The placebo effect can be incredibly powerful, performing nearly as well as carefully designed and tested drugs, substituting for actual surgeries and even generating side effects. But it's a tricky thing to apply outside of experiments. After all, not everyone will have a strong placebo response, so it's unethical to use it in place of actual treatments.

Now, some researchers in Germany have figured out a way to harness the placebo effect to increase the impact of a normal drug treatment. The procedure involves getting patients to associate a taste with a powerful drug that has problematic side effects. Once the association is made, the patients were given a mix of normal drugs and a placebo, along with the flavor they'd associated with the drug. This experiment enhanced their response to the drug, providing an avenue to potentially reduce its dose and, thus, its side effects. And the whole thing worked despite the fact that the patients knew exactly what was going on.

The drug at issue, cyclosporine A, is a powerful suppressor of the immune system, which makes it useful for patients who have received organ transplants or who have a strong autoimmune disorder. But the immune system isn't the only system affected by this drug; it also kills off kidney and nerve cells and causes heart problems and hypertension. These effects are independent of any changes to the immune system, but nobody has figured out a way to target the body's response specifically to immune cells. As a result, people taking this drug have to carefully balance its useful features against its toxicity.

But our immune systems are also highly sensitive to mental states like stress and depression, making them good candidates for influence by the placebo effect. There's evidence from rodents that this effect can include suppressing the immune system, so the team behind the work developed a protocol in rodents that could specifically drive immunosuppression through the placebo effect. That work prompted the researchers to test the same procedure in a small population of healthy humans, which indicated it also worked in us. A new paper now describes using the procedure in a population where it matters: people who have to be on immunosuppressive drugs the rest of their lives.

The basic outline of the procedure is pretty simple. For three days, patients who had received a kidney transplant took their normal dose of immunosuppressant drugs accompanied by a novel-tasting drink (the authors don't describe what the drink tastes like, just that the taste is distinctive). For two days after that, they took the same drink/drugs combination, but they additionally took a combo of placebo pills and drink four times a day. During the second day of the placebo treatment, they had blood taken to check on immune function.

It worked. Compared to a control population of people taking only immunosuppressives, the people taking the placebo had reduced signs of immune cell activity (T cell proliferation was down by about 30 percent) and saw a very weak reduction in the expression of an immune signaling molecule called gamma interferon.

Based on the T cell proliferation, it appears that the effect of the immunosuppressant was enhanced by the placebo treatment, even though all the patients knew they were engaging in a placebo-based trial.

The results are even stranger than they sound. In mice, the researchers had figured out that the placebo effect was driven by release of the signaling molecule called noradrenaline. But in these patients, noradrenaline was completely unchanged. Some of the patients also happened to be on common drugs called beta blockers, which inhibit the noradrenaline receptor. The immune response in patients taking beta blockers was indistinguishable from that of patients who weren't using these drugs. So the researchers really have no idea how the trained placebo effect is working in humans.

Beyond questions about the mechanics, there's a lot we'd still want to know before using this as a treatment. We don't know how long this effect would persist or whether there are ways to maintain the placebo effect for something that's a lifetime treatment. We also don't know if this procedure is really a treatment—whether the enhanced effect on immune function is large enough to have any effect on symptoms or if it's safe to reduce the dose of the real drug in placebo-treated patients. Still, the results are promising enough that longer-term trials are clearly called for here.

PNAS, 2018. DOI: 10.1073/pnas.1720548115 (About DOIs).