ArticleAddiction (Abingdon, England)2025
Disentangling the effects of nicotine versus non-nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.
Article in Addiction (Abingdon, England), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Longitudinal Transitions Between Internalizing and Externalizing Symptoms and Associations with Substance Use among US Young Adults, 2016-2023.Epidemiology (Cambridge, Mass.) · 2026Article
- Impact of reducing nicotine in cigarettes on mortality, economic costs and major depression in the USA.Tobacco control · 2026Article
- Nicotine metabolite ratio and clinically significant depressive symptoms in U.S. adults: A smoker-specific association.Medicine · 2026Observational
- Disentangling Nicotine vs Non-Nicotine Components of Tobacco Exposure in Psoriasis and Psoriatic Arthritis: A Multivariable and Trans-Ethnic Mendelian Randomization Study.Clinical, cosmetic and investigational dermatology · 2026Article
- Health, Equity, and Economic Impacts of a Nicotine Product Standard in the United States for People With and Without Major Depression.medRxiv : the preprint server for health sciences · 2025Article
- Disentangling the effects of nicotine versus non-nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.Addiction (Abingdon, England) · 2025Article
- Scoping of Policy Impacts for Regulating E-cigarettes (SPIRE): findings from a data and decision analytic model mapping project.NIHR open research · 2025Article
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Authors and funding
8 authors.
Funding
Abstract
BACKGROUND AND
aimsThere is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g. nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to measure the independent effect of nicotine on depression, by adjusting the effect of circulating nicotine exposure [via nicotine metabolite ratio (NMR)] for the overall effect of smoking heaviness [via cigarettes per day (CPD)] to account for the non-nicotine constituents of tobacco smoke.
designUnivariable MR and multivariable MR (MVMR) were used to measure the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses. SETTING AND
participantsFor the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n = 143 210) and NMR (n = 5185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual-level data from UK Biobank (n = 35 871-194 881). MEASUREMENTS: Genetic variants associated with NMR (n = 6) and CPD (n = 53).
findingsUnivariable MR-IVW indicated a causal effect of CPD on MDD [odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04-1.23, P = 0.003] but no clear evidence for an effect of NMR on MDD (OR = 0.98, 95% CI = 0.97-1.00, P = 0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (IVW: OR = 1.19, 95% CI = 1.03-1.37, P = 0.017; Egger: OR = 1.13, 95% CI = 0.89-1.43, P = 0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (IVW: OR = 0.98, 95% CI = 0.96-1.00, P = 0.057; Egger: OR = 0.98, 95% CI = 0.96-1.00, P = 0.038).
conclusionsThe role of nicotine exposure in risk of depression cannot be entirely dismissed. However, the causal effect of tobacco smoking increasing depression risk appears to be largely independent of circulating nicotine exposure, which implies the role of alternative causal pathways.
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