Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A genetically informed study on the association of cannabis, alcohol, and tobacco smoking with suicide attempt


Use of substances such as cannabis, alcohol, and tobacco, has been associated with increased risk of suicide attempt in several observational studies. However, establishing whether these associations are causal is challenging when using observational designs. To evaluate the potential causal contributions of cannabis use, alcohol use, and tobacco smoking to suicide attempt, we applied two-sample Mendelian randomization, an instrumental variable approach using single-nucleotide polymorphisms (SNPs) as instrumental variables for three exposures: lifetime cannabis use (yes/no; 42 instrument SNPs; GWAS sample size [N] = 162,082), alcohol use (drinks-per-week; 53 instrument SNPs; N = 941,280), and tobacco smoking (initiation, yes/no; 156 instrument SNPs; N = 1,232,091; heaviness; 27 instrument SNPs; N = 337,334). The main outcome was suicide attempt measured from hospital records (N = 50,264). All data come from publicly available summary statistics of genome-wide association studies of participants of European ancestry. We found evidence supporting a possible causal role of cannabis (OR = 1.18; 95% CI = 1.01–1.37, P = 0.032), alcohol (OR = 1.95; 95% CI = 1.15–3.32, P = 0.013), and smoking (initiation, OR = 1.90; 95% CI = 1.54–2.34, P < 0.001; heaviness, OR = 2.13; 95% CI = 1.13–3.99; P = 0.019) on suicide attempt. Using multivariable Mendelian randomization, we found that only cannabis showed a direct pathway to suicide attempt (P = 0.001), suggesting that the effect of alcohol and smoking was mediated by the other substance use phenotypes. No evidence was found for reverse causation, i.e., associations of suicide attempt on cannabis (P = 0.483), alcohol (P = 0.234), smoking initiation (P = 0.144), and heaviness (P = 0.601). In conclusion, evidence from this quasi-experimental study based on genetic data from large-scale GWASs are consistent with a causal role of cannabis, alcohol, and tobacco smoking on suicide attempt.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Schematic representation of the Mendelian randomization design.
Fig. 2: Mendelian randomization scatter plots for the associations of cannabis, alcohol, and tobacco smoking with suicide attempt.

Code availability

Analyses were performed using the R packages TwoSampleMR [32], Mendelian Randomization [33], and MR-PRESSO (R version 3.5.2). The computer code is available upon request.


  1. 1.

    Turecki G, Brent DA. Suicide and suicidal behaviour. Lancet. 2016;387:1227–39.

    PubMed  Article  Google Scholar 

  2. 2.

    WHO. WHO | Suicide data. WHO. 2015. Accessed 24 Feb 2018.

  3. 3.

    Nock MK, Green JG, Hwang I, McLaughlin KA, Sampson NA, Zaslavsky AM, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry. 2013;70:300–10.

    PubMed  Article  Google Scholar 

  4. 4.

    Goldman-Mellor SJ, Caspi A, Harrington H, Hogan S, Nada-Raja S, Poulton R, et al. Suicide attempt in young people: a signal for long-term health care and social needs. JAMA Psychiatry. 2014;71:119–27.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    GBD 2016 Alcohol and Drug Use Collaborators. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry. 2018;5:987–1012.

    Article  Google Scholar 

  6. 6.

    Berlin I, Hakes JK, Hu M-C, Covey LS. Tobacco use and suicide attempt: longitudinal analysis with retrospective reports. PLOS ONE. 2015;10:e0122607.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Chang HB, Munroe S, Gray K, Porta G, Douaihy A, Marsland A, et al. The role of substance use, smoking, and inflammation in risk for suicidal behavior. J Affect Disord. 2019;243:33–41.

    PubMed  Article  Google Scholar 

  8. 8.

