How Placebo Effects Work to Change Our Biology & Psychology
welcome to the huberman Lab podcast
where we discuss science and
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[Music]
life I'm Andrew huberman and I'm a
professor of neurobiology and
Opthalmology at Stanford school of
medicine today we are discussing Placebo
effects we will also be discussing what
are called nobo effects as well as
belief effects all three of these
Placebo nobo and belief effects are all
related to our brains in inedible
ability to place an expectation on what
is about to happen and actually change
what is about to happen independent of
the physical and chemical properties of
a drug or some sort of other treatment
solution for things like pain
Parkinson's disease irritable bowel
syndrome asthma stress and on and on and
on now one of the most incredible things
about these effects is that despite the
fact that it would appear that they are
simply psychological or the power of the
Mind Over Matter it's not that at all
Placebo nobo and belief effects actually
change the way your biology your
physiology Works in fact you have neural
circuits within your brain that are
dedicated to how your expectation of
what will happen actually changes some
of the most core biological functions
within your brain and body modifying for
instance heart rate blood pressure the
release of specific neurom modulators
such as dopamine and adrenaline and so
powerfully so that these types of
effects can actually work along with
traditional drug treatments or
behavioral treatments in order to vastly
change the way that your brain and body
work so if you think of the word Placebo
as an inert substance or treatment that
is merely a control it's merely
something introduced to an experiment or
a clinical trial to try and figure out
you know what's happening normally in
somebody's brain or body as a comparison
to some drug or other type type of
treatment well while that can be true
and Placebo controls are vital for
certain clinical studies it's also the
case that placebos nobos and belief
effects have powerful impact on our
physiology entirely separate from all of
that so much so that several highly
esteemed researchers in the medical
community around the world believe that
Placebo nobo and belief effects should
actually be leveraged in the treatment
of various diseases as their own unique
treatment so by the end of today's
episode you you are going to have a
clear understanding of what Placebo nobo
and belief effects are their biological
underpinnings and the way that you can
leverage them toward your mental health
physical health and performance 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 science related tools to the
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about Placebo effects I will also be
talking about no sibo effects and just
establish the difference between those
Placebo effects are when an inert
substance or behavioral treatment that
is a substance or behavioral treatment
that is not going to have any kind of
direct biological or psychological
activity right it shouldn't do anything
on its own somehow does in the direction
of improving symptoms or performance now
let's contrast that with no sibo no sibo
is when a drug or behavioral
Intervention which is inert it should
have no impact on symptoms or
performance of any kind but with no sibo
it turns out these substances or
behavioral interventions actually worsen
symptoms or performance now often times
people will just say a placebo effect
it's a little bit more rare for people
to distinguish between Placebo and no
sibo effects but I do think it's
important to know their difference going
forward I'll mostly just refer to these
as Placebo effects but I'll talk about
No sibo Effects a little bit later I'll
also talk about belief effects so let's
just establish what belief effects are
belief effects are when you or somebody
else learns specific knowledge that
changes your expectation about what is
going to happen in reference to say
stress or consuming a given food or
taking a given drug or doing a specific
behavioral protocol and the specific
information you learn or assimilate
actually leads to that specific outcome
so in many ways belief effects and
Placebo effects are similar it's just
that the word Placebo or placebo effect
effects is commonly used to refer to
drugs and behavioral interventions
belief effects are a more specific
language used to describe when
information of any kind changes the
outcome of some physiological or
psychological process now what's common
to Placebo nobo and belief effects is
that they all work by changing
expectation and anytime we talk about
expectation we're talking about the
function of the nervous system and
specifically the brain and specifically
the prefrontal cortex within the brain
the pre frontal cortex is neural real
estate which is just fancy nerd speak
for the neurons and their connections
that reside just behind your forehead
just in the front of your skull now the
prefrontal cortex has a lot of different
subdivisions or regions the overall
function of the prefrontal cortex can be
described as having the ability to
either activate or suppress other neural
circuits deeper in the brain some people
in fact a previous guest on the hubman
Lab podcast a neurosurgeon said the
prefrontal cortex can generally be
described as the structure in the brain
that controls other structures in the
brain by saying sh or suppressing their
function so for instance if you have the
impulse to move or to shout the
prefrontal cortex suppresses that
movement or suppresses that desire to
shout or that shouting if you've ever
had the experience of you know going to
the edge of a cliff or being on a high
bridge and thinking oh my goodness like
you know you just have this spontaneous
thought which please don't do this in
action but one will have this thought
like oh my goodness like what if I just
jumped off and people think oh my
goodness you know do I have some sort of
um Death Wish well no the prefrontal
cortex being largely a context
evaluating and prediction machine is
essentially looking at that landscape
and predicting what would happen indeed
how bad it would be if you were to jump
off that bridge or jump off that cliff
and then you feel that oh my goodness
like what's wrong with me why would I
think this but the fact that you think
it even for a moment but you don't do it
and the fact that you recognize that
it's sort of a uh you know dangerous
thought certainly a dangerous action
again please don't engage in the action
tells you that your prefrontal cortex is
working properly again the prefrontal
cortex is involved in suppressing
certain types of behaviors and what
sorts of behaviors well the larger theme
of the prefrontal cortex that we need to
consider today is that it is an
expectation or prediction making machine
it is a bunch of neurons that release
chemicals and have electrical activity
that're speaking with and receiving
information from other areas of the
brain and it's evaluating a number of
things like context like what's going on
in this room what's going on in this
scene what's supposed to happen here
what might I do what should I do what
should I not do etc etc now the other
thing about the prefrontal cortex given
that it has all these different
subdivisions is that some of those
subdivisions have a unique what we call
labeled line communication like a unique
Highway that leads to specific brain
areas that control specific bodily
functions including heart rate blood
pressure Etc and a little bit later in
the episode I'll talk about a specific
paper it's one of my favorite papers in
which a specific prefrontal cortical
region is identified as controlling very
primitive aspects of our physiology such
as body temperature and heart rate in
reference to beliefs or what's happening
in a social scene and this is very
different from the way that say getting
into cold water or experiencing some
other sort of stressor causes increase
in heart rate or Vaso constriction what
we're talking about here when we talk
about Placebo nobo and belief effects
are the way in which you learn
information or you are told information
like hey this pill is going to do blank
um maybe because the label says it maybe
because the um scientist or the doctor
tells you that this pill does blank or
this injection will do blank or maybe
you learn some information about what
some specific drug or supplement or
behavioral protocol will do and in that
learning you come to expect a specific
set of effects and certain neural
circuits in the prefrontal cortex become
active and start to activate certain
neural circuits deeper in the brain in
areas like the hypothalamus these are
