Background Poor mental health has consistently been associated with substance use (smoking, alcohol drinking, cannabis use, and consumption of caffeinated drinks). To properly inform public health policy it is crucial to understand the mechanisms underlying these associations, and most importantly, whether or not they are causal. Methods In this pre-registered systematic review, we assessed the evidence for causal relationships between mental health and substance use from Mendelian randomization (MR) studies, following PRISMA. We rated the quality of included studies using a scoring system that incorporates important indices of quality, such as the quality of phenotype measurement, instrument strength, and use of sensitivity methods. Results Sixty-three studies were included for qualitative synthesis. The final quality rating was ‘−’ for 16 studies, ‘– +’ for 37 studies, and ‘+’for 10 studies. There was robust evidence that higher educational attainment decreases smoking and that there is a bi-directional, increasing relationship between smoking and (symptoms of) mental disorders. Another robust finding was that higher educational attainment increases alcohol use frequency, but decreases binge-drinking and alcohol use problems, and that mental disorders causally lead to more alcohol drinking without evidence for the reverse. Conclusions The current MR literature increases our understanding of the relationship between mental health and substance use. Bi-directional causal relationships are indicated, especially for smoking, providing further incentive to strengthen public health efforts to decrease substance use. Future MR studies should make use of large(r) samples in combination with detailed phenotypes, a wide range of sensitivity methods, and triangulate with other research methods.

Background Structural variation in subcortical brain regions has been linked to substance use, including the most commonly used substances nicotine and alcohol. Pre-existing differences in subcortical brain volume may affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. Aims We assess the causal nature of the complex relationship of subcortical brain volume with smoking and alcohol use, using bi-directional Mendelian randomisation. Method Mendelian randomisation uses genetic variants predictive of a certain ‘exposure’ as instrumental variables to test causal effects on an ‘outcome’. Because of random assortment at meiosis, genetic variants should not be associated with confounders, allowing less biased causal inference. We used summary-level data of genome-wide association studies of subcortical brain volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus; n = 50 290) and smoking and alcohol use (smoking initiation, n = 848 460; cigarettes per day, n = 216 590; smoking cessation, n = 378 249; alcoholic drinks per week, n = 630 154; alcohol dependence, n = 46 568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. Results There was strong evidence that liability to alcohol dependence decreased amygdala and hippocampal volume, and smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. Conclusions Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and likely mental health, warranting more recognition in public health efforts.

Background: Structural variation in subcortical brain regions has been linked to substance use, including the most prevalent substances nicotine and alcohol. It may be that pre-existing differences in subcortical brain volume affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. We assess the causal nature of this complex relationship with bi-directional Mendelian randomization (MR). Methods: MR uses genetic variants predictive of a certain trait (exposure) as instrumental variables to test causal effects on a certain outcome. Due to random assortment at meiosis, genetic variants shouldnt be associated with confounders, allowing less biased causal inference. We employed summary-level data of the largest available genome-wide association studies of subcortical brain region volumes (nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, and thalamus; n=50,290) and smoking and alcohol use (smoking initiation, n=848,460; cigarettes per day, n=216,590; smoking cessation, n=378,249; alcohol drinks per week, n=630,154; alcohol dependence, n=46,568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. Results: There was strong evidence that alcohol dependence decreased amygdala and hippocampal volume and that smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. Conclusions: Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and most likely mental health, warranting more recognition in public health efforts.