Cigarette smoking is the single most significant cause of preventable death in the world. Tobacco smoking causes exposure to thousands of chemicals and disrupts biological pathways. It impacts several organs, including the brain, where its effects are mediated by nicotinic acetylcholine receptors. Women seem to be more susceptible to the negative health effects of smoking. In this study we focused on the changes in the metabolic profile of human postmortem frontal cortex and cerebrospinal fluid samples associated with high levels of the nicotine metabolite cotinine. We used non-targeted metabolomics to analyze post-mortem frontal cortex and cerebrospinal fluid (CSF) samples from the Tampere Sudden Death Study cohort. We identified 137 cases (24 females) with high cotinine levels, indicating nicotine exposure. For controls, we identified 82 subjects (20 females) with no cotinine in the frontal cortex or CSF samples and no known history of smoking based on medical records and autopsy reports. Cases had significantly higher levels of 1-methylhistamine (Cohen′s d=0.66, p<0.0001) and N-acetylputrescine (d=0.84, p<0.0001), and lower levels of aspartic acid (d=-0.53, p<0.001), 3-methylhistidine (d=-0.58, p=0.0004), and taurine (d=-0.47, p=0.0002) in the frontal cortex compared to controls. Compared to the frontal cortex, differences between cases and controls were smaller in the CSF samples. Most of the observed differences were similar in both sexes, with a few exceptions like low ergothioneine levels, observed especially in female cases. In conclusion, smoking or nicotine exposure is associated with alterations in metabolites linked to increased oxidative stress and neuroinflammation, as well as reduced neurotransmitter levels in the frontal cortex.

OK and KH are founders of Afekta Technologies Ltd., a company offering metabolomics analysis services. Other authors report no potential conflicts of interest.

This study is funded by the Finnish Foundation for Alcohol Studies (OK), VTR funding (JT, PJK), European Union 7th Framework Program grant number 201668 for AtheroRemo Project (PJK), by State Research Funding for Tampere University Hospital (PJK), Pirkanmaa Regional Fund of the Finnish Cultural Foundation (PJK), Finnish Cultural Foundation (EK), Jane and Aatos Erkko Foundation (PJK, KH), Research Council of Finland (KH), and the Finnish Foundation for Cardiovascular Research (PJK).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Tampere Sudden Death Study (TSDS) protocol was approved by the Ethics Committee of Pirkanmaa Hospital District (Permission number R09097) and the National Supervisory Authority for Welfare and Health Valvira (Dnro 564/05.01.00.06/2010). This was in accordance with the Declaration of Helsinki.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors.