Placebo effect is getting stronger

Wired's Steve Silberman explores the fascinating and increasingly important placebo effect, which appears to be getting stronger:
The upshot is fewer new medicines available to ailing patients and more financial woes for the beleaguered pharmaceutical industry. Last November, a new type of gene therapy for Parkinson's disease, championed by the Michael J. Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn's disease, an intestinal ailment, citing an "unusually high" response to placebo. Two days later, Eli Lilly broke off testing of a much-touted new drug for schizophrenia when volunteers showed double the expected level of placebo response...

Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit. But then Benedetti came across a study, done years earlier, that suggested the placebo effect had a neurological foundation. US scientists had found that a drug called naloxone blocks the pain-relieving power of placebo treatments. The brain produces its own analgesic compounds called opioids, released under conditions of stress, and naloxone blocks the action of these natural painkillers and their synthetic analogs. The study gave Benedetti the lead he needed to pursue his own research while running small clinical trials for drug companies.

Now, after 15 years of experimentation, he has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.

In one study, Benedetti found that Alzheimer's patients with impaired cognitive function get less pain relief from analgesic drugs than normal volunteers do. Using advanced methods of EEG analysis, he discovered that the connections between the patients' prefrontal lobes and their opioid systems had been damaged. Healthy volunteers feel the benefit of medication plus a placebo boost. Patients who are unable to formulate ideas about the future because of cortical deficits, however, feel only the effect of the drug itself. The experiment suggests that because Alzheimer's patients don't get the benefits of anticipating the treatment, they require higher doses of painkillers to experience normal levels of relief.

Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why. (Thanks, Steve!)


  1. Perhaps its a sign of the declining value of critical thought, unbiased observation, and skepticism in the general public? If someone makes a habit of critical thinking, chances are a placebo won’t work as well on them.

    It seems that many of the drugs mentioned in the article treat things like depression, pain, anxiety, lethargy, “hopelessness”, impotence… conditions that are (arguably) “all in the head.” Show me a placebo that works as well as an antibiotic, and I’ll be very impressed!

  2. I wonder if this one would feed on itself for positive effect– once everyone assumes that green pills calm you down, red ones pep you up, etc, etc, do the green and red ones work better?

    Oddly enough, this could be one of the positive sides of drug advertisements- convincing the consumer that the drug works better in a remotely ethical way.

  3. @5- It could just be a locus of control issue. You get one message that says “Pills can change how your brain works”, the doctor says “Here’s a pill that’ll make you happy/calm/sleepy/wakeful” and aha! It happens.

    How strange that we don’t train children to alter how they think and feel to best suit their own health and happiness.

    “I feel sad.”
    “Do you want to feel sad?”
    “Then stop.”

  4. When people criticise and ridicule others for believing that homeopathy and the placebo effect, as though those things are somehow unreal and unworthy of study, I think of the thousands of people made worse or killed by allopathic medicine.

    It’s also instructive to remember that very many of the thins which go wrong with people are caused within the body – allergic reactions, immunity disruptions, auto-immune diseases are caused by the body’s reactions to its environment. Is it so hard to believe that the body may also be able to cure the things it can cause?

  5. I agree with Fee. What we really need is a second placebo-control group in the studies that is aware they are taking the placebo.

    If a sugar pill creates a statistically significant effect, why would we not utilize that as a treatment?

  6. @#9- Meaningless to think of the people killed or sickened by allopathic medicine unless you can contrast it with the number killed or made worse by homeopathy. Or, rather, by the diseases which homeopathy didn’t actually treat.

    Since data on the latter are scanty, it’s meaningless to claim that homeopathy is safer. However, since data on efficacy of homeopathy are also scanty, we also can’t say its effective, either.

    Consider how this equivalent statement would sound: “When people denigrate using crystal balls to predict lottery numbers, I think of the thousands of people who lost money investing in the stock market.”

  7. cicada @ 8 – sounds rather like my childhood.

    cicada @ 11 – I sort of do think that. Many of the people who have invested in the stock market (or in tulip bulbs, for that matter) were conned using the same woo psychics (or homeopaths, or CEO’s) use.

  8. Great article, but it missed the possibility that pharma nudged test results in the past to make placebos appear not as good as the drugs. And now that testing is becoming more controlled, transparent, and rigorous, they can’t cheat as much.

    Personally, I take several vitamins every day mostly for the placebo effect. Taking several pills is better than just a single multivitamin.

