Researchers have identified a novel mechanism that helps explain the power of the placebo effect as well as its mysterious twin, the nocebo effect.
The new findings, published online in the September 10 issue of the Proceedings of the National Academy of Sciences, demonstrate that the placebo effect can be activated outside of conscious awareness, and provide an explanation for how patients can show clinical improvement even when they receive treatments that don’t contain active ingredients or have little known therapeutic efficacy.
“Weused a novel experimental design and found that placebo and nocebo effects rely on brain mechanisms that are not dependent on cognitive awareness,” said Karin Jensen, HMS research fellow in psychiatry at Massachusetts General Hospital and the Program in Placebo Studies and the Therapeutic Encounter (PiPS) at Beth Israel Deaconess Medical Center, and first author of the paper.
“A person can have a placebo or nocebo response even if he or she is unaware of any suggestion of improvement or anticipation of getting worse," Jensen said.
Researchers have long believed that placebo responses are related to conscious beliefs or thoughts: When given an inert pill or therapy, patients get better because they have the expectation that they will get better. It is the oppositein the case of nocebos,when patients get worse because they anticipate that they will get worse.
More recently, however, scientists have recognized humans’ ability tolearn to expect reward andthreat quickly and automatically,without needing to consciously register the idea in their brains. Neuroimaging studies of the human brain suggestthat certain structures, such as the striatum and the amygdala, can process incoming stimuli before they reach conscious awareness, according to the authors of the study. As a result,these structures may mediate nonconscious effects on human cognition and behavior.
In order to determine whether placebo and nocebo responses might be activated outside of a person’s conscious awareness, Jensen and her collaborators conducted two different experiments in 40 volunteers.In the first experiment, researchers administered heat to the participants’ arms while simultaneously showing them images of faces on a computer screen. The first face was associated with low pain stimulations, the second with high pain. Patients were asked to rate their pain on a scale of 0 to 100, with 0 being no pain and 100 being the worst imaginable pain. The patients didn’t know that all the stimulations had the same moderate heat intensity. As predicted, the results correlated with previously learned associations, with an average pain rating of 19 when the subjects saw the low pain face and a rating of 53 with the high pain face.
In the second experiment, the participants were given the same levels of heat stimulation. Once again, the facial images were projected on the computer screen,but this time, they flashed by tooquickly for the participants to consciously recognize them. The participants once again rated their pain and, despite a lack of consciously recognizable cues, the participants reported a mean pain rating of 25 in response to the low pain face (placebo) and a rating of 44 in response to the high pain face (nocebo), despite not being able to fullyrecognize the faces on the screen.
“Such a mechanism would generally be expected to be more automatic and fundamental to our behavior compared to deliberate judgments and expectations,” said Jian Kong, HMS assistant professor of psychiatry at Mass General and PiPS, and senior author on the paper.
“Most important, this study provides a unique model that allows us to further investigate placebo and nocebo mechanisms by using tools such as neuroimaging," Kong said.
“It’s not what patients think will happen [that influences outcomes], it’s what the nonconscious mind anticipates despite any conscious thoughts,” said Ted Kaptchuk, HMS associate professor of medicine and director of PiPs.
“These findings open an entirely new door toward understanding placebos and the ritual of medicine," Kaptchuk said.
This study was supported, in part, by grants from the Swedish Society for Medical Research and the Swedish Council for Working Life and Social Research and Grants R21AT004497 (National Center for Complementary and Alternative Medicine, NCCAM), R03AT218317 (National Institute on Drug Abuse), and R01AT006364 (NCCAM); K24AT004095 (NCCAM); and R01AT005280 (NCCAM).
Adapted from a Beth Israel Deaconess Medical Center news release. Courtesy Mass General.