Childhood maltreatment has been implicated in adulthood externalizing behaviors. However, this relationship could be explained by confounding factors (e.g., externalizing risk factors that co-occur with childhood maltreatment), rather than a direct effect of maltreatment on externalizing behavior. The current study extends this research using a longitudinal sibling study. Specifically, we leveraged the sibling-comparison design, which compares siblings from the same family to each other to examine whether greater maltreatment exposure at baseline (M age = 16.9) is associated with greater increases in externalizing behavior through young adulthood (M age = 29.1). Thus, this approach controls for familial risk factors shared by siblings. Participants included 365 probands and 376 siblings who were followed across three assessment waves. Participants were administered clinical interviews at each wave to assess alcohol use disorder (AUD), illicit substance use disorder (SUD), and antisocial behavior (ASB), and a self-report survey of exposure to physical abuse, emotional abuse, sexual abuse, and neglect. Greater adolescent exposure to neglect and physical abuse were both associated with greater adolescent levels of AUD and ASB. Adolescent physical abuse, but not neglect, was also associated with greater illicit SUD symptoms. Additionally, greater emotional abuse was associated with steeper increases in AUD and illicit SUD symptoms through young adulthood. Importantly, none of these effects were explained by familial confounds. These findings provide strong evidence for adolescent emotional abuse playing a causal role in later AUD/SUD, suggesting that preventing such abuse and mitigating its effects may have downstream effects on reducing AUD/SUD.

BACKGROUND:The effects of cannabis use on gastrointestinal function are unclear. We conducted a preliminary study on whether cannabis use frequency was associated with appetite, eating behavior, and anthropometrics phenotypically and after controlling for genetic and environmental factors via a co-twin control design. METHODS:We first tested the phenotypic associations between cannabis use frequency (average number of days per week) with appetite, eating behavior, anthropometrics, and diet in simple unadjusted models and then re-estimated those associations in models adjusting for alcohol and nicotine use frequency as covariates. Significant phenotypic effects were next analyzed with multilevel models to test these associations between- and within-twin pairs. Between-family effects capture shared familial variance (additive genetics 'A' and common environment 'C') and within-twin pair effects capture residual variance after accounting for shared components (unique environment 'E'). Participants included 90 adults (40 complete twin pairs) who use cannabis at least weekly. RESULTS:In unadjusted analyses, higher cannabis use frequency was associated with lower appetite (β = -0.199, p = .046), eating fewer meals per day (β = -0.234, p = .007), and eating a less nutritious diet (β = -0.237, p = .025); no phenotypic effects remained significant after adjusting for alcohol and nicotine use frequencies. Multi-level models showed significant between-family effects between higher cannabis use frequency and eating fewer meals per day (β = -0.318, p = .015) and eating a less nutritious diet (β = -0.296, p = .028); for all outcomes the within-twin effects were much smaller in magnitude compared to between-family effects, and non-significant. CONCLUSIONS:Our results do not suggest a causal association between cannabis use frequency with eating behavior or anthropometrics.

Background:Subjective effects (SEs) are positively associated with substance use disorders in clinical samples. However, the etiology of these associations remains unclear. The present study utilized a clinical sample selected for elevated polysubstance use disorder (SUD) criteria to address the following questions: Are positive and negative polysubstance SEs and SUD criteria associated? Are cross-sectional and longitudinal results consistent? Is there evidence for common genetic influences between SEs and SUDs? Methods:Cross-sectional and longitudinal analyses using the Defries Fulker regression method were conducted in clinical probands (n = 476) and their full (n = 557) and half siblings (n = 65). SEs were assessed in adolescence and SUD criteria were assessed once in adolescence and twice in adulthood. Results:SEs were correlated with SUD criteria from adolescence to adulthood in clinical probands (r = 0.12-0.40) and during adolescence (r = 0.36-0.39) in full siblings of clinical probands. Results were inconsistent with common genetic influences between elevated SUDs and SEs. Conclusions:Elevated SUDs and SEs were mostly explained by familial influences independent of genetics. There was little support for common genetic influences on elevated SUDs and SEs, possibly due to low power. Future research should focus on individual factors driving associations between these constructs.

We examined the association of recreational cannabis legalization (RCL) with frequency of using cannabis, alcohol, and sleep medication for sleep and with co-use of cannabis with other sleep aids. We used linear regression models to examine these associations in a population-based sample of adult twins (n = 3,141). Participants (Mage = 37 (SD = 5)) were primarily White (93%), with 5% Hispanic/Latinx, and female (61%). RCL was associated with using cannabis for sleep more frequently even after controlling for cohort, demographics, sleep quality, anxiety, depression, physical health, season, and pre-legalization cannabis use frequency (β = 0.123, p = .001). RCL was not associated with frequency of using alcohol or sleep medication for sleep, or with co-use of cannabis and other sleep aids. More research is needed to determine whether RCL leads to more frequent use of cannabis for sleep.

