How Placebo Effects Work to Change Our Biology & Psychology | Huberman Lab

Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life.

I'm Andrew Huberman and I'm a professor of neurobiology and

Ophthalmology at Stanford School of Medicine. Today we are discussing placebo effects.

We will also be discussing what are called no-sebo effects as well as belief effects. All three of these placebo, no-sebo and

belief effects are all related to our brain's incredible 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, no-sebo, 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 neuromodulators 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 of treatment.

Well, while that can be true and placebo controls are vital for certain clinical studies,

it's also the case that placeboes, no-seboes, 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, no-sebo, 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 are going to have a clear understanding of what placebo, no-sebo, 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.

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Okay, let's talk about placebo effects. I will also be talking about no-cebo effects, and let's

just establish the difference between those placebo effects, or 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. 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-cebo. No-cebo 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-cebo, it turns out these substances or behavioral interventions actually

worsen symptoms or performance. Now, oftentimes people would just say a placebo effect. It's a

little bit more rare for people to distinguish between placebo and no-cebo 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-cebo 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 learn 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 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,

no-cebo 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 prefrontal cortex is neural real

estate, which is just fancy nerdspeak 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 Huberman 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, 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 going to the edge of a cliff or being on a

high bridge and thinking, oh my goodness, you just have this spontaneous thought, which please

don't do this in action, but one will have this thought, oh my goodness, what if I just jumped off?

And people think, oh my goodness, I have some sort of 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, you know, a 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 are 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, et cetera. 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's, say, getting into cold

water or experiencing some other sort of stressor causes increase in heart rate or vasoconstriction.

What we're talking about here, when we talk about placebo, nocebo, 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, maybe because the label says it, maybe because the 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. They exist in essentially all mammals and even in reptiles. The prefrontal

cortex also communicates with areas of your brainstem, 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, nocebo, 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 Fabrizio Benedetti. I hope

I pronounced that right. Fabrizio and your talins out there if I didn't do it correctly. I apologize.

It's an absolutely wonderful book. I confess I've never met Fabrizio 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 substantioneigra, which is an area of the brain in the kind of bottom

back part of the brain for you. Aficionados is 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 one's hand to right, 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's. 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 dopamine, orgic, meaning dopamine containing and releasing neurons in the

brain. So people with Parkinson's will often be given LDopa, 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 LDopa, things like

apomorphine, broma cryptine, etc., to placebo control drugs. And one of the interesting takeaways from

those studies is that, yes, drugs like LDopa, broma cryptine, etc., increased 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, as nothing

do with animals, is the positron emission tomography device, and these people had been injected with

or consumed something called a raclopride. It sounds really weird and dangerous, but actually

raclopride 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 raclopride

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 raclopride, 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 dopamine-inergic 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 aldopa and apomorphine, broma-cryptine as compared to placebo? 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 a placebo effect. Well, the strength of that expectation is really hard to anchor across

individuals. In fact, if people realize they're taking a placebo, the magnitude of the dopamine

increase is actually decreased. 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.

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. 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. He relies 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 expectation of what that drug or supplement will do. 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 and 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. 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. 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. After the drug treatments, they come back and they are injected

with saline, which has no specific biological effect. It's simply salt water. 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 right. 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

in the same way. 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 received the placebo. You're about to get an injection of something that's going to

decrease growth hormone. But rather, they experience a genuine increase in growth hormone and decrease

in cortisol in the exact same way they did when they received the active drug, sumatriptan.

So this wild type of scenario has to be explained. In order to explain it, we need to zoom out from

the experiment and ask what's the similarity between day two 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 received the placebo. 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. 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 that there was a

pairing within the nervous system. There was 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 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, our hormone

length, 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 on the final day of the experiment, the subject has been injected

with a different drug that, for instance, 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 syringe and the injection we don't know which to lead to some sort of paired

association in the brain and body that led to increased growth hormone, decrease cortisol,

which mimicked the drug effect. But the whole scenario here, as wild as it is, really speaks to

the fact that oftentimes 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 these kinds of

organized receivables 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 the 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 is 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,

as 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 is in 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 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

salivate 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 mirror ringing of a bell could evoke salivation from

those dogs. So are we all just like salivating dogs? I guess we are. I'd like to take a brief

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Okay, so given that context is a powerful modifier of the placebo effect and in fact,

maybe central to the placebo effect. I just want to rattle off a 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 will go into in a bit more detail

in a few minutes, perhaps context is also changing the way that active drugs, not placebo's,

but active drugs are impacting your brain and body. The examples I'd like to give are 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

made up name. You don't know what the drug 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. 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 subject's 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 talking about taking the red pill. 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

antidepressant effect, the subjects that took the yellow placebo get the biggest antidepressant

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 then 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 antidepressant 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 of pills that will increase

alertness and attention. They were given one of three different colors, the red pills at 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 experience the

greatest relief of depressive symptoms. Now that's pretty wild, but what perhaps is even wilder

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 a nerd, 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 and neurons.

