Boosting the Pain-relieving Placebo Effect in The Laboratory

Placebos can make us feel better. Mild electric zaps to the brain can make that effect even stronger, scientists report online May 3 in Proceedings of the National Academy of Sciences. The finding raises the possibility of enhancing the power of expectations to improve treatments. This is the first study to boost placebo and blunt pain-inducing nocebo effects by altering brain activity. The placebo effect arises when someone feels better after taking an inactive substance, like a sugar pill, because they expect the substance to help. The nocebo effect is the placebo’s evil twin: A person feels worse after taking an inactive substance that they expect to have unpleasant effects.

To play with people’s expectations, Kong’s team primed 81 participants for painful heat. The heat was delivered by a thermal stimulator to the forearm while participants lay in a functional MRI scanner. Each person received three creams, each to a different spot on their arms. One cream, participants were told, was a numbing lidocaine cream, one was a regular cream and one was a pain-increasing capsaicin cream. But in fact, all the creams were the same inert lotion, dyed different colors.

Participants reported lower pain intensity from the heat on the “lidocaine” patch of skin, an expected placebo effect. People also reported higher pain intensity on the “capsaicin” skin, an expected nocebo effect. Before testing the placebo and nocebo effects, researchers had delivered electric currents to some participants’ brains with a method called transcranial direct current stimulation, or tDCS. During these tDCS sessions, two electrodes attached to the scalp delivered weak electric current to the brain to change the behavior of brain cells.

Some participants received tDCS targeted at a brain area thought to be important in placebo and nocebo effects, the right dorsolateral prefrontal cortex. Researchers used two types of current: positive anodal tDCS, which typically makes nerve cells more likely to fire off signals, and negative cathodal tDCS, which usually makes cells quieter. Compared with people who didn’t receive tDCS, people who received cathodal tDCS reported stronger placebo effects when heat was applied to the skin with “lidocaine” cream. For people who received anodal tDCS, the stimulation dampened the nocebo effect of the “capsaicin” cream. Brain stimulation affected neural pathways that were already thought to be involved in the placebo and nocebo effects. Cathodal tDCS, for instance, boosted connections between the targeted brain area with a nearby area involved in emotion and cognition. This strengthened pattern correlated with participants reporting a stronger placebo effect, Kong and his colleagues found.

CITATIONS Y. Tu et al. Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability. Proceedings of the National Academy of Sciences. Published online May 3, 2021. doi: 10.1073/pnas.2101273118.