A Case Against the Placebo Effect

I think this essay is valuable in helping me clarify just what is meant by placebo effects, and their putative biological mechanisms and processes.<p>The arguments should not be summarily dismissed (a lot of thinking and research went into this essay). The arguments should be taken apart and critiqued individually.<p>In particular I agree with the key idea that it is important to critically evsluate the strength of evidence and the strength of experimental designs that favor long-lasting functional placebo effects.<p>If a design is a perfectly implemented triple-blinded study (<a href="https:&#x2F;&#x2F;www.scribbr.com&#x2F;methodology&#x2F;double-blind-study&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.scribbr.com&#x2F;methodology&#x2F;double-blind-study&#x2F;</a>) in which a reliable outcome measure is significantly affected with a reasonably large effect size—-for example, a Cohen’s d score above 0.2) then the evidence in favor would be pretty compelling (<a href="https:&#x2F;&#x2F;www.statology.org&#x2F;interpret-cohens-d&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.statology.org&#x2F;interpret-cohens-d&#x2F;</a>). And very compelling us independently replicated in a second case&#x2F;control study.<p>But how many studies reach this level? I doubt that there are any in animal model research with which I am more familiar.<p>If “faith and prayer” are regarded as a placebo effect then how much does this reduce the incidence and impact of illness when controlling well for socioeconomic factors? Was COVID severity modulated by said factors (or ivermectin ;-) ?

Might be true, but I don&#x27;t think the case presented here is very compelling.<p>The general problem is it interprets the evidence to fit the conclusion: studies showing a placebo effect are interpreted as having bad methodology while ones showing no effect are interpreted as having correct methodology.<p>Of course, study design can exaggerate the effect. Does that mean it&#x27;s doesn&#x27;t exist, though?<p>Probably the more general problem is that contrarian views get clicks (and all that goes with that) which creates an unfortunate incentive.

I have a friend who potentially contributed to the placebo effect for a study she was in.<p>She was in a study to see if a vitamin supplement would have a beneficial effect to a condition she suffered. She didn’t know if she was getting placebo or the supplement so after two weeks of not feeling any positive effect, she decided to start taking additional supplements of the vitamin in question on her own next to the study tablets to “be sure”. I remember choking on my coffee when she casually told me this later. I’m a scientist and it never occurred to me that anyone would act like this in a study.

Did anyone manage to read the whole essay? I often notice with text like these, that they try to imitate scientific writing, but never quite manage (they always end in some kind of uncanny valley). The author states his premise quite nicely in the abstract, but the article does not really provide a consise supporting argument and instead just makes semi related points. This is another pattern I noticed, layman authors often seem to think that dumping lots of loosely related &quot;evidence&quot; somehow strengthens the argument.<p>I wonder if there are good resources which would help lay scientists to write good articles (maybe an opportunity for an LLM proofreader?)

They could do with defining what &quot;the placebo effect&quot; they are refuting actually <i>is</i>.<p>I thought placebo proponents were usually advocating it for things like pain relief, tinnitus, fatigue, etc. Things where what you are consciously thinking can make a difference to your experience even if it doesn&#x27;t actually fix the underlying issue.<p>I think that&#x27;s quite a bit different from thinking that placebos actually heal wounds.

Note that placebos aren&#x27;t just limited to areas like pain and depression, but were also used in clincal trials that involved infectious disease treatments, including antibiotics and vaccines. In these cases, the issue is not the effect of the mind&#x2F;brain&#x2F;nervous system so much as the body&#x27;s immune and biochemical processing systems (liver&#x2F;kidneys).<p>Thus, in some kinds of infectious disease, the body is entirely capable of clearing the infection on its own in most cases as long as the subject isn&#x27;t suffering some kind of immunodeficiency (e.g. all the strange diseases that HIV patients succumbed to before antiviral therapy was introduced). Studies like this led to the movement to reduce antibiotic treatment for minor infections that are very unlikely to lead to issues like sepsis etc, given the deleterious side effects on the human microbiome and so on. A placebo study might also reveal significant problems with toxicity, such as liver-kidney damage to the subject caused by a problem with the antibiotic under study.<p>Likewise with vaccines, careful study with placebos could demonstrate that the vaccine under study didn&#x27;t prevent transmissibility of the infectious virus any better than the placebo did. Notably this was a problem with all the Sars-Cov2 vaccines, none seem to have prevented transmision from an infected person to a vaccinated person. Why wasn&#x27;t this seen in the clincal trials, one wonders?<p>As far as depression&#x2F;mental health studies, placebos are often readily detectable by the patient, which is a big problem in today&#x27;s research into the 5-HT2a receptor drug research (eg psilocybin, LSD, DMT, mescaline). They&#x27;ve tried to get around this by giving subjects drugs like methyphenidate and methamphetamine as the &#x27;placebo&#x27; (because the subject clearly can tell when they&#x27;ve been given a powerful psychoactive substance), but this is not a usual placebo, it&#x27;s an alternative treatment.

&gt; Although placebo and “mind-cure” beliefs are widespread, the most parsimonious interpretation of the evidence is that the “placebo effect” is not a real healing effect, but a product of response bias and questionable research practices<p>This article is built upon a questionable definition of the placebo effect. Debatably, it’s a straw man argument that sidesteps the complexities of placebo response by using an oversimplification that is easier to dismiss.<p>The placebo effect varies by treatment and illness. Placebo isn’t fixing broken legs or making cancer disappear. Placebo effects are strongest where measures involve perception and are related to more complex mental processes.<p>Pain is a common example. Pain is a sensation, but sharp pain is associated with additional fear and panic response. Placebo addresses some of the fear and panic response, thereby addressing part of the pain. I agree that some of the studies showing placebo performing as well as fentanyl and morphine are likely flawed. We have a lot of studies showing dose-response curves for pain management using OTC analgesics, so it’s laughable to see a study showing a dose-response curve that is basically flat or inverted (placebo == 0mg dose).<p>The placebo effect gets much more complicated in the context of mental health. Anti-depressant studies are the classic example, with placebo often performing close to (but not as well) as powerful SSRIs. This has created internet backlash that “SSRIs are almost placebo” but the truth is that placebo groups improve dramatically during the study, too. There is something about the hope of receiving treatment, the way patients are told that they’re possibly receiving a treatment, the act of self-measuring and reporting mental health scores, and the interactions with clinicians that causes many (though not all) people to turn a corner and start improving. It’s almost as if they’ve received a signal that the end of their suffering is near so they start reactivating themselves, thereby improving the depression. The SSRI groups usually perform better by a statistically significant amount, but the challenge is that the placebo group improves so much that there is little numeric resolution left in the depression inventory to see much signal!<p>It’s a strange phenomenon, but I don’t think this article is a good overview of the effect let alone a rebuttal to it.

The article claims that the placebo effect has never been shown as a physical, objectively measurable effect, but this is wrong. For example, I look at autoimmune studies a lot. In those studies, when placebo-controlled, a fair number (often 20-30%) of patients on the placebo arm see significant improvement in symptoms across many objective, physical metrics. Measurement errors exist, of course, but I would expect physical measurements to not be prone to so much psychological bias, especially if double-blinded, that this would explain away the difference in results.<p>The article is also wrong about there not being a physiological mechanism. Dopamine and endorphins can be powerful mediators of pain relief, for example.

Here’s an interesting study we could do.<p>Is there a placebo effect for car repair. And how does it compare to human “repair”?<p>You could pretend to fix peoples car issues and see if they report it improving.<p>Assuming the mind can’t fix cars mentally it would let you isolate what part of the placebo effect is perception.<p>Discuss..

&quot;The current scientific consensus is that the placebo effect is a real healing effect operating through belief and suggestion.&quot;<p>I disagree, based on my understanding of the placebo affect: The placebo effect causes people to genuinely feel better - no more or less than that. The placebo effect does NOT indicate a &quot;real healing effect&quot; per se - just that it makes people feel better, and clearly only in situations where such a thing is possible. Meaning that nobody believes in a placebo effect for a broken arm. Only for things where people could plausibly think something HAS gotten better. Like a cold, or mild pain, etc.

&gt; The picture that emerges is that a placebo pill has almost no effect when administered by researchers who do not care about the placebo effect, but the exact same pill has an enormous effect larger than all existing treatments when administered by a researcher who really wants the placebo effect to be real.<p>Stopped reading right here because it is nonsense. Antidepressant researchers would love nothing more than the 30-50% placebo response rate to go away and yet there it is, competing with whatever tiny effect their pill does.

