Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity | Huberman Lab Podcast

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

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 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 your nervous system's 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 nootrophic Factor brain derived

nootrophic 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 about science and

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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 phen cycladine 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 you know cop shows on

television and the lore was that PCP

would eliminate 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 PCP

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 suicide

reality 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 ETC

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 it's 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

compelled 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 oh 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 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

has all this interest surrounding it and

really this has to do with our

understanding of what depression is and

what depression isn't so I'd like to

just take one or two minutes and 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 monoamine 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 are 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 serotonin and needs

serotonin dopamine also plays important

roles in the body

etc etc the monoamine 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 that increase

serotonin or drugs like bupren 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

them and they have a lot of side effects

now some people are lucky enough that

they can use a low enough dose or

perhaps even a high enough dose that

gives them relief from their depressive

symptoms but does not give them side

effects that make it so uncomfortable

for them to use that drug that they

would choose rather to not take that

drug however a lot of people that do get

depression relief from things like

Zoloft or Paxil or from buprone find

that the side effects which include

things like dry mouth although more

commonly reductions or increases in

appetite or 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

percent 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 percent

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 properties 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 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 a

reduction in anxiety to falling asleep

to a sleep to the point where even if

someone were to pinch your toe or your

arm like a 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 State 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 while 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 as

we'll 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 in what's

called atroche that dissolves under the

tongue or it's injected and then it's

injected into the vein or

intramuscularly Etc each of those can

produce very different effects in terms

of this 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 Laboratories that

were studying animal models what we call

pre-clinical 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 pre-clinical model of

depression that's pretty common in

Laboratories that involves taking 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 and see at what point it

gives up because what happens is if you

put a rat or Mouse into water it will

attempt to save its own life by swimming

but at some point it will just give up

and it will just start sinking and then

of course the researcher needs to rescue

the router Mouse put it back into its

home cage dry it off give it some food

Etc this preclinical model is called the

model of learn helplessness and it's

become a prominent pre-clinical model of

depression because of course we can't

ask mice or rats if they are depressed

or 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 could

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 pre-clinical 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 routes and mice put them into water

see how long it took before they gave up

and then to give them different drugs to

see whether or not any of those drugs

either hastened sped up or prolonged the

duration over which the animal would

attempt to save its own life this

actually has some meaningful parallels

to human depression you know one of the

Hallmarks of depression is that people

stop thinking positively about their

future depression of course can include

a lot of other symptoms you know one of

the most prominent symptoms of

depression for instance is consistently

waking up around 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 pre-clinical 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 antagonist 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 neuroplasticity so put

differently here's a drug that blocks

the receptor that's critical for

neuroplasticity 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 going to

walk away from that I'm going to work on

something far simpler and then there's

this other category of scientists 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 pre-clinical 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 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 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

atypical 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've provided a link to in the show note

captions it's a small study okay so it

doesn't involve many subjects at all it

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 or sublingual

ketamine and as it relates to things

like the k-hole or the dissociative

State 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 experienced 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 effects

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 relief 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 dreamliked associative state

and they get some relief from their

depression immediately and yet there's

persistent 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 an incredibly

attractive drug for the treatment of

depression especially depression that

hasn't responded to other forms of

treatment which is that people get

relief very very quickly indeed the same

day that they initiate the treatment

now this is especially important when

you think about the fact that the

monoamine hypothesis of depression which

drove the discovery and development of

all these drugs like ssris Wellbutrin

etc those drugs often can provide

support for people with depression again

only 40 of people get true relief from

their depression and again there are

some side effect issues or major side

effect issues in some cases that have to

be dealt with but even the positive

effects even under the best conditions

oftentimes 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 the 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 drug that's just not how biology

works there's always an interplay

between pharmacology between our

behaviors and what we choose to do or

not do this is a topic we'll get into a

little bit later when we talk about

anti-depressive behaviors and the role

of ketamine in bringing about

anti-depressive behaviors for the relief

of depression now with that said the

study that I just mentioned as well as

many many other studies that followed

emphasize that 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 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

although more commonly nowadays called

bipolar depression I did an 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

hubermanlab.com just put into the search

function bipolar and it will take you to

that episode ketamine has 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 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 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 State 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 their

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 that 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

regimen twice a week for three weeks

then take some time off repeat twice a

week for three weeks take some time off

repeat some have explored giving

ketamine once per week or even three

times per week or doing it once a week

for five weeks and then taking an

extended period of time off before

repeating the treatment schedule there

are a bunch of different studies out

there but when one looks at all of those

studies and mass together it's very

clear that ketamine is providing relief

from depressive symptoms immediately and

in the days after the treatment but that

when those treatments are act 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 mechanisms short medium and

long-term mechanisms that produce the

kinds of changes in neurochemistry and

more importantly changes in actual

neural circuit wiring that allows

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 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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how is ketamine really working we

already established that ketamine blocks

the nmda receptor and that the nmda

receptor is critical for many 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 neurons in order to bind ketamine

it's there 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

it 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 the

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 it 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 an and gate as the name suggests is

a function in a cell or in a system

where two things have to be present in

fact for those of you that have a bit of

an engineering or computer programming

background you'll be familiar with and

gates for those of you that don't don't

worry about it I'm going to explain what

an 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 is 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 that 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 from my spinal cord to 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 ampa

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 it's not very

interesting to watch the point is just

that I'm going to put my finger down in

one two three points on the desk in

front of me and then three two one point

coming back to me now that's obviously a

motor sequence that I can perform I just

did it so clearly I can perform it but

if I were to do that for let's say an

hour

what would happen is the neurons that

are involved in generating that motor

sequence of one two three three two one

one two three three two one would be

active over and over and over again and

what would likely happen because of that

unusual frankly motor behavior is that

the neurons 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 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 they the nmda receptor is

going to be activated and then

Downstream of nmda receptor activation

are a bunch of what we call

intracellular 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 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 Etc

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 its 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 respect respond to that activity in

the future you have in mind the

conceptual basis for understanding how

ketamine works because 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 meaning 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 neurotransmission in the

brain is called inhibitory

neurotransmission inhibitory

neurotransmission 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

gaba's 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's going on around them in

those moments they're shaking quite a

lot Etc there are many causes of

seizures but to get to the heart of what

a seizure is it is essentially runaway

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 it recruits a lot of

neurons in a fairly non-specific 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

Aura there's a whole discussion to be

had about seizure and by the way seizure

can occur in a lot of different contexts

of course it can occur in epilepsy it

can occur after a head injury

Etc we'll cover seizure in a future

episode of this podcast of course but

one of the major causes of seizure and

by extension lack of seizure is that

ordinarily inhibitory 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 neuron are

suppressing the activity of many neurons

so that those many neurons don't get

runaway excitation 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 to 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

neuroplasticity 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 onto excitatory neurons

when that happens the excitatory neurons

in specific circuits of the brain are

allowed to increase their activity they

do 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 it

actually doesn't make a sound in the

brain but if you were to record from one

of these neurons which people have done

many times over and then you were to

convert the electrical signal in those

neurons to an audio monitor you would

hear the firing the action potential of

those neurons as a that's what it

actually sounds like on the Audio

Monitor it 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 burst

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

realized what I just told you is a lot

of information in fact what I just

described represents essentially what 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 it 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 functions of engaging

neuroplasticity in ways that aren't

obvious if you just ask you know what

does ketamine do when you inject it what

does 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 bloodstream and then it makes

its way into the brain once it's in the

brain it binds to a particular category

of receptors called the nmda receptor

the nmda receptor is a receptor that

normally is quiescent 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 to

detect abnormal levels of neural

activity and in doing so recruit changes

to cells receptors Etc literally 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 the

