Supplementary Material for: Experimental approach to inducing anti-histaminergic placebo effects – A randomized controlled trial in healthy volunteers

Introduction: Allergies are an increasingly widespread health problem and prior evidence suggests that psychological factors are involved in their occurrence and alleviation. This study aimed to investigate how placebo treatment can reduce type-I allergic symptoms in a skin prick-test in healthy volunteers. Methods: Healthy volunteers of all genders were included in the study (N = 88) and were randomized into three groups. i) A classically conditioned group receiving the anti-histaminergic drug cetirizine as unconditioned stimuls (US) and a novel gustatory stimulus as conditioned stimulus (CS), ii) a context-control group receiving cetirizine (US) and water as CS and iii) an open-label placebo group. In the spirit of ethical application of placebo, participants were not blinded with regard to the study question. Histamine skin prick-tests were conducted at baseline, after five acquisition trials, before evocation as well as after three and five evocation trials. Self-rated itch and wheal size measurements served as outcome parameters. Results: Itch was significantly reduced after medication and (open) placebo intake. Wheal size was only reduced significantly after medication intake during acquisition. After 9 days of wash-out, itch ratings were lower in participants who had received open-label placebo compared to those who had initially received cetirizine. During the evocation week, the decline in wheal size did not reach statistical significance and there was no significant differential effect of group allocation. Reported expectations of symptom relief at the last visit correlated positively with reductions of wheal size. Conclusion: These results support the theory that treatment expectations correlate with reductions in allergic skin symptoms. Participants of all groups experienced a reduction in itch, while wheal size was only reduced in those participants with high expectations, based on prior experiences and group allocation. Future studies should investigate the underlying neuropsychological mechanisms of these expectation-induced anti-histaminergic effects.