Episode 99 - Expectations Matter: Harnessing the Power of Placebo for Medicine

Brad: 00:00:00

What is up, Brad fans? How you doing? How you living? And let me ask you today, how you feeling?

Because did you know that listening to this podcast, this specific podcast, can reduce your anxiety by up to 10%? Did you also know that by me just saying this and you expecting that to be true, it could actually be true? That's right.

We're talking about placebo, that weird effect that we've all heard about, where just because you believe that you're getting a treatment, you can actually feel positive effects of a treatment. So we often think of this in terms of the clinical studies, right?

So two groups are given the same treatment, except one is given a sugar pill, while one is given the actual. The actual drug, the medicine. And you always see that a certain amount of people who have taken the sugar pill actually get better, right?

This is the placebo effect.

You can also think of it more in your everyday life, as when you're a child, or if you have a child that gets injured and they start crying and you give them a little kiss on the knee where they scrape their knee or something, we're not actually doing anything. It's not actually a pain relieving mechanism or anything like that.

But the expectation of the child that is going to make them feel better is all they need.

And this part of the placebo effect, the expectation, is a big part of our discussion today with doctor Helena Hartman, who is a neuroscientist and postdoctoral researcher who is part of a group, a large research group spread across several universities in Germany called the treatment and expectations group. This group is working on many aspects of placebo, from animal studies to clinical trials to working with patients.

All of it, though, is focused on how do we use placebo, or what we know about placebo and placebo effects, and importantly, expectations, people's expectation about treatments, about getting better, all of these things to actually improve drug treatments or any kind of treatments that you're receiving, medical treatments that you're receiving. So expectation is a big part of that. And that's one of the things that Doctor Helena Hartman studies.

And we had a really great conversation and covered a lot of ground in terms of this whole phenomenon of placebo. And then how, again, how it might be specifically wielded, let's say, in a clinical setting.

We talked about the intertwined brain mechanisms behind pain, empathy and placebo. You can think of placebo as the body's internal pharmacy. That was an interesting point, expectation, like I just mentioned.

So how do you actually build positive expectations and reduce negative expectations in medical practice? We talked about open label placebo.

So when you know you're getting a placebo, but you're also informed of the benefits of the placebo, how can that improve your treatment? The ethics of using placebo, this was a big part of the conversation, and we focus on sort of two different ways. Right.

Because it inherently feels like it's kind of tricky, right. Like you're tricking people into getting better. So how when you're thinking about implementing placebo as a medical practice, it's not really that.

It's not there yet. But as you're thinking about this, what are sort of the ethical questions that a clinician would have to balance?

You know, overhyping something really, you know, sort of being upfront about using a placebo, for sure, in a medical practice, in a medical situation, you're never going to be given a placebo without sort of knowing, unless you're part of a clinical trial, in which case you've agreed to that.

But then we also talked about the ethics in terms of, or rather, let's say, the challenges of working in this space, promoting this kind of stuff while trying to avoid over interpretation of the placebo effect. And specifically, I think of, you know, wellness influencers who sell the idea that you can heal yourself. You don't need medicine.

You can heal yourself with just, you know, whether it's meditation or something like that.

And they often latch onto these placebo, you know, type arguments in that it's like the body has this power to, when you think about it, release neurotransmitters or like the opioids in your brain to reduce pain and stuff like that. So they're like, if you just tap into that, you can be you, you know, you can heal yourself and you don't need any.

Any medicine or any medical advice or whatever. And obviously that's not true. There's also things like, you know, homeopathy, which is placebo, but they don't wanna admit that it's placebo.

So there's questions around there, too, of like, how do you promote this stuff?

Again, I think it comes down to sort of being upfront and honest about this is placebo, and if it works great, like, it doesn't, you know, the placebo doesn't have to be a dirty word, I kind of thing, but we got to know the limits of it and not over hype it. Right?

And as Helena says in the episode, the treatment and expectations group, who is linked to in the show notes, has a lot of information for patients who may have questions about this kind of stuff so you can go to their website and inform yourself. We also talked about side effects, how side effects can be used to boost treatment effects.

So again, in this placebo and expectation kind of way, if you experience a side effect, can that be used to enhance the expectation that something's actually working? If I feel a side effect, it must mean it's working.

Then we talk a little bit on the challenges of placebo with regards to the psychedelic clinical trials. Of course, we had to have psychedelics in this episode.

That was one of the big things that came out of the recent FDA decision to nothing, approve MDMA assisted therapy. It's like, well, what are we doing with this placebo thing? Because in those trials, it's very hard to design a placebo for a psychedelic drug. Right.

People who take the placebo often know that they're taking the placebo and then that ruins the whole thing. So yeah, there's a lot of interesting placebo implications in that world as well. Um, so it was a really fascinating conversation.

This is, you know, it's one, again, it's one of those topics that we've all heard about and we all kind of know how it works. But when you start in depth talking about it, it's so, it's, it's, it's just so interesting all over again.

Like when you first learn it, it's one of those, like, whoa, your brain actually, you know, releases, you know, painkilling chemicals as if a drug triggered it to do it. But it's just your belief in that, you know, that's such a, a weird thing to think about.

But it's really fascinating when we put the actual scientific process to it to understand how that works and then start to see the ways in which you can potentially get to a place where just by the next generation of doctors being trained on things like this expectation, making sure your patients feel heard, making sure that they feel like you are giving them the best chance at recovery and all of that kind of thing, how these little things can go a long way to actually improving our medicine. So thank you to Helena Hartman for coming on the show. I really, really enjoyed it. She's a great speaker.

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Here is my conversation with doctor Helena Hartman, all about placebo and expectation.

Helena, welcome to the show. Thank you so much for taking the time to be here to talk about placebo expectations.

Some interesting, interesting research in this area because as we will discuss, I think this is something that everyone's kind of heard of placebo, but maybe there's some updates that you have from when we all heard about this when we were in like high school or whatever. But why don't you start first? Just introduce yourself and maybe like, how did you find yourself working on placebo?

