Objective: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of nicotine compared with placebo in the treatment of Parkinson’s disease (PD).

Background: Levodopa remains the most effective treatment for Parkinson’s disease (PD); however, its long-term use is associated with dyskinesia and motor fluctuations, leading to diminished benefits in advanced stages of the disease [1]. Studies have shown that smokers have a lower risk of developing PD, suggesting a potential protective effect of nicotine and its possible role as a therapeutic agent [2-4].

Method: We systematically searched four databases, PubMed, Embase, CINAHL, and Web of Science, from inception until February 18, 2025, for relevant studies. We included RCTs comparing nicotine against placebo or standard treatment. The primary outcomes were changes in UPDRS III scores and the incidence of adverse events (AEs) during the intervention period. Data collection and assessment of the quality of included RCTs were done by two independent reviewers. The Cochrane Risk of Bias Tool 2.0 (ROB 2.0) was used for quality assessment. A random-effect meta-analysis model was performed on R 4.3.2 to report standardized mean differences (SMDs), and Risk Ratios (RRs), with 95% confidence intervals.

Results: We included four RCTs with 88 patients in our systematic review. One crossover study [5] was excluded from the meta-analysis. Two studies assessed transdermal nicotine patches [5, 6], while the other two evaluated nicotine gum or dietary incorporation [7,8]. The most recent study found significant improvement in the UPDRS III motor score compared to placebo [8]. Two studies found no significance compared to the placebo group [6,7]. Another study found worse results when compared to the placebo group [5]. There was an increased risk in total AEs in the nicotine group compared to placebo (RR = 1.65 [1.19, 2.27]), with gastrointestinal AEs being the most common (RR = 3.35 [1.49, 7.51]).

Conclusion: Nicotine demonstrated inconsistent effects on motor function in PD patients, with some studies reporting benefits, while others found no improvement or worsening function. Further well-designed RCTs are needed to clarify its therapeutic potential in PD.

Figure 1 – UPDRS Change

Figure 2 – Total AEs

Figure 3 – GI-related AEs

References: [1] Aradi SD, Hauser RA. Medical management and prevention of motor complications in Parkinson’s disease. Neurotherapeutics. 2020;17(4):1339–65. doi:10.1007/s13311-020-00889-4.

[2] Heilbron K, Jensen MP, Bandres-Ciga S, Fontanillas P, Blauwendraat C, Nalls MA, et al. Unhealthy behaviours and risk of Parkinson’s disease: a Mendelian randomisation study. J Parkinsons Dis. 2021;11(4):1981–93. doi:10.3233/jpd-202487.

[3] Li X, Li W, Liu G, Shen X, Tang Y. Association between cigarette smoking and Parkinson’s disease: a meta-analysis. Arch Gerontol Geriatr. 2015;61(3):510–6. doi:10.1016/j.archger.2015.08.004.

[4] Thiriez C, Villafane G, Grapin F, Fenelon G, Remy P, Cesaro P. Can nicotine be used medicinally in Parkinson’s disease? Expert Rev Clin Pharmacol. 2011;4(4):429–36. doi:10.1586/ecp.11.27.

[5] Ebersbach G, Stöck M, Müller J, et al. Worsening of motor performance in patients with Parkinson’s disease following transdermal nicotine administration. Mov Disord. 1999;14(6):1011–3. doi:10.1002/1531-8257(199911)14:6<1011::aid-mds1016>3.0.co;2-f.

[6] Villafane G, Thiriez C, Audureau E, Straczek C, Kerschena P, Cormier-Dequaire F, et al. High-dose transdermal nicotine in Parkinson’s disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study. Eur J Neurol. 2018;25(1):120–7. doi:10.1111/ene.13474.

[7] Clemens P, Baron JA, Coffey D, Reeves A. The short-term effect of nicotine chewing gum in patients with Parkinson’s disease. Psychopharmacology (Berl). 1995;117(2):253–6. doi:10.1007/BF02246206.

[8] Amiri HL, Javanbakht MH, Baghbanian SM, Parsaeian M. The effect of a nicotine-rich diet with/without redistribution of dietary protein on motor indices in patients with Parkinson’s disease: a randomized clinical trial. J Clin Neurosci. 2024;129:110845. doi:10.1016/j.jocn.2024.110845.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-and-safety-of-nicotine-in-parkinsons-disease-a-systematic-review-and-meta-analysis/