How Placebo Effects Work to Change Our Biology & Psychology

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.920 | for everyday life.

00:00:05.940 | I'm Andrew Huberman,

00:00:10.320 | and I'm a professor of neurobiology and ophthalmology

00:00:13.480 | at Stanford School of Medicine.

00:00:15.480 | Today, we are discussing placebo effects.

00:00:18.320 | We will also be discussing what are called nocebo effects,

00:00:21.900 | as well as belief effects.

00:00:23.880 | All three of these, placebo, nocebo, and belief effects,

00:00:27.920 | are all related to our brain's incredible ability

00:00:31.200 | to place an expectation on what is about to happen

00:00:34.240 | and actually change what is about to happen

00:00:37.120 | independent of the physical and chemical properties

00:00:40.440 | of a drug or some sort of other treatment solution

00:00:43.780 | for things like pain, Parkinson's disease,

00:00:47.480 | irritable bowel syndrome, asthma, stress,

00:00:51.120 | and on and on and on.

00:00:53.440 | Now, one of the most incredible things about these effects

00:00:56.180 | is that despite the fact that it would appear

00:00:59.240 | that they are simply psychological

00:01:01.120 | or the power of the mind over matter, it's not that at all.

00:01:06.120 | Placebo, nocebo, and belief effects

00:01:08.600 | actually change the way your biology, your physiology works.

00:01:13.460 | In fact, you have neural circuits within your brain

00:01:15.960 | that are dedicated to how your expectation

00:01:18.800 | of what will happen actually changes

00:01:21.320 | some of the most core biological functions

00:01:23.780 | within your brain and body.

00:01:25.080 | Modifying, for instance, heart rate, blood pressure,

00:01:28.320 | the release of specific neuromodulators

00:01:30.580 | such as dopamine and adrenaline.

00:01:32.460 | And so powerfully so that these types of effects

00:01:35.400 | can actually work along with traditional drug treatments

00:01:39.120 | or behavioral treatments in order to vastly change

00:01:42.320 | the way that your brain and body work.

00:01:44.380 | So if you think of the word placebo as an inert substance

00:01:48.000 | or treatment that is merely a control,

00:01:50.340 | it's merely something introduced to an experiment

00:01:52.520 | or a clinical trial to try and figure out

00:01:55.400 | what's happening normally in somebody's brain or body

00:01:57.880 | as a comparison to some drug or other type of treatment.

00:02:01.040 | Well, while that can be true

00:02:02.840 | and placebo controls are vital for certain clinical studies,

00:02:07.080 | it's also the case that placebos, nocebos,

00:02:10.000 | and belief effects have powerful impact on our physiology

00:02:13.720 | entirely separate from all of that.

00:02:15.640 | So much so that several highly esteemed researchers

00:02:18.100 | in the medical community around the world

00:02:20.140 | believe that placebo, nocebo, and belief effects

00:02:23.020 | should actually be leveraged in the treatment

00:02:24.900 | of various diseases as their own unique treatment.

00:02:28.120 | So by the end of today's episode,

00:02:29.760 | you're going to have a clear understanding

00:02:31.660 | of what placebo, nocebo, and belief effects are,

00:02:34.400 | their biological underpinnings,

00:02:36.060 | and the way that you can leverage them

00:02:38.080 | toward your mental health, physical health, and performance.

00:02:40.940 | Before we begin, I'd like to emphasize that this podcast

00:02:43.420 | is separate from my teaching and research roles at Stanford.

00:02:46.180 | It is, however, part of my desire and effort

00:02:48.100 | to bring zero cost to consumer information

00:02:49.920 | about science and science-related tools

00:02:51.960 | to the general public.

00:02:53.400 | In keeping with that theme,

00:02:54.520 | I'd like to thank the sponsors of today's podcast.

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00:07:24.800 | Okay, let's talk about placebo effects.

00:07:27.000 | I will also be talking about nocebo effects,

00:07:29.240 | and let's just establish the difference between those.

00:07:30.980 | Placebo effects are when an inert substance

00:07:34.140 | or behavioral treatment that is a substance

00:07:36.220 | or behavioral treatment that is not going to have

00:07:38.980 | any kind of direct biological or psychological activity,

00:07:42.780 | right, it shouldn't do anything on its own,

00:07:44.860 | somehow does in the direction

00:07:46.900 | of improving symptoms or performance.

00:07:49.860 | Now let's contrast that with nocebo.

00:07:51.820 | Nocebo is when a drug or behavioral intervention

00:07:55.940 | which is inert, it should have no impact on symptoms

00:07:58.980 | or performance of any kind, but with nocebo,

00:08:02.220 | it turns out these substances or behavioral interventions

00:08:05.180 | actually worsen symptoms or performance.

00:08:08.420 | Now, oftentimes people will just say a placebo effect.

00:08:11.560 | It's a little bit more rare for people to distinguish

00:08:13.620 | between placebo and nocebo effects,

00:08:16.200 | but I do think it's important to know their difference.

00:08:18.400 | Going forward, I'll mostly just refer to these

00:08:20.460 | as placebo effects, but I'll talk about nocebo effects

00:08:23.420 | a little bit later.

00:08:24.420 | I'll also talk about belief effects.

00:08:26.260 | So let's just establish what belief effects are.

00:08:28.480 | Belief effects are when you or somebody else

00:08:31.540 | learns specific knowledge that changes your expectation

00:08:36.440 | about what is going to happen in reference to say stress

00:08:40.500 | or consuming a given food or taking a given drug

00:08:43.180 | or doing a specific behavioral protocol

00:08:45.100 | and the specific information you learn or assimilate

00:08:49.660 | actually leads to that specific outcome.

00:08:53.780 | So in many ways, belief effects and placebo effects

00:08:56.180 | are similar, it's just that the word placebo

00:08:58.540 | or placebo effects is commonly used to refer to drugs

00:09:01.060 | and behavioral interventions.

00:09:02.380 | Belief effects are more specific language used to describe

00:09:05.860 | when information of any kind changes the outcome

00:09:09.100 | of some physiological or psychological process.

00:09:11.980 | Now what's common to placebo, nocebo and belief effects

00:09:15.940 | is that they all work by changing expectation.

00:09:19.860 | And anytime we talk about expectation,

00:09:22.020 | we're talking about the function of the nervous system

00:09:24.480 | and specifically the brain and specifically

00:09:26.660 | the prefrontal cortex within the brain.

00:09:28.940 | The prefrontal cortex is neural real estate,

00:09:31.900 | which is just fancy nerd speak for the neurons

00:09:34.540 | and their connections that reside just behind your forehead,

00:09:37.980 | just in the front of your skull.

00:09:39.940 | Now the prefrontal cortex has a lot of different

00:09:42.040 | subdivisions or regions.

00:09:44.180 | The overall function of the prefrontal cortex

00:09:46.520 | can be described as having the ability to either activate

00:09:50.460 | or suppress other neural circuits deeper in the brain.

00:09:53.740 | Some people, in fact, a previous guest

00:09:55.260 | on the Huberman Lab podcast, a neurosurgeon said,

00:09:57.880 | "The prefrontal cortex can generally be described

00:10:00.220 | as the structure in the brain that controls other structures

00:10:03.420 | in the brain by saying shh or suppressing their function."

00:10:06.900 | So for instance, if you have the impulse to move

00:10:09.220 | or to shout, the prefrontal cortex suppresses that movement

00:10:13.020 | or suppresses that desire to shout or that shouting.

00:10:15.980 | If you've ever had the experience of, you know,

00:10:18.180 | going to the edge of a cliff or being on a high bridge

00:10:20.840 | and thinking, oh my goodness, like, you know,

00:10:22.460 | you just have this spontaneous thought,

00:10:23.880 | which please don't do this in action,

00:10:25.860 | but one will have this thought like, oh my goodness,

00:10:27.780 | like what if I just jumped off?

00:10:28.920 | And people think, oh my goodness, you know,

00:10:30.080 | do I have some sort of death wish?

00:10:32.000 | Well, no.

00:10:32.840 | The prefrontal cortex being largely a context evaluating

00:10:37.140 | and prediction machine is essentially looking

00:10:40.500 | at that landscape and predicting what would happen,

00:10:43.240 | indeed how bad it would be,

00:10:44.920 | if you were to jump off that bridge or jump off that cliff.

00:10:48.780 | And then you feel that, oh my goodness,

00:10:50.480 | like what's wrong with me, why would I think this?

00:10:52.020 | But the fact that you think it even for a moment,

00:10:54.680 | but you don't do it and the fact that you recognize

00:10:57.080 | that it's sort of a, you know, a dangerous thought,

00:11:00.240 | certainly a dangerous action, again,

00:11:01.980 | please don't engage in the action,

00:11:03.660 | tells you that your prefrontal cortex is working properly.

00:11:06.600 | Again, the prefrontal cortex is involved

00:11:09.300 | in suppressing certain types of behaviors

00:11:12.100 | and what sorts of behaviors?

00:11:13.440 | Well, the larger theme of the prefrontal cortex

00:11:15.980 | that we need to consider today is that it is an expectation

00:11:19.280 | or prediction making machine.

00:11:21.940 | It is a bunch of neurons that release chemicals

00:11:24.240 | and have electrical activity that are speaking with

00:11:26.720 | and receiving information from other areas of the brain.

00:11:30.280 | And it's evaluating a number of things like context,

00:11:33.040 | like what's going on in this room,

00:11:34.520 | what's going on in this scene,

00:11:35.920 | what's supposed to happen here, what might I do,

00:11:38.160 | what should I do, what should I not do, et cetera, et cetera.

00:11:41.520 | Now, the other thing about the prefrontal cortex,

00:11:43.920 | given that it has all these different subdivisions

00:11:45.720 | is that some of those subdivisions have a unique,

00:11:49.020 | what we call labeled line communication,

00:11:51.600 | like a unique highway that leads to specific brain areas

00:11:54.800 | that control specific bodily functions,

00:11:57.320 | including heart rate, blood pressure, et cetera.

00:11:59.360 | And a little bit later in the episode,

00:12:00.840 | I'll talk about a specific paper,

00:12:02.360 | it's one of my favorite papers,

00:12:03.900 | in which a specific prefrontal cortical region

00:12:06.240 | is identified as controlling very primitive aspects

00:12:09.980 | of our physiology, such as body temperature and heart rate,

00:12:14.220 | in reference to beliefs

00:12:16.200 | or what's happening in a social scene.

00:12:18.400 | And this is very different from the way that say,

00:12:21.520 | getting into cold water

00:12:22.720 | or experiencing some other sort of stressor

00:12:25.080 | causes increase in heart rate or vasoconstriction.

00:12:27.720 | What we're talking about here,

00:12:28.780 | when we talk about placebo, nocebo and belief effects

00:12:31.580 | are the way in which you learn information

00:12:33.680 | or you are told information like,

00:12:35.220 | "Hey, this pill is going to do blank."

00:12:37.600 | Maybe because the label says it,

00:12:38.700 | maybe because the scientist or the doctor tells you

00:12:42.440 | that this pill does blank or this injection will do blank.

00:12:45.340 | Or maybe you learn some information

00:12:47.600 | about what some specific drug or supplement

00:12:50.600 | or behavioral protocol will do.

00:12:52.360 | And in that learning,

00:12:53.560 | you come to expect a specific set of effects

00:12:56.480 | and certain neural circuits in the prefrontal cortex

00:12:59.320 | become active and start to activate certain neural circuits

00:13:02.880 | deeper in the brain in areas like the hypothalamus.

00:13:05.780 | These are ancient, very well-conserved across animals,

00:13:08.440 | areas of the brain that control very primitive functions.

00:13:10.920 | Okay, they exist in essentially all mammals

00:13:12.640 | and even in reptiles.

00:13:14.040 | The prefrontal cortex also communicates

00:13:15.720 | with areas of your brainstem,

00:13:17.680 | controlling things like breathing, et cetera.

00:13:19.720 | So the prefrontal cortex is a sophisticated area

00:13:22.320 | of your brain that takes into account context,

00:13:25.400 | both in the present, as well as memories from the past.

00:13:28.060 | It can take into consideration goals about the future

00:13:30.560 | and then combines all of that into neural signals

00:13:33.600 | to areas of the brain

00:13:34.440 | that control basic physiological functions

00:13:36.600 | related to the immune system, the stress system,

00:13:38.820 | the reward system, the pleasure system and on and on.

00:13:43.300 | So when we talk about placebo, nocebo and belief effects,

00:13:46.520 | what we're really talking about

00:13:48.080 | is the ability for information and specific experiences

00:13:52.640 | to lead to expectations within us

00:13:55.440 | about what's going to happen

00:13:57.020 | and then our physiology of our brain and body

00:13:59.540 | fundamentally changes such that those things happen.

00:14:03.840 | So let's talk about some specific examples of placebo effects

00:14:07.040 | from the research literature.

00:14:08.680 | And today we're gonna cover a lot of different examples

00:14:10.800 | from different systems, but as we do that,

00:14:14.080 | I will specifically be selecting examples

00:14:16.600 | that illustrate different types of placebo effects

00:14:19.200 | and illustrate what those different types

00:14:20.780 | of placebo effects are.

00:14:22.240 | Now, I should mention that

00:14:23.800 | if you're interested in placebo effects,

00:14:25.680 | there's a wonderful book

00:14:27.240 | that describes many, many different placebo effects

00:14:30.160 | and their biological underpinnings

00:14:32.720 | in cases where those biological underpinnings are understood.

00:14:35.480 | And the book I'm referring to

00:14:36.480 | is one that I used prominently in researching this episode.

00:14:39.160 | It's called none other than Placebo Effects,

00:14:41.980 | Understanding the Other Side of Medical Care.

00:14:44.860 | And the book is by Fabrizio Benedetti.

00:14:47.640 | I hope I pronounced that right, Fabrizio.

00:14:50.080 | And to you Italians out there,

00:14:51.540 | if I didn't do it correctly, I apologize.

00:14:53.880 | It's an absolutely wonderful book.

00:14:55.720 | I confess I've never met Fabrizio Benedetti.

00:14:58.480 | I confess I have no relation to the publisher

00:15:00.840 | or to the book itself,

00:15:02.100 | except that I absolutely love the book.

00:15:03.660 | So highly recommend this book.

00:15:05.300 | I'll be pulling from a number of different examples

00:15:07.280 | described in this book today.

00:15:09.060 | To my mind, one of the most interesting examples

00:15:11.180 | of placebo effect is where placebo is given

00:15:15.280 | and can profoundly change levels

00:15:17.180 | of dopamine release in the brain.

00:15:19.340 | Now, the study I'm about to describe

00:15:20.960 | was done in Parkinson's patients.

00:15:23.000 | People with Parkinson's have degeneration of neurons

00:15:26.100 | in an area of the brain called the substantia nigra,

00:15:28.980 | which is an area of the brain

00:15:30.220 | in the kind of bottom back part of the brain.

00:15:32.320 | For you aficionados, it's the ventral tegmental area,

00:15:35.160 | but you don't need to know that name.

00:15:36.520 | These neurons contain dopamine and are essential

00:15:39.280 | for the generation of smooth movement patterns,

00:15:41.800 | including walking and reaching

00:15:43.360 | and moving one's hand to write, et cetera.

00:15:46.320 | And of course, dopamine is involved

00:15:47.960 | in a bunch of other things too,

00:15:49.340 | including motivation and reward.

00:15:51.840 | In people with Parkinson's,

00:15:53.000 | depending on how severe and advanced the Parkinson's is,

00:15:56.640 | they suffer deficits in the ability

00:15:58.900 | to generate smooth movements

00:16:00.480 | and often deficits in motivation

00:16:02.640 | and reward pathways as well.

00:16:05.000 | Now, there are many different treatments for Parkinson's,

00:16:06.920 | some more successful than others.

00:16:08.540 | Unfortunately, it's still not completely curable,

00:16:11.260 | at least not at this time,

00:16:12.840 | but most of the drugs that are successful

00:16:15.460 | in treating Parkinson's to some degree or another

00:16:18.160 | are drugs that increase levels of dopamine within the brain

00:16:21.680 | for obvious reasons.

00:16:22.600 | As I just mentioned,

00:16:23.840 | Parkinson's is a degeneration of the dopaminergic,

00:16:27.560 | meaning dopamine containing and releasing neurons

00:16:30.200 | in the brain.

00:16:31.160 | So people with Parkinson's will often be given L-DOPA,

00:16:33.920 | which is a precursor to dopamine,

00:16:35.660 | or other types of drugs that increase dopamine

00:16:38.540 | within the brain.

00:16:39.560 | Now, there've been a number of studies

00:16:40.760 | that have compared certain drugs

00:16:42.400 | known to increase dopamine, such as L-DOPA,

00:16:45.420 | things like apomorphine, bromocriptine, et cetera,

00:16:48.680 | to placebo control drugs.

00:16:51.240 | And one of the interesting takeaways from those studies

00:16:53.920 | is that yes, drugs like L-DOPA, bromocriptine, et cetera,

00:16:58.480 | increase dopamine and at least can partially

00:17:00.560 | or transiently improve symptoms of Parkinson's in many,

00:17:03.400 | not all patients with Parkinson's.

00:17:05.500 | The placebo drugs given in many of those studies,

00:17:08.000 | which were simply a sugar pill or some other inert pill,

00:17:11.160 | it doesn't contain any chemicals

00:17:13.260 | that are known to directly bind to

00:17:15.680 | or increase dopamine in the brain.

00:17:17.360 | And yet nonetheless,

00:17:19.200 | when the brains of certain patients were imaged,

00:17:22.940 | it was clear that not only was there an improvement

00:17:25.480 | in symptomology,

00:17:26.480 | but there were increases in dopamine release

00:17:29.260 | within those patients' brains,

00:17:30.520 | which on the face of it should make no sense.

00:17:33.160 | However, when people with Parkinson's

00:17:35.560 | or people who even don't have Parkinson's

00:17:38.280 | are told a given drug can increase dopamine,

00:17:41.400 | and then they put these people into a brain imaging device,

00:17:45.920 | it's called a PET device, has nothing to do with animals,

00:17:48.420 | it's the positron emission tomography device,

00:17:50.620 | and these people had been injected with

00:17:52.420 | or consumed something called a raclopride.

00:17:54.780 | It sounds really weird and dangerous,

00:17:56.320 | but actually raclopride looks a little bit

00:17:59.240 | like dopamine itself chemically,

00:18:01.100 | and it has a little tag or label on it,

00:18:02.920 | and it can bind to certain receptors in the brain

00:18:05.620 | where dopamine would normally bind.

00:18:07.660 | What was observed is that the placebo itself

00:18:10.700 | was causing reduced binding of this raclopride

00:18:15.160 | to areas of the brain that have dopamine receptors,

00:18:17.600 | which meant unequivocally

00:18:19.320 | that there was more dopamine released in the brain,

00:18:22.640 | because if more dopamine is released in the brain

00:18:25.320 | and parks in those receptors,

00:18:27.080 | well, then the raclopride,

00:18:28.360 | which looks a lot like dopamine,

00:18:29.580 | can't also park or bind to those receptors.

00:18:32.980 | Simply put, a placebo drug,

00:18:35.800 | again, a drug that has no direct action

00:18:38.060 | on the dopaminergic system,

00:18:40.180 | if it's given to somebody who has Parkinson's or who doesn't,

00:18:43.320 | and they are told,

00:18:44.340 | this drug is going to increase levels of dopamine

00:18:46.680 | in your brain and potentially improve

00:18:48.260 | your symptoms of Parkinson's or have some other effect,

00:18:51.600 | well, it succeeded in increasing dopamine levels

00:18:55.320 | within the brain,

00:18:56.340 | which basically should make us all sit back and say,

00:18:59.100 | okay, what are we to think of drugs like L-DOPA

00:19:02.720 | and apomorphine, bromocriptine as compared to placebo?

00:19:05.680 | Why isn't everyone just taking placebo?

00:19:07.220 | Why aren't we just telling people,

00:19:08.420 | hey, this sugar pill is going to increase dopamine?

00:19:11.020 | Well, two important points to answer that.

00:19:13.360 | First of all, the increases in dopamine

00:19:15.860 | that are observed from placebo

00:19:17.640 | plus information about what that placebo ought to do

00:19:20.280 | for increasing dopamine are not as robust,

00:19:23.300 | or I should say generally not as robust

00:19:25.380 | as the increases in dopamine observed

00:19:27.280 | from an actual drug known to increase dopamine transmission

00:19:31.200 | or release within the brain.

00:19:32.880 | The second point is that the structure

00:19:34.400 | of the information given to somebody

00:19:36.400 | and the belief that they form about what ought to happen,

00:19:39.720 | that is the expectation effect,

00:19:41.380 | which you'll start to realize more and more

00:19:43.240 | across today's episode,

00:19:44.800 | that expectation effect really is the underpinning

00:19:47.320 | of a placebo effect.

00:19:48.820 | Well, the strength of that expectation

00:19:50.960 | is really hard to anchor across individuals.

00:19:54.080 | And in fact, if people realize they're taking a placebo,

00:19:57.220 | the magnitude of the dopamine increase

00:19:59.820 | is actually decreased.

00:20:01.480 | So this is why we use placebo controls in clinical trials.

00:20:06.360 | We want to establish the real difference

00:20:08.040 | between the effect of a given drug on a biological system,

00:20:12.320 | in this case, increasing dopamine,

00:20:14.400 | from the belief or the expectation

00:20:16.880 | of what that drug will do.

00:20:18.400 | So in that sense, the placebo is really a measure

00:20:20.800 | of expectation of what a drug treatment will do,

00:20:24.060 | at least in the context of a drug trial.

00:20:26.080 | So I mentioned this somewhat complicated example,

00:20:28.420 | because first of all,

00:20:29.580 | many people are interested in dopamine.

00:20:31.100 | We all make dopamine.

00:20:32.180 | It's involved in motivation, drive, and focus, and reward,

00:20:35.560 | all sorts of things that we hear a lot about these days.

00:20:37.660 | Second of all, it really illustrates that placebo,

00:20:41.440 | that is expectation about what will happen,

00:20:43.880 | is impacting, of course, placebo effects.

00:20:46.580 | You realize that now.

00:20:47.820 | But it then also has to be the case

00:20:50.260 | that placebo effects are playing into any effect

00:20:54.140 | that we might observe from taking a given drug or supplement

00:20:57.700 | based on our expectation

00:20:59.020 | of what that drug or supplement will do.

00:21:00.920 | And miraculously, or at least what I find miraculous,

00:21:04.160 | is that placebo effects,

00:21:06.080 | these expectations based on knowledge and beliefs,

00:21:09.180 | are highly specific,

00:21:10.900 | which raises all sorts of questions about, for instance,

00:21:13.160 | if you were given a drug that increases dopamine levels,

00:21:16.780 | but you weren't told that it increases dopamine levels,

00:21:19.660 | that perhaps you were told, you were lied to,

00:21:21.900 | and told that it increases the activity of a different

00:21:24.300 | neuromodulator like serotonin, would it?

00:21:26.820 | Well, let's explore that because as wild as that seems,

00:21:30.060 | it turns out that what we believe

00:21:31.500 | about a given drug treatment or behavioral treatment

00:21:33.820 | actually has a high degree of specificity.

00:21:36.860 | So to illustrate the incredible specificity

00:21:39.200 | of placebo effects,

00:21:40.940 | I want to describe a study related to hormone function.