Was this something that always interests you or did your academic path, your career path sort of you ended up stumbling upon upon this area?

Helena Hartman: 00:09:15

Yeah. Thanks for having me, by the way.

I think it's, yeah, I'm always happy to be on podcasts and talk about my work because that's where I can rave about it. So love that. Yeah. My name is Helena. I am a postdoc. I work in Germany now, but I did my PhD in Vienna and I also spent some time in Amsterdam.

So I've been around a bit now I'm back in Germany.

And my story how I got into placebo is actually a bit like around the corner weird because I did my PhD in a lab that was researching social cognition abilities, for example, empathy, so how we perceive emotions in other people. So that doesn't really have anything to do with placebos in the first place.

But my supervisor at the time, he had some really cool studies before I came on the project where he wanted to see whether placebos that are associated with a pain reduction, that's also called placebo analgesia.

So we feel less pain because we took a placebo, whether that would transfer from feeling less pain yourself to feeling less empathy for other people's pain. So basically kind of like a social placebo.

So whether the placebo you take not only dampens your own responses, but also has effects on how you perceive the responses in other people.

Brad: 00:10:39

Yeah.

Helena Hartman: 00:10:40

To me that sounded like really, really cool at the time. It still does, honestly. And so I was kind of following up on this, on this research line.

And so that's how I got introduced to placebos in the first place.

But I wasn't giving them to necessarily show pain reduction in the participation themselves, but to see whether it transfers to empathy and then later also to prosocial behavior, which is helping behavior. So I gave. In the.

In my first study, I used a cream, and it was introduced to participants as a strong local anesthetic that will reduce their pain in this location.

So in my case, it was a right hand, and then on the left hand, they got another cream that was the so called control cream that we introduced just as a skin cream with no anesthetic properties. Properties. And then I look, I. You know, I collected a lot of data. One and a half years went by super quickly, me just being in the lab all the time.

And then I had a look at the data, and I was amazed that many, many of my participants had a really strong placebo effect.

So that means that the pain that they received on their right hand, where they had received this placebo cream, the local anesthetic, in quotation marks, they felt less pain on that hand compared to the other hand, where they had received a skin cream. And just to make it clear, again, both of these creams were actually identical, so there was nothing in them. No anesthetic, no analgesic whatsoever.

So proper placebo. And, I mean, yes, I was interested in the empathy part as well, but that was the first time where I was like, oh, my God, this actually works.

Like, you see it directly in a person.

When they compare the pain they get on two of their extremities, like two hands, they feel a difference by a cream that I have described to them as being able to reduce their pain.

Brad: 00:12:35

It's wild.

Helena Hartman: 00:12:38

That was just magic to me. And I think from that point on, I was pretty much hooked. And I was like, okay, I need to research that more. I did my PhD.

I looked at all kinds of transfer and generalization effects of this placebo effect to social abilities. And then after the PhD, I said to myself, okay, which lab can I go to for my postdoc that does exactly that placebo stuff?

And so I found my lab now, basically.

Brad: 00:13:05

Oh, great. So just quickly, now I'm intrigued. Does it have an effect on empathy and prosocial behavior?

Helena Hartman: 00:13:14

That's a bit of a tricky question to answer, as all the questions in science. So all the studies before me said, yes.

So what they found is that basically people who took a pill that was told them would reduce their pain, it was a painkiller that actually had an effect on empathy. So that means that people who took the painkiller felt less pain themselves.

So the placebo painkiller, but they also felt less pain, less empathy, for the pain of other people.

I was doing a bit of a kind of extension of that, where I was looking at a specific brain region that relates to processing the physical qualities of pain. So it was a bit more of a specification. And here I didn't find the effect again, but that's fine. But I did find it on prosocial behavior.

That means that people who took a placebo were less prosocial compared to people who didn't take the placebo.

And then I kind of tried to put that in relation with the empathy again, and I found that the placebo reduced people's own pain, which reduced their empathy, which then in turn made them help less often, so reduce their social behavior. So that was kind of all connected. So that was nice.

Brad: 00:14:35

Is that. Is that.

I mean, again, probably a tricky question to answer, but just thinking about, like, what the theory behind why that would work, why that extension would go, is it similar brain regions involved? Is that sort of the basic of it?

Helena Hartman: 00:14:55

Yeah, exactly. So there's this theory that I was also investigating during the PhD.

It's called the theory of shared representations, and it basically posits or says that when I see you hitting your elbow and being in pain, the regions in my brain will light up, that are also lighting up when I hit my own elbow. So we kind of share the same brain regions.

And this was the theory that kind of brought about this whole research line, because the idea was, okay, if these two processes, your first hand pain and empathy for pain, are really based on the same neural mechanisms in the brain, what happens now if we manipulate one of them?

So if we change self pain, according to this theory, this should also automatically have an effect on empathy for pain, because if it uses the same brain regions and, you know, they are being, let's say, down regulated through a painkiller or a placebo, that should have an effect on empathy as well. And that was the whole theory why we started it.

Brad: 00:15:58

Yeah, interesting. And so then, you know, it's not a complete answer, but there's some evidence that that is kind of what's happening.

Helena Hartman: 00:16:08

There is evidence. And so where the distinction comes in is the different components of pain processing. So usually we divide pain.

Pain is a very multidimensional, very complex experience that is kind of put together of multiple components, and one of them is the sensory components. So the physical qualities, like, where's the pain? Is it stabbing or is it more dull? How long is it.

So these more yet basic qualities, this is represented in the brain, for example, in the somatosensory cortex. And then on the other side, we have the effective or emotional component of pain processing, where we subjectively judge how we feel about that pain.

So is it unpleasant? Do I want to remove myself from it? And this is represented in other regions, like the anterior insula or the cingulate cortex.

And interestingly, this theory of shared representation seems to hold in the effective part of pain processing and empathy. So there we see a sharing of these regions and a manipulation by the placebo, but we don't see it so much in the sensory component.

And if you think about it, it also makes sense, because I don't necessarily have empathy with your left elbow, but I have empathy with you as you are in pain. So I use this effective emotional component to share the pain.

And maybe the exact location of pain or the quality of the pain is less important when I feel empathy.

Brad: 00:17:38

Right, right.

So in that kind of thinking, then, like an actual painkiller, like an actual local painkiller wouldn't have the same, might not have the same effect on empathy because it's more specific, or I guess maybe.

Helena Hartman: 00:17:58

So that was what we thought I used. Exactly. In my experiment, I used a local anesthesia manipulation. So I basically used a local painkiller. And that kind of didn't work. They had.

But they actually, the interesting thing was, in general, the ratings were reduced. So there was some kind of general empathic reduction, but it just wasn't localized to a specific body part.

So there was some evidence for what I just said with the distinction between the effective and the sensory component.

Brad: 00:18:29

But then I guess what I'm saying too, is like, if it was a real painkiller, like, not a placebo painkiller, but like, I.

So it actually took away the sensory, sort of acted more strongly on the sensory thing, whereas the placebo thing, these other emotional areas are involved, have to be involved, I would imagine, in order to get the sort of placebo effect. But if you just used an actual numbing thing, would you maybe expect that there wouldn't be the same empathy?

Because then I'm thinking, all these people are walking around taking painkillers and stuff. We're all just less empathetic. Or is it just with the placebo?

Helena Hartman: 00:19:09

So I was actually waiting for you to ask that questions, because I do have an answer for that.

Brad: 00:19:15

I'm glad I'm so transparent in where my questions are going.

Helena Hartman: 00:19:21

So I think one to three years after those first studies came out by our lab, there was a follow up by some people from the US, and they gave people paracetamol. So a real painkiller, they did exactly the same thing, and they found that it also reduced people's empathy.

And even in my case, in my second study with the helping behavior, I gave people a pill, and people thought it was a painkiller.

And the really crucial point I want to make here is placebos, especially placebos that target pain perception, have very similar mechanisms as real Medicaid, real pain medications. So both engage the endogenous opioid system and are kind of associated with the release of these opioids, which lead to analgesic effects.

So they're also called endorphins. Those are released in the brain when we expect or get a pain reduction, and then we feel less pain.

And this is the case for real painkillers, but it is also the case for placebos.

And it has been shown multiple times that placebo effects have real and measurable changes on the body and brain, even up to changing activity in the spinal.

Brad: 00:20:45

Cord, so also the sensory component. Okay, good. And actually, maybe this is great, because we jumped right into some of this stuff, which is great, is awesome.

But that actually maybe brings us back to a sort of general description of placebo, and an important one, I think, an important point you make where it's. And maybe not everybody understands this because we think of placebo as this magic thing, right? And that it's sort of.

We don't really understand exactly how it works, which, yes, in part, but the placebo effect, that expectation, that belief that you took some kind of active agent, actually stimulates the release of neurotransmitters, these opioids and stuff in the brain. So your brain is actually behaving physically as though it had received something.

It's not just a sort of unquantifiable, like, ah, you just believe it kind of thing. You see, where I'm trying to guide the audience, I think, to that there is a physical response happening.

And that's really, really interesting when it comes to these, these placebo things, because it's either a drug interacts with the brain receptors on the cells and stimulates this release, or you can kind of do it yourself by believing.

Helena Hartman: 00:22:06

Yeah, and that's. So my boss has a really nice metaphor for this. She describes it as the body's internal pharmacy. So every.

Every one of us, you know, yeah, we take real medications, and sometimes this medication is necessary. For example, in cancer, you need to take medication in order to get better. Right. Or to have the chance, but it interacts with the placebo effect.

And even when you take real medications, you have the placebo effect on top. So the medication has a drug effect, a pharmacological effect that works if you take it. Right.

But on top of that, and part of the, let's say what you see in the end about the effectiveness of the medication is also, in part, expectations, past experiences, learning mechanisms. So this is the placebo part of it, right?

And there have been studies showing that, you know, you have this drug effect, but on top of that, you always have this additional effect. And this can be so important because it can also make real medications work better or worse, depending on this changeable part at the top. Right?

So the placebo part. So let's say I give you a painkiller, and I say, oh, it didn't work in my neighbor, but how about you just give it a try?

Your expectations might be actually quite negative, or at least not very positive. So you take the medication with the expectation, it might not work.

And studies show that in these cases, the medication actually works less well than if I would have given it to you and told you, oh, that did wonders in my neighbor, give it a try. It will work for sure for you. This will induce much more positive expectations in you.

However, I think there's a curve where the expectations might be too unrealistic. Of course, I don't want to tell you it works 100% of the time. You will always experience the best effectiveness, whatever. That's not very realistic.

So I think, especially in clinical practice, we're all about trying to find this sweet spot of positive expectations that we can induce that lead to positive outcomes and avoid negative expectations.

Brad: 00:24:21

So this is interesting, and this is what I think is really cool about your group, because, again, we've all sort of heard about this placebo thing, but now we're talking about with the treatment and expectations group, exactly this. How do we sort of optimize this?

What sorts of things can we do to actually make our real drug treatments that we need, like you said, for cancer or something like that?

What are the surrounding factors, these sort of maybe emotional components or expectation or whatever, to actually, how can we harness that rather than just being like, ah, you know, it's this thing that happens. It kind of screws up our clinical studies every once in a while or something like this.

But like, what is it that we can actually, you know, harness, let's say, in this? So what are the sorts of things that you have to sort of to then look at?

So brain, you know, mechanisms would be one I can think of, but are we talking about the conditions of a hospital room or how the drugs are described to the patients? Maybe you can give us, again, a general. How do we start narrowing in on what we can use placebo for?

Helena Hartman: 00:25:45

Yeah, and honestly, I think the placebo effect is made up of all the things you just said. So you can think of it as everything that is accompanying the intake of a medication or taking something. Right or getting a treatment.

