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Does tobacco cause psychosis?

by Marcus Munafo @MarcusMunafo

This blog originally appeared on the Mental Elf site on 30th July 2015.

Hot on the heels of a recent study suggesting a dose-response relationship between tobacco smoking and subsequent risk of psychosis, a systematic review and meta-analysis (including the data from that prospective study) has now been published, again suggesting that we should be considering the possibility that smoking is a causal risk factor for schizophrenia.

As I outlined in my earlier post, smoking and psychotic illness (e.g., schizophrenia) are highly comorbid, and smoking accounts for much of the reduced life expectancy of people with a diagnosis of schizophrenia. For the most part, it has been assumed that smoking is a form of self-medication, to either alleviate symptoms or help with the side effects of antipsychotic medication.

It's widely thought that people with psychosis or schizophrenia use smoking as a way to self-medicate and relieve their symptoms.

Methods

This new study reports the results of a systematic review and meta-analysis of prospective, case-control and cross-sectional studies. The authors hoped to test four hypotheses:

  1. That an excess of tobacco use is already present in people presenting with their first episode of psychosis
  1. That daily tobacco use is associated with an increased risk of subsequent psychotic disorder
  1. That daily tobacco use is associated with an earlier age at onset of psychotic illness
  1. That an earlier age at initiation of smoking is associated with an increased risk of psychotic disorder

The authors followed MOOSE and PRISMA guidelines for the conduct and reporting of systematic reviews and meta-analyses, and searched Embase, Medline and PsycINFO for relevant studies. They included studies that used ICD or DSM criteria for psychotic disorders (including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, non-affective psychotic disorder, atypical psychosis, psychotic depression, and bipolar mania with psychotic features).

To test the first hypothesis, studies with a control group were used to calculate an odds ratio. To test the second, prospective studies in which rates of smoking were reported for patients who developed psychotic disorders compared to controls were included, so risk ratios could be calculated. To test the third and fourth, prospective and case-control studies were included, and for the onset of psychosis, cross-sectional studies were also included.

Effect size estimates (weighted mean difference for continuous data, and odds ratios for cross-sectional data or relative risks for prospective data) were combined in a random-effects meta-analysis.

Results

A total of 61 studies comprising 72 independent samples were analysed. The overall sample included 14,555 tobacco users and 273,162 non-users.

  1. The overall prevalence of smoking in people presenting with their first episode of psychosis was higher than controls (12 case-control samples, odds ratio 3.22, 95% CI 1.63 to 6.33, P = 0.001). This supports hypothesis 1.
  2. Compared with non-smokers, the incidence of new psychotic disorders was higher overall (6 longitudinal prospective samples, risk ratio 2.18, 95% CI 1.23 to 3.85, P = 0.007). This supports hypothesis 2.
  3. Daily smokers developed psychotic illness at an earlier age compared with non-smokers (26 samples, weighted mean difference -1.04 years, 95% CI -1.82 to -0.26, P = 0.009). This supports hypothesis 3.
  4. Age at initiation of smoking cigarettes did not differ between patients with psychosis and controls (15 samples, weighted mean difference -0.44 years, 95% CI 1-.21 to 0.34, P = 0.270). This does not support hypothesis 4.

Daily tobacco use is associated with an increased risk of psychosis and an earlier age at onset of psychotic illness.

Conclusion

The authors conclude that the results of their systematic review and meta-analysis show that daily tobacco use is associated with an increased risk of psychotic disorder and an earlier age at onset of psychotic illness, although the magnitude of the association is relatively small.

Interestingly, the authors interpret their results in the context of the Bradford Hill criteria for inferring causality (which consider the strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy of an association). They argue that, where these criteria can be applied (the specificity criterion cannot be applied because smoking affects so many disease processes, while the experiment criterion is not met because animal models of psychotic illness that capture important features such as delusions are impossible), they do appear to be met by the evidence available.

