Pharmacological treatments of REM sleep behaviour disorder in synucleinopathies: a systematic review of effectiveness and safety.

PURPOSE: the aim of this study was to systematically evaluate the effectiveness and safety of pharmacological treatments for REM sleep behaviour disorder (RBD) in synucleinopathies, including Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and isolated RBD (iRBD) as a prodromal synucleinopathy. METHODS: a systematic review was conducted as per PRISMA guidelines. MEDLINE/PubMed, Embase, and the Cochrane Library were searched from inception to 1 March 2026. Eligible studies included randomised, crossover, open-label, and observational studies evaluating pharmacological interventions for RBD in synucleinopathies. Only studies with video-polysomnography (vPSG) confirmed RBD were included. Risk of bias was assessed using RoB 2 and the Newcastle-Ottawa Scale. Due to heterogeneity in study design, interventions, and outcomes, results were synthesised narratively. PROSPERO registration: CRD420261340322. RESULTS: 18 studies met inclusion criteria. The most frequently evaluated treatments were clonazepam, melatonin, and pramipexole; other agents included cannabidiol, nelotanserin, ramelteon, rivastigmine, rotigotine, sodium oxybate, safinamide, and 5-hydroxytryptophan. Subjective clinical improvement was reported more often than objective vPSG improvement. Clonazepam and melatonin remain the principal treatments in practice, but evidence was limited and inconsistent. Clonazepam showed possible benefit but raised important safety concerns in vulnerable synucleinopathy populations. Melatonin appeared better tolerated, but efficacy was inconsistent across synucleinopathy phenotypes and current evidence remains insufficient for definitive subgroup conclusions. Evidence for other agents was preliminary. CONCLUSION: pharmacological treatment of synucleinopathy-associated RBD remains supported by limited and heterogeneous evidence. Larger randomised trials using standardised clinical and vPSG outcomes are needed to clarify efficacy and safety.