BACKGROUND: Multiple System Atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disease, with no effective treatment. Estimating the placebo and nocebo responses will help better design and interpret clinical trials. Objective: To estimate the placebo and nocebo responses in MSA and explore their determinants. METHODS: Electronic databases were searched up to November 2020. Randomized, blinded, placebo- or sham-controlled trials of patients with MSA were included if quantitative data were extractable on the placebo arm. The primary outcomes were: placebo response, defined as the within-group change from baseline, using any scale measuring motor outcomes; and nocebo response, defined as the proportion of patients experiencing adverse effects in the placebo arm. Random-effects meta-analyses were used to pool data. Several predetermined subgroup analyses and metaregressions were performed. PROSPERO registration number: CRD42021222915. RESULTS: We included 21 randomized controlled trials (614 participants). Pooled placebo response was an increase in the Unified MSA Rating Scale (UMSARS) parts I and II of 9.09 points (95% CI 7.78 to 10.31, I2=94.00%, 9 studies, 304 participants). Pooled nocebo response was 63,88% (CI 95% 41.15 to 84.05, I2 =93.03%, 13 studies, 331 participants). Both placebo and nocebo responses were greater in trials with longer duration, whereas nocebo response was also higher in studies testing pharmacological interventions when compared with non-pharmacological interventions. CONCLUSIONS: There may be a favorable response associated with the placebo, but this data needs to be compared with a 'no treatment group' in order to validate its real impact. The nocebo response is high and should be considered in future clinical trial design and interpretation.

The authors have declared no competing interest.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All the information was available trought screening of medical articles available on PubMed.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript