We conducted the first systematic review of MR studies investigating causal relationships between mental health and substance use. From a total of 63 studies, we can draw important conclusions regarding if and how mental health and substance use are causally related.

Smoking was the most investigated, resulting in particularly strong evidence that higher educational attainment causally decreases smoking (lower risk of initiating, smoking fewer cigarettes, and more likely to quit). Although smoking prevalence has rapidly decreased in the past two decades, this decline has been most prominent among those with high educational attainment, leading to an increasing (health) gap (Agaku, Odani, Okuyemi, & Armour, 2020). The causal role of education we report is important for policy-makers going forward. Interestingly, causal effects from education are neither mediated by cognitive ability (Sanderson et al., 2019) nor were there clear evidence that cognitive ability by itself affects smoking (Adams, 2019; Davies et al., 2019). The studies included in this review cannot determine exactly why educational attainment affects smoking. Smoking initiation usually occurs during adolescence, at which time the home environment and peer influences are important. Adolescents in lower educational groups tend to experience lower levels of parental involvement, parental monitoring, and self-perceived social competence, factors associated with a higher odds of initiating smoking (Mahabee-Gittens, Xiao, Gordon, & Khoury, 2013; Simons-Morton, 2002). As for smoking heaviness and difficulty quitting, causal mechanisms may involve job opportunities that depend on educational attainment. A lower education often leads to jobs characterized by low skill discretion, high psychological demands and high physical exertion, potentially leading to stress and smoking to cope (Dobson, Gilbert-Ouimet, Mustard, & Smith, 2018a).

Another striking pattern was that of bi-directional, increasing effects between smoking and mental disorders. There was more robust evidence that smoking causally increases the odds of mental disorders than vice versa – most notably for depression, bipolar disorder, and schizophrenia. This concurs with accumulating evidence from longitudinal cohort studies (Taylor et al., 2014b) and animal research (Jobson et al., 2019) indicating neuropsychiatric effects of smoking. A causal mechanism may be that nicotine binds to nicotinic acetylcholine receptors in the brain, given that these are involved in regulating central nervous system pathways relevant to mental disorders (Berk et al., 2011). There is some evidence that repeated nicotine exposure can lead to desensitization of these receptors (Mineur & Picciotto, 2009). Inflammation and oxidative stress induced by toxic compounds from inhaled cigarette smoke is another potential mechanism (Berk et al., 2011). Our conclusion that smoking is detrimental to the brain warrants increased efforts to prevent (heavy) substance use. For individuals with a mental disorder, it implies that smoking cessation may be beneficial to alleviate symptoms. This is an important message given that smokers in this population are not always encouraged to quit (Taylor et al., 2020a). Although not an easy task, it should be communicated to health professionals that there are effective ways to help smokers with a co-morbid mental disorder quit.

A higher education increased alcohol use frequency but decreased the risk of problematic use. Those with higher education tend to drink alcohol more often but spread across multiple drinking occasions, and without developing a dependency. Those with lower education, on the other hand, are at increased odds of developing a problematic relationship with alcohol. This pattern of opposite effects was recently also highlighted in a study that computed genetic correlations and reported high alcohol use frequency to be genetically correlated with higher socio-economic status and lower risk of psychiatric disorders, whereas high alcohol consumption quantity was genetically correlated with lower socio-economic status and higher psychiatric disorder risk (Marees et al., 2019). Similar to smoking, it could be that excessive alcohol use is a way to cope with job stress (Dobson, Ibrahim, Gilbert-Ouimet, Mustard, & Smith, 2018b). There was also consistent evidence that mental disorders increase (problematic) alcohol use, without strong effects in the other direction. The latter implies that observational findings indicating that alcohol use increases mental disorders were due to confounding and/or reverse causality. Indeed, associations between heavy drinking and subsequent increases in depressive symptoms disappeared after adjustment for confounders (Li et al., 2020). It should be noted that this is in contrast to clinical observations where in the short-term, treating alcohol use disorder makes pre-existing depression symptoms disappear (Charlet & Heinz, 2017). This discrepancy may be because MR assesses ‘lifetime’ (longer-term) effects of alcohol on mental health (Labrecque & Swanson, 2019), and the fact that only a small proportion of those with an alcohol use disorder will receive treatment [<9% (Mark, Kassed, Vandivort-Warren, Levit, & Kranzler, 2009)]. In sum, the current MR literature suggests that co-morbidity between poor mental health and alcohol use is primarily the result of alcohol being used as a type of ‘self-medication.’

There was stronger evidence that liability to schizophrenia increases the odds to initiate cannabis, than that cannabis initiation increases schizophrenia risk, as also indicated recently by others (Gillespie & Kendler, 2021). However, these results should be regarded as tentative, given that the genetic instrument for schizophrenia was more powerful than that for cannabis use, and more insightful analyses, with measures of cannabis use frequency, have not yet been performed. This is an important direction for future MR studies, now that such large-scale cannabis studies are becoming available (Hines, Treur, Jones, Sallis, & Munafò, 2020).

For caffeine, the predominantly studied relationships were with cognitive functioning and sleep. Overall, there was no clear evidence that a high average intake of caffeine (negatively or positively) affects cognitive measures or sleep. This is consistent with recent evidence that average (high) caffeine intake does not necessarily result in changes in alertness or sleep patterns, due to the fact that adaptation occurs after repeated intake (Weibel et al., 2020).