  9. @12 On the other hand, we can compare the efficacy of lottery tickets and the stock market. Quantitative analysis is important here– of course in both you can either lose money, make money, or keep about the same amount of money. In the one, however, you’re going to lose money almost all of the time, and in the other you stand a pretty good chance of making some.
    This is why we have (for medicine) things like comparative trials to sort out the more effective from the less.

  10. Just where does this article show any evidence of the placebo effect getting stronger or propose a mechanism for such an effect?

    This seems like rather feeble special pleading and post hoc moving of goal posts to me worryingly similar to that frequently used by CAM proponents.

    It also fails to recognize the blindingly obvious. If the methodology of the research was sound then the size of the placebo response should be equal in both test arms. The only variation would have come from from any active ingredient in the drug under test. It’s also factually inaccurate, Placebo treatment is considerably older the WWII, having been written about for hundreds of years.

    I’m afraid the reporting at Wired is increasingly becoming sloppy and inaccurate concentrating on the sensation over the story (witness their iPhone’s in Japan story). Plus their layout is entirely style over legibility… I must be getting old…

  11. @9 Homeopathy is not ridiculed so much because it doesn’t work (which it probably does through a placebo action) but because its promoted by people that have no idea how it works, why it works, and indeed, how it compares to a placebo (the answer to all those questions is “it is a placebo”).

    Yes, there are studies that show that.

  12. Also @9 The concern people have about CAM therapies is that they carry what is known as an ‘opportunity cost’ with them. I.e. while you are quaffing vibrated water or sugar pills you may or may not feel better but the underlying cause of your symptoms has diagnosed .

    If you are suffering from a self-limiting condition such as lower back pain you will tend to seek treatment when you are at your worst, there is then a ‘regression to the mean’, i.e. you can’t stay as bad as that for ever. If you consultant an acupuncturist or homeopath during this regression of your symptoms you will tend to disproportionately attribute your improvement to their ministrations.

    But if your condition is a more sinister pathological one then being confidently treated by a CAM therapist may make you feel better, however your condition may be progressing during this time making it harder to treat when it is diagnosed. You have therefore lost your opportunity to get better faster and more effectively and paid for the privilege of doing so…

  13. Don’t know what happened to the end of the 1st paragraph. Should have read:

    …symptoms has not been diagnosed by a qualified medical professional.

  14. @ NOSEHAT:

    The moment neurotransmitters begin working as an antibiotic you’ll get your placebo pill for it. Expect to wait.

    “If someone makes a habit of critical thinking, chances are a placebo won’t work as well on them.”

    Current publications suggest that patients with greater neuro-availability of dopamine and mu-opioids respond the best to placebos. AFAIK there are no proven correlations between those and (in)capacity for critical thought.

  15. @Audiotherapist
    That is predicated on the assumption that the conventional medical attempt is benign, or at least more benign than the the CAM and has been vetted by hopefully strong research. Also that the MD will catch a disease the average CAM doctor/provider will not.

    NSAIDs are a common medical treatment with little evidence for efficacy vs. watchful waiting for resolving underlying pain syndromes. Toxicity is well noted:

    If the patient also has renal or hepatic disease, the risk of these is elevated.

    Adverse effects of non-herbal CAM such as chiropractic or acupuncture are less frequent.

    Treating non-self limiting back pain that has been ineffectively treated by medication, including opiates, is my day job. Often it’s progressed while being “treated” (pharmaceutically) by the medical professional, while they delay referring to a PT or a chiropractor who actually can do something about the underlying cause of the condition.

  16. I wonder if possibly what they’re seeing is placebo vs. placebo — the fake cure working remarkably well against the fake symptoms?

    When you’re already selling as many pills as possible to people who are actualy sick, the only recourse is to create more sick people. The pharma industry has worked very hard to convince us that EVERYTHING is a pathology. Upset stomach? Do a quick Google search, and a lot of people will become convinced it’s Crohn’s Disease.

    So I’m not too surprised that they’re finding the psychological effects of their marketing are no match for the pyschological AND physical effects of placebo.

    Serves ’em right.

  17. @Nosehat @2
    There’s an unintentional irony to your last sentence. The desire for the “magic pill” has lead to the overprescribing of antibiotics, including for conditions which some studies state they’re only as effective as placebo (sinusitis, otitis media, most RTI’s). Due to antibiotic resistance, antibiotics are in many cases now only placebos.