ancient very well conserved across
animals areas of the brain that control
very primitive functions okay they exist
in essentially all mammals and even in
reptiles the prefrontal cortex also
communicates with areas of your brain
stem controlling things like breathing
Etc so the prefrontal cortex is a
sophisticated area of your brain that
takes into account context both in the
present as well as memories from the
past it can take into consideration
goals about the future and then combines
all of that into neural signals to areas
of the brain that control basic
physiological functions related to the
immune system the stress system the
reward system the pleasure system and on
and on so when we talk about Placebo
nobo and belief effects what we're
really talking about is the ability for
information and specific experiences to
lead to expectations within us about
what's going to happen and then our
physiology of our brain and body
fundamentally changes such that those
things happen so let's talk about some
specific examples of placebo effects
from the research literature and today
we're going to cover a lot of different
examples from different systems but as
we do that I will specifically be
selecting examples that illustrate
different types of placebo effects and
illustrate what those different types of
placebo effects are now I should mention
that if you're interested in Placebo
effects there's a wonderful book that
describes many many different Placebo
effects and their biological
underpinnings in cases where those
biological underpinnings are understood
and the book I'm referring to is one
that I used prominently in researching
this episode It's called none other than
Placebo effects understanding the other
side of medical care and the book is by
fabrio Benedetti I hope I pronounced
that right fabrio um and to your
Italians out there if I didn't do it
correctly I apologize it's an absolutely
wonderful book I confess I've never met
fabrio Benedetti I confess I have no
relation to the publisher or to the book
itself except that I absolutely love the
book so highly recommend this book I'll
be pulling from a number of different
examples described in this book today to
my mind one of the most interesting
examples of placebo effect is where
Placebo is given and can profoundly
change levels of dopamine release in the
brain now the study I'm about to
describe was done in Parkinson's
patients people with Parkinson's have
degeneration of neurons in an area of
the brain called the substantia
which is an area of the brain in the
kind of bottom back part of the brain
for ufan AOS it's the ventral tegmental
area but you don't need to know that
name these neurons contain dopamine and
are essential for the generation of
smooth movement patterns including
walking and reaching and moving um one's
hand to write Etc and of course dopamine
is involved in a bunch of other things
too including motivation and reward in
people with Parkinson's depending on how
severe and advanced the Parkinson's is
they suffer deficits in the ability to
generate smooth movements and often
deficits in motivation and reward
Pathways as well now there are many
different treatments for Parkinson some
more successful than others
unfortunately it's still not completely
curable at least not at this time but
most of the drugs that are successful in
treating Parkinson's to some degree or
another are drugs that increase levels
of dopamine within the brain for obvious
reasons as I just mentioned Parkinson's
is a degeneration of the dopaminergic
meaning dopamine containing and
releasing neurons in the brain so people
with Parkinson's will often be given L
Doopa which is a precursor to dopamine
or other types of drugs that increase
dopamine within the brain now there have
been a number of studies that have
compared certain drugs known to increase
dopamine such as lopa things like
apomorphine bromocryptine
Etc to Placebo control drugs and one of
the interesting takeaways from those
studies is that yes drugs like elopa
bromocryptine Etc increase dopamine and
at least can partially or transiently
improve symptoms of Parkinson's in many
not all patients with Parkinson's the
placebo drugs given in many of those
studies which were simply a sugar pill
or some other inert pill it doesn't
contain any chemicals that are known to
directly bind to or increase dopamine in
the brain and yet nonetheless when the
brains of certain patients were imaged
it was clear that Not only was there an
improvement in symptomology but there
were increases in dopamine release
within those patients brains which on
the face of it should make no sense
however when people with Parkinson's or
people who even don't have Parkinson's
are told a given drug can increase
dopamine and then they put these people
into a brain Imaging device it's called
a pet device has nothing to do with
animals it's the patron emission
tomography device and these people had
been injected with or consumed something
called raclopride it sounds really weird
and dangerous but actually ride looks a
little bit like dopamine itself
chemically and it has a little tag or
label on it and it can bind to certain
receptors in the brain where dopamine
would normally bind what was observed is
that the placebo itself was causing
reduced binding of this rack Pride to
areas of the brain that have dopamine
receptors which meant unequivocally that
there was more dopamine released in the
brain because if more dopamine is
released in the brain and parks in those
receptors well then the rprod which
looks a lot like dopamine can't also
park or bind to those receptors simply
put a placebo drug again a drug that has
no direct action on the dopaminergic
system if it's given to somebody who has
Parkinson's or who doesn't and they are
told this drug is going to increase
levels of dopamine in your brain and
potentially improve your symptoms of
Parkinson's or have some other effect
well it succeeded in increasing dopamine
levels within the brain which basically
should make us all sit back and say okay
what are we to think of drugs like elopa
and apomorphine bromocryptine as
compared to placeo why isn't everyone
just taking Placebo why aren't we just
telling people hey this sugar pill is
going to increase dopamine well two
important points to answer that first of
all the increases in dopamine that are
observed from Placebo plus information
about what that Placebo ought to do for
increasing dopamine are not as robust or
I should say generally not as robust as
the increases in dopamine observed from
an actual drug known to increase
dopamine transmission or release within
the brain the second point is that the
structure of the information given to
somebody and the belief that they form
about what ought to happen that is the
expectation effect which you'll start to
realize more and more across today's
episode that expectation effect really
is the underpinning of the placebo
effect well the strength of that
expectation is really hard to Anchor
across individuals and in fact if people
realize they're taking a placebo the
magnitude of of the dopamine increase is
actually decreased so this is why we use
Placebo controls in clinical trials we
want to establish the real difference
between the effect of a given drug on a
biological system in this case
increasing dopamine from the belief or
the expectation of what that drug will
do so in that sense the placebo is
really a measure of expectation of what
a drug treatment will do at least in the
context of a drug trial so I mentioned
this somewhat complicated example
because first of all many people are
interested in dopamine we all make
dopamine it's involved in motivation
drive and focus and reward all sorts of
things that we hear a lot about these
days second of all it really illustrates
that Placebo that is expectation about
what will happen is impacting of course
Placebo effects you realize that now but
it then also has to be the case that
Placebo effects are playing into any
effect that we might observe from taking
a given drug or supplement based on our
our expectation of what that drug or
supplement will do and miraculously or
at least what I find miraculous is that
Placebo effects these expectations based
on knowledge and beliefs are highly
specific which raises all sorts of
questions about for instance if you were
given a drug that increases dopamine
levels but you weren't told that it
increases dopamine levels that perhaps
you were told you were lied to and told
that it increases the activity of a
different neuromodulator like serotonin
would it well let's explore that because
as wild as that seems it turns out that
what we believe about a given drug
treatment or behavioral treatment
actually has a high degree of