00:21:45.140 | Hormones come in many different forms.

00:21:47.340 | We have testosterone, estrogen, growth hormone,

00:21:49.260 | cortisol, et cetera.

00:21:51.180 | There's a study that was carried out in humans

00:21:53.580 | in which subjects were informed

00:21:55.580 | about growth hormone release and cortisol release.

00:21:58.460 | Growth hormone is a hormone released from a gland

00:22:01.300 | in the brain called the pituitary.

00:22:03.340 | The pituitary has different parts.

00:22:04.900 | The anterior pituitary releases growth hormone.

00:22:06.880 | Each night when you go to sleep,

00:22:07.900 | it's involved in protein synthesis, tissue repair,

00:22:10.320 | bodily growth, appendage growth, and many other things.

00:22:13.260 | Cortisol is a hormone that's released from the adrenals.

00:22:17.660 | It can also be synthesized and released

00:22:19.380 | in a couple other places in the brain and body.

00:22:21.460 | And it's involved in immune system function,

00:22:24.120 | in anti-inflammatory action.

00:22:25.580 | A lot of people think cortisol is bad,

00:22:27.040 | but it's actually an important hormone for our daily health,

00:22:29.740 | our alertness and waking up in the morning, et cetera.

00:22:32.860 | In any event, subjects in this study

00:22:34.540 | learned about growth hormone and cortisol

00:22:36.860 | and their release, where they're released from,

00:22:39.180 | what they do, just as you did.

00:22:41.220 | And then their growth hormone and cortisol levels

00:22:43.800 | were measured, and not surprisingly, they didn't change.

00:22:47.260 | Just learning about growth hormone and cortisol

00:22:49.740 | did not change growth hormone or cortisol levels

00:22:52.660 | in these human subjects.

00:22:54.520 | Now, on days two and three of this experiment,

00:22:57.900 | subjects received an injection of a drug.

00:23:00.100 | The drug is called sumatriptan.

00:23:02.660 | And sumatriptan is known to increase levels

00:23:05.940 | of growth hormone and reduce levels of cortisol.

00:23:08.720 | And indeed, that's what they observed.

00:23:10.300 | When people received these injections

00:23:11.920 | and then their blood was drawn,

00:23:13.460 | growth hormone levels went up, cortisol levels went down.

00:23:17.860 | Now, the interesting part of the study

00:23:19.620 | is a separate day, okay?

00:23:21.860 | So after the drug treatments,

00:23:23.100 | they come back and they are injected with saline,

00:23:26.300 | which has no specific biological effect.

00:23:28.420 | It's simply saltwater, okay?

00:23:30.420 | They're injected with saline,

00:23:32.560 | and they experience increases in growth hormone

00:23:36.940 | and decreases in cortisol,

00:23:39.000 | which on the face of it might seem like,

00:23:40.680 | wow, that's incredible.

00:23:42.100 | But based on what you've learned thus far

00:23:44.060 | in today's episode,

00:23:45.520 | you can imagine that knowledge about growth hormone

00:23:48.260 | and cortisol somehow combined with the injection

00:23:51.500 | to lead to an expectation of increases in growth hormone

00:23:55.440 | and decreases in cortisol,

00:23:56.620 | which would be amazing in its own right, okay?

00:23:58.660 | After all, saline is inert.

00:24:00.420 | It doesn't do anything directly and specifically

00:24:02.840 | to the growth hormone or cortisol system.

00:24:05.220 | But get this, it turns out that a saline injection,

00:24:09.180 | which does nothing on its own on day four or five

00:24:13.460 | after people have received this drug treatment,

00:24:15.780 | increases growth hormone and decreases cortisol

00:24:19.140 | independent of what people are told

00:24:21.760 | they are being injected with.

00:24:23.200 | Even if they're told they're being injected with a drug

00:24:26.060 | that has completely different effects than sumatriptan.

00:24:29.460 | So why would this be?

00:24:31.180 | How could this be?

00:24:32.660 | In fact, there was even a condition

00:24:34.140 | in which subjects were told

00:24:35.500 | on the day they received the placebo,

00:24:37.540 | you're about to get an injection of something

00:24:39.260 | that's going to decrease growth hormone,

00:24:42.100 | but rather they experienced a genuine increase

00:24:45.300 | in growth hormone and decrease in cortisol

00:24:48.140 | in the exact same way they did

00:24:49.900 | when they received the active drug sumatriptan.

00:24:52.860 | Okay, so this wild type of scenario has to be explained.

00:24:56.660 | And in order to explain it,

00:24:57.840 | we need to zoom out from the experiment

00:24:59.540 | and ask what's the similarity

00:25:01.780 | between day two and three of the experiment,

00:25:05.620 | meaning the days in which the people received

00:25:07.380 | the actual active drug sumatriptan

00:25:09.940 | that increases growth hormone, reduces cortisol,

00:25:12.440 | and the day in which they received the placebo.

00:25:14.780 | And the one thing that anchors both those days together,

00:25:18.240 | meaning the one thing in common

00:25:19.620 | that can explain this effect is that those were the days

00:25:22.380 | in which people received an injection.

00:25:25.700 | And in fact, through various control experiments

00:25:27.700 | and a few other experiments

00:25:28.940 | that were done subsequent to this,

00:25:30.460 | because this experiment has been more or less repeated

00:25:32.920 | in different forms in different laboratories,

00:25:34.900 | it became clear that the brain and body

00:25:38.140 | somehow came to expect that receiving an injection

00:25:43.140 | leads to increases in growth hormone and cortisol.

00:25:46.220 | Now, this is not an indefinite effect, right?

00:25:48.220 | People will get injections of other things in the future,

00:25:50.300 | presumably active drugs, not just saline,

00:25:52.700 | that will change hormone levels

00:25:54.220 | or change neurotransmitter levels.

00:25:55.900 | But in this experiment, what happened is,

00:25:58.020 | is that there was a pairing within the nervous system.

00:26:01.360 | There was somehow a binding of the notion

00:26:04.560 | of getting an injection with a syringe,

00:26:06.600 | which in the first case was of a drug

00:26:08.180 | that increases growth hormone, decreases cortisol.

00:26:10.300 | And then when subjects came back and were injected,

00:26:14.120 | with a different syringe, presumably, I would hope so,

00:26:16.480 | with a different syringe filled with saline,

00:26:19.200 | even though the saline should do nothing,

00:26:21.100 | the body and brain had somehow formed a pairing,

00:26:24.220 | an association between syringe injection

00:26:27.720 | and increased growth hormone, decreased cortisol,

00:26:31.420 | which is incredible given that these systems,

00:26:33.820 | the anterior pituitary, the adrenal glands,

00:26:36.040 | I mean, these are ancient systems that to our knowledge,

00:26:39.700 | we can't directly control with our mind.

00:26:41.500 | I can't simply close my eyes and grit my teeth

00:26:43.540 | and cause the release of growth hormone.

00:26:44.940 | I can't simply decide to deploy cortisol from my adrenals.

00:26:48.320 | Although if I thought about something very, very stressful

00:26:50.340 | for a long time,

00:26:51.180 | there'd probably be some cortisol secretion.

00:26:52.720 | But to our knowledge, there is no way to use thoughts,

00:26:56.620 | to use beliefs, to use understanding of knowledge,

00:27:00.700 | to cause changes in our endocrine glands, right?

00:27:04.540 | Our hormone length, the pituitary, the adrenals.

00:27:07.140 | But here we have a case where a drug

00:27:10.620 | that increases certain hormones and decreases other hormones

00:27:13.540 | simply by virtue of the fact

00:27:14.780 | that it was injected into somebody,

00:27:17.160 | leads to a case where subsequent injections,

00:27:19.440 | at least in the short run,

00:27:20.940 | lead to the exact same hormone changes,

00:27:23.560 | simply because in the mind and or body of these individuals,

00:27:28.820 | injection comes to equal increase in growth hormone,

00:27:32.080 | decrease in cortisol, independent of what's being injected.

00:27:35.300 | Now, a key point is that

00:27:36.620 | had on the final day of the experiment,

00:27:38.660 | the subject's been injected with a different drug

00:27:40.580 | that for instance, increases serotonin

00:27:43.540 | or reduces epinephrine,

00:27:46.100 | I doubt that they would have instead experienced increases

00:27:50.020 | in growth hormone and reductions in cortisol.

00:27:52.180 | That's simply not the case.

00:27:53.220 | The fact that there was only saline in there

00:27:55.480 | meant that there was an opportunity for the syringe

00:27:58.980 | and the injection, we don't know which,

00:28:00.740 | to lead to some sort of paired association

00:28:02.620 | in the brain and body

00:28:03.460 | that led to increased growth hormone, decreased cortisol,

00:28:05.680 | which mimicked the drug effect.

00:28:07.280 | But the whole scenario here, as wild as it is,

00:28:09.800 | really speaks to the fact that oftentimes

00:28:11.720 | we think a given treatment is causing a given effect

00:28:15.060 | only because of the action of the drug

00:28:17.520 | or the action of a given behavioral protocol.

00:28:19.840 | But in fact, the drug and the protocol

00:28:22.600 | exist in a big context of different things

00:28:24.720 | that the brain and body are integrating

00:28:26.500 | and trying to make sense of,

00:28:27.540 | and that often gets lumped together.

00:28:29.840 | I often say that your brain is, yes, a prediction machine,

00:28:32.780 | but it's also trying to simplify things in those predictions.

00:28:35.380 | It's not taking into account all the information.

00:28:37.660 | It's often lumping information together

00:28:39.540 | and coming up with ideas about what's going to happen and why

00:28:42.420 | and doing this subconsciously

00:28:44.760 | in a way that, as you just learned,

00:28:46.260 | can have profound effects on what happens within us,

00:28:49.400 | even at the level of something as basic as hormone release.

00:28:52.380 | Now, what I just described is a pretty extreme example,

00:28:54.980 | and it's a very experimental condition type example.

00:28:58.500 | I mean, it's rare that people are undergoing

00:29:01.380 | these kinds of organized receivable of information

00:29:04.740 | followed by specific drug treatments

00:29:06.320 | and placebo injections, et cetera.

00:29:07.980 | But you've all experienced the placebo effect in action

00:29:11.580 | by way of what's called classical conditioning

00:29:13.980 | simply by virtue of the fact

00:29:15.380 | that the smells of certain foods

00:29:17.200 | and your past experience of certain foods

00:29:19.660 | can lead to the release of a hormone called insulin.

00:29:22.420 | Insulin is a hormone that is involved

00:29:24.540 | in regulating blood glucose, blood sugar.

00:29:27.660 | And typically when insulin levels go up in the bloodstream,

00:29:30.360 | glucose levels are going to go down

00:29:31.940 | because of the way that insulin controls blood sugar levels.

00:29:35.060 | Now, if you've ever had the experience

00:29:36.880 | of walking past a bakery or a pizza shop

00:29:39.500 | where a delicious smell is wafting out into the environment,

00:29:43.500 | you may notice that it "makes you hungry."

00:29:46.300 | And indeed it does make you hungry

00:29:48.620 | because presumably you've had the experience

00:29:50.460 | of certain smells being associated

00:29:52.500 | with the consuming of certain foods,

00:29:54.640 | maybe bakery foods, maybe pizza,

00:29:56.100 | maybe steak, whatever it is.

00:29:58.180 | And the consumption of those foods

00:29:59.860 | actually leads to increases in insulin in your bloodstream.

00:30:03.320 | Well, there's the so-called conditioning effect

00:30:06.120 | whereby the smell of the food itself

00:30:09.240 | starts to lead to increases in insulin.

00:30:11.900 | But the conditioning effects of different stimuli,

00:30:15.060 | different things in the context of eating

00:30:17.860 | and specific foods leading to increases in insulin

00:30:21.300 | is actually highly, highly modifiable.