This is what the brain does. And of course, the prefrontal cortex being part of the brain,

those are the mechanisms as employees to change the activity of hormone releasing 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 contexts. 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, 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 mind body techniques or mind body 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

and the context of immunotherapy and the context of any bona fide 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 in 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 Capchick's 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 Capchick 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 Capchick

lab. And their colleagues there at Harvard Medical School just incredible work. And one of my favorite

studies from the Capchick lab is one published in the New England Journal of Medicine some years ago

in which they took people who had asthma. So these are people diagnosed with asthma. These are people

who have challenges breathing and they experience 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 taken 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 received the drug for the treatment of asthma not surprisingly had improvements

in breathing and less discomfort. 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 symptomology 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. Whereas as I mentioned before, there are drugs

bona fide 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 in 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 placebo effect

itself, but they are not what we call omnipotent. They can't do anything and everything.

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Tracker.com slash Huberman. 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

induced 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 protocols 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 will be better to not vape than to vape at all. I didn't entire episode about

nicotine. 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

vasoconstriction, 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

squishing, like focusing in the context of a lot of distraction, et cetera, et cetera. So in this

study, nicotine related beliefs induced host 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 nicotinic 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, then did the people

who were told that 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 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 beautifully, 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're 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

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. Aliyah Krum. She's been a guest on the

Hubertman 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 Ali'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 Ali's lab entitled Mind over Milk Shakes. Mindsets, not just nutrients, determine the

Grelan response. So here I'll just briefly describe the study. I'll paraphrase the abstract.

On two separate occasions, people consumed a 380 calorie milk shake. 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, Grelan was measured. Grelan 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 milk shake,

anticipatory, meaning just prior to consuming the milk shake and post-consumption, 90 minutes after

consuming the milk shake. And then Grelan 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. It has a lot of calories, a lot of fat,

et cetera. In the other case, this shake has very few calories. It contains healthy ingredients,

et cetera. Now you can probably guess where this is going. The people that consumed the milk shake,

but were told it was a high calorie indulgent shake. And also, by the way, consumed information

about it being high calorie and indulgent, or they were reading that on the label,

experienced steeper reductions in this hunger-associated hormone called Grelan, as compared to the group

that also consumed the same 380 calorie shake, but thought that the shake was a sensible shake with

fewer calories. That was a healthier shake. Those people experienced reductions in Grelan 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. Grelan, 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 forebrain. 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, Pavlov's dogs are in this case, we are the Pavlov's 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 an 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 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

that Dr. Krum herself described Kim about because she was talking to one of her academic advisors,

this was before she opened her own laboratory. And you know, Alia's an athlete. She was actually a

division one athlete. She's an incredibly impressive individual by the way. She's a tenured

professor at Stanford. She was a division one athlete. She has a degree or rather a certification

in clinical psychology. So she's an extremely accomplished individual, but exercise and athletics

have always been a big part of her life. And one day she was talking to her advisor and her advisor

offered the possibility that and here I'm paraphrasing from a different conversation. Perhaps

all the positive effects of exercise are placebo. That's actually what her advisor said. And

Alia said, no, there's no way, right? And 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 advisor 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 this study was that simply on the basis of whether or not

people were told and therefore believed that their daily activities would lead to improvements

in these different health metrics, reductions in blood pressure, reductions in basal 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. Crum's advisor 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 I've 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

well, I already established that they are not infinite, right? The prefrontal cortex can't control

everything, meaning if I give you some information like just thinking about and believing that

your left quadricep is going to be 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 thinking about strength can make muscle stronger and on and on. 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, vasoconstriction, 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 neuroanatomy, teaching neuroanatomy,

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 DPDTT for short. So instead of saying dorsal

peduncular cortex and dorsal tenea tecta, so just say DPDTT. 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 subregion

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

conservative 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 generating

cardinal features of the stress response. Things like increased blood pressure, things like increased

vasoconstriction, 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 subregions of the prefrontal cortex, the DPDTT, 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 changed blood pressure, how they actually

cause vasoconstriction 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, what we call

vasoconstriction, in the periphery. My blood is shuttle 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 your digits, your appendages are going to get far less blood flow to them

because of this vasoconstriction. That's achieved by an output from the dorsal medial hypothalamus,

okay? So the second hub along this chain to an area of the brainstem called the

rostral medialary raffae. Okay, again, fancy name. You don't have to remember the name if you don't

want to. Maybe you'll see an auto's want to. But what we're doing here is we're moving from the

prefrontal cortex to the hypothalamus, then to the brainstem, and then from the brainstem

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

brainstem, they're not really primitive in the sense that they do very sophisticated things,

is 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 they're

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 COMT gene, which encodes for something called

catacole-O-methal-transface. Catacole-O-methal-transface, as the name suggests, because it has an ace

in there in the context of a discussion about biology that almost always means you're talking about an

enzyme. Catacole-O-methal-transface is an enzyme involved in the regulation of the so-called

catacolamines. Catacolamines 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 human allowed 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, COMT, catacole-O-methal-transface, 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, after 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 COMT 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 effect show up at different

levels in 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 and 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 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

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[Understanding Placebo, Nocebo, and Belief Effects: The Science of Expectation]-[How Placebo Effects Work to Change Our Biology & Psychology]

📋 Summary

The Science of Expectation: Placebo, Nocebo, and Belief Effects

Defining the Core Concepts

Biological Underpinnings and Specificity

The Role of Context and Intensity

The Limits of Expectation

Dose-Dependent Beliefs and Mindsets

Conclusion: The Biological Reality

🎯Key Sentences

📝Key Phrases

📖 Transcript