specificity so to illustrate the
incredible specificity of placebo
effects I want to describe a study
related to hormone function hormones
come in many different forms we have
testosterone estrogen growth hormone
cortisol Etc there's a study that was
carried out in humans in which subjects
were informed about growth hormone
release and cortisol release growth
hormone is a hormone released from a
gland in the brain called the pituitary
the pituitary has different parts the
anterior pituitary releases growth
hormone each night when you go to sleep
it's involved in protein synthesis
tissue repair bodily growth appendage
growth and many other things cortisol is
a hormone that's released from the
adrenals it can also be synthesized and
released a couple other places in the
brain and body and it's involved in
immune system function in
anti-inflammatory action a lot of people
think cortisol is bad but it's actually
an important hormone for our daily
Health our alertness and waking up in
the morning Etc in any event subjects in
this study learned about growth hormone
and cortisol and their release where
they're released from what they do just
as you did and then their growth hormone
and cortisol levels were measured and
not surprisingly they didn't change just
learning about growth hormone and
cortisol did not change growth hormone
or cortisol levels in these human
subjects now on days two and three of
this experiment subjects received an
injection of a drug the drug is called
sumatriptan and sumatriptan is known to
increase levels of growth hormone and
reduce levels of cortisol and indeed
that's what they observed when people
received these injections and then their
blood was drawn growth hormone levels
went up cortisol levels went down now
the interesting part of the study is a
separate day okay so after the drug
treatments they come back and they are
injected with saline which has no
specific biologic effect it's simply
saltwater okay they're injected with
saline and they experience increases in
growth hormone and decreases in cortisol
which on the face of it might seem like
wow that's incredible but based on what
you've learned thus far in today's
episode you could imagine that knowledge
about growth hormone and cortisol
somehow combined with the injection to
lead to an expectation of increases in
growth hormone and decreases in cortisol
which would be amazing in its own r
right okay after all saline is inert it
doesn't do anything directly and
specifically to the growth hormone or
cortisol system but get this it turns
out that a saline injection which does
nothing on its own on day four or five
after people have received this drug
treatment increases growth hormone and
decreases cortisol independent of what
people are told they are being injected
with even if they are told they are
being injected with a drug that has
completely different effects than
sumatriptan so why would this be how
could this be in fact there was even a
condition in which subjects were told on
the day they receed the placebo you're
about to get an injection of something
that's going to decrease growth hormone
but rather they experienced a genuine
increase in growth hormone and decrease
in cortisol in the exact same way they
did when they received the active drug
Summa triptan okay so this wild type of
scenario has to be explained and in
order to explain it we need to zoom out
from the experiment and ask what's the
similarity between Day 2 and three of
the experiment meaning the days in which
the people received the actual active
drug sumatriptan that increases growth
hormone reduces cortisol and the day in
which they receive the placebo and the
one thing that anchors both those days
together meaning the one thing in common
that can explain this effect is that
those were the days in which people
received an injection and in fact
through various control experiments and
a few other experiments that were done
subsequent to this because this
experiment has been more or less
repeated in different forms in different
Laboratories it became clear that the
brain and body somehow came to expect
that receiving an injection leads to
increases in growth hormone and cortisol
now this is not an indefinite effect
right people will get injections of
other things in the future presumably
active drugs not just saline that will
change hormone levels or change
neurotransmitter levels but in this
experiment what happened is is is that
there was a pairing within the nervous
system there was a somehow a binding of
the notion of getting an injection with
a syringe which in the first case was of
a drug that increases growth hormone
decreases cortisol and then when
subjects came back and were injected
with a different syringe presumably I
would hope so with a different syringe
filled with saline even though the
saline should do nothing the body and
brain had somehow formed a pairing an
association between syringe injection
and increased growth hormone decreased
cortisol which is incredible given that
these systems the anterior pituitary the
adrenal glands I mean these are ancient
systems that to our knowledge we can't
directly control with our mind I can't
simply like close my eyes and grit my
teeth and cause the release of growth
hormone I can't simply decide to deploy
cortisol from my adrenals although if I
thought about something very very
stressful for a long time there'd
probably be some cortisol secretion but
to our knowledge there is no way to use
thoughts to use beliefs to use
understanding of knowledge to cause
changes in our endocrine glands right
our hormone glands the pituitary the
adrenals but here we have a case where a
drug that increases certain hormones and
decreases other hormones simply by
virtue of the fact that it was injected
into somebody leads to a case where
subsequent injections at least in the
short run lead to the exact same hormone
changes simply because in the mind and
or body of these individuals injection
comes to equal increase in growth
hormone decrease in cortisol independent
of what's being injected now a key point
is that had on the final day of the
experiment the subject's been injected
with a different drug that for instance
you know increases serotonin or reduces
epinephrine I doubt that they would have
instead experienced increases in growth
hormone and reductions in cortisol
that's simply not the case the fact that
there was only saline in there meant
that there was an opportunity for the
the syringe and the injection we don't
know which to lead to some sort of pair
dissociation in the brain and body that
led to increased growth hormone
decreased cortisol which mimic the drug
effect but the whole scenario here as
wild as it is really speaks to the fact
that often times we think a given
treatment is causing a given effect only
because of the action of the drug or the
action of a given behavioral protocol
but in fact the drug and the protocol
exist in a big context of different
things that the brain and body are
integrating and trying to make sense of
and that often gets lumped together I
often say that your brain is yes a
prediction machine but it's also trying
to simplify things in those predictions
it's not taking into account all the
information it's often lumping
information together and coming up with
ideas about what's going to happen and
why and doing this subconsciously in a
way that as you just learned can have
profound effects on what happens within
us even at the level of something as
basic as hormone release now what I just
described is a pretty extreme example
and it's a very experimental condition
type example I mean it's rare that
people are undergoing uh you know these
kinds of organized receival of
information followed by specific drug
treatments and Placebo injections Etc
but you've all experienced the placebo
effect in action by way of what's called
classical conditioning simply by virtue
of the fact that the smells of certain
foods and your past experience of
certain foods can lead to the release of
a hormone called insulin insulin is a
hormone that is involved in regulating
blood glucose blood sugar and typically
when insulin levels go up in the
bloodstream glucose levels are going to
go down because of the way that insulin
controls blood sugar levels now if
you've ever had the experience of
walking past a bakery or a pizza shop
where a delicious smell is wafting out
into the environment you may notice that
it quote unquote makes you hungry and
indeed it does make you hungry because
presumably you've had the experience of
certain smells being associated with the
consuming of certain foods maybe Bakery
Foods maybe pizza maybe steak whatever
it is
and the consumption of those Foods
actually leads to increases in insulin
