BackgroundExperimental and observational studies suggest that β-adrenoreceptor drugs (β2-agonists/β-antagonists) are associated with Parkinson's disease (PD) risk. Previous epidemiological studies may be hampered by reverse causation/confounding.ObjectiveWe examined the association of β-adrenoreceptor drugs with PD incidence, while addressing reverse causation and confounding in the E3N cohort study (2004-2018) using a new-user design.MethodsIncident β2-agonists/β-antagonists users were identified through drug claims databases. Incident PD was ascertained using multiple sources and validated by experts. Drugs-PD associations were assessed using time-varying Cox proportional hazards models adjusted for multiple confounders. Main analyses used a 5y-exposure lag to address reverse causation; sensitivity analyses used a 2y-lag or no lag. We set up a nested case-control study to compare trajectories of β2-agonists/β-antagonists prescriptions before diagnosis using logistic mixed models.ResultsAnalyses for β2-agonists were based on 81,890 women; 15,169 started using β2-agonists and 579 developed PD. PD incidence was 36% lower (hazard ratio = 0.64, 95% confidence interval = 0.41-0.98; p-trend = 0.04 for the number of claims) in users of long-acting/ultra-long-acting β2-agonists (LABAs/ultra-LABAs) compared to never users. There was no significant association for β2-agonists overall and short-acting β2-agonists. Analyses for β-antagonists were based on 75,896 women; 13,081 started using β-antagonists and 552 developed PD. PD incidence was similar in ever and never users in analyses with a 5y-lag but was higher in ever than never users in analyses with 2y-lag or no lag.ConclusionsIncident use of LABAs/ultra-LABAs is associated with lower PD incidence in women. Conversely, the association between β-antagonists and PD in women is likely due to reverse causation.