  18. @Snig. I’ll take the self-correcting progressive research based model of conventional medicine employing the scientific method of inquiry over the magical thinking of D.D. Palmer & sons any day.

    Conventional medicine may make mistakes but it attempts to learn from them in a systematic and responsible way through international projects such as the Cochrane Collaboration.

    There have been no shortage of cases of permanent injury from CAM treatments, including Chiropracty. Unfortunately because of their disparate and informal nature this data is not collected in a systematic, centralized and responsible manner. This makes CAM treatments even more of a gamble for the end user.

    Your nonsensical scaremongering over NSAID’s is typical of the FUD statements made by CAM practitioners. I assure that information is well understood by medical practitioners who may be expected to know a wee bit more than Wikipedia on the subject…

  19. By the by, what on earth do you think you mean when you say ‘the assumption that the conventional medical attempt is benign, or at least more benign than the the CAM and has been vetted by hopefully strong research. Also that the MD will catch a disease the average CAM doctor/provider will not’?

    On what freaky bizarre conspiratorial plane do you exist where you would believe that the intentions of those practicing conventional medicine are NOT benign?

    And yes, without any question whatsoever there is copious proof that conventional medicine is better vetted and researched than CAM. There is the gloriously recent example of the British Chiropractic Association’s ‘Plethora’ of research in the Simon Singh case which turned out to cherry picked poor quality nonsense of the first order when they were finally forced to release it.

    I think that there is little to no chance that a CAM practitioner is capable of diagnosing disease better than a qualified medical doctor. That is a delusional belief on your part I’m afraid…

  20. Sounds like they need to market Placebatraxâ„¢. I guess the problem is it’s basically fraud in the eyes of the FDA if you don’t disclose that it’s a neutral substance, yet if you tell the patient, it won’t work. Catch-22.

    The list of side effects would go on for hours, though, since it’s been compared so much with other medicines..

    I guess the real problem here is nobody can patent it other than exclusive flavor formulas for “icky tasting medicine”.

  21. I always speculated that placebo counteracted stress. Like, you hurt yourself and the process of worrying about it makes you stressed, so the doctor gives you a “Plac E Bo” prescription, you go to the pharmacy and get it filled, and then you feel less stressed. I think there have been studies showing that it’s easier to recover from illness if you’re not stressed. Kind of like those people that practice alternative medicine.

  22. OK here’s the last word on the subject!

    That Mitchell and Webb Look: Homeopathic A&E


    TV Medical Drama – the funniest by far!

  23. Audiotherapist @ #16

    “Just where does this article show any evidence of the placebo effect getting stronger or propose a mechanism for such an effect?”

    Did you actually read the article? It pretty clearly stated that older drugs which had done well against placebo in past clinical trials were doing worse and worse against placebo in newer repeated trials.

    Now, this could be interpreted in other ways (as somebody else pointed out, it could be older trials were less rigorous, but 1 – we’re not talking about that long ago, a couple decades and 2- this apparently shows up in big secretive internal data sets, not just the stuff they have to show the FDA). But unless the active ingredients have stopped working, it seems a reasonable interpretation especially given how sensitive the placebo effect is to psychological factors.

    “If the methodology of the research was sound then the size of the placebo response should be equal in both test arms. The only variation would have come from from any active ingredient in the drug under test.”

    Now you’re really missing the point. Yes, if all conditions were exactly equal, then presumably any variance would come from the active ingredient. However, one of those conditions to be considered is the cultural background and expectations of the patient. As the article points out, the same test done in different states and countries can yield different placebo strengths. Different colored placebo pills yield different strengths (and there is some cultural dependence on the color-response as well).

    So, is it really better to only use people from one location with one cultural background and one mindset? What if a drug works better than placebo in Texas but not New York, does it still go to market?

  24. The idea of Placebos upsets my emotionally charged belief in conventional reality and the non-existence of magic.


  25. Hi there Anonymous, nice of you to step up!

    Thank you, I am capable of reading an article from beginning to end and understanding its content.

    Evidence based medicine really only started gaining serious traction in 1988 so a couple of decades is pretty important in terms of research design and critical appraisal.

    You are reaching now to the point of idiocy. Cultural factors can indeed alter placebo response but they won’t alter human physiology. Within the context of the trial and its location those effects will be nullified by good experimental design. Once again only the effects of the active ingredient should register.

    What point precisely is it that you are stumbling over making?

  26. #12 and #17 are on the right track – it’s not the placebo effect that is changing, it is the methodology that is changing, and the drugs that are being brought to phase III.
    The author doesn’t mention:
    1.Several decades ago, companies were allowed to say that some trials had “anomalously” high placebo or background rates, and keep them out of their FDA application – that’s how Prozac was approved. These days companies have to publicly register all their trials at the start; there is also less room for companies to creatively (mis)interpret the results of the study – changing endpoints, dropping inconvenient data sets, etc., than there was in the past.

    2. There is more pressure these days within the front offices of pharma companies to advance drug candidates to phase II and III, even when the researcher think the candidates are failures. It doesn’t matter if you’re a mortgage banker or a pharma VP, if your incentive is your year end bonus rather than options that won’t vest for 5 years, you will make decisions with short term rather than long term success in mind. Your bonus will be jack- $#!# if you let all of your candidates die in phase I this year and you’re paying your phase II-III R&D staff to sit on their thumbs til you lay them off. Much better to look busy.

  27. I wonder, if you give a sample of patients a pill that will make them sick, and another sample a sugar pill, and you tell both groups that the pill will make them better, what percentage of the group taking the pill that makes them sick will report they are getting better and will that differ from the sugar pill group?

  28. It’s an unethical false dichotomy with utterly predictable results and an inadequate control

  29. Audiotherapist @ #34

    Maybe you are capable of reading and understanding an article, but you still seemed to have missed one important fact – the placebo effect does affect physiology. Hell, as the article points out there are drugs that can block placebo pain relief.

    Now, I assume your point is that if we have Response(placebo) + Response(drug), we can independently measure Response(placebo), subtract it out, and voila see what Response(drug) is no matter the cultural variance in size of Response(placebo).

    A) This assumes Response(placebo) and Response(drug) are both independent and additive properties. As the placebo-pain-relief-blocking drug shows, they are not necessarily independent. Furthermore, it should hardly be surprising that many biological systems are not strictly additive in the sense they do not obey Response(x+y) = Response(x) + Response(y).

    B) Even if they are independent and additive, you still run into problems with statistical significance. If we regard the placebo effect as noise, then many genuine treatments don’t have great signal to noise ratios. Is it wrong to try to work with populations that don’t have high placebo responses so as to make it easier to prove statistical significance?

  30. @29- They sort of beat you to that idea. Back in the day before the web showed how all the tricks work and when defrauding a patient was a little cooler, your doc might prescribe some Obecalp for you if you kept complaining with no verifiable cause. Obecalp came in several colors (specified by the prescriber), was fairly cheap, and thoroughly guaranteed by physician and pharmacist to be effective. I imagine it often was.

    Now, as to the ethical considerations of giving someone a capsule full of lactose to get them to go away…well, we see why we don’t use much Obecalp anymore. Oh, and people now generally want to know what drug they’re taking, and the pharmacist is generally obliged to tell them. Lets the cat right out of the bag.

  31. Mr Anonymouse,

    At no point did I suggest there was no physiological response to placebo, you’re just making stuff up now aren’t you?

    You’re not making any sense at all re statistical significance, I wonder if you have studied statistics at all? If a result fails to be statistically significant it means that that result could be purely a result of chance, i.e. NOT REAL!

    Clearly you are a supporter of poorly evidenced alternative special magic cures with an axe to grind. Again I ask – what point are you trying to make?

  32. Audiotherapist @ #40

    “At no point did I suggest there was no physiological response to placebo”

    “Cultural factors can indeed alter placebo response but they won’t alter human physiology.”

    IF ([placebo affects physiology] AND [culture affects placebo]) THEN culture can affect physiology.

    Yes I’ve studied statistics, and yes I know what it means if a result fails to be statistically significant. You seem to have made up your mind on what I believe and are coloring all your responses in that light.

    “Clearly you are a supporter of poorly evidenced alternative special magic cures”

    However, what is clear to you is laughably wrong. I am an athiest physicist who doesn’t believe in homeopathy, chakras, crystals, whatever. My issue is with the way you so casually dismiss article.

    Yeah, sure big pharma is greedy, and that always taints things, but that doesn’t mean nothing’s going on. Gosh, they were even willing to share data with each other!

    Now if you can show what specific mistakes the particular studies they mentioned showing statistically significant effects from Valium in France but not in the USA, then I’ll be interested. Until then I’ll find it interesting if not conclusive.