in your bloodstream well there's the
so-called conditioning effect whereby
the smell of the food itself starts to
lead to increases in insulin but the
conditioning effects of different
stimuli different things in the context
of eating and specific Foods leading to
increases in insulin is actually highly
highly modifiable so much so that
experiments have been done where for
instance
somebody eats a particular food or in
some cases it's just directly injected
with insulin but more often consumes a
particular food and just prior to
consuming or during consuming that food
there's a bell ringing or a buzzer in
the background going off and they do
that a few times and then I'm sure
you're anticipating what's coming
somebody can just hear the buzzer or the
Bell can simply ring and that person
will experience an increase in insulin
so what I'm describing is a conditioned
insulin response a stimulus such as a
bell or a buzzer that on its own should
have zero effect on insulin release has
been paired with a food that genuinely
increases insulin within the bloodstream
and then even if the food isn't present
the stimulus the buzzer the Bell Etc can
evoke the insulin response now this is
an important example to understand
because it's a common one that we've
presumably all experienced and that
exists within the wiring of our brain
right now but it's different than the
smell evoking the insulin response
because delicious food which evokes an
insulin response having a particular
odor that makes sense in the context of
food but here we're talking about
something completely unrelated to the
food not the odor not the taste not the
appearance just something that happened
to be in the environment in which you
ate the food leading to an increase in
insulin and it just screams placebo
effect but it also screams that the
placebo effect is strongly modifiable
according to context again the
prefrontal cortex being the seat of the
anticipation or placebo effect effect
and the prefrontal cortex taking into
account lots of things in the
environment trying to understand what's
here what sounds what smells what colors
and then lumping all of that together
and eventually through the activation of
specific neural circuits leading to a
very basic hormonal response in this
case the release of insulin and of
course what I just described is
classical conditioning Allah Pavlov
Pavlov won the Nobel Prize for his
description of classical conditioning in
which dogs could be induced to Elevate
in anticipation of food by way of a
stimulus completely unrelated to food
itself not the smell not the look not
the taste rather just a bell rung before
the consumption of food in a dog
eventually led to a situation where the
mere ringing of a bell could evoke
salivation from those dogs so are we all
just like salivating dogs I guess we are
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huberman okay so given that context is a
powerful modifier of the placebo effect
and in fact may be Central to the
placebo effect I just want to Rattle off
of few of the known Placebo effects that
have been demonstrated which show the
extent to which your brain and my brain
are coming up with ideas about what
given drugs or given behavioral
treatments ought to do and in that way
shaping what happens when you take a
placebo or and this is an idea that
we'll go into in a bit more detail in a
few minutes perhaps context is also
changing the way that active drugs not
placebos but active drugs are impacting
your brain and body the examples i' like
to give our from laboratory studies
about the placebo effect but that relate
to very common at home and normal life
scenarios okay they are not unique to
the laboratory and they are the
following first of all Placebo effects
are strongly modifiable by the
expectation of the quality of a given
treatment for instance if you are given
a placebo that has a brand name on it or
a name of a drug it could even be a
madeup name you don't know what the drug
does does but it has trademark TM there
in the corner of the name so brand name
as opposed to generic Placebo the brand
name Placebo has a stronger effect
moreover if a placebo is placed into a
package not just put in front of you on
a little tray or in a little dish but
rather in a package where you have to
push it through that little foil
wrapping or you have to take it out of a
bottle and especially if that wrapping
or bottle has a label on it or it looks
as if it's a quote unquote real drug
well then the placebo has an even
greater placebo effect the color of a
given drug can even have an effect based
on our association or expectation of
what different colors relate to in terms
of our physiology for
instance if subjects are given pills
that they are told will help them fall
and stay
asleep and some subjects are given blue
pills other subjects are given Red pills
other subjects are given yellow pills
the subjects that take the blue pills
tend to sleep better even though all the
pills regardless of color are Placebo
they contain no active substance okay so
for some reason most people associate
the color blue with sleep whereas or I
should say by contrast if people are
given a blue a red or a yellow pill and
they are told it's a stimulant the
subjects taking the red pill here I mean
the actual literal red pill I'm not
talking about any kind of cultural red
pill I haven't seen The Matrix yet
people tell me I need to see it but I'm
not talking about taking the red pill
quote unquote I'm talking about taking a
pill that is the color red in an
experiment the people that take that
pill experience a greater Placebo
induced stimulant effect as opposed to
when subjects take a blue or a yellow
pill for some reason the color red is
associated with a quote unquote upper
effect or stimulant effect moreover if
subjects are given a blue a red or a
yellow pill and they are told that the
pill will have an anti- depressant
effect the subjects that took the yellow
Placebo get the biggest anti-depressant
effect so color of a given pill even
impacts the direction or in this case
the magnitude of the placebo effect and
I should mention that in every one of
those studies yes there was information
about what the given pill should do it
was not the case that if people took the
red pill they felt a stimulant effect if
they took a blue pill they felt a sleepy
effect and if they took the yellow pill
they felt an anti-depressant effect
these were three separate experiments
one on sleep where subjects were given
one of the three colors of pills blue
had the strongest effect or a study of
stimulant effects they were told it's a
study pills that will increase alertness
and attention they were given one of
three different colors the red pills had
the biggest effect and the third
experiment subjects were told this is a
pill that will alleviate to some degree
your symptoms of depression the people
who took the yellow pill experienced the
greatest relief of depressive symptoms
now that's pretty wild but what perhaps
is even Wild ER is the more invasive a
placebo intervention is the greater the
placebo effect so capsules have a bigger
effect than tablets I don't know if
that's more invasive but I guess it
looks more medicinal to have a capsule
versus a tablet who knows why but that's
what's been observed an injection of a
placebo has a greater effect than a
consumption of a capsule or a tablet of
course and if people are placed into a
medical device or machine especially in
cases where one of their limbs or both
of their limbs or even their whole body
is placed into a device even though the
device is doing absolutely nothing
specifically to our biological system it
is inert right a bunch of buttons and a
bunch of noises and a bunch of humming
as if something were happening but
nothing is happening that directly
relates to any one specific biological
system except and now you know what I'm
about to say except expectation of what
the machine is doing well that has the
greatest placebo effect of all
so for some reason as the level of
invasiveness or the let's just say the
complexity of a given treatment is
increased well then the magnitude of the
placebo effect is also increased and
what this tells us is that the human
brain has come to associate level of
invasiveness level of complexity of a
given treatment or machine to equate to
bigger outcomes and in some sense that's
completely logical but again we have to
remember in absolutely zero of these
conditions whether or not it's a tablet
a capsule an injection or a medical
device is there anything being done to
these human subjects that impacts a
specific biological function except one
and that one again is the activation of
specific neural circuits in the
prefrontal cortex that then are able to
