To Ask or Not to Ask: Does Inquiring About Participants' Expectations Influence the Placebo Effect? A Placebo Mechanism Study in Healthy Volunteers.

BACKGROUND: Expectations are considered a key mechanism in placebo effects, yet the impact of assessing expectations on placebo responding remains unknown. This placebo mechanism study examined whether assessing participants' expectations influenced placebo effect magnitude. METHODS: Sixty-four healthy participants were exposed to individually calibrated heat pain during conditioning with verbal suggestions and during two test conditions: application of an inert cream described as analgesic (placebo) and no cream (no-treatment). Participants were randomised to rate expected pain before stimulation (Group 1: expectations assessed) or not (Group 2: expectations not assessed). All participants rated perceived pain during testing and completed a brief interview on expectations at study end. RESULTS: Overall, pain intensity and unpleasantness were significantly lower in the placebo than in the no-treatment condition (both p < 0.001, d = 0.42-0.45). Group 1 showed significant medium-sized placebo effects for both outcomes (both p < 0.001, d = 0.51-0.57), whereas Group 2 showed small effects (intensity, p = 0.052, d = 0.32; unpleasantness, p = 0.017, d = 0.35). However, no significant between-group differences were observed in placebo effect magnitude. Expectations significantly predicted placebo effects in Group 1 (p ≤ 0.010). Retrospective reports indicated predominantly positive expectations, with no or negative expectations slightly more prevalent in Group 1. CONCLUSIONS: These findings call for further investigation of the extent to which inquiring about participants' expectations influences the magnitude of placebo effects. They also highlight the importance of bridging placebo mechanism research and clinical trial methodology to better understand how psychological factors influence trial outcomes. SIGNIFICANCE STATEMENT: This study addresses an unresolved methodological question in placebo research: whether assessing participants' expectations may itself influence placebo responding. Using an experimental placebo analgesia paradigm, it shows that assessing expectations may, to some extent, influence placebo effect magnitude, although no significant differences were observed between participants assessing expectations and those not assessing expectations. Further research is needed to determine the extent of this influence, with potential methodological implications for the design and interpretation of placebo mechanism studies and clinical trials.