Comparative dementia and Parkinson’s disease risk associated with melatonin, benzodiazepine, or zolpidem use in patients with sleep disorders: a retrospective cohort study

Melatonin is widely used for sleep disorders and has been hypothesized to exert neuroprotective effects. However, real-world evidence regarding its long-term association with neurodegenerative outcomes remains limited and may be confounded by prodromal sleep disturbances related to early neurodegenerative disease. We conducted a retrospective target trial emulation using the TriNetX Global Collaborative Network between 2015 and 2024. Adults aged ≥ 50 years with sleep disorders identified using ICD-10-CM diagnostic codes and newly prescribed melatonin, benzodiazepines, or zolpidem were eligible. Medication exposure was defined using prescription records documented in the electronic health record system. Two active-comparator cohorts were constructed: melatonin versus benzodiazepines and melatonin versus zolpidem. Outcomes included incident all-cause dementia (ICD-10-CM F01-F03), vascular dementia (F01), Parkinson's disease (G20), and Alzheimer's disease (G30). Analyses were performed in 1:1 propensity score-matched cohorts adjusted for demographic characteristics, healthcare utilization, body mass index, comorbidities, psychosocial risk factors, and selected comedications. Sensitivity analyses incorporated lag periods, varying follow-up durations, and alternative matching approaches. Among 91,216,302 eligible individuals in the TriNetX Global Collaborative Network, 189,858 matched pairs were included in the melatonin versus benzodiazepine analysis and 190,889 matched pairs in the melatonin versus zolpidem analysis. Median follow-up duration was 1.88 versus 2.88 years in the melatonin versus benzodiazepine cohorts and 2.37 versus 3.70 years in the melatonin versus zolpidem cohorts. Melatonin use was associated with higher observed risk of all-cause dementia compared with benzodiazepines (HR 2.09, 95% CI 2.01-2.16) and zolpidem (HR 1.74, 95% CI 1.67-1.82). Elevated risks were also observed for vascular dementia (HR 2.39, 95% CI 2.21-2.60; HR 1.99, 95% CI 1.81-2.19), Parkinson's disease (HR 1.63, 95% CI 1.51-1.76; HR 1.44, 95% CI 1.33-1.57), and Alzheimer's disease (HR 2.11, 95% CI 1.96-2.26; HR 1.54, 95% CI 1.41-1.67). Across sensitivity analyses, including lag-time analyses up to 4 years, the direction of associations remained consistent. Melatonin initiation was associated with higher observed risks of dementia and Parkinson's disease outcomes compared with benzodiazepine or zolpidem initiation among older adults with sleep disorders. These findings should not be interpreted as evidence of a causal pharmacologic effect of melatonin and may instead reflect residual confounding, confounding by indication, and prodromal neurodegenerative disease.