The impact of pharmaceutical form and simulated side effects in an open-label-placebo RCT for improving psychological distress in highly stressed students

Abstract

Open-label placebo (OLP) may be utilized to reduce psychological distress. Yet, potential contextual effects have not been explored. We investigated the impact of pharmaceutical form and the simulation of side effects in a parallel group RCT (DRKS00030987). A sample of 177 highly stressed university students at risk of depression were randomly assigned by computer generated tables to a 1-week intervention with active or passive OLP nasal spray or passive OLP capsule or a no-treatment control group. After the intervention, groups differed significantly in depressive symptoms but not regarding other outcomes of psychological distress (stress, anxiety, sleep quality, somatization), well-being or treatment expectation. OLP groups benefitted significantly more compared to the no-treatment control group (d = .40), OLP nasal spray groups significantly more than the OLP capsule group (d = .40) and the active OLP group significantly more than the passive OLP groups (d = .42). Interestingly, before intervention, most participants, regardless of group assignment, believed that the OLP capsule would be most beneficial. The effectiveness of OLP treatments seems to be highly influenced by the symptom focus conveyed by the OLP rationale. Moreover, pharmaceutical form and simulation of side effects may modulate efficacy, while explicit treatment expectation seems to play a minor role.

Working with patients’ treatment expectations – what we can learn from homeopathy

“…In most OLP studies, this rationale contains information about (1) the effectiveness of placebos, (2) possible mechanisms (i.e., classical conditioning), (3) the role of expectations, and (4) the need to take the pills faithfully, and is provided interactively in the context of an empathic and supportive patient-provider interaction. Several recent RCTs suggest that OLP can effectively improve symptoms in patients suffering from irritable bowel syndrome ( Kaptchuk et al, 2010 ), major depressive disorder ( Kelley et al, 2012 ; Nitzan et al, 2020 ), allergic rhinitis ( Schaefer et al, 2016 , 2018 ), chronic lower back pain ( Carvalho et al, 2016 ; Kleine-Borgmann et al, 2019 ), cancer-related fatigue ( Hoenemeyer et al, 2018 ; Zhou et al, 2018 ), and psychological well-being in stressed students ( Kleine-Borgmann et al, 2021 ; Winkler et al, 2023 ). A recent meta-analysis of 11 OLP studies found a large positive effect size for symptom reduction across different pathologies in OLP groups compared to untreated controls ( von Wernsdorff et al, 2021 ).…”