Why do placebos work? Scientists identify key brain pathway

https://www.science.org/content/article/why-do-placebos-work-scientists-identify-key-brain-pathway

by pseudolus • 5 years ago

169 81 5 years ago

science.org

dairylee• 5 years ago

The placebo effect can bring powerful relief

Can it? I don't believe there are any studies that actually show this.

Pyramus5• 5 years ago

Yes, that's the reason RCTs are contrasted against placebo not no treatment.

If you want too see how powerful this effect can become look no further than acupuncture. Or, for a nocebo result, people have actually died because they thought they had been cursed. Or, maybe less dramatic, people who are given an alcohol placebo still get drunk.

Not all, but some do, and we don't know why they specifically and why at all.

lotsofpulp2• 5 years ago

Or, for a nocebo result, people have actually died because they thought they had been cursed

Source?

I have yet to hear about an objective malady that can be fixed via placebo/nocebo, like stage 4 cancer, type 1 diabetes, etc.

allturtles• 5 years ago

Yes, that's the reason RCTs are contrasted against placebo not no treatment.

I don't think so. Placebo is used to blind participants to which study arm they are in. The placebo effect was then discovered after the fact.

wyager4• 5 years ago

Placebos probably don’t do much of anything compared to no treatment. It’s almost all mean reversion. https://pubmed.ncbi.nlm.nih.gov/12535498/

wyager4• 5 years ago

Good question. It’s a shame that you’re being downvoted. It’s not clear that placebos actually do anything. https://pubmed.ncbi.nlm.nih.gov/12535498/

Pyramus5• 5 years ago

Do you expect a single study to overturn decades of research and medical practice? Leaving aside that 'absence of evidence is not evidence of absence', that would need to be extraordinary evidence, right?

I'm not surprised at all you doubt the existence - it's a very common phenomenon that modern medicine/science struggles to explain (yet) and it's a very weird phenomenon. E.g. placebos still work when you know it's a placebo, it works for animals, it works so well that insurance will cover it etc.

Maybe Bad Science by Ben Goldacre is a good starting point as a book.

PaulDavisThe1st4• 5 years ago

See my other response to this link at https://news.ycombinator.com/item?id=29028133

andrewon• 5 years ago

That reminds me of the idea that brain as a predictive engine that constantly refine its internal model to match anticipated sensory outcome. In this case the inference is way more complex based on cognition that the placebo would help relieve pain.

Based on this idea, however, the study does not identify the key pathway responsible for placebo effect, but only the result of it. If the brain anticipate relief of pain, the parts related to pain would activate. If it anticipates other effects, other parts of the brain would do.

WORMS_EAT_WORMS• 5 years ago

Super interesting comment and thoughts. Thanks for sharing - I never thought of it this way.

rtkaratekid• 5 years ago

If the brain anticipates relief from pain, wouldn’t the parts of the brain relates to pain be depressed rather than activated?

refurb• 5 years ago

Think further downstream, beyond the pain sensing part of the brain.

So opioids are know to be great pain relievers. What is interesting is for certain types of pain, they don’t actually make the pain go away, they just change the perception and emotional response to it.

Patients who receive opioids say “i can still feel the pain, but it doesn’t bother me now”.

So to your question, the impact of opioids isn’t necessarily on the pain sensing centers but rather further downstream in terms of how those sensations are perceived.

If you take a placebo and expect it to relieve pain, your brain adjusts to assume that outcome.

It’s not that different than asking you if you’re tired right now. If you have to go to work you might say “yes”, but if you’re about to jump on a plane for a vacation you might say “no”.

nefitty3• 5 years ago

My likely oversimplified understanding of dopamine is that the brain is constantly simulating the outcomes of possible actions. Simulated actions that result in "success" states generate dopamine, with different pathways generating varying levels at any one time. The pathway that generates the greatest net dopamine is pursued, the realized outcome of which then reinforces/dampens the path's simulation function by generating other neurotransmitters.

richardatlarge3• 5 years ago

an example of the complexity of dopamine: a study allowed animals to self-administer cocaine. Other animals were administered the drug in the brain on the same schedule but without 'choosing' to take it. The findings showed that the areas of the brain affected differed depending on these two conditions. This is a study with rats, and yet the effects of a seemingly small environmental/psychological difference changed everything

Another study on electrical brain stimulation showed that while animals would self-administer it, when it was automatically administered, the same animals would respond always to turn it off

gfody• 5 years ago

the predictive processing model, the best introduction to it imo is this review of "surfing uncertainty" - https://slatestarcodex.com/2017/09/05/book-review-surfing-un...

7. The Placebo Effect. We hear a lot about “pain gating” in the spine, but the PP model does a good job of explaining what this is: adjusting pain based on top-down priors. If you believe you should be in pain, the brain will use that as a filter to interpret ambiguous low-precision pain signals. If you believe you shouldn’t, the brain will be more likely to assume ambiguous low-precision pain signals are a mistake. So if you take a pill that doctors assure you will cure your pain, then your lower layers are more likely to interpret pain signals as noise, “cook the books” and prevent them from reaching your consciousness.
Psychosomatic pain is the opposite of this; see Section 7.10 of the book for a fuller explanation.

MrBuddyCasino3• 5 years ago

brain as a predictive engine that constantly refine its internal model

And a pretty effective one at that. Stereotype accuracy is one of the most solid and replicable findings in psychology. There are very strong correlations between what people think is true about statistical discrepancies between groups and what the truth actually is. The relationships consistently replicate and are much stronger than most effects found in social psychology [0].

We must thus understand wokeism as a war on pattern recognition.

[0] https://cspicenter.org/reports/the-accuracy-of-stereotypes-d...

wolverine8767• 5 years ago

Prejudice is a serious problem - the most serious one. The horrors it has inflicted on people are a long catalog, maybe the worst one. What do you hope to achieve by supporting it?

The underlying issue is about reactionary politics, which exists only to stop progress. I think if we look deep down, we know reactionary politics will object no matter what the issue or facts - therefore the objection has nothing to do with the question at hand or its outcomes. You can see it in climate change denial, as a simpler example. That is its purpose and reason - to object. Along the way, lots and lots of people will die and suffer. Blood, lost generations, are on our hands. And for what?

archibaldJ• 5 years ago

Could perhaps be about reducing the cost structure of forming connections in the pathway while increasing in some, and thus more likely that some connections are formed/deformed (ie without the actual presence of agonists/antagonists)?

grp000• 5 years ago

The simple explanation is that humans are 40K orks.

captainmuon• 5 years ago

I've never understood placebos. Naively you'd assume they work the other way around, as the body attempts to achive homeostatis. So if you think you have taken a pain killer, the body would ramp up pain sensitivity to counter it. But as far as I know a lot of studies have shown placebos work.

One thing I haven't seen discussed is that maybe there is a subconcious social pressure element to placebos. Like: I just got a big injection from the doctor, surely it is going to help, I can't complain yet again about it. Sometimes I wonder, what if people take a placebo, report that they feel better, but continue to suffer internally? And are not even able to identify this, because their internal pain gauge is affected by the placebo. They think it helps. Maybe you could detect this by non-voluntary indicators of pain - avoidance reflexes, concentration loss, etc..

Back to the homeostatis argument, there are placebo-like effects that accidentially work. In autogenic training, you can warm up your body parts by imagining fire. What I think happens is, the body anticipates heat, widens the blood vessels to regulate against the heat, but in the cold environment this actually warms up your arms or legs.

notjosh• 5 years ago

I think my favourite simple example to illustrate this is thinking of (or image searching a picture of) a lemon. A lot of people can feel increased saliva production under their tongue, despite nothing at all actually changing, in anticipation of the sourness. Brains are magical :)

iamcurious• 5 years ago

You are onto something factoring social pressure. Social pressure has a direction, if a doctor says you are going to get better it is creating a pressure on yourself to get better. In many cases that pressure might be all you need.

The homeostasis effect might happen in an adversial situation. Say instead of a doctor, an opponent says something. It might cause to overcompensate in the opposite way. We could call that reverse placebo or by its more common name "spite".

locallost• 5 years ago

There is a lot to how you perceive something that influences how you will react to what's going on.

I was just today thinking about the difference between how both my children were born. There were so similar in the time they happened, how they were late, how the birth was triggered etc. But in the first case we were picked up by an emergency vehicle (there was no emergency, they just told us to do this), so it was dark, with this scary blue light as if somebody is dying, to some hectic in the hospital. And in the second we went very quietly to our appointment, rode the bus on a sunny day, took a relaxing walk outside the hospital as we were waiting etc.

When it was done with the first, my wife was pale and shivering, completely out of everything, and with the second she was just exhausted but could still smile and enjoy taking our newborn. And she looked happy.

Of course there is the case of the first being more scary because of the unknowns, but you could also make a case that it was so traumatic that it should've ruined the second one.

I also fell down on ice once and had a case of whiplash. I got worried as I was reading about the potential long term, especially in the US. And I then switched to the German Wikipedia that said doctors in Germany tell patients to relax for a few days and it will go away, and that long term issues are virtually unknown.

You could go on and on really. When you go to a doctor and they have almost no time for you, you will not feel better. Compare that with going in to somebody doing homeopathy. A friend told me they went and got a cup of tea and an hour to talk about their health issues.

So the body is obviously complicated.

pygy_2• 5 years ago

For social species, when resources are limited, evolution favors groups whose rejected members fall sick and die.

The placebo effect comes from social support and goes beyond pain.

As for the implementation details, expectations play a role. A drug that modulates the cholecystokinin neurotransmission in the brain (involved in expectation processing) was found to enhance the placebo effect of a placebo pill (on mobile, can’t search right now, but with “ cholecystokinin” and “placebo” you should find the paper on google scholar).

jagraff2• 5 years ago

evolution favors groups whose rejected members fall sick and die.

Do you have a source on this? I don't understand how evolution could favor such a negative trait on the individual level, and as far as I understand group selection has been mostly rejected by modern evolutionary biologists

oehpr• 5 years ago

I'd never thought about placebo's being a social mechanism.

As a bit of a tangent, one of things I've always wondered is "how much pain do animals feel compared to humans?" The null hypothesis here would be that they feel the same amount, of course. On the other hand, what's an animal going to do with joint pain? Humans are unique in our ability to perform interventions. Suppose two people have cancer, one shows symptoms and one does not. A tumor can be excised before it becomes malignant. One would live and the other would die. Is there a pressure on us to have pain so that we can seek treatment?

To bring this around to your comment. I wonder if we've demonstrated placebo effects on animals. That seems like an awfully hard study to conduct.

hyperpallium2• 5 years ago

It's been experimentally shown that the placebo effect is enhanced by being administered in a hospital-like setting, by a person dressed as a doctor, with a big + on a big pill.

My personal theory is that if you have convincing evidence that you are safe and being looked after, your body can divert resources to deal with the problem, instead of being on guard.

jrs235• 5 years ago

Which begs the question: If placebos (sometimes) work, (particularly when administered in hospital settings and when expensive, at least in the eyes/brain of the patient) is it unethical to administer/provide them?

pfortuny• 5 years ago

It is unethical to say that you are administering a medicine when you are not doing it, except in trials to which the subject has agreed.

Buttons840• 5 years ago

Placebos work even when people know it's a placebo. We might want to establish a baseline, like the pretender has to remind the patient he's just a pretender once a year. But if a pretend doctor can help, then go for it.

agumonkey• 5 years ago

I agree. Similarly relativism can evaporate some pain. You can feel pretty bad if you think you're alone in a situation. Just knowing someone went through the same issue relieves part of the pain, even though nothing changed in your life.

vlovich123• 5 years ago

Is there any research into the variation of susceptibility to placebos? My gut feeling is that there are people who are much more susceptible and those who are much less, and I’m curious if that’s supported by any research and, if so, how that difference is developed.

Also, I’m confused by the conclusion of the article. If they’re literally exciting or dampening a control pathway in the brain that controls pain, how is this placebo/nocebo? Sounds like a straight up causal effect, not a vague one controlled by the patient’s expectation….

cariaso• 5 years ago

yes

https://www.snpedia.com/index.php/Rs4680

and the others mentioned at

https://www.snpedia.com/index.php/Placebo

tantalor• 5 years ago

Seems strange they would use petroleum jelly which is a well known treatment for burns. It is not a placebo; it's not inert like sugar pill or saline. This could seriously skew the results towards "pain relief" end of spectrum.

dcow• 5 years ago

It’s a moisturizer that treats water loss and protects skin in the presence of real burns. It doesn't do anything to pain. These people weren’t burned. And I think Lubaderm is more commonly “well known” these days.

lngnmn2• 5 years ago

Brain is conditioned by the sensory input augmented with "verbal knowledge" (how it is encoded is irrelevant).

Religious and mystic experiences work exactly the same way. When many other people around you do strange things they start to make sense.

So, basically, it is fooling of neural nets by giving strong cues or whatever you might call them.

In religion such strong cues are other people's facial expressions and body language.

