The most important study on the placebo effect is Hróbjartsson and Gøtzsche’s Is The Placebo Powerless?, updated three years later by a systematic review and seven years later with a Cochrane review. All three looked at studies comparing a real drug, a placebo drug, and no drug (by the third, over 200 such studies) – and, in general, found little benefit of the placebo drug over no drug at all. There were some possible minor placebo effects in a few isolated conditions – mostly pain – but overall H&G concluded that the placebo effect was clinically insignificant. Despite a few half-hearted tries, no one has been able to produce much evidence they’re wrong. This is kind of surprising, since everyone has been obsessing over placebos and saying they’re super-important for the past fifty years.

What happened? Probably placebo effects rode on the coattails of a more important issue, regression to the mean. That is, most sick people get better eventually. This is true both for diseases like colds that naturally go away, and for diseases like depression that come in episodes which remit for a few months or years until the next relapse. People go to the doctor during times of extreme crisis, when they’re most sick. So no matter what happens, most of them will probably get better pretty quickly.

In the very old days, nobody thought of this, so all their experiments were hopelessly confounded. Then people started adding placebo groups, this successfully controlled for not just placebo effect but regression to the mean, and so people noticed their studies were much better. They called the whole thing “placebo effect” when in fact there was no way to tell without further study how much was real placebo effect and how much was just regression to the mean. If we believe H&G, it’s pretty much all just regression to the mean, and placebo was a big red herring.

The rare exceptions are pain and a few other minor conditions. From H&G #3:

We found an effect on pain, SMD -0.28 (95% CI -0.36 to -0.19)); nausea, SMD -0.25 (-0.46 to -0.04)), asthma (-0.35 (-0.70 to -0.01)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)). The effect on pain was very variable, also among trials with low risk of bias. Four similarly-designed acupuncture trials conducted by an overlapping group of authors reported large effects (SMD -0.68 (-0.85 to -0.50)) whereas three other pain trials reported low or no effect (SMD -0.13 (-0.28 to 0.03)). The pooled effect on nausea was small, but consistent. The effects on phobia and asthma were very uncertain due to high risk of bias.

So the acupuncture trials seem to do pretty well. This probably isn’t because acupuncture works – some experiments have found sham acupuncture works equally well. It could be because acupuncture researchers have flexible research ethics. But Kamper & Williams speculate that acupuncture does well because it’s an optimized placebo. Normal placebos are just some boring little pill that researchers give because it’s the same shape as whatever they really want to give. Acupuncture – assuming that it doesn’t work – has been tailored over thousands of years to be as effective a pain-relieving placebo as possible. Maybe there’s some deep psychological reason why having needles in your skin intuitively feels like the sort of thing that should alleviate pain.

I want to add my own experience here, which is that occasionally I see extraordinary and obvious cases of the placebo effect. I once had a patient who was shaking from head to toe with anxiety tell me she felt completely better the moment she swallowed a pill, before there was any chance she could have absorbed the minutest fraction of it. You’re going to tell me “Oh, sure, but anxiety’s just in your head anyway” – but anxiety was one of the medical conditions that H&G included in their analysis. Plausibly they studied chronic anxiety, and pills are less good chronically than they are at aborting a specific anxiety attack the first time you take them. Or maybe her anxiety was somehow related to a phobia, one of the conditions H&G find some evidence in support of a placebo for. (Really? Phobia but not anxiety? Whatever.)

Surfing Uncertainty had the the best explanation of the placebo effect I’ve seen. Perceiving the world directly at every moment is too computationally intensive, so instead the brain guesses what the the world is like and uses perception to check and correct its guesses. In a high-bandwidth system like vision, guesses are corrected very quickly and you end up very accurate (except for weird things like ignoring when the word “the” is twice in a row, like it’s been several times in this paragraph already without you noticing). In a low-bandwidth system like pain perception, the original guess plays a pretty big role, with real perception only modulating it to a limited degree (consider phantom limb pain, where the brain guesses that an arm that isn’t there hurts, and nothing can convince it otherwise). Well, if you just saw a truck run over your foot, you have a pretty strong guess that you’re having foot pain. And if you just got a bunch of morphine, you have a pretty strong guess that your pain is better. The real sense-data can modulate it in a Bayesian way, but the sense-data is so noisy that it won’t be weighted highly enough to replace the guess completely.

If this is true, placebo should be strongest in subjective perceptions of conditions sent to the brain through low-bandwidth relays. That covers H&G’s pain and nausea. It doesn’t cover asthma and phobias quite as well, though I wonder if “asthma” is measured as subjective sensation of breathing difficulty.

What about depression? My gut would have told me depressed people respond very well to the placebo effect, but H&G say no.

I think that depressed mood may respond well to the placebo effect on a temporary basis – after all, mood seems noisy and low-bandwidth and hard to be sure of in the same way pain and nausea are. But most studies of depression use tests like the HAM-D, which measure the clinical syndrome of depression – things like sleep disturbance, appetite disturbance, and motor disturbance. These seem a lot less susceptible to subjective changes in the way the brain perceives things, so probably HAM-D based studies will show less placebo effect than just asking patients to subjectively assess their mood.