Trait Neuroticism and the Nocebo Effect: The Mediating Role of Side-Effect Expectations

Neuroticism has not only been linked to heightened negative expectations and general somatic complaints but also to increased nocebo responses following medical treatments. Since side-effect expectations are considered a main driver of nocebo responses, we tested whether side-effect expectations mediate the neuroticism-nocebo relationship in a pharmacological study of healthy individuals.

Participants (N = 275) provided self-reported neuroticism and pretreatment side-effect expectations before completing a 2 × 2 factorial design, receiving a placebo or the dopamine antagonist sulpiride (400 mg), which typically does not cause noticeable side effects after a single dose. Regardless of substance, participants received a substance vs. placebo expectation manipulation. We assessed self-reported somatic symptoms at baseline and during the intervention.

Neuroticism correlated with baseline somatic symptoms and with preintervention side-effect expectations. Both neuroticism and side-effect expectations, but not the pharmacological treatment or the explicit expectation manipulation, were associated with nocebo responses, defined as the relative increase in somatic symptoms from before to after the intervention. Crucially, path analyses indicated preintervention expectations partially mediated the neuroticism-nocebo link.

These results suggest that negative expectations associated with neuroticism contribute to nocebo responses, potentially creating a feedback loop whereby negative expectations heighten side effects, reinforcing negative expectations in future treatments.