It is what other people tell you that can be friends, neighbors, family members, the doctor. How is the doctor dressed? Do you feel the doctor is warm? Do you feel they are competent? How do they give this information?

What information they give to you? Are they talking a lot about side effects? Are they telling you that this is the right medication for you?

Does it feel like the doctor thought about it and gives you the best treatment possible? And then how do you feel about it afterwards? Do you have questions? Did you ask all of them? Were they all answered?

It can even be something like personality and genes. So some people are just a little bit more anxious than others about taking new medication.

For example, some people are inherently a little bit more optimistic, and they go into new treatments with a bit more positive expectations. And so that's kind of the one side, and the other side is the negative expectations. So do you feel anxious? Do you feel nervous?

Do you have negative experiences? Did you hear of other people experiencing negative things? And then it's also the medication itself. Do you feel okay about taking it?

Do you have side effects? How do you interpret these side effects? Do you adhere to the medication?

All of these things together make up this effect, or this can kind of guide our expectations.

Brad: 00:27:32

So that sounds like a lot to sort of tease through, right. So then that's. That's kind of one of the. And I know that there's, like, probably different.

Different people in different labs kind of tackling each sort of angle from a different approach or whatever. But in general, that feels like a lot to sort of tease out.

And again, I think that's what gives placebo this kind of mystical aura about it, right, is because it's like we can't really describe it fully yet. We got a pretty good description of it. But for each person, it's going to be different. Right.

Because there's the personal variability, how anxious I am. Maybe some of the genetics play a role in that, all that. But then my doctor. Is my doctor cold? Are they warmed? All this stuff?

So how do you actually go about sort of teasing this through? I'm assuming animal studies play a role, but then when we're talking about. Yeah, like, human studies and stuff, like, what do you do?

You try and, like, envision a scenario where, like, well, what if we looked at, you know, how nice the doctor is or something like that, and then just kind of knock them down one by one to sort of build a protocol for doctors to be like, you should be friendly, you should be this, you should be that.

Helena Hartman: 00:28:44

Yeah, it's difficult because there's so many things you should research. You need to start somewhere. Right? So that's kind of what our collaborative research center is doing.

So I'm part of a big group of people in Germany, in three cities, many different labs, many different groups, who are all researching everything surrounding treatment expectations. And so we have some labs who do animal work. We have some who do clinical proof of concept studies. They investigate patient groups.

We have some who investigate healthy, neurotypical participants. So people without any pre existing conditions.

And we kind of hope that all of these little strings will go together in the end to form a coherent picture. Right? And then, as you said, I think it's about looking at one aspect at a time, because otherwise it's going to be really hard to disentangle.

So, for example, there was one study, part of this collaborative research center, who looked at warmth and competence of the provider or the doctor, and they varied that systematically. So either the person was very warm but not competent, competent but not warm, or both, or neither.

And the interesting thing is that then they see a different difference in the. In the outcome expectations. So how people. How much people.

How good people felt afterwards about a certain treatment or about, you know, feeling better and so warm. The providers who were warm and competent had the highest benefit, basically, while people who were neither the least.

So that was one study trying to look at exactly that, for example. And there's other studies who look at what the doctor says, for example. So we had one study recently where participants received a lumbar puncture.

So that is, they get a big needle in their back to tap some spinal fluid. That's quite painful, and it can also lead to headache.

And we wanted to see if the instruction that people get before this procedure will influence the amount of headaches. And actually, the verdict is still out. The study is still ongoing.

But that is really interesting, because here, then, we look at, okay, the instruction that people get before a procedure does that, and that leads to expectations, and those, again, can influence outcomes or how people feel later.

And the cool thing is, we really try to integrate subjective perceptions of people with objective measurements, like brain activity, heart rate, bodily cortisol stress measures and try to put everything together and have all of these little puzzle pieces fit.

Brad: 00:31:36

Yeah, because I guess that's the other thing, is there's always that self reporting has to go on. Like, how did you feel? And even pain reporting can be so subjective.

Having those physical biomarkers to sort of complete the picture is really interesting.

So there's a couple studies that I'd like to ask you about specifically, but here's one that kind of just popped into my head, and I think it gets mentioned in some of the studies I was reading as the ethics of placebo and placebo research. Right. And I think that this is. I hadn't really thought of a question about it.

But just as we're talking about it, some of the studies you're describing, you can see that there's an ethical question with placebo.

And I think, again, people familiar with clinical studies, we know that there's sort of an agreement when you go into a clinical study that you might get the placebo. Everybody knows that. And we accept that because it's a good way of determining efficacy of a compound. Right.

Like, it's the best way we have to do that question. But when we're talking about this, you know, so in a way, like, I don't want to make it sound negative, but in a way, it sounds kind of tricky. Right?

Like, it's like, yeah, we're just tricking you into, like, you know, so there's a question of, like, conducting the trial, conducting these experiments where you put somebody in a situation where they feel like they don't have a competent provider. You know, there's that which I think we can navigate by, you know, consent, you know, all that kind of stuff.

But just in general, this idea of sort of, you know, tricking people into getting better. I mean, the end goal is noble, right? We want the treatments to work better, but, like.

Helena Hartman: 00:33:29

But the way is important.

Brad: 00:33:30

The way there. Yeah, exactly. So is that like, what are the discussions, like in, you know, maybe in your group and your people you work with in this area? What is.

Is it sort of like, well, the ends justify the means? Or do you have to be careful about, like you said, you can't push it too far, right?

Like, you can't be overly optimistic and be like, oh, it's going to work amazing, and then expect that it will.

So what are the types of things that you think about when you're talking with your peers or whatever, or thinking about these questions in terms of placebo?

Helena Hartman: 00:34:01

Yeah.

Yeah, it's a very big and ongoing discussion, to be honest, we talk about placebos all the time, but actually, I have to make clear that placebos, especially what we call deceptive placebos, where people do not know that they're getting a placebo or they're not sure. That happens only in studies.