OBJECTIVES:To examine: 1) cross-sectional associations between past-month use of cannabis for sleep with mental health, substance use, and related factors in adults and 2) the role of genetic and early environmental factors shared by twins (familial confounds) in explaining significant associations. METHODS:In a population-based sample of adult twins (n = 3,165, Mage36.7) we ran regression (phenotypic) and multilevel (co-twin control) models examining associations between past-month use of cannabis for sleep without comes of interest. We controlled for cannabis frequency and sleep quality except when each was the outcome of interest. RESULTS:Recent use of cannabis for sleep was associated with multiple mental health, substance use, and related factors in phenotypic models. In co-twincontrol models, within-family effects were significant between using cannabis for sleep with more problems from cannabis use, higher cannabis frequency, worse sleep quality, and more frequent use of alcohol and medication for sleep. CONCLUSIONS:Familial confounds may explain many, but not all, associations between recent use of cannabis for sleep and mental health, substance use, and related factors. Longitudinal work is needed to clarify the directionality of associations not explained by familial confounds, and whether they are risks of using cannabis for sleep.

Background. Aggression is a worldwide issue that has significant consequences for both the victims and societies. However, aggression is an umbrella terms with subcomponents such as motivation (i.e., Reactive versus Proactive) and forms (i.e., Physical versus Verbal) which aggressive behaviors may occur. Yet, brain circuits differentiating these subcomponents remains largely unknown.Method. A systematic search strategy was conducted up to May 1st 2023, using PubMed, Google Scholar, and Web of Science, to identify relevant studies. Coordinate-based meta-analysis was conducted on General Aggression, Reactive Aggression, Proactive Aggression, Physical Aggression and Verbal Aggression using spatial convergence (ALE) and effect-size (SDM-PSI) approaches.Results. Sixty-seven studies met the inclusion criteria. Meta-analysis revealed similar yet distinct neural correlates for General Aggression (i.e., Amygdala, Precuneus, Intraparietal Sulcus, Angular and Middle Temporal Gyri), Reactive Aggression (i.e., Amygdala, Periaqueductal Grey, Posterior Insula, & Central Opercular Cortex), Proactive Aggression (i.e., Septal Area, & Amygdala), Physical Aggression (i.e., Dorsal Premotor Cortex, Dorsal Caudate, & Dorsal Anterior Cingulate Cortex), and Verbal (i.e., Dorsal Anterior Cingulate Cortex). Exploratory analyses revealed the importance of affective, cognitive and social cognition processes as well as serotoninergic, dopaminergic, and cholinergic systems in the neural underpinnings of aggressive behaviors.Conclusion. Our findings highlight the importance of examining the subcomponents of aggression (i.e., motivation and forms) within a transdiagnostic framework. Hence, characterizing the neurobiological substrates of aggression may expand our search for targeted neuromodulation and pharmacological treatments.

Aggression is a worldwide issue that has significant consequences for both the victims and societies. However, aggression may vary in its underlying motivation (i.e., reactive versus proactive) and the forms in which it occurs (i.e., physical versus verbal). Yet, functional brain correlates differentiating these types remains largely unknown. A systematic search was conducted up to May 1st 2023, using PubMed, Google Scholar, and Web of Science, to identify relevant functional neuroimaging studies that included measures of General Aggression, Reactive Aggression, Proactive Aggression, Physical Aggression and Verbal Aggression. Coordinate-based meta-analysis was conducted using both spatial convergence (ALE) and effect-size (SDM-PSI) approaches. Sixty-seven functional neuroimaging studies met the inclusion criteria. Meta-analysis revealed similar yet distinct neural correlates for General Aggression (i.e., Amygdala, Precuneus, Intraparietal Sulcus, Angular and Middle Temporal Gyri), Reactive Aggression (i.e., Amygdala, Periaqueductal Grey, Posterior Insula, & Central Opercular Cortex), Proactive Aggression (i.e., Septal Area, & Amygdala), Physical Aggression (i.e., Dorsal Premotor Cortex, Dorsal Caudate, & Dorsal Anterior Cingulate Cortex), and Verbal (i.e., Dorsal Anterior Cingulate Cortex). Exploratory analyses revealed the importance of affective, cognitive and social cognition processes as well as serotoninergic, dopaminergic, and cholinergic systems in the neural underpinnings of aggressive behaviors. Our findings highlight the importance of examining the types of aggression (i.e., motivation and forms) within a transdiagnostic framework. Therefore, characterizing the neurobiological substrates of aggression may expand our search for targeted neuromodulation and pharmacological treatments.

