Most previous studies only used self-reported measures like questionnaires to ask subjects to rate how depressed, anxious, or stressed they feel. These are subjective evaluations, which may be influenced by response bias, in which participants do not accurately report what they are feeling. Instead, Guevarra's team wanted to obtain an objective neural measure about what happens in response to non-deceptive placebos. Again, they recruited 198 healthy college students and gave them the saline spray placebo, with and without deception. This time, while showing the participants the negative pictures, they measured the electrical activity in each person's brain using electroencephalography. EEG measures the electrical signals emitted from the entire brain, as recorded from electrodes stuck to the participant's head.

Specifically, they looked at an indicator of emotional response called the late positive potential (LPP), an increase in electrical activity as a response to an emotional stimulus, such as distressing images. Strategies such as positive reappraisal, in which a person reinterprets a negative experience in a positive manner, can suppress this activity, which has led researchers to believe that LPP can be used to track emotional regulation--in this case, it would show the brain responding less intensely after an upsetting or emotional event.

When the researchers looked at the EEG readings from the two groups, they saw that the magnitude of the LPP of participants in the non-deceptive placebo group was smaller than those that had been deceived, meaning that their brains responded less to the distressing images than the other group. Three seconds after they were shown the distressing image, participants who received the non-deceptive placebo had an LPP amplitude of about 0.5 microvolts, while those that did not had an amplitude of about 3 microvolts. An analysis of this difference revealed that non-deceptive placebos had a moderate effect on the LPP over the control conditions, suggesting that they can modulate and dampen early neural reactions to emotional distress. In other words, the spray worked--even though participants knew it was a fake.

For Guevarra, this was evidence that the effect of the placebos was not response bias, but rather a real change in the brain. "I think it's a genuine psychobiological effect," he says. "The manipulation we have really fine-tunes and leverages people's expectations."

How might this work translate to the real world of mental health treatment? While the idea is still theoretical, Guevarra feels that non-deceptive placebos might be tried for conditions that consistently respond to expectations, such as anxiety, depression, and pain--and for mild to moderate cases. He envisions them being used by therapists as a first, cost-effective step or as co-interventions, given along with established treatments such as antidepressants and cognitive behavioral therapy, a type of talk therapy that has become an important tool in psychology. "Let's give them placebo pills first and see how it goes," he says.

If the placebo doesn't work, then they could move on to other alternatives. "The beauty of this is that it's relatively low-cost and arguably side effect-free," says University of Michigan psychology professor Ethan Kross, the principal investigator on the study.