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 stronger in the same way a neuron

can change the way it functions in

response to experience and neurons don't

know experience of life in any other way

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 it increases it 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 the 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 ramp up their

activity they're 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 we'll 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 was several fold

first of all I do believe it's important

to understand the key components of

neuroplasticity which is this remarkable

feature of our brain and nervous system

that we all have right this ability to

change our own brain circuits no other

organ in the body as far as we know can

direct its own changes but we can direct

our own brain changes and the nmda

receptor is absolutely critical for that

I also think 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 to everything not just

preventing seizures but it's Central to

learning it's Central to vision is

Central to hearing it's 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 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 or 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 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 two time a week over

three week type regimen of taking

ketamine or some variant on that now it

might start to make sense as to why yes

there is immediate and short-term

benefit of taking 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

consequence of actual neural circuit

reward 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 but I

didn't tell you how now you already

could imagine some of the mechanisms it

could be insertion of those new

glutamate receptors those ampa 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 nootrophic Factor brain derived

nootrophic 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 B

receptor trkb Trek B receptor when bdnf

binds to track B receptors on neurons it

does a lot of things it sets off a whole

Cascade of things including

the insertion of new glutamate receptors

so that those neurons become extra

sensitive to any input they get and 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

that can I mean 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 pre-clinical 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 suggest

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 task 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 well 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

it's 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 Etc in other

words all the appropriate control

experiments have been done that's

pre-clinical 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 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 B

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 than we normally

hear about nowadays we hear a lot about

ketamine and ketamine therapy we also

hear 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 depression

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 for the treatment of

depression I went into a lot of depth

about how psilocybin can induce

neuroplasticity 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 brainwide

changes those brain wide changes seem to

change one's reflection on oneself

so-called ego dissolution changes and

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 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

circuits bdnf being released and

changing neural circuits 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

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huberman so basically I've discussed two

major mechanism for how ketamine can

induce neuroplasticity 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 ketamine

works and when I say how ketamine 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 refers specifically to

people taking exogenous opioids taking

opioids right so taking pills that

activate particular receptors in the

brain that lead to

analgesia in some cases so pain relief

that lead to changes in mood there'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

drugs bind to are 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

the MU opioid receptor the Kappa opioid

receptor Etc 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

effects 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 one to two

milligrams per kilogram of body weight

now you're talking about anesthetic

Doses and when that happens you're going

to get full parking full saturation of

all the potential receptors that

ketamine can bind to those nmda

receptors it's going to block those it's

also going to bind to the so-called mu

opioid receptors and maybe this other

type as well for those of you that want

to know you Aficionado is 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 or all of the effects of ketamine

are due to the opioid system

and they want to know which effects

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 is hydroxy nor ketamine now I

don't expect you to 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 MU 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 hydroxine or ketamine is

selectively activating the opioid system

so this led researchers to ask at 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 or is it the consequence of

something happening in the opioid system

okay 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

symptomology when people take ketamine

recreationally so what researchers slash

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 is a study

done by 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 given

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 metabolite 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 from 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 talk 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

they're 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 think it's going to be an either

or situation however because drugs like

ketamine psilocybin 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 their experience of what

they saw what they heard how they felt

while they were under the influence of

the drug was actually the stimulus that

created the relief from their clinical

condition like depression but what these

data on combined treatment with ketamine

and Naltrexone to block the MU 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 one when

they do that therapy in the proper

context

it is not clear at all that it is that

experience and 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 wave front 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 and in fact multiple series 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 or maybe even

years and a really important thing to

underscore in the context of 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 are

going back to work they are engaging in

relationships again they are viewing

themselves differently again hopefully

they're getting morning sunlight and

exercising and eating well 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 relieved 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

antidepressive in fact we know that one

particular behavior that is viewing blue

light in the middle of the night between

the hours of say 11 pm and 4 AM is known

to invoke a pro-dopressive circuit it

involves a structure called the habenula

I've talked about this on previous

podcasts it tends to lower dopamine and

increase cortisol and the day is

following that exposure to light

Etc et cetera 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

quality 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 feed back on and combine