Over the past two decades, cannabis policies have liberalized in the United States, culminating in the legalization of recreational cannabis in Colorado and Washington state in 2012. This review will focus on the impact of recreational cannabis legalization in Colorado. While the prevalence of past-year and past-month cannabis use has remained relatively steady among adolescents post-legalization, the prevalence of young adult use has continued to rise. Cannabis products with increased potency have become more prevalent and widely used. There are concerns that the use of products with increased potency will increase risk for cannabis use and comorbid mental health disorders, particularly cannabis-induced psychosis and suicidal behavior, although more research is needed to fully understand the impact of high-potency products. Since the legalization of recreational cannabis, numerous additional public health concerns have emerged: unintentional overdoses requiring acute care visits, electronic vaping-associated lung injury, increased motor vehicle collisions related to cannabis consumption, and higher rates of cannabis use during pregnancy. Lessons learned from the first decade of cannabis legalization emphasize the need for research efforts to provide evidence-based guidelines, inform prevention strategies, and implement selective interventions for at-risk populations including youth, individuals with comorbid mental health disorders, and individuals who are pregnant.

Background: Cannabis use is associated with outcomes like income, legal problems, and psychopathology. This finding rests largely on correlational research designs, which rely at best on statistical controls for confounding. Here, we control for unmeasured confounders using a longitudinal study of twins. Method: In a sample of 4,078 American adult twins first assessed decades ago, we used cotwin control mixed effects models to evaluate the effect of lifetime average frequency of cannabis consumption measured on substance use, psychiatric, and psychosocial outcomes. Results: On average, participants had a lifetime cannabis frequency of about one to two times per month, across adolescence and adulthood. As expected, in individual-level analyses, cannabis use was significantly associated with almost all outcomes in the expected directions. However, when comparing each twin to their cotwin, which inherently controls for shared genes and environments, we observed within-pair differences consistent with possible causality in three of the 22 assessed outcomes: cannabis use disorder symptoms (beta(W-Pooled) = .15, SE = .02, p = 1.7 x10(-22)), frequency of tobacco use (beta(W-Pooled) = .06, SE = .01, p = 1.2 x10(-5)), and illicit drug involvement (beta(W-Pooled) = .06, SE = .02, p = 1.2 x 10(-4)). Covariate specification curve analyses indicated that within-pair effects on tobacco and illicit drug use, but not cannabis use disorder, attenuated substantially when covarying for lifetime alcohol and tobacco use. Conclusions: The cotwin control results suggest that more frequent cannabis use causes small increases in cannabis use disorder symptoms, approximately 1.3 symptoms when going from a once-a-year use to daily use. For other outcomes, our results are more consistent with familial confounding, at least in this community population of twins.

Abstract Introduction Using cannabis as a sleep aid is common. However, little is known about how this practice relates to mental health and substance use. To address this, we examined associations between using cannabis as a sleep aid with mental health and substance use outcomes using a co-twin control design. Methods Participants were 3,165 adults (Mage=36.7 (SD=5.3)) from two population-based twin cohorts. Outcomes of interest included mental health constructs (e.g. depression, impulsivity), substance use measures (frequency and problems from use of specific substances), and use of other substances for sleep. First, we conducted regression models to test phenotypic associations between endorsing past month use of cannabis to aid sleep (yes/no) and the above outcomes. Next, we used multilevel models to examine whether significant phenotypic associations were due to between-family effects (genetic and environmental factors shared by co-twins) or within-twin pair effects (genetic and environmental factors which differ between co-twins). All analyses controlled for sleep quality and cannabis frequency. Results The sample was 56.7% monozygotic twins, 39.6% male, and 92.7% Caucasian. Phenotypic associations were significant between endorsement of using cannabis for sleep and most outcomes. All significant associations were in the direction of worse mental health, greater use of other substances for sleep, and greater frequency of, and problems from, substance use. All significant phenotypic effects remained significant at the between-family level, but not all remained significant at the within-family level. At the within-family level, the twin who endorsed using cannabis as a sleep aid (vs. their co-twin who did not) reported more frequent use of alcohol (B=0.44, p<.001) and medication (B=0.26, p=.022) for sleep, greater frequency of alcohol use (B=13.0, p=.018), and more problems from cannabis use (B=0.85, p=.007). Conclusion Associations between using cannabis for sleep with worse mental health, after controlling for sleep quality and cannabis frequency, are likely due to shared genetic and/or environmental factors. Associations with substance use measures that were not accounted for by shared genetic and/or environmental factors include greater alcohol use frequency, more problems from cannabis use, and more frequent use of other substances for sleep. Support (if any) DA042755, DA057894, DA053693, DA056408, DA032555, DA054212, MH125758 (NIH), 1101101 (ICR)