00:30:24.720 | So much so that experiments have been done

00:30:26.660 | where for instance, somebody eats a particular food

00:30:29.900 | or in some cases it's just directly injected with insulin,

00:30:32.300 | but more often consumes a particular food.

00:30:34.620 | And just prior to consuming or during consuming that food,

00:30:37.540 | there's a bell ringing or a buzzer

00:30:39.680 | in the background going off.

00:30:41.260 | And they do that a few times.

00:30:42.760 | And then I'm sure you're anticipating what's coming.

00:30:45.780 | Somebody can just hear the buzzer

00:30:47.900 | or the bell can simply ring

00:30:49.440 | and that person will experience an increase in insulin.

00:30:52.300 | So what I'm describing is a conditioned insulin response.

00:30:56.000 | A stimulus such as a bell or a buzzer

00:30:58.860 | that on its own should have zero effect on insulin release

00:31:03.220 | has been paired with a food

00:31:04.500 | that genuinely increases insulin within the bloodstream.

00:31:07.660 | And then even if the food isn't present,

00:31:10.740 | the stimulus, the buzzer, the bell, et cetera,

00:31:13.940 | can evoke the insulin response.

00:31:15.780 | Now, this is an important example to understand

00:31:17.560 | because it's a common one

00:31:18.780 | that we've presumably all experienced

00:31:20.620 | and that exists within the wiring of our brain right now.

00:31:23.840 | But it's different than the smell

00:31:26.660 | evoking the insulin response

00:31:27.980 | because delicious food which evokes an insulin response,

00:31:30.840 | having a particular odor,

00:31:32.020 | that makes sense in the context of food.

00:31:33.640 | But here we're talking about something

00:31:34.880 | completely unrelated to the food,

00:31:36.500 | not the odor, not the taste, not the appearance,

00:31:38.480 | just something that happened to be in the environment

00:31:40.640 | in which you ate the food

00:31:42.060 | leading to an increase in insulin.

00:31:43.820 | And it just screams placebo effect,

00:31:46.940 | but it also screams that the placebo effect

00:31:49.380 | is strongly modifiable according to context.

00:31:52.940 | Again, the prefrontal cortex

00:31:54.400 | being the seat of the anticipation or placebo effect

00:31:57.500 | and the prefrontal cortex

00:31:59.540 | taking into account lots of things in the environment

00:32:01.940 | trying to understand what's here, what sounds, what smells,

00:32:04.820 | what colors, and then lumping all of that together

00:32:08.820 | and eventually through the activation

00:32:10.800 | of specific neural circuits

00:32:11.940 | leading to a very basic hormonal response,

00:32:14.840 | in this case, the release of insulin.

00:32:16.700 | And of course, what I just described

00:32:18.060 | is classical conditioning a la Pavlov.

00:32:20.460 | Pavlov won the Nobel Prize

00:32:22.100 | for his description of classical conditioning

00:32:24.780 | in which dogs could be induced to salivate

00:32:28.340 | in anticipation of food by way of a stimulus

00:32:32.040 | completely unrelated to food itself,

00:32:34.660 | not the smell, not the look, not the taste,

00:32:36.700 | rather just a bell rung

00:32:37.980 | before the consumption of food in a dog

00:32:40.340 | eventually led to a situation

00:32:41.800 | where the mere ringing of a bell

00:32:43.940 | could evoke salivation from those dogs.

00:32:46.500 | So are we all just like salivating dogs?

00:32:49.800 | I guess we are.

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00:34:18.180 | Okay, so given that context is a powerful modifier

00:34:20.900 | of the placebo effect,

00:34:22.140 | and in fact may be central to the placebo effect,

00:34:25.780 | I just want to rattle off a few of the known placebo effects

00:34:29.020 | that have been demonstrated,

00:34:30.420 | which show the extent to which your brain and my brain

00:34:33.480 | are coming up with ideas about what given drugs

00:34:37.380 | or given behavioral treatments ought to do,

00:34:39.780 | and in that way, shaping what happens

00:34:41.680 | when you take a placebo.

00:34:43.540 | Or, and this is an idea that we'll go into

00:34:45.600 | in a bit more detail in a few minutes,

00:34:48.260 | perhaps context is also changing the way that active drugs,

00:34:51.600 | not placebos, but active drugs

00:34:53.660 | are impacting your brain and body.

00:34:56.240 | The examples I'd like to give are from laboratory studies

00:34:58.900 | about the placebo effect,

00:35:00.580 | but that relate to very common at-home

00:35:03.380 | and normal life scenarios, okay?

00:35:05.180 | They are not unique to the laboratory,

00:35:07.060 | and they are the following.

00:35:08.780 | First of all, placebo effects are strongly modifiable

00:35:12.160 | by the expectation of the quality of a given treatment.

00:35:17.100 | For instance, if you are given a placebo

00:35:20.380 | that has a brand name on it or a name of a drug,

00:35:24.860 | it could even be a made-up name,

00:35:26.080 | you don't know what the drug does,

00:35:27.080 | but it has trademark TM there in the corner of the name,

00:35:30.160 | so brand name as opposed to generic placebo,

00:35:33.620 | the brand name placebo has a stronger effect.

00:35:36.880 | Moreover, if a placebo is placed into a package,

00:35:39.880 | not just put in front of you on a little tray

00:35:42.160 | or in a little dish, but rather in a package

00:35:44.700 | where you have to push it through that little foil wrapping,

00:35:47.420 | or you have to take it out of a bottle,

00:35:49.780 | and especially if that wrapping or bottle has a label on it,

00:35:52.820 | or it looks as if it's a quote-unquote real drug,

00:35:55.420 | well, then the placebo has an even greater placebo effect.

00:35:59.860 | The color of a given drug can even have an effect

00:36:02.860 | based on our association or expectation

00:36:05.840 | of what different colors relate to

00:36:08.280 | in terms of our physiology.

00:36:09.860 | For instance, if subjects are given pills

00:36:13.500 | that they are told will help them fall and stay asleep,

00:36:17.340 | and some subjects are given blue pills,

00:36:19.980 | other subjects are given red pills,

00:36:21.440 | other subjects are given yellow pills,

00:36:23.440 | the subjects that take the blue pills

00:36:26.140 | tend to sleep better even though all the pills,

00:36:29.140 | regardless of color, are placebo,

00:36:31.720 | they contain no active substance.

00:36:33.900 | Okay, so for some reason, most people associate

00:36:36.180 | the color blue with sleep, whereas,

00:36:39.500 | or I should say by contrast,

00:36:41.380 | if people are given a blue, a red, or a yellow pill,

00:36:45.660 | and they are told it's a stimulant,

00:36:47.680 | the subject's taking the red pill,

00:36:50.260 | here I mean the actual literal red pill,

00:36:52.700 | I'm not talking about any kind of cultural red pill,

00:36:55.100 | I haven't seen "The Matrix" yet,

00:36:56.380 | people tell me I need to see it,

00:36:57.660 | but I'm not talking about taking the red pill quote-unquote,

00:36:59.460 | I'm talking about taking a pill that is the color red

00:37:02.580 | in an experiment, the people that take that pill

00:37:06.820 | experience a greater placebo-induced stimulant effect

00:37:10.820 | as opposed to when subjects take a blue or a yellow pill.

00:37:14.500 | For some reason, the color red is associated

00:37:17.260 | with a quote-unquote upper effect or stimulant effect.

00:37:20.900 | Moreover, if subjects are given a blue, a red,

00:37:22.780 | or a yellow pill, and they are told that the pill

00:37:25.900 | will have an antidepressant effect,

00:37:27.500 | the subjects that took the yellow placebo

00:37:31.140 | get the biggest antidepressant effect.

00:37:32.860 | So color of a given pill even impacts the direction

00:37:36.300 | or in this case, the magnitude of the placebo effect.

00:37:39.540 | And I should mention that in every one of those studies,

00:37:41.520 | yes, there was information about

00:37:42.940 | what the given pill should do.

00:37:44.300 | It was not the case that if people took the red pill,

00:37:47.400 | they felt a stimulant effect,

00:37:48.940 | if they took a blue pill, they felt a sleepy effect,

00:37:51.140 | and if they took the yellow pill,

00:37:52.220 | they felt an antidepressant effect.

00:37:53.820 | These were three separate experiments,

00:37:55.220 | one on sleep where subjects were given

00:37:58.020 | one of the three colors of pills,

00:38:00.120 | blue had the strongest effect,

00:38:01.380 | or a study of stimulant effects.

00:38:03.700 | They were told it's a study of pills

00:38:05.340 | that will increase alertness and attention.

00:38:07.480 | They were given one of three different colors,

00:38:09.040 | the red pills had the biggest effect.

00:38:11.000 | And the third experiment, subjects were told

00:38:13.880 | this is a pill that will alleviate to some degree

00:38:17.900 | your symptoms of depression.

00:38:19.500 | The people who took the yellow pill

00:38:20.620 | experienced the greatest relief of depressive symptoms.

00:38:23.560 | Now that's pretty wild, but what perhaps is even wilder

00:38:26.960 | is the more invasive a placebo intervention is,

00:38:31.660 | the greater the placebo effect.

00:38:34.180 | So capsules have a bigger effect than tablets.

00:38:37.580 | I don't know if that's more invasive,

00:38:38.860 | but I guess it looks more medicinal

00:38:40.300 | to have a capsule versus a tablet, who knows why,

00:38:43.100 | but that's what's been observed.

00:38:44.680 | An injection of a placebo has a greater effect

00:38:47.220 | than a consumption of a capsule or a tablet, of course.

00:38:51.960 | And if people are placed into a medical device or machine,

00:38:55.080 | especially in cases where one of their limbs

00:38:57.100 | or both of their limbs or even their whole body

00:38:59.580 | is placed into a device,

00:39:01.980 | even though the device is doing absolutely nothing

00:39:04.900 | specifically to our biological system, it is inert, right?

00:39:08.540 | A bunch of buttons and a bunch of noises

00:39:11.360 | and a bunch of humming as if something were happening,

00:39:13.120 | but nothing is happening that directly relates

00:39:16.180 | to any one specific biological system except,

00:39:19.200 | and now you know what I'm about to say,

00:39:20.760 | except expectation of what the machine is doing.

00:39:23.500 | Well, that has the greatest placebo effect of all.

00:39:27.140 | So for some reason, as the level of invasiveness

00:39:29.840 | or the, let's just say the complexity

00:39:32.340 | of a given treatment is increased,

00:39:35.200 | well then the magnitude of the placebo effect

00:39:38.300 | is also increased.

00:39:39.900 | And what this tells us is that the human brain

00:39:42.080 | has come to associate level of invasiveness,

00:39:45.040 | level of complexity of a given treatment or machine

00:39:49.980 | to equate to bigger outcomes.

00:39:51.940 | And in some sense, that's completely logical,

00:39:54.220 | but again, we have to remember in absolutely zero

00:39:58.220 | of these conditions, whether or not it's a tablet,

00:40:00.140 | a capsule, an injection, or a medical device,

00:40:03.140 | is there anything being done to these human subjects

00:40:06.440 | that impacts a specific biological function except one?

00:40:09.700 | And that one again is the activation

00:40:11.980 | of specific neural circuits in the prefrontal cortex

00:40:15.100 | that then are able to communicate with other areas

00:40:17.680 | of the brain and body through bonafide biological mechanisms

00:40:22.600 | of neurotransmitter release and electrical activity

00:40:24.640 | in neurons, this is what the brain does.

00:40:26.080 | And of course, the prefrontal cortex being part

00:40:27.920 | of the brain, those are the mechanisms it employs

00:40:30.480 | to change the activity of hormone releasing glands,

00:40:32.960 | to change the activity of other neurons.

00:40:35.120 | In other words, the belief effects,

00:40:37.040 | the expectations are real.

