Addiction Biology最新文献

{"title":"Arginine Metabolism and Adenosine Receptor Signals in the Cerebellum Contribute to Nicotine Withdrawal-Induced Anxiety/Depression-Like Behaviours","authors":"Wenjuan Zhang,&nbsp;Yu Tian,&nbsp;Xiao Yang,&nbsp;Baojiang He,&nbsp;Haifeng Zhang,&nbsp;Qi Zhang,&nbsp;Yingwu Mei","doi":"10.1111/adb.70076","DOIUrl":"https://doi.org/10.1111/adb.70076","url":null,"abstract":"<p>Recent studies have established a strong association between the cerebellum and various psychiatric disorders, as well as drug addiction and withdrawal processes. However, the mechanisms underlying the cerebellum's role in nicotine withdrawal symptoms have yet to be explored. In this study, we employed transcriptome sequencing, untargeted metabolomics and integrative multi-omics analysis to elucidate the molecular mechanisms underlying nicotine withdrawal-induced affective symptoms, specifically anxiety and depression-like behaviours, within the cerebellum. Our findings demonstrate that enhanced purine metabolism and disrupted arginine metabolism in the cerebellum significantly contribute to the development of anxiety and depression-like behaviours in mice undergoing nicotine withdrawal. Treatment with the non-selective adenosine receptor antagonist, theobromine, markedly alleviates these behaviours. This mechanism likely involves inhibiting adenosine signalling and restoring arginine metabolism in the cerebellum.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 8","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome Variation in Alcohol Use Disorder by Whole-Exome Sequencing","authors":"Lei Liu,&nbsp;Bo Zhang,&nbsp;Yong Dong,&nbsp;Li Ping Liu,&nbsp;Jing Ying Wang,&nbsp;Jun Liu,&nbsp;Guang Yu Zhou,&nbsp;Chuan Yi Kang,&nbsp;Xiaorui Hu,&nbsp;Chang Cheng,&nbsp;Na Zhao,&nbsp;Jia Lu,&nbsp;Huaizhi Wang,&nbsp;Jian Hu,&nbsp;Xiaohong Wang","doi":"10.1111/adb.70070","DOIUrl":"https://doi.org/10.1111/adb.70070","url":null,"abstract":"<p>Alcohol use disorder is closely related to genetic and environmental factors. However, the contribution of coding variation to alcohol use disorder susceptibility remains poorly understood. We aimed to identify genetic mutations in alcohol use disorder by whole exon sequencing. We performed whole-exome sequencing in 83 patients with alcohol use disorder and compared it with exome sequences of healthy controls that were collected from the 1000 Genomes Project. GO and KEGG enrichment analysis and protein interaction analysis were performed for the mutated genes in each group. Three online protein function prediction sites were used to predict whether SNPs/InDels cause protein coding changes. Further, we conducted a rare variant exploration. We identified 106 525 SNV and 19 826 InDel gene mutations in alcohol use disorder. In the healthy and alcohol use disorder groups, mutations in CNTNAP3, ZNF683, ALDPH2, CCHCR1, ZNF45 and ESRRA loci were found to be deleterious mutations in all three sites; CNTNAP3, ZNF683, ALDPH2, CCHCR1, ZNF45 and ESRRA may be potential targets for future precision treatment of alcohol use disorders, and further provide new ideas for drug development.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 8","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grey Matter Volume in Substance Use: A Preregistered, Dimensional Approach to Disentangle Substance Use and Disorder Severity","authors":"Kristina Schwarz,&nbsp;Malin K. Hildebrandt,&nbsp;Nele Sauer,&nbsp;Raoul Wüllhorst,&nbsp;Tanja Endrass","doi":"10.1111/adb.70075","DOIUrl":"https://doi.org/10.1111/adb.70075","url":null,"abstract":"<p>This preregistered study investigates whether altered grey matter volume (GMV) in the insula and ventromedial prefrontal/anterior cingulate cortex (vmPFC/ACC) - regions commonly implicated in substance use disorder (SUD) - is associated with the degree of substance use or with the severity of substance-related problems, two distinct but correlated facets of SUD. Baseline structural MRI and behavioural assessment of substance use, substance-related problems (i.e., DSM-5 disorder severity) and negative urgency were conducted in 134 (poly-)substance users. At 1-year follow-up, behavioral assessments were repeated in 120 participants. Linear regression analyses tested associations between GMV in predefined regions (insula, vmPFC and ACC) and (1) degree of use, (2) substance-related problems and (3) substance-related problems controlled for use. Mediation analyses tested whether negative urgency mediated the problem-specific associations. GMV in all regions negatively related to substance-related problems and use (<i>p</i>_<i>BH</i> &lt; 0.05). Controlled for use, GMV in the insula and vmPFC (<i>p</i>_<i>BH</i> &lt; 0.05) but not ACC (<i>p</i>_<i>BH</i> = 0.06) related to substance-related problems. Follow-up results revealed differential