Generalization and enhancement of the effects of an active placebo nasal spray on sadness

Introduction: The placebo effect, i.e., the psychobiological response arising from administering an inert treatment, influences various domains, such as pain perception and emotional regulation. Positive framing might enhance this effect. This study tested whether the effect of an active placebo (mimicking drug side effects to enhance treatment credibility) on is generalized between two different contexts of sadness induction and if positive framing of side effects enhances this effect. Methods: Ninety-six healthy participants were randomly assigned to one of three groups: Placebo+positive framing (PPF), Placebo+standard information (PSI), or no treatment control (NTC). Participants underwent a sadness induction protocol during an in-person lab session and a 20-min online follow-up at home six hours later. Primary outcome was self-reported sadness, secondary outcome was self-reported side effects. Results: Both the PPF and PSI groups showed a significant decrease in sadness compared to the NTC group after placebo administration during the lab session (p < 0.001) and at follow-up (p < 0.05). At follow-up, only the PPF group did not experience a significant increase in sadness. Positive framing did not improve side effect tolerability. Limitations: Self-reported measures introduce subjective bias. The sample restriction to healthy volunteers limits generalizability. The six-hour period may not capture clinically relevant long-term effects. Conclusions: The active placebo nasal spray effectively reduced sadness, with effects persisting for six hours and across different contexts. Positive framing did not enhance side effect tolerability but may have helped maintain effectiveness at follow-up. Further research is needed in clinical populations and to explore long-term effects.