00:40:39.320 | They are having effects through true biological circuitry.

00:40:43.080 | It's just that the pills and the treatments

00:40:44.880 | and the machines are not doing anything specific at all

00:40:48.280 | except activating expectation.

00:40:51.200 | So we've been talking about the placebo effect

00:40:53.360 | and I've been giving examples of strong placebo effects.

00:40:56.600 | And while all of what I told you is substantiated by data,

00:40:59.680 | I do not wanna give you the impression

00:41:01.480 | that the placebo effect is limitless

00:41:03.420 | because it is not limitless.

00:41:05.680 | For instance, placebos have been used to help

00:41:08.520 | in the treatment of cancer,

00:41:10.240 | but their effects within the treatment of cancer

00:41:12.560 | are limited to a very specific set of symptoms and contexts.

00:41:17.160 | So for instance, people who are told a given drug

00:41:20.020 | will help them with their cancer

00:41:21.880 | by reducing their symptoms of chemotherapy

00:41:24.720 | or radiation therapy, often experience reductions

00:41:27.920 | in the negative symptoms of chemotherapy

00:41:31.200 | or radiation therapy, reduced pain, reduced nausea,

00:41:34.960 | and by consequence, improved feelings of wellbeing

00:41:38.320 | compared to people who do not receive the placebo

00:41:41.880 | and who are not told, hey, this drug,

00:41:44.880 | which in reality is a placebo,

00:41:47.000 | is going to help you with your treatment.

00:41:48.840 | It's going to make it less uncomfortable, okay?

00:41:51.240 | So in the context of cancer treatment,

00:41:53.080 | placebo can reduce the discomfort

00:41:55.360 | of various cancer treatments.

00:41:57.280 | However, placebos cannot reduce the size

00:42:00.960 | or eliminate tumors.

00:42:03.300 | If people who unfortunately have tumors, okay, cancer,

00:42:07.480 | are given a placebo and told this drug,

00:42:11.040 | which actually is a placebo, unbeknownst to them,

00:42:13.680 | is going to reduce the size of your tumors

00:42:15.920 | or eliminate your tumors,

00:42:17.960 | that placebo is not effective in reducing the size

00:42:22.140 | or eliminating those tumors.

00:42:24.480 | This is very important to understand

00:42:25.860 | because as you recall, placebo effects

00:42:28.240 | are expectation effects.

00:42:29.600 | Expectation effects are driven in large part

00:42:32.200 | by the prefrontal cortex and its connectivity

00:42:34.520 | to other areas of the brain and thereby to the body,

00:42:38.240 | but the outputs of the prefrontal cortex are limited.

00:42:42.480 | There are a certain number of them,

00:42:44.000 | and indeed there are many of them,

00:42:45.840 | but those connections do not extend to tumors themselves

00:42:50.200 | or biological systems or circuitries

00:42:52.600 | that allow one's beliefs to reduce the size of

00:42:55.760 | or eliminate tumors.

00:42:57.280 | And this is very important because unfortunately,

00:42:59.580 | there are many sufferers of cancer

00:43:01.240 | and there are many theories

00:43:02.200 | about accelerating the treatment of

00:43:03.880 | or improving the treatment of,

00:43:05.160 | or even curing cancer using so-called mind-body techniques

00:43:09.840 | or mind-body tools.

00:43:11.200 | And we need to be fair to the data

00:43:12.540 | which have conclusively shown that reductions in stress,

00:43:15.280 | improvements in sleep, social support,

00:43:17.960 | a number of things can improve cancer treatment outcomes.

00:43:21.900 | Now, those are not placebo effects.

00:43:24.880 | Those are all practices for which we know

00:43:27.440 | there are reductions in inflammation,

00:43:29.760 | reductions in stress hormones that lead to improved outcomes

00:43:34.000 | in the context of radiation therapy,

00:43:36.500 | in the context of immunotherapy,

00:43:38.960 | in the context of any bona fide treatments

00:43:41.640 | known to reduce tumor size.

00:43:43.840 | So what we need to do is separate out three things here.

00:43:46.760 | Behavioral practices, such as meditation,

00:43:49.040 | sleep, social support,

00:43:50.400 | known to reduce inflammation and stress,

00:43:53.120 | and that can improve cancer outcomes.

00:43:54.600 | Those are not placebo effects.

00:43:56.100 | Those are real effects.

00:43:58.240 | There are also drugs, radiation, chemotherapy,

00:44:01.320 | immunotherapy, and devices known to reduce tumor size

00:44:04.920 | and hopefully eliminate cancerous tumors.

00:44:07.000 | That would be the hope.

00:44:08.060 | Those are real effects.

00:44:09.480 | And then there are the placebo effects,

00:44:11.580 | the knowledge and belief and expectation

00:44:14.660 | about what a given treatment will do.

00:44:16.580 | In some cases, it's knowledge about what a given drug will do

00:44:20.200 | that improves the outcome achieved with that drug.

00:44:24.060 | In some cases, it's people being given

00:44:26.280 | a completely inert substance or solution,

00:44:29.260 | like saline solution,

00:44:30.300 | but being told this is going to help

00:44:31.740 | with your nausea symptoms,

00:44:33.000 | this is going to help with your pain

00:44:34.660 | during your immunotherapy, radiation, et cetera.

00:44:37.240 | And those are real effects,

00:44:39.080 | but they can only be explained

00:44:41.700 | by virtue of expectation and knowledge,

00:44:44.260 | AKA placebo effects.

00:44:46.280 | And I want to emphasize that those placebo effects

00:44:48.500 | are not acting directly on tumors

00:44:51.820 | to reduce their size or eliminate them.

00:44:54.300 | Another example of how placebo effects can be very powerful

00:44:57.780 | and yet still have limits to them

00:45:00.140 | is yet another study from Dr. Ted Kaptchuk's lab

00:45:04.040 | at Harvard Medical School.

00:45:05.280 | And by the way, many, not all of the studies

00:45:07.900 | that I've been describing today

00:45:09.400 | have been done by the Kaptchuk lab.

00:45:10.960 | He's done beautiful work on placebo effects

00:45:13.880 | for a very long time now.

00:45:14.980 | He's considered a real pioneer

00:45:17.020 | and a leader in the study of placebo.

00:45:19.580 | And he's also been a big proponent

00:45:21.100 | of exploring the placebo effect,

00:45:23.120 | not simply as a contrast to drug effects or device effects,

00:45:28.020 | but as their own specific effect

00:45:31.220 | that perhaps can be leveraged

00:45:32.820 | in the context of treating disease.

00:45:34.980 | So hats off, literally, plural hats off

00:45:37.780 | because they've had oh so many discoveries

00:45:39.520 | in the context of placebo and their powerful effects

00:45:41.780 | and their possible uses from the Kaptchuk lab

00:45:45.860 | and their colleagues there at Harvard Medical School.

00:45:48.140 | Just incredible work.

00:45:49.420 | And one of my favorite studies from the Kaptchuk lab

00:45:51.740 | is one published in the New England Journal of Medicine

00:45:54.460 | some years ago in which they took people

00:45:57.100 | who had asthma, so these are people diagnosed with asthma.

00:46:00.020 | These are people who have challenges breathing

00:46:02.140 | and they experience a lot of discomfort

00:46:04.260 | in trying to breathe normally

00:46:05.960 | unless they are taking their asthma medication.

00:46:08.400 | In this study, they took people off

00:46:10.740 | of their asthma medication, of course, not indefinitely,

00:46:13.360 | but for a short period of time and as expected,

00:46:16.420 | those people experienced challenges in breathing

00:46:18.780 | and discomfort associated with the challenges in breathing.

00:46:21.780 | One group received no treatment.

00:46:25.060 | They were just taken off their asthma meds and evaluated

00:46:28.260 | and then of course, put back on their asthma meds.

00:46:30.640 | Another group received a placebo treatment

00:46:33.380 | and another group received a drug

00:46:36.460 | known to improve the symptoms of asthma.

00:46:39.780 | Now, what was interesting is that the people

00:46:41.600 | who received the drug for the treatment of asthma,

00:46:44.240 | not surprisingly, had improvements in breathing

00:46:47.120 | and less discomfort, exactly what you'd expect.

00:46:50.500 | However, the people with placebo

00:46:52.620 | also experienced less discomfort in breathing,

00:46:56.900 | but their patterns of breathing didn't change.

00:46:59.940 | So again, this really speaks to the fact

00:47:01.600 | that placebo effects can be very powerful,

00:47:03.800 | but that they're very specific.

00:47:05.620 | They are not simply wiping out a condition like asthma

00:47:09.540 | or completely eliminating all symptomology

00:47:12.460 | of a given condition like cancer.

00:47:14.420 | This study illustrates very clearly

00:47:16.260 | that placebo is effective in reducing the discomfort

00:47:19.220 | associated with the challenges of breathing,

00:47:21.920 | but not eliminating challenges with breathing per se.

00:47:25.600 | Whereas, as I mentioned before,

00:47:27.620 | there are drugs, bona fide prescription drug treatments

00:47:30.980 | that can both restore normal patterns of breathing

00:47:33.760 | and relieve the discomfort.

00:47:35.480 | So what this really speaks to is the fact

00:47:37.620 | that the prefrontal cortex and its involvement

00:47:40.060 | and expectation can have powerful effects

00:47:42.960 | on things like pain, powerful effects

00:47:45.420 | on things like dopamine, powerful effects

00:47:47.420 | on any number of different brain and body systems,

00:47:49.640 | but not all of them.

00:47:51.500 | Our beliefs and expectations are powerful

00:47:54.500 | as evidenced by the placebo effect itself,

00:47:56.960 | but they are not what we call omnipotent.

00:47:59.020 | They can't do anything and everything.

00:48:02.080 | I'd like to take a quick break

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00:48:23.840 | A major problem with a lot of blood tests out there,

00:48:25.940 | however, is that you get information back

00:48:28.320 | about metabolic factors, lipids and hormones and so forth,

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00:48:35.460 | because they have a personalized platform

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00:48:42.440 | but it gives you specific directives that you can follow

00:48:45.320 | that relate to nutrition, behavioral modification,

00:48:47.640 | supplements, et cetera,

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00:49:03.280 | One of my all-time favorite studies

00:49:05.280 | in the context of placebo

00:49:07.040 | is a paper that was published pretty recently.

00:49:09.500 | And the title of this paper is "Nicotine-Related Beliefs

00:49:12.620 | Induce Dose-Dependent Responses in the Human Brain."

00:49:15.760 | And if ever there was a paper that pointed to the fact

00:49:18.480 | that our belief systems can really shape the way

00:49:21.340 | that different drugs, different supplements,

00:49:24.280 | different behavioral protocols can impact

00:49:27.080 | the way that our physiology and our brain work,

00:49:30.320 | it's this paper.

00:49:31.640 | It's a pretty straightforward study.

00:49:33.320 | It was, of course, carried out in humans.

00:49:35.560 | And what they did is they had people vape nicotine.

00:49:39.980 | Nicotine is a known cognitive enhancer.

00:49:43.760 | Nicotine, so named because it binds

00:49:46.440 | to nicotinic acetylcholine receptors in the brain,

00:49:48.680 | which is just fancy nerd speak for the receptors,

00:49:51.520 | the little parking spots for acetylcholine,

00:49:54.040 | a neuromodulator that's involved in attention,

00:49:56.900 | and by virtue of being involved in attention

00:49:59.580 | is critical for the performance of certain focused tasks.

00:50:04.480 | So most people associate nicotine with smoking,

00:50:06.480 | vaping, dipping, or snuffing.

00:50:08.160 | Here, we're talking about nicotine that's vaped.

00:50:11.040 | However, I want to be very clear.

00:50:12.480 | I am not encouraging people to vape nicotine.

00:50:15.280 | Yes, vaping is probably healthier for you than smoking,

00:50:18.460 | but vaping is not good for you.