patterns, but when controlling for use, GMV reductions at baseline did not significantly relate to follow-up substance-related problems (insula: <i>p</i>_<i>BH</i> = 0.06; ACC/vmPFC: <i>p</i>_<i>BH</i> &gt; 0.23). Negative urgency related to GMV in the vmPFC (<i>p</i>_<i>BH</i> = 0.02) and mediated the association between vmPFC volume and substance-related problems controlled for use (indirect effect: CI [−0.12, −0.02]). We demonstrate that smaller GMV in the vmPFC and insula specifically relates to substance-related problems beyond substance use, albeit with distinct predictive value for prospective symptom development. This highlights the importance of distinguishing between the two facets of SUD to understand why some substance users develop SUD.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPA Receptor Within the Prelimbic Cortex Regulates Propofol-Induced Locomotor Sensitization","authors":"Chi Pan,&nbsp;Xinyu Mao,&nbsp;Yujie Jiang,&nbsp;Chenchen Jiang,&nbsp;Jiani Qiu,&nbsp;Yantong Zhang,&nbsp;Gang Chen,&nbsp;Mengting Xu,&nbsp;Jun Li,&nbsp;Binbin Wu","doi":"10.1111/adb.70078","DOIUrl":"https://doi.org/10.1111/adb.70078","url":null,"abstract":"<p>Propofol is recognized as an addictive substance in both humans and animals. Increasing evidence suggests that the prelimbic cortex (PL) within the medial prefrontal cortex (mPFC), plays an important role in mediating drug addiction. In this study, we trained adult male Sprague–Dawley rats to establish a model of locomotor sensitization (LS). Moreover, optogenetic inhibition of glutamatergic neurons within the PL inhibited the LS of propofol, whereas optogenetic activation of glutamatergic neurons within the PL promoted the LS of propofol. This effect could be blocked by NBQX (a competitive AMPAR antagonist) pretreatment. Subsequently, a microinjection of NBQX (0.25-1 μg/0.3 μL/site) or saline was administered into the bilateral PL to further examine the impact of AMPARs on the LS of propofol. We found that NBQX pretreatment significantly inhibited both the distance and activity in sensitized rats. The expressions of GluA1 and GluA2 subunits of AMPARs, phosphorylated NR1 subunit of NMDARs, D1Rs, phosphorylated ERK and phosphorylated CREB within mPFC were statistically significantly decreased after NBQX pretreatment, whereas, the expressions of total ERK, total CREB and total NR1 subunit remained unchanged. This evidence verifies the instrumental role of AMPARs within the PL in mediating the LS of propofol, and the NMDAR-D1R/ERK/CREB signalling pathway may act as a potential mechanism.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Interference Control in Individuals With Internet Addiction: Evidence From Event-Related Potentials and Brain Oscillations","authors":"Farzad Rostami,&nbsp;Ali Esteki,&nbsp;Sepideh Khoniveh,&nbsp;Rana Ghamari,&nbsp;Atiye Sarabi-Jamab","doi":"10.1111/adb.70062","DOIUrl":"https://doi.org/10.1111/adb.70062","url":null,"abstract":"<p>Individuals with Internet addiction disorder (IAD) exhibit deficits in cognitive control, particularly in interference control; however, the behavioural and neural mechanisms underlying these impairments remain unclear. In this study, classic and modified Stroop tasks were administered to individuals with IAD and healthy control (HC) participants, whereas electroencephalography (EEG) was recorded. We hypothesized that individuals with IAD would demonstrate impaired interference control, as evidenced by longer reaction times (RTs) on incongruent trials and that these behavioural deficits would be accompanied by reduced ERP activity in both early and late medial frontal negativity (MFN) components, as well as diminished conflict slow potential (SP). Additionally, our event-related spectral perturbation (ERSP) analysis was designed to examine oscillatory dynamics, including a reduced Stroop effect in theta power along with compensatory increases in beta2 and gamma band activity. The results revealed that individuals with IAD exhibited prolonged RTs, with this difference becoming more pronounced under increased cognitive demands. Furthermore, ERP responses and ERSP patterns across frequency bands were distinct in the IAD group, pointing to deficits in conflict detection and resolution, as well as compensatory neural mechanisms. These findings suggest that cognitive slowing in individuals with IAD is exacerbated under conditions requiring greater interference control, contributing to the executive dysfunction.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empirical Derivation and Prediction of Treatment Trajectories in Harmonized AUD Clinical Trial Datasets","authors":"Robert J. Kohler,&nbsp;Yasmin Zakiniaeiz,&nbsp;Terril L. Verplaetse,&nbsp;C. Leonardo Jimenez Chavez,&nbsp;MacKenzie R. Peltier,&nbsp;Hang Zhou,&nbsp;Sherry A. McKee,&nbsp;Walter Roberts","doi":"10.1111/adb.70069","DOIUrl":"https://doi.org/10.1111/adb.70069","url":null,"abstract":"<p>In clinical settings targeting alcohol use disorder (AUD), it is often unclear whether a treatment option may best suit a patient's clinical needs. Clinicians providing AUD treatment are often required to predict patients' responses to guide treatment decisions. Recently, machine learning approaches have been used as tools in precision medicine to help guide these clinical decisions. However, the extent of their clinical utility in populations undergoing treatment is largely unknown. Using data from four Phase 2 randomized clinical trials affiliated with the NIAAA Clinical Investigations Group and a Phase 3 trial sponsored by the NIAAA, we developed a machine learning model to predict treatment response phenotypes derived from clustering drinking rates at the end of treatment. Harmonized data included demographics and baseline data from biological and clinical assessments. Follow-up analyses were performed to characterize treatment response phenotypes. Three clusters corresponding to mild (M_SDU = 1.3), moderate (M_SDU = 6.70) and severe (M_SDU = 15.3) alcohol consumption were identified from end-of-treatment drinking data. Performance of the tree-based classifier using out-of-sample test data was 71% with baseline drinking included and 61% without. Exploratory analyses revealed participants clustered as mild drinkers showed reductions in drinking across treatment (<i>M</i>_{<i>Difference</i>} = −0.731, SE = 0.114, <i>p</i> &lt; 0.001) whereas participants clustered as severe had escalation in use (<i>M</i>_{<i>Difference</i>} = 6.82, SE = 0.52, <i>p</i> &lt; 0.001). Although males drank more than females at baseline (<i>M</i>_{<i>Difference</i>} = 1.46, SE = 0.287, <i>p</i> &lt; 0.001), no significant differences in consumption emerged at the end of treatment. Findings from this work indicate that alcohol use derived from patterns of consumption at the end of treatment maps onto unique treatment response trajectories for mild and severe forms of AUD. Furthermore, the identified clusters revealed sex-specific differences in alcohol consumption patterns across different phases of treatment. Overall, this highlights the utility of computational methods for deriving clinically meaningful AUD-related phenotypes across multiple studies, each with different treatments and participant characteristics.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amygdala–Ventral Striatum Functional Connectivity Underlies Craving in Gambling Disorder: A Mediating Role of Depressive Symptoms","authors":"Yuzuki Ishikawa,&nbsp;Kentaro Katsuragi,&nbsp;Takahiko Inagaki,&nbsp;Kota Ebina,&nbsp;Yoshiteru Mutsuda,&nbsp;Morio Aki,&nbsp;Mami Shibata,&nbsp;Ayaka Hamamoto,&nbsp;Tsuyoshi Ando,&nbsp;Akihisa Iriki,&nbsp;Takashi Miyagi,&nbsp;Hiroto Mizuta,&nbsp;Ariyoshi Takemura,&nbsp;Takuro Murao,&nbsp;Hideaki Takeuchi,&nbsp;Ryosaku Kawada,&nbsp;Naoya Oishi,&nbsp;Hidehiko Takahashi,&nbsp;Toshiya Murai,&nbsp;Kosuke Tsurumi","doi":"10.1111/adb.70065","DOIUrl":"https://doi.org/10.1111/adb.70065","url":null,"abstract":"<p>Craving is an intense, strong urge to engage in addictive behaviours. Craving is supposed to be modulated by the connectivity between the amygdala and the ventral striatum (VS), a pivotal pathway for reward-seeking behaviours. However, whether and how this connectivity underlies craving for gambling remains unclear, limiting our understanding of the pathophysiology of gambling disorder (GD). To address this issue, we analysed resting-state functional connectivity (rs-FC) between the amygdala and VS in 51 GD patients and 45 healthy participants. Craving for gambling was assessed using the Gambling Craving Scale (GACS). Among three GACS subscales, Desire exhibited a significant correlation with rs-FC in the right amygdala–VS, while Anticipation and Relief showed no significant associations. Causal mediation analysis revealed that depressive symptoms significantly mediated the relationship between rs-FC in the right amygdala–VS and Desire. These findings suggest that the amygdala–VS connectivity elicits the intense desire for gambling through negative emotions.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Comment on: ‘Sex differences in neural networks recruited by frontloaded binge alcohol drinking’","authors":"","doi":"10.1111/adb.70068","DOIUrl":"https://doi.org/10.1111/adb.70068","url":null,"abstract":"<p><b>RETRACTION</b>: J. Xu, H. Zhao, and Y. Wang, “Comment on: ‘Sex differences in neural networks recruited by frontloaded binge alcohol drinking’,” <i>Addiction Biology</i> 29, no. 10 (2024): e70002, https://doi.org/10.1111/adb.70002.</p><p>The above article, published online on 15 October 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Rainer Spanagel; the Society for the Study of Addiction; and John Wiley &amp; Sons Ltd.