    Darvishi N, Farhadi M, Haghtalab T, Poorolajal J. Alcohol-related risk of suicidal ideation, suicide attempt, and completed suicide: a meta-analysis. PLoS ONE. 2015;10:e0126870.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Flensborg-Madsen T, Knop J, Mortensen EL, Becker U, Sher L, Grønbæk M. Alcohol use disorders increase the risk of completed suicide—irrespective of other psychiatric disorders. A longitudinal cohort study. Psychiatry Res. 2009;167:123–30.

    PubMed  Article  Google Scholar 

  10. 10.

    Gobbi G, Atkin T, Zytynski T, Wang S, Askari S, Boruff J, et al. Association of Cannabis use in adolescence and risk of depression, anxiety, and suicidality in young adulthood: a systematic review and meta-analysis. JAMA Psychiatry. 2019;76:426–34.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Korhonen T, Sihvola E, Latvala A, Dick DM, Pulkkinen L, Nurnberger J, et al. Early-onset tobacco use and suicide-related behavior—a prospective study from adolescence to young adulthood. Addict Behav. 2018;79:32–8.

    PubMed  Article  Google Scholar 

  12. 12.

    Li D, Yang X, Ge Z, Hao Y, Wang Q, Liu F, et al. Cigarette smoking and risk of completed suicide: a meta-analysis of prospective cohort studies. J Psychiatr Res. 2012;46:1257–66.

    PubMed  Article  Google Scholar 

  13. 13.

    Malone KM, Waternaux C, Haas GL, Cooper TB, Li S, Mann JJ. Cigarette smoking, suicidal behavior, and serotonin function in major psychiatric disorders. Am J Psychiatry. 2003;160:773–9.

    PubMed  Article  Google Scholar 

  14. 14.

    Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–28.

    PubMed  Article  Google Scholar 

  15. 15.

    Pingault J-B, O’Reilly PF, Schoeler T, Ploubidis GB, Rijsdijk F, Dudbridge F. Using genetic data to strengthen causal inference in observational research. Nat Rev Genet. 2018;19:566–80.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet. 2009;373:68–81.

    PubMed  Article  Google Scholar 

  17. 17.

    Fergusson DM, Horwood LJ, Ridder EM, Beautrais AL. Suicidal behaviour in adolescence and subsequent mental health outcomes in young adulthood. Psychol Med. 2005;35:983–93.

    PubMed  Article  Google Scholar 

  18. 18.

    Marschall-Lévesque S, Castellanos-Ryan N, Parent S, Renaud J, Vitaro F, Boivin M, et al. Victimization, suicidal ideation, and alcohol use from age 13 to 15 years: support for the self-medication model. J Adolesc Health. 2017;60:380–7.

    PubMed  Article  Google Scholar 

  19. 19.

    Steinhausen H-C, Bösiger R, Metzke CW. Stability, correlates, and outcome of adolescent suicidal risk. J Child Psychol Psychiatry. 2006;47:713–22.

    PubMed  Article  Google Scholar 

  20. 20.

    Glass TA, Goodman SN, Hernán MA, Samet JM. Causal inference in public health. Annu Rev Public Health. 2013;34:61–75.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30:543–52.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Erlangsen A, Appadurai V, Wang Y, Turecki G, Mors O, Werge T, et al. Genetics of suicide attempts in individuals with and without mental disorders: a population-based genome-wide association study. Mol Psychiatry. 2018.

  24. 24.

    Pasman JA, Verweij KJH, Gerring Z, Stringer S, Sanchez-Roige S, Treur JL, et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21:1161.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Liu M, Jiang Y, Wedow R, Li Y, Brazel DM, Chen F, et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019;51:237.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Wootton RE, Lawn RB, Millard LAC, Davies NM, Taylor AE, Munafò MR, et al. Evaluation of the causal effects between subjective wellbeing and cardiometabolic health: mendelian randomisation study. BMJ. 2018;362:k3788.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Choi KW, Chen C-Y, Stein MB, Klimentidis YC, Wang M-J, Koenen KC, et al. Assessment of bidirectional relationships between physical activity and depression among adults: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry. 2019.

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.

    PubMed  Article  Google Scholar 

  29. 29.

    Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Math Stat. 2018. arXiv:180109652.

  30. 30.

    Burgess S, Thompson SG. Multivariable Mendelian Randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol. 2015;181:251–60.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. 2018.

    PubMed Central  Article  Google Scholar 

  32. 32.

    Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. ELife. 2018;7:e34408.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Yavorska OO, Burgess S. Mendelian randomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017;46:1734–9.

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Borges G, Bagge CL, Orozco R. A literature review and meta-analyses of cannabis use and suicidality. J Affect Disord. 2016;195:63–74.

    PubMed  Article  Google Scholar 

  35. 35.

    Agrawal A, Nelson EC, Bucholz KK, Tillman R, Grucza RA, Statham DJ, et al. Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study. Lancet Psychiatry. 2017;4:706–14.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Lynskey MT, Glowinski AL, Todorov AA, Bucholz KK, Madden PAF, Nelson EC, et al. Major depressive disorder, suicidal ideation, and suicide attempt intwins discordant for cannabis dependence and early-onset cannabis use. Arch Gen Psychiatry. 2004;61:1026–32.

    PubMed  Article  Google Scholar 

  37. 37.

    Staff J, Schulenberg JE, Maslowsky J, Bachman JG, O’Malley PM, Maggs JL, et al. Substance use changes and social role transitions: proximal developmental effects on ongoing trajectories from late adolescence through early adulthood. Dev Psychopathol. 2010;22:917–32.

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC. Smoking and major depression. A causal analysis. Arch Gen Psychiatry. 1993;50:36–43.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Kendler KS, Lönn SL, Sundquist J, Sundquist K. Smoking and schizophrenia in population cohorts of Swedish women and men: a prospective co-relative control study. Am J Psychiatry. 2015;172:1092–1100.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Fergusson DM, Boden JM, Horwood LJ. Tests of causal links between alcohol abuse or dependence and major depression. Arch Gen Psychiatry. 2009;66:260–6.

    PubMed  Article  Google Scholar 

  41. 41.

    Pompili M, Serafini G, Innamorati M, Dominici G, Ferracuti S, Kotzalidis GD, et al. Suicidal behavior and alcohol abuse. Int J Environ Res Public Health. 2010;7:1392–431.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Green M, Turner S, Sareen J. Smoking and suicide: biological and social evidence and causal mechanisms. J Epidemiol Community Health. 2017;71:839–40.

    PubMed  Article  Google Scholar 

  43. 43.

    Vinod KY, Hungund BL. Role of the endocannabinoid system in depression and suicide. Trends Pharmacol Sci. 2006;27:539–45.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–25.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Bowden J, Del Greco MF, Minelli C, Davey Smith G, Sheehan NA, Thompson JR. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int J Epidemiol. 2016;45:1961–74.

    PubMed  PubMed Central  Article  Google Scholar 

Download references


MO is funded by the European Union’s Horizon 2020 research and innovation program (grant agreement no. 793396). GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award, and is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899). MCG, JRS, and GT are supported by the Fonds de recherche du Québec—Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. MCG receives funding from the American Foundation for Suicide Prevention and holds a Canada Research Chair (Tier 2). NCR and MCG are fellows of the Fonds de Recherche en Santé du Québec. NCR and JRS are supported by grants from the CIHR (PJT-148551) and a CIHR-Canadian Center on Substance Use and Addiction Catalyst Grant. JRS is also supported by the Fond Monique Gaumond pour la recherche sur les maladies affectives. RET is funded by the Social Sciences and Humanities Research Council of Canada. Funders have no role in study design, data analysis, interpretation of the data, writing of the paper.

Author information



Corresponding author

Correspondence to Massimiliano Orri.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Orri, M., Séguin, J.R., Castellanos-Ryan, N. et al. A genetically informed study on the association of cannabis, alcohol, and tobacco smoking with suicide attempt. Mol Psychiatry (2020).

Download citation


Quick links