00:50:20.660 | It would be better to not vape than to vape at all.

00:50:24.040 | I did an entire episode about nicotine.

00:50:26.040 | So I want to leave aside the issue

00:50:28.040 | of whether or not you decide to use nicotine.

00:50:29.800 | Okay, that's all covered in the episode on nicotine.

00:50:31.640 | I'll provide a link to that in the show note captions.

00:50:33.800 | There's a lot of considerations there.

00:50:35.200 | It does increase blood pressure

00:50:36.520 | and it increases vasoconstriction and on and on.

00:50:39.560 | But as I mentioned, nicotine is a cognitive enhancer.

00:50:42.280 | It can increase focus and attention

00:50:44.740 | and in doing so, it can allow your brain

00:50:47.240 | to do certain things better like task switching,

00:50:49.840 | like focusing in the context of a lot of distraction,

00:50:52.720 | et cetera, et cetera.

00:50:54.080 | So in this study, nicotine-related beliefs

00:50:56.320 | induce dose-dependent responses in the human brain.

00:50:58.960 | Subjects used a vape to ingest nicotine

00:51:03.960 | and they were told that they were either ingesting

00:51:06.640 | a low, medium, or high concentration of nicotine.

00:51:10.520 | And a really nice thing about this study

00:51:12.020 | is that they actually measured how much nicotine

00:51:15.160 | people vaped.

00:51:16.000 | So they were able to measure how much nicotine

00:51:18.200 | made it into the bloodstreams of these people.

00:51:20.380 | And they were also able to evaluate brain activity

00:51:22.760 | in areas of the brain known to have

00:51:24.920 | these nicotinic receptors and to also be involved

00:51:28.160 | in certain cognitive tasks.

00:51:30.080 | So just to get to the grand conclusion of the study,

00:51:32.420 | what they found is that people who were told

00:51:35.240 | that they ingested a high concentration

00:51:37.600 | or a medium concentration of nicotine

00:51:39.920 | performed better on a cognitive task that we know

00:51:43.200 | is dependent on or can be modified

00:51:46.360 | by the amount of acetylcholine transmission

00:51:48.180 | in a certain area of the brain,

00:51:49.700 | then did individuals who were told that they ingested

00:51:53.660 | a small concentration of nicotine.

00:51:56.880 | Now, the interesting part of the study

00:51:58.800 | is that everybody consumed the same amount of nicotine.

00:52:03.040 | So here we have a situation where there is a so-called

00:52:06.160 | dose-dependent placebo effect.

00:52:08.200 | Everyone gets the same amount of nicotine,

00:52:10.540 | but people are either told,

00:52:12.280 | meaning they were lied to in some cases,

00:52:14.160 | that they got a small, medium,

00:52:16.200 | or high concentration of nicotine.

00:52:18.240 | And for the group that was told that they received

00:52:20.120 | a medium concentration of nicotine,

00:52:22.120 | they performed better on a cognitive task,

00:52:24.280 | then did the people who were told they received

00:52:26.280 | a smaller concentration of nicotine.

00:52:28.860 | Moreover, people who were told that they received

00:52:32.560 | a high concentration of nicotine performed better

00:52:35.960 | than either the individuals who were told

00:52:38.360 | they received a medium or small concentration of nicotine.

00:52:41.780 | But as I mentioned before,

00:52:43.320 | everyone received the same concentration of nicotine.

00:52:46.800 | So this tells us that not only are placebo effects

00:52:48.960 | related to expectation,

00:52:50.860 | but that the expectation somebody has

00:52:53.400 | of the degree of an effect they should experience

00:52:55.960 | actually creates a different level of experience.

00:52:59.480 | Put differently, if you're told that you're getting

00:53:02.480 | a small amount of drug, a medium amount of drug,

00:53:05.280 | or a high amount of drug,

00:53:06.400 | and that the size of an effect gets bigger

00:53:09.320 | as you go from small, medium to high,

00:53:11.600 | well, then you will experience the small, medium,

00:53:15.460 | or high effect depending on which group you were in,

00:53:17.560 | even if you all got the same dose of drug.

00:53:20.440 | Now I need to be very clear, everybody got actual nicotine.

00:53:24.320 | The placebo effect here is related to what people believed

00:53:28.520 | about the dose of nicotine they got,

00:53:30.980 | but everyone got active nicotine.

00:53:33.320 | Now here's where it gets really cool.

00:53:35.280 | As I mentioned earlier in this study,

00:53:36.740 | they imaged the brains of people

00:53:38.720 | that were in either the group that was told

00:53:40.400 | they got a small or medium

00:53:42.320 | or high concentration of nicotine.

00:53:44.400 | And what they found is that in the specific area

00:53:47.840 | of the brain that is known to respond to nicotine

00:53:50.240 | and that is involved in cognitive functioning

00:53:53.480 | related to the task that these subjects were given,

00:53:56.720 | they saw increased levels of activity of the neurons

00:53:59.620 | in that brain region that scaled up

00:54:02.560 | according to whether or not people were told

00:54:04.520 | they got a small, medium, or high amount of nicotine.

00:54:08.440 | Again, everyone got the same amount of nicotine.

00:54:10.600 | They were simply told small, medium, or high,

00:54:13.160 | and the brain area itself changed its level of activity,

00:54:17.620 | which in turn changed the outcome on the cognitive task,

00:54:20.480 | which basically puts everything in a really nice box,

00:54:23.420 | wraps it up with wrapping paper beautifully,

00:54:25.560 | puts it in a bow and says, okay, placebo effects are real.

00:54:29.860 | And placebo effects scale

00:54:32.460 | with the degree of expectation that one has.

00:54:35.580 | So anytime we are told that a small dose of something

00:54:38.220 | is going to lead to a small effect,

00:54:39.820 | a medium dose of something

00:54:41.420 | is going to lead to a bigger effect,

00:54:42.820 | and a high dose will lead to an even higher effect,

00:54:45.180 | well, whether or not that occurs is going to depend a lot

00:54:48.780 | on what sorts of quote unquote effects we are expecting.

00:54:52.020 | Again, you can't use placebo to eliminate tumors.

00:54:54.820 | There's a limit to what placebo effects can occur,

00:54:56.980 | but assuming that the effect that one is interested in

00:55:01.140 | is modifiable by knowledge and expectation,

00:55:04.580 | well, the size of that effect will scale

00:55:07.020 | with how big you expect the effect to be,

00:55:10.220 | and it's not purely psychological.

00:55:12.340 | That's the point here.

00:55:13.240 | It's not just about your beliefs

00:55:15.900 | and you doing something very different

00:55:17.460 | in the context of a task or in a sports event.

00:55:20.340 | Your physiology, in this case,

00:55:22.060 | the activity of a specific brain region

00:55:24.260 | increases its level of output

00:55:26.300 | according to your expectation

00:55:28.100 | of the level of drug you consumed.

00:55:30.700 | So in my description of that recently published study,

00:55:33.460 | you notice I said placebo effects,

00:55:35.700 | but in many ways what I was describing were belief effects.

00:55:38.960 | It's a little bit difficult to disentangle

00:55:40.620 | what's a placebo effect and what's a belief effect.

00:55:42.980 | In general, belief effects

00:55:44.580 | have to do with acquiring a bit more information

00:55:48.240 | or specificity of information

00:55:49.820 | about what the expectation should be.

00:55:52.260 | So I suppose the study I just described

00:55:54.900 | could easily fall under the category of belief effects

00:55:57.200 | and not just placebo effects,

00:55:58.900 | but nonetheless, belief effects are powerful.

00:56:02.260 | And they're especially powerful

00:56:03.680 | because as one starts to layer in different amounts

00:56:06.540 | and different types of information

00:56:08.740 | as to what a given drug treatment

00:56:10.340 | or behavioral treatment will do,

00:56:11.860 | one can start to see really nuanced outcomes

00:56:15.180 | as well as truly surprising outcomes.

00:56:17.500 | And some of my favorite studies on belief effects

00:56:20.200 | were done by my colleague at Stanford.

00:56:22.780 | She's in the Department of Psychology.

00:56:24.100 | Her name is Dr. Alia Crum.

00:56:25.380 | She's been a guest on the Huberman Lab podcast before.

00:56:27.900 | We will also provide a link to that episode.

00:56:29.920 | And Ali's lab studies mindsets.

00:56:32.980 | Mindsets, of course, incorporate a lot of things

00:56:35.020 | besides beliefs.

00:56:35.980 | They involve prior knowledge.

00:56:37.540 | They tend to have even more information woven into them

00:56:40.400 | than either placebo effects or belief effects.

00:56:42.540 | But Ali's really one of the world leaders

00:56:45.400 | in understanding these belief effects

00:56:47.200 | and has done some just gorgeous work

00:56:49.060 | in illustrating the incredible range

00:56:51.620 | and extent of belief effects that exist.

00:56:54.120 | One of my favorite studies in this context

00:56:56.080 | is the paper from Ali's lab entitled Mind Over Milkshakes.

00:57:00.020 | Mindsets, not just nutrients, determine the ghrelin response.

00:57:03.900 | So here, I'll just briefly describe the study.

00:57:05.620 | I'll paraphrase the abstract.

00:57:07.340 | On two separate occasions,

00:57:09.260 | people consumed a 380 calorie milkshake.

00:57:13.540 | And they were either told that it was a 620 calorie,

00:57:17.620 | quote unquote, indulgent shake, or a 140 calorie,

00:57:21.620 | quote unquote, sensible shake.

00:57:24.100 | Then the hormone ghrelin was measured.

00:57:27.020 | Ghrelin is a hormone associated with hunger.

00:57:29.780 | It is released from and binds to various sites

00:57:32.480 | within the brain and body.

00:57:33.920 | But it's generally associated with the hunger response,

00:57:37.220 | the desire for food.

00:57:38.440 | Then their subjects had their blood drawn

00:57:40.620 | at three different time points.

00:57:42.040 | So at baseline, prior to consumption of the milkshake.

00:57:45.260 | Anticipatory, meaning just prior to consuming the milkshake.

00:57:50.220 | And post-consumption, 90 minutes

00:57:52.600 | after consuming the milkshake.

00:57:54.420 | And then ghrelin was measured within the blood samples

00:57:57.640 | that the people provided.

00:57:59.040 | Now, as you recall,

00:57:59.880 | everyone is consuming the same 380 calorie shake,

00:58:03.580 | but that's unbeknownst to them.

00:58:05.660 | One group thinks they're drinking an indulgent shake

00:58:08.100 | that has lots of calories.

00:58:09.020 | The other group thinks they're ingesting a quote unquote,

00:58:11.620 | sensible shake with fewer calories.

00:58:14.100 | And it's important to note that in the study,

00:58:16.940 | the individuals were asked to read the labels of the shake

00:58:19.840 | and get information about, okay, this is an indulgent shake.

00:58:22.900 | Has a lot of calories, a lot of fat, et cetera.

00:58:26.020 | In the other case, this shake has very few calories.

00:58:29.180 | It contains healthy ingredients, et cetera.

00:58:31.120 | Now you can probably guess where this is going.

00:58:32.820 | The people that consumed the milkshake,

00:58:35.500 | but we're told it was a high calorie indulgent shake.

00:58:37.740 | And also by the way, consumed information

00:58:40.380 | about it being high calorie and indulgent,

00:58:42.820 | or they're reading that on the label,

00:58:44.740 | experienced steeper reductions

00:58:46.540 | in this hunger associated hormone called ghrelin,

00:58:50.100 | as compared to the group that also consumed

00:58:53.780 | the same 380 calorie shake,

00:58:55.880 | but thought that the shake was a sensible shake

00:58:58.420 | with fewer calories that was a healthier shake.

00:59:01.620 | Those people experienced reductions in ghrelin as well,

00:59:04.480 | but they were less steep.