communicate with other areas of the
brain and body through Bonafide
biological mechanisms of
neurotransmitter release and electrical
activity in neurons this is what the
brain does and of course the prefrontal
cortex being part of the brain those are
the mechanisms it employs to change the
activity of hormone relasing glands to
change the activity of other neurons in
other words the belief effects the
expectations are real they are having
effects through true biological
circuitry it's just that the pills and
the treatments and the machines are not
doing anything specific at all except
activating expectation so we've been
talking about the placebo effect and
I've been giving examples of strong
Placebo effects and while all of what I
told you is substantiated by data I do
not want to give you the impression that
the placebo effect is Limitless because
it is not Limitless for instance
placebos have been used to help in the
treatment of cancer but their effects
within the treatment of cancer are
limited to a very specific set of
symptoms and context so for instance
people who are told a given drug will
help them with their cancer by reducing
their symptoms of chemotherapy or
radiation therapy all often experience
reductions in the negative symptoms of
chemotherapy or radiation therapy
reduced pain reduced nausea and by
consequence improved feelings of
well-being compared to people who do not
receive the placebo and who are not told
hey this drug which in reality is a
placebo is going to help you with your
treatment it's going to make it less
uncomfortable okay so in the context of
cancer treatment Placebo can reduce the
discomfort of various cancer treatments
however placebos cannot reduce the size
or eliminate tumors if people who
unfortunately have tumors okay cancer
are given a placebo and told this drug
which actually is a placebo unbeknownst
to them is going to reduce the size of
your tumors or eliminate your tumors
that Placebo is not effective in
reducing the size or eliminating those
tumors this is very important to
understand because as you recall Placebo
effects are expectation effects
expectation effects are driven in large
part by the prefrontal cortex and its
connectivity to other areas of the brain
and thereby to the body but the outputs
of the prefrontal cortex are limited
there are a certain number of them and
indeed there are many of them but those
connections do not extend to tumors
themselves or biological systems or
circuitries that allow one's beliefs to
reduce the size of or eliminate tumors
and this is very important because
unfortunately there are many sufferers
of cancer and there are many theories
about accelerating the treatment of or
improving the treatment of or even
curing cancer using so-called mindbody
techniques or mindbody tools and we need
to be fair to the data which have
conclusively shown that reductions in
stress improvements in sleep social
support a number of things can improve
cancer treatment outcomes now those are
not Placebo effects those are all
practices for which we know there are
reductions in inflammation reductions in
stress hormones that lead to improved
outcomes in the context of radiation
therapy in the context of um
immunotherapy in the context of any
Bonafide treatments known to reduce
tumor size so what we need to do is
separate out three things here
behavioral practices such as meditation
sleep social support known to reduce
inflammation and stress and that can
improve cancer outcomes those are not
Placebo effects those are real effects
there are also drugs radiation
chemotherapy immunotherapy and devices
known to reduce tumor size and hopefully
eliminate cancerous tumors that would be
the hope those are real effects and then
there are the placebo effects the
knowledge and belief and expectation
about what a given treatment will do in
some cases it's knowledge about what a
given drug will do that improves the
outcome achieved with that drug in some
cases it's people being given a
completely inert substance or solution
like saline solution but being told this
is going to help with your nausea
symptoms this is going to help with your
pain during your immunotherapy radiation
Etc and those are real effects but they
can only be explained by virtue of
expectation and knowledge AKA Placebo
effects and I want to emphasize that
those Placebo effects are not acting
directly on tumors to reduce their size
or eliminate them another example of how
placebo effects can be very powerful and
yet still have limits to them is yet
another study from Dr Ted cap truks Lab
at Harvard Medical School and by the way
many not all of the studies that I've
been describing today have been done by
the captrick lab he's done beautiful
work on Placebo effects for a very long
time now he's considered a real Pioneer
and a leader in the study of placebo and
he's also been a big proponent of
exploring the placebo effect not simply
as a contrast to drug effects or device
effects but as their own specific effect
that perhaps can be leveraged in the
context of treating disease so hats off
literally plural hats off because
they've had oh so many discoveries in
the context of placebo and their
powerful effects and their possible uses
from the capu lab and their colleagues
there at Harvard Medical School just
incredible work and one of my favorite
studies from the cap lab is one
published in the New England Journal of
Medicine some years ago in in which they
took people who had asthma so these are
people diagnosed with asthma these are
people who have challenges breathing and
they experienced a lot of discomfort in
trying to breathe normally unless they
are taking their asthma medication in
this study they took people off of their
asthma medication of course not
indefinitely but for a short period of
time and as expected those people
experienced challenges in breathing and
discomfort associated with the
challenges in
breathing one group received no
treatment they were just taking off
their
asthma meds and evaluated and then of
course put back on their asthma meds
another group received a placebo
treatment and another group received a
drug known to improve the symptoms of
asthma now what was interesting is that
the people who receiv received the drug
for the treatment of asthma not
surprisingly had improvements in
breathing and less discomfort it's
exactly what you'd expect however the
people with Placebo also experienced
less discomfort in breathing
but their patterns of breathing didn't
change so again this really speaks to
the fact that Placebo effects can be
very powerful but that they're very
specific they are not simply wiping out
a condition like asthma or completely
eliminating all simpology of a given
condition like cancer this study
illustrates very clearly that Placebo is
effective in reducing the discomfort
associated with the challenges of
breathing but not eliminating challenges
with breathing per se where as as I
mentioned before there are drugs
Bonafide prescription drug treatments
that can both restore normal patterns of
breathing and relieve the discomfort so
what this really speaks to is the fact
that the prefrontal cortex and its
involvement and expectation can have
powerful effects on things like pain
powerful effects on things like dopamine
powerful effects on any number of
different brain and body systems but not
all of them our beliefs and expectations
are powerful as evidenced by the place
EO effect itself but they are not what
we call omnipotent they can't do
anything and everything I'd like to take
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docomo one of my all-time favorite
studies in the context of placebo is a
paper that was published pretty recently
and the title of this paper is nicotine
related beliefs induce dose dependent
responses in the human brain and if ever
there was a paper that pointed to the
fact that our belief systems can really
shape the way that different drugs
different supplements different
behavioral protocol s can impact the way
that our physiology and our brain work
it's this paper it's a pretty
straightforward study it was of course
carried out in humans and what they did
is they had people Vape
nicotine nicotine is a known cognitive
enhancer nicotine so named because it
binds to nicotinic acetylcholine
receptors in the brain which is just
fancy nerd speak for The receptors the
little parking spots for acetylcholine a
neuromodulator that's involved in
attention and by virtue of being
involved in attention is critical for
the performance of certain focused tasks
okay so most people associate nicotine
with smoking vaping dipping or snuffing
here we're talking about nicotine that's
Vaped however I want to be very clear I
