Molecular classification of the placebo effect in nausea

PLoS One. 2020 Sep 23;15(9):e0238533. doi: 10.1371/journal.pone.0238533. eCollection 2020.


In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acupuncture Therapy
  • Adult
  • Blood Proteins / analysis*
  • Electric Stimulation Therapy
  • Female
  • Humans
  • Male
  • Motion Sickness / blood
  • Motion Sickness / therapy
  • Nausea / blood*
  • Nausea / therapy*
  • Placebo Effect*
  • Proteomics
  • Young Adult


  • Blood Proteins

Grant support

KM (ME3675/1-1), DFG Research Unit FOR 1328, German Research Foundation, The funder played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.