with the effects of the drug that one is

hoping for in this case depression

relief okay so I've been bookending this

conversation about ketamine at two very

Divergent levels meaning we've been

talking about high level stuff relief

from depressive symptoms right 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 that we're 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 seller

molecular level we're talking about

receptors and binding of receptors and

neuroplasticity and track B and all that

stuff we've completely neglected meaning

I've completely neglected until now

what Bridges those two levels of

understanding and what Bridges those two

levels of understanding are the neural

circuits that actually change when one

takes ketamine whether or not those

changes occur quickly whether or not

they take a longer period of time

whether or not they involve an MDA

receptors or 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 realize 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 the 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-dopressive symptoms in animal models

and very likely in humans as well and it

does so we know by reducing dopamine and

increasing cortisol there is evidence

that when people undergo ketamine

therapy connections between the habenula

what we can broadly just talk about is a

structure involved in gen generating a

feeling of disappointment

the connections between the habenula 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 mesolimbic reward pathway it

has 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 the changes in neural circuits

that we're talking about that can come

about from taking a drug well those

changes don't actually do a whole lot

unless those circuits are reinforced by

particular behaviors so this relates

back to what I said just a few minutes

ago about

pro-depressive and anti-depressive

behaviors somebody can take ketamine and

potentially get relief from depression

but if they continue to engage in

pro-dopressive 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 habenula to

the reward circuitry of the brain and

they do engage in behaviors such as

seeking out work that stimulates them

seeking out social engagement taking

good care of their body their mental

health their physical health 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 it's 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 when 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 a 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-dopressive

behaviors in circuits and you have

anti-depressive behaviors in 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 neuroplasticity

within the reward pathway itself in

particular with connections with the

frontal cortex and for those of you that

aren't familiar with the frontal cortex

your frontal cortex does a lot of things

but one of the things that your frontal

cortex is absolutely critical for is for

establishing

context-dependent strategy meaning for

allowing you to say okay 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 Etc your frontal cortex is that

part of your cortex that's always

churning ideas it's always wondering am

I doing well am I 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 mementine

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 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 described 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 body 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 dissociation 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 the changes in the MU 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

personing of self-effect and insofar as

we know it has to do with an uncoupling

of certain brain circuits in particular

neocortical brain circuits the neocortex

is the part of the brain the lumpy

outside part of the brain that's

associated with action planning it does

a lot of things really 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 phen cycladine PCP

there's an uncoupling of those networks

acquiring 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

Alpha rhythms or Alpha patterns of

activity that's just dominant patterns

of activity associated with particular

brain States 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 dream-like 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 a

Theta pattern of activity in your brain

at that moment

just prior to when you woke up whereas

when you're more alert you see 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 anesthetic 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 context 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 by

prescription and taking it at home which

is becoming a more common practice they

will often take it orally in pill form

or they will take it 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 percent of the

active form of ketamine makes it into

the bloodstream and when they take it

sublingually typically only about 35

percent 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 kilograms so if I

were to be in one of these studies which

I have not been but if I were

I would be given 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

milligrams by way of injection in a

study and I went to a different study

and they said okay we want to recreate

that effect we're going to give you a

pill typically they're going to give me

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 realize 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

questions about ketamine on Twitter and

I got many many questions some X

excellent ones they're 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-anesthetized 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 are 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

associative 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 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 are going to respond to it

based on some crude understanding of

dosages but when people talk about a

k-hole what they're talking about is

taking ketamine at a dose 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 ranges that you hear about

when hearing about ketamine are

extremely Broad and so is the

variability to any one 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 planes 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 pronoun 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 nmda 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 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 than to 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 some 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

intraectally 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 R 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 evidence

for instance I could find papers I did

find papers that said that the r form of

ketamine had a much greater affinity for

the nmda receptor than did the S 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