</p><p>The retraction of this article, a Letter to the Editor, has been agreed by all parties due to concerns raised by a third party that it contains major scientific flaws. These flaws, which were confirmed during post-publication review, were not identified during the original evaluation process and make the letter irrelevant to the published article on which it comments.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Oxytocin and Oxytocin Gene Receptor Methylation During Withdrawal Therapy in Males With Alcohol Use Disorder","authors":"Phileas J. Proskynitopoulos,&nbsp;Alissa F. Haarmeyer,&nbsp;Stefan Bleich,&nbsp;Helge Frieling,&nbsp;Thomas Hillemacher,&nbsp;Alexander Glahn,&nbsp;Mathias Rhein","doi":"10.1111/adb.70060","DOIUrl":"https://doi.org/10.1111/adb.70060","url":null,"abstract":"<p>Oxytocin is a promising therapeutic target in the treatment of alcohol use disorder (AUD). However, many studies report contradicting evidence regarding its effect on drug craving, relapse risk and withdrawal symptoms. Epigenetic regulation of the oxytocin and oxytocin receptor (OXTR) gene is altered in several mental disorders and influences social behaviour, often depending on the underlying sex. Evidence suggests that altered promoter methylation could result in oxytocin and OXTR expression differences, thereby possibly influencing drug craving and relapse risk. It is unclear whether promoter methylation changes throughout alcohol withdrawal and is linked to craving and withdrawal symptoms. In this exploratory study, we investigated the effect of 2-week alcohol withdrawal therapy in 99 males on methylation levels (oxytocin and OXTR) compared with 31 healthy controls. We found significantly higher mean methylation values of the OXTR gene in controls than patients across withdrawal (<i>p</i> &lt; 0.001). Regarding oxytocin, we found no differences in mean methylation in healthy controls compared with patients. Across withdrawal, mean methylation decreased in both genes. Fitting a mixed linear model, craving and withdrawal symptoms were associated with changes in methylation levels of the oxytocin gene (<i>p</i> &lt; 0.001), which was also true for the OXTR gene when considering age and smoking as additional covariates. Our study is the first to report an association between AUD, oxytocin and OXTR gene methylation. Methylation of the OXTR gene is reduced in AUD compared with healthy controls, with OT gene methylation linked to craving and withdrawal severity. Our results suggest that investigations of oxytocin as a therapeutic agent need to consider epigenetic regulation of its receptor and gene as a mechanism that could influence oxytocin's effect on craving and withdrawal symptoms.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Genomic Data to Examine the Causal Impact of Alcohol, Tobacco, Cannabis, and Opioid Use on Biological and Cognitive Ageing","authors":"Jared V. Balbona,&nbsp;Paul Jeffries,&nbsp;Aaron J. Gorelik,&nbsp;Elliot C. Nelson,&nbsp;Ryan Bogdan,&nbsp;Arpana Agrawal,&nbsp;Emma C. Johnson","doi":"10.1111/adb.70066","DOIUrl":"https://doi.org/10.1111/adb.70066","url":null,"abstract":"<p>Although substance use is associated with a shortened lifespan, impeded health and accelerated biological ageing, the factors contributing to the associations between substance use and ageing are poorly understood. We used summary statistics from genome-wide association studies (GWAS) to investigate whether substance involvement (<i>N</i> from 28K to 2M)—including alcohol, tobacco, cannabis and opioid use and use disorders—is genetically correlated with various ageing metrics (<i>N</i> from 162K to 2.7M) and whether these correlations reflect shared genetic etiologies or putative causal relationships. Using Linkage Disequilibrium Score Regression (LDSC), we found widespread evidence of genetic correlations between substance use/use disorders and indices of physical, cognitive and biological ageing. We then employed a series of Mendelian randomization–based approaches, finding significant causal effects of genetic predispositions to both tobacco use disorder and quantity of tobacco smoked on various markers of ageing. Causal effects of problematic alcohol use and cannabis use disorder were also found, though findings were mixed. Evidence of reverse causality (i.e., ageing causing substance use), meanwhile, was scant. Collectively, these results demonstrate strong triangulation across approaches and highlight the importance of integrating genetic insights into public health strategies for reducing the burden of SUDs across the lifespan.</p>","PeriodicalId":7289,"journal":{"name":"Addiction Biology","volume":"30 7","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/adb.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}