You will never find a doctor in clinical practice that is supposed to give you a real medication and then secretly gives you a placebo. That is not ethical at all, and that is also not allowed. So if you go to a doctor, you will get real treatments for sure.

But one avenue that has been explored in the last few years is so called open label placebos, or honest placebos.

And in that situation, people know they are taking a placebo, but they also know about the positive benefits of the placebo effect and expectation effects, and they know of the benefits that this thinking and this expecting something positive can have unreal outcomes. And so there's been lots of studies in clinical populations.

For example, people with irritable bowel syndrome, migraine, chronic back pain, that's just in the pain field.

But there are a bunch of others in the immune system or in other diseases and conditions that show that people feel relief from their symptoms in different conditions by taking something regularly as a routine, let's say, twice a day, morning and evening, even though they know what they're taking is basically a sugar pill. So it has nothing in it. But that shows the power of the placebo effect, because even if you know that I'm taking nothing, it is the whole context.

As we discussed before, it is the moment where you take it, how you think about it, how optimistic or positive you feel about it, and what the doctor told you about the placebo effect and what your personality kind of tells you how this will work. All of this goes together, and we see improvements, especially in people who are in need of symptom relief. So, especially in clinical populations.

We've done a few studies as well in healthy participants, and there it's actually a little bit more difficult to see effects. And that could be just because these people don't really have anything to improve on. Right.

So, for example, I did a study where I checked whether open label placebos can improve cognitive functioning. So they did a bunch of, you know, working memory and other attention tests, and then they took an open label placebo for three weeks.

And then I did the tests again. I didn't see any changes. And that could just be because people are already good in these tests.

They don't really need to improve, so they don't really have any positive expectation towards this taking, while patients who for some, it may even be the last resort, they've tried a lot of medications, they didn't work. They feel very hopeless. Right. And then the doctor says, let's try this.

I have had positive experiences with other patients, and then it's kind of like this, oh, maybe this helps me. And so that's how I at least explain many of the patient studies that find this symptom relief, which is really, really cool that we can use that.

And often, or at least I see in the future, it can be used as a kind of addition to the normal medication.

So it doesn't mean that we now should stop giving people real medication and just give them open label placebos because there is obviously, as I also said before, kind of a border. So some conditions just need real medication.

If you had an operation, you will need pain medication, but you can try to reduce the dosage of that pain medication. You can take additional placebos to kind of boost the effectivity of that medication.

And if that's what we can go towards, then I think that's already a very big step.

Brad: 00:38:07

Yeah. Yeah. And I guess I didn't mean to be, to give the perception or whatever to the audience that, like, the ethical quandary is that, yeah.

If you go to a doctor, they might give you a placebo. Like that, of course, doesn't exist. Right. That's not the thing.

I guess I was thinking about it more in terms of, like, you know, this trying to set up the expectations of the patient for success, you know? And I think it's like, again, like, I don't see, you know, logically, I hear it. Emotionally, I hear it. I'm like, yeah, of course you want to.

You would want to be. This could work for you. We're positive that it has some effects on other people, all those kind of things.

Again, talking about a real drug, but adding that extra layer on to boost the efficiency of an actual drug. But then there's this other side that I'm thinking of, again, overselling it. Or like, if, let's say the outcome is uncertain, right?

Like this is a new medication or, you know, it doesn't actually work in a lot of people. Like, it's a 50 50, but in order to try and maximize that person's chances and success, you might maybe sell. It a bit more.

Right. So I guess that's the kind of ethical thing I'm thinking of. Is that some, like, how do you, how do you think about that?

Or is that maybe too far down the line because we're not there yet?

Helena Hartman: 00:39:38

No, no, I don't think it is. I think it is right there because we're talking a lot about how to give instructions, how to tell people about placebos.

I'm also currently part of a group that is trying to write a little how to, how to do an open label placebo studies, how to actually start, you know, what do we need to know? And the verdict is still out. Definitely. I would say it's not.

There's no hundred percent answer, but I think there's a few things that we can say that weigh the costs and benefits and are honest, honestly communicated. So for ethics, it's always, at least for ethics departments at my universities that I've been to, it's always about risks and benefits.

Do the benefits, as you said before, outweigh the risks? Right. And in our case, if we want to give someone an open label placebo, they really have nothing to lose because they will not.

You know, the worst thing that can happen is that it doesn't work. It's not going to give them anything negative, as opposed if you give them a real drug that might have side effects. Right.

So it is really all about that, managing the expectations in a way that whatever people get, they feel positive about.

And the difficult thing there is really individual differences because we can give 100 people an open label placebo, but a certain percentage of them might just not respond to it at all. Some other people might respond a little bit, and others respond really strongly and honestly.

So far, we have not figured out why because there's, as we discussed, so many factors that can play a role from personality, genes, past experiences.

And this is just very hard to control in the lab because everybody comes with their own little package of what they heard, what they saw, what they know, what they expect. Right. So it's very hard to. We try to control as much as possible, but it's very hard to handle.

Brad: 00:41:39

Yeah.

Yeah, exactly. Okay. And then again, this is not what I had sent in an email to you that we would talk about.

But I just, it's, again, now that we're on this trend, I have a. Or a path. I have another question, and that is, yeah.

When communicating this type of research, do you feel, again, sort of a responsibility to be clear on it?

Because I think that there's a lot of stuff, let's say, in the health and wellness space that could latch on to placebo and this kind of thing and just start selling people the idea that they're in complete control of their, you know, whatever, their internal pharmacy, as you mentioned before, you know, that kind of thing. And, like, you could harness this. You don't really need a doctor. You see what I'm saying?

Like, there's that sort of, you know, other side to it that needs to be balanced. So what do you say about that kind of thing?

I think, you know, my gut feeling is just that it's like, yeah, that's obviously overselling this whole effect because we don't really know, as you said, we don't really know why one person responds higher than another. So the idea that you could just will your way to pain free or whatever seems like a bit far fetched.

But then you look at all these interesting studies and all these cool things that are happening, it's like, well, yeah, but, well, maybe. Maybe I'm the one.