  33. Audiotherapist:
    “Benign” indicates effect, it does not signify intent. Many well-meaning researchers developed and well meaning doctors prescribed medications only to find out later there were previously unknown toxic effects. NSAIDS are generally recognized to be less benign by the medical profession and in responsible quarters are generally being less utilized. Cox II inhibitors as a class of medications were thought to be initially relatively benign, now we recognize they did cary unknown risks. Oxycontin was recognized as dangerous, for some patients the danger was greater than expected. There was no easy way of finding this information out, and I don’t blame anyone for it. Much of this happened since 1988,when you state EBM was born. I’m not happy about the toxicity. I saw a few patients who felt Vioxx or Celebrex changed their life, only to have chronic pain return when they went off it after more substantial health risks were revealed. Misery does not make me happy. I would like CAM and conventional medicine to be more evidence based.

    Also, I think there are definitely patients who use all the medications above, including Oxycontin, who’s quality of life is enhanced. I used wiki for it’s relative neutrality, not as a cudgel to bash medicine. There are websites equally as biased the other way as the one you represented, but I don’t cite as I don’t have an axe to grind with medicine. I work with/talk with/refer patients to MD’s daily. I like good good conventional medicine. What I don’t like is your tone. To assume all conventional is good (now that EBM has been around since 1988) and all CAM is rubbish is naive.

    Malpractice rates are an indication of risk. Actuaries do centrally measure injury and risk. My malpractice cost about $1000. For many MD’s, it costs generally ten times that, sometimes more. It’s not because actuaries think I’m pretty.

  34. So, basicly, all those flaky people who believe that the mind has some power to heal the body?

    Not so flaky.

  35. Might it just be increased exposure to information?

    Now, someone who gets diagnosed with a serious disease can very easily spend time researching various gene therapies and “promising new treatments” that are in development via the web, whereas up until qutie recently that information was difficult to get hold of.

    Might I suggest that the sort of people who are likely to volunteer for clinical trials are also the sort of people who are more likely to be searching actively for a wonder drug that will help them, and that the internet and new media in general provide an easy way to do that?

    “Well, I know p&g and Smithkline are researching new treatments for my disease and their quarterly reports called them “very promising”; now Glaxxo are inviting me for a clinical trial! I bet it’s the same thing!”

  36. All I know is if I am brought into hospital unconscious I would prefer them not to treat me with drugs that rely on the placebo effect.

  37. @Audiotherapist:

    Thank you for linking “what’s the harm” website. I always suspected that chiropractic hurt far fewer people than so-called conventional medicine, nice to see some evidence (admittedly not rigorous) bearing that out. Chiropractic for the win!

    It is interesting to see that the site includes totally fraudulent criminal activity (people using methods that have nothing to do with spinal manipulation, like the chiropractor that poisoned a woman and was convicted of murder) with their information. Still, inflating the figures that way allows for a nice margin of error and clearly shows the bias of the site owners, both of which are good things.

  38. Blimy again. Hard to know which Anonymous I’m dealing with here so I think I’ll give it up as a bad job.

    Just to clarify though… SNIG – I make no such assumption about conventional medicine. What I feel is significantly different is that conventional medicine submits it’s theories to the rigours of the scientific method and changes its practice when findings indicate that it should. CAM modalities as a whole tend to crow loudly about marginally positive or borderline findings and have an enormous blind spot when results are in the negative. They then whinge, as the King’s Fund in Britain have just done, that the scientific method JUST AIN’T FAIR for them and they should have nice special tests that only show positive results. And SNIG, it’s just that aversion to a critical tone that undermines your skeptical credentials…

    Anon 47 you must be high on homeopathic crack if you pulled that information from that site, there is absolutely no data to support your clearly biased assertion.

    Denial’s not just a river in Egypt for you, clearly…

  39. Here’s a theory:
    Suppose that beyond the 5 external senses (sight, hearing, etc), the mind also has many internal senses. Suppose that one of them is the ability to sense when an organism is taking actions that it believes are beneficial to its own well-being (regardless of whether those actions are effective).

    Wouldn’t it make evolutionary sense that it could stimulate other bodily defenses that aren’t normally under direct conscious control? That would give an evolutionary boost to individuals in that species who look out for their own well-being and would more quickly weed out individuals whose mental makeup doesn’t drive them to “take care of themselves”.

    Just a thought.

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