern of activity is the one that's associated with a dreamlike state. It's the one that resides more or less at that liminal border between wakefulness and sleep. If you've ever been falling asleep and you were thinking something like you were running and you kicked your leg. It's very likely that you were in Theta
pattern of activity, in your brain, at that moment. Just prior to when you woke up. Whereas when you're more alert, you
Patterns of activity that are higher frequency, things like Alpha Beta rhythms and so forth.
So ketamine produces particular patterns of brain activity and this sense of dissociation, when it's taken at sub anaesthetic doses, if you recall, the clinical studies, 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 ketamine, they will take it by different routes of delivery. And now, here we have to expand our conversation to include both the clinical
Text research studies and recreational use. Now
I do that because typically when people take ketamine in a study in a clinical study, they will get an intravenous
into the vein or an intramuscular into the muscle injection of half a milligram per kilogram of body weight ketamine.
However, when people are taking ketamine recreationally, or when they are accessing ketamine legally, buy
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 sublingually by putting it under the tongue or in their cheek and then that so-called troche
dissolves and the ketamine goes into their system. Now, an
important thing to understand is that when people take ketamine orally only 25% of the active form of ketamine, makes it into the bloodstream. And when they take it sublingually, typically only about 35% of the total amount of ketamine they take, is converted into metabolically, active ketamine, that
acts on the neurons in their brain.
So, when you hear about the
Dosages used in studies. They are going to generally involve injections of ketamine and
far lower doses of ketamine than when you hear about people taking ketamine orally or sublingually.
So for instance, I weigh 220 pounds. That's 100 kg. So if I were to be in one of these studies, which I have not been, but if I were, I would be given 50 milligrams of ketamine by way of injection. However, if I were going to try to achieve the same amount of active ketamine in my bloodstream and brain, as I would through injection,
I would need to ingest three times as
much ketamine by way of
pill, and perhaps a little bit more by way of sublingual ketamine, if I wanted to get the same
effects. So if I were to take 50 mg
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
150 milligrams of ketamine in a pill
form or 200
milligrams of ketamine in the troche sublingual form. Now
It's really important to understand this dose dependence according to delivery business
because I realized that nowadays especially a lot of people are
taking ketamine 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're taking higher dose ketamine and they're taking it
sublingually or orally. So it's very important to understand this dose. Dependence according to mode of delivery business.
Now in anticipation of this episode, I put out a request for
Shins about ketamine on Twitter and I got many, many questions. It's an excellent ones there in, but one of the more common questions was what is a k-hole in. Scientific terms, a k-hole is what's used to
describe the subjective experience of when somebody takes ketamine typically recreationally
and they end up in basically a pseudo anesthetize 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 of ketamine.
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 ketamine differently depending on how quickly and how thoroughly they metabolize ketamine. So
in the clinical context injections of ketamine into the vein, or
into the muscle,
Done at this half a milligram per kilogram dose and they have clinicians there. They have researchers, there who are
paying attention to whether or not the person is in a dissociative 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 ketamine in the context of a legal clinical setting. However, I'd be remiss if I didn't
acknowledge that, a lot of people are getting ketamine legally, but then taking it at home.
Hopefully not alone. Hopefully there's someone there to monitor them where they're in session with their
A physician over Zoom, that's actually happening more and more these days through Telehealth.
But that itself also
has certain risks, right? Because if the person needs 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 ketamine recreationally
regardless of how they're acquiring it, they're taking it and
they are guessing how they're 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 ketamine at
Dos that for them, takes them beyond the mild or perhaps even an extreme dissociation and starts placing them into full-blown, anesthesia. And that itself actually can be dangerous
going into anesthesia 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 range is
that you hear about when hearing about ketamine,
Are extremely Broad
and so is the variability to anyone given dose 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 ketamine to take you into deep deep Plains of unconsciousness and in some cases, death. And of course, as with any sedative, 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 of ketamine,
additionally? For those of you
that are seizure prone either due to epilepsy or prior head
injury or maybe your seizure prone and you don't know, it can mean can induce
seizures and it should be completely obvious to you. Now why that's the case, ketamine blocks
and MDA receptors on inhibitory
neurons and quiets their activity which of course can lead to Runaway excitation in the brain. If you are seizure prone,
when I put out the request for questions about ketamine on social media, I also got a lot of questions.
Questions about the different forms
of ketamine.
When I say different forms that included questions about whether or not intranasal was better than oral was better than sublingual. Etc, etc. To be fair with one exception, the different modes of delivery, probably relate more to dosage that actually gets metabolized 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 orally or sublingually, or in
Cases. By the way, people will take it rectally and the
reason people take ketamine rectally is that rectal. Administration. Bypasses the liver and indeed ketamine can be
hard on the liver to metabolize, it can dramatically increase liver
enzymes so oftentimes people that are taking ketamine frequently and don't want to create damage to the liver, they
will opt for a rectal Administration.