Like, now I'm thinking, like, if I was ever, you know, in a situation where I had to take some medication for something, I'm like, I'm gonna go in being the most positive person I can be. I'm gonna be like, yeah, this is gonna work. I'm gonna, you know, and you see that a lot with cancer treatments, right?

Like, people are always like, I'm gonna fight this. I'm gonna. There's that language that gets used around it.

So what do you think of that in terms of, again, maybe the ethical thing or, like, not overselling this kind of stuff?

Helena Hartman: 00:43:41

Yeah, yeah, yeah. It's a super important point.

I think there are many so called treatments out there that are not, you know, that just use the placebo effect, and they have basically nothing. I mean, homeopathy is one of these. They actually. They don't like saying that it's a placebo effect.

And it's up to groups like ours and centers like ours to give out information that people can trust and give them information that people can use when they go to new treaties or they see a new treatment online to assess whether that is quality wise, helpful, or useful for them, or whether that is something that they should stay away from.

In the end, everybody makes their own decisions, but it is up to healthcare professionals and scientists to also not only do the studies, but communicate the findings to people around us so that patients can go on our website and look at how do I behave the next time I go to the doctor? What do I do if I find this online? How do I find credible information that all kind of goes together?

And we actually have a lot of information about that on our website that.

Brad: 00:44:56

Can be no doubt.

Helena Hartman: 00:44:59

Basically, that is exactly what we're trying to do. And one of my biggest passions is science communication. I don't only want to do the science, I want to communicate it.

I want to see what people can take away from it. And it is exactly these points that you raised. It is how do I distinguish bad treatments from the placebo effect?

How can I use it but not overuse it so that it's going in the opposite direction and it's actually going to long term decrease my expectations and my mood because it just is not working. But I think this will require a lot of communication with the healthcare professionals, and we need to.

So one of the things we do in the research center is to try to develop curricula and learning materials for medical students so that already in their studies, before they have patient contact, they learn about these things and the placebo effect and expectations and how they can manage the expectations in their patients, in their future patients. So I think we need to start very at the bottom.

So on the one hand, we need to communicate to patients how they can find good information online, how to distinguish bad from good treatments. And on the other hand, we need to educate healthcare professionals to help patients help themselves, basically.

Yeah. Because I guess it's like, it's, again, you would want to set people up to be able to make that risk reward calculation themselves.

If I come across a homeopathy, someone who's selling me homeopathy, and I have maybe headaches or whatever it is, the risk for me trying this is low. It's homeopathy. There's nothing in it. I'm not going to have a bad side effect or anything.

The reward might be that my headaches go away or something like that. But then, you know, you wouldn't want to do that for like a tumor, right?

That's not necessarily going to go away just on it, you know, like you actually need.

So I guess it's that sort of, you know, and I get this kind of, this is a bit like just a personal grievance of mine is all the health and wellness stuff, because in my job, with some health reporting and stuff that I do, it's just you're inundated with this and you see it all over social media and stuff, too. Like these people just like, you know, meditation will cure, like, everything and blah, blah, blah. And it's like, I see a benefit for meditation.

Like, obviously there's something, but it's like that line, right? And so I guess, yeah. Educating people on. It's okay to, I don't know, get tricked by the placebo, I guess.

But as long as you're, as you know, the limits of it sort of thing, I guess, I don't know.

Yeah.

I think it's about educating people that they can ask their doctor or healthcare professionals questions and if they find something that they think could help them go to someone who you think, you know, has experience with it and just ask, like, I found that online. Is that a thing? Is that okay?

Or maybe if you're, you know, a little bit more, do it yourself, go on these websites, check sources, read the actual papers and try to understand, is that actually founded in a solid, on a solid basis? Like, does that actually make sense to take this? So you need to inform yourself a little bit more and you need to know where to look.

And groups like ours and others are trying to make it easier for people to find this information. But in the end, our health is up to each and every one of us, right? Yeah.

And I think there will be people who are asking Doctor Google when they have pain somewhere in their body and there will always be the answer, oh, you have a tumor. Oh, you have cancer for sure. And then it boils down to the personality.

So how people react to this information, some people like you or me, we might be like, yeah, okay, that clearly looks like a weird treatment. I'm not going to do that. But others, especially if you're desperate, you've tried so many things, they have nothing else. Right.

So that's maybe something that will give them strength. But then it's important to loop in the doctor and other healthcare professionals and kind of double check. Is that good for me?

Is that what I'm supposed to do? Because those people have the expertise in the background to give health information.

Brad: 00:49:25

Yeah. But then it's like, again, another side to this then would be that person. If the doctor is very dismissive of that kind of stuff, right.

Then you can have that sort of negative effect. And I know that it's not uncommon for people to feel that their doctor is being dismissive of their, their ideas or their symptoms and stuff.

So I guess that's another angle of this whole thing is it's not just like boosting, but it's also, like you said earlier, you kind of said, avoiding the negative effects as well.

Helena Hartman: 00:49:58

And that's hard because doctors have no time these days. They see a patient, they have five minutes before the next patient.

So that's what I mean with we have to try to start at the beginning and try to educate new emerging doctors, even if you have five minutes, make sure that the patient goes out of your practice with a feeling of, I was able to ask all my questions, I got answers, I was heard, and that is from that side. So it's not only that the patients have to do a lot, but also the healthcare professionals.

Everybody has to do their part to reach a successful conclusion.

I think it is a price we or healthcare professionals will have to pay so that the people maybe come to their practice less often because they feel confident.

They feel like, you know, they've gotten all the information, they can finish their treatment on their own, and they feel fine about it, as opposed to people coming back and coming back because they're unsure, they haven't gotten their questions answered, and they're just scared.

Brad: 00:50:57

Yeah.

Yeah. So it's like a whole.

You got all this data and information and practical things that we're learning about this, but there's also this culture shift in terms of implementing some of these basic ideas of feeling heard, incompetence and warmth and all that stuff that would just maybe make all of our medicines more effective, all of our treatments, which is a very nice goal, a very nice outcome. Yeah. Okay, so before I let you go, that was a bit of.

