The article "Clearing the Smoke: What Protects Smokers from Parkinson’s Disease?" by Kenneth N. Rose, Michael A. Schwarzschild, and Stephen N. Gomperts explores the intriguing link between smoking and a reduced risk of Parkinson's disease (PD). Despite the strong epidemiological evidence, the exact mechanisms by which smoking might protect against PD remain unclear. The authors review several candidate molecules and mechanisms, with nicotine being the most extensively studied. However, clinical trials have shown that nicotine does not benefit motor function in PD patients. Other potential mediators, such as carbon monoxide (CO), monoamine oxidase-B (MAO-B) inhibitors, and changes in the gut microbiome, are discussed as possible contributors to the neuroprotective effects of smoking. The article also addresses non-causal explanations, including reverse causation and shared genetic determinants, and emphasizes the need for further research to identify and evaluate the disease-modifying potential of smoking-related molecules and mechanisms. The authors conclude that the robust association between smoking and reduced PD risk offers a significant clue to protection against the disease and suggests potential therapeutic opportunities.The article "Clearing the Smoke: What Protects Smokers from Parkinson’s Disease?" by Kenneth N. Rose, Michael A. Schwarzschild, and Stephen N. Gomperts explores the intriguing link between smoking and a reduced risk of Parkinson's disease (PD). Despite the strong epidemiological evidence, the exact mechanisms by which smoking might protect against PD remain unclear. The authors review several candidate molecules and mechanisms, with nicotine being the most extensively studied. However, clinical trials have shown that nicotine does not benefit motor function in PD patients. Other potential mediators, such as carbon monoxide (CO), monoamine oxidase-B (MAO-B) inhibitors, and changes in the gut microbiome, are discussed as possible contributors to the neuroprotective effects of smoking. The article also addresses non-causal explanations, including reverse causation and shared genetic determinants, and emphasizes the need for further research to identify and evaluate the disease-modifying potential of smoking-related molecules and mechanisms. The authors conclude that the robust association between smoking and reduced PD risk offers a significant clue to protection against the disease and suggests potential therapeutic opportunities.