Does cigarette smoking cause psychosis?
Authors: Helen L Alderson, Stephen M Lawrie
Journal: The Lancet Psychiatry (2015)

Many psychiatrists note that their patients, particularly those with schizophrenia, smoke cigarettes—and usually smoke heavily. This association has typically been assumed to be some form of self-medication, but in The Lancet Psychiatry, a systematic review by Pedro Gurillo and colleagues1Gurillo P Jauhar S Murray RM MacCabe JH Does tobacco use cause psychosis? Systematic review and meta-analysis.Lancet Psychiatry. 2015; (published online July 10.)http://dx.doi.org/S2215-0366(15)00152-2Summary Full Text Full Text PDF Scopus (196) Google Scholar brings together evidence showing that cigarette smoking might actually be a cause of psychosis. In case-control studies, an overall increase was noted in the odds of first-episode psychosis in cigarette smokers versus non-smokers (odds ratio 3·22, 95% CI 1·63–6·33), albeit with some evidence of publication bias. Daily smokers also developed psychotic illness about 1 year earlier than did non-smokers. In prospective studies, of which only five were identified by the systematic review, the relative risk of new psychotic disorders in daily smokers versus non-smokers was 2·18 (95% CI 1·23–3·85). This difference in apparent risk by study design suggests recall bias in the case-control estimate, but the self-medication hypothesis is not mutually exclusive with the possibility that smoking is a causal risk factor for psychosis. The most likely explanation of these findings is that cigarette smoking is associated with an increased risk for schizophrenia. Taking up, and continuing, smoking could be self-medication for anxiety, depression, or psychotic symptoms. It could also be shared with other risk factors for psychosis, such as family history, urban upbringing, or childhood adversity. Each of these risk factors, in addition to early and regular cannabis use, seems to have an additive effect in terms of phenotypes such as psychosis and age at onset.2Large M Sharma S Compton MT Slade T Nielssen O Cannabis use and earlier onset of psychosis: a systematic meta-analysis.Arch Gen Psychiatry. 2011; 68: 555-561Crossref PubMed Scopus (421) Google Scholar, 3Esterberg ML Trotman HD Holtzman C Compton MT Walker EF The impact of a family history of psychosis on age-at-onset and positive and negative symptoms of schizophrenia: a meta-analysis.Schizophr Res. 2010; 120: 121-130Crossref PubMed Scopus (85) Google Scholar, 4Stepniak B Papiol S Hammer C et al.Accumulated environmental risk determining age at schizophrenia onset: a deep phenotyping-based study.Lancet Psychiatry. 2014; 1: 444-453Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar Primacy, the strength of an association, dose response, and specificity are among the best indicators of causality in an association. Little doubt exists that cigarette smoking usually precedes psychosis, but prospective studies are scant and few of those published have carefully addressed possible confounders. Few readers will view a relative risk of 2·18 to be convincing. Smoking is also unlikely to be judged a specific cause of psychosis. Moreover, the age-at-onset data do not really help to establish causality, because smoking could advance age at onset without necessarily causing psychosis. One intriguing possible interpretation of these findings is that the genes for psychosis overlap with those for cigarette smoking. Indeed, they probably do. The Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) described 108 separate genetic loci associated with an increased risk of schizophrenia.5Schizophrenia Working Group of the Psychiatric Genomics ConsortiumBiological insights from 108 schizophrenia-associated genetic loci.Nature. 2014; 511: 421-427Crossref PubMed Scopus (5221) Google Scholar One of these is located in a cluster of genes—CHRNA5, CHRNA3, and CHRNB5—on chromosome 15, and this region is associated with both early age at onset of smoking and heavy smoking.6Hartz SM Short SE Saccone NL et al.Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.Arch Gen Psychiatry. 2012; 69: 854-860Crossref PubMed Scopus (61) Google Scholar, 7Gage SH Munafò MR Rethinking the association between smoking and schizophrenia.Lancet Psychiatry. 