Now, I realize that unless it's somehow related to your profession, anytime somebody says, intra rectally it raises a few eyebrows and people, you know, kind of 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 drug metabolism. Depending on whether or not people take something orally sublingually by injection or rectally another common question. I
got when I solicited for questions, about ketamine on social media was about the our versus S versus RS forms of ketamine.
And I must tell you that sent me down a deep deep Rabbit Hole of research in which I discovered very contradictory.
Jury evidence.
For instance, I could find papers. I did find papers that said that the our form of ketamine had a much greater affinity for the nmda receptor. Then did
the SS form of ketamine. 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. Nolan Williams who's a triple board certified neurologist psychiatrist at Stanford, School of Medicine who's laboratory specialized
Has in the use of ketamine for studies of treating depression and for treating depression in the clinical population. So I
asked him what's the deal here. I'm getting very contradictory evidence and
he spelled it all out for me.
It appears based on the clinical data in humans. A non-binding studies that the S form of ketamine is
more potent that is it can more robustly bind to the nmda receptor.
And in addition to that the S form of ketamine tends to produce
Is less dissociation at a given
dosage. Then does the combined Sr form of ketamine or pure are ketamine. He also added and sent me a study that I'll link in the show notes captions that there was recently clinical trial of our ketamine. So pure are ketamine 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 s ketamine is the preferred form.
It produces less dissociation 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 Sr form of ketamine, seems to be the most potent for relieving
depressive symptoms.
The S form of ketamine 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 sublingual dosing. And it's what is typically given by way of injection, in clinical studies, where they do injections
And it appears that the our form of
ketamine is the least potent and effective in treating
depression. Now, I realize that by putting this out into the larger world and assuming that there are experts in ketamine 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, our form was more effective for me than the S form versus the SR form etcetera, just to reiterate from the clinical trials that have been done. We know that the combined Sr form is more potent and effective than the pure
Form, which is still more effective than the pure our 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're 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 or
not people have used ketamine prescription from their doctor whether or not they
participated in a clinical study or whether or not they're doing it recreationally, I imagine that I will
About those experiences and I will take note of them.
Another commonly asked question, I received was
what about micro dosing of ketamine. There's a lot of interest in micro dosing. Nowadays, people are micro dosing, psilocybin, people are micro dosing,
all sorts of things. Hoping to get some of the same effects, as the macro doses, but by using dosages of compounds, that are below, what would induce say
in the case of psilocybin hallucinations or in the case of
ketamine below, what would
induce the kind of dissociation and euphoric effects that
That one would have to lie down for a few hours and disengage for the rest of the day.
I consulted with my clinician colleagues about this and they told me that at present. Meaning, as of yesterday, there is zero. Published clinical evidence that they are aware of, and by way of extension that I am aware of in which micro dosing ketamine has been effective for the treatment of depression. All of the positive effects on depression that I've talked about during this episode are gleaned from studies where people used this half milligram per
Dosage of ketamine or its equivalent by way of some other route of administration, not injected, but oral or sublingual.
So, are there any benefits to micro dosing ketamine? 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 talked about what ketamine is, remember, ketamine and PCP, angel dust very similar compounds. Both block the nmda receptor. We also talked about what sorts of subjective
effects that produces.
Association and Mild
Euphoria. And third-person thing of
self. That's the dissociation,
when taken at low dosages
and when taking it higher dosages, it can
induce full-blown anesthesia and put people into subconscious States and
there's actually a potential even for seizure and death. If the dosage is high enough for that person again, I want to emphasize that people do sensitivity
varies, tremendously route of delivery will impact
that and on. And on
we also talked about how the nmda receptor itself.
And the activation of this
incredible molecule, bdnf, brain-derived neurotrophic, Factor
seemed to be important for at least some of the antidepressant effects of ketamine, both in the days and weeks,
following ketamine Administration.
And in addition to that, I described how ketamine impacts the opioid receptor system and how we simply cannot Overlook the
involvement of the opioid receptor system in producing the antidepressant effects of
ketamine. And we also talked about the brain circuits and the brain waves associated with dissociative States. And the
Pression relief that seems to arrive for many people who take ketamine. And I tried to highlight some of the unique features of ketamine. 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 multi times per week,
over multiple weeks, kind of fashion to produce what I call durable changes, which almost certainly involve changes in neural plasticity, 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 ketamine 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 anti-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 who is expert in this area once. So aptly said Better Living Through Chemistry.
Tree
still requires Better Living.
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