am not encouraging people to vape
nicotine yes vaping is probably
healthier for you than smoking but
vaping is not good for you it would be
better to not vape than to vape at all I
did an entire episode about Nic
so I want to leave aside the issue of
whether or not you decide to use
nicotine okay that's all covered in the
episode on nicotine I'll provide a link
to that in the show note captions
there's a lot of considerations there it
does increase blood pressure and it
increases vasal constriction and on and
on but as I mentioned nicotine is a
cognitive enhancer it can increase focus
and attention and in doing so it can
allow your brain to do certain things
better like task switching like focusing
in the context of a lot of distraction
etc etc so in this study Nick nicotine
related beliefs induced dose dependent
responses in the human brain
subjects used a vape to ingest nicotine
and they were told that they were either
ingesting a low medium or high
concentration of nicotine and a really
nice thing about this study is that they
actually measured how much nicotine
people Vaped so they were able to
measure how much nicotine made it into
the bloodstreams of these people and
they were also able to evaluate brain
activity in areas of the brain known to
have these Nic IC receptors and to also
be involved in certain cognitive tasks
so just to get to the Grand conclusion
of the study what they found is that
people who were told that they ingested
a high concentration or a medium
concentration of nicotine performed
better on a cognitive task that we know
is dependent on or can be modified by
the amount of acetylcholine transmission
in a certain area of the brain then did
individuals who were told that they
ingested a small concentration of
nicotine now the interesting part of the
study is that everybody consumed the
same amount of nicotine so here we have
a situation where there is a so-called
dose dependent placebo effect everyone
gets the same amount of nicotine but
people are either told meaning they were
lied to in some cases that they got a
small medium or high concentration of
nicotine and for the group that was told
that they received a medium
concentration of nicotine they performed
better on a cognitive task than did the
people who were told they received a
smaller concentration of
nicotine moreover people who were told
that they received a high concentration
of nicotine performed better than either
the individuals who were told they
received a medium or small concentration
of nicotine but as I mentioned before
everyone received the same concentration
of nicotine so this tells us that not
only are Placebo effects related to
expectation but that the expectation
somebody has of the degree of an effect
they should expect experience actually
creates a different level of experience
put differently if you're told that
you're getting a small amount of drug a
medium amount of drug or a high amount
of drug and that the size of an effect
gets bigger as you go from small medium
to high well then you will experience
the small medium or high effect
depending on which group you were in
even if you all got the same dose of
drug now I need to be very clear
everybody got actual nicotine the
placebo effect here is related to what
people believed about the dose of
nicotine they got but everyone got
active nicotine now here's where it gets
really cool as I mentioned earlier in
this study they imaged the brains of
people that were in either the group
that was told they got a small or medium
or high concentration of nicotine and
what they found is that in the specific
area of the brain that is known to
respond to nicotine and that is involved
in cognitive functioning related to the
task that these subjects were given they
saw increased levels of activity of the
neurons in that brain region that scaled
up according to whether or not people
were told they got a small medium or
high amount of nicotine again everyone
got the same amount of nicotine they
were simply told small medium or high
and the Brain area itself changed its
level of activity which in turn changed
the outcome on the cognitive task which
basically puts everything in a really
nice box wraps it up with wrapping paper
beautiful puts it in a bow and says okay
Placebo effects are real and Placebo
effects scale with the degree of
expectation that one has so anytime we
are told that a small dose of something
is going to lead to a small effect a
medium dose of something is going to
lead to a bigger effect and a high dose
will lead to an even higher effect well
whether or not that occurs is going to
depend a lot on what sorts of quote
unquote effects we are expecting again
you can't use Placebo to eliminate
tumors there's a limit to what Placebo
effects can occur but assuming that the
effect that one is interested in is
modifiable by knowledge and expectation
well the size of that effect will scale
with how big you expect the effect to be
and it's not purely psychological that's
the point here it's not just about your
beliefs and you doing something very
different in the context of a task or in
a sports event your physiology in this
case the activity of a specific brain
region increases its level of output
according to your expectation of the
level of drug you consumed so in my
description of that recently published
study you notice I said Placebo effects
but in many ways what I was describing
were belief effects it's a little bit
difficult to disentangle what's a
placebo effect and what's a belief
effect in general belief effects have to
do with acquiring a bit more information
or specificity of information about what
the expectation should be so I suppose
the study I just described could would
easily fall under the category of belief
effects and not just Placebo effects but
nonetheless belief effects are powerful
and they're especially powerful because
as one starts to layer in different
amounts and different types of
information as to what a given drug
treatment or behavioral treatment will
do one can start to see really nuanced
outcomes as well as truly surprising
outcomes and some of my favorite studies
on belief effects were done by my
colleague at Stanford she's in the
department of psychology her name is Dr
alah crumb she's been a guest on the
hubman Lab podcast before we will also
provide a link to that episode and Ali's
lab studies mindsets mindsets of course
incorporate a lot of things besides
beliefs they involve prior knowledge
they tend to have even more information
woven into them than either Placebo
effects or belief effects but alli's
really one of the world leaders in
understanding these belief effects and
has done some just gorgeous work in
illustrating the incredible range and
extent of belief effects that exist one
of my favorite studies in this context
is the paper from alli's lab entitled
Mind Over milkshakes mindsets not just
nutrients determine the grin response so
here I'll just briefly describe the
study I'll paraphrase the abstract on
two separate occasions people consumed a
380 calorie milkshake and they were
either told that it was a 620 calorie
quote unquote indulgent shake or a 140
calorie quote unquote sensible Shake
then the hormone gin was measured gin is
a hormone associated with Hunger it is
released from and binds to various sites
within the brain and body but it's
generally associated with The Hunger
response the desire for food then their
subjects had their blood drawn at three
different time points so at Baseline
prior to consumption of the milkshake
anticipatory meaning just prior to
consuming the milkshake and post
consumption 90 minutes after consuming
the milkshake and then gin was measured
within the blood samples that the people
provided now as you recall everyone is
consuming the same 380 calorie Shake but
that's unbeknownst to them one group
thinks they're drinking an indulgent
shake that has lots of calories the
other group thinks they're ingesting a
quote unquote sensible shake with fewer
calories and it's important to note that
in the study the individuals were asked
to read the labels of the shake and get
information about okay this is an
indulgent Shake has a lot of calories a
lot of fat it's Etc in the other case
this shake has very few calories it
contains healthy ingredients Etc now you
can probably guess where this is going
the people that consumed the milkshake
but were told it was a high calorie
indulgent shake and also by the way
consumed information about it being high
calorie and indulgent and they were
reading that on the label experienced
steeper reductions in this hunger
Associated hormone called gin as
compared to the group that also consumed
the same 300 180 calorie Shake but
thought that the shake was a sensible
