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

Abstract

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. ab0010 Graphical abstract This infographic summarizes mechanistic findings from a systematic review and meta-analysis of nicotine’s effects in experimental PD models. Nicotine’s chemical structure highlights key functional groups mediating binding to nicotinic acetylcholine receptors (nAChRs). In vitro studies in SH-SY5Y cells show nicotine prevents salsolinol-induced apoptosis via α3 nAChR activation. In vivo models, including C. elegans, rodents, and primates, demonstrate neuroprotection of dopaminergic neurons, reduced α-synuclein aggregation, and improved motor function through pathways such as JNK/ERK and DAF-16/SOD-3. Hybrid studies reveal suppression of endoplasmic reticulum stress, modulation of microglial activation, and inhibition of proinflammatory cytokines via α7 nAChR signaling. A randomized clinical trial of transdermal nicotine (7–28 mg/day) in early PD patients showed good tolerability but no slowing of disease progression, indicating translational challenges. Overall, nicotine exerts anti-apoptotic, anti-inflammatory, and synaptic plasticity–modulating effects that support dopaminergic neuron survival (Supplementary Figure 5). http://www.w3.org/1999/xlink lk0030 float portrait ga1.webp fig0030 anchor portrait graphical ab0015 Highlights • Nicotine consistently protects dopaminergic neurons in cell and animal models of PD. u0005 • Nicotine decreases neuronal apoptosis, oxidative stress, and neuroinflammatory responses. u0010 • Nicotine enhances mitochondrial activity and increases synaptic protein expression. u0015 • The only completed human randomized controlled trial did not show significant clinical benefit. u0020 • Further studies should focus on clinical trials with precise dosing, duration, and targeted nicotinic receptor agonists. u0025 simple li0005 author-highlights ab0020