2015; 2: 118-119Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar The PGC might have data available, or could possibly gather it, to test the possibility that this genetic proxy for heavy smoking is associated with schizophrenia in smokers but not in non-smokers and, thus, provide evidence that smoking is on the causal pathway to schizophrenia. If cigarette smoking is causal, one has to ask why the typical age of taking up regular daily smoking is during the teenage years, but the usual age at onset of psychosis is around 25 years. Regular smoking is unlikely to take years to exert a psychotogenic effect but, then again, most smoking-related diseases only arise after prolonged exposure. Perhaps smoking cigarettes acts as a so-called gateway drug to cannabis and other psychotomimetics; conversely, the association of cannabis with psychosis could be attributable to the tobacco with which most cannabis is consumed. Thus far, no studies have investigated the age at onset of psychotic illness while measuring both cannabis and cigarette smoking. In a previous meta-analysis, a pooled interval of 5·3 years was estimated between age at initiation of daily tobacco use and onset of psychosis.8Myles N Newall HD Curtis J Nielssen O Shiers D Large M Tobacco use before, at, and after first-episode psychosis: a systematic meta-analysis.J Clin Psychiatry. 2012; 73: 468-475Crossref PubMed Scopus (107) Google Scholar It is noteworthy in that study that the difference in age at onset of psychosis in cannabis users was 2·7 years, compared with 1·0 years for cigarette smokers.1Gurillo P Jauhar S Murray RM MacCabe JH Does tobacco use cause psychosis? Systematic review and meta-analysis.Lancet Psychiatry. 2015; (published online July 10.)http://dx.doi.org/S2215-0366(15)00152-2Summary Full Text Full Text PDF Scopus (196) Google Scholar What is also apparent from published work is that co-use of both cigarettes and cannabis is common in young people and is associated with a worsening of mental health symptoms.9Ramo DE Liu H Prochaska JJ Tobacco and marijuana use among adolescents and young adults: a systematic review of their co-use.Clin Psychol Rev. 2012; 32: 105-121Crossref PubMed Scopus (221) Google Scholar Kandel and Kandel10Kandel ER Kandel DB Shattuck lecture: a molecular basis for nicotine as a gateway drug.N Engl J Med. 2014; 371: 932-943Crossref PubMed Scopus (148) Google Scholar have summarised an impressive amount of in vitro and in vivo work, in keeping with the view that tobacco is a gateway drug to other substances of misuse, but epidemiological evidence is, as yet, absent. Large, longitudinal, prospective studies are needed to investigate the relations between smoking tobacco and cannabis and development of anxiety, depression, and psychotic disorders, adjusting for the effects of other substances, to enable more stringent examination of whether cigarette smoking has a causal role in the development of psychosis. Such studies will allow us to assess the public health importance of the results presented here. To say that smoking causes psychosis would be premature, but the time might not be too much longer before cigarette smoking is recognised as a risk factor for psychosis as well as anxiety and depression. This online publication has been corrected. The corrected version first appeared at thelancet.com/psychiatry on July 15, 2015 This online publication has been corrected. The corrected version first appeared at thelancet.com/psychiatry on July 15, 2015 SML reports personal fees from Janssen and Sunovion, grants and personal fees from Roche, and grants from Pfizer and Abbvie, outside the submitted work. HLA declares no competing interests. Does tobacco use cause psychosis? Systematic review and meta-analysisDaily tobacco use is associated with increased risk of psychosis and an earlier age at onset of psychotic illness. The possibility of a causal link between tobacco use and psychosis merits further examination. Full-Text PDF Open AccessCorrectionsAlderson HL, Lawrie SM. Does cigarette smoking cause psychosis? Lancet Psychiatry 2015; published online July 10. http://dx.doi.org/10.1016/S2215-0366(15)00239-4—This Comment has been made Gold Open Access, and is now distributed under the terms of CC BY-NC-ND. This correction has been made to the online version as of July 15, 2015. Full-Text PDF Open Access