shake with fewer calories that was a
healthier shake those people experienced
reductions in Gin as well but they were
less steep they occurred less quickly
over time and in addition their
subjective level of satiety of fullness
or of feeling as if they had enough food
to quell off hunger was also related to
whether or not they thought they had
consumed the higher calorie indulgent
shake or the lower calorie sensible
Shake there are a bunch of other
interesting aspects to this study I'm
just giving you a cursory overview of
the major effects but the takeaway is
very straightforward what we believe
about the foods we are consuming
strongly impacts the downstream hormonal
effects of consuming those Foods gin
after all is a peptide hormone that is
secreted from the stomach okay yes the
stomach has neurons but as far as we
know the stomach doesn't have a little
thinking brain in there the stomach is
operating in a very kind of crude
language of the nervous system as
compared to the thinking and analytic
language of the brain the forbrain but
what's happening here is that knowledge
indeed specific knowledge about what
more calories means as opposed to fewer
calories what the word indulgent means
as opposed to sensible all of that is
being combined and then communicating
with neurons and other systems of the
gut to literally create a different
hormonal response to food and that's
incredible because the hormonal response
to food is a very strongly evolutionary
conserved set of mechanisms and yet this
study and other studies like it
including the conditioned insulin
response that we talked about earlier
you know Pavlov's dogs or in this case
we are the pavlos dogs we're the ones
that can get conditioned to a bell or
the smell of a food or the sight of a
sign on a bakery to get a insulin
increase all of that stuff that is
primitive hard wiring of the brain and
body is also being strongly impacted by
the more let's call it sophisticated or
analytic as aspects of the wiring of the
brain such as the prefrontal cortex such
that what we believe is going to happen
is actually what happens now the other
study on belief effects and mindsets and
how they can impact outcomes in terms of
our physiology relates to exercise and
this is a study um that Dr Crum herself
described came about because she was
talking to one of her academic advisers
this was before she opened her own
laboratory and you know Aaliyah's an
athlete she was actually a division
athlete she's an incredibly impressive
individual by the way she's a tenure
professor at Stanford uh she was a
division one athlete she has a degree or
rather a certification in Clinical
Psychology so um she's an extremely
accomplished individual but exercise in
athletics have always been a big part of
her life and one day she was talking to
her adviser and her adviser offered the
possibility that and here I'm
paraphrasing from a different
conversation perhaps all the positive
effects of excise exercise are Placebo
that's actually what her adviser said
and allly said no there's no way right
we know that you exercise you sure get
an increase in heart rate and blood
pressure during exercise but that leads
to lower levels of Baseline blood
pressure and heart rate afterwards after
you adapt to that exercise and her
adviser said well okay that might be
true but why don't you go test it so she
did test it what she did is she took
hotel service workers so these are
people that clean hotel rooms for a
living and these are very active people
right they're vacuuming they're changing
sheets they're going upstairs they're
folding laundry they're doing a bunch of
different things throughout the day and
they divided them into two groups one
group was told that doing a great job
and being diligent is very good for you
they were told all sorts of things about
their job and how it was important and
indeed their job is important right we
need people who can perform these roles
of turning over hotel rooms and doing
those sorts of things so that hotel
rooms can be clean and beautiful When we
arrive the other group however was told
that the normal daily activities that
these people were partaking in the
folding of the laundry going up and down
the stairs pushing of carts Etc was
exercise and more importantly that it
was the type of movement that could for
instance lead to reductions in blood
pressure reductions in body weight
improvements in lots of different Health
metrics now the incredible outcome of
the study was that simply on the basis
of whether or not people were told and
therefore believ that their daily
activities would lead to improvements in
these different Health metrics
reductions in blood pressure reductions
in basil heart rate reductions in body
weight well that's exactly what happened
people who received the information
about how exercise was healthy and their
work mimicked exercise experienced the
health metric changes whereas people who
were simply told your work is important
you know it's important to do a good job
etc etc they did not experience the same
Health metric improvements so that
provides support for what Dr crumb's
adviser had suggested that at least some
of the effects of exercise are likely
due to mindsets or beliefs AKA belief
effects so throughout today's episode
I've been talking about how our
expectations and beliefs and mindsets
can impact these really deep layers of
our physiology things like hormone
release things like level of discomfort
or pain during a given treatment and on
and on and talked a lot about the
prefrontal cortex as critical for
understanding what's happening in a
given context and for setting those
expectations because the prefrontal
cortex as you recall is a prediction
machine and context is important for
prediction and on and on what I haven't
yet told you is how it is that the
prefrontal cortex actually does this I
mean what are these magical output
Pathways of the prefrontal cortex and
while I already established that they
are not infinite right the prefrontal
cortex can't control everything meaning
if I give you some information like you
know just thinking about and believing
that um your left quadricep is going to
be you know much stronger than your
right quadricep and if you just keep
perseverating on meaning you keep
thinking about that and looping on in
your mind and I give you some examples
of how you know thinking about strength
can make Muscle stronger and on and on
you know in the classic context of the
placebo effect all that expectation
ought to lead to an improvement in
strength and perhaps size of your left
quadricep but that's not what happens
why or more accurately why not well as
far as we know there isn't a direct
neural circuit or hormonal pathway
whereby thoughts from the prefrontal
cortex can impact the growth of muscles
in your left quadricep however there are
output Pathways from the prefrontal
cortex to regions of the brain that are
known to control very basic bodily and
brain functions such as the hypothalamus
and those pathways are known to be able
to change certain parameters of our for
instance stress response so blood
pressure heart rate Vaso constriction
even body temperature so I just want to
take a moment and describe what I
consider one of the more beautiful
studies illustrating a specific pathway
from the prefrontal cortex to the
hypothalamus that allows control of the
so-called stress response in the context
of very specific psychological stressors
now this paper is important not just for
our discussion of placebo belief and
mindset effects but also for any
discussion about so-called psychosomatic
effects or the idea that our modes of
thinking whether or not they are related
to calmness or to stress can strongly
impact our physical health and the title
of the paper is a Central master driver
of Psychosocial stress responses in the
rat goodness that's a tongue twister
psychosocial stress responses in the rat
now the fact that this study was
performed in the rat should not cause us
to lean away from it or to think that
it's not relevant to humans because the
very same circuitries that are described
within this study have analogous
circuitries within the human brain I
know that to be true from my work in
neuron Anatomy teaching neuron anatomy
and other groups separate from the group
that did this study have explored
similar circuitries in the human brain
now in this study what they were able to
do was to identify these two particular
regions which I'll just call them dpdt
for short so instead of saying dorsal
peduncular cortex and dorsal tat tecta
so just say DP dtt this is this area of
the prefrontal cortex okay don't let
these acronyms and names scare you these
are just names of a little sub region
within the prefrontal cortex send