00:59:05.780 | They occurred less quickly over time.

00:59:07.900 | And in addition, their subjective level of satiety,

00:59:11.060 | of fullness or a feeling as if they had enough food

00:59:14.580 | to quell off hunger was also related

00:59:17.820 | to whether or not they thought they had consumed

00:59:19.460 | the higher calorie indulgent shake

00:59:21.140 | or the lower calorie sensible shake.

00:59:23.140 | There are a bunch of other interesting aspects

00:59:24.680 | to this study.

00:59:25.820 | I'm just giving you a cursory overview of the major effects,

00:59:28.420 | but the takeaway is very straightforward.

00:59:31.400 | What we believe about the foods we are consuming

00:59:34.540 | strongly impacts the downstream hormonal effects

00:59:39.140 | of consuming those foods.

00:59:40.420 | Ghrelin, after all, is a peptide hormone

00:59:42.820 | that is secreted from the stomach, okay?

00:59:45.200 | Yes, the stomach has neurons, but as far as we know,

00:59:48.240 | the stomach doesn't have a little thinking brain in there.

00:59:50.400 | The stomach is operating in a very kind of crude language

00:59:53.840 | of the nervous system as compared to the thinking

00:59:56.300 | and analytic language of the brain, the forebrain.

00:59:59.700 | But what's happening here is that knowledge,

01:00:01.860 | indeed specific knowledge about what more calories means

01:00:05.340 | as opposed to fewer calories,

01:00:06.460 | what the word indulgent means as opposed to sensible,

01:00:08.980 | all of that is being combined and then communicating

01:00:12.420 | with neurons and other systems of the gut

01:00:14.700 | to literally create a different hormonal response to food.

01:00:18.740 | And that's incredible because the hormonal response to food

01:00:21.680 | is a very strongly evolutionary conserved set of mechanisms.

01:00:25.620 | And yet this study and other studies like it,

01:00:28.060 | including the conditioned insulin response

01:00:30.500 | that we talked about earlier, you know, Pavlov's dogs,

01:00:32.700 | or in this case, we are the Pavlov's dogs.

01:00:34.780 | We're the ones that can get conditioned to a bell

01:00:36.560 | or the smell of a food or the sight of a sign on a bakery

01:00:40.780 | to get a insulin increase.

01:00:42.740 | All of that stuff that is primitive hard wiring

01:00:47.460 | of the brain and body is also being strongly impacted

01:00:50.760 | by the more let's call it sophisticated or analytic aspects

01:00:54.980 | of the wiring of the brain, such as the prefrontal cortex,

01:00:57.360 | such that what we believe is going to happen

01:01:00.020 | is actually what happens.

01:01:02.120 | Now, the other study on belief effects and mindsets

01:01:04.840 | and how they can impact outcomes

01:01:07.220 | in terms of our physiology relates to exercise.

01:01:10.620 | And this is a study that Dr. Crum herself

01:01:13.980 | described came about because she was talking

01:01:16.760 | to one of her academic advisors.

01:01:18.620 | This was before she opened her own laboratory.

01:01:20.940 | And, you know, Aliyah is an athlete.

01:01:23.380 | She was actually a division one athlete.

01:01:25.060 | She's an incredibly impressive individual, by the way.

01:01:27.540 | She's a tenured professor at Stanford.

01:01:30.020 | She was a division one athlete.

01:01:31.660 | She has a degree or rather a certification,

01:01:34.700 | in clinical psychology.

01:01:35.980 | So she's an extremely accomplished individual,

01:01:39.040 | but exercise and athletics

01:01:40.720 | have always been a big part of her life.

01:01:42.700 | And one day she was talking to her advisor

01:01:45.100 | and her advisor offered the possibility that,

01:01:48.900 | and here I'm paraphrasing from a different conversation,

01:01:51.860 | perhaps all the positive effects of exercise are placebo.

01:01:56.260 | That's actually what her advisor said.

01:01:58.040 | And Aliyah said, no, there's no way, right?

01:02:00.580 | And we know that you exercise, you sure get an increase

01:02:03.840 | in heart rate and blood pressure during exercise,

01:02:05.620 | but that leads to lower levels of baseline blood pressure

01:02:08.540 | and heart rate afterwards,

01:02:09.860 | after you adapt to that exercise.

01:02:11.880 | And her advisor said, well, okay, that might be true,

01:02:15.160 | but why don't you go test it?

01:02:16.560 | So she did test it.

01:02:17.420 | What she did is she took hotel service workers.

01:02:20.380 | So these are people that clean hotel rooms for a living.

01:02:23.500 | And these are very active people, right?

01:02:25.540 | They're vacuuming, they're changing sheets,

01:02:27.060 | they're going upstairs, they're folding laundry,

01:02:29.220 | they're doing a bunch of different things

01:02:30.500 | throughout the day.

01:02:31.660 | And they divided them into two groups.

01:02:33.780 | One group was told that doing a great job

01:02:36.080 | and being diligent is very good for you.

01:02:38.340 | They were told all sorts of things about their job

01:02:40.420 | and how it was important.

01:02:41.960 | And indeed, their job is important, right?

01:02:44.440 | We need people who can perform these roles

01:02:46.380 | of turning over hotel rooms and doing those sorts of things

01:02:49.440 | so that hotel rooms can be clean and beautiful

01:02:51.320 | when we arrive.

01:02:53.000 | The other group, however, was told

01:02:55.580 | that the normal daily activities

01:02:58.320 | that these people were partaking in,

01:02:59.820 | the folding of the laundry, going up and down the stairs,

01:03:01.700 | pushing of carts, et cetera, was exercise.

01:03:04.900 | And more importantly, that it was the type of movement

01:03:08.020 | that could, for instance, lead to reductions

01:03:10.700 | in blood pressure, reductions in body weight,

01:03:13.460 | improvements in lots of different health metrics.

01:03:16.620 | Now, the incredible outcome of this study

01:03:18.940 | was that simply on the basis of whether or not

01:03:21.900 | people were told and therefore believed

01:03:24.520 | that their daily activities would lead to improvements

01:03:26.820 | in these different health metrics,

01:03:28.580 | reductions in blood pressure,

01:03:30.260 | reductions in basal heart rate,

01:03:32.220 | reductions in body weight.

01:03:35.000 | Well, that's exactly what happened.

01:03:37.980 | People who received the information

01:03:40.340 | about how exercise was healthy

01:03:42.420 | and their work mimicked exercise

01:03:44.620 | experienced the health metric changes.

01:03:47.540 | Whereas people who were simply told your work is important,

01:03:51.180 | you know, it's important to do a good job,

01:03:52.620 | et cetera, et cetera,

01:03:53.500 | they did not experience the same health metric improvements.

01:03:57.900 | So that provides support for what Dr. Crum's advisor

01:04:00.800 | had suggested that at least some of the effects of exercise

01:04:04.020 | are likely due to mindsets or beliefs, AKA belief effects.

01:04:08.780 | So throughout today's episode,

01:04:10.120 | I've been talking about how our expectations and beliefs

01:04:13.260 | and mindsets can impact these really deep layers

01:04:16.180 | of our physiology, things like hormone release,

01:04:18.780 | things like level of discomfort or pain

01:04:21.380 | during a given treatment and on and on.

01:04:23.720 | And I've talked a lot about the prefrontal cortex

01:04:25.900 | as critical for understanding what's happening

01:04:28.940 | in a given context and for setting those expectations

01:04:31.680 | because the prefrontal cortex, as you recall,

01:04:33.620 | is a prediction machine

01:04:35.220 | and context is important for prediction and on and on.

01:04:38.380 | What I haven't yet told you is how it is

01:04:40.660 | that the prefrontal cortex actually does this.

01:04:42.740 | I mean, what are these magical output pathways

01:04:44.920 | of the prefrontal cortex?

01:04:45.940 | And while I already established

01:04:47.980 | that they are not infinite, right?

01:04:49.220 | The prefrontal cortex can't control everything,

01:04:51.620 | meaning if I give you some information like, you know,

01:04:54.580 | just thinking about and believing

01:04:56.460 | that your left quadricep is going to be, you know,

01:05:01.040 | much stronger than your right quadricep.

01:05:03.580 | And if you just keep perseverating on,

01:05:05.260 | meaning you keep thinking about that

01:05:06.460 | and looping on in your mind,

01:05:07.700 | and I give you some examples of how, you know,

01:05:09.740 | thinking about strength can make muscle stronger

01:05:11.860 | and on and on, you know,

01:05:13.220 | in the classic context of the placebo effect,

01:05:16.220 | all that expectation ought to lead to an improvement

01:05:19.140 | in strength and perhaps size of your left quadricep.

01:05:22.180 | But that's not what happens.

01:05:23.620 | Why? Or more accurately, why not?

01:05:26.320 | Well, as far as we know,

01:05:27.840 | there isn't a direct neural circuit or hormonal pathway

01:05:32.240 | whereby thoughts from the prefrontal cortex

01:05:34.580 | can impact the growth of muscles in your left quadricep.

01:05:38.140 | However, there are output pathways

01:05:39.780 | from the prefrontal cortex to regions of the brain

01:05:42.660 | that are known to control very basic bodily

01:05:45.560 | and brain functions, such as the hypothalamus.

01:05:48.140 | And those pathways are known to be able to change

01:05:51.340 | certain parameters of our, for instance, stress response.

01:05:55.000 | So blood pressure, heart rate, vasoconstriction,

01:05:58.080 | even body temperature.

01:05:59.740 | So I just want to take a moment and describe

01:06:01.920 | what I consider one of the more beautiful studies

01:06:04.740 | illustrating a specific pathway

01:06:06.620 | from the prefrontal cortex to the hypothalamus

01:06:09.740 | that allows control of the so-called stress response

01:06:13.860 | in the context of very specific psychological stressors.

01:06:17.800 | Now, this paper is important,

01:06:18.820 | not just for our discussion of placebo belief

01:06:21.240 | and mindset effects, but also for any discussion

01:06:24.160 | about so-called psychosomatic effects,

01:06:26.640 | or the idea that our modes of thinking,

01:06:29.900 | whether or not they are related to calmness or to stress,

01:06:32.840 | can strongly impact our physical health.

01:06:35.660 | And the title of the paper is

01:06:37.700 | a central master driver of psychosocial stress responses

01:06:40.900 | in the rat.

01:06:41.860 | Goodness, that's a tongue twister.

01:06:43.180 | Psychosocial stress responses in the rat.

01:06:46.100 | Now, the fact that this study was performed in the rat

01:06:49.340 | should not cause us to lean away from it

01:06:52.940 | or to think that it's not relevant to humans,

01:06:54.660 | because the very same circuitries that are described

01:06:56.660 | within this study have analogous circuitries

01:06:59.820 | within the human brain.

01:07:01.040 | I know that to be true from my work in neuroanatomy,

01:07:03.500 | teaching neuroanatomy, and other groups,

01:07:06.300 | separate from the group that did this study,

01:07:08.420 | have explored similar circuitries in the human brain.

01:07:11.340 | Now, in this study, what they were able to do

01:07:13.720 | was to identify these two particular regions,

01:07:17.440 | which I'll just call them DPDTT for short.

01:07:20.500 | So instead of saying dorsal peduncular cortex

01:07:22.460 | and dorsal tinea tecta, so just say DPDTT.

01:07:25.980 | This is this area of the prefrontal cortex.

01:07:28.120 | Okay, don't let these acronyms and names scare you.

01:07:29.940 | These are just names of a little sub-region

01:07:32.000 | within the prefrontal cortex.

01:07:34.320 | Send connections, little wires that we call axons,

01:07:38.040 | to a area of the brain called the dorsomedial hypothalamus.

01:07:42.240 | The dorsomedial hypothalamus

01:07:44.140 | is a highly conserved structure,

01:07:45.420 | meaning whether or not you look in mouse or in rat

01:07:47.980 | or in apes or in humans or in dogs.

01:07:51.200 | The dorsomedial hypothalamus contains neurons

01:07:53.260 | that are involved in generating cardinal features

01:07:56.540 | of the stress response, things like increased blood pressure,

01:07:59.420 | things like increased vasoconstriction,

01:08:01.300 | things like increased body temperature,

01:08:03.660 | things like increased brown fat thermogenesis.

01:08:06.440 | Now, we can even go a step further,

01:08:09.060 | because that's what they did in this study.

01:08:10.500 | They mapped the connections from these specific sub-regions

01:08:13.920 | of the prefrontal cortex, the DPDTT,

01:08:16.880 | down to the dorsomedial hypothalamus

01:08:18.960 | and a very specific set of neurons

01:08:20.620 | within the dorsomedial hypothalamus.

01:08:22.760 | But even there, we're still in the brain.

01:08:25.000 | We haven't yet established how activation

01:08:28.660 | of these specific neurons in the dorsomedial hypothalamus

01:08:30.860 | actually change blood pressure,

01:08:32.300 | how they actually cause vasoconstriction in the periphery,

01:08:34.820 | 'cause that's what happens when you get very stressed.

01:08:37.100 | Whether or not it's from social stress or from cold water,

01:08:39.560 | there's a constriction, what we call vasoconstriction,

01:08:42.400 | in the periphery, right?

01:08:43.420 | Blood is shuttled toward the core of the body

01:08:45.260 | to keep your core organs alive.

01:08:47.640 | You're still going to get blood to the big limbs

01:08:50.500 | of your body, so you can move, run if you need to,

01:08:53.180 | but your digits, your appendages are going to get

01:08:56.340 | far less blood flow to them

01:08:57.760 | because of this vasoconstriction,

01:08:59.100 | and that's achieved by an output

01:09:01.480 | from the dorsomedial hypothalamus, okay,

01:09:03.800 | so the second hub along this chain,

01:09:05.980 | to an area of the brainstem called

01:09:09.700 | the rostral medullary raphe.

01:09:11.980 | Okay, again, fancy name, you don't have to remember the name

01:09:14.180 | if you don't want to, maybe you aficionados want to,

01:09:16.560 | but what we're doing here is we're moving

01:09:18.180 | from the prefrontal cortex to the hypothalamus,

01:09:20.680 | then to the brainstem, and then from the brainstem

01:09:23.840 | out to what we call the periphery, to the body,

01:09:25.700 | to the spinal cord, to the blood vessels themselves,

01:09:28.380 | to the organs of the body, like the gut and the heart

01:09:31.620 | and the lungs, all the things that we associate

01:09:33.940 | with the so-called stress response.

01:09:36.100 | So as we've been learning about placebo effects

01:09:39.160 | and belief effects and mindset effects and learning that,

01:09:42.000 | okay, just our knowledge about something, our anticipation,

01:09:45.580 | our thinking can influence levels of a hunger hormone,

01:09:49.500 | isn't that wild, or can influence the amount of pain

01:09:52.420 | that we experience in response to a cancer treatment,

01:09:54.640 | or can change the amount of dopamine in the brain

01:09:56.720 | in the context of a placebo given to people with Parkinson's,

01:10:00.600 | well, all of that seems very, very surprising

01:10:03.880 | until you look at studies of the sort

01:10:05.900 | that I've been describing in the last few minutes

01:10:08.220 | that are starting to establish

01:10:10.400 | the very precise neural circuitries

01:10:12.640 | that lead from areas of the brain,

01:10:14.500 | like the prefrontal cortex that are associated with thought

01:10:17.080 | and context and planning and prediction,

01:10:20.480 | down to, I don't want to call them the deeper

01:10:22.580 | or more primitive layers of the brain,

01:10:24.860 | because these areas like the hypothalamus

01:10:26.980 | and the medulla, the brainstem,

01:10:29.140 | they're not really primitive in the sense

01:10:30.680 | that they do very sophisticated things,

01:10:33.420 | it's just that they tend to be present

01:10:35.640 | in both mammals and reptiles, they're present in fish,

01:10:40.420 | whereas the prefrontal cortex is a brain structure

01:10:43.060 | that has undergone fairly significant elaboration

01:10:46.760 | as you move from animals like say cats, dogs,

01:10:51.720 | up to great apes and to humans,

01:10:54.260 | and at least to our knowledge as a field

01:10:56.260 | of neuroscientists and biologists,

01:10:58.180 | humans have the most sophisticated

01:11:00.380 | or rather elaborate prefrontal cortex,

01:11:03.560 | the most number of different sub areas

01:11:05.820 | of the prefrontal cortex,

01:11:06.820 | and every time there's an investigation of those sub areas,

01:11:09.060 | what they do, what their anatomies are,

01:11:11.060 | meaning where they connect to and who connects back to them,

01:11:14.060 | it's found that there is a tremendous degree of specificity,

01:11:17.400 | all of which is to say that we shouldn't be surprised at all

01:11:21.840 | that these placebo belief and mindset effects occur,

01:11:24.940 | because there's a clear biological substrate for them.

01:11:28.380 | So up until now, we've been talking

01:11:29.860 | about the placebo effect as these incredible set of effects

01:11:33.640 | that have a real biological substrate.

01:11:35.860 | There are anatomical pathways, hormonal pathways,

01:11:38.380 | neurotransmitters involved, and that's all true,

01:11:42.300 | but what's also true is that the placebo effect

01:11:44.820 | can vary in size tremendously between individuals

01:11:48.720 | and across different studies.

01:11:50.500 | And in fact, this was described in the first formal study

01:11:53.120 | of the placebo effect.

01:11:54.420 | In that study, it was shown that approximately 30%

01:11:57.640 | of the individuals in the study

01:11:59.180 | showed a robust placebo effect,

01:12:01.440 | but that the other 70% showed a less robust placebo effect.

01:12:06.100 | And that result, meaning that variation in susceptibility

01:12:10.120 | to the placebo effect has borne out again and again

01:12:13.240 | and again across different studies.

01:12:15.120 | Now, modern science has now taught us

01:12:17.260 | that if you look at the genomes,

01:12:18.740 | the genes that happen to be expressed

01:12:20.860 | in one individual versus the next,

01:12:22.940 | versus the next, versus the next,

01:12:24.700 | there are certain genes, not a lot of them,

01:12:26.740 | but there are certain genes that seem to correlate

01:12:29.820 | with certain types of placebo effect

01:12:32.140 | being greater or lesser in certain individuals.

01:12:35.420 | And while there are a lot of these different genes

01:12:37.900 | and a lot of different placebo effects,

01:12:39.420 | one of the more interesting ones is the COMT gene,

01:12:43.380 | which encodes for something called

01:12:45.540 | catechol-O-methyltransferase.

01:12:47.620 | Catechol-O-methyltransferase, as the name suggests,

01:12:50.000 | 'cause it has an ace in there

01:12:51.980 | in the context of a discussion about biology

01:12:53.820 | that almost always means you're talking about an enzyme.

01:12:56.660 | Catechol-O-methyltransferase is an enzyme

01:12:59.060 | involved in the regulation of the so-called catecholamines.

01:13:04.060 | Catecholamines being dopamine, epinephrine,

01:13:06.620 | and norepinephrine.

01:13:07.980 | Okay, we've already talked about dopamine

01:13:09.520 | in the context of Parkinson's.

01:13:10.880 | I've talked about dopamine a lot, frankly,

01:13:12.980 | on the "Huberman Lab" podcast

01:13:14.360 | because it's involved in motivation,

01:13:16.060 | it's involved in focus, pursuit of reward,

01:13:18.500 | it's involved in movement, as we discussed earlier.

01:13:20.820 | Norepinephrine and epinephrine

01:13:22.860 | also do many different things in the brain and body,

01:13:25.500 | but not the least of which

01:13:27.460 | is to increase activation state for heightened focus,

01:13:30.940 | for increasing the bias toward movement of the body,

01:13:33.900 | and on and on.

01:13:35.340 | In any event, this gene, COMT,

01:13:37.620 | catechol-O-methyltransferase,

01:13:40.000 | seems to show strong variation in individuals

01:13:43.000 | that show strong variation in the placebo response

01:13:45.840 | to certain types of placebo conditions.

01:13:48.540 | And I just mention it because,

01:13:50.380 | A, I think it's super interesting.

01:13:53.020 | After all, a lot of the studies that have demonstrated

01:13:55.700 | placebo effects have shown those effects

01:13:57.860 | in the context of changes in dopamine,

01:14:00.500 | epinephrine, and norepinephrine.

01:14:02.300 | So it's not without context

01:14:03.880 | that we're talking about the COMT gene,

01:14:05.820 | but also just as a general theme,

01:14:08.300 | the fact that there are genes

01:14:10.420 | that encode for specific biological substrates,

01:14:14.060 | in this case, regulation of dopamine,

01:14:16.100 | epinephrine, and norepinephrine,

01:14:17.860 | and those genes show up at different levels

01:14:20.480 | in different individuals,

01:14:21.500 | and the placebo effect show up at different levels

01:14:23.420 | in different individuals.

01:14:24.700 | And now, there are studies that are starting to show

01:14:27.780 | that the levels of those genes

01:14:29.180 | and the degree to which one experiences the placebo effect,

01:14:31.940 | either elevated response or reduced response

01:14:34.440 | to the placebo effect,

01:14:35.700 | seem to be fairly strongly correlated.

01:14:38.340 | So this again is more evidence that,

01:14:40.580 | yes, the placebo effect is based on knowledge,

01:14:44.280 | belief, expectation,

01:14:46.100 | but that it has a real biological substrate,

01:14:48.440 | just as there are anatomical pathways

01:14:50.260 | out of the prefrontal cortex to the hypothalamus,

01:14:52.340 | down to the brainstem and out to the body.

01:14:54.580 | There are also genes expressed in specific cells

01:14:58.280 | within our brain and body

01:14:59.700 | that allow for our beliefs and expectations

01:15:02.400 | that are carried through that prefrontal cortex circuitry

01:15:05.520 | to have either a greater or lesser effect.

01:15:08.720 | So throughout today's episode,

01:15:09.860 | I've been talking about how knowledge,

01:15:12.460 | your belief and understanding about what might happen,

01:15:15.980 | ought to happen, or very likely will happen,

01:15:19.240 | influences whether or not that thing actually happens,

01:15:22.540 | the so-called placebo effect,

01:15:23.640 | or belief effect, or mindset effect.

01:15:26.100 | And what I hope I've made clear

01:15:27.280 | during the course of our discussion

01:15:29.100 | is that while placebo effects arrive

01:15:31.980 | through our cognitive understanding

01:15:34.380 | of what might, ought to, or is likely to happen,

01:15:37.400 | the downstream effects, the effects on asthma,

01:15:42.300 | irritable bowel syndrome, insulin, growth hormone,

01:15:45.740 | you know, pick your favorite biological system.

01:15:47.740 | Essentially, every system within the brain and body

01:15:49.820 | has been shown to be susceptible to placebo effects.

01:15:53.160 | What I hope is becoming clear is that in every case,

01:15:56.480 | the placebo effect is a biological effect.

01:15:59.960 | It's not just, you know, our thoughts tricking us

01:16:03.060 | into thinking something happened that didn't happen.

01:16:05.800 | It's our thoughts, our mind,

01:16:07.840 | creating real biological effects.

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01:18:02.460 | Thank you for joining me for today's discussion,

01:18:04.480 | all about placebo and belief effects.

01:18:06.760 | And last, but certainly not least,

01:18:09.120 | thank you for your interest in science.

01:18:11.120 | [MUSIC PLAYING]

01:18:14.160 | you

How Placebo Effects Work to Change Our Biology & Psychology

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