The brain's neural networks recognize strong signals of "taking positive actions" or whatever.

ramblenode• 5 years ago

This is the connection more people should be making. The placebo effect is a social effect. Somebody else whom you trust has given you something. More generally it is an expectation, but the double-blind nature of placebo studies means that it is also always a social transaction. The effect is boosted by the perceived authority of the prescriber (white coat, hospital, colored pill). The same mechanism probably underlies higher survival of religious-minded cancer patients.

podiki2• 5 years ago

While I always thought placebo (and nocebo) is quite amazing, I've had that tempered from some reading of it perhaps not being a large effect beyond a regression to the mean. For example, here's one paper [0], with a quote from the abstract "Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean."

Or from [1] in their summary: "In clinical practice, the phenomenon [regression to the mean] can lead to misinterpretation of results of tests, new treatments, and the placebo effect"

This has been discussed in some popular sources as well, like the fun book The Math of Life and Death by Kit Yates.

[0] https://pubmed.ncbi.nlm.nih.gov/15975061/

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1125994/

Edit: see also this helpful explanation elsewhere in the comments [2]. The thread there highlights this paper [3] with the key conclusion of "There was no evidence that placebo interventions in general have clinically important effects. A possible moderate effect on subjective continuous outcomes, especially pain, could not be clearly distinguished from bias."

[2] https://news.ycombinator.com/item?id=29025886

[3] https://pubmed.ncbi.nlm.nih.gov/12535498/

Pyramus5• 5 years ago

A couple of comments (not a medical expert):

It's likely that the placebo/nocebo effect is confounded by regression to the mean - a typical example are diseases with some sort of cyclical pattern, e.g. some forms of depression.

But there is strong evidence that there is an effect beyond that: E.g. cancer patients die significantly sooner when they get a negative prognosis [1]. Acupuncture is so effective for treating certain forms of chronic (!) pain that in some cases it's covered by German health insurance since 2007 [2]. If you have been treated in a hospital for pain related issues, e.g. after a surgery, it's not unlikely you have received placebo instead of pain killers (depends a lot on jurisdiction).

Regarding [3] specifically, the obvious elephant in the room is that 'absence of evidence is not evidence of absence'. Also see the refutations pointed out by user PaulDavisThe1st [4]. What I take away from that study is that yes, in some contexts, regression to the mean may account for a major portion of the placebo effect.

[1] https://doi.org/10.1016/S0140-6736(73)91754-6

[2] https://www.verbraucherzentrale.de/wissen/gesundheit-pflege/...

[3] https://pubmed.ncbi.nlm.nih.gov/12535498/

[4] https://news.ycombinator.com/item?id=29028133

podiki2• 5 years ago

Good points, and I didn't mean to say that there isn't some placebo/nocebo effect. There's lots of evidence for the connection between mind and body, so it certainly seems plausible this happens (also not a medical expert).

I've always found the placebo effect fascinating, but does seem, at least in popular coverage?, to be puffed up more when there's a lot we don't know. And of course it can be very hard to untangle when some people will just get or feel better for who knows what reason. Medical and human research can be very messy, much as the physicist in me just wants to see the hard stats showing a strong (causal) relationship.

m3kw9• 5 years ago

Psychological effect can amplify the pain you are experiencing. By really noticing and associating the pain with something worse than it is, it makes it hurt more. Placebo can take your mind off it and make it less noticeable.

twofornone• 5 years ago

So how does one deliberately trick oneself to benefit from the placebo effect when knowingly receiving a placebo?

I guess ignorance really is bliss.

mathattack2• 5 years ago

Call me a pedant but it kills me when these are done on such a small sample size. (27 participants)

wolverine8767• 5 years ago

Volunteer for studies?

mdp2021• 5 years ago

If that were the problem, improve recruitment.

wolverine8767• 5 years ago

I would love to see a thread of people describing their own placebo responses, but one difficult part of understanding the response is that few people will admit to it.

Noe2097• 5 years ago

This article/study is all and only about "pain modulation".

Is it to say that there is only one placebo effect, which is always reducing pain? Aren't there placebo effects going "beyond" pain relieving? (Or is it the title that is generalizing the scope of the analysis too much?)

richardatlarge3• 5 years ago

We did a spoof ad for a psychiatry magazine when I was at Adbusters:

https://static.substack.com/p/now-available

paperoli• 5 years ago

The reason it works is because consciousness is fundamental to reality as shown by double slit experiments. The viewer creates their reality. A tree doesn’t fall in the woods if no one is there to see it.

Why do placebos work? Scientists identify key brain pathway

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