The &quot;role playing&quot; aspect is treated as fake and inconsequential here, but for a doctor, doesn&#x27;t it translate to &quot;this patient is all set and will not call later saying the problem got worse&quot;?<p>In contrast, hearing from your doctor that &quot;your labs are normal, you just have anxiety&quot; is a common and horrible experience. It&#x27;s likely the end of the doctor-patient relationship and if anything is being missed, maybe even a lawsuit.<p>I get that there are some interesting Objective Science issues here but for studies aimed at improving real world clinical practice, subjective outcomes matter.

There’s this whole genre of scientific questions it seems we’re just going to go back and forth about and mostly your opinion is based on your priors&#x2F;personal beliefs. Kinda interesting but doesn’t seem like there will ever be a real definitive answer on the placebo effect. I wonder if there’s some kind of proof you could do on certain questions that would categorize them in this way.

Did anyone actually manage to read the whole essay? I noticed that often texts like these try to imitate

&gt; The current scientific consensus is that the placebo effect is a real healing effect operating through belief and suggestion.<p>Wait what? I’ve never heard this being the <i>scientific</i> consensus. It’s more like the lay person’s view. I think that many scientists agree that the placebo effect is primarily a combination of regression to the mean and participant’s desire to please the experimenter (ie the literal definition of “placebo”).

Far from being convinced. It sounds like superstition.

It&#x27;s placebo effect all the way down

The case against cases.<p>Even the most compelling and logically consistent case stands upon &quot;mere&quot; observation, convention and authority.

<i>&quot;&quot;&quot; From mind–body medicine to AI as interpreter of our body–mind<p>&#x27;Words and drugs have the same mechanism of action&#x27; (Fabrizio Benedetti)<p>The focus of current approaches to biomedicine and bioengineering are largely bottom-up – via implementation of specific functions by control of the lowest-level components (proteins, DNA sequences, etc.). However, biology uses an integrated, multiscale competency architecture in which higher levels of organization make decisions about the types of system-level outcomes we would like to control – large-scale shape and complex physiological states. The ultimate example of this is in the nervous system, where cognitive states (goals, beliefs, hopes, intentions, etc.) must connect to the functionality of the body. Recent and classic work on biofeedback, mind–body medicine (e.g., gene expression changes in the brain following meditative practices or exposure to music), psychoneuroimmunology, and placebo&#x2F;nocebo effects have clearly shown that physiological and genetic states can be controlled by high-level nodes. It is crucial to note that mind–body control is not some unusual corner case relegated to exceptional circumstances such as hypnotic states. Every time one gets out of bed in the morning to begin a day of tasks, what allows this to happen is a multiscale transduction mechanism that converts executive-level metacognitive intent into depolarization of muscle cell resting potential. Thus, our embodied minds already have the capacity to control complex molecular events and harness them toward adaptive actions without each level knowing the details of the levels below and above it. The work of pioneers such as Fabrizio Benedetti [110–113], who showed that the same mechanisms are activated by drug exposure and by expectation of drug, demonstrate a crucial aspect of our evolved architecture that can be exploited therapeutically. This ability of cognitive states to implement complex downstream changes is not a unique feature of brains – instead, intelligence and distributed control are baked into all somatic cells and tissues, and are potential therapeutic targets. The native bioelectric interface linking complex goals (e.g., grow an organ of the appropriate size and shape) to the molecular implementation machinery opens a transformative possibility that artificial intelligence can serve as a powerful GPS that can guide control of living tissue to navigate transcriptional, physiological, and anatomical landscapes. New advances such as large language models offer the possibility of literally being translators between our minds (and their goals of inducing health) and the primitive intelligence of the body by helping to derive stimuli, training protocols, and experiences as therapeutics that shape the behavior of physiological and anatomical subsystems to increase healthspan. &quot;&quot;&quot;</i><p>from:<p>&quot;Future medicine: from molecular pathways to the collective intelligence of the body ( Eric Lagasse1 ; Michael Levin )&quot;<p><a href="https:&#x2F;&#x2F;www.cell.com&#x2F;trends&#x2F;molecular-medicine&#x2F;fulltext&#x2F;S1471-4914(23)00142-9" rel="nofollow">https:&#x2F;&#x2F;www.cell.com&#x2F;trends&#x2F;molecular-medicine&#x2F;fulltext&#x2F;S147...</a>