Nowadays, the testing of new drugs often involves comparisons not only with placebos but also with older established drugs in three-way double-blind tests. What is emerging from these trials is that the placebo effect seems to be getting stronger, which means that new drugs in clinical trials are having a harder time showing that they are better than the placebo. Another consequence of stronger placebo responses is that some well-known drugs used is the trials as the older standard (and that had beaten the placebo in earlier tests) seem not to be able to do so now.

As Steve Silberman in Wired Magazine says:

Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late ’90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.

It’s not that the old meds are getting weaker, drug developers say. It’s as if the placebo effect is somehow getting stronger.

But why would the sugar pill placebos be having a stronger effect now? One possibility is that we are getting better at doing double-blind tests, thus eliminating spurious effects that escaped detection earlier. For example it is found that certain assumptions used in drug testing (that geography does not matter) are now found to be not valid. Not only does the placebo response of the patient vary from place to place, so do the ratings by trial observers, leading to the unfortunate possibility that drug companies may ‘placebo-shop’, choosing for their clinical tests those areas where the placebo response is low in order to have their drugs seem more effective.

But the more interesting thing that Silberman points out is that the rising strength of the placebo response may be telling us something valuable about the power of the brain to influence our biochemical processes. The placebo effect may be more of a physiological response than a psychological one, and something that can be harnessed in favor of better treatments. Many of these effects are related to pain-reducing compounds called opiods that are produced by the brain. Placebos can act like catalysts, triggering the release of these opiods.

Researcher Fabrizio Benedetti at the University of Turin finds that:

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.

What seems to be going on is that our expectations of what the future will be like seem to play a significant role in how our brain influences our body. If we feel that a good result will ensue from a treatment, the brain releases chemicals that assist in creating that result. What placebos seem to be doing is manipulating those expectations.

It also works in reverse. There are things called ‘nocebos’ that work opposite to placebos, suppressing the beneficial brain functioning. “Cancer patients undergoing rounds of chemotherapy often suffer from debilitating nocebo effects—such as anticipatory nausea—conditioned by their past experiences with the drugs.”

This has led to a revision in attitudes towards placebos, shifting them from a problem to be overcome to viewing them as an additional form of treatment that should be better harnessed. Of course, there are limits to what placebos and the brain can do. As Silberman says, a placebo “can ease the discomfort of chemotherapy, but it won’t stop the growth of tumors.”

The success of modern medicine in treating many ailments may have strengthened the placebo effect by instilling greater confidence in patients that their treatment will work, triggering the release of opiods and dopamine. Furthermore, drug companies also advertise heavily these days, promoting the benefits of their products to relieve all manner of ailments and associating taking it with good things in life, such as beautiful sunsets, playing with children, enjoying the outdoors, sex, sports, etc. So placebos may be getting stronger because people believe that the drugs will give them a better future.

As a result, the very success of drugs in the past may be working against the drug companies now by increasing the expectations of drugs and thus creating a stronger placebo response. Furthermore,

Existing tests also may not be appropriate for diagnosing disorders like social anxiety and premenstrual dysphoria—the very types of chronic, fuzzily defined conditions that the drug industry started targeting in the ’90s, when the placebo problem began escalating. The neurological foundation of these illnesses is still being debated, making it even harder for drug companies to come up with effective treatments.

What all of these disorders have in common, however, is that they engage the higher cortical centers that generate beliefs and expectations, interpret social cues, and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson’s, and many other ailments that respond robustly to placebo treatment. To avoid investing in failure, researchers say, pharmaceutical companies will need to adopt new ways of vetting drugs that route around the brain’s own centralized network for healing.

It seems like there need to be developments in two areas. One is to find better ways to test for the true effectiveness of drugs that go even beyond the current double-blind testing. What may be necessary is to incorporate ‘open/hidden’ tests where the test subjects don’t know when they being given any treatment at all, whether it be placebo or drug. This will remove the placebo effect of expectations, giving a better measure for the effectiveness of the drugs.

The second development is to learn how to better use the brain-based nature of the placebo response as part of therapy. A judicious combination of truly effective drugs and the placebo response may be an important part of the future of medicine.

POST SCRIPT: This Modern World

Tom Tomorrow’s comic strip imagines how the health insurance industry would have operated in medieval times if it behaved the way it does now.