How Placebo Effects Work to Change Our Biology & Psychology

welcome to the huberman Lab podcast

where we discuss science and

science-based tools for everyday

[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

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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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