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder for which genetic factors explain up to 75% of the variance. In this study, we performed a genome-wide association meta-analysis (GWAMA) of ADHD symptom measures, with an effective sample size of 120,092 (71,733 unique individuals from 28 population-based cohorts, with 288,887 quantitative ADHD symptom measures). Next, we meta-analyzed the results with a genome-wide association study (GWAS) of ADHD diagnosis. The GWAMA of ADHD symptoms returned no genome-wide significant variants. However, we estimated strong genetic correlations between our study of quantitative ADHD symptoms and the earlier study of ADHD diagnosis ( r g= 1.00, SE= 0.06). Moderate negative genetic correlations ( r g< -0.40) were observed with several cognitive traits. Genetic correlations between ADHD and aggressive behavior and antisocial behavior were around 1. This provides further evidence of the wide pleiotropic effects of genetic variants and the role that genetic variants play in the co-occurrence with (mental) health traits. The GWAMAs of ADHD symptoms and diagnosis identified 2,039 genome-wide significant variants, representing 39 independent loci, of which 17 were new. Using a novel fine-mapping and functional annotation method, we identified 22 potential effector genes which implicate several new potential biological processes and pathways that may play a role in ADHD. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts in large-scale GWAS can be useful to identify novel genes implicated in ADHD and related symptoms. ### Competing Interest Statement J.A.R.Q. was on the speakers bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubio, Uriach, Technofarma and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubio, Takeda, Bial and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubio. M.C. has received fees to give talks for TAKEDA and Laboratorios RUBIO. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. ### Clinical Protocols <https://www.action-euproject.eu/sites/default/files/Action%20AGG%20AP%20SOP.pdf> ### Funding Statement The project was supported by the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information are included in the Supplementary text. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval was obtained from the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Center, Amsterdam (NTR 25th of May 2007 and ACTION 2013/41 and 2014.252), an Institutional Review Board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal-wide Assurance-FWA00017598; IRB/institute codes). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at <link to follow>

An earlier version of this article was published in error. Our prior publication was missing reference to a prior study on this topic. Our prior research has not found an association between recreational cannabis legalization (RCL) and negative psychosocial and psychiatric outcomes. We reported significant associations between RCL with greater cannabis frequency and fewer alcohol use disorder symptoms. The current study expands on our previous research by using a cross-sectional design and different measures of problems from cannabis and alcohol use and including additional substance use variables. The current study found similar results to our previous research.

Saving disposition, the tendency to save rather than consume, has been found to be associated with economic outcomes. People lacking the disposition to save are more likely to experience financial distress. This association could be driven by other economic factors, behavioral traits, or even genetic effects. Using a sample of 3,920 American twins, we develop scales to measure saving disposition and financial distress. We find genetic influences on both traits, but also a large effect of the rearing family environment on saving disposition. We estimate that 44% of the covariance between the two traits is due to genetic effects. Saving disposition remains strongly associated with lower financial distress, even after controlling for family income, cognitive ability, and personality traits. The association persists within families and monozygotic twin pairs; the twin who saves more tends to be the twin who experiences less financial distress. This result suggest that there is a direct association between saving disposition and financial distress, although the direction of causation remains unclear.

Abstract Background The causal impacts of recreational cannabis legalization are not well understood due to the number of potential confounds. We sought to quantify possible causal effects of recreational cannabis legalization on substance use, substance use disorder, and psychosocial functioning, and whether vulnerable individuals are more susceptible to the effects of cannabis legalization than others. Methods We used a longitudinal, co-twin control design in 4043 twins (N = 240 pairs discordant on residence), first assessed in adolescence and now age 24–49, currently residing in states with different cannabis policies (40% resided in a recreationally legal state). We tested the effect of legalization on outcomes of interest and whether legalization interacts with established vulnerability factors (age, sex, or externalizing psychopathology). Results In the co-twin control design accounting for earlier cannabis frequency and alcohol use disorder (AUD) symptoms respectively, the twin living in a recreational state used cannabis on average more often (βw = 0.11, p = 1.3 × 10−3), and had fewer AUD symptoms (βw = −0.11, p = 6.7 × 10−3) than their co-twin living in an non-recreational state. Cannabis legalization was associated with no other adverse outcome in the co-twin design, including cannabis use disorder. No risk factor significantly interacted with legalization status to predict any outcome. Conclusions Recreational legalization was associated with increased cannabis use and decreased AUD symptoms but was not associated with other maladaptations. These effects were maintained within twin pairs discordant for residence. Moreover, vulnerabilities to cannabis use were not exacerbated by the legal cannabis environment. Future research may investigate causal links between cannabis consumption and outcomes.