The effects of nicotine on Parkinson's disease: A systematic review and meta-analysis of experimental evidence

Background and Aims: The relationship between nicotine exposure and Parkinson's disease (PD) remains controversial. Experimental studies, particularly preclinical trials in animal models, suggest that nicotine may exert neuroprotective effects. However, these findings have not been adequately validated in randomized controlled trials (RCTs) involving humans. This systematic review and meta-analysis aimed to evaluate experimental evidence on whether nicotine exposure exerts neuroprotective or neurodegenerative effects in PD. Methods: Comprehensive searches of PubMed, Web of Science, Scopus, and Google Scholar identified 1363 studies, of which 13 met the inclusion criteria. Random-effects meta-analysis was conducted using RevMan 5.4 and R 4.1.1. Heterogeneity was assessed using the I² statistic, publication bias using funnel plots and Egger's test, and study quality using SYRCLE and ToxRTool criteria. The review followed PRISMA guidelines and was registered in PROSPERO (CRD420250633808). Results: The findings of our study showed that nicotine significantly reduced apoptosis (RR, 0.49; 95 % CI, 0.34-0.71), oxidative stress (RR, 0.55; 95 % CI, 0.41-0.73), and neuroinflammation (RR, 0.62; 95 % CI, 0.49-0.79), while enhancing dopaminergic neuron survival (RR, 1.67; 95 % CI, 1.35-2.06), and mitochondrial function (RR, 1.55; 95 % CI, 1.12-2.14). The only human randomized trial showed no clinical benefit (RR, 1.00; 95 % CI, 0.84-1.49). Subgroup and meta-regression analyses identified study design, dose, duration, and model type as sources of heterogeneity. Conclusion: Experimental evidence suggested that nicotine exposure confers neuroprotection against PD; however, clinical efficacy remains unproven. These findings highlighted the need for well-designed RCTs to confirm if preclinical neuroprotective effects translate into clinical benefits in humans.