Clearing the Smoke: What Protects Smokers from Parkinson's Disease?

The link between smoking and a lower risk of Parkinson's disease (PD) is one of the strongest environmental or lifestyle associations in neuroepidemiology. Growing evidence supports the hypothesis that the association is based on a neuroprotective effect of smoking on PD, despite the plausible alternative that smoking serves as a marker for a proximal protective influence without itself conferring benefit. But how smoking could protect against neurodegeneration in PD is not well understood. Of several candidate molecules and mechanisms that have been nominated, nicotine has received the most attention. However, randomized controlled clinical trials of nicotine in PD have failed to demonstrate benefit on motor endpoints, including the NIC-PD study in which recently diagnosed participants were randomly assigned to placebo or nicotine treatment for 1 year. Given these results, the time is right to evaluate the neuroprotective potential of other molecules and biochemical cascades triggered by smoking. Here, we review the evidence supporting smoking's possible protective effect on PD, compounds in tobacco and smoke that might mediate such benefit, and non-causal classes of explanation, including reverse causation and the prospect of shared genetic determinants of smoking and PD resistance. The therapeutic potential of non-nicotine components of smoke is suggested by studies supporting multiple alternative mechanisms ranging from monoamine oxidase inhibitors to gut microbiome disruption to antioxidant response induction by chronic exposure to low levels of carbon monoxide. Rigorous investigation is warranted to evaluate this molecule and others for disease-preventing and disease-modifying activity in PD models and, if warranted, in clinical trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.