A potential biological mechanism for the bi-directional causal effects of smoking, schizophrenia and depression could be neuroadaptations in the dopaminergic and serotonin systems. Nicotine acts on nicotinic cholinergic receptors in the brain stimulating the release of neurotransmitters including dopamine and serotonin (Benowitz, 2010). Dopamine and serotonin dysfunction have been implicated in the aetiology of schizophrenia and depression, respectively (Howes, McCutcheon, & Stone, 2015; Jakubovski, Varigonda, Freemantle, Taylor, & Bloch, 2015). It is plausible, therefore, that disruption of these pathways has a causal effect on these disorders. Alternatively, cannabis use could be a mediating mechanism for the effects of smoking on schizophrenia and depression. In prospective studies, cigarette smoking has been shown to increase risk of cannabis dependence (Hindocha et al., 2015). There is strong evidence suggesting that cannabis use increases the risk of psychosis and affective disorders (Moore et al., 2007). This vertical pleiotropy does not violate the assumptions of MR, but simply means there are intermediate mechanisms operating between the exposure and the outcome. However, the strong effects we observe for lifetime smoking suggest that any mediating influence of