A bit of a detour from what I was planning, but I actually really enjoyed that, that part of the conversation, because it kind of speaks again to what I do, like communication and science communication and the sort of real world sort of, you know, effects of some of this stuff. Right.

But there was one paper that I wanted to talk to you about that you. So it was a commentary on another paper.

It's the side effects study, which I just thought was super interesting, because this is one of those really sort of powerful examples of the placebo effect that makes you kind of go like, wow, it works that well, kind of thing. And so I'll try and maybe summarize the study a bit, and then you could point me to details that I missed or something.

But essentially, what the researchers, I believe the point of it, what they were doing is everybody was getting a placebo in the trial, but some of them had, some of the placebos actually produced a side effect. So, like a burning or a tingling sensation or something in a nasal spray? I believe it was a nasal spray.

And so just the presence of a side effect, that it has nothing to do with the supposed treatment or anything like that, just this side effect increased the efficacy of the treatment, increased the outcome.

You have a placebo, but if that placebo gives you some kind of side effect, it increases it, which, again, when we think about placebo, it makes sense if you're, if you're thinking that, oh, well, I felt something, so I must have got the real thing, that that's already going to increase that expectation. So that was the big takeaway for me. What did you think of this piece you wrote, this perspective or this commentary on it?

What jumped out to you about this one? What got you excited about?

Because I think the title two was like, side effects, a gift and a curse or something along those lines, which I thought was a great title.

Helena Hartman: 00:53:41

Yeah. Cursed curse has been a blessing. Yeah. I think it was fascinating to read it just because it's very counterintuitive.

So we tend to think side effects are bad, and that's something we want to avoid, but they are kind of present just in some medications and we have to deal with it. But this paper kind of puts out a hypothesis that we could potentially use side effects to boost treatment effects.

So we could use these side effects that are inherently negative to our advantage and kind of turn it around from being a curse to a blessing. And obviously, that's like, you know, I'm already fantasizing about the future, but you basically, you describe pretty well what they did.

And I think it just, you know, the simple effect that if you compare two nasal sprays that have no active ingredients and one of them produces a burning sensation in your nose, this seems to indicate, or seem to indicate to the participants that something was working and it led to higher pain reduction. So analgesia. And interestingly, they also did some additional analysis.

So they found out, and I'm going to look at my little graphic to get this right, is that the side effects that people perceived were worked together with the, with the belief that stronger treatments have more side effects.

So that, you know, if I have a side effect, it indicates a stronger treatment, which in turn influenced people's treatment expectations, and that led to reduced pain.

So it was really this expectation part and these beliefs, and this is what we were talking about the whole session until now, that had an effect on the actual outcome, which is the pain rating. And I think it's very interesting in that case, it was a mild side effect. So it was a slight burning of the nose. Right.

But in the comment we discuss that, you obviously cannot if you take it further, and the side effect is so strong that people, you know, it's really present that might not have the same beneficial effect on your pain, for example, because we kind of think there's like an inverted u.

So there is benefits up to a certain extent of side effects, but at some point it tips over and then it becomes the opposite, which we haven't talked about, which is a nocebo effect.

And I think that is something we discuss in the paper, that we need to be really careful when we conduct follow up studies and how we can make use of this very interesting finding that we can use side effects, but maybe we need to use them responsibly in a way.

Brad: 00:56:26

Well, yeah. And then it gets like. That's what I thought again, with the whole discussion we had about ethics.

Like, you know, obviously, you wouldn't intentionally give a side effect that could be harmful. Of course not.

But, you know, is that sort of, you know, what is the sort of gray area there of just, like, tricking somebody into, like, you know, so you're getting the actual, you know, pain reliever or whatever.

You know, you're getting the ingredient, but we just make it like, make you make your stomach a little nauseous or something so you really feel like it's going. There's that. But I think what was interesting in the. In the.

In the reading about this was, again, the conversation around side effects that doctors could be having with their patients.

And so setting up that sort of expectation in a way that, like, and again, I think about cancer right away just because it's one that we all hear about all the time or know somebody with, and that has the treatment has really negative side effects often. Right.

But if the conversation, the framing of the experience that you're about to go through getting this treatment is, look, there is side effects. They're difficult, but this is part of the medicine working. This is part of the whole thing.

You could actually maybe not only just alleviate some anxiety and maybe discomfort about the side effects themselves, but a conversation like that might actually, you know, in a way, be subtly pushing treatment efficacy as well.

Helena Hartman: 00:57:55

Yeah, I completely agree. One of the things we could. We could do is use these, you know, in a systematic way.

But I think, as you said, there's also this ethical, ethical component of trying to not induce overly positive expectations. And I think it also depends on the type of side effect. For example.

So I think if you take a painkiller and then you feel more pain in another body part as a side effect, I don't know if that would be very helpful. In that case, it was a side effect that wasn't really related to the pain that they got on their arm. Right. So I think it also depends on that.

And there's so much more to figure out, and I want to. As a scientist, I also feel that I have a responsibility to say that one single study is not the final, you know, word.

And as scientists, we just, our profession is basically to figure out how the world works cumulatively. So we do studies, we do more studies, and we try to collect evidence.

So what we now have is one study that shows evidence that side effects may in some cases be not only a curse, but a blessing. But now we need replication. So we need people to do the same study again.

We need higher, bigger samples, testing in different populations, testing in patients and in healthy participants, and seeing whether those effects appear again and again. And only then can we be sure that that is maybe something we believe in.

Brad: 00:59:26

Yeah, yeah, exactly.

And I mean, I think that's why it's really cool that this whole treatment expectations group, you know, there's like you said, three cities, three universities, three cities, all these people adding, you know, little pebbles to the pile to grow that pile of evidence bigger and bigger to something that we can then eventually maybe use or incorporate, like we said, like in a. In teaching new doctors, that kind of thing.