connections little wires that we call
axons to a area of the brain called the
dorsal medial hypothalamus the dorsal
medial hypothalamus is a highly
conserved structure meaning whether or
not you look in mouse or in rat or in
apes or in humans or in dogs the dorsal
medial hypothalamus contains neurons
that are involved in and generating
Cardinal features of the stress response
things like increased blood pressure
things like increased phasal
constriction things like increased body
temperature things like increased Brown
fat thermogenesis now we can even go a
step further because that's what they
did in this study they mapped the
connections from these specific sub
regions of the prefrontal cortex the
dpdt down to the dorsal medial
hypothalamus and a very specific set of
neurons within the dorsal medial
hypothalamus but even there we're still
in the brain we haven't yet established
how activation of these specific neurons
in the dorsal medial hypothalamus
actually change blood pressure how they
actually cause Vaso constriction in the
periphery because that's what happens
when you get very stressed whether or
not it's from social stress or from cold
water there's a constriction we call
Vaso constriction in the periphery right
blood is shuttled toward the core of the
body to keep your core organs alive
you're still going to get blood to the
big limbs of your body so you can move
run if you need to but you're digits
your appendages are going to get far
less blood flow to them because of this
phasal constriction and that's achieved
by an output from the dorsam medial
hypothalamus okay so the second Hub
along this chain to an area of the brain
stem called the rostral medular raap
okay again fancy name you don't have to
remember the name if you don't want to
maybe you afficionados want to but what
we're doing here is we're moving from
the prefrontal cortex to the
hypothalamus then to the brain stem and
then from the brain stem out to what we
call the periphery to the body to the
spinal cord to the blood vessels
themselves to the organs of the body
like the gut and the heart and the lungs
all the things that we associate with
the so-called stress response so as
we've been learning about Placebo
effects and belief effects and mindset
effects and learning that okay just our
knowledge about something our
anticipation our thinking can influence
levels of a hunger hormone isn't that
wild or can influence the amount of pain
that we experience in response to a
cancer treatment or can change the
amount of dopamine in the brain in the
context of a placebo given to people
with Parkinson's well all of that seems
very very surprising until you look at
studies of the sort that I've been
describing in the last few minutes that
are starting to establish the very
precise neural circuitries that lead
from areas of the brain like the
prefrontal cortex that are associated
with thought and context and planning
and prediction down to I don't want to
call them the deeper or more primitive
layers of the brain because these areas
like the hypothalamus and the medulla
the brain stem they're not really
primitive in the sense that they do very
sophisticated things it's just that they
tend to be present in both mammals and
reptiles they're present in fish whereas
the prefrontal cortex is a brain
structure that has undergone fairly
significant elaboration As you move from
animals like say cats dogs up to great
apes and to humans and at least to our
knowledge as a field of neuroscientists
and biologists humans have the most
sophisticated or rather elaborate
prefrontal cortex the most number of
different sub areas of the prefrontal
cortex and every time there's an
investigation of those sub areas what
they do what Their anatomies are meaning
where they connect to and who connects
back to them it's found that there is a
tremendous degree of specificity all of
which is to say that we shouldn't be
surprised at all that these Placebo
belief and mindset effects occur because
there's a clear biological substrate for
them so up until now we've been talking
about the placebo effect as these
incredible set of effects that have a
real biological substrate there are
anatomical Pathways hormonal Pathways
neurotransmitters involved and that's
all true but what's also true is that
the placebo effect can vary in size
tremendously between individuals and
across different studies and in fact
this was described in the first formal
study of the placebo effect in that
study it was shown that approximately
30% of the individuals in the study
showed a robust placebo effect but that
the other 70% showed a less robust
placebo effect and that result meaning
that variation in susceptibility to the
placebo effect has borne out again and
again and again across different studies
now modern science has now taught us
that if you look at the genomes the
genes that happen to be expressed in one
individual versus the next versus the
next versus the next there are certain
genes not a lot of them but there are
certain genes that seem to correlate
with certain types of placebo effect
being greater or lesser in certain
individuals and while there are a lot of
these different genes and a lot of
different Placebo effects one of the
more interesting ones is the CT Gene
which encodes for something called
catacol o methyl transfer cacal Oyl
trans phrase as the name suggests
because it has a Ace in there in the
context of a discussion about bi ology
that almost always means you're talking
about an enzyme catacol om methyl
transferase is an enzyme involved in the
regulation of the so-called catac
colomines catac colomines being dopamine
epinephrine and norepinephrine okay
we've already talked about dopamine in
the context of Parkinson's I've talked
about dopamine a lot frankly on the
huberman LA podcast because it's
involved in motivation it's involved in
Focus pursuit of reward it's involved in
movement as we discussed earlier
norepinephrine and epinephrine also do
many different things in the brain and
body but not the least of which is to
increase activation state for heightened
Focus for increasing the bias toward
movement of the body and on and on in
any event this Gene CT catacol o methyl
transferase seems to show strong
variation in individuals that show
strong variation in the placebo response
to certain types of placebo conditions
and I just mention it because a I think
it's super interesting uh after all all
a lot of the studies that have
demonstrated Placebo effects have shown
those effects in the context of changes
in dopamine epinephrine and
norepinephrine so it's not without
context that we're talking about the CT
Gene but also just as a general theme
the fact that there are genes that
encode for specific biological
substrates in this case regulation of
dopamine epinephrine and norepinephrine
and those genes show up at different
levels in different individuals and the
placebo effects show up at different
levels and different individuals and now
there are studies that are starting to
show that the levels of those genes and
the degree to which one experiences the
placebo effect either elevated response
or reduced response to the placebo
effect seem to be fairly strongly
correlated so this again is more
evidence that yes the placebo effect is
based on knowledge belief expectation
but that it has a real biological
substrate just as there are anatomical
Pathways out of the prefrontal cortex of
the hypothalamus down to the brain stem
out to the body there are also genes
expressed in specific cells within our
brain and body that allow for our
beliefs and expectations that are
carried through that prefrontal cortex
circuitry to have either a greater or
lesser effect so throughout today's
episode I've been talking about how
knowledge your belief and understanding
about what might happen ought to happen
or very likely will happen influences
whether or not that thing actually
happens the so-called placebo effect or
belief effect or mindset effect and what
I hope I've made clear during the course
of our discussion is that while Placebo
effects arrive through our cognitive
understanding of what might ought to or
is likely to happen the downstream
effects the effects on asthma irritable
bowel syndrome insulin growth hormone
you know pick your favorite biological
system essentially every system within
the brain and body has been shown to be
susceptible to Placebo effects but what
I hope is becoming clear is that in
every case the placebo effect is a
biological effect it's not just you know
our thoughts tricking us into thinking
something happened that didn't happen
it's our thoughts our mind creating real
biological effects if you're learning
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