ALSAPC. Suzanne Gage and Marcus Munafo are members of the UK Centre for Tobacco and Alcohol Studies. This publication is the work of the authors and Suzanne Gage, Matt Hickman, and Stan Zammit serve as guarantors for the contents of this paper. JH is supported by the UK Medical Research Council (Grants G0800612 and G0802736) and this work was also supported by MRC grant G0701503 and Wellcome Trust grant 084268/Z/07/Z. The funders were not involved in the design, data collection, analysis or write up of the study. All authors are independent of the funders.

Competing Interests: The authors have declared that no competing interests exist.

\section{Conclusions}
Whilst evidence of association between cannabis use and depression persisted after adjusting for pre-term and childhood confounders, our results highlight the difficulties in trying to estimate and interpret independent effects of cannabis and tobacco on psychopathology. Complementary methods are required to robustly examine effects of cannabis and tobacco on psychopathology.

\section{Background}
A variety of mental health problems, including depression and anxiety, occur more commonly in substance users than non-users. \cite{1,2,3,4} However, discerning causation from confounding, reverse causation, or selection or measurement bias in observational studies is problematic. \cite{5} The cannabinoid system in the brain has been implicated in emotional regulation, \cite{6} but biological mechanisms that might underlie the association between cannabis use and depression are not known, and indeed effects of cannabis may differ between the short and long term. For example, while people often report that cannabis acutely elevates their mood, long-term cannabis users show an increased risk of a number of adverse outcomes, including poorer education and social functioning, \cite{7} which might be expected to increase risk of depression.

A recent systematic review and meta-analysis of longitudinal studies reported a 1.17-fold increase in odds of depression (95\% CI 1.05, 1.30) in cannabis users, with a larger effect (OR = 1.62, 95\% CI 1.21, 2.16) for heavy use, \cite{8} and concluded that cannabis is associated with a modest increase in risk of developing depressive disorders. An earlier meta-analysis reported a similar association, but the authors argued that the majority of contributing studies did not adequately account for the possibility of reverse causation. \cite{9} They also noted the wide variation in the number and type of confounders adjusted for. In particular, about half the studies included in their meta-analysis made no adjustment for alcohol or other drug use, which, given their potential depressogenic and anxiogenic effects during intoxication and withdrawal, \cite{10,11} strongly suggests the potential for residual confounding. Similar problems are likely to exist for determining the causal role of cannabis on anxiety. \cite{9}

Tobacco use is also more common in people with depression and anxiety compared to the general population, \cite{1,3} and determining if these associations are causal is beset with the same difficulties as for cannabis. Whilst some studies indicate that smoking may be a self-medication behaviour, \cite{12} other studies provide evidence in support of a biological causal mechanism for this association. For example, findings from animal studies suggest that nicotine effects on strengthening excitatory synapses on midbrain dopamine neurons might weaken coping mechanisms. \cite{13}

The main aim of this study was to investigate the association between cannabis and cigarette use and incident depression and anxiety, whilst attempting to address issues relating to confounding, reverse causation and bias as robustly as we could. Furthermore, as cannabis and cigarette use are also associated with psychotic experiences (PEs), and we recently reported such associations within this sample, \cite{14} we also examine the specificity of cannabis and cigarettes by comparing their effects on depression with those for PEs.