This whole not paradigm shift, but culture shift in terms of how we talk about medicine and, you know, the patient doctor relationship, all of these kind of things that could sort of help. I'll throw one more at you. And I know it's not your field, but it's something that I followed a lot.

It's the psychedelic research that's going on that I kind of mentioned in email. Just because it. There was a recent. Everyone kind of expected that MDMA assisted therapy was going to be approved in the US and then it wasn't.

And a big part of it was this placebo. Right. Because in this case, it makes me think of the side effect thing.

And I was just wondering if maybe you could, if you had some thoughts, general thoughts or something.

Because again, that's the idea is like when you take doing a, doing a placebo controlled trial with such an active compound, such as a psychedelic, it's going to unblind the trial right away. Like when they do the follow up surveys and people, I think it's like 90% or 95 or higher, get it right. I was in the placebo group. I was not.

And there's two things going on there, right?

There's the expectation of I'm feeling this side effect, so I know I got the active compound and then there's the nocebo of I'm not feeling anything, therefore I must be in the placebo, therefore it's not going to work. Right.

So you have this, like. But it seems like, how would you even tackle this? Right?

And I know people have talked about active placebos, but in your just, again, kind of totally different because, again, it's not pain necessarily. It's more of it's a mental health condition which is, again, a bit more nuanced.

But what do you think about in terms of, like, is this something that we kind of just have to accept with sort of these kind of studies that there's going to be this problem that we can't and that maybe the ideas, well, try and lean into it rather than control it. All the variables. Any general thoughts on that?

Helena Hartman: 01:01:58

Yeah, so first of all, we can link a really, really amazing science slam on exactly that topic by a colleague of mine in our research center that talks exactly about that. Like placebo controls in, you know, studies with Ketone and DMA and all of these things.

What I can say is, I think it's really tricky and obviously it's not finished.

We are still trying to figure out how to do it, but maybe in these kind of research fields or when it comes to these compounds, it's just nearly impossible to figure out which part of the treatment is the drug and which part is placebo or the expectation effect. So maybe we have to accept to some extent that there is some part of both and they work together and we have a hard time teasing apart each of these.

But maybe we don't need to. I mean, usually in clinical trials, you need to show that the drug works better than placebo. Right? In that case, you can't.

And I think researchers in that field, and also, you know, clinical, let's say pharmaceutical people who do pharmaceutics, they need to figure out how they can continue with this. And as you said, active placebos might be a promising avenue.

So having a placebo that also has side effects so that people, it's, again, it has to do with ethics so that, again, people have a harder time figuring out which one is the real drug and which one is the placebo, or at least having similar side effects. Obviously, you can't do that.

You know, if you take MDMA, it has very specific things, but maybe there's a way to induce some of these side effects in a mild way so that at least it becomes a bit.

More comparable, I guess. But I think it seems really tricky.

And it also seems that like, maybe, like you said, like, accepting that there's, that there's going to be this, you know, assumption. Let's say that placebo is playing a role here. Right.

And it also feels like, just like maybe it's just a, you know, again, the culture or the regulatory, you know, the way that we think about these things, that's not a satisfactory. It doesn't feel right to do that. But I would think, too, that maybe it's just like that risk reward balance. Right?

Would offering this type of therapy, accepting that a certain amount of it is placebo, is there a downside to that? And that's what I don't really see it, but I'm also not an expert in there as well.

Well, I guess you could also say as a, you know, FDA or a company that actually approves these drug, drug trials or these drugs, you could say that if you can't prove that it's better than a placebo, they can give people the placebo, and it's much less harmful than giving people MDMA or other drugs. Right. So that is kind of the argument that this side of the pond says.

But, yeah, it's about, in the end, it's about how people feel, and we want to make people feel better. Right. So it's a very tricky line of, again, costs, benefits. So how do we harm people the least and give them the most benefit?

Brad: 01:05:31

Yeah, yeah, yeah. All right.

Helena Hartman: 01:05:34

Well, I definitely don't have the answer, of course.

Brad: 01:05:37

No. Yeah, yeah. We all expected this was going to be the podcast that answered all the questions. At least that was my expectation.

So because I had such good expectations, I gonna leave this podcast feeling like I got all my questions answered and I'm in a really good mood. So I'll give you a chance if you want to. Like I said, we'll link all of those things that you mentioned in the show notes.

But is there anything upcoming or things that people should be aware of in terms of, you know, your research, your group that they might want to check out?

Helena Hartman: 01:06:11

Yeah. So next to my, let's say, day research job, I'm writing short stories to explain science.

So if people are interested in my topic and what I do, but also maybe in just learning about other research fields and about science and new papers that come out, I try to make it a bit more palatable by telling people a story before. So I guess we can link to my website where I explain science with short stories and then people can have a look.

I also have comics and dance videos and lots of different ways of explaining science. So there's. I think there's something for everyone.

Brad: 01:06:47

Yeah, no, that's great. Thank you so much. Yeah, once again, thanks for thanks for joining the show. I find this, yeah, this stuff is just super interesting.

This gray area of the mind and the physical body and the drug interactions. It's just so fascinating. So I really enjoyed the conversation. Thank you so much for taking the time.

Helena Hartman: 01:07:09

Me too. Thanks.

Brad: 01:07:13

Well, I truly hope that that podcast.

Got you feeling better and even if you knew it was a placebo effect, that you do feel a little brighter going into your day. Once again, thank you to doctor Helena Hartman for joining me on the show.

She was a great communicator, great explainer of all of these interesting ideas, and she went with the curveball on ethics that I threw out there. I really appreciate that.

Check the show notes for all the links to the research and the research group to learn more about this really fascinating thing, placebo and how it can be used. And you know, follow us on Instagram ugrad four. Uh, follow the show wherever you get your podcast, subscribe rate review comment. That really helps us out a lot.

We really appreciate it. By we, I mean me. I'm the only one here. Thank you to freak motif for the music and Sebastian Aboudheen for our logos. And until next time, take care.

Stay safe, be nice to each other. Bye for now.