Limitations

There are a number of important limitations to this study, which the authors themselves acknowledge:

  • The first is that all analyses relied on observational data, which makes strong causal inference impossible. Longitudinal prospective studies help somewhat in this respect, but only a small number were available for inclusion in the analysis of risk of developing psychosis between smokers and non-smokers. Moreover, even these studies cannot exclude the possibility that symptoms present before a first full episode of psychosis may have led to smoking initiation (i.e., self medication).
  • Another important limitation is that very few studies measured or adjusted for use of other substances (most importantly, perhaps, cannabis, which has been widely discussed as a potential risk factor for schizophrenia). This is a potentially very important source of bias.

Nevertheless, this is a well-conducted systematic review and meta-analysis that brings together a reasonably large literature. The results appear robust, although given the observational nature of the data, and the fact that only data that were comparable across studies could be meta-analysed, any conclusions regarding causality need to be very tentative.

Very few studies in this review, measured or adjusted for use of other substances such as cannabis.

Summary

It seems that we should seriously consider the possibility that smoking is a causal risk factor for schizophrenia. Of course, the data available to date aren’t definitive, and we need to be very cautious about inferring causality from observational data, but this does feel like an area where there is growing, converging evidence from multiple studies using multiple methods.

It’s also worth bearing in mind that even if smoking is a causal risk factor, this does not preclude the possibility that smoking is also used as a form of self-medication. There are several thousand constituents of tobacco smoke; it is possible that some of these alleviate symptoms, while others exacerbate them. For this reason, we shouldn’t assume that nicotine is necessarily the culprit if smoking is indeed a causal risk factor; it may be (and Gurillo and colleagues discuss the biological plausibility of nicotine in this context), but that will need to be tested.

This last point is particularly important in the content of ongoing debate regarding the potential harms and benefits of electronic cigarettes. If smoking does turn out to be a causal risk factor for schizophrenia, then whether nicotine or something else in tobacco smoke is identified as the culprit will have an important bearing on this debate, and attitudes towards these products.

There are several thousands constituents of tobacco smoke; it is possible that some of these alleviate symptoms, while others exacerbate them

Links

Primary paper

Gurillo P, Jauhar S, Murray RM, MacCabe J. (2015) Does tobacco use cause psychosis? Systematic review and meta-analysis. Lancet Psychiatry 2015. doi: 10.1016/S2215-0366(15)00152-2 (Open access paper: features audio interview with authors)

Munafo M. Smoking and risk of schizophrenia: new study finds a dose-response relationship. The Mental Elf, 1 Jul 2015.

– See more at: http://www.nationalelfservice.net/mental-health/psychosis/does-tobacco-use-cause-psychosis/#sthash.sxUwJPIF.dpuf

High potency cannabis and the risk of psychosis

By Eleanor Kennedy @Nelllor_

This blog originally appeared on the Mental Elf site on 24th March 2015

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Smoking higher-potency cannabis may be a considerable risk factor for psychosis according to research conducted in South London (Di Forti, et al., 2015).

Cannabis is the most widely used illicit drug in the UK and previous research has suggested an association between use of the drug and psychosis, however the causal direction and underlying mechanism of this association are still unclear.

This recent case-control study published in Lancet Psychiatry, aimed to explore the link between higher THC (tetrahydrocannabinol) content and first episode psychosis in the community.

To compare the impact of THC content on first episode psychosis, participants were asked whether they mainly consumed skunk or hash. Analysis of seized cannabis suggests that skunk has THC content of between 12-16%, while hash has a much lower THC content ranging from 3-5% (Potter, Clark, & Brown, 2008; King & Hardwick, 2008).

Cannabis hash and skunk have very different quantities of the active THC component.

Methods

The researchers used a cross-sectional case-control design. Patients presenting for first-episode psychosis were recruited from a clinic in the South London and Maudsley NHS Foundation Trust; patients who had an identifiable medical reason for the psychosis diagnosis were excluded. Control participants were recruited from the local area using leaflets, internet and newspaper adverts. There were 410 case-patients and 370 controls recruited.

Researchers gathered data on participants’ cannabis use in terms of lifetime history and frequency of use as well as type of cannabis used, i.e. skunk or hash. Participants were also asked about their use of other drugs including alcohol and tobacco, as well as providing demographic information.

Results

The case-patients and control participants were different in a couple of key areas (note: psychosis is more common in men and in ethnic minorities):

Case patients Control participants 
Male 66% 56%
Age 27.1 years 30.0 years
Caribbean or African ethnic origin 57% 30%
Completed high level of education 57% 90%
Ever been employed 88% 95%
Lifetime history of ever using cannabis 67% 63%

Participants with first episode psychosis were more likely to:

  • Use cannabis every day
  • Use high-potency cannabis
  • Have started using cannabis at 15 years or younger
  • Use skunk every day

A logistic regression adjusted for age, gender, ethnic origin, number of cigarettes smoked, alcohol units, and lifetime use of illicit drugs, education and employment history showed thatcompared to participants who had never used cannabis:

  • Participants who had ever used cannabis were not at increased risk of psychosis
  • Participants who had used cannabis at age 15 were at moderately increased risk of psychotic disorder
  • People who used cannabis or skunk everyday were roughly 3 times more likely to have diagnosis of psychotic disorder

A second logistic regression was carried out to explore the effects of a composite measure of cannabis exposure which combined data on the frequency of use and the type of cannabis used.Compared with participants who had never used cannabis:

  • Individuals who mostly used hash (occasionally, weekends or daily) did not have any increased risk of psychosis
  • Individuals who smoked skunk less than once a week were nearly twice as likely to be diagnosed with psychosis
  • Individuals who smoked skunk at weekends were nearly three times as likely to be diagnosed with psychosis
  • Individuals who smoked skunk daily were more than five times as likely to be diagnosed with psychosis

The population attributable factor (PAF) was calculated to estimate the proportion of disorder that would be prevented if the exposure were removed:

  • 19.3% of psychotic disorders attributable to daily cannabis use
  • 24.0% of psychotic disorders attributable to high potency cannabis use
  • 16.0% of psychotic disorders attributable to skunk use every day

These findings raising awareness among young people of the risks associated with the use of high-potency cannabis

Conclusions

The results of this study support the theory that higher THC content is linked with a greater risk of psychosis, with daily use of skunk conferring the highest risk. Recruiting control participants from the same area as the case participants meant that the two groups were more likely to be matched on not only demographic factors but also in terms of the actual cannabis that both groups were consuming.

The study has some limits, such as the cross-sectional design which cannot be used to establish causality. Also the authors have not included any comparison between those who smoke hash and those who consume skunk so no conclusions can be drawn about the relative harm of hash.

Media reports about the study have mainly focussed on the finding that ‘24% of psychotic disorders are attributable to high potency cannabis use’. This figure was derived from a PAF calculation which assumes causality and does not allow for the inclusion of multiple, potentially interacting, risk factors. Crucially the PAF depends on both the prevalence of the risk factor and the odds ratio for the exposure; the PAF can be incredibly high if the risk factor is common in a given population.

In this case, the prevalence rate of lifetime cannabis use was over 60% in both participant groups. According to EMCDDA, the lifetime prevalence of cannabis use in the UK is 30% among adults aged 15-64, so it is arguable that this study sample is not representative of the rest of the UK. The authors themselves note that “the ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies”, which is a more accurate interpretation than media reports claiming that “1 in 4 of all new serious mental disorders” is attributable to skunk use.

Future studies looking at the relationship between cannabis and psychosis should also aim to differentiate high and low potency cannabis. Longitudinal cohort studies are particularly useful as they have the same advantages as a case-control design but data about substance use could be more reliable as ‘lifetime use’ can be gathered from multiple measurements collected at a number of time points across the lifetime.

This innovative study is the first to distinguish between different strengths of cannabis in this way.

Links

Primary study

Di Forti M. et al (2015). Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study (PDF). The Lancet Psychiatry, 2(3), 233-238.

Other references

King L, & Hardwick S. (2008). Home Office Cannabis Potency Study (PDF). Home Office Scientific Development Branch.

Potter DJ, Clark P, & Brown MB. (2008). Potency of Delta(9)-THC and other cannabinoids in cannabis in England in 2005: Implications for psychoactivity and pharmacology (PDF). Journal